• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    method for treating a tissue matrix; acellular tissue matrix method for treating tissue matrices and tissue matrices produced according to the methods are provided. methods may include treating a tissue matrix with a proteolytic enzyme to produce a desired malleability of the tissue matrix.
    公开号:BR112013027307B1
    申请号:R112013027307
    申请日:2012-04-27
    公开日:2020-02-04
    发明作者:Chen Yi
    申请人:Lifecell Corp；
    IPC主号:
    专利说明:

    METHOD FOR TREATING A FABRIC MATRIX [001] This application claims priority under 35 U.S.C. § 119 to provisional application No. US61 / 479,937 that was filed on April 28, 2011.
    [002] The present disclosure relates to tissue matrices and, more particularly, to methods for controlling the malleability of tissue matrices by treating the matrices with proteolytic enzymes.
    [003] Various tissue products are used to regenerate, repair or otherwise treat diseased or damaged tissues and organs. Such products may include intact tissue grafts and / or reconstituted acellular or acellular tissues (e.g., acellular tissue matrices of the skin, intestine or other tissues, with or without cell seeding). Such products generally have mechanical properties determined by the tissue source (i.e., the type of tissue and the animal from which it originated) and by the processing parameters used to produce the tissue products. Since tissue products are often used for surgical applications and / or tissue augmentation or replacement, the mechanical properties of tissue products are important. For example, surgeons generally prefer tissues that feel more natural and / or are easy to manipulate during surgical procedures. However, some fabric products are undesirably stiff and have an unnatural feel. Consequently, methods for treating fabric products to produce more desirable mechanical properties are provided.
    SUMMARY [004] According to certain modalities, a
    Petition 870190106565, of 10/21/2019, p. 7/27
    2/17 method for treating a tissue matrix is provided. The method may comprise selecting a tissue matrix containing collagen and contacting the tissue matrix with a proteolytic enzyme under conditions sufficient to produce a desired level of malleability in the tissue matrix.
    [005] In another embodiment, a method for treating a tissue matrix is provided. The method may comprise selecting an acellular tissue matrix containing collagen and contacting the tissue matrix with a proteolytic enzyme under conditions sufficient to produce a desired level of malleability in the tissue matrix and to increase the porosity of the tissue matrix.
    [006] In some embodiments, an acellular tissue matrix is provided. The matrix can be prepared by a process comprising selecting an acellular tissue matrix and contacting the tissue matrix with a proteolytic enzyme under conditions sufficient to produce a desired level of malleability in the tissue matrix.
    DESCRIPTION OF THE DRAWINGS [007] Figure 1A to Figure 1D show acellular tissue arrays after treatment with enzymes using the methods of the present disclosure, as well as untreated controls.
    [008] Figure 2 is a plot of tensile strength test data box for treated and control samples.
    [009] Figure 3 is a plot of suture resistance test data box for treated and control samples.
    [010] Figure 4 is a data box plot
    Petition 870190106565, of 10/21/2019, p. 8/27
    3/17 tear resistance test for treated and control samples.
    [011] Figure 5 is a plot of the elastase degradation test data box for treated and control samples.
    [012] Figure 6 is a plot of yield strength test data box for treated and control samples.
    DESCRIPTION ______ DE______DETERMINATES______ EXEMPLIFICATIVE MODALITIES [013] Reference will now be made in detail to certain exemplary modalities in accordance with the present disclosure, certain examples of which are illustrated in the accompanying drawings. Whenever possible, the same reference numbers will be used by all drawings to refer to the same or similar parts.
    [014] The section headings used in this document are for organizational purposes only and should not be construed as limiting the material described. All documents or portions of documents cited in this application including, but not limited to, patents, patent applications, articles, books and research are expressly incorporated by reference in their entirety for reference for any purpose.
    [015] As used herein, “tissue product” will refer to any human or animal tissue that contains an extracellular matrix protein. “Tissue products” may include acellular or partially decellularized tissue arrays, decellularized tissue arrays that have been repopulated with cells
    Petition 870190106565, of 10/21/2019, p. 9/27
    4/17 exogenous and / or cellular tissues that have been processed to change the orientation of at least some collagen fibers within the extracellular matrix of the tissue.
    [016] Various human and animal tissues can be used to produce the products to treat patients. For example, various tissue products for the regeneration, repair, augmentation, strengthening and / or treatment of human tissues that have been damaged or lost due to various diseases and / or structural damage (for example, from trauma, surgery, atrophy and / or long-term wear and tear) have been produced. Such products may include, for example, acellular tissue arrays, allografts or xenografts of tissue and / or reconstituted tissues (i.e., at least partially decellularized tissues that have been seeded with cells to produce viable materials).
    [017] For surgical applications, it is often desirable to produce tissue products that have certain mechanical properties. For example, the fabric product that may include a sheet of the material must be strong enough to withstand the intended use. For example, certain tissue products can be used to repair defects (for example, hernias), to support surrounding tissues or implants (for example, for breast augmentation and / or reconstruction) or to replace damaged or lost tissue (for example, after trauma or surgical resection). Whatever the particular use, the fabric product must have sufficient strength, elasticity and / or other mechanical properties to function until tissue regeneration and / or repair occurs.
    [018] Additionally, fabric products
    Petition 870190106565, of 10/21/2019, p. 10/27
    5/17 must have a desirable feeling. For example, surgeons generally prefer materials that have a similar feel to natural tissue (for example, they are sufficiently soft, flexible and / or elastic). Furthermore, after implantation, it is desirable that the fabric products have a more natural feel. For example, the tissues used for breast augmentation should not be overly rigid in order to produce a breast with a more natural feel.
    [019] However, some fabric products can be overly rigid. For example, some surgeons note that pig-derived dermal materials, such as STRATTICE ™, are less flexible than human dermal products, such as ALLODERM®. However, processes to improve the feel of such products must not adversely affect the biological and / or mechanical properties of the products. Specifically, processing the products to improve the feel of the products must not produce an undesirable decrease in other mechanical properties such as tensile strength and must not alter the protein matrix in such a way that the material does not support regeneration and / or repair. of fabric.
    [020] The present disclosure provides methods for treating fabrics to improve the feel of fabric products made from fabrics. The revelation also provides tissue products produced using treatment methods. In addition, the present disclosure provides methods for treating fabrics to control the porosity of the fabric products produced from the fabrics. In some cases, controlling porosity can improve cell infiltration and tissue regeneration and / or repair.
    Petition 870190106565, of 10/21/2019, p. 11/27
    6/17 [021] Consequently, in one embodiment, a method for treating a tissue matrix is provided. The method may comprise selecting a tissue matrix containing collagen and contacting the tissue matrix with a proteolytic enzyme under conditions sufficient to produce a desired level of malleability in the tissue matrix. In another embodiment, a method for treating a tissue matrix is provided. The method may comprise selecting an acellular tissue matrix containing collagen and contacting the tissue matrix with a proteolytic enzyme under conditions sufficient to produce a desired level of malleability in the tissue matrix and to increase the porosity of the tissue matrix. THE
    Figure 1A to Figure 1D show acellular tissue arrays (STRATTICE ™) after treatment with enzymes using the methods of the present disclosure, as well as untreated controls. As shown, the treated samples are significantly more flexible.
    [022] In various modalities, the treatment of tissue matrices with proteolytic enzymes provides improved mechanical properties without causing degradation in one or biological properties. For example, treatment of tissue matrices can produce desired stiffness, sensation, tactile properties and / or desired porosity without causing increased inflammation or scar formation and / or without causing a reduction in the ability of tissue matrices to promote internal growth and cell regeneration.
    [023] Fabrics can be selected to provide a variety of different biological and mechanical properties. For example, an acellular tissue matrix or other tissue product can be selected to allow
    Petition 870190106565, of 10/21/2019, p. 12/27
    7/17 internal tissue growth and remodeling to assist in tissue regeneration normally found at the site where the matrix is implanted. For example, an acellular tissue matrix, when implanted on or inside the fascia, can be selected to allow regeneration of the fascia without scarring or excessive fibrosis. In certain embodiments, the tissue product can be formed from ALLODERM® or STRATTICE ™ which are acellular dermal matrices of humans and pigs, respectively. Alternatively, other suitable acellular tissue arrays can be used, as further described below. Tissues can be selected from a variety of tissue sources including skin (dermis or the entire skin), fascia, pericardial tissue, dura, umbilical cord tissue, placental tissue, heart valve tissue, ligament tissue, tendon tissue, arterial tissue, poisonous tissue, nerve connective tissue, urinary bladder tissue, ureter tissue and intestinal tissue. The methods described in this document can be used to process any type of collagenous tissue and for any tissue product matrix. For example, several biological framework materials are described by Badylak et al. and the methods of the present disclosure can be used to treat these or other tissue products known in the art. Badylak et al., “Extracellular Matrix as a Biological Scaffold Material: Structure and Function,” Acta Biomaterialia (2008), doi: 10.1016 / j.actbio.2008.09.013.
    [024] In some cases, the tissue matrix may be supplied as a decelluralized tissue matrix. Suitable acellular tissue arrays are further described below. In other cases, the method may include
    Petition 870190106565, of 10/21/2019, p. 13/27
    8/17 additionally processing the intact tissue to remove cells or other materials. The tissues can be completely or partially de-culturalized to yield acellular tissue arrays or extracellular tissue materials to be used for patients. For example, various tissues, such as skin, intestine, bone, cartilage, nerve (e.g., nerve or hard fibers), tendons, ligaments or other tissues can be completely or partially decellularized to produce tissue products useful for patients. In some cases, these decellularized products can be used without the addition of exogenous cellular materials (for example, stem cells). In certain cases, these decellularized products can be seeded with cells from autologous sources or other sources to facilitate treatment. Suitable processes for producing acellular tissue arrays are described below.
    [025] Several different enzymes can be used to treat tissue matrices. For example, suitable enzymes can include sulfhydryl proteases, such as bromelain. In addition, they may include include bromelain, papain, ficin, actinidine or combinations thereof. Enzymes can be purchased commercially or extracted from fruit sources. For example, a source of bromelain is MCCORMICK MEAT TENDERIZER®, but enzymes can
    also be extracted pineapple and / or acquired in an medical grade formulation.[026] Enzymes can be contacted with the fabrics to increase the malleability of fabric without cause
    undesirable degradation in other mechanical and / or biological properties. For example, when a batch of materials is produced with or without the enzyme treatments discussed in
    Petition 870190106565, of 10/21/2019, p. 14/27
    9/17 of this document, enzyme treatments will not produce an undesirable change in at least one of the tensile strength, tear strength, suture resistance, yield strength, collagenase susceptibility, glycosaminoglycan content, lectin content, resistance to rupture, thermal transition temperature or combinations thereof. In some cases, an undesirable change is a statistically significant reduction in any of tensile strength, tear strength, suture strength, yield strength, glycosaminoglycan content, lectin content, resistance to breakage; an increase in the susceptibility of collagenase; or a change (up or down) in the thermal transition temperature (as measured using differential scanning calorimetry).
    [027] As noted above, in some embodiments, tissues are treated with an enzyme to increase tissue porosity. In several modalities, the increase in tissue porosity is performed to increase the number and / or size of the channels, which can improve the rate of cell infiltration and tissue regeneration.
    [028] In some cases, enzymes are selected in such a way that they can cause cleavage with specificity for protein site within tissues. For example, it has been revealed that the treatment of pig dermal materials with bromelain does not cause additional changes in the matrix structure after a certain amount of treatment. Therefore, treatment of the dermis with bromelain does not cause a further change in the matrix with prolonged exposure or after extended periods of time.
    Petition 870190106565, of 10/21/2019, p. 15/27
    10/17 [029] Additionally, the enzyme can be applied to tissues in a variety of suitable solutions. For example, bromelain has been shown to be effective when applied to tissues in normal saline, but other suitable buffers (eg, PBS) can be used.
    ACELLULAR TISSUE MATRICES [030] The term "acellular tissue matrix", as used herein, generally refers to any tissue matrix that is substantially free of cells and / or cellular components. The skin, parts of the skin (e.g., dermis) and other tissues such as blood vessels, heart valves, fascia, cartilage, bone and nervous connective tissue can be used to create acellular matrices within the scope of the present disclosure. Acellular tissue arrays can be tested or evaluated to determine whether they are substantially free of cells and / or cellular components in a variety of ways. For example, processed tissues can be inspected with light microscopy to determine whether cells (alive or dead) and / or cellular components remain. In addition, certain assays can be used to identify the presence of cells or cellular components. For example, DNA or other nucleic acid assays can be used to quantify nuclear material remaining within the tissue arrays. Generally, the absence of DNA or other remaining nucleic acids will be indicative of complete decellularization (ie, removal of cells and / or cellular components). Finally, other assays that identify cell-specific components (for example, surface antigens) can be used to determine whether tissue matrices are acellular. THE
    Petition 870190106565, of 10/21/2019, p. 16/27
    11/17 skin, parts of the skin (e.g., dermis) and other tissues such as blood vessels, heart valves, fascia, cartilage, bone and nervous connective tissue can be used to create acellular matrices within the scope of the present disclosure.
    [031] In general, the steps involved in producing an acellular tissue matrix include harvesting tissue from a donor (for example, a human cadaver or animal source) and removing cells under conditions that preserve biological and structural function. In certain embodiments, the process includes chemical treatment to stabilize the tissue and prevent biochemical and structural degradation together with or before removal of cells. In several embodiments, the stabilization solution stops and prevents osmotic, hypoxic, autolytic and proteolytic degradation, protects against microbial contamination and reduces the mechanical damage that can occur with tissues containing, for example, smooth muscle components (for example , blood vessels). The stabilizing solution may contain an appropriate buffer, one or more antioxidants, one or more oncotic agents, one or more antibiotics, one or more protease inhibitors and / or one or more smooth muscle relaxants.
    [032] The tissue is then placed in a decellularization solution to remove viable cells (eg, epithelial cells, endothelial cells, smooth muscle cells and fibroblasts) from the structural matrix without damaging the biological and structural integrity of the collagen matrix. . The decellularization solution may contain a suitable buffer, salt, an antibiotic, one or more detergents (for example, TRITON X-100 ™, sodium deoxycholate, sodium monooleate).
    Petition 870190106565, of 10/21/2019, p. 17/27
    12/17 polyoxyethylene (20) sorbitan), one or more agents to prevent cross-linking, one or more protease inhibitors and / or one or more enzymes. In some embodiments, the decellularization solution comprises TRITON X-100 ™ at 1% in RPMI medium with Gentamicin and EDTA at 25 mM (ethylenediaminetetraacetic acid). In some embodiments, the tissue is incubated in the decellularization solution overnight at 37 ° C with gentle shaking at 90 rpm. In certain embodiments, additional detergents can be used to remove grease from the tissue sample. For example, in some embodiments, 2% sodium deoxycholate is added to the decellularization solution.
    [033] After the decellularization process, the tissue sample is washed carefully with saline. In some exemplary embodiments, for example, when xenogenic material is used, the decellularized tissue is then treated overnight at room temperature with a deoxyribonuclease (DNase) solution. In some embodiments, the tissue sample is treated with a DNase solution prepared in the DNase buffer (20 mM HEPES (4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid), 20 mM CaCl2 and 20 mM MgCl2) . Optionally, an antibiotic solution (for example, Gentamicin) can be added to the DNase solution. Any suitable buffer can be used as long as the buffer provides adequate DNase activity.
    [034] Although an acellular tissue matrix can be made from one or more individuals of the same species as the recipient of the acellular tissue matrix graft, this is not necessarily the case. So, for example, an acellular tissue matrix can be made from pig tissue
    Petition 870190106565, of 10/21/2019, p. 18/27
    13/17 and implanted in a human patient. Species that serve as receptors for the acellular tissue matrix and donors of tissues or organs for the production of the acellular tissue matrix include, without limitation, mammals, such as humans, non-human primates (eg monkeys, baboons or chimpanzees), pigs, cows, horses, goats, sheep, dogs, cats, rabbits, guinea pigs, gerbils, hamsters, rats or mice.
    [035] Elimination of α-gal epitopes from collagen-containing material may decrease the immune response against collagen-containing material. The α-gal epitope is expressed in non-primate mammals and New World monkeys (South American monkeys) as well as macromolecules such as proteoglycans from extracellular components. U. Galili et al., J. Biol. Chem. 263: 17755 (1988). This epitope is absent in Old World primates (monkeys from Asia and Africa and apes) and humans, however. Id. Anti-gal antibodies are produced in humans and primates as a result of an immune response to α-gal epitope carbohydrate structures in gastrointestinal bacteria. U. Galili et al., Infect. Immun. 56: 1730 (1988); R. M. Hamadeh et al., J. Clin. Invest. 89: 1223 (1992).
    [036] Since non-primate mammals (for example, pigs) produce α-gal epitopes, xenotransplantation of the collagen-containing material of these mammals into primates often results in rejection because of the binding of primate anti-Gal to these epitopes in material that contains collagen. The binding results in the destruction of collagen-containing material by complement fixation and by antibody-dependent cellular cytotoxicity. U. Galili et al., Immunology Today 14: 480 (1993); M. Sandrin et al., Proc.
    Petition 870190106565, of 10/21/2019, p. 19/27
    14/17
    Natl. Acad. Sci. USA 90: 11391 (1993); H. Good et al.,
    Transplant. Proc. 24: 559 (1992); B. H. Collins et al., J.
    Immunol. 154: 5500 (1995). Furthermore, xenotransplantation results in the main major activation of the immune system to produce increased amounts of high-affinity anti-gal antibodies. Consequently, in some embodiments, when animals that produce α-gal epitopes are used as the tissue source, the substantial elimination of α-gal epitopes from cells and extracellular components of collagen-containing material and the prevention of re- expression of cellular α-gal epitopes can decrease the immune response against collagen-containing material associated with anti-gal antibody binding to α-gal epitopes.
    [037] To remove epitopes from α-gal, after carefully washing the tissue with saline to remove the DNase solution, the tissue sample can be subjected to one or more enzyme treatments to remove certain immunogenic antigens, if present in the sample. In some embodiments, the tissue sample can be treated with an α-galactosidase enzyme to eliminate α-gal epitopes if present in the tissue. In some embodiments, the tissue sample is treated with α-galactosidase at a concentration of 300 U / l prepared in the 100 mM phosphate buffer at pH 6.0. In other modalities, the concentration of α-galactosidase is increased to 400 U / l for adequate removal of αgal epitopes from the harvested tissue. Any suitable concentration of enzyme and buffer can be used as long as sufficient antigen removal is achieved.
    [038] Alternatively, instead of treating tissue with enzymes, animals that have been genetically
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    15/17 modified to lack one or more antigenic epitopes can be selected as the tissue source. For example, animals (for example, pigs) that have been genetically engineered to lack the chemical portion of terminal α-galactose can be selected as the tissue source. For descriptions of the appropriate animals, see the copending application of U.S. Serial No. 10 / 896,594 and Patent No. U.S.6.166.288, the disclosures of which are hereby incorporated by reference in their entirety for reference. In addition, certain exemplary methods of tissue processing to produce acellular matrices with or without reduced amounts of or not having chemical portions of alpha-1,3-galactose are described in Xu, Hui. et al., “A Porcine-Derived Acellular Dermal Scaffold that Supports Soft Tissue Regeneration: Removal of Terminal Galactose -« - (1,3) Galactose and Retention of Matrix Structure ”, Tissue Engineering, Volume 15, 1 to 13 (2009) , which is incorporated by reference in its entirety.
    [039] After the acellular tissue matrix is formed, viable histocompatible cells can optionally be seeded into the acellular tissue matrix to produce a graft that can be further remodeled by the host. In some embodiments, viable histocompatible cells can be added to the matrices by standard in vitro cell co-culture techniques before transplantation or by in vivo repopulation following transplantation. In vivo repopulation may be by the recipient's own cells migrating to the acellular tissue matrix or by infusion or injection of cells obtained from the recipient or histocompatible cells from another donor in the matrix
    Petition 870190106565, of 10/21/2019, p. 21/27
    16/17 of acellular tissue in situ. Various types of cells can be used, including embryonic stem cells, adult stem cells (for example, mesenchymal stem cells) and / or neuronal cells. In various modalities, cells can be applied directly to the inner portion of the acellular tissue matrix just before or after implantation. In certain embodiments, cells can be placed within the acellular tissue matrix to be implanted and cultured before implantation.
    EXAMPLE [040] The following example illustrates a process for treating acellular pig dermal tissue arrays with bromelain to increase the malleability of the material. As discussed below, the treatment did not cause an undesirable change in various mechanical properties. Additionally, the treatment increases the porosity of the material which can improve the rate of cell infiltration and tissue regeneration.
    [041] For this experiment, acellular tissue arrays of STRATTICE ™, as obtained from LIFECELL CORPORATION (Branchburg, NJ) were used. STRATTICE ™ is available in a flexible form and in a firmer version, depending on the anatomical location from which the material was obtained. Both types were used for this experiment. The samples used for the test were cut into quarters and three quarters were treated. The untreated samples (1 quarter) were used as controls; controls were refrigerated during treatment. STRATTICE ™ is packaged in a solution and therefore does not require rehydration. The treated samples were placed in 0.5 liter of cold tap water containing 55g of MCCORMICK MEAT TENDERIZER.
    Petition 870190106565, of 10/21/2019, p. 22/27
    17/17 [042] Figures 1A to 1D show acellular tissue arrays after treatment with enzymes using the methods of the present disclosure, as well as untreated controls. Figures 2 to 6 are box plots of tensile strengths, suture strengths, tear strengths, elastase degradation and yield strength for each treated and control sample. The treated samples had a noticeably increased malleability compared to controls, but did not have a significant reduction in other mechanical properties. In addition, no significant changes in thermal transition temperature or susceptibility to collagenase have been revealed. The general paired t-test showed no statistical difference between the control and treatment groups.
    权利要求:
    Claims (5)
    [1]
    1. METHOD FOR TREATING A FABRIC MATRIX, characterized by understanding:
    select an array of acellular tissue that contains collagen;
    contacting the tissue matrix with a proteolytic enzyme, the proteolytic enzyme producing an increased level of malleability in the tissue matrix.
    [2]
    METHOD according to claim 1, characterized in that the acellular tissue matrix comprises a dermal tissue matrix.
    [3]
    3. METHOD, according to claim 1, characterized in that the acellular tissue matrix is selected from fascia, pericardial tissue, dura, umbilical cord tissue, placental tissue, heart valve tissue, ligament tissue, tendon tissue, arterial tissue , venous tissue, nerve connective tissue, urinary bladder tissue, ureter tissue and intestinal tissue.
    [4]
    4. METHOD according to any one of claims 1 to 3, characterized in that the enzyme is selected from among bromelain, papain, ficin, actinidine or combinations thereof.
    [5]
    METHOD according to any one of claims 1 to 4, characterized in that the enzyme is bromelain.
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    法律状态:
    2017-12-19| B15I| Others concerning applications: loss of priority|
    2018-02-27| B12F| Appeal: other appeals|
    2019-03-06| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|
    2019-07-23| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|
    2019-11-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-02-04| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/04/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201161479937P| true| 2011-04-28|2011-04-28|
    PCT/US2012/035361|WO2012149253A1|2011-04-28|2012-04-27|Method for enzymatic treatment of tissue products|
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