CA2202511A1 - Targeted delivery via biodegradable polymers - Google Patents
Targeted delivery via biodegradable polymersInfo
- Publication number
- CA2202511A1 CA2202511A1 CA002202511A CA2202511A CA2202511A1 CA 2202511 A1 CA2202511 A1 CA 2202511A1 CA 002202511 A CA002202511 A CA 002202511A CA 2202511 A CA2202511 A CA 2202511A CA 2202511 A1 CA2202511 A1 CA 2202511A1
- Authority
- CA
- Canada
- Prior art keywords
- microparticles
- biologically active
- active molecules
- molecules
- targeted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Delivery of bioactive molecules such as nucleic acid molecules encoding a protein can be significantly enhanced by immobilization of the bioactive molecule in a polymeric material adjacent to the cells where delivery is desired, where the bioactive molecule is encapsulated in a vehicle such as liposomes which facilitates transfer of the bioactive molecules into the targeted tissue. Targeting of the bioactive molecules can also be achieved by selection of an encapsulating medium of an appropriate size whereby the medium serves to deliver the molecules to a particular target. For example, encapsulation of nucleic acid molecules or biologically active proteins within biodegradable, biocompatible polymeric microparticles which are appropriately sized to infiltrate, but remain trapped within, the capillary beds and alveoli of the lungs can be used for targeted delivery to these regions of the body following administration to a patient by infusion or injection.
Description
CA 02202~ill 1997-04-11 WO 96~11671 PCT/IJS9~114103 T~ r.~T~n DELIVERY VIA ~ r~ .K~nz~F;r.r.~ POLYMERS
Background oi~ the Invention This invention is generally in the area of drug delivery and gene therapy devices and more specifically in the area of delivery of drugs and gene transfer via polymeric microparticles, including~ lipQsomes in a polymeric matrix.
A variety of :materials have been developed for dèlivery of drugs, nucleic acids, and biologics . ~ ~xamples include microspheres, microcapsules ~ and microparticles formed of biodegradable or non-biodegradable pol=ymers which release the incorporated material over time or following expQsure to specific conditions.
Targeting of the~ materials, other than through direct administration at the targeted site, has been very dif ficult . Most are administered systemically if multiple release sites are required .
~ More recently, polymeric geIs or films have been utilized for drug delivery and gene therapy, especially of small oligonucleotides such as antisense.- 3.iposomes have also been utilized for delivery of genetic material, with varying degrees~ of success, primarily due to theiuherent instability and short half-lives of the liposomes.
Gene therapy is typically used to refer to delivery of nucleic acid molecule~ which control eXpression of a particular endogenous gene, or to delivery and expression of an exogenous gene, which functions in a~dition~ to, or in place~of, a defective or missing endogenous gene.
Three methodologies have~been developed as the principal me~h~n~ for gene t~erapy-delivery via cationic lipids, for example, in the form of liposomes OI vesicles, molecular conjugatea, and recombinant viral vectors. These CA 02202~i11 l997-04-ll Wo 96/11671 PCT/US95114103
Background oi~ the Invention This invention is generally in the area of drug delivery and gene therapy devices and more specifically in the area of delivery of drugs and gene transfer via polymeric microparticles, including~ lipQsomes in a polymeric matrix.
A variety of :materials have been developed for dèlivery of drugs, nucleic acids, and biologics . ~ ~xamples include microspheres, microcapsules ~ and microparticles formed of biodegradable or non-biodegradable pol=ymers which release the incorporated material over time or following expQsure to specific conditions.
Targeting of the~ materials, other than through direct administration at the targeted site, has been very dif ficult . Most are administered systemically if multiple release sites are required .
~ More recently, polymeric geIs or films have been utilized for drug delivery and gene therapy, especially of small oligonucleotides such as antisense.- 3.iposomes have also been utilized for delivery of genetic material, with varying degrees~ of success, primarily due to theiuherent instability and short half-lives of the liposomes.
Gene therapy is typically used to refer to delivery of nucleic acid molecule~ which control eXpression of a particular endogenous gene, or to delivery and expression of an exogenous gene, which functions in a~dition~ to, or in place~of, a defective or missing endogenous gene.
Three methodologies have~been developed as the principal me~h~n~ for gene t~erapy-delivery via cationic lipids, for example, in the form of liposomes OI vesicles, molecular conjugatea, and recombinant viral vectors. These CA 02202~i11 l997-04-ll Wo 96/11671 PCT/US95114103
-2-methods were recently reViewed by Morgan, Ann. Rev.
Biochem., 62:191 (1993~, Mulligan, ~Science 260:926 (1993 ), and Tolstoshev, Ann . Rev . Pharm. Toxicol ., 32: 573 (1993 ) .
~ Altkough the three maj or: groups of gene transduction methodology are relatively efficient, the percentage of targeted cells that ~an be .~, transduced in vivo remains relatively low. To treat conditions requiring a higher percentage of ~
gene transduction, new technologies for increasing the percentage of transduced cells would be very usef ul .
Purthermore, it ~is very difficult to target cells for delivery of genes, other than through local administration or through selection of viral vectors which infect only ~certain types of celIs, such as replicating cells. Local delivery has advantages i~n that the effective locaI
concentration is much higher than can normally be achieve by systemic administration, while the systemic concentration remains very low, thereby avoiding serious side effects. There are ~few methods available~, however, which allow one to target scattered areas throughout the ~ody~ to achieve local release without systemic involvemen~=t.
The ability to express recombinant genes in the blood vessel wall has raised prospects for gene therapy of vascular disease. Two general approaches to introducing genes into the vessel wall have been studied. ~ :~n one aE~proach, referred to as direct gene_ transfer, target cells are first isolated and gene transfer is accomplished in vitro; cells that express the re~nmh~ t gene product are then selected and transplanted irlto the host vessel wall. In the second approach, genes are delivered ~ in si tu" to cells within the vessel wall; this direct, in vivo approach to delivery of CA 02202~i11 1997-04-11 Wo 96/11671 PCT/IJS95/14103 genes is attractive as a therapeutic modality since it mitigates the need to remove vascular cells from the -patient. Since direct gene transfer precludes the c~OL ~ ity to select for positive 5 transfectants, however, it is essential that an adequate amount of DNA be introduced ana expressed by the target tissue. Vascular smooth muscle cells may be suitable targets for the dIrect gene transfer approach because of their proximity to the l0 lumen surface a=nd abundance in-the vessel wall.
Furthermore, abnormal accumuIation of smooth muscle cells is a feature of atherosclerosis and of certain accelerated forms of vascular disease, such as restenosis following balloon angioplasty.
One potential means of transfecting smooth muscle cells within the vessel wall is through the use of cationic liposomes. Liposome-t~(l gene transfer is a convenient_method of transferring recombinant DNA into cells= and has 20 been used to directly transfect the arterial wall of live animals . The ef f iciency of successful gene transfer. using cationlc liposomes, however, is variable and highly dependent on the cell type.
Most in vi tro experience to date has b en with 25 t~nt i n~ us/immortal animal cells lines . The results studied using these types of cells, however, have uncertain implications for the 1 i kl-1 ih~)od success of direct arterial gene transfer in patients. ~ ~
Biochem., 62:191 (1993~, Mulligan, ~Science 260:926 (1993 ), and Tolstoshev, Ann . Rev . Pharm. Toxicol ., 32: 573 (1993 ) .
~ Altkough the three maj or: groups of gene transduction methodology are relatively efficient, the percentage of targeted cells that ~an be .~, transduced in vivo remains relatively low. To treat conditions requiring a higher percentage of ~
gene transduction, new technologies for increasing the percentage of transduced cells would be very usef ul .
Purthermore, it ~is very difficult to target cells for delivery of genes, other than through local administration or through selection of viral vectors which infect only ~certain types of celIs, such as replicating cells. Local delivery has advantages i~n that the effective locaI
concentration is much higher than can normally be achieve by systemic administration, while the systemic concentration remains very low, thereby avoiding serious side effects. There are ~few methods available~, however, which allow one to target scattered areas throughout the ~ody~ to achieve local release without systemic involvemen~=t.
The ability to express recombinant genes in the blood vessel wall has raised prospects for gene therapy of vascular disease. Two general approaches to introducing genes into the vessel wall have been studied. ~ :~n one aE~proach, referred to as direct gene_ transfer, target cells are first isolated and gene transfer is accomplished in vitro; cells that express the re~nmh~ t gene product are then selected and transplanted irlto the host vessel wall. In the second approach, genes are delivered ~ in si tu" to cells within the vessel wall; this direct, in vivo approach to delivery of CA 02202~i11 1997-04-11 Wo 96/11671 PCT/IJS95/14103 genes is attractive as a therapeutic modality since it mitigates the need to remove vascular cells from the -patient. Since direct gene transfer precludes the c~OL ~ ity to select for positive 5 transfectants, however, it is essential that an adequate amount of DNA be introduced ana expressed by the target tissue. Vascular smooth muscle cells may be suitable targets for the dIrect gene transfer approach because of their proximity to the l0 lumen surface a=nd abundance in-the vessel wall.
Furthermore, abnormal accumuIation of smooth muscle cells is a feature of atherosclerosis and of certain accelerated forms of vascular disease, such as restenosis following balloon angioplasty.
One potential means of transfecting smooth muscle cells within the vessel wall is through the use of cationic liposomes. Liposome-t~(l gene transfer is a convenient_method of transferring recombinant DNA into cells= and has 20 been used to directly transfect the arterial wall of live animals . The ef f iciency of successful gene transfer. using cationlc liposomes, however, is variable and highly dependent on the cell type.
Most in vi tro experience to date has b en with 25 t~nt i n~ us/immortal animal cells lines . The results studied using these types of cells, however, have uncertain implications for the 1 i kl-1 ih~)od success of direct arterial gene transfer in patients. ~ ~
3 0 ~ ~ ~ ~ocal delivery of growth f actors has been attempted in several ways. Takeshita, et al., J.
Clin. Invest., 93:662-670, (1994), delivered a bolus of a transforming vestor for the growth factor V13GF to rabbits. Unfortunately, delivery 35 was not limited to a local area. U.~S. Patent No.
5,238,470 Nabel et al discloses administering transforming ~vectors to~ arteries Yla a CA 02202~i11 1997-04-11 WO96/11671 PCTII~S9~114103
Clin. Invest., 93:662-670, (1994), delivered a bolus of a transforming vestor for the growth factor V13GF to rabbits. Unfortunately, delivery 35 was not limited to a local area. U.~S. Patent No.
5,238,470 Nabel et al discloses administering transforming ~vectors to~ arteries Yla a CA 02202~i11 1997-04-11 WO96/11671 PCTII~S9~114103
-4- ~
double-balloon catheter. A major limitation to :
this method is that the genetic material is admi}~istered all at once, resulting in inefficient tr~ l~; on. A further- limitation is that ~abel_
double-balloon catheter. A major limitation to :
this method is that the genetic material is admi}~istered all at once, resulting in inefficient tr~ l~; on. A further- limitation is that ~abel_
5 requires a substantial instillation time, approximately 30 minutes, resulting in prolonged arterial blockage. ~
There is therefQre a need for an improved, specif ic delivery means f or nucleic acid lO molecules and other drugs, or bioactive molecules.
It is therefore ~an object of the present invention to provide a IrLethod and means f or targeted delivery of bioactive molecules, especially nucleic acid molecules, to tissues or 15 cells in a patient.
It is a further object of the prèsent ~
invention to provide a delivery means that protect6 the bioactive molecules from proteases and nucleases.
It is still a further object of the present invention to provide a means f or locally administering bioactive m~olecules to tissues, or =
cells in a patient in a controlled, sustained manner .
.3ummary o the I~vention Delivery of bioactive molecules: such a~s nucleic acid molecules encoding a protein can be~
significantly enhanced by immobilization of the bioactive molecule in a polymeric material adj acent 3 0 to the cells where delivery is desired, where the bioactive molecule is encapsulated in a vehicle~
such as liposomes which facilitates transfer of the bioactive molecu~es into the targeted tissue.
Targeting of the bioactive molecules can also be achieved by selection of an encapsulating medium of an- d~ Liate size whereby the medium serves to CA 02202~i11 1997-04-11 Wo 96/11671 PCT/US~S/14103 deliver the molecules to a particular target. For example, encapsulation of nucleic acid molecules or biologically active proteins within biodegradable, biocompatible polymeric micropartlcles w_ich are 5 d~u~iate sized to infiltrate, but remain trapped within, the capillary beds and alveoli of the lungs can be used f or targeted dellvery to these regions of the body following administration to a patient by infusion or injection.
Examples demonstrate delivery of DNA via a polymeric gel and encapsulated within liposomes which are i h; l; zed in polymeric gel.
Immobilization of the DNA in the gel increases delivery approximately 300~ h; 1; 7~tion Df the 15 DNA in a penetration ~nh::nrr~r, such as liposomes, which are then i hi 1 i 7r~1 in the polymeric gel increases the delivery approximately 600 to 7009;.
This is measured based on luciferase -expressïon and detection of Turner ~ight units.
Detailed Description of the Invention Targeted, ~nh:qn~ l delivery of biologically ~a~ctive molecules is enhanced by the use of polymeric carriers for targeting of the molecules to specific areas. In one embodiment, the polymeric carrier is a hydrogel which serves to immobilize the bioactive molecules at the site of release. In another embodiment, the polymeric carrie~ is in: the form. of microparticles that are targeted by size and degradation and release properties to ~particular regions of the body, especially the alveDli and capillaries.
Polymeria Carriers Selection of PolYmeric Material Polymeric carriers must be biodegradable, sufficiently porous to permit efflux of the biologically active molecules, and sufficiently WO 96/11671 PCI;'IJS95/14103 -- 6 -- =
non-infli tory and biocompatible so that inf lammatory responses do not prevent the delivery of the biologlcally active molecules to the tis6ue.
It iB advantageous if the carrier also provides at least partial protection of the biologically active molecules f rom adverse ef f ects of proteases and nucleases. In addition, it is advantageous if controlled, sustained de=livery can be obtained using the polymeric carriers.
~ Many polymers can be utilized to orm tke carrier, which can be a hydrogel, organogel, film, or microparticle. Microparticles include microspheres, microcapsules, and, as used herein, liposomes, which can be further encapsulated within a polymeric matrix. The polymeric matrix serves to immobilize the microparticles at a particular site, enhancing targeted delivery of the encapsulated biolosically active molecules.
Suitable polyme~s that can be used include soluble and insoluble, biodegradable and ~
nonbiodegradable polymers. These can be hydrogeIs or thermoplastics, homopolymers, copolymers cr blends, natural or synthetic.
Rapidly bioerodible polymers such as poly[lactide-co=glycolide~, polyanhydrides, and polyorthoesters, whose carboxylic groups are-exposed on the .~ ~ni~l surface as their smooth surace erodes, are excellent candidates f or drug delivery systems. In addition, polymers containing labile bonds, such as polyanhydrides and polyesters, are well known for their hydrolytic reactivity. ~heir hydroIytic desradation rates can generally be altered by simple changes in- the polymer backbone. ~ ~
~ Representative natural polymers include proteins, such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and -CA 02202~ill 1997-04-11 ---7 ~
polysaccharides, such as cellulose, dextràns, E~olyhyaluronic acid, polymers of acrylic and methacrylic esters and alginic acid.
Representative synthetic polymers= include 5 polyphosrh~71rf~c, poly(vinyl alcohols), polyamides, polycarbpnates, polyalkylenes, po~yacrylamides, polyalkylene glycols, polyalkylené oxides, polyalkylene terf~rhth~l Al-~'l, polyvinyl ethers, polyvinyl esters, polyvinyl halides, 10 polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof. Synthetically modified natur=al polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and 15 nitrocelluloses. Other polymers of interest~
include, but are not limited to,~ methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, h~dL~ y~L~l methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, celIulose propionate, 2 0 cellulose ace~ate butyrate, cellulose acetate E'hthalate, carboxymethyl cellulose, ce3 lulose triacetate, cellulose sulf ate sodium salt~, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), 25 E1oly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly ( lauryl methacrylate), poly (pheny methacrylate), poly (methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), 30 poly (octadecyl acrylate) polyethylene, ~
polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene ter~rh~h~l~te), poly(vinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, and polyvinylphenol.
35 Representative bioerodible polymers include polylactides, polyglycolides and copolymers thereof , poly (ethylene terephthalate), poly (butic -CA 02202~11 1997-04-11 -acid), poly (valeric acid), poly (lactide-co-caprolactone), poly [làctide-co-glycolide], polyai~hydrides, polyorthoesters, blends and ~ ~
copolymers thereof.
5: These polymers can be obtained f rom sources such as Sigma Chemical Co ., St Louis , MO ., Polysciences, Warrenton, PA, Aldrich, Milwaukee, WI, Fluka, Rnnknnknm-, NY, and BioRad, Richmond, ~
CA. or else synthesized from monomers obtained from lO these suppliers using standard techniques.
Suitable pQlymer- compositions preferabIy have intrinsic and ~nntrol 1 ~3ble biodegradability, so that they persist for about a wçek to about six months; are non-toxic, cnnti~;ning no significant 15 : toxic monomers and degrading into non-toxic components; are biocompatible; are chemically compatible with the substances to be delivered, and tend not to açnature the active substance; are ~-sufficiently porous to allow the incorporation of 20 biologically active molecules and their subsequent liberation from the polymer by diffusion, erosion or a combination thereof; are able to..remain at the site of application by adherehce or by geometric factors, such as by being formed in place or ~
25 softened and subsequently molded or formed into microparticles which are trappçd at a desired location; are capable of being delivered by techniques of minimum invasivity, such as by catheter, laparoscope or endoscope.~ ~ypes of 3 0 monomers, macromers, and polymers that can be used are described in more detail below.
~ydrogels Hydrogels are preferred~embodiments for application to a tissue for direct delivery since 35 they intrinsically have most of these desirable ~
propertiçs. Particularly preferred are gels which are composed pr,-tln~nin~ntly of polyethylene glycol.
CA 02202~ill l997-04-ll These can be applied by direct photopolymerization with an initiator, by chemical polymerization with a peroxygen, or by "interfdcial"
photopolymerization, with a dye adsorbed to the 5 ~issue to be coated, as described below.
Examples of these macromers are:- PEG-oligolactyl-acrylates, as described by ~iii-West, et al., Proc. Natl. Acad. Sci. USA 91:5967-5971, 1994; Obst. & Gynecol. 83:59-64, i~994. The choice 10 of d~Lu~Liate end caps permits rapid ~ =
photopolymerization and gelation; acrylates can be polyrnerized using several initiati~ng systems, e.g., an eosin dye, by brief exposure to ultraviolet or visible light.~ Poly (ethyleneglycol) or a~ PEG
15 central structural unlt ~ (core) is useful on the basis of its high hydrophilicity ana water=
solubility, ~ om~n i ed by excellent biocompatibility. A short poly (~-hydroxy acid), such as polyglycolic acid, is a preferred chain 20 extension because it rapidly degrades by hydrolysis of the ester linkage Into glycolic acid, a harmless metabolite. = Although highly crystalline polyglycolic acid is insoluble in water and most common organic solvents, the entire macromer is 25 water-soluble and can be rapidly gelled into a biodegradable network while in contact with aqueous tissue fluids. Such networks can be used to entrap and homogeneously disperse water-soluble drugs and enzymes an-d to deliver them at a controlled rate.
30 Other preferred chain extensions are polylactic acid, polycaprolactone, polyorthoesters, ana polyanhydrides. Polypeptides may a~so ~be used.
These materials are particularly useful for controlled delivery, especialIy of hydrophilic 35 materials, since the water aoluble regions of the polymer enable access of water to the r-tf~ri ;~l entrapped within the polymer. Moreover, it is ~ =
CA 02202~i11 1997-04-11 pos6ible to polymeri2e the macromer ~nn~i~in;n~ the material to be entrapped without~exposing the material to organic solvents. Release may occur by diffusion of the material from the polymer prior to 5 degradation and/or by dif fusion of the material from the polymer as it degrades, depending upon the characteristic pore sizes within thq polymer, which is controlled by the molecular weight between crosslinks and the crgsslink density. Deactivation lO of the entrapped material is reduced d~ue to the ;~rn~hil;7;n~ and protective effect of the gel and catastrophic burst effects associated with other controlled-release systems are avoided. When the entrapped material is an enzyme, the enzyme can be 15 exposed to substrate while the enzyme is entrapped, provided the gel proportions are chosen to~allow _ the substrate to permeate the gel. ~ Degradation of the polymer facilitates eventual controlled=~elease of free macromolecules in vivo by gradual 20 hydrolysis of the terminal ester linkages.
An advantage of these ~acrQmers are~ that they can be polymerized rapidly in an ~aqueous surrounding. Precisely conforming, semi-permeable, biodegradable f ilms or membranes can thus be f ormed 25 on tissue in=situ to serve as biodegradable barriers, as carriers for 1 iYing cells or ~other~
biologically active materials, and as surgical adhesives~. In a particularly preferred embodiment, the macromers are applied to tissue having a 3 0 ~ photoinitiator bound thereto, and polymerized to form= an ultrathin coating. This is especially useful in forming coatings on the inside of_t,issue lumens such as blood vessels where th~re is a concern regarding restenosis, and in forming tissue 35 ` barriers during surgery which thereby prevent adhesions from forming.
CA 02202~11 1997-04-11 In gene~ral terms, the macromers are:
polymers that are soluble in aqueous s~lutions, or nearly aqueous solutions, such as water with added dimethylsulfoxide. They have three components including a biodegradable regiont=preferably hydrolyzable under in vivo conditions, a water solubl~ region, and at least two photopolymerizable regions. The term "at least suhst~nt~lly water soluble" is indicative that-the sorubility should be at least about 5 g/lOO ml of aqueous solution.
The term ~polymerizable" means that the regions have the capacity to f orm additional covalent bonds resulting in macromer interlinking, for example, carbon-carbon double bonds of acrylate-type molecules. Such polymerization is characteristically initiated by free=radical formation resulting from photon absorption of certain dyes and chemical compounds to ultimately produce f ree - radi c a 1 s .
In a preferred l~mhn~imt~nt, a hydrogel is formed from a biodegradable, polymerizable, macromer ;nrll~lln~ a core, an extension on each end of the core, and an end cap on each extension. The core is a hydrophilic polymer or ~ oligomer; each extengion is a biodegradable oligomer; and each end cap is an oligomer, dimer or- monomer=capable of cross-linking the macromers. ~ In a particularly preferred embodiment, the core ;nrl~ hydrophilic poly (ethylene glycol~ olïgomers of ~molecular weight between about 400 and 30,000 Da; each t~ttnqi~n includes biodegradable poly (~-hydroxy acid) oligomers of molecular weight between about 200 and 12 0 0 Da, and each end cap includes an acrylate- type monomer or oligomer (i.e., r~nt~in;n~ carbon-carbon double bonds) of molecular weight between about 50 and 200 Da which are capable of cross-linking and polymerization between copolymers. More CA 02202~i11 1997-04-11 Wo 96/11671 PCT/lJ59~/14103 -12~
specifically, a preferred embodiment incorporates a core cousisti~g of poly (ethylene glycol) Qligomers of molecular weight about 10,000 Da; ,-~t,-~.c;~ns consisting of poly (glycolic acid) oligomers of 5 molecular weight about 250 Da; and end caps-consisting acrylate moieties of about 100 Da molecular weight.
Examples of sui:table materials for 4se as the core water soluble region are poly (ethylene 10 glycol), poly(ethylene oxide), poly(vinyl alcohol), poly (vinylpyrrolidone), poly (ethyloxazoline), poly ( ethylene oxide ) - co -po1y (propyle~eoxide) block copolymers, polysaccharides or carbohydrates such as hyaluronic acid, dextran, heparin sulfate, 15 chondroitin sulfate, heparin, or alginate, or proteins such as gelatinl collagen, albumin, or ovalbumin .
siodegradable regions can be constructed from polymers or monomers using linkages 20 susceptible to biodegradation, such as ester, peptide, anhydride, orthoester, and phosphoester ~
bQnds .
Examples of biodegradable components which are hydrolyzable are polymers and oligomers 2~ of glycolide, lactide, ~-caprolactone, other u- -hydroxy acids, and other biologically degr~dable pQlymers that yield materials that are non-toxic or .
present as normal metabolites in the body.
Preferred poly (u-hydroxy acid~ s are poly (glycolic 30 acid), poly(DL-lactic acid) and poly(L-lactic acid) . Other useful materials include poly ~aminQ
acids), poly(anhydrides), poly(orthoesters), and poly (phosphoesters) . Polylactones such as poly ( e -caprolactone), poly ( ~ - caprolactone), poly ( ~ -35 valerolactone) ana poly(gamma-butyrolactone), for example, are also useiul.
CA 02202~i11 1997-04-11 Wo 96111671 PCT/lJS95/14103 The polymerizable regions are pre~erably polymerized using free ~adicals generated by a photoinitiator. The photoinitiator preferably uses the vlsible or long wavelength 5 ultraviolet radiation. Preferred polymerizàble regions are acrylates, diacrylates, oligoacrylates, dimethacrylates, oligomethoacrylates, or other biologically acceptable photopolymerizable groups.
A preferre~ tertiary amine is triethanol amine.
Useful photoinitiators are those- which initiate free radical polymerization of the macromers without -cytotoxicity and within a short time frame, minutes at most and preferably seconds.
Preferred initiators for initiation using long 15 wavelength ultraviolet photoradiation are ethyl eosin, 2,2-dimethoxy-2-phenyl acetophenone, other~
acetophenone derivatives, and camphorquinone. In all cases, crosslinking and polymerization are initiated among copolymers by a light-activated 20 free-radical polymerization initiator such as 2,2-dimethoxy-2-phenylacetophenone or a combination of ethyl eosin (lO-4-lO-2 mM) and triethanol amine (O.OOl to O.l M), for example.
In another embodiment, the process is 25 carried out by providing a material that is conformable, at least temporarily, at body temperature, yet which may be rendered non-conformable u~on completion of the deposition -- ~ =
process, such as a poloxamer~q (a polyethylene 30 oxide-poIyethylene glycol block copolymer) .
Poloxamer~ can be selected which are=liquid at room temperature and solid ~at body temperature.
Pavings or Fi~
In other embodiments, such as that 35 ~ described in U.S. Patent No. 5,231,580 to Slepian, polymeric pavings or f ilms are ap~lied to the tis~ue using a catheter, endoscope~or laparoscope.
CA 02202~11 1997-04-11 = = = = =
--14-- ~ ~-- ~
Preferred polymers include polyhydroxy acids such as polylactic acid, polyglycolic acid and copolymers thereof, polycaprolactone, polyanhydrides, polyorthoesters, and other 5 materials commonly used for implantation or sutures .
The basic xequixements for the material to be used ir the process are biocompatibility and the capacity to be chemically or physically 10 reconfigured under conditions which can be achieved ill vivo. Such reconfiguration conditions preferably involve photopolymerization, but can involve heating, cooling, ~mechanical deformation~ ~
(æuch as stretching), or c:hemioal reaotions s,uch as 15 ~ polymerizatiQn or cxoaslinking.
In their cor,formable state, =the coating materials may exhibit a wide variety of forms.
They can be present as polymers, monomers, macromers or combinations thereof, r~int~;ned as0 solutions, suspensions, or dispersions.
~icroparticles In a pref erred embodiment, the microparticle has a .li i ~t~r which is selected tQ
lodge in particular re~ions of ~the body. Use of 25 micxospheres that lodge w:ithin organs or reglons is known in studies of blood flow (Flaim et al, J
Pharmacol. Meth. 11:1-39, lsB4; Xeymann et al, Prog. Cardiovasc. Dis. 20:55--79, 1977), but not in delivery of active materials. For example, a 30 microparticle selected to lodge in a~ capillary will typically have a diameter of between lo tD 25, m-ost pref erably 15 to 2 o microns . Numerous methods are known for preparing microparticles of any particular size range. In the various applicati~ons 35 of the present invention, the sizes may range from 0 . 2 micron up to 100 microns . Synthetic methods for g-el microparticles, or for microparticles from CA 02202~ill l997-04-ll WO 96/11671 PCT/US9~/14103 molten materials, are known, and include ~:~
polymerization in~emulsion, in sprayed drops, and in separated=phases. For solid~~materials or preformed gels, known methods include wet or dry 5 milling or grinding, pulverization, classification by air j et or sieve, and the like .
Microparticles can be fabricated from different porymers using a variety of different methods known to those skllled in~ the art .
10 ExempIary methods include those set forth below.
Polylactic acid blank mïcroparticles were fabricated using three methods: solvent evaFQration, as described by E. Mathiowitz, et al., J. Scanninq Microsco~Y, 4, 329 (19gO)~; L.R. Beck, et al., Fertil. Steril., 31, 545 (1979); and S.
Benita, et al., J. Pharm. Sci., 73, 1721 (1984);
hot-melt microencapsulation, as described by E.
Mathiowitz, et al., Reactive Polvmers, 6, 275 (1987); and spray drying. Polyanhydrides made of 20 bis-carboxyphenoxypropane and sebacic acid with molar ratio of 20:80 P(CPP-SA) (20:80) (Mw 20,000) were prepared by hot-melt microencapsulation.
Poly(fumaric-co-sebacic? (20:80) (Mw 15,000) blank microparticles were prepared by hot-melt 25 microencapsulation. Polystyrene microparticles were prepared by solvent evaporation.
Hydrogel microparticles were prepared by dripping a polymer solution from a reserYoir though microdroplet forming device intQ a~: stirred ionic 30 bath. ~he specific cQnditions for alginate, chitosan, alginate/polyethylenimide (PEI) and carboxymethyl cellulose (C~[C) are llsted in Table 1.
a. Solvent Eva~oration. In this method 35 the polymer is dissolved in a volatile organic solvent, such as methylene chloride. ~:Che drug (either so~uble or dispersed as fine particles) is CA 02202~i11 1997-04-11 WO 96/11671 PCT/USgS114103 -external surf aces o~ spheres prepared with this technique are_usually smooth and dense. This procedure is used to prepare microparticles made of polyesters and polyanhydrides. However, this method is limited to polymers with molecular -weights between 1000-50, 000.
c. Solvent ~emoval. This technique is primarily designed for po~anhydrides. In this method, the drug is dispersed or dissolved-in a solution of the selected polymer in a vola~ile organic solvent like methylene chloride. This mixture is suspended by stirring in an organic oil (such as silicon oil) to~ orm an emulsion. = Unlike solvent evaporation, this method can be used to make microparticles from polymers with high melting points and different molecular weights.
Microparticles that rang=e~between 1-300 microns can be obtained by this procedure . The ~ rn ~
morphology of spheres produced with this technique is highly dependent on the type o~ polymer used.
d.~ S~rav-Dryinq In this method, the polymer is dissolved in methylene chloride_ ( 0 . o4:
g~mL) . A known amount of the active drug is suspended (insoluble drugs) or co-dissolved ~ _ (soluble drugs) in the polymer solution. ~he solution or the dispersion is then ~pray-dried. ~
Typical process Farameters for a mini-spray drier (Buchi) ara as followE: polymer concentration =
0.04 g/mL, lnlet temperature = -24C,~outlet te~perature = 13-15 C, aspirator setting = 15, pump setting~ = 10 mL/minute, spray flow = =600 Nl/hr, and nozzle diameter = 0.5 ~n.
Microparticles ranging between 1-10 microns are obtained with a morphology which depends on the type of polymer used. This method is primarily used for preparing microparticles designed to improve imaging of the intestinal tract, since for CA 02202~ill l997-04-ll -added to the solution, and the mixture is suspended in an aq~leous solution that contains a surface active agent such as poly (vinyl alcohol) . The resulting emulsion is stirred until most of the organic solvent evaporat d, leaving solid microparticles. Several different polymer concentrations were used: 0.05-0.20 ~/ml. The solution is loaaed with a drug and s~lqp~nrl~rl in 200 ml of vigorously stirred distilled water rrn~inlnr 1~; (w/v) poly(vinyl alcohol) (Sigma) After ~
hours of stirring, the organic solYent evaporates from the polymer, and the resultinr microparticles are washed with water and dried overnight in a lyophilizer. Microparticles with different sizes (l-1000 mIcrons) and morphblogies~can be obtained by this method. This method is useful for - -relatively stable polyme=rs like polyesters and polystyrene.
However, labile polymers, such as polyanhydrides, may degrade during the fabrication process due to the presence Qf water_ For these polymers, the following two methods, which are performed in completely anhydrous: organic solvents, are more useful.
=~ b. Eot Melt Microenca~sulation. In this method, the polymer is first melted and then mixed with the solid particles of dye or drug tE~at have:
been sieved to less than 50 microns. The mixture is suspended in a non-miscible solvent (like silicon oll), ana, with continuous stirring, heated to 5C
above the melting point of the pQlymer Once the emulsion is stabilized, it is cooled until the polymer particles solidify . The r~q~ i nr microparticles are washed by decantation wïth petroleum ether to give a free-flowing powder.
Microparticles with sizes between one to 100Q
microns are obtained with this method. The ~ = =
CA 02202~ill 1997-04-11 Wo 96111671 PcrllJS9S/14103 this application, particle size should not exceed 10 Il.
e. HYdroqel Microparticles.
Microparticles made. of gel-type polymers, such as ~-5 alginate, are produced ehrough trA~1t;~n~1 ionic .gelation techniques . The polymers are f irst dissolved in an aqueous solution, mixed with barium sulfate or some bioactive agent, and then extruded through a microdroplet forming device, which in 10 some instances employs a flow of nitrogen gas to ~:
break off the droplet ~~ s-lowly stirred (approximately 100-170 RPM) ionic hardening bath is positioned below the extruding de~ice to catch the forming microdroplets. ~ The microparticles are left 15 to incubate in the bath for twenty to thirty minutes in order tQ allow sufficient time for ~
gelation to occur. Microparticle particle size is controlled by using various size extruders or varying either the nitrogen gas~or polymer solution 20 flow rates The`matrix is preferably in the form of a microparticle such as a miçrosphere (where ~the biologically active molecules are dispersed throughout a solid polymeric matrix) or 25 microcapsule (where the biologically active molecules are encapsulated in the core of a polymeric shelll The size and composition of the polymeric device is selected to result in favorable release kinetics in tissue. The size is also 3 0 selected according to the method c-f delivery which is to be used, typically inj ection into .a tissue or administration of a suspension by aerosol into the nasal and/or pulmonary areas, and where d~L~Liate, entrapment at the site where release 35 is desired The matrix composition can be selected to not only have f avorable= deqradation rates, but to be formed of a material which is bioadhesive, to CA 02202~ill l997-04-ll --19-- =
further increase the effectiveness of transfer when administered to a mucosal surface,-- or selected not to degrade in=itially but to release by diffusion over an extended period. ~ =~
5 ~ ~ Liposomes are available commercially from a variety of suppliers. Alternatively, liposomes can be prepared according to methods known to those skilled in the art, for example, as descrïbed in U. S . Patent No . 4, 522, 811 (which is incorporated 10 here~n by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid (s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) 15 in an inorganic solvent that ~is th~en evaporated, leaving behind a thin film of dried lipid on the surface of the cnnt~inl~r. An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives are 20 then introduçed into the cnntAin~-r~ The container is then swirled by hand to free lipid material from the sides of the cnnt;lin~r-and to disperse lipid aggregates, thereby forming the liposomal suspension. ~ :
~ siologically Active Molecules Biologically active molecules whiçh can be incorporated into the polymeric carrier, directly and/or indirectly, i . e ., within microparticles which are immobilized in the carrier,~ include proteins, nucleic acid molecules, carbohydrates, lipids, and combinations thereof.
Examples of Froteins include cytokines such as interferons and interleukins, poetins, and colony stimulating factors,= growth factors, angiogenic factors and fragments thereof. ExampIes of nucleic acid molecules include genes~and cD~As CA 02202~11 1997-04-11 Wo 96/1167~ PCTIUS9~/14103 Pn~o~in~ proteins, expression vectors, antisense and other oligonucleotides such as ribozymes which can be used to regulate or=prevent gene expression.
Carbohydratçs include Sialyl LewisX which has been 5 shown to bind to :receptors ~for selectins to inhibit inf lammation . Growth f actors in the broad sense are preferred biologically activ-e molecules_ A
~ de l iver abl e growt h f a c to r equ iva lerlt " ( abbrevi at ed DGFE) is a growth factor for a cell,or tissue, 10 broadly construed, including growth factors, cytokines, interf erons, interleukins, proteins, colony-stimulating factors, gibberellins, auxins, and vitamins; further including peptide fragments or other active fragments of the above- and further 15 including vectors , i . e ., nucleic acid cQnstructs =
capable of synthesizing suoh factors in the target cells, whether by transformation or transient ~
expression; and further including effectors which stimulate or depress the synthesis~ ~f such factors 20 in the tissue, including natural signal molecules, antisense and triplex nucleic acids, and the like.
Particularly preferred DGFE' s are vascular endothelial growth factor ~(VEGF), Pn~nthPl i ~l cell growth factor (ECGF), basic fibroblast growth 25 actQr (bFGF), bone morphogenetic protein (BMP), and platelet derived growth factor~ (PDGF), and DNA' s encoding for them. Preferred clot dissolving agents are tissue pl ~cm;nff~en activator, streptokinase, urokinase and heparin.
IncG ~OI ~tion o~ B;r~o5ir:ll1y Active ~olecules into the Polymeric Carriers Generally, the biologically active molecules arç mixed with the pQlymer at the time the ~tPr; ~l is either polymerized or when the polymer is formed into a microparticle or lip;osome, in a concentration which will release an effective amount at the targeted site in a patient. Fqr -~
çxample, in the case of a hydrogel, the macromer, CA 02202~ill 1997-04-11
There is therefQre a need for an improved, specif ic delivery means f or nucleic acid lO molecules and other drugs, or bioactive molecules.
It is therefore ~an object of the present invention to provide a IrLethod and means f or targeted delivery of bioactive molecules, especially nucleic acid molecules, to tissues or 15 cells in a patient.
It is a further object of the prèsent ~
invention to provide a delivery means that protect6 the bioactive molecules from proteases and nucleases.
It is still a further object of the present invention to provide a means f or locally administering bioactive m~olecules to tissues, or =
cells in a patient in a controlled, sustained manner .
.3ummary o the I~vention Delivery of bioactive molecules: such a~s nucleic acid molecules encoding a protein can be~
significantly enhanced by immobilization of the bioactive molecule in a polymeric material adj acent 3 0 to the cells where delivery is desired, where the bioactive molecule is encapsulated in a vehicle~
such as liposomes which facilitates transfer of the bioactive molecu~es into the targeted tissue.
Targeting of the bioactive molecules can also be achieved by selection of an encapsulating medium of an- d~ Liate size whereby the medium serves to CA 02202~i11 1997-04-11 Wo 96/11671 PCT/US~S/14103 deliver the molecules to a particular target. For example, encapsulation of nucleic acid molecules or biologically active proteins within biodegradable, biocompatible polymeric micropartlcles w_ich are 5 d~u~iate sized to infiltrate, but remain trapped within, the capillary beds and alveoli of the lungs can be used f or targeted dellvery to these regions of the body following administration to a patient by infusion or injection.
Examples demonstrate delivery of DNA via a polymeric gel and encapsulated within liposomes which are i h; l; zed in polymeric gel.
Immobilization of the DNA in the gel increases delivery approximately 300~ h; 1; 7~tion Df the 15 DNA in a penetration ~nh::nrr~r, such as liposomes, which are then i hi 1 i 7r~1 in the polymeric gel increases the delivery approximately 600 to 7009;.
This is measured based on luciferase -expressïon and detection of Turner ~ight units.
Detailed Description of the Invention Targeted, ~nh:qn~ l delivery of biologically ~a~ctive molecules is enhanced by the use of polymeric carriers for targeting of the molecules to specific areas. In one embodiment, the polymeric carrier is a hydrogel which serves to immobilize the bioactive molecules at the site of release. In another embodiment, the polymeric carrie~ is in: the form. of microparticles that are targeted by size and degradation and release properties to ~particular regions of the body, especially the alveDli and capillaries.
Polymeria Carriers Selection of PolYmeric Material Polymeric carriers must be biodegradable, sufficiently porous to permit efflux of the biologically active molecules, and sufficiently WO 96/11671 PCI;'IJS95/14103 -- 6 -- =
non-infli tory and biocompatible so that inf lammatory responses do not prevent the delivery of the biologlcally active molecules to the tis6ue.
It iB advantageous if the carrier also provides at least partial protection of the biologically active molecules f rom adverse ef f ects of proteases and nucleases. In addition, it is advantageous if controlled, sustained de=livery can be obtained using the polymeric carriers.
~ Many polymers can be utilized to orm tke carrier, which can be a hydrogel, organogel, film, or microparticle. Microparticles include microspheres, microcapsules, and, as used herein, liposomes, which can be further encapsulated within a polymeric matrix. The polymeric matrix serves to immobilize the microparticles at a particular site, enhancing targeted delivery of the encapsulated biolosically active molecules.
Suitable polyme~s that can be used include soluble and insoluble, biodegradable and ~
nonbiodegradable polymers. These can be hydrogeIs or thermoplastics, homopolymers, copolymers cr blends, natural or synthetic.
Rapidly bioerodible polymers such as poly[lactide-co=glycolide~, polyanhydrides, and polyorthoesters, whose carboxylic groups are-exposed on the .~ ~ni~l surface as their smooth surace erodes, are excellent candidates f or drug delivery systems. In addition, polymers containing labile bonds, such as polyanhydrides and polyesters, are well known for their hydrolytic reactivity. ~heir hydroIytic desradation rates can generally be altered by simple changes in- the polymer backbone. ~ ~
~ Representative natural polymers include proteins, such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and -CA 02202~ill 1997-04-11 ---7 ~
polysaccharides, such as cellulose, dextràns, E~olyhyaluronic acid, polymers of acrylic and methacrylic esters and alginic acid.
Representative synthetic polymers= include 5 polyphosrh~71rf~c, poly(vinyl alcohols), polyamides, polycarbpnates, polyalkylenes, po~yacrylamides, polyalkylene glycols, polyalkylené oxides, polyalkylene terf~rhth~l Al-~'l, polyvinyl ethers, polyvinyl esters, polyvinyl halides, 10 polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof. Synthetically modified natur=al polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and 15 nitrocelluloses. Other polymers of interest~
include, but are not limited to,~ methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, h~dL~ y~L~l methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, celIulose propionate, 2 0 cellulose ace~ate butyrate, cellulose acetate E'hthalate, carboxymethyl cellulose, ce3 lulose triacetate, cellulose sulf ate sodium salt~, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), 25 E1oly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly ( lauryl methacrylate), poly (pheny methacrylate), poly (methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), 30 poly (octadecyl acrylate) polyethylene, ~
polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene ter~rh~h~l~te), poly(vinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, and polyvinylphenol.
35 Representative bioerodible polymers include polylactides, polyglycolides and copolymers thereof , poly (ethylene terephthalate), poly (butic -CA 02202~11 1997-04-11 -acid), poly (valeric acid), poly (lactide-co-caprolactone), poly [làctide-co-glycolide], polyai~hydrides, polyorthoesters, blends and ~ ~
copolymers thereof.
5: These polymers can be obtained f rom sources such as Sigma Chemical Co ., St Louis , MO ., Polysciences, Warrenton, PA, Aldrich, Milwaukee, WI, Fluka, Rnnknnknm-, NY, and BioRad, Richmond, ~
CA. or else synthesized from monomers obtained from lO these suppliers using standard techniques.
Suitable pQlymer- compositions preferabIy have intrinsic and ~nntrol 1 ~3ble biodegradability, so that they persist for about a wçek to about six months; are non-toxic, cnnti~;ning no significant 15 : toxic monomers and degrading into non-toxic components; are biocompatible; are chemically compatible with the substances to be delivered, and tend not to açnature the active substance; are ~-sufficiently porous to allow the incorporation of 20 biologically active molecules and their subsequent liberation from the polymer by diffusion, erosion or a combination thereof; are able to..remain at the site of application by adherehce or by geometric factors, such as by being formed in place or ~
25 softened and subsequently molded or formed into microparticles which are trappçd at a desired location; are capable of being delivered by techniques of minimum invasivity, such as by catheter, laparoscope or endoscope.~ ~ypes of 3 0 monomers, macromers, and polymers that can be used are described in more detail below.
~ydrogels Hydrogels are preferred~embodiments for application to a tissue for direct delivery since 35 they intrinsically have most of these desirable ~
propertiçs. Particularly preferred are gels which are composed pr,-tln~nin~ntly of polyethylene glycol.
CA 02202~ill l997-04-ll These can be applied by direct photopolymerization with an initiator, by chemical polymerization with a peroxygen, or by "interfdcial"
photopolymerization, with a dye adsorbed to the 5 ~issue to be coated, as described below.
Examples of these macromers are:- PEG-oligolactyl-acrylates, as described by ~iii-West, et al., Proc. Natl. Acad. Sci. USA 91:5967-5971, 1994; Obst. & Gynecol. 83:59-64, i~994. The choice 10 of d~Lu~Liate end caps permits rapid ~ =
photopolymerization and gelation; acrylates can be polyrnerized using several initiati~ng systems, e.g., an eosin dye, by brief exposure to ultraviolet or visible light.~ Poly (ethyleneglycol) or a~ PEG
15 central structural unlt ~ (core) is useful on the basis of its high hydrophilicity ana water=
solubility, ~ om~n i ed by excellent biocompatibility. A short poly (~-hydroxy acid), such as polyglycolic acid, is a preferred chain 20 extension because it rapidly degrades by hydrolysis of the ester linkage Into glycolic acid, a harmless metabolite. = Although highly crystalline polyglycolic acid is insoluble in water and most common organic solvents, the entire macromer is 25 water-soluble and can be rapidly gelled into a biodegradable network while in contact with aqueous tissue fluids. Such networks can be used to entrap and homogeneously disperse water-soluble drugs and enzymes an-d to deliver them at a controlled rate.
30 Other preferred chain extensions are polylactic acid, polycaprolactone, polyorthoesters, ana polyanhydrides. Polypeptides may a~so ~be used.
These materials are particularly useful for controlled delivery, especialIy of hydrophilic 35 materials, since the water aoluble regions of the polymer enable access of water to the r-tf~ri ;~l entrapped within the polymer. Moreover, it is ~ =
CA 02202~i11 1997-04-11 pos6ible to polymeri2e the macromer ~nn~i~in;n~ the material to be entrapped without~exposing the material to organic solvents. Release may occur by diffusion of the material from the polymer prior to 5 degradation and/or by dif fusion of the material from the polymer as it degrades, depending upon the characteristic pore sizes within thq polymer, which is controlled by the molecular weight between crosslinks and the crgsslink density. Deactivation lO of the entrapped material is reduced d~ue to the ;~rn~hil;7;n~ and protective effect of the gel and catastrophic burst effects associated with other controlled-release systems are avoided. When the entrapped material is an enzyme, the enzyme can be 15 exposed to substrate while the enzyme is entrapped, provided the gel proportions are chosen to~allow _ the substrate to permeate the gel. ~ Degradation of the polymer facilitates eventual controlled=~elease of free macromolecules in vivo by gradual 20 hydrolysis of the terminal ester linkages.
An advantage of these ~acrQmers are~ that they can be polymerized rapidly in an ~aqueous surrounding. Precisely conforming, semi-permeable, biodegradable f ilms or membranes can thus be f ormed 25 on tissue in=situ to serve as biodegradable barriers, as carriers for 1 iYing cells or ~other~
biologically active materials, and as surgical adhesives~. In a particularly preferred embodiment, the macromers are applied to tissue having a 3 0 ~ photoinitiator bound thereto, and polymerized to form= an ultrathin coating. This is especially useful in forming coatings on the inside of_t,issue lumens such as blood vessels where th~re is a concern regarding restenosis, and in forming tissue 35 ` barriers during surgery which thereby prevent adhesions from forming.
CA 02202~11 1997-04-11 In gene~ral terms, the macromers are:
polymers that are soluble in aqueous s~lutions, or nearly aqueous solutions, such as water with added dimethylsulfoxide. They have three components including a biodegradable regiont=preferably hydrolyzable under in vivo conditions, a water solubl~ region, and at least two photopolymerizable regions. The term "at least suhst~nt~lly water soluble" is indicative that-the sorubility should be at least about 5 g/lOO ml of aqueous solution.
The term ~polymerizable" means that the regions have the capacity to f orm additional covalent bonds resulting in macromer interlinking, for example, carbon-carbon double bonds of acrylate-type molecules. Such polymerization is characteristically initiated by free=radical formation resulting from photon absorption of certain dyes and chemical compounds to ultimately produce f ree - radi c a 1 s .
In a preferred l~mhn~imt~nt, a hydrogel is formed from a biodegradable, polymerizable, macromer ;nrll~lln~ a core, an extension on each end of the core, and an end cap on each extension. The core is a hydrophilic polymer or ~ oligomer; each extengion is a biodegradable oligomer; and each end cap is an oligomer, dimer or- monomer=capable of cross-linking the macromers. ~ In a particularly preferred embodiment, the core ;nrl~ hydrophilic poly (ethylene glycol~ olïgomers of ~molecular weight between about 400 and 30,000 Da; each t~ttnqi~n includes biodegradable poly (~-hydroxy acid) oligomers of molecular weight between about 200 and 12 0 0 Da, and each end cap includes an acrylate- type monomer or oligomer (i.e., r~nt~in;n~ carbon-carbon double bonds) of molecular weight between about 50 and 200 Da which are capable of cross-linking and polymerization between copolymers. More CA 02202~i11 1997-04-11 Wo 96/11671 PCT/lJ59~/14103 -12~
specifically, a preferred embodiment incorporates a core cousisti~g of poly (ethylene glycol) Qligomers of molecular weight about 10,000 Da; ,-~t,-~.c;~ns consisting of poly (glycolic acid) oligomers of 5 molecular weight about 250 Da; and end caps-consisting acrylate moieties of about 100 Da molecular weight.
Examples of sui:table materials for 4se as the core water soluble region are poly (ethylene 10 glycol), poly(ethylene oxide), poly(vinyl alcohol), poly (vinylpyrrolidone), poly (ethyloxazoline), poly ( ethylene oxide ) - co -po1y (propyle~eoxide) block copolymers, polysaccharides or carbohydrates such as hyaluronic acid, dextran, heparin sulfate, 15 chondroitin sulfate, heparin, or alginate, or proteins such as gelatinl collagen, albumin, or ovalbumin .
siodegradable regions can be constructed from polymers or monomers using linkages 20 susceptible to biodegradation, such as ester, peptide, anhydride, orthoester, and phosphoester ~
bQnds .
Examples of biodegradable components which are hydrolyzable are polymers and oligomers 2~ of glycolide, lactide, ~-caprolactone, other u- -hydroxy acids, and other biologically degr~dable pQlymers that yield materials that are non-toxic or .
present as normal metabolites in the body.
Preferred poly (u-hydroxy acid~ s are poly (glycolic 30 acid), poly(DL-lactic acid) and poly(L-lactic acid) . Other useful materials include poly ~aminQ
acids), poly(anhydrides), poly(orthoesters), and poly (phosphoesters) . Polylactones such as poly ( e -caprolactone), poly ( ~ - caprolactone), poly ( ~ -35 valerolactone) ana poly(gamma-butyrolactone), for example, are also useiul.
CA 02202~i11 1997-04-11 Wo 96111671 PCT/lJS95/14103 The polymerizable regions are pre~erably polymerized using free ~adicals generated by a photoinitiator. The photoinitiator preferably uses the vlsible or long wavelength 5 ultraviolet radiation. Preferred polymerizàble regions are acrylates, diacrylates, oligoacrylates, dimethacrylates, oligomethoacrylates, or other biologically acceptable photopolymerizable groups.
A preferre~ tertiary amine is triethanol amine.
Useful photoinitiators are those- which initiate free radical polymerization of the macromers without -cytotoxicity and within a short time frame, minutes at most and preferably seconds.
Preferred initiators for initiation using long 15 wavelength ultraviolet photoradiation are ethyl eosin, 2,2-dimethoxy-2-phenyl acetophenone, other~
acetophenone derivatives, and camphorquinone. In all cases, crosslinking and polymerization are initiated among copolymers by a light-activated 20 free-radical polymerization initiator such as 2,2-dimethoxy-2-phenylacetophenone or a combination of ethyl eosin (lO-4-lO-2 mM) and triethanol amine (O.OOl to O.l M), for example.
In another embodiment, the process is 25 carried out by providing a material that is conformable, at least temporarily, at body temperature, yet which may be rendered non-conformable u~on completion of the deposition -- ~ =
process, such as a poloxamer~q (a polyethylene 30 oxide-poIyethylene glycol block copolymer) .
Poloxamer~ can be selected which are=liquid at room temperature and solid ~at body temperature.
Pavings or Fi~
In other embodiments, such as that 35 ~ described in U.S. Patent No. 5,231,580 to Slepian, polymeric pavings or f ilms are ap~lied to the tis~ue using a catheter, endoscope~or laparoscope.
CA 02202~11 1997-04-11 = = = = =
--14-- ~ ~-- ~
Preferred polymers include polyhydroxy acids such as polylactic acid, polyglycolic acid and copolymers thereof, polycaprolactone, polyanhydrides, polyorthoesters, and other 5 materials commonly used for implantation or sutures .
The basic xequixements for the material to be used ir the process are biocompatibility and the capacity to be chemically or physically 10 reconfigured under conditions which can be achieved ill vivo. Such reconfiguration conditions preferably involve photopolymerization, but can involve heating, cooling, ~mechanical deformation~ ~
(æuch as stretching), or c:hemioal reaotions s,uch as 15 ~ polymerizatiQn or cxoaslinking.
In their cor,formable state, =the coating materials may exhibit a wide variety of forms.
They can be present as polymers, monomers, macromers or combinations thereof, r~int~;ned as0 solutions, suspensions, or dispersions.
~icroparticles In a pref erred embodiment, the microparticle has a .li i ~t~r which is selected tQ
lodge in particular re~ions of ~the body. Use of 25 micxospheres that lodge w:ithin organs or reglons is known in studies of blood flow (Flaim et al, J
Pharmacol. Meth. 11:1-39, lsB4; Xeymann et al, Prog. Cardiovasc. Dis. 20:55--79, 1977), but not in delivery of active materials. For example, a 30 microparticle selected to lodge in a~ capillary will typically have a diameter of between lo tD 25, m-ost pref erably 15 to 2 o microns . Numerous methods are known for preparing microparticles of any particular size range. In the various applicati~ons 35 of the present invention, the sizes may range from 0 . 2 micron up to 100 microns . Synthetic methods for g-el microparticles, or for microparticles from CA 02202~ill l997-04-ll WO 96/11671 PCT/US9~/14103 molten materials, are known, and include ~:~
polymerization in~emulsion, in sprayed drops, and in separated=phases. For solid~~materials or preformed gels, known methods include wet or dry 5 milling or grinding, pulverization, classification by air j et or sieve, and the like .
Microparticles can be fabricated from different porymers using a variety of different methods known to those skllled in~ the art .
10 ExempIary methods include those set forth below.
Polylactic acid blank mïcroparticles were fabricated using three methods: solvent evaFQration, as described by E. Mathiowitz, et al., J. Scanninq Microsco~Y, 4, 329 (19gO)~; L.R. Beck, et al., Fertil. Steril., 31, 545 (1979); and S.
Benita, et al., J. Pharm. Sci., 73, 1721 (1984);
hot-melt microencapsulation, as described by E.
Mathiowitz, et al., Reactive Polvmers, 6, 275 (1987); and spray drying. Polyanhydrides made of 20 bis-carboxyphenoxypropane and sebacic acid with molar ratio of 20:80 P(CPP-SA) (20:80) (Mw 20,000) were prepared by hot-melt microencapsulation.
Poly(fumaric-co-sebacic? (20:80) (Mw 15,000) blank microparticles were prepared by hot-melt 25 microencapsulation. Polystyrene microparticles were prepared by solvent evaporation.
Hydrogel microparticles were prepared by dripping a polymer solution from a reserYoir though microdroplet forming device intQ a~: stirred ionic 30 bath. ~he specific cQnditions for alginate, chitosan, alginate/polyethylenimide (PEI) and carboxymethyl cellulose (C~[C) are llsted in Table 1.
a. Solvent Eva~oration. In this method 35 the polymer is dissolved in a volatile organic solvent, such as methylene chloride. ~:Che drug (either so~uble or dispersed as fine particles) is CA 02202~i11 1997-04-11 WO 96/11671 PCT/USgS114103 -external surf aces o~ spheres prepared with this technique are_usually smooth and dense. This procedure is used to prepare microparticles made of polyesters and polyanhydrides. However, this method is limited to polymers with molecular -weights between 1000-50, 000.
c. Solvent ~emoval. This technique is primarily designed for po~anhydrides. In this method, the drug is dispersed or dissolved-in a solution of the selected polymer in a vola~ile organic solvent like methylene chloride. This mixture is suspended by stirring in an organic oil (such as silicon oil) to~ orm an emulsion. = Unlike solvent evaporation, this method can be used to make microparticles from polymers with high melting points and different molecular weights.
Microparticles that rang=e~between 1-300 microns can be obtained by this procedure . The ~ rn ~
morphology of spheres produced with this technique is highly dependent on the type o~ polymer used.
d.~ S~rav-Dryinq In this method, the polymer is dissolved in methylene chloride_ ( 0 . o4:
g~mL) . A known amount of the active drug is suspended (insoluble drugs) or co-dissolved ~ _ (soluble drugs) in the polymer solution. ~he solution or the dispersion is then ~pray-dried. ~
Typical process Farameters for a mini-spray drier (Buchi) ara as followE: polymer concentration =
0.04 g/mL, lnlet temperature = -24C,~outlet te~perature = 13-15 C, aspirator setting = 15, pump setting~ = 10 mL/minute, spray flow = =600 Nl/hr, and nozzle diameter = 0.5 ~n.
Microparticles ranging between 1-10 microns are obtained with a morphology which depends on the type of polymer used. This method is primarily used for preparing microparticles designed to improve imaging of the intestinal tract, since for CA 02202~ill l997-04-ll -added to the solution, and the mixture is suspended in an aq~leous solution that contains a surface active agent such as poly (vinyl alcohol) . The resulting emulsion is stirred until most of the organic solvent evaporat d, leaving solid microparticles. Several different polymer concentrations were used: 0.05-0.20 ~/ml. The solution is loaaed with a drug and s~lqp~nrl~rl in 200 ml of vigorously stirred distilled water rrn~inlnr 1~; (w/v) poly(vinyl alcohol) (Sigma) After ~
hours of stirring, the organic solYent evaporates from the polymer, and the resultinr microparticles are washed with water and dried overnight in a lyophilizer. Microparticles with different sizes (l-1000 mIcrons) and morphblogies~can be obtained by this method. This method is useful for - -relatively stable polyme=rs like polyesters and polystyrene.
However, labile polymers, such as polyanhydrides, may degrade during the fabrication process due to the presence Qf water_ For these polymers, the following two methods, which are performed in completely anhydrous: organic solvents, are more useful.
=~ b. Eot Melt Microenca~sulation. In this method, the polymer is first melted and then mixed with the solid particles of dye or drug tE~at have:
been sieved to less than 50 microns. The mixture is suspended in a non-miscible solvent (like silicon oll), ana, with continuous stirring, heated to 5C
above the melting point of the pQlymer Once the emulsion is stabilized, it is cooled until the polymer particles solidify . The r~q~ i nr microparticles are washed by decantation wïth petroleum ether to give a free-flowing powder.
Microparticles with sizes between one to 100Q
microns are obtained with this method. The ~ = =
CA 02202~ill 1997-04-11 Wo 96111671 PcrllJS9S/14103 this application, particle size should not exceed 10 Il.
e. HYdroqel Microparticles.
Microparticles made. of gel-type polymers, such as ~-5 alginate, are produced ehrough trA~1t;~n~1 ionic .gelation techniques . The polymers are f irst dissolved in an aqueous solution, mixed with barium sulfate or some bioactive agent, and then extruded through a microdroplet forming device, which in 10 some instances employs a flow of nitrogen gas to ~:
break off the droplet ~~ s-lowly stirred (approximately 100-170 RPM) ionic hardening bath is positioned below the extruding de~ice to catch the forming microdroplets. ~ The microparticles are left 15 to incubate in the bath for twenty to thirty minutes in order tQ allow sufficient time for ~
gelation to occur. Microparticle particle size is controlled by using various size extruders or varying either the nitrogen gas~or polymer solution 20 flow rates The`matrix is preferably in the form of a microparticle such as a miçrosphere (where ~the biologically active molecules are dispersed throughout a solid polymeric matrix) or 25 microcapsule (where the biologically active molecules are encapsulated in the core of a polymeric shelll The size and composition of the polymeric device is selected to result in favorable release kinetics in tissue. The size is also 3 0 selected according to the method c-f delivery which is to be used, typically inj ection into .a tissue or administration of a suspension by aerosol into the nasal and/or pulmonary areas, and where d~L~Liate, entrapment at the site where release 35 is desired The matrix composition can be selected to not only have f avorable= deqradation rates, but to be formed of a material which is bioadhesive, to CA 02202~ill l997-04-ll --19-- =
further increase the effectiveness of transfer when administered to a mucosal surface,-- or selected not to degrade in=itially but to release by diffusion over an extended period. ~ =~
5 ~ ~ Liposomes are available commercially from a variety of suppliers. Alternatively, liposomes can be prepared according to methods known to those skilled in the art, for example, as descrïbed in U. S . Patent No . 4, 522, 811 (which is incorporated 10 here~n by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid (s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) 15 in an inorganic solvent that ~is th~en evaporated, leaving behind a thin film of dried lipid on the surface of the cnnt~inl~r. An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives are 20 then introduçed into the cnntAin~-r~ The container is then swirled by hand to free lipid material from the sides of the cnnt;lin~r-and to disperse lipid aggregates, thereby forming the liposomal suspension. ~ :
~ siologically Active Molecules Biologically active molecules whiçh can be incorporated into the polymeric carrier, directly and/or indirectly, i . e ., within microparticles which are immobilized in the carrier,~ include proteins, nucleic acid molecules, carbohydrates, lipids, and combinations thereof.
Examples of Froteins include cytokines such as interferons and interleukins, poetins, and colony stimulating factors,= growth factors, angiogenic factors and fragments thereof. ExampIes of nucleic acid molecules include genes~and cD~As CA 02202~11 1997-04-11 Wo 96/1167~ PCTIUS9~/14103 Pn~o~in~ proteins, expression vectors, antisense and other oligonucleotides such as ribozymes which can be used to regulate or=prevent gene expression.
Carbohydratçs include Sialyl LewisX which has been 5 shown to bind to :receptors ~for selectins to inhibit inf lammation . Growth f actors in the broad sense are preferred biologically activ-e molecules_ A
~ de l iver abl e growt h f a c to r equ iva lerlt " ( abbrevi at ed DGFE) is a growth factor for a cell,or tissue, 10 broadly construed, including growth factors, cytokines, interf erons, interleukins, proteins, colony-stimulating factors, gibberellins, auxins, and vitamins; further including peptide fragments or other active fragments of the above- and further 15 including vectors , i . e ., nucleic acid cQnstructs =
capable of synthesizing suoh factors in the target cells, whether by transformation or transient ~
expression; and further including effectors which stimulate or depress the synthesis~ ~f such factors 20 in the tissue, including natural signal molecules, antisense and triplex nucleic acids, and the like.
Particularly preferred DGFE' s are vascular endothelial growth factor ~(VEGF), Pn~nthPl i ~l cell growth factor (ECGF), basic fibroblast growth 25 actQr (bFGF), bone morphogenetic protein (BMP), and platelet derived growth factor~ (PDGF), and DNA' s encoding for them. Preferred clot dissolving agents are tissue pl ~cm;nff~en activator, streptokinase, urokinase and heparin.
IncG ~OI ~tion o~ B;r~o5ir:ll1y Active ~olecules into the Polymeric Carriers Generally, the biologically active molecules arç mixed with the pQlymer at the time the ~tPr; ~l is either polymerized or when the polymer is formed into a microparticle or lip;osome, in a concentration which will release an effective amount at the targeted site in a patient. Fqr -~
çxample, in the case of a hydrogel, the macromer, CA 02202~ill 1997-04-11
6~1 = = PCT/U595/14103 photoinitiatcr, and biologically actIve molecules to be encapsulated are mixed in an aqueous mixture.
Particles of the mixture are f ormed using standard techniques, for example, by mixing in oil to form 5 an emulsion, forming droplets in oll using a nozzle, or fo--rming droplets in air using a nozzle.
The suspension or droplets are ~irradiated ~with a light suitable for photopolymerization of the~
macromer . = - =
The biologically active~ molecules to be delivered can be mixed with the polymeric material in any of a variety of ratios, depending on the dosage Qf active molecule desired.~: ~ The polymer in the gel will typically be at a volume concentration of 5 to 25~ (wt/volume), or 50 ~to 250 mg/ml .
Biological actives will be present at .-..n~-~nt~ations at or below 1 to 10 microgram/ml for DNA and the like, and may range up~ to 10 to_~50 mg~ml for act=lve proteins a:nd the like. ~he exact 20 concentration :will depend on the particular active molecule, and on the effect-to be achieved.
Characterization studies can be performed at different lQadings to investigate encaps=ulation properties and morphological charac`~erist~ics of the 25 microparticles. Particle size can be measured by quasi-elastic light scattering ~Q~LS) . Drug loading can be measured by dissolving lyophilized microparticlefi into an appropriate solvent and assaying~the amount of biologic:ally açtive~
3 0 molecules specFrophotometrically or by other d~L~Liate means. ~ ~
Adrlinistration of the Polymeric Carrier The poIymeric carrier can be aaministered direct~y, for example, by spraying or application 35 of a solution, or Indirectly, through a catheter, endoscope, or laparoscope. ~ When aelivered to the CA 02202~11 1997-04-11 Wo 96/11671 PCT/US9Y1~103 --2 2~ ~ -interior of a hollow organ, the process of application must not caus:e ~collateral iniury by prolo1lged blockage of flow through the organ. _ Pref erred delive~y - methods are those 5 which are minimally invasive or disruptive to the~
subj ect . These include administration of microparticles as ~ell as percutaneous ~app=lication to~ the interior Qf hollow organs ar ~natural bqdy cavities of a polymeric coating, film, ~gel, or lO stent. Suitable delivery devices for providing a polymer coating or layer~on the surface of tissues are catheters, laparoscopes, and endoscopes, as defined in PCT/US94/94~24 by Pathak et al.
A~plication of a ~vdro~el ~ Photopolymerization of a hydrogel using the macromers described above can be carried out in as little as 10 second5, using a portable, low powered long wave ~V (~W~V) emitting source.
Visible laser light is also useful for polymerizatiQn. ~ow intensity and short exposure times make visible laser light virtually harmless to living cells since the ~radiation is not strongly absorbed in t`he absence of the pr=oper chromophore-.
Laser light can also be transported using fiber 2s -Qptics and can be fQcused to a ver~ small àrea.
For~example, 0.2 ml of a~ 3096 w/v photosensitive =
oligomer solution is mixed with ethyl eosin (lO-~ M) and triethanol amine ( 0 . Ol to o . l M) and the sQlution is irradiated with an argon ion laser (American argon ion laser_model 905 emitting at 514 nm) at a power of 0.2-0.5 W/cm2. ~ The beam i5 1 to a diameter of 3 mm and the sample is~ ~
slowly scanned until gelation occurs.
In a particularly preferred application o~ these materials, an ultrathin coating is applied to the surface of a tissue, ~most preferably the:
lumen of -a tissue such as a blood vessel. ~ The ~ -CA 02202~i11 1997-04-11 Wo 96/11671 PC~IUS95/14103 23-- -- ~
photoinitiatc~r is applied to ~the surf ace of the tissue, allowed to react and bond to tissue, the unbo~md photoinitiator is removed by dilution or rinsing, and the macromer solution is applied and 5 polymerized. This method is capabie of creating uniform polymeric coating of between lO and 500 microns in thickness, more typically 50 to 200 microns, which does not evoke thrombosis or localized inf lammation . ~
10 ~ A~l~lication of a Pavinq or CQatinq Local administrat ion of ~ a pQ~ymeric material can be perf ormed by loading the composition in a balloon catheter, and then applying the composition directly tQ the inside of 15 a tissue lumen within a zone occluded by the catheter balloons. The tissue surface may be an ;ntl~rn~l or ~-~tFrn~l surface, and can include the interior cf a tissue lumen or hollow space wl~ether naturally occurring or occurring as a result of 20 surgery, percutaneous techniques, trauma or disease. The polymeric material can then be reconfiqured to form a coating or ~paving~ layer in intimate and conforming contact~ with the surfacé.
The resulting paving laye=r :optionally can have a 25 sealing function. As used herein, the term ~'sealing" or "seal" means a coating of sufficiently low porosity that the coating provides a barrier function. The term ~paving~ refers to coatings in general wherein the coatings are porous or 30 perfQrated or are of a low porosity "sealing~
variety. The coating preferably has a thickness on the tissue surface on the order of 0 . OOl-l . 0 mm, however, coatings having a tlli ckn~cs outside that range m~ay be used as well. By approl?rïate ~ ~
35 selection of the material empIoyed and of the conf iguration of the paving material, the process =
CA 02202~ill l997-04-ll Wo 96/11671 PCT/US9511~103 -can be tailored tQ- satisfy a wide variety of biological or clinical situations.
The monomers, macromers and polymers that can be used for this application are selected from 5 the same group as described a~ove for ~ormation of microparticles. ~?referably, the polymeric~material has a variable degree of conformability in response to a stimulus. The material is preferabIy substantially non-conformable in vivo :upon lQ .completion of the coating~process. The material, in its conformable form, can be positioned in contact with a- tissue or~ cellular surface tQ be coated and then stimulated to render it non-conf ormable . The material is_pref erably rendered 15 non-conformab~le by applying photochemical stimulus, but can optionally be achieved solely by chemical or thermal stimulus. The material is positioned at either an internal or external treatment location and contacted with the ti~sue or ~ r surf ace 20 to be paved or sealed, and the material is then converted into a non-confDrmable state to form a biocompatible coating on the tissue surface.
The coating can be applied using a catheter, such as a modified PT~A catheter. The 25 material is preferably applied using a si~gle catheter with single or multiple balloons and lumens. The catheter shQuld be o relatively low cross-sectional area. A long thin tubular catheter:
~ r"l ated using fluoroscopic guidance is 30 preferred for p~:o~iding access to the interior o organ or vascular areas. The material can a so be applied to the surface tQ be coated hy spray ng,~ -extruding or otherwise internally delivering the material in a conformable form via a long flexible 35 tubular device having single or multiple luméns.
During the step of positioning the material at the desired location, the location may CA 02202~i11 1997-04-11 Wo 96/11671 PCT/IJS95/14103 be accessed by either invasive surgical techl~liques or by relatïvely non- invasive techniques such as laparoscopic procedures or percutaneous transluminal procedures. The process of fixing the 5 shape of the material can be accomplished in several ways, depending on the character of the original material For example, in its conformable state the material can be formed using the balloon portlon of a balloon catheter~ after which the l0 conditions are adjusted such that the material is rendered non-conformable. In the preferred embodiment, gels are rendered non-conformable at the treatment site by photopolymerization using infrared, visible, W, or ultrasonic:radiation to 15 the material. Optionally, the polymers can be rendered non-conformable by localized heating or by chemical means. Thermal control can be l?rovided, for example, using a fluia flow through or into the balloon, or using a partially perforated balloon 2 0 such that temperature control f luid passes through the balloon into the lumen. Thermal control can also be :provided using electrical resistance heating via a wire running along the length of the catheter body in contact with resistive heating 25 elements. This type of heating element can make use of ~ DC or radio frequency (RF) current or ~ t~rnAl RF or microwave radiation. Other methods of achieving temperature control c~an a:lso be used, in~ ;ng light-induced heating using an ;nt~rnAl 3 0 optical f ibe~r- (naked or lensed) .
In one embodiment, the step in which the conformable material is contacted with the tissue surface may be considered as a "moldingl' procedure in which the conformable material is molded into 35 substAnt;Ally conforming contact with the body tissue before~ rendering it non-conformable. It is noted that the transition of the material from a CA 02202~11 1997-04-11 Wo 96/1 1671 PCT/IJS9~14103 conformable to- a non-conformable 6tate may involve~
a phase change in the material, however, 6uch a pha6e change is not neces6ary. For e~:ample, in certain embodiments, the terms "conformable~' and =
5 ~non-conformable~ are primarily relative de6criptions of a material which undergoes a significant ,change in viscosity and flowability without undergoing an actual phase shan~ge~ ~
Alternatively, the tran6ition of the material lO between its conformable and non-conformable=6tate6 may be the result of an ac~ual pha6e change in~ the material re6ulting either from the addition or removal of energy from the_material.
The polymeric materials may be applied ir, 15 ` cu6tom de6ign6, with varying thickne66e6, lengths ,~
and three-dimensional geometrie6 (e.g. spot~, -6tellate, linear, cylindrical, arcuate, 6piral) to achieve varying f ini6hed geometrie6 . Further, ~ the proce6s may be u6ed to apply material to the inner 20 6urface6 of hollow, cavernou6, or tubular biological structure6 (whether natural or artificially formed) in either= 6ingle or multi-layer conf iguration6 . The proce66 may al60 be used, when appropriate, to~occlude a ti66ue lumen 2~ completely.
The paving coating may be a~plied a6 a continuou6 layer either with o:r without perforation6. In the case in which the paving coating is applied without perforations, it is 3 0 ref erred to a6 a " seal " to act as a ,barrier, layer on the 6urface of the ti6sue. The coating can al60 be applied to l~ r 6urfaces, for example, ~to coat or encap6ulate indivillual or multiple~cell6.
Admini6tration of Micro~article6 ~ The injectable microparticle6 can be :
admini6tered to a patient intravenously, intramu6cularly, or= 6ubcutaneously or in other -CA 02202~i11 1997-04-11 WO 96/11671 PCT/lJ595/14103 --27-- =
known ways approFriate to the therapeutic effect desired, including as an aerosol~Qr spray for lungs or by direct lavage through orif iQes . ~ The particles can be lyophilized and then formulated into an aqueous suspension in a range of microgram/ml to lO0 mg/ml prior to use.
The desired concentration of biologically active molecules in the polymeric . carrier will depend on absorption, inactivation, and excretion rates of the drug as well as the ~deIivery rate of the molecules from the carrier. It is to be noted that dosage values will also yary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the indiYidual need_and the professional judgment of ~the person administering or superYising the administration o~ the compositions .
The microparticles can be administered once, or may be divided into~ a number of smaller doses to be administered at varying interyals of time, depending on the release rate of the particle, and the desired dosage. ~ :
~ ~olutions ~r suspensions used for intravenous, intramuscular, or topical application, or other delivery route can include any of the following components, ~as required: a sterile diluent such as water for injection, saline solution,~fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic =
solvents; antibacterial agents such~as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;: chelating agents such as ethyl~n~ min~tetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such= as sodium =
CA 02202~i11 1997-04-11 wog6/lr671 PCT/US95J14103 --2 8 ~
chloride or dextrose. The=parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline ~ -(PBS) .
Catheters can be made of any known - =
material, including metals, such as steel, and thermoplastic polymers. ~-~ccluding balloons can be maae from compliant materials such as latex or silicone, or non-compliant materials such as polyethylene -ter~ t7l~l Ate (PET) . The expansible member is preferably made from non-compliant materials such as PET, (PVC), polye~hylene or nylon. If used, the balloon catheter portion~ of a dilatation may optionally be coated with materials such as silicones, polytetrafluorQethylene~ (PTFE), hydrophilic materials like hydrated hydrogels and other lubricous materials to aid~in separation of~
the polymer coating.
In addition to blood vess~els, the process may be utilized for other ~applications such as coating the interior of veins, ureters, urethras, bronchi, biliary and pancreatic duct systems, the gut,~nasolacrimal ducts, sinus ca~r~ties, the eye, and eustachian, spermatic and fallopian tubes.
Llkewise the process can be used to provide a paving layer in the context of transhepatic .
portosystemic shunting, dialysis grafts, arterio-3 0 venous f istulae, and aortic and other arterial aneurysms. The paving ana sealing material of the process can also be used in other direct clinical applications even at the ~coronary level. These include but are not limited to the treatment of abrupt vessel reclosure post PCTA, the ~patching~
of significant vessel dissection, the sealing of vessel wall " f laps " either secondary to catheter~
CA 02202~i11 1997-04-11 Wo 96/11671 PCT/IJS95114103 injury or sp~ntaneously occurring, or the sealing of aneurysmal coronary dilations associated with various arteritidies. Further, the method provides intraoperative uses such as sealing of vessel 5 anastomoses during coronary artery bypass graf ting and the ability to: provide a "bandaged~ smooth polymer surface. = = ~
Treatment of gpecific Disorders Vascularization lO ~ A~=common proble~ in aging is atherosclerosis affecting the arteries of ~the lower limbs. This can cause claudication, or sharp pain when walking. This disease can be treated by inducing the creation of additional collateral 15 c--lrcuIation in the affected region (in this case, the leg) by introducing a growth factor such as VEGF (vascular endothelial growth factor), or a DNA
which can express it. The growth factor or DNA can be delivered~either by creating a thin coating 20 .-f,ntAin;n~ the factor inside an artery leading to the region, or by injecting microparticles containing the f actor into the artery f eeding the affected limb or region. In the latter case, the microparticles are preferably at least 15 microns 25 in diameter, preferab~y 20 microns or more, to cause the delivery particles to localize pr~ ;nAntly in the region. (It should be noted that some microparticles will probably exit the treated region, and lodge in,the lungs or 30 elsewhere; this eEfect must be accounted for in treatment planning . ) Another application includes ~
revascularization in cardiac tissue including the myocardium, and revascularization==a~ter stroke or 35 ischemia CA 02202~11 1997-04-11 Wo 96111671 PCr/lJS95114103 - 3 0 ~
Reqeneration or Repair of Tissues Yet another application is in regeneration or repair of particular~ organs .
Delivery of variou6 bone mo~rphogenetic proteins can 5 be useful for controlled remodeling of bone, or de novo bone or cartilage formation, in which it is critical that the developmental or morphogenetic effects be strictly r~nfin~l to the target site, and not exhibited throughout the organlsm. Local l0 deposition of biologically active molecules_can be useful in repairing bone in area6 such as the nasal passages and sinuses, where precise control of;
positioning is required.
Examples o~ other tissues which can be 15 treated in this manner include the stomach and intestines, where growth factors help accelerate repair of uIceration, repair of external ulceration of skin, and general wound repair.
Other organ systems susce_tible to 20 treatment include any organ system in which material f lows through the organ f rom a source, so that a factor can be admini6tered, either in a coating or as particles, for inst;llAtirn into the organ to he treated by flQW. R~ mrlAry organs 25 include lymph nodes, the bile duct, the urinary tract, the lungs, the spac-e occupied by the cerebro-spinal fluid, and the like.
The present invention wilI be further understood by reference to the ~ollowing non~
3 0 limiting examples .
Example l: Gene delivery from a gel in vitro.
Previous work on gene transfer into ~ -arteries has involved administration of DNA in a liquid vehicle, in-cluding pressïng the liquid into 35 artery walls with a balloon catheter. For more efficient local delivery, a thin, locally-deposited CA 02202~11 1997-04-11 gel, from which DNA can diffuse into-the target tissue, was utilized.
Transfection Procedure Positively-charged liposomes - 5 (Transfection-reagent, Boehringer Mannheim) t-nnt;~;nlng the catlonic lipid analogue 1,2-dioleoyloxy-3 - 3trimethylammonium) propane (DOTAP) ' were used fOR transfections. Plasmid DNA was purified by centrifugation through a cesium chloride gradient. Five ~Lg of DNA was mIxed with 30 ~g of liposomes in 200 IlL of Hanks Balanced Salt Solution (~IBSS, Gibco) .
Expression Vectors and Analysis of ~Recombinant Gene Express ion The lucif erase expression vector employed wa~ pRSVLUC (gift of Dr. A. Brasier, Galveston, TX, to Dr . Jeffrey M. Isner, St. Elizabeth' s Hospital, Boston, MA, who provided the vector) . This contains a 5' deletion of firefly luciferase cDNA, with transcription under the contrQl of the Rous sarcoma virus long terminal repeat~promoter. Use of this reporter gene allows for quantification of gene exFression in cell lysates. Cells were washed 3 times with calcium-free HBSS and extracts prepared using a cell lysis reagent (Promega,~
Madison WI) c~-nt~in;n~ l~ Triton-Xl00~M. Half of the extract was taken for analysis of total protein content, performed using the Biorad Microassay procedure. Bovine serum albumen (lmg/ml) was added to the other half as a carrier protein and luciferase activity was measured. For this, a 20 ~l aliquot was mixed at room temperature with l00 ~1 of luciferase assay reagent (Promega) c~nt~inin~
beetle luciferin. Emission of light, integrated Alternative nomenclature: N= [l- (2, 3 -Dioleoyloxy) propyl] -N, N, N, trïmethyl -ammonium methylsulf ate .
CA 02202~11 1997-04-11 WO 96~11671 PCTNS95114103 --32- i =
over 10 seconds, was measured using a luminometer (Turner Designs, Model 20e,~ Sunnyvale CA) .
Results, read as light units, were within the linear range of the detection system as evaluated -~
using serial dilutions o~ a known amount of ~ -luciferase (Sigma, Product No~ ~-9009) . Backgrouna activity, measured using phosphate-buffered saline or lysates of nontransfected cells, was consistently zero.
The plasmid pRSVLUC, ~ht:~;n.~ll from the laboratory of Dr. Jeffrey Isner of St. Elizabeth' s hospital in Boston, which encodes the enzyme luciferase under the control of a SV40 promoter, was dissolved in a gelling prepolymer. The prepolymer had a core of polyethylene glycol, MW8000, with about 5 lactate residues at each end, capped by an acrylate group at each end, synthesized accordin-g to the t~hin~q of PCT US
93/17669 by Hubbell et al., hereby incorporated by 20 reference. The polymer concentration was 1096. The application method was otherwise essentially;
identical to that described in Hill-West et al, Proc. Nat. Acad. Sci. USA 91:5967-5971, 1994.
Tissue sur~aces were stained by application of 1 mM
25 Eosin Y, and washed. The polymer solution containing the DNA, and also 100 mM ethanolamine and ~.15% n-vinyl pyrrolidone, and was polymerized essentially as in Hill-West. The amount o~ plasmid in the delivery vehicle was between 0 . 02 and 2 3 0 micrograms . ~iposomes as described above were optionally included. The luminal surface: of rabbit arterial strips, which were mi~lnt~;nf~tl in tissue culture essentially a~ described by Takeshita et =
al ., ;J. Clin. Invest ., 93 :~652-661, (1994), were 35 stained with a photoinitiating dye, Eosin Y, according to PCT US 93/01776 by Hubbell et al., and washed in medium. Prepolymer solution (23g~ wt CA 02202~11 1997-04-11 Wo 96/1167~ PCT/USgS/14103 prepolymer so~ution in saline) -nnt~;n;ng D=NA, with or without added lipQSomes (at a rdtio of 4 parts by weight of liposomes per part of DNA), was applied as a spot to stained arterial strips. The 5 solution was photopolymerized with green light to form a hydrogel. As controls, artery strips were treated with DNA/prepolymer solution, which was not gelled by photQillumination. After 7 days in culture, luciferase~ expression was measured in 10 Turner ~ight Unit9 per gram of tissue=(T~U/g), by standard methods. ~ ~
At the optimal level of n~NA application (2 micrQgrams/dose) controls had 3 . 3 +3 . 3 TLU/g;
tissue treated with gels cont~3;n;ng DNA nQt encapsulated within liposomes had 10 . 7+3 . 6 T~U/g;
and tissue treated with gels ~-~,nt~3;n;n~ DNA
encapsulated within liposomes had 2 0 . 8 + 1. 7 Tl.U/g .
The results demonstrate that gene transfer and expression can be accomplished by 20 delivery with a gel, with or without liposomes, and that the efficiency of delivery is significantly higher than when the DNA is merely applied tQ the tissue surface. EIowever, the results also inQicate that the ef i~icacy of transfer can be greatly 25 increased by incorporation Qf the DNA into liposomes prior to immobilization.
Exa~ple 2: In vivo Lucifera~e Gene Delivery via Photopolymerizable Xydrogel.
In vivo gene delivery was demonstrated 30 using the rat carotid artery model. Interfacially polymerized gels, prepared as described in example - 1, were f ormed in the right carotid artery of rats .
The le~t side was untreated and served as control.
Gels contained 25 mi~yld~.., DNA per ml of 35 - prepolymer solution c~n~; n; ng 10~ w/v prepolymer encapsulated in 100 micrograms liE~osomes/nLl of prepolymer, and otherwise were deposited as described by Xill-West et al. Arteries were CA 02202~11 1997-04-11 WO 96/11671 PCT/U`395/14103 =
illuminated with green light to polymerize the macromer, resulting in a layer about lOo micrometers thick. After 3 days, rats were~ _ sacrificed and tissue ~m;n~ for luciferase ' 5 expression.
No gene expression was evident in~ control (unt~eated) arteries, - while treated arteries had 8 . 2 + 6 . 2 TLU/g .
As additional controls, DNA/macromer lO solutio~s were applied either to the adventitial (outside) surface of arteries, and flushed with saline; or were applied to the i~terior surfac~e, -and not illuminated . The f ormer treatment gave 0 . 85 + . 21 TI.U/g, and the~ latter gave 3 . 9 . + 3 . 7 ~~
15 TLU/g.
Variations and modificatio~s of the claimed i~vention will be obvious to those skilled in the art from the foregoing detailed description of the invention. It is intended that all of ,these 20 variations and modifications be included within the scope of the appended claims. =~
Particles of the mixture are f ormed using standard techniques, for example, by mixing in oil to form 5 an emulsion, forming droplets in oll using a nozzle, or fo--rming droplets in air using a nozzle.
The suspension or droplets are ~irradiated ~with a light suitable for photopolymerization of the~
macromer . = - =
The biologically active~ molecules to be delivered can be mixed with the polymeric material in any of a variety of ratios, depending on the dosage Qf active molecule desired.~: ~ The polymer in the gel will typically be at a volume concentration of 5 to 25~ (wt/volume), or 50 ~to 250 mg/ml .
Biological actives will be present at .-..n~-~nt~ations at or below 1 to 10 microgram/ml for DNA and the like, and may range up~ to 10 to_~50 mg~ml for act=lve proteins a:nd the like. ~he exact 20 concentration :will depend on the particular active molecule, and on the effect-to be achieved.
Characterization studies can be performed at different lQadings to investigate encaps=ulation properties and morphological charac`~erist~ics of the 25 microparticles. Particle size can be measured by quasi-elastic light scattering ~Q~LS) . Drug loading can be measured by dissolving lyophilized microparticlefi into an appropriate solvent and assaying~the amount of biologic:ally açtive~
3 0 molecules specFrophotometrically or by other d~L~Liate means. ~ ~
Adrlinistration of the Polymeric Carrier The poIymeric carrier can be aaministered direct~y, for example, by spraying or application 35 of a solution, or Indirectly, through a catheter, endoscope, or laparoscope. ~ When aelivered to the CA 02202~11 1997-04-11 Wo 96/11671 PCT/US9Y1~103 --2 2~ ~ -interior of a hollow organ, the process of application must not caus:e ~collateral iniury by prolo1lged blockage of flow through the organ. _ Pref erred delive~y - methods are those 5 which are minimally invasive or disruptive to the~
subj ect . These include administration of microparticles as ~ell as percutaneous ~app=lication to~ the interior Qf hollow organs ar ~natural bqdy cavities of a polymeric coating, film, ~gel, or lO stent. Suitable delivery devices for providing a polymer coating or layer~on the surface of tissues are catheters, laparoscopes, and endoscopes, as defined in PCT/US94/94~24 by Pathak et al.
A~plication of a ~vdro~el ~ Photopolymerization of a hydrogel using the macromers described above can be carried out in as little as 10 second5, using a portable, low powered long wave ~V (~W~V) emitting source.
Visible laser light is also useful for polymerizatiQn. ~ow intensity and short exposure times make visible laser light virtually harmless to living cells since the ~radiation is not strongly absorbed in t`he absence of the pr=oper chromophore-.
Laser light can also be transported using fiber 2s -Qptics and can be fQcused to a ver~ small àrea.
For~example, 0.2 ml of a~ 3096 w/v photosensitive =
oligomer solution is mixed with ethyl eosin (lO-~ M) and triethanol amine ( 0 . Ol to o . l M) and the sQlution is irradiated with an argon ion laser (American argon ion laser_model 905 emitting at 514 nm) at a power of 0.2-0.5 W/cm2. ~ The beam i5 1 to a diameter of 3 mm and the sample is~ ~
slowly scanned until gelation occurs.
In a particularly preferred application o~ these materials, an ultrathin coating is applied to the surface of a tissue, ~most preferably the:
lumen of -a tissue such as a blood vessel. ~ The ~ -CA 02202~i11 1997-04-11 Wo 96/11671 PC~IUS95/14103 23-- -- ~
photoinitiatc~r is applied to ~the surf ace of the tissue, allowed to react and bond to tissue, the unbo~md photoinitiator is removed by dilution or rinsing, and the macromer solution is applied and 5 polymerized. This method is capabie of creating uniform polymeric coating of between lO and 500 microns in thickness, more typically 50 to 200 microns, which does not evoke thrombosis or localized inf lammation . ~
10 ~ A~l~lication of a Pavinq or CQatinq Local administrat ion of ~ a pQ~ymeric material can be perf ormed by loading the composition in a balloon catheter, and then applying the composition directly tQ the inside of 15 a tissue lumen within a zone occluded by the catheter balloons. The tissue surface may be an ;ntl~rn~l or ~-~tFrn~l surface, and can include the interior cf a tissue lumen or hollow space wl~ether naturally occurring or occurring as a result of 20 surgery, percutaneous techniques, trauma or disease. The polymeric material can then be reconfiqured to form a coating or ~paving~ layer in intimate and conforming contact~ with the surfacé.
The resulting paving laye=r :optionally can have a 25 sealing function. As used herein, the term ~'sealing" or "seal" means a coating of sufficiently low porosity that the coating provides a barrier function. The term ~paving~ refers to coatings in general wherein the coatings are porous or 30 perfQrated or are of a low porosity "sealing~
variety. The coating preferably has a thickness on the tissue surface on the order of 0 . OOl-l . 0 mm, however, coatings having a tlli ckn~cs outside that range m~ay be used as well. By approl?rïate ~ ~
35 selection of the material empIoyed and of the conf iguration of the paving material, the process =
CA 02202~ill l997-04-ll Wo 96/11671 PCT/US9511~103 -can be tailored tQ- satisfy a wide variety of biological or clinical situations.
The monomers, macromers and polymers that can be used for this application are selected from 5 the same group as described a~ove for ~ormation of microparticles. ~?referably, the polymeric~material has a variable degree of conformability in response to a stimulus. The material is preferabIy substantially non-conformable in vivo :upon lQ .completion of the coating~process. The material, in its conformable form, can be positioned in contact with a- tissue or~ cellular surface tQ be coated and then stimulated to render it non-conf ormable . The material is_pref erably rendered 15 non-conformab~le by applying photochemical stimulus, but can optionally be achieved solely by chemical or thermal stimulus. The material is positioned at either an internal or external treatment location and contacted with the ti~sue or ~ r surf ace 20 to be paved or sealed, and the material is then converted into a non-confDrmable state to form a biocompatible coating on the tissue surface.
The coating can be applied using a catheter, such as a modified PT~A catheter. The 25 material is preferably applied using a si~gle catheter with single or multiple balloons and lumens. The catheter shQuld be o relatively low cross-sectional area. A long thin tubular catheter:
~ r"l ated using fluoroscopic guidance is 30 preferred for p~:o~iding access to the interior o organ or vascular areas. The material can a so be applied to the surface tQ be coated hy spray ng,~ -extruding or otherwise internally delivering the material in a conformable form via a long flexible 35 tubular device having single or multiple luméns.
During the step of positioning the material at the desired location, the location may CA 02202~i11 1997-04-11 Wo 96/11671 PCT/IJS95/14103 be accessed by either invasive surgical techl~liques or by relatïvely non- invasive techniques such as laparoscopic procedures or percutaneous transluminal procedures. The process of fixing the 5 shape of the material can be accomplished in several ways, depending on the character of the original material For example, in its conformable state the material can be formed using the balloon portlon of a balloon catheter~ after which the l0 conditions are adjusted such that the material is rendered non-conformable. In the preferred embodiment, gels are rendered non-conformable at the treatment site by photopolymerization using infrared, visible, W, or ultrasonic:radiation to 15 the material. Optionally, the polymers can be rendered non-conformable by localized heating or by chemical means. Thermal control can be l?rovided, for example, using a fluia flow through or into the balloon, or using a partially perforated balloon 2 0 such that temperature control f luid passes through the balloon into the lumen. Thermal control can also be :provided using electrical resistance heating via a wire running along the length of the catheter body in contact with resistive heating 25 elements. This type of heating element can make use of ~ DC or radio frequency (RF) current or ~ t~rnAl RF or microwave radiation. Other methods of achieving temperature control c~an a:lso be used, in~ ;ng light-induced heating using an ;nt~rnAl 3 0 optical f ibe~r- (naked or lensed) .
In one embodiment, the step in which the conformable material is contacted with the tissue surface may be considered as a "moldingl' procedure in which the conformable material is molded into 35 substAnt;Ally conforming contact with the body tissue before~ rendering it non-conformable. It is noted that the transition of the material from a CA 02202~11 1997-04-11 Wo 96/1 1671 PCT/IJS9~14103 conformable to- a non-conformable 6tate may involve~
a phase change in the material, however, 6uch a pha6e change is not neces6ary. For e~:ample, in certain embodiments, the terms "conformable~' and =
5 ~non-conformable~ are primarily relative de6criptions of a material which undergoes a significant ,change in viscosity and flowability without undergoing an actual phase shan~ge~ ~
Alternatively, the tran6ition of the material lO between its conformable and non-conformable=6tate6 may be the result of an ac~ual pha6e change in~ the material re6ulting either from the addition or removal of energy from the_material.
The polymeric materials may be applied ir, 15 ` cu6tom de6ign6, with varying thickne66e6, lengths ,~
and three-dimensional geometrie6 (e.g. spot~, -6tellate, linear, cylindrical, arcuate, 6piral) to achieve varying f ini6hed geometrie6 . Further, ~ the proce6s may be u6ed to apply material to the inner 20 6urface6 of hollow, cavernou6, or tubular biological structure6 (whether natural or artificially formed) in either= 6ingle or multi-layer conf iguration6 . The proce66 may al60 be used, when appropriate, to~occlude a ti66ue lumen 2~ completely.
The paving coating may be a~plied a6 a continuou6 layer either with o:r without perforation6. In the case in which the paving coating is applied without perforations, it is 3 0 ref erred to a6 a " seal " to act as a ,barrier, layer on the 6urface of the ti6sue. The coating can al60 be applied to l~ r 6urfaces, for example, ~to coat or encap6ulate indivillual or multiple~cell6.
Admini6tration of Micro~article6 ~ The injectable microparticle6 can be :
admini6tered to a patient intravenously, intramu6cularly, or= 6ubcutaneously or in other -CA 02202~i11 1997-04-11 WO 96/11671 PCT/lJ595/14103 --27-- =
known ways approFriate to the therapeutic effect desired, including as an aerosol~Qr spray for lungs or by direct lavage through orif iQes . ~ The particles can be lyophilized and then formulated into an aqueous suspension in a range of microgram/ml to lO0 mg/ml prior to use.
The desired concentration of biologically active molecules in the polymeric . carrier will depend on absorption, inactivation, and excretion rates of the drug as well as the ~deIivery rate of the molecules from the carrier. It is to be noted that dosage values will also yary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the indiYidual need_and the professional judgment of ~the person administering or superYising the administration o~ the compositions .
The microparticles can be administered once, or may be divided into~ a number of smaller doses to be administered at varying interyals of time, depending on the release rate of the particle, and the desired dosage. ~ :
~ ~olutions ~r suspensions used for intravenous, intramuscular, or topical application, or other delivery route can include any of the following components, ~as required: a sterile diluent such as water for injection, saline solution,~fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic =
solvents; antibacterial agents such~as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;: chelating agents such as ethyl~n~ min~tetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such= as sodium =
CA 02202~i11 1997-04-11 wog6/lr671 PCT/US95J14103 --2 8 ~
chloride or dextrose. The=parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline ~ -(PBS) .
Catheters can be made of any known - =
material, including metals, such as steel, and thermoplastic polymers. ~-~ccluding balloons can be maae from compliant materials such as latex or silicone, or non-compliant materials such as polyethylene -ter~ t7l~l Ate (PET) . The expansible member is preferably made from non-compliant materials such as PET, (PVC), polye~hylene or nylon. If used, the balloon catheter portion~ of a dilatation may optionally be coated with materials such as silicones, polytetrafluorQethylene~ (PTFE), hydrophilic materials like hydrated hydrogels and other lubricous materials to aid~in separation of~
the polymer coating.
In addition to blood vess~els, the process may be utilized for other ~applications such as coating the interior of veins, ureters, urethras, bronchi, biliary and pancreatic duct systems, the gut,~nasolacrimal ducts, sinus ca~r~ties, the eye, and eustachian, spermatic and fallopian tubes.
Llkewise the process can be used to provide a paving layer in the context of transhepatic .
portosystemic shunting, dialysis grafts, arterio-3 0 venous f istulae, and aortic and other arterial aneurysms. The paving ana sealing material of the process can also be used in other direct clinical applications even at the ~coronary level. These include but are not limited to the treatment of abrupt vessel reclosure post PCTA, the ~patching~
of significant vessel dissection, the sealing of vessel wall " f laps " either secondary to catheter~
CA 02202~i11 1997-04-11 Wo 96/11671 PCT/IJS95114103 injury or sp~ntaneously occurring, or the sealing of aneurysmal coronary dilations associated with various arteritidies. Further, the method provides intraoperative uses such as sealing of vessel 5 anastomoses during coronary artery bypass graf ting and the ability to: provide a "bandaged~ smooth polymer surface. = = ~
Treatment of gpecific Disorders Vascularization lO ~ A~=common proble~ in aging is atherosclerosis affecting the arteries of ~the lower limbs. This can cause claudication, or sharp pain when walking. This disease can be treated by inducing the creation of additional collateral 15 c--lrcuIation in the affected region (in this case, the leg) by introducing a growth factor such as VEGF (vascular endothelial growth factor), or a DNA
which can express it. The growth factor or DNA can be delivered~either by creating a thin coating 20 .-f,ntAin;n~ the factor inside an artery leading to the region, or by injecting microparticles containing the f actor into the artery f eeding the affected limb or region. In the latter case, the microparticles are preferably at least 15 microns 25 in diameter, preferab~y 20 microns or more, to cause the delivery particles to localize pr~ ;nAntly in the region. (It should be noted that some microparticles will probably exit the treated region, and lodge in,the lungs or 30 elsewhere; this eEfect must be accounted for in treatment planning . ) Another application includes ~
revascularization in cardiac tissue including the myocardium, and revascularization==a~ter stroke or 35 ischemia CA 02202~11 1997-04-11 Wo 96111671 PCr/lJS95114103 - 3 0 ~
Reqeneration or Repair of Tissues Yet another application is in regeneration or repair of particular~ organs .
Delivery of variou6 bone mo~rphogenetic proteins can 5 be useful for controlled remodeling of bone, or de novo bone or cartilage formation, in which it is critical that the developmental or morphogenetic effects be strictly r~nfin~l to the target site, and not exhibited throughout the organlsm. Local l0 deposition of biologically active molecules_can be useful in repairing bone in area6 such as the nasal passages and sinuses, where precise control of;
positioning is required.
Examples o~ other tissues which can be 15 treated in this manner include the stomach and intestines, where growth factors help accelerate repair of uIceration, repair of external ulceration of skin, and general wound repair.
Other organ systems susce_tible to 20 treatment include any organ system in which material f lows through the organ f rom a source, so that a factor can be admini6tered, either in a coating or as particles, for inst;llAtirn into the organ to he treated by flQW. R~ mrlAry organs 25 include lymph nodes, the bile duct, the urinary tract, the lungs, the spac-e occupied by the cerebro-spinal fluid, and the like.
The present invention wilI be further understood by reference to the ~ollowing non~
3 0 limiting examples .
Example l: Gene delivery from a gel in vitro.
Previous work on gene transfer into ~ -arteries has involved administration of DNA in a liquid vehicle, in-cluding pressïng the liquid into 35 artery walls with a balloon catheter. For more efficient local delivery, a thin, locally-deposited CA 02202~11 1997-04-11 gel, from which DNA can diffuse into-the target tissue, was utilized.
Transfection Procedure Positively-charged liposomes - 5 (Transfection-reagent, Boehringer Mannheim) t-nnt;~;nlng the catlonic lipid analogue 1,2-dioleoyloxy-3 - 3trimethylammonium) propane (DOTAP) ' were used fOR transfections. Plasmid DNA was purified by centrifugation through a cesium chloride gradient. Five ~Lg of DNA was mIxed with 30 ~g of liposomes in 200 IlL of Hanks Balanced Salt Solution (~IBSS, Gibco) .
Expression Vectors and Analysis of ~Recombinant Gene Express ion The lucif erase expression vector employed wa~ pRSVLUC (gift of Dr. A. Brasier, Galveston, TX, to Dr . Jeffrey M. Isner, St. Elizabeth' s Hospital, Boston, MA, who provided the vector) . This contains a 5' deletion of firefly luciferase cDNA, with transcription under the contrQl of the Rous sarcoma virus long terminal repeat~promoter. Use of this reporter gene allows for quantification of gene exFression in cell lysates. Cells were washed 3 times with calcium-free HBSS and extracts prepared using a cell lysis reagent (Promega,~
Madison WI) c~-nt~in;n~ l~ Triton-Xl00~M. Half of the extract was taken for analysis of total protein content, performed using the Biorad Microassay procedure. Bovine serum albumen (lmg/ml) was added to the other half as a carrier protein and luciferase activity was measured. For this, a 20 ~l aliquot was mixed at room temperature with l00 ~1 of luciferase assay reagent (Promega) c~nt~inin~
beetle luciferin. Emission of light, integrated Alternative nomenclature: N= [l- (2, 3 -Dioleoyloxy) propyl] -N, N, N, trïmethyl -ammonium methylsulf ate .
CA 02202~11 1997-04-11 WO 96~11671 PCTNS95114103 --32- i =
over 10 seconds, was measured using a luminometer (Turner Designs, Model 20e,~ Sunnyvale CA) .
Results, read as light units, were within the linear range of the detection system as evaluated -~
using serial dilutions o~ a known amount of ~ -luciferase (Sigma, Product No~ ~-9009) . Backgrouna activity, measured using phosphate-buffered saline or lysates of nontransfected cells, was consistently zero.
The plasmid pRSVLUC, ~ht:~;n.~ll from the laboratory of Dr. Jeffrey Isner of St. Elizabeth' s hospital in Boston, which encodes the enzyme luciferase under the control of a SV40 promoter, was dissolved in a gelling prepolymer. The prepolymer had a core of polyethylene glycol, MW8000, with about 5 lactate residues at each end, capped by an acrylate group at each end, synthesized accordin-g to the t~hin~q of PCT US
93/17669 by Hubbell et al., hereby incorporated by 20 reference. The polymer concentration was 1096. The application method was otherwise essentially;
identical to that described in Hill-West et al, Proc. Nat. Acad. Sci. USA 91:5967-5971, 1994.
Tissue sur~aces were stained by application of 1 mM
25 Eosin Y, and washed. The polymer solution containing the DNA, and also 100 mM ethanolamine and ~.15% n-vinyl pyrrolidone, and was polymerized essentially as in Hill-West. The amount o~ plasmid in the delivery vehicle was between 0 . 02 and 2 3 0 micrograms . ~iposomes as described above were optionally included. The luminal surface: of rabbit arterial strips, which were mi~lnt~;nf~tl in tissue culture essentially a~ described by Takeshita et =
al ., ;J. Clin. Invest ., 93 :~652-661, (1994), were 35 stained with a photoinitiating dye, Eosin Y, according to PCT US 93/01776 by Hubbell et al., and washed in medium. Prepolymer solution (23g~ wt CA 02202~11 1997-04-11 Wo 96/1167~ PCT/USgS/14103 prepolymer so~ution in saline) -nnt~;n;ng D=NA, with or without added lipQSomes (at a rdtio of 4 parts by weight of liposomes per part of DNA), was applied as a spot to stained arterial strips. The 5 solution was photopolymerized with green light to form a hydrogel. As controls, artery strips were treated with DNA/prepolymer solution, which was not gelled by photQillumination. After 7 days in culture, luciferase~ expression was measured in 10 Turner ~ight Unit9 per gram of tissue=(T~U/g), by standard methods. ~ ~
At the optimal level of n~NA application (2 micrQgrams/dose) controls had 3 . 3 +3 . 3 TLU/g;
tissue treated with gels cont~3;n;ng DNA nQt encapsulated within liposomes had 10 . 7+3 . 6 T~U/g;
and tissue treated with gels ~-~,nt~3;n;n~ DNA
encapsulated within liposomes had 2 0 . 8 + 1. 7 Tl.U/g .
The results demonstrate that gene transfer and expression can be accomplished by 20 delivery with a gel, with or without liposomes, and that the efficiency of delivery is significantly higher than when the DNA is merely applied tQ the tissue surface. EIowever, the results also inQicate that the ef i~icacy of transfer can be greatly 25 increased by incorporation Qf the DNA into liposomes prior to immobilization.
Exa~ple 2: In vivo Lucifera~e Gene Delivery via Photopolymerizable Xydrogel.
In vivo gene delivery was demonstrated 30 using the rat carotid artery model. Interfacially polymerized gels, prepared as described in example - 1, were f ormed in the right carotid artery of rats .
The le~t side was untreated and served as control.
Gels contained 25 mi~yld~.., DNA per ml of 35 - prepolymer solution c~n~; n; ng 10~ w/v prepolymer encapsulated in 100 micrograms liE~osomes/nLl of prepolymer, and otherwise were deposited as described by Xill-West et al. Arteries were CA 02202~11 1997-04-11 WO 96/11671 PCT/U`395/14103 =
illuminated with green light to polymerize the macromer, resulting in a layer about lOo micrometers thick. After 3 days, rats were~ _ sacrificed and tissue ~m;n~ for luciferase ' 5 expression.
No gene expression was evident in~ control (unt~eated) arteries, - while treated arteries had 8 . 2 + 6 . 2 TLU/g .
As additional controls, DNA/macromer lO solutio~s were applied either to the adventitial (outside) surface of arteries, and flushed with saline; or were applied to the i~terior surfac~e, -and not illuminated . The f ormer treatment gave 0 . 85 + . 21 TI.U/g, and the~ latter gave 3 . 9 . + 3 . 7 ~~
15 TLU/g.
Variations and modificatio~s of the claimed i~vention will be obvious to those skilled in the art from the foregoing detailed description of the invention. It is intended that all of ,these 20 variations and modifications be included within the scope of the appended claims. =~
Claims (15)
1. A method for targeted local delivery of biologically active molecules to cells and tissue, the method comprising:
selecting biodegradable microparticles comprising biologically active molecules and having a diameter causing the microparticles to lodge in at least one targeted distal site in an animal where treatment is needed, upon administration of the microparticles to the animal;
and administering the microparticles to the animal thereby to cause the microparticles to lodge at the targeted distal site within the body where release is desired for a sufficient amount of time to permit controlled release of a therapeutically effective amount of the biologically active molecules at the targeted site.
selecting biodegradable microparticles comprising biologically active molecules and having a diameter causing the microparticles to lodge in at least one targeted distal site in an animal where treatment is needed, upon administration of the microparticles to the animal;
and administering the microparticles to the animal thereby to cause the microparticles to lodge at the targeted distal site within the body where release is desired for a sufficient amount of time to permit controlled release of a therapeutically effective amount of the biologically active molecules at the targeted site.
2. The method of claim 1, wherein the microparticles have a diameter of 1 to 100 microns, and are administered into a region or organ so as to lodge or adhere at a distal locus within the region or organ.
3. The method of claim 1 wherein the microparticles have a diameter of 1 to 100 microns and are administered into the circulation and release the biologically active molecules after entrapment at at least one site where occlusion has occurred, or at a region where the microparticle selectively lodges.
4. The method of claim 1 wherein the microparticles are in the form of liposomes.
5. The use of biodegradable microparticles in the manufacture of a medicament for targeted local delivery of biologically active molecules to cells and tissue wherein the microparticles comprise biologically active molecules and have a diameter causing the microparticles to lodge in at least one targeted distal site in an animal where treatment is needed, upon administration of the microparticles to the animal, for a sufficient amount of time to permit controlled release of a therapeutically effective amount of the biologically active molecules at the targeted site.
6. The use of claim 5 wherein the the microparticles have a diameter of 1 to 100 microns.
7. The method of claim 1 wherein the biologically active molecules are selected from the group consisting of proteins, nucleic acid molecules, carbohydrates, lipids, and combinations thereof.
8. The method of claim 7 wherein the proteins are selected from the group consisting of growth factors, angiogenesis factors, cytokines, and immunosuppressants.
9. The method of claim 8 to promote vascularization or revascularization of a tissue wherein the growth factor is vascular endothelial growth factor.
10. The method of claim 1 wherein the microparticles are administered in a pharmaceutically acceptable carrier by a route of administration selected from the group consisting of intravenous, intramuscular, subcutaneous, direct lavage and aerosol administration.
11. The method of claim 1 wherein the microparticles are administered intravenously.
12. The method of claim 1 wherein the microparticles are administered intravascularly.
13. The method of claim 1 wherein the biologically active molecules comprise deliverable growth factors.
14. The use of claim 5 wherein the biologically active molecules comprise deliverable growth factors.
15. The use of claim 5 wherein the biologically active molecules are selected from the group consisting of proteins, nucleic acid molecules, carbohydrates, lipids, and combinations thereof.
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Families Citing this family (401)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030032610A1 (en) * | 1996-06-03 | 2003-02-13 | Gilchrest Barbara A. | Method to inhibit cell growth using oligonucleotides |
US6147056A (en) * | 1995-06-06 | 2000-11-14 | Trustees Of Boston University | Use of locally applied DNA fragments |
US7094766B1 (en) | 1995-06-06 | 2006-08-22 | Trustees Of Boston University | Use of locally applied DNA fragments |
WO1997017063A1 (en) | 1995-11-09 | 1997-05-15 | Microbiological Research Authority | Microencapsulated dna for vaccination and gene therapy |
US6270795B1 (en) | 1995-11-09 | 2001-08-07 | Microbiological Research Authority | Method of making microencapsulated DNA for vaccination and gene therapy |
US6143037A (en) * | 1996-06-12 | 2000-11-07 | The Regents Of The University Of Michigan | Compositions and methods for coating medical devices |
WO1998012243A1 (en) * | 1996-09-23 | 1998-03-26 | Focal, Inc. | Polymerizable biodegradable polymers including carbonate or dioxanone linkages |
DE59707744D1 (en) * | 1996-10-23 | 2002-08-22 | Sueddeutsche Kalkstickstoff | METHOD FOR PRODUCING BIOLOGICALLY ACTIVE POLYMERNANOPARTICLE-NUCLEIC ACID CONJUGATES |
US6387700B1 (en) * | 1996-11-04 | 2002-05-14 | The Reagents Of The University Of Michigan | Cationic peptides, Cys-Trp-(LYS)n, for gene delivery |
US5833651A (en) * | 1996-11-08 | 1998-11-10 | Medtronic, Inc. | Therapeutic intraluminal stents |
US6335010B1 (en) * | 1996-11-08 | 2002-01-01 | University Of California At San Diego | Gene therapy in coronary angioplasty and bypass |
CA2274004A1 (en) * | 1996-12-03 | 1998-06-11 | Osteobiologics, Inc. | Biodegradable polymeric film |
US20020182258A1 (en) * | 1997-01-22 | 2002-12-05 | Zycos Inc., A Delaware Corporation | Microparticles for delivery of nucleic acid |
US5783567A (en) * | 1997-01-22 | 1998-07-21 | Pangaea Pharmaceuticals, Inc. | Microparticles for delivery of nucleic acid |
US20050033132A1 (en) | 1997-03-04 | 2005-02-10 | Shults Mark C. | Analyte measuring device |
US20030191496A1 (en) | 1997-03-12 | 2003-10-09 | Neomend, Inc. | Vascular sealing device with microwave antenna |
US6371975B2 (en) | 1998-11-06 | 2002-04-16 | Neomend, Inc. | Compositions, systems, and methods for creating in situ, chemically cross-linked, mechanical barriers |
US5899917A (en) * | 1997-03-12 | 1999-05-04 | Cardiosynopsis, Inc. | Method for forming a stent in situ |
AU6769098A (en) * | 1997-03-20 | 1998-10-12 | Focal, Inc. | Biodegradable tissue retractor |
US10028851B2 (en) * | 1997-04-15 | 2018-07-24 | Advanced Cardiovascular Systems, Inc. | Coatings for controlling erosion of a substrate of an implantable medical device |
US6240616B1 (en) * | 1997-04-15 | 2001-06-05 | Advanced Cardiovascular Systems, Inc. | Method of manufacturing a medicated porous metal prosthesis |
US8172897B2 (en) * | 1997-04-15 | 2012-05-08 | Advanced Cardiovascular Systems, Inc. | Polymer and metal composite implantable medical devices |
IL134084A0 (en) * | 1997-07-18 | 2001-04-30 | Infimed Inc | Biodegradable macromers for the controlled release of biologically active substances |
ZA987019B (en) * | 1997-08-06 | 1999-06-04 | Focal Inc | Hemostatic tissue sealants |
US5952405A (en) * | 1997-08-26 | 1999-09-14 | National Starch And Chemical Investment Holding Corporation | Lactide graft copolymers and hot melt adhesives prepared from same |
US5980548A (en) | 1997-10-29 | 1999-11-09 | Kensey Nash Corporation | Transmyocardial revascularization system |
US7070607B2 (en) * | 1998-01-27 | 2006-07-04 | The Regents Of The University Of California | Bioabsorbable polymeric implants and a method of using the same to create occlusions |
WO1999053961A1 (en) * | 1998-04-23 | 1999-10-28 | The Regents Of The University Of Michigan | Peptides for efficient gene transfer |
US6206914B1 (en) | 1998-04-30 | 2001-03-27 | Medtronic, Inc. | Implantable system with drug-eluting cells for on-demand local drug delivery |
WO1999058134A1 (en) * | 1998-05-11 | 1999-11-18 | Purdue Research Foundation | Methods and compositions for nucleic acid delivery |
GB9810236D0 (en) | 1998-05-13 | 1998-07-08 | Microbiological Res Authority | Improvements relating to encapsulation of bioactive agents |
US6406719B1 (en) | 1998-05-13 | 2002-06-18 | Microbiological Research Authority | Encapsulation of bioactive agents |
US6350463B1 (en) | 1998-05-23 | 2002-02-26 | Andre Bieniarz | Method of treatment for premature rupture of membranes in pregnancy (PROM) |
US6641576B1 (en) * | 1998-05-28 | 2003-11-04 | Georgia Tech Research Corporation | Devices for creating vascular grafts by vessel distension using rotatable elements |
US6663617B1 (en) | 1998-05-28 | 2003-12-16 | Georgia Tech Research Corporation | Devices for creating vascular grafts by vessel distension using fixed post and moveable driver elements |
US6548302B1 (en) | 1998-06-18 | 2003-04-15 | Johns Hopkins University School Of Medicine | Polymers for delivery of nucleic acids |
US20020022588A1 (en) * | 1998-06-23 | 2002-02-21 | James Wilkie | Methods and compositions for sealing tissue leaks |
US6994686B2 (en) | 1998-08-26 | 2006-02-07 | Neomend, Inc. | Systems for applying cross-linked mechanical barriers |
US6458147B1 (en) | 1998-11-06 | 2002-10-01 | Neomend, Inc. | Compositions, systems, and methods for arresting or controlling bleeding or fluid leakage in body tissue |
WO2000012726A2 (en) * | 1998-08-27 | 2000-03-09 | Massachusetts Institute Of Technology | Rationally designed heparinases derived from heparinase i and ii |
US7056504B1 (en) | 1998-08-27 | 2006-06-06 | Massachusetts Institute Of Technology | Rationally designed heparinases derived from heparinase I and II |
US7662409B2 (en) * | 1998-09-25 | 2010-02-16 | Gel-Del Technologies, Inc. | Protein matrix materials, devices and methods of making and using thereof |
US7067144B2 (en) * | 1998-10-20 | 2006-06-27 | Omeros Corporation | Compositions and methods for systemic inhibition of cartilage degradation |
US6949114B2 (en) | 1998-11-06 | 2005-09-27 | Neomend, Inc. | Systems, methods, and compositions for achieving closure of vascular puncture sites |
US7279001B2 (en) | 1998-11-06 | 2007-10-09 | Neomend, Inc. | Systems, methods, and compositions for achieving closure of vascular puncture sites |
US6899889B1 (en) | 1998-11-06 | 2005-05-31 | Neomend, Inc. | Biocompatible material composition adaptable to diverse therapeutic indications |
US6830756B2 (en) | 1998-11-06 | 2004-12-14 | Neomend, Inc. | Systems, methods, and compositions for achieving closure of vascular puncture sites |
AU3347000A (en) | 1999-01-19 | 2000-08-01 | Children's Hospital Of Philadelphia, The | Hydrogel compositions for controlled delivery of virus vectors and methods of use thereof |
US6500807B1 (en) | 1999-02-02 | 2002-12-31 | Safescience, Inc. | Modified pectin and nucleic acid composition |
US6709465B2 (en) | 1999-03-18 | 2004-03-23 | Fossa Medical, Inc. | Radially expanding ureteral device |
US7214229B2 (en) | 1999-03-18 | 2007-05-08 | Fossa Medical, Inc. | Radially expanding stents |
US6597996B1 (en) | 1999-04-23 | 2003-07-22 | Massachusetts Institute Of Technology | Method for indentifying or characterizing properties of polymeric units |
US7261881B1 (en) * | 1999-05-20 | 2007-08-28 | Yale University | Modulation of angiogenesis and wound healing |
US6586011B2 (en) | 1999-06-10 | 2003-07-01 | Southpac Trust International, Inc. | Microencapsulated plasminogen activators |
AU769853B2 (en) | 1999-06-11 | 2004-02-05 | Atossa Genetics, Inc. | Gel composition for filing a breast milk duct prior to surgical excision of the duct or other breast tissue |
AU5624500A (en) * | 1999-06-18 | 2001-01-09 | Collaborative Group, Ltd., The | Hyaluronic acid microspheres for sustained gene transfer |
US6521431B1 (en) * | 1999-06-22 | 2003-02-18 | Access Pharmaceuticals, Inc. | Biodegradable cross-linkers having a polyacid connected to reactive groups for cross-linking polymer filaments |
US6375970B1 (en) | 1999-07-07 | 2002-04-23 | Andre Bieniarz | Methods and materials for preterm birth prevention |
US6770740B1 (en) | 1999-07-13 | 2004-08-03 | The Regents Of The University Of Michigan | Crosslinked DNA condensate compositions and gene delivery methods |
US7030097B1 (en) | 1999-07-14 | 2006-04-18 | Cornell Research Foundation, Inc. | Controlled nucleic acid delivery systems |
US6709427B1 (en) * | 1999-08-05 | 2004-03-23 | Kensey Nash Corporation | Systems and methods for delivering agents into targeted tissue of a living being |
US6785400B1 (en) * | 1999-08-17 | 2004-08-31 | Image Therm Engineering, Inc. | Spray data acquisition system |
JP4394322B2 (en) * | 1999-08-17 | 2010-01-06 | プロベリス サイエンティフィック コーポレイション | Spray data analysis and characterization system |
US7279176B1 (en) * | 1999-09-02 | 2007-10-09 | Rice University | Nitric oxide-producing hydrogel materials |
US7052711B2 (en) * | 1999-09-02 | 2006-05-30 | Rice University | Nitric oxide-producing hydrogel materials |
US7807211B2 (en) * | 1999-09-03 | 2010-10-05 | Advanced Cardiovascular Systems, Inc. | Thermal treatment of an implantable medical device |
US20070032853A1 (en) * | 2002-03-27 | 2007-02-08 | Hossainy Syed F | 40-O-(2-hydroxy)ethyl-rapamycin coated stent |
US6329348B1 (en) | 1999-11-08 | 2001-12-11 | Cornell Research Foundation, Inc. | Method of inducing angiogenesis |
US7195780B2 (en) * | 2002-10-21 | 2007-03-27 | University Of Florida | Nanoparticle delivery system |
US20050238686A1 (en) * | 1999-12-23 | 2005-10-27 | Advanced Cardiovascular Systems, Inc. | Coating for implantable devices and a method of forming the same |
CA2396628A1 (en) | 2000-01-25 | 2001-08-02 | Edwards Lifesciences Corporation | Delivery systems for treatment of restenosis and anastomotic intimal hyperplasia |
WO2001055360A1 (en) * | 2000-01-28 | 2001-08-02 | Infimed Therapeutics, Inc. | Slow release protein polymers |
US6869789B2 (en) * | 2000-03-08 | 2005-03-22 | Massachusetts Institute Of Technology | Heparinase III and uses thereof |
EP1263802B1 (en) * | 2000-03-13 | 2005-11-23 | BioCure, Inc. | Hydrogel biomedical articles |
ATE373682T1 (en) | 2000-03-13 | 2007-10-15 | Biocure Inc | EMBOLIC COMPOSITIONS |
US6652883B2 (en) * | 2000-03-13 | 2003-11-25 | Biocure, Inc. | Tissue bulking and coating compositions |
WO2001072281A2 (en) | 2000-03-24 | 2001-10-04 | Biosphere Medical Inc. | Microspheres for active embolization |
AU2001245987A1 (en) * | 2000-03-24 | 2001-10-08 | Biosphere Medical, Inc. | Compositions and methods for gene therapy |
EP2363133A1 (en) * | 2000-03-31 | 2011-09-07 | Trustees of Boston University | Composition comprising DNA fragments and medical and cosmetic uses thereof |
US8109994B2 (en) | 2003-01-10 | 2012-02-07 | Abbott Cardiovascular Systems, Inc. | Biodegradable drug delivery material for stent |
US6527801B1 (en) * | 2000-04-13 | 2003-03-04 | Advanced Cardiovascular Systems, Inc. | Biodegradable drug delivery material for stent |
US7875283B2 (en) * | 2000-04-13 | 2011-01-25 | Advanced Cardiovascular Systems, Inc. | Biodegradable polymers for use with implantable medical devices |
US6589549B2 (en) | 2000-04-27 | 2003-07-08 | Macromed, Incorporated | Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles |
WO2001085637A2 (en) * | 2000-05-09 | 2001-11-15 | Pearl Technology Holdings, Llc | Biodegradable fiber optic |
US20020115603A1 (en) * | 2000-06-22 | 2002-08-22 | Chiron Corporation | Methods and compositions for the treatment of peripheral artery disease |
US6875212B2 (en) * | 2000-06-23 | 2005-04-05 | Vertelink Corporation | Curable media for implantable medical device |
US6964667B2 (en) * | 2000-06-23 | 2005-11-15 | Sdgi Holdings, Inc. | Formed in place fixation system with thermal acceleration |
US6899713B2 (en) * | 2000-06-23 | 2005-05-31 | Vertelink Corporation | Formable orthopedic fixation system |
US6821277B2 (en) * | 2000-06-23 | 2004-11-23 | University Of Southern California Patent And Copyright Administration | Percutaneous vertebral fusion system |
JP4911865B2 (en) * | 2000-09-12 | 2012-04-04 | マサチューセッツ インスティテュート オブ テクノロジー | Methods and products related to low molecular weight heparin |
EP1322337A2 (en) * | 2000-09-25 | 2003-07-02 | Board of Regents, The University of Texas System | Pei : dna vector formulations for in vitro and in vivo gene delivery |
US6953560B1 (en) * | 2000-09-28 | 2005-10-11 | Advanced Cardiovascular Systems, Inc. | Barriers for polymer-coated implantable medical devices and methods for making the same |
WO2002032406A2 (en) | 2000-10-18 | 2002-04-25 | Massachusetts Institute Of Technology | Methods and products related to pulmonary delivery of polysaccharides |
US7807210B1 (en) | 2000-10-31 | 2010-10-05 | Advanced Cardiovascular Systems, Inc. | Hemocompatible polymers on hydrophobic porous polymers |
US7481790B2 (en) * | 2000-12-27 | 2009-01-27 | Advanced Cardiovascular Systems, Inc. | Vessel enlargement by arteriogenic factor delivery |
GB0100761D0 (en) | 2001-01-11 | 2001-02-21 | Biocompatibles Ltd | Drug delivery from stents |
US7008642B1 (en) | 2001-02-12 | 2006-03-07 | Advanced Cardiovascular Systems, Inc. | Compositions for achieving a therapeutic effect in an anatomical structure and methods of using the same |
WO2002071980A2 (en) * | 2001-03-09 | 2002-09-19 | Georgia Tech Research Corporation | Intravascular device and method for axially stretching blood vessels |
US6780424B2 (en) | 2001-03-30 | 2004-08-24 | Charles David Claude | Controlled morphologies in polymer drug for release of drugs from polymer films |
US7056967B2 (en) * | 2001-04-10 | 2006-06-06 | Ciba Specialty Chemicals Corporation | Stabilized medium and high voltage cable insulation composition |
US6660211B2 (en) | 2001-04-23 | 2003-12-09 | Kimberly-Clark Worldwide, Inc. | Methods of making biodegradable films having enhanced ductility and breathability |
US6905759B2 (en) * | 2001-04-23 | 2005-06-14 | Kimberly Clark Worldwide, Inc. | Biodegradable films having enhanced ductility and breathability |
US20020197253A1 (en) * | 2001-05-22 | 2002-12-26 | Cheek Dennis J. | Compositions and methods for promoting or inhibiting NDPK |
AU2002310046A1 (en) * | 2001-05-22 | 2002-12-03 | Duke University | Compositions and methods for inhibiting metastasis |
US6743462B1 (en) * | 2001-05-31 | 2004-06-01 | Advanced Cardiovascular Systems, Inc. | Apparatus and method for coating implantable devices |
US6702744B2 (en) * | 2001-06-20 | 2004-03-09 | Advanced Cardiovascular Systems, Inc. | Agents that stimulate therapeutic angiogenesis and techniques and devices that enable their delivery |
US6799090B2 (en) | 2001-06-21 | 2004-09-28 | Image Therm Engineering, Inc. | Precise position controlled actuating method and system |
US8741378B1 (en) | 2001-06-27 | 2014-06-03 | Advanced Cardiovascular Systems, Inc. | Methods of coating an implantable device |
US6695920B1 (en) * | 2001-06-27 | 2004-02-24 | Advanced Cardiovascular Systems, Inc. | Mandrel for supporting a stent and a method of using the mandrel to coat a stent |
US7682669B1 (en) | 2001-07-30 | 2010-03-23 | Advanced Cardiovascular Systems, Inc. | Methods for covalently immobilizing anti-thrombogenic material into a coating on a medical device |
US8303651B1 (en) * | 2001-09-07 | 2012-11-06 | Advanced Cardiovascular Systems, Inc. | Polymeric coating for reducing the rate of release of a therapeutic substance from a stent |
US7989018B2 (en) * | 2001-09-17 | 2011-08-02 | Advanced Cardiovascular Systems, Inc. | Fluid treatment of a polymeric coating on an implantable medical device |
US7285304B1 (en) * | 2003-06-25 | 2007-10-23 | Advanced Cardiovascular Systems, Inc. | Fluid treatment of a polymeric coating on an implantable medical device |
US6863683B2 (en) | 2001-09-19 | 2005-03-08 | Abbott Laboratoris Vascular Entities Limited | Cold-molding process for loading a stent onto a stent delivery system |
US6753071B1 (en) * | 2001-09-27 | 2004-06-22 | Advanced Cardiovascular Systems, Inc. | Rate-reducing membrane for release of an agent |
JP2005518827A (en) * | 2001-10-05 | 2005-06-30 | サーモディクス,インコーポレイテッド | Particle fixing coating and use thereof |
US7195913B2 (en) * | 2001-10-05 | 2007-03-27 | Surmodics, Inc. | Randomly ordered arrays and methods of making and using |
US8608661B1 (en) | 2001-11-30 | 2013-12-17 | Advanced Cardiovascular Systems, Inc. | Method for intravascular delivery of a treatment agent beyond a blood vessel wall |
US20030139333A1 (en) * | 2002-01-18 | 2003-07-24 | Genetix Pharmaceuticals, Inc. | Methods and compositions for promoting angiogenesis |
US8364229B2 (en) | 2003-07-25 | 2013-01-29 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US7613491B2 (en) | 2002-05-22 | 2009-11-03 | Dexcom, Inc. | Silicone based membranes for use in implantable glucose sensors |
AU2003214171A1 (en) * | 2002-03-12 | 2003-09-29 | Harold Brem | Method for treating diabetic ulcers |
US8623393B2 (en) * | 2002-04-29 | 2014-01-07 | Gel-Del Technologies, Inc. | Biomatrix structural containment and fixation systems and methods of use thereof |
PL374188A1 (en) * | 2002-05-09 | 2005-10-03 | Ultrast Llc | Medium for contrast enhancement use for ultrasonic, endoscopic and other medical examinations |
US7217426B1 (en) | 2002-06-21 | 2007-05-15 | Advanced Cardiovascular Systems, Inc. | Coatings containing polycationic peptides for cardiovascular therapy |
US7794743B2 (en) * | 2002-06-21 | 2010-09-14 | Advanced Cardiovascular Systems, Inc. | Polycationic peptide coatings and methods of making the same |
US7033602B1 (en) | 2002-06-21 | 2006-04-25 | Advanced Cardiovascular Systems, Inc. | Polycationic peptide coatings and methods of coating implantable medical devices |
US8506617B1 (en) | 2002-06-21 | 2013-08-13 | Advanced Cardiovascular Systems, Inc. | Micronized peptide coated stent |
US7056523B1 (en) | 2002-06-21 | 2006-06-06 | Advanced Cardiovascular Systems, Inc. | Implantable medical devices incorporating chemically conjugated polymers and oligomers of L-arginine |
US7396539B1 (en) * | 2002-06-21 | 2008-07-08 | Advanced Cardiovascular Systems, Inc. | Stent coatings with engineered drug release rate |
US7361368B2 (en) * | 2002-06-28 | 2008-04-22 | Advanced Cardiovascular Systems, Inc. | Device and method for combining a treatment agent and a gel |
AU2003268167B2 (en) * | 2002-08-20 | 2009-10-22 | Exactech, Inc. | Composition for the carrying and delivery of bone growth inducing material and methods for producing and applying the composition |
US7429382B2 (en) | 2002-10-16 | 2008-09-30 | Corixa Corporation | Antibodies that bind cell-associated CA 125/O772P and methods of use thereof |
US20060271168A1 (en) * | 2002-10-30 | 2006-11-30 | Klaus Kleine | Degradable medical device |
US6896965B1 (en) * | 2002-11-12 | 2005-05-24 | Advanced Cardiovascular Systems, Inc. | Rate limiting barriers for implantable devices |
US7758880B2 (en) | 2002-12-11 | 2010-07-20 | Advanced Cardiovascular Systems, Inc. | Biocompatible polyacrylate compositions for medical applications |
US7776926B1 (en) | 2002-12-11 | 2010-08-17 | Advanced Cardiovascular Systems, Inc. | Biocompatible coating for implantable medical devices |
US7074276B1 (en) * | 2002-12-12 | 2006-07-11 | Advanced Cardiovascular Systems, Inc. | Clamp mandrel fixture and a method of using the same to minimize coating defects |
US7758881B2 (en) | 2004-06-30 | 2010-07-20 | Advanced Cardiovascular Systems, Inc. | Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device |
US20060002968A1 (en) * | 2004-06-30 | 2006-01-05 | Gordon Stewart | Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders |
US8435550B2 (en) | 2002-12-16 | 2013-05-07 | Abbot Cardiovascular Systems Inc. | Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device |
US7173342B2 (en) * | 2002-12-17 | 2007-02-06 | Intel Corporation | Method and apparatus for reducing electrical interconnection fatigue |
US7223826B2 (en) | 2003-01-30 | 2007-05-29 | 3M Innovative Properties Company | Amide-functional polymers, compositions, and methods |
US20040151691A1 (en) | 2003-01-30 | 2004-08-05 | Oxman Joel D. | Hardenable thermally responsive compositions |
US7063884B2 (en) * | 2003-02-26 | 2006-06-20 | Advanced Cardiovascular Systems, Inc. | Stent coating |
US20060269924A1 (en) * | 2003-04-11 | 2006-11-30 | Trustees Of Boston University | Modulation of telomere-initiated cell signaling |
CA2520801C (en) * | 2003-04-14 | 2012-10-23 | Image Therm Engineering, Inc. | Measuring manual actuation of spray devices |
US8038991B1 (en) | 2003-04-15 | 2011-10-18 | Abbott Cardiovascular Systems Inc. | High-viscosity hyaluronic acid compositions to treat myocardial conditions |
US8821473B2 (en) | 2003-04-15 | 2014-09-02 | Abbott Cardiovascular Systems Inc. | Methods and compositions to treat myocardial conditions |
US7641643B2 (en) * | 2003-04-15 | 2010-01-05 | Abbott Cardiovascular Systems Inc. | Methods and compositions to treat myocardial conditions |
US7473267B2 (en) * | 2003-04-25 | 2009-01-06 | Warsaw Orthopedic, Inc. | System and method for minimally invasive posterior fixation |
US7279174B2 (en) * | 2003-05-08 | 2007-10-09 | Advanced Cardiovascular Systems, Inc. | Stent coatings comprising hydrophilic additives |
US7186789B2 (en) * | 2003-06-11 | 2007-03-06 | Advanced Cardiovascular Systems, Inc. | Bioabsorbable, biobeneficial polyester polymers for use in drug eluting stent coatings |
US8465537B2 (en) * | 2003-06-17 | 2013-06-18 | Gel-Del Technologies, Inc. | Encapsulated or coated stent systems |
US20050118344A1 (en) | 2003-12-01 | 2005-06-02 | Pacetti Stephen D. | Temperature controlled crimping |
US20050021127A1 (en) * | 2003-07-21 | 2005-01-27 | Kawula Paul John | Porous glass fused onto stent for drug retention |
US9763609B2 (en) | 2003-07-25 | 2017-09-19 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US20070173710A1 (en) * | 2005-04-08 | 2007-07-26 | Petisce James R | Membranes for an analyte sensor |
US7785512B1 (en) | 2003-07-31 | 2010-08-31 | Advanced Cardiovascular Systems, Inc. | Method and system of controlled temperature mixing and molding of polymers with active agents for implantable medical devices |
US7591801B2 (en) | 2004-02-26 | 2009-09-22 | Dexcom, Inc. | Integrated delivery device for continuous glucose sensor |
US20050037047A1 (en) * | 2003-08-11 | 2005-02-17 | Young-Ho Song | Medical devices comprising spray dried microparticles |
US7920906B2 (en) | 2005-03-10 | 2011-04-05 | Dexcom, Inc. | System and methods for processing analyte sensor data for sensor calibration |
US7198675B2 (en) | 2003-09-30 | 2007-04-03 | Advanced Cardiovascular Systems | Stent mandrel fixture and method for selectively coating surfaces of a stent |
TW200526253A (en) * | 2003-11-14 | 2005-08-16 | Chugai Pharmaceutical Co Ltd | Cross-linked polysaccharide microparticles and process for producing the same |
US7261946B2 (en) | 2003-11-14 | 2007-08-28 | Advanced Cardiovascular Systems, Inc. | Block copolymers of acrylates and methacrylates with fluoroalkenes |
US9247900B2 (en) | 2004-07-13 | 2016-02-02 | Dexcom, Inc. | Analyte sensor |
US9114198B2 (en) * | 2003-11-19 | 2015-08-25 | Advanced Cardiovascular Systems, Inc. | Biologically beneficial coatings for implantable devices containing fluorinated polymers and methods for fabricating the same |
US8192752B2 (en) * | 2003-11-21 | 2012-06-05 | Advanced Cardiovascular Systems, Inc. | Coatings for implantable devices including biologically erodable polyesters and methods for fabricating the same |
EP1691746B1 (en) * | 2003-12-08 | 2015-05-27 | Gel-Del Technologies, Inc. | Mucoadhesive drug delivery devices and methods of making and using thereof |
US7220816B2 (en) * | 2003-12-16 | 2007-05-22 | Advanced Cardiovascular Systems, Inc. | Biologically absorbable coatings for implantable devices based on poly(ester amides) and methods for fabricating the same |
US7435788B2 (en) * | 2003-12-19 | 2008-10-14 | Advanced Cardiovascular Systems, Inc. | Biobeneficial polyamide/polyethylene glycol polymers for use with drug eluting stents |
US8808228B2 (en) | 2004-02-26 | 2014-08-19 | Dexcom, Inc. | Integrated medicament delivery device for use with continuous analyte sensor |
WO2009048462A1 (en) | 2007-10-09 | 2009-04-16 | Dexcom, Inc. | Integrated insulin delivery system with continuous glucose sensor |
US8685431B2 (en) * | 2004-03-16 | 2014-04-01 | Advanced Cardiovascular Systems, Inc. | Biologically absorbable coatings for implantable devices based on copolymers having ester bonds and methods for fabricating the same |
US20050214339A1 (en) * | 2004-03-29 | 2005-09-29 | Yiwen Tang | Biologically degradable compositions for medical applications |
US8778014B1 (en) | 2004-03-31 | 2014-07-15 | Advanced Cardiovascular Systems, Inc. | Coatings for preventing balloon damage to polymer coated stents |
JP2008501640A (en) * | 2004-04-21 | 2008-01-24 | ザ ユニヴァーシティー オヴ シカゴ | Myosin light chain kinase inhibitor and use thereof |
US20050265960A1 (en) * | 2004-05-26 | 2005-12-01 | Pacetti Stephen D | Polymers containing poly(ester amides) and agents for use with medical articles and methods of fabricating the same |
US7820732B2 (en) * | 2004-04-30 | 2010-10-26 | Advanced Cardiovascular Systems, Inc. | Methods for modulating thermal and mechanical properties of coatings on implantable devices |
US8293890B2 (en) * | 2004-04-30 | 2012-10-23 | Advanced Cardiovascular Systems, Inc. | Hyaluronic acid based copolymers |
US9561309B2 (en) * | 2004-05-27 | 2017-02-07 | Advanced Cardiovascular Systems, Inc. | Antifouling heparin coatings |
US20050271700A1 (en) * | 2004-06-03 | 2005-12-08 | Desnoyer Jessica R | Poly(ester amide) coating composition for implantable devices |
US7563780B1 (en) | 2004-06-18 | 2009-07-21 | Advanced Cardiovascular Systems, Inc. | Heparin prodrugs and drug delivery stents formed therefrom |
US8568469B1 (en) | 2004-06-28 | 2013-10-29 | Advanced Cardiovascular Systems, Inc. | Stent locking element and a method of securing a stent on a delivery system |
US8241554B1 (en) | 2004-06-29 | 2012-08-14 | Advanced Cardiovascular Systems, Inc. | Method of forming a stent pattern on a tube |
US20050287184A1 (en) * | 2004-06-29 | 2005-12-29 | Hossainy Syed F A | Drug-delivery stent formulations for restenosis and vulnerable plaque |
US8170803B2 (en) | 2004-07-13 | 2012-05-01 | Dexcom, Inc. | Transcutaneous analyte sensor |
US20070045902A1 (en) | 2004-07-13 | 2007-03-01 | Brauker James H | Analyte sensor |
US8747878B2 (en) | 2006-04-28 | 2014-06-10 | Advanced Cardiovascular Systems, Inc. | Method of fabricating an implantable medical device by controlling crystalline structure |
US20060020330A1 (en) * | 2004-07-26 | 2006-01-26 | Bin Huang | Method of fabricating an implantable medical device with biaxially oriented polymers |
US8778256B1 (en) | 2004-09-30 | 2014-07-15 | Advanced Cardiovascular Systems, Inc. | Deformation of a polymer tube in the fabrication of a medical article |
US7971333B2 (en) * | 2006-05-30 | 2011-07-05 | Advanced Cardiovascular Systems, Inc. | Manufacturing process for polymetric stents |
US8747879B2 (en) * | 2006-04-28 | 2014-06-10 | Advanced Cardiovascular Systems, Inc. | Method of fabricating an implantable medical device to reduce chance of late inflammatory response |
US7731890B2 (en) * | 2006-06-15 | 2010-06-08 | Advanced Cardiovascular Systems, Inc. | Methods of fabricating stents with enhanced fracture toughness |
US8357391B2 (en) | 2004-07-30 | 2013-01-22 | Advanced Cardiovascular Systems, Inc. | Coatings for implantable devices comprising poly (hydroxy-alkanoates) and diacid linkages |
US7494665B1 (en) * | 2004-07-30 | 2009-02-24 | Advanced Cardiovascular Systems, Inc. | Polymers containing siloxane monomers |
US7311980B1 (en) | 2004-08-02 | 2007-12-25 | Advanced Cardiovascular Systems, Inc. | Polyactive/polylactic acid coatings for an implantable device |
US20060041102A1 (en) * | 2004-08-23 | 2006-02-23 | Advanced Cardiovascular Systems, Inc. | Implantable devices comprising biologically absorbable polymers having constant rate of degradation and methods for fabricating the same |
US9283099B2 (en) * | 2004-08-25 | 2016-03-15 | Advanced Cardiovascular Systems, Inc. | Stent-catheter assembly with a releasable connection for stent retention |
US7648727B2 (en) * | 2004-08-26 | 2010-01-19 | Advanced Cardiovascular Systems, Inc. | Methods for manufacturing a coated stent-balloon assembly |
US7244443B2 (en) * | 2004-08-31 | 2007-07-17 | Advanced Cardiovascular Systems, Inc. | Polymers of fluorinated monomers and hydrophilic monomers |
US20070275874A1 (en) * | 2004-09-03 | 2007-11-29 | Yale University | Use of Leptin in Wound Healing |
US7229471B2 (en) * | 2004-09-10 | 2007-06-12 | Advanced Cardiovascular Systems, Inc. | Compositions containing fast-leaching plasticizers for improved performance of medical devices |
US8110211B2 (en) * | 2004-09-22 | 2012-02-07 | Advanced Cardiovascular Systems, Inc. | Medicated coatings for implantable medical devices including polyacrylates |
US9011831B2 (en) | 2004-09-30 | 2015-04-21 | Advanced Cardiovascular Systems, Inc. | Methacrylate copolymers for medical devices |
US8173062B1 (en) | 2004-09-30 | 2012-05-08 | Advanced Cardiovascular Systems, Inc. | Controlled deformation of a polymer tube in fabricating a medical article |
US7875233B2 (en) | 2004-09-30 | 2011-01-25 | Advanced Cardiovascular Systems, Inc. | Method of fabricating a biaxially oriented implantable medical device |
US8043553B1 (en) | 2004-09-30 | 2011-10-25 | Advanced Cardiovascular Systems, Inc. | Controlled deformation of a polymer tube with a restraining surface in fabricating a medical article |
US7166680B2 (en) * | 2004-10-06 | 2007-01-23 | Advanced Cardiovascular Systems, Inc. | Blends of poly(ester amide) polymers |
US7235592B2 (en) * | 2004-10-12 | 2007-06-26 | Zimmer Gmbh | PVA hydrogel |
US20060089485A1 (en) * | 2004-10-27 | 2006-04-27 | Desnoyer Jessica R | End-capped poly(ester amide) copolymers |
US8603634B2 (en) | 2004-10-27 | 2013-12-10 | Abbott Cardiovascular Systems Inc. | End-capped poly(ester amide) copolymers |
US7390497B2 (en) * | 2004-10-29 | 2008-06-24 | Advanced Cardiovascular Systems, Inc. | Poly(ester amide) filler blends for modulation of coating properties |
US7481835B1 (en) | 2004-10-29 | 2009-01-27 | Advanced Cardiovascular Systems, Inc. | Encapsulated covered stent |
US20060095122A1 (en) * | 2004-10-29 | 2006-05-04 | Advanced Cardiovascular Systems, Inc. | Implantable devices comprising biologically absorbable star polymers and methods for fabricating the same |
US7214759B2 (en) * | 2004-11-24 | 2007-05-08 | Advanced Cardiovascular Systems, Inc. | Biologically absorbable coatings for implantable devices based on polyesters and methods for fabricating the same |
US8609123B2 (en) * | 2004-11-29 | 2013-12-17 | Advanced Cardiovascular Systems, Inc. | Derivatized poly(ester amide) as a biobeneficial coating |
US7892592B1 (en) | 2004-11-30 | 2011-02-22 | Advanced Cardiovascular Systems, Inc. | Coating abluminal surfaces of stents and other implantable medical devices |
US20060115449A1 (en) * | 2004-11-30 | 2006-06-01 | Advanced Cardiovascular Systems, Inc. | Bioabsorbable, biobeneficial, tyrosine-based polymers for use in drug eluting stent coatings |
ES2490610T3 (en) * | 2004-12-08 | 2014-09-04 | Shire Regenerative Medicine, Inc. | Materials and methods for minimally invasive administration of a fluid composition containing cells |
US7854944B2 (en) | 2004-12-17 | 2010-12-21 | Advanced Cardiovascular Systems, Inc. | Tissue regeneration |
US7604818B2 (en) | 2004-12-22 | 2009-10-20 | Advanced Cardiovascular Systems, Inc. | Polymers of fluorinated monomers and hydrocarbon monomers |
US7419504B2 (en) * | 2004-12-27 | 2008-09-02 | Advanced Cardiovascular Systems, Inc. | Poly(ester amide) block copolymers |
US8007775B2 (en) * | 2004-12-30 | 2011-08-30 | Advanced Cardiovascular Systems, Inc. | Polymers containing poly(hydroxyalkanoates) and agents for use with medical articles and methods of fabricating the same |
US7202325B2 (en) | 2005-01-14 | 2007-04-10 | Advanced Cardiovascular Systems, Inc. | Poly(hydroxyalkanoate-co-ester amides) and agents for use with medical articles |
US20060239986A1 (en) * | 2005-01-26 | 2006-10-26 | Perez-Luna Victor H | Method for the formation of hydrogel multilayers through surface initiated photopolymerization |
US8017139B2 (en) * | 2005-02-23 | 2011-09-13 | Zimmer Technology, Inc. | Blend hydrogels and methods of making |
US9381279B2 (en) | 2005-03-24 | 2016-07-05 | Abbott Cardiovascular Systems Inc. | Implantable devices formed on non-fouling methacrylate or acrylate polymers |
US7700659B2 (en) * | 2005-03-24 | 2010-04-20 | Advanced Cardiovascular Systems, Inc. | Implantable devices formed of non-fouling methacrylate or acrylate polymers |
US20060224226A1 (en) * | 2005-03-31 | 2006-10-05 | Bin Huang | In-vivo radial orientation of a polymeric implantable medical device |
WO2006110193A2 (en) | 2005-04-08 | 2006-10-19 | Dexcom, Inc. | Cellulosic-based interference domain for an analyte sensor |
US8744546B2 (en) | 2005-05-05 | 2014-06-03 | Dexcom, Inc. | Cellulosic-based resistance domain for an analyte sensor |
US7381048B2 (en) * | 2005-04-12 | 2008-06-03 | Advanced Cardiovascular Systems, Inc. | Stents with profiles for gripping a balloon catheter and molds for fabricating stents |
US20080125745A1 (en) * | 2005-04-19 | 2008-05-29 | Shubhayu Basu | Methods and compositions for treating post-cardial infarction damage |
US8828433B2 (en) | 2005-04-19 | 2014-09-09 | Advanced Cardiovascular Systems, Inc. | Hydrogel bioscaffoldings and biomedical device coatings |
US9539410B2 (en) | 2005-04-19 | 2017-01-10 | Abbott Cardiovascular Systems Inc. | Methods and compositions for treating post-cardial infarction damage |
US8187621B2 (en) * | 2005-04-19 | 2012-05-29 | Advanced Cardiovascular Systems, Inc. | Methods and compositions for treating post-myocardial infarction damage |
US8303972B2 (en) * | 2005-04-19 | 2012-11-06 | Advanced Cardiovascular Systems, Inc. | Hydrogel bioscaffoldings and biomedical device coatings |
ATE470701T1 (en) * | 2005-04-21 | 2010-06-15 | Massachusetts Inst Technology | MATERIALS AND METHODS FOR ALTERING AN IMMUNE RESPONSE TO EXOGENE AND ENDOGENE IMMUNOGENES, INCLUDING GENIDENTIC AND NON-GENIDENTIC CELLS, TISSUES OR ORGANS |
US7795467B1 (en) | 2005-04-26 | 2010-09-14 | Advanced Cardiovascular Systems, Inc. | Bioabsorbable, biobeneficial polyurethanes for use in medical devices |
US8778375B2 (en) | 2005-04-29 | 2014-07-15 | Advanced Cardiovascular Systems, Inc. | Amorphous poly(D,L-lactide) coating |
WO2006121661A2 (en) * | 2005-05-05 | 2006-11-16 | Dexcom, Inc. | Cellulosic-based resistance domain for an analyte sensor |
AU2006245950B2 (en) | 2005-05-09 | 2012-01-12 | Biosphere Medical S.A. | Compositions and methods using microspheres and non-ionic contrast agents |
US7637941B1 (en) | 2005-05-11 | 2009-12-29 | Advanced Cardiovascular Systems, Inc. | Endothelial cell binding coatings for rapid encapsulation of bioerodable stents |
US7291166B2 (en) * | 2005-05-18 | 2007-11-06 | Advanced Cardiovascular Systems, Inc. | Polymeric stent patterns |
US7628800B2 (en) * | 2005-06-03 | 2009-12-08 | Warsaw Orthopedic, Inc. | Formed in place corpectomy device |
CN102743792B (en) | 2005-06-21 | 2014-09-24 | 夏尔再生医学公司 | Methods and compositions for enhancing vascular access |
US7823533B2 (en) * | 2005-06-30 | 2010-11-02 | Advanced Cardiovascular Systems, Inc. | Stent fixture and method for reducing coating defects |
US8021676B2 (en) | 2005-07-08 | 2011-09-20 | Advanced Cardiovascular Systems, Inc. | Functionalized chemically inert polymers for coatings |
US7785647B2 (en) * | 2005-07-25 | 2010-08-31 | Advanced Cardiovascular Systems, Inc. | Methods of providing antioxidants to a drug containing product |
US7735449B1 (en) | 2005-07-28 | 2010-06-15 | Advanced Cardiovascular Systems, Inc. | Stent fixture having rounded support structures and method for use thereof |
US7658880B2 (en) * | 2005-07-29 | 2010-02-09 | Advanced Cardiovascular Systems, Inc. | Polymeric stent polishing method and apparatus |
US7297758B2 (en) * | 2005-08-02 | 2007-11-20 | Advanced Cardiovascular Systems, Inc. | Method for extending shelf-life of constructs of semi-crystallizable polymers |
US20070038290A1 (en) * | 2005-08-15 | 2007-02-15 | Bin Huang | Fiber reinforced composite stents |
US7476245B2 (en) * | 2005-08-16 | 2009-01-13 | Advanced Cardiovascular Systems, Inc. | Polymeric stent patterns |
US20070045255A1 (en) * | 2005-08-23 | 2007-03-01 | Klaus Kleine | Laser induced plasma machining with an optimized process gas |
US20070045252A1 (en) * | 2005-08-23 | 2007-03-01 | Klaus Kleine | Laser induced plasma machining with a process gas |
US9248034B2 (en) * | 2005-08-23 | 2016-02-02 | Advanced Cardiovascular Systems, Inc. | Controlled disintegrating implantable medical devices |
US20070098799A1 (en) * | 2005-10-28 | 2007-05-03 | Zimmer, Inc. | Mineralized Hydrogels and Methods of Making and Using Hydrogels |
US20100204783A1 (en) * | 2005-12-06 | 2010-08-12 | Helen Marie Nugent | Methods and compositions for enhancing vascular access |
US20070128246A1 (en) * | 2005-12-06 | 2007-06-07 | Hossainy Syed F A | Solventless method for forming a coating |
AU2006321809A1 (en) * | 2005-12-07 | 2007-06-14 | Zimmer, Inc. | Methods of bonding or modifying hydrogels using irradiation |
US20070135909A1 (en) * | 2005-12-08 | 2007-06-14 | Desnoyer Jessica R | Adhesion polymers to improve stent retention |
US7591841B2 (en) | 2005-12-16 | 2009-09-22 | Advanced Cardiovascular Systems, Inc. | Implantable devices for accelerated healing |
US7976891B1 (en) | 2005-12-16 | 2011-07-12 | Advanced Cardiovascular Systems, Inc. | Abluminal stent coating apparatus and method of using focused acoustic energy |
US7638156B1 (en) | 2005-12-19 | 2009-12-29 | Advanced Cardiovascular Systems, Inc. | Apparatus and method for selectively coating a medical article |
US7867547B2 (en) | 2005-12-19 | 2011-01-11 | Advanced Cardiovascular Systems, Inc. | Selectively coating luminal surfaces of stents |
JP2007177244A (en) * | 2005-12-22 | 2007-07-12 | Zimmer Inc | Perfluorocyclobutane crosslinked hydrogel |
US20070151961A1 (en) * | 2006-01-03 | 2007-07-05 | Klaus Kleine | Fabrication of an implantable medical device with a modified laser beam |
US20070156230A1 (en) * | 2006-01-04 | 2007-07-05 | Dugan Stephen R | Stents with radiopaque markers |
US7951185B1 (en) | 2006-01-06 | 2011-05-31 | Advanced Cardiovascular Systems, Inc. | Delivery of a stent at an elevated temperature |
JP5819579B2 (en) * | 2006-01-13 | 2015-11-24 | サーモディクス,インコーポレイティド | Microparticles containing matrices for drug delivery |
US20070179219A1 (en) * | 2006-01-31 | 2007-08-02 | Bin Huang | Method of fabricating an implantable medical device using gel extrusion and charge induced orientation |
US20070196428A1 (en) * | 2006-02-17 | 2007-08-23 | Thierry Glauser | Nitric oxide generating medical devices |
US7601383B2 (en) * | 2006-02-28 | 2009-10-13 | Advanced Cardiovascular Systems, Inc. | Coating construct containing poly (vinyl alcohol) |
US7713637B2 (en) * | 2006-03-03 | 2010-05-11 | Advanced Cardiovascular Systems, Inc. | Coating containing PEGylated hyaluronic acid and a PEGylated non-hyaluronic acid polymer |
US8110242B2 (en) * | 2006-03-24 | 2012-02-07 | Zimmer, Inc. | Methods of preparing hydrogel coatings |
US20070231363A1 (en) * | 2006-03-29 | 2007-10-04 | Yung-Ming Chen | Coatings formed from stimulus-sensitive material |
US7964210B2 (en) * | 2006-03-31 | 2011-06-21 | Abbott Cardiovascular Systems Inc. | Degradable polymeric implantable medical devices with a continuous phase and discrete phase |
US20070254012A1 (en) * | 2006-04-28 | 2007-11-01 | Ludwig Florian N | Controlled degradation and drug release in stents |
US20070259101A1 (en) * | 2006-05-02 | 2007-11-08 | Kleiner Lothar W | Microporous coating on medical devices |
US8304012B2 (en) * | 2006-05-04 | 2012-11-06 | Advanced Cardiovascular Systems, Inc. | Method for drying a stent |
US8069814B2 (en) | 2006-05-04 | 2011-12-06 | Advanced Cardiovascular Systems, Inc. | Stent support devices |
US7985441B1 (en) | 2006-05-04 | 2011-07-26 | Yiwen Tang | Purification of polymers for coating applications |
US7761968B2 (en) * | 2006-05-25 | 2010-07-27 | Advanced Cardiovascular Systems, Inc. | Method of crimping a polymeric stent |
US7951194B2 (en) | 2006-05-26 | 2011-05-31 | Abbott Cardiovascular Sysetms Inc. | Bioabsorbable stent with radiopaque coating |
US8752268B2 (en) | 2006-05-26 | 2014-06-17 | Abbott Cardiovascular Systems Inc. | Method of making stents with radiopaque markers |
US7775178B2 (en) * | 2006-05-26 | 2010-08-17 | Advanced Cardiovascular Systems, Inc. | Stent coating apparatus and method |
US7959940B2 (en) * | 2006-05-30 | 2011-06-14 | Advanced Cardiovascular Systems, Inc. | Polymer-bioceramic composite implantable medical devices |
US8343530B2 (en) * | 2006-05-30 | 2013-01-01 | Abbott Cardiovascular Systems Inc. | Polymer-and polymer blend-bioceramic composite implantable medical devices |
US20070282434A1 (en) * | 2006-05-30 | 2007-12-06 | Yunbing Wang | Copolymer-bioceramic composite implantable medical devices |
US7842737B2 (en) | 2006-09-29 | 2010-11-30 | Abbott Cardiovascular Systems Inc. | Polymer blend-bioceramic composite implantable medical devices |
US8568764B2 (en) * | 2006-05-31 | 2013-10-29 | Advanced Cardiovascular Systems, Inc. | Methods of forming coating layers for medical devices utilizing flash vaporization |
US20080058916A1 (en) * | 2006-05-31 | 2008-03-06 | Bin Huang | Method of fabricating polymeric self-expandable stent |
US9561351B2 (en) * | 2006-05-31 | 2017-02-07 | Advanced Cardiovascular Systems, Inc. | Drug delivery spiral coil construct |
US20070281073A1 (en) * | 2006-06-01 | 2007-12-06 | Gale David C | Enhanced adhesion of drug delivery coatings on stents |
US8486135B2 (en) | 2006-06-01 | 2013-07-16 | Abbott Cardiovascular Systems Inc. | Implantable medical devices fabricated from branched polymers |
US8034287B2 (en) * | 2006-06-01 | 2011-10-11 | Abbott Cardiovascular Systems Inc. | Radiation sterilization of medical devices |
US20070282433A1 (en) * | 2006-06-01 | 2007-12-06 | Limon Timothy A | Stent with retention protrusions formed during crimping |
US8703167B2 (en) | 2006-06-05 | 2014-04-22 | Advanced Cardiovascular Systems, Inc. | Coatings for implantable medical devices for controlled release of a hydrophilic drug and a hydrophobic drug |
US8778376B2 (en) * | 2006-06-09 | 2014-07-15 | Advanced Cardiovascular Systems, Inc. | Copolymer comprising elastin pentapeptide block and hydrophilic block, and medical device and method of treating |
US20070286882A1 (en) * | 2006-06-09 | 2007-12-13 | Yiwen Tang | Solvent systems for coating medical devices |
US20070286941A1 (en) * | 2006-06-13 | 2007-12-13 | Bin Huang | Surface treatment of a polymeric stent |
US8603530B2 (en) | 2006-06-14 | 2013-12-10 | Abbott Cardiovascular Systems Inc. | Nanoshell therapy |
US8114150B2 (en) | 2006-06-14 | 2012-02-14 | Advanced Cardiovascular Systems, Inc. | RGD peptide attached to bioabsorbable stents |
US20080095918A1 (en) * | 2006-06-14 | 2008-04-24 | Kleiner Lothar W | Coating construct with enhanced interfacial compatibility |
US8048448B2 (en) | 2006-06-15 | 2011-11-01 | Abbott Cardiovascular Systems Inc. | Nanoshells for drug delivery |
US8535372B1 (en) | 2006-06-16 | 2013-09-17 | Abbott Cardiovascular Systems Inc. | Bioabsorbable stent with prohealing layer |
US8333000B2 (en) | 2006-06-19 | 2012-12-18 | Advanced Cardiovascular Systems, Inc. | Methods for improving stent retention on a balloon catheter |
US20070290412A1 (en) * | 2006-06-19 | 2007-12-20 | John Capek | Fabricating a stent with selected properties in the radial and axial directions |
US8017237B2 (en) | 2006-06-23 | 2011-09-13 | Abbott Cardiovascular Systems, Inc. | Nanoshells on polymers |
US9072820B2 (en) * | 2006-06-26 | 2015-07-07 | Advanced Cardiovascular Systems, Inc. | Polymer composite stent with polymer particles |
US8128688B2 (en) | 2006-06-27 | 2012-03-06 | Abbott Cardiovascular Systems Inc. | Carbon coating on an implantable device |
US20070299511A1 (en) * | 2006-06-27 | 2007-12-27 | Gale David C | Thin stent coating |
EP2037977A2 (en) * | 2006-06-28 | 2009-03-25 | SurModics, Inc. | Active agent eluting matrices with particulates |
US7794776B1 (en) | 2006-06-29 | 2010-09-14 | Abbott Cardiovascular Systems Inc. | Modification of polymer stents with radiation |
US8956640B2 (en) * | 2006-06-29 | 2015-02-17 | Advanced Cardiovascular Systems, Inc. | Block copolymers including a methoxyethyl methacrylate midblock |
US7740791B2 (en) * | 2006-06-30 | 2010-06-22 | Advanced Cardiovascular Systems, Inc. | Method of fabricating a stent with features by blow molding |
US20080008736A1 (en) * | 2006-07-06 | 2008-01-10 | Thierry Glauser | Random copolymers of methacrylates and acrylates |
US20080009938A1 (en) * | 2006-07-07 | 2008-01-10 | Bin Huang | Stent with a radiopaque marker and method for making the same |
US9028859B2 (en) * | 2006-07-07 | 2015-05-12 | Advanced Cardiovascular Systems, Inc. | Phase-separated block copolymer coatings for implantable medical devices |
US7823263B2 (en) | 2006-07-11 | 2010-11-02 | Abbott Cardiovascular Systems Inc. | Method of removing stent islands from a stent |
US20080014244A1 (en) * | 2006-07-13 | 2008-01-17 | Gale David C | Implantable medical devices and coatings therefor comprising physically crosslinked block copolymers |
US7757543B2 (en) | 2006-07-13 | 2010-07-20 | Advanced Cardiovascular Systems, Inc. | Radio frequency identification monitoring of stents |
US7998404B2 (en) * | 2006-07-13 | 2011-08-16 | Advanced Cardiovascular Systems, Inc. | Reduced temperature sterilization of stents |
US7794495B2 (en) * | 2006-07-17 | 2010-09-14 | Advanced Cardiovascular Systems, Inc. | Controlled degradation of stents |
US7886419B2 (en) * | 2006-07-18 | 2011-02-15 | Advanced Cardiovascular Systems, Inc. | Stent crimping apparatus and method |
US7732190B2 (en) * | 2006-07-31 | 2010-06-08 | Advanced Cardiovascular Systems, Inc. | Modified two-component gelation systems, methods of use and methods of manufacture |
US8016879B2 (en) * | 2006-08-01 | 2011-09-13 | Abbott Cardiovascular Systems Inc. | Drug delivery after biodegradation of the stent scaffolding |
US20080091262A1 (en) * | 2006-10-17 | 2008-04-17 | Gale David C | Drug delivery after biodegradation of the stent scaffolding |
US8703169B1 (en) | 2006-08-15 | 2014-04-22 | Abbott Cardiovascular Systems Inc. | Implantable device having a coating comprising carrageenan and a biostable polymer |
US9242005B1 (en) | 2006-08-21 | 2016-01-26 | Abbott Cardiovascular Systems Inc. | Pro-healing agent formulation compositions, methods and treatments |
US9173733B1 (en) | 2006-08-21 | 2015-11-03 | Abbott Cardiovascular Systems Inc. | Tracheobronchial implantable medical device and methods of use |
US20080058954A1 (en) * | 2006-08-22 | 2008-03-06 | Hai Trieu | Methods of treating spinal injuries using injectable flowable compositions comprising organic materials |
US7923022B2 (en) * | 2006-09-13 | 2011-04-12 | Advanced Cardiovascular Systems, Inc. | Degradable polymeric implantable medical devices with continuous phase and discrete phase |
CN103230414A (en) * | 2006-11-07 | 2013-08-07 | 夏尔再生医学公司 | Materials and methods for treating and managing angiogenesis-mediated diseases |
WO2008060484A2 (en) * | 2006-11-10 | 2008-05-22 | Proveris Scientific Corporation | Automated nasal spray pump testing |
US9005672B2 (en) | 2006-11-17 | 2015-04-14 | Abbott Cardiovascular Systems Inc. | Methods of modifying myocardial infarction expansion |
US8741326B2 (en) * | 2006-11-17 | 2014-06-03 | Abbott Cardiovascular Systems Inc. | Modified two-component gelation systems, methods of use and methods of manufacture |
WO2008064058A2 (en) * | 2006-11-21 | 2008-05-29 | Abbott Laboratories | Use of a terpolymer of tetrafluoroethylene, hexafluoropropylene, and vinylidene fluoride in drug eluting coatings |
US7713541B1 (en) * | 2006-11-21 | 2010-05-11 | Abbott Cardiovascular Systems Inc. | Zwitterionic terpolymers, method of making and use on medical devices |
US8192760B2 (en) * | 2006-12-04 | 2012-06-05 | Abbott Cardiovascular Systems Inc. | Methods and compositions for treating tissue using silk proteins |
US8099849B2 (en) | 2006-12-13 | 2012-01-24 | Abbott Cardiovascular Systems Inc. | Optimizing fracture toughness of polymeric stent |
US8597673B2 (en) * | 2006-12-13 | 2013-12-03 | Advanced Cardiovascular Systems, Inc. | Coating of fast absorption or dissolution |
US8017141B2 (en) * | 2006-12-15 | 2011-09-13 | Advanced Cardiovascular Systems, Inc. | Coatings of acrylamide-based copolymers |
US8758407B2 (en) * | 2006-12-21 | 2014-06-24 | Warsaw Orthopedic, Inc. | Methods for positioning a load-bearing orthopedic implant device in vivo |
US7771476B2 (en) | 2006-12-21 | 2010-08-10 | Warsaw Orthopedic Inc. | Curable orthopedic implant devices configured to harden after placement in vivo by application of a cure-initiating energy before insertion |
US8663328B2 (en) * | 2006-12-21 | 2014-03-04 | Warsaw Orthopedic, Inc. | Methods for positioning a load-bearing component of an orthopedic implant device by inserting a malleable device that hardens in vivo |
US8480718B2 (en) * | 2006-12-21 | 2013-07-09 | Warsaw Orthopedic, Inc. | Curable orthopedic implant devices configured to be hardened after placement in vivo |
US20080243228A1 (en) * | 2007-03-28 | 2008-10-02 | Yunbing Wang | Implantable medical devices fabricated from block copolymers |
US8262723B2 (en) | 2007-04-09 | 2012-09-11 | Abbott Cardiovascular Systems Inc. | Implantable medical devices fabricated from polymer blends with star-block copolymers |
US20080286332A1 (en) | 2007-05-14 | 2008-11-20 | Pacetti Stephen D | Implantable medical devices with a topcoat layer of phosphoryl choline acrylate polymer for reduced thrombosis, and improved mechanical properties |
US8147769B1 (en) | 2007-05-16 | 2012-04-03 | Abbott Cardiovascular Systems Inc. | Stent and delivery system with reduced chemical degradation |
US20200037875A1 (en) | 2007-05-18 | 2020-02-06 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US9056155B1 (en) | 2007-05-29 | 2015-06-16 | Abbott Cardiovascular Systems Inc. | Coatings having an elastic primer layer |
US7829008B2 (en) * | 2007-05-30 | 2010-11-09 | Abbott Cardiovascular Systems Inc. | Fabricating a stent from a blow molded tube |
US7959857B2 (en) * | 2007-06-01 | 2011-06-14 | Abbott Cardiovascular Systems Inc. | Radiation sterilization of medical devices |
US8202528B2 (en) * | 2007-06-05 | 2012-06-19 | Abbott Cardiovascular Systems Inc. | Implantable medical devices with elastomeric block copolymer coatings |
US8293260B2 (en) * | 2007-06-05 | 2012-10-23 | Abbott Cardiovascular Systems Inc. | Elastomeric copolymer coatings containing poly (tetramethyl carbonate) for implantable medical devices |
US20080306582A1 (en) * | 2007-06-05 | 2008-12-11 | Yunbing Wang | Implantable medical devices with elastomeric copolymer coatings |
AU2008262018A1 (en) | 2007-06-08 | 2008-12-18 | Dexcom, Inc. | Integrated medicament delivery device for use with continuous analyte sensor |
US8425591B1 (en) | 2007-06-11 | 2013-04-23 | Abbott Cardiovascular Systems Inc. | Methods of forming polymer-bioceramic composite medical devices with bioceramic particles |
US20100185156A1 (en) * | 2007-06-13 | 2010-07-22 | Pervasis Therapeutics, Inc. | Methods and Devices for Minimally-Invasive Delivery of Cell-Containing Flowable Compositions |
US8048441B2 (en) | 2007-06-25 | 2011-11-01 | Abbott Cardiovascular Systems, Inc. | Nanobead releasing medical devices |
US8109904B1 (en) | 2007-06-25 | 2012-02-07 | Abbott Cardiovascular Systems Inc. | Drug delivery medical devices |
US7901452B2 (en) * | 2007-06-27 | 2011-03-08 | Abbott Cardiovascular Systems Inc. | Method to fabricate a stent having selected morphology to reduce restenosis |
US7955381B1 (en) | 2007-06-29 | 2011-06-07 | Advanced Cardiovascular Systems, Inc. | Polymer-bioceramic composite implantable medical device with different types of bioceramic particles |
US7731988B2 (en) * | 2007-08-03 | 2010-06-08 | Zimmer, Inc. | Multi-polymer hydrogels |
US20090041845A1 (en) * | 2007-08-08 | 2009-02-12 | Lothar Walter Kleiner | Implantable medical devices having thin absorbable coatings |
US8062739B2 (en) * | 2007-08-31 | 2011-11-22 | Zimmer, Inc. | Hydrogels with gradient |
WO2009036368A2 (en) * | 2007-09-14 | 2009-03-19 | Nitto Denko Corporation | Drug carriers |
US7947784B2 (en) | 2007-11-16 | 2011-05-24 | Zimmer, Inc. | Reactive compounding of hydrogels |
US8598165B2 (en) | 2007-11-26 | 2013-12-03 | University Of Kansas | Morpholines as selective inhibitors of cytochrome P450 2A13 |
WO2009086483A2 (en) * | 2007-12-26 | 2009-07-09 | Gel-Del Technologies, Inc. | Biocompatible protein particles, particle devices and methods thereof |
US8034362B2 (en) * | 2008-01-04 | 2011-10-11 | Zimmer, Inc. | Chemical composition of hydrogels for use as articulating surfaces |
BRPI0906746A8 (en) * | 2008-01-29 | 2019-05-14 | Implantica Patent Ltd | apparatus for treating gastresophageal reflux disease |
US8828354B2 (en) * | 2008-03-27 | 2014-09-09 | Warsaw Orthopedic, Inc. | Pharmaceutical gels and methods for delivering therapeutic agents to a site beneath the skin |
US8583204B2 (en) | 2008-03-28 | 2013-11-12 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US8682408B2 (en) | 2008-03-28 | 2014-03-25 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US11730407B2 (en) | 2008-03-28 | 2023-08-22 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
EP2265293B1 (en) * | 2008-04-18 | 2015-11-04 | SurModics, Inc. | Coating systems for the controlled delivery of hydrophilic bioactive agents |
US20100124533A1 (en) * | 2008-11-20 | 2010-05-20 | Medtronic Vascular, Inc. | Large Animal Model for Human-Like Advanced Atherosclerotic Plaque |
US20120093914A1 (en) * | 2008-11-24 | 2012-04-19 | Moma Therapeutics | Implantable liposome embedded matrix composition, uses thereof, and polycaprolactone particles as scaffolds for tissue regeneration |
US8287840B2 (en) | 2009-07-24 | 2012-10-16 | Abbott Cardiovascular Systems Inc. | Method of treating malignant solid tumors using transcatheter arterial chemoembolization (TACE) |
CN106913902A (en) | 2009-11-09 | 2017-07-04 | 聚光灯技术合伙有限责任公司 | Polysaccharide based aquagel |
US8795727B2 (en) | 2009-11-09 | 2014-08-05 | Spotlight Technology Partners Llc | Fragmented hydrogels |
US8568471B2 (en) | 2010-01-30 | 2013-10-29 | Abbott Cardiovascular Systems Inc. | Crush recoverable polymer scaffolds |
US8808353B2 (en) | 2010-01-30 | 2014-08-19 | Abbott Cardiovascular Systems Inc. | Crush recoverable polymer scaffolds having a low crossing profile |
WO2011119822A1 (en) * | 2010-03-24 | 2011-09-29 | Northeastern University | Multimodal diagnostic technology for early stage cancer lesions |
US8685433B2 (en) | 2010-03-31 | 2014-04-01 | Abbott Cardiovascular Systems Inc. | Absorbable coating for implantable device |
US9232805B2 (en) | 2010-06-29 | 2016-01-12 | Biocure, Inc. | In-situ forming hydrogel wound dressings containing antimicrobial agents |
US8726483B2 (en) | 2011-07-29 | 2014-05-20 | Abbott Cardiovascular Systems Inc. | Methods for uniform crimping and deployment of a polymer scaffold |
WO2016004103A1 (en) | 2014-06-30 | 2016-01-07 | Proveris Scientific Company | Sampling apparatus for determining the amount and uniformity of a delivered dose of drug related methods |
US9492594B2 (en) | 2014-07-18 | 2016-11-15 | M.A. Med Alliance SA | Coating for intraluminal expandable catheter providing contact transfer of drug micro-reservoirs |
US11406742B2 (en) | 2014-07-18 | 2022-08-09 | M.A. Med Alliance SA | Coating for intraluminal expandable catheter providing contact transfer of drug micro-reservoirs |
WO2016037169A1 (en) * | 2014-09-06 | 2016-03-10 | Integral Biosystems Llc | Methods and biocompatible compositions to achieve sustained drug release in the eye |
US9999527B2 (en) | 2015-02-11 | 2018-06-19 | Abbott Cardiovascular Systems Inc. | Scaffolds having radiopaque markers |
US9700443B2 (en) | 2015-06-12 | 2017-07-11 | Abbott Cardiovascular Systems Inc. | Methods for attaching a radiopaque marker to a scaffold |
CA3016890A1 (en) | 2016-03-09 | 2017-09-14 | Proveris Scientific Corporation | Methods for measuring dose content uniformity performance of inhaler and nasal devices |
US11331022B2 (en) | 2017-10-24 | 2022-05-17 | Dexcom, Inc. | Pre-connected analyte sensors |
CN209606445U (en) | 2017-10-24 | 2019-11-08 | 德克斯康公司 | Pre-connection analyte sensor |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3663687A (en) * | 1968-06-26 | 1972-05-16 | Minnesota Mining & Mfg | Biodegradable parenteral microspherules |
US4345588A (en) * | 1979-04-23 | 1982-08-24 | Northwestern University | Method of delivering a therapeutic agent to a target capillary bed |
US4708861A (en) * | 1984-02-15 | 1987-11-24 | The Liposome Company, Inc. | Liposome-gel compositions |
JPS61353A (en) * | 1984-06-13 | 1986-01-06 | テルモ株式会社 | Drug administration apparatus |
US4900556A (en) * | 1985-04-26 | 1990-02-13 | Massachusetts Institute Of Technology | System for delayed and pulsed release of biologically active substances |
US5328470A (en) * | 1989-03-31 | 1994-07-12 | The Regents Of The University Of Michigan | Treatment of diseases by site-specific instillation of cells or site-specific transformation of cells and kits therefor |
US5238714A (en) * | 1990-10-02 | 1993-08-24 | Board Of Regents, The University Of Texas System | Efficient microcapsule preparation and method of use |
US5206023A (en) * | 1991-01-31 | 1993-04-27 | Robert F. Shaw | Method and compositions for the treatment and repair of defects or lesions in cartilage |
ES2153378T3 (en) * | 1992-02-28 | 2001-03-01 | Univ Texas | PHOTOPOLIMERIZABLE BIODEGRADABLE HYDROGELS AS FABRIC CONTACT MATERIALS AND CONTROLLED DISCHARGE CARRIER. |
AU696691C (en) * | 1993-03-12 | 2003-09-18 | American National Red Cross, The | Supplemented and unsupplemented tissue sealants, methods of their production and use |
WO1995022316A1 (en) * | 1994-02-17 | 1995-08-24 | New York Blood Center, Inc. | Biologic bioadhesive compositions containing fibrin glue and liposomes, methods of preparation and use |
-
1995
- 1995-10-11 AU AU39720/95A patent/AU700903B2/en not_active Ceased
- 1995-10-11 DE DE69520044T patent/DE69520044T2/en not_active Expired - Fee Related
- 1995-10-11 EP EP95937688A patent/EP0785774B1/en not_active Revoked
- 1995-10-11 EP EP99202631A patent/EP1004293A3/en not_active Withdrawn
- 1995-10-11 WO PCT/US1995/014103 patent/WO1996011671A1/en not_active Application Discontinuation
- 1995-10-11 AT AT95937688T patent/ATE198979T1/en active
- 1995-10-11 ES ES95937688T patent/ES2155534T3/en not_active Expired - Lifetime
- 1995-10-11 CA CA002202511A patent/CA2202511A1/en not_active Abandoned
- 1995-10-11 JP JP8513488A patent/JPH10509696A/en active Pending
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1997
- 1997-01-23 US US08/787,647 patent/US5879713A/en not_active Expired - Lifetime
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WO1996011671A1 (en) | 1996-04-25 |
DE69520044D1 (en) | 2001-03-08 |
JPH10509696A (en) | 1998-09-22 |
DE69520044T2 (en) | 2001-06-13 |
EP0785774B1 (en) | 2001-01-31 |
AU700903B2 (en) | 1999-01-14 |
AU3972095A (en) | 1996-05-06 |
EP1004293A3 (en) | 2001-10-04 |
EP1004293A2 (en) | 2000-05-31 |
ES2155534T3 (en) | 2001-05-16 |
ATE198979T1 (en) | 2001-02-15 |
EP0785774A1 (en) | 1997-07-30 |
US5879713A (en) | 1999-03-09 |
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