WO1991008718A1 - Prothese creuse pour viscere et methode d'implantation - Google Patents

Prothese creuse pour viscere et methode d'implantation Download PDF

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Publication number
WO1991008718A1
WO1991008718A1 PCT/US1990/007233 US9007233W WO9108718A1 WO 1991008718 A1 WO1991008718 A1 WO 1991008718A1 US 9007233 W US9007233 W US 9007233W WO 9108718 A1 WO9108718 A1 WO 9108718A1
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WO
WIPO (PCT)
Prior art keywords
collagen
substrate
prosthetic device
tissue
synthetic substrate
Prior art date
Application number
PCT/US1990/007233
Other languages
English (en)
Inventor
Jeffrey L. Orth
Richard E. Hoffer
Original Assignee
Biosynthesis, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Biosynthesis, Inc. filed Critical Biosynthesis, Inc.
Publication of WO1991008718A1 publication Critical patent/WO1991008718A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • 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
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • 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
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006—Properties of materials and coating materials
    • A61F2002/30062—(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
    • A61F2002/30064—Coating or prosthesis-covering structure made of biodegradable material
    • 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
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389—The prosthesis being coated or covered with a particular material
    • A61F2310/00976—Coating or prosthesis-covering structure made of proteins or of polypeptides, e.g. of bone morphogenic proteins BMP or of transforming growth factors TGF
    • A61F2310/00982—Coating made of collagen

Definitions

  • This invention relates to products and techniques used in the repair or reconstruction of the walls of organs or other body parts which have been breached by accidental trauma or resected by surgical necessity. More particularly, this invention relates to implantable prostheses capable of being incorporated into the surrounding tissue for restoration of portions of walls of organs or replacement of entire organ walls when such organs or body parts are not susceptible ,to reconstruction by traditional techniques, such as grafting or end-to-end anastomosis.
  • the diseased one or by substitution of tissue from other organs, as in graft reconstructions.
  • the esophagus may be replaced by a sub ⁇ stituted portion of the colon, or more commonly by esopha- gogastrectomy.
  • the lower urinary tract may be treated by 0 partial to total cystectomy with ureteroileostomy.
  • the use of a reservoir ileostomy and mucosal proctectomy with ileoanal anastomosis has been utilized following coelectomy, although more recent procedures using mechanical stomal occluding devices have been ad- 5 vanced.
  • Collagen a fibrous protein which is the major extracellular structural protein of connective tissue and bone, forms a structural continuum in binding cells to ⁇ gether to form tissue.
  • the collagen has been shown to encourage epithelial growth across the substrate.
  • the collagen is eventually absorbed by the body, leaving a layer of epithelial tissue positioned on top of the synthetic substrate.
  • epithelialization across the sub- strate does occur in these devices, significant problems have still been encountered.
  • the growing epithelial layer lacks vascularization and growth event ⁇ ually is restricted.
  • epithelialization may not occur completely across the sub ⁇ strate.
  • growth cannot be controlled and excess connective tissue growth may result in stenosis of the tract. Ineffective methods of collagen application have also led to implants which leak.
  • the problems associated with implantation of synthetic prosthetic devices may be overcome by providing a prosthesis which will encourage primary interfacing between the prosthesis and the body's connective tissue which will promote epithelial growth within the lumen of the prosthesis or organ while promot ⁇ ing vascularization and anchoring of connective tissue through the pores of the synthetic material.
  • the instant invention presents a unique material for implantation into the tissue or viscera of a body which addresses the difficulties encountered with prior synthetic prosthetic forms. That is, through controlled application of collagen to a synthetic substrate, the invention encourages regulated growth of connective tissue for ultimate incorporation of the device into the sur- rounding body tissue.
  • the invention includes a porous synthetic polymeric substrate to which collagen has been applied so that the pores of the substrate become occluded with the collagen, thereby rendering the substrate impermeable to liquid and bacterial invasion.
  • This impermeability is particularly important when the invention is used in urinary tract, respiratory tract, or gastrointestinal tract for reconstruction or replacement.
  • the synthetic substrate may generally be formed of any tissue-compatible and relatively inert synthetic polymer, such as polyethylene, polyurethane, poly ⁇ propylene, silicone rubber, or teflon.
  • the pores formed therethrough may have uniform or irregular shape and size. Irregularity of porosity, however, enhances the strength of epithelial bonding to -the substrate and also controls the amount of granulation tissue (initial connective tissue) forming therethrough.
  • a porous synthesized metal ⁇ lic material, such as tantalum, may also be used in the invention.
  • Synthetic refers to any material, whether metallic, polymeric or of natural ori ⁇ gin, which is not otherwise naturally occurring in the desired form and which must be specially fabricated for the purposes of this invention.
  • Controlled growth of connective tissue into the pores of the substrate is important in assuring optimal incorporation of the invention into the body. That is, the rate at which the collagen is absorbed by the body, and the resulting formation of the connective tissue therefor, affects the rate of epithelialization -across the substrate and affects the ultimate rate of incorporation of the device. For example, it has been observed in pre ⁇ vious collagen coated implants that if insufficient con ⁇ nective tissue ingrowth occurs through the substrate to the lumen, epithelial growth from the suture line toward the center of the implant stops. This is due to outgrowth of the blood supply in the connective tissue resulting in sloughing of the epithelium back to the suture line.
  • the connective tissue continues to grow and produces stenosis of the lumen of the viscus.
  • Controlled application of collagen to the substrate ameliorates, insufficient ingrowth or excessive ingrowth of connective.tissue into the substrate, and regulates optimal growth of connective tissue.
  • Enhancement and control of connective tissue ingrowth into the substrate, and subsequent epithelializa ⁇ tion, may be furthered by the addition of fibroblasts to the collagen as a coating on the substrate.
  • Fibroblasts are fibrillar cells found in abundance in connective tissue, and are the source of collagen in connective tissue. When added to the collagen, fibroblasts interact with the collagen to the substrate, and produce their own collagen, thus promoting the ingrowth of connective tissue on the substrate to effect complete incorporation of the implant into the surrounding tissue.
  • the collagen coating may be cross-linked by any of several means, including irradiation, ultraviolet light, glutaraldehyde, or polyglycerol polyglycidylether (PPE) .
  • Cross-linking causes increased density and strength of the collagen and causes the collages to expand slightly within the substrate pores to increase the anchoring of collagen to the substrate.
  • cross- linking increases the density and strength of the collagen coating to the substrate pores, cross-linking may not be required or even desirable in some applications.
  • porous synthetic polymer used as a substrate other synthetic materials may be associated with the substrate which lend elasticity to the implant or prosthesis as needed. That is, in some applications a certain amount of elasticity is desirable.
  • An example would be prosthetic implants for the urinary bladder where expansion and contraction of the implant is required during filling and evacuation.
  • Typical elastic materials which might be used include silicone rubber (S ilastic R) or P°l yu r et h a n es #
  • Optimum efficacy of the implant may be achieved through association of mucosal epithelium from the sur- rounding viscus or tissue with the intraluminal surface of the implant.
  • the epithelial lining of many organs is im ⁇ portant to the function of that organ.
  • the mucosal lining of the trachea contains cilia which move debris out of the lungs.
  • a graft of mucosal epithelium from the trachea or nasal sinus may be attached to the surface of the implant or prosthesis which will be directed intraluminally. With vascularization through the synthetic substrate and epithelialization, the intraluminal graft may eventually assume its function.
  • the incorporable material of the present invention may be adaptable to a variety of medical or surgical applications.
  • the incorporable material may be produced in the form of a patch for use in repairing or reconstructing holes in a viscus produced by accidental trauma or necessary surgical resection, or for expanding a stenotic lumen.
  • nine percent of infants placed on ventilators develop subglottic stenosis. This often pro ⁇ gresses to the point where the glottis is totally occluded.
  • the incorporable material may be formed into a tube for implantation into a trachea, eso ⁇ phagus, or intestine where end-to-end anastomosis is made impossible. Most esophageal resections are performed for cancer of the esophagus or cancer at the cardioesophageal junction. Esophageal resections are also required for some benign lesions and chemical burns.
  • the use of radiotherapy or chemotherapy, either individually or in combination, has not eliminated the continued need for surgical resection of the esophagus for the management of carcinoma of the esophagus.
  • the non-surgical palliative use of the intraluminal esophageal tube to maintain a lumen for the passage of saliva and food has proved to be generally unsatisfactory and inferior to surgical resection as a palliation of esophageal cancer.
  • the intraluminal tube is sometimes used as a last resort, or not used at all.
  • Both palliative esophageal resection and wide extended resection of carcinoma of the esophagus provide most patients with a very limited survival time of less than two years from time of diagnosis.
  • a major surgical procedure which may include surgical invasion of both the thorax and abdomen for production of a graft.
  • the maximum amount of trachea that can be successfully resected is six to eight centimeters due to tension.
  • Nevile prosthesis a medical grade silicone copolymer tube with polyester- covered Dacron sewing rings at either end
  • This does not permit intraluminal connective tissue ingrowth or epithelial ingrowth, and it often extrudes or forms fistulas.
  • These major surgical procedures in mostly elderly or debilitated patients, may have a high rate of morbidity.
  • the use of an artificial segment of esophagus would allow the surgical procedure to be limited to the thorax and possibly the neck, without the necessity of an abdominal procedure. The elimination of the abdominal procedure would allow most patients immediate restoration of nutrition postoperatively through • the gastrointestinal tract.
  • the invention may be used as a prosthetic replacement for an entire organ or organ system.
  • urinary bladder replacement is indicated following cystectomy for bladder cancer. Reported cases of bladder cancer range from 37,000 to 40,000 cases per year, about 25% of which eventually require cystectomy.
  • neurogenic disorders and pelvic exenteration (selective evisceration) for cervical or rectal cancer or contracted urinary bladder often require urinary tract diversion or cystectomy.
  • Current methods for post-cystectomy urinary diversion utilize intestinal conduits, usually from ileum or colon.
  • the present invention by being capable of incorporation into the surrounding tissues, overcomes the consequences associated with previous prosthetic devices, and provides a functional device in such applications.
  • FIG. 1 is a perspective view in partial cut-away illustrating a porous synthetic substrate
  • FIG. 2 is a cross-section view of a substrate illustrating the open-celled arrangement of pores
  • FIG. 3 is a cross-section view of a substrate in contact with collagen
  • FIG. 4 is a cross-section view of an implanted prosthetic device illustrating ingrowth of connective tissue and a layer of epithelium on the intraluminal and extraluminal surface;
  • FIG. 5 is a cross-section view of a prosthetic device illustrating host graft epithelium on a intraluminal surface
  • FIG. 6 is a perspective view of an embodiment of the invention comprising a prosthetic patch
  • FIG. 7 is a perspective view of an embodiment of the invention comprising a hollow tube.
  • FIG. 8 is a perspective view in partial cut-away of an embodiment comprising a prosthetic bladder.
  • the invention generally includes a porous sub ⁇ strate material which is contacted with either collagen or a mixture of collagen and fibroblasts.
  • a layer of autogenous graft or tissue-cultured mucosal epithelium may be applied to one surface of the material, the intra- luminal surface, to promote growth of host mucosal epithe ⁇ lium.
  • the prosthetic material of the invention may take any form, including an implantable patch, prosthetic tube, or prosthetic organ. The basic material and prosthetic forms are discussed more fully below.
  • the substrate of the material may be any porous synthetic material which is tissue-compatible, including metallic materials and organic polymers.
  • Organic polymers which are inert in the body are preferable, such as poly ⁇ ethylene or polyurethane.
  • the substrate is a polyethylene material which has formed therethrough a substantial number of irregularly shaped, open-celled pores.
  • An example of such material is Medpor manufactured by Porex Medical Co. (Fairburn, Ga.).
  • the pores 22 in synthetic material 20 of this type are pores which are irregular in shape and size and do not necessarily define a straight path.
  • the diameter of the pores or the pore opening width can vary from a fraction of a micron to a few hundred microns.
  • a pore size of between about 100 microns and 360 microns is preferred.
  • the thickness of the substrate affects the rate and amount of connective tissue ingrowth. That is, the thicker the substrate, the greater the depth of the pores through which the connective tissue must grow. Therefore, the thickness of the substrate may vary from between about 0.25 millimeters (mm) to about 1.50 centimeters (cm).
  • mm millimeters
  • cm centimeters
  • the irregular porosity in the substrate provides a stronger adherence of collagen or collagen and fibroblasts to the substrate. Additionally, the ingrowth of connective tissue through the irregularly shaped pores provides greater strength and adherence of the tissue to the substrate leading to assured incorporation of the prosthesis into the living tissue.
  • the substrate is contacted with collagen in any manner which allows adherence of the collagen to the sub- strate and which causes the collagen to fill the pores sufficiently to produce a liquid-impermeable seal.
  • the collagen 28 substantially fills the pores of the substrate 30 and defines a thin.layer of collagen 32 on one surface of the substrate.
  • the prosthetic material of the present invention allows controlled ingrowth of epithelium by controlling the ingrowth of vascularized connective tissue. This is done by varying the thickness and/or density (i.e the concentration of collagen in solution) of the collagen applied to the substrate, and by varying the thickness of the substrate.
  • the thickness of the collagen may be from about 0.025 mm to about 1.00 mm.
  • the rate of absorption of collagen, and subsequent ingrowth of connective tissue may also be controlled by varying the depth to which collagen or collagen and fibroblasts are applied in the pores of the substrate. Collagen absorption may also be controlled by cross-linking of collagen, as described below.
  • FIG. 4 illustrates how collagen 36 is replaced by connective tissue 38 which grows into pores 40 of the substrate 42.
  • the vascularization 44 of the connective tissue retains the viability of the tissue so that epithelium 46 may grow.
  • any type of non-antigenic collagen may be used to coat the substrate.
  • atelocollagen (Koken Tokyo, Japan) is used.
  • Atelocollagen is an enzyme- solubilized collagen lacking in the strongest antigenic determinants and, as a result, has little antigenic activity to the body.
  • Atelocollagen is biodegradable, shows significantly little inflammatory response, and is particularly suitable for sealing the pores of the substrate due to its viscosity.
  • the dry atelocollagen is solubilized in 0.01M
  • CH COOH (glacial acetic acid) in a suitable size (usually 20 ml) glass vial with a screw cap.
  • the rate of collagen absorp ⁇ tion may be regulated by varying the density of collagen which is applied to the substrate. Density, as used in this disclosure, refers to the concentration of collagen molecules in solution. The concentration of collagen may vary from one to five percent.
  • a 5% solution of collagen is prepared by adding one gram of solubilized collagen to nineteen illiliters (ml) of 0.10M CH.COOH. The solution is maintained for about 24 hours to completely dissolve the collagen. The solution is stirred two to three times during this period. The collagen is then stored in the refrigerator. Once the collagen is dissolved, the solu ⁇ tion may be used for up to four months after it is prepared if no signs of contamination are present.
  • the concentration of collagen in the solution is determined according to the desired use of the device. Thus, if fast dissolution of the collagen is necessary, a lower percentage of collagen is used. If slower connective tissue ingrowth is required, a higher collagen percentage is used.
  • One method of contacting atelocollagen with the substrate may be obtained by the method set forth in the following example: -
  • a piece of Medpor (Porex, Inc., Fairburn, Ga.) having a pore size of approximately 100 to 300 micrometers was cut with scissors to an approximate patch size of two centimeters (cm) by four cm.
  • the patch was weighed, measuring 14 p.
  • An equal amount of prepared 5% solubilized collagen, 14 gm. was weighed out.
  • the collagen was spread over the Medpor with a spatula to coat the upper surface of the Medpor.
  • the coated Medpor was immediately immersed in 100 ml of 5% NaCl solution for one hour. The collagen became cloudy and began to produce random, non-parallel fibrils of collagen.
  • the coated piece of Medpor may be immersed in 100 ml of phosphate buffered saline (PBS) immediately after coating the piece of Medpor- This procedure produces native or parallel placed fibrils of collagen.
  • PBS phosphate buffered saline
  • the contacting of collagen to a porous substrate of irregular porosity increases the anchoring of . the col ⁇ lagen to the substrate due to the collagen seeping into the labyrinthine cavities of the pores. As a result of this mechanical anchoring, additional bonding between the collagen and substrate is not necessary.
  • the fibroblast culture medium causes the atelocollagen, a normally gelatinous substance, to become more liquid in consistency.
  • the contacting of atelocollagen and fibroblasts to the substrate, in that liquified state increases the ability of the atelocollagen to seep into the irregular pores of the substrate so that further bonding is not required.
  • telocollagen Two and one-half percent to five percent atelocollagen is normally very soluble and will not maintain itself in a fluid environment. In order to decrease the solubility of atelocollagen and have it persist longer before being absorbed by the body, it may be cross-linked. Cross-linking increases the density of the collagen by inducing linking between the collagen polymer chains. The greater the degree of cross-linking the more dense and less biodegradable is the collagen. Thus, it can be appreciated that the rate of absorption of collagen is dependent upon the concentration of collagen in the coating, the amount of cross-linking between these collagen chains, and the degree of porosity or void volume of the pores in the substrate.
  • Cross-linking is a technique well known in the art and can be accomplished by many methods, including irradiation, ultraviolet light, or chemicals such as glutaraldehyde.
  • a substrate measuring 2 cm x 4 cm was. coated with collagen (as described in Example A, above) , and precipitated by immersing the coated substrate patch in 5% NaCl solution.
  • glutaraldehyde crosslinking solution were prepared by adding together 50 ml of MeOH and 50 ml of H O. The solution was maintained in a 150 ml Erlenmeyer flask on a magnetic stir plate. The pH of the solution was adjusted to 11.5 by adding 0.5 ml of 1 N NaOH. Forty milliliters of 25% glutaraldehyde were added to the solution, and the pH was adjusted to 12 by the addition of 0.1 ml of IN NaOH. The solution was stirred slowly for one hour on the plate.
  • the patch was immediately placed into glutaraldehyde solution in a capped vial. The patch was completely submerged in the solution.
  • the vial was placed in a shaking water bath at 25-26°C. for two hours to produce a high degree of cross- linking. (Lesser time is required if faster dissolution of the collagen is required.)
  • phosphate buffered solution containing sodium azide (NaN ) .
  • Phosphate buffered solution is prepared by adding 0.272 gm/1 potassium phosphate (KH.PO ) , 1.136 gm/1 sodium phosphate (Na 2 HP0 4 ) , and 8.474 gm/1 sodium chloride (NaCl) to 250 ml distilled water, then adding a quantity of distilled water sufficient to make 1000 ml of solution. To that is added 1 gm/1 of sodium azide (NaN ) .)
  • the patch in PBS and sodium azide was kept in a shaking water bath for 5 to 7 days at 25-26°C.
  • the solu ⁇ tion was changed twice a day for the first 3 days, and at least once a day thereafter. This procedure of changing solutions was performed to remove any unreacted glutaraldehyde which might have been left in the collagen.
  • the patch was kept in saline solution with sodium azide and kept in the refrigerator until 24 hours prior to surgical implant.
  • the patch was removed from the sodium azide-saline bath. It was then placed in a sterile container with sterile saline. The saline was changed, using sterile techniques, five to six times in the first 12 hours. The final change was into sterile saline containing 1 gm/1000 ml cefadyl solution. The patch was stored in the refrigerator during this time.
  • devices prepared by the foregoing procedure are considered ready for implantation, and are to be handled using sterile techniques.
  • the substrate may be contacted with either atelocollagen alone, as described above, or an admixture of atelocollagen and fibroblasts may be applied to the substrate.
  • Fibroblasts are present in all types of fibrillar tissues and membranes, such as areolar, dense fibrous, and elastic tissue, and are the source of collagen fibrils. Fibroblasts which have been tissue- cultured are added to atelocollagen and are then contacted with the porous substrate. The fibroblasts produce their own collagen and cause the atelocollagen to shrink and become more dense. Because this shrinking and increased density causes the collagen-fibroblast coating to adhere more strongly to the pores of the substrate, cross-linking is not required. Additionally, cross-linking may damage or kill the living fibroblasts.
  • the living cellular content formed by the fibroblasts within the substrate en- . hances the ingrowth of connective tissue.
  • This living membrane within the substrate should also transfer nutrients across the substrate more rapidly,than cross- linked atelocollagen. The transfer of nutrients is important to the growth of connective tissue and therefore ensures better survival of free mucosal or tissue-cultured mucosal grafts.
  • One method of contacting a porous substrate with a collagen and fibroblast- ixture may be illustrated by the following example.
  • Canine buccal mucosa is harvested, washed with 1 liter (1) phosphate buffered solution (PBS) , and cut with a knife into small explants of approximately 2 cm by 2 cm. These explants are placed on the upper seam of a 25 cubic cm flask and are fed 9 ml of Dulbecco's modified Eagle medium (DMEM) with 10% Fetal Bovine serum (FBS) .
  • Dulbecco's modified Eagle medium is a tissue culture medium purchased from Gibco Labs, Grand Island, N.Y.
  • the medium is prepared by mixing together 1000 ml of distilled, deionized water, 10 grams (g) DMEM powder (#430-1600, Gibco Catalog), 3.7 g sodium bicarbonate, 0.3 g 1-glutamine, 4.76 g N-2 hydroxyethylpiperazine-N'-2- ethanesulfonic acid (HEPES) , 2.5 mg/10.5 ml Amphotericin- B, and 10 ml Penicillin-Streptomycin. The pH of the mixture is raised to 7.3 with 1M NaOH. The mixture is filtered using sterile techniques. Then 100 ml of fetal bovine serum (FBS) , purchased from Hyclone Labs, Logan, Utah, is added. Fetal bovine serum is blood serum which is extracted from fetal calf blood, and it provides a nutrient medium for cell growth.
  • FBS fetal bovine serum
  • Fibroblast Coating Patches of Medpor R porous synthetic substrate measuring 2 cm by 3 cm are coated with 1 ml of 1.25% atelocollagen applied by pipette.
  • the coated patches are allowed to stand for 16 to 24 hours at 37°C to seal the pores of the substrate.
  • 1 ml of 1.25% atelocollagen containing approximately 4 x 10 fibroblasts is pipetted on each patch.
  • the coated patches are then placed in 5 ml DME with 10% FBS. As the fibroblasts proliferate, they begin collagen production of their own. After two weeks, the patches are tested for leakage. This is done by placing the patch on a ring above the medium dish.
  • One-half milliliter of DMEM is pipetted onto the patch, and the patch is observed for five minutes to detect any filtering of DMEM through the patch. If any leakage is observed, another 1 ml of 1.25% collagen and fibroblasts is added to each patch as before. Testing for leakage is done every two weeks until the patches are sealed.
  • autogenous grafts of epithelial tissue such as buccal mucosal epithelium
  • autogenous refers to donor tissue taken from the host viscus or surrounding tissue. The tissue may be taken from the same individual upon whom the surgical procedure is being performed.
  • FIG. 5 illustrates the placement of graft epithelium 50 on a substrate 52 which has been coated with collagen 54 and fibroblasts 56. Autogenous graft ' epithelium may be applied to the collagen- or collagen/fibroblast-covered substrate in either a direct manner, or through in vitro culturing.
  • a collagen-coated substrate readied for implantation, is placed within a surgical bowl.
  • the sub- strate is then pre-clotted with blood taken from the patient.
  • a strip of buccal or respiratory mucosa 1/2 cm wide is harvested from the patient.
  • the strip is sutured onto the lumen surface of the substrate with absorbable suture.
  • the lumen surface may be coated with a synthetic biodegradable material such as fibrin glue to protect the graft.
  • the substrate is sutured into place in the area to be repaired.
  • the device is kept moist with Dulbecco's tissue media.
  • explants are placed on the collagen-coated side of the patch or that which will become the inter-luminal surface (approximately 5 explants per cm 2 ) .
  • the patches are then placed in 60 x 15 mm tissue culture dishes and are fed 5 ml of tissue culture medium [Keratinocyte Growth Medium
  • KGM KGM
  • DMEM Dulbecco's modified Eagle medium
  • the col ⁇ lagen or collagen-fibroblast layer prevents bacteria or contamination from penetrating into the substrate while allowing connective tissue (granulation tissue) to grow into the substrate from the surrounding tissue.
  • connective tissue granulation tissue
  • FIG. 4 by the time the collagen, collagen/fibroblast layer has been biodegraded by the invading connective tissue, the pores 40 are filled with a bacteriocidal layer of granulation tissue 38 (immature connective tissue) .
  • This granulation tissue provides the blood supply necessary for the epithelium to survive and for the epithelium to ingrow from the suture site.
  • Collagen fibroblasts also allow the osmotic transport of nutrients from the surrounding tissue to keep the epithelium viable and growing.
  • the basic material of the prosthesis may be formed into any number of devices for use in reconstruction of areas of damage, or for replacement of entire viscera.
  • the material may be formed into a patch, or single layer of collagen-covered substrate, as illustrated in FIG. 6. This particular embodiment may be used to reconstruct areas of damage in tissues or viscera where end-to-end anastomosis of the tissue or viscera is impossible.
  • the patch may be made in any shape or size as dictated by the area to be reconstructed.
  • FIG. 6 illustrates, by way of example, a rounded piece of porous substrate 60 which has been coated, in part, by a film of collagen 62, and is thus ready for implantation.
  • a tube 64 can be formed from the porous synthetic substrate and contacted with collagen 66 or collagen and fibroblasts.
  • An additional layer of autogenous graft epithelium may be added.
  • the tube thus formed can be used for reconstructing the trachea, esopha ⁇ gus, or varying lengths of the intestinal tract where end- to-end anastomosis is made impossible by resection of too much tissue.
  • the basic material may be formed into a prosthetic organ, such as a urinary bladder, for replacement of the natural organ.
  • FIG. 8 illustrates a urinary bladder 68, shown in partial cut-away, formed from porous synthetic substrate 70.
  • an autogenous layer of, for example, bladder mucosal tissue 76 to the intraluminal surface, as shown in FIG. 8.
  • the ureters 72 and urethra 74 of the patient have been sutured to the prosthesis.
  • Trachea or glottis patch implants The trachea or glottis of a patient is longitudinally incised. A patch is selected which is the same longitudinal length as the defect. The width of the defect is determined by the size of the area to be patched. Patches measuring 2 by 3 cm having coatings of 5% collagen, 2 1/2% collagen, 2 1/2% collagen/fibroblast, and 2 1/2% collagen fibroblasts with buccal mucosa tissue culture have been implanted. The mucosa is dissected from the cartilage creating a 2 mm flange of tissue.
  • the mucosal flange is sutured to the luminal aspect of the patch with a continuous preplaced absorbable suture. After the mucosal suture is tied, the cartilage is placed in the groove or under the flange and fixed with interrupted non-absorbable sutures and pledgets.
  • Epithelial ingrowth from the sutures line occurred up to 2 cm from each end.
  • One tube, with a free buccal mucosal graft demonstrated complete epithelization of a 7 cm long tube.
  • the bowel segment was isolated.
  • the ucosa-submucosa was dissected from the sero-muscular layer.
  • the mucosa was sutured inside the lumen of the implant with pre-placed continuous absorbable suture.
  • the sero-muscular layer was sutured on the outside of the implant with continuous suture of non-absorbable material.
  • One end of the isolated bowel was closed; the other end was brought to the outside as a colostomy.
  • the implant was wrapped with omentum and the omentu was sutured in place about the tube. There was no leak, or infection. All tubes demon ⁇ strated a luminal layer of connective tissue by 4 weeks post-operatively.
  • Patches measuring 2 by 4 cm in size with a coating of 5% collagen, 2 1/2% collagen, 2 1/2% collagen/fibroblasts with autologous uroepithelium or buccal epithelium tissue cultured onto the collagen were implanted in the urinary bladder of dogs. The urinary bladder was exposed. A deffect the same size as the patch was created in the bladder.
  • the mucosa-submucosa was dissected from the sero-muscular layer creating a 2 mm flange.
  • the mucosal layer was sutured to the,cultured (lumen) surface of the patch with a continuous suture of absorbable material.
  • the sero-muscular layer was sutured to the outside of the patch with absorbable continuous suture.
  • the patch was covered with omentum and sutured in place. There was no evidence of infection or urine leakage. Most patches demonstrated connective tissue ingrowth around the edges. The 2 1/2% collagen/fibro ⁇ blast/cultured patch demonstrated connective tissue ingrowth in the center of the patch and some evidence of tissue cultured cell survival.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Transplantation (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dispersion Chemistry (AREA)
  • Prostheses (AREA)
  • Materials For Medical Uses (AREA)

Abstract

Un dispositif prothétique pouvant être implanté dans un tissu vivant comporte un substrat synthétique poreux (52) ayant des surfaces opposées et une matière collagéneuse (54) qui est mise en contact avec le substrat poreux. Dans une réalisation préférée, le substrat est constitué par une matière synthétique à porosité irrégulière. Des fibroblastes (56) peuvent également être mis en contact avec la matière collagéneuse (54) et le substrat synthétique poreux (52). L'objet de l'invention est utile à la réparation ou au remplacement des tissus corporels ou des viscères.
PCT/US1990/007233 1989-12-07 1990-12-07 Prothese creuse pour viscere et methode d'implantation WO1991008718A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44704889A 1989-12-07 1989-12-07
US447,048 1989-12-07

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EP (1) EP0504262A4 (fr)
JP (1) JPH05502178A (fr)
AU (1) AU6908591A (fr)
CA (1) CA2070294A1 (fr)
WO (1) WO1991008718A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0742020A2 (fr) * 1995-04-25 1996-11-13 Nicem Ltd Prothèse contenant des matériaux biorésorbables insolubilisés sans réactifs chimiques et son procédé de préparation
US6537313B2 (en) 1995-03-15 2003-03-25 Vettivetpillai Ketharanathan Surgical prostheses
EP1306096A3 (fr) * 2001-10-26 2004-04-07 St. Jude Medical, Inc. Prothèse valvulaire ayant un substrat poreux
EP1537839A1 (fr) * 2003-12-02 2005-06-08 Dr. h. c. Robert Mathys Foundation Dispositif prothétique pour la réparation de cartilage

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1003443T3 (da) * 1995-10-25 2004-05-10 Sm Technologies Llc Fremgangmåde til fremstilling af en genstand af poröst materiale

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4539716A (en) * 1981-03-19 1985-09-10 Massachusetts Institute Of Technology Fabrication of living blood vessels and glandular tissues
US4642117A (en) * 1985-03-22 1987-02-10 Collagen Corporation Mechanically sheared collagen implant material and method
US4842575A (en) * 1984-01-30 1989-06-27 Meadox Medicals, Inc. Method for forming impregnated synthetic vascular grafts

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4553272A (en) * 1981-02-26 1985-11-19 University Of Pittsburgh Regeneration of living tissues by growth of isolated cells in porous implant and product thereof
EP0107711A4 (fr) * 1982-04-19 1985-10-24 Massachusetts Inst Technology Prothese multi-couches bioremplacable de vaisseaux sanguins.
IL78950A (en) * 1985-06-06 1991-12-15 Univ Jefferson Coating for prosthetic devices
JPS62246371A (ja) * 1986-04-19 1987-10-27 株式会社　高研 人工皮膚及びその製造方法
GB8803697D0 (en) * 1988-02-17 1988-03-16 Deltanine Research Ltd Clinical developments using amniotic membrane cells
JP2678945B2 (ja) * 1989-04-17 1997-11-19 有限会社ナイセム 人工血管とその製造方法及び人工血管用基質
ATE119787T1 (de) * 1989-04-25 1995-04-15 Childrens Medical Center Implantaten für grosse mengen von zellen auf polymerische matrizen.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4539716A (en) * 1981-03-19 1985-09-10 Massachusetts Institute Of Technology Fabrication of living blood vessels and glandular tissues
US4842575A (en) * 1984-01-30 1989-06-27 Meadox Medicals, Inc. Method for forming impregnated synthetic vascular grafts
US4642117A (en) * 1985-03-22 1987-02-10 Collagen Corporation Mechanically sheared collagen implant material and method

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0504262A4 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6537313B2 (en) 1995-03-15 2003-03-25 Vettivetpillai Ketharanathan Surgical prostheses
EP0742020A2 (fr) * 1995-04-25 1996-11-13 Nicem Ltd Prothèse contenant des matériaux biorésorbables insolubilisés sans réactifs chimiques et son procédé de préparation
EP0742020A3 (fr) * 1995-04-25 1999-12-29 Nicem Ltd Prothèse contenant des matériaux biorésorbables insolubilisés sans réactifs chimiques et son procédé de préparation
EP1306096A3 (fr) * 2001-10-26 2004-04-07 St. Jude Medical, Inc. Prothèse valvulaire ayant un substrat poreux
US7371258B2 (en) 2001-10-26 2008-05-13 St. Jude Medical, Inc. Valved prosthesis with porous substrate
EP1537839A1 (fr) * 2003-12-02 2005-06-08 Dr. h. c. Robert Mathys Foundation Dispositif prothétique pour la réparation de cartilage
WO2005053578A1 (fr) * 2003-12-02 2005-06-16 Stiftung, Robert, Mathys Dispositif prothetique destine a la reparation des cartilages
US8206457B2 (en) 2003-12-02 2012-06-26 Dr. h. c. Roberts Mathys Stiftung Prosthetic device for cartilage repair

Also Published As

Publication number Publication date
EP0504262A4 (en) 1993-06-30
AU6908591A (en) 1991-07-18
CA2070294A1 (fr) 1991-06-08
JPH05502178A (ja) 1993-04-22
EP0504262A1 (fr) 1992-09-23

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