US20020155096A1 - Rapid preparation of stem cell matrices for use in tissue and organ treatment and repair - Google Patents

Rapid preparation of stem cell matrices for use in tissue and organ treatment and repair Download PDF

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US20020155096A1
US20020155096A1 US10/081,835 US8183502A US2002155096A1 US 20020155096 A1 US20020155096 A1 US 20020155096A1 US 8183502 A US8183502 A US 8183502A US 2002155096 A1 US2002155096 A1 US 2002155096A1
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stem cells
matrix material
matrix
tissue
repair
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Michael Chancellor
Johnny Huard
Christopher Capelli
Steve Chung
Michael Sacks
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University of Pittsburgh
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Assigned to UNIVERSITY OF PITTSBURGH reassignment UNIVERSITY OF PITTSBURGH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHANCELLOR, MICHAEL B., CAPELLI, CHRISTOPHER, HUARD, JOHNNY, SACKS, MICHAEL S., CHUNG, STEVE
Publication of US20020155096A1 publication Critical patent/US20020155096A1/en
Priority to US11/138,168 priority patent/US7906110B2/en
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF PITTSBURGH
Priority to US13/046,120 priority patent/US8790680B2/en
Priority to US14/322,092 priority patent/US20150017220A1/en
Priority to US14/972,402 priority patent/US9744267B2/en
Abandoned legal-status Critical Current

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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
    • A61L27/38—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 containing added animal cells
    • A61L27/3804—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 containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
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    • 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
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    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A—HUMAN NECESSITIES
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    • A61L2430/00—Materials or treatment for tissue regeneration
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    • C12N2533/92—Amnion; Decellularised dermis or mucosa

Definitions

  • the present invention generally relates to cellular-based tissue engineering and methods of preparing cell and biologically compatible matrix combinations. More specifically, the invention relates to muscle-derived stem cell-based matrix compositions and products and to a rapid method of producing and utilizing such compositions and products at a tissue or organ site of need.
  • One aspect of the present invention provides methods of preparing stem cell matrices, particularly biomatrices, for use in tissue and organ repair.
  • stem cells are employed rather than other cell types (e.g., differentiated or non-stem cells).
  • the stem cells and the matrix material are admixed or combined shortly before or immediately prior to use, thereby eliminating the need for long-term incubations or culture of cells with matrix material.
  • the methods are rapid and allow the preparation of a stem cell-based biomatrix material as needed.
  • the stem cell-biomatrix material can be in the form of a sling, patch, wrap, such as are employed in surgeries to correct, strengthen, or otherwise repair tissues and organs in need of such treatment.
  • a sling can comprise a material placed beneath deficient sphincter to provide support, e.g., a pubvaginal sling to repair stress urinary incontinence.
  • a patch can comprise a material that is applied over a section of weak, thin, or deficient organ or tissue that is either solid or hollow, e.g., a tissue engineering patch of heart or bladder.
  • a wrap refers to a circumferential patch, e.g., a material placed around a blood vessel or gastroesophageal sphincter.
  • Another aspect of the present invention provides stem cell-matrix compositions for in vivo tissue and/or organ repair, or surgical or wound healing, that can be produced at the “point-of-service”, i.e., at the bedside or surgical suite just before the medical procedure for tissue and/or organ treatment or repair occurs. According to this invention, prolonged delays (as well as increased costs) resulting from commercial preparation of a cell matrix material are alleviated.
  • stem cell-biological, physiologically compatible adhesive i.e., bioadhesive
  • biological matrix i.e., biomatrix
  • these combinations, or compositions thereof can be applied to organs such as the liver, spleen, thymus, spinal cord and bone.
  • the stem cells or progenitor cells can be autologous (obtained from the recipient, including humans) or allogeneic (obtained from a host source other than the recipient, including humans).
  • a further aspect of the present invention provides an implantable, innervatable physiologically acceptable three-dimensional scaffolding for tissue and organ repair comprising a preparation of stem cells and a physiologically acceptable biological substrate, preferably small intestine submucosa (SIS).
  • the stem cells are obtained from muscle.
  • the stem cell-biomatrix material, or stem cell-three-dimensional scaffolding, as described herein, are capable of contractility, particularly when the stem cells employed are obtained from muscle.
  • FIG. 1 presents the results of experiments performed to test areal strain of small intestine submucosa (SIS) containing muscle stem cells (MDSC/SIS) compared with non-stem cell containing SIS (control).
  • SIS small intestine submucosa
  • MDSC/SIS muscle stem cells
  • control non-stem cell containing SIS
  • FIG. 2 presents results of experiments performed to test the contractility of muscle stem cells incorporated into a SIS scaffold. (Example 9). As observed in FIG. 2, none of the SIS strips at any time point up to 8-weeks showed any contractile activity. In the 8-week of MDSC/SIS preparations, spontaneous contractile activity was observed cultures (8 of 8 specimens). Also, in 8-week MDSC/SIS preparations, the frequency and amplitude of spontaneous contractile activity were decreased by the addition of 20 ⁇ M succinylcholine.
  • the present invention involves methods of preparing stem cell or progenitor cell matrices for use in tissue and organ repair, comprising a medically- or physiologically-acceptable matrix material and autologous and/or allogeneic stem cells, preferably, muscle-derived stem cells.
  • the invention involves admixing, such as by inoculating or seeding the stem cells into the medically- or physiologically-acceptable matrix material and using the combined stem cell-matrix composition or product almost immediately for in vivo tissue or organ treatment and repair.
  • the stem cell matrices are made for in vivo use in tissue or organ treatment and repair without the need for prolonged, prior in vitro incubation of the stem cell matrices after the cells have been inoculated or introduced into a given biomatrix.
  • previous cell matrices made for in vivo tissue or organ repair have depended on a prolonged incubation of the cells in the matrix prior to use.
  • stem cell-matrix compositions that can be used almost immediately after preparation at the time of use are now possible. This is important because stem cell-matrix compositions provided for in vivo tissue and/or organ treatment or repair can be produced at the “point-of-service”, i.e., at the bedside or surgical suite just before the medical procedure for tissue and/or organ treatment or repair occurs. Prolonged delays (as well as increased costs) resulting from sending cells to an outside laboratory for incorporation and incubation into a matrix, and then waiting for several weeks to receive the cell-matrix material for medical use (e.g., for in vivo tissue or organ treatment or repair procedures) are obviated and avoided in view of the present invention.
  • a short duration mixture of stem cells on a scaffold with non-uniform or irregular coverage of cells, on and/or within the scaffold results in the proliferation of stem cells in and on the matrix to result in cellular differentiation, the release of factors by the stem cells, and improved outcome.
  • a biologic device e.g., a biological matrix
  • the stem cells were capable of releasing factors that allowed improved therapy, treatment and overall function.
  • the stem cells can be mixed with the matrix material in vitro not long before application to a tissue or organ site in vivo.
  • the stem cells can be mixed with, or inoculated onto, the matrix material just at the time of use.
  • the admixing of stem cells and matrix material, or the inoculation of stem cells onto matrix material needs no more time than the time that it takes to combine the stem cells and the matrix at the point of use.
  • the in vitro incubation of stem cells with matrix material is performed for from about 5 seconds to less than about 12 hours, preferably for from about 5 seconds to about 30 minutes.
  • the in vitro incubation of stem cells with matrix material according to this invention is generally less than about 3 hours, preferably, less than about 1 hour, more preferably, less than about 30 minutes.
  • stem cell-matrix material i.e., stem cell-matrix material composition
  • stem cell-matrix combinations and compositions can be used in wound healing; surgical procedures; the sealing of openings, fissures, incisions, and the like; and the augmentation, filling, or reconstitution of tissues and organs of the body, for example, following surgery, or as the result of diseases, disorders, conditions, accidents, or therapies.
  • compositions of the invention can be used in treatments for diseases such as impaired muscle contractility of the heart, diaphragm, gastrointestinal tract, and genitourinary tract.
  • Use of the present invention is also made for a variety of treatments, repair, augmentation, filling and healing of skin (dermis and epidermis) and soft tissue, muscle, bone, ligaments, and the like, so as to reduce scarring that results from conventional techniques.
  • a variety of biological or synthetic solid matrix materials are suitable for use in this invention.
  • the matrix material is preferably medically acceptable for use in in vivo applications.
  • Nonlimiting examples of such medically acceptable and/or biologically or physiologically acceptable or compatible materials include, but are not limited to, solid matrix materials that are absorbable and/or non-absorbable, such as small intestine submucosa (SIS), e.g., porcine-derived (and other SIS sources); crosslinked or non-crosslinked alginate, hydrocolloid, foams, collagen gel, collagen sponge, polyglycolic acid (PGA) mesh, polyglactin (PGL) mesh, fleeces, foam dressing, bioadhesives (e.g., fibrin glue and fibrin gel) and dead de-epidermized skin equivalents in one or more layers.
  • SIS small intestine submucosa
  • PGA polyglycolic acid
  • PGL polyglactin
  • fibrin glue preparations have been described in WO 93/05067 to Baxter International, Inc., WO 92/13495 to Fibratek, Inc. WO 91/09641 to Cryolife, Inc., and U.S. Pat. Nos. 5,607,694 and 5,631,019 to G. Marx.
  • the stem cell-biomatrix material can be in the form of a sling, patch, wrap, such as are employed in surgeries to correct, strengthen, or otherwise repair tissues and organs in need of such treatment.
  • a sling can comprise a material placed beneath deficient sphincter to provide support, e.g., a pubvaginal sling to repair stress urinary incontinence.
  • a patch can comprise a material that is applied over a section of weak, thin, or deficient organ or tissue that is either solid or hollow, e.g., a tissue engineering patch of heart or bladder.
  • a wrap refers to a circumferential patch, e.g., a material placed around a blood vessel or gastroesophageal sphincter.
  • the stem cells or progenitor cells can be autologous (obtained from the recipient, including humans) or allogeneic (obtained from a donor source other than the recipient, including humans).
  • allogeneic stem cell or progenitor cell sources the closest possible immunological match between donor and recipient is desired. If an autologous source is not available or warranted, donor and recipient Class I and Class II histocompatibility antigens can be analyzed to determine the closest match available. This minimizes or eliminates immune rejection and reduces the need for immunosuppressive or immunomodulatory therapy. If required, immunosuppressive or immunomodulatory therapy can be started before, during, and/or after the matrix is applied or introduced into a patient.
  • cyclosporin A or other immunosuppressive drugs
  • Immunological tolerance may also be induced prior to transplantation by alternative methods known in the art (D. J. Watt et al., 1984, Clin. Exp. Immunol. 55 : 419 ; D. Faustman et al., 1991, Science 252:1701).
  • stem cells or progenitor cells are prepared, isolated or obtained from a variety of sources.
  • the stem cells or progenitor cells may be from bone marrow or from muscle (e.g., skeletal muscle).
  • muscle-derived stem cells MDSC
  • MSC muscle stem cells
  • WO 99/56785 Universality of Pittsburgh
  • the stem cells utilized in the stem cell matrix compositions can be combinations of different types of stem cells, e.g., heterogeneous populations of stem cells obtained from autologous or allogeneic donor sources, or they can be homogeneous stem cell populations (from autologous or allogeneic sources). Combinations of stem cells of different origins (e.g., a combination of bone marrow and muscle stem cells) are also envisioned.
  • the stem cells can be obtained from animal tissues, including human tissue, such as muscle, adipose, liver, heart, lung and the nervous system, as non-limiting examples. In addition, the tissues may be adult, fetal, or embryonic tissues.
  • the stem cell-bioadhesive or biomatrix combinations, or compositions thereof can be directly applied to the external surface of organs such as skin, skeletal muscle and smooth muscle, e.g., the diaphragm, bladder, intestine and heart.
  • these combinations, or compositions thereof can be applied to organs such as the liver, spleen, thymus, spinal cord and bone.
  • the stem cells can be genetically modified to contain an expression vector, e.g., plasmid or viral, containing one or more heterologous genes which are expressed and whose expression products are produced at the site at which the stem cell-matrix is applied or introduced in vivo.
  • the cells may be genetically engineered to contain one or more nucleic acid sequence(s) encoding one or more active biomolecules, and to express these biomolecules, including proteins, polypeptides, peptides, hormones, metabolites, drugs, enzymes, and the like.
  • the stem cell-matrix composition or product can serve as a long-term local delivery system for a variety of treatments, for example, for the treatment of various diseases and pathologies, such as cancer, tissue regeneration and reconstitution, and to deliver a gene product, such as a therapeutic agent, e.g., hormone or factor, to a tissue or organ site.
  • a therapeutic agent e.g., hormone or factor
  • the stem cells may be genetically engineered by a variety of molecular techniques and methods known to those having skill in the art, for example, transfection, infection, transduction, or direct DNA injection.
  • Transduction as used herein commonly refers to cells that have been genetically engineered to contain a foreign or heterologous gene via the introduction of a viral or non-viral vector into the cells. Viral vectors are preferred.
  • Transfection more commonly refers to cells that have been genetically engineered to contain a foreign gene harbored in a plasmid, or non-viral vector.
  • the stem cells can be transfected or transduced by different vectors and thus can serve as gene delivery vehicles to allow the gene products to be expressed and produced at the tissue or organ site.
  • viral vectors are preferred, those having skill in the art will appreciate that the genetic engineering of cells to contain nucleic acid sequences encoding desired proteins or polypeptides, cytokines, and the like, may be carried out by methods known in the art, for example, as described in U.S. Pat. No. 5,538,722, including fusion, transfection, lipofection mediated by precipitation with DEAE-Dextran (Gopal, 1985) or calcium phosphate (Graham and Van Der Eb, 1973, Virology, 52:456-467; Chen and Okayama, 1987, Mol. Cell. Biol. 7:2745-2752; Rippe et al., 1990, Mol. Cell.
  • Non-cytopathic viral vectors are typically derived from non-cytopathic eukaryotic viruses in which non-essential genes have been replaced with the nucleic acid sequence(s) of interest.
  • Non-cytopathic viruses include retroviruses, which replicate by reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. In general, the retroviruses are replication-deficient, i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle.
  • Retroviruses from which the retroviral plasmid vectors may be derived include, but are not limited to, Moloney murine leukemia virus, spleen necrosis virus, retroviruses such as Rous sarcoma virus, Harvey sarcoma virus, avian leukosis virus, gibbon ape leukemia virus, human immunodeficiency virus, adenovirus, myeloproliferative sarcoma virus, and mammary tumor virus.
  • the retroviruses used to create a viral vector are preferably debilitated or mutated in some respect to prevent disease transmission.
  • Standard protocols for producing replication-deficient retroviruses including the steps of 1) incorporating exogenous genetic material into a plasmid, 2) transfecting a packaging cell line with plasmid, production of recombinant retroviruses by the packaging cell line, 3) collecting viral particles from tissue culture media, and 4) infecting the target cells with viral particles, are provided in M. Kriegler, 1990, “ Gene Transfer and Expression, A Laboratory Manual ,” W. H. Freeman Co., N.Y.; and E. J. Murry, Ed., 1991, “ Methods in Molecular Biology ,” vol. 7, Humana Press, Inc., Clifton, N.J.
  • Expression vectors containing all the necessary elements for expression are commercially available and known to those skilled in the art. See, e.g., Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual , Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; F. M. Ausubel et al. (eds), 1995, Current Protocols in Molecular Biology , John Wiley & Sons, Inc., New York, N.Y.; D. N. Glover (ed), 1985, DNA Cloning: A Practical Approach, Volumes I and II ; M. L.
  • Illustrative examples of vehicles or vector constructs for transfection or infection of the stem cells of the present invention include replication-defective viral vectors, DNA virus or RNA virus (retrovirus) vectors, such as adenovirus, herpes simplex virus and adeno-associated viral vectors. Preferred are adenovirus vectors.
  • Such vectors will include one or more promoters for expressing the bioactive molecule.
  • Suitable promoters which may be employed include, but are not limited to, adenoviral promoters, such as the adenoviral major late promoter; or heterologous promoters, such as the cytomegalovirus (CMV) promoter; the respiratory syncytial virus (RSV) promoter; inducible promoters, such as the MMT promoter, the metallothionein promoter; heat shock promoters; the albumin promoter; the ApoAl promoter; human globin promoters; viral thymidine kinase promoters, such as the Herpes Simplex thymidine kinase promoter; retroviral LTRs (including the modified retroviral LTRs herein above described); the ⁇ -actin promoter; and human growth hormone promoters.
  • the promoter also may be the native promoter that controls the nucleic acid sequence encoding the polypeptide
  • the vectors are typically substantially free of any prokaryotic DNA and may comprise a number of different functional nucleic acid sequences.
  • functional sequences include nucleic acid, e.g., DNA or RNA, sequences comprising transcriptional and translational initiation and termination regulatory sequences, including promoters (e.g., strong promoters, inducible promoters, and the like) and enhancers which are active in esophagus or small intestine cells.
  • promoters e.g., strong promoters, inducible promoters, and the like
  • enhancers which are active in esophagus or small intestine cells.
  • an open reading frame nucleic acid sequence
  • Flanking sequences may also be included for site-directed integration. In some situations, the 5′-flanking sequence will allow for homologous recombination, thus changing the nature of the transcriptional initiation region, so as to provide for inducible or noninducible transcription to increase or decrease the level of transcription, as an example
  • the nucleic acid sequence desired to be expressed by the stem cell in the biological matrix is that of a structural gene, or a functional fragment, segment or portion of the gene, which is heterologous to the cell serving as delivery vehicle and which encodes a desired protein or polypeptide product.
  • the encoded and expressed product may be intracellular, i.e., retained in the cytoplasm, nucleus, or an organelle of a cell, or may be secreted by the cell.
  • the natural signal sequence present in the structural gene may be retained, or a signal sequence that is not naturally present in the structural gene may be used.
  • a signal sequence may be provided so that, upon secretion and processing at the processing site, the desired protein will have the natural sequence.
  • genes of interest for use in accordance with the present invention include genes encoding cell growth factors, suppressor molecules, cell differentiation factors, cell signaling factors and programmed cell death factors.
  • a marker is present for the selection of cells containing the vector construct.
  • the marker may be an inducible or non-inducible gene and will generally allow for positive selection under induction, or without induction, respectively. Examples of commonly used marker genes include neomycin, dihydrofolate reductase, glutamine synthetase, and the like.
  • the vector employed also generally includes an origin of replication and other genes that are necessary for replication in the host cells, as routinely employed by those having skill in the art. As an example, the replication system comprising the origin of replication and any proteins associated with replication encoded by a particular virus may be included as part of the construct.
  • the replication system is preferably selected so that the gene(s) encode products that are necessary for replication, but do not ultimately transform the stem cells.
  • Such replication systems are represented by replication-defective adenovirus constructed as described, for example, by G. Acsadi et al., 1994, Hum. Mol. Genet. 3:579-584, and by Epstein-Barr virus.
  • replication defective vectors particularly, retroviral vectors that are replication defective, are described by Price et al., 1987, Proc. Natl. Acad. Sci. USA, 84:156; and Sanes et al., 1986, EMBO J., 5:3133.
  • the final gene construct may contain one or more genes of interest, for example, a gene encoding a bioactive metabolic molecule or a gene encoding a suppressor molecule, such as p53.
  • cDNA, synthetically produced DNA or chromosomal DNA may be employed utilizing methods and protocols known and practiced by those having skill in the art.
  • a vector may be transduced into the cells through any means known in the art. Non-limiting methods include electroporation, liposomes, and calcium phosphate precipitation.
  • the retroviral or plasmid vector can be encapsulated into a liposome, or coupled to a lipid, and then introduced into a cell.
  • the cells are preferably engineered to contain a plasmid or viral vector in an ex vivo approach.
  • the stem cells can be admixed with, or introduced into, the biologically compatible matrix by a number of methods known to those having skill in the art. For example, inoculation can be used if the matrix comprises a solid or semi-solid material that does not readily mix with cells in suspension. As another example, a suspension of the stem cells can mixed with a suitable biological or synthetic adhesive (bioadhesive) matrix and the combination can be spread, sprayed, painted, or otherwise applied onto a tissue or organ site where the stem cell matrix forms, e.g., by gelling or solidifying in situ.
  • a suitable biological or synthetic adhesive bioadhesive
  • the stem cell-biomatrix combination may be applied by spreading, painting or coating using a spreading or coating means, such as a small brush, spatula, knife, or other device suitable for medically coating a surface, such as a tissue or organ surface.
  • a spreading or coating means such as a small brush, spatula, knife, or other device suitable for medically coating a surface, such as a tissue or organ surface.
  • compressed air may be used to spray or foam a stem cell-biomatrix mixture or suspension onto a wound or biological surface.
  • the stem cells are attached to, introduced into, or applied to a biomatrix using another type of biomatrix material, for example, a biological adhesive (bioadhesive), such as, but not limited to, fibrin glues or gels.
  • bioadhesives and fibrin glues can be photoactivated, or activated by temperature or calcium and are also suitable for use.
  • from about 2.5 ⁇ 10 3 to about 1 ⁇ 10 6 preferably about 5 ⁇ 10 3 to about 1 ⁇ 10 6 stem cells can be used for admixing with, inoculating, seeding, or otherwise introducing onto or into, the medically or physiologically acceptable matrix material.
  • about 1 ⁇ 10 5 stem cells are deposited per 1 cm 2 of matrix material.
  • a unique processing of stem cells with a biological adhesive and unique application for stem cell tissue engineering are provided.
  • a significant limitation of present tissue engineering approaches, especially heart and blood vessel tissue engineering, is the need for either systemic vascular injection of cells or direct needle inoculation of specific sites in the heart.
  • Each of the aforementioned procedures has significant disadvantages.
  • a method is provided which allows the attachment of stem cells to the external surface of the target organ, as exemplified and described in the examples herein.
  • the invention overcomes the limitations that currently exist for heart and blood vessel tissue engineering procedures.
  • the stem cell and biologic matrix composition can be applied through a minimally invasive fiberoptic scope (e.g., laparoscope) to multiple sites including, but not limited to, bone, cartilage, ligaments. spinal cord, brain, heart, lung, kidney, digestive and genitourinary organs.
  • a minimally invasive fiberoptic scope e.g., laparoscope
  • MSC muscle stem cells
  • bioadhesive, or biomatrix material are applied, for example, through a laparoscope to spray or coat kidney or ureter surgical anastomoses to enhance healing and prevent stricture.
  • a combination of MSC and bioadhesive, or biomatrix material are applied via orthopedic endoscopy to coat the outside of damaged or weakened bone or disc to promote and/or improve healing and strength, and/or to prevent degeneration.
  • specifically engineered stem cells which can deliver the expression products of genes encoding bone factors or growth factors at the site during the treatment, repair, or healing process.
  • a method of the present invention involves admixing a stem cell preparation with a physiologically acceptable matrix material to form a stem cell matrix and incubating the stem-cell matrix in vitro for about 5 seconds to less than about 12 hours prior to use in the tissues or organs of a recipient.
  • any suitable physiologically acceptable matrix material can be used, e.g., alginate, fibrin glue, fibrin gel, small intestine submucosa (SIS).
  • a method of the present invention involves admixing a stem cell preparation with a first physiologically acceptable matrix material to form a first stem cell-matrix combination; introducing the first stem cell-matrix combination onto a second physiologically acceptable matrix material to form a second stem cell-matrix material, wherein the first stem cell-matrix combination and the second physiologically acceptable matrix material are incubated in vitro for between about 5 seconds to less than 12 hours; and applying the second stem cell-matrix material on or in a tissue or organ site in a recipient.
  • the first medically acceptable matrix material is preferably a bioadhesive such as fibrin glue or gel.
  • the stem cell-fibrin glue biomatrix is then applied to a second medically acceptable biomatrix material, e.g., SIS and the like.
  • a second medically acceptable biomatrix material e.g., SIS and the like.
  • a preparation or suspension of stem cells can be simultaneously applied with the bioadhesive material to the second medically acceptable biomatrix material, such as via a syringe, and then spread, or allowed to coat this material, which is then used to treat a tissue or organ site.
  • the stem cells and the bioadhesive material can be mixed together and then the stem cell-bioadhesive mixture can be applied to the second matrix material.
  • the present invention also provides methods which are not likely to be hampered by the usual regulatory barriers. There is a need for a cost effective combination therapy comprising medical devices and cellular therapy. Keeping the medical devices and stem cells separate until combined at the point of service (e.g., bedside or site of use) provides the solution to the need.
  • a significant advantage of the present invention is moving biological stem cell tissue engineering out of the site of commercial manufacture, e.g., the factory, to the point of service, where the stem cell-matrix product is prepared and used “on location”.
  • the stem cell-biological matrix product according to the present invention is rapidly prepared just before, or at the time of, use. There is no requirement for the cells and the matrix material to be incubated or cultured for long durations, e.g., days or weeks, prior to application or introduction at the tissue or organ site by the practitioner.
  • the stem cell-matrix material after combination, allows new structures to form, which was unexpected.
  • the stem cells in the biomatrix combination can change the biomechanical properties of the biological scaffold and create new 2-dimensional and 3-dimensional tissue, muscle and organ structures. For example, muscle stem cells were shown to seed porcine small intestine submucosa (SIS) at the point of service so as to improve the SIS tissue properties (Example 2), for vascular intervention.
  • SIS porcine small intestine submucosa
  • Example 2 SIS tissue properties
  • the stem cells seeding the biological or synthetic matrix afford advantages to the use of the present invention for numerous surgical and treatment procedures.
  • muscle stem cells can be added onto a scaffold, which has been demonstrated to behave in a manner similar to that of muscle, providing innervation with neuromuscular receptors.
  • the present invention allows 3-dimensional muscle repair to a variety of tissues and organs, e.g., sphincters, including the urethra, gastroesophageal sphincter, anal sphincter, as well as wrap and patch including the bladder, intestine and stomach, blood vessels and heart, diaphragm, tendons, muscle and ligaments, thereby extending the advantages of the invention to include not only the tissue engineering of an MSC/SIS patch, for tissue repair, for example, but also the engineering of 3-dimensional repair scaffolding utilizing muscle stem cells
  • Muscle stem cells were harvested from rat hindleg muscle using the pre-plate technique (see WO 99/56785). After obtaining a late plate (i.e., post PP5, preferably, PP6) cell population, 100,000 cells, transduced with a retrovirus vector containing LacZ, were then suspended in 200 microliters of Hank's Buffered Salt Solution (HBSS; Gibco BRL, Grand Island, N.Y.) for use. A 1 cm 2 piece of Alginate (Johnson & Johnson Medical, Arlington, Tex.) was cut, dipped into the MSC suspension to prepare the Alginate+MSC composition and immediately placed on a 1 cm 2 full-thickness wound defect on the upper dorsum of rat.
  • HBSS Hank's Buffered Salt Solution
  • Single layer SIS (Cook Biologic, Inc., Indianapolis, Ind.) was initially incubated in Hank's Buffered Salt Solution for one hour at 37° C. 100,000 late preplate (e.g., PP6), (See, WO 99/56785; and U.S. Serial Nos. 09/302,896, filed Apr. 30, 1999, and 09/549,937, filed Apr. 14, 2000, to M. Chancellor et al.) rat MSC cells (transduced with a retroviral vector containing Lac Z) were placed onto 1 cm diameter circular SIS to form an MSC-SIS matrix composition. The MSC-SIS matrix was placed into a 24-well culture plate.
  • Hank's Buffered Salt Solution for one hour at 37° C. 100,000 late preplate (e.g., PP6), (See, WO 99/56785; and U.S. Serial Nos. 09/302,896, filed Apr. 30, 1999, and 09/549,937, filed Apr. 14, 2000, to M. Chancellor et
  • SIS and MSC were then incubated for 3 days, 1 week, and 2 weeks, respectively, to assess cell viability at 37° C., with daily media changes with Dulbecco's Modified Eagle Media (DMEM, Gibco BRL, Grand Island, N.Y.) supplemented to contain 10% horse serum and 10% fetal bovine serum.
  • DMEM Dulbecco's Modified Eagle Media
  • the SIS+MSC matrix combination was harvested and sectioned for staining.
  • cell viability was evident.
  • the MSC continued to proliferate and form myotubes (evident with Myosin Heavy Chain Staining) at all time intervals.
  • Rat MSC from a late preplate were obtained using the preplate technique (see, WO 99/56785; and U.S. Serial Nos. 09/302,896, filed Apr. 30, 1999, and 09/549,937, filed Apr. 14, 2000, to M. Chancellor et al.).
  • Fibrin glue was obtained from Baxter Healthcare Corporation (Glendale, Calif.).
  • Fibrin glue is an FDA approved sealant that is composed of human thrombin, calcium chloride, bovine fibrinolysis inhibitor solution, and human sealer protein concentrate. The elements are combined prior to use and injected using a needle syringe.
  • Rat MSC were obtained using the pre-plate technique (see, WO 99/56785; and U.S. Serial Nos. 09/302,896, filed Apr. 30, 1999, and 09/549,937, filed Apr. 14, 2000, to M. Chancellor et al.)
  • Single layered SIS was seeded with MSC. After a one day incubation in vitro, the MSC/SIS matrix composition was folded into vessel-like lumen. Cell viability was intact after prolonged incubation time (i.e., two weeks) with seeding throughout the vessel lumen.
  • SISTM sheets soft-tissue freeze-dried graft, Cook Biotech Incorporated, West Lafayette, Ind.
  • the SIS material was kept sealed until testing. Prior to testing, the sheets were cut into the appropriate size to fit into specifically designed sterilized cell culture wells. MSC (1 ⁇ 10 5-6 ) were placed onto the SIS and were fed with culture medium (SMEM). The culture medium was refreshed every 24 hours. The cell culture inserts were incubated at 37° C. for 10 or 20 days. After this time, the specimens were cut into 25 mm square patches and placed into the biaxial mechanical testing setup. (see, e.g., K. L. Billiar and M. S.
  • each side of the test specimen was attached to the motor carriages of the biaxial mechanical testing device with sutures looped around two small pulleys on each side of a horizontal common axle, which was connected, in turn, to a vertical pivoting rod, thus allowing near-frictionless rotation in three dimensions.
  • a surgical staple was connected to both ends of each suture line for attachment to the specimen, resulting in a total of four staples per specimen side.
  • Each pulley ensured that the force on each line end was equal; the pivoting rod ensured that the forces were the same on each pair.
  • Small floats were attached to each staple to make the mounted sample neutrally buoyant.
  • Tissue deformations were measured by monitoring the real-time movements of four graphite markers forming a 5-mm square region using real-time video marker tracking. From the marker displacements the 2D in-plane Green's finite strain tensor was computed, where EL and ET denote the Green's strain along the longitudinal and transverse directions, respectively. Both the load and deformation in both axes were continuously recorded at 12-15 Hz during testing. All preparations were tested in Hank's buffered saline solution (HBSS) at room temperature. Each test involved 10 contiguous cycles with a period of 20-30 seconds, with a total of seven runs. Testing began with equi-biaxial preconditioning to the maximum stress level.
  • HBSS Hank's buffered saline solution
  • the positions of the optical markers at three different stages were recorded during mechanical testing.
  • the first measurement was obtained in the unloaded conditions, with the specimen free-floating in the bath.
  • the second set of marker positions was taken after the sample had attached to the device and a 0.5 gm load was applied to both axes.
  • the preconditioned reference state produced the most stable stress-strain response, and was considered as the most physiological-like state.
  • the marker positions recorded after the first preconditioning run were used for all subsequent strain computations.
  • the areal strain was used to assess the compliance of the specimen.
  • Areal strain which is a measure of tissue compliance under biaxial loading, represents the change in tissue area when the tissue is equally loaded along two directions. Areal strain was measured using the following formula:
  • the frequency and amplitude of isometric contractions were measured with strain gauge transducers coupled with a TBM4 strain gauge amplifier and recorded on a computer using a data acquisition program (Windaq, DATAQ Instruments Inc. Akron, Ohio). After 60 minutes of equilibration, electrical field stimuli (10 Hz, 150 volt, 0.5 ms, 60 sec) were applied in the bath. Pharmacological evaluations were performed with succinylcholine (S-Chol), (4, 10 and 20 ⁇ M); carbachol (10 and 20 ⁇ M); KCl, (7%, 1M); Ca ++ -free Krebs solution with EGTA (200 ⁇ M); or distilled water, were each added to the bath sequentially at 30 minute intervals. The frequency, amplitude, and pattern of contraction of the specimens were compared among the different groups.
  • halothane anesthetized rats underwent bilateral sciatic nerve transection and periurethral sling placement using a SIS/MDSC patch.
  • the sling comprised an SIS strip with dimensions of 14 mm in length and 3 mm in width. This sling was placed posterior to the urethra via a transabdominal approach, and was sutured bilaterally into the pubic bone using 4.0 prolene, 6 mm lateral to the pubic symphysis.
  • An intraurethral catheter (PE20) was inserted prior to tying the sling sutures in place to ensure that the sling would not produce obstruction. Care was taken not alter the natural bladder/urethral angle.

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