CA2131021C - Use of injectable biomaterials for the repair and augmentation of the anal sphincters - Google Patents
Use of injectable biomaterials for the repair and augmentation of the anal sphincters Download PDFInfo
- Publication number
- CA2131021C CA2131021C CA002131021A CA2131021A CA2131021C CA 2131021 C CA2131021 C CA 2131021C CA 002131021 A CA002131021 A CA 002131021A CA 2131021 A CA2131021 A CA 2131021A CA 2131021 C CA2131021 C CA 2131021C
- Authority
- CA
- Canada
- Prior art keywords
- collagen
- crosslinked
- beads
- biomaterial
- activated polymer
- 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.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/0004—Closure means for urethra or rectum, i.e. anti-incontinence devices or support slings against pelvic prolapse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
Abstract
This invention discloses methods of repairing structurally defective or inadequately functioning muscles of the anal sphincter and methods of improving the competency of incompetent anal sphincters by administering an effective amount of an injectable biomaterial into the defect or into the anal sinuses. Preferred biomaterials to be used in this invention are collagen formulations.
Description
USE OF INJECTABLE BIOMATERIALS FOR THE REPAIR AND
AUGMENTATION OF THE ANAL SPHINCTERS
Technical Field This invention is in the field of medical implants and prostheses. More particularly, it concerns a nonsurgical technique for repairing structurally defective or inadequately functioning anal sphincters and for improving the competency of anal sphincters by injecting biomaterials into the defect or into the anal sinuses.
BACKGROUND OF THE INVENTION
Anal sphincters are muscular structures that assist in controlling the flow of body wastes (feces and flatus) from the colon. The internal anal sphincter (IAS) and the external anal sphincter (EAS) encircle the anal canal and comprise the anorectal ring. The IAS is a thickening of the gastrointestinal smooth muscle; it maintains continence at rest. The EAS is composed of striated, voluntary muscle. The EAS, the puborectalis, and the levator ani muscles work in concert to prevent leakage of flatus and feces when there is an increase in abdominal pressure or when the internal anal sphincter relaxes after rectal distention.
When one or both sphincters become defective or incompetent, the control of feces and/or flatus is impaired.
Incontinence of the feces and flatus is socially and psychologically disabling for the afflicted patient. It is a major factor prejudicing the rehabilitation and placement prospects of the elderly and disabled, preventing many of them from being cared for at home.
The normal mechanisms of anorectal continence include the motor function of the anal sphincters and pelvic floor muscles, the role of the rectum and sigmoid colon as a fecal reservoir with capacitance and compliance and as a W093/16658 ~ ~~ ~ PCT/US93/01879 propulsive force with intrinsic motor activity, the effects of stool consistency, volume and delivery rate, the anorectal angle, and anorectal sensation. It is the coordinated integration of these factors that confers continence.
There are two distinct etiologies for anorectal incontinence. The most common cause of anorectal incontinence is a structural deformity due to anatomic disruption of the sp:~incter mechanism, which may be caused by obstetric injuries (perineal laceration and improper7.y performed median episiotomies), complications of fistula or fissure surgery (keyhole deformities), traumatic injuries (e. g., impalement injuries), or cancer. Alternatively, anorectal incontinence may result from deterioration of the sphincter muscles due to age, congenital disorders, systemic and metabolic diseases, acquired neurological defects, and diseases of the colon and rectum.
Present treatment modalities for anorectal incontinence include nonsurgical and surgical therapy.
Nonsurgical therapy for incontinence must be tailored to each individual: patients suffering from urgency incontinence may benefit from the use of bulk-forming agents and laxatives or enemas: individuals with minor degrees of incontinence may find biofeedback and perineal strengthening exercises beneficial in alleviating symptoms of seepage and occasional loss of control.
Current nonsurgical treatments for anorectal incontinence include the use of electrical stimulation to improve contraction of the sphincter muscles and the use of anorectal plugs which are designed to expand post-insertion.
U.S..Patents 3,650,275 and 3,749,100 describe an electrostimulation device to maintain contraction of the sphincter muscle. A magnetic artificial anus closing device is described in U.S. Patent 3,952,726. U.S. Patent 4,209,009 discloses an anus closure tampon with nonhomogeneous sections having differential diametrical compressibility to provide a plug effect. U.S. Patent 4,401,107 describes an intestinal control valve arranged to surround the anal-terminating descending intestine, thereby functioning as an artificial sphincter. A device comprising three inflatable chambers (the first, positioned outside the recaum; the second, within the anal sphincter muscle: the third, outside the body between the . buttocks) to maintain anal continence is disclosed in U.S.
Patent 4,686,985. U.S. Patents 4,781,176 and 4,969,902 teach an artificial anus comprising a hollow tubular support member and a releasable plug for sealing closed the support member. A
pressure transducer or electrical contact is provided on the support member and connected to an electrode in contact with tire patient's skin, so that when the colon becomes pressurized the patient is signalled that the plug should be released.
U.S. Patent 4,904,256 describes a magnetic artificial anus assembly, having a sphincter function similar to the natural anus, which comprises an annular bag structure filled with a magnetic fluid and a plug structure having a magnet member.
Surgical therapy must also be individualized, and is directed either at (i) repair of the disrupted sphincter or (ii) augmentation (with autogenic transplanted muscle or commercially available Silastic sheet prostheses) of existing structures to improve physiologic function. Diverting colostomy is rarely necessary.
Unfortunately, there are inherent difficulties and risks in these corrective methods. For example, anorectal plugs will often cause infection, fibrosis of the mucosa, or muscularis of the bowel near the plug. Also, patients complain about the discomfort and inconvenience of temporary plugs that function similar to absorbent pads. An artificial sphincter may extrude or malfunction, necessitating additional surgery or corrective action. Surgery also can result in infection or other complications, such as host-graft rejection, and is a significant expense. Therefore, it is desirable to treat anal sphincter deficiencies on a cost-effective, outpatient basis, such that the inherent difficulties presented by the current methods are avoided.
Injectable biomaterials, e.g., Polytef~ paste (polytetrafluoride, Mentor), injectable liquid silicone, and collagen, have been used to augment incompetent lower W093/16658 ~ ~~~~ PCT/US93/01879 esophageal sphincters and urinary sphincters over the past ten years. These so-called sphincters, however, are not true sphincteric muscles because they are controlled by pressure changes, rather than neurological stimulation from the brain.
Furthermore, the use of injectable biomaterials for treating lower esophageal and urinary sphincters is simply to bulk up the surrounding tissue by injecting the biomaterial to close tre respective orifice.
In contrast to the lower esophageal and urinary sphincters, the anal sphincters are highly vascular and muscular areas with involuntary contracture by the IAS and voluntary contracture by the EAS mechanisms. If either of these sphincters is rendered incampetent due to any of the previously described causes, varying degrees of anorectal incontinence may be the result. One aspect of this invention is a method for repairing or replacing structurally defective or inadequately functioning muscles of the anal sphincters by administering an effective amount of an injectable biomaterial perianally into the defect or structural deformity. The invention further includes a method for improving the competency of incompetent anal sphincters by administering an effective amount of an injectable biomaterial into the anal sinuses between the blood vessels. Another aspect of the invention is a method of inducing wound healing of a structurally defective anal sphincter by administering an effective amount of an injectable biomaterial containing one or more wound healing agents, such as a biologically active protein growth factor, into the defect. In some instances, the biomaterial, particularly when it is a collagen material, may create a fibrolytic bridge between the ends of the sphincter.
A method for repairing defective or incompetent anal sphincter muscles ideally would include a nonsurgical procedure utilizing biocompatible material:a that are non-immunogenic, have a low risk for infection, and are easy to administer. The present invention provides such an effective method for WO 93/16658 ~ ~. ~ ~ PCT/US93/01879 repairing defective or incompetent anal sphincter muscles by administering an injectable biocampatible biomaterial.
DETAILED DESCRIPTION OF THE INVENTION
The invention is a method for repairing structurally defective or inadequately functioning muscles of the anal sphincters by perianally administering an effective amount of an injectable biomaterial(s), with and without wound healing agents, into the defect or structural deformity. The invention further comprises a method for improving the competency of incompetent anal sphincters by administering injectable biomaterials into the anal sinuses between the blood vessels.
Improvement of the sphincter's competence will improve fecal and flatus continence and increase the anorectal squeeze pressure, resulting in improved control.
The term "incompetent,." as used herein, refers to sphincter muscles that are inadequately functioning or non-functioning due to the deterioration of the sphincter muscles or due to a structural deformity caused by anatomic disruption of the sphincter mechanism.
The term "improving the competency," as used herein, means augmenting the existing sphincter muscle to improve the patient's baseline continence level. Improved competence would result in increased resting squeeze pressure, maximal squeeze pressure, and threshold volume as can be measured by standard manometric tests. An alternative method for measuring improved competence is by a change in clinical grading from major incontinence to minor incontinence to continence. Major incontinence occurs when there is deficient control or lack of control of stool of normal consistency. Minor incontinence is a disorder in which there is partial soiling or occasional incontinence of flatus or of loose or watery stools.
Continence is when there is no soiling or occasional incontinence to flatus or loose or watery stools.
The term "effective amount" as used herein, means the quantity of biomaterial needed to repair anal sphincter muscle or to achieve improved competence as measured by standard manometry or the quantity c~f wound healing agents needed to achieve improved healing. The effective amount of biomaterial administered may vary depending on the patient's own ability to <~bsorb or break down the biomaterial, the consistency <~nd concentration of the material, and the site and condition being treated.
Furthermore, the biomaterial rnay be administered over a number of treatment sessions t:o achieve and maintain improved competence as measured by standard manometry.
The biomaterial used in t:he invention may be selected from a number of sources; however, it must be injectable, biocompatible, es~~entially non-immunogenic, and persist at the site of placement for at least three months. Alternatively, the biomaterial may be an aqueous suspension of a biopolymer with a biocompatible fluid lubricant to improve the intrusion of the biopolymer into the tissue. See U.S. Patent 9:,803,075. Commercially available suspensions of a biopolymer and fluid lubricant may be obtained from Bioplasty, Inc. (Minneapolis, Minnesota) under the tradename Bioplastique Micro-Implants. Fluid lubricants may include: hyaluronic acid, dextran sulfate, dextran, succinylated non-crosslinked collagen, methylated non-crosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids, egg yolk phospholipids, heparin, and the like. Biopolymers may include:
atelopeptide fibrillar, crosslinked or non-crosslinked collagen, gelatin beads, polytetrafluoroethylene beads, silicone rubber beads, hydrogel beads, silicon carbide beads, glass beads, and the like.
A preferred biomaterial comprises a collagen formulation. Most preferred are those collagen formulations wherein the collagen is atelopeptide fibrillar, crosslinked, or non.-crosslinked collagen, or collagen mixed with a mineral material. Collagen is a major protein component of bone, cartilage, skin, and connective tissue in animals. Collagen in its native form . 2131021 is typically a rigid, rod-shaped molecule approximately 300 nanometers (nm) long and 1.5 nm in diameter. It is composed of three collagen polypeptides which form a tight triple helix. The collagen polypeptides are characterized by a long midsection having the repeating sequence -Gly-X-Y-, where X anal Y are often proline or hydroxyproline, bounded at each end by the "telopeptide"
regions, which constitute less than about 5 percent (%) of the molecule. The telopeptide region of the collagen chains are typically responsi~~le for the crosslinking between chains and for the imrr~unogenicity of the protein.
Collagen occurs in types, of varying physical properties;
the most abundant are Types I-III.
The collagen used in the invention may be collected from any number of mammalian sources, such as bovine or porcine corium and human placenta. The preparation of purified, substantially nonantigenic collagen in solution from the skin is basically a three-step process involving solubilization, enzyme treatment, and purification. See U.S. Patents 4,140,537 and 4,488,911. The term "collagen" or "collagen material" as used herein refers to all forms of collagen, including those which have been processed or otherwise modified.
Preferred collagens are treated to remove the immunogenic telopeptide regions ("atelopeptide collagen"), are soluble, and will have been reconstituted into the fibrillar form ("atelopeptide fibrillar"). The reconstituted fibrillar collagen may optionally be crosslinked using methods generally known in the art, such as by heat, radiation, or chemical crosslinking agents. Commercially reconstituted collagens are available under the tradenames Zyderm Collagen Implant and Zyplast Collagen Implant (Collagen Corporation, Palo Alto, California). See U.S. Patents 4,582,640 and 3,949,073 U.S. Patent 4,424,208, discloses an improved collagen formulation suitable for use in soft tissue r-' 2131021 augmentation. The formulation comprises reconstituted fibrillar atelopeptide collagen,in combination with particulate, crosslinked atelc>peptide collagen dispersed in an aqueous medium. The addition of particulate crosslinked collagen improves the biomaterial's persistence, or ability to ree;ist shrinkage following injection.
U.S. Patent 4,557,764, discloses a "second nucleation" collagen precipitate which exhibits a desirable malleability and putty-like consistency.
Collagen is provided in solution [e. g., at 2-4 milligrams per milliliter (mg/ml)], and a. "first nucleation product"
is precipitated by rapid titration and centrifugation.
The remaining supernatant (containing the bulk of the original collagen) is then decanted and allowed to stand overnight. The precipitated second nucleation product is collected by centrifugation.
Another embodiment of the: biomaterial to be used in the invention includes an improved injectable collagen formulation which is conjugated to a chemically activated polymer, such as polyethylene glycol. The conjugated collagen has improved persistence at the implantation site. The collagen material can also be crosslinked with a bifunctional-activated polymer in situ, such as polyethylene glycol. This im~~roved process method allows the collagen implant to be crosslinked to the host tissue by the activated polymer.
Another embodiment of the: biomaterial to be used in the invention includes a high collagen concentration formulation. Briefly, collagen in solution (Vitrogen 100 Collagen, Celtrix Laboratories, Palo Alto, California) is reconstituted to fibril form t~y neutralizing the solution with the addition of a phosphate buffer at ambient temperatures. The resultant fibrillar collagen may be optionally crosslinked using standard techniques known in the art prior to concentration.. The high concentration collagen materials disclosed r.erein are passed through a D
homogenizer (HC5000, Microflu:idics corporation, Newton, Massachusetts) to improve the extrudability of the material through a fine gauge needle. High concentrations of non-crosslinked and crosslinked fibrillar collagen are expected to have improved persistence compared to commercially available forms.
Another particularly uses=ul biomaterial to be used is an injectable collagen/cer<~mic formulation. Briefly, porous and/or non-porous cerarnic particles are prepared to have a uniform particle size distribution in the range of about 50-250 microns. The preferred ceramic particles are admixed with fibrillar co7_lagen to produce an injectable ceramic/collagen formulation. The addition of the ceramic particles improve~~ the persistence of the injectable collagen formulation.
Other commercially available biomaterials useful in the described invention are a polytetrafluoride (Teflon*) paste, known as Polytef Paste, and a porcine collagen particulate suspended in saline, known as Fibrel*
Gelatin Matrix Implant (both available from Mentor Corporation, Santa Barbara, California). further biomaterials include fluid suspensions containing: gelatin beads, glass beads, hydrogel beads, silicone rubber or carbide beads, polytetrafluoride beads, and the like.
An effective amount of wound healing agents may be added to the biomaterial used in the invention to improve long-term restoration of the sphincter defect. These agents include protein growth factors such as fibroblast growth factors (FGFs), platelet derived growth factors (PDGFs), epidermal growth factors (EGFs), connective tissue activated peptides (CTA.Ps), transforming growth factors (TGFs), and the like. These biologically active agents are known to facilitate regrowth of connective tissue cells and accumulation of fibroblasts, endothelial cells, and wound healing regulatory cells to speed wound healing. One or more of these agents in combination can be used in the invention. The amount of wound *Trade-mark WO 93/16658 ~~~~~ PCT/US93/01879 healing agents) to be included with the biomaterial may vary, depending upon the biomaterial used, the patient (age, sex, medical history) and the site being treated. Typically the weight ratio of wound healing agents) to the biomaterial would be in the range of about 1:5,000 to 1:50,000.
The wound healing agents may be isolated from native or natural sources, such as from mammalian cells, or may be prepared synthetically, such as by recombinant DNA or by chemical processes. In addition, analogs, fragments, or 1C derivatives of these agents may be used, provided they exhibit some of the biological activity or wound healing properties of the native molecule. For example, analogs can be prepared by expression of genes altered by site-specific mutagenesis or other genetic engineering techniques.
These agents may be added to the biomaterial during preparation or just prior to treatment. It is preferred that the wound healing agents be incorporated into the biomaterial such that the agents are released through a sustained delivery.
In this way, the agents can be released over an extended period of time into the anal sphincter sites and surrounding areas, promoting wound healing. It is most preferred that these agents will be included in the patient's treatment in those instances where the biomaterial is being used to repair the anal sphincter muscles.
optionally, antimicrobial additives and/or antibodies may be added to these biomaterials to reduce the potential for infection at the treatment site. In addition, local anesthetics may be used at the injection site. Any appropriate additive may be utilized as long as it is compatible with the biomaterial used and the patient.
A preferred method of 'the invention is performed in an outpatient setting under aseptic conditions with the patient in the lithotomy position. A retractor is used to clearly visualize the anal orifice and the biomaterial is typically supplied ~.n a sterile 3.0 cubic centimeters (cc) syringe fitted with a 25 gauge needle.
~~WO 93/16658 ~ ~ ~ 1 ~ ~ ~ PCT/US93/01879 An anorectal examination is preferably conducted prior to treatment. The examination includes direct visualization of the lower rectum and anal canal, as well as palpation of the perianal area and anorectal ring. An anoscope (a metal device approximately three inches in length) will be used to visualize the tissues of t:he anal canal and lower rectum: the sphincter mass and function will be assessed by palpation of the sphincter mechanism while the patient is asked to strain and squeeze. Pre-examination preparation is not 1G required (i.e., Fleet*enema) and the examination is of minimal duration (1-2 minutes).
When repairing structurally defective sphincters, such as a keyhole deformity resulting from surgery or trauma, the biomaterial, optimally containing wound healing agents, is injected perianally into the deformity, using one or more injections, until the physician observes that the treated area has been restored to its original form and the defect is repaired (i.e., the hole or defect is no longer visible to the skilled physician). The patient's continence level is then measured using standard manometry.
The process of evaluating anal continence is divided into two areas: subjective reporting of the patient's symptoms and objective measurement of the change in anal sphincter pressure.
A scale has been created to measure change in patients' reporting of their symptoms. The data being measured includes complaints of itching, bleeding, difficulty or ease of evacuation, nocturnal sleep disturbance, staining of undergarments, prolapse of tissue, and need for other forms of therapy. Typically the scale is as follows (based upon degree of complaint): 1+=minimal complaint, 2+=moderate, 3+=severe, and 4+=incapacitating.
Objective data is obtained through the use of anal manometry. Manometry, by measurement of pressure, supplies information about muscle activity at the time of actual measurement. Baseline continence levels are measured both prior to and following treatment. Anal manometric evaluation *Trade-mark 11 -.
r_ helps to define the results of improved continence based upon the pressures obtained p.re- and post-treatment. The apparatus used typically comprises a four-channel radially perfused balloon-tipped catheter, pressure transducers, and a multichannel recorder. The following are measured and are recorded on the appropriate medical record: resting squeeze pressure, maximal squeeze pressure, anorectal reflex, and threshold volume. Although anal :manometry will show variations during the course of the day, measuring basal and opening pressures before and after injection in the same patient will allow for determination of the efficacy of the technique on increasing anal sphincter pressure. Each patient will therefore act as his/her own control.
To improve, restore, and/or supplement the competency of the incompetent sphincters, the biomaterial is injected into the submucosa of the anal sinuses. It is important that the biomaterial is not injected into the blood vessels, as this may cause vascular occlusion, infarction, or embolic phenomena. A preferred amount of biomaterial to be used in the repair of structural defects varies from patient to patient, however, is about between 1-40 cc.
A preferred amount of biomaterial to be used is about between 15-40 cc, most preferably about 20-30 cc for augmentation of the anal sphincters: whereas about 5-10 cc of biomaterial may be used in muscle repair. The amount of material necessary to effect repair of structural defects or restoration of competency will, of course, vary with the degree of tissue loss or destruction to the area. Alternatively, the treating physician may wish to augment treatment for repairing structurally defective sphincters by injecting the biomaterial, optionally containing wound healing agent(s), into the submucosa of the anal sinuses, before or after perianal injection of the biomaterial into the defect or structural deformity. Then the patient's continence level is measured using standard manometry. Successful treatment is also defined in terms of the patient's report of a decrease in incontinent episodes.
WO 93/16658 2 ~ 3 1 0 Z ~ PCT/US93/01879 Improvements in continence and repair of damaged tissue is expected to last a minimum of about 3 to 6 months.
The injections may optionally be repeated on a regular basis to maintain continence and correction of damaged tissue. It is expected that subsequent injections will require less material than the initial treatment.
Methods for repairing structurally defective or ir:adequately functioning muscles of the anal sphincters may be conducted by perianally administering an injectable 1G biomaterial, with or without wound healing agents, into the structural deformity. Also disclosed are methods for improving the competency of the anal sphincter by administering an injectable biomaterial into the anal sinuses. These methods provide nonsurgical approaches for treating anorectal incontinence.
The following experimental section is offered by way of example and not by limitation. The invention is described below in some detail for the purposes of clarity and understanding. It will be apparent, however, that certain changes and modifications may be practiced within the scope of the appended claims.
EXPERIMENTAL
A patient presented a complaint of anal leakage secondary to a posterior anal (keyhole) deformity which was secondary to excision of a fissure several years before. Local care failed to control the symptoms of anal leakage and, approximately three months later, a sphincteroplasty and loop sigmoid colostomy were performed. About two months later closure of the colostomy was accomplished and the patient remained continent for about six months. Due to the marked scarring in the area of the anal sphincter surgery, the repair slowly failed and within ten months of the colostomy closure, the patient again had marked anal leakage.
Because of the patient's refusal to undergo further surgery, a decision was made to "bolster" the defect and enhance the sphincter function with an injection of WO 93/16658 ~~ O PCT/US93/01879 !J
commercially available atelopeptide fibrillar collagen. Twenty cc of collagen was injected into the defect and surrounding tissues without any analgesia or anesthesia in an outpatient setting. For six months the patient remained completely continent without any symptoms. At that point, signs and symptoms of anal leakage developed.
1~
AUGMENTATION OF THE ANAL SPHINCTERS
Technical Field This invention is in the field of medical implants and prostheses. More particularly, it concerns a nonsurgical technique for repairing structurally defective or inadequately functioning anal sphincters and for improving the competency of anal sphincters by injecting biomaterials into the defect or into the anal sinuses.
BACKGROUND OF THE INVENTION
Anal sphincters are muscular structures that assist in controlling the flow of body wastes (feces and flatus) from the colon. The internal anal sphincter (IAS) and the external anal sphincter (EAS) encircle the anal canal and comprise the anorectal ring. The IAS is a thickening of the gastrointestinal smooth muscle; it maintains continence at rest. The EAS is composed of striated, voluntary muscle. The EAS, the puborectalis, and the levator ani muscles work in concert to prevent leakage of flatus and feces when there is an increase in abdominal pressure or when the internal anal sphincter relaxes after rectal distention.
When one or both sphincters become defective or incompetent, the control of feces and/or flatus is impaired.
Incontinence of the feces and flatus is socially and psychologically disabling for the afflicted patient. It is a major factor prejudicing the rehabilitation and placement prospects of the elderly and disabled, preventing many of them from being cared for at home.
The normal mechanisms of anorectal continence include the motor function of the anal sphincters and pelvic floor muscles, the role of the rectum and sigmoid colon as a fecal reservoir with capacitance and compliance and as a W093/16658 ~ ~~ ~ PCT/US93/01879 propulsive force with intrinsic motor activity, the effects of stool consistency, volume and delivery rate, the anorectal angle, and anorectal sensation. It is the coordinated integration of these factors that confers continence.
There are two distinct etiologies for anorectal incontinence. The most common cause of anorectal incontinence is a structural deformity due to anatomic disruption of the sp:~incter mechanism, which may be caused by obstetric injuries (perineal laceration and improper7.y performed median episiotomies), complications of fistula or fissure surgery (keyhole deformities), traumatic injuries (e. g., impalement injuries), or cancer. Alternatively, anorectal incontinence may result from deterioration of the sphincter muscles due to age, congenital disorders, systemic and metabolic diseases, acquired neurological defects, and diseases of the colon and rectum.
Present treatment modalities for anorectal incontinence include nonsurgical and surgical therapy.
Nonsurgical therapy for incontinence must be tailored to each individual: patients suffering from urgency incontinence may benefit from the use of bulk-forming agents and laxatives or enemas: individuals with minor degrees of incontinence may find biofeedback and perineal strengthening exercises beneficial in alleviating symptoms of seepage and occasional loss of control.
Current nonsurgical treatments for anorectal incontinence include the use of electrical stimulation to improve contraction of the sphincter muscles and the use of anorectal plugs which are designed to expand post-insertion.
U.S..Patents 3,650,275 and 3,749,100 describe an electrostimulation device to maintain contraction of the sphincter muscle. A magnetic artificial anus closing device is described in U.S. Patent 3,952,726. U.S. Patent 4,209,009 discloses an anus closure tampon with nonhomogeneous sections having differential diametrical compressibility to provide a plug effect. U.S. Patent 4,401,107 describes an intestinal control valve arranged to surround the anal-terminating descending intestine, thereby functioning as an artificial sphincter. A device comprising three inflatable chambers (the first, positioned outside the recaum; the second, within the anal sphincter muscle: the third, outside the body between the . buttocks) to maintain anal continence is disclosed in U.S.
Patent 4,686,985. U.S. Patents 4,781,176 and 4,969,902 teach an artificial anus comprising a hollow tubular support member and a releasable plug for sealing closed the support member. A
pressure transducer or electrical contact is provided on the support member and connected to an electrode in contact with tire patient's skin, so that when the colon becomes pressurized the patient is signalled that the plug should be released.
U.S. Patent 4,904,256 describes a magnetic artificial anus assembly, having a sphincter function similar to the natural anus, which comprises an annular bag structure filled with a magnetic fluid and a plug structure having a magnet member.
Surgical therapy must also be individualized, and is directed either at (i) repair of the disrupted sphincter or (ii) augmentation (with autogenic transplanted muscle or commercially available Silastic sheet prostheses) of existing structures to improve physiologic function. Diverting colostomy is rarely necessary.
Unfortunately, there are inherent difficulties and risks in these corrective methods. For example, anorectal plugs will often cause infection, fibrosis of the mucosa, or muscularis of the bowel near the plug. Also, patients complain about the discomfort and inconvenience of temporary plugs that function similar to absorbent pads. An artificial sphincter may extrude or malfunction, necessitating additional surgery or corrective action. Surgery also can result in infection or other complications, such as host-graft rejection, and is a significant expense. Therefore, it is desirable to treat anal sphincter deficiencies on a cost-effective, outpatient basis, such that the inherent difficulties presented by the current methods are avoided.
Injectable biomaterials, e.g., Polytef~ paste (polytetrafluoride, Mentor), injectable liquid silicone, and collagen, have been used to augment incompetent lower W093/16658 ~ ~~~~ PCT/US93/01879 esophageal sphincters and urinary sphincters over the past ten years. These so-called sphincters, however, are not true sphincteric muscles because they are controlled by pressure changes, rather than neurological stimulation from the brain.
Furthermore, the use of injectable biomaterials for treating lower esophageal and urinary sphincters is simply to bulk up the surrounding tissue by injecting the biomaterial to close tre respective orifice.
In contrast to the lower esophageal and urinary sphincters, the anal sphincters are highly vascular and muscular areas with involuntary contracture by the IAS and voluntary contracture by the EAS mechanisms. If either of these sphincters is rendered incampetent due to any of the previously described causes, varying degrees of anorectal incontinence may be the result. One aspect of this invention is a method for repairing or replacing structurally defective or inadequately functioning muscles of the anal sphincters by administering an effective amount of an injectable biomaterial perianally into the defect or structural deformity. The invention further includes a method for improving the competency of incompetent anal sphincters by administering an effective amount of an injectable biomaterial into the anal sinuses between the blood vessels. Another aspect of the invention is a method of inducing wound healing of a structurally defective anal sphincter by administering an effective amount of an injectable biomaterial containing one or more wound healing agents, such as a biologically active protein growth factor, into the defect. In some instances, the biomaterial, particularly when it is a collagen material, may create a fibrolytic bridge between the ends of the sphincter.
A method for repairing defective or incompetent anal sphincter muscles ideally would include a nonsurgical procedure utilizing biocompatible material:a that are non-immunogenic, have a low risk for infection, and are easy to administer. The present invention provides such an effective method for WO 93/16658 ~ ~. ~ ~ PCT/US93/01879 repairing defective or incompetent anal sphincter muscles by administering an injectable biocampatible biomaterial.
DETAILED DESCRIPTION OF THE INVENTION
The invention is a method for repairing structurally defective or inadequately functioning muscles of the anal sphincters by perianally administering an effective amount of an injectable biomaterial(s), with and without wound healing agents, into the defect or structural deformity. The invention further comprises a method for improving the competency of incompetent anal sphincters by administering injectable biomaterials into the anal sinuses between the blood vessels.
Improvement of the sphincter's competence will improve fecal and flatus continence and increase the anorectal squeeze pressure, resulting in improved control.
The term "incompetent,." as used herein, refers to sphincter muscles that are inadequately functioning or non-functioning due to the deterioration of the sphincter muscles or due to a structural deformity caused by anatomic disruption of the sphincter mechanism.
The term "improving the competency," as used herein, means augmenting the existing sphincter muscle to improve the patient's baseline continence level. Improved competence would result in increased resting squeeze pressure, maximal squeeze pressure, and threshold volume as can be measured by standard manometric tests. An alternative method for measuring improved competence is by a change in clinical grading from major incontinence to minor incontinence to continence. Major incontinence occurs when there is deficient control or lack of control of stool of normal consistency. Minor incontinence is a disorder in which there is partial soiling or occasional incontinence of flatus or of loose or watery stools.
Continence is when there is no soiling or occasional incontinence to flatus or loose or watery stools.
The term "effective amount" as used herein, means the quantity of biomaterial needed to repair anal sphincter muscle or to achieve improved competence as measured by standard manometry or the quantity c~f wound healing agents needed to achieve improved healing. The effective amount of biomaterial administered may vary depending on the patient's own ability to <~bsorb or break down the biomaterial, the consistency <~nd concentration of the material, and the site and condition being treated.
Furthermore, the biomaterial rnay be administered over a number of treatment sessions t:o achieve and maintain improved competence as measured by standard manometry.
The biomaterial used in t:he invention may be selected from a number of sources; however, it must be injectable, biocompatible, es~~entially non-immunogenic, and persist at the site of placement for at least three months. Alternatively, the biomaterial may be an aqueous suspension of a biopolymer with a biocompatible fluid lubricant to improve the intrusion of the biopolymer into the tissue. See U.S. Patent 9:,803,075. Commercially available suspensions of a biopolymer and fluid lubricant may be obtained from Bioplasty, Inc. (Minneapolis, Minnesota) under the tradename Bioplastique Micro-Implants. Fluid lubricants may include: hyaluronic acid, dextran sulfate, dextran, succinylated non-crosslinked collagen, methylated non-crosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids, egg yolk phospholipids, heparin, and the like. Biopolymers may include:
atelopeptide fibrillar, crosslinked or non-crosslinked collagen, gelatin beads, polytetrafluoroethylene beads, silicone rubber beads, hydrogel beads, silicon carbide beads, glass beads, and the like.
A preferred biomaterial comprises a collagen formulation. Most preferred are those collagen formulations wherein the collagen is atelopeptide fibrillar, crosslinked, or non.-crosslinked collagen, or collagen mixed with a mineral material. Collagen is a major protein component of bone, cartilage, skin, and connective tissue in animals. Collagen in its native form . 2131021 is typically a rigid, rod-shaped molecule approximately 300 nanometers (nm) long and 1.5 nm in diameter. It is composed of three collagen polypeptides which form a tight triple helix. The collagen polypeptides are characterized by a long midsection having the repeating sequence -Gly-X-Y-, where X anal Y are often proline or hydroxyproline, bounded at each end by the "telopeptide"
regions, which constitute less than about 5 percent (%) of the molecule. The telopeptide region of the collagen chains are typically responsi~~le for the crosslinking between chains and for the imrr~unogenicity of the protein.
Collagen occurs in types, of varying physical properties;
the most abundant are Types I-III.
The collagen used in the invention may be collected from any number of mammalian sources, such as bovine or porcine corium and human placenta. The preparation of purified, substantially nonantigenic collagen in solution from the skin is basically a three-step process involving solubilization, enzyme treatment, and purification. See U.S. Patents 4,140,537 and 4,488,911. The term "collagen" or "collagen material" as used herein refers to all forms of collagen, including those which have been processed or otherwise modified.
Preferred collagens are treated to remove the immunogenic telopeptide regions ("atelopeptide collagen"), are soluble, and will have been reconstituted into the fibrillar form ("atelopeptide fibrillar"). The reconstituted fibrillar collagen may optionally be crosslinked using methods generally known in the art, such as by heat, radiation, or chemical crosslinking agents. Commercially reconstituted collagens are available under the tradenames Zyderm Collagen Implant and Zyplast Collagen Implant (Collagen Corporation, Palo Alto, California). See U.S. Patents 4,582,640 and 3,949,073 U.S. Patent 4,424,208, discloses an improved collagen formulation suitable for use in soft tissue r-' 2131021 augmentation. The formulation comprises reconstituted fibrillar atelopeptide collagen,in combination with particulate, crosslinked atelc>peptide collagen dispersed in an aqueous medium. The addition of particulate crosslinked collagen improves the biomaterial's persistence, or ability to ree;ist shrinkage following injection.
U.S. Patent 4,557,764, discloses a "second nucleation" collagen precipitate which exhibits a desirable malleability and putty-like consistency.
Collagen is provided in solution [e. g., at 2-4 milligrams per milliliter (mg/ml)], and a. "first nucleation product"
is precipitated by rapid titration and centrifugation.
The remaining supernatant (containing the bulk of the original collagen) is then decanted and allowed to stand overnight. The precipitated second nucleation product is collected by centrifugation.
Another embodiment of the: biomaterial to be used in the invention includes an improved injectable collagen formulation which is conjugated to a chemically activated polymer, such as polyethylene glycol. The conjugated collagen has improved persistence at the implantation site. The collagen material can also be crosslinked with a bifunctional-activated polymer in situ, such as polyethylene glycol. This im~~roved process method allows the collagen implant to be crosslinked to the host tissue by the activated polymer.
Another embodiment of the: biomaterial to be used in the invention includes a high collagen concentration formulation. Briefly, collagen in solution (Vitrogen 100 Collagen, Celtrix Laboratories, Palo Alto, California) is reconstituted to fibril form t~y neutralizing the solution with the addition of a phosphate buffer at ambient temperatures. The resultant fibrillar collagen may be optionally crosslinked using standard techniques known in the art prior to concentration.. The high concentration collagen materials disclosed r.erein are passed through a D
homogenizer (HC5000, Microflu:idics corporation, Newton, Massachusetts) to improve the extrudability of the material through a fine gauge needle. High concentrations of non-crosslinked and crosslinked fibrillar collagen are expected to have improved persistence compared to commercially available forms.
Another particularly uses=ul biomaterial to be used is an injectable collagen/cer<~mic formulation. Briefly, porous and/or non-porous cerarnic particles are prepared to have a uniform particle size distribution in the range of about 50-250 microns. The preferred ceramic particles are admixed with fibrillar co7_lagen to produce an injectable ceramic/collagen formulation. The addition of the ceramic particles improve~~ the persistence of the injectable collagen formulation.
Other commercially available biomaterials useful in the described invention are a polytetrafluoride (Teflon*) paste, known as Polytef Paste, and a porcine collagen particulate suspended in saline, known as Fibrel*
Gelatin Matrix Implant (both available from Mentor Corporation, Santa Barbara, California). further biomaterials include fluid suspensions containing: gelatin beads, glass beads, hydrogel beads, silicone rubber or carbide beads, polytetrafluoride beads, and the like.
An effective amount of wound healing agents may be added to the biomaterial used in the invention to improve long-term restoration of the sphincter defect. These agents include protein growth factors such as fibroblast growth factors (FGFs), platelet derived growth factors (PDGFs), epidermal growth factors (EGFs), connective tissue activated peptides (CTA.Ps), transforming growth factors (TGFs), and the like. These biologically active agents are known to facilitate regrowth of connective tissue cells and accumulation of fibroblasts, endothelial cells, and wound healing regulatory cells to speed wound healing. One or more of these agents in combination can be used in the invention. The amount of wound *Trade-mark WO 93/16658 ~~~~~ PCT/US93/01879 healing agents) to be included with the biomaterial may vary, depending upon the biomaterial used, the patient (age, sex, medical history) and the site being treated. Typically the weight ratio of wound healing agents) to the biomaterial would be in the range of about 1:5,000 to 1:50,000.
The wound healing agents may be isolated from native or natural sources, such as from mammalian cells, or may be prepared synthetically, such as by recombinant DNA or by chemical processes. In addition, analogs, fragments, or 1C derivatives of these agents may be used, provided they exhibit some of the biological activity or wound healing properties of the native molecule. For example, analogs can be prepared by expression of genes altered by site-specific mutagenesis or other genetic engineering techniques.
These agents may be added to the biomaterial during preparation or just prior to treatment. It is preferred that the wound healing agents be incorporated into the biomaterial such that the agents are released through a sustained delivery.
In this way, the agents can be released over an extended period of time into the anal sphincter sites and surrounding areas, promoting wound healing. It is most preferred that these agents will be included in the patient's treatment in those instances where the biomaterial is being used to repair the anal sphincter muscles.
optionally, antimicrobial additives and/or antibodies may be added to these biomaterials to reduce the potential for infection at the treatment site. In addition, local anesthetics may be used at the injection site. Any appropriate additive may be utilized as long as it is compatible with the biomaterial used and the patient.
A preferred method of 'the invention is performed in an outpatient setting under aseptic conditions with the patient in the lithotomy position. A retractor is used to clearly visualize the anal orifice and the biomaterial is typically supplied ~.n a sterile 3.0 cubic centimeters (cc) syringe fitted with a 25 gauge needle.
~~WO 93/16658 ~ ~ ~ 1 ~ ~ ~ PCT/US93/01879 An anorectal examination is preferably conducted prior to treatment. The examination includes direct visualization of the lower rectum and anal canal, as well as palpation of the perianal area and anorectal ring. An anoscope (a metal device approximately three inches in length) will be used to visualize the tissues of t:he anal canal and lower rectum: the sphincter mass and function will be assessed by palpation of the sphincter mechanism while the patient is asked to strain and squeeze. Pre-examination preparation is not 1G required (i.e., Fleet*enema) and the examination is of minimal duration (1-2 minutes).
When repairing structurally defective sphincters, such as a keyhole deformity resulting from surgery or trauma, the biomaterial, optimally containing wound healing agents, is injected perianally into the deformity, using one or more injections, until the physician observes that the treated area has been restored to its original form and the defect is repaired (i.e., the hole or defect is no longer visible to the skilled physician). The patient's continence level is then measured using standard manometry.
The process of evaluating anal continence is divided into two areas: subjective reporting of the patient's symptoms and objective measurement of the change in anal sphincter pressure.
A scale has been created to measure change in patients' reporting of their symptoms. The data being measured includes complaints of itching, bleeding, difficulty or ease of evacuation, nocturnal sleep disturbance, staining of undergarments, prolapse of tissue, and need for other forms of therapy. Typically the scale is as follows (based upon degree of complaint): 1+=minimal complaint, 2+=moderate, 3+=severe, and 4+=incapacitating.
Objective data is obtained through the use of anal manometry. Manometry, by measurement of pressure, supplies information about muscle activity at the time of actual measurement. Baseline continence levels are measured both prior to and following treatment. Anal manometric evaluation *Trade-mark 11 -.
r_ helps to define the results of improved continence based upon the pressures obtained p.re- and post-treatment. The apparatus used typically comprises a four-channel radially perfused balloon-tipped catheter, pressure transducers, and a multichannel recorder. The following are measured and are recorded on the appropriate medical record: resting squeeze pressure, maximal squeeze pressure, anorectal reflex, and threshold volume. Although anal :manometry will show variations during the course of the day, measuring basal and opening pressures before and after injection in the same patient will allow for determination of the efficacy of the technique on increasing anal sphincter pressure. Each patient will therefore act as his/her own control.
To improve, restore, and/or supplement the competency of the incompetent sphincters, the biomaterial is injected into the submucosa of the anal sinuses. It is important that the biomaterial is not injected into the blood vessels, as this may cause vascular occlusion, infarction, or embolic phenomena. A preferred amount of biomaterial to be used in the repair of structural defects varies from patient to patient, however, is about between 1-40 cc.
A preferred amount of biomaterial to be used is about between 15-40 cc, most preferably about 20-30 cc for augmentation of the anal sphincters: whereas about 5-10 cc of biomaterial may be used in muscle repair. The amount of material necessary to effect repair of structural defects or restoration of competency will, of course, vary with the degree of tissue loss or destruction to the area. Alternatively, the treating physician may wish to augment treatment for repairing structurally defective sphincters by injecting the biomaterial, optionally containing wound healing agent(s), into the submucosa of the anal sinuses, before or after perianal injection of the biomaterial into the defect or structural deformity. Then the patient's continence level is measured using standard manometry. Successful treatment is also defined in terms of the patient's report of a decrease in incontinent episodes.
WO 93/16658 2 ~ 3 1 0 Z ~ PCT/US93/01879 Improvements in continence and repair of damaged tissue is expected to last a minimum of about 3 to 6 months.
The injections may optionally be repeated on a regular basis to maintain continence and correction of damaged tissue. It is expected that subsequent injections will require less material than the initial treatment.
Methods for repairing structurally defective or ir:adequately functioning muscles of the anal sphincters may be conducted by perianally administering an injectable 1G biomaterial, with or without wound healing agents, into the structural deformity. Also disclosed are methods for improving the competency of the anal sphincter by administering an injectable biomaterial into the anal sinuses. These methods provide nonsurgical approaches for treating anorectal incontinence.
The following experimental section is offered by way of example and not by limitation. The invention is described below in some detail for the purposes of clarity and understanding. It will be apparent, however, that certain changes and modifications may be practiced within the scope of the appended claims.
EXPERIMENTAL
A patient presented a complaint of anal leakage secondary to a posterior anal (keyhole) deformity which was secondary to excision of a fissure several years before. Local care failed to control the symptoms of anal leakage and, approximately three months later, a sphincteroplasty and loop sigmoid colostomy were performed. About two months later closure of the colostomy was accomplished and the patient remained continent for about six months. Due to the marked scarring in the area of the anal sphincter surgery, the repair slowly failed and within ten months of the colostomy closure, the patient again had marked anal leakage.
Because of the patient's refusal to undergo further surgery, a decision was made to "bolster" the defect and enhance the sphincter function with an injection of WO 93/16658 ~~ O PCT/US93/01879 !J
commercially available atelopeptide fibrillar collagen. Twenty cc of collagen was injected into the defect and surrounding tissues without any analgesia or anesthesia in an outpatient setting. For six months the patient remained completely continent without any symptoms. At that point, signs and symptoms of anal leakage developed.
1~
Claims (45)
1. Use of an injectable biomaterial to repair structurally defective or inadequately functioning muscles of the anal sphincters.
2. Use as in Claim 1 wherein said injectable biomaterial is atelopeptide fibrillar, crosslinked or non-crosslinked collagen.
3. Use as in Claim 1 wherein said injectable biomaterial is an aqueous suspension of a biopolymer with a biocompatible fluid lubricant.
4. Use as in Claim 3 wherein said biopolymer is selected from the group consisting of: atelopeptide fibrillar, crosslinked or non-crosslinked collagen, gelatin beads, polytetrafluoroethylene beads, silicone rubber beads, hydrogel beads, silicon carbide beads, and glass beads.
5. Use as in either Claims 3 or 4 wherein said biocompatible fluid lubricant is selected from the group consisting of: hyaluronic acid, dextran sulfate, dextran, succinylated non-crosslinked collagen, methylated non-crosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids, egg yolk phospholipids, and heparin.
6. Use as in Claim 1 wherein said injectable biomaterial is a second nucleation collagen.
7. Use as in Claim 2 wherein said collagen is conjugated to a chemically activated polymer.
8. Use as in Claim 7 wherein said chemically activated polymer is polyethylene glycol.
9. Use as in Claim 2 wherein said collagen is crosslinked with a bifunctional activated polymer.
10. Use as in Claim 9 wherein said collagen and said bifunctional activated polymer crosslink in situ.
11. Use as in Claim 9 wherein said bifunctional activated polymer is polyethylene glycol.
12. Use as in Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 wherein said biomaterial further comprises a ceramic or a mineral material.
13. Use as in claim 12 wherein said ceramic material comprises ceramic particles in the size range of about 50-250 microns.
14. Use as in Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or 13 wherein said biomaterial further comprises one or more wound healing agents.
15. Use as in Claim 14 wherein said wound healing agent is selected from the group consisting of:
fibroblast growth factors (FGFs), platelet derived growth factors (PDGFs), epidermal growth factors (EGFs), connective tissue activating peptides (CTAPs), and transforming growth factors (TGFs), and biologically active analogs, derivatives, or fragments thereof.
fibroblast growth factors (FGFs), platelet derived growth factors (PDGFs), epidermal growth factors (EGFs), connective tissue activating peptides (CTAPs), and transforming growth factors (TGFs), and biologically active analogs, derivatives, or fragments thereof.
16. Use as in Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 wherein said biomaterial further comprises an antimicrobial additive or an antibiotic.
17. Use of an injectable biomaterial to improve the competency of incompetent anal sphincters.
18. Use as in Claim 17 wherein said injectable biomaterial is atelopeptide fibrillar, crosslinked or non-crosslinked collagen.
19. Use as in Claim 17 wherein said injectable biomaterial is an aqueous suspension of a biopolymer with a biocompatible fluid lubricant.
20. Use as in Claim 19 wherein said biopolymer is selected from the group cons fisting of: atelopeptide fibrillar, crosslinked or non-crosslinked collagen, gelatin beads, polytetrafluoroethylene beads, silicone rubber beads, hydrogen beads, silicon carbide beads, and glass beads.
21. Use as in either Claims 19 or 20 wherein said biocompatible fluid lubricant is selected from the group consisting of: hyaluronic acid, dextran sulfate, dextran, succinylated non-crosslinked collagen, methylated non-crosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids, egg yolk phospholipids, and heparin.
22. Use as in Claim 17, wherein said injectable biomaterial is a second nucleation collagen.
23. Use as in Claim 18 wherein said collagen is conjugated to a chemically activated polymer.
24. Use as in Claim 23 wherein said chemically activated polymer is polyethylene glycol.
25. Use as in Claim 18 wherein said collagen is crosslinked with a bifunctional activated polymer.
26. Use as in Claim 25 wherein said collagen and said bifunctional activated polymer crosslink in situ.
27. Use as in Claim 25 wherein said bifunctional activated polymer is polyethylene glycol.
28. Use as in Claim 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 wherein said biomaterial further comprises a ceramic or a mineral material.
29. Use as in Claim 28 wherein said ceramic material comprises ceramic particles in the size range of about 50 - 250 microns.
30. Use as in Claim 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 wherein said biomaterial further comprises an antimicrobial additive or an antibiotic.
31. Use of an injectable biomaterial, containing a wound healing agents, to induce wound healing of a structurally defective anal sphincter.
32. Use as in Claim 31 wherein said injectable biomaterial is atelopeptide fibrillar, crosslinked or non-crosslinked collagen.
33. Use as in Claim 31 wherein said injectable biomaterial is an aqueous suspension of a biopolymer with a biocompatible fluid lubricant.
34. Use as in Claim 33 wherein said biopolymer is selected from the group consisting of: atelopeptide fibrillar, crosslinked or non-crosslinked collagen, gelatin beads, polytetrafluoroethylene beads, silicone rubber beads, hydrogel beads, silicon carbide beads, and glass beads.
35. Use as in either Claims 33 or 34 wherein said biocompatible fluid lubricant is selected from the group consisting of: hyaluronic acid, dextran sulfate, dextran, succinylated non-crosslinked collagen, methylated non-crosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids, egg yolk phospholipids, and heparin.
36. Use as in Claim 31 wherein said injectable biomaterial is a second nucleation collagen.
37. Use as in Claim 32 wherein said collagen is conjugated to a chemically activated polymer.
38. Use as in Claim 37 wherein said chemically activated polymer is polyethylene glycol.
39. Use as in Claim 32 wherein said collagen is crosslinked with a bifunctional activated polymer.
40. Use as in Claim 39 wherein said collagen and said bifunctional activated polymer crosslink in situ.
41. Use as in Claim 39 wherein said bifunctional activated polymer is polyethylene glycol.
42. Use as in Claim 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or 41 wherein said biomaterial further comprises a ceramic or a mineral material.
43. Use as in Claim 42 wherein said ceramic material comprises ceramic particles in the size range of about 50 - 250 microns.
44. Use as in Claim 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 or 43 wherein paid wound healing agent is selected from the group consisting of: fibroblast growth factors (FGFs), platelet derived growth factors (PDGFs), epidermal growth factors (EGFs), connective tissue activating peptides (CTAPs), or transforming growth factors (TGFs), and biologically active analogs, derivatives, or fragments thereof, and combinations thereof.
45. Use as in Claim 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44 wherein said biomaterial further comprises an antimicrobial additive or an antibiotic.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/843,124 US5480644A (en) | 1992-02-28 | 1992-02-28 | Use of injectable biomaterials for the repair and augmentation of the anal sphincters |
US07/843,124 | 1992-02-28 | ||
PCT/US1993/001879 WO1993016658A1 (en) | 1992-02-28 | 1993-02-17 | Use of injectable biomaterials for the repair and augmentation of the anal sphincters |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2131021A1 CA2131021A1 (en) | 1993-09-02 |
CA2131021C true CA2131021C (en) | 2000-06-27 |
Family
ID=25289129
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002131021A Expired - Fee Related CA2131021C (en) | 1992-02-28 | 1993-02-17 | Use of injectable biomaterials for the repair and augmentation of the anal sphincters |
Country Status (9)
Country | Link |
---|---|
US (2) | US5480644A (en) |
EP (1) | EP0627900B1 (en) |
JP (1) | JP2711181B2 (en) |
AT (1) | ATE179877T1 (en) |
AU (1) | AU674308B2 (en) |
CA (1) | CA2131021C (en) |
DE (1) | DE69324909T2 (en) |
ES (1) | ES2134843T3 (en) |
WO (1) | WO1993016658A1 (en) |
Families Citing this family (218)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5510418A (en) * | 1988-11-21 | 1996-04-23 | Collagen Corporation | Glycosaminoglycan-synthetic polymer conjugates |
CA2071137A1 (en) * | 1991-07-10 | 1993-01-11 | Clarence C. Lee | Composition and method for revitalizing scar tissue |
US7968110B2 (en) * | 1992-02-11 | 2011-06-28 | Merz Aesthetics, Inc. | Tissue augmentation material and method |
US6537574B1 (en) | 1992-02-11 | 2003-03-25 | Bioform, Inc. | Soft tissue augmentation material |
US7060287B1 (en) * | 1992-02-11 | 2006-06-13 | Bioform Inc. | Tissue augmentation material and method |
US6592859B1 (en) | 1992-08-20 | 2003-07-15 | Ethicon, Inc. | Controlled expansion sphincter augmentation media |
US5691423A (en) * | 1992-08-24 | 1997-11-25 | The United States Of America As Represented By The Department Of Health And Human Services | Polysaccharide-bound nitric oxide-nucleophile adducts |
US6009877A (en) * | 1994-06-24 | 2000-01-04 | Edwards; Stuart D. | Method for treating a sphincter |
US6044846A (en) * | 1994-06-24 | 2000-04-04 | Edwards; Stuart D. | Method to treat esophageal sphincters |
US6056744A (en) * | 1994-06-24 | 2000-05-02 | Conway Stuart Medical, Inc. | Sphincter treatment apparatus |
US6405732B1 (en) * | 1994-06-24 | 2002-06-18 | Curon Medical, Inc. | Method to treat gastric reflux via the detection and ablation of gastro-esophageal nerves and receptors |
US6092528A (en) * | 1994-06-24 | 2000-07-25 | Edwards; Stuart D. | Method to treat esophageal sphincters |
US6733495B1 (en) | 1999-09-08 | 2004-05-11 | Curon Medical, Inc. | Systems and methods for monitoring and controlling use of medical devices |
US5583114A (en) | 1994-07-27 | 1996-12-10 | Minnesota Mining And Manufacturing Company | Adhesive sealant composition |
USRE38827E1 (en) | 1994-07-27 | 2005-10-11 | 3M Innovative Properties Company | Adhesive sealant composition |
DE69521025T2 (en) * | 1995-03-07 | 2001-10-04 | Menlo Care Inc | Means to improve sphincter function with controlled expansion |
US5750146A (en) * | 1995-04-28 | 1998-05-12 | Matrix Pharmaceutical, Inc. | Translucent collagen formulations with a cytotoxic drug |
US5752974A (en) * | 1995-12-18 | 1998-05-19 | Collagen Corporation | Injectable or implantable biomaterials for filling or blocking lumens and voids of the body |
US5855615A (en) * | 1996-06-07 | 1999-01-05 | Menlo Care, Inc. | Controller expansion sphincter augmentation media |
US5792478A (en) * | 1996-07-08 | 1998-08-11 | Advanced Uro Science | Tissue injectable composition and method of use |
US5813411A (en) * | 1996-08-20 | 1998-09-29 | Menlo Care, Inc. | Method of deforming tissue with a swollen hydrogel |
US7049346B1 (en) | 1996-08-20 | 2006-05-23 | Menlo Care Div Of Ethicon, Inc. | Swollen hydrogel for sphincter augmentation |
US8353908B2 (en) | 1996-09-20 | 2013-01-15 | Novasys Medical, Inc. | Treatment of tissue in sphincters, sinuses, and orifices |
US6464697B1 (en) * | 1998-02-19 | 2002-10-15 | Curon Medical, Inc. | Stomach and adjoining tissue regions in the esophagus |
US7767452B2 (en) * | 1997-02-20 | 2010-08-03 | Kleinsek Don A | Tissue treatments with adipocyte cells |
EP0973562B1 (en) * | 1997-04-05 | 2005-10-26 | Tyco Healthcare Group LP | Implantation composition comprising glass particles |
GB2326344A (en) * | 1997-06-18 | 1998-12-23 | John Overton Hudson | Filling means for repairing an intestinal diverticulum |
US6306154B1 (en) | 1997-06-18 | 2001-10-23 | Bhk Holding | Hemostatic system for body cavities |
US9023031B2 (en) * | 1997-08-13 | 2015-05-05 | Verathon Inc. | Noninvasive devices, methods, and systems for modifying tissues |
WO1999011196A1 (en) * | 1997-09-04 | 1999-03-11 | Point Biomedical Corporation | Injectable tissue reconstruction material |
AU2317899A (en) * | 1998-01-14 | 1999-08-02 | Conway-Stuart Medical, Inc. | Gerd treatment apparatus and method |
AU2114299A (en) * | 1998-01-14 | 1999-08-02 | Conway-Stuart Medical, Inc. | Electrosurgical device for sphincter treatment |
US6440128B1 (en) | 1998-01-14 | 2002-08-27 | Curon Medical, Inc. | Actively cooled electrode assemblies for forming lesions to treat dysfunction in sphincters and adjoining tissue regions |
US8906010B2 (en) * | 1998-02-19 | 2014-12-09 | Mederi Therapeutics, Inc. | Graphical user interface for association with an electrode structure deployed in contact with a tissue region |
US6355031B1 (en) | 1998-02-19 | 2002-03-12 | Curon Medical, Inc. | Control systems for multiple electrode arrays to create lesions in tissue regions at or near a sphincter |
US7165551B2 (en) * | 1998-02-19 | 2007-01-23 | Curon Medical, Inc. | Apparatus to detect and treat aberrant myoelectric activity |
US6273886B1 (en) | 1998-02-19 | 2001-08-14 | Curon Medical, Inc. | Integrated tissue heating and cooling apparatus |
US6790207B2 (en) | 1998-06-04 | 2004-09-14 | Curon Medical, Inc. | Systems and methods for applying a selected treatment agent into contact with tissue to treat disorders of the gastrointestinal tract |
US6402744B2 (en) | 1998-02-19 | 2002-06-11 | Curon Medical, Inc. | Systems and methods for forming composite lesions to treat dysfunction in sphincters and adjoining tissue regions |
US6358245B1 (en) | 1998-02-19 | 2002-03-19 | Curon Medical, Inc. | Graphical user interface for association with an electrode structure deployed in contact with a tissue region |
US6258087B1 (en) | 1998-02-19 | 2001-07-10 | Curon Medical, Inc. | Expandable electrode assemblies for forming lesions to treat dysfunction in sphincters and adjoining tissue regions |
US20100114087A1 (en) * | 1998-02-19 | 2010-05-06 | Edwards Stuart D | Methods and devices for treating urinary incontinence |
CA2319517A1 (en) | 1998-02-19 | 1999-08-26 | Curon Medical, Inc. | Electrosurgical sphincter treatment apparatus |
US6325798B1 (en) | 1998-02-19 | 2001-12-04 | Curon Medical, Inc. | Vacuum-assisted systems and methods for treating sphincters and adjoining tissue regions |
US6423058B1 (en) | 1998-02-19 | 2002-07-23 | Curon Medical, Inc. | Assemblies to visualize and treat sphincters and adjoining tissue regions |
US20030135206A1 (en) * | 1998-02-27 | 2003-07-17 | Curon Medical, Inc. | Method for treating a sphincter |
WO1999044522A1 (en) * | 1998-03-06 | 1999-09-10 | Conway-Stuart Medical, Inc. | Apparatus to electrosurgically treat esophageal sphincters |
US7018392B2 (en) | 1998-04-08 | 2006-03-28 | Arthrocare Corporation | Hemostatic system for body cavities |
US6706051B2 (en) | 1998-04-08 | 2004-03-16 | Bhk Holding, Ltd. | Hemostatic system for body cavities |
WO1999055245A1 (en) * | 1998-04-30 | 1999-11-04 | Edwards Stuart D | Electrosurgical sphincter treatment apparatus |
US6802841B2 (en) * | 1998-06-04 | 2004-10-12 | Curon Medical, Inc. | Systems and methods for applying a selected treatment agent into contact with tissue to treat sphincter dysfunction |
US20110071468A1 (en) * | 1998-06-04 | 2011-03-24 | Mederi Therapeutics, Inc. | Systems and methods for applying a selected treatment agent into contact with tissue to treat sphincter dysfunction |
US6595910B2 (en) * | 1998-12-11 | 2003-07-22 | Scimed Life Systems, Inc. | Method for treating fecal incontinence |
US6251064B1 (en) | 1998-12-11 | 2001-06-26 | Enteric Medical Technologies, Inc. | Method for creating valve-like mechanism in natural body passageway |
US6238335B1 (en) | 1998-12-11 | 2001-05-29 | Enteric Medical Technologies, Inc. | Method for treating gastroesophageal reflux disease and apparatus for use therewith |
US7132582B2 (en) * | 2003-05-30 | 2006-11-07 | Council Of Scientific And Industrial Research | Catalytic process for the preparation of isolongifolene |
AU4696100A (en) | 1999-05-04 | 2000-11-17 | Curon Medical, Inc. | Electrodes for creating lesions in tissue regions at or near a sphincter |
US6358197B1 (en) * | 1999-08-13 | 2002-03-19 | Enteric Medical Technologies, Inc. | Apparatus for forming implants in gastrointestinal tract and kit for use therewith |
CA2384025A1 (en) * | 1999-09-08 | 2001-03-15 | Curon Medical, Inc. | System for controlling a family of treatment devices |
AU7352500A (en) | 1999-09-08 | 2001-04-10 | Curon Medical, Inc. | Systems and methods for monitoring and controlling use of medical devices |
JP2003517858A (en) * | 1999-11-05 | 2003-06-03 | ジェリジーン メディカル コーポレーション | Augmentation and repair of age-related soft tissue defects |
US20090074729A2 (en) * | 1999-11-05 | 2009-03-19 | Donald Kleinsek | Augmentation and repair of spincter defects with cells including fibroblasts |
US20080267923A2 (en) * | 1999-11-05 | 2008-10-30 | Donald Kleinsek | Hair undifferentiated cells |
US7799325B2 (en) * | 1999-11-05 | 2010-09-21 | Kleinsek Donald A | Removal of hypertrophic scars |
US20080286242A2 (en) * | 1999-11-05 | 2008-11-20 | Donald Kleinsek | Augmentation and repair of spincter defects with cells including mesenchymal cells |
US20040215235A1 (en) | 1999-11-16 | 2004-10-28 | Barrx, Inc. | Methods and systems for determining physiologic characteristics for treatment of the esophagus |
US20060095032A1 (en) | 1999-11-16 | 2006-05-04 | Jerome Jackson | Methods and systems for determining physiologic characteristics for treatment of the esophagus |
CA2388861C (en) * | 1999-11-16 | 2013-09-03 | Robert A. Ganz | System and method of treating abnormal tissue in the human esophagus |
US6547776B1 (en) | 2000-01-03 | 2003-04-15 | Curon Medical, Inc. | Systems and methods for treating tissue in the crura |
US6652883B2 (en) | 2000-03-13 | 2003-11-25 | Biocure, Inc. | Tissue bulking and coating compositions |
GB0011053D0 (en) | 2000-05-09 | 2000-06-28 | Hudson John O | Medical device and use thereof |
US8845632B2 (en) | 2000-05-18 | 2014-09-30 | Mederi Therapeutics, Inc. | Graphical user interface for monitoring and controlling use of medical devices |
US6423332B1 (en) | 2000-05-26 | 2002-07-23 | Ethicon, Inc. | Method and composition for deforming soft tissues |
US6540789B1 (en) | 2000-06-15 | 2003-04-01 | Scimed Life Systems, Inc. | Method for treating morbid obesity |
US6663589B1 (en) | 2000-06-20 | 2003-12-16 | Haim Halevy | Catheter system |
US7608578B2 (en) * | 2000-08-11 | 2009-10-27 | Temple University - Of The Commonwealth System Of Higher Education | Obesity controlling method |
US7737109B2 (en) * | 2000-08-11 | 2010-06-15 | Temple University Of The Commonwealth System Of Higher Education | Obesity controlling method |
US20020025340A1 (en) * | 2000-08-30 | 2002-02-28 | Dyer Wallace K. | Methods and compositions for tissue augmentation |
US7306591B2 (en) | 2000-10-02 | 2007-12-11 | Novasys Medical, Inc. | Apparatus and methods for treating female urinary incontinence |
US20090130066A1 (en) * | 2000-11-06 | 2009-05-21 | Gerigene Medical Corporation | Augmentation and repair of sphincter defects with cells including muscle cells |
US20040087936A1 (en) * | 2000-11-16 | 2004-05-06 | Barrx, Inc. | System and method for treating abnormal tissue in an organ having a layered tissue structure |
US20030078466A1 (en) * | 2001-08-31 | 2003-04-24 | Silverman David E. | Method for treating muscle in wall and apparatus for same |
CN1277584C (en) * | 2001-10-25 | 2006-10-04 | 康涅狄格大学 | Bioactive materials, methods of making bioactive materials and method of use thereof |
US7131997B2 (en) * | 2002-03-29 | 2006-11-07 | Scimed Life Systems, Inc. | Tissue treatment |
US7094369B2 (en) * | 2002-03-29 | 2006-08-22 | Scimed Life Systems, Inc. | Processes for manufacturing polymeric microspheres |
US7462366B2 (en) | 2002-03-29 | 2008-12-09 | Boston Scientific Scimed, Inc. | Drug delivery particle |
US7053134B2 (en) * | 2002-04-04 | 2006-05-30 | Scimed Life Systems, Inc. | Forming a chemically cross-linked particle of a desired shape and diameter |
WO2003105917A2 (en) | 2002-06-12 | 2003-12-24 | Scimed Life Systems, Inc. | Bulking agents |
US7449236B2 (en) * | 2002-08-09 | 2008-11-11 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
US7842377B2 (en) | 2003-08-08 | 2010-11-30 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
US8012454B2 (en) | 2002-08-30 | 2011-09-06 | Boston Scientific Scimed, Inc. | Embolization |
US8240937B2 (en) * | 2002-09-05 | 2012-08-14 | Colgate-Palmolive Company | Oral care implement with bead retention |
IL152030A0 (en) * | 2002-09-30 | 2003-05-29 | Nvr Labs Ltd Neural & Vascular | Cohesive biopolymers comprising sulfated polysaccharides and fibrillar proteins and use thereof for tissue repair |
US7588825B2 (en) * | 2002-10-23 | 2009-09-15 | Boston Scientific Scimed, Inc. | Embolic compositions |
US7883490B2 (en) * | 2002-10-23 | 2011-02-08 | Boston Scientific Scimed, Inc. | Mixing and delivery of therapeutic compositions |
GB0224986D0 (en) * | 2002-10-28 | 2002-12-04 | Smith & Nephew | Apparatus |
FR2850282B1 (en) * | 2003-01-27 | 2007-04-06 | Jerome Asius | INJECTABLE IMPLANT BASED ON CERAMIC FOR THE FILLING OF WRINKLES, CUTANEOUS DEPRESSIONS AND SCARS, AND ITS PREPARATION |
US7976823B2 (en) * | 2003-08-29 | 2011-07-12 | Boston Scientific Scimed, Inc. | Ferromagnetic particles and methods |
US7645229B2 (en) | 2003-09-26 | 2010-01-12 | Armstrong David N | Instrument and method for endoscopic visualization and treatment of anorectal fistula |
US11298453B2 (en) | 2003-10-28 | 2022-04-12 | Smith & Nephew Plc | Apparatus and method for wound cleansing with actives |
US7901770B2 (en) * | 2003-11-04 | 2011-03-08 | Boston Scientific Scimed, Inc. | Embolic compositions |
US7150745B2 (en) | 2004-01-09 | 2006-12-19 | Barrx Medical, Inc. | Devices and methods for treatment of luminal tissue |
CN1909840B (en) | 2004-01-21 | 2012-03-21 | 库克公司 | Implantable graft to close a fistula |
US7736671B2 (en) * | 2004-03-02 | 2010-06-15 | Boston Scientific Scimed, Inc. | Embolization |
US8173176B2 (en) | 2004-03-30 | 2012-05-08 | Boston Scientific Scimed, Inc. | Embolization |
US20070190101A1 (en) * | 2004-03-31 | 2007-08-16 | Chunlin Yang | Flowable bone grafts |
US8062272B2 (en) | 2004-05-21 | 2011-11-22 | Bluesky Medical Group Incorporated | Flexible reduced pressure treatment appliance |
US10058642B2 (en) | 2004-04-05 | 2018-08-28 | Bluesky Medical Group Incorporated | Reduced pressure treatment system |
US7909805B2 (en) | 2004-04-05 | 2011-03-22 | Bluesky Medical Group Incorporated | Flexible reduced pressure treatment appliance |
US20050238870A1 (en) * | 2004-04-22 | 2005-10-27 | Marcia Buiser | Embolization |
US7753894B2 (en) | 2004-04-27 | 2010-07-13 | Smith & Nephew Plc | Wound cleansing apparatus with stress |
GB0409446D0 (en) | 2004-04-28 | 2004-06-02 | Smith & Nephew | Apparatus |
US10413644B2 (en) | 2004-04-27 | 2019-09-17 | Smith & Nephew Plc | Wound treatment apparatus and method |
US8529548B2 (en) | 2004-04-27 | 2013-09-10 | Smith & Nephew Plc | Wound treatment apparatus and method |
US7311861B2 (en) * | 2004-06-01 | 2007-12-25 | Boston Scientific Scimed, Inc. | Embolization |
CA2572603C (en) * | 2004-06-29 | 2013-01-15 | Biocure, Inc. | Spinal disc nucleus pulposus implant |
AU2005260560B2 (en) * | 2004-06-30 | 2011-01-20 | Covidien Lp | Isocyanate-based compositions and their use |
US8425550B2 (en) * | 2004-12-01 | 2013-04-23 | Boston Scientific Scimed, Inc. | Embolic coils |
US7727555B2 (en) * | 2005-03-02 | 2010-06-01 | Boston Scientific Scimed, Inc. | Particles |
US7858183B2 (en) * | 2005-03-02 | 2010-12-28 | Boston Scientific Scimed, Inc. | Particles |
US7963287B2 (en) * | 2005-04-28 | 2011-06-21 | Boston Scientific Scimed, Inc. | Tissue-treatment methods |
US20070004973A1 (en) * | 2005-06-15 | 2007-01-04 | Tan Sharon M L | Tissue treatment methods |
JP2008543504A (en) | 2005-06-21 | 2008-12-04 | クック・インコーポレイテッド | Implantable graft to close the fistula |
US9463426B2 (en) * | 2005-06-24 | 2016-10-11 | Boston Scientific Scimed, Inc. | Methods and systems for coating particles |
US20070065415A1 (en) * | 2005-09-16 | 2007-03-22 | Kleinsek Donald A | Compositions and methods for the augmentation and repair of defects in tissue |
US20070083219A1 (en) * | 2005-10-12 | 2007-04-12 | Buiser Marcia S | Embolic coil introducer sheath locking mechanisms |
US8007509B2 (en) * | 2005-10-12 | 2011-08-30 | Boston Scientific Scimed, Inc. | Coil assemblies, components and methods |
US7959627B2 (en) | 2005-11-23 | 2011-06-14 | Barrx Medical, Inc. | Precision ablating device |
US8702694B2 (en) | 2005-11-23 | 2014-04-22 | Covidien Lp | Auto-aligning ablating device and method of use |
US7997278B2 (en) | 2005-11-23 | 2011-08-16 | Barrx Medical, Inc. | Precision ablating method |
US8152839B2 (en) * | 2005-12-19 | 2012-04-10 | Boston Scientific Scimed, Inc. | Embolic coils |
US8101197B2 (en) | 2005-12-19 | 2012-01-24 | Stryker Corporation | Forming coils |
US20070142859A1 (en) * | 2005-12-19 | 2007-06-21 | Boston Scientific Scimed, Inc. | Embolic coils |
US7947368B2 (en) * | 2005-12-21 | 2011-05-24 | Boston Scientific Scimed, Inc. | Block copolymer particles |
US7501179B2 (en) * | 2005-12-21 | 2009-03-10 | Boston Scientific Scimed, Inc. | Block copolymer particles |
US20070142560A1 (en) * | 2005-12-21 | 2007-06-21 | Young-Ho Song | Block copolymer particles |
US20070149641A1 (en) * | 2005-12-28 | 2007-06-28 | Goupil Dennis W | Injectable bone cement |
US20070184087A1 (en) * | 2006-02-06 | 2007-08-09 | Bioform Medical, Inc. | Polysaccharide compositions for use in tissue augmentation |
US20070299461A1 (en) * | 2006-06-21 | 2007-12-27 | Boston Scientific Scimed, Inc. | Embolic coils and related components, systems, and methods |
US8414927B2 (en) | 2006-11-03 | 2013-04-09 | Boston Scientific Scimed, Inc. | Cross-linked polymer particles |
US20080145658A1 (en) * | 2006-12-15 | 2008-06-19 | Boston Scientific Scimed, Inc. | Freeze Thaw Methods For Making Polymer Particles |
KR101428122B1 (en) | 2006-12-15 | 2014-08-07 | 라이프본드 엘티디. | Gelatin-transglutaminase hemostatic dressings and sealants |
US8641711B2 (en) | 2007-05-04 | 2014-02-04 | Covidien Lp | Method and apparatus for gastrointestinal tract ablation for treatment of obesity |
US8784338B2 (en) | 2007-06-22 | 2014-07-22 | Covidien Lp | Electrical means to normalize ablational energy transmission to a luminal tissue surface of varying size |
US20090004455A1 (en) * | 2007-06-27 | 2009-01-01 | Philippe Gravagna | Reinforced composite implant |
US20090012518A1 (en) * | 2007-07-06 | 2009-01-08 | Utley David S | Method and Apparatus for Ablation of Benign, Pre-Cancerous and Early Cancerous Lesions That Originate Within the Epithelium and are Limited to the Mucosal Layer of the Gastrointestinal Tract |
CN102688092B (en) * | 2007-07-06 | 2015-04-22 | 柯惠有限合伙公司 | Ablation in the gastrointestinal tract to achieve hemostasis and eradicate lesions with a propensity for bleeding |
US8251992B2 (en) | 2007-07-06 | 2012-08-28 | Tyco Healthcare Group Lp | Method and apparatus for gastrointestinal tract ablation to achieve loss of persistent and/or recurrent excess body weight following a weight-loss operation |
US8646460B2 (en) | 2007-07-30 | 2014-02-11 | Covidien Lp | Cleaning device and methods |
US8273012B2 (en) | 2007-07-30 | 2012-09-25 | Tyco Healthcare Group, Lp | Cleaning device and methods |
US9308068B2 (en) | 2007-12-03 | 2016-04-12 | Sofradim Production | Implant for parastomal hernia |
CA2728186A1 (en) * | 2008-06-18 | 2009-12-23 | Lifebond Ltd | Methods and devices for use with sealants |
JP5450612B2 (en) | 2008-06-18 | 2014-03-26 | ライフボンド リミテッド | Improved cross-linking composition |
EP2303341A2 (en) * | 2008-06-18 | 2011-04-06 | Lifebond Ltd | A method for enzymatic cross-linking of a protein |
US20090318914A1 (en) * | 2008-06-18 | 2009-12-24 | Utley David S | System and method for ablational treatment of uterine cervical neoplasia |
US8282298B2 (en) * | 2008-06-26 | 2012-10-09 | Colgate-Palmolive Company | Oral care implement |
US9242026B2 (en) | 2008-06-27 | 2016-01-26 | Sofradim Production | Biosynthetic implant for soft tissue repair |
FR2949688B1 (en) | 2009-09-04 | 2012-08-24 | Sofradim Production | FABRIC WITH PICOTS COATED WITH A BIORESORBABLE MICROPOROUS LAYER |
WO2011037621A2 (en) | 2009-09-22 | 2011-03-31 | Mederi Therapeutics Inc. | Systems and methods for controlling use and operation of a family of different treatment devices |
US10386990B2 (en) | 2009-09-22 | 2019-08-20 | Mederi Rf, Llc | Systems and methods for treating tissue with radiofrequency energy |
US9750563B2 (en) | 2009-09-22 | 2017-09-05 | Mederi Therapeutics, Inc. | Systems and methods for treating tissue with radiofrequency energy |
US9775664B2 (en) | 2009-09-22 | 2017-10-03 | Mederi Therapeutics, Inc. | Systems and methods for treating tissue with radiofrequency energy |
US9474565B2 (en) | 2009-09-22 | 2016-10-25 | Mederi Therapeutics, Inc. | Systems and methods for treating tissue with radiofrequency energy |
WO2011057131A1 (en) | 2009-11-09 | 2011-05-12 | Spotlight Technology Partners Llc | Polysaccharide based hydrogels |
AU2010314994B2 (en) | 2009-11-09 | 2016-10-06 | Spotlight Technology Partners Llc | Fragmented hydrogels |
BR112012015029A2 (en) | 2009-12-22 | 2017-06-27 | Lifebond Ltd | cross-linked matrix, method for controlling the formation of a matrix, method or matrix, method for sealing a tissue against leakage of a body fluid, hemostatic agent or surgical seal, composition for sealing a wound, use of the composition, composition for a delivery vehicle drug composition, tissue engineering composition, and method for modifying a composition |
US8858577B2 (en) | 2010-05-19 | 2014-10-14 | University Of Utah Research Foundation | Tissue stabilization system |
US8945156B2 (en) | 2010-05-19 | 2015-02-03 | University Of Utah Research Foundation | Tissue fixation |
US9232805B2 (en) | 2010-06-29 | 2016-01-12 | Biocure, Inc. | In-situ forming hydrogel wound dressings containing antimicrobial agents |
US8961544B2 (en) | 2010-08-05 | 2015-02-24 | Lifebond Ltd. | Dry composition wound dressings and adhesives comprising gelatin and transglutaminase in a cross-linked matrix |
US8852214B2 (en) | 2011-02-04 | 2014-10-07 | University Of Utah Research Foundation | System for tissue fixation to bone |
FR2972626B1 (en) | 2011-03-16 | 2014-04-11 | Sofradim Production | PROSTHETIC COMPRISING A THREE-DIMENSIONAL KNIT AND ADJUSTED |
US10278774B2 (en) | 2011-03-18 | 2019-05-07 | Covidien Lp | Selectively expandable operative element support structure and methods of use |
US8915941B2 (en) | 2011-06-14 | 2014-12-23 | Cook Medical Technologies Llc | Fistula closure devices and methods |
FR2977789B1 (en) | 2011-07-13 | 2013-07-19 | Sofradim Production | PROSTHETIC FOR UMBILIC HERNIA |
FR2977790B1 (en) | 2011-07-13 | 2013-07-19 | Sofradim Production | PROSTHETIC FOR UMBILIC HERNIA |
WO2013046058A2 (en) | 2011-09-30 | 2013-04-04 | Sofradim Production | Reversible stiffening of light weight mesh |
FR2985170B1 (en) | 2011-12-29 | 2014-01-24 | Sofradim Production | PROSTHESIS FOR INGUINAL HERNIA |
FR2985271B1 (en) | 2011-12-29 | 2014-01-24 | Sofradim Production | KNITTED PICOTS |
US8403927B1 (en) | 2012-04-05 | 2013-03-26 | William Bruce Shingleton | Vasectomy devices and methods |
US9427309B2 (en) | 2012-07-30 | 2016-08-30 | Conextions, Inc. | Soft tissue repair devices, systems, and methods |
US9629632B2 (en) | 2012-07-30 | 2017-04-25 | Conextions, Inc. | Soft tissue repair devices, systems, and methods |
US10835241B2 (en) | 2012-07-30 | 2020-11-17 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
US10390935B2 (en) | 2012-07-30 | 2019-08-27 | Conextions, Inc. | Soft tissue to bone repair devices, systems, and methods |
US10219804B2 (en) | 2012-07-30 | 2019-03-05 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
US11944531B2 (en) | 2012-07-30 | 2024-04-02 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
US11253252B2 (en) | 2012-07-30 | 2022-02-22 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
FR2994185B1 (en) | 2012-08-02 | 2015-07-31 | Sofradim Production | PROCESS FOR THE PREPARATION OF A POROUS CHITOSAN LAYER |
FR2995779B1 (en) | 2012-09-25 | 2015-09-25 | Sofradim Production | PROSTHETIC COMPRISING A TREILLIS AND A MEANS OF CONSOLIDATION |
FR2995778B1 (en) | 2012-09-25 | 2015-06-26 | Sofradim Production | ABDOMINAL WALL REINFORCING PROSTHESIS AND METHOD FOR MANUFACTURING THE SAME |
FR2995788B1 (en) | 2012-09-25 | 2014-09-26 | Sofradim Production | HEMOSTATIC PATCH AND PREPARATION METHOD |
AU2013322268B2 (en) | 2012-09-28 | 2017-08-31 | Sofradim Production | Packaging for a hernia repair device |
EP2994176B1 (en) | 2013-05-10 | 2020-07-08 | Smith & Nephew plc | Fluidic connector for irrigation and aspiration of wounds |
FR3006578B1 (en) | 2013-06-07 | 2015-05-29 | Sofradim Production | PROSTHESIS BASED ON TEXTILE FOR LAPAROSCOPIC PATHWAY |
FR3006581B1 (en) | 2013-06-07 | 2016-07-22 | Sofradim Production | PROSTHESIS BASED ON TEXTILE FOR LAPAROSCOPIC PATHWAY |
US11583384B2 (en) | 2014-03-12 | 2023-02-21 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
EP3000433B1 (en) | 2014-09-29 | 2022-09-21 | Sofradim Production | Device for introducing a prosthesis for hernia treatment into an incision and flexible textile based prosthesis |
EP3000432B1 (en) | 2014-09-29 | 2022-05-04 | Sofradim Production | Textile-based prosthesis for treatment of inguinal hernia |
EP3029189B1 (en) | 2014-12-05 | 2021-08-11 | Sofradim Production | Prosthetic porous knit, method of making same and hernia prosthesis |
EP3059255B1 (en) | 2015-02-17 | 2020-05-13 | Sofradim Production | Method for preparing a chitosan-based matrix comprising a fiber reinforcement member |
EP3085337B1 (en) | 2015-04-24 | 2022-09-14 | Sofradim Production | Prosthesis for supporting a breast structure |
ES2676072T3 (en) | 2015-06-19 | 2018-07-16 | Sofradim Production | Synthetic prosthesis comprising a knitted fabric and a non-porous film and method of forming it |
EP3195830B1 (en) | 2016-01-25 | 2020-11-18 | Sofradim Production | Prosthesis for hernia repair |
US11696822B2 (en) | 2016-09-28 | 2023-07-11 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
EP3312325B1 (en) | 2016-10-21 | 2021-09-22 | Sofradim Production | Method for forming a mesh having a barbed suture attached thereto and the mesh thus obtained |
EP3398554A1 (en) | 2017-05-02 | 2018-11-07 | Sofradim Production | Prosthesis for inguinal hernia repair |
US11547397B2 (en) | 2017-12-20 | 2023-01-10 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
CA3091800A1 (en) | 2018-02-20 | 2019-08-29 | Conextions, Inc. | Devices, systems, and methods for repairing soft tissue and attaching soft tissue to bone |
US11246644B2 (en) | 2018-04-05 | 2022-02-15 | Covidien Lp | Surface ablation using bipolar RF electrode |
US11324512B2 (en) | 2018-10-26 | 2022-05-10 | Torax Medical, Inc. | Magnetic sphincter augmentation device for urinary incontinence |
US11051931B2 (en) | 2018-10-31 | 2021-07-06 | Cilag Gmbh International | Active sphincter implant to re-route flow through gastrointestinal tract |
EP3653171A1 (en) | 2018-11-16 | 2020-05-20 | Sofradim Production | Implants suitable for soft tissue repair |
US11376146B2 (en) | 2018-12-17 | 2022-07-05 | Cilag Gmbh International | Tissue interface features for implantable sphincter assistance device |
US11071619B2 (en) | 2018-12-17 | 2021-07-27 | Cilag Gmbh International | Coupling assembly for implantable sphincter assistance device |
US11478347B2 (en) | 2018-12-17 | 2022-10-25 | Cilag Gmbh International | Sphincter sizing instrument |
US10842496B2 (en) | 2018-12-17 | 2020-11-24 | Ethicon Llc | Implantable sphincter assistance device with tuned magnetic features |
US11399928B2 (en) | 2018-12-19 | 2022-08-02 | Cilag Gmbh International | Linking elements for implantable sphincter assistance device |
US11298136B2 (en) | 2018-12-19 | 2022-04-12 | Cilag Gmbh International | Implantable sphincter assistance device with deformable elements |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3197369A (en) * | 1962-02-15 | 1965-07-27 | Scherer Gmbh R P | Coated gelatin capsules |
US2696456A (en) * | 1950-04-24 | 1954-12-07 | Lambert Company | Dual element suppository |
US3749100A (en) * | 1968-08-13 | 1973-07-31 | Bio Controls Corp | Suppository electrode structure |
US3650275A (en) * | 1968-08-13 | 1972-03-21 | Bio Controls Corp | Method and apparatus for controlling anal incontinence |
US3952726A (en) * | 1973-12-20 | 1976-04-27 | Gerhard R. Hennig | Medical device |
US3949073A (en) * | 1974-11-18 | 1976-04-06 | The Board Of Trustees Of Leland Stanford Junior University | Process for augmenting connective mammalian tissue with in situ polymerizable native collagen solution |
DE2722286C2 (en) * | 1977-05-17 | 1986-04-17 | Coloplast A/S, Espergaerde | Non-magnetic tampon for closing an artificial anus and process for its production |
US4424208A (en) * | 1982-01-11 | 1984-01-03 | Collagen Corporation | Collagen implant material and method for augmenting soft tissue |
US4582640A (en) * | 1982-03-08 | 1986-04-15 | Collagen Corporation | Injectable cross-linked collagen implant material |
US4401107A (en) * | 1982-04-20 | 1983-08-30 | Haber Terry M | Intestinal control valve |
US4686985A (en) * | 1985-05-15 | 1987-08-18 | Lottick Edward A | Anal dilator and occluder |
JPH0624551B2 (en) * | 1986-02-24 | 1994-04-06 | 名糖産業株式会社 | Magnetic colostomy with constriction function |
US4760131A (en) * | 1986-04-23 | 1988-07-26 | Collagen Corporation | Wound-healing composition |
US4803075A (en) * | 1986-06-25 | 1989-02-07 | Collagen Corporation | Injectable implant composition having improved intrudability |
US4969902A (en) * | 1987-02-20 | 1990-11-13 | Biagio Ravo | Implantable device |
US4781176A (en) * | 1987-02-20 | 1988-11-01 | Biagio Ravo | Implantable device |
US4950483A (en) * | 1988-06-30 | 1990-08-21 | Collagen Corporation | Collagen wound healing matrices and process for their production |
US5162430A (en) * | 1988-11-21 | 1992-11-10 | Collagen Corporation | Collagen-polymer conjugates |
-
1992
- 1992-02-28 US US07/843,124 patent/US5480644A/en not_active Expired - Lifetime
-
1993
- 1993-02-17 EP EP93907146A patent/EP0627900B1/en not_active Expired - Lifetime
- 1993-02-17 WO PCT/US1993/001879 patent/WO1993016658A1/en active IP Right Grant
- 1993-02-17 AT AT93907146T patent/ATE179877T1/en not_active IP Right Cessation
- 1993-02-17 CA CA002131021A patent/CA2131021C/en not_active Expired - Fee Related
- 1993-02-17 DE DE69324909T patent/DE69324909T2/en not_active Expired - Fee Related
- 1993-02-17 ES ES93907146T patent/ES2134843T3/en not_active Expired - Lifetime
- 1993-02-17 JP JP5515122A patent/JP2711181B2/en not_active Expired - Fee Related
- 1993-02-17 AU AU37853/93A patent/AU674308B2/en not_active Ceased
-
1995
- 1995-05-18 US US08/444,187 patent/US5490984A/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
AU3785393A (en) | 1993-09-13 |
AU674308B2 (en) | 1996-12-19 |
ES2134843T3 (en) | 1999-10-16 |
DE69324909D1 (en) | 1999-06-17 |
US5480644A (en) | 1996-01-02 |
DE69324909T2 (en) | 1999-09-16 |
WO1993016658A1 (en) | 1993-09-02 |
US5490984A (en) | 1996-02-13 |
EP0627900A4 (en) | 1995-02-15 |
JPH07505146A (en) | 1995-06-08 |
EP0627900B1 (en) | 1999-05-12 |
CA2131021A1 (en) | 1993-09-02 |
JP2711181B2 (en) | 1998-02-10 |
ATE179877T1 (en) | 1999-05-15 |
EP0627900A1 (en) | 1994-12-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2131021C (en) | Use of injectable biomaterials for the repair and augmentation of the anal sphincters | |
Kershen et al. | New advances in injectable therapies for the treatment of incontinence and vesicoureteral reflux | |
Dmochowski et al. | Injectable agents in the treatment of stress urinary incontinence in women: where are we now? | |
Harriss et al. | Peri‐urethral silicone microimplants (Macroplastique) for the treatment of genuine stress incontinence | |
Mayer et al. | Preliminary evaluation of calcium hydroxylapatite as a transurethral bulking agent for stress urinary incontinence | |
KR100316212B1 (en) | Biocompatible hydrogel | |
Lee et al. | Periurethral autologous fat injection as treatment for female stress urinary incontinence: a randomized double-blind controlled trial | |
EP0918498B1 (en) | Improved tissue injectable composition | |
US9017709B2 (en) | Composition comprising polymeric, water-insoluble, anionic particles, processes and uses | |
US20020176893A1 (en) | Compositions, implants, methods, and kits for closure of lumen openings, repair of ruptured tissue, and for bulking of tissue | |
EP1287048B2 (en) | Polyacrylamide hydrogel and its use as an endoprosthesis | |
Stenberg et al. | DiHA Dextran Copolymer, a new biocompatible material for endoscopic treatment of stress incontinent women, Short term results | |
Pycha et al. | Implantable microballoons: an attractive alternative in the management of intrinsic sphincter deficiency | |
Colombo et al. | The use of polydimethylsiloxane in the treatment of incontinence after radical prostatectomy | |
Yoo et al. | Detachable self-sealing membrane system for the endoscopic treatment of incontinence | |
Schultheiss | A brief history of urinary incontinence and its treatment | |
EP0679404B1 (en) | Use of human fibrin glue in the non-surgical treatment of urinary incontinence | |
DARSON et al. | Periurethral injection of the genitourinary spheroidal membrane | |
JPH07504413A (en) | Use of injectable biological materials in the treatment of hemorrhoids | |
Echols et al. | Persistence of delayed hypersensitivity following transurethral collagen injection for recurrent urinary stress incontinence | |
Elzayat et al. | Urethral injectables in the management of stress urinary incontinence | |
LaTorre | Bulking agents and faecal incontinence | |
de la Portilla | Approaches to Internal Anal Sphincter Augmentation | |
KR20040044018A (en) | Polyacrylamide hydrogel and its use as an endoprosthesis | |
Herschorn et al. | Urethral Injectables in the Management of SUI and Hypermobility |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKLA | Lapsed |