WO2013102810A2 - Biologically active graft for skin replacement therapy - Google Patents
Biologically active graft for skin replacement therapy Download PDFInfo
- Publication number
- WO2013102810A2 WO2013102810A2 PCT/IB2012/057150 IB2012057150W WO2013102810A2 WO 2013102810 A2 WO2013102810 A2 WO 2013102810A2 IB 2012057150 W IB2012057150 W IB 2012057150W WO 2013102810 A2 WO2013102810 A2 WO 2013102810A2
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- Prior art keywords
- esophagus
- warm
- tissue
- skin
- graft
- Prior art date
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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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/60—Materials for use in artificial skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K35/24—Mucus; Mucous glands; Bursa; Synovial fluid; Arthral fluid; Excreta; Spinal fluid
-
- 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
- A61L27/3604—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
Definitions
- the present invention relates to a biologically active graft composition and methods for its preparation and use. More particularly, the present invention is intended for manufacture of non-immunogenic tissue graft compositions comprising esophagus mucosa, basement membrane and tunica submucosa of an esophagus of a warm-blooded vertebrate capable of being utilized as a substitute for skin autograft for skin replacement therapies and for inducing stromal cells regeneration when implanted into warm-blooded vertebrates including humans.
- a biologically active graft (BAG) composition comprising esophagus mucosa, basement membrane and tunica submucosa as intact natural sheet forms (Ad integrum), delaminated from the tunica muscularis and adventitia of a esophagus of a warm-blooded vertebrate, and therapeutic applications arising from their utilization is described.
- This new BAG composition differs from previously known tissue derived from esophagus mucosal tissues of U.S. Pat. No 5300306, by the inclusion or retention of a mainly intact basement membrane and connective tissue (tunica submucosa) in the present invention.
- This connective tissue is critical to regenerating the in vivo milieu at the wound site, and the three-dimensional structure of the new construct acts as a substitute for skin autograft in skin replacement therapies and for inducing stromal cells regeneration.
- the BAG composition adheres to connective tissues, promotes angiogenesis, and achieves permanent engraftment of Dermis and has been used for many years in humans without evidence of adverse immunological outcomes.
- the BAG composition is capable of being utilized as a substitute for skin autograft in skin replacement therapies, and for inducing stromal cells regeneration with levels of performance and outcome very similar to the most sophisticated commercially available tissue-engineered product that is INTEGRA ® (Integra Life Sciences Corp., Plainsboro, NJ, USA).
- the Applicants are co-inventors of a Tissue-equivalent membrane from bovine esophageal tissue that is useful for the proliferation of epidermal cells in treating skin loss or injury. See U.S. Pat. No. 5300306
- This new BAG composition differs from previously known tissue compositions derived from esophagus mucosal tissues, by the inclusion of a mainly intact basement membrane and connective tissue (tunica submucosa) in the present invention.
- This connective tissue are critical to regenerating and maintaining the in vivo milieu at the wound site, and the three-dimensional structure of the new construct serves as a substitute for skin autograft in skin replacement therapies, and for inducing stromal cells regeneration.
- the BAG composition has physical and physiological properties similar to that of the native tissue architecture of the organ to be replaced/repaired, since there is an outer epidermal analog (non-keratinized stratified squamous epithelium), and inner dermal analog (basement membrane and connective tissue).
- a solid composition can be produced that has greater physical strength than is the case with an epithelial mucosa alone, consequently it is suitable for surgical handling to ensure a long-lasting barrier function.
- the composition can be utilized at the site of tissue removal to facilitate in-growth of connective tissue.
- the BAG composition adheres to connective tissue, promotes angiogenesis, and achieves permanently engraftment of Dermis.
- the BAG composition a xenograft by nature, moves away from the typical performance and documented complication of these materials.
- the BAG composition is capable of being utilized as a substitute for skin autograft in skin replacement therapies and for inducing stromal cells regeneration with levels of performance and outcome very similar to the most sophisticated commercially available tissue-engineered product that is INTEGRA ® (Integra Life Sciences Corp., Plainsboro, NJ, USA).
- Integra ® (Integra Life Sciences Corp., Plainsboro, NJ, USA) is a dermal regeneration template consisting of bovine collagen, chondroitin-6-sulphate and a silastic membrane. This product has gained widespread use in the clinical treatment of deep partial-thickness and full-thickness burn wounds, full-thickness skin defects of different etiologies, chronic wounds and in soft tissue defects (Elliot et al, 1973) (Song et al, 1966)(Halim et al, 2010)( Van der Veen et al, 2010)( Hansen et al, 2001)( Burke JF, Yannas IV et al, 1981)( Heimbach et al, 1988).
- the bovine collagen dermal analogue integrates with the patient's own cells and the temporary epidermal silicone is peeled away as the dermis regenerates. A very thin autograft is then grafted onto the neo-dermis (Pham et al, 2007).
- matrix products supporting cells growth include preparations derived from small intestinal submucosa or SIS now commercially available, include, but are not limited to, OasisTM, SurgisisTM, Surgisis-ESTM, StratasisTM, and Stratasis-ESTM (Cook Urological Inc.; Indianapolis, Ind.) and GraftPatchTM (Organogenesis Inc.; Canton Mass.) and the ECM derived from urinary bladder(UBM).
- Commercially available preparations include, but are not limited to UBM (Acell Corporation; Jessup, Md.).
- tissue repair consists of the treatment of tissue with a biodegradable polymeric material which, acting as a scaffold; include biodegradable polymeric material formed from crosslinked collagen molecules that are covalently bonded to glycosaminoglycan molecules.
- U.S. Pat. No. 6,893,666 discloses a composition and methods for using a tissue regenerative matrix to promote the restoration, remodeling or repair of connective tissue.
- the composition of the matrix comprises devitalized mammalian epithelial basement membrane of the intestine and tunica basement, which can further include submucosa, tunica muscularis, growth factors, a cell, or a polymer.
- devitalized means acellular or substantially acellular which differs in the present invention which preserves the cells in their natural form.
- Antiseptic - A substance that inhibits the growth and development of microorganisms without necessarily killing them. Antiseptics are usually applied to body surfaces.
- basement membrane Between the epidermis and dermis lies the basement membrane (basal lamina), which keeps the outer layer adhered closely to the lower layer, term usually used in light microscopy.
- Biocide A general term for any agent that kills organisms.
- Biocompatible - refers to compositions (e.g. cells, tissues, matrices, etc.) that do not substantially disrupt the normal biological functions of other compositions to which they contact
- Connective tissue - refers to tissue that protects and supports the body and its organs, and tissues that bind organs together.
- Chemical germicide - A chemical or a mixture of chemicals used to kill microorganisms.
- Decontamination Any process for removing and/or killing microorganisms.
- Dermal autograft - Skin autograft from which epidermis and subcutaneous fat have been removed; used instead of fascia in various plastic (surgery) procedures.
- Debridement - Is the removal of loose, devitalized, necrotic, and/or contaminated tissue, foreign bodies, and other debris on the wound using mechanical or sharp techniques
- Disinfectant A chemical or mixture of chemicals used to kill microorganisms, usually applied to inanimate surfaces or objects.
- Disinfection A physical or chemical means of killing microorganisms, but not necessarily spores.
- Dressing Any of various materials utilized for covering and protecting a wound.
- Engraftment - Incorporation of grafted tissue into the body of the host
- Epithelial tissue - refers to the cellular (typically avascular) layer covering all the free surfaces, cutaneous, mucous, and serous, including the glands and other structures derived there from.
- Excision - Is a surgical procedure requiring incision through the deep dermis (including subcutaneous and deeper tissues) of open wounds, burn eschar, or burn scars.
- Granulation tissue Newly formed vascular tissue normally produced in the healing of wounds of soft tissue and ultimately forming the scar; it consists of small, translucent, red, nodular masses of granulations that have a velvety appearance.
- Host - refers to an individual (whether human or non-human) into whom cells, tissue, blood, or organs are transplanted.
- Matrix - refers to a composition comprising a plurality of pores dividing free space into partially enclosed interstices wherein said interstices are in fluidic communication
- Microbicide - A chemical or mixture of chemicals that kills microorganisms.
- Sterilization A process that kills and/or removes all classes of microorganisms and spores.
- Substitute - Is used only as a noun in the context of 'substitute for skin graft'.
- Skin allograft An allograft consisting of intact viable or non-viable epidermal and dermal tissue.
- Skin autograft An autograft consisting of intact viable epidermal and dermal tissue.
- Skin Substitute - A biomaterial, engineered tissue, or combination of biomaterials and cells or tissues that can be substituted for a skin allograft, a skin autograft, an epidermal autograft, or a dermal autograft in a clinical procedure.
- Stroma The supportive framework of an organ usually composed of connective tissue.
- Tissue regeneration - Healing in which lost tissue is replaced by proliferation of cells which reconstruct the normal architecture.
- Tissue repair - Healing in which lost tissue is replaced by a fibrous scar, which is produced from granulation tissue.
- the invention is directed to biologically active graft , methods of producing the same, and therapeutic applications arising from their utilization.
- the term ' biologically active graft', ' (BAG)' or 'graft' refers to three-dimensional structure for implantation or transplantation that induced stromal cells regeneration .
- any reference to 'including humans' placed after references to 'warm blooded vertebrates' is intended to clarify that whilst humans are contemplated as recipients of the BAG, human donors of such tissue are not contemplated, this clarification is provided because the term 'warm blooded vertebrates' is used both in the meaning of donor and recipient within this document.
- the esophagus of a warm-blooded vertebrate is used in the preparation of a biologically active graft (BAG) composition.
- BAG biologically active graft
- tissue graft compositions enables a surgeon to utilize this composition in a diverse range of surgical applications such as burns, wounds, scalps, cancer removal, vascular skin complications (chronic ulcers) or extensive injuries presented in theaters of war .
- the preparation of a (BAG) composition from the esophagus of warm-blooded vertebrate in accordance with the invention is carried out by separating the mucosa, basement membrane and tunica submucosa from the esophagus of warm-blooded vertebrate in a manner that ensures minimal disruption or damage to this natural arrangement.
- the method comprises the steps of delaminating the mucosa, basement membrane and tunica submucosa from the whole esophagus of warm-blooded vertebrate.
- one embodiment of this invention provides a method for preparing a natural cellular/nonliving composition
- a natural cellular/nonliving composition comprising non-keratinized stratified squamous epithelium (Mucosa), basement membrane and connective tissue (tunica submucosa) in its natural sheet forms (Ad integrum) from the esophagus of a warm-blooded vertebrate.
- the mucosa, basement membrane and tunica submucosa for use in the (BAG) composition in accordance with the invention are typically prepared from the esophagus of a warm-blooded vertebrate harvested from animals including, for example, pigs, cattle, sheep or other warm-blooded vertebrates and does not exclude the use of the esophagus of cold-blooded aquatic animals and other marine mammals.
- this invention provides a process for preparing a biocompatible graft composition from the oesophagus of warm-blooded vertebrate, and in general, the method for preparing the mucosa, basement membrane and tunica submucosa comprises the steps of obtain freshly harvested esophagus of warm-blooded vertebrate from proper suppliers that ensure full traceability and in a First Process the material is washed in a large volume of circulating water to remove adhering blood and residues of food, followed by immersing in 0.1% (v/v) peracetic acid and 95.9% (v/v) sterile water for two hours.
- PBS Buuffered saline
- the applicant can opt for placing the material in the freezer and this preserves it well until the time of its use, with a storage life of more than one year free of microorganisms (which has been confirmed by multiple cultivation of random samples).
- another embodiment of this invention is a method of implanting into the vertebrate the BAG composition, prepared as described above comprising mucosa, basement membrane and tunica submucosa of esophagus of warm-blooded vertebratein an amount effective to induce cells regenerationof connective tissues at the site of administration of the graft.
- the BAG composition produced and used in accordance with this invention upon implantation, can serve as a template for supporting the growth of new endogenous connective tissue and for induced stromal cells regeneration in the warm-blooded vertebrate including humans .
- Connective tissues for the purposes of the present invention include the dermal layer of skin.
- the tissue graft compositions are used beneficially to induce the formation of stromal cells at a desired site in a warm-blooded vertebrate including humans.
- t he inclusion of a mainly intact basement membrane and connective tissue (tunica submucosa) from the esophagus of warm-blooded vertebratein the present invention produces a template with more consistent physical properties and more acceptable clinical composition than the previous description by the applicant.
- the BAG composition of the invention may contain additional bioactive components including, for example, one or more of glycosaminoglycans, glycoproteins, proteoglycans, and/or growth factors naturally found in tissues where the scaffolding is implanted for applications such as, for example, tissue repair or regeneration.
- this invention provides a method of implanting a graft of this invention in a subject for immediate wound closure and permanent regeneration of dermis, as show in example # 2 in this discovery.
- the size and form of said biologically active graft is a function of the tissue into which the graft is to be implanted.
- the biologically active graft is implanted with the mucous side facing outward and the remaining layer side facing inward in direct contact with the wound bed.
- the membrane becomes sufficiently adhered to the graft bed so that the graft becomes thoroughly integrated at all levels and will promote the regeneration of the dermis, induces angiogenesis from the surrounding connective tissue and can help prepare the wound area for skin autograft where such is considered additionally required.
- use of the graft for repair, regeneration of tissue is in cases where native tissue is damaged, in one embodiment, by trauma, or in another embodiment, by burns, cancer, vascular skin complications (chronic ulcers) or extensive injuries presenting in theaters of war.
- esophagus mucosa, basement membrane and tunica submucosa from the esophagus of a warm-blooded vertebrate for the manufacture of other treatment methods or medical applications or products which have not been discussed in the present application, e.g., topical formulations (creams, ointments, gels), transdermal systems or used for the purpose of improving, developing or enhancing other biotechnological/biological products.
- the biologically active graft (BAG) composition is made from the oesophagus of warm blood vertebrates.
- the esophagus comprises distinct layers. From the inner to the outside, these are: mucosa, submucosa, muscle and adventitia.
- the mucosa and submucosa (include the basement membrane) forms the main foundation in the present invention.
- the biologically active graft (BAG) composition is obtained from animals that have passed ante mortem and post mortem inspection and meet regulatory requirements for not poisonous products. Only materials from proper suppliers that ensure full traceability should be used. Manufacturers should provide a certificate of compliance for every lot of materials should take into account the quality of tissues to be removed and their appropriate handling after removal.
- Evisceration stages At the site of animal sacrifice the oesophagus was separated from the trachea and lungs in order to tie it, which allowed the lungs to be removed through the diaphragm without rupturing the oesophagus. This is primarily a hand and/or knife operation. Both the inner and outer layers of the esophagus are carefully removed, and appropriate gloves must be wearing for all procedures.
- the primary material is transfer toanareathat allows copious amounts of circulating fresh waterfor cleaning itsexternal and internal surfaces and mainly run water through the lumen of the esophagus.
- Next desirable processes of the invention involve immersing the tissue source (e. g. by submersing) in 0.1% (v/v) peracetic acid and 95.9% (v/v) sterile water for two hours.
- Laboratory working areas The laboratory should be kept neat, clean and free of materials that are not pertinent to the work.
- the surfaces of Stainless steel table should be decontaminated before and after each use and application of pressure with vigorous scrubbing greatly improves the removal of grease and other unwanted contaminants from a preparation surface.
- Freshly prepared hypochlorite solutions recommended for decontamination at 1 g/l. All instruments used during the procedure should be sterile and stored on sterile drape.
- Process TWO In the previously disinfected surface of Stainless steel table and covered with a sterile drape, the tissues may be removed fromtheir container and laid upontable, using an aseptic technique with sterile cloths and gloves.
- the material thus obtained was placed over the area to be processed with the plane mucous put downward.
- surgical instruments such as Metzenbaum scissors or scalpel, carefully proceed to separate the adventitia and muscular layers (which is recognized by its red color) in order to preserve intact theinner structures because they are the primary material of the present invention.
- the mucosa, basement membrane and tunica submucosa are separated easily and consistently from the whole esophagus and should be examined to confirm there is minimal tissue debris on its surface.
- Each tissue should be packaged individually as soon as possible packaging into a vacuum bag (multi-layer synthetic bag). Air is removed from the bag by means of the vacuum packaging machine and the bag then is sealed.
- a vacuum bag multi-layer synthetic bag
- Freezing and frozen storage can give a storage life of more than one year.
- the antigens were obtained by aqueous extracts in P.B.S. (Phosphate buffered saline) with pH 7.2.
- the precipitating antibodies, the immediate and delayed skin test were negative in the 100% of the cases.
- This invention provides a proven technology to produce a non-immunogenic tissue graft compositions comprising esophagus mucosa, basement membrane and tunica submucosa of an esophagus of a warm-blooded vertebrate.
- the composition can be utilized for implanting at the site of tissue removal for immediate wound closure in cases where native tissue is damaged, in one embodiment, by trauma, or in another embodiment, by burns, cancer, vascular skin complications (chronic ulcers) or extensive injuries presenting in theaters of war (full-thickness burn- wounds defects).
- composition has physical and physiological properties similar to that of the native tissue architecture of the organ to be replaced/repaired, since in a histological point of view is very similar to human skin, thus becomes an considerable importance of the invention and the general research intensity in the field of skin replacement therapy.
- the patent aims to protect the claims related to the process for producing the composition, and claims relating to the methods used to implant the composition by surgical techniques in human subjects.
Abstract
The present invention relates to a biologically active graft (BAG) composition and methods for its preparation and use. More particularly, it details a method for preparing a non-immunogenic tissue graft composition comprising esophagus mucosa, basement membrane and tunica submucosa as intact natural sheet forms (Ad integrum), delaminated from the tunica muscularis and adventitia of an esophagus of a warm-blooded vertebrate. The composition is capable of serving as a substitute for skin autograft for skin replacement therapy and induces stromal cells regeneration when implanted in warm-blooded vertebrate including human subjects.
Description
This application is being filed as a US provisional
patent application No. 61/583,138 filed 04 January 2012 by the same
applicant/inventor of the present application. The previous application claims
have been reduced.
FIELD OF THE INVENTION
The present invention relates to a biologically
active graft composition and methods for its preparation and use. More
particularly, the present invention is intended for manufacture of
non-immunogenic tissue graft compositions comprising esophagus mucosa, basement
membrane and tunica submucosa of an esophagus of a warm-blooded vertebrate
capable of being utilized as a substitute for skin autograft for skin
replacement therapies and for inducing stromal cells regeneration when
implanted into warm-blooded vertebrates including humans.
DESCRIPTION
A biologically active graft (BAG) composition
comprising esophagus mucosa, basement membrane and tunica submucosa as intact
natural sheet forms (Ad integrum), delaminated from the tunica muscularis and
adventitia of a esophagus of a warm-blooded vertebrate, and therapeutic
applications arising from their utilization is described.
This new BAG composition differs from previously
known tissue derived from esophagus mucosal tissues of U.S. Pat. No 5300306, by
the inclusion or retention of a mainly intact basement membrane and connective
tissue (tunica submucosa) in the present invention.
This connective tissue is critical to
regenerating the in vivo milieu at the wound site, and the three-dimensional
structure of the new construct acts as a substitute for skin autograft in skin
replacement therapies and for inducing stromal cells regeneration.
The BAG composition adheres to connective tissues,
promotes angiogenesis, and achieves permanent engraftment of Dermis and has
been used for many years in humans without evidence of adverse immunological
outcomes.
At the beginning of our study, several years ago,
the goal was to find the absolutely optimal dermal substitute, an objective
that is fulfilled by the present invention.
The BAG composition is capable of being utilized as
a substitute for skin autograft in skin replacement therapies, and for inducing
stromal cells regeneration with levels of performance and outcome very similar
to the most sophisticated commercially available tissue-engineered product that
is INTEGRA® (Integra Life Sciences Corp., Plainsboro, NJ, USA).
BACKGROUND OF THE INVENTION
The Applicants are co-inventors of a
Tissue-equivalent membrane from bovine esophageal tissue that is useful for the
proliferation of epidermal cells in treating skin loss or injury. See U.S. Pat.
No. 5300306
This new BAG composition differs from previously
known tissue compositions derived from esophagus mucosal tissues, by the
inclusion of a mainly intact basement membrane and connective tissue (tunica
submucosa) in the present invention.
This connective tissue are critical to
regenerating and maintaining the in vivo milieu at the wound site, and the
three-dimensional structure of the new construct serves as a substitute for
skin autograft in skin replacement therapies, and for inducing stromal cells
regeneration.
In one non-limiting example, the BAG composition
has physical and physiological properties similar to that of the native tissue
architecture of the organ to be replaced/repaired, since there is an outer
epidermal analog (non-keratinized stratified squamous epithelium), and inner
dermal analog (basement membrane and connective tissue).
In this manner, a solid composition can be produced
that has greater physical strength than is the case with an epithelial mucosa
alone, consequently it is suitable for surgical handling to ensure a
long-lasting barrier function.
For example and without limitation, where a patient
has had tissue removed due to trauma, debridement and/or removal of damaged,
diseased or cancerous tissue, or other surgical intervention, the composition
can be utilized at the site of tissue removal to facilitate in-growth of
connective tissue.
The BAG composition adheres to connective tissue,
promotes angiogenesis, and achieves permanently engraftment of Dermis.
The BAG composition, a xenograft by nature, moves
away from the typical performance and documented complication of these
materials.
On the other hand, the BAG composition is capable
of being utilized as a substitute for skin autograft in skin replacement
therapies and for inducing stromal cells regeneration with levels of
performance and outcome very similar to the most sophisticated commercially
available tissue-engineered product that is INTEGRA® (Integra Life
Sciences Corp., Plainsboro, NJ, USA).
The ability of complex substrates to support cell
growth has been previously reported, and matrix products supporting such growth
are commercially available. For example, U.S. Pat. No. 4,060,081 (Yannas et al,
1977), the teachings of which are hereby incorporated by reference, discloses a
multilayer membrane suitable for use as synthetic skin commercially available
at this time by the name of Integra®.
Integra® (Integra Life Sciences Corp.,
Plainsboro, NJ, USA) is a dermal regeneration template consisting of bovine
collagen, chondroitin-6-sulphate and a silastic membrane. This product has
gained widespread use in the clinical treatment of deep partial-thickness and
full-thickness burn wounds, full-thickness skin defects of different
etiologies, chronic wounds and in soft tissue defects (Elliot et al, 1973)
(Song et al, 1966)(Halim et al, 2010)( Van der Veen et al, 2010)( Hansen et al,
2001)( Burke JF, Yannas IV et al, 1981)( Heimbach et al, 1988). The bovine
collagen dermal analogue integrates with the patient's own cells and the
temporary epidermal silicone is peeled away as the dermis regenerates. A very
thin autograft is then grafted onto the neo-dermis (Pham et al, 2007).
Also matrix products supporting cells growth
include preparations derived from small intestinal submucosa or SIS now
commercially available, include, but are not limited to, Oasis™, Surgisis™,
Surgisis-ES™, Stratasis™, and Stratasis-ES™ (Cook Urological Inc.;
Indianapolis, Ind.) and GraftPatch™ (Organogenesis Inc.; Canton Mass.) and the
ECM derived from urinary bladder(UBM). Commercially available preparations
include, but are not limited to UBM (Acell Corporation; Jessup, Md.).
Another approach to tissue repair consists of the
treatment of tissue with a biodegradable polymeric material which, acting as a
scaffold; include biodegradable polymeric material formed from crosslinked
collagen molecules that are covalently bonded to glycosaminoglycan
molecules.
These polymer materials have been described in the
scientific literature and the patent literature. See, for example, U.S. Pat.
No. 4,505,266 (Mar. 19, 1985); U.S. Pat. No. 4,448,718 (May 15, 1984); U.S.
Pat. No. 4,418,691 (Dec. 6, 1983); U.S. Pat. No. 4,458,678 (July 10, 1984);
U.S. Pat. No. 4,350,629 (Sept. 21, 1982); U.S. Pat. No. 4,522,753 (June 11,
1985); U.S. Pat. No. 4,280,954 (July 28, 1981); U.S. Pat. No. 4,252,759 (Feb.
24, 1981); and U.S. Pat. No. 4,060,081 (Nov. 29, 1977) the teachings of which
are incorporated herein by reference.
U.S. Pat. No. 6,893,666 discloses a composition and
methods for using a tissue regenerative matrix to promote the restoration,
remodeling or repair of connective tissue. The composition of the matrix
comprises devitalized mammalian epithelial basement membrane of the intestine
and tunica propria, which can further include submucosa, tunica muscularis,
growth factors, a cell, or a polymer. For the purposes of this invention,
devitalized means acellular or substantially acellular which differs in the
present invention which preserves the cells in their natural form.
These other synthetic skin substitutes generally
lack basement membrane and architecture that resemble human skin configuration
but the material of this invention differs in this important aspect: the
esophagus of warm-blooded vertebrate that retains its basement membrane in its
native composition and in a histological point of view: is very similar to
human skin.
The inventor notes that for every facet in this
process, further research is still needed.
Current data in the form of large, randomized,
controlled trials are lacking; however, the data that is available suggests
that reliable, definitive, long-term repair of complicated burns-wound defects
and other types of injury are achievable.
In conclusion it can be stated that much progress
has been already been made in the past ten years, and that the results obtained
thus far show great promise with regard to the future clinical application of
the new biologically active graft (BAG) composition.
DEFINITIONS
In the discussions herein, a number of terms are
used. In order to provide a clear and consistent understanding of the
specification and claims, the following definitions are provided.
Allograft - Graft of tissue between
individuals of the same species but of disparate genotype.
Antiseptic - A substance that inhibits the
growth and development of microorganisms without necessarily killing them.
Antiseptics are usually applied to body surfaces.
Autograft - Graft of tissue derived from
another site in or on the body of the organism receiving it.
Basement membrane - Between the epidermis
and dermis lies the basement membrane (basal lamina), which keeps the outer
layer adhered closely to the lower layer, term usually used in light
microscopy.
Biocide - A general term for any agent that
kills organisms.
Biocompatible - Refers to compositions
(e.g. cells, tissues, matrices, etc.) that do not substantially disrupt the
normal biological functions of other compositions to which they contact
Connective tissue - Refers to tissue that
protects and supports the body and its organs, and tissues that bind organs
together.
Chemical germicide - A chemical or a
mixture of chemicals used to kill microorganisms.
Decontamination - Any process for removing
and/or killing microorganisms.
Dermal autograft - Skin autograft from
which epidermis and subcutaneous fat have been removed; used instead of fascia
in various plastic (surgery) procedures.
Debridement - Is the removal of loose,
devitalized, necrotic, and/or contaminated tissue, foreign bodies, and other
debris on the wound using mechanical or sharp techniques
Disinfectant - A chemical or mixture of
chemicals used to kill microorganisms, usually applied to inanimate surfaces or
objects.
Disinfection - A physical or chemical means
of killing microorganisms, but not necessarily spores.
Dressing - Any of various materials
utilized for covering and protecting a wound.
Engraftment - Incorporation of grafted
tissue into the body of the host.
Epithelial tissue - Refers to the cellular
(typically avascular) layer covering all the free surfaces, cutaneous, mucous,
and serous, including the glands and other structures derived there from.
Excision - Is a surgical procedure
requiring incision through the deep dermis (including subcutaneous and deeper
tissues) of open wounds, burn eschar, or burn scars.
Graft - Any tissue or organ for
implantation of transplantation.
Granulation tissue - Newly formed vascular
tissue normally produced in the healing of wounds of soft tissue and ultimately
forming the scar; it consists of small, translucent, red, nodular masses of
granulations that have a velvety appearance.
Host - Refers to an individual (whether
human or non-human) into whom cells, tissue, blood, or organs are
transplanted.
Matrix - Refers to a composition comprising
a plurality of pores dividing free space into partially enclosed interstices
wherein said interstices are in fluidic communication
Microbicide - A chemical or mixture of
chemicals that kills microorganisms.
Replacement - Is used only as an adjective
in the context of 'skin replacement surgery'
Sterilization - A process that kills and/or
removes all classes of microorganisms and spores.
Substitute - Is used only as a noun in the
context of 'substitute for skin graft'.
Skin allograft - An allograft consisting of
intact viable or non-viable epidermal and dermal tissue.
Skin autograft - An autograft consisting of
intact viable epidermal and dermal tissue.
Skin Substitute - A biomaterial, engineered
tissue, or combination of biomaterials and cells or tissues that can be
substituted for a skin allograft, a skin autograft, an epidermal autograft, or
a dermal autograft in a clinical procedure.
Stroma -The supportive framework of an
organ usually composed of connective tissue.
Tissue regeneration - Healing in which lost
tissue is replaced by proliferation of cells which reconstruct the normal
architecture.
Tissue repair - Healing in which lost
tissue is replaced by a fibrous scar, which is produced from granulation
tissue.
Xenograft
- A graft of tissue transplanted between animals
of different species
The invention is directed to biologically active
graft , methods of producing the same, and therapeutic applications arising
from their utilization.
In one embodiment, the term ' biologically
active graft', ' (BAG)' or 'graft' refers to three-dimensional structure
for implantation or transplantation that induced stromal cells regeneration
.
In another embodiment, any reference to 'including
humans' placed after references to 'warm blooded vertebrates' is intended to
clarify that whilst humans are contemplated as recipients of the BAG, human
donors of such tissue are not contemplated, this clarification is provided
because the term 'warm blooded vertebrates' is used both in the meaning of
donor and recipient within this document.
In accordance with one embodiment, the esophagus of
a warm-blooded vertebrate is used in the preparation of a biologically active
graft (BAG) composition. Such tissue graft compositions enables a surgeon to
utilize this composition in a diverse range of surgical applications such as
burns, wounds, scalps, cancer removal, vascular skin complications (chronic
ulcers) or extensive injuries presented in theaters of war .
The preparation of a (BAG) composition from the
esophagus of warm-blooded vertebrate in accordance with the invention is
carried out by separating the mucosa, basement membrane and tunica submucosa
from the esophagus of warm-blooded vertebrate in a manner that ensures minimal
disruption or damage to this natural arrangement.
Conservation of these components from the esophagus
of warm-blooded vertebrates results in the preparation of a (BAG) composition
that is non-immunogenic, and, thus, does not induce an adverse host immune
response when it is implanted into a host.
The method comprises the steps of delaminating the
mucosa, basement membrane and tunica submucosa from the whole esophagus of
warm-blooded vertebrate.
Accordingly, one embodiment of this invention
provides a method for preparing a natural cellular/nonliving composition
comprising non-keratinized stratified squamous epithelium (Mucosa), basement
membrane and connective tissue (tunica submucosa) in its natural sheet forms
(Ad integrum) from the esophagus of a warm-blooded vertebrate.
In another embodiment the mucosa, basement membrane
and tunica submucosa for use in the (BAG) composition in accordance with the
invention are typically prepared from the esophagus of a warm-blooded
vertebrate harvested from animals including, for example, pigs, cattle, sheep
or other warm-blooded vertebrates and does not exclude the use of the esophagus
of cold-blooded aquatic animals and other marine mammals.
In another embodiment, this invention provides a
process for preparing a biocompatible graft composition from the oesophagus of
warm-blooded vertebrate, and in general, the method for preparing the mucosa,
basement membrane and tunica submucosa comprises the steps of obtain freshly
harvested esophagus of warm-blooded vertebrate from proper suppliers that
ensure full traceability and in a First Process the material is washed in a
large volume of circulating water to remove adhering blood and residues of
food, followed by immersing in 0.1% (v/v) peracetic acid and 95.9% (v/v)
sterile water for two hours.
Then, in a Second Process the operator proceeds to
cut the material in the longitudinal axis using surgical instruments, and
carefully proceed to separate the adventitia and muscular layers in order to
preserve intact the inner structures (mucosa, basement membrane and tunica
submucosa ) because they are the primary material of the present invention.
Then the Larger pieces of esophagus can be cut in segments 8 cm long x 5 cm
wide. Next, in each segment, the peracetic acid residue is removed by washing
twice for 15 minutes with PBS (Buffered saline) (pH=7.4) and twice for 15
minutes with sterile water in order to remove any residual
disinfectant-sterilizing agent. Each tissue should be packaged individually as
soon as possible into a vacuum bag (multi-layer synthetic bag). Air is removed
from the bag by means of the vacuum packaging machine and the bag then is
sealed.
For preservation, the applicant can opt for placing
the material in the freezer and this preserves it well until the time of its
use, with a storage life of more than one year free of microorganisms (which
has been confirmed by multiple cultivation of random samples).
Thus, another embodiment of this invention is a
method of implanting into the vertebrate the BAG composition, prepared
as described above comprising mucosa, basement membrane and tunica submucosa of
esophagus of warm-blooded vertebratein an amount effective to induce cells
regenerationof connective tissues at the site of administration of the
graft.
The BAG composition produced and used in
accordance with this invention, upon implantation, can serve as a template for
supporting the growth of new endogenous connective tissue and for induced
stromal cells regeneration in the warm-blooded vertebrate including humans
.
Connective tissues for the purposes of the present
invention include the dermal layer of skin. In accordance with this embodiment,
the tissue graft compositions are used beneficially to induce the formation of
stromal cells at a desired site in a warm-blooded vertebrate including
humans.
In another embodiment, t he inclusion of a mainly
intact basement membrane and connective tissue (tunica submucosa) from the
esophagus of warm-blooded vertebratein the present invention,produces a
template with more consistent physical properties and more acceptable clinical
composition than the previous description by the applicant.
In another embodiment it is also expected that
the BAG composition of the invention may contain additional bioactive
components including, for example, one or more of glycosaminoglycans,
glycoproteins, proteoglycans, and/or growth factors naturally found in tissues
where the scaffolding is implanted for applications such as, for example,
tissue repair or regeneration.
In another embodiment, this invention provides a
method of implanting a graft of this invention in a subject for immediate wound
closure and permanent regeneration of dermis, as show in example # 2 in this
discovery.
In one embodiment, the size and form of said
biologically active graft is a function of the tissue into which the graft is
to be implanted.
In another embodiment, the biologically active
graft is implanted with the mucous side facing outward and the remaining layer
side facing inward in direct contact with the wound bed.
In one embodiment, the membrane becomes
sufficiently adhered to the graft bed so that the graft becomes thoroughly
integrated at all levels and will promote the regeneration of the dermis,
induces angiogenesis from the surrounding connective tissue and can help
prepare the wound area for skin autograft where such is considered additionally
required.
In another embodiment, use of the graft for repair,
regeneration of tissue is in cases where native tissue is damaged, in one
embodiment, by trauma, or in another embodiment, by burns, cancer, vascular
skin complications (chronic ulcers) or extensive injuries presenting in
theaters of war.
In another embodiment, is contemplated the use of
esophagus mucosa, basement membrane and tunica submucosa from the esophagus of
a warm-blooded vertebrate for the manufacture of other treatment methods or
medical applications or products which have not been discussed in the present
application, e.g., topical formulations (creams, ointments, gels), transdermal
systems or used for the purpose of improving, developing or enhancing other
biotechnological/biological products.
As can be seen from the forgoing description, the
concepts of the present disclosure provide numerous advantages
The following examples are presented in order to
more fully illustrate the preferred embodiments of the invention. They should
in no way be construed, however, as limiting the broad scope of the
invention.
EXAMPLE 1 (Mode for Invention)
Method of Making the Biologically Active Graft
composition
Description
The biologically active graft (BAG) composition is made from the oesophagus of warm blood vertebrates. The esophagus comprises distinct layers. From the inner to the outside, these are: mucosa, submucosa, muscle and adventitia. The mucosa and submucosa (include the basement membrane) forms the main foundation in the present invention.
The biologically active graft (BAG) composition is made from the oesophagus of warm blood vertebrates. The esophagus comprises distinct layers. From the inner to the outside, these are: mucosa, submucosa, muscle and adventitia. The mucosa and submucosa (include the basement membrane) forms the main foundation in the present invention.
Source:
The biologically active graft (BAG)
composition is obtained from animals that have passed ante mortem and post
mortem inspection and meet regulatory requirements for not poisonous products.
Only materials from proper suppliers that ensure full traceability should be
used. Manufacturers should provide a certificate of compliance for every lot of
materials should take into account the quality of tissues to be removed and
their appropriate handling after removal.
Process ONE:
Evisceration stages: At the site of animal
sacrifice the oesophagus was separated from the trachea and lungs in order to
tie it, which allowed the lungs to be removed through the diaphragm without
rupturing the oesophagus. This is primarily a hand and/or knife operation. Both
the inner and outer layers of the esophagus are carefully removed, and
appropriate gloves must be wearing for all procedures.
After harvest the esophagus, should be inspected
in relation to the smell, irregularity or abnormality in shape or color and
discard the material if any such defect be present. Them the primary material
is transfer toanareathat allows copious amounts of circulating fresh waterfor
cleaning itsexternal and internal surfaces and mainly run water through the
lumen of the esophagus.
Next desirable processes of the invention involve
immersing the tissue source (e. g. by submersing) in 0.1% (v/v) peracetic acid
and 95.9% (v/v) sterile water for two hours. Laboratory working areas The laboratory should be kept neat, clean and free of materials that are not pertinent to the work. The surfaces of Stainless steel table should be decontaminated before and after each use and application of pressure with vigorous scrubbing greatly improves the removal of grease and other unwanted contaminants from a preparation surface. Freshly prepared hypochlorite solutions recommended for decontamination at 1 g/l. All instruments used during the procedure should be sterile and stored on sterile drape. Process TWO: In the previously disinfected surface of Stainless steel table and covered with a sterile drape, the tissues may be removed fromtheir container and laid upontable, using an aseptic technique with sterile cloths and gloves. |
Using surgical scissors or scalpels proceed to
cut the material completely in the longitudinal axis, to identify
macroscopically the structures that make the composition. The mucosal layer is
found inside the cylindrical tube which in the normal esophagus is recognized
for having smooth surface and white color.
The material thus obtained was placed over the
area to be processed with the plane mucous put downward. Using surgical
instruments, such as Metzenbaum scissors or scalpel, carefully proceed to
separate the adventitia and muscular layers (which is recognized by its red
color) in order to preserve intact theinner structures because they are the
primary material of the present invention.
The mucosa, basement membrane and tunica
submucosa are separated easily and consistently from the whole esophagus and
should be examined to confirm there is minimal tissue debris on its
surface.
Larger pieces of esophagus tissues can be reduced
in size and cut in segments 8 cm long x 5 cm wide (this may vary slightly
according to the animal that is used as source material).
Next, in each segment, the peracetic acid residue
is removed by washing twice for 15 minutes with PBS (Buffered saline) (pH=7.4)
and twice for 15 minutes with sterile water in order to remove any residual
disinfectant-sterilizing agent.
Each tissue should be packaged individually as
soon as possible packaging into a vacuum bag (multi-layer synthetic bag). Air
is removed from the bag by means of the vacuum packaging machine and the bag
then is sealed.
For preservation it is permitted to place the
material in the freezer and keep well until the time of its use, this has been
a preferred method, which has resulted in a stable material, free of
microorganisms (which have been confirmed by multiple cultivation of random
samples of the packaging material). Freezing and frozen storage can give a
storage life of more than one year.
It is contemplated the use of other method for
final sterilization, such as exposure to ultraviolet radiation, low temperature
hydrogen peroxide sterilization, or gamma irradiation.
EXAMPLE NO. 2
Biologically active graft (BAG) placement
procedure
- 1. Preventive aspect: In elective surgery, patients should abstain from taking aspirin for 10-14 days before surgery; alcohol, vitamin E, and NSAIDs for 4-5 days before surgery; and Coumadin for 3-5 days before surgery which may contribute to postoperative hematoma or seroma formation. The (BAG) composition is not suitable for placement onto infected wounds.
- 2. Management of the recipient wound bed: this is probably the most important prerequisite for successful skin grafting of the BAG composition. In essence, in fresh wound beds (surgical wound or recent accidental wounds) where is possible, the recipient bed should be vascular and free of infection and devitalized or necrotic tissue, and in burn patients careful excision or serial tangential debridement is perhaps the most important step prior to BAG composition placement. To guarantee intimate contact with BAG composition, the wound bed needs to be a uniform and flat surface.
- 3. (BAG) placement procedure: The procedure for implanting the device is analogous to the procedure used to implant Full thickness graft (entire epidermis and dermis are transplanted to the recipient site), and in this case saidBAG compositionis implanted proximally to a host tissue surface,placed with the mucous side facing outward and the remaining layer side facing inward in direct contact with the wound bed. Next, the graft is tacked into place by using interrupted sutures of 6-0 fast-absorbing catgut along its circumference and some sutures to affix the central part of the graft. The applicant prefers to use interrupted sutures rather than running sutures.The patient is placed under general anesthetic.Pain medications are utilized as necessary following surgery.
- 4. Dressings Fixation and compression are of significant importance to ensure the graft adheres to the wound without shear. The preferred Dressings to protect the BAG composition as follows: A: High-quality white nylon net. B: A Tubular Elastic Bandage applied over nylon net, to protect the site and to reduce the potential of shearing and graft dislodgement. The graft and the dressings can be left in place for extended periods without detrimental effects to the underlying wound.
- 5. Post-Operative details: To avoid unnecessary concerns, the patient should be made aware that a significant amount of serous and serosanguineous fluid may drain from the wound during the period of healing. Is normal that the graft changes color: of the white initial color to brown in the subsequent days. If a minor amount of bleeding occurs post-operatively or if the periphery of the graft losses viability, a slight crust or necrotic area can be gently removed.
- 6. Graft withdrawal: The applicant usually soaks the primary and secondary dressing with saline prior to removal the epidermal equivalent.
- 7. Second stage procedure : commonly the dermal analogue integrates with the patient's own cells and the neo-dermis exhibit a healthy granulation surface suitable for grafting a very thin autograft.
- 8. Complications : The following complications are possible with the use of any wound dressings. If any of the conditions occur, the BAG composition should be removed: infection, inflammation, allergic reaction, excessive redness, pain or swelling. Complications that the surgeon may encounter further than infection include seroma and/or hematoma formation, and graft contracture. Although wound infection is rare, when this is suspected, appropriate bacterial identification is obligatory and according to the cultivated microorganisms antibiotics should be prescribed. More extensive black necrotic tissue involving part or all of the grafted may signal partial or complete loss of the graft. Debridement should not be performed until the area of necrosis is clearly demarcated.
EXAMPLE NO. 3
Determination of Humoral Immune Response in
Graft Recipients
Forty patients 30 days after treatment were tested
for a humoral immune response to a BAG graft components by mean to
precipitation antibodies and skin test evaluation. The precipitating antibodies
were tested by immunodifussion in agar gel and skin test were done by
intradermic application of 0.02 ml and evaluated at 10 minutes and at 48
hours.
The antigens were obtained by aqueous extracts in
P.B.S. (Phosphate buffered saline) with pH 7.2.
The precipitating antibodies, the immediate and
delayed skin test were negative in the 100% of the cases.
This study was conducted by the Dr. Roberto
Maselli, Professor of Immunology of the Faculty of Medical Sciences (University
of San Carlos of Guatemala) specialized in the University of Colorado, USA.
This invention provides a proven technology to
produce a non-immunogenic tissue graft compositions comprising esophagus
mucosa, basement membrane and tunica submucosa of an esophagus of a
warm-blooded vertebrate. The composition can be utilized for implanting at the
site of tissue removal for immediate wound closure in cases where native tissue
is damaged, in one embodiment, by trauma, or in another embodiment, by burns,
cancer, vascular skin complications (chronic ulcers) or extensive injuries
presenting in theaters of war (full-thickness burn- wounds defects).
The applicant observed that the composition has
physical and physiological properties similar to that of the native tissue
architecture of the organ to be replaced/repaired, since in a histological
point of view is very similar to human skin, thus becomes an considerable
importance of the invention and the general research intensity in the field of
skin replacement therapy.
The patent aims to protect the claims related to
the process for producing the composition, and claims relating to the methods
used to implant the composition by surgical techniques in human subjects.
FOREIGN PATENT DOCUMENTS:
WO/1998/025636 | STOMACH SUBMUCOSA DERIVED TISSUE GRAFT |
WO/1998/025637 | BIOMATERIAL DERIVED FROM VERTEBRATE LIVER TISSUE |
-WO/1998/022158 | GRAFT PROSTHESIS, MATERIALS AND METHODS |
US Patent References:
6358284 | Tubular grafts from purified submucosa | Fearnot et al. | |
5885619 | Large area submucosal tissue graft constructs and method for making the same | Patel et al. | |
5866414 | Submucosa gel as a growth substrate for cells | Badylak et al. | |
5755791 | Perforated submucosal tissue graft constructs | Whitson et al. | |
5733337 | Tissue repair fabric | Carr, Jr. et al. | |
5607476 | Processing of fibrous connective tissue | Prewett et al. | |
5571181 | Soft tissue closure systems | Li | |
5565210 | Bioabsorbable wound implant materials | Rosenthal et al. | |
5507810 | Processing of fibrous connective tissue | Prewett et al. | |
5489022 | Ultraviolet light absorbing and transparent packaging laminate | Baker | |
5460962 | Peracetic acid sterilization of collagen or collagenous tissue | Kemp | |
5447536 | Method for fixation of biological tissue | Girardot et al. | |
5372821 | Graft for promoting autogenous tissue growth | Badylak et al. | |
5275826 | Fluidized intestinal submucosa and its use as an injectable tissue graft | Badylak et al. | |
4994084 | Reconstructive surgery method and implant | Brennan | |
4970298 | Biodegradable matrix and methods for producing same | Silver et al. | |
4956178 | Tissue graft composition | Badylak et al. | |
4902508 | Tissue graft composition | Badylak et al. |
NON-PATENT REFERENCES:
1 Elliot RA, Hoehn JG. Use of commercial porcine
skin for wound dressing. Plast Reconstr Surg 1973; 52: 401-405.
2 Song IC, Bromberg BE, Mohn MP, Koehnlein E.
Heterografts as biological dressings for large skin wounds. Surgery 1966:59;
576-83.
3 Halim AS, Khoo TL, Shah JM. Biologic and
synthetic skin substitutes: An overview. Indian J Plast Surg [serial online]
2010 [cited 2011 Nov 13];43:23-8. Available from:
http://www.ijps.org/text.asp?2010/43/3/23/70712
4 van der Veen VC, van der Wal MB, van Leeuwen MC,
Ulrich MM, Middelkoop E. Biological background of dermal substitutes. Burns
2010;36:305-21.
5 Hansen SL, Voigt DW, Wiebelhaus P, Paul CN.
Using skin replacement products to treat burns and wounds. Adv Skin Wound Care
2001;14:37-44.
6 Burke JF, Yannas IV, Quinby WC, Jr., Bondoc CC,
Jung WK. Successful use of a physiologically acceptable artificial skin in the
treatment of extensive burn injury. Ann Surg 1981;194:413-28.
7 Heimbach D, Luterman A, Burke J, Cram A, Herndon
D, Hunt J, et al. Artificial dermis for major burns. A multi-center randomized
clinical trial. Ann Surg 1988;208:313-20
8 Pham C, Greenwood J, Cleland H,
Woodruff P, Maddern G. Bioengineered skin substitutes for the management of
burns: a systematic review. Burns 2007; 33:946-57.
Claims (1)
1. A Biologically active graft (BAG) composition capable of
serving as a substitute for skin autograft utilized in skin replacement
therapy, which has the effect of inducing stromal cells regeneration. It
comprises esophagus mucosa, basement membrane and tunica submucosa as intact
natural sheet forms (Ad integrum), delaminated from the tunica muscularis and
adventitia of an esophagus of a warm-blooded vertebrate.
2. The Biologically active graft composition of claim 1,
wherein the layers of that construct comprises non-keratinized stratified
squamous epithelium (Mucosa), basement membrane and connective tissue (tunica
submucosa) as intact natural sheet forms (Ad integrum) of an esophagus of a
warm-blooded vertebrate.
3. The use of esophagus mucosa, basement membrane and tunica
submucosa prepared without disruption of the natural cellular/nonliving
structures from the esophagus of a warm-blooded vertebrate for the manufacture
of a tissue graft construct capable of being utilized as a substitute for skin
autograft in skin replacement therapy and for inducing stromal cells
regeneration when implanted in warm-blooded vertebrate including human
subjects.
4. The method of claim 3, wherein the Biologically active
graft composition is implanted by surgical means into the warm-blooded
vertebrate including human subjects, wherein said method is used in the
treatment of skin loss or damage caused by any type of injury or disease or
surgical intervention conducted according to the methods of this
invention.
5. A method for inducing the formation of endogenous tissue
at a site in need of endogenous tissue growth in a warm blooded vertebrate
including human subjects, said method consist of contacting said site with a
graft composition comprising esophagus mucosa, basement membrane and tunica
submucosa of an esophagus of a warm blooded vertebrate
6. The use of esophagus mucosa, basement membrane and tunica
submucosa from the esophagus of warm-blooded vertebrate in the manufacture of
other treatment methods or medical applications which have not been discussed
in the present application, e.g., topical formulations (creams, ointments,
gels), transdermal systems or used for the purpose of improving, developing or
enhancing other biotechnological/biological products.
Applications Claiming Priority (2)
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US201261583138P | 2012-01-04 | 2012-01-04 | |
US61/583,138 | 2012-01-04 |
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WO2013102810A4 WO2013102810A4 (en) | 2014-02-27 |
Family
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6893666B2 (en) * | 1999-12-22 | 2005-05-17 | Acell, Inc. | Tissue regenerative composition, method of making, and method of use thereof |
US20100028396A1 (en) * | 2008-07-30 | 2010-02-04 | Ward Brian Roderick | Tissue scaffolds derived from forestomach extracellular matrix |
-
2012
- 2012-12-10 WO PCT/IB2012/057150 patent/WO2013102810A2/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6893666B2 (en) * | 1999-12-22 | 2005-05-17 | Acell, Inc. | Tissue regenerative composition, method of making, and method of use thereof |
US20100028396A1 (en) * | 2008-07-30 | 2010-02-04 | Ward Brian Roderick | Tissue scaffolds derived from forestomach extracellular matrix |
Non-Patent Citations (3)
Title |
---|
BADYLAK S F ET AL.: 'Extracellular matrix as a biological scaffold material: Structure and function.' ACTA BIOMATERIALIA vol. 5, no. 1, January 2009, ISSN 1742-7061 pages 1 - 13 * |
BHRANY AMIT D ET AL.: 'Development of an esophagus acellular matrix tissue scaffold.' TISSUE ENGINEERING. vol. 12, no. 2, February 2006, ISSN 1076-3279 pages 319 - 330 * |
OZEKI M ET AL.: 'Evaluation of decellularized esophagus as a scaffold for cultured esophageal epithelial cells.' JOURNAL OF BIOMEDICAL MATERIALS RESEARCH - PART A vol. 79, no. 4, 15 December 2006, ISSN 0021-9304 pages 771 - 778 * |
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