CA2149324C - Fluidized intestinal submucosa and its use as an injectable tissue graft - Google Patents
Fluidized intestinal submucosa and its use as an injectable tissue graft Download PDFInfo
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- CA2149324C CA2149324C CA002149324A CA2149324A CA2149324C CA 2149324 C CA2149324 C CA 2149324C CA 002149324 A CA002149324 A CA 002149324A CA 2149324 A CA2149324 A CA 2149324A CA 2149324 C CA2149324 C CA 2149324C
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- tunica
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- 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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3695—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the function or physical properties of the final product, where no specific conditions are defined to achieve this
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- A—HUMAN NECESSITIES
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/37—Digestive system
- A61K35/38—Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
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- 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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3629—Intestinal tissue, e.g. small intestinal submucosa
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- A—HUMAN NECESSITIES
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- 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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
- A61L27/367—Muscle tissue, e.g. sphincter
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- A—HUMAN NECESSITIES
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- 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
- A61F2/28—Bones
- A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30667—Features concerning an interaction with the environment or a particular use of the prosthesis
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- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
Abstract
A fluidized, injectable tissue graft composition is described. The composition comprises comminuted intestinal submucosa or protease-digested intestinal submucosa. Methods for the preparation and use of injectable tissue graft compositions are described.
In preferred embodiments the tissue graft material is prepared from the intestinal submucosa comprising the tunics submucosa and basilar portions of the tunics mucosa of a segment of intestinal tissue of a warm-blooded vertebrate: Effective amounts of the fiuidized graft compositions can be injected to promote repair tissue defects by inducing formation of endogenous tissues.
In preferred embodiments the tissue graft material is prepared from the intestinal submucosa comprising the tunics submucosa and basilar portions of the tunics mucosa of a segment of intestinal tissue of a warm-blooded vertebrate: Effective amounts of the fiuidized graft compositions can be injected to promote repair tissue defects by inducing formation of endogenous tissues.
Description
~~:,~ 1~C? 94/1100 ~ ~ ~ ~ ~ PGT/US93/10~61 FLUIDIZED INTESTINAL SUBMUCO~A AHD
gTB ;JEE A~ AN IN~ECTAELE TISSUE GRAFT
Bac~~",ound and Summary of the Invention The present invention relates to an injectable tissue graft composition and methods for its preparation and use. More particularly, the pres~fat invention is directed to inj.ectabZe, non-immunogenic tissue graft compositions derived from intestinal subznucosa. Upon deposition in vivo in an area of a tissue defect, the present fluid~.~ed tissue graft compositions promote growth of endogenous tissue to repair the defect.
It has been reported that compositions comprising the submucosa and the,basilar portions of the tunics mucosa of the intestine of warm-b2ooded vertebrates can be used as tissue graft materials in sheet form. See U.S. Patent No.
4,902,508:- The preferred trilamihate'shee compositions described-and claimed in that patent are characterized by, excellent mechanical properties, including-high compliance, a high burst pressure point, and any effective porosity index which allowed such compositions to be used beneficially i~or vascular graft constructs: The graft materia~,s disclosed in that patient are also useful in tendon and ligament replacement applications: When used in 25' such applications:'the preferred trilaminato'graft constructs appear to serve as a matrix-for the regrowth:of the tissues replaced by the graft constructs. It was believed that such properties derived from the unique trilaminate sheet structures of the intestinal issue derived graft constructs.
Surprisingly, it has been discovered that intestinal': submucosa can be fluidized by aomminuting and/or protease digestion', without logs of its apparent biotropic properties, for use in less invasive methods ~f r S i .r, ~ ~~r 1y094/~~00$ ~, ~, ..., ~, , PCT/US93/1~86 ,:.~_,, 214332~~
_2_ administration (e. g., injection or topical) to host tissues in need of repair.
According to tY~e present invention, an injectable, non-immunogenic tissue graft composition is provided. In one embodiment the composition comprises comminuted large or small intestinal submucosa, preferably in an aqueaus suspension. In another aspect of the invention, there is provided a composition comprising protease-digested intestinal submucosa:
The fluidized composition i~ used advantageously in a method for inducing formation of endogenous. tissue including bone and soft tissues such as musole and connective tissues in a warm--blooded vertebrate. The method comprises the step of injecting into the vertebrate 25 a composition comprising a suspension of comminuted intestinal submucosa or a protease digest thereof in an amount effective'to ia~duce endogenous tissue growth in the locale of the injected fluidized tissue graft composition.
Endogenous connective tissues induced to grow in accordance with this invention include collagen, elastin and muscle.
In another more specifis aspect of the present invention, a method is provided for augmenting sphincter function in a warm-blooded mammal, the method comprising the step of injecting into tissue foaming said sphincter an effective amount ~f a tissue graft composition comprising an aqueous suspension of comminuted ,intesta:nal submucc~~a .
In yet a further aspect of the present invention, a method is provided for augmenting sphincter,function in which the injectable composition comprises: protease digested, 3D intestinal ~ubmucosa:
Tk~e injectable or "fluidized" compositions in, accordance with the present invention can be used in a wide variety c~~ ta,ssue r~pazr dr tissue reconstruction applications. They cah be used alone or in combination with the graft material described in U.S. Patent 4,902,30.
For example, the compositions of the present invention can be used for surgical reconstruction of a collagenous meniscus at the interface of articulating bones. In such reconstruction a sheet of a first tissue graft composition, preferably itself comprising intestinal submucosa of a warm-blooded vertebrate, is formed into a sealed pouch and filled with a fluidized tissue graft composition of this invention.
In one aspect, there is described a method of preparing a tissue graft composition, said method comprising the steps of comminuting intestinal tissue comprising intestinal submucosa and hydrating the resultant comminuted intestinal tissue to provide said tissue graft composition as a fluid having a viscosity of about 2 to about 300,000 cps at 25°C.
In another aspect, there is described a method of preparing a tissue graft composition, said method comprising the step of digesting intestinal submucosa in aqueous solution with a protease for a period of time sufficient to solubilize said submucosa to form a substantially homogeneous solution.
In another aspect, there is described a tissue composition comprising a suspension of comminuted tunica submucosa in an aqueous medium.
In another aspect, there is described a tissue composition comprising a suspension of comminuted intestinal tissue comprising tunica submucosa in an aqueous medium.
In another aspect, there is described use of a sheet of a first tissue graft composition in the manufacture of a tissue graft construction, for surgical reconstruction of a collagenous meniscus at the interface of articulating bones, wherein the first tissue graft composition comprises the tunica submucosa and basilar portions of the tunica mucosa, -3a-said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of a segment of intestine of a warm-blooded vertebrate, said sheet being formed into a sealed pouch and filled with a second tissue graft composition comprising comminuted intestinal tissue comprising tunica submucosa or protease digested intestinal tissue comprising tunica submucosa, wherein the tissue graft construction is suitable for surgical implantation into said interface.
In another aspect, there is described use, for surgical reconstruction of a collagenous meniscus at the interface of articulating bones, of a tissue graft construction comprising a sheet of a first tissue graft composition comprising the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of a segment of intestine of a warm-blooded vertebrate, said sheet being formed into a sealed pouch and filled with a second tissue graft composition comprising comminuted intestinal tissue comprising tunica submucosa or protease digested intestinal tissue comprising tunica submucosa, wherein the tissue graft construction is suitable for surgical implantation into said interface.
In another aspect, there is described use in the manufacture of a medicament for promoting wound healing, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue in an aqueous medium or a solution of protease digested intestinal tissue in an aqueous carrier, wherein said intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and -3b-the luminal portion of the tunica mucosa of the intestine of a warm-blooded vertebrate, wherein the tissue graft composition is suitable for application onto a wound.
In another aspect, there is described use for promoting wound healing, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue in an aqueous medium or a solution of protease digested intestinal tissue in an aqueous carrier, wherein said intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of the intestine of a warm-blooded vertebrate, wherein the tissue graft composition is suitable for application onto a wound.
In another aspect, there is described a tissue graft construction comprising intestinal tissue formed into a sealed pouch and containing a fluidized tissue graft composition comprising a suspension of comminuted intestinal tissue or protease digested intestinal tissue, wherein said intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of the intestine of a warm-blooded vertebrate.
In another aspect, there is described dried intestinal submucosa in powder form.
In another aspect, there is described dried protease-solubilized intestinal submucosa in powder form.
In another aspect, there is described use in the manufacture of a medicament for inducing the formation of -3c-endogenous tissue of a warm-blooded vertebrate in a locale at which formation of endogenous tissue is desired, of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising tunica submucosa or a protease digest thereof in an amount effective to induce endogenous tissue growth in the locale.
In another aspect, there is described use for inducing the formation of endogenous tissue of a warm-blooded vertebrate in a locale at which formation of endogenous tissue is desired, of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising tunica submucosa or a protease digest thereof in an amount effective to induce endogenous tissue growth in the locale.
In another aspect, there is described use in the manufacture of a medicament for augmenting sphincter function in a warm-blooded mammal, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising the tunica submucosa or a protease digest of intestinal tissue comprising the tunica submucosa, wherein the tissue graft composition is suitable for injection into tissue forming said sphincter.
In another aspect, there is described use for augmenting sphincter function in a warm-blooded mammal, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising the tunica submucosa or a protease digest of intestinal tissue comprising the tunica submucosa, wherein the tissue graft composition is suitable for injection into tissue forming said sphincter.
Additional objects, features, and advantages of the invention will become apparent to those skilled in the art upon consideration of the following detailed description of -3d-preferred embodiments exemplifying the best mode of carrying out the invention as presently perceived.
Detailed Description of the Preferred Embodiments One preferred starting material for the compositions in accordance with the present invention comprises the tunica submucosa along with basilar portions of the tunica mucosa of a segment of intestinal tissue of a warm-blooded vertebrate.
In particular, the preferred starting material comprises the tunica submucosa along with the lamina muscularis mucosa and the stratum compactum of a segment of small intestine, said layers being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said segment. Such a material is referred to herein as Small Intestine Submucosa ("SIS") or "SIS trilaminate".
The preparation of SIS from a segment of small intestine is detailed in U.S. Patent No. 4,902,508. A segment of intestine is first subjected to abrasion using a longitudinal wiping motion to remove both the outer layers (particularly the tunica serosa and the tunica muscularis) and the inner layers (the luminal portions of the tunica mucosa).
Typically the SIS is WO 9411100 ~ ~, ~ ~ ~ ~.,1~ . . . PCT/US93/10~
t. ~,i ~i.'w rinsed with saline and optionally stored in a hydrated or dehydrated state until use as described below.
The present fluidiz~d compositions are prepared as solutions or suspensions of intestinal submucosa by comminuting and/or'digesting the submucosa with a protease, such as tryp~in or pepsin; for a period of time sufficient to solubilize said'tissue and form a substantially homogeneous solution. The intestinal submucosa starting material is comminuted by tearing; cutting, grinding;
1.0 shearing and the like. Grinding the suk~mucosa in a frozen or freeze-dried state is, preferred although'good results can be obtained as well by subjecting a suspension of pieces of the submucosa to treatment in a high speed (high shear) blender and dewatering, if necessary, by x5 centrifuging and decanting excess water. The comminuted intestinal submucosa can be dried to dorm a submucosa powder. Thereafter, it can be hydrated; that is, combined with water or buffered saline and optionally other pharmaceutically acceptable excipients to form a ti sue 20 graft composition as a fluid having,~a vi cosity of about 2 to about 300,000 cps at 25°C. The higher viscosity graft compositions can have a gel or paste consistency. The present compositions can be sterilized using art-recognized sterilization techniques such as exposure to ionizing 25 radiation. .
The fluidized intestinal submucasa compositions of this invention can b~ used fnx~ the production of antibodies to the tissue graft material described in U.S.
latent 4,902,508'using art-recognized hybridoma technology.
30 The fluidized submucosa derived from SI5 is ir~~ected into an imamunologically competent animal to evoke the production' of antibody-producing Tymphoeytes in'the animal's spleen.
The lymphocytes are''fused with'myeloma ells to form hybrid cells (hybr3domas) which are screened for submucosa-.35 antibody production: The monoclonal antibodies produced by ~~ ~ ~ ~ ' ' PGT/US93/I0861 ~~y ~ WO 94/11008 L°' culturing the selected hybridomas are i,so,lated and used for detecting submucasal tissue in vivo and in vitro:
The fluidi'zed submucosa of this invention also finds use as an injectable heterograft for tissues, for 5. examgle, bone or soft tissues, in need of repair or augmentation most typically to correct trauma,or disease-induced tissue defects. The present, fluidized submucosa compositions are also used advantageously as a filler for implant constructs comprising, for example; one or more sheets of SIS formed into sealed (sutured) pouches or "pillows" for use in cosmetic or trauma-treating surgical procedures.
FXAMF~t E 1 - SIS Suspension SIS specimens prepared ss described above are minced or chopped into arbitrarily small pieces using tissue scissors, a single-edged razor blade, or other appropriate cutting implement. The specimens are placed in a flat bottom stainless steel container and liquid nitrogen is introduced into the container to freeze the specimens to pr~,pare them for comminuting.
The frozen SIS specimens are then comminuted to form a coarse SIS powder. Such processing can be carried out; for example, with a manual arbor gress with' a cylindrical brass ingot placed on top of the frozen specimens: The ingot serves as an interface between the specimens and the arbor of the press. It is typically necessary to. add liquid nitrogen periodically to the STS specimens to keep them frozen.
Other methods for comminuting SIS specimens may be utilized to produce an SIS powder usable in accordance with the: present~invention: For example, SIS specimens can be freeze-dried and then,ground using a manual arbor press or other grinding means. Alternatively, SIS can be 1~'U 94/x 1008 ~ PGT/US93/1086.
214~v 2!~
processed in a high shear blender to produce, upon dewatering and drying, an SIS powder.
Further grinding of the SIS powder,using a pre-chilled mortar and pestle can be used to produce consistent, more finely divided product. Again, liquid nitrogen is used as needed' to maintain solid frozen particles during-final grinding. The powder can be easily hydrated using, for example, buffered alive to produce a fluidized tissue graft material of this invention at the desired viscosity.
EXAMPLF,~, 2 SIS Solution SIS powder is sifted through a wire mesh into any convenient vessel: The powder as then subjected to proteolytic digestion to form a substantially homogeneous solution: In one embodiments the powder is digested with 1 mg/ml of pepsin (Sigma Chemical Co.,'St: Louis, ~i0) in 0.T
M acetic acid, adjusted to pH 2.5 with HCl; aver a 48 hour period at room temperature. The reaction medium is 2Q neutralized with sodium hydroxide t,p inactivate the peptic activity: The solubilized submucosa may then be concentrated by salt precipitation of the solution and separated for 'further purification 'and/or freeze drying to form a protease solubilized intestinal submu~osa in powder form:
The viscosity of fluidized submucosa compositions in accordance with:this invention can be manipulated by controlling the concentration of the submucosa component and the degree of'hydration. The viscosity can be adjusted to a range of about 2 to about 300,000 cps at~25°C. Low viscosity submucosa compositions are better adapted for intraarticular applicat~.ons or applications within body cavities, 'Higher viscosity formulations, for example, gels, can be prepared from he STS digest solutions by 35' adjusting the pH of such solutions to about 6.0 to about ~
=_:. WO 94/11008 ~ ~ 3 ~ P~'/US93/10861 G~:
7Ø Gel farms of the present compositions, as submucosa suspensions or submucosa digest solutions, are typically preferred for subcutaneous or intramuscular applications using syringes or catheicers.
~XAMPL~ 3 Applications A: SIS as a suspension was utilized as a meniscus in five dogs. Specifically, the medial meniscus of normal crossbred adult dogs was removed and then replaced by a newly constructed SIS meniscus. This S1S
meniscus consisted of a sheet of SIS (with stratum compactum °'inside"} formed into a semicircular pillow. The pillow was then tilled with a suspension of SIS and the suture line of the pillow was attached to the medial collateral ligament. Thus, the substance of the pillow served as the weight bearing 5hoek absorber between the medial femoral condyle and the'tibial plateau. Three of the animals have been sacrificed. The first animal was sacrificed four months and four days after surgery: The second animal .wee sacrificed three months and twenty-one days after surgery and the fourth animal was sacrificed four months and three days after surgery. The results for all three animals were similar. The SIS/meniscus had formed a partially organized fibrocartilage material indistinguishable by-histo3ogic methods from the fibrocartilage of the normal meniscus: The shape of this newly formed meniscus was unlike a nr~rmal meniscus but the purpose of the study was simply to see whether connective tissue remode~.ing would-occur and whether nr not there would be any,adverse reaction. There was absolutely r~~
evidence of rejection, inflammation, or infection. Animals three and five are still liv~:ng.' In tho above studies, ~aig STS was used in the dog host:
8. SIS solution was injected in the subcutaneous ~5 site in four separate locations on the dog. In addition, ,......
r.,.
21~~~24 _g_ the solution (pH = 8:0) was injected in submucosal location of the vaginal wall and into the medial collateral ligament area of the knee. There was no evidence of rejection;
infection, or abnormal physiologic response of the host animal. There is'thickening of the injection sites, Control sites where saline was used as the injection material howed complete resorption of the material with no evidence for connective tissue thickening.
C. SIS suspension has been used to augment the urethral sphincter in hree separate pigs. The suspension of SIS material was injected via endoscopy: and via laparoseopy into the submucasal and subserosal locations of the pig urinary bladder. In addition, injections of the material (approximately 4 ml) have been injected in the l~ submucosal location around tk~e ureteral orifice bilaterally, and in the urinary bladder wall. One pig was sacrificed nine weeks after the initial injection and ahowed connective tissueremodeling with an infiltration of spindle shaped myofibroblasts which are positive for smooth ZO muscZ~ action. This type of connective tissue response. is very similar to that seen in the use of SIS tubes in the arterial location: Control sites where saline was used as the injection material; showed no response: It was concluded'that SIS stimulates an appropriate connective 25~ tissue remodeling such that augmentation of urinary bladder.
wall'and/or urinary bladder sphincter can be accomplished with suspended SxS material.
The fluidized submucosa composit'ians of this invention find'wide application both'in tissue replacement 30' and repair. The fluidized submucosal compositions are used' in accordance with the present'method to induce regrow~h of natural connective tissue or bone in an area of an existent defect. By injecting an effective amount of a ~luidized submucosa composition into'the locale of a tissue defect or 3~: a-wound in need of healing; one can readil~r take advantage 11 WO 94/11008 ~ ~ '-~ ~ PCTt1JS93l10861 _g_ of the graft compositions biotropic properties without the need for more invasive surgical techniques.
Perhaps the most remarkable aspect of the compositions of the present invention is their ability to induce regro~wth of natural tissue in an affected area. By injecting an effective amount of a fluidized submucosa composition inter the locale of a tissue defect or a wound in need of healing, one can readily hake advantage of this surprising property without the need for major invasive operations .
Although the invention has been described in.
detail with reference to certain ~ref~rred'embodim~nts, variations and modifications exist wiahin the cope and spirit of the invention as described and defined in the following claims:
gTB ;JEE A~ AN IN~ECTAELE TISSUE GRAFT
Bac~~",ound and Summary of the Invention The present invention relates to an injectable tissue graft composition and methods for its preparation and use. More particularly, the pres~fat invention is directed to inj.ectabZe, non-immunogenic tissue graft compositions derived from intestinal subznucosa. Upon deposition in vivo in an area of a tissue defect, the present fluid~.~ed tissue graft compositions promote growth of endogenous tissue to repair the defect.
It has been reported that compositions comprising the submucosa and the,basilar portions of the tunics mucosa of the intestine of warm-b2ooded vertebrates can be used as tissue graft materials in sheet form. See U.S. Patent No.
4,902,508:- The preferred trilamihate'shee compositions described-and claimed in that patent are characterized by, excellent mechanical properties, including-high compliance, a high burst pressure point, and any effective porosity index which allowed such compositions to be used beneficially i~or vascular graft constructs: The graft materia~,s disclosed in that patient are also useful in tendon and ligament replacement applications: When used in 25' such applications:'the preferred trilaminato'graft constructs appear to serve as a matrix-for the regrowth:of the tissues replaced by the graft constructs. It was believed that such properties derived from the unique trilaminate sheet structures of the intestinal issue derived graft constructs.
Surprisingly, it has been discovered that intestinal': submucosa can be fluidized by aomminuting and/or protease digestion', without logs of its apparent biotropic properties, for use in less invasive methods ~f r S i .r, ~ ~~r 1y094/~~00$ ~, ~, ..., ~, , PCT/US93/1~86 ,:.~_,, 214332~~
_2_ administration (e. g., injection or topical) to host tissues in need of repair.
According to tY~e present invention, an injectable, non-immunogenic tissue graft composition is provided. In one embodiment the composition comprises comminuted large or small intestinal submucosa, preferably in an aqueaus suspension. In another aspect of the invention, there is provided a composition comprising protease-digested intestinal submucosa:
The fluidized composition i~ used advantageously in a method for inducing formation of endogenous. tissue including bone and soft tissues such as musole and connective tissues in a warm--blooded vertebrate. The method comprises the step of injecting into the vertebrate 25 a composition comprising a suspension of comminuted intestinal submucosa or a protease digest thereof in an amount effective'to ia~duce endogenous tissue growth in the locale of the injected fluidized tissue graft composition.
Endogenous connective tissues induced to grow in accordance with this invention include collagen, elastin and muscle.
In another more specifis aspect of the present invention, a method is provided for augmenting sphincter function in a warm-blooded mammal, the method comprising the step of injecting into tissue foaming said sphincter an effective amount ~f a tissue graft composition comprising an aqueous suspension of comminuted ,intesta:nal submucc~~a .
In yet a further aspect of the present invention, a method is provided for augmenting sphincter,function in which the injectable composition comprises: protease digested, 3D intestinal ~ubmucosa:
Tk~e injectable or "fluidized" compositions in, accordance with the present invention can be used in a wide variety c~~ ta,ssue r~pazr dr tissue reconstruction applications. They cah be used alone or in combination with the graft material described in U.S. Patent 4,902,30.
For example, the compositions of the present invention can be used for surgical reconstruction of a collagenous meniscus at the interface of articulating bones. In such reconstruction a sheet of a first tissue graft composition, preferably itself comprising intestinal submucosa of a warm-blooded vertebrate, is formed into a sealed pouch and filled with a fluidized tissue graft composition of this invention.
In one aspect, there is described a method of preparing a tissue graft composition, said method comprising the steps of comminuting intestinal tissue comprising intestinal submucosa and hydrating the resultant comminuted intestinal tissue to provide said tissue graft composition as a fluid having a viscosity of about 2 to about 300,000 cps at 25°C.
In another aspect, there is described a method of preparing a tissue graft composition, said method comprising the step of digesting intestinal submucosa in aqueous solution with a protease for a period of time sufficient to solubilize said submucosa to form a substantially homogeneous solution.
In another aspect, there is described a tissue composition comprising a suspension of comminuted tunica submucosa in an aqueous medium.
In another aspect, there is described a tissue composition comprising a suspension of comminuted intestinal tissue comprising tunica submucosa in an aqueous medium.
In another aspect, there is described use of a sheet of a first tissue graft composition in the manufacture of a tissue graft construction, for surgical reconstruction of a collagenous meniscus at the interface of articulating bones, wherein the first tissue graft composition comprises the tunica submucosa and basilar portions of the tunica mucosa, -3a-said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of a segment of intestine of a warm-blooded vertebrate, said sheet being formed into a sealed pouch and filled with a second tissue graft composition comprising comminuted intestinal tissue comprising tunica submucosa or protease digested intestinal tissue comprising tunica submucosa, wherein the tissue graft construction is suitable for surgical implantation into said interface.
In another aspect, there is described use, for surgical reconstruction of a collagenous meniscus at the interface of articulating bones, of a tissue graft construction comprising a sheet of a first tissue graft composition comprising the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of a segment of intestine of a warm-blooded vertebrate, said sheet being formed into a sealed pouch and filled with a second tissue graft composition comprising comminuted intestinal tissue comprising tunica submucosa or protease digested intestinal tissue comprising tunica submucosa, wherein the tissue graft construction is suitable for surgical implantation into said interface.
In another aspect, there is described use in the manufacture of a medicament for promoting wound healing, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue in an aqueous medium or a solution of protease digested intestinal tissue in an aqueous carrier, wherein said intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and -3b-the luminal portion of the tunica mucosa of the intestine of a warm-blooded vertebrate, wherein the tissue graft composition is suitable for application onto a wound.
In another aspect, there is described use for promoting wound healing, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue in an aqueous medium or a solution of protease digested intestinal tissue in an aqueous carrier, wherein said intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of the intestine of a warm-blooded vertebrate, wherein the tissue graft composition is suitable for application onto a wound.
In another aspect, there is described a tissue graft construction comprising intestinal tissue formed into a sealed pouch and containing a fluidized tissue graft composition comprising a suspension of comminuted intestinal tissue or protease digested intestinal tissue, wherein said intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of the intestine of a warm-blooded vertebrate.
In another aspect, there is described dried intestinal submucosa in powder form.
In another aspect, there is described dried protease-solubilized intestinal submucosa in powder form.
In another aspect, there is described use in the manufacture of a medicament for inducing the formation of -3c-endogenous tissue of a warm-blooded vertebrate in a locale at which formation of endogenous tissue is desired, of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising tunica submucosa or a protease digest thereof in an amount effective to induce endogenous tissue growth in the locale.
In another aspect, there is described use for inducing the formation of endogenous tissue of a warm-blooded vertebrate in a locale at which formation of endogenous tissue is desired, of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising tunica submucosa or a protease digest thereof in an amount effective to induce endogenous tissue growth in the locale.
In another aspect, there is described use in the manufacture of a medicament for augmenting sphincter function in a warm-blooded mammal, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising the tunica submucosa or a protease digest of intestinal tissue comprising the tunica submucosa, wherein the tissue graft composition is suitable for injection into tissue forming said sphincter.
In another aspect, there is described use for augmenting sphincter function in a warm-blooded mammal, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising the tunica submucosa or a protease digest of intestinal tissue comprising the tunica submucosa, wherein the tissue graft composition is suitable for injection into tissue forming said sphincter.
Additional objects, features, and advantages of the invention will become apparent to those skilled in the art upon consideration of the following detailed description of -3d-preferred embodiments exemplifying the best mode of carrying out the invention as presently perceived.
Detailed Description of the Preferred Embodiments One preferred starting material for the compositions in accordance with the present invention comprises the tunica submucosa along with basilar portions of the tunica mucosa of a segment of intestinal tissue of a warm-blooded vertebrate.
In particular, the preferred starting material comprises the tunica submucosa along with the lamina muscularis mucosa and the stratum compactum of a segment of small intestine, said layers being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said segment. Such a material is referred to herein as Small Intestine Submucosa ("SIS") or "SIS trilaminate".
The preparation of SIS from a segment of small intestine is detailed in U.S. Patent No. 4,902,508. A segment of intestine is first subjected to abrasion using a longitudinal wiping motion to remove both the outer layers (particularly the tunica serosa and the tunica muscularis) and the inner layers (the luminal portions of the tunica mucosa).
Typically the SIS is WO 9411100 ~ ~, ~ ~ ~ ~.,1~ . . . PCT/US93/10~
t. ~,i ~i.'w rinsed with saline and optionally stored in a hydrated or dehydrated state until use as described below.
The present fluidiz~d compositions are prepared as solutions or suspensions of intestinal submucosa by comminuting and/or'digesting the submucosa with a protease, such as tryp~in or pepsin; for a period of time sufficient to solubilize said'tissue and form a substantially homogeneous solution. The intestinal submucosa starting material is comminuted by tearing; cutting, grinding;
1.0 shearing and the like. Grinding the suk~mucosa in a frozen or freeze-dried state is, preferred although'good results can be obtained as well by subjecting a suspension of pieces of the submucosa to treatment in a high speed (high shear) blender and dewatering, if necessary, by x5 centrifuging and decanting excess water. The comminuted intestinal submucosa can be dried to dorm a submucosa powder. Thereafter, it can be hydrated; that is, combined with water or buffered saline and optionally other pharmaceutically acceptable excipients to form a ti sue 20 graft composition as a fluid having,~a vi cosity of about 2 to about 300,000 cps at 25°C. The higher viscosity graft compositions can have a gel or paste consistency. The present compositions can be sterilized using art-recognized sterilization techniques such as exposure to ionizing 25 radiation. .
The fluidized intestinal submucasa compositions of this invention can b~ used fnx~ the production of antibodies to the tissue graft material described in U.S.
latent 4,902,508'using art-recognized hybridoma technology.
30 The fluidized submucosa derived from SI5 is ir~~ected into an imamunologically competent animal to evoke the production' of antibody-producing Tymphoeytes in'the animal's spleen.
The lymphocytes are''fused with'myeloma ells to form hybrid cells (hybr3domas) which are screened for submucosa-.35 antibody production: The monoclonal antibodies produced by ~~ ~ ~ ~ ' ' PGT/US93/I0861 ~~y ~ WO 94/11008 L°' culturing the selected hybridomas are i,so,lated and used for detecting submucasal tissue in vivo and in vitro:
The fluidi'zed submucosa of this invention also finds use as an injectable heterograft for tissues, for 5. examgle, bone or soft tissues, in need of repair or augmentation most typically to correct trauma,or disease-induced tissue defects. The present, fluidized submucosa compositions are also used advantageously as a filler for implant constructs comprising, for example; one or more sheets of SIS formed into sealed (sutured) pouches or "pillows" for use in cosmetic or trauma-treating surgical procedures.
FXAMF~t E 1 - SIS Suspension SIS specimens prepared ss described above are minced or chopped into arbitrarily small pieces using tissue scissors, a single-edged razor blade, or other appropriate cutting implement. The specimens are placed in a flat bottom stainless steel container and liquid nitrogen is introduced into the container to freeze the specimens to pr~,pare them for comminuting.
The frozen SIS specimens are then comminuted to form a coarse SIS powder. Such processing can be carried out; for example, with a manual arbor gress with' a cylindrical brass ingot placed on top of the frozen specimens: The ingot serves as an interface between the specimens and the arbor of the press. It is typically necessary to. add liquid nitrogen periodically to the STS specimens to keep them frozen.
Other methods for comminuting SIS specimens may be utilized to produce an SIS powder usable in accordance with the: present~invention: For example, SIS specimens can be freeze-dried and then,ground using a manual arbor press or other grinding means. Alternatively, SIS can be 1~'U 94/x 1008 ~ PGT/US93/1086.
214~v 2!~
processed in a high shear blender to produce, upon dewatering and drying, an SIS powder.
Further grinding of the SIS powder,using a pre-chilled mortar and pestle can be used to produce consistent, more finely divided product. Again, liquid nitrogen is used as needed' to maintain solid frozen particles during-final grinding. The powder can be easily hydrated using, for example, buffered alive to produce a fluidized tissue graft material of this invention at the desired viscosity.
EXAMPLF,~, 2 SIS Solution SIS powder is sifted through a wire mesh into any convenient vessel: The powder as then subjected to proteolytic digestion to form a substantially homogeneous solution: In one embodiments the powder is digested with 1 mg/ml of pepsin (Sigma Chemical Co.,'St: Louis, ~i0) in 0.T
M acetic acid, adjusted to pH 2.5 with HCl; aver a 48 hour period at room temperature. The reaction medium is 2Q neutralized with sodium hydroxide t,p inactivate the peptic activity: The solubilized submucosa may then be concentrated by salt precipitation of the solution and separated for 'further purification 'and/or freeze drying to form a protease solubilized intestinal submu~osa in powder form:
The viscosity of fluidized submucosa compositions in accordance with:this invention can be manipulated by controlling the concentration of the submucosa component and the degree of'hydration. The viscosity can be adjusted to a range of about 2 to about 300,000 cps at~25°C. Low viscosity submucosa compositions are better adapted for intraarticular applicat~.ons or applications within body cavities, 'Higher viscosity formulations, for example, gels, can be prepared from he STS digest solutions by 35' adjusting the pH of such solutions to about 6.0 to about ~
=_:. WO 94/11008 ~ ~ 3 ~ P~'/US93/10861 G~:
7Ø Gel farms of the present compositions, as submucosa suspensions or submucosa digest solutions, are typically preferred for subcutaneous or intramuscular applications using syringes or catheicers.
~XAMPL~ 3 Applications A: SIS as a suspension was utilized as a meniscus in five dogs. Specifically, the medial meniscus of normal crossbred adult dogs was removed and then replaced by a newly constructed SIS meniscus. This S1S
meniscus consisted of a sheet of SIS (with stratum compactum °'inside"} formed into a semicircular pillow. The pillow was then tilled with a suspension of SIS and the suture line of the pillow was attached to the medial collateral ligament. Thus, the substance of the pillow served as the weight bearing 5hoek absorber between the medial femoral condyle and the'tibial plateau. Three of the animals have been sacrificed. The first animal was sacrificed four months and four days after surgery: The second animal .wee sacrificed three months and twenty-one days after surgery and the fourth animal was sacrificed four months and three days after surgery. The results for all three animals were similar. The SIS/meniscus had formed a partially organized fibrocartilage material indistinguishable by-histo3ogic methods from the fibrocartilage of the normal meniscus: The shape of this newly formed meniscus was unlike a nr~rmal meniscus but the purpose of the study was simply to see whether connective tissue remode~.ing would-occur and whether nr not there would be any,adverse reaction. There was absolutely r~~
evidence of rejection, inflammation, or infection. Animals three and five are still liv~:ng.' In tho above studies, ~aig STS was used in the dog host:
8. SIS solution was injected in the subcutaneous ~5 site in four separate locations on the dog. In addition, ,......
r.,.
21~~~24 _g_ the solution (pH = 8:0) was injected in submucosal location of the vaginal wall and into the medial collateral ligament area of the knee. There was no evidence of rejection;
infection, or abnormal physiologic response of the host animal. There is'thickening of the injection sites, Control sites where saline was used as the injection material howed complete resorption of the material with no evidence for connective tissue thickening.
C. SIS suspension has been used to augment the urethral sphincter in hree separate pigs. The suspension of SIS material was injected via endoscopy: and via laparoseopy into the submucasal and subserosal locations of the pig urinary bladder. In addition, injections of the material (approximately 4 ml) have been injected in the l~ submucosal location around tk~e ureteral orifice bilaterally, and in the urinary bladder wall. One pig was sacrificed nine weeks after the initial injection and ahowed connective tissueremodeling with an infiltration of spindle shaped myofibroblasts which are positive for smooth ZO muscZ~ action. This type of connective tissue response. is very similar to that seen in the use of SIS tubes in the arterial location: Control sites where saline was used as the injection material; showed no response: It was concluded'that SIS stimulates an appropriate connective 25~ tissue remodeling such that augmentation of urinary bladder.
wall'and/or urinary bladder sphincter can be accomplished with suspended SxS material.
The fluidized submucosa composit'ians of this invention find'wide application both'in tissue replacement 30' and repair. The fluidized submucosal compositions are used' in accordance with the present'method to induce regrow~h of natural connective tissue or bone in an area of an existent defect. By injecting an effective amount of a ~luidized submucosa composition into'the locale of a tissue defect or 3~: a-wound in need of healing; one can readil~r take advantage 11 WO 94/11008 ~ ~ '-~ ~ PCTt1JS93l10861 _g_ of the graft compositions biotropic properties without the need for more invasive surgical techniques.
Perhaps the most remarkable aspect of the compositions of the present invention is their ability to induce regro~wth of natural tissue in an affected area. By injecting an effective amount of a fluidized submucosa composition inter the locale of a tissue defect or a wound in need of healing, one can readily hake advantage of this surprising property without the need for major invasive operations .
Although the invention has been described in.
detail with reference to certain ~ref~rred'embodim~nts, variations and modifications exist wiahin the cope and spirit of the invention as described and defined in the following claims:
Claims (47)
1. ~A method of preparing a tissue graft composition, said method comprising the steps of comminuting intestinal tissue comprising intestinal submucosa and hydrating the resultant comminuted intestinal tissue to provide said tissue graft composition as a fluid having a viscosity of about 2 to about 300,000 cps at 25°C.
2. ~The method of claim 1, wherein the comminuting step includes the step of freezing the intestinal tissue and grinding the frozen intestinal submucosa.
3. ~The method of claim 1 wherein the.
comminuting step includes the steps of freeze-drying the intestinal tissue and grinding the freeze-dried intestinal tissue.
comminuting step includes the steps of freeze-drying the intestinal tissue and grinding the freeze-dried intestinal tissue.
4. ~The method of claim 1 wherein the comminuting step includes the step of processing the intestinal tissue in a high shear blender.
5. ~The method of claim 1 further comprising the step of sterilizing the tissue graft composition.
6. ~The method of claim 1 wherein the intestinal tissue comprises the tunics submucosa and basilar portions of the tunics mucosa, said tunics submucosa and basilar portions of the tunics mucosa being delaminated from the tunics muscularis and the luminal portion of the tunics mucosa of the intestine of a warm-blooded vertebrate.
7. ~The method of claim 6 wherein the intestinal tissue consists essentially of the tunics submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
8. ~The method of claim 1 further comprising the step of digesting the comminuted intestinal tissue with a protease for a period of time sufficient to solubilize said tissue to provide the tissue graft composition as a substantially homogeneous solution.
9. The method of claim 8, further comprising the step of neutralizing the substantially homogeneous solution to inactivate the protease.
10. The method of claim 8 wherein the intestinal tissue comprises the tunics submucosa and basilar portions of the tunics mucosa, said tunics submucosa and basilar portions of the tunics mucosa being delaminated from the tunics muscularis and the luminal portion of the tunics mucosa of the intestine of a warm-blooded vertebrate.
11. The method of claim 10 wherein the intestinal tissue consists essentially of the tunics submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
12. The method of claim 10, further comprising the step of separating the solubilized tissue from the substantially homogeneous solution.
13. A method of preparing a tissue graft composition, said method comprising the step of digesting intestinal submucosa in aqueous solution with a protease for a period of time sufficient to solubilize said submucosa to form a substantially homogeneous solution.
14. The method of claim 13, further comprising the step of neutralizing the substantially homogeneous solution to inactivate the protease.
15. The method of claim 13, further comprising the step of separating the solubilized tissue from the substantially homogeneous solution.
16. The method of claim 13, wherein the intestinal tissue comprises the tunics submucosa and basilar portions of the tunics mucosa, said tunics submucosa and basilar portions of the tunics mucosa being delaminated from the tunics muscularis and the luminal portion of the tunica mucosa of a segment of vertebrate intestine.
17. The method of claim 16 wherein the intestinal tissue consists essentially of the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
18. A tissue composition comprising a suspension of comminuted tunica submucosa in an aqueous medium.
19. A tissue composition comprising a suspension of comminuted intestinal tissue comprising tunica submucosa in an aqueous medium.
20. The composition of claim 18 or 19 having a viscosity of about 2 to about 300,000 cps at 25°C
21. The composition of claim 19, wherein the intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa of a segment of small intestine of a warm-blooded vertebrate, said tunica submucosa and basilar portions of the tunica being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said section of small intestine.
22. The composition of claim 21 wherein the intestinal tissue consists essentially of the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
23. A composition comprising protease digested intestinal tissue comprising tunica submucosa in an aqueous carrier.
24. The composition of claim 23 having a viscosity of about 2 to about 300,000 cps at 25°C.
25. The composition of claim 23 or 24, wherein the intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa of a segment of small intestine of a warm-blooded vertebrate, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said section of small intestine.
26. The composition of claim 25 wherein the intestinal tissue consists essentially of the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
27. The composition of claim 23, wherein the composition is substantially free of protease.
28. Use of a sheet of a first tissue graft composition in the manufacture of a tissue graft construction, for surgical reconstruction of a collagenous meniscus at the interface of articulating bones, wherein the first tissue graft composition comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of a segment of intestine of a warm-blooded vertebrate, said sheet being formed into a sealed pouch and filled with a second tissue graft composition comprising comminuted intestinal tissue comprising tunica submucosa or protease digested intestinal tissue comprising tunica submucosa, wherein the tissue graft construction is suitable for surgical implantation into said interface.
29. Use, for surgical reconstruction of a collagenous meniscus at the interface of articulating bones, of a tissue graft construction comprising a sheet of a first tissue graft composition comprising the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of a segment of intestine of a warm-blooded vertebrate, said sheet being formed into a sealed pouch and filled with a second tissue graft composition comprising comminuted intestinal tissue comprising tunica submucosa or protease digested intestinal tissue comprising tunica submucosa, wherein the tissue graft construction is suitable for surgical implantation into said interface.
30. The use of claim 28 or 29 wherein the first and second tissue graft compositions consist essentially of the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
31. Use in the manufacture of a medicament for promoting wound healing, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue in an aqueous medium or a solution of protease digested intestinal tissue in an aqueous carrier, wherein said intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of the intestine of a warm-blooded vertebrate, wherein the tissue graft composition is suitable for application onto a wound.
32. Use for promoting wound healing, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue in an aqueous medium or a solution of protease digested intestinal tissue in an aqueous carrier, wherein said intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of the intestine of a warm-blooded vertebrate, wherein the tissue graft composition is suitable for application onto a wound.
33. The use of claim 31 or 32 wherein the intestinal tissue consists essentially of the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
34. A tissue graft construction comprising intestinal tissue formed into a sealed pouch and containing a fluidized tissue graft composition comprising a suspension of comminuted intestinal tissue or protease digested intestinal tissue, wherein said intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of the intestine of a warm-blooded vertebrate.
35. The tissue graft construction of claim 34 wherein the intestinal tissue consists essentially of the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
36. Dried intestinal submucosa in powder form.
37. Dried protease-solubilized intestinal submucosa in powder form.
38. Use in the manufacture of a medicament for inducing the formation of endogenous tissue of a warm-blooded vertebrate in a locale at which formation of endogenous tissue is desired, of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising tunica submucosa or a protease digest thereof in an amount effective to induce endogenous tissue growth in the locale.
39. Use for inducing the formation of endogenous tissue of a warm-blooded vertebrate in a locale at which formation of endogenous tissue is desired, of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising tunica submucosa or a protease digest thereof in an amount effective to induce endogenous tissue growth in the locale.
40. The use of claim 38 or 39 wherein the intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa of a segment of small intestine of a warm-blooded vertebrate, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said segment.
41. The use of claim 40 wherein the intestinal tissue consists essentially of the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
42. The use of any one of claims 38 to 41 wherein the growth induced endogenous tissue is bone or connective tissue comprising collagen, elastin or muscle.
43. The use of any one of claims 38 to 41 wherein the tissue graft composition is suitable for injection into tissue forming a sphincter in a warm-blooded mammal and the growth induced tissue is tissue forming the sphincter.
44. Use in the manufacture of a medicament for augmenting sphincter function in a warm-blooded mammal, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising the tunica submucosa or a protease digest of intestinal tissue comprising the tunica submucosa, wherein the tissue graft composition is suitable for injection into tissue forming said sphincter.
45. Use for augmenting sphincter function in a warm-blooded mammal, of an effective amount of a tissue graft composition comprising a suspension of comminuted intestinal tissue comprising the tunica submucosa or a protease digest of intestinal tissue comprising the tunica submucosa, wherein the tissue graft composition is suitable for injection into tissue forming said sphincter.
46. The use of claim 44 or 45, wherein the intestinal tissue comprises the tunica submucosa and basilar portions of the tunica mucosa of a segment of small intestine of a warm-blooded vertebrate, said tunica submucosa and basilar portions of the tunica mucosa being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said segment.
47. The use of claim 46 wherein the intestinal tissue consists essentially of the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of vertebrate intestine.
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US07/976,156 US5275826A (en) | 1992-11-13 | 1992-11-13 | Fluidized intestinal submucosa and its use as an injectable tissue graft |
PCT/US1993/010861 WO1994011008A1 (en) | 1992-11-13 | 1993-11-10 | Fluidized intestinal submucosa and its use as an injectable tissue graft |
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CA2149324C true CA2149324C (en) | 2005-01-18 |
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CA002149324A Expired - Lifetime CA2149324C (en) | 1992-11-13 | 1993-11-10 | Fluidized intestinal submucosa and its use as an injectable tissue graft |
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1993
- 1993-11-10 ES ES94900605T patent/ES2148309T3/en not_active Expired - Lifetime
- 1993-11-10 HU HU9501403A patent/HU218891B/en not_active IP Right Cessation
- 1993-11-10 AU AU55523/94A patent/AU677974B2/en not_active Ceased
- 1993-11-10 DK DK94900605T patent/DK0671922T3/en active
- 1993-11-10 NZ NZ258032A patent/NZ258032A/en unknown
- 1993-11-10 SK SK610-95A patent/SK282122B6/en unknown
- 1993-11-10 JP JP51232594A patent/JP3534408B2/en not_active Expired - Lifetime
- 1993-11-10 EP EP94900605A patent/EP0671922B1/en not_active Expired - Lifetime
- 1993-11-10 PL PL93309000A patent/PL174426B1/en not_active IP Right Cessation
- 1993-11-10 WO PCT/US1993/010861 patent/WO1994011008A1/en not_active Application Discontinuation
- 1993-11-10 NZ NZ299279A patent/NZ299279A/en unknown
- 1993-11-10 PT PT94900605T patent/PT671922E/en unknown
- 1993-11-10 CA CA002149324A patent/CA2149324C/en not_active Expired - Lifetime
- 1993-11-10 BR BR9307419-0A patent/BR9307419A/en not_active Application Discontinuation
- 1993-11-10 DE DE69328625T patent/DE69328625T2/en not_active Expired - Lifetime
- 1993-11-10 AT AT94900605T patent/ATE192654T1/en not_active IP Right Cessation
- 1993-11-10 RU RU95112505A patent/RU2148379C1/en active
- 1993-11-10 CZ CZ951240A patent/CZ124095A3/en unknown
- 1993-11-11 MX MX9307046A patent/MX9307046A/en not_active IP Right Cessation
-
1994
- 1994-11-22 US US08/343,204 patent/US5516533A/en not_active Expired - Lifetime
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1995
- 1995-05-12 FI FI952337A patent/FI952337A/en unknown
- 1995-05-12 NO NO951881A patent/NO951881L/en not_active Application Discontinuation
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2000
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HU218891B (en) | 2000-12-28 |
BR9307419A (en) | 1999-08-31 |
MX9307046A (en) | 1995-01-31 |
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GR3034144T3 (en) | 2000-11-30 |
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NO951881L (en) | 1995-05-12 |
PL174426B1 (en) | 1998-07-31 |
FI952337A (en) | 1995-05-12 |
ES2148309T3 (en) | 2000-10-16 |
EP0671922A4 (en) | 1996-08-21 |
JPH08506799A (en) | 1996-07-23 |
DK0671922T3 (en) | 2000-08-28 |
JP3534408B2 (en) | 2004-06-07 |
HUT73965A (en) | 1996-10-28 |
EP0671922A1 (en) | 1995-09-20 |
US5275826A (en) | 1994-01-04 |
HU9501403D0 (en) | 1995-06-28 |
NZ258032A (en) | 1997-05-26 |
EP0671922B1 (en) | 2000-05-10 |
NZ299279A (en) | 2000-08-25 |
SK282122B6 (en) | 2001-11-06 |
SK61095A3 (en) | 1995-11-08 |
PT671922E (en) | 2000-08-31 |
PL309000A1 (en) | 1995-09-18 |
AU677974B2 (en) | 1997-05-15 |
CA2149324A1 (en) | 1994-05-26 |
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