fabric treatment composition

专利摘要:
abstract fabric treatment composition; kit; method of creating a fabric treatment product; treatment method; and method of treating a surgical site in a sinus following a lumpectomy procedure are elongated tissue treatment products and high aspect ratio. Methods of creating and using fabric treatment products are also provided. Tissue care products can be used as implants that conform to the implant site and resist migration from their implant site in vivo. 1/1
公开号:BR112014018047B1
申请号:R112014018047
申请日:2013-01-17
公开日:2019-11-26
发明作者:T Kibalo Benjamin；Bachrach Nathaniel；Roock Timothy
申请人:Lifecell Corp；
IPC主号:

专利说明:

TISSUE TREATMENT COMPOSITION [001]
This request claims priority from the
Provisional Application No. U.S. 61 / 590,035, filed on January 24, 2012, which is incorporated into this document as a reference in its entirety.
[002]
The present disclosure generally relates to methods of creating and using dies of elongated fabric and, more particularly, to methods of creating and using fabric dies that have a high aspect ratio.
[003]
Various tissue products are used to repair, regenerate, heal or otherwise treat diseased or damaged tissues and organs. Such products may include grafts of intact tissue and / or tissues partially or completely decellularized. These fabric care products generally have a shape that is defined by their original fabric. For example, dermal or intestinal products will generally comprise sheets of relatively flexible materials. However, not all wounds, voids, and / or other tissue treatment sites are amenable to treatment with tissue matrices in the form of a sheet. For example, a potential disadvantage of using sheet material is the inability to fully conform the sheet to the shape of the vacuum, wound or tissue to be treated. Similarly, treatment with injectable materials (for example, a non-sheet of particulate material delivered via syringe) can also be potentially challenging in cases where the injectable matrix has a tendency to migrate from the vacuum, wound or tissue to be treated. This migration could be a cosmetic and / or physiologically concern.
[004]
In order to treat, repair, heal or
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2/52 to regenerate certain tissue or organ defects, it may be desirable to use materials with the capacity to maintain shapes or configurations that conform more closely to the anatomical structures to be treated and that reduce the migration rate of the implant site. Consequently, methods of producing elongated acellular tissue matrices that can be used to fill a vacuum, wound, or other space in the tissue in need of treatment, repair, healing, or regeneration are disclosed herein. Elongated tissue arrays can be shaped to fill a desired shape, while also reducing the risk that the implant will migrate from the implant site. Treatment methods using such matrices are also disclosed in this document.
DESCRIPTION OF THE DRAWINGS [005] Figure 1 is a photograph of an acellular tissue treatment product in accordance with certain embodiments of the present disclosure.
[006] Figure 2 shows calculated ultrasound volumes (measured in cubic centimeters) for certain tissue treatment products four weeks after implantation in a Yucatan minipore mammary gland, as described in example 2.
[007] Figure 3 is an ultrasound volume scheme (measured in cubic centimeters) against dry tissue mass for certain tissue treatment products, measured four weeks after implantation in a Yucatan minipore mammary gland, as described in example 2.
[008] Figure 4 is a calibration analysis of
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3/52 ultrasound that was performed by comparing the ultrasound volume calculated immediately after implantation with the actual volumes of implanted material, as described in example 2.
[009] Figure 5 is a graph showing the indentation tonometry results conducted on certain tissue treatment products four weeks after implantation in a Yucatan mini-breast mammary gland, as described in example 2. A larger value indicates a lighter (more compatible) implant site, while a lower value indicates a heavier (less compatible) implant site.
[010] Figure 6 compares indentation tonometry results for certain tissue treatment products that have been implanted in a Yucatan mini-breast mammary gland, as described in example 2. The tonometry results are schematized at times of T = 0 and T = 4 weeks.
[011] Figure 7 is a scheme of stiffness values for certain tissue treatment products that have been implanted in a Yucatan mini-breast mammary gland as measured by BTC-2000 ™ (SRLI Technologies, Nashville, TN) as described in example 2.
[012] Figure 8 is a photograph of an elevated mammary gland four weeks after implantation of a representative tissue treatment product in a Yucatan minipore mammary gland, as described in example 2.
[013] Figure 9 is a cavity depth scheme, as measured by non-tonometry.
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4/52 loading, for certain tissue treatment products four weeks after implantation in a Yucatan mini-breast mammary gland, as described in example 2.
[014] Figure 10 shows X-ray imaging of a Yucatan mini-breast mammary gland before surgery (Figure 10A) and four weeks after implantation of tissue treatment products (Figure 10B), as described in example 2.
[015] Figure 11 is a photograph showing the gross anatomical structure of a high aspect ratio tissue treatment product (in PBS) four weeks after implantation in a Yucatan minipore mammary gland, as described in example 2 .
[016] Figure 12 is a photograph showing the gross anatomical structure of a high aspect ratio tissue treatment product (in a preservative solution) four weeks after implantation in a Yucatan minipore mammary gland, as described in example 2.
[017] Figure 13 shows the H&E ax of a high aspect ratio tissue treatment product (in PBS) four weeks after implantation in a Yucatan mini-breast mammary gland, as described in example 2.
[018] Figure 14 shows the H&E butch of a high aspect ratio tissue treatment product (in a preservative solution) four weeks after implantation in a Yucatan mini-breast mammary gland, as described in example 2.
[019] Figure 15 shows the classification of
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5/52 histology of H&E stained tissue treatment products four weeks after implantation in a Yucatan minipore mammary gland, as described in example 2. Tissue treatment products were classified for fibroblasts (Figure 15A), revascularization ( Figure 15B), and inflammation (Figure 15C).
[020] Figure 16 compares ultrasound volume (measured in cubic centimeters) for certain tissue treatment products four weeks and twenty weeks after implantation in a Yucatan mini-breast mammary gland, as described in example 2.
[021] Figure 17 is a comparison of elevated or cavity implants containing certain tissue treatment products four weeks (Figure 17A) and twenty weeks (Figure 17B) after implantation in a Yucatan minipore mammary gland, as described in example 2.
[022] Figure 18 shows the H&E butch of a high aspect ratio tissue treatment product (in PBS) twenty weeks after implantation in a Yucatan mini-breast mammary gland, as described in example 2.
[023] Figure 19 shows the H&E ax of a high aspect ratio tissue treatment product (in a preservative solution) twenty weeks after implantation in a Yucatan minipore mammary gland, as described in example 2.
[024] Figure 20 shows the histology classification of H&E stained tissue treatment products four weeks and twenty weeks after implantation in a Yucatan minipore mammary gland, as described
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6/52 in example 2. Tissue treatment products were classified for fibroblasts (Figure 20A), revascularization (Figure 20B), and inflammation (Figure 20C).
DESCRIPTION ______ DE______DETERMINATES______ EXEMPLIFICATIVE MODALITIES [025] Reference will now be made in detail to certain exemplary modalities in accordance with the present disclosure, the examples of which are illustrated in the accompanying drawings.
[026] Fabric treatment products are disclosed in this document. In various embodiments, a fabric treatment product comprises a collection of elongated elements, in which each elongated element comprises a fabric matrix that has been at least partially decellularized, and in which each elongated element has a flexible three-dimensional structure comprising a dimension of length, a width dimension, and a height dimension, and where one dimension is substantially larger than the other two dimensions (for example, at least about 2, 3, 4, 5, 10, 20, 50 or 100 times greater or any value between them). In some embodiments, tissue treatment products can be used as implants that will conform to the anatomical shape of an implant site by resisting migration from the implantation site and / or preventing significant hardening or elevation / swelling of the implant (for example , due to inflammation and / or the formation of granulation or scar tissue around the implant), as compared to an implanted tissue treatment product that does not comprise elongated or high aspect ratio elements. For example, a subcutaneous implant
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7/52 hardened and / or raised may be cosmetically undesirable or may result in complications requiring implant removal.
[027] Various human or other animal tissues and various methods can be used to prepare tissue treatment products. For example, compositions can be prepared by selecting human or porcine tissue; decellularizing the tissue to produce a tissue matrix containing collagen; and applying mechanical forces (for example, laminating, freezing, and / or cutting acellular tissue) to produce an elongated tissue matrix. For example, one or more sheets of acellular tissue matrix can be laminated into a cylindrical structure of desired length and diameter, frozen, and then optionally sliced, (for example, in a deli slicer) to produce tissue treatment products whose elements have a high aspect ratio structure. The elongated elements or elements of high aspect ratio may comprise a structure that has a dimension of length, a dimension of width, and a dimension of height, and in which one dimension is substantially larger than the other two dimensions (e.g., at least about 2, 3, 4, 5, 10, 20, 50 or 100 times greater or any value in between).
[028] Compositions produced in this way can be used, in certain modalities, to regenerate, repair, heal, enlarge, strengthen, and / or treat tissues that have been damaged or lost due to various diseases and / or structural damage (for example, trauma, surgery, atrophy, and / or long-term wear and tear
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8/52 degeneration). In some embodiments, matrices of elongated tissue can be folded, compressed or otherwise shaped to fill a desired anatomical shape at an implantation site. In some embodiments, the elongated elements are capable of being included within a syringe or similar device for injection into an implant. In certain embodiments, the ability of elongated tissue arrays to fill an anatomical space allows for greater preservation of a more natural aspect or sensation after implantation (that is, a more natural aspect or sensation after the completion of implantation surgery and / or after natural healing following implantation). In addition, in several modalities, the elongated elements of these tissue treatment products resist migration from the implant site, while also allowing continued fluid passage and preventing fluid accumulation at the implant site. In addition, in some embodiments, the elongated elements prevent significant induration or elevation / swelling of the implant (for example, due to inflammation and / or the formation of granulation or scar tissue around the implant), as compared to a treatment product of implanted tissue that does not comprise elongated or high aspect ratio elements.
[029] The compositions of the present disclosure can also be used, in certain modalities, for cosmetic purposes to repair or alter the appearance or sensation of a native fabric. In some embodiments, elongated fabric care products can be folded, compressed or otherwise shaped to fill a space between separate fabrics, regardless of the shape of the fabric.
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9/52 space. In various embodiments, the compositions will not migrate from the implantation site as it also allows the passage of continued fluid and prevents the accumulation of fluid at the implantation site.
[030] The materials and methods provided in this document can be used to create a biocompatible implant. As used herein, a biocompatible composition is one that has the ability to withstand the migration and proliferation of native cells from surrounding tissue in an implanted tissue treatment product. The biocompatible compositions support native cell activity necessary for tissue regeneration, repair, healing or treatment and do not obtain a substantial immune response that prevents such cell activity. As used herein, a substantial immune response is one that avoids partial or complete tissue regeneration, repair, healing or treatment.
[031] As used herein, the term native cells and native tissue means that the cells or tissue present in the recipient organ or tissue prior to implantation of a tissue treatment product or the cells or tissue produced by the host animal after implantation .
[032] 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, which include, without limitation, patents, patent applications, articles, books, and research, are expressly incorporated into this document for reference in its entirety for all purposes . Extent of publications and
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10/52 patents or applications for extension patents incorporated by reference that contradict the invention contained in the specification, the specification will supplant any contradictory material.
[033] In this application, the use of the singular includes the plural unless specifically stated otherwise. Also in this application, the use of or means and / or unless otherwise stated. Furthermore, the use of the term include, as well as other forms, such as includes and included, are not limiting. Any range described here will be understood to include the end points and all values between the end points.
TISSUE TREATMENT COMPOSITIONS [034] In certain embodiments, a tissue treatment product is provided. As used herein, a tissue treatment product comprises human or animal tissue that has been at least partially decellularized. Tissue treatment products may contain tissue that is acellular, partially decellularized, and / or decellularized tissue that has been repopulated with exogenous cells, provided that the tissue retains at least some extracellular support matrices found in the prior native tissue prior to decellularization.
[035] In some modalities, tissue treatment products are processed so that they can conform to the shape of an anatomical implant site. It can be beneficial to conform the shape of the tissue matrices to the desired shape of the anatomical site in a way that is not easily done with a sheet of acellular tissue. Several processes are known to change the
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11/52 three-dimensional shape of a sheet of acellular tissue, but adding them together can also change the tissue matrix undesirably. For example, chemical crosslinking can be used to alter the three-dimensional structure of an acellular tissue matrix, however excessive crosslinking can also alter the biological properties of tissue, and chemical crosslinking agents can be harmful to patients when
implanted on a patient. Consequently, methods alternatives for control the Format in products in treatment of fabric, by avoiding migration From products of one implant site, would be beneficial and are revealed at the
this document.
[036] In certain embodiments, a tissue treatment product comprises a collection of elongated elements or subunits (hereinafter referred to as an “elongated tissue treatment product). In some embodiments, each elongated element comprises a fabric matrix that has been at least partially decellularized, and each elongated element has a flexible three-dimensional structure comprising a length dimension, a
dimension wide, and an dimension tall, and in which one dimension (this is, O "axis geometric long) is substantially larger of that the other two dimensions. O
“substantially in this context means having a dimension that is at least 10% larger than either of the remaining two dimensions. In some embodiments, the elongated element is at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70 %, 75%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 750%, 1,000%,
2,000% or 5,000% (or any percentage between them)
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12/52 bigger in one dimension. The elongated element may be regular (for example, an ellipsoid, cylinder, rectangular cuboid, etc.) or irregular (that is, it lacks a uniform structure, but generally has an elongated geometric axis). In certain embodiments, the elongated element is in the form of a cylinder made up of one or more (e.g., 1, 2, 3, 4, 5, 10, 20 or more) laminated pieces or sheets of acellular tissue. The laminated acellular tissue cylinder can be held in place by natural adhesion or by freezing, lyophilization, dehydration or by any other method of fixing acellular tissue that is known in the art (for example, through mild to moderate chemical crosslinking).
[037] In certain embodiments, the elongated elements of a tissue treatment product are further processed to produce elements that have a high aspect ratio. As used in this document, an element of “high aspect ratio is an element that has a three-dimensional structure (that is, a length, a width, and a height), a dimension (that is, the long geometric axis) that is substantially larger than the other two dimensions, and two remaining dimensions that are substantially smaller than the long geometric axis and are generally measured on the macrometer in the millimeter range (for example, two dimensions of less than 50 mm, 40 mm, 30 mm, 20 mm, 15 mm, 10 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1.5 mm, 1 mm, 900pm, 800pm, 700pm, 600pm, 500pm, 400pm, 300pm, 200pm or 100pm or whatever between them). The term substantially in this context means to have a long geometric axis that is at least 10% larger than either of the remaining two dimensions. In some modalities, the
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13/52 high aspect ratio fabric treatment product is at least 50%, 55%, 60%, 65%, 70%, 75%, 100%, 150%, 200%, 250%, 300%, 350 %, 400%, 450%, 500%, 750%, 1,000%, 2,000% or 5,000% (or any percentage between them) greater in one dimension.
[038] For example, elements with a high aspect ratio can be prepared by slicing elongated elements parallel to the long geometric axis or across the face of the two smaller dimensions to form thin elements that have a long geometric axis and a high aspect ratio. aspect (for example, fine fibers, threads, noodles or other thin filaments) of desired dimensions. See Figure 1. As used in this document, thin means having two smaller dimensions that are measured on the macrometer on the millimeter scale (for example, two dimensions of less than 50 mm, 40 mm, 30 mm, 20 mm, 15 mm , 10 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1.5 mm, 1 mm, 900pm, 800pm, 700pm, 600pm, 500pm, 400pm, 300pm, 200pm or 100pm or any value in between). A high aspect ratio element prepared by slicing an elongated element can have a long geometric axis equivalent in length to the long geometric axis or equal in length to the circumference of an elongated element before processing or the high product aspect elements can be further processed (for example, by manual cutting) to yield a long geometric axis that is less than the total length of the long geometric axis or the circumference of the original elongated element.
[039] In certain modalities, elements of high aspect ratio can be organized to form a mesh, braid or other tertiary structure. Per
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For example, high aspect ratio filaments can be twisted to form a larger mesh of acellular tissue. As used herein, a mesh is any composition that comprises interconnected tissues or filaments of biological fibers. Someone skilled in the art will recognize that the firmness of the braid or mesh will vary depending on the desired physical properties of the tertiary structure (eg, mechanical strength, porosity, flexibility, etc.). In other embodiments, the high aspect ratio filaments of a tissue treatment product are maintained in a loose concentration (that is, without an organized tertiary structure) to facilitate separation and / or surgical delivery to an implant site.
[040] Tissue treatment products may comprise elements that have an acellular tissue matrix and / or elements that have an intact or partially decellularized tissue matrix. In one embodiment, the tissue treatment product comprises elements that have an acellular dermal tissue matrix. In certain embodiments, the tissue from which the acellular or partially decellularized tissue matrix is derived is selected from one or more of the fascia, pericardial tissue, dura, umbilical cord tissue, placental tissue, cardiac valve tissue, ligament tissue, tissue of tendon, arterial tissue, venous tissue, neural connective tissue, urinary bladder tissue, urethral tissue, skin, dermal, subdermal tissue, heart tissue, lung tissue, liver tissue, and intestinal tissue.
[041] In various modalities, a fabric treatment product comprises elongated elements that have
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15/52 a flexible three-dimensional shape that can conform to the anatomical structure of an implant site. For example, tissue care products may be useful for supporting breast implants, for example, for use in breast augmentation and / or reconstruction. For example, a tissue treatment product that has elongated or high aspect ratio elements can be placed around a breast implant and used to fill the space between the implant and the surrounding native tissue, thus providing a smoother contour. and / or look and feel more natural for the implant. The elongated or high aspect ratio elements within a tissue treatment product can either naturally resist the migration of their position surrounding an implant, or can be attached (for example, with sutures) to the fascia, muscle or other native tissue surrounding area, thereby helping to secure an implant in an appropriate position, to reduce or prevent scar formation or otherwise alter the aesthetic appearance of an implant.
[042] Fabric treatment products can be selected to provide a variety of different biological and mechanical properties. For example, a tissue treatment product can be selected to provide a support matrix in which native tissue cells surrounding an implanted tissue treatment product can migrate and proliferate, thereby enhancing the overall speed or level of repair. , regeneration, healing or treatment of native tissue. For example, an acellular tissue matrix, when implanted on or in the fascia, can be selected to allow regeneration of the fascia without excessive inflammation, fibrosis or formation of the
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16/52 scar tissue (for example, selecting a fully decellularized tissue product). In some embodiments, the loose porous structure of an elongated or high aspect ratio acellular tissue treatment product prevents obstruction and subsequent construction of fluid within the implant site, while also preventing a support matrix for native cells, tissue , and vasculature migrate and proliferate. In some embodiments, elongated or high aspect ratio acellular tissue treatment products resist migration from the implant site.
[043] In certain embodiments, the elongated or high aspect ratio treatment products of the present disclosure can be shaped to adapt to any desired three-dimensional structure (for example, to fill the anatomical structure of an implant site) without require undesirable chemical changes in the tissue matrix. In various embodiments, elongated or high aspect ratio elements within a fabric treatment product have substantial stretching, torsion or compression capabilities. In some embodiments, the elongated or high aspect ratio elements within a tissue treatment product are able to quickly return to their original dimensions after releasing a compression, tension or torsion force. In some embodiments, elongated or high aspect ratio fabric care products can be molded into a three-dimensional structure and maintained without excessive crosslinking. Although crosslinking can assist in maintaining a desired three-dimensional shape, excessive crosslinking can alter the biological properties of
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17/52 fabric. In some embodiments, the elongated or high aspect ratio elements are joined to form desired three-dimensional structures (for example, spheres, columns or other shapes intended to fit into anatomical implant sites) using natural adhesion or by freezing, lyophilization, dehydration or any other method of fixing the three-dimensional shape of acellular tissue that is known in the art (for example, through mild to moderate chemical cross-linking).
[044] Tissue crosslinking can be measured by increasing the denaturation temperature of a tissue matrix, as measured with differential scanning calorimetry. Consequently, in some embodiments, the tissue treatment products of the present disclosure include an acellular or partially decellularized tissue matrix that has a denaturation temperature, as measured by differential scanning calorimetry, which is within 5 ° C (i.e., within 5 ° C, 4 ° C, 3 ° C, 2 ° C or 1 ° C or any temperature in between) of the denaturation temperature of the tissue from which the matrix is produced.
[045] The extracellular matrix within the elements of a tissue treatment product may consist of collagen, elastin, and / or other fibers, as well as proteoglycans, polysaccharides and / or growth factors. In some embodiments, the acellular tissue matrix may retain some or all of the extracellular matrix components that are found naturally in a tissue prior to decellularization or several undesirable components may be removed by chemical, enzymatic or
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18/52 genetic. In general, the acellular matrix provides a structural network in which native tissue and vasculature can migrate, grow, and proliferate. The exact structural components of the extracellular matrix will depend on the tissue selected and the processes used to prepare the acellular tissue.
[046] A tissue treatment product can be derived from any tissue that is suitable for decellularization and subsequent implantation. Exemplary tissues include, but are not limited to, bone, skin, dermis, intestine, urinary bladder, tendon, ligament, muscle, fascia, neurological tissue, vessel, liver, heart, lung, kidneys, cartilage, and / or any other suitable tissue . In certain embodiments, the tissue treatment product may include lightweight mammalian tissue. For example, in certain embodiments, the tissue treatment product may include partially or completely decellularized mammalian dermis. In other embodiments, the tissue treatment product may comprise partially or partially decellularized small intestinal submucosa. In certain embodiments, the decellularized tissue may come from human or non-human sources. Suitable exemplary non-human tissue sources include, but are not limited to, pigs, sheep, goats, rabbits, monkeys, and / or other non-human mammals.
[047] In certain embodiments, tissue treatment products can be formed from ALLODERM® or STRATTICE ™, which are human and porcine dermal matrices respectively (Lifecell Corp., Branchburg, NJ). Alternatively, any other acellular arrays
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19/52 of fabric can be used. For example, a number of biological support matrix materials are described by Badylak et al., And the methods of the present disclosure can be used to produce a stable three-dimensional acellular tissue matrix using any of these materials or any other similar materials . Badylak et al., “Extracellular Matrix as a Biological Scaffold Material: Structure and Function, Acta Biomaterialia (2008), doi: 10.1016 / j.actbio.2008.09.013, incorporated by reference in its entirety for reference.
[048] In certain modalities, a tissue treatment product lacks certain undesirable antigens. For example, certain animal tissues contain alpha-galactose (α-gal) epitopes that are known to produce reactions in humans. Therefore, acellular tissue treatment products derived from various animal tissues can be produced or processed to lack certain antigens, such as α-gal. In some embodiments, tissue treatment products substantially lack all molar portions of α-gal. The removal of α-gal epitopes from a tissue treatment product can decrease the immune response in the composition. U. Galili et al., J. Biol. Chem. 263: 17755 (1988). Since primate mammals (for example, pigs) produce α-gal epitopes, xenotransplantation of material acellular tissue matrix from these primate mammals can result in rejection due to the binding of primate anti-gal to the α-gal epitopes in the matrix of acellular tissue. The binding results in the destruction of the acellular tissue by complement fixation and by cell-dependent cytotoxicity
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20/52 antibody. U. Galili et al., Immunology Today 14: 480 (1993); M. Sandrin et al., Proc. Natl. Acad. Sci. U.S. 90: 11391 (1993); H. Good et al., Transplant. Proc. 24: 559 (1992); B. H. Collins et al., J. I mmunol. 154: 5,500 (1995).
[049] As described in detail below, in various modalities, tissue treatment products can be processed to remove antigens such as α-gal, for example, by chemical or enzymatic treatment. Alternatively, tissue treatment products can be produced from animals that have been genetically modified to lack these epitopes.
[050] In various modalities, tissue treatment products have reduced biocharge (that is, a reduced number of microorganisms that grow in the compositions). In some embodiments, tissue treatment products substantially lack the entire biocharge (that is, tissue treatment products are aseptic or sterile). As used in this document, “substantially lacking all biocharge means tissue treatment products in which the concentration of growing microorganisms is less than 1%, 0.1%, 0.01%, 0.001% or 0.0001 % (or any percentage among them) of growth in untreated tissue treatment products.
[051] In certain embodiments, tissue treatment products are completely or substantially free of all cells normally present in the tissue from which the tissue treatment product is derived. As used herein, “substantially free of all cells means that the
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21/52 tissue contains less than 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% or 0.0001% (or any percentage in between) of normally growing cells within the acellular matrix of the tissue before decellularization.
[052] In some embodiments, tissue treatment products may include matrices of partially decellularized tissue and / or matrices of decellularized tissue that have been repopulated with viable cells. Various cell types can be used for restocking, including stem cells such as embryonic stem cells, adult stem cells (eg, mesenchymal stem cells), and / or neuronal cells. Any other viable cells that are histocompatible with the patient in which they are implanted can also be used. In some embodiments, histocompatible cells are mammalian cells. Such cells can promote migration, proliferation, and / or vascularization of native tissue. In various embodiments, viable cells are applied to the acellular tissue matrix before or after implantation of a tissue treatment product.
[053] In certain embodiments, tissue treatment products comprise one or more additional agents. In some embodiments, the additional agent may comprise an anti-inflammatory agent, an analgesic or any other desired therapeutic or beneficial agent. In certain embodiments, the additional agent may comprise, for example, at least one added growth factor or signaling (eg, a cell growth factor, an angiogenic factor, a differentiating factor, a cytokine, a hormone, and / or an
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22/52 chemokine). These additional agents can promote migration, proliferation, and / or vascularization of native tissue. In some embodiments, the growth factor or signaling is encoded by a nucleic acid sequence contained within an expression vector. Preferably, the expression vector is in one or more of the viable cells that can be optionally added to a tissue treatment product. As used herein, the term "expression vector refers to any nucleic acid construct that is capable of being picked up by a cell, contains a nucleic acid sequence that encodes a desired protein, and contains the other nucleic acid sequences necessary (for example, promoters, intensifiers, initiation and termination codons, etc.) to ensure at least minimal expression of the protein desired by the cell.
[054] The tissue treatment products, as described above, can be supplied in some modalities in conditioned, hydrated, frozen, lyophilized, and / or dehydrated form. In certain embodiments, packaged tissue treatment products are sterile. In certain embodiments, the tissue treatment products are provided in a kit, which comprises a packaged tissue treatment product and instructions for preparing and / or using the tissue treatment products.
[055] Production methods [056] Methods of creating fabric treatment products that comprise elongated and / or high aspect ratio elements are disclosed in this document. In some modalities, the method comprises selecting a
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23/52 tissue containing an extracellular collagen matrix; partially or completely decellularize the tissue; and applying mechanical forces to the tissue matrix to produce the elongated or high aspect ratio elements of the tissue treatment product.
[057] A tissue treatment product can be prepared from any tissue that is suitable for decellularization and subsequent implantation. Exemplary tissues include, but are not limited to, at least one of bone, skin, adipose, dermis, subdermal tissue, intestine, urinary bladder, tendon, ligament, muscle, fascia, neurological tissue, vessel, liver, heart, lung , kidneys, cartilage, and / or any other suitable tissue. In certain embodiments, the tissues may include lightweight mammalian tissue. For example, in certain embodiments, the tissue may comprise mammalian dermis. In certain embodiments, the dermis can be separated from the surrounding epidermis and / or other tissues, such as subcutaneous fat. In certain embodiments, the tissue may comprise small intestinal submucosa. In certain embodiments, the tissue may include human and / or non-human sources. Suitable exemplary non-human tissue sources include, but are not limited to, pigs, sheep, goats, cows, rabbits, monkeys, and / or other non-human mammals.
[058] In some embodiments, a tissue treatment product is prepared by collecting and decellularizing partially or completely donor tissue. Exemplary methods for decellularizing tissue are disclosed in U.S. Patent Document No. 6,933,326 and
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24/52
U.S. Patent Application No. 2010/0272782, which are incorporated herein by reference in their entirety for reference. In some embodiments, the decellularized tissue provides a porous extracellular support matrix structure in which cells of surrounding native tissue can migrate and proliferate after implantation of a tissue treatment product in a host site. In certain exemplary embodiments, the acellular tissue comprises ALLODERM® or STRATTICE ™, which are human acellular skin products and porcine skin products, respectively, and are available from LifeCell Corporation (Branchburg, NJ).
[059] In several modalities, the general steps involved in the production of an acellular tissue matrix include collecting tissue from a donor (for example, a human corpse or human source) and removing cells under conditions that preserve biological and structural functions. In certain embodiments, the collected tissue can be washed to remove any cryoprotectants and / or other residual contaminants. The solutions used for washing can be any physiologically compatible solution. Examples of suitable washing solutions include distilled water, phosphate buffered saline (PBS) or any other biocompatible saline solution.
[060] In certain modalities, the decellularization process includes chemical treatment to stabilize the collected tissue in order to avoid biochemical and structural degradation before, during or after cell removal. In several modalities, the stabilization solution retains and prevents osmotic, hypoxic, autolytic, and / or proteolytic degradation; protects against microbial contamination; and / or reduces mechanical damage that can occur during
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25/52 decellularization of tissues that contain, for example, smooth muscle components (eg, 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 light muscle relaxants.
[061] In various modalities, the tissue is then placed in a decellularization solution to remove viable cells (eg, epithelial cells, endothelial cells, smooth muscle cells, and fibroblasts, etc.) from the extracellular matrix without damaging biological integrity and / or structural of the extracellular matrix. The decellularization solution may contain an appropriate buffer, salt, an antibiotic, one or more detergents (for example, TRITON X100 ™, sodium dodecyl sulfate, sodium oxylate, polyoxyethylene (20) sorbitan monooleate, etc.), one or more agents to prevent cross-linking, one or more protease inhibitors, and / or one or more enzymes. In some modalities, the
decellularization solution comprises 0.1%, 0.2%, 0, 3%, 0, 4%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0% , 3.5%, 4.0%, 4.5% or 5.0% (or any percentage between the same) from TRITON X- 100 ™ and, optionally, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm or 50 mm EDTA (acid
ethylenediaminetetraacetic) (or any concentration between them). In some embodiments, the tissue is incubated in the decellularization solution at 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 or 42 ° C (or any temperature in between) , and optionally with light agitation at 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 or 150 rpm (or any rpm in between). Incubation can be
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26/52 for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 24, 36 or 48 hours (or any time between them). The duration of time or concentration of detergent can be adjusted to partially or more fully decellularize the fabric. In certain embodiments, additional detergents can be used to remove grease from the tissue sample. For example, in some embodiments, 1, 2, 3, 4 or 5% sodium oxylate (or any percentage between them) is added to the decellularization solution in order to remove fat from the tissue.
[062] In some embodiments, after decellularization, the tissue sample is washed thoroughly. Any physiologically compatible solutions can be used for washing. Examples of suitable washing solutions include distilled water, phosphate buffered saline (PBS) or any other biocompatible saline solution. In certain 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 DNase Buffer (20 mm (4- (2hydroxyethyl) -1-piperazineethanesulfonic acid HEPES), 20 mm CaCl2 and 20 mm MgCl2). Optionally, an antibiotic solution (for example, Gentamicin) can be added to the DNase solution. Any suitable DNase buffer can be used, as long as the buffer provides adequate DNase activity.
[063] Although an acellular tissue matrix can be derived from tissue from one or more donor animals
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27/52 of the same species as the intended recipient animal, this is not necessarily the case. Thus, for example, an acellular tissue matrix can be derived from porcine tissue and implanted in a human patient. Species that can serve as donors and / or recipients of acellular tissue arrays include, without limitation, mammals, such as humans, non-human primates (for example, monkeys, baboons or chimpanzees), pigs, cows, horses, goats, sheep, dogs, cats, rabbits, guinea pigs, gerbils, hamsters, rats or mice.
[064] In certain embodiments, the decellularized tissue can be treated with one or more enzymes to remove unwanted antigens, for example, an antigen not normally expressed by the recipient animal and thus likely to induce an immune response and / or rejection of the product treatment of implanted tissue. For example, in certain embodiments, decellularized tissue can be treated with alpha-galactosidase to remove molar portions of alpha-galactose (α-gal). In some embodiments, to enzymatically remove epitopes from α-gal, after washing the tissue entirely with saline, the tissue may be subjected to one or more enzymatic treatments to remove α-gal antigens, if present, in the sample. In certain embodiments, the tissue can be treated with an α-galactosidase enzyme to eliminate epitopes from α-gal. In one embodiment, the tissue is treated with α-galactosidase at a concentration of 0.2 U / ml prepared from 100 mm of phosphate buffered saline at pH 6.0. In other embodiments, the concentration of α-galactosidase is reduced to 0.1 U / ml or increased to 0.3, 0.4 or 0.5 U / ml (or any value between
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28/52 same). In other embodiments, any suitable enzyme concentration and buffer can be used, as long as sufficient antigen removal is achieved. In addition, certain exemplary tissue processing methods for reducing or removing molar portions of alpha-1,3galactose are described in Xu et al., Tissue Engineering, Vol. 15, 1 to 13 (2009), which is incorporated into this document by reference title in its entirety.
[065] In certain embodiments, animals that have been genetically modified to lack one or more antigenic epitopes can be selected as the tissue source for a tissue treatment product. For example, animals (for example, pigs) that have been genetically engineered to lack the molar portion of terminal α-galactose can be selected as the tissue source. For descriptions of appropriate animals and methods of producing transgenic animals for xenotransplantation, see U.S. Patent Application Serial No. 10 / 896,594 and U.S. Patent Document No. 6,166,288, which are incorporated by reference in their entirety for reference.
[066] In some embodiments, decellularized tissue can be treated to reduce biocharge (that is, to reduce the number of microorganisms that grow in the tissue). In some embodiments, the tissue is treated in such a way that it lacks substantially all of the biocharge (that is, the tissue is aseptic or sterile). As used herein, substantially the entire biocharge means that the concentration of microorganisms that grow in the tissue is less than 1%, 0.1%, 0.01%, 0.001% or 0.0001% of that growth tissue or untreated or
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29/52 any percentage among them. Methods of reducing suitable bioburden are known to someone of skill in the art, and may include exposing the tissue treatment product to radiation. Irradiation can substantially reduce or eliminate biocharge. In some embodiments, an absorbed dose of 15 to 17 kGy electron beam radiation is delivered in order to substantially reduce or eliminate the biocharge. In various embodiments, the amount of radiation to which the tissue treatment product is exposed can be between 5 Gy and 50 kGy. Suitable forms of radiation may include gamma radiation, electron beam radiation, and X-ray radiation. Other irradiation methods are described in application No. US 2010/0272782, the disclosure of which is incorporated by reference in its entirety by reference in its entirety. .
[067] In certain embodiments, after the acellular tissue matrix is formed, viable histocompatible cells can be optionally seeded in the acellular tissue matrix. In some embodiments, viable histocompatible cells can be added to the matrices by in vitro standard cell co-culture techniques before transplantation or by in vivo restocking following transplantation. In vivo repopulation may be by migration of native cells from surrounding tissue in the acellular tissue matrix or by the infusion or injection of histocompatible cells obtained from the recipient or another donor into the acellular tissue matrix in situ. Various cell types can be used, including stem cells such as embryonic stem cells and / or adult stem cells (for example, mesenchymal stem cells). Any other cells
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30/52 that are histocompatible with the patient in which they are implanted can also be used. In some embodiments, histocompatible cells are mammalian cells. Such cells can promote migration, proliferation, and / or vascularization of native tissue. In various modalities, the cells can be directly applied to the acellular tissue matrix just before or after implantation.
[068] In certain embodiments, one or more additional agents can be added to the acellular tissue matrix. In some embodiments, the additional agent may comprise an anti-inflammatory agent, an analgesic or any other desired therapeutic or beneficial agent. In certain embodiments, the additional agent may comprise at least one added growth factor or signaling (for example, a cell growth factor, an angiogenic factor, a differentiating factor, a cytokine, a hormone, and / or a chemokine). These additional agents can promote migration, proliferation, and / or vascularization of native tissue. In some embodiments, the growth factor or signaling is encoded by a nucleic acid sequence contained within an expression vector. Preferably, the expression vector is in one or more of the viable cells that can be optionally included with the acellular tissue matrix. As used herein, the term "expression vector refers to any nucleic acid construct that is capable of being picked up by a cell, contains a nucleic acid sequence that encodes a desired protein, and contains the other necessary nucleic acid sequences (for example, promoters, intensifiers, termination codon, etc.) for
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31/52 ensure at least minimal expression of the protein desired by the cell.
[069] In various modalities, both before and after decellularization, the acellular tissue matrix can be modeled and / or processed in a desired shape, such as an elongated structure. Consequently, a method for modeling an acellular tissue matrix is provided. In some embodiments, the acellular tissue may be laminated, wrapped, folded, compressed or otherwise shaped into a desired shape, such as a sphere, cube, cylinder, ellipsoid, rectangular cuboid or any other regular or irregular shape. One or more separate pieces of acellular tissue (for example, 1, 2, 3, 4, 5, 10 or more pieces) can be incorporated into the desired shape. For example, one or more pieces of acellular tissue (for example, 1, 2, 3, 4, 5, 10 or more pieces) can be laminated into a cylinder or a similar elongated shape to form an elongated element of a tissue treatment product. Laminated tissue can retain its shape by natural adhesion or by freezing, lyophilization, dehydration or by any other method of fixing acellular tissue that is known in the art (for example, through mild to moderate chemical crosslinking).
[070] In certain embodiments, the elongated elements of a tissue treatment product can be further processed to produce elements that have a high aspect ratio. For example, elongated elements can be sliced (for example, using a knife, deli slicer, grater, etc.) parallel to its long geometric axis or across the face of its two dimensions
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32/52 smaller in order to form thin elements that have a long geometric axis and a high aspect ratio (for example, a pasta structure). As used in this document, a high aspect ratio means having two dimensions that are measured on the macrometer on the millimeter scale (for example, two dimensions of less than 50 mm, 40 mm, 30 mm, 20 mm, 15 mm, 10 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, 900 pm, 800 pm, 7 00 pm, 600 pm, 500 pm, 4 00 pm, 300 pm, 200 pm or 100 pm or any value between themselves). The high aspect ratio elements of a fabric care product produced in this way can have a long geometric axis equivalent to the circumference length or long geometric axis of an elongated product element before slicing or the high aspect ratio elements can be additionally processed (for example, by manual cutting) to yield a long geometric axis that is less than the total length of the long geometric axis or circumference of the original elongated elements. In some embodiments, the long geometric axis of the high aspect ratio element has a dimension that is at least 50% larger than either of the remaining two dimensions. In some embodiments, the high aspect ratio element is at least about 50%, 55%, 60%, 65%, 70%, 75%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 750%, 1,000%,
2,000% or 5,000% (or any percentage between them) greater in one dimension.
[071] In some embodiments, elongated cylindrical elements containing one or more pieces or sheets of frozen and laminated acellular tissue are sliced (for example, with the use of a knife, deli slicer, grater, etc.)
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33/52 to form the high aspect ratio elements of a tissue treatment product. Slicing can be done to a desired thickness to produce elements of high aspect ratio of desired dimensions. In some embodiments, the high aspect ratio elements may have a long geometric axis equivalent to the circumference length of the frozen cylindrical elements. In other embodiments, elements with a high aspect ratio can be cut (for example, with the use of a knife, scalpel or other blade) so that their long-axis geometry is shortened.
[072] In certain embodiments, a slicing device, such as a deli slicer, is used to slice through the circular face of a laminated acellular tissue cylinder, thus producing elements of high aspect ratio (for example, noodles) thick predetermined, where the thickness depends on the thickness adjustment of the device used to slice the cylinder. In some embodiments, the laminated acellular tissue cylinder is frozen to allow easier slicing (for example, to allow for more consistent slicing).
[073] In certain embodiments, the high aspect ratio elements of a fabric care product can be further processed to form a mesh, braid or other tertiary structure. For example, high aspect ratio filaments can be twisted to form a larger mesh of acellular tissue. As used herein, a mesh is any composition that comprises interconnected tissue or filaments of biological fibers. Someone skilled in the art will recognize that
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34/52 firmness of the braid or mesh may vary depending on the desired physical properties of the tertiary structure (for example, mechanical strength, porosity, flexibility, etc.). In some embodiments, the tertiary structure is held together by natural adhesion or by freezing, lyophilization, dehydration or by any other method of fixing the acellular tissue that is known in the art (for example, through mild to moderate chemical crosslinking). In other embodiments, the high aspect ratio elements of a tissue treatment product are maintained in a loose concentration (that is, without an organized tertiary structure) to facilitate separation and / or surgical delivery to an implant site.
[074] Methods of Use [075] One goal when using tissue products to regenerate, repair, heal or otherwise treat diseased or damaged tissues and organs is to provide an implant with the ability to maintain shapes or configurations that conform closer to the anatomical structures that are treated, while also reducing or preventing implant migration from the implant site. Consequently, methods of using tissue treatment products that comprise the collection of elongated or high-aspect elements such as fillers to pack an empty space, wound or other tissue in need of treatment, repair, healing or regeneration are revealed in certain modalities. . As used herein, a collection means at least 2 pieces or elements (for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 , 45, 50, 75 or 100 pieces or
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35/52 any number between them). The individual pieces of tissue within the collection may have the same or different structures. The tissue treatment product comprising a collection of elongated or high aspect ratio fabric matrices can be shaped to fill a desired shape while reducing the risk of the implant migrating from the implant site. In some embodiments, the tissue treatment product can also be used for cosmetic or intensification purposes (for example, as a cosmetic implant or as an adjunct to a traditional cosmetic implant).
[076] In certain modalities, following the creation of space between tissue planes as a result of disease, trauma or surgical intervention, a tissue treatment product comprising one or a collection of elongated or high aspect ratio elements is placed between the separate fabric plans. In certain embodiments, the implanted tissue treatment product can be used to completely fill and conform to the shape of a space in a host tissue. In some embodiments, the product can be folded, compressed or otherwise shaped to fill the anatomical space of an implant site.
[077] In certain embodiments, the elements of an implanted tissue treatment product may have an organized tertiary structure, such as a mesh, braid or other organized structure, or the elements may be present in a loose form that lacks a tertiary structure organized. In some embodiments, tissue treatment products can be folded, compressed,
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36/52 wrapped or otherwise shaped to fill the space between separate tissue planes, regardless of the shape of the space (for example, an irregularly formed wound can be filled with a tissue treatment product until the entire space inside wound is filled with tissue treatment product). In one example, the implanted tissue treatment product comprises elements that have a high aspect ratio. In certain embodiments, the high aspect ratio elements can be folded, compressed or otherwise molded into an implant site until all the empty space at the implant site is filled. In some modalities, elements of high aspect ratio can also be organized in a mesh, braid or other organized tertiary structure.
[078] In some embodiments, a tissue treatment product can be used for tissue volume (for example, to fill the space surrounding a breast implant or as a support material between bone and cartilage or in the submucosal layer of the nasal passage who follows otorhinolaryngology surgery). In other embodiments, tissue treatment products are used to completely fill the empty space (for example, after tumor removal), to form volume in native tissue (for example, for nasal reconstruction) or for aesthetic enhancement purposes. tissue (for example, as a complement to breast implants that are used to soften contours and fill the space surrounding the implant).
[079] In certain embodiments, a tissue treatment product is implanted in a host tissue
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37/52 and remains in place through the natural tendency of elongated elements or high aspect ratio to resist migration from the implant site. In other embodiments, tissue treatment products are attached to native tissue plans that involve an implant site using any known method that results in the temporary or permanent physical association of tissue treatment products with the surrounding tissue. For example, biodegradable sutures can be used to physically attach the tissue treatment product to the surrounding native tissue. Alternatively, positive external pressure (for example, a dressing or bandage around the implant site) can be applied to compress the surrounding native tissue and keep the native tissue in contact with the implanted tissue treatment products, thus preventing migration of the tissue treatment products from the implant site.
[080] A benefit of implanting a tissue treatment product that comprises a collection of elongated or high aspect ratio elements is that the elongated or high aspect ratio structure of these elements can prevent or reduce the tendency of an implant to migrate from the implant site. Thus, in some embodiments, tissue treatment products can be used without requiring undesirable chemical modification or physical attachment to native tissue that is otherwise necessary in order to avoid migration from an implant site. In several modalities, the ability to retain a tissue treatment product at an implant site without requiring chemical or physical intervention (for example, crosslinking or suturing) can be important when using a tissue treatment product
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38/52 to fill the empty space (for example, after tumor removal), to form volume in native tissue (for example, for nasal reconstruction) or for aesthetic tissue enhancement purposes (for example, as a complement to implants which is used to soften contours and fill the space surrounding the implant). In these contexts, tissue treatment products can be implanted and will not migrate from the implant site, while still preventing the irradiation or loss of biocompatibility associated with chemical or physical processing to attach an implant to the surrounding tissue.
[081] In certain embodiments, a tissue treatment product comprising a collection of elements with a high aspect ratio (for example, noodles) is used. The flexible filaments of high aspect ratio tissue treatment products can be folded, compacted, and / or molded to fill an implant site. The high aspect ratio elements allow for continued fluid mobility within the implant site, thus preventing undesirable fluid accumulation. At the same time, high aspect ratio elements provide an acellular support matrix in which native cells and vasculature can migrate and proliferate, thereby promoting or intensifying tissue repair, regeneration, and / or healing. In addition, the high structure aspect ratio of the elements can prevent the tissue treatment product from migrating from the implant site, without requiring the use of chemical crosslinking agents or other interventions designed to immobilize the tissue treatment product. For example, fabric care products that comprise a collection of elements
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39/52 high aspect ratio can be used to fill the space surrounding a breast implant. High aspect ratio tissue treatment products can be used in this context to support the breast implant and prevent the implant from deviating from the appropriate location, while also providing a more natural look and feel to the implant by filling it. if the space between the breast implant and surrounding tissue, for example, avoiding and / or reducing inflammation or the formation of granulation or scar tissue surrounding the implant that could result in an undesirably hardened or elevated implant. In another example, treatment products
fabric of high reason in aspect can be used for wrap a wound or another space between fabrics separated resulting in disease, damage or intervention surgical. [082] In some modalities, O use of a
tissue treatment product comprising a collection of elongated or high aspect ratio elements can result in an implant that has increased persistence at the implantation site, as compared to implanted sheets of acellular tissue. Persistence refers to the volume of implanted material that remains in an implantation site over time. Persistence can be measured in a number of ways that will be familiar to someone skilled in the art. For example, the persistence of the tissue treatment product at the implantation site can be measured with the use of ultrasound in order to calculate the volume of tissue treatment product that remains in an implantation site over time.
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40/52 [083] In some embodiments, the use of a tissue treatment product that comprises a collection of elongated or high aspect ratio elements can result in an implanted tissue treatment product that has enhanced biomechanical properties, as compared to the implanted sheets of acellular tissue. Biomechanical properties can be assessed in a number of ways that will be familiar to someone skilled in the art. For example, the lightness of an implant over time can be assessed by looking at the implant's tonometry (that is, the level of displacement that occurs when the implant is placed under load). For example, indentation tonometry can be used, involving measuring the depth of indentation produced by a rod of known weight when placed above the implantation site. A higher indentation value indicates a lighter implant site, while a lower value indicates a heavier site. Similarly, in another example, implant stiffness over time can be assessed using BTC-2000 ™ (SRLI Technologies, Nashville, TN), which can be used to measure stiffness and other skin and biomechanical properties underlying light tissue. In some embodiments, an implanted tissue treatment product that comprises a collection of elongated or high aspect ratio elements can result in a firmer implant site, as compared to the surrounding tissue.
[084] In certain embodiments, high aspect ratio fabric treatment products that have been arranged to form a mesh, braid or other tertiary structure are implanted in a host tissue.
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41/52
The mesh, braid or other tertiary structure can be used to fill the implantation site. For example, a mesh can be used to wrap a wound or other space between separate tissues resulting from illness, damage or surgical intervention. The flexible mesh can be compacted to more firmly fill a space between separate tissues, or it can be used to provide structural support and reinforcement for a tissue that follows the removal of native tissue from the implantation site. For example, following the removal of the tumor, a tissue or tissue treatment product can be used to fill the space left after the surgical intervention and to reinforce the structure of the tissue remaining at the implantation site. For example, following breast sinus surgery (for example, lumpectomy), a knit or tissue treatment product can be implanted to preserve the structural appearance and sensation of the breast, and to promote regeneration of native tissue. In certain embodiments, the mesh, braid or other tertiary structure allows the continued mobility of fluid within the implant site, thus preventing undesirable fluid accumulation. At the same time, the mesh, braid or other tertiary structure provides an acellular support matrix in which the native cells and vasculature can migrate and proliferate, thus promoting or intensifying repair, regeneration, and / or tissue healing. In addition, in some modalities, the mesh structure prevents the tissue treatment product from migrating from the implantation site; the use of chemical cross-linking agents or other interventions to immobilize the tissue treatment product may not be required in these modalities.
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42/52 [085] In various modalities, a tissue treatment product that comprises a collection of elongated or high aspect ratio elements is used after surgical removal of a tumor. In some embodiments, the tumor is a breast tumor. In other embodiments, the tumor is an abdominal or dermal tumor or any other tumor for which surgical removal is indicated and subsequent replacement with a tissue filler is desirable. In various modalities, tissue treatment products are used to fill the space left by surgical removal of a tumor. Tissue treatment products can be used, in some modalities, to fill the space left by tumor removal while also allowing for continued fluid mobility within the implant site, thus preventing undesirable fluid accumulation. At the same time, tissue treatment products provide an acellular support matrix in which native cells and vasculature can migrate and proliferate, thereby promoting or intensifying tissue repair, regeneration, and / or healing. In addition, in certain embodiments, the elongated or high aspect ratio structure of the elements within a tissue treatment product may prevent the tissue treatment product from migrating from the implantation site; the use of chemical cross-linking agents or other interventions to immobilize tissue treatment products is not required in these modalities.
[086] In certain embodiments, a fabric treatment product comprising a collection of elongated or high aspect ratio elements is used to fill a space between separate fabric layers that
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43/52 results from surgical intervention, illness or trauma. For example, tissue care products can be used to fill a wound or to wrap the space between layers of tissue that were separated during surgery. Tissue treatment products provide an acellular support matrix in which native cells and vasculature can migrate and proliferate, thereby promoting or intensifying tissue repair, regeneration, and / or healing. At the same time, tissue treatment products allow for continued fluid mobility within the implant site, thereby preventing unwanted fluid accumulation. In addition, the elongated or high aspect ratio structure of the collection of elements within a tissue treatment product prevents the tissue treatment product from migrating from the implantation site; the use of chemical crosslinking agents or other interventions to immobilize the tissue treatment product is not required in these modalities.
[087] In various modalities, fabric treatment products that comprise a collection of elongated or high aspect ratio elements are used for aesthetic purposes. For example, tissue care products can be used alone or in conjunction with additional implant materials to enhance or alter the shape, texture, lightness, elasticity, stiffness, contours or other properties of tissue in the breast, lips, nose, buttocks or any other fabric. For example, tissue care products can be used to fill the space between a traditional breast implant and surrounding tissue in order to provide a more natural look and feel by preventing fluid buildup in the void around the implant. In a way
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44/52 similarly, in certain modalities, tissue treatment products can be used to fill the space between a traditional implant and surrounding tissue in order to support and anchor the traditional implant and prevent it from moving or distorting after implantation . In some embodiments, tissue treatment products can also promote native tissue repair, regeneration, and / or healing around a traditional implant by providing an acellular support matrix in which native cells and vasculature can migrate and proliferate. In some modalities, the implanted tissue treatment products do not interfere with clinical mammography.
EXAMPLES[088] The examples Next serve for to illustrate, and not limit in no way, the present revelation .[089] Example 1a: Preparation of products of
tissue treatment [090] Approximately 500 g of sheets of acellular dermal porcine tissue (PADM) were rinsed and washed and then treated with PRTM freezing solution in a 5: 1 ratio of tissue solution for 6 hours to 36 hours. The sheets of acellular dermal porcine tissue were then laminated in a cylinder and placed at -80 ° C overnight. A deli slicer was set up inside a clean and entirely clean room using Spor-Klenz and 70% IPA.
[091] A sharp and clean deli slicer was used to slice frozen PADM. To keep the slicer cold, liquid nitrogen gas was allowed to flow behind the blade
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45/52 cut of the deli slicer. The frozen cylinder of acellular tissue was placed inside a container to aid management during cutting, and was sliced in the deli slicer to produce tissue treatment products that have a high aspect ratio, for example, a shape similar to a pasta . The circular face of the laminated frozen tissue cylinder was kept flat and the cylinder was kept perpendicular to the slicer blade. The thickness of the high fabric aspect ratio produced in this way could be varied by changing the setting of the deli slicer. The deli slicer was set to 1.5 mm in diameter and the laminated fabric rolls were sliced individually or sets of laminated rolls were sliced together.
[092] After slicing, half the noodles were washed in a preservative solution and the other half in PBS. The noodles were washed twice in each solution for 2 hours. Each wash was in a 5: 1 ratio of solution to fabric, was shaken at 100 rpm. Washed noodles were stored at 4 ° C.
[093] Hydrated noodles were weighed and packed aseptically in a syringe. For biocharge testing, half of the syringe content was extruded into a sterile bag, with the remaining half retained in the syringe and saved for sterilization and implantation. The syringes were placed in foil pockets for sterilization and were irradiated by an electron beam in 15.9 to 21.5 kGy.
[094] Example 1b: Preparation of tissue treatment products [095] STRATTICE ™ (Lifecell Corp.) was pre
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46/52 conditioned by manual cutting in samples of 50.8 mm by 50.8 mm (2 inches by 2 inches). The samples were passed through a bench meat grinder with a 127 / 152.4 mm (5/16 inch) cutter setting, then passed a second time through the grinder with a 76.2 / 152.4 mm setting (3/16 inch). The fabric was sent to the Sympak Group (Mandelein, IL) for additional microcutting with the use of 0.35 and 0.9 mm cut adjustments. The final cut tissue tended to agglomerate and formed larger fibers when laminated together.
[096] Example 2: Yucatan mini-breast mammary gland test [097] Yucatan mini-breast mammary glands were used to simulate clinical lumpectomy and to test and compare different implanted tissue treatment products used in vivo to treat lumpectomy failures. Four 20cc faults per animal were created using electrocautery. Each gap was filled with one of six different tissue treatment products comprising PADM tissue fillers (noodles in PBS, noodles in a preservative solution, fiber mass in PBS, fiber mass in a preservative solution, consolidated fiber filaments (CFS) and STRATTICE® acellular sheets) or left unfilled. The Yucatan minipore mammary gland lumpectomy model shared several similarities with the clinical lumpectomy, including the hardening of reconstructed and unrepaired flaws, cavity of un Constructed flaws, and an elevated appearance to many of the reconstructed flaws.
[098] The surgical techniques used in these
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47/52 experiments resulted in the production of significant granulation tissue. Granulation tissue was observed for all surgical implantation sites, including empty voids (for example, sites where the tissue was removed, but no implants were used to fill the void). In contrast, the implantation of tissue treatment products without creating a surgical vacuum resulted in little evidence of granulation tissue, as compared to the same material when implanted in a prepared vacuum. This suggests that tissue treatment products alone are not the main cause of granulation tissue in these experiments.
[099] The implanted tissue treatment products were evaluated for persistence, biomechanics, biological response, and interference with mammography. Implant characteristics were assessed at three time points (0, 4, and 12 weeks). The implants generally persisted, as evidenced by a lack of cavity formation, gross appearance, and ultrasound data. Persistence was measured by ultrasound and cavity depth. Biomechanics was assessed by measuring the displacement of implanted tissue treatment product when placed under load (tonometry), using BTC2000 ™ (SRLI Technologies, Nashville, TN) to measure the rigidity and other biomechanical properties of the skin and tissue underlying, and, for mass implants, by rheology (tissue viscosity). The biological response was assessed by histology. Interference with mammography was assessed by X-ray imaging.
[0100] Ultrasound was used to evaluate the implant volume for the six different treatment products
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48/52 tissue implanted four weeks after implantation. Transverse and longitudinal images were acquired for each implant site, and the volume was calculated as 4 / 3nabc. Figure 2 shows the volume of ultrasound calculated for each of the different implants four weeks after implantation. Figure 3 is an ultrasound volume scheme against the dry tissue mass for the various implants, measured four weeks after implantation. The ultrasound calibration calculations were performed by comparing the ultrasound volume calculated at time T = 0 with the actual volumes of implanted material. Figure 4. The calibration analysis illustrated that ultrasound tends to underestimate the volume of the implant and had considerable between and within site variability. Thus, although the volume of ultrasound is suitable for purposes of trend, it is not suitable for quantification or to detect small differences between implants. Figure 16 provides a comparison of ultrasound volume for the different implants at four weeks and twenty weeks after implantation. Significant volume is lost for all implants except CFS.
[0101] Indentation tonometry (ie, measurement of displacement under load) was used to evaluate the biomechanical properties of implanted tissue treatment product. A 12.7 mm (0.5 inch) 176 gram nail was placed at each implant site and the nail penetration depth was measured. A higher value indicates a lighter (more compatible) implant site, while a lower value indicates a heavier (less compatible) implant site. Figure 5 illustrates the results of indentation tonometry in the various tissue treatment products
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49/52 implanted 4 weeks after implantation. Figure 6 compares indentation tonometry results at time T = 0 and T = 4 weeks for each tissue treatment product. All tissue treatment products became less compatible after 4 weeks, as measured by indentation tonometry. These quantitative results were confirmed by manual palpitation. Due to the formation of an implant well in 12 weeks, the tonometry data were inconsistent and therefore not reported except for CFS implants and mass implants in a preservative solution that did not form a well (did not show).
[0102] For further evaluation of the biomechanical properties of implanted tissue treatment products, BTC-2000 ™ (SRLI Technologies, Nashville, TN) was used to measure the rigidity of tissue implants at implantation time and after 4 weeks. BTC-2000 can be used for quantitative and sensitive analysis of the biomechanical properties of skin and light fabrics, as well as the intact and / or disruptive characteristics of elastic materials. Figure 7 indicates that implant stiffness decreased in 4 weeks compared to pre-surgery. This is in contrast to the increased rigidity over time observed by indentation tonometry.
[0103] Finally, the impact of tissue treatment products implanted in tissue contour was assessed by measuring the cavity depth for submerged implant sites, as well as by photographic observation of elevated implant sites. Figure 8 is a representative example of an elevated location. Such locations were estimated to be elevated by 5 to 10 mm. The depth of
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cavity was measured with use in tonometry in no loading. A 176g rod was used for measure the depth cavity while O Weight of the stem was
supported from above so that the measurement would not incorporate additional depth due to displacement or compression of the fabric under load. Figure 9 is a four-week cavity depth scheme, as measured by non-loading tonometry, for the various implanted tissue treatment products, including implanted noodles. Figure 17 is a comparison of elevated or cavity implants at 4 weeks and 12 weeks for each type of implant.
[0104] In order to assess the potential of tissue treatment products implanted to interfere with mammography, the Yucatan mini-breast mammary glands were imaged by 70 KV x-ray before surgery and 4 weeks after implantation of a treatment product of pasta tissue (Figure 10A and B, respectively). No difference in tissue density between implant site and surrounding tissue was detected by X-ray following the implantation of pasta. However, the 70 KV energy used in this experiment was greater than the 15 to 52 KV normally used in mammography, which may have prevented the detection of differences in tissue density.
[0105] To assess the biological response to implanted tissue treatment products, including implanted noodles, gross observation was recorded and histology was performed four weeks and twenty weeks after implantation.
[0106] After four weeks, gross observations were recorded by photo for implanted noodles
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51/52 in PBS and noodles implanted in a preservative solution. Refer to Figures 11 and 12, respectively. Histology was performed with hematoxylin and eosin (H&E) stain to assess the restocking, inflammation, and fibroblast revascularization. Figures 13 and 14 show the H&E stain for noodles implanted in PBS and in a preservative solution, respectively. Figure 15 shows histology classification of H&E stained tissue for fibroblasts (Figure 15A), revascularization (Figure 15B), and inflammation (Figure 15C). Histology classification was conducted on stained samples of various tissue treatment products, including implanted noodles, four weeks after implantation.
[0107] After twenty weeks, noodles implanted in PBS demonstrated significant fibroblast restocking and mild revascularization. There was also a moderate inflammatory response, as evidenced by the presence of lymphocytes, macrophages, and giant cells. Dense connective tissue was observed among the implanted noodles. Figure 18. For noodles in a preservation solution, significant fibroblast restocking and moderate revascularization was again observed. A mild inflammatory response was observed. The dense connective tissue was observed among the implanted noodles. Figure 19. Figure 20 shows histology classification of H&E stained tissue for fibroblasts (Figure 20A), revascularization (Figure 20B), and inflammation (Figure 20C) at four weeks and twenty weeks after implantation.
[0108] The preceding examples are intended to illustrate and not to limit in any way the present disclosure.
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Other modalities of the devices and methods disclosed will be evident to those skilled in the art from consideration of the descriptive and practical report of the devices and methods disclosed in this document.

权利要求:
Claims (11)
[1]
1. TISSUE TREATMENT COMPOSITION, characterized by comprising:
a collection of elongated elements, without an organized tertiary structure, each elongated element comprising a fabric matrix that has been decellularized, and in which each elongated element has a flexible three-dimensional structure comprising a length dimension, a width dimension, and a dimension in height, and where one dimension is larger than the other two dimensions, and the dimension aspect ratio compared to the other two dimensions is at least 50: 1.
[2]
2. COMPOSITION according to claim 1, characterized in that the tissue treatment product comprises a matrix of decellularized tissue from one of human, non-human primate, pig, cow, horse, goat, sheep, dog, cat, rabbit, guinea pig, gerbil, hamster, rat, or mouse.
[3]
COMPOSITION according to claim 2, characterized in that the tissue treatment product comprises a matrix of porcine acellular tissue.
[4]
COMPOSITION according to any one of claims 1 to 3, characterized in that the tissue treatment product comprises the decellularized tissue matrix of one of bone, skin, dermis, intestine, vascular, urinary bladder, tendon, ligament tissue, muscle, fascia, neurological tissue, vessel, liver, heart, lung, kidneys or cartilage.
[5]
5. COMPOSITION, according to claim 4, characterized by the tissue treatment product
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2/3 comprise a matrix of dermal acellular tissue.
[6]
COMPOSITION according to any one of claims 1 to 5, characterized in that the tissue treatment product comprises an acellular tissue matrix from one or more animal or tissue sources.
7. COMPOSITION, in wake up with Any of them of claims 1 to 6, featured by product in treatment of fabric lack of all at molar portions in alpha-galactose .8. COMPOSITION, in wake up with Any of them of claims 1 to 7, characterized for understanding additionally an ormore viable cells and histocompatible, in what at cells histocompatible are
non-human embryonic stem cells.
9. COMPOSITION, according to claim 8, characterized by one or more cells be cells of mammals.10. COMPOSITION, according to claim 9,
characterized by one or more cells being stem cells.
[7]
11. COMPOSITION according to any one of claims 1 to 10, characterized by additionally comprising an additional factor selected from an anti-inflammatory agent, an analgesic, a cell growth factor, an angiogenic factor, a differentiating factor, a cytokine , a hormone and a chemokine.
[8]
12. COMPOSITION according to claim 11, characterized in that said additional factor is encoded by a nucleic acid sequence, contained within an expression vector.
[9]
13. COMPOSITION, according to claim 12,
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3/3 characterized by the expression vector being contained within viable and histocompatible cells.
[10]
COMPOSITION according to any one of claims 1 to 13, characterized in that the tissue treatment product has a reduced biocharge or lacks all biocharge.
[11]
COMPOSITION according to any one of claims 1 to 14, characterized in that each elongated element has a dimension that is 100 times as large as the other two dimensions.

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同族专利:

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公开号 | 公开日

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CA2861048A1|2013-08-01|

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US10327884B2|2019-06-25|

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EP3797801A1|2021-03-31|

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US9271821B2|2016-03-01|

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ES2705823T3|2019-03-26|

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AU2013212592A1|2014-07-24|

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WO2013112350A1|2013-08-01|

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EP2806907B1|2018-11-21|

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US20160135940A1|2016-05-19|

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CA3078056A1|2013-08-01|

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CA2861048C|2021-01-12|

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EP2806907A1|2014-12-03|

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EP3461508A1|2019-04-03|

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US20190262121A1|2019-08-29|

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US20130190893A1|2013-07-25|

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DK2806907T3|2019-02-18|

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AU2013212592B2|2016-06-30|

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法律状态:
2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2019-01-15| B06T| Formal requirements before examination|

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2019-04-16| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|

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2019-10-22| B09A| Decision: intention to grant|

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2019-11-26| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/01/2013, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/01/2013, OBSERVADAS AS CONDICOES LEGAIS |

优先权:

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申请号 | 申请日 | 专利标题

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US201261590035P| true| 2012-01-24|2012-01-24|

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PCT/US2013/021909|WO2013112350A1|2012-01-24|2013-01-17|Elongated tissue matrices|

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