WO2008082444A2

WO2008082444A2 - Articles and methods for tissue repair

Info

Publication number: WO2008082444A2
Application number: PCT/US2007/021217
Authority: WO
Inventors: Jeffrey Carbeck; Pj. Anand; Karen M. Mcnally-Heintzelman; Milan Mrksich; Christopher Chen; Christian Hodneland; Carmichael Roberts; Jeffrey N. Bloom; Mark T. Duffy
Original assignee: Arsenal Medical, Inc.
Priority date: 2006-10-03
Filing date: 2007-10-03
Publication date: 2008-07-10
Also published as: JP2010505517A; WO2008082444A9; CA2664285A1; EP2063789A2; WO2008082444A3

Abstract

Articles and methods for tissue repair are provided. A support may include a patterned adhesive that provides regions of discrete adhesion points. An adhesive isolating material may cover all or a portion of the adhesive and may delay adhesion between the support and the tissue until the isolating material is removed from the support (e.g., by biodegradation), thereby exposing the adhesive. Adhesion between the support and the tissue surface may be varied after repositioning, for example, by controlling the amount of adhesive exposed to the tissue and/or the composition of the adhesive. Methods of applying a support to a tissue using a transfer device are also provided. A support may be transferred to a tissue surface and/or a material may be removed from a tissue surface by contact adhesion, e.g., where the adhesion strength between the support and the tissue (or material and removal instrument) is greater than the adhesion strength between the support and the transfer device (or material and tissue surface).

Description

ARTICLES AND METHODS FOR TISSUE REPAIR

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 60/848,922, filed October 3, 2006, and entitled "Composite Adhesives, and Methods of Use Thereof; U.S. Provisional Patent Application No. 60/910,521, filed April 6, 2007, and entitled "Composite Adhesives, and Methods of Use Thereof; U.S. Provisional Patent Application No. 60/848,964, filed October 3, 2006, and entitled "Methods of Providing Adjustable Seals"; U.S. Provisional Patent Application No. 60/848,907, filed October 3, 2006, and entitled "In Vivo Printing"; U.S. Provisional Patent Application No. 60/910,539, filed April 6, 2007, and entitled "In Vivo Printing"; U.S. Provisional Patent Application No. 60/848,958, filed October 3, 2006, and entitled "Minimally Invasive Extraction Methods"; and U.S. Provisional Patent Application No. 60/910,553, filed April 6, 2007, and entitled "Minimally Invasive Extraction Methods", each of which is incorporated herein by reference in its entirety.

FIELD OF INVENTION

The present invention relates generally to articles and methods for tissue repair, and more specifically, to articles and methods comprising supports and adhesives for tissue repair.

BACKGROUND

Although various articles and techniques have been used for tissue repair, e.g., the use of bandages and sutures, improvements that would allow a practitioner more control over the tissue repair process would be beneficial.

SUMMARY OF INVENTION

Articles and methods for tissue treatment, and more specifically, articles and methods comprising supports and adhesives for tissue repair are provided. Various aspects of the invention involve the use of adhesives in suitable forms for adhering tissue to tissue, adhering a support (such as a prosthetic, scaffold, mesh, film, etc.) to a tissue surface, removing a portion of tissue from a tissue surface (such as in a biopsy or biopsy- like procedure), deploying a support at a desired tissue site, and in other techniques.

Some aspects of the invention involve the control of adhesive activity at a site, such as by inhibiting or otherwise controlling bonding of the adhesive to a site, arranging adhesive to enhance natural healing processes, selectively activating adhesives or components of adhesives so as to cause polymerization or other bonding at desired times, and so on. In short, aspects of the invention involve the use of adhesives in a wide variety of applications.

In one embodiment, a method of medically treating a tissue comprises directing a transfer device to a tissue surface, the transfer device having associated therewith a patterned array of an adhesive, and transferring at least a portion of the patterned array of adhesive from the transfer device to the tissue surface by contact adhesion. The method also includes moving the transfer device away from the tissue surface, positioning an article to be adhered adjacent at least a portion of the adhesive, and adhering the article to the tissue surface using the adhesive.

In another embodiment, a method of medically treating a tissue comprises adhering an article comprising a support and a patterned array of an adhesive to a transfer device, transferring the article from the transfer device to a tissue surface by contact adhesion, and moving the transfer device away from the tissue surface.

In another embodiment, a method of medically treating a tissue comprises forming a patterned array of an adhesive on a surface of an article by contact adhesion, and positioning an article adjacent at least a portion of a tissue surface. The method also includes adhering the article to the tissue surface using the adhesive so as to immobilize the article with respect to the tissue surface within 1 minute after initial contact between the article and the tissue surface.

In another embodiment, a method of medically treating a tissue comprises positioning an article comprising an adhesive on a tissue surface and adhering the article to the tissue surface to a first degree. The method also includes repositioning the article, and adhering the article to the tissue surface to a second degree, wherein the second degree is greater than the first degree.

In another embodiment, a method of medically treating a tissue comprises contacting a tissue surface with a biocompatible material capable of forming or breaking adhesive or cohesive bonds, and adhering at least a portion of the biocompatible material to the tissue surface. The method also includes performing a medical act associated with or proximate the tissue surface, and observing a response of the tissue while maintaining adhesion between the tissue surface and the portion of material. The strength of adhesion between the tissue surface and the portion of material is adjusted by forming or breaking adhesive or cohesive bonds in response to the observing step.

In another embodiment, a method for treating an eye comprises providing an eye having a sclera and muscle tissue attached to the sclera, and applying an adhesive to one of the sclera and the muscle tissue in an array including at least two non-contiguous regions of adhesive. The method also includes adhering the muscle tissue to the sclera using the adhesive array.

In another embodiment, a kit for use in treatment of an eye is provided. The kit comprises a support constructed and arranged to be adhered over a muscle tissue/sclera joint and help support the muscle tissue/sclera joint during a healing process, and an adhesive suitable for adhering the muscle tissue to the sclera. The kit also includes an adhesive applicator including a set of surface features adapted to carry adhesive and deploy the adhesive at a tissue site in a suitable array.

In another embodiment, an article adapted for medical applications is provided. The article comprises a support and a patterned array of an adhesive applied to at least a portion of the support. The article also includes an adhesive isolating material covering at least a portion of the adhesive, wherein the adhesive isolating material is constructed and arranged to be deployed with the support and the adhesive at a tissue surface, to initially resist contact between a portion of the adhesive and the tissue surface, and to later allow contact between the portion of adhesive and the tissue surface.

In another embodiment, an article adapted for medical applications comprises a support, a first layer comprising a first biocompatible material positioned adjacent the support, and a second layer comprising a second biocompatible material adjacent at least a portion of the first layer. At least one of the first and second layers is arranged in the form of a patterned array. In some cases, at least one of the first and second materials comprises an adhesive. Furthermore, at least one of the first and second materials is adapted to biodegrade, dissolve, or fracture while in contact with a tissue.

In another embodiment, a method of medically treating a tissue comprises positioning an article comprising a support, an adhesive, and an adhesive isolating material adjacent a tissue surface, and removing at least a portion of the adhesive isolating material, thereby exposing the tissue surface to at least a portion of the adhesive. The method also includes adhering the article to the tissue surface using the adhesive. In another embodiment, a method of retrieving material from tissue is provided. The method includes directing an instrument to the surface of the tissue, contacting the instrument with the surface of the tissue, and withdrawing the instrument and material from the tissue, wherein the adherence of the material to the instrument is greater than the adherence of the material to the tissue.

Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and/or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and/or inconsistent disclosure with respect to each other, then the document having the later effective date shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. In the figures:

FIG. IA shows a perspective view of a non-patterned adhesive on a support, according to one embodiment of the invention; FIG. IB shows a cross-section of the article shown in FIG. IA in contact with a surface of interest, according to one embodiment of the invention;

FIG. 1C shows a cross-section of an article in contact with a surface of interest, the article comprising a plurality of adhesive portions on protrusions and indentations of a support, according to one embodiment of the invention; FIG. ID shows a cross-section of an article including a plurality of adhesive portions forming a patterned array of adhesive in contact with a surface of interest, according to one embodiment of the invention; FIG. IE shows a cross-section of a patterned array of adhesive on a surface of interest according to one embodiment of the invention;

FIG. 2 shows a perspective view of an article including a patterned continuous array of adhesive associated with a support, according to one embodiment of the invention;

FIG. 3 shows a perspective view of an article including a discontinuous adhesive array associated with a support, according to one embodiment of the invention;

FIG. 4 shows another perspective view of an article including a discontinuous adhesive array associated with a support, according to one embodiment of the invention; FIG. 5 A shows a perspective view of a patterned, discontinuous, and non-ordered array of adhesive associated with a support, according to one embodiment of the invention;

FIG. 5B shows a perspective view of a patterned, discontinuous, and ordered array of adhesive associated with a support, according to one embodiment of the invention;

FIG. 5C shows a perspective view of a patterned, continuous, and non-ordered array of adhesive associated with a support, according to one embodiment of the invention;

FIG. 6 shows a perspective view of a patterned, discontinuous, and ordered array of adhesive in the form of a geometric pattern associated with a support, according to one embodiment of the invention;

FIGS. 7A-7D show a method of transferring material from one surface to another surface by contact adhesion to form a patterned array of material on a surface, according to one embodiment of the invention; FIGS. 8A-8F are images of a transfer device used to form a patterned array of adhesive on a surface and the resulting articles formed by such a process, according to one embodiment of the invention;

FIGS. 9A-9I show images of adhesives patterned on various polymer supports in continuous, ordered arrays, according to one embodiment of the invention; FIG. 10 shows an image of an adhesive pattern on an electrospun PCL support, according to one embodiment of the invention; FIGS. 1 IA-11C show patterns of adhesive on a support in a discontinuous, non- ordered array (FIG. 1 IA), a continuous, ordered array (FIG. HB), and a continuous, non-ordered array (FIG. HC), according to embodiments of the invention;

FIGS. 12A and 12B show patterns of fibrin adhesive formed on a electrospun PCL support, according to one embodiment of the invention;

FIGS. 13A-13C are images showing patterns of protein solders on an electrospun PLGA support, according to one embodiment of the invention;

FIGS. 14A and 14B show cross-sectional views of supports that can include adhesives disposed in indentations of the support, according to one embodiment of the invention;

FIGS. 15A-15C show images of polymeric articles containing adhesive-filled channels and wells, according to one embodiment of the invention;

FIG. 16 shows a cross-sectional view of an article comprising a support, a patterned adhesive, and at least one bioactive agent in contact with a surface of interest, according to one embodiment of the invention;

FIGS. 17A-17E are cross-sectional views of articles comprising bioactive agents according to embodiments of the invention;

FIG. 18 shows a cross-sectional view of an article comprising a gradient of a bioactive agent disposed in a support where a portion of the article is in contact with a tissue surface, according to one embodiment of the invention;

FIGS. 19A-19D are images showing transfer of a bioactive agent to porcine skin tissue using a patterned array of adhesive (FIGS. 19B and 19D) and non-patterned adhesive (FIGS. 19A and 19C), according to one embodiment of the invention;

FIGS. 20A-20H show various configurations of adhesives and adhesive isolating materials associated with a support, according to embodiments of the invention;

FIG. 21 shows an example of an article that includes an adhesive isolating layer that is removed prior to contact with a tissue surface, according to one embodiment of the invention;

FIG. 21 B shows a support sandwiched between two Teflon sheets, according to one embodiment of the invention;

FIGS. 22A-22D show a method of forming a patterned array of adhesive directly on a surface of interest, according to one embodiment of the invention; FIGS. 23 A and 23B show images of structures formed by direct transfer of bioactive agents on tissue surfaces, according to one embodiment of the invention; FIGS. 24 A and 24B show images of additional structures formed by direct transfer of bioactive agents on tissue surfaces, according to one embodiment of the invention;

FIGS. 25 A and 25B show a method of transferring an article to a surface of interest using adhesive forces, according to one embodiment of the invention;

FIGS. 26 A and 26B show another method of transferring a support to a surface of interest, according to one embodiment of the invention; FIGS. 27 A and 27B show the formation of a patterned array of an adhesive on a surface after transferring a patterned array of an adhesive precursor to the surface, according to one embodiment of the invention;

FIGS. 28A-28D show articles comprising adhesives on at least two sides of the article, according to one embodiment of the invention; FIGS. 29A-29C show patterned arrays of adhesive positioned on at least two sides of the support that can be expanded to cause transfer of the adhesives to a surface of interest, according to one embodiment of invention;

FIG. 3OA shows images demonstrating transfer of a support from two sides of a transfer device to a tissue surface, according to one embodiment of the invention; FIG. 30B shows images demonstrating transfer of a support from a single side of a transfer device to a tissue surface, according to one embodiment of the invention;

FIGS. 31 A and 3 IB show an example of a transfer device that includes a textural material comprising an outer differential geometry to aid transfer of material from a device to a surface of interest, according to one embodiment of the invention; FIGS. 32A-32D show various examples of how articles of the invention can be used to repair tissue, according to one embodiment of the invention;

FIG. 33 A shows repair of porcine skin tissue having an incision through the center of the tissue, according to one embodiment of the invention;

FIG. 33B is a graph showing the results of mechanical testing of adhesion of the embodiment shown in FIG. 33 A, according to one embodiment of the invention;

FIGS. 34A and 34B show mechanical testing of tissues joined by a support of the invention, according to one embodiment of the invention; FIG. 35 is a graph showing the results of mechanical testing of the embodiments shown in FIGS. 34A and 34B, according to one embodiment of the invention;

FIGS. 36A-36D show mechanical testing of tissues joined by an article comprising a patterned array of adhesives, according to one embodiment of the invention;

FIGS. 37 and 38 show side and top schematic views of an eye in a normal configuration;

FIGS. 39 and 40 show side and top schematic views of an eye with muscle tissue detached from the sclera and an adhesive array applied to the eye in accordance with one aspect of the invention; FIGS. 41 and 42 show side and top schematic views of an eye with the muscle tissue adhered to the sclera by way of the adhesive array in accordance with one aspect of the invention;

FIGS. 43 and 44 show side and top schematic views of an eye with a support adhesively attached over the muscle tissue/sclera junction in accordance with an aspect of the invention;

FIG. 45 shows a schematic side view of a corneal flap being lifted from an eye;

FIG. 46 shows laser treatment of the stromal bed of the eye with the corneal flap folded away;

FIG. 47 shows an adhesive applied to the eye tissue in preparation for securing the corneal flap in place in accordance with aspects of the invention;

FIGS. 48 and 49 show top and side views of an instrument being inserted into eye tissue and applying adhesive to the eye wound in accordance with aspects of the invention;

FIGS. 50 and 51 show top and side views of the adhesive applied as shown in FIGS. 48 and 49 securing the eye wound;

FIGS. 52 and 53 show schematic side and top views of a process removing at least a portion of corneal tissue from an eye;

FIGS. 54 and 55 shows schematic side and top views of a donor corneal tissue adhered in place of the removed corneal tissue in accordance with aspects of the invention;

FIG. 56 shows a schematic view of a support securing a portion of damaged retinal tissue in accordance with aspects of the invention; and FIG. 57 shows a schematic view of a support securing a portion of damaged retinal tissue with glial cell overgrowth in accordance with aspects of the invention.

DETAILED DESCRIPTION Articles and methods comprising supports and adhesives for tissue repair are provided. In some embodiments, a support includes a patterned adhesive that provides regions of discrete adhesion points for attachment to a tissue surface. In some cases, the discrete adhesion points enable the adhered support to exhibit greater normalized shear strength compared to a similar arrangement using the same amount of adhesive applied to the support in a uniform manner. A wide variety of such patterned adhesive arrangements are described below. In some cases, bonding of the adhesive may be controlled to help better control deployment of a support. For example, the support may optionally include an adhesive isolating material that covers all or a portion of the adhesive. In some cases, the isolating material delays adhesion between the support and the tissue until the isolating material is removed from the support (e.g., by degradation, dissolving, absorption, erosion, or fracturing), thereby exposing the adhesive to the tissue surface after some delay time. Advantageously, the delay of adhesion can allow a user sufficient time to reposition the support on the tissue if so needed. In addition, adhesion between the support and the tissue surface may be varied after repositioning, for example, by controlling the amount of adhesive exposed to the tissue and/or the composition of the adhesive (e.g., the amount or speed of polymerization). The support may optionally include one or more bioactive agents that can be delivered to the tissue site. In some embodiments, the support is biodegradable.

In another aspect, methods of applying a support to a tissue using a transfer device are provided. In some cases, deploying an adhesive-carrying support can be problematic, e.g., because mishandling can cause the adhesive to contact the deployment instrument, tissue and/or other undesired objects, possibly causing fouling of the instruments or other objects as well as damage to the support and adhesive. In one embodiment, a support is transferred from the transfer device to a tissue surface by contact adhesion, e.g., where the support is adhered to the deployment instrument and the adhesion strength between the support and the tissue is greater than the adhesion strength between the support and the transfer device, and/or wherein the adhesion strength between the adhesive and the tissue surface is greater than the cohesive forces of the adhesive material. As a result, the support can be initially "stuck" on the transfer device, transported to the deployment site, and then disengaged from the transfer device by adhering the support to the tissue site and pulling the transfer device away. The use of a transfer device of the invention can allow a support and/or an adhesive to be applied to a tissue with precision and control.

The articles and methods described herein can be used in a variety of applications involving tissue repair. One such application includes repair of ophthalmic tissues, as described in more detail below.

FIG. IA shows a perspective view of an article 1 that can be used for tissue repair. The article comprises a support 10 and an adhesive 12. As illustrated, the adhesive covers a portion of the support within an adhesive boundary 18, which is defined by an area circumscribing every area of adhesive on a surface. In this particular embodiment, the adhesive is not patterned on the support and is substantially uniformly applied across the surface, the support having the same adhesion strength across its surface within the adhesive boundary. Thus, when the article is positioned conformally on a surface of interest (e.g., a tissue surface or a surface of a biocompatible implant), all portions of the adhesive adhere uniformly to the surface. Although such an embodiment may be used in some aspects of the invention, in many cases, this example is shown, in part, to contrast with other articles including patterned arrays of adhesives. Advantageously, in some embodiments of the invention, an article including a patterned array of an adhesive can exhibit greater normalized shear strength, be less prone to fracture, promote greater tissue growth, reduce cytotoxic reactions of the tissue by decreasing the total amount of adhesive, and/or allow greater control of transfer of bioactive agents from the article to a tissue compared to articles having non-patterned adhesives (such as that shown in FIG. IA). For example, in one particular embodiment, an article including a patterned array of adhesive attached to a tissue surface can exhibit approximately three times the amount of normalized shear strength compared to a non- patterned adhesive, all other factors being equal. A patterned array of adhesive can also allow the practitioner to use only the amount of adhesive necessary for a particular application, since in some instances, an adhesive may be toxic to the tissue or surrounding cells. Other potential advantages are described further below.

In some embodiments, a patterned array of an adhesive on a surface of interest includes at least two first regions of an adhesive having a first adhesion strength relative to the surface that, when taking a cross-section through an adhesive boundary, are separated from each other by at least a second region having a second, different adhesion strength relative to the surface. The patterned array of adhesive may be functionally different than a uniform application of either the first adhesive or the second adhesive on the surface, all other factors being equal. In some embodiments, the second adhesion strength is substantially different from the first adhesion strength. In one embodiment, a substantially different adhesion strength refers to a difference between the first and second adhesion strength of at least 20%. In such embodiments, points of non-uniform adhesion occur at the interface between the adhesive and a surface of interest across the adhesive boundary. In certain embodiments, the first and second adhesion strength may differ by at least 40%, at least 60%, or at least 80%. If the two regions of adhesive are separated by a non-adhesive region (e.g., an adhesion strength of about 0), the difference in adhesion strength is 100%. Of course, an article may include third, fourth, fifth, etc. regions of adhesives that have an adhesion strength that differs by at least 20% compared to another region of adhesive. As used herein, "adhesion strength" refers to a tensile strength or a shear strength corresponding to the maximum load under tensile or shear, respectively, divided by the interfacial area between the articles. Adhesion strength can also refer to the average load per total interfacial area between. the articles as measured by a T-peel test, as described in more detail below. The percent difference in adhesive strength may be calculated by taking the difference between the adhesive strength of the two adhesive regions (e.g., as measured on two separate articles, one having the adhesive of the first region and the second having the adhesive/material of the second region) and dividing by the larger value. Methods of measuring adhesive strength are described in more detail below. Surprisingly, the inventors have discovered that in certain embodiments, patterned adhesives comprising first regions of adhesive separated by a material (or the absence of a material) having a difference in adhesion strength of at least 20%, at least 40%, at least 60%, or at least 80% within an adhesive boundary allows the patterned array to have greater normalized shear strength and be less prone to fracture compared to an adhesive that is uniformly applied across a tissue surface. Furthermore, in some cases, such embodiments promote greater tissue growth and allow for increased transfer of bioactive agents and can reduce cytotoxic reaction of the tissue by decreasing the total amount of adhesive. The first regions having a first adhesion strength and/or the second region having a second adhesion strength may, in some embodiments, have at least one cross-sectional dimension of less than 5 mm, less than 3 mm, less than 1 mm, less than 500 microns, less than 250 microns, less than 100 microns, less than 75 microns, less than 50 microns, less than 25 microns, less than 10 microns, less than 1 micron, or less than 0.1 microns. In some cases, the cross-sectional dimension having the above values is a width or a length of the region; in other cases, the cross-sectional dimension is a height. In other embodiments, the length of the first and/or second region along a cross-section taken through an adhesive boundary is defined by one of the above values. In some embodiments, a patterned array of adhesive refers to a pattern of adhesive associated with an article (e.g., a support or a tissue) prior to contact of the article with a surface of interest. In other embodiments, a patterned array of adhesive refers to a pattern of adhesive associated with an article while the article is in contact with a surface of interest. Sometimes, the features (e.g., squares, lines, circles, etc.) of a patterned array associated with an article prior to contact with a surface of interest has one or more substantially similar dimensions (e.g., width, height, and length) as the features of the array after initial contact between the article and the surface of interest. For example, in some embodiments, patterned adhesives in the form of thin films have substantially similar dimensions on the article before contact as those after contact with a surface of interest. In other embodiments, the features of a patterned array associated with an article prior to contact with a surface of interest has different dimensions as the features of the array after initial contact between the article and the surface of interest. For example, in some embodiments, the features of a patterned array of liquid adhesive has larger cross-sectional dimensions after being in initial contact (e.g., before dissolution, erosion, etc. of the adhesive) with a surface of interest than before contact with the surface. The average difference in cross-sectional dimension of the features after being in initial contact compared to before contact with a surface of interest depends, of course, on the amount of adhesive applied and the applied pressure between the surfaces. In some cases, this average difference is less than 80%, 60%, 40%, 20%, or 10% of the cross-sectional dimension of the features before contact with the surface of interest.

FIG. IB shows a cross-sectional view of article 1 of FIG. IA in contact with a surface of interest 13 (e.g., a tissue surface or a surface of a biocompatible implant). According to one embodiment, the article does not include regions of adhesion strength that differ by at least 20% when taking any cross-section through the adhesive boundary; therefore, adhesive 12 is not patterned. In other embodiments, a test for a patterned array of adhesive includes taking at least 2 cross-sections, or at least 3 cross-sections, through the adhesive boundary and if there are no regions of adhesion strength that differ by at least 20% along any of the cross-sections, the adhesive is not patterned. In some such embodiments, the at least 2 or at least 3 cross-sections are separated from one another by at least 15 degrees, 30 degrees, 45 degrees, 60 degrees, 75 degrees, or 90 degrees, for example. In contrast, as shown in the embodiment illustrated in FIG. 1C, an article 2 includes adhesive portions 14 positioned on surface features in the form of raised portions 16 (e.g., protrusions) of support 10. Adhesive portions 14 have a first adhesion strength relative to a surface 13. The article also includes adhesive portions 15 having a second adhesion strength relative to surface 13 positioned on lower portions 17 (e.g., indentations) of the support. Even though adhesive portions 14 and 15 comprise the same adhesive and have a uniform thickness across the surface of the support, the adhesion strength of the portions differ by greater than 20% relative to surface 13 because adhesive portions 14 are in contact with the surface to a greater extent than that of adhesive portions 15. Accordingly, adhesive 12 is in the form of a patterned array and non-uniform adhesion occurs at the interface between the article and surface 13. FIG. ID shows another example of an article having a patterned array of adhesive. As illustrated, article 3 includes portions of a first adhesive 12 separated by portions of a second adhesive 19. The adhesion strength of adhesives 12 and 19 differ by at least 20% relative to surface 13. For example, in one embodiment, adhesive 12 is strongly adhesive towards surface 13 and adhesive 19 is a weakly adhesive towards surface 13, the adhesion strength differing by at least 20%. Thus, adhesives 12 and 19 form patterned arrays and promote non-uniform adhesion at the interface between the article and surface 13, even though a uniform thickness of adhesive (e.g., adhesives 12 and 19) is applied across the support surface. In some cases, the article can include a non-adhesive material in place of second adhesive 19.

In other embodiments, an adhesive portion is separated by a surface portion that is absent an intervening material. For example, as shown in the embodiment illustrated in FIG. IE, portions of adhesive 12, which form a patterned array on surface 13, are separated by intervening surface portions 20. In such embodiments, the difference in adhesion strength between portions of adhesive 12 and the intervening portions is 100%.

In certain embodiments, a patterned array of adhesive includes a first portion occupying at least 20% of the total area within an adhesive boundary, the first portion having an adhesion strength that differs by at least 20% from a second, adhesive portion. In certain embodiments, the combined area of the first portion may be at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, or at least 90% of the total area within the adhesive boundary. The combined area of the first portion may include a non- adhesive material in some cases, or no material at all in other cases. In such embodiments, points of non-uniform adhesion occur at the interface between the adhesive and a surface of interest across the adhesive boundary.

Surprisingly, the inventors have discovered that in certain embodiments, a first portion (e.g., a non-adhesive material, the absence of an adhesive material, or a less adhesive material) occupying at least 20%, at least 40%, at least 50%, at least 70%, or at least 90% of the total area within an adhesive boundary allows a patterned array of adhesive to withstand greater normalized shear strength and be less prone to fracture compared to an adhesive that is uniformly applied across a tissue surface. Furthermore, in some cases, such embodiments promote greater tissue growth and allow for increased transfer of bioactive agents and can reduce cytotoxic reactions of the tissue by decreasing the total amount of adhesive.

The first and/or second portions may have, in some embodiments, at least one cross-sectional dimension of less than 5 mm, less than 3 mm, less than 1 mm, less than 500 microns, less than 250 microns, less than 100 microns, less than 75 microns, less than 50 microns, less than 25 microns, less than 10 microns, less than 1 micron, or less than 0.1 microns. In some cases, the cross-sectional dimension having the above values is a width or a length of the portion; in other cases, the cross-sectional dimension is a height.

As shown in a perspective view of the embodiment illustrated in FIG. 2, article 25 includes a support 10 including an adhesive 12 associated therewith. Support 10 may be in the form of a rigid or semi-rigid structure, and may include a surface that is substantially flat, or have topographies such as raised regions, lowered trenches or the like, as described in more detail herein. Adhesive 12 is in the form of a patterned array as there are non-adhesive portions 28 that have a combined area of at least 20% of the area bound by adhesive boundary 18. Accordingly, adhesive 12 imparts non-uniform adhesion across adhesive boundary 18 when the article is adhered to a surface. As illustrated, the pattern formed by adhesive 12 is a continuous pattern, as all portions of the adhesive are interconnected; that is, any one region of adhesive is connected to any other region of adhesive by adhesive portions.

As mentioned above, in some cases an article includes first portions of an adhesive having a first adhesion strength and second portions of an adhesive having a second adhesion strength which are not separated by non-adhesive portions. For example, similar to article 2 of FIG. 1C, article 25 of FIG. 2 may include a second adhesive in place of non-adhesive portions 28, the second adhesive having a different degree of adhesion strength than that of adhesive 12. In some cases, the first and second adhesion strength differ by at least 20%, at least 40%, at least 60%, or at least 80%. In such embodiments, the adhesives are in the form of patterned arrays as the adhesives impart non-uniform adhesion within adhesive boundary 18. FIGS. 3 and 4 show examples of articles that include patterned, discontinuous arrays of adhesives on a support. As illustrated, articles 30 and 32 include strips of adhesives 12 on supports 10 within adhesive boundaries 18. The strips of adhesive are separated by portions 36 and 38 that are uncovered with adhesive within the adhesive boundaries of the respective articles. The combined area of uncovered portions 36 is greater than 20% of the area within adhesive boundary 18 of FIG. 3. Likewise, the combined area of uncovered portions 38 is greater than 20% of the area within adhesive boundary 18 of FIG. 4. The patterned array of each of the articles is discontinuous as different strips of adhesive 12 are not connected by intervening adhesive portions. The discontinuous, patterned arrays of adhesive shown in FIGS. 3 and 4 are arranged such that a directional component is introduced into the structures. Thus, articles 30 and 32 may exhibit different degrees of shear strength depending on the direction of the applied force. For example, the effect of lateral forces upon article 32 of FIG. 4 in the direction of arrow 37 may be different than the effect of lateral forces in the direction of arrow 39. The articles shown in FIGS. 3 and 4 can be described as one dimensionally anisotropic with respect to adhesion strength.

FIG. 5 A shows an example of a patterned array of adhesive that is discontinued and non-ordered. As shown in the embodiment illustrated in FIG. 5 A, adhesive 12 is non-ordered on support 10 because the arrangement of the adhesive portions within adhesive boundary 18 is random and does not form a recognizable pattern. The area of portion 40 uncovered with adhesive is greater than 20% of the area within adhesive boundary 18. Accordingly, the patterned array of adhesive imparts non-uniform adhesion between the article and a surface within the adhesive boundary. In some embodiments, adhesives described herein are in the form of a patterned array that is discontinuous and ordered. For example, as shown in the embodiment illustrated in FIG. 5B, adhesive 12 is arranged in a non-random pattern on support 10. The combined area of portion 42 uncovered with adhesive is greater than 20% of the area within adhesive boundary 18. Accordingly, the patterned array of adhesive imparts non- uniform adhesion between the article and a surface within the adhesive boundary.

As illustrated in FIGS. 3-5B, a surface may include adhesive 12 in the form of discrete, non-interconnected portions having various shapes (e.g., dots, lines, triangles, squares, circles, arcs, ovals, irregular shapes, etc.). The number of such discrete adhesive portions that form a patterned array may be, for example, greater than or equal to 2, greater than or equal to 5, greater than or equal to 9, greater than or equal to 16, greater than or equal to 25, greater than or equal to 50, greater than or equal to 75, greater than or equal to 100, greater than or equal to 150, greater than or equal to 200, or greater than or equal to 500. For example, in some embodiments, larger numbers of discrete adhesive portions (e.g., greater than about 50) may be useful for facilitating tissue growth across the surface of an article compared to the same amount of adhesive applied in fewer discrete portions, or applied uniformly to the article. In some embodiments, smaller numbers of discrete adhesive portions (e.g., less than about 50) may be useful for reducing tissue growth across an article.

In some embodiments, one or a plurality of discrete adhesive portions of a patterned array has at least one (or at least two, in some instances) cross-sectional dimension(s) of less than 5 mm, less than 3 mm, less than 1 mm, less than 500 microns, less than 250 microns, less than 100 microns, less than 75 microns, less than 50 microns, less than 25 microns, less than 10 microns, less than 1 micron, or less than 0.1 microns. In some cases, the cross-sectional dimension having the above values is a width or a length of an adhesive portion; in other cases, the cross-sectional dimension is a height.

As shown in the embodiment illustrated in FIG. 5C, patterned arrays of adhesives may also be continuous and non-ordered. The combined area of portions 44 uncovered with adhesive 12 is greater than 20% of the area within adhesive boundary 18. Accordingly, the patterned array of adhesive imparts non-uniform adhesion between the article and a surface within the adhesive boundary.

In some embodiments, adhesive arrays of the invention form geometric patterns, such as, for example, circles, squares, rectangles, grids of lines or droplets, and combinations thereof. For instance, FIG. 6 shows an article 60 including a discontinuous and ordered patterned array of adhesive 12 on a support 10. In this illustrative embodiment, the adhesive area forms a geometric pattern in the form of concentric circles within adhesive boundary 18. The combined area of portions 62 uncovered with adhesive 12 is greater than 20% of the area within adhesive boundary 18. Accordingly, the patterned array of adhesive imparts non-uniform adhesion between the article and a surface within the adhesive boundary.

It should be understood that the patterns of adhesives shown in connection with FIGS. lC-6 are exemplary and that adhesives and patterned arrays of adhesives described herein can include a variety of shapes and configurations. Furthermore, although many of the patterned arrays of adhesives shown in FIGS. lC-6 involve adhesives associated with a support, in certain embodiments of the invention, patterned arrays of adhesive may be positioned on a tissue surface directly without the use of a support. These and other embodiments are described in more detail below.

A variety of methods can be used to form articles comprising supports and adhesives. For example, an adhesive (as well as other components such as bioactive agents and isolating materials) can be printed on a support by methods such as ink jet printing, rolling, and pressing. In one particular embodiment, patterned arrays of adhesives such as those shown in FIGS. lC-6 are formed by stamping adhesives on a support. In one such embodiment, stamping comprises microcontact printing, i.e., the use of conformable materials (e.g., elastomers) to affect transfer of a material from a stamp to a surface of interest by conformally contacting the stamp and the surface of interest. Microcontact printing is described in more detail in, for example, U.S. Patent Nos. 6,060,121; 6,776,094; 6,752,942; 6,686,184; 6,660,192; 6,355,198; 6,180,239; 5,776,748; and 5,512,131 to Whitesides et al., which are incorporated herein by reference in their entirety.

As described herein, in some embodiments, patterned articles are formed by methods comprising transferring material from one surface to another surface by contact adhesion; that is, the material is secured to a first surface (e.g., a transfer surface) and is transferred to a second surface (e.g., a surface of interest) through adhesive forces. Such transfer may be used to transfer adhesive to a support or tissue surface, transfer a support to a tissue surface (where the support may carry an adhesive and/or adhesive is carried on the tissue surface), transfer a material (such as a sample of cells) from a tissue site to a biopsy instrument, and others discussed in more detail below. Adhesive forces as used herein means adherences through a favorable free energy of interaction when two or more surfaces are brought into contact, and is meant to distinguish from other methods of material transfer which rely primarily on mechanical forces. In some cases, contact adhesion comprises conformal contact between the article and the surface of interest; in other embodiments, non-conformal contact comprises non-conformal contact between the article and the surface of interest.

An example of a method involving transfer by contact adhesion is shown in FIGS. 7A-7D. As illustrated in FIG. 7A, a transfer device in the form of a stamp 100 having protrusions 102 and indentations 104 is placed in contact with an adhesive 108 positioned on a surface 1 10. Adhesive 108 may be in any suitable form such as a liquid, a solid, a gel, a plurality of particles, a film, a monolayer, etc. As shown in this particular embodiment, adhesive 108 is only transferred to surfaces 112 of the protrusions; however, in other embodiments, an adhesive can also be transferred to the indentations of a surface. As shown in FIGS. 7B and 7C, stamp 100 with adhesive 108 patterned thereon can be brought in contact with a support 120. Upon removal of stamp 100 from surface 122 of the support, adhesive portions 124 can be transferred to the support. As illustrated, the pattern of adhesive on the support substantially matches the pattern of adhesive that was on stamp 100 prior to transfer, as well as the pattern formed by the protrusions. The thickness of adhesive portions 124 on the support may be, for example, between one monolayer and 5 mm. For instance, the thickness may be less than 5 mm, less than 3 mm, less than 1 mm, less than 500 microns, less than 250 microns, less than 100 microns, less than 75 microns, less than 50 microns, less than 25 microns, less than 10 microns, less than 1 micron, or less than 0.1 microns. In some cases, a monolayer of adhesive is formed on the support.

It should be understood that adhesive forces may include any suitable associations or interactions between the adhesive, the surface of the transfer device, and the surface of interest. For example, referring to FIG. 7, adhesive 108 may have one or more types of associations with surfaces 112 of stamp 100 (e.g., a transfer surface) and surface 122 of support 120 (e.g., a surface of interest) to allow transfer of the adhesive from the transfer surface to the surface of interest. Association between adhesive 108 and surfaces 112 and/or 122 may comprise, for example, adsorption, absorption, Van der Waals interactions, hydrogen bonding, covalent bonding, ionic bonding, cross linking, magnetic interactions, electrostatic interactions, and combinations thereof. In some instances, the type of association(s) between the adhesive and the transfer surface is the same as those between the adhesive and the surface of interest. For example, the interactions between adhesive 108 and surfaces 112 and 122 may both be predominantly non-covalent interactions (e.g., van der Waals interactions). However, in other embodiments, the interactions between the adhesive and the two surfaces is different. For example, the adhesive may be magnetically attracted to surface 112 (which may be magnetically susceptible), but upon contact of stamp 100 with surface 122 of the support, the adhesive may transfer to surface 122 due to covalent bonding between the adhesive and surface 122. In some such embodiments, the combined adhesive interactions (e.g., adhesion strength) between the adhesive and the surface of interest may be greater than the combined adhesive interactions between the adhesive and the transfer surface, such that transfer of the adhesive occurs upon contact between the surfaces. In other embodiments, the combined cohesive interactions of the material making up the adhesive is less than the combined adhesive interactions between the adhesive and the surface of interest, such that transfer of the adhesive takes place. It should be noted that in embodiments described herein, all or only a portion of the adhesive may be transferred from a transfer device to a surface of interest.

In some cases, a pressure is applied to facilitate transfer of an adhesive from one surface to another by contact adhesion.

In addition, as described further below, an adhesive may be an initial adhesive, e.g., one that works upon contact and does not need activation, or an activatable adhesive, e.g., one that requires activation by an auxiliary agent such as energy (e.g., heat, light) and chemical reagents. In some embodiments the bulk and/or surface of a transfer device (e.g., a stamp) and/or a surface of interest to which a material is transferred (e.g., a support or a tissue surface) may be modified to make the surfaces either more or less susceptible to adhesive transfer of the material. In one embodiment, one or more portions of a surface is/are chemically modified to make the portions either more or less susceptible to adhesion of the material. For example, a stencil of a predetermined pattern or random arrangement may be laid down on a support surface, blocking some portions of the support while leaving other portions exposed. The exposed surfaces may then be chemically modified to make them either more or less hydrophobic, for example. Such a modification may be carried out, for example, by oxidizing or reducing the exposed surfaces. A material such as an adhesive and/or a bioactive agent may then be chosen that adheres selectively to either type of surface. The pattern of material may be formed on the article, for example, by contacting the modified article with the material (e.g., by dipping the article into a solution of the material) and allowing the material to adhere only to the modified (or unmodified) portions of the article. Such techniques are known in the art and. are described in U.S. Patent Nos. 6,752,942; 6,686,184; 6,660,192; 6,355,198; 6,180,239; 5,776,748; and 5,512,131; incorporated herein by reference in their entirety.

In another embodiment, transfer by contact adhesion or other methods can be used to first treat portions of a surface with a reagent, the treated portions allowing greater or less adhesion of a material compared to untreated portions of the surface. For example, a material may adhere to the transfer device through electrostatic forces, but be modified to adhere more strongly to the tissue surface by introducing common reactive groups such as nucleophilic and/or electrophilic groups. Non-limiting examples of nucleophilic groups include hydroxy, amino, and thiol groups, and non-limiting examples of electrophilic groups include carbonyl groups such as carboxylic acids, esters, and aldehyde groups. In another embodiment, adherence to either the transfer device or tissue may be assisted by one of the adhesives discussed below.

An example of the method illustrated in FIG. 7 for forming a patterned array of adhesive on a support is shown in FIGS. 8A-8F. As illustrated in FIGS. 8A and 8B, transfer device 160 includes a handle 162 and a stamp 150 having a plurality of protrusions 154. After bringing protrusions 154 in contact with an adhesive, portions of adhesive can be transferred to the surface of the protrusions. A patterned array of adhesive 166 can be formed on support 164 by bringing the transfer device in contact with a surface of the support. Surface portions 168 that were not in contact with the protrusions of the transfer device are not patterned with adhesive. As illustrated, the patterned array of adhesive 166 on the support is substantially similar to the patterned array of adhesive on protrusions 154 prior to transfer and to the pattern of protrusions on the device. FIGS. 8D-8F show that changing the pattern of protrusions on the transfer device results in different patterns of adhesive on a support. Accordingly, one method of varying the pattern of adhesive on a support is to vary the pattern of protrusions on a transfer device. Another method may include varying the pressure applied during transfer.

FIGS. 9-13 show various patterns of adhesive on polymer supports that can be formed using methods described herein. The methods and materials used to form the structures are described in more detail in the examples section.

FIGS. 9A-9I show arrays of adhesives patterned on various polymer supports in continuous, ordered arrays. This technique was illustrated using supports made of polystyrene (FIG. 9A), poly(D,L-lactide-co-glycolide) (DL-PLGA, FIGS. 9 and 9C), poly(ε-caprolactone) (PCL, FIGS. 9D and 9E), poly(glycerol sebacate) (PGS, FIGS. 9F and 9G) and polyethylene glycol), (PEG, FIGS. 9H and 91).

FIG. 10 shows bands of adhesive patterned on an electrospun PCL support. FIGS. 1 IA-1 1C shows patterns of adhesive on a support in a discontinuous, non- ordered array (FIG. 1 IA), a continuous, ordered array (FIG. 1 IB), and a continuous, non-ordered array (FIG. HC). The adhesive in FIGS. 1 IA and 1 IB included cyanoacrylate without pluronic. The adhesive in FIG. 11C was a pluronic-containing cyanoacrylate. Non-porous PLGA supports were used in FIGS. 1 IA and 1 1C, and an electrospun PCL support was used in FIG. 1 IB. The scale bar in each image represents one millimeter.

FIGS. 12A and 12B show patterns of fibrin adhesive stamped and onto an electrospun PCL support in a discontinuous, ordered array (FIG. 12A) and an electrospun PLGA support in a continuous, ordered array (FIG. 12B). FIGS. 13A-13C show patterns of protein solders in a discontinuous, ordered array of ICG on electrospun PLGA (FIG. 13A), a discontinuous ordered array of MB on electrospun PLGA (FIG. 13B), and a discontinuous ordered array of ICG on electrospun PLGA (FIG. 13C).

As described herein, an article, which can be used as a transfer device or a support for example, may include one or more indentations (e.g., an array of wells or channels) or protrusions on at least one surface of the article. The shape and size of the indentations can vary and may include, for example, the patterns shown in FIGS. 1C- ID and/or FIGS. 2-6. The depth of the indentations or height of the protrusions may be between 1 micron and 5 mm, and may be chosen at least in part depending on the particular application. For example, the depth of one or more indentations of an article may be greater than or equal to 1 micron, greater than or equal to 25 microns, greater than or equal to 50 microns, greater than or equal to 75 microns, greater than or equal to 100 microns, greater than or equal to 250 microns, greater than or equal to 500 microns, greater than or equal to 1 mm, greater than or equal to 3 mm, or greater than or equal to 5 mm.

Examples of articles having a plurality of indentations and protrusions are shown in FIGS. 14A-14B. As shown in the illustrative embodiment of FIG. 14A, article 200, which can be used as a stamp or a support for example, includes structure 206 having protrusions 210 and indentations 212. As illustrated in FIG. 14B, indentations 212 may include adhesives 218 disposed therein. In one embodiment, all or a portion of adhesive 218 can be transferred from article 202 to a surface of interest (e.g., a surface of a support or a surface of a tissue) by placing the article in proximity to the surface of interest, and then removing support 206 away from the surface of interest. The pattern of adhesive formed on the surface of interest may be substantially similar to the pattern of adhesive in article 202.

In another embodiment, adhesive 212 allows adhesion between article 202 and the surface of interest occurs while the article is in contact with the surface. In some embodiments, this adhesion occurs immediately upon contact between the article and the surface of interest; however, as described in more detail below, adhesion may be delayed until an amount of time after initial contact between the article and the surface of interest. For example, adhesive 218 may be coated all or in part by an adhesive isolating material, as described further below. In some embodiments, indentations 212 contain one or more bioactive agents in addition to or in the place of adhesive 218.

Formation of indentations in a material can be performed using standard techniques known to those of ordinary skill in the art. For example, the indentations may be formed by molding (e.g., injection molding or soft lithography), embossing, casting, laser drilling, or machining, which are methods known in the art. FIGS. 15A-15C show examples of polymeric articles containing adhesive-filled channels and wells. The articles include a support 220 including indentations 222 in various arrangements. Methods of forming such structures are described in more detail in the examples section. As described herein, in some embodiments an article comprising a support and an adhesive can be brought in contact with a tissue surface. As shown in the embodiment illustrated in FIG. 16, article 240 comprises a support 244 and an array of adhesive 248 patterned on a surface 250 of the article. Adhesive 248 may cause article 240 to adhere to a surface 254 (e.g., a tissue surface). Optionally, the bulk of support 244 may include one or more bioactive materials that can be transferred from the support to surface 254 in the direction of arrows 256. In some embodiments, the bioactive agent is transferred only at portions 258 that are not covered with adhesive. That is, the adhesive may act as an isolating material to isolate portions of the bioactive agent from parts of the tissue surface. In other embodiments, however, portions of adhesive 248 may be permeable to the bioactive agent and delivery of the bioactive agent across the surface of article 240 may be substantially uniform. Accordingly, the transfer of a bioactive agent from an article to a surface of interest can be controlled by choosing appropriate materials for the support and adhesive, the arrangement of adhesive on the support, as well as other methods described below.

FIGS. 17A-17E show examples of articles comprising bioactive agents that can be used for tissue healing. In some embodiments, the articles shown in FIGS. 17A-17E may be used to deliver a gradient of bioactive agents. For example, different bioactive agents may be eluted at different rates, and/or different concentrations of bioactive agents may be delivered over time. In some cases, the rate of delivery of a bioactive agent gradually declines as a tissue surface starts to heal itself.

As shown in the embodiment illustrated in FIG. 17 A, article 300 can include a support 306 and a plurality of bioactive agent portions 308 that may be in the form of a patterned array. In some embodiments, at least a portion of a bioactive agent portion 308 is covered with an adhesive 310, which may allow article 300 to adhere to a surface of interest e.g., a tissue surface. As shown, adhesive 310 may also be in the form of a patterned array. In some embodiments, after contacting the article with a surface of interest, exposed portion 312 of the adhesive is removed (e.g., by biodegradation, dissolvation, fracture, etc.). In some instances where adhesive 310 is removable, portions 314 of the bioactive agent may be released only after adhesive 310 is removed from the support. In one embodiment, adhesive 310 is not removable and portions 314 of the bioactive agent are released to the surface of interest only after diffusing out towards portions 312. In yet another embodiment, portions 314 of the bioactive agent may permeate through adhesive portions 310 to reach the surface of interest. In yet other embodiments, bioactive agents may be released by application of an external energy source (e.g., light and heat), as described in more detail below. In these and other embodiments, adhesive portions 310 may act as an isolating material that is constructed and arranged to initially resist contact between bioactive agent portion 314 and a tissue surface and to later allow contact between the bioactive agent portion and the tissue surface. In other embodiments, one or more portions of a bioactive portion is covered by an isolating material that does not comprise an adhesive.

A number of bioactive agents can be used in embodiments of the invention. Non-limiting examples of bioactive agents include analgesics for reducing the amount of post-surgical pain and discomfort, antibiotics for reducing the probability of postsurgical infections, and growth factors for helping a muscle adhere more quickly to a tissue (e.g., the sclera, for certain ophthalmic applications), reducing the risk of a lost muscle. In one particular embodiment, a growth factor may be beneficial if the adhesive needs to be removed in a short amount of time. Specific examples and classes of bioactive agents are described in more detail below.

In some cases, bioactive agent portions 308 each include one particular bioactive agent. In other embodiments, a mixture of two or more bioactive agents can be included in bioactive agent portions 308. In other embodiments, certain bioactive agent portions 308 may include one or more types of bioactive agent, and other bioactive agent portions 308 may include at least one different type of bioactive agent. In addition, different concentrations of the same bioactive agent may be contained in different bioactive agent portions 308 or at different locations within the same bioactive agent portion 308.

As shown in the embodiment illustrated in FIG. 17B, article 301 may include support 306 with alternating patterns of bioactive agent portions 308 and adhesive portions 310. In some such embodiments, bioactive agent portions 308 may be delivered to a tissue surface upon contact.

As shown in the embodiment illustrated in FIG. 17C, article 302 may include support 306 comprising indentations 318 having contained therein bioactive portions 308. Adhesive portions 310 may be on surfaces of protrusions 320 which can allow article 302 to adhere to a tissue surface.

In some cases, bioactive agent portion 308 is not in the form of a patterned array, for example, as illustrated in FIG. 17D. Article 303 includes support 306 including a layer of bioactive agent 308 on at least one surface of the support. Adhesive portions 310 can cover one or more portions of the layer of bioactive agent.

In yet another embodiment, as illustrated in FIG. 17E, article 304 includes a support 306 with one or more bioactive agent portions 308 embedded therein. Bioactive agent portions 308 may be in the form of layers, tubules, films, or the like. Article 304 may optionally include one or more portions of adhesive positioned on a surface of the support.

It should be understood that bioactive agent portions 308 may be in any suitable form. For example, a bioactive agent may be dispersed within a polymer to form bioactive agent portions 308. A bioactive agent may dispersed as particles (e.g., nanoparticles and beads) or a bioactive agent may be linked to a particle (e.g., a nanoparticle, bead, magnetic particle, and the like). In another embodiment, a bioactive agent is incorporated into a polymer (e.g., by covalent bonding or ionic bonding) that is shaped to form bioactive agent portions 308. A bioactive agent may be released from a polymer or any other suitable material by a variety methods such as biodegradation, dissolution, or fracture of the material, or upon exposure of the material to a chemical reagent or an external energy source (e.g., light or heat).

In some cases, bioactive portions 308 are in the form of a film such as a self- assembled monolayer. Films and layers of bioactive agent may have any suitable dimension. For example, a film, layer, or a portion of a bioactive agent may have a cross-sectional dimension of, for example, less than 5mm, less than 3mm, less than lmm, less than 500 microns, less than 250 microns, less than 100 microns, less than 75 microns, less than 50 microns, less than 25 microns, less than 10 microns, less than 1 micron, or less than 0.1 microns. In some cases, the cross-sectional dimension having the above values is a width or a length of the portion; in other cases, the cross-sectional dimension is a height.

As shown in the embodiment illustrated in FIG. 18, in some cases a portion but not all of a support is placed in direct contact with a tissue surface. For example, article 305 may include a support 306, a portion 324 of which is in direct contact with tissue surface 328, while a portion 330 of the support is not in direct contact with the tissues surface. In some embodiments, a portion of surface 332 of the support is covered with an isolating material 334 that can inhibit contact between that portion and a portion of the tissue surface. In one particular embodiment, portion 324 includes no bioactive agent, while portion 330 includes at least one bioactive agent. As illustrated in FIG. 18, a bioactive agent may be present in the support as a gradient with less bioactive agent near portion 324 and more bioactive agent near portion 330. Articles that allow directional delivery and/or delivery in a controlled manner at a particular location, such as that shown in FIG. 18, may be useful, for example, when the bioactive agent provides a therapeutic effect at one portion of a tissue, but has a less desirable effect at a second portion of the tissue. A specific example of FIG. 18 for ophthalmic applications is described in the examples section. FIGS. 19A-19D illustrate transfer of a bioactive agent to porcine skin tissue using a patterned array of adhesive and a non-patterned adhesive. Supports (fabricated from electrospun PLGA supports loaded with vitamin B 12) with a non-patterned adhesive (FIG. 19A) and a patterned array of adhesive (FIG. 19B) were brought into contact with porcine skin tissue. When the supports were removed, those with non-patterned adhesive (FIG. 19C) yielded less transfer of the bioactive agent than supports with a patterned array of adhesive (FIG. 19D).

In another aspect of the invention, an article adapted for medical applications comprises at least one portion of an adhesive and an adhesive isolating material adjacent at least a portion of the adhesive. The adhesive isolating material may be removed shortly before use (e.g., by peeling), or while in contact with a tissue surface. The adhesive isolating material may be constructed and arranged to be deployed with the support and adhesive at a surface of interest (e.g., a tissue surface), e.g., to initially resist contact between a portion of the adhesive and the tissue surface, and to later allow contact between the portion of adhesive and the tissue surface. Such an embodiment may allow delay of adhesion of the article to a tissue, thus giving the practitioner more time to adjust the article (e.g., the location of the article relevant to the tissue surface). For example, before an article sets, surgeons generally require approximately 20 seconds for application of a bioadhesive to a surgical site to allow time to realign the article or a muscle before final adhesion. Accordingly, embodiments described herein may delay adhesion for at least 1 second, at least 5 seconds, at least 10 seconds, at least 15 seconds, at least 20 seconds, at least 30 seconds, at least 1 minute, at least 5 minutes, at least 10 minutes, at least 30 minutes, at least 1 hour, or at least 24 hours after the article is initially placed in contact with a surface of interest. Other variations in delay of adhesion times are also possible.

An adhesive isolating material may be activated to cause removal of all or portions of the material from a tissue surface by a variety of methods. For instance, the adhesive isolating material may be light activated, pressure activated, sound activated, heat activated, chemically activated, or combinations thereof. Thus, the adhesive isolating material may be removed to allow exposure of at least a portion of the adhesive material by, for example, biodegradation, dissolution, erosion, fracture, mechanical rupture, thermal release, permeation, delayed and targeted relief, pH and osmotic release, photolytic release and triggered release. In some embodiments, an adhesive isolating material is removed while in contact with a tissue surface of the body (e.g., in vivo) by absorption, biodegredation, erosion, dissolution and/or fracture. In other embodiments, the adhesive isolating material is removed while not in contact with a tissue surface of a body by absorption, degredation, erosion, dissolution and/or fracture. In some cases, the adhesive isolating material is water soluble and can be dissolved upon contact with tissue. In some embodiments, the adhesive isolating material dissolves instantly upon contact with tissue. Non-limiting examples of dissolvable materials include polyvinyl alcohol, hydroxypropyl methylcellulose, and pullulan (e.g., the dissolvable polysaccharide used in Listerine TM breath strips), dextran, and dextran sulfate. Accordingly, in some cases the adhesive isolating material is adapted to be removed (e.g., biodegraded, dissolved, or fractured) due to contact with a tissue portion without the need of an auxiliary agent (e.g., an agent other than those present at the tissue surface itself). However, in other embodiments, the adhesive isolating material is adapted to be removed upon application of an auxiliary agent which may be present within the support, or applied externally from the support (e.g., application of energy). In some such and other embodiments, the adhesive isolating material comprises a non-dissolvable such as polyethylene. Additional examples of adhesive isolating materials are described in more detail below.

Films, layers, and portions of adhesive isolating portions may have any suitable dimension. For example, a film, layer, or a portion of an adhesive isolating material may have a cross-sectional dimension of, for example, less than 5mm, less than 3mm, less than lmm, less than 500 microns, less than 250 microns, less than 100 microns, less than 75 microns, less than 50 microns, less than 25 microns, less than 10 microns, less than 1 micron, or less than 0.1 microns. In some cases, the cross-sectional dimension having the above values is a width, a length, or a diameter of the portion; in other cases, the cross-sectional dimension is a height.

FIGS. 20A-20H show various configurations of adhesives and adhesive isolating materials associated with a support. As shown in the embodiment illustrated in FIG. 2OA, article 350 comprises a support 306 and adhesive portions 310 in the form of a patterned array. Adhesive portions 310 are partially covered with an adhesive isolating material 358, which are also in the form of a patterned array. Upon removal of adhesive isolating portions 358, adhesive 310 may be allowed to contact a tissue surface. As described herein, any suitable method for removing all or portions of adhesive isolating portions 358 may be used depending on the particular application.

As illustrated in FIG. 2OB, in some embodiments patterned portions of adhesive 310 are covered by a non-patterned layer of adhesive isolating material 358. In yet other embodiments, as shown in FIG. 2OC, only portions of adhesive portions 310 exposed to a surface of interest are covered by adhesive isolating materials 358. In some such embodiments, exposed adhesive portions 360 can come into contact with and adhere to a tissue surface at a first point in time; then, covered adhesive portions 362 may contact and adhere to a portion of a tissue surface only after adhesive isolating material 358 covering those portions is removed. This configuration can allow, for example, adhesion of the article to a tissue surface to a first degree upon initial contact with the tissue surface, and adhesion to the tissue surface to a second degree after the initial contact with the tissue surface. In one embodiment, the second degree of adhesion is greater than the first degree of adhesion. In another embodiment, the article can be repositioned using any suitable method before the article is adhered to the tissue surface to the second degree. Methods of varying adhesion at different points in time and repositioning of articles are described in more detail below.

As shown in the embodiment illustrated in FIG. 2OD, support 306 may include a non-patterned adhesive 310 and a patterned array of adhesive isolating portions 358 covering portions of adhesive 310. In some cases, such an embodiment can allow exposed adhesive portions 360 to come into initial contact with a tissue surface, e.g., to allow adhesion of those portions to the tissue surface; covered adhesive portions 362 may come into contact with the tissue after adhesive isolating portions 358 have been removed. In some embodiments, an article may include at least two discrete adhesive portions that are positioned in different layers of the article. For example, as shown in the embodiment illustrated in FIG. 2OE, an article 354 may include first adhesive portions 310 that can cause initial adhesion to a tissue surface, below which resides an adhesive isolating material 358. When the adhesive isolating material is removed, a second adhesive 368 is exposed and can cause further adhesion of the article to the tissue surface. The first and second adhesives may be the same or different, and may have a same or different adhesion strengths relative to the surface of interest. For example, in some cases, an outer-most facing adhesive (e.g., adhesive portions 310) has weaker adhesion strength to a surface of interest than an inner-most facing adhesive (e.g., adhesive 368). In other cases, an outer-most facing adhesive has stronger adhesion strength to a surface of interest than an inner-most facing adhesive.

Although adhesive isolating material 358 is shown as a non-patterned layer in FIG. 2OE, in other embodiments, adhesive isolating material 358 may be patterned. Additionally, an article may include a plurality of pairs of alternating adhesive/adhesive isolating layers.

As illustrated in FIG. 2OF, in some cases an article includes both a non-patterned adhesive and a non-patterned adhesive isolating layer. A plurality of pairs of alternating adhesive/adhesive isolating layers is also possible. In other embodiments, as illustrated in FIG. 2OG, an article includes adhesive portions 358 that are in the form of capsules which are encapsulated by adhesive isolating layer 358. Methods of encapsulating materials are described in more detail below.

In yet other embodiments, as shown in FIG. 2OH, a support 306 includes indentations 318 and protrusions 320. An adhesive 310 can be contained within all or a portion of indentations 318. As illustrated, adhesive isolating material 358 may be in the form of a layer covering the adhesive portions, however, in other embodiments, the adhesive isolating material may be patterned on all or a portion of the adhesive portions. It should be understood that the embodiments shown in FIGS. 20A-20H are only exemplary configurations of articles comprising a support, an adhesive and an adhesive isolating material, and that combinations of such embodiments and embodiments that are not shown in these figures are also possible. In addition, one or more bioactive agents may be combined with the support, the adhesive portions, the adhesive isolating portions, or as separate portions in certain embodiments of the invention. For example, in some embodiments, an article adapted for medical applications comprises a support and a first layer comprising a first biocompatible material (e.g., an adhesive, an adhesive isolating material, or a bioactive agent) positioned adjacent the support. The article may also include a second layer comprising a second biocompatible material (e.g., an adhesive, an adhesive isolating material, or a bioactive agent) adjacent at least a portion of the first layer. For example, the second biocompatible material may be directly adjacent the portion of the first layer, or adjacent the portion of the first layer via an intermediate layer. At least one of the first and second layers may be arranged in the form of a patterned array. In some cases, at least one of the first and second materials comprises an adhesive. Furthermore, at least one of the first and second materials may be adapted to be removed (e.g., biodegrade, dissolve or fracture) while in contact with the tissue. In certain embodiments, the article further comprises a third layer positioned between the first layer and the support. For instance, the third layer may include one or more of an adhesive, adhesive isolating material, and a bioactive agent.

As described herein, a method of medically treating a tissue may include positioning an article (e.g., such as those shown in FIGS. 2OA -20H) at a tissue surface, the article comprising a support, an adhesive, an adhesive isolating material, and optionally a bioactive agent. In some cases, an adhesive isolating material is removed prior to contacting the article with a tissue surface. For example, the adhesive isolating material may be part of a package used to store the article. In other cases, the adhesive isolating material remains as a part of the article as the article is positioned adjacent a tissue surface. After contacting the article with the tissue surface, at least a portion of the adhesive isolating material may be removed, thereby exposing the tissue surface to at least a portion of the adhesive. In some instances, the adhesive exposed to the tissue surface at this point in time is in the form of a patterned array. This exposure of the adhesive can cause the article to adhere to the tissue surface with a first adhesive strength at a first point in time. Sometimes, the adhesion strength between the article and the tissue is relatively weak at the first point in time so as to allow the article to be repositioned by a practitioner (e.g., by using a transfer device or by any other suitable method). For example, the first and second adhesion strengths (e.g., measured as shear strength) may have one of the values indicated below. FIGS. 21 A and 21 B show examples of articles comprising an adhesive isolating layer that can be removed prior to contact with a tissue surface. As shown in the embodiment illustrated in FIG. 2 IA, a support 306 may include a patterned array of adhesive 310. The support may be positioned on a first sheet 370 of an adhesive isolating material. A second sheet 372 of an adhesive isolating material may be positioned on top of the support. The first and second sheets may be adhered to one another using adhesive 376 to form article 380. Sheets 370 and 372 may be formed of any suitable material. For example, if article 380 is to be stored for a prolonged period of time, sheets 370 and 372 may be formed of materials that can protect the support from degrading, from being contaminated, and/or from exposure to the environment. As such, sheets 370 and 372 may form an air-tight and/or a moisture-tight seal and may provide a sterile environment in some embodiments. In addition, sheets 370 and 372 may be opaque so as to protect the support from exposure to light.

During use, sheet 372 may be removed from the article (e.g., by peeling) to expose a portion of the support. In one embodiment, the exposed portions of the support can be placed in contact with a tissue surface, after which sheet 370 can be removed from the support. The support may remain on the tissue surface by adhering adhesive 310 to portions of the tissue surface.

FIG. 21 B shows a support sandwiched between two Teflon sheets and is described in more detail in the examples sections.

In another aspect, a method of the invention involves transferring a material such as an adhesive, an adhesive precursor, an isolating material (e.g., an adhesive or a bioactive agent isolating material), a bioactive agent, a crosslinking agent, a contrast agent, a dye, a fluophore, a ligand, a cell (e.g., a bacterial cell or a mammalian cell), a virus, a nanoparticle, a micropaiticle, a nanoshell, a plurality and/or a combination thereof, or another component directly to a tissue surface. In some embodiments, transfer of the material takes place by in vivo printing, which refers to methods of transferring material from a transfer device to a tissue surface wherein the material is secured to the transfer device and subsequently to the tissue surface through adhesive forces. As described above, adhesive forces refers to adherences through a favorable free energy of interaction when two or more surfaces are brought into contact, and is meant to distinguish from other methods of material transfer which rely primarily on mechanical forces. Importantly, the adherence of the material to the tissue is stronger than the adherence of the material to the transfer device to affect transfer. One advantage of in vivo printing is that the material may be set in a controlled manner (e.g., controlled quantity, thickness, orientation, etc.) upon the transfer device and then delivered in the same manner to the tissue surface. Adhesion can afford the practitioner greater control over the transferred material than obtained with mechanical forces.

Additionally, as described above, in some embodiments a pressure is applied to the transfer device toward the tissue surface to facilitate transfer of the material. Thus, controlled transfer of material can be carried out, in some embodiments, by adjusting the pressure in which the material is contacted with the tissue surface. As shown in the embodiment illustrated in FIGS. 22A-22D, a transfer device 400 includes a support 404 having a patterned surface 408. The support includes a plurality of protrusions 412 and indentations 416. The transfer device may also include a handle 420 for facilitating manipulation of the device. The transfer device may be placed in contact with an adhesive 424, causing surface 408 of the protrusions to be covered by adhesive 424, thereby forming adhesive portions 426. The transfer device can then be placed in contact with a tissue surface 430 (FIG. 22B), which can allow transfer of all or a portion of adhesive portions 426 from the transfer device to the tissue surface (FIG. 22C). Subsequently, the transfer device may be moved in a direction away from the tissue surface; that is, transfer of the adhesive may take place without adhering the transfer device to the tissue surface (e.g., directly or indirectly via a support) or without leaving the transfer device immobilized in proximity to the tissue surface.

As illustrated in FIG. 22C, the pattern of adhesive portions 426 may be substantially similar to the pattern of protrusions 412 of the transfer device. Accordingly, by designing the transfer device with a particular pattern such as those shown in FIGS. lC-6, similar patterns of adhesive can be formed on a tissue surface. Adhesive portions 426 can be transferred from the transfer device to the tissue by any suitable interaction between the tissue surface and the adhesive. For example, adhesive forces may comprise adsorption, absorption, van der Waals interactions, hydrogen bonding, covalent bonding, ionic bonding, cross linking, magnetic interactions, or a combination thereof. In some embodiments, the adhesive portions are transferred from the transfer device to the tissue by contact adhesion, e.g., wherein the adhesion strength between the adhesive and the tissue surface is greater than the adhesion strength between the adhesive and the transfer device. In other embodiments, contact adhesion comprises an adhesion strength between the adhesive and the tissue surface being greater than the cohesive forces of the adhesive material. In one particular embodiment, contact adhesion comprises both of the above-mentioned embodiments.

As shown in FIG. 22D, an article 434 to be adhered to the tissue surface is positioned adjacent adhesive portions 426, which causes adhesion of the article to the tissue surface using the adhesive. Article 434 may be any suitable article that can facilitate repair of a tissue. For example, article 434 may be a support that may optionally include bioactive agents that can be transferred to the tissue surface. In another embodiment, article 434 may be a second tissue, such as a muscle. Additional examples of tissue repair are described in more detail below.

Optionally, after forming adhesive portions 426 on the protrusions of the transfer device, e.g., as shown in FIG. 22B, the transfer device can then be brought in contact with an adhesive isolating material or other material to form a second layer of material on the protrusions of the device. Upon contact between the transfer device and a tissue surface, a patterned array of two-layered portions can be formed on the surface. In one embodiment, the two-layered portion comprises an adhesive portion that is separated from the tissue surface via an adhesive isolating material, e.g., until the adhesive isolating material is removed from the tissue surface. Of course, patterned arrays comprising 2-, 3-, 4-, 5-, etc. layered portions of materials can be formed on a tissue surface in this fashion. Additionally or alternatively, a first transfer device can be used to form a first patterned array of a first material on a tissue surface, e.g., as shown in FIG. 22C, and then a second transfer device having the same or a different pattern as that of the first transfer device can be used to transfer a second patterned array of a second material on the same tissue surface. The second patterned array of second material may cover all, a portion, or none of the first patterned array of first material. Accordingly, multiple patterns of materials in one or more layers can be formed on a single tissue surface using this approach. The methods described herein demonstrate that contact adhesion can allow control of the positioning, amount, and orientation of materials transferred to a tissue surface. In some embodiments, the method described in connection with FIGS. 22A-22D for patterning an adhesive on a tissue surface can be applied to patterning of a bioactive agent directly on a tissue surface. For example, instead of transfer device 420 being placed in contact with adhesive 424, the transfer device can be placed in contact with a layer of bioactive agent to cause transfer of the bioactive agent to the protrusions of the transfer device. Examples of structures formed by the transfer of bioactive agents to surfaces are shown in FIGS. 23 and 24, which are described in more detail in the examples section. In another embodiment of the invention, a method of medically treating a tissue involves transferring a support from a transfer device to a surface of interest (e.g., a tissue surface) by contact adhesion. As shown in the embodiment illustrated in FIG. 25A, a transfer device 450 may be associated with support 454 by adhesive forces. As illustrated, support 454 includes a plurality of protrusions 456 and indentions 458. A patterned array of adhesive 460 is positioned on the surfaces of the protrusions. (It should be appreciated, however, that the support 454 may have any suitable arrangement, such as no protrusions/indentations, no adhesive, etc.) One or more bioactive agents 462 can be positioned in the indentations of the support. Transfer device 450 can be brought into contact with tissue surface 466 to effect transfer of the support from the transfer device to the tissue surface, as illustrated in FIG. 25B. Adhesion between portions of adhesive 460 and the tissue surface may be stronger than the adhesion between transfer device 450 and surface 452 of the support, thereby allowing the transfer device to be moved in a direction away from the tissue surface after transfer.

It should be understood that any suitable support can be transferred to a tissue surface using the method described in connection with FIGS. 25A and 25B. For example, in other embodiments, the support and/or patterned arrays of adhesive shown in any of the figures included herein can be used in place of support 454. In addition, the support may further include an isolating material which can isolate all or portions of an adhesive and/or a bioactive agent. Moreover, as described above, one or more portions of the surface of the transfer device and/or one or more portions of a surface of the support (e.g., surface 452 or a surface in contact with a tissue surface) can be modified (e.g., chemically) to facilitate transfer of the support from the transfer device to the tissue surface. In some cases, a portion of the tissue surface or other surface of interest can be modified (e.g., chemically, with an intervening layer of material, etc.) to facilitate transfer of a material to the tissue site.

In some cases, a tissue such as muscle can be transferred from a transfer device to a tissue surface by contact adhesion, e.g., by slight modification of the methods described in connection with FIGS. 25A and 25B. In one particular embodiment, after positioning and adhering a tissue to a tissue surface of interest to form a combined tissue, a support may be transferred from a transfer device to the combined tissue, e.g., to one or both of the tissue surfaces, thereby allowing the support to adhere to one or more portions of the tissue surfaces. This method can be used to securely fasten tissues in medical applications, and is described in more detail below.

Thus, it should be understood that various methods described herein can be used in combination for medically treating a tissue.

It should also be understood that although many examples described herein involve transferring an article and/or an adhesive to a surface of interest by contact adhesion, in some embodiments, transfer can take place by mechanical forces. For example, the use of forceps, syringes, pipettes, sutures, and other devices can be used to transfer an article and/or an adhesive in some embodiments of the invention.

FIGS. 26 A and 26B show another method of transferring a support to a tissue surface according to another embodiment of the invention. Transfer device 470 may include a surface 472 that is brought into contact with support 474. In some cases, all or portions of surface 472 are modified with material that can facilitate adhesion between the surface and the surface of the support. For example, surface 472 may be treated with a polymeric layer that preferentially adheres to the support. Next, a second transfer device 478 may include a patterned array of adhesive 480 on surfaces of protrusions 482. Indirect contact between transfer devices 470 and 478 via support 474 can allow transfer of the patterned array of adhesive 480 from the surfaces of protrusions 482 to the back surface of support 474. In this particular instance, adhesion between adhesive 480 and support 474 is greater than the adhesion between the adhesive and the surfaces of protrusions 482 of transfer device 478. This can allow transfer device 478 to be moved away from support 474 after transfer. Support 474 can then be transferred to a tissue surface 486 by directing transfer device 470 towards the tissue surface, allowing contact between support 474 and the tissue surface, and then moving transfer device 470 in away from the tissue surface. In such an embodiment, surface 472 may have an appropriate adhesion strength such that the adhesion between surface 472 and support 474 is weaker than the adhesion between the support and tissue surface 486.

FIG. 26B shows an article comprising a support and an adhesive conformally adhered to a transfer device. The transfer device was brought into contact with porcine skin to effect transfer of the support from the transfer device to the porcine skin. The last image shows the support adhered to the porcine skin tissue.

In one embodiment of the invention, a patterned array of an adhesive on a surface can be formed after transferring a patterned array of an adhesive precursor to the surface. For instance, an adhesive precursor can be transferred from a transfer device to a surface of interest, after which the adhesive precursor undergoes a chemical change to form an adhesive. In some cases, the adhesive precursor is in the form of a patterned array so as to form a patterned array of adhesive on the surface of interest. The adhesive precursor can be transferred to a tissue directly from a transfer device, or the adhesive precursor may be patterned on a support that is directed towards a tissue. FIGS. 27 A and 27B show transfer of a support 474 having patterned thereon a discontinuous, ordered array of fibrinogen 481 (e.g., a first adhesive precursor) onto porcine skin 487 that has been treated with thrombin (e.g., a second adhesive precursor). Fibrin adhesive is formed when the fibrinogen and thrombin are contacted. In some embodiments, supports of the invention include adhesives positioned on at least two sides of the support. Some such embodiments can allow the support to adhere to two different surfaces simultaneously. For example, as shown in the embodiments illustrated in FIGS. 28A-28D, a variety of configurations of adhesives can be positioned on the supports. As illustrated in the exemplary embodiment of FIG. 28 A, support 500 may include a first side 502 and a second side 504. The first side of the support can include a first adhesive 508 and the second side may include a second adhesive 510. Adhesives 508 and 510 may be uniformly applied to the support. Adhesives 508 and 510 may be the same in some embodiments, or different in other embodiments. As shown in the embodiment illustrated in FIG. 28B, adhesive 508 may be in a form of a patterned array. In other embodiments, the support may include patterned arrays of adhesive on both sides of the support (FIG. 28C). As shown in FIG. 28D, in some cases the support includes protrusions 512 and indentations 514. Adhesive 508 may fill all or a portion of indentations 514 to form a patterned array of adhesive. It should be understood that adhesives can be positioned on any suitable arrangement on at least two sides of a support and that the arrangements shown in FIGS. 28A-28D are only exemplary. In addition, in other embodiments, one or more portions of adhesive may be positioned on more than two sides of the support, e.g., at least three, at least four, at least five, or at least six sides of a support. Furthermore, in some cases, an adhesive isolating material can be positioned on all or a portion of an adhesive. Examples of arrangements of adhesive isolating materials are shown in FIG. 20. In addition, one or more bioactive agents may be incorporated into a support or on a surface thereof, e.g., in the configurations shown in FIG. 17.

Using a support having at least two sides associated with adhesives can be useful in a variety of applications involving tissue repair. For example, the support may be adhered to a first tissue surface using a first adhesive associated with the support, and an article such as a second tissue surface or a second support may be adhered to a second side of the support using the second adhesive. Additional examples of tissue repair are described in more detail below.

In another embodiment, a patterned array of adhesive can be positioned on at least two sides of a support, and all or a portion of the adhesives can be transferred from the support to a surface of interest. For example, as shown in the embodiment illustrated in FIGS. 29A-29C, a support 520 may be in the form of a transfer device having a first side 522 and a second side 524. Support 520 may be a catheter or a stent, for example. First adhesive 530 may be in the form of a patterned array on both sides 522 and 524; similarly, second adhesive 532 may be in the form of a patterned array on both sides of the support. The support may be positioned proximate tissue surfaces 536 and 538. In the embodiment illustrated in FIG. 29B, the support is designed to expand to allow contact between the adhesives and surfaces of the tissue. In some such embodiments, the adhesion strength between the patterned arrays of adhesives and the surfaces of support 520 is less than the adhesion strength between the adhesives and tissue surfaces 536 and 538. This difference in adhesion strength can allow the adhesives to remain on the surfaces of the tissue upon removal of support 520 from the tissue. Advantageously, this and other methods can be used to deliver a number of adhesive compositions and adhesive portions, which may include one or more bioactive agents dispersed therein, to a particular location and with controlled amounts on one or more tissue surfaces. In some cases, transfer of the adhesive composition(s) to more than one surface of a tissue can be performed simultaneously. In other embodiments, the adhesive composition(s) are transferred sequentially.

FIG. 30A shows images involving transfer of a support from two sides of a spatula which is used as a transfer device. Surfaces of the spatula were modified by attaching PDMS films to both sides of the spatula. A support was folded and conformally adhered to the spatula via the PDMS films. Adhesive was attached to both sides of the spatula by contact adhesion, which allowed formation of a patterned array of adhesive on the support. The support was then inserted into a tissue pocket. After contacting the support to the tissue, the spatula was retracted from the tissue. FIG. 3OB demonstrates transfer of a support from a single side of a spatula. The materials used in these experiments are described in more detail in the examples section.

In some embodiments, a transfer device includes a textural material (e.g., a material having a non-smooth surface) comprising an outer differential geometry to aid transfer of a material from the device to a surface of interest. The outer differential geometry may include, for example, protrusions, indentations, and the like. In such embodiments, the material is transferred in part by controlling the shear force of the material. For example, as shown in the embodiment illustrated in FIGS. 31 A and 3 IB, the textural material can have internal grooves for gripping a cylindrical transfer device such as a catheter, and barbs on its outer surface oriented in one direction. FIG. 3 IA shows a side view of a material 550 proximate tissue surfaces 554 (e.g., lumenal walls). Material 550 comprises a series of barbs 556 on its outer surface. The barbs are oriented for easy movement in the direction of catheter 558. Once material 550 is at the site of transfer, removing the catheter in the opposite direction causes the barbs to catch on tissue surfaces 554, thereby assisting in the transfer of material 550 to the tissue surface. Material 550 comprises an inner space 560 shown in FIG. 3 IB. Inner space 56 can be lined with a series of grooves 564 for a temporary fastening to catheter 558. It should be noted that differential geometry may be utilized for the delivery of a material to a transfer site, but that actual transfer and adherence to a tissue surface can still occur by adhesion.

As described herein, articles, adhesives, bioactive agents, and/or isolating materials of the invention can be used for various applications involving tissue repair. Tissue repair may involve, for example, healing, joining, aligning, and/or sealing tissues. In many instances, tissue repair involves biological tissue; however, in some cases, tissue repair involves a non-biological surface such as a surface of a biocompatible implant. The method of repairing, joining, aligning, and/or sealing tissue may be part of an internal or external surgical procedure. The methods of the invention are especially suited for emergency procedures where control is an important factor. In some embodiments involving tissue repair, an article of the invention can be used to allow alignment of the apposed tissue edges. In some cases, the article can also help ensure that the strength at which the apposed edges are held in place is sufficient for healing to occur without the use of sutures, staples, clips, or other mechanical closures or means of reinforcement. By keeping the tissue edges in direct apposition, the article can help foster primary intention healing and direct re-apposition internally. Thus, the article can function as a bridge or framework for the apposed edges of severed tissue. The article may act as a scaffold, e.g., for in growth of cells, in some embodiments.

FIGS. 32A-32D show various examples of how articles of the invention can be used to repair tissue. As shown in the embodiment illustrated in FIG. 32A, an article 570, which may be a support or a tissue, for example, may be positioned on a surface 572 of a tissue 574 proximate a tear or incision 576. Article 570 can be transferred to surface 572 by any suitable method, e.g., by using a transfer device as illustrated in FIGS. 25A and 25B or by mechanical forces (e.g., by using forceps or an equivalent device). The article may be adhered to the tissue surface so as to immobilize (e.g., restrict movement of) the article with respect to the surface. The adherence of the support to the tissue surface can promote healing of tear or incision 576. In one embodiment, article 570 includes an adhesive patterned thereon prior to contact between the article and tissue surface 572. In another embodiment, prior to contact between the article and surface 572, surface 572 may be patterned with an adhesive, for example, using the method shown in FIGS. 22A-22D. Article 570 may then be brought into contact with patterned surface 572 to cause adhesion between the support and the tissue surface.

As shown in the embodiment illustrated in FIG. 32B, in some cases article 570 is used to attach two tissues 574 and 578 using a single side of the article. Article 570 may adhere to the tissues by methods described herein.

As shown in the embodiment illustrated in FIG. 32C, two sides of article 570 can be used to join tissues 574 and 578. In some such embodiments, article 570 may comprise adhesives, which may be in the form of patterned arrays, on both sides of the support. Adhesion between the surfaces of the support and the tissue surfaces can occur after contact between the surfaces, or, in other cases, a patterned array of adhesive can be transferred to each of the surfaces of tissues 574 and 578, and article 570 can then be brought into contact with each of the surfaces. In another embodiment, articles of the invention can be applied over the edge at least one tissue. As illustrated in FIG. 32D, tissues 574 and 578, which may be torn, for example, may be repaired by placing article 570 over a portion of each of the tissues. The article can then adhere to each of the tissues and facilitate healing and/or sealing of the tissues. In one particular embodiment, prior to placing tissue 578 on top of tissue 574, one or both of the surfaces of tissues 574 and 578 can be patterned with an adhesive (e.g., by contact adhesion) which promotes adhesion between tissues 574 and 578 after contact. Afterwards, article 570 can be positioned over a portion of each of the tissues to secure adhesion between the tissues. In some embodiments, article 570 is a support and is biodegradable in vivo. This can allow the support to facilitate healing of the tissue, after which the support can be removed from the tissue site.

Adhesion between article 570 and surface 572 of FIGS. 32A-32D may occur instantly upon contact, or in other embodiments, after being in contact with the tissue surface for a certain period of time. In some cases, the article is adhered to the tissue surface to a first degree upon initial contact, and to a second (e.g., greater) degree after a time delay. The time delay of adhesion (e.g., of greater adhesion in some embodiments, or less adhesion in other embodiments) after initial contact with the tissue surface may be, for example, at least 5 seconds, at least 10 seconds, at least 20 seconds, at least 30 seconds, at least 40 seconds, at least 1 minute, at least 10 minutes, at least 30 minutes, at least 1 hour, at least 6 hours, at least 12 hours, at least 1 day, at least 1 week, or at least 1 month. For instance, in some cases, adhesion to a second degree takes place postoperatively. In some embodiments, adhesion refers to immobilization (e.g., restriction of movement) of one surface with respect to another surface. Immobilization may occur, for example, within the time periods mentioned above; for instance, within 1 minute after initial contact between the article and the tissue surface or upon contact between the surfaces.

As described herein, delay of adhesion between two surfaces can be brought about by a variety of methods such as by using adhesive isolating materials and by forming additional adhesive or cohesive bonds. In some embodiments, as described in more detail below, delay of adhesion can be controlled by external forces such as by application of light and heat, which can activate the adhesive properties of the adhesive. Advantageously, adhesion strength between an article and a surface of interest may be greater when using a patterned array of adhesive compared to the same amount of adhesive applied in a uniform manner. For example, an article adhered to a surface of interest by a patterned array of adhesive may, in certain embodiments, exhibit at least 2, at least 3, at least 5, at least 7, at least 10, at least 15, or at least 20 times the amount of normalized shear strength compared to the application of the same amount of adhesive but in a non-patterned fashion, all other factors being equal. For example, the normalized shear strength of an article including a patterned array of adhesive may be greater than 10 kPa/mg, greater than 20 kPa/mg, greater than 30 kPa/mg, greater than 40 kPa/mg, greater than 60 kPa/mg, greater than 80 kPa/mg, greater than 100 kPa/mg, greater than 150 kPa/mg, greater than 200 kPa/mg, greater than 300 kPa/mg, or greater than 500 kPa/mg (e.g., normalized with respect to the mass of the adhesive used). Accordingly, a lesser amount of adhesive may be required when using a patterned array of adhesive to achieve a particular adhesion strength between two articles compared to a non-patterned adhesive.

In some embodiments involving first and second adhesion strengths (e.g., adhesion of an article to first and second degrees with respect to a surface of interest), the first adhesion strength may be in a range such that the article is attached to the surface of interest reversibly; that is, upon moving or removal of the article with respect to the surface, the surface of interest and/or the article is not damaged or irritated to an unacceptable degree. In some such embodiments, the article can be repositioned after initial adhesion to the surface of interest. For example, the first adhesion strength may be measured as a shear strength having a value of less than about 0.1 kPa to 2 MPa. For example, the first shear strength may be less than 2 MPa, less than 1 MPa, less than 500 kPa, less than 200 kPa, less than 100 kPa, less than 10 kPa, less than 1 kPa, less than 0.1 kPa, less than 0.05 kPa, less than 0.01 kPa, less than 0.005 kPa, or less than 0.001 kPa in some cases. The second adhesion strength may be in a range such that the article is immobilized on the surface of interest; that is, movement of the article relative to the surface is restricted. In some such embodiments, moving and/or removal of the article from the surface causes the article and/or surface of interest to be damaged or irritated to an unacceptable degree. The second shear strength may be greater than about 0.1 kPa. For instance, the second shear strength may be greater than 0.1 kPa, greater than 1 kPa, greater than 10 kPa, greater than 100 kPa, greater than 200 kPa, greater than 500 kPa, greater than 1 MPa, greater than 2 Mpa, or greater than 4 MPa in some instances. In some cases, the second shear strength can have any value greater than the first shear strength. In some embodiments, methods involving adhering an article to a surface of interest may involve adhesion strengths having one of the above-mentioned values regardless of the number of times the article is adhered to the surface (e.g., having only one adhesion strength).

A variety of screening tests can be used to help select suitable adhesives and materials to define transfer surfaces and surfaces of interest, e.g., to determine suitable materials for transfer by contact adhesion and/or to determine relative adhesion strength between materials. In some embodiments, mechanical testing of tensile strength or shear strength can be performed. For example, two surfaces may be joined by a suitable adhesive and opposite forces can be applied until the surfaces are no longer joined. The (absolute) tensile strength or shear strength is determined by measuring the maximum load under tensile or shear, respectively, divided by the interfacial area between the articles (e.g., the surface area of overlap between the articles). The normalized tensile strength or shear strength can be determined by dividing the tensile strength or shear strength, respectively, by the mass of the adhesive applied to the articles.

As those of ordinary skill in the art of adhesives are aware, another relatively straight forward "T-Peel test" can be used to assess adhesion strength. A peel test typically involves placing a flexible article against where an adhesive lies between the interfacial surfaces of the two articles. The flexible article then is pulled away from the other article in a set manner. For example, where the flexible article is a piece of tape, the tape is pulled away from the surface of the other article by lifting one edge and pulling that edge in a direction approximately perpendicular to the article so that as the tape is being removed, it continually defines a strip bent at approximately 90 degrees to the point at which it diverges from the other article.

Factors that can be determined from such tests include overall adhesion strength and/or a comparison of adhesive forces versus cohesive forces between any of the transfer surface, the surface of interest, or the adhesive itself. For example, such a test may determine whether the surface of interest, under the conditions of the test, has sufficient cohesive stabilities such that portions of its surface in contact with the adhesive are not removed during the test. Similarly, adhesive versus internally cohesive characteristics of the adhesive itself can be determined by observing whether the adhesive (where tape is used) remains essentially completely adhered to the tape, or remains on the other surface, or is divided between the two surfaces after the test.

Various materials defining the transfer surface, the surface of interest, and the adhesive can be changed during various tests. In addition, their adhesive and cohesive characteristics, in relation to other materials involved in the test, can be assessed. Conditions of the test can, of course, be adjusted in a variety of ways. For example, a particular degree of pressure can be applied between the two articles as they are joined prior to the tests. Furthermore, the tests can be carried out under particular conditions of temperature, humidity, or other environmental conditions. In some embodiments, an article can be removed differently than by removing essentially perpendicularly from the other article. For example, after joining two articles by an adhesive, opposite axial forces can be applied to the articles to determine adhesion strength, as described in more detail below. Where two relatively rigid articles are studied, the articles can simply be separated from each other by prying, magnetic forces, gripping, or any other means. So long as conditions between various tests are kept identical or similar, different materials and/or adhesives can be compared for selection of a combination suitable for a particular purpose.

The adhesion strength between an article comprising a patterned array of adhesive and a surface of interest can be tuned by a variety of methods. Adhesion strength can be varied prior to contact between the article and a surface of interest (e.g., during design of the article) and/or after initial contact between the article and the surface of interest. Non-limiting examples of methods that can be used to tune adhesion strength include: varying a particular form of the array (e.g., continuous or discontinuous, and ordered or non-ordered), the amount of adhesive portions compared to non-adhesive portions within an adhesive boundary, the amount of adhesive exposed to a surface over time (e.g., using adhesive isolating materials), the material(s) used to form patterned array of adhesive, the cross-sectional dimensions of the adhesive portions, the material used to form the biodegradable support, the number of discrete adhesive portions, and by controlling the composition of the adhesive such as by forming or breaking the adhesive or cohesive bonds after being in contact with the surface, as described herein.

FIG. 33 A shows an image of a repaired porcine skin tissue previously having an incision through the center of the tissue. A support was positioned over the incision and

43 mechanical testing of adhesion was measured (FIG. 33B). Experimental details are described in the examples section.

FIGS. 34A and 34B show mechanical testing of tissues joined using a support of the invention. Tissues 580 and 582 were joined using a support 586 having a patterned array of adhesive 588. The tissues were joined and opposite forces in the direction of arrows 590 and 592 were applied to determine the maximum load that the adhesion can withstand before failure; the shear strength of the adhesion was determined by dividing the maximum load by the cross-sectional area. Additional details are described in more detail in the examples section. The results of the test are shown in FIG. 35. FIGS. 36A-36D show mechanical testing of adhesion between an article including a patterned array of adhesive and two tissues according to another embodiment of the invention. FIG. 36B shows mechanical testing data (load vs. extension data) of a full thickness incision in porcine skin that has been repaired using a support having patterned thereon discontinuous bands of adhesive. FIG. 36C shows repair of a full thickness incision in porcine skin using an article having adhesive-filled channels.

FIG. 36D shows mechanical testing data using the article shown in FIG. 36C. Additional experimental details are described in the examples section.

Another aspect of the invention includes methods of adjusting tissue seals using an article capable of forming or breaking adhesive or cohesive bonds. An "adhesive bond" as used herein refers to a bond formed by a favorable free energy change upon contact between two or more different substances. Generally, an adhesive bond binds the material to the tissue. For example, in an embodiment wherein the article comprises a support, adhesive bonds can bind the support to the tissue. Adhesive bonds are thus differentiated from cohesive bonds, because adhesive bonds are binding two or more different substances, whereas cohesive bonds are bonds within the same substance. A "cohesive bond", therefore, refers to a bond within the material itself. Cohesive bonds can give a material its shape and structure. For example, in an embodiment wherein an article comprises a support, cohesive bonds may include the bonds that make up the support itself. Advantageously, articles that are formed of or include materials that are capable of forming or breaking adhesive or cohesive bonds affords the practitioner control over placement of the article and the degree of adhesion strength between the article and the tissue surface. In certain embodiments, an article of the invention comprises a support, an activatable component and/or a deactivatable component, and optionally, an initial adhesive. The article can optionally comprise one or more bioactive agents (e.g., small molecules or macromolecules with biological activity, drugs, and prodrugs), adhesive isolating materials, and bioactive agent isolating materials. The role of the initial adhesive is to supply the initial means to secure the article to a tissue surface. In some instances, the material used to form the article itself allows it to adhere to a surface of interest, and in such embodiments, an initial is not required. The role of the activatable component may be to provide additional adhesive or cohesive bonds as needed, which can increase the adhesion between the support and the tissue surface. For example, a component may be activated by application of light, heat, a chemical reagent, etc. to the article, e.g., while the article is in contact with a tissue surface, to cause formation of additional covalent bonds, ionic bonds, crosslinking, magnetic interactions, electrostatic interactions, hydrogen bonding and the like which can increase adhesive or cohesive bonds. In some cases, the strength of adhesion between the article and the tissue can be increased by such a method.

A deactivatable component may facilitate the breaking of adhesive or cohesive bonds, thereby weakening the adhesion between the support and the tissue surface. For example, a component may be deactivated by application of light, heat, a change in pH, a chemical reagent, etc. to the article, e.g., while the article is in contact with a tissue surface, to facilitate the breaking of adhesive or cohesive bonds (e.g., including chain cleavage). In some embodiments, deactivation of a component occurs by biodegradation or dissolution of the component. The component may biodegrade or dissolve immediately upon contact with the tissue surface, or at a time after initial contact with the tissue surface, e.g., at least 1 second, at least 5 seconds, at least 10 seconds, at least 15 seconds, at least 20 seconds, at least 30 seconds, at least 40 seconds, at least 1 minute, at least 10 minutes, at least 30 minutes, at least 1 hour, at least 6 hours, at least 12 hours, at least 1 day, at least 1 week, or at least 1 month after the component is initially placed in contact with the tissue surface. It should be understood that an activatable component and/or a deactivatable component of an article may be included in all or only portions of the article. For example, in one embodiment, the support comprises an activatable component and/or a deactivatable component. In another embodiment, an adhesive comprises an activatable component and/or a deactivatable component. In another embodiment, an isolating material (e.g., adhesive or bioactive agent isolating material) comprises an activatable component and/or a deactivatable component. In yet another embodiment, a bioactive agent comprises an activatable component and/or a deactivatable component. In certain embodiments, an article includes a combination of the above-mentioned embodiments.

The categories of initial adhesive, activatable component, and deactivatable component can overlap in several of the embodiments described herein. For example, where an article comprises a support and an initial adhesive, the initial adhesive may also be the activatable or deactivatable component by being capable of forming or breaking more adhesive bonds, respectively. The support itself may be the deactivatable component through the breaking of cohesive bonds, especially when the support comprises a polymer. Specific examples of activatable and deactivatable components are described in more detail below.

The present methods can be used in a variety of applications involving tissue repair. In some cases, the methods offer an improved substitute for using a needle and suture in surgery because post adjustments do not require additional surgery. Methods described herein can also allow varying the degree of adhesion, which can be easily tuned or modified postoperatively to meet the individual patient's needs.

In some embodiments, a method of medically treating a tissue comprises positioning an article comprising an adhesive on a tissue surface and adhering the article to the tissue surface to a first adhesion strength (e.g., using an initial adhesive or by exposing only portions of an adhesive to the tissue surface). In some such embodiments, the first adhesion strength between the article and the tissue is relatively weak so as to allow the article to be repositioned by a practitioner. For example, a first adhesion strength may be less than about 0.1, 1, 10, 100 or 200 kPa or other values described herein. The article can then be repositioned if needed, e.g., during or after surgery, and the article can be adhered to the tissue surface to a second degree. In some cases, the second adhesion strength is less than the first adhesion strength. For instance, adhesive or cohesive bonds may be broken after the repositioning step by methods and mechanisms described herein. In other embodiments, the second adhesion strength is greater than the first adhesion strength. For instance, after repositioning the article, a more permanent seal may be formed. The more permanent seal may be formed, for example, by activating a component of the article as described herein, e.g., to cause formation of additional cohesive bonds and/or adhesive bonds, and/or by exposing more of an adhesive to the tissue surface. In some such embodiments, the second adhesion strength may be greater than at least about 0.1, 1, 10, 100 or 200 kPa or other values described herein. Examples of various time delays of adhesion between the occurrences of the first and second adhesion strengths are described above. In some cases, a method of medically treating a tissue includes contacting a tissue surface with a biocompatible material capable of forming or breaking adhesive or cohesive bonds, and adhering at least a portion of the biocompatible material to the tissue surface. A medical act associated with or proximate the tissue surface may be performed, and a response of the tissue may be observed, while maintaining adhesion between the tissue surface and the portion of material. For example, for certain ophthalmic applications, the observing step may comprise observing overfiltration or underdrainage of an eye. If needed, the strength of adhesion between the tissue surface and the portion of material may be adjusted by forming or breaking adhesive or cohesive bonds in response to the observing step, e.g., to adjust the overfiltration or underdrainage. In some instances, the performance of the medical act is performed before the contacting step. In other embodiments, the medical act is performed after contact between the tissue surface and the biocompatible material.

As described herein, the articles of the invention may be used in wide variety of applications not limited to replacing traditional sutures or bandages whenever surgery or first aid (especially an emergency procedure) is performed. A main advantage of the articles described herein over previous articles is the greater control they offer the user. For example, in some embodiments, an adhesive is applied to a support in a patterned array on at least one surface of the support. A patterned adhesive may reduce the amount of adhesive necessary for adhering/joining surfaces compared to a uniform application of the adhesive; in some embodiments, this reduction reduces the cytotoxicity of the surrounding tissue due to the adhesive. Moreover, the adhesive may be activated or allowed to adhere to a surface when needed by, for example, removing an adhesive isolating layer, or by releasing it from encapsulation. These and other methods can allow for a temporary setting that can be adjusted by the user before letting the adhesive set more permanently.

Another aspect of the invention provides methods and apparatus for retrieving material from tissue surfaces using adhesion. In some embodiments, the adherence of the retrieved material to a retrieving instrument is greater than the adherence of the material to the tissue surface. In some arrangements, extraction methods in accordance with aspects of the invention may afford the practitioner greater selectivity over the type of material retrieved, and/or offer a wide range of applications. Other potential benefits of extraction by adhesion include minimal disruption of the tissue, greater control and selectivity over the material extracted, and greater access to tissue sites since the extraction methods may be amenable to a wide variety of instruments.

In one aspect of the invention, a method of retrieving material from tissue involves directing an instrument (e.g., a transfer device) to the surface of the tissue, contacting the instrument with the surface of the tissue, and withdrawing the instrument and at least a portion of the material from the tissue. The adherence of the material to the instrument may be greater than the adherence of the material to the tissue, thus allowing the material to be removed from the tissue site and used for testing, etc. In certain embodiments, contacting the instrument to the surface of the tissue is done in a controlled manner, such as controlling the contact time and/or pressure. Additionally, in some embodiments, portions but not all of the material may be removed from the tissue so as to form a patterned array of material on the surface of the tissue. Such retrieval methods may be used with a wide variety of tissue types including, but not limited to, eye, liver, spleen, pancreas, dura mater, vascular, lumenal, alimentary, gastrointestinal, dental, tendon, ligament, or tumor tissue. In certain embodiments, the tissue is vascular tissue such as an artery wall.

The instrument used to retrieve material from a tissue surface can have any suitable arrangement that achieves access to the tissue surface. In one embodiment, the instrument includes an expandable instrument, such as a stent or a balloon. In other embodiments, the instrument may include a non-expandable instrument such as a spatula, needle, trephine, stamping device, swab, and/or a patch. In one embodiment, a portion of the surface of the instrument may include an adhesive; for example, the instrument may include a patterned array of adhesive. The adhesive may be a specific adhesive or a non-specific adhesive, as described in more detail below. It is also possible for more than one type of adhesive to be used in the extraction methods.

In another embodiment, an instrument may comprise a composite made up of a support and an adhesive. The support offers a platform upon which the adhesive material is applied to at least one side of the support. The support and/or adhesive material may be any of the various types described above or below, and the support may carry the adhesive in any suitable arrangement. For example, the adhesive material may be provided on at least one side of the support in a patterned array.

The material retrieved from the tissue surface may be any material capable of adhering to the instrument with greater strength than adherence to the tissue. Generally, the material retrieved may be material useful for biopsies. For example, the material may be a small molecule, ion, protein, nucleic acid, cell, cell fragment, pathogen, or plaque material. In a further embodiment, the ion is a calcium or phosphate ion. In a further embodiment, the pathogen is a toxin, poison, or virus, or portion thereof. By way of a non-limiting example, one can envision a material such as an antibody adhered to the surface of a support to form an article. The article is secured to an instrument which is then used to deliver the article to the tissue site. Contact of the antibody comprising article to the tissue results in the antibody binding a recognized antigen. Because adherence to the antibody is greater than adherence of the antigen to the tissue, the antigen is retrieved along with the instrument.

Some of the biopsy methods to which aspects of the invention relating to adherence-based retrieval of material include: Abdominal wall fat pad biopsy, Adrenal biopsies, Bilary tract biopsy, Bladder biopsy, Bone lesion biopsy and a bone marrow biopsy, Breast biopsy, Bronchoscopy with transbronchial biopsy, Carpal tunnel biopsy, Cervical biopsy, Chorionic villus sampling (CVS), Gum biopsy, Liver biopsy, Lung needle biopsy, Lymph node biopsy, Muscle biopsy, Nasal mucosal biopsy, Oropharynx lesion biopsy, Polyp biopsy, Salivary gland biopsy, Skin lesion biopsy, Small bowel biopsy , Testicular biopsy, Tongue biopsy, and Ureteral retrograde brush biopsy cytology. In another aspect of the invention, a method for treating an eye for attachment of muscle tissue to the eye with or without the use of sutures is provided. Avoiding the use of sutures may be advantageous in some cases since the lack of sutures may reduce or eliminate the potential for perforation of the sclera and/or other eye tissues, potentially exposing the eye to infection. In one illustrative embodiment, muscle tissue may be attached to the sclera of an eye by way of an adhesive and/or a support applied over the muscle tissue/sclera joint. The muscle tissue may be initially adhered to the sclera using a patterned array of adhesive that is arranged to provide suitable attachment force, yet allow for rapid healing and more robust attachment of the muscle tissue to the sclera. The optional overlying support may help to additionally secure the muscle tissue and sclera during the healing process.

FIGS. 37 and 38 show a side view and a top view, respectively, of an eye 1010 with muscle tissue attached in a normal fashion to the sclera of the eye 1010. For various reasons, the muscle tissue 1020 may be detached from the sclera, e.g., as shown in FIGS. 39 and 40. Such detachment may be intentional, such as when performing strabismus surgery, or unintentionally as in the case of damage to the eye caused in surgical or non-surgical situations. In accordance with one aspect of the invention, muscle tissue 1020 may be reattached to the eye sclera by way of an adhesive that is applied directly to the sclera. Thereafter, the muscle tissue 1020 may be attached to the sclera by way of the adhesive. For example, in the illustrative embodiment shown in FIGS. 39 and 40, an array of adhesive 1030 is applied to the sclera. Any suitable technique may be used to apply the adhesive 1030, including a direct printing or stamping of the adhesive array 1030 on the eye 1010, e.g., as shown in FIGS. 22A-22D. For example, and as discussed above, an adhesive applicator may include a set of surface features (e.g., protrusions) having raised portions arranged in a pattern that corresponds to the pattern of adhesive to be applied to the eye 1010. The surface features may be formed on the adhesive applicator, for example, by molding the features into a suitable material, such as poly(dimethylsiloxane) (PDMS). The applicator and its set of surface features may then have a suitable adhesive applied, e.g., by dipping the surface features in a bath of adhesive. Thereafter, the adhesive applicator may be used to apply the adhesive carried by the surface features onto the eye 1010. In the illustrative embodiment shown, the adhesive 1030 is applied to the eye 1010 so as to form a row of discrete spots of adhesive, e.g., including four adhesive spots having a size of about 0.75 mm that are spaced about 1.5 mm apart. Although any suitable adhesive may be used, in this illustrative embodiment, a 2-octyl-cyanoacrylate adhesive (e.g., Dermabond available from Ethicon, Incorporated, Somerville, New Jersey) was used. The total volume of adhesive applied may be any suitable amount, and in this illustrative embodiment is about 0.2 μl. Thereafter, as shown in FIGS. 41 and 42, the muscle tissue 1020 may be positioned over the adhesive 1030 and the sclera so that the muscle tissue 1020 is adhered to the eye 1010. In accordance with an aspect of the invention, the adhesive may be arranged so that if the muscle tissue 1020 is not suitably positioned relative to the eye 1010, the muscle tissue 1020 may be separated from the eye 1010 (e.g., by peeling the muscle tissue 1020 away from the eye 1010) without substantial damage to the eye or muscle tissue. The muscle tissue 1020 may then be repositioned relative to the eye 1010, by re-applying an array of adhesive 1030 and again adhering the muscle tissue 1020 to the eye 1010 via the adhesive 1030.

Attachment of the muscle tissue 1020 to the eye 1010 may be enhanced by applying a support over the muscle tissue/sclera joint, as shown for example, in FIGS. 43 and 44. Although any suitable support 1040 may be used and may be attached in any suitable way, in this embodiment, the support 1040 is a salt-leached polymer support made from 85:15 L-PLGA l.v.l.50-1.49 dL/g made by Biolnvigor, Taipei, Taiwan. The support 1040 may have any suitable size, and in this example has a size of about 8 mm in length and 5 mm in width. The support 1040 may be secured over the muscle tissue/sclera joint in any suitable way, such as by sutures, adhesive and/or other. In this illustrative embodiment, a suitable adhesive (not shown) is applied to one side of the support 1040 and the support 1040 is placed adhesive side down over the muscle tissue/sclera junction. In this embodiment, the support 1040 is arranged so that its long dimension spans across the muscle tissue/sclera junction, but may be arranged in other ways. Any suitable adhesive and amount of adhesive may be used, and in this case, the Dermabond adhesive in an amount of about 6 μl may be applied to the support 1040. The support 1040 may be generally centered over the muscle/sclera joint and pressure applied to ensure sufficient contact of the adhesive with the eye and muscle tissue.

The inventors have found that by adhering the muscle tissue 1020 to the eye 1010 using an array of adhesive 1030 that includes discrete adhesive portions (e.g., spots), at least two potential advantages may be obtained. First, the muscle 1020 may be initially adhered to the eye 1010 in a way that allows the muscle 1020 to be separated from the eye 1010 without causing damage if the muscle 1020 is improperly positioned relative to the eye 1010. This feature may allow a surgeon to reposition the muscle 1020 in the case that is determined that the muscle 1020 should be better positioned relative to the eye. Second, the discrete positioning or arrangement of the adhesive 1030 may allow for more intimate contact between the muscle tissue and the eye without any intervening adhesive, thereby allowing natural healing processes to more rapidly join the muscle and eye tissues together. Accordingly, use of a patterned array of adhesive to join the muscle tissue and eye may provide a stronger muscle/sclera joint during the early period of healing (e.g., around two days after the procedure is performed) compared to methods involving non-patterned adhesives.

It should be appreciated that the techniques described above with respect to attachment of muscle tissue to an eye may incorporate one or more of the aspects of the invention described above. For example, the support 1040 may include a patterned adhesive layer and/or an adhesive isolation layer over the adhesive. Such an isolation layer may be deployed with the support 1040 and help to delay a time over which the support 1040 adheres to the eye and muscle tissue, thereby providing time for the surgeon to properly position the support 1040 relative to the muscle/eye junction. Similarly, adhesive used to attach the muscle and eye and/or used on the support may include encapsulation features as described above, such as small droplets of adhesive contained within an encapsulating material. Similarly, the support and adhesive carried on the support may be completely or partially encapsulated, such as by an outer covering or other structure. In another aspect of the invention described above, the support 1040 may be applied to the muscle/eye junction by way of contact adhesion via a transfer device, e.g., a device to which the support is relatively lightly adhered and from which the device is removed by adhering the support 1040 at the muscle/eye junction. Thus, one or more aspects of the invention described above may be incorporated (or not) into the eye treatment technique described above.

In accordance with another aspect of the invention, a kit may be provided for use in treatment of an eye, e.g., using the techniques described above. The kit may include a support constructed and arranged to be adhered over a muscle tissue/sclera joint and help support the muscle tissue/sclera joint during a healing process. The support may be arranged in any suitable way, such as having an adhesive applied to one or more sides of the support, encapsulating the support and adhesive combination, and so on. The kit may also include an adhesive suitable for adhering the muscle tissue to the sclera, and a transfer device (e.g., an adhesive applicator) for applying the adhesive in a suitable array for attaching the muscle tissue to the sclera. The transfer device may include a set of surface features, e.g., a set of raised cylindrical portions arranged in a row or other suitable arrangement, so that adhesive may be applied to the surface features and then printed or otherwise transferred to the eye and/or muscle tissue. As described above, the transfer device may be arranged in the form of a stamp that is molded of a suitable material, such as PDMS.

In another aspect of the invention, a method for securing a corneal flap or other structure is provided. For example, in laser-assisted in situ keratomileusis (LASIK) procedures, a thin flap of the cornea is cut leaving a hinge at one end of the flap so that the flap may be folded back to reveal the stroma, as shown in FIG. 45. With the flap 1050 folded back as shown in FIG. 46, pulses from a computer-controlled laser 1060 may vaporize a portion of the stroma to achieve the desired change in the stromal tissue and affect on the patient's vision. Once this process is completed, the flap 1050 may be folded back into position on the eye. In accordance with an aspect of the invention, an adhesive may be applied to the stromal bed and/or the corneal flap 1050 to secure the corneal flap 1050 in place on the stroma. For example, the adhesive may be applied in an annular shape to the stromal bed around the pupillary axis and thereafter the flap 1050 may be folded back into position and adhered by way of the adhesive. FIG. 47 shows a side view of the eye 1010 with the adhesive 1030 applied to the stromal bed and before the flap 1050 has been folded back into place. This technique may provide advantages of preventing movement of the flap 1050 relative to the eye 1010, thereby potentially avoiding distortion of the curvature of the cornea that could result in astigmatism. Also, the adhesive 1030 may prevent entry of bacteria and/or epithelial ingrowth at the joint between the flap 1050 and the remaining eye tissue. In one embodiment, the rate of polymerization or other curing aspect of the adhesive may be controlled to allow for suitable time in positioning the flap 1050 relative to the eye 1010. In other embodiments, the adhesive material may include antibiotics, antiinflammatories and/or other compounds to promote healing at the flap 1050. Thus, the adhesive 1030 may in fact be a composite material that includes not only adhesive, but also other suitable compounds.

Aspects of the invention also provide an ophthalmic adhesive that can secure eye tissue in place, promote natural healing, persist sufficiently to allow healing yet degrade over time, induce minimal astigmatism, provide a microbial barrier to infection, be transparent and/or have elastic mechanical properties. For example, in cataract surgery and/or the closure of the non-surgical wounds, the adhesive may be delivered to edges of the corneal tissue, e.g., using a needle-like delivery instrument or spatula-like instrument. For corneal transplant surgery, the adhesive may be delivered to edges of the corneal tissue using a trephine-like device.

For example, in shown in FIGS. 48 and 49, a corneal incision may be closed by applying an adhesive to a spatula-like instrument 1080 and using the instrument 1080 to apply adhesive to edges of the wound. Thereafter, the instrument 1080 may be withdrawn and the edges of the wound may be adhered to each other by way of the adhesive 1030, as shown in FIGS. 50 and 51. The adhesive 1030 may operate in any suitable way, such as polymerizing or otherwise curing in response to contact with water or bodily fluids, by exposure to light, heat or other stimulus, and so on. The adhesive may include other compounds, such as antiinflammatories, analgesics, antibiotics, growth factors and/or other materials to improve wound healing or provide the adhesive with other desired features.

In another aspect of the invention, sutureless corneal transplant, penetrating keratoplasty (PKP) or lamellar keratoplasty (LKP) may be provided. For example, as shown in FIGS. 52 and 53, a portion or all of the diseased cornea 1070 may be removed using a trephine-like device 1011 and a donor button 1090 may be placed where the scared or diseased cornea was removed as shown in FIGS. 54 and 55. The donor button 1090 may be secured in place using an adhesive 1030 in accordance with aspects of the invention that is delivered to the edge of the recipient corneal bed and/or the edge of the donor button 1090. As in the examples above, the adhesive may function in any suitable way, such as polymerizing or otherwise curing when exposed to bodily fluids, a suitable light source, etc.

Other aspects of the invention provide for treatment of retinal tears. For example, a support with or without a suitable adhesive may be provided at a retinal tear site via an infusion tube passing through a sclerotomy hole. The support/adhesive may be rolled or folded in an umbrella-like configuration when inside the infusion tube and can be deployed so that the support unfolds or unrolls at the retinal tear site. The support may be manipulated and properly positioned via a second instrument, e.g., delivered through a second sclerotomy hole. For example, as shown in FIG. 56, the support 1040 may be positioned over a torn portion of a retina 111. The side of the support that faces the retina may, in some embodiments, have an irregular surface that provides adhesion points and reinforcement for increasing the strength and toughness of the adhesive used to secure the support 1040 to the retina 111. The vitreous facing side of the support 1040 may have a substantially smooth surface and may be coated with a material, such as fibronectin, to promote glial cell migration, as shown for example in FIG. 57. The support 1040 may be arranged so that the majority of the support dissolves or otherwise biodegrades before the fibronectin is depleted so that the retina 111 is sealed with a glial scar and without traction.

In another aspect of the invention, a tunable implant for sutureless trabeculectomy is provided. A trabeculectomy is a partial thickness filtration operation that decreases eye pressure via the establishment of a limbal fistula through which aqueous humor drains into the conjunctival space, establishing a filtering bleb. Current techniques involve the creation of a conjunctival incision and dissection of a scleral flap to provide access to the trabeculectomy site. The corneal sclera tissue block in the drainage angle of the eye is then excised to create an opening and the opening is subsequently covered with a flap of tissue from the sclera and conjunctiva, which are closed with sutures. The new opening allows aqueous humor to drain out of the eye, bypassing the clogged drainage channels of the trabecular mesh work. In accordance with aspects of the invention, after the corneal sclera block and the drainage angle of the eye is excised to create an opening, a support with a suitable adhesive is placed in the bed of the trap door. The opening is subsequently partially covered with a flap of tissue from the sclera and conjunctiva. However, instead of closing the scleral flap and conjunctiva with sutures, the support may include a light activated adhesive that serves to secure the flap in place allowing aqueous humor to drain into the sub-conjunctival space and form a filtering bleb. If over filtration or under drainage are observed during or after the surgery, the degree of filtration can be tuned or otherwise adjusted, e.g., by using light energy to activate a light-activated adhesive deployed with the support to create more adhesions between the support and the tissue so as to reduce fluid flow. Alternately, the porosity of the support and/or adhesive may be adjusted to allow more fluid flow.

In other embodiments, aspect of the invention can be applied to other areas of surgery including, but not limited to: repair of liver, spleen, or pancreas traumatic lacerations, dural laceration/incision closure, pneumothorax repair during thoracotomy, sealing points of vascular access following endovascular procedures, vascular anastomoses, tympanoplasty, endoscopic treatment of gastrointestinal ulcers/bleeds, dental applications for mucosal ulcerations or splinting of injured teeth, tendon and ligament repair in orthopedics, and episotomy/vaginal tear repair in gynecology. Additionally, as minimally invasive techniques become more common, the application of the articles and methods described herein to endoscopic, laparoscopic or endovascular techniques is very promising. As described herein, an article of the invention may include a support in some embodiments. All or portions of the article and/or support may comprise a synthetic or biological material. A suitable biological support may comprise SIS (small intestine submucosa), polymerized collagen, polymerized elastin, or other similarly suitable biological materials. Suitable synthetic materials include both organic and inorganic materials. Examples of synthetic materials suitable for use as a support include, but are not limited to, various poly(alpha ester)s such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(DL-lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) and poly(ethylene glycol) (PEG), as well as poly(alpha ester)s, poly(ortho ester)s, poly(anhydrides), polyurethane, polyvinyl alcohol, carbohydrate-based polymers such as chitosan and hyaluronic acid, poly(dioxanone), poly(glycolide-co-trimethylene carbonate), poly(hydroxybutyrate), poly(hydroxyvalerate) and their copolymers, poly(maleic acid) and their esters, poly(sebacic anhydride) (PSA), poly(bis carboxyphenoxypropane) (PCCP), and PSA-co-PCCP, poly(lactic acid-co-lysine), polyglutamic acid, poly(phosphazenes), PLA-PEG, PLA-PEG-PLA, and polysiloxanes, and copolymers (e.g., random/block copolymers) thereof.

In some embodiments, all or portions of an article and/or support is made in a polymer. A polymer includes a molecule (e.g., protein, polyether, polyacetal, polyester, polysaccharide) formed by the union or bonding of chemically similar or chemically distinct units (e.g., monomers such as amino acids, esters). In some cases, a polymer includes a molecule comprising greater than about 30 units. The polymers can be, for example, inorganic polymers such as siloxanes or polyphosphates and derivatives thereof. Alternatively, or additionally, the polymer can be organic. Organic polymers can be natural organic polymers such as polysaccharides, starch, cellulose, pectin, inulin, agarose, chondroitinsulfate, heparin, dextrans, polypeptides (e.g., casein, albumin, globulin, keratin, insulin, polylysine) and derivatives thereof. Organic polymers can be synthetic organic polymers such as polyacetals, polyacrylates, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyesters, polyamides, polyamines and derivatives thereof. Organic polymers may be semisynthetic organic polymers such as methylcellulose, modified starches and derivatives thereof. Polymer architectures include linear, crosslinked, branched, comb and dendrimer.

In one embodiment, the polymer component of an article and/or support is a biocompatible polymer component. In some such embodiments, the polymer does not invoke an adverse reaction (e.g., immune response) from an organism (e.g., a mammal), a tissue culture or a collection of cells, or if the adverse reaction does not exceed an acceptable level. In certain embodiments, the polymer is biodegradable. The biocompatible or biodegradable polymer may be selected from the group consisting of, but not limited to, the following: polyesters, including poly(glycolic acid), poly(L-lactic acid) (PLA), poly (DL-lactic-co-glycolic acid) (PLGA), poly (epsilon-caprolactone)

(PCL), and poly (malic acid); poly anhydrides, including poly(sebacic anhydride) (PSA), poly(bis carboxyphenoxypropane) (PCCP), and PSA-co-PCCP; poly(ethylene glycol) (PEG); poly(ethylene glycol-propylene glycl) copolymers, including pluronics and reversed pluronics; poly(dioxanone); poly(glycolide-co-trimethyl carbonate); poly(lactic acid-co-lysine); PLA-PEG; PLA-PEG-PLA; polyphosphazenes; chitosan; hyaluronate; small intestine submucosa; polymerized collagen; and polymerized elastin.

In another embodiment, the biocompatible or biodegradable polymer is cross- linked.

The polymer used to form all or portions of an article and/or support may be one or more chemically similar polymers (e.g., polyester polymer : polyester polymer, polyether polymer : polyether polymer) or chemically distinct polymers (e.g., a polyester polymer and a polypeptide polymer, a polyether polymer and a polyester polymer; a polyester polymer, a polypeptide polymer, and a polyether polymer). In another embodiment, the polymer component includes at least two chemically similar or chemically distinct polymers.

In alternative embodiments, the support is engineered for specific applications of the article by adjusting one or more of its properties. For example, the support may include a substantially smooth surface. In some such embodiments, a surface of a support may have an average surface roughness of less than 20 microns, less than 10 microns, less than 5 microns, less than 1 micron, less than 0.1 microns, or less than 0.01 microns, for example. Alternatively or additionally, the support may include a textured surface. Key properties of the support are surface regularity or irregularity, elasticity, strength, porosity, surface area, degradation rate, and flexibility. As described herein, in some embodiments, the article is engineered to allow it to function as a depot for various dopants or bioactive materials, such as antibiotics, anesthetics, antiinflammatories, bacteriostatic or bacteriocidals, chemotherapeutic agents, vitamins, anti- or pro- neovascular or tissue cell growth factors, hemostatic and thrombogenic agents. This can be accomplished by altering the macromolecular structure of the support in order to adjust, for example, its porosity and/or degradation rate.

A support may be prepared by known methods in the art. For example, the support may be prepared by solvent casting, melt processing, extrusion, rolling, electrospinning, molding (e.g., soft lithography or injection molding processes), embossing, casting or machining. In some particular embodiments, soft lithography is used to form a flexible support, e.g., as described in U.S. Patent Nos. 6,060,121; 6,776,094; 6,752,942; 6,686,184; 6,660,192; 6,355,198; 6,180,239; 5,776,748; and 5,512,131 to Whitesides et al. In some embodiments, a support is a biocompatible support. In addition, a support may be seeded with cells or may be used to grow a tissue prior to application of the support to a surface of interest.

In some embodiments of the invention, a method of medically repairing tissue involves the use of an adhesive. The mechanism by which an adhesive bonds to a surface of interest depends at least in part on the selection of the adhesive material. As described above, adhesion refers to lowering the favorable free energy between two or more surfaces when those surfaces are brought in contact with each other. The lowering of the favorable free energy may be brought about by, for example, electrostatic forces, formation of covalent bonds, or other types of interactions as described above. The lowering of the favorable free energy requirement distinguishes adhesive interactions from mechanical interactions such as using forceps to place a material on a tissue surface. However, as described above, mechanical forces can be used to medically repair tissue in some embodiments described herein.

The adhesives used in embodiments of the invention may be natural or synthetic, or initial or activatable. An initial adhesive is one that works upon contact and does not need activation. In contrast, an activatable adhesive is one that requires activation. Examples of natural, initial adhesives include, but are not limited to, serum albumin, collagen, fibrin, fibrinogen, fibronectin, thrombin, barnacle glues and marine algae. Examples of synthetic, initial adhesives include, but are not limited to, cyanoacrylate (e.g., ethyl-, propyl-, butyl- and octyl-) glues. These materials are known to breakdown in the body over time. Some initial adhesives require an initiator (other than laser energy) to cause or accelerate bonding. For example, polymerization of octyl- cyanoacrylates can be accelerated through contact with a chemical initiator such as that contained in the tip of the applicator of Ethicon's Dermabond™. Cohesion's CoStasis and Cryolife's Bioglue also rely on the addition of an initiator at the time of application, namely, fibrinogen and glutaraldehyde, respectively. Other examples of adhesives include polyurethanes, polyepoxides, and polysiloxanes. Non-limiting examples of activatable adhesives include light activated, pressure activated, heat activated, and chemically activated adhesives. In certain embodiments, the activatable adhesive is a light activated adhesive, and the activator is a wavelength of light sufficient to activate the light activated adhesive. In one embodiment, the adhesive is a UV curable light activatable adhesive. Non-limiting examples of light activated adhesives include solid or liquid tissue solders, including protein solders comprising serum albumin, fibrinogen, collagen or elastin. Light energy (e.g., electromagnetic radiation with a wavelength in the range of infrared, visible or ultraviolet light) may be delivered to a light-activated adhesive to activate its adhesive properties (e.g., induce cross linking and the like). Examples of suitable sources of light energy for use in connection with the invention include lasers having a suitable operating wavelength that would allow the radiation to be absorbed by the adhesive, and an intense pulsed light source (IPL or IPLS) used in conjunction with suitable optical filters to obtain the desired absorption wavelength range.

Light absorbers can be used in laser-tissue soldering to enhance the amount of light energy or radiation that is absorbed by the solder. Chromophores, i.e., chemical groups or residues that impart some decided color to the compound of which it is an ingredient, are one example of light absorbers. The safety of the degradation products of commonly-used chromophores such as indocyanine green (ICG) and methylene blue (MB) following irradiation may be uncertain. Also, many chromophores that absorb light can decay with continued exposure to light. The inventors have shown that red, green, and blue food colorings may be used effectively as chromophoric dyes in tissue soldering and have improved degradation characteristics over the commonly-used ICG. Another example of a light absorber is a pH indicator, such as phenothaline red. Such a pH indicator may be incorporated into the solder material, in some embodiments. If the solder material is kept at a pH that does not cause the pH indicator to turn color, the indicator will not absorb light and decay. A small amount of dilute acid or base can be added when the solder material is ready for use, causing the indicator to change color and thus assist in specific light activation.

A pharmaceutical drug that absorbs electromagnetic radiation may be used, in yet another embodiment. Such drugs may be used for photochemical or photothermal activation of the adhesive. Any drug or medication that absorbs radiation having a wavelength in the electromagnetic spectrum (including, but not limited to, ultraviolet, visible, or infrared radiation) may be suitable for use as a light absorber and combined with an adhesive. For example, a commercially-available drug such as estradiol, which absorbs light at a wavelength of approximately 400 run, may be used. Other possible pharmaceutical alternatives include rifampins, licopenes, and phenazopyridine. Such light absorbers may offer the additional therapeutic advantage of providing medication to a wound or repair site.

Water, including water contained within the adhesive, is another alternative light absorber that can be used in some embodiments. Water absorbs light from a number of infrared sources, including, but not limited to: carbon dioxide (CO₂), thulium-holmium- chromium, holmium, thulium and neodymium rare earth doped garnets (THC: YAG, Ho:YAG, Tm: YAG or Nd: YAG), and gallium aluminum arsenide (GaAlAs) diode lasers.

Hemoglobin is yet another alternative light absorber. Hemoglobin absorbs light c from a number of sources of visible light, including, but not limited to potassium-titanyl- phosphate (KTP) frequency-doubled Nd:YAG and argon lasers.

Further, it has been shown that light-activated adhesives may be used in a wide range of applications, including internal surgeries, external wound closures, and certain ophthalmic surgeries. Studies have been conducted to evaluate the performance of a scaffold-enhanced light-activated solder in ophthalmic applications. Studies have also been conducted to evaluate performance in internal and external applications. See for example U.S. Published Patent Application No. 20040236371, incorporated herein by reference in its entirety. In one embodiment, the adhesive may be "switchable," that is, the adhesive may vary between being strong and weak in response to a stimulus. The stimulus may be, for example, pH or a compound. For example, a balloon delivery device can deliver a compound, or an acid or base that causes the adhesive that is adhering the material to the balloon surface to weaken once at the delivery site thus facilitating transfer. Conversely, the compound, acid, or base may strengthen the adhesive that binds the material to the tissue surface and facilitate transfer that way.

In some embodiments, an adhesive is a specific or non-specific adhesive. Examples of a non-specific synthetic adhesives include cyanoacrylates such as ethyl, propyl, butyl, or octyl cyanoacrylate. Non-specific adhesives also include activatable adhesives where the activatable adhesive is a light activated, pressure activated, heat activated, or chemically activated adhesive. Additional examples of non-specific (natural) adhesives include serum albumin, collagen, fibrin, fibrinogen, fibronectin, thrombin, barnacle glues, and marine algae. Specific adhesives are designed to bind to a specific material. In one embodiment, they include a specifically designed synthetic polymer. In another example, a synthetic adhesive comprises boronic acid for binding with diols. In another embodiment, the adhesive is a natural adhesive which may be further classified as nonspecific or specific. Natural, specific adhesives are designed to bind to a specific material, e.g., a material having a coating of biotin may be designed to specifically adhere to a material having a coating of avidin. In one embodiment, the specific adhesive comprises an affinity reagent. In another embodiment, the specific adhesive comprises an antibody, DNA, cells, or bacteria expressed protein.

As described herein, in some embodiments, a component of an article such as an adhesive, a bioactive agent, a portion of a support, or other component is covered all or in part by an isolating material (e.g., an adhesive isolating material, a bioactive agent isolating material, etc.). Non-limiting examples of materials that can be used as isolating materials include proteins, polysaccharides, starches, waxes, fats, natural and synthetic polymers, and resins. Examples of water soluble materials that can be used as isolating materials include polyvinyl alcohol, polyvinyl pyrrolidone, polyhydroxyethyl methacrylate, hydroxypropyl methylcellulose, pullulan, polyethylene glycol, polyethylene-co-propyleneglycol, OLA-PEG, polyacrylic acid, hyaluronate, chitosan, alginate, dextran, dextran sulfate, and carrageenanm.

In certain embodiments, encapsulation techniques can be used to cover all or a portion of a component of an article with an isolating material. Encapsulation techniques include physical methods such as stationary coextrusion, centrifugal coextrusion, submerged nozzle coextrusion, vibrating nozzle, rotating disk, pan coating, fluid bed, and spray drying, and chemical methods such as simple/complex coacervation, phase separation, interfacial polymerization, solvent evaporation, in situ polymerization, liposome, sol-gel methods, and nanoencapsulation. Table 1 presents the capsule size ranges generally associated with these techniques

Table 1. Encapsulation method and size range.

As described herein, in some embodiments, an article of the invention comprises a bioactive agent. The article may act as a delivery vehicle for the bioactive agent to a surface of interest. Non-limiting examples of bioactive agents include, for example, small molecules or macromolecules with biological activity, drugs, and prodrugs.

A small molecule refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. In certain embodiments, small molecules are biologically active in that they produce a local or systemic effect in animals, preferably mammals, more preferably humans. Typically, small molecules have a molecular weight of less than about 1500 g/mol. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use by the appropriate governmental agency or body. For example, drugs for human use listed by the FDA under 21 C.F.R. sections 330.5, 331 through 361, and 440 through 460; drugs for veterinary use listed by the FDA under 21 C.F.R. sections 500 through 589, incorporated herein by reference, are all considered suitable for use with certain embodiments of the invention.

Specific classes of small molecule drugs that can be used in embodiments described herein include, but are not limited to, vitamins, anti-AIDS substances, anticancer substances, antibiotics, immunosuppressants, anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, anti-histamines, lubricants, tranquilizers, anti- convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and muscle contractants including channel blockers, miotics and anticholinergics, anti- glaucoma compounds, anti-parasite and/or anti-protozoal compounds, modulators of cell-extracellular matrix interactions including cell growth inhibitors and anti-adhesion molecules, vasodilating agents, inhibitors of DNA, RNA or protein synthesis, anti- hypertensives, analgesics, anti-pyretics, steroidal and non-steroidal anti-inflammatory agents, anti-angiogenic factors, anti-secretory factors, anticoagulants and/or antithrombotic agents, local anesthetics, ophthalmics, prostaglandins, anti-depressants, anti-psychotic substances, anti-emetics, imaging agents.

A macromolecule refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have a relatively high molecular weight, generally above 1500 g/mole. Macromolecules may be biologically active in that they exert a biological function in animals such as humans. Non-limiting examples of macromolecules include proteins, enzymes, growth factors, cytokines, peptides, polypeptides, polylysine, proteins, lipids, polyelectrolytes, immunoglobulins, DNA, RNA, ribozymes, plasmids, and lectins. For the purpose of this disclosure, supramolecular constructs such as viruses and protein associates (e.g., dimers) are considered to be macromolecules. In one embodiment, a bioactive agent is a drug. The drug may be a therapeutic drug, which refers to a drug used to treat, remediate or cure a disorder or a disease (e.g., hereditary diseases, viral diseases such as AIDS, cancer). In another embodiment, the drug is a diagnostic drug (e.g., a radioactive diagnostic drug, a fluorescent diagnostic drug, a paramagnetic diagnostic drug, superparamagnetic diagnostic drug, an x-ray dense diagnostic drug or an electron dense diagnostic drug). A diagnostic drug refers to a drug employed to determine the nature or extent of a disease, or employed to confirm the presence of a disorder or a disease. In some cases, a drug is an analgesic, antibiotic, antiinflammatory, or growth factor. It is recognized by the inventors that each type of drug plays a role in tissue healing and that in some applications more than one type may be used. For example, analgesics may reduce the amount of post-surgical pain and discomfort. Antibiotics can reduce the probability of post-surgical infections. Antiinflammatories may reduce post operative scarring which adds to the difficulty of re- operations or adversely affects muscle movement, especially when the tissue is eye tissue. Growth factors may help the muscle to adhere more quickly to the tissue, e.g. to the sclera, reducing the risk of a lost muscle, especially if the adhesive needs to be cleared in a short amount of time.

In other embodiments, the drug can be, for example, an anticancer drug, antiviral drug, antibiotic drug, anti-inflammatory drug, analgesic drug, growth factor drug, or antiprotozoal drug. The drug can also be, for example, anthracycline, actinomycin, anthracenedione, bleomycin, mithramycin, chromomycin, olivomycin, protein, peptide, carbohydrate, polyamine, polycation, actinomycin D, daunorubicin, doxorubicin, idarubicin, bis-anthracycline, mitoxantrone, bleomycin A2, distamycin, netropsin, cisplatin, carboplatin, a silver ion and particle, or a gold ion and particle. A more complete, although not exhaustive, listing of classes and specific drugs suitable for use in the disclosure may be found in "Pharmaceutical Substances: Syntheses, Patents, Applications" by Axel Kleemann and Jurgen Engel, Thieme Medical Publishing, 1999 and the "Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals", Edited by Susan Budavari et al., CRC Press, 1996, both of which are incorporated herein by reference.

Also included as suitable bioactive agents described herein are pharmaceutically acceptable addition salts and complexes of the bioactive agents. In cases wherein the bioactive agents may have one or more chiral centers, unless specified, the disclosure comprises each unique racemic compound, as well as each unique nonracemic compound.

In cases in which the bioactive agents have unsaturated carbon-carbon double bonds, both the cis and trans (or Z or E) isomers are within the scope of this disclosure. In cases wherein the bioactive agents may exist in tautomeric forms, such as keto-enol

O OR¹ tautomers, such as ^^ and -^⁵= , each tautomeric form is contemplated as being included within this disclosure, whether existing in equilibrium or locked in one form by appropriate substitution with R¹. The meaning of any substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence.

Also included as suitable bioactive agents used in the methods of the invention are prodrugs of the bioactive agents. Prodrugs are considered to be any covalently bonded carriers which release the active parent compound in vivo.

A bioactive agent may be incorporated into an article in any suitable method. For example, as described above, a bioactive agent may be printed on a surface of a support. In another embodiment, a bioactive agent can be dispersed homogeneously throughout the support material. For example, the bioactive agent may be added and mixed in with the components of the support during its preparation. In another embodiment, the bioactive agent exists in a gradient within the support, e.g., the bioactive agent is not dispersed homogeneously throughout the support. This embodiment may be prepared, for example, by adhering two support materials together to form a single support structure. One of the support materials may contain the bioactive agent homogeneously dispersed and the other support material does not contain the bioactive agent, or contains a different bioactive agent. The result is a support where the bioactive agent exists in a gradient. Another way of achieving a gradient is by using a support comprising indentations (e.g., wells or channels) on at least one side of the support. Certain wells or channels in closer proximity to one end of the support may be filled with a bioactive agent while the others are not, or they may be filled with a different bioactive agent. This embodiment is a good example of the versatility that can be achieved with the articles of the invention where adhesive is applied to the article in a controlled manner. In another embodiment, a gradient is achieved by placing a bioactive agent in microtubules or capsules which are then placed adjacent to each other within the support. Different bioactive agents may be eluded at different rates depending on the microtubule or capsule composition. The rate of delivery may also be adjusted by adjusting the concentration of bioactive agent.

A bioactive agent may be associated with an article of the invention in an effective amount, i.e., the amount necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a bioactive agent may vary depending on such factors as the desired biological endpoint, the bioactive agent to be delivered, the composition of the encapsulating matrix, the target tissue, etc. As described herein, methods of medically repairing a tissue may involve the use of a transfer device in some embodiments. The transfer device used may be any suitable instrument generally used in the medical field for tissue repair, or any instrument that allows the practitioner to deliver material in the proximity of tissue. Commonly used instruments falling under these categories include, for example, a spatula, a trephine, an infusion tube, a stamping device, a balloon catheter, and a stent.

A spatula is envisioned by the inventors for use when, for instance, the tissue surface is readily accessible, such as skin or the interior of one's mouth. In one example, when the transfer device is a spatula, the material may be transferred from one side of the spatula, or from both sides of the spatula. In a further example, when the tissue is eye tissue the method comprises cornea repair. As with the previous methods of the disclosure, the material may comprise a bioactive agent such as, for example, analgesics, antibiotics, antiinflammatories, and/or growth factors.

A trephine is a surgical instrument having a cylindrical blade. A trephine may be used for any application involving cutting a hole in or harvesting tissue; for example, trephines may be used on bone (e.g., the skull) or for cutting out a round piece of the cornea for eye surgery. In some embodiments, a trephine-like device can be used as a transfer device, e.g., to cut a hole in a tissue while transferring material (e.g., adhesive) from the outer surface of the device to the surface of tissue. Additionally, the hollow tube of the trephine-like device may further deliver other materials, including other tissue, to the transferred material. For example, when the tissue is eye tissue, a cornea button may be transferred from the hollow portion of the trephine-like device to a cornea recipient. As with the previous methods of the disclosure, the material may comprise a bioactive agent such as, for example, analgesics, antibiotics, antiinflammatories, and/or growth factors.

An infusion tube is a cylindrical, needle like device that is particularly useful for accessing difficult to reach parts of the body. An infusion tube is particularly useful for retina repair in eye surgery. For example, when the transfer device is an infusion tube and the tissue is eye tissue the material may be transferred between the retina and vitreous cavity of the eye tissue. As with the previous methods of the disclosure, the material may comprise a bioactive agent such as, for example, analgesics, antibiotics, antiinflammatories, and/or growth factors. A stamping device transfers the material in one motion and, generally, in one quick motion. In some cases, a stamping device comprises an article or support of the invention. Adhesives may be used with this device, e.g., such that the adhesive adhering the material to the stamping device is much weaker than the adhesive adhering the material to the tissue surface. The advantage of a stamping device is that the material is delivered quickly and evenly in a predetermined pattern. This device is particularly useful when it is important for the material transferred to avoid a certain area, or for when the material is transferred in a geometric shape, such as a circle. For example, sealing ocular tissue during eye surgery involves in certain cases sealing circular shaped eye tissue without obscuring the pupillary axis. The stamping device may function on the practioners application of pressure, or it may comprise a means of applying a predetermined amount of pressure for ease and consistency of application.

For example, in one embodiment, when the transfer device is a stamping device the material may be applied to the tissue surface in the form of a ring. When the tissue is eye tissue, the procedure may be used for sealing, joining, or aligning the corneal flap and stromal bed for cornea repair. The material may be applied to the stromal bed outside the pupillary axis and inside the boundary formed by the corneal flap. As with the previous methods of the disclosure, the material may comprise a bioactive agent such as, for example, analgesics, antibiotics, antiinflammatories, and/or growth factors.

Catheters are well known in the art and can be used to allow access by surgical instruments. In certain embodiments, the catheter is a balloon catheter as commonly used in angioplasty. Balloon catheters include all types of balloon catheters including double balloon and porous balloon catheters. In one such embodiment, the material to be transferred is adhered to a surface of the balloon. Expansion of the balloon allows contact of the material with the tissue surface where greater adhesion leads to the transfer.

A stent encompasses both an expandable wire mesh or hollow perforated tube. The main purpose of a stent is to overcome important decreases in vessel or duct diameter. Stents are often used to diminish pressure differences in blood flow to organs beyond an obstruction in order to maintain an adequate delivery of oxygen.

When the transfer device is a balloon catheter or stent, the tissue surface may be luminal tissue. Although perhaps the most popular use of these devices is linked to the coronary arteries, they are widely used in several other structures, such as peripheral arteries and veins, bile ducts, esophagus, colon, trachea or large bronchi, ureters, and urethra. When the transfer device is a stamping device, trephine, infusion tube, or spatula, a wide array of tissues and materials may be involved. For example, tissue type may include eye, liver, spleen, pancreas, dura mater, vascular, gastrointestinal, dental, tendon, or ligament tissue. In certain embodiments, the tissue is eye tissue or vascular tissue. Modifying the surface may include sealing, joining, or aligning incised tissue.

It should be understood that the transfer device may allow transfer of a material (e.g., an adhesive, an isolating material, a bioactive agent, etc.) in a variety of shapes, e.g., dots, lines, triangles, squares, circles, arcs, ovals, irregular shapes, etc., and combinations thereof. Accordingly, in certain embodiments, one or more surfaces of the transfer device may also include one or more such shapes (e.g., in the form of protrusions or indentations).

The following examples are intended to illustrate certain embodiments of the present invention, but are not to be construed as limiting and do not exemplify the full scope of the invention. Example 1

Preparation of Discontinuous Ordered Arrays of Adhesive on Teflon Supports

To prepare articles comprising patterned arrays of adhesive, the desired pattern was first created using Macromedia Freehand and then converted to an Autocad file. A master was created by machining the pattern into an aluminum block with features ~500 μm deep using a CNC milling machine (T & H Machine Technology, Hampton, NH). Poly(dimethyl siloxane) (PDMS) Sylgard 184 (Dow Corning) was then mixed according to manufacturer instructions, poured over the master, degassed under vacuum, and cured for 2 hours at 8O⁰C. After curing, the PDMS was peeled from the master, and PDMS stamps with the selected features were cut out and attached to handles using silicone adhesive (FIG. 8).

The fabricated PDMS stamps were used as transfer devices to stamp adhesive patterns onto Teflon and polystyrene supports by first "inking" them in an adhesive solution. A pluronic-containing formulation, formulation two (F2), of cyanoacrylate was also used. This formulation was prepared by combining 10 wt% of Pluronic F- 127 to 2- octyl-cyanoacrylate (Chemence, Alpharetta, GA); methanesulfonic acid and 2,6-di-tert- butyl-4-methylphenol (Sigma, St. Louis, MO) were added at 0.3 wt% and 0.05 wt%, respectively. A blue dye, D & C Violet #2 (Spectrum, New Brunswick, NJ), was added to allow for visualization of the adhesive. The adhesive was then transferred by contact adhesion to Teflon sheets, purchased from Small Parts Inc (Miami Lakes, FL), using the PDMS stamp (FIG. 8).

Example 2

Preparation of Discontinuous Ordered Arrays of Adhesive on Polystyrene Supports

Polystyrene (PS) dishes were purchased from VWR (Bridgeport, NJ) and cut into pieces (circles with 1 cm diameters) that were used as supports using a die punch. A discontinuous ordered array of adhesive was stamped on the support (e.g., by contact adhesion) using the adhesive and methods as described in Example 1.

Example 3 Preparation of Discontinuous Ordered Arrays of Adhesive on L-PLGA Supports

L-PLGA supports were prepared using a solvent casting method. A solution of L-PLGA (85:15 L-PLGA, LV. 1.50-2.49 dL/g, Biolnvigor, Taipei, Taiwan) in dichloromethane (10% w/v) was cast into a glass Petri dish. The dish was covered and left in a fume hood overnight to allow for solvent evaporation. Using the adhesive formulation and methods described in Example 1 , a discontinuous ordered array of adhesive was stamped onto the support; the patterned adhesive transferred from the stamp to the support by contact adhesion (FIG. 9). Example 4 Preparation of Discontinuous Ordered Arrays of Adhesive on PCL Supports

Electrospun PCL supports were prepared using a solution of PCL (10 wt% in 5:1 by vol chlorofornrmethanol). The electrospinning setup consisted of a syringe pump (KD Scientific, Holliston, MA), power supply (Gamma High Voltage Research, Ormond Beach, FL), and a square grounded copper plate (lO cm x 10 cm x 0.16 cm). A lO mL syringe was filled with the polymer solution, and the syringe was then fitted with a blunt 18 gauge needle (Brico Medical Supplies, Inc, Metuchen, NJ). The positive lead from the power supply was attached to the needle. A copper plate located a distance of 15 cm from the end of the needle was grounded. During electrospinning, the solution was ejected through the needle at a flow rate of 8 mL/hr while a voltage of 14 kV was applied; the fibers were collected onto the grounded copper plate. After electrospinning for 4 minutes, nonwoven electrospun sheets were removed and dried overnight in a dessicator. Using the adhesive formulation and methods described in Example 1, a discontinuous ordered array of adhesive was stamped on the support; the patterned adhesive transferred from the stamp to the support by contact adhesion (FIG. 9).

Example 5 Preparation of Discontinuous Ordered Arrays of Adhesive on PGS Supports

PGS supports were made by curing PGS prepolymer. To do so, PGS prepolymer was first synthesized using a 1 : 1 mol ratio of glycerol isebacic acid (both from Sigma, St. Louis, MO). The monomers were mixed for 24 hr at 12O⁰C under argon. The mixture was reacted for another 24 hr at 12O⁰C under high vacuum to obtain the prepolymer. For curing, PGS prepolymer was mixed with a catalyst, tin II ethylhexanoate (1 wt%, from Sigma, St. Louis, MO). Curing occurred in a convection oven at 140°C for 8.5 hours. Using the adhesive formulation and methods described in Example 1, a discontinuous ordered array of adhesive was stamped on the support; the patterned adhesive transferred from the stamp to the support by contact adhesion (FIG. 9).

Example 6 Preparation of Discontinuous Ordered Arrays of Adhesive on PEG Supports PEG supports were synthesized using poly(ethylene glycol diacrylate, MW=700, Sigma, St. Louis, MO). Equal masses of PEG and solvent (solvent: 50% ethanol and 50% water by volume) were combined; a UV initiator, dimethoxy-2-phenyl- acetophenone (DMPA), was added at 1 wt% of the total mass. The mixture (monomer, solvent, and initiator) was pipetted between glass slides separated by Teflon spacers and placed under a UV lamp for 10 minutes. The polymer film was removed from the glass slides and placed in water for 3 days to leach any unreacted monomers. Using the adhesive formulation and methods described in Example 1, a discontinuous ordered array of adhesive was stamped on the support; the patterned adhesive transferred from the stamp to the support by contact adhesion (FIG. 9).

Example 7 Preparation of Articles with Discontinuous Ordered Arrays of Bands

Masters for patterns consisting of bands were created using Macromedia Freehand, and a high resolution lithography transparency was printed at Page Works

(Cambridge, MA). A silicone wafer photoresist master with features ~100 μm deep was created using photoresist SU8 2100 (MicroChem Corp. Newton, MA) following the manufacturer's instructions. Stamps were created from the masters using the procedure described in Example 1. PCL electrospun supports fabricated as described in Example 4 were then stamped with bands of adhesives formulated as described in Example 1 (FIG. 10).

Example 8 Preparation of Composites with Discontinuous Non-Ordered Arrays

A discontinuous, non-ordered array stamp was made by randomly attaching PDMS circles with diameters of 2 and 3 mm to a handle using silicone adhesive. PDMS circles were cut from a film of PDMS, and prepared as described in Example 1, using die punches. L-PLGA supports were prepared as described in Example 3. An adhesive formulation (Fl) containing 94.3 vol% 2-octyl-cyanoacrylate (Chemence, Alpharetta, GA) with 5.5 vol% acetyl tributyl citrate, 50 ppm sulfuric acid, and 200 ppm acetic acid (Sigma, St. Louis, MO) was prepared. The stamp was then used to transfer adhesive to the support by contact adhesion (FIG. 1 IA). Example 9 Preparation of Articles with A Continuous Ordered Array

A continuous, ordered array stamp was prepared by first making a sheet of PDMS as described in Example 1. Four circles with diameters of 2 mm were punched from a 1 cm² square piece of PDMS in an ordered pattern. This PDMS stamp was attached to a handle using silicone adhesive. An electrospun PCL support was prepared as described in Example 4. Adhesive formulation Fl (as described in Example 8) was stamped onto the PCL support by contact adhesion (FIG. HB).

Example 10 Preparation of Articles with A Continuous Non-Ordered Array

Adhesive was applied to a support in a continuous, non-ordered array using a pipette. The adhesive was applied by hand to the support in a continuous, non-ordered array (FIG. 11C). L-PLGA supports were fabricated and adhesive was formulated (F2) as described in Examples 2 and 1, respectively. This example shows that in some embodiments, patterned arrays of adhesive can be patterned on a support by methods other than contact adhesion.

Example 11 Preparation of Articles with a Non-uniform Array of Fibrin Adhesive Fibrin adhesive is a two-component adhesive that is active only when the two components, fibrinogen and thrombin, make contact in the presence of calcium. Following a commercially available formulation (TISEEL VH fibrin sealant, Baxter Healthcare Corp, Deerfield, IL), fibrin adhesive was prepared in house. To do so, the first component was made by dissolving fibrinogen (100 mg/mL) in a solution of glycine (25 mg/mL), Tween-80 (0.5 mg/mL), and aprotinin (3000 KIU/mL). Methylene blue was added to the solution (1 mg/mL) to allow for visualization. The solution was gently stirred at 37⁰C. The second component was prepared by dissolving thrombin (500 KIU/mL) in solution of glycine (3 mg/mL) and calcium chloride (100 μM). The thrombin solution was kept at 37⁰C until use. All chemicals were purchased from Sigma-Aldrich and used as received (St. Louis, MO). Electrospun PCL supports were fabricated as described in Example 4. Electrospun PLGA supports were prepared using methods described in Example 4; however, a L-PLGA solution (10 wt% in 5:1 by vol chloroform:methanol) was used with an applied voltage of 14.5 kV, distance of 17.5 cm, and a flowrate of 8 mL/hr.

The thrombin component (10 μL) was then spread onto thesupports. Using methods described in Examples 1-9, the fibrinogen component (e.g., an adhesive precursor) was stamped onto the PLGA and PCL supports using a discontinuous ordered and a continuous ordered stamp, respectively. The adhesive precursors were transferred from the stamp to the supports by contact adhesion. In the areas where the fibrinogen was stamped, the two components made contact, and fibrin adhesive was formed (FIG. 12).

Example 12 Preparation of Articles with a Non-uniform Array of Light Activatable Adhesive

Light activated protein solders were made by combining bovine serum albumin (BSA) with one of two commonly used chromophores, indocyanine green (ICG) or methylene blue (MB). ICG absorbs light at -800 nm which causes localized heating and coagulation of the albumin protein solder leading to tissue adhesion. Methylene blue can be activated by light at -650 nm to an excited state which, in turn, activates oxygen to yield oxidizing radicals. These radicals can cause crosslinking of amino acid residues on proteins leading to tissue adhesion. Protein solders were made by mixing -75 mg of BSA in 1 niL of distilled water with 2 mg of either ICG or MB. (All chemicals were purchased from Sigma-Aldrich (St. Louis, MO) and used as received.)

Solvent cast and electrospun L-PLGA supports were prepared as described in Examples 3 and above, respectively. Using methods described in Examples 1-9, the ICG and MB protein solders were stamped onto an electrospun PLGA using a stamp comprising a discontinuous, ordered pattern of features (FIGS. 13A and 13B). Also, a continuous non-ordered array of protein solder on the electrospun support was prepared using a pipette as described in Example 12 (FIG. 13C). Example 13 Preparation of Articles with Discontinuous Ordered Arrays of Channels & Wells

Supports containing channels were fabricated from PDMS stamps of bands, prepared as described in Example 7. To do so, a solution of L-PLGA in dichloromethane was spin-coated onto 4 cm² PDMS stamps of bands. Spin coating was done in two steps: 2.5% w/v L-PLGA solution was spun onto the PDMS array for 15 s at 1000 RPM followed by 5% w/v L-PLGA solution spun for 15 s at 1000 RPM. After spin coating, 1 mL of 5% w/v L-PLGA solution was added to the top of the stamps and allowed to evaporate overnight in a covered glass petri-dish. The L-PLGA support was then removed from the PDMS. Channels were filled individually with adhesive F2, foπnulated as described in Example 1, using a pipette (FIG. 15). Supports containing wells were fabricated similarly; however, the initial PDMS stamp was made up of dots rather than bands (FIG. 15).

Example 14

Article as a Temporary Reservoir for the Directional Release of Bioactive Agents such as Antiinflammatories and Growth Factors

In some embodiments, antiinflammatories at a scleral-muscle interface can inhibit required wound healing of muscle insertion to globe, so directional delivery or delivery in a controlled location may be beneficial. The purpose of this directional antiinflammatory (or other barrier/inhibitor to scarring) drug delivery is to prevent the postoperative scarring on the dorsal surface of the muscle which adds to the difficulty of re- operations or adversely affects the movement of the eye postoperatively. In this prophetic example, FIG. 18 shows first 5 mm of article in close proximity to a scleral/muscle attachment point, containing no anti-inflammatory. Further down the length of the article, away from the attachment point, the article contains an antiinflammatory. This anti-inflammatory may be present at a graded level, with less drug present at the end closest to the attachment point.

Example 15 Article for Graded Delivery of Bioactive Agents In this prophetic example, microtubules embedded in a flexible covering or sheet can be used to provide a gradient of drug delivery in terms of what is being delivered (e.g., different drugs eluded at different rates) or the concentration of drugs delivered (e.g., rate of drug delivery may gradually decline as the tissue starts to heal itself). Survival times can determine this time period. Bioactive agents for this kind of delivery include, but are not limited to, analgesics for reducing the amount of post-surgical pain and discomfort; antibiotics for reducing the probability of post-surgical infections; and growth factors for helping the muscle to adhere more quickly to the sclera, reducing the risk of a lost muscle (in fact, a growth factor may be beneficial if the adhesive needs to be cleared in a short amount of time). Different drugs can be carried in adjacent tubules). Different concentrations of the same drug can be contained in different tubules or at different locations within the same tubule (e.g., walled-off) along its length. The composition of these tubules may permit a graded release of drug, which is predetermined or able to be modulated by application of an external, postoperative energy source.

Example 16 PLGA Supports Containing Aspirin

Non-porous L-PLGA supports containing the analgesic aspirin were solvent cast. To do so, a 5% w/v solution of L-PLGA in dichloromethane was prepared. Aspirin (acetylsalicylic acid, Sigma, St. Louis, MO) was added at a concentration of 0.5% w/v. The solution (4 mL) was cast into a glass Petri dish. The dish was covered and left in a fume hood overnight to allow for solvent evaporation. NMR was performed to confirm that the process of incorporating aspirin in the PLGA supports did not affect the structure, and presumably the activity, of the aspirin. NMR samples were prepared by dissolving 35 mg of the aspirin/PLGA film in 2 mL of a CDC1₃:DMSO solvent (50:50 by vol). NMR samples of PLGA and aspirin separately (35 mg in CDCl₃IDMSO) were also prepared as references. NMR spectra of all three samples showed that since the protons of the aspirin in the PLGA/aspirin sample have the same chemical shifts as in the reference aspirin sample, the process of solvent casting does not affect the structure of the aspirin. Example 17

Transfer of a Bioactive Agent: Comparison of Non-Patterned and Patterned

Adhesives

Electrospun L-PLGA was prepared in the same manner as electrospun PCL as previously described (Example 4). A vitamin B 12 solution using ethanol as a solvent (0.85 wt%). The electrospun support was immersed in the vitamin B12 solution overnight. The support was then removed from the solution and air dried. Sections of the support were cut (10 x 10 mm) using a Sizzix die cutter (Lake Forest, CA). Adhesive formulation Fl was applied to the support in either a non-patterned fashionor in a patterned array. Patterned application of the adhesive on a support was achieved using a PDMS stamp (e.g., as a transfer device), e.g., as described in Examples 1-9. To apply adhesive uniformly in a non-patterned fashion, the support was dipped in the adhesive and then the surface was gently wiped. The articles with uniform application of adhesive and patterned adhesive arrays were adhered to the dermis surface of porcine skin (FIGS. 19A and 19B, respectively). After 4 minutes at room temperature, the articles were removed from the tissue surface. Greater transfer of the vitamin B 12 was observed in the article with adhesive applied in a patterned array (FIGS. 19C and 19D).

Example 18 Tissue Repair: Comparison of Non-Patterned and Patterned Adhesives Solvent cast L-PLGA was prepared as previously described in Example 3; sections (5 mm by 3.18 mm) were cut from larger pieces using an ASTM standard die cutter (ASTM D638 V) and a razor blade. Dogbones of porcine skin (Brennen Medical, MN Mediskin Xenograft 1-188) were cut out using the same die cutter. A full thickness incision was made through the center of the gage length. For non-patterned arrays of adhesive, 2 μL ( 1.4 mg) of Dermabond™ was spread across one side of the support using a pipette. Patterned arrays were made by stamping Dermabond on one side of the support using a stamp comprising features of discontinuous dots (e.g., dots with 0.75 mm in diameter spaced 2 mm apart). The mass of the adhesive transferred using the dot stamp was approximately 0.3 mg (measured by weighing 10 stamp transfers on a glass slide). After the adhesive had been applied to the supports, the articles were placed across the incision such that the adhesive side of the support was in contact with the epidermis surface of the skin.

After repair, the dogbones were allowed to sit for 10 minutes at room temperature and then loaded into the grips of an Instron tensile testing machine. The sample was loaded to failure at a constant cross-head speed of 5mm/min. The load at failure was recorded and maximum shear strength was calculated as the load at failure divided by the overlap area (15.9 mm²). Table 2 compares the measurements for the non-patterned and patterned articles. When normalized for mass of glue, the normalized shear strength for the patterned array is approximately three times greater than for the uniform array.

Table 2. Comparison of strength of tissue repair using articles with adhesive (Dermabond) in non-patterned and patterned arrays (fabricated from solvent cast L- PLGA supports).

Example 19 Preparation of Articles Comprising Isolating Materials

L-PLGA electrospun supports were prepared as described above. A section of the support was cut and placed on a Teflon sheet. Double sided tape was placed around the support. The support was stamped with adhesive formulation F2 (prepared as described above) in a discontinuous,^' ordered array. The article was covered with another sheet of Teflon such that it was sealed between the two Teflon sheets (FIG. 21B). The top Teflon sheet was peeled off revealing the article; the article was removed from the bottom Teflon sheet. When placed in contact with the dermis surface of porcine skin, the article adhered to the tissue.

Example 20

Patterning of Biological Agents (e.g., Vitamin B12 and Aspirin) onto Tissue

Surfaces: Stamps were used to transfer bioactive agents onto the dermis surface of porcine skin. To do so, Vitamin B12 (Fluka Biochemika, Ronkonkoma, NY) was dissolved in glycerol (VWR, Bridgeport, NJ) at a concentration of 4 wt%. Also, an aspirin solution was made by combining acetylsalicylic acid (0.06 wt%) and hylauronic acid (0.1 wt%) in an aqueous solution; D & C Violet #2 was added to allow for visualization of the aspirin. The solution was heated for approximately 3 minutes at 14O⁰C in order to increase the viscosity of the solution. Bioactive agents were transferred to a stamp (e.g., a transfer device) fabricated as described above in Examples 1 and 2 (FIG. 23). The stamp was placed in contact with the porcine skin to transfer the bioactive agents in discontinuous, ordered arrays by contact adhesion.

Example 21 Patterning of Chemotherapeutic Agents onto Tissue Surfaces

PDMS stamps were fabricated as described above. A solution of a chemotherapeutic was made by dissolving paclitaxel (Sigma, St. Louis, MO) in ethanol (2 wt%); D & C Violet #2 was added to allow for visualization of the solution. Bioactive agents were then printed onto the dermis surface of porcine skin in discontinuous, ordered arrays using stamps fabricated as described above in Examples 1 and 2 (FIG. 24).

Example 22

Patterning of Composite Materials onto Tissue Surfaces

A stamping device used to transfer adhesive was created by attaching a one inch disk of PDMS (fabricated as described above and cut using a die punch) to a handle using silicone adhesive. Non-porous L-PLGA supports (25 μm thick) were prepared by spin coating a solution of L-PLGA (85:15 L-PLGA, LV. 1.50-2.49 dL/g, Biolnvigor, Taipei, Taiwan) in dichloromethane onto a PDMS flat disk. The spin coating procedure was as follows: two coats of 5% w/v L-PLGA solution spun for 15 s at 1000 RPM and then 15 s at 2000 RPM. After spin coating, the samples were dried on a hotplate at 6O⁰C for 10 minutes and removed from the PDMS. All supports were cut into squares (10 x 10 mm) using a Sizzix die (Lake Forest, CA). The L-PLGA support was then conformally adhered to the PDMS layer (e.g., by non-specific interactions). A PDMS stamp comprising features in the form of dots (1 mm dots spaced 1 mm apart) fabricated as described above was used to transfer adhesive to one side of the support by contact adhesion. A cyanoacrylate adhesive formulation was used and was prepared by combining 94.3 vol% 2-octyl-cyanoacrylate (Chemence, Alpharetta, GA) with 5.5 vol% acetyl tributyl citrate, 50 ppm sulfuric acid, and 200 ppm acetic acid (Sigma, St. Louis, MO). When the stamp was brought in contact with the porcine skin tissue (dermis surface), the article adhered to the tissue; the transfer device was then moved away from the tissue surface (FIG. 26).

Example 23

Patterning of Composite Materials onto Tissue Surfaces

Transfer devices comprising a uniform layer of PDMS were fabricated as described in Example 1. Electrospun PLGA supports were prepared using a solution of PLGA (10 wt% in 5:1 by vol chloroform:methanol). The electrospinning setup included a syringe pump (KD Scientific, Holliston, MA), power supply (Gamma High Voltage Research, Ormond Beach, FL), and a square grounded copper plate (10 cm x 10 cm x 0.16 cm). A 10 mL syringe was filled with the polymer solution, and the syringe was then fitted with a blunt 18 gauge needle (Brico Medical Supplies, Inc, Metuchen, NJ). The positive lead from the power supply was attached to the needle. A copper plate located a distance of 17.5 cm from the end of the needle was grounded. During electrospinning, the solution was ejected through the needle at a flow rate of 8 mL/hr while a voltage of 14.5 kV was applied; the fibers were collected onto the grounded copper plate. After electrospinning for 3 minutes, nonwoven electrospun sheets were removed and dried overnight in a dessicator. Supports were cut into squares (10 x 10 mm) using a Sizzix die (Lake Forest, CA).

The L-PLGA electrospun support was then conformally adhered to the PDMS layer of the stamping device (e.g., by non-specific interactions). The fibrinogen and thrombin components (e.g., adhesive precursors) of the fibrin adhesive were prepared as described above. The fibrinogen component was stamped onto the L-PLGA support using a stamp having features in the form of a discontinuous, ordered array pattern (1 x 3 mm bands). Porcine skin was prepared by applying 10 μL of the thrombin component onto a 1 cm² area. The transfer device was used to deliver the article to the prepared tissue area by contact adhesion. When the stamp was brought in contact with the porcine skin tissue (dermis surface), the article adhered to the tissue; the transfer device was then moved away from the tissue (FIG. 27).

Example 24

Tissue Repair Using Discontinuous, Ordered Bands of Fibrin Adhesive

Electrospun L-PLGA supports were prepared as described above. Sections of the support were cut from larger pieces using an ASTM standard die cutter (ASTM D638) and scissors into pieces with dimensions of 10 mm by 3.18 mm. Dogbones of porcine skin (Brennen Medical, MN Mediskin Xenograft 1-188) were cut out using the ASTM die cutter. A full thickness incision was made through the center of the gage length. The fibrinogen and thrombin components of the fibrin adhesive were prepared as described above. The thrombin solution (10 μL) was spread across the entire gage length. A stamp having features in the form of a discontinuous, ordered array of bands was used to transfer the fibrinogen component to one side of the support using methods described in Examples 1-9. The incision was repaired by placing the article across the top of the incision with the adhesive side towards tissue (FIG. 33A). After 10 minutes at room temperature, the dogbones were loaded into the grips of an Instron tensile testing machine. The sample was loaded to failure at a constant cross-head speed of 5 mm/min. The load at failure was recorded, and maximum shear strength was calculated as the load at failure divided by the overlap area (31.8 mm²). The shear strength at failure (n=6) was 4 ± 2 kPa.

Example 25

Treatment of Pterygium: An In Vivo Application of Patterned Adhesives

Articles comprising adhesive patterned onto polymer supports were investigated for their potential in pterygium surgery. Pterygium is a fibrovascular wedge-shaped growth of conjunctiva believed to be associated with UV exposure. Symptoms may include irritation, redness, and tearing. While surgical removal is the most common treatment, there is a high incidence of recurrence. Using articles with patterned arrays of adhesive to seal the incised area has potential for reducing this recurrence rate. Three types of polymer supports were used: electrospun, microfabricated, and nonporous L-PLGA supports. Electrospun L-PLGA supports were fabricated as previously described. Microfabricated L-PLGA supports were prepared by spin coating a solution of 85:15 L-PLGA in dichloromethane onto a PDMS support comprising an array of 100 μm high posts 400 μm in diameter and spaced 500 μm apart. Spin coating was done in two steps: first 2.5% w/v L-PLGA solution was spun for 15 s at 1000 RPM, and then two coats of 5% w/v L-PLGA solution were spun for 5 s at 1000 RPM and 30 s at 2000 RPM. Non-porous L-PLGA supports were prepared by spin coating a solution of L-PLGA in dichloromethane onto a flat PDMS disk. The spin coating procedure was as follows: two coats of 5% w/v L-PLGA solution spun for 15 s at 1000 RPM and then 15 s at 2000 RPM. After spin coating, the samples were dried on a hotplate at 6O⁰C for 10 minutes and removed from the PDMS. All supports were cut into squares (10 x 10 mm) using a Sizzix die cutter (Lake Forest, CA) and then cut in half to give pieces 10 x 5 mm for implantation. Adhesive articles were fabricated by stamping these polymer supports with

Dermabond® (Ethicon) adhesive. Stamping was performed using a PDMS stamp which was fabricated as previously described. A stamp included an array comprising features in the form of 750 μm posts spaced 2 mm apart (overall dimensions of 10 mm x 5 mm).

Adhesive articles were then implanted in New Zealand white rabbits (Black Creek Rabbitry, McNeil, MS) by first excising a section of conjunctiva from the sclera. The article was implanted such that it covered the exposed sclera. To do so, animals were first randomly assigned to an experimental study group (group I - microfabricated L-PLGA, group II - nonporous L-PLGA, group III - electrospun L-PLGA). Rabbits were then anesthetized with a combination of ketamine and xylazine (50 mg/kg ketamine and 5 mg/kg xylazine) administered by intramuscular injection. One drop of proparacaine hydrochloride 0.5% ophthalmic solution was administered to each eye. When the rabbit did not respond to noxious stimuli (foot pinch and corneal stimulation), the eyelashes were taped down with Tegaderm (3M), and the eye proptosed for full exposure of the surgery site. Using sterile conjunctiva scissors and forceps, a section of conjunctiva (approximately 10 mm x 5 mm) was excised from the eye between the superior and lateral rectus muscles with the long axis parallel to the limbus. A total of eleven animals were used: three rabbits were used for each experimental group and two controls. The controls involved suturing the excised conjunctive back into place using 10-0 vicryl suture.

After implantation, the animals were monitored until they were fully awake. Animals were housed separately and given water and food ad lib throughout the study. A treatment of Vigamox (Alcon, Forth Worth, TX) was administered twice a day immediately after the surgery and continuing for 3 days, then once per day until the end of the study. After 28 days, animals were sacrificed. The animals were first anesthetized with a ketamine/xylazine mixture (50 mg ketamine/kg + 5 mg xylazine/kg) which was delivered intramuscularly, than euthanized with intravenous injection of 100 mg pentobarbital sodium/kg.

Examinations were made at 7, 14, and 28 days using a slit lamp biomicroscope, and pictures were taken of each operated eye. Inflammation was graded in a blinded manner on a 0-4 basis. After sacrifice, the explanted articles and surrounding tissues were placed in formalin for at least an hour. Afterwards, samples were dried in an ethanol gradient (70% to 100%), submerged in xylene, and then embedded in parrafin. Sections (5 μm) were cut using a microtome and stained using hematoxylin and eosin (H&E).

Example 26 Patterning of Composite Materials onto Tissue Surfaces Using a Spatula A double sided spatula transfer device was created by attaching two thin films of

PDMS (fabricated as described above) to both sides of a metal spatula using silicone adhesive. A 25 μm thick support of L-PLGA (fabricated as described above) was folded in the middle and conformally adhered to both PDMS layers. A PDMS stamp comprising a patterned array of dots (1 mm dots spaced 1 mm apart) fabricated as described above was used to print adhesive to both exposed sides of the support. A cyanoacrylate adhesive formulation was used and was prepared by combining 94.3 vol% 2-octyl-cyanoacrylate (Chemence, Alpharetta, GA) with 5.5 vol% acetyl tributyl citrate, 50 ppm sulfuric acid, and 200 ppm acetic acid (Sigma, St. Louis, MO).

A tissue pocket was simulated by folding the porcine skin in half. The spatula transfer device was inserted into the pocket to transfer the composite to the tissue (FIG. 30). The composite adhered to both sides of the tissue pocket, and the transfer device was retracted (e.g., moved away from the tissue).

Similarly, a single sided spatula transfer device was created by attaching a thin film of PDMS to one side of a metal spatula using silicone adhesive. Microfabricated L- PLGA supports were prepared by spin coating a solution of 85: 15 L-PLGA in dichloromethane onto a PDMS array including features comprising 100 μm high posts 400 μm in diameter spaced 500 μm apart (fabricated as described above). Spin coating was done in two steps: first 2.5% w/v L-PLGA solution was spun for 15 s at 1000 RPM, and then two coats of 5% w/v L-PLGA solution were spun for 5 s at 1000 RPM and 30 s at 2000 RPM. After spin coating, the samples were dried on a hotplate at 6O⁰C for 10 minutes and removed from the PDMS. All supports were cut into squares (10 x 10 mm) using a Sizzix die.

The 100 μm thick microfabricated support was conformally adhered to the transferring device. Cyanoacrylate was printed onto one of the exposed support surfaces as previously described. The transfer device was brought in contact with porcine skin. The composite was transferred to the tissue by contact adhesion, and the transfer device was retracted (FIG. 30).

Example 27 Discontinuous, Ordered Arrays to Join Porcine Skin Tissue

Non-porous L-PLGA supports were solvent cast as described previously. Sections with dimensions 5 mm by 3.18 mm were cut from larger pieces using a razor blade. Dogbones of porcine skin (Brennen Medical, MN Mediskin Xenograft 1-188) were cut out using an ASTM standard die cutter (ASTM D638, Northeast Cutting Die Company, Portsmouth, NH). A full thickness incision was made through the center of the gage length. A stamp having features comprising dots (1 mm dots spaced 0.5 mm apart) was used to transfer adhesive Fl to both sides of the PLGA support. The article was then placed between the two dogbones of porcine skin (lap shear configuration). Placement was such that the dermis side of the skin was in contact with the support, and the overlap area was 5 mm (FIG. 34A). After 10 minutes at room temperature, the dogbones were loaded into the grips of an Instron tensile testing machine (FIG. 34B).

The sample was loaded to failure at a constant cross-head speed of 5 mm/min). The load at failure was recorded, and maximum shear strength was calculated as the load at failure divided by the overlap area (15.9 mm²). The shear strength at failure (n=5) was 93 ± 48 kPa. The normalized shear strength was 310 ± 160 kPa/mg which was calculated by dividing the shear strength at failure by the mass of the adhesive used (0.3 mg). An article with a uniform application of adhesive (e.g., non-patterned adhesive) was used as a control and gave a normalized shear strength of 148 kPa/mg. This example shows, therefore, that an article comprising a patterned array of adhesive can withstand greater normalized shear than an article comprising a non-patterned adhesive.

Example 28

Discontinuous, Ordered Arrays (Bands & Channels) to Join Porcine Skin Tissue

Non-porous L-PLGA supports were solvent cast as described previously. Sections with dimensions 5 mm by 3.18 mm were cut from larger pieces using a razor blade. Dogbones of porcine skin were cut out using an ASTM standard die cutter (ASTM D638). The skin was placed with the dermis side up, and a full thickness incision was made through the center of the gage length. A stamp having features comprising bands (1 mm x 3 mm bands spaced 1 mm apart) was used to transfer adhesive Fl to one side of the PLGA support. The article was placed across the top of the incision (adhesive side down) to join the tissues in the configuration shown in FIG. 36A. Placement was such that the dermis side of the skin was in contact with the support, and the overlap area was 5 mm. After 10 minutes at room temperature, the dogbones were loaded into the grips of an Instron tensile testing machine (FIG. 36A). The sample was loaded to failure at a constant cross-head speed of 5 mm/min). The load at failure was recorded, and maximum shear strength was calculated as the load at failure divided by the overlap area (15.9 mm²). The shear strength at failure (n=5) was 73 ± 58 kPa.

Similarly, L-PLGA supports were fabricated with channels (1 mm x 3 mm spaced 1 mm apart) as described previously. The channels were filled with adhesive Fl using a pipet. The article was placed across the top of full thickness incisions in porcine skin dogbones (FIG. 36C). After 10 minutes, mechanical testing was performed as described above). The shear strength at failure (n=5) was 250 ± 60 kPa. Example 29 Extraction of Tissue from Porcine Skin Using Uniform Supports

In examples 29-32, two formulations of 2-octylcyanoacrylate adhesive were used. The first (Fl) was 2-octylcyanoacrylate (Chemence, Alpharetta, GA) used as received from manufacturer. The second formulation (F2) contained 2- octylcyanoacrylate with 20% w/v Pluronic F-127 (Sigma-Aldrich, St. Louis, MO), 2.5 mL of methanesulfonic acid per mL of 2-octylcyanoacrylate, and 0.5 mg of 2,6-Di-tert- butyl-4-methylphenol per mL of 2-octylcyanoacrylate. A blue dye, D & C Violet #2 (Spectrum, New Brunswick, NJ), 2 mg/mL, was added to both formulations to allow for visualization of the adhesives.

Polymer supports (~ 1 cm x 1 cm or ~ 1 cm x 0.5 cm, non-porous L-PLGA, electrospun L-PLGA, and PGS-acrylate) were dipped in the adhesive Fl, placed on the epidermis or dermis side of porcine skin, allowed to adhere for 10 min, and lifted with tweezers. After removal from tissue, the supports were fixed in 2.5 % gluteraldehyde for two hours and stained in solutions of hematoxylin (10 min) and eosin (10 min) (H&E). Control supports were prepared by dipping the polymers into the adhesive Fl and allowing the adhesive to polymerize in air for 24 hours. Control supports were stained in a procedure identical to that for supports on tissue. The resulting pink color on the sample supports (in contrast to the control supports) is indicative of tissue transfer.

Example 30

Extraction of Tissue from Epidermis Using Supports

To create patterned arrays of adhesive, the desired pattern was first created using Macromedia Freehand and then converted to an Autocad file. A master was created by machining the pattern into an aluminum block with features ~500 μm deep using a CNC milling machine. Poly(dimethyl siloxane) (PDMS) Sylgard 184 (Dow Corning) was then mixed according to manufacturer instructions, poured over the master, degassed under vacuum, and cured for 2 hours at 8O⁰C. After curing, the PDMS was peeled from the master, and PDMS stamps with the selected features were cut out and attached to handles using silicon adhesive. The outstanding features of the stamp were inked with adhesive F2, pressed against an electrospun L-PLGA support to transfer the adhesive in a pattern, and the support was placed on epidermis for 10 min. The support was stained as described above. The control support was prepared by stamping the adhesive with a stamp and allowing the adhesive to polymerize in air.

Example 31 Extraction of Tissue from Porcine Sclera Using Supports Conjuctiva of a porcine eye was dissected from the sclera, and an electrospun L-

PLGA support, dipped in adhesive Fl, was placed on the sclera for 3 minutes. The support was lifted from the sclera using tweezers, fixed in 2.5% gluteraldehyde for 2 hours, and stained with H&E as described above.

While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.

All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms. The indefinite articles "a" and "an," as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean "at least one.

It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

In the claims, as well as in the specification above, all transitional phrases such as

"comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and

"consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining

Procedures, Section 2111.03. What is claimed is:

Claims

1. A method of medically treating a tissue comprising: directing a transfer device to a tissue surface, the transfer device having associated therewith a patterned array of an adhesive; transferring at least a portion of the patterned array of adhesive from the transfer device to the tissue surface by contact adhesion; moving the transfer device away from the tissue surface; positioning an article to be adhered adjacent at least a portion of the adhesive; and adhering the article to the tissue surface using the adhesive.

2. A method as in claim 1, wherein contact adhesion comprises an adhesion strength between the adhesive and the tissue surface being greater than the adhesion strength between the adhesive and the transfer device.

3. A method as in claim 1, wherein contact adhesion comprises an adhesion strength between the adhesive and the tissue surface being greater than the cohesive forces of the adhesive.

4. A method as in claim 1 , wherein the patterned array of adhesive is adhered to the transfer device directly.

5. A method as in claim 1 , wherein the patterned array of adhesive is adhered to the transfer device indirectly via a support, the method further comprising transferring both the support and the adhesive from the transfer device to the tissue surface.

6. A method as in claim 1 , wherein the patterned array of adhesive is in the form of a liquid prior to the adhering step.

7. A method as in claim 1, wherein the article adhered to the tissue surface comprises a second tissue.

8. A method as in claim 1 , wherein the article adhered to the tissue surface comprises a muscle and/or a support.

9. A method as in claim 1 , wherein the transfer device comprises a set of surface features that is substantially similar to the pattern of adhesive.

10. A method as in claim 1, wherein the article to be adhered comprises a second tissue, the method further comprising positioning a biodegradable support over at least a portion of the second tissue.

11. A method as in claim 10, wherein the biodegradable support includes a patterned array of adhesive associated therewith.

12. A method of medically treating a tissue comprising: adhering an article comprising a support and a patterned array of an adhesive to a transfer device; transferring the article from the transfer device to a tissue surface by contact adhesion; and moving the transfer device away from the tissue surface.

13. A method as in claim 12, wherein the step of adhering comprises: providing the article on the support; and applying the patterned array of an adhesive onto the article while the article is on the support.

14. A method as in claim 12, wherein contact adhesion comprises an adhesion strength between the article and the tissue surface being greater than the adhesion strength between the article and the transfer device.

15. A method as in claim 12, wherein contact adhesion comprises an adhesion strength between the article and the tissue surface being greater than the cohesive forces of the adhesive.

16. A method as in claim 12, wherein the article adheres to the tissue surface to a first degree upon transfer, and to a second degree after being in contact with the tissue surface after at least 10 seconds.

17. A method as in claim 16, wherein the second degree of adhesion is greater than the first degree of adhesion.

18. A method as in claim 17, wherein the second degree of adhesion is caused at least in part by polymerization of the adhesive.

19. A method as in claim 17, wherein the second degree of adhesion is caused at least in part by applying energy to the adhesive.

20. A method as in claim 19, wherein the energy comprises light.

21. A method as in claim 12, wherein the patterned array of adhesive is positioned on a surface of the support facing the tissue surface.

22. A method as in claim 12, wherein the article further comprises an adhesive isolating material covering at least a portion of the adhesive.

23. A method as in claim 12, wherein the article further comprises an analgesic, an antibiotic, an anti-inflammatory, or a growth factor.

24. A method of medically treating a tissue comprising: forming a patterned array of an adhesive on a surface of an article by contact adhesion; positioning an article adjacent at least a portion of a tissue surface; and adhering the article to the tissue surface using the adhesive so as to immobilize the article with respect to the tissue surface within 1 minute after initial contact between the article and the tissue surface.

25. A method as in claim 24, wherein the forming step comprises directing a transfer device to the tissue surface, the transfer device having associated therewith a patterned array of an adhesive; and transferring at least a portion of the patterned array of adhesive from the transfer device to the surface of an article by contact adhesion.

26. A method as in claim 24, wherein the forming step comprises using the article as a stamp to form the patterned array of adhesive.

27. A method as in claim 24, wherein the article and the tissue surface have a shear strength between 0.1 kPa to 2 MPa after initial contact between the article and the tissue surface.

28. A method as in claim 24, wherein the adhesive comprises cyanoacrylate.

29. A method as in claim 24, wherein the positioning step comprises transferring the article from a transfer device to the tissue surface by contact adhesion.

30. A method as in claim 24, wherein the positioning step comprises the use of forceps.

31. A method as in claim 24, wherein immobilization occurs upon initial contact between the article and the tissue surface.

32. A method of medically treating a tissue comprising: positioning an article comprising an adhesive on a tissue surface; adhering the article to the tissue surface to a first degree; repositioning the article; and adhering the article to the tissue surface to a second degree, wherein the second degree is greater than the first degree.

33. A method as in claim 32, wherein the article is positioned on the tissue surface by contact adhesion.

34. A method as in claim 32, wherein the time between adhering the article to the first degree and adhering the article to the second degree is at least 10 seconds.

35. A method as in claim 32, wherein the first degree of adhesion has a shear strength that is less than about 100 kPa and the second degree of adhesion has a shear strength that is greater than the first degree of adhesion.

36. A method as in claim 32, wherein the second degree of adhesion is caused at least in part by polymerization of the adhesive.

37. A method as in claim 32, wherein the second degree of adhesion is caused at least in part by applying energy to the adhesive.

38. A method as in claim 37, wherein the energy comprises light.

39. A method as in claim 32, wherein a patterned array of adhesive is positioned on a surface of the support facing the tissue surface.

40. A method as in claim 32, wherein the article further comprises an adhesive isolating material covering at least a portion of the adhesive prior to the adhering steps.

41. A method as in claim 32, wherein the article further comprises an analgesic, an antibiotic, an anti-inflammatory, or a growth factor.

42. A method of medically treating a tissue comprising: contacting a tissue surface with a biocompatible material capable of forming or breaking adhesive or cohesive bonds; adhering at least a portion of the biocompatible material to the tissue surface; performing a medical act associated with or proximate the tissue surface; observing a response of the tissue while maintaining adhesion between the tissue surface and the portion of material; and adjusting the strength of adhesion between the tissue surface and the portion of material by forming or breaking adhesive or cohesive bonds in response to the observing step.

43. A method as in claim 42, wherein the performing step is performed before the contacting step.

44. A method as in claim 42, wherein adjusting the strength of adhesion between the tissue surface and the biocompatible material comprises forming adhesive or cohesive bonds.

45. A method as in claim 44, wherein the adhesion strength between the tissue surface and the biocompatible material before the adjusting step is measured as shear strength and has a value greater than about 100 kPa.

46. A method as in claim 42, wherein adjusting the strength of adhesion between the tissue surface and the biocompatible material comprises breaking adhesive or cohesive bonds.

47. A method as in claim 46, wherein the adhesion strength between the tissue surface and the biocompatible material after the adjusting step is measured as shear strength and has a value of less than about 100 kPa.

48. A method as in claim 42, wherein the biocompatible material comprises a patterned array of adhesive.

49. A method as in claim 42, wherein the biocompatible material includes a support and/or a tissue.

50. A method as in claim 42, wherein the observing step comprises observing overfiltration or underdrainage of an eye.

51. A method for treating an eye, comprising: providing an eye having a sclera and muscle tissue to be attached to the sclera; applying an adhesive to one of the sclera and the muscle tissue in an array including at least two non-contiguous regions of adhesive; and adhering the muscle tissue to the sclera using the adhesive array.

52. The method of claim 51, further comprising: adhering a support over a joint between the muscle tissue and the sclera.

53. The method of claim 51, wherein the step of applying an adhesive comprises: providing an adhesive stamp including a set of surface features that correspond to the array of adhesive applied to the sclera or muscle tissue.

54. The method of claim 53, wherein the step of applying an adhesive comprises: applying adhesive to the set of surface features on the adhesive stamp; and positioning the adhesive stamp relative to the sclera or muscle tissue so that at least some of the adhesive on the set of surface features is transferred to the sclera or muscle tissue.

55. The method of claim 54, wherein the set of surface features includes a set of raised circular areas spaced from each other in a row.

56. The method of claim 51, wherein the array includes a plurality of areas of adhesive arranged in a row.

57. The method of claim 56, wherein the areas of adhesive are about 0.75 mm in diameter and are spaced about 1.5 mm apart.

58. The method of claim 51, wherein the step of applying an adhesive comprises: applying the adhesive to the sclera.

59. The method of claim 51, wherein the step of adhering comprises: placing the muscle tissue and sclera into contact with the array of adhesive positioned between the muscle tissue and sclera.

60. The method of claim 59, further comprising: determining incorrect placement of the muscle tissue relative to the sclera has occurred; separating the muscle tissue and sclera at a location where the array of adhesive formerly adhered the muscle tissue and sclera together; performing the applying an adhesive and adhering steps again to adhere the muscle tissue to the sclera.

61. The method of claim 60, wherein the step of separating includes: pulling the muscle tissue and sclera apart.

62. The method of claim 51, further comprising: adhering a support over the muscle tissue and sclera, the support including adhesive on a side of the support that contacts the muscle tissue and sclera that adheres the support to the muscle tissue and sclera.

63. The method of claim 62, wherein the portion of muscle tissue is attached to the sclera via the array of adhesive and support so as to resist maximum forces normally experienced in the eye.

64. A kit for use in treatment of an eye, comprising: a support constructed and arranged to be adhered over a muscle tissue/sclera joint and help support the muscle tissue/sclera joint during a healing process; adhesive suitable for adhering the muscle tissue to the sclera; and an adhesive applicator including a set of surface features adapted to carry adhesive and deploy the adhesive at a tissue site in a suitable array.

65. The kit of claim 64, wherein the array includes a plurality of discrete areas of adhesive.

66. The kit of claim 65, wherein the array includes a plurality of discrete areas of adhesive arranged in a row.

67. The kit of claim 64, wherein the support includes an array of adhesive formed on a surface of the support.

68. The kit of claim 67, wherein the array of adhesive on the support includes a plurality of discrete, non-contiguous areas of adhesive.

69. An article adapted for medical applications comprising: a support; a patterned array of an adhesive applied to at least a portion of the support; and an adhesive isolating material covering at least a portion of the adhesive, wherein the adhesive isolating material is constructed and arranged to be deployed with the support and the adhesive at a tissue surface, to initially resist contact between a portion of the adhesive and the tissue surface, and to later allow contact between the portion of adhesive and the tissue surface.

70. An article as in claim 69, wherein the adhesive isolating material is adapted to biodegrade or dissolve while in contact with a portion of the tissue.

71. An article as in claim 69, wherein the adhesive isolating material is adapted to biodegrade or dissolve due to contact with the portion of tissue without the need of an auxiliary agent.

72. An article as in claim 69, wherein the adhesive isolating material is adapted to biodegrade or dissolve by external application of an auxiliary agent.

73. An article as in claim 69, wherein the auxiliary agent is light, heat, or a chemical reagent.

74. An article as in claim 69, wherein the patterned array of adhesive is bound by an adhesive boundary, and wherein at least 20% of the area within the adhesive boundary comprises a non-adhesive material.

75. An article as in claim 69, wherein the patterned array of adhesive is bound by an adhesive boundary, and wherein at least 40% of the area within the adhesive boundary comprises a non-adhesive material.

76. An article as in claim 69, wherein the patterned array of adhesive is bound by an adhesive boundary such that when taking a cross-section through the adhesive boundary, at least two adhesive regions are separated by a second region having a different adhesion strength relative to the tissue surface than the adhesion strength between each of the at least two adhesive portions and the tissue surface.

77. An article as in claim 76, wherein the difference in adhesion strength is at least 20%.

78. An article as in claim 76, wherein a length of the second region along the cross- section is at least 100 microns.

79. An article as in claim 69, wherein the patterned array of adhesive is bound by an adhesive boundary such that when taking a cross-section through the adhesive boundary, at least two adhesive regions are separated by a non-adhesive region within the adhesive boundary.

80. An article as in claim 69, wherein the patterned array of adhesive includes a plurality of discrete adhesive portions.

81. An article as in claim 69, wherein the patterned array of adhesive is one dimensionally anisotropic.

82. An article as in claim 69, wherein the adhesive isolating layer is adapted to resist contact between a portion of the adhesive and the tissue surface for at least 20 seconds after initial contact between the article and the tissue surface.

83. An article as in claim 69, wherein the article comprises an analgesic, an antibiotic, an anti-inflammatory, or a growth factor.

84. An article as in claim 69, wherein the patterned array of adhesive and adhesive isolating material is positioned on a first side of the support, and wherein a second adhesive and a second adhesive isolating material are positioned on a second side of the support.

85. An article adapted for medical applications comprising: a support; a first layer comprising a first biocompatible material positioned adjacent the support; and a second layer comprising a second biocompatible material adjacent at least a portion of the first layer, wherein at least one of the first and second layers is arranged in the form of a patterned array, wherein at least one of the first and second materials comprises an adhesive, and wherein at least one of the first and second materials is adapted to biodegrade, dissolve, or fracture while in contact with a tissue.

86. An article as in claim 85, further comprising a third layer positioned between the first layer and the support.

87. An article as in claim 86, wherein the third layer comprises an adhesive.

88. A method of medically treating a tissue, comprising: positioning an article comprising a support, an adhesive, and an adhesive isolating material adjacent a tissue surface; removing at least a portion of the adhesive isolating material, thereby exposing the tissue surface to at least a portion of the adhesive; and adhering the article to the tissue surface using the adhesive.

89. A method as in claim 88, wherein the step of positioning comprises: positioning the adhesive isolating material adjacent a tissue surface, and positioning the support and adhesive over the adhesive isolating material.

90. A method as in claim 88, wherein removing comprises dissolving, fracturing or biodegrading.

91. A method as in claim 88, wherein the support is positioned at the tissue surface using a transfer device, and wherein the support is transferred from the transfer device to the tissue by contact adhesion.

92. A method as in claim 88, wherein at least one of the adhesive and adhesive isolating material is in the form of a patterned array.

93. A method as in claim 88, wherein the adhesive is in the form of a patterned array.

94. A method as in claim 88, wherein the article includes a support and/or a tissue.

95. A method of retrieving material from tissue comprising:

directing an instrument to the surface of the tissue;

contacting the instrument with the surface of the tissue; and

withdrawing the instrument and material from the tissue, wherein the adherence of the material to the instrument is greater than the adherence of the material to the tissue.

96. A method of claim 95, wherein the step of contacting includes manipulating the instrument in a controlled manner.

97. A method of claim 96, wherein the controlled manner comprises controlling the contact time at which contact occurs and/or controlling the pressure at which contact occurs.

98. A method of claim 95, wherein the tissue is selected from the group consisting of eye, liver, spleen, pancreas, dura mater, vascular, lunienal, alimentary, gastrointestinal, dental, tendon, ligament, or tumor tissue.

99. A method of claim 95, wherein the instrument includes a support and adhesive applied to the support.

100. A method of claim 95, wherein the instrument is an expandable instrument.

101. A method of claim 100, wherein the non-expandable instrument is a spatula, needle, trephine, stamping device, swab, or a patch.

102. A device for the retrieval of material from tissue comprising an instrument wherein at least a portion of the surface of the instrument has been modified with an adhesive to adhere the material from the tissue, wherein adherence of the material to the instrument is greater than adherence to the tissue.

103. A device of claim 102, wherein the instrument is an expandable instrument.

104. A device of claim 102, wherein the instrument is a non-expandable instrument.

105. A device of claim 102, wherein the adhesive is a composite comprising a support and an adhesive material.