WO2007055882A2 - Systeme d’augmentation mammaire et de reconstruction - Google Patents

Systeme d’augmentation mammaire et de reconstruction Download PDF

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Publication number
WO2007055882A2
WO2007055882A2 PCT/US2006/040786 US2006040786W WO2007055882A2 WO 2007055882 A2 WO2007055882 A2 WO 2007055882A2 US 2006040786 W US2006040786 W US 2006040786W WO 2007055882 A2 WO2007055882 A2 WO 2007055882A2
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Prior art keywords
breast
cells
matrix
stem cells
template
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PCT/US2006/040786
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WO2007055882A3 (fr
Inventor
Hosheng Tu
Rodolfo C. Quijano
Kenneth J. Williams
Robert L. Carter
Alexander Kiselyov
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Priority claimed from US11/268,392 external-priority patent/US20070104692A1/en
Priority claimed from US11/414,860 external-priority patent/US20070104694A1/en
Priority claimed from US11/490,431 external-priority patent/US20070104695A1/en
Application filed by Individual filed Critical Individual
Publication of WO2007055882A2 publication Critical patent/WO2007055882A2/fr
Publication of WO2007055882A3 publication Critical patent/WO2007055882A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/55—Glands not provided for in groups A61K35/22 - A61K35/545, e.g. thyroids, parathyroids or pineal glands
    • 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
    • A61L27/3839—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
    • A61L27/36—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
    • A61L27/3895—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 using specific culture conditions, e.g. stimulating differentiation of stem cells, pulsatile flow conditions
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0625—Epidermal cells, skin cells; Cells of the oral mucosa
    • C12N5/0631—Mammary cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/13—Coculture with; Conditioned medium produced by connective tissue cells; generic mesenchyme cells, e.g. so-called "embryonic fibroblasts"
    • C12N2502/1305—Adipocytes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers
    • C12N2533/40—Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable polymers

Definitions

  • the present invention is related to a breast augmentation system for treatment of breast tissue defect, more particularly, the present invention relates to breast augmentation and reconstruction system with a stem cells delivery means thereof to repair, augment or reconstruct a breast tissue defect in a patient.
  • Adipose-derived stem cells might be engulfed in injured heart muscle following a heart attack-like injury.
  • Adipose also known as fat tissue, contains a specialized class of stem cells, which are comprised of multiple cell types that might promote healing and repair. It appears that adipose-derived stem cells home in on specific sites of injury through biological signaling that occurs naturally during heart attacks.
  • Non-embryonic multipotent stem cells include, for example, neural stem cells, mesenchymal stem cells, bone marrow stem cells and stem cells obtained from liposuction. It is important to note that the adult multipotent stem cells described in the prior art have limited potential, in that they have not been demonstrated to give rise to any and all cell types of the body.
  • a stem cell shows ability of a clonal stem cell population to self-renew, ability of a clonal stem cell population to generate a new, terminally differentiated cell type in vitro and ability of a clonal stem cell population to replace an absent terminally differentiated cell population when transplanted into an animal depleted of its own natural cells.
  • Mesenchymal stem cells are adult multipotent cells derived from multiple sources, including bone marrow stroma, blood, dermis, and periosteum. These cells can be cultured continuously in vitro without spontaneous differentiation. However, under the proper conditions, mesenchymal stem cells can be induced to differentiate into cells of the mesenchymal lineage, including adipocytes, chondrocytes, osteocytes, tenocytes, ligamentogenic cells, myogenic cells, bone marrow stroma cells, and dermogenic cells (U.S. Pat. No. 5,736,396).
  • mesenchymal cells upon injection into either mouse or rat brains, are capable of migrating through the brain, engrafting, surviving, and differentiating into astrocytes, ependymal cells, or neurons, suggesting the capacity of mesenchymal stem cells to give rise to cells of a non-mesenchymal lineage (U.S. Pat. No. 5,197,985, No. 5,226,914, No. 5,486,359, and No. 5,736,396).
  • Adipose tissue is an anatomical term for loose connective tissue composed of adipocytes. Its main role is to store energy in the form of fat, although it also cushions and insulates the body. It has an important endocrine function in producing hormones such as leptin, resistin and TNF- ⁇ . It also functions as a reservoir of nutrients. Adipose tissue has an "intracellular matrix,” rather than an extracellular one. Adipose tissue is divided into lobes by small blood vessels. The cells of this layer are adipocytes.
  • embryonic stem cells are the building blocks for all of the cell types in the body
  • adult stem cells are a more specialized type of progenitor cell.
  • Adult stem cells are found in specific tissues and have the ability to regenerate themselves, as well as differentiate into all of the cell types found in that tissue.
  • the specific differentiation pathway that these cells enter depends upon various influences from mechanical influences and/or endogenous bioactive factors, such as growth factors, cytokines, and/or local microenvironmental conditions established by host tissues.
  • Using cells from the developed individual, rather than an embryo, as a source of autologous or allogeneic stem cells would overcome the problem of tissue incompatibility associated with the use of transplanted embryonic stem cells, as well as solve the ethical dilemma associated with embryonic stem cell research.
  • Adipose tissue offers a potential source of multipotential stromal stem cells.
  • Adipose tissue is readily accessible and abundant in many individuals. Obesity is a condition of epidemic proportions in the United States, where over 50% of adults exceed the recommended BMI based on their height. Adipocytes can be harvested by liposuction on an outpatient basis. This is a relatively noninvasive procedure with cosmetic effects that are acceptable to the vast majority of patients. It is well documented that adipocytes are a replenishable cell population. Even after surgical removal by liposuction or other procedures, it is common to see a recurrence of adipocytes in an individual over time. This suggests that adipose tissue contains stromal stem cells that are capable of self-renewal. SUMMARY OF THE INVENTION
  • One object of the invention is to provide a method and compositions for directing adipose-derived stromal cells cultivated in vitro to differentiate into breast tissue lipocyte stem cells derived from subcutaneous fat cells or the fat stem cells with enough angiogenesis factors for implantation into a recipient for the therapeutic treatment of pathologic conditions in breast tissue.
  • the stem-cell-seeded porous scaffold or construct is an implant to repair or augment a breast tissue defect in a patient.
  • the adipose-derived stem cells home in on specific sites of breast defect or injury through biological signaling that occurs naturally for a breast defect or pathologic conditions.
  • Some aspects of the invention provide stem cells for cosmetically modifying breast tissue, wherein the 3D stem-cell-seeded scaffold or construct is an implant to cause breast tissue defect due to implantation and provides breast tissue regeneration through stem cells of stem-cell-seeded scaffold or construct for repairing or augmenting the breast tissue defect in a patient.
  • Some aspects of the invention relate to a method of treating a breast defect in a patient, the method comprising differentiating an isolated human adipose tissue derived stromal cell into subcutaneous fat stem cells with enough angiogenesis factors and administering the fat stem cells with enough angiogenesis factors to a breast defect area in the patient.
  • the fat stem cells with enough angiogenesis factors further comprises a biocompatible shaped matrix (including scaffold), wherein the biocompatible matrix may be non-biodegradable or biodegradable.
  • the biodegradable matrix may be made of a material selected from a group consisting of polymers or copolymers of lactide, glycolide, caprolactone, polydioxanone, trimethylene carbonate, polymers or copolymers of polyorthoesters and polyethylene oxide, and polymers or copolymers of aliphatic polyesters, alginate, cellulose, chitin, chitosan, collagen, copolymers of glycolide, copolymers of lactide, elastin, fibrin, glycolide/1-lactide copolymers (PGA/PLLA), glycolide/trimethylene carbonate copolymers (PGA/TMC), glycosaminoglycans, and hydrogel.
  • the biocompatible matrix comprises a material selected from a group consisting of alginate, agarose, fibrin, collagen, methylcellulose, and combinations thereof.
  • the breast defect is traumatically created by any of the following conditions or processes: inserting the biocompatible matrix into the patient, lumpectomy, mastectomy, breast reconstruction, breast injury, or other breast surgical procedures.
  • Scarring is a major problem in the breast reconstruction application and it comes from fat necrosis. What one would want to inject would be lipocytes or adipocytes that are stromal only with no ductal or lobular developmental potential.
  • Some aspects of the invention provide a breast matrix system for treating a breast defect of a patient, comprising an implantable breast matrix and stem cells component, wherein stem cells are derived 1 from adipose tissue, and wherein the breast matrix is made of biodegradable material, wherein the stem cells component comprises breast tissue progenitor cells.
  • the breast matrix system further comprises a delivery instrument for delivering the breast matrix to a breast of the patient for treating the breast defect
  • the delivery instrument comprises a hollow tubular sheath having a distal tip, a lumen having an opening at the distal tip, and a handle portion; a plunger inside the lumen, wherein the plunger is activated by a pushing mechanism located at the handle portion; and wherein the lumen is sized and configured for appropriately receiving the breast matrix at a pre-deployment profile.
  • Some aspects of the invention provide a breast matrix system and a medium for containing the stem cells or breast tissue progenitor cells, wherein the medium comprises at least one growth factor, or at least one nutrient selected from a group consisting of vitamin A, retinoic acid, vitamin B series, and vitamin C.
  • the medium is a temperature-sensitive carrier of methylcellulose or poly(N-isopropyl acrylamide).
  • a breast template for delivering stem cell formulation to a breast defect of a patient, comprising a flexible substantially flat band with at least one throughput hole for guiding an injecting needle to penetrate into a breast of the patient, wherein the flexible band is configured to be placed intimately against a surface of the breast.
  • the stem cells of the stem cell formulation are derived from adipose tissue, comprise breast tissue progenitor cells or subcutaneous fat stem cells with enough angiogenesis factors, or comprise lipocytes or adipocytes that are stromal only with no ductal or lobular developmental potential.
  • the breast template covers one-half or a quarter of a breast periphery, or is a ring-like substantially flat template.
  • Some aspects of the invention provide a bra apparatus for stimulating growth of a population of administered cells in a breast, the bra apparatus comprising a treatment applicator mounted on the bra apparatus having a capacitative coupling stimulation means, wherein an effective amount of electric energy is delivered via the capacitative coupling stimulation means to the population of cells for stimulating growth of the population, wherein the administered cells are stem cells or breast tissue progenitor cells.
  • the fat stem cells with enough angiogenesis factors further comprises a biocompatible cell carrier, wherein the cell carrier may be in a form selected from a group consisting of slurry, gel, colloid, solution, or suspension that is flowable.
  • the cell carrier or gel is malleable.
  • the cell cai ⁇ ier is selected from a group consisting of alginate, agarose, fibrin, collagen, chitosan, gelatin, elastin, and combinations thereof.
  • the biocompatible cell carrier is biodegradable. The subcutaneous fat stem cells with enough angiogenesis factors is to stimulated a viable sustainable graft that won't develop avascular necrosis nor turn up with cancer sometime down the road.
  • Some aspects of the invention relate to a method of treating a breast defect in a ipMi'ent, ffie'thetnWco ⁇ pT ⁇ slnglii ⁇ lerentiatmg an isolated human adipose tissue derived stromal cell into a breast tissue stem cell and administering the breast tissue stem cell to a breast defect area in the patient, wherein following administration of the stem cell to a breast defect area in the patient, the stem cell further differentiates in situ in the patient.
  • Some aspects of the invention provide a composition for treating a breast defect of a patient, comprising stem cells derived from adipose tissue and a temperature-sensitive cell carrier, wherein the stem cells may comprise breast tissue progenitor cells or subcutaneous fat stem cells with enough angiogenesis factors.
  • the temperature-sensitive cell carrier is methylcellulose, poly(N-isopropyl acrylamide), or the like.
  • the temperature-sensitive cell carrier is characterized by a first solution phase at a lower temperature and a second gel phase at a higher temperature.
  • the temperature-sensitive cell carrier is characterized by an expanded conformation at a lower temperature and a collapsed conformation at a higher temperature.
  • the composition is a compressible foam, a shaped scaffold, a porous matrix or flowable/malleable material.
  • the breast matrix system further comprises a medium for containing the stem cells.
  • the medium comprises at least one growth factor selected from a group consisting of transforming growth factor- ⁇ , insulin-like growth factor, platelet derived growth factor, epidermal growth factor, acidic fibroblast growth factor, basic Fibroblast growth factor, and hepatocytic growth factor.
  • the medium comprises at least one nutrient selected from a group consisting of vitamin A, retinoic acid, vitamin B series, and vitamin C.
  • a breast template for delivering stem cell formulation or composition to a breast defect of a patient, comprising a flexible substantially flat band or sheet apparatus with at least one throughput hole for guiding an injecting needle to penetrate into a breast of the patient, wherein the flexible band or apparatus is configured to be placed intimately against a surface of the breast.
  • FIG. 1 shows a schematic diagram of a method for treating a breast defect.
  • FIG. 2 shows a bra apparatus having capability for electromagnetic stimulation functions.
  • FIG. 3 shows a breast implant embodiment of the fishbone design: (A) an expanded profile, and (B) a collapsed profile.
  • FIG. 4 shows a first breast implant embodiment of the umbrella design: (A) a delivery instrument, (B) an expanded device profile, and (C) a collapsed device profile.
  • FIG. 5 shows a second breast implant embodiment of the umbrella design: (A) a delivery instrument, (B) a proximal cross-sectional view, (C) a distal cross-sectional view, and (D) an expanded device profile.
  • FIG. 6 shows a breast implant of the wrap-around design: (A) an expanded profile, (B) a collapsed profile, and (C) a simulated profile.
  • FIG. 7 shows a breast implant of the yo-yo design.
  • FIG. 8 shows a cross-sectional view of the breast template that is flexible to fit a range of breast sizes.
  • FIG. 9 shows a perspective view of placing the breast template onto a breast of the patient.
  • FIG. 10 shows one embodiment of components of an injecting needle.
  • FIG. 11 shows an illustrative view of the injecting needle.
  • FIG. 12 shows a system for delivering stem cell formulation to a patient.
  • the preferred embodiments of the present invention described below relate particularly to methods and a composition for the differentiation and culture of adipose tissue-derived stromal cells into breast tissue cells.
  • the cells produced by the processes of the invention are useful in providing a source of fully differentiated and functional cells for tissue regeneration to treat human breast defect, repair and augment.
  • the invention provides a method for differentiating adipose tissue-derived stromal cells into breast tissue cells comprising culturing stromal cells in a composition that comprises a medium capable of supporting the growth and differentiation of stromal cells into functional breast cells.
  • This invention further provides methods for the introduction and position of these stromal cells in breast defect areas for repair or augmentation.
  • progenitor it is meant an oligopotent or multipotent stem cell which is able ⁇ to divide without limit and, under specific conditions, can produce daughter cells which terminally differentiate such as into breast cells. These cells can be used for transplantation into a heterologous, autologous, or non-autologous host.
  • heterologous is meant a host other than the animal from which the progenitor cells were originally derived.
  • autologous is meant the identical host from which the cells were originally derived.
  • Cell suspensions in culture medium are supplemented with certain specific growth factor that allows for the proliferation of target progenitor cells and seeded in any receptacle capable of sustaining cell ' s, though as set out above, preferably in culture flasks or roller bottles.
  • Cells typically proliferate within 3-4 days in a 37° C incubator, and proliferation can be reinitiated at any time after that by dissociation or purification of the cells and re-suspension in fresh medium containing specific growth factors.
  • the medium for cells suspension is also considered one type of cell carriers.
  • adipose is meant any fat tissue.
  • the adipose tissue may be brown or white adipose tissue, derived from subcutaneous, omental/visceral, mammary, gonadal, or other adipose tissue site.
  • a convenient source of adipose tissue is from liposuction surgery, however, the source of adipose tissue or the method of isolation of adipose tissue is not critical to the invention.
  • stromal cells are desired for autologous transplantation into a subject, the adipose tissue will be isolated from that subject and administered to the specific breast defect site for tissue regeneration.
  • Liposuction is the most frequently performed procedure in plastic surgery.
  • Liposuction or suction-assisted lipectomy removes fat cells from parts of the body where excess fat cells exist.
  • the liposuction procedure involves making one or more small poke wounds in areas like the abdomen, hips or thighs. Through these small incisions, a long metal tube (a cannula), with small holes at one end and connected to one atmosphere of negative pressure at the other end, is inserted.
  • the cannula in the 3-5 mm diameter range, is repeatedly moved in and out of the surgical site.
  • a network of holes like a sponge or Swiss cheese, is made in the bulging area and the fat is liquefied and removed.
  • ultrasound vibrational energy is added to enhance the fat emulsification (ultrasound-assisted liposuction).
  • the overlying skin is compressed with a binder or girdle to tighten the tissues for a couple of weeks.
  • the area to be suctioned is filled with saline solution, local anesthetic, and vasoconstrictor.
  • the saline serves to emulsify and soften the fat and makes it easier to remove.
  • Any medium capable of supporting stromal cells in tissue culture may be used, for example, Dulbecco's Modified Eagle's Medium that supports the growth of fibroblasts. Growth factors are generally added to the medium for supporting stromal cells in tissue culture. Typically, 0 to 20% Fetal Bovine Serum (FBS) is added to the above medium in order to support the growth of stromal cells. The cells could be incubated at a temperature around 37 0 C with the carbon dioxide content maintained between 1% to 10% and the oxygen content between 1% and 20%.
  • FBS Fetal Bovine Serum
  • Non-limiting examples of media useful in the methods of the invention can contain fetal serum of bovine or other species at a concentration of at least 1% to about 30%, preferably at least about 5% to 15%, mostly preferably about 10%.
  • Embryonic extract of chicken or other species can be present at a concentration of about 1% to 30%, preferably at least about 5% to 15%, most preferably about 10%.
  • the growth factors of the invention may include, but not limited to, transforming growth factor- ⁇ (TGF- ⁇ l, TGF- ⁇ 2, TGF- ⁇ 3 and the like), insulin-like growth factor, platelet derived growth factor, epidermal growth factor, acidic fibroblast growth factor, basic fibroblast growth factor, hepatocytic growth factor, and the like.
  • concentration of growth factors is about 1 to about 100 ng/ml.
  • the matrix for incorporating the stromal cells is a component of the collagenous extracellular matrix such as collagen I (particularly in the form of a gel).
  • vitamin A such as retinoic acid
  • vitamin B series such as retinoic acid
  • vitamin C such as vitamin C
  • vitamin C analogue or other vitamins may be added to the medium.
  • concentration of retinoic acid or other nutrient is about 0.1 to about 10 ⁇ g/ml.
  • the present invention also provides a method for formulating adipose derived stromal cells, either after in vitro culture or in absence of in vitro culture, with a biocompatible pharmaceutical carrier for injecting into the breast of a subject.
  • the biocompatible carrier may be in the form of slurry, gel, a malleable gel, colloid, solution, or suspension.
  • a process for manufacturing an implantable cells-seeded gel material may comprise the steps of: providing a biocompatible carrier and stem cells source; combining the cells and the carrier in a uniformly suspended form; and applying a pressurizing force to the combined fluid for either injecting into the breast of the subject or for collapsing into a malleable gel before administering into the breast.
  • adipose tissue derived stromal cells useful in the methods of invention may be isolated by a variety of methods known to those skilled in the art.
  • adipose tissue is isolated from a mammalian subject, preferably a human subject.
  • a preferred source of adipose tissue is omental adipose.
  • the adipose is typically isolated by liposuction. If the cells of the invention are to be transplanted into a human subject, it is preferable that the adipose tissue be isolated from that same subject so as to provide for an autologous transplant. Alternatively, the administered tissue may be allogenic.
  • Stem cells also provide promise for improving the results of gene therapy.
  • a patient's own stem cells could be genetically altered in vitro, then reintroduced in vivo to produce a desired gene product.
  • These genetically altered stem cells would have the potential to be induced to differentiate to form a multitude of cell types for implantation at specific sites in the body, or for systemic application.
  • heterologous stem cells could be genetically altered to express the recipient's major histocompatibility complex (MHC) antigen, or no MHC, to allow transplant of those cells from donor to recipient without the associated risk of rejection.
  • MHC major histocompatibility complex
  • the cells produce therapeutic enzymes, proteins, or other products in the human so that genetic defects are corrected.
  • a method of using the cells for gene therapy in a subject in need of therapeutic treatment involving genetically altering the cells by introducing into the cell an isolated pre-selected DNA encoding a desired gene product, expanding the cells in culture, and introducing the cells into the body of the subject to produce the desired gene product.
  • the present invention provides a method of repairing damaged tissue in a human subject in need of such repair by expanding the isolated multipotent adult stem cells in culture, and contacting an effective amount of the expanded cells with the damaged tissue of the subject.
  • the cells may be introduced "into the body of the subject by localized injection.
  • the cells may be introduced into the body of the subject in conjunction with a suitable matrix scaffold (the terms matrix, scaffold, and matrix scaffold are interchangeably used throughout the disclosure).
  • the matrix scaffold may provide additional genetic material, cytokines, growth factors, or other factors to promote growth and differentiation of the cells.
  • the cells may be encapsulated or co-mixed prior to introduction into the body of the subject, such as with a polymer capsule or other biodegradable substrate.
  • an adipose tissue derived stromal cell induced to express at least one phenotypic characteristic of a neuronal, astroglial, hepatic, hematopoietic, or breast tissue cell is provided.
  • Phenotypic markers of the desired cells are well known to those of ordinary skill in the art, and copiously published in the literature. Additional phenotypic markers continue to be disclosed or can be identified without undue experimentation. Any of these markers can be used to confirm that the adipose cell has been induced to a differentiated state. Lineage specific phenotypic characteristics can include cell surface proteins, cytoskeletal proteins, cell morphology, and secretory products.
  • the crosslinking present in the material causes the material to be rehydrated as a sponge or foam, wherein the structure or shape is maintained, rather than forming a flowable hydrogel or putty.
  • Some aspects of the invention provide a crosslinked gel material as a shaped article loaded with adipose-derived stem cells or progenitor breast tissue cells.
  • the biocompatible cell carrier (for example, for cells to home in) or matrix may be a shaped construct, structure, or 3-dimensional scaffold.
  • biocompatible carrier material include alginate, agarose, Fibrin, collagen, chitosan, gelatin, elastin, and combinations thereof.
  • the biocompatible cell carrier is biodegradable or bioresorbable.
  • biodegradable matrix material may include, but not limited to, polymers or copolymers of lactide, glycolide, caprolactone, polydioxanone, and trimethylene carbonate.
  • biodegradable matrix material may also include polyorthoesters and polyethylene oxide.
  • biodegradable polymers for construction of the matrix may include aliphatic polyesters, alginate, cellulose, chitin, chitosan, collagen, copolymers of glycolide, copolymers of lactide, elastin, fibrin, glycolide/1-lactide copolymers (PGA/PLLA), glycolide/trimethylene carbonate copolymers (PGA/TMC), glycosaminoglycans, hydrogel, lactide/tetramethylglycolide copolymers, lactide/trimethylene carbonate copolymers, lactide/ ⁇ -capro-lactone copolymers, lactide/ ⁇ - valerolactone copolymers, 1-lactide/dl-lactide copolymers, methyl methacrylate-N-vinyl pyrrolidone copolymers, modified proteins, nylon-2 PHBA/ ⁇ -hydroxyvalerate copolymers (PHBA/HVA), PLA/poly
  • One aspect of the invention discloses co-administration of stem cells and gene transfer for therapeutic vasculogenesis, wherein viability of stem cells could be further enhanced with endothelial precursor cells (EPCs), which are capable of generating blood vessels.
  • EPCs endothelial precursor cells
  • the same methodology could be used to modulate neo-vascularization in breast augmentation process of the invention. For instance, treatment with the EPCs that carried an angiogenic protein enhances blood vessel formation.
  • circulating EPCs have been shown to be mobilized endogenously in response to tissue ischemia or exogenously by cytokine therapy, after which they augmented the neo-vascularization of ischemic tissues (Nat Med. 1999;5:434-438).
  • endothelial cells may derive from circulating stem cells (Science
  • FIG. 1 shows a method of treating a breast defect in a patient, the method comprising: a) differentiating an isolated human adipose tissue derived stromal cell into a breast tissue cell; and b) administering the breast tissue cell to a breast defect area in the patient.
  • the fat tissue from the donor is further differentiated into adipocytes in an in vitro procedure, followed by isolation to obtain a concentrated substance of breat tissue cells prior to the step of administering.
  • the breast tissue defect is created as an adjunct step for promoting stem cells differentiation and tissue regeneration at about the defect site.
  • the fat tissue extraction step 11 may be carried out, for example by liposuction from a donor 10.
  • the adipose tissue isolation step 12 may include breakup of the fat mass and removal of the unwanted non-cellular material.
  • In vitro culture step 13 may be optional; however, nutrients, growth factors and other substance may be added to enhance cell differentiation into breast tissue cells.
  • the breast tissue cells 14 can be formulated with biocompatible cell carrier 15 for injection into a recipient 17.
  • the breast tissue cells 14 can be further deposited onto a biocompatible matrix 16 for implantation into a recipient 18. It is one object of the present invention to provide a recipient 19 with created tissue defect enabling the stem cells tissue regeneration via the injection route 17 or the implantation route 18.
  • support cells are used to promote the differentiation of the adipose-derived stromal cells prior to or following implantation into the defect breast site of a recipient.
  • the support cells can be human or non-human animal derived cells.
  • Adipose- derived cells are isolated and ' cultured within a population of cells; most preferably, the population is a defined population.
  • the population of cells is heterogeneous and includes support cells for supplying factors to the progenitor or stem cells of the invention.
  • Support cells include other cell types that will promote the differentiation, growth and maintenance of the desired cells.
  • adipose- derived stromal cells are first isolated by any of the means described above, and grown in culture in the presence of other support cells.
  • the support cells are derived from primary cultures of these cell types taken from cultured human organ tissue.
  • the support cells are derived from immortalized cell lines. In some embodiments, the support cells are obtained autologously.
  • the formula consisting of breast tissue cells and cell carriers can be injected to the defect site of the breast using a syringe or other fluid delivery apparatus.
  • the formula is intended to enhance revascularization in situ.
  • the formula is intended to promote growth or multiplication of fat cells in the breast.
  • the biocompatible matrix for cells to home in or adhere for intended differentiation purposes may comprise a foam or sponge that is compressible for inserting into the breast with a small opening.
  • the biocompatible foam or sponge construct is characterized with plural pores, wherein at least a portion of the pores is interconnected and open to the outside of the construct.
  • the foam or sponge can be cut, sized, and shaped as an implant.
  • the formula consisting of breast tissue cells and cell carriers may be loaded on the biocompatible matrix/foam before matrix/foam delivery into a recipient.
  • the formula consisting of breast tissue cells and cell carriers may be injected by a needle to about the matrix/form site after the matrix/foam is implanted in place.
  • the needle may have a curved or straight tip and a sharp stylet that would protrude past the needle tip to facilitate perforation of the skin.
  • the needle is usually about 15 gauges (14 to 17 gauges) or with metal wings attached to the needle hub.
  • the Huber point needle has a long, sharp, curved tip designed to lessen the pain of an injection and decrease the risk of depositing plugs of skin into underlying tissues.
  • the advantages of the Huber non-corning needle or substantially equivalent others to be utilized in the invention show that the end of the needle is curved or hooded, and "shrouds" the corning end to eliminate severing tissue in a 360 degree circle.
  • the end of the needle may be equipped with a simple plug that could be removed and replaced from inside the outer needle or rotated to an open (180 degree rotation) position, like the gates on the side of the needle apparatus.
  • FIG. 8 shows a cross-sectional view of the breast template 80 that is flexible and may have different sizes to fit a range of breast sizes or contours.
  • the template 80 comprises a flexible elongate band or apparatus with certain thickness having an inner surface 81 to be placed against the breast skin and an exterior surface 82 facing a physician.
  • the elongate band is sized and configured for intimately resting on the breast skin of a patient.
  • the exterior side of the elongate band comprises a plurality of protrusions 83, each protrusion having a throughput hole for inserting the needle.
  • the throughput hole of the protrusion 83 has a needle entrance port 84 and needle exit port 85 that are sized appropriately for guided penetration.
  • the throughput hole is configured at an angle with respect to the inner surface 81 and the exterior surface 82 for guided penetration.
  • FIG. 9 shows a perspective view of placing the breast template 80 onto a breast
  • the breast template 80 may be placed at lower half or lower quarter of the breast.
  • the needle entrance port 84 of the protrusion 83 is used to guide the needle to penetrate into the breast at the front side or the rear side of the nipple 25.
  • the stem cell formulation (or composition) can be released from the needle outlet port(s).
  • the breast template is a ring-like complete circle so as to finish the delivery of stem cell formulation by placing the ring-like breast template only once against the target breast.
  • the breast temperate covers one-half or a quarter of the breast periphery.
  • Tissues are highly organized in their geometry and architecture with respect to how cells are positioned relative to each other, as well as to the surrounding soluble factors and extracellular matrix molecules within a given microenvironment.
  • the engineered microscale biomaterials may be formulated into 3D cellular microenvironment to generate homogeneous microtissues by controlling the spatial distribution of cells and molecules within hydrogels and directly engineer the microvasculature into 3D structures.
  • the syringe can be a double barrel mixing element that mixes the slurry (or cell carrier with growth factors) with the progenitor cells (or subcutaneous fat stem cells with enough angiogenesis factors) in a spiral barrel so the mixing is substantially homogeneous and complete when the mixed substrate exits the distal end of the syringe.
  • the gel or foam of the present invention may comprise methylcellulose, a temperature-sensitive polymer.
  • Methylcellulose (MC) is a water-soluble polymer derived from cellulose, the most abundant polymer in nature. As a viscosity-enhancing polymer, it thickens solutions without precipitation over a wide pH range.
  • a novel method using a temperature-sensitive polymer (Methylcellulose) to thermally gel aqueous alginate blended with distinct salts (CaCl 2 , Na 2 HPO 4 , or NaCl), as a pH-sensitive hydrogel was developed for protein drug delivery (Biomacromolecules 2004;5:1917-1925).
  • stem cells is well-mixed to the dissolved aqueous methylcellulose or methylcellulose/alginate blended with salts at 4°C and then gel by elevating the temperature to 37 0 C.
  • the blend stem cells or adipose- derived breast tissue progenitor cells plus aqueous methylcellulose
  • the blend is injected into the breast of a recipient and become a gel in situ because of the body temperature at 37 0 C, a characteristic temperature for methylcellulose.
  • methylcellulose compositions exhibit the classical physical behavior of cellulose ethers, changing from a solution at lower temperature to a gel at elevated temperatures.
  • the methylcellulose shows an initial period of relatively constant viscosity.
  • the solution undergoes an abrupt increase in viscosity at a characteristic temperature corresponding to initiation of the first gelation phenomenon.
  • the temperature at which gelation is initiated can be altered by varying a number of factors, including concentration of methylcellulose polymer, formulation of the aqueous solvent, additives, and heating rate.
  • Methylcellulose was reported biocompatible with little toxicity due to degraded byproducts (Biomaterials 2001;22:l 113- 1123). It was reported that injectable methylcellulose appears to be a suitable scaffold for bridging traumatically injured tissue when a cavity forms within the first few days following a traumatic insult to the cortex.
  • adipose-derived breast tissue progenitor cells or stem cells are mixed with poly(N-isopropyl acrylamide) to form an injectable gel material. After loading the gel material into the breast of a recipient at adjacent the porous scaffold, the gel material collapses and squeezes into the pores of the scaffold, where the stem cells start differentiation and proliferation to repair or treat breast tissue defect.
  • the delivery system of the presentation is catheter based.
  • the ability to repair itself continuously comprises delivering cell seeding slurry or concentrated cultured stem cells that is programmed to develop fat cells to augment the breast defect, wherein the cells may be derived from bone marrow stem cells or omentum fat cells.
  • Some aspects of the present invention relate to various breast implant embodiments with stem cells loaded configuration or post-implantation stem cells receivable configuration and delivery systems thereof.
  • a woman breast comprises fatty tissue, muscle, ducts, and a nipple, among others.
  • One embodiment of the present invention is to deliver a breast implant through the nipple and extendably follow the duct or the space under the subcutaneous layer of the breast.
  • Another embodiment of the delivery route is similar to that of the silicone-gel breast implant placement.
  • FIG. 3 shows a breast implant embodiment of the fishbone design 30 at (A) an expanded profile, and (B) a collapsed profile.
  • the fishbone implant 30 comprises an expandable construct 31 with a plurality of close cells 3 ' 8 formed between the longitudinal elements 35 and the connecting transverse elements 36, wherein the construct 31 is enclosed and loaded within the lumen of a sheath 32 during the initial delivery phase, the sheath being unobstructively movable substantially along the same direction 33 of the construct 31.
  • the sheath 32 is a solid cylinder, a meshed cylinder, or a flexible tubular apparatus that is detachable from the construct at the end of the delivery phase.
  • the distal ends 37 of the construct 31 form a circular shape 34 after the implant is delivered to the breast site of a recipient.
  • stem cells or adipose-derived breast tissue progenitor cells may be loaded on the breast implant before delivery or injected to adjacent the implant after the implant is delivered in place.
  • FIG. 4 shows a first breast implant embodiment of the umbrella design 40 with
  • the umbrella implant 40 comprises a plurality of radially expandable extending elements 42, each having a distal end 43 and a proximal end 44. In one embodiment, the proximal ends 44 of all extending elements are secured together at one point.
  • the delivery instrument 41 may comprise a lumen 45 with a pushing plunger 46, wherein the plunger is activated by a pushing mechanism 47 located at the handle of the delivery instrument. In operations, the needle tip 48 of the delivery instrument 41 contacts or partially penetrates the nipple of a recipient, the plunger is activated until the umbrella implant is fully deployed, which is indicated by a pre-marked marker 49 on the delivery instrument 41.
  • a delivery instrument for delivering an umbrella-configured breast matrix to a breast of a patient comprising: a hollow tubular sheath having a distal needle tip, a lumen having an opening at the distal tip, and a handle portion; a plunger inside the lumen, wherein the plunger is activated by a pushing mechanism located at the handle portion; and wherein the lumen is sized and configured for appropriately receiving an umbrella-configured breast matrix at a collapsed profile.
  • FIG. 5 shows a second breast implant embodiment of the umbrella design 50 with (A) a delivery instrument 51, (B) a proximal cross-sectional view of the delivery instrument, (C) a distal cross-sectional view of the delivery instrument, and (D) at an expanded device profile.
  • the breast implant 50 is loaded outside of the delivery instrument 51 in FIG. 5.
  • the second umbrella implant 50 comprises extending elements 55 and some connecting members 54 between the elements 55 to form an umbrella shape.
  • the connecting member 54 may comprise netting, strings, threads, porous membranes, porous biodegradable films, biocompatible polymers, etc. as disclosed above.
  • the instrument tip 53 of the delivery instrument 51 contacts and penetrates into the nipple of a recipient, the instrument 51 is pushed forward until the umbrella implant 50 at its collapsed profile is fully deployed inside the breast, which is indicated by a pre-marked marker 52 on the delivery instrument 51.
  • a delivery instrument for delivering an umbrella-configured breast matrix to a breast of a patient comprising a tubular applicator having a distal tip, a distal portion and a handle portion, wherein the distal portion is sized and configured for appropriately receiving an umbrella-configured breast matrix at a collapsed profile over the distal portion.
  • FIG. 6 shows a breast implant of the wrap-around design 60, (A) at an expanded profile, (B) at a collapsed profile, and (C) with a simulated profile.
  • the wrap-around implant 60 may be made of shape memory polymer, shape memory biodegradable polymer or shape memory alloy, such as Nitinol.
  • a pre-shaped implant 60 is sized and shaped as a straight wire with a few small curvatures 61 at a first configuration (as shown in FIG. 6B).
  • the implant is delivered into the breast, say from the nipple. After the implant is in place, the implant 60 is changed to a second 3-D configuration (as shown in FIG.
  • the shape transition temperature is configured to be a few degrees, preferably 1 to 5 0 C, above the body temperature.
  • at least a major portion of the implant in the second configuration 63 is placed at a space under the subcutaneous layer of the breast (as shown in FIG. 6C) serving as a scaffold for stem cell deposition/differentiation leading to cell proliferation and tissue regeneration.
  • FIG. 7 shows a breast implant of the yo-yo design 70.
  • the implant comprises a plurality of circular rings 71 with varying diameters.
  • at least a portion of the circular rings 71 is an open ring with two ends 72 so that the ring can be inserted into the breast by first entering one end of the open ring into the nipple.
  • at least two rings are releasably secured to each other by a circular semi-ring 73 to form a bowl-like configuration.
  • each component (the circular rings or the circular semi-ring) of the yo-yo implant occupies certain locations of the breast for intended tissue regeneration by the loaded adipose-derived stem cells.
  • the aforementioned breast implant is delivered to the breast by surgical operations or other penetration methods so that the implant serves as the supporting matrix for stem cells to repair or augment a breast tissue defect in a patient.
  • the "breast implant” herein is intended to mean a scaffold, matrix, or stent to partially support the breast and partially support the loaded stem cells composition for tissue repair/augmentation, whereas the breast implant does not herein include or indicate any breast silicone prosthesis.
  • FIG. 10 shows one embodiment of several components of an injecting needle 90
  • FIG. 11 shows an illustration view and a cross-sectional view of the injecting needle, respectively.
  • the needle of the invention 90 comprises an outer tubular member 91 having a fluid passageway connected to at least one opening 94 that is sized and configured for releasing the stem cell formulation from the fluid passageway at a desired location inside the breast and a desired timing.
  • the needle further comprises an intermediate tubular member 92 having a slit opening 95 that is ⁇ zed and configured for releasing the stem cell formulation.
  • the needle comprises an inner elongate member 93 having a distal end 97, at least one recess section 96A and at least one circular expanded section 96B that fits inside the inner void of the intermediate member 92.
  • the distal end 97 may be sharpened to penetrate into the breast skin.
  • the clearance between the circular section 96B and the inner void is sized and configured for rotating the inner member 93 effortlessly relative to the intermediate member 92, but preventing any leakage from one recess section to an adjacent recess section.
  • the inner elongate member 93 further comprises a central lumen or passageway that has at least one opening at each recess section and is in fluid communication through a proximal port 89 to an outside pressure source (not shown) or a pressurized supply of stem cell formulation.
  • FIG. 12 shows a system for delivering stem cell formulation or composition to a patient.
  • the system comprises the needle portion 90 and a syringe-like supplier 98 of the stem cell formulation that is connected through a flexible connecting means 99 to the proximal port 89 of the needle portion 90.
  • the system comprises the needle portion 90 and an external pressure source that is configured to push the stem cell formulation out of the recess section 96A of the inner member 93 to the surrounding tissue.
  • FIG. 2 shows a bra apparatus having capability for electromagnetic stimulation functions.
  • the bra 180 has a pair of cups 184, preferably molded of silicon, having an interior surface 185 facing the skin of a breast and an exterior surface facing the outer cloths.
  • the cups 184 are substantially oval in shape and are slightly contoured to fit intimately over and cover the breasts of the user.
  • the cups 184 include a periphery 188.
  • a flange 183 is attached to each of the cups 184 by extending outwardly from a portion of the periphery 188 of the cups 184.
  • the flanges 183 each have a first surface 182, an upper tab 189, and a side tab 186.
  • the flange 183 for each cup 184 extends outwardly from a portion of the periphery 188 of that cup 184.
  • a treatment applicator 181 are attached to the interior surface 185 of each of the cups 184 for providing electromagnetic energy to the breast when the bra 180 is worn by the user and the energy is activated.
  • the treatment applicator is connected to a remote energy generator 187 for supplying the needed dosage of electromagnetic energy.
  • the power controller is located in a pocket on the cloths for the patient to start/stop the stimulation process or to adjust the stimulation dosage as needed/prescribed.

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Abstract

L’invention a pour objet un implant fait d’une structure poreuse ensemencée de cellules-souches et des systèmes de pose pour le traitement d’une lésion du tissu mammaire ou son augmentation. L’invention concerne également une matrice mammaire pour l’administration de la formulation de cellules-souches au niveau de la lésion mammaire afin de la traiter ou d’augmenter le tissu mammaire, comprenant une bande souple percée d’au moins un trou pour guider une aiguille d’injection dans la poitrine de la patiente, la bande souple étant conçue pour être posée en contact étroit avec la surface de la poitrine.
PCT/US2006/040786 2005-11-07 2006-10-20 Systeme d’augmentation mammaire et de reconstruction Ceased WO2007055882A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US11/268,392 US20070104692A1 (en) 2005-11-07 2005-11-07 Breast tissue regeneration
US11/268,392 2005-11-07
US11/414,860 US20070104694A1 (en) 2005-11-07 2006-05-01 Breast stimulation and augmentation system
US11/414,860 2006-05-01
US11/490,431 US20070104695A1 (en) 2005-11-07 2006-07-20 Breast augmentation and reconstruction system
US11/490,431 2006-07-20

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WO2007055882A2 true WO2007055882A2 (fr) 2007-05-18
WO2007055882A3 WO2007055882A3 (fr) 2007-12-27

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US5716404A (en) * 1994-12-16 1998-02-10 Massachusetts Institute Of Technology Breast tissue engineering
US6638308B2 (en) * 1997-10-10 2003-10-28 John D. Corbitt, Jr. Bioabsorbable breast implant
PT1261694E (pt) * 2000-02-26 2008-04-03 Artecel Inc Células estaminais pluripotentes produzidas a partir de células estromais derivadas de tecido adiposo e suas utilizações.

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