US20030007954A1 - Methods for using a three-dimensional stromal tissue to promote angiogenesis - Google Patents

Methods for using a three-dimensional stromal tissue to promote angiogenesis Download PDF

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US20030007954A1
US20030007954A1 US09/411,585 US41158599A US2003007954A1 US 20030007954 A1 US20030007954 A1 US 20030007954A1 US 41158599 A US41158599 A US 41158599A US 2003007954 A1 US2003007954 A1 US 2003007954A1
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cells
tissue
stromal
stromal tissue
dimensional
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Gail K. Naughton
Jonathan Noel Mansbridge
Robert Emmett Pinney
Joan Zeltinger
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THEREGEN Inc A DELAWARE Corp
Advanced Tissue Sciences Inc
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Advanced Tissue Sciences Inc
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Priority to US09/411,585 priority Critical patent/US20030007954A1/en
Assigned to ADVANCED TISSUE SCIENCES, INC. reassignment ADVANCED TISSUE SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PINNEY, ROBERT E., NAUGHTON, GAIL K., MANSBRIDGE, JONATHAN N., ZELTINGER, JOAN
Priority to DE60033381T priority patent/DE60033381T2/de
Priority to PCT/US2000/009848 priority patent/WO2000061204A1/en
Priority to EP00925950A priority patent/EP1169069B1/de
Priority to AT00925950T priority patent/ATE353676T1/de
Priority to EP07003001A priority patent/EP1782849A3/de
Priority to AU44564/00A priority patent/AU777853C/en
Priority to ES00925950T priority patent/ES2282105T3/es
Priority to CA002367507A priority patent/CA2367507C/en
Priority to IL14589200A priority patent/IL145892A0/xx
Priority to JP2000610535A priority patent/JP4709393B2/ja
Priority to IL145892A priority patent/IL145892A/en
Publication of US20030007954A1 publication Critical patent/US20030007954A1/en
Priority to US10/851,938 priority patent/US20040219134A1/en
Assigned to IKEN TISSUE THERAPEUTICS reassignment IKEN TISSUE THERAPEUTICS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ATS LIQUIDATING TRUST
Assigned to IKEN TISSUE THERAPEUTICS reassignment IKEN TISSUE THERAPEUTICS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FREEMAN, JOHN T.
Priority to US12/420,716 priority patent/US8128924B2/en
Priority to US12/981,260 priority patent/US20110213470A1/en
Assigned to THEREGEN, INC. reassignment THEREGEN, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: IKEN TISSUE THERAPEUTICS
Assigned to THEREGEN, INC., A DELAWARE CORPORATION reassignment THEREGEN, INC., A DELAWARE CORPORATION MERGER (SEE DOCUMENT FOR DETAILS). Assignors: THEREGEN, INC., A CALIFORNIA CORPORATION
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    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—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
    • A61L27/3886—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 comprising two or more cell types
    • 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
    • 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
    • A61L27/38—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
    • 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
    • A61L27/38—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
    • A61L27/3826—Muscle cells, e.g. smooth muscle cells
    • 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
    • A61L27/38—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
    • A61L27/3839—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 the site of application in the body
    • 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
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves

Definitions

  • the present invention relates to a method for promoting method relates to implantation or attachment of a three-dimensional stromal tissue to promote endothelialization and vascularization in the heart and related tissues.
  • Coronary heart disease is the single leading cause of death in America today (American Heart Association's “1999 Heart and Stroke Statistical Update”). This disease, as with various other cardiovascular disorders, is characterized by the narrowing of arteries and inadequate blood flow to critical tissues.
  • vascular endothelial growth factor vascular endothelial growth factor
  • the present invention relates to a method for promoting blood vessel formation in tissues and organs.
  • the method relates to implantation or attachment of a three-dimensional stromal tissue to promote endothelialization and angiogenesis in the heart and related tissues.
  • the invention has a variety of applications including, but not limited to, promoting repair of and regeneration of damaged cardiac muscle, promoting vascularization and healing during cardiac surgery (e.g. by-pass surgery or heart valve replacement), promoting blood vessel formation at anastomosis sites, and promoting vascularization and healing of ischemic or otherwise damaged tissues such as skeletal muscle, smooth muscle, brain tissue or connective tissue.
  • the invention is based in part on the discovery that three-dimensional stromal tissue constructs, when implanted in the wound bed of patients with diabetic foot ulcers, are capable of inducing rapid endothelialization and vascularization, resulting in new capillary formation and reduced inflammation in the wounded tissue.
  • the three-dimensional stromal tissue implants secrete a variety of growth factors critical to tissue regeneration and angiogenesis, most notably vascular endothelial growth factor, or VEGF (Table II).
  • VEGF vascular endothelial growth factor
  • the invention encompasses the application of the three-dimensional stromal tissue to damaged tissues, such as damaged cardiac muscle, to induce a new local blood supply to the area and support rapid tissue remodeling.
  • a three-dimensional stromal tissue implant may also be used to promote formation of a “natural” carotid by-pass to assist in, or obviate the need for, carotid endarterectomy surgery (which can often result in stroke due to downstream flow of particles dislodged during the procedure).
  • FIGS. 1 A- 1 D Photomicrographs showing engineered stromal tissue-stimulated angiogenesis in a chick chorioallantoic membrane(CAM).
  • FIGS. 1A and 1B show macroscopic view, while FIGS. 1C and 1D show histology.
  • FIG. 1A shows scaffold alone, FIG. 1C shows non-viable , and
  • FIGS. 1B and 1D show Three-dimensional stromal tissue treated membrane.
  • FIG. 2 Bar graph depicting the effect of engineered stromal tissue on capillary blood vessel formation in a chick chorioallantoic membrane. Bars represent 95% confidence intervals.
  • FIG. 3 Bar graph depicting blood vessel formation stimulated by engineered stromal tissue in a rat aortic ring assay.
  • FIG. 4 Bar graph depicting proliferation of human umbilical vein endothelial cell (HUVEC) in vitro following stimulation by engineered stromal tissue conditioned medium.
  • HAVEC human umbilical vein endothelial cell
  • FIG. 5 Bar graph depicting stimulation of endothelial cell motility by engineered stromal tissue.
  • FIG. 6 Graphs depicting stimulation of endothelial cell chemotaxis by engineered stromal tissue (left side shows standard curve using purified VEGF at indicated concentrations).
  • FIG. 7 Flow cytometry result depicting induction of integrin ⁇ v ⁇ 3 expression on endothelial cells by engineered stromal tissue.
  • FIGS. 8A and 8B Photomicrographs depicting inhibition of endothelial cell apoptosis cultured on “MATRIGEL” in the presence of engineered stromal tissue. The cells were stained with low density lipoprotein and sytox, which stained nuclei of apoptotic cells.
  • FIGS. 9A and 9C show the wound bed before treatment, while FIGS. 9B and 9D show the wound bed after treatment.
  • the present invention relates to a method for promoting blood vessel formation in tissues and organs of a subject, particularly a human subject.
  • the method relates to implantation or attachment of an engineered three-dimensional stromal tissue to promote endothelialization and angiogenesis in the heart and related tissues.
  • the invention has a variety of applications including, but not limited to, promoting repair of and regeneration of damaged cardiac muscle, promoting vascularization and healing during cardiac surgery (e.g. by-pass surgery or heart valve replacement), promoting blood vessel formation at anastomosis sites, and promoting vascularization and repair of damaged skeletal muscle, connective tissue, or other tissues.
  • the invention is based, in part, on the discovery that three-dimensional stromal tissues, when implanted in the wound bed of patients with diabetic foot ulcers, are capable of inducing endothelialization and vascularization, resulting in new capillary formation and reduced inflammation in the wounded tissue.
  • the three-dimensional stromal tissue comprises stromal cells grown on a three-dimensional substrate or framework composed of a biocompatible, non-living material formed into a three-dimensional structure having interstitial spaces bridged by the stromal cells.
  • the stromal cells preferably comprise fibroblasts with or without additional cells and/or elements described more fully herein below.
  • the additional cells may comprise smooth muscle cells, cardiac muscle cells, endothelial cells or skeletal muscle cells.
  • the fibroblasts and/or other cells may be fetal or adult in origin, and may be derived from convenient sources such as skin, cardiac muscle, smooth muscle, skeletal muscle, liver, pancreas, brain etc.
  • Such tissues and or organs can be obtained by appropriate biopsy or upon autopsy.
  • cadaver organs may be used to provide a generous supply of stromal cells and elements.
  • vascular smooth muscle cells preferably aortic smooth muscle cells
  • aortic smooth muscle cells are known to produce substantially more VEGF than human dermal fibroblasts. Therefore, by utilizing aortic smooth muscle cells instead of or in addition to fibroblasts, one can culture three-dimensional stromal tissues with enhanced angiogenic activity.
  • a three-dimensional stromal tissue implant that is genetically engineered to have improved properties for inducing angiogenesis may be used to promote formation of new blood vessels in the heart or other tissues.
  • the invention encompasses a method of treatment of eschemic damage to heart, brain, visceral organs or peripheral tissues.
  • one embodiment of the invention entails attaching a three-dimensional stromal tissue to an ischemic region of a heart following myocardial infarction to promote vascularization of the heart and regeneration of damaged cardiac muscle cells.
  • the three dimensional stromal tissue implant may include fibroblasts, neural glial cells, neural stem cells, astrocytes, fibroblasts transfected with nerve growth factor, or a combination thereof.
  • Such a stromal tissue implant is placed directly on the cerebral cortex or surgically implanted in the region of ischemia.
  • the invention encompasses application of the three-dimensional stromal tissue to any tissue or organ to promote angiogenesis with the proviso that the organ or tissue is not a diabetic foot ulcer or a veinous ulcer.
  • stromal cells are inoculated upon a three-dimensional framework, and grown to develop a stromal tissue.
  • the three-dimensional support framework may be of any material and/or shape that: (a) allows cells to attach to it (or can be modified to allow cells to attach to it); and (b) allows cells to grow in more than one layer.
  • a substantially two-dimensional sheet or membrane may be used to culture monolayers of cells.
  • a number of different materials may be used to form the framework, including but not limited to: nylon (polyamides), dacron (polyesters), polystyrene, polypropylene, polyacrylates, polyvinyl compounds (eg., polyvinylchloride; PVC), polycarbonate, polytetrafluorethylene (PTFE; TEFLON), thermanox (TPX), nitrocellulose, cotton, polyglycolic acid (PGA), cat gut sutures, cellulose, gelatin, dextran, etc. Any of these materials may be woven into a mesh to form the three-dimensional framework. Certain materials, such as nylon, polystyrene, etc., are poor substrates for cellular attachment.
  • nylon screens could be treated with 0.1 M acetic acid, and incubated in polylysine, fetal bovine serum, and/or collagen to coat the nylon.
  • Polystyrene could be similarly treated using sulfuric acid.
  • biodegradable materials such as PGA, catgut suture material, collagen, polylactic acid, or hyaluronic acid.
  • these materials may be woven into a three-dimensional framework such as a collagen sponge or collagen gel.
  • non-degradable materials such as nylon, dacron, polystyrene, polyacrylates, polyvinyls, teflons, cotton, etc. may be preferred.
  • a convenient nylon mesh which could be used in accordance with the invention is Nitex, a nylon filtration mesh having an average pore size of 140 ⁇ m and an average nylon fiber diameter of 90 ⁇ m (#3-210/36, Tetko, Inc., N.Y.).
  • Stromal cells comprising fibroblasts, with or without other cells and elements described below, are inoculated onto the framework.
  • These stromal cells may be derived from tissues or organs, such as skin, heart, blood vessels, skeletal muscle, liver, pancreas, brain etc., which can be obtained by biopsy (where appropriate) or upon autopsy.
  • fibroblasts and other stromal cells can be obtained in quantity rather conveniently from any appropriate cadaver organ.
  • fetal fibroblasts can be used to form a “generic” three-dimensional stromal tissue that will support the growth of a variety of different cells and/or tissues that come in contact with it.
  • a “specific” stromal tissue may be prepared by inoculating the three-dimensional framework with stromal cells derived from the heart and/or from a particular individual who is later to receive the cells and/or tissues grown in culture in accordance with the three-dimensional culture of the invention.
  • Stromal cells may be readily isolated by disaggregating an appropriate organ or tissue. This may be readily accomplished using techniques known to those skilled in the art.
  • the tissue or organ can be disaggregated mechanically and/or treated with digestive enzymes and/or chelating agents that weaken the connections between neighboring cells making it possible to disperse the tissue into a suspension of individual cells without appreciable cell breakage.
  • Enzymatic dissociation can be accomplished by mincing the tissue and treating the minced tissue with any of a number of digestive enzymes either alone or in combination.
  • the suspension can be fractionated into subpopulations from which the fibroblasts and/or other stromal cells and/or elements can be obtained. This also may be accomplished using standard techniques for cell separation including, but not limited to, cloning and selection of specific cell types, selective destruction of unwanted cells (negative selection), separation based upon differential cell agglutinability in the mixed population, freeze-thaw procedures, differential adherence properties of the cells in the mixed population, filtration, conventional and zonal centrifugation, centrifugal elutriation (counter-streaming centrifugation), unit gravity separation, countercurrent distribution, electrophoresis and fluorescence-activated cell sorting.
  • standard techniques for cell separation including, but not limited to, cloning and selection of specific cell types, selective destruction of unwanted cells (negative selection), separation based upon differential cell agglutinability in the mixed population, freeze-thaw procedures, differential adherence properties of the cells in the mixed population, filtration, conventional and zonal centrifugation, centrifugal elu
  • stromal cells may, for example, be carried out as follows: fresh tissue samples are thoroughly washed and minced in Hanks balanced salt solution (HBSS) in order to remove serum. The minced tissue is incubated from 1-12 hours in a freshly prepared solution of a dissociating enzyme such as trypsin. After such incubation, the dissociated cells are suspended, pelleted by centrifugation and plated onto culture dishes. All stromal cells will attach before other cells, therefore, appropriate stromal cells can be selectively isolated and grown. The isolated stromal cells can then be grown to confluency, lifted from the confluent culture and inoculated onto the three-dimensional framework (U.S. Pat. No.
  • HBSS Hanks balanced salt solution
  • fibroblasts In addition to fibroblasts, other cells may be added to form the three-dimensional stromal tissue required to support long term growth in culture.
  • other cells found in loose connective tissue may be inoculated onto the three-dimensional framework along with, or instead of, fibroblasts.
  • Such cells include but are not limited to endothelial cells, pericytes, macrophages, monocytes, adipocytes, skeletal muscle cells, smooth muscle cells, cardiac muscle cells, etc.
  • Such cells may be inoculated onto the three-dimensional framework in the absence of fibroblasts.
  • These stromal cells may readily be derived from appropriate tissues or organs such as skin, heart, blood vessels, etc., using methods known in the art such as those discussed above.
  • fibroblasts are inoculated onto the framework.
  • vascular smooth muscle cells preferably aortic smooth muscle cells
  • aortic smooth muscle cells are known to produce substantially more VEGF than human dermal fibroblasts. Therefore, by utilizing aortic smooth muscle cells instead of or in addition to fibroblasts, one can culture three-dimensional stromal tissues with enhanced angiogenic activity.
  • the cultured cells are to be used for transplantation or implantation in vivo, it is preferable to obtain the stromal cells from the patient's own tissues.
  • the growth of cells in the presence of the three-dimensional stromal support framework may be further enhanced by adding to the framework, or coating it with proteins (e.g., collagens, elastin fibers, reticular fibers) glycoproteins, glycosaminoglycans (e.q., heparan sulfate, chondroitin-4-sulfate, chondroitin-6-sulfate, dermatan sulfate, keratan sulfate, etc.), a cellular matrix, and/or other materials.
  • proteins e.g., collagens, elastin fibers, reticular fibers
  • glycoproteins e.g., glycoproteins, glycosaminoglycans (e.q., heparan sulfate, chondroitin-4-sulfate,
  • the three-dimensional framework should be incubated in an appropriate nutrient medium.
  • Many commercially available media such as RPMI 1640, Fisher's, Iscove's, McCoy's, and the like may be suitable for use. It is important that the three-dimensional stromal tissue be suspended in the medium during the incubation period in order to maximize proliferative activity.
  • the culture should be “fed” periodically to remove the spent media, depopulate released cells, and add fresh media.
  • the stromal cells will grow linearly along and envelop the filaments of the three-dimensional framework before beginning to grow into the openings of the framework.
  • the openings of the framework should be of an appropriate size to allow the stromal cells to stretch across the openings. Maintaining actively growing stromal cells which stretch across the framework enhances the production of growth factors which are elaborated by the stromal cells, and hence will support long term cultures. For example, if the openings are too small, the stromal cells may rapidly achieve confluence but be unable to easily exit from the mesh; trapped cells may exhibit contact inhibition and cease production of the appropriate factors necessary to support proliferation and maintain long term cultures. If the openings are too large, the stromal cells may be unable to stretch across the opening; this will also decrease stromal cell production of the appropriate factors necessary to support proliferation and maintain long term cultures.
  • openings ranging from about 140 ⁇ m to about 220 ⁇ m will work satisfactorily.
  • other sizes may work equally well.
  • any shape or structure that allows the stromal cells to stretch and continue to replicate and grow for lengthy time periods will work in accordance with the invention.
  • ECM extracellular matrix
  • Different proportions of the various types of collagen deposited on the framework can affect the growth of the cells that come in contact with the three dimensional stromal tissue.
  • the proportions of extracellular matrix (ECM) proteins deposited can be manipulated or enhanced by selecting fibroblasts which elaborate the appropriate collagen type. This can be accomplished using monoclonal antibodies of an appropriate isotype or subclass that is capable of activating complement, and which define particular collagen types. These antibodies and complement can be used to negatively select the fibroblasts which express the desired collagen type.
  • the stroma used to inoculate the framework can be a mixture of cells which synthesize the appropriate collagen types desired. The distribution and origins of the various types of collagen is shown in Table I.
  • the appropriate stromal cell(s) may be selected to inoculate the three-dimensional framework.
  • proliferating cells may be released from the framework. These released cells may stick to the walls of the culture vessel where they may continue to proliferate and form a confluent monolayer. This should be prevented or minimized, for example, by removal of the released cells during feeding, or by transferring the three-dimensional stromal tissue to a new culture vessel. The presence of a confluent monolayer in the vessel may “shut down” the growth of cells in the three-dimensional culture. Removal of the confluent monolayer or transfer of the stromal tissue to fresh media in a new vessel will restore proliferative activity of the three-dimensional culture system.
  • the culture system could be agitated to prevent the released cells from sticking, or instead of periodically feeding the cultures, the culture system could be set up so that fresh media continuously flows through the system.
  • the flow rate could be adjusted to both maximize proliferation within the three-dimensional culture, and to wash out and remove cells released from the culture, so that they will not stick to the walls of the vessel and grow to confluence.
  • the released stromal cells can be collected and cryopreserved for future use.
  • Genetically engineered three-dimensional stromal tissue may be prepared as described in U.S. Pat. No. 5,785,964 which is incorporated herein by reference.
  • a genetically-engineered stromal tissue may serve as a gene delivery vehicle for sustained release of angiogenic factors in vivo.
  • Stromal cells may be engineered to express an exogenous gene product.
  • Stromal cells that can be genetically engineered include, but are not limited to, fibroblasts, smooth muscle cells, cardiac muscle cells, mesenchymal stem cells, and other cells found in loose connective tissue such as endothelial cells, macrophages, monocytes, adipocytes, pericytes, reticular cells found in bone marrow, etc.
  • the cells and tissues may be engineered to express a target gene product which may impart a wide variety of functions, including, but not limited to, enhanced function of the genetically engineered cells and tissues to promote angiogenesis when implanted in vivo.
  • the target gene product may be a peptide or protein, such as an enzyme, hormone, cytokine, a regulatory protein, such as a transcription factor or DNA binding protein, a structural protein, such as a cell surface protein, or the target gene product may be a nucleic acid such as a ribosome or antisense molecule.
  • the target gene products which provide enhanced properties to the genetically engineered cells include but are not limited to, gene products which enhance cell growth, e.g., vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), fibroblast growth factors (FGF), platelet derived growth factor (PDGF), epidermal growth factor (EGF), and transforming growth factor (TGF).
  • VEGF vascular endothelial growth factor
  • HGF hepatocyte growth factor
  • FGF fibroblast growth factors
  • PDGF platelet derived growth factor
  • EGF epidermal growth factor
  • TGF transforming growth factor
  • the cells and tissues are genetically engineered to express target gene products which result in cell immortalization, e.g. oncogenes or telomerese.
  • the cells may be engineered to express a suicide gene product on cue, e.g., thymidine kinase.
  • the cells and tissues are genetically engineered to express gene products which provide protective functions in vitro such as cyropreservation and anti-desiccation properties, e.g., trehalose (U.S. Pat. Nos. 4,891,319; 5,290,765; 5,693,788).
  • the cells and tissues of the present invention may also be engineered to express gene products which provide a protective function in vivo, such as those which would protect the cells from an inflammatory response and protect against rejection by the host's immune system, such as HLA epitopes, major histocompatibility epitopes, immunoglobulin and receptor epitopes, epitopes of cellular adhesion molecules, cytokines and chemokines.
  • the target gene products may be engineered to be expressed by the cells and tissues of the present invention.
  • the target gene products may be engineered to be expressed constitutively or in a tissue-specific or stimuli-specific manner.
  • the nucleotide sequences encoding the target gene products may be operably linked to promoter elements which are constitutively active, tissue-specific or induced upon presence of a specific stimuli.
  • the nucleotide sequences encoding the target gene products are operably linked to regulatory promoter elements that are responsive to shear or radial stress.
  • the promoter element would be turned on by passing blood flow (shear) as well as the radial stress that is induced as a result of the pulsatile flow of blood through the heart or vessel.
  • Examples of other regulatory promoter elements include tetracycline responsive elements, nicotine responsive elements, insulin responsive element, glucose responsive elements, interferon responsive elements, glucocorticoid responsive elements estrogen/progesterone responsive elements, retinoid acid responsive elements, viral transactivators, early or late promoter of SV40 adenovirus, the lac system, the trp system, the TAC system, the TRC system, the promoter for 3-phosphoglycerate and the promoters of acid phosphatase.
  • artificial response elements could be constructed, composed of multimers of transcription factor binding sites and hormone-response elements similar to the molecular architecture of naturally-occurring promoters and enhancers (e.g., see Herr, W & Clarke, J Cell (1986) 45(3): 461-70).
  • Such artificial composite regulatory regions could be designed to respond to any desirable signal and be expressed in particular cell-types depending on the promoter/enhancer binding sites selected.
  • the three-dimensional stromal tissue of the present invention may be used in a variety of applications including, but not limited to, promoting repair of and regeneration of damaged cardiac muscle, promoting vascularization and healing during cardiac surgery (e.g. by-pass surgery or heart valve replacement), promoting blood vessel formation at anastomosis sites, and promoting vascularization and repair of ischemic or otherwise damaged smooth muscle, cardiac muscle, skeletal muscle, connective tissue or brain tissue.
  • stromal tissue may be used as a freshly cultured tissue, as a cryopreserved tissue, or even as a killed tissue.
  • the three-dimensional stromal tissue of the present invention may be attached to various locations on the heart, including the eipcardium, myocardium and endocardium, to promote angiogenesis in the region of attachment.
  • Means for attachment include, but are not limited to, direct adherence between the stromal tissue and the heart tissue, biological glue, synthetic glue, laser dyes, or hydrogel.
  • hemostatic agents and sealants include “SURGICAL” (oxidized cellulose), “ACTIFOAM” (collagen), “FIBRX” (light-activated fibrin sealant), “BOHEAL” (fibrin sealant), “FIBROCAPS” (dry powder fibrin sealant), polysaccharide polymers p-GlcNAc (“SYVEC” patch; Marine Polymer Technologies), Polymer 27CK (Protein Polymer Tech.). Medical devices and apparatus for preparing autologous fibrin sealants from 120 ml of a patient's blood in the operating room in one and one-half hour are also known (e.g. Vivostat System).
  • the three-dimensional stromal tissue is placed directly onto the heart or an adjoining vessel and the product attaches via natural cellular attachment. This method has been demonstrated in studies of wound healing in patients with diabetic foot ulcers.
  • a three-dimensional stromal tissue is attached to the heart or adjoining vessel using a surgical glue, preferably a biological glue such as a fibrin glue.
  • a surgical glue preferably a biological glue such as a fibrin glue.
  • fibrin glue as a surgical adhesive is well known.
  • Fibrin glue compositions are known (e.g., see U.S. Pat. Nos. 4,414,971; 4,627,879 and 5,290,552) and the derived fibrin may be autologous (e.g., see U.S. Pat. No. 5,643,192).
  • the glue compositions may also include additional components, such as liposomes containing one or more agent or drug (e.g., see U.S. Pat. Nos.
  • a laser dye is applied to the heart and/or vessel wall, the three-dimensional stromal tissue, or both, and activated using a laser of the appropriate wavelength to adhere to the tissues.
  • the laser dye has an activation frequency in a range that does not alter tissue function or integrity. For instance, 800 nm light passes through tissues and red blood cells.
  • ICG indocyan green
  • laser wavelengths that pass through tissue may be used.
  • a solution of 5 mg/ml of ICG is painted onto the surface of the three-dimensional stromal tissue (or target site) and the ICG binds to the collagen of the tissue.
  • a 5 ms pulse from a laser emitting light with a peak intensity near 800 nm is used to activate the laser dye, resulting in the denaturation of collagen which fuses elastin of the adjacent tissue to the modified surface.
  • the three-dimensional stromal tissue is attached to the heart or vessel using a hydrogel.
  • a hydrogel A number of natural and synthetic polymeric materials are sufficient for forming suitable hydrogel compositions.
  • polysaccharides e.g., alginate
  • polyphosphazenes and polyacrylates are crosslinked ionically or by ultraviolet polymerization (U.S. Pat. No. 5,709,854).
  • a synthetic surgical glue such as 2-octyl cyanoacrylate (“DERMABOND”, Ethicon, Inc., Somerville, N.J.) may be used to attach the three-dimensional stromal tissue.
  • the three-dimensional stromal tissue is secured to the heart or a blood vessel vessels using one or more sutures, including, but not limited to, 5-O, 6-O and 7-O proline sutures (Ethicon Cat. Nos. 8713H, 8714H and 8701H), poliglecaprone, polydioxanone, polyglactin or other suitable non-biodegradable or biodegradable suture material.
  • sutures including, but not limited to, 5-O, 6-O and 7-O proline sutures (Ethicon Cat. Nos. 8713H, 8714H and 8701H), poliglecaprone, polydioxanone, polyglactin or other suitable non-biodegradable or biodegradable suture material.
  • suturing double armed needles are typically, although not necessarily, used.
  • the three-dimensional stromal tissue is grown in a bioreactor system (e.g., U.S. Pat. Nos. 5,763,267 and 5,843,766) in which the framework is slightly larger than the final tissue-engineered product.
  • the final product contains a border, one edge, flap or tab of the scaffold material, which is used as the site for application of the biological/synthetic glue, laser dye or hydrogel.
  • the scaffold weave may be used as an attachment for suturing or microsuturing.
  • the three-dimensional stromal tissue may be implanted to promote vascularization, repair and regeneration of damaged cardiac muscle.
  • the three-dimensional stromal tissues will be applied to a vessel to sprout new blood vessels to by-pass clogged or blocked arteries and restore blood flow to the heart.
  • the three-dimensional stromal tissue will be applied directly to the heart using a minimally invasive procedure.
  • the tissue can be applied to promote vascularization and blood flow to minimize necrosis and/or promote regeneration of heart tissue following a myocardial infarction.
  • attaching a three-dimensional stromal tissue patch to the endocardium may be accomplished by inserting a catheter or similar device into a ventricle of the heart and adhering or attaching the stromal patch to the wall of the ventricle. It is preferred that the site of attachment should have a reasonably good blood flow to support angiogenesis.
  • the angiogenic activity of the three-dimensional stromal tissues may also be used for treating anastomoses.
  • An anastomosis is defined as an operative union between two hollow or tubular structures or an opening created by surgery, trauma or disease between two or more separate spaces or organs (see, e.g., Stedman's Medical Dictionary, 26 th Ed, Williams & Wilkins, Baltimore, Md.).
  • anastomotic sites arise from the introduction of a vascular graft during a coronary artery bypass graft (CABG) procedure, during a bowel resection or organ transplant.
  • CABG coronary artery bypass graft
  • a three-dimensional tissue is placed at the site of downstream attachment of the bypass graft to promote angiogenesis upon restoration of blood flow to that site, i.e. to form additional arteries arising from the connection sites in addition to promoting healing of the site.
  • vascular field include, but are not limited to, precapillary (between arterioles), Riolan's (marginal artery of the colon connecting the middle and left colic arteries), portal-systemic (superior-middle/inferior rectal veins; portal vein-inferior vena cava), termino-terminal (artery to vein) and cavo-pulmonary (treating cyanotic heart disease by anastomosing the right pulmonary artery to the superior vena cava).
  • the three-dimensional stromal tissue is wrapped around the anastomotic site to promote healing of the site (i.e., endothelialization).
  • the cells of the three-dimensional stromal tissue are killed (e.g., by freezing and thawing) and the resulting product is applied to the site (i.e., “TRANSCYTE”).
  • a method for treating ischemic damage in tissues including, but not limited to, heart, brain peripheral tissues and visceral organs.
  • a three-dimensional stromal tissue implant is attached to the ischemic site using natural adherence, a suture, adhesive or other means as described above.
  • the implanted three-dimensional stromal tissue promotes formation of new blood vessels and healing of the damaged tissue.
  • kits for promoting angiogenesis comprising a three-dimensional stromal tissue and a means for attaching such tissue to the heart or vessels.
  • Such means for attachment include a composition of surgical glue, hydrogel, preloaded prolene needles for microsuturing.
  • stromal tissue a fibroblast-based three-dimensional stromal tissue (“stromal tissue”) was capable of inducing endothelialization and vascularization. Providing such a biologically active material has been observed to induce new capillary formation and reduce inflammation in the wound bed of patients with diabetic foot ulcers.
  • angiogenic properties of three-dimensional stromal tissues are described below using a wide range of techniques including the chick chorioallantoic membrane assay, the rat aortic ring assay, stimulation of endothelial cell proliferation, chemokinesis, chemotaxis, inhibition of apoptosis, and in vivo induction of angiogenesis in ischemic heart tissue.
  • these assays cover a wide range of the individual events in angiogenesis as well as the overall process.
  • the fibronectin present in the extracellular matrix also has been shown to stimulate the proliferation of endothelial cells, while the denatured collagen has been proven to be a favorable substrate for human endothelial cell attachment.
  • Bound growth factors in the matrix include TGF ⁇ and HGF which are important in stimulating new capillary formation and endothelialization.
  • the matrix also contains laminin-1 which can serve to inhibit initial hyperplasia via the YIGSR peptide. The combination of these matrix proteins along with naturally secreted growth factors offers a physiological solution to the in vivo induction of angiogenesis.
  • RNA samples were estimated by quantitative RT-PCR using the ABI TaqMan method (Perkin-Elmer, Foster City, Calif.). RNA was extracted from the cells using a Rapid RNA Purification Kit (Amresco, Solon, Ohio). The RNA was reverse transcribed using Superscript II (Life Technologies, Grand Island, N.Y.) with random hexamer primers (Sigma, St. Louis, Mo.). Amplification of samples of cDNA containing 200 ng total RNA was detected in real time and compared with the amplification of plasmid-derived standards for specific mRNA sequences using a copy number over a range of 5 orders of magnitude with 40-4,000,000/reaction.
  • mRNA sequences for PDGF B chain, VEGF or TGF ⁇ 1 were added to RNA isolations, and their yield measured by the TaqMan procedure.
  • the control mRNA sequences were obtained by T7 RNA polymerase transcription of plasmids containing the corresponding sequence. The values were normalized using glyceraldehyde-3-phosphate dehydrogenase as a control.
  • the hole was covered with a piece of clear adhesive tape and the eggs were incubated for 72 hours at 37° C. to allow blood vessel growth.
  • the treated section of the membrane was then removed, photographed, and fixed in methanol.
  • the number of fine blood vessel branch points in the region of the sample was counted. Biopsy samples were fixed in methanol and sections stained with Masson's Trichrome.
  • aortic ring assay the ability of the endothelial blood vessel lining to generate microvessels was used to demonstrate angiogenesis.
  • Thoracic aortas removed from 1 to 2 month old Sprague Dawley male rats were transferred to serum-free MCDB131.
  • the peri-aortic fibroadipose tissue was carefully removed, the aortas washed 8 to 10 times and cut into 1 mm lengths.
  • Wells were punched in a 1.5% agarose gel and filled with clotting fibrinogen solution (20 ⁇ L 50 NIH units/mL bovine thrombin in 1 mL fibrinogen).
  • the aortic rings were placed into the centers of the wells. After clotting, the dishes were flooded with serum-free MCDB131.
  • the cultures were incubated at 37° C. with 5% CO 2 , with medium changes every 3 days. Newly formed microvessels were counted on days 3, 7 and 14.
  • Endothelial cell proliferation is a critical component of angiogenesis.
  • the ability of the stromal tissue to stimulate this activity was determined by [ 3 H]-thymidine incorporation.
  • Various growth factors and concentrated conditioned medium samples were assessed for their influence on the proliferation of HUVEC. Confluent cultures were detached and re-suspended in HUVEC growth medium to a final concentration of 2.5 ⁇ 10 4 cells/ml. 24-well plates were pre-treated with Attachment Factor Solution (Cell Applications, Inc.) and cells were added at 1 ml cell suspension per well.
  • Endothelial Serum Free Medium Cell Applications, Inc.
  • fibroblast culture medium or medium conditioned by monolayer or three-dimensional fibroblast cultures On day two, the cells received fresh serum free medium supplemented as appropriate with 1 ⁇ Curie/ml [ 3 H]-thymidine.
  • medium On day three, medium was removed, cells were washed three times with PBS, and 250 ⁇ l 2.3% sodium dodecyl sulfate (SDS) was added to solubilize the cells. After 30 minutes, the SDS extract and one ml of a PBS wash were transferred to a scintillation vial. Five ml of “SCINTIVERSE” (Fair Lawn, N.J.) was added to vials and radioactivity was determined using a Beckman LS6500 Scintillation Counter (Fullerton, Calif.).
  • Endothelial cells were grown on Cytodex-2 beads.
  • the assay estimated the dissociation of cells from the beads and re-association with a culture plate. The cells on the plate were stained and counted.
  • the Boyden Chamber was assembled as follows: 30 ⁇ l of sample or standard was added to the bottom wells, the gelatin coated membrane was placed on top, and 50 ⁇ l cell suspension was added to the upper wells. The chamber was incubated at 37° C. for 3 hours. Membranes were then carefully removed from the chamber and the cell-side was rinsed in PBS and drawn across a wiper blade to remove non-migrated cells. The membranes were stained with Wright's Giemsa stain and either the number of cells counted or the density of staining was reported against a standard curve generated with 20, 10, 5.0 and 0 ng/ml purified VEGF.
  • the ⁇ v ⁇ 3 integrin has been shown to play an important role in angiogenesis and neutralizing antibodies directed at it are capable of blocking capillary blood vessel formation. It is induced by VEGF and is thought to play a critical role in the endothelial cell migration.
  • integrins and cell surface receptors were determined by flow cytometry on a FACStar by Cytometry Research Services, San Diego, Calif. Cells were prepared for analysis as follows: HUVECs were trypsinized and the cells re-suspended at 1 ⁇ 10 6 cells/ml. 250 ⁇ L to 500 ⁇ L of the cell suspensions were washed three times with Hank's Balanced Salt Solution (HBSS, GibcoBRL, Grand Island, N.Y.), and finally re-suspended in 10% FBS in Hank's balanced salt solution (HBSS).
  • HBSS Hank's Balanced Salt Solution
  • the cells were incubated for 30 minutes with primary antibodies diluted to 1 ⁇ g/ml in 10% FBS in HBSS, washed three times with HBSS, incubated for 30 minutes with secondary antibodies diluted to 1 ⁇ g/mL in 10% FBS in HBSS, washed three times with HBSS, and fixed in 200 ⁇ L 10% Formalin (Baxter, Deerfield, Ill.) at a density of 10 6 cells/mL.
  • DMEC cells of each culture were stained by incubating the culture in a solution of 10 ⁇ g/ml di-l-acetyl-low density lipoprotein for 2-4 hours (e.g., see Voyta et al., 1984, J. Cell Biol. 99:2034-2040) and a solution of “SYTOX”, which stained cell nuclei (Molecular Probes, Eugene, Oreg.).
  • Cultured three-dimensional stromal tissue provides many of the components of healthy skin essential for wound healing, including important mediators of angiogenesis like VEFG and transforming growth factor- ⁇ (TGF ⁇ ).
  • Laser Doppler imaging was used to study microvascular perfusion at the base of foot ulcers treated with three-dimensional stromal tissue, to investigate whether healing of these lesions was associated with an increase in blood flow that might in turn reflect angiogenesis.
  • Three-dimensional stromal tissue-stimulated vascularization was examined in vivo using a Severe Combined Immunodeficiency (SCID) mouse epicardial implant model.
  • SCID Severe Combined Immunodeficiency
  • Mice were divided into three groups: viable/cryopreserved three-dimensional stromal tissue implant (“viable stromal patch”), non-viable three-dimensional stromal tissue implant (“non-viable stromal patch”), and control/sham.
  • viable stromal patch viable/cryopreserved three-dimensional stromal tissue implant
  • non-viable stromal patch non-viable three-dimensional stromal tissue implant
  • control/sham Each group had at least six animals per group at two separate time points (14 days and 30 days). The animal study was performed in accordance with applicable regulations of the United States Food and Drug Administration.
  • SCID mice (University of Arizona, Arlington, Ariz.) were housed 2 per cage in micro-isolator cages on wood shavings and received “TECH-LAD 4% MOUSE/RAT DIET” and tap water ad libitum. Mice were housed under controlled temperatures of 74° F. ⁇ 10° F. and humidity 50% ⁇ 20% in accordance with the NIH “Guide for the Care and Use of Laboratory Animals”.
  • a coronary occlusion of the left coronary artery just below the left atrium was performed by thermal occlusion using standard methods known to those of skill in the art. Occlusion results in an area of non-viable, ischemic tissue located primarily in the left ventricle near the apex.
  • a 4 mm viable stromal patch or non-viable stromal patch was sutured onto the surface of the ischemic epicardial/myocardial tissue of surviving mice using a single suture. For control mice, only a suture was introduced at the site of ischemic damage. Following implantation, the lungs were re-expanded using positive pressure at end expiration.
  • the chest cavity was closed in layers using 6-0 silk (Ethicon, Inc.) and the animal were gradually weaned from the respirator. Once spontaneous respiration was resumed, the tracheal tube was removed, and the neck closed. The animals remained in a supervised setting until fully conscious and the post-operative general health status of each animal was determined daily.
  • mice Prior to explant, an echocardiogram was performed to measure ventricular wall thickness and compare to that prior to occlusion. At 14 days or 30 days, mice were re-anesthetized and the three-dimensional stromal tissue patches with surrounding tissue and control heart tissues were harvested. Mice were euthanized after material harvest using an overdose (150 mg/kg) of pentobarbital IP.
  • the gross morphology of a representative heart from each group was examined to access the tissue viability in the ischemic region.
  • the gross morphology of the heart was examined by injecting one explanted heart from each group with the dye tetrazolium red (2,3,5-triphenyltetrazolium chloride) (Sigma/Aldrich Chemical Co., St. Louis, Mo.). Tetrazolium red reacts with viable heart tissue producing a bright red color. In contrast, non-viable tissue does not react with tetrazolium red thus leaving non-viable tissue a pale white color.
  • tetrazolium red 2,3,5-triphenyltetrazolium chloride
  • GS-1 is a commercially available lectin that primarily binds to the surface of endothelial cells (Sigma/Aldrich Chemical Co.).
  • VEGF production by FBET was important in its angiogenic activities.
  • aortic rings of rat thoracic aortas were co-cultured with FBET, there was a significant increase in the number of microvessels formed (FIG. 3). It is believed that the FBET produces a combination of angiogenic factors in naturally-secreted ratios that may have a synergistic effect.
  • the conditioned medium obtained from monolayer culture dermal fibroblasts showed no inhibition of apoptosis with the cells forming tubules and undergoing apoptosis (FIG. 8A).
  • the conditioned medium obtained from three-dimensional fibroblast cultures maintained cellular proliferation and morphology similar to that observed for angiogenic factors such as bFGF and VEGF (FIG. 8B).

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IL145892A0 (en) 2002-07-25
ES2282105T3 (es) 2007-10-16
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WO2000061204A1 (en) 2000-10-19
DE60033381T2 (de) 2007-11-29
CA2367507C (en) 2009-12-29
EP1169069A1 (de) 2002-01-09
JP4709393B2 (ja) 2011-06-22
EP1169069B1 (de) 2007-02-14
US8128924B2 (en) 2012-03-06
DE60033381D1 (de) 2007-03-29
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