WO1993016711A1 - Use of injectable biomaterials in the treatment of hemorrhoids - Google Patents
Use of injectable biomaterials in the treatment of hemorrhoids Download PDFInfo
- Publication number
- WO1993016711A1 WO1993016711A1 PCT/US1993/001391 US9301391W WO9316711A1 WO 1993016711 A1 WO1993016711 A1 WO 1993016711A1 US 9301391 W US9301391 W US 9301391W WO 9316711 A1 WO9316711 A1 WO 9316711A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- collagen
- hemorrhoids
- crosslinked
- biomaterial
- beads
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/755—Polymers containing halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/695—Silicon compounds
-
- 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
- A61K38/18—Growth factors; Growth regulators
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
-
- 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
Definitions
- This invention is in the field of medical implants and prostheses. Specifically, it concerns a nonsurgical technique for treating hemorrhoids and pruritis ani, a related condition, by injecting biomaterials into the soft tissue of the anal verge.
- the anatomy of the region known as the anal canal is complex and the etiology of the condition known as hemorrhoids has long been the subject of research and reexamination.
- the anal columns (folds of epithelia and muscle tissue) and anal sinuses (furrows separating the anal columns from each other) are found at the upper end of the anal canal.
- the anal sinuses end in valve-like folds, called the anal valves, and the anal canal is vascularized by veins derived from the superior and inferior rectal (hemorrhoidal) veins.
- the vascular tissues of the anal canal are found in the left lateral, right posterior, and right anterior positions of the anal canal, at or above the level of the anal valves.
- the anal cushions are submucosal and comprise blood vessels (mainly veins) supported by smooth muscle (Treitz's muscle) and connective tissue.
- the anal verge refers to the external or distal boundary of the anal canal; that is, the line where the anal walls contact during the normal state of apposition.
- Hemorrhoids are believed to be caused by breakdown in the connective tissue and smooth muscle that support the anal cushions, causing displacement of the cushions into the lumen of the distal canal. This is especially likely to occur when there is a history of constipation or prolonged straining at stool, leading to stretching or disruption of Treitz's muscle together with venous engorgement. Once the cushions are displaced, the venous engorgement may be perpetuated by a tight internal anal sphincter.
- Each hemorrhoid consists of an internal and external component.
- the internal component lies above the line of the anal valves, known as the dentate or pectinate line.
- the external component lies below this line.
- the internal and external component are clearly distinguished by a groove and by a differential epithelial covering.
- the internal component is usually covered with columnar epithelium, while the external is covered with skin and stratified squamous epithelium.
- hemorrhoids A number of predisposing factors for the development of hemorrhoids are known, such as heredity, pregnancy, and pelvic tumors. However, in the majority of patients, no explanation for the onset of hemorrhoids can be found. Hemorrhoids, rarely present before the third decade of life, are commonly associated with the aging process. In fact, aging weakens the connective tissue support of the anal cushions, resulting in increased venous dilatation. Although hemorrhoids occur in both sexes, they predominate in men, despite the predisposing factor of pregnancy.
- hemorrhoids Although not a life-threatening condition, the symptoms of hemorrhoids can cause the sufferer a great deal of discomfort and concern. Symptoms of hemorrhoids include anorectal bleeding during defecation; discomfort, pain, and/or itching in the perianal area (pruritis ani) ; prolapse of submucosal tissue into the anus during defecation; swelling at the anal margin due to the external component of the hemorrhoid becoming engorged with blood; and excessive mucus production and discharge due to inflammation.
- First degree hemorrhoids are characterized by bleeding only.
- Second degree hemorrhoids involve prolapse of submucosal tissue at defecation (with or without bleeding) with spontaneous return of the tissue to the anal canal; whereas third degree hemorrhoids are defined by prolapse (with or without bleeding) requiring manual replacement of tissue into the anal canal.
- Fourth degree hemorrhoids protrude permanently and cannot be reduced or replaced manually.
- Hemorrhoids are treated in response to a patient's complaints of symptoms. Dietary modification, specifically increasing the consumption of dietary fiber, has been shown to have moderate success in the treatment of minor bleeding.
- Topical ointments, pharmaceutical preparations, and related application devices have long been described in the art for the treatment of mild symptoms.
- 3,826,242 describes a tubular member that is inserted into the anal canal, engaging the walls of the canal and the area around the rectal opening, which maintains pressure on the hemorrhoidal veins of the anal canal, lower rectum, and anal area during defecation to prevent swelling and distention of the hemorrhoidal veins and extrusion of the internal hemorrhoidal veins out of the anal canal during defecation.
- a device that is inserted into the rectum to treat hemorrhoids by application of gentle pressure against the dilated veins is disclosed in U.S. Patent 4,583,542.
- U.S. Patent 4,906,239 describes a cone-shaped hemorrhoid treatment rod to dilate the anus.
- U.S. Patent 4,932,397 discloses a therapeutic, horseshoe-shaped rectal device, comprising a malleable core element surrounded by a resilient covering, for alleviating hemorrhoids by protecting the irritated anorectal area from pressure and friction.
- U.S. Patent 4,898,169 describes an instrument for direct current electrical therapy of hemorrhoids.
- U.S. Patents 4,142,529 and 4,227,535 disclose a suppository appliance that intimately contacts the anal canal wall and hemorrhoids.
- the appliance contains an internal electrical resistor for generating heat in response to the application of electrical energy, which maintains the temperature of the appliance above body temperature and below 45°C, thereby facilitating the opening of the vascular channels and allowing shrinkage of the hemorrhoids.
- a chemical-containing device for insertion into the anal canal that raises the temperature of the wall surface to approximately 45°C is described in U.S. Patent 4,696,302.
- Paten 4,331,151 describes a hemorrhoid bandage or cold pack that is positioned within the anal canal to continuously supply a cool fluid to provide a controlled temperature within the rectal area for extended periods of time in connection with the treatment of hemorrhoids.
- U.S. Patent 4,563,182 discloses the use of a cylindrical insert comprising a water-expandable polymer which has been previously frozen that is inserted into the rectum to treat hemorrhoids.
- a cryogenic proctologic insert for treating hemorrhoids by lowering the surface temperature of the affected portion of the rectal canal is disclosed in U.S. Patent 4,841,970.
- Any electrical, mechanical, or thermal device that is inserted into the body is unfortunately subject to complications resulting from the malfunction, breakage, or displacement of the device. Any such device is also inherently not “natural" to the body. Therefore, other methods are used to treat hemorrhoids.
- traditional nonsurgical therapies for hemorrhoids include sclerotherapy, rubber band ligation, anal dilatation, cryotherapy, and photocoagulation. These procedures all have comparable success rates in the treatment of first and second degree hemorrhoids. However, all have side effects and result in tissue destruction. Complications range from flatulence to death as a result of infection or excessive bleeding.
- Sclerotherapy involves the injection of solutions containing carbolic acid into the submucosa proximal to the hemorrhoidal mass to induce fibrosis of the hemorrhoid. This procedure is seldom used in the treatment of hemorrhoids due to unpredictable results and because the procedure is very subject to physical error. Complications of this therapy may include ulceration, pain, abscess and oleogranuloma (if oil-containing solutions are used) , bleeding, and bacteremia.
- rubber band ligation is generally more uncomfortable than sclerotherapy.
- This treatment involves applying a rubber band to the non- innervated portion of mucosa above the hemorrhoidal mass to induce necrosis of the hemorrhoid. Though rare, complications may be potentially serious or life-threatening. Delayed hemorrhage due to localized infection and ulceration occurs in about one percent (%) of patients and may result in massive bleeding requiring hospitalization.
- Cryotherapy relies on the thermal destruction of hemorrhoidal cells. Complications include discomfort, swelling and edema associated with excessive drainage, and prolonged drainage and recovery time when compared with the other nonsurgical techniques. Photocoagulation involves the use of infrared rays to coagulate the hemorrhoidal mass, resulting in tissue necrosis. Complications include discomfort and minor bleeding.
- a condition often related to hemorrhoids is pruritis ani.
- the prolapsing or inflamed hemorrhoids can cause excessive moisture and itching in the perianal region.
- the appearance of the perianal skin varies from patient to patient depending upon the severity of the condition. In mild cases, the skin may appear completely normal. If the condition is acute, the skin may be erythematous and weeping, with numerous excoriations. In chronic cases, the skin is thickened, leathery, and white. For mild conditions, dietary modifications, such as increasing fiber, or topical treatments are sufficient to alleviate the burning and itching.
- hemorrhoids are normal anatomical structures, they preferably should not be removed or destroyed except in very advanced disease cases. Therefore, an ideal treatment for hemorrhoids and/or pruritis ani would comprise an effective nonsurgical procedure that is easy to administer, with little likelihood of physician error, a low rate of complications, no serious side effects, little tissue destruction, and a low risk for infection.
- An ideal hemorrhoid treatment would also be "natural" to the body and would not comprise any device that could potentially malfunction, break, or be displaced from its intended position.
- the present invention meets all of the above criteria.
- the invention teaches a method for treating hemorrhoids and/or pruritis ani by perianally administering an effective amount of an injectable biomaterial(s) into the soft tissues of the anal verge, thereby preventing the displacement of submucosal tissue into the anal canal.
- the invention is a nonsurgical method for treating hemorrhoids and/or pruritis ani by perianally administering an effective amount of an injectable biomaterial into the soft tissues of the anal verge to prevent the displacement of the submucosal tissue into the anal canal.
- effective amount means the quantity of biomaterial needed to achieve significant improvement in the symptoms of hemorrhoids or pruritis ani or the quantity of wound healing agents needed to achieve improved healing.
- the effective amount of biomaterial administered may vary depending on the patient's own ability to absorb or break down the biomaterial, the consistency and concentration of the material, and the site and condition being treated.
- the biomaterial may be administered over a number of treatment sessions in order to effect the improvement of hemorrhoid and related pruritis ani symptoms.
- the biomaterial used in the invention may be selected from a number of sources; however, it must be injectable, biocompatible, essentially non-immunogenic, and persist at the site of placement for at least three months.
- 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 4,803,075, which is incorporated herein by reference. Commercially available suspensions of a biopolymer and fluid lubricant may be obtained from Bioplasty, Inc.
- 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.
- Biopoly ers 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.
- Collagen is a major protein component of bone, cartilage, skin, and connective tissue in animals.
- Collagen in its native form 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 and Y are often proline or hydroxyproline, bounded at each end by the "telopeptide" regions, which constitute less than about 5% of the molecule.
- the telopeptide region of the collagen chains are typically responsible for the crosslinking between chains and for the immunogenicity of the protein.
- Collagen occurs in types, of varying physical properties; the most abundant are Types I-II .
- 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
- 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; which are incorporated herein by reference.
- U.S. Patent 4,424,208 discloses an improved collagen formulation suitable for use in soft tissue augmentation.
- the formulation comprises reconstituted fibrillar atelopeptide collagen in combination with particulate, crosslinked atelopeptide collagen dispersed in an aqueous medium.
- the addition of particulate crosslinked collagen improves the biomaterial's persistence, or ability to resist 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.
- Copending U.S. Patent Application Serial No. 07/433,441 discloses 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.
- Also disclosed in the pending application is a method for crosslinking the collagen material with a bifunctional activated polymer in situ, such as polyethylene glycol. This improved 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, which is disclosed in copending U.S. Patent Application Serial No. (Attorney Number 05921-13) incorporated herein by reference. Briefly, collagen in solution (Vitrogen 100 Collagen, Celtrix Laboratories, Palo Alto, California) is reconstituted to fibril form by 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 herein are passed through a homogenizer (HC5000, Microfluidics Corporation, Newton, Massachusetts) to improve the extrudability of the material through a fine gauge needle.
- 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.
- wound healing agents may be added to the biomaterial used in the invention.
- 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 (CTAPs) , transforming growth factors (TFGs) , and the like.
- FGFs fibroblast growth factors
- PDGFs platelet derived growth factors
- EGFs epidermal growth factors
- CAPs connective tissue activated peptides
- TGFs transforming growth factors
- the amount of wound healing agent(s) 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 agent(s) 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.
- analogs, fragments, or derivatives of these agents may be used provided they exhibit some of the biological activity or wound healing properties of the native molecule.
- 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 hemorrhoid sites and surrounding areas, promoting wound healing.
- these agents will be included in the treatment of patients with hemorrhoids associated with inflammatory bowel disease, whose wounds may heal poorly, worsening symptoms.
- antimicrobial additives and/or antibodies may be added to these biomaterials to reduce the potential for infection at the treatment site.
- 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 in a sterile 3.0 cubic centimeters (cc) syringe fitted with a 25 gauge needle.
- a complete anorectal examination should be conducted prior to treatment.
- the exam includes inspection, palpation, sigmoidoscopy, and proctoscopy. Inspection will provide the physician with a great deal of information regarding the severity and degree of a patient's hemorrhoids. Palpation will help the physician to estimate the tone of the anal sphincter. Any thrombosed area will feel indurated, but it should be emphasized that uncomplicated hemorrhoids are not palpable. As the symptoms of hemorrhoids may resemble those of serious colorectal disease, namely cancer and inflammatory bowel disease, sigmoidoscopy is performed to rule out other problems.
- the biomaterial When treating hemorrhoids, the biomaterial is injected perianally into the soft tissues and/or skin of the anal verge until the treated area is completely filled with biomaterial.
- a preferred amount of biomaterial to be used is approximately 1-10 cc, most preferably 5 cc.
- the amount of material necessary to restore the tissue to its original position will, of course, vary from person to person. The exact amount of material used is therefore left to the discretion of the administering physician.
- treatment success is defined by a patient's report of an improvement in symptoms. Improvement is expected to last approximately 3 to 12 months as a result of treatment.
- the injections may optionally be repeated on a regular basis to maintain patient comfort level. Subsequent injections will likely require the use of less material than the initial treatment.
- methods for treating hemorrhoids and/or pruritis ani may be conducted by perianally administering an injectable biomaterial, with or without wound healing agents, into the soft tissues of the anal verge. These methods provide nonsurgical approaches to relieve the symptoms of hemorrhoids and related conditions.
- the invention has been described above 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.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93906001A EP0627927A1 (en) | 1992-02-28 | 1993-02-17 | Use of injectable biomaterials in the treatment of hemorrhoids |
JP5514930A JPH07504413A (en) | 1992-02-28 | 1993-02-17 | Use of injectable biological materials in the treatment of hemorrhoids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US84337992A | 1992-02-28 | 1992-02-28 | |
US07/843,379 | 1992-02-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993016711A1 true WO1993016711A1 (en) | 1993-09-02 |
Family
ID=25289797
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/001391 WO1993016711A1 (en) | 1992-02-28 | 1993-02-17 | Use of injectable biomaterials in the treatment of hemorrhoids |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0627927A1 (en) |
JP (1) | JPH07504413A (en) |
AU (1) | AU3720493A (en) |
CA (1) | CA2130993A1 (en) |
WO (1) | WO1993016711A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9144631B2 (en) | 2003-01-27 | 2015-09-29 | Benedicte Asius | Ceramic-based injectable implants which are used to fill wrinkles, cutaneous depressions and scars, and preparation method thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4424208A (en) * | 1982-01-11 | 1984-01-03 | Collagen Corporation | Collagen implant material and method for augmenting soft tissue |
US4557764A (en) * | 1984-09-05 | 1985-12-10 | Collagen Corporation | Process for preparing malleable collagen and the product thereof |
US4803075A (en) * | 1986-06-25 | 1989-02-07 | Collagen Corporation | Injectable implant composition having improved intrudability |
US5110604A (en) * | 1988-06-30 | 1992-05-05 | Collagen Corporation | Processes for producing collagen matrixes and methods of using same |
US5128136A (en) * | 1990-07-16 | 1992-07-07 | The Oregon Health Sciences University | Wound healing kit comprised of gelable collagen |
US5162430A (en) * | 1988-11-21 | 1992-11-10 | Collagen Corporation | Collagen-polymer conjugates |
-
1993
- 1993-02-17 CA CA002130993A patent/CA2130993A1/en not_active Abandoned
- 1993-02-17 EP EP93906001A patent/EP0627927A1/en not_active Withdrawn
- 1993-02-17 WO PCT/US1993/001391 patent/WO1993016711A1/en not_active Application Discontinuation
- 1993-02-17 JP JP5514930A patent/JPH07504413A/en active Pending
- 1993-02-17 AU AU37204/93A patent/AU3720493A/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4424208A (en) * | 1982-01-11 | 1984-01-03 | Collagen Corporation | Collagen implant material and method for augmenting soft tissue |
US4557764A (en) * | 1984-09-05 | 1985-12-10 | Collagen Corporation | Process for preparing malleable collagen and the product thereof |
US4803075A (en) * | 1986-06-25 | 1989-02-07 | Collagen Corporation | Injectable implant composition having improved intrudability |
US5110604A (en) * | 1988-06-30 | 1992-05-05 | Collagen Corporation | Processes for producing collagen matrixes and methods of using same |
US5162430A (en) * | 1988-11-21 | 1992-11-10 | Collagen Corporation | Collagen-polymer conjugates |
US5128136A (en) * | 1990-07-16 | 1992-07-07 | The Oregon Health Sciences University | Wound healing kit comprised of gelable collagen |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9144631B2 (en) | 2003-01-27 | 2015-09-29 | Benedicte Asius | Ceramic-based injectable implants which are used to fill wrinkles, cutaneous depressions and scars, and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
CA2130993A1 (en) | 1993-09-02 |
JPH07504413A (en) | 1995-05-18 |
EP0627927A1 (en) | 1994-12-14 |
AU3720493A (en) | 1993-09-13 |
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