WO2008134305A2 - Dispositifs et procédés de manipulation de tissus pour organes à lumière - Google Patents

Dispositifs et procédés de manipulation de tissus pour organes à lumière Download PDF

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Publication number
WO2008134305A2
WO2008134305A2 PCT/US2008/061132 US2008061132W WO2008134305A2 WO 2008134305 A2 WO2008134305 A2 WO 2008134305A2 US 2008061132 W US2008061132 W US 2008061132W WO 2008134305 A2 WO2008134305 A2 WO 2008134305A2
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WO
WIPO (PCT)
Prior art keywords
tissue
matrix
minced
agents
bladder
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PCT/US2008/061132
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English (en)
Other versions
WO2008134305A3 (fr
Inventor
Sridevi Dhanaraj
Jeffrey C. Geesin
Ziwei Wang
Dhanuraj Shetty
Joseph J. Hammer
Daniel Keeley
Original Assignee
Johnson & Johnson Regenerative Therapeutics, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Johnson & Johnson Regenerative Therapeutics, Llc filed Critical Johnson & Johnson Regenerative Therapeutics, Llc
Priority to CN200880013669.7A priority Critical patent/CN101687063A/zh
Priority to EP08769154A priority patent/EP2150284A2/fr
Priority to JP2010506429A priority patent/JP2010524644A/ja
Priority to CA002685048A priority patent/CA2685048A1/fr
Publication of WO2008134305A2 publication Critical patent/WO2008134305A2/fr
Publication of WO2008134305A3 publication Critical patent/WO2008134305A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—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
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A61L27/3679—Hollow organs, e.g. bladder, esophagus, urether, uterus, intestine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • 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
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem 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
    • A61L27/3882—Hollow organs, e.g. bladder, esophagus, urether, uterus
    • 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
    • A61L2430/22—Materials or treatment for tissue regeneration for reconstruction of hollow organs, e.g. bladder, esophagus, urether, uterus
    • 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
    • A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking

Definitions

  • the present invention relates to methods and materials for tissue reconstruction, repair, augmentation, and replacement. More specifically, the present invention provides for the treatment of patients using an implantable device that is comprised of a biocompatible, biodegradable, synthetic or natural polymeric matrix shaped to conform to at least a part of a luminal organ or tissue structure and seeded with minced tissue.
  • the human urinary bladder is a luminal organ constituting a musculomembranous sac situated in the anterior portion of the pelvic cavity, The bladder serves as a reservoir for urine, which this organ receives through the ureters and discharges through the urethra.
  • me bladder is found in the pelvis behind the pelvic bone (pubis symphysis) and the urethra, which exits to the outside of the body.
  • the bladder, ureters, and urethra are all similarly constituted in that they comprise muscular structures lined with a membrane comprising urothelial cells coated with mucus that is impermeable to me normal soluble substances of me mine.
  • the trigone of the bladder is a smooth triangular portion of the mucous membrane at the base of the bladder.
  • the bladder tissue is elastic and compliant, i.e., the bladder changes shape and size according to the amount of urine it contains.
  • a bladder resembles a deflated balloon when empty, but becomes somewhat pear-shaped and rises into me abdominal cavity when the amount of urine increases.
  • the bladder wall has three main layers of tissues: the mucosa, submucosa, and detrusor.
  • the mucosa comprising urothelial cells, is the innermost layer and is composed of transitional cell epithelium.
  • the submucosa lies immediately beneath the mucosa and its basement membrane. It is composed of blood vessels mat supply the mucosa with nutrients and the lymph nodes, which aid in the removal of waste products.
  • the detrusor is a layer of smooth muscle cells that expands to store urine and contracts to expel urine.
  • bladder deterioration may result from infectious diseases, neoplasms, and developmental abnormalities. Bladder deterioration may also occur as a result of trauma from, for example, car accidents and sports injuries.
  • Naturally derived materials such as lyophilized dura, de- epithelialized bowel segments, and small intestinal submucosa have also been proposed for bladder replacement.
  • bladder augmented with dura, peritoneum, and placenta and fascia contract over time.
  • De- epithelialized bowel segments demonstrated an adequate urothelial covering for use in bladder reconstruction, but difficulties remain with mucosal regrowth, segment fibrosis, or both. It has been shown that de-epithelialization of the intestinal segments may lead to mucosal regrowth, whereas removal of the mucosa and submucosa may lead to retraction of the intestinal segment.
  • bladder reconstruction is directly related to the availability of donor tissue.
  • the limited availability of bladder tissue prohibits the frequent routine reconstruction of bladder using normal bladder tissue.
  • the bladder tissue that is available and considered usable may itself include inherent imperfections and disease. For example, in a patient suffering from bladder cancer, the remaining bladder tissue may be contaminated with metastasis. The patient is thus predestined to less than perfect bladder function.
  • An embodiment of the present invention relates to an organ reconstruction method comprising the steps of: providing a biodegradable polymer matrix conforming to a portion of a laminarly arranged luminal organ; obtaining autologous, allogeneic or xenogeneic tissue comprising multiple cell populations; processing the tissue to obtain a minced tissue composition; seeding the matrix with the composition; and implanting into a patient the seeded polymer matrix.
  • An embodiment of the present invention relates to an organ reconstruction method comprising the steps of: providing a biodegradable polymer matrix conforming to a portion of a laminarly arranged luminal organ; obtaining autologous, allogeneic or xenogeneic tissue comprising multiple cell populations; processing the tissue to obtain a first minced tissue composition and a second minced tissue composition; seeding a first area of the matrix with the first minced tissue composition, and seeding a second area of the matrix with the second minced tissue composition; and implanting into a patient the seeded polymer matrix.
  • Yet another embodiment of the present invention relates to an organ reconstruction device comprising an implantable, biodegradable polymer matrix conforming to a portion of a laminarly arranged luminal organ, wherein said matrix is capable of being seeded with a processed tissue composition, which comprises minced autologous, allogeneic or xenogeneic tissue comprising multiple cell populations.
  • Figure 1 depicts the anatomy of a normal human bladder.
  • Figure 2 depicts the tissue layers of various cell types that may be used in the minced tissue composition of the present invention.
  • Figure 3 A, 3B, and 3C depicts the cell migration, distribution and organization of urothelial and smooth muscle cells from bladder minced tissue into resorbable scaffolds. Arrows (1) point to urothelial cell clusters and layers; arrows (2) point to organization of smooth muscle like cells around the urothelial cells; and star denotes the cavity within the newly organized urothelium and smooth muscle structures.
  • the present invention provides for methods and materials for the reconstruction, repair, augmentation, or replacement of shaped hollow organs or tissue structures that exhibit a laminar segregation of different cell types and that have a need to retain a general luminal shape.
  • Luminal organs or tissue structures containing a smooth muscle cell layer to impart compliant or contractible properties to the organ or structure are particularly well-suited to the methods and devices of the present invention.
  • a luminal organ suitable for application of the present invention is a bladder, which has an inner layer of a first cell type that comprises urothelial-tissue, a middle layer of submucosa, and an outer layer of a second cell type that comprises smooth muscle tissue.
  • This organization is also present in other genitourinary organs and tissue structures such as the renal pelvis ureters and urethra.
  • Laminarily organized organs or tissues refer to any organ or tissue made up of, or arranged in laminae, including ductal tissue.
  • Suitable laminarily organized luminal organs, tissue structure, or ductal tissues to which the present invention is directed include vas deferens, fallopian tubes, lacrimal ducts, trachea, stomach, intestines, vasculature, biliary duct, ductus ejaclatoruis, ductus epididymidis, ductus parotideus, ureters, urethras, and surgically created shunts.
  • the present invention may be suitable for the treatment of such conditions as bladder extrophy, bladder volume insufficiency, reconstruction of bladder following partial or total cystectomy, repair of bladders damaged by trauma, and the like.
  • organs or tissues such as bladder, ureter, urethra, renal pelvis, and the like, can be reconstructed, repaired, augmented, or replaced with polymeric matrixes seeded with the appropriate minced tissue.
  • the devices and methods of the invention can be further applied to the reconstruction, repair, augmentation, and replacement of vascular tissue (see, e.g., Zdrahala, R. J., J. Biomater. Appl.
  • the patient to be treated may be of any species of mammals, such as a dog, cat, pig, horse, cow, or human, in need of reconstruction, repair, augmentation, or replacement of an organ or tissue structure.
  • the source of the minced tissue of the present invention may be of the same or different tissue origin than that intended to be reconstructed, repaired, augmented, and replaced.
  • the minced tissue may derive from urethral tissue to facilitate the reconstruction, repair, augmentation, and replacement of bladder tissue.
  • the morphologic similarity of luminal organs, such as bladder and urethral tissue, for example, is known in the art, see Dass et al., 165 J. Urol. 1294-1299 (2001), and the use of bladder tissue in urethra reconstruction has been reported, A. Atala, 4 (Suppl. 6) Am. J. of Transplantation 5873 (2004).
  • bladder reconstruction is directly related to the availability of donor tissue.
  • the limited availability of bladder tissue prohibits the frequent routine reconstruction of bladder using normal bladder tissue.
  • the bladder tissue that is available and considered usable may itself include inherent imperfections and disease. For example, in a patient suffering from bladder cancer, the remaining bladder tissue may be contaminated with metastasis. The patient is thus predestined to less than perfect bladder function.
  • the methods of the present invention provide a biocompatible synthetic or natural polymeric matrix that is shaped to conform to its use as a part or all of the bladder structure to be repaired, reconstructed, augmented or replaced.
  • a biocompatible material is any substance not having toxic or injurious effects on biological function.
  • synthetic polymer refers to polymers that are not found in nature, even if the polymers are made from naturally occurring biomaterials.
  • natural polymer refers to polymers that are naturally occurring.
  • the shaped, synthetic or natural polymeric matrix is preferably porous to allow for cell deposition and migration both on and in the pores of the matrix. It can be made from various scaffolding materials such as lyophilized foams, nonwoven scaffolds, or melt- blown scaffolds.
  • Lyophilization or freeze-drying, removes a solvent from a polymer-solvent solution through sublimation, leaving behind a porous solid. More specifically, the process separates a solvent from a frozen solution through a solid to gas phase transition. This transition, called sublimation, removes the solvent without it ever entering a liquid state.
  • the final construct is a porous solid structure made out of the remaining solute often described as a foam.
  • Liquid solution comprising any natural or synthetic biocompatible, biodegradable polymer, or any blend of such polymers, dissolved in a solvent that can be removed through sublimation, is poured into an open- ended, hinged mold and mechanically rotated during freezing.
  • the mold is hinged shut and partially filled with solution. During filling, some of the mold's volume remains empty. After lyophilization, the volume of solution poured into the mold will make up the scaffold volume whereas the empty volume will make up the hollow void.
  • the mold may be rotated in a number of ways. When the mold is held vertically and spun quickly, a centrifugal force acts on the liquid solution, pushing it away from the mold's center and up upon its sides.
  • the spinning mold may then be cooled slowly or flash frozen by submersion in liquid nitrogen.
  • the mold may also be held horizontally and rotated slowly whereby gravity allows the polymer to settle upon one side of the mold. Assuming that the temperature of the mold is lower than the temperature of the ambient air, a layer of frozen liquid will gradually build up on the mold's interior, resulting in an internal frozen skin. Both methods will produce a frozen construct that has a shape and texture consistent with the mold's internal geometry. Once fully frozen, the construct is placed in a vacuum for sublimation.
  • a variety of absorbable polymers can be used to make foams.
  • suitable biocompatible, bioabsorbable polymers that could be used include polymers selected from the group consisting of aliphatic polyesters, poly(amino acids), copoly(ether-esters), polyalkylene oxalates, polyamides, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamindoesters, polyoxaesters containing amine groups, poly(anhydrides), polyphosphzenes, biomolecules (i.e., biopolymers such as collagen, elastin, bioabsorbable starches, etc.), and blends thereof.
  • Suitable solvents include but are not limited to solvents selected from a group consisting of formic acid, ethyl formate, acetic acid, hexafluoroisopropanol (HFIP), cyclic ethers (i.e., THF, DMF, and PDO), acetone, acetates of C 2 to C 5 alcohol (such as ethyl acetate and t-butylacetate), glyme (i.e., monoglyme, ethyl glyme, diglyme, ethyl diglyme, triglyme, butyl diglyme, and tetraglyme), methylethyl ketone, dipropyleneglycol methyl ether, lactones (such as ⁇ -valerolactone, ⁇ -valerolactone, ⁇ -butyrolactone, ⁇ -butyrolactone), 1,4- dioxane, 1,3-dioxolane
  • the applicable polymer concentration or amount of solvent which may be utilized will vary with each system. Suitable phase diagram curves for several systems have already been developed. However, if an appropriate curve is not available, this can be readily developed by known techniques. The amount of polymer will depend to a large extent on the solubility of the polymer in a given solvent and the final properties of the foam desired.
  • a parameter that may be used to control foam structure is the rate of freezing of the polymer-solvent solution.
  • the type of pore morphology that gets locked in during the freezing step is a function of the solution thermodynamics, freezing rate, temperature to which it is cooled, concentration of the solution, homogeneous or heterogeneous nucleation, etc.
  • phase separation phenomenon can be found in the references provided herein. See A. T. Young, “Microcellular foams via phase separation," J. Vac. Sci. Technol. A 4(3), May/June 1986; S. Matsuda, "Thermodynamics of Formation of Porous Polymeric Membrane from Solutions," Polymer J. Vol. 23, No. 5, pp 435- 444, 1991).
  • a foam scaffold may also be constructed by a two-step mold where one part of the mold consists of a hollow section and another part consists of a core. This design is similar to that used in a typical injection molding process.
  • the solution can be filled via the space between the cavity and the core. The space can be determined by the thickness of the final construct. Once the filling is complete, the solution can be frozen by the steps above.
  • Another embodiment of the present invention may include nonwoven scaffolds.
  • Preferred nonwoven materials include flexible, porous structures produced by interlocking layers or networks of fibers, filaments, or film- like filamentary structures. Such nonwoven materials can be formed from webs of previously prepared/formed fibers, filaments, or films processed into arranged networks of a desired structure.
  • nonwoven materials are formed by depositing the constituent components (usually fibers) on a forming or conveying surface. These constituents may be in a dry wet, quenched, or molten state. Thus, the nonwoven can be in the form of a dry laid, wet laid, or extrusion-based material, or hybrids of these types of nonwovens can be formed.
  • the fibers or other materials from which the nonwovens can be made are typically polymers, either synthetic or naturally occurring.
  • Dry laid scaffolds may include those nonwovens formed by garneting, carding, and/or aerodynamically manipulating dry fibers in the dry state.
  • wet laid nonwovens may be formed from a fiber-containing slurry that is deposited on a surface, such as moving conveyor. The nonwoven web can be formed after removing the aqueous component and drying the fibers.
  • Extrusion-based nonwovens may include those formed from spun bond fibers, melt blown fibers, and porous film systems. Hybrids of these nonwovens can be formed by combining one or more layers of different types of nonwovens by a variety of lamination techniques.
  • the nonwoven may also be reinforced with a woven, knit or mesh fabric.
  • the nonwovens of the present invention preferably have a density designed to obtain mechanical characteristics ideal for augmenting bladder repair.
  • the density may be measured by determining the felt dimensions (length and width), for example, obtaining two measurements in each direction to calculate the average length and width for each nonwoven felt.
  • the trimmed felt may be weighed, and the weight recorded.
  • the average thickness of each nonwoven felt may be obtained using a Shirley gauge.
  • the density may be calculated by the following formula:
  • Density (weight of felt (W) (grams))/(lengthx width
  • scaffolds may be manufactured by use of melt-blowing technology whereby fibrous webs from molten polymer resin are extruded from spinnarettes onto a rotating collapsible object in the presence of a porogen.
  • the collapsible object can be made to rotate or otherwise move therefore allowing a coating of extruded polymer to layer itself substantially evenly on the collapsible object. Continuous rotation of the surface will produce an increasingly thick or dense layer due to more polymer being deposited.
  • the use of a collapsible object creates seamless, three-dimensional shapes of polymer web.
  • the final product may be a hollow shape with a single outlet from which the collapsed shape has been removed.
  • More complex geometries may be achieved by using suitably shaped tooling such as a mold or mandrel to guide the formation of the melt-blown filaments into a specific shape. This method is described in detail by Keeley et al. in US Patent Application serial number 11/856,743.
  • a scaffold constructed of either material is both biocompatible and resorbable but may not be sufficiently porous to facilitate optimal proliferation of cells or advanced tissue ingrowth.
  • a porogen may be added during the fabrication of the non- woven web. Porogens such as salt or glucose spheres can be dusted or blown onto the molten fibers during their extrusion. Gelatin microspheres can also be used. The resulting scaffold's porosity can be controlled by the amount of porogen added, while the pore size is dependent on the size of the spheres. As these particles enter the turbulent air, they are randomly incorporated into the web.
  • the porous structure may undergo an annealing process with the porogen material in place. Once the porogen-fiber composite is annealed, the entire construct may then be submerged in water so that the porogens dissolve or leach out of the web.
  • the resulting matrix contains polymer fibers but with increased distance between them to effect porosities. In one embodiment, the matrix has more porogen and hence, more porosity, the porosity in excess of 90%.
  • the polymers or polymer blends that are used to form the biocompatible, biodegradable scaffold may also contain pharmaceutical compositions.
  • the previously described polymer may be mixed with one or more pharmaceutical prior to forming the scaffold.
  • such pharmaceutical compositions may coat the scaffold after it is formed.
  • the variety of pharmaceuticals that can be used in conjunction with the scaffolds of the present invention includes any known in the art.
  • compositions of the invention include, without limitation: anti-infectives such as antibiotics and antiviral agents; chemotherapeutic agents; anti-rejection agents; analgesics and analgesic combinations; anti-inflammatory agents; hormones such as steroids; growth factors; and other naturally derived or genetically engineered (recombinant) proteins, polysaccharides, glycoproteins, or lipoproteins.
  • Scaffolds containing these materials may be formulated by mixing one or more agents with the polymer used to make the scaffold or with the solvent or with the polymer- solvent mixture.
  • an agent could be coated onto the scaffold, preferably with a pharmaceutically acceptable carrier. Any pharmaceutical carrier may be used that does not substantially degrade the scaffold.
  • the pharmaceutical agents may be present as a liquid, a finely divided solid, or any other appropriate physical form. Typically, but optionally, they will include one or more additives, such as diluents, carriers, excipients, stabilizers or the like.
  • various biologic compounds such as antibodies, cellular adhesion factors, growth factors, and the like, may be used to contact and/or bind delivery agents of choice (e.g., pharmaceuticals or other biological factors) to the scaffold of the present invention.
  • Synthetic polymers can also be modified in vitro before use, and can carry growth factors and other physiologic agents such as peptide and steroid hormones, which promote proliferation and differentiation.
  • the polyglycolic acid polymer undergoes biodegradation over a four month period; therefore as a cell delivery vehicle it permits the gross form of the tissue structure to be reconstituted in vitro before implantation with subsequent replacement of the polymer by an expanding population of engrafted cells.
  • the polymeric matrix may be shaped into any number of desirable configurations to satisfy any number of overall systems, geometries, or space restrictions.
  • the matrix in the use of the polymeric matrix for bladder reconstruction, the matrix may be shaped to conform to the dimensions and shapes of the whole or a part of a bladder.
  • the polymeric matrix may be shaped in different sizes and shapes to conform to the bladders of differently sized patients.
  • the polymeric matrix should be shaped such that after its biodegradation, the resulting reconstructed bladder may be collapsible when empty in a fashion similar to a natural bladder.
  • the polymeric matrix may also be shaped in other fashions to accommodate the special needs of the patient.
  • a previously injured or disabled patient may have a different abdominal cavity and may require a bladder reconstructed to adapt to fit it.
  • the portion of a laminarly arranged luminal organ to which the polymeric matrix can be conformed may be relatively minor. For example, 70% to 80%, or more, of the luminal organ could be replaced using the methods and materials of the present invention.
  • the polymeric matrix of the present invention includes a biocompatible scaffold having at least a portion in contact with a minced tissue suspension.
  • the minced tissue suspension can be disposed on the outer surface of the scaffold, on an inner region of the scaffold, and any combination thereof, or alternatively, the entire scaffold can be in contact with the minced tissue suspension.
  • the tissue can be obtained using any of a variety of conventional techniques, such as for example, by biopsy or surgical removal.
  • the tissue sample is obtained under aseptic conditions.
  • the sample can then be processed under sterile conditions to create a suspension having at least one minced, or finely divided, tissue particle.
  • the particle size and shape of each tissue fragment can vary, for example, the tissue size can be in the range of about 0.1 and 3 mm 3 , in the range of about 0.5 and 1 mm 3 , in the range of about 1 to 2 mm 3 , or in the range of about 2 to 3 mm 3 , but preferably the tissue particle is less than 1 mm 3 .
  • the shape of the tissue fragments can include slivers, strips, flakes or cubes as examples. Some methods include mechanical fragmentation or optical/laser dissections.
  • the tissue samples used in the present invention are obtained from a donor (autogeneic, allogeneic, or xenogeneic) using appropriate harvesting tools.
  • the tissue samples can be finely minced and divided into small particles either as the tissue is collected, or alternatively, after it is harvested and collected outside the body.
  • Mincing the tissue can be accomplished by a variety of methods. In one embodiment, the mincing is accomplished with two sterile scalpels using a parallel direction, and in another embodiment, the tissue can be minced by a processing tool that automatically divides the tissue into particles of a desired size.
  • the minced tissue can be separated from the physiological fluid and concentrated using any of a variety of methods known to those having ordinary skill in the art, such as for example, sieving, sedimenting or centrifuging.
  • the suspension of minced tissue preferably retains a small quantity of fluid in the suspension to prevent the tissue from drying out.
  • the suspension of minced tissue is not concentrated, and the minced tissue can be directly delivered to the site of tissue repair via a high concentration tissue suspension or other carrier such as for example, a hydrogel, fibrin glue, or collagen.
  • the minced tissue suspension can be covered by any of the biocompatible scaffolds described above to retain the tissue fragments in place.
  • the minced tissue can then be distributed onto a scaffold using a cell spreader or other tools known in the art.
  • the minced tissue can be dispersed onto a scaffold in one of several ways.
  • a biopsy of tissue sample comprising of full thickness of the bladder can be obtained.
  • Tissue can be minced as a whole and distributed on the scaffold.
  • a partial thickness biopsy of tissue sample can be obtained and minced as a whole and distributed on the scaffold. The difference in these two methods is the proportion of the urothelial cells to other cells, for example, smooth muscle cells.
  • a third example includes separating the urothelial layer and seromuscular layer and subsequently mincing the layers separately before distributing each onto to surfaces of the scaffold.
  • the urothelial minced tissue can be distributed on a scaffold seeded with isolated smooth muscle cells.
  • the minced smooth muscle tissue can be combined with a scaffold seeded with isolated urothelial cells.
  • the urothelial and or smooth muscle minced tissue can be combined with stem cells seeded on the scaffold.
  • the minced tissue has at least one viable cell that can migrate from the tissue fragment onto the scaffold.
  • the tissue contains an effective amount of cells that can migrate from the tissue fragment and begin populating the scaffold.
  • the minced tissue particles can be formed as a suspension in which the tissue particles are associated with a physiological buffering solution. Suitable physiological buffering solutions include, but are not limited to, saline, phosphate buffer solution, Hank's balanced salts, Tris buffered saline, Hepes buffered saline and combinations thereof.
  • the tissue can be minced in any standard cell culture medium known to those having ordinary skill in the art, either in the presence or absence of serum. Prior to depositing the suspension of minced tissue on the scaffold or at the site of tissue/organ injury, the minced tissue suspension can be filtered and concentrated, such that only a small quantity of physiological buffering solution remains in the suspension.
  • the minced tissue fragments may be contacted with a matrix-digesting enzyme to facilitate cell migration out of the extracellular matrix and into the scaffold material.
  • Suitable matrix-digesting enzymes that can be used in the present invention include, but are not limited to, collagenase, chondroitinase, trypsin, elastase, hyaluronidase, peptidase, thermolysin, and protease.
  • Example 1 Healthy intact bladder tissue was be obtained from a porcine source. The bladder tissue was dissected open, and intravesicular fluid within the bladder was aspirated out. The bladder tissue was then rinsed three times with phosphate buffered saline (PBS), and partial thickness biopsies were obtained from the bladder consisting of the urothelium layer, submucosa and a portion of the smooth muscle layer. The biopsied tissue was minced to a fine paste. This tissue paste was then distributed evenly on a 5mm punch of bioresorbable scaffold such that the minced tissue paste completely covered the scaffold. The scaffold loaded with minced tissue was implanted subcutaneously into severe combined immunodeficiency (SCID) mice for 4 weeks.
  • SCID severe combined immunodeficiency
  • FIG. 3 shows the extent of cell migration into the polymer scaffolds from the minced bladder tissue fragments. Clusters of urothelial cells are observed surrounded by smooth muscle cells. The size of the organized clusters range from small ones with central urothelial clusters (Fig. 3A), to larger ones with a central cavity (Fig. 3B). As these clusters grew they also began to coalesce to form a larger structure (Fig. 3C) with well organized urothelial cell layers surrounded by smooth muscle like cell layer with a central cavity. These structures resemble the organization seen in typical normal bladder. These figures demonstrate that the cells are able to migrate from the minced tissue into the scaffolds and are able to segregate and reorganize themselves into bladder like structures.

Abstract

L'invention concerne des dispositifs et des procédés de manipulation de tissus permettant de reconstruire, de réparer, d'augmenter ou de remplacer un organe à lumière ou une structure tissulaire. Les procédés selon l'invention impliquent l'utilisation d'une matrice de polymère biodégradable se conformant à une partie d'un organe à lumière laminaire, le traitement du tissu autologue, allogène ou xénogène comprenant de multiples populations cellulaires pour obtenir une composition de tissu émincée, l'ensemencement de la matrice avec la composition, et l'implantation de la matrice de polymère ensemencée chez le patient.
PCT/US2008/061132 2007-04-26 2008-04-22 Dispositifs et procédés de manipulation de tissus pour organes à lumière WO2008134305A2 (fr)

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CN200880013669.7A CN101687063A (zh) 2007-04-26 2008-04-22 用于管腔器官的组织工程装置与方法
EP08769154A EP2150284A2 (fr) 2007-04-26 2008-04-22 Dispositifs et procédés de manipulation de tissus pour organes à lumière
JP2010506429A JP2010524644A (ja) 2007-04-26 2008-04-22 内腔器官用の組織工学装置及び方法
CA002685048A CA2685048A1 (fr) 2007-04-26 2008-04-22 Dispositifs et procedes de manipulation de tissus pour organes a lumiere

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US60/907,994 2007-04-26

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WO2013157969A1 (fr) 2012-04-17 2013-10-24 Politechnika Łodzka Matériel médical pour reconstruction de vaisseaux sanguins, son procédé de fabrication et utilisation du matériel médical pour la reconstruction de vaisseaux sanguins
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US11123375B2 (en) 2017-10-18 2021-09-21 Lifecell Corporation Methods of treating tissue voids following removal of implantable infusion ports using adipose tissue products
US11246994B2 (en) 2017-10-19 2022-02-15 Lifecell Corporation Methods for introduction of flowable acellular tissue matrix products into a hand
US11633521B2 (en) 2019-05-30 2023-04-25 Lifecell Corporation Biologic breast implant
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CN104188734B (zh) * 2014-09-04 2016-05-18 浙江省人民医院 一种可降解球形人工膀胱

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JP2012517319A (ja) * 2009-02-11 2012-08-02 ナンヤン テクノロジカル ユニヴァーシティ 多層外科的プロテーゼ
JP2015147098A (ja) * 2009-02-11 2015-08-20 ナンヤン テクノロジカル ユニヴァーシティＮａｎｙａｎｇ Ｔｅｃｈｎｏｌｏｇｉｃａｌ Ｕｎｉｖｅｒｓｉｔｙ 多層外科的プロテーゼ
US9486302B2 (en) 2009-02-11 2016-11-08 Nanyang Technological University Multi-layered surgical prosthesis
US20160271295A1 (en) * 2011-04-14 2016-09-22 Lifecell Corporation Regenerative materials
US10828391B2 (en) * 2011-04-14 2020-11-10 Lifecell Corporation Regenerative materials
WO2013157969A1 (fr) 2012-04-17 2013-10-24 Politechnika Łodzka Matériel médical pour reconstruction de vaisseaux sanguins, son procédé de fabrication et utilisation du matériel médical pour la reconstruction de vaisseaux sanguins
US10821205B2 (en) 2017-10-18 2020-11-03 Lifecell Corporation Adipose tissue products and methods of production
US11123375B2 (en) 2017-10-18 2021-09-21 Lifecell Corporation Methods of treating tissue voids following removal of implantable infusion ports using adipose tissue products
US11246994B2 (en) 2017-10-19 2022-02-15 Lifecell Corporation Methods for introduction of flowable acellular tissue matrix products into a hand
US11826488B2 (en) 2017-10-19 2023-11-28 Lifecell Corporation Flowable acellular tissue matrix products and methods of production
US11633521B2 (en) 2019-05-30 2023-04-25 Lifecell Corporation Biologic breast implant

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WO2008134305A3 (fr) 2009-09-03
CN101687063A (zh) 2010-03-31
CA2685048A1 (fr) 2008-11-06
JP2010524644A (ja) 2010-07-22

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