Universal biological acellular dermal matrix (ADM) prosthesis for use in body reconstruction processes, and production method

Abstract

The invention relates to a universal biological acellular dermal matrix (ADM) prosthesis for use in body reconstruction processes, comprising: a first layer of ADM of biological origin, arranged at the bottom to delimit a cavity with a bottom edge; a packing material which is arranged in the cavity surrounded by the first ADM layer and consists of ground ADM material having the consistency of a fibrous pulp; and a second layer of ADM of biological origin which is arranged on the upper part and covers the packing material and the top edge of which rests, at its periphery, on the bottom edge of the first layer of ADM, thereby defining a rim; wherein the first layer of ADM and the second layer of ADM are joined by precisely arranging the upper edge of the first layer of ADM on top of the bottom edge of the rim, at the periphery, using a biocompatible glue or using sutures made of resorbable thread; wherein the first layer of ADM, the second layer of ADM and the ADM packing material are not immunogenic; and wherein the ADM comprises collagen fibres, fibronectin, elastin, laminin, glycosaminoglycans and hyaluronic acid. The invention also relates to a method for producing same.

Description

Description Acellular dermal matrix (ADM) biological universal prosthesis intended for use in body reconstruction processes and manufacturing method

[0001] Scope of the invention

[0002] The field of the present invention is that of tissue engineering and biological prosthetic implants. The present invention relates to biological prostheses based on acellular dermal matrices using bioengineering to prepare said prostheses from clean tissue material derived from animals. The prosthetic grafts of the invention are prepared by methods that preserve the biocompatibility, i.e., the cellular compatibility, strength, and bioremodeling of the treated tissue matrix. The biological prostheses are used for implantation and / or repair in a mammalian host.

[0003] Description of prior art

[0004] Surgery has undergone a tremendous transformation in modern times. It has evolved from ablative cancer surgery to organ transplantation surgery. Following the work of Siebert, Harrison, and others, regenerative surgery has emerged. The patient's own formation of a membrane under the guidance of an acellular dermis, known as dermal integration, has been observed.

[0005] Harnessing the pluripotency of stem cells and enabling an organ to regenerate represents a shift in strategy. Until now, physicians have harvested, transplanted, and cultured cells. With regenerative medicine, the patient themselves does the cultivating. The patient cultivates their own health through the regeneration of their heart, liver, skin, and so on.

[0006] Since 1994, components of the extracellular matrix have been used in the healing of deep wounds, observing discontinuities that quickly filled their beds.

[0007] Given that mammalian acellular dermal matrices do not generate immunological rejection, coverage methods using porcine acellular dermis are being developed. This technique is based on the work of Chih-chun Yang et al., who in 1982 already used the concept of a dermal cradle. These laboratory-treated dermis do not exhibit rejection, remain present in the bed, and can carry seeded keratinocytes or support thin autologous graft sheets.

[0008] This accumulated knowledge enabled us to file a patent application, publication number AR085537A1, filed on March 22, 2012, entitled: "Process for obtaining porcine acellular dermal matrix and acellular dermal matrix obtained by said process." It concerns a process for obtaining porcine acellular dermal matrix and the acellular dermal matrix obtained by this process. The process is carried out using pig hide; it eliminates the entire cellular component of the hide, leaving the structure of the dermal fibers intact. This acellular dermal matrix is ​​immunologically inert, and its technical development ensures that the fibers' strength is not altered.This procedure involves a series of steps during which a pigskin is cleaned, then divided to the desired size. The epidermis is removed and separated, leaving the dermis. Fat is removed from the dermis, the cleaned dermis is laminated, a cellular component removal process is performed, necessary cleaning operations are carried out, and it is packaged and sterilized. The Acellular Dermal Matrix obtained by this procedure is a biomaterial suitable for reconstructing the surface or volume of tissues affected by various conditions.

[0009] Acellular Dermal Matrices

[0010] Acellular Dermis Matrices (ADMs) have been used in soft tissue reconstruction since 1995, initially for the treatment of burns. In 2005, Breuing and Warren were the first to publish the use of an ADM in breast reconstruction; however, Salzberg et al. performed the procedure in 2001, but did not publish their results until later, in 2006, and again in 2011. Since then, synthetic meshes as well as biological ADMs have been introduced for the breast reconstruction, using an implant approach in one or two phases.

[0011] Retrospective database studies have reported marginal differences in overall complication rates compared to traditional breast reconstruction techniques.

[0012] What is the concept of ADM?

[0013] A dermal matrix (DM) is essentially a biological material derived from dermal tissue originating from an animal or human. This material must be processed to remove cells and antigenic components through a specific procedure. The processed dermal matrix typically comprises collagen fibers, elastin, hyaluronic acid, fibronectin, and proteoglycans. The relative amounts of these components vary depending on the raw materials used and the specific manufacturing processes. Some of these processes involve chemically induced collagen cross-linking to produce collagen that is more resistant to degradation and, consequently, more resilient to stress.

[0014] Producers of these dermal matrices aim to completely eliminate cells from the products to minimize the host's response to the graft. The materials are sterilized during processing. It is important to note that dermal matrices are biodegradable tissue materials with significant regenerative potential. They act as a scaffold, revascularizing and repopulating with the host's own cells after implantation in the host's body.

[0015] Among the biological ADMs in breast reconstructions, eleven products made from human, porcine or bovine tissue can be identified, namely: AlloDermVR (LifeCell Corp., Branchburg, NJ), AlloDerm-Ready-To-UseTM (LifeCell Corp., Branchburg, NJ), AlloMaxTM (Davol Inc., Murray Hill, NJ), FlexHDVR (Ethicon Inc., Somerville, NJ), DermaMatrixTM (MTF / Synthes CMF, West Chester, PA), DermACELLVR (Life Net Health, Virginia Beach, VA), NeoFormVR (Mentor, Santa Barbara, CA), StratticeTM (LifeCell Corp., Branchburg, NJ), PermacolTM (Covidien, Boulder, CO), y SurgimendVR PRS (TEI Biosciences Inc., Boston, MA), PELCURPON (Dr. Lenox SA).

[0016] Biomechanical aspects

[0017] The native collagen framework and the composition of the extracellular matrix (ECM) can contribute to the variable elastic properties and resistance of dermal matrices outside of packaging.

[0018] After implantation of said dermal matrices, the degree of degradation and cellular infiltration have an influence on these properties.

[0019] Melman et al. [8] demonstrated this on a porcine model in which three matrices were evaluated: AlloDerm, Strattice and Permacol, the latter being recommended for mammary reconstructions.

[0020] Biochemical aspects

[0021] Although different manufacturers take care to eliminate all antigenic components and retain only the native ECM, there are significant differences between the various products. Carruthers et al. conducted in vitro analyses on AlloDerm and AlloMax and observed that AlloMax contained more soluble proteins than AlloDerm.

[0022] Remodeling and histology

[0023] The ADM constitutes a biological scaffold for an implant. After the implant is placed, the patient's blood infiltrates the dermal matrix of the universal biological prosthesis, bringing stem cells from the implant's host which attach to the matrix, differentiate and promote neovascularization and incorporation of the implant into the surrounding tissues.

[0024] US patent 1,163,352, B2, entitled "Biological Breast Implant," provides tissue products produced from adipose tissue, as well as methods for obtaining said tissue products. These tissue products may include acellular tissue matrices for breast treatment.

[0025] ADMs derived from human or animal tissue retain a substantial amount of natural collagen, other proteins, proteoglycans, and necessary glycoproteins that serve as scaffolding to support tissue regeneration.

[0026] ADMs differ from purified collagen materials, such as acid-extracted purified collagen, due to their substantial lack of other proteins. The matrix is ​​altered and does not retain the natural microstructural characteristics of the tissue matrix due to the purification processes. These ADMs can be associated with exogenous cells, such as, for example, stem cells or cells from a patient into whom these matrices are implanted.

[0027] On the other hand, a "decellularized adipose tissue matrix" refers to adipose tissue from which all cells have been removed to produce an extracellular adipose matrix. A "decellularized adipose tissue matrix" may include an intact matrix or a matrix that has undergone additional processing as described in this document, including mechanical processing, sponge formation, and / or further processing to produce a particulate matrix.

[0028] The term "acellular" or "decellularized" tissue matrix refers to tissue matrices in which no cells are visible under an optical microscope.

[0029] Several human and animal tissues are used to manufacture products for patient treatment. Indeed, numerous tissue products have been manufactured for the regeneration, repair, augmentation, reinforcement, and / or treatment of human tissues that have been damaged or lost as a result of various diseases and / or structural damage, such as trauma, surgery, atrophy, and / or long-term degradation and degeneration. These products may include, for example, acellular tissue matrices, tissue allografts or xenografts, and / or reconstituted tissues—that is, tissues that are at least partially decellularized and have been seeded with cells to produce viable materials.

[0030] Several tissue products have been manufactured for the treatment of soft and hard tissues. For example, Alloderm® and Strattice® (Lifecell Corporation, Branchburg, NJ) are two acellular dermal tissue matrices made from human and porcine dermis, respectively. While these materials are very useful for treating certain types of conditions, materials with different biological and mechanical properties may be desirable for some conditions. For example, Alloderm® and Strattice® have been used to assist in the treatment of structural defects and / or to provide tissue support. for example for abdominal walls or in breast reconstruction, and their strength and biological properties make them well suited for such uses.

[0031] Patent application published under number US 20230310142 A1, entitled "Retromammary Breast Conservative Surgery with Acellular Dice Dermal Matrix for Volume Replacement in Breast Cancer," relates to breast surgery, which includes the removal of a tumor by means of breast-conserving surgery (BCS), with volume replacement using ADM for breast cancer. The surgical method according to the present invention is effective from both an oncological and cosmetic point of view with respect to reducing postoperative fat necrosis, and can readily preserve the volume and shape of the preoperative breast mound.The effective shortening of the duration of the surgical procedure and the significant reduction of intraoperative bleeding can considerably reduce the incidence of postoperative complications such as postoperative intramammary fat necrosis and skin flap necrosis following the onset of subcutaneous fat necrosis.

[0032] A DMA comprising a dermal matrix obtained from human skin using cellular element removal technology is provided and it may be a commercially available cubed or diced DMA product or obtained by removing an epidermal layer and skin tissue cells.

[0033] US patent application 2012158134 A1, titled "Prosthesis and Method for Breast Mastopexy and Reconstruction," relates to a breast mastopexy and reconstruction prosthesis and implantation method that enables radiographic imaging of breast tissue. The prostheses are arched and elongated, optionally meshed to conform to breast tissue during implantation. The prostheses are made from a natural extracellular matrix, primarily collagen, allowing for mammographic imaging without the interferences expected with synthetic materials.

[0034] The present invention relates to methods for manufacturing tissue-engineered prostheses from clean tissue material in which the methods do not require adhesives, sutures, or staples to bond the layers, while maintaining the bioremodelable nature of the prostheses. Tissue-engineered prostheses are fabricated from processed tissue matrices derived from native tissues that are biocompatible with the patient or host into which they are implanted.

[0035] Specifically, this application provides a device composed primarily of porcine type I collagen, approximately >95% in its native form, with less than approximately 0.7% lipids and undetectable levels of glycosaminoglycans (approximately <0.6%) and DNA (approximately <0.1 Ng / pl). However, these materials may not be ideal for the regeneration, repair, replacement, and / or augmentation of collagen-containing tissues. Consequently, this disclosure provides tissue products that are useful for treating tissue defects / imperfections affecting collagen-containing tissues.

[0036] In view of current problems concerning implants, a biological prosthesis made up of dermal cellular matrices of porcine, human, bovine or caprine origin has been developed.

[0037] Brief summary of the invention

[0038] The present invention therefore relates to a universal biological prosthesis of acellular dermal matrix (ADM) for its use in body reconstruction processes, comprising: a first layer of biologically sourced ADM arranged inferiorly to delimit a cavity with a lower edge; a filling material disposed in the cavity surrounded by the first layer of ADM consisting of a ground ADM having the consistency of a fibrous paste; and a second layer of biologically sourced ADM arranged on the upper part covering the filling material and whose upper edge rests peripherally on the lower edge of the first layer of ADM, thus defining a rim;

[0039] where the first layer of ADM and the second layer of ADM are joined by careful overlapping along the upper edge of the first layer of ADM with the lower edge of the peripheral rim using a biocompatible glue, or by absorbable suture; where the first layer of ADM, the second layer of ADM and the ADM filling material are not immunogenic; and where the ADM comprises collagen fibers, fibronectin, elastin, laminin, glycosaminoglycans and hyaluronic acid.

[0040] Preferably, the ADM of the universal biological prosthesis is of cadaveric human, porcine, bovine or caprine origin.

[0041] Preferably, the ADM of the universal biological prosthesis is of porcine origin.

[0042] Preferably, the first and second layers of ADM should also have a thickness between 300 microns and 1 mm.

[0043] Preferably, the biocompatible adhesive is chosen from poly(methyl methacrylate) (PMMA); methyl-, ethyl-, N-butyl-, hexyl- and octyl-2- cyanoacrylates; fibrin-based adhesives combining fibrinogen and thrombin to form a clot; adhesives based on polyphenolic proteins obtained from the mollusc Mytilus edulis; adhesives based on polymers derived from resorcinol and gelatin activated by formaldehyde or glutaraldehyde; adhesives based on hydrogels formed by polymeric networks of polyethylene glycol, polymers derived from ethylene vinyl alcohol, dimethyl sulfoxide and tantalum; adhesives based on four-arm polycaprolactone (PCL, a biodegradable low-melting-point polymer) modified by N-hydroxy succinimide (star-PCL-NHS); adhesives based on a hydrogel composed of chitosan (CS) and star-shaped polycaprolactone (stPCL).

[0044] Incidentally, the biocompatible glue is combined with a collagen cream.

[0045] Incidentally, the biocompatible glue is also combined with a resorbable suture.

[0046] Preferably, the rim of the universal biological prosthesis has a width of approximately 0.8 to 1.2 cm around the entire circumference, allowing for suturing to fix it to the internal fascia of the patient's cavities to be filled.

[0047] Preferably, the universal biological prosthesis also consists of an implant of breast, buttocks, heels, cheekbones, chin, ears, meniscus or parts of bone.

[0048] In particular, the volume of the universal biological prosthesis is capable of expanding by approximately 45% to 55% with the patient's tissue fluids after implantation.

[0049] Also in particular, the universal biological prosthesis is flexible and can be folded in half for manipulation during implantation in a patient.

[0050] In addition, the universal biological prosthesis allows for the addition of volume using an extra filling material in a quadrant that needs to be augmented using a trocar.

[0051] In principle, the universal bioprosthesis is inserted into a mold of the shape of the prosthesis in order to preserve its format.

[0052] Essentially, the universal biological prosthesis is inserted into a primary vacuum-sealed polyethylene package.

[0053] Essentially, the universal biological prosthesis is packaged in a secondary vacuum-sealed polyethylene container.

[0054] Thus, the primary and secondary packaging of the universal biological prosthesis is made of polyethylene of approximately 80 to 100 microns.

[0055] Typically, the universal biological prosthesis is sterilized by gamma radiation.

[0056] In addition, the universal biological prosthesis is packaged in a commercial tertiary package. Another object of the present invention is a method for manufacturing a universal biological prosthesis of Acellular Dermal Matrix (ADM) for use in body reconstruction processes for patients who require it, comprising the following steps: a) provide a mold with a cavity that defines the external shape of the prosthesis to be manufactured; b) mold a first layer of ADM onto the cavity of the mold that gives shape to the biological prosthesis by adhering it to its surface to form a cavity; c) fill the inside of the cavity with a filling material made of ADM granules with the consistency of a fibrous paste by distributing it within the cavity; d) cover the filling material inside the cavity with a second layer of ADM, carefully overlapping the upper and lower edges to form a rim around the periphery and eliminate air pockets; e) join the first layer of ADM to the second layer of ADM along said upper and lower edges of the rim using a biocompatible adhesive or by means of a resorbable suture; f) insert the product obtained at point e) into a mold of the shape of the prosthesis in order to preserve its format;(g) introduce the product obtained at point (f) into a primary polyethylene package and apply a vacuum; (h) introduce the product obtained at point (g) into a secondary polyethylene package and apply a vacuum; (i) sterilize the product obtained at point (h) by gamma radiation; and (j) package the product obtained at point (i) into a commercial tertiary package.

[0057] Preferably, the ADM used in the method is of cadaveric human, porcine, bovine or caprine origin.

[0058] Preferably, the ADM used in the method is of porcine origin.

[0059] Preferably, the first and second layers of ADM should also have a thickness between 300 microns and 1 mm

[0060] Preferably, the biocompatible adhesive used in the method is chosen from poly(methyl methacrylate) (PMMA); methyl-, ethyl-, N-butyl-, hexyl- and octyl-2-cyanoacrylates; fibrin-based adhesives combining fibrinogen and thrombin to form a clot; protein-based adhesives polyphenolics obtained from the mollusc Mytilus edulis; adhesives based on polymers derived from resorcinol and gelatin activated by formaldehyde or glutaraldehyde; adhesives based on hydrogels formed by polymeric networks of polyethylene glycol, polymers derived from ethylene vinyl alcohol, dimethyl sulfoxide and tantalum; adhesives based on four-arm polycaprolactone (PCL, a biodegradable low-melting-point polymer) modified by N-hydroxy succinimide (star-PCL-NHS); adhesives based on a hydrogel composed of chitosan (CS) and star-shaped polycaprolactone (stPCL).

[0061] Incidentally, the biocompatible glue is combined with a collagen cream.

[0062] Incidentally, the biocompatible glue is also combined with a resorbable suture.

[0063] Preferably, the rim has a width of approximately 0.8 to 1.2 cm around the entire perimeter, allowing for suturing to fix it to the internal fascia of the cavities to be filled.

[0064] In particular, the primary and secondary packaging is made of polyethylene of approximately 80 to 100 microns.

[0065] Preferably, the universal biological prosthesis obtained by the method constitutes an implant of breast, buttocks, heels, cheekbones, chin, ears, meniscus or parts of bone.

[0066] In particular, the volume of the universal biological prosthesis obtained by the method is capable of expanding by approximately 45% to 55% with the patient's tissue fluids after implantation.

[0067] Also in particular, the universal biological prosthesis obtained by the method is flexible and can be folded in half for manipulation during implantation.

[0068] In addition, the universal biological prosthesis obtained by the method allows for the addition of extra volume in a quadrant that must be augmented using a trocar.

[0069] In addition, the extra volume includes ADM in fibrous paste form alone or mixed with patient fat.

[0070] Brief Description of the Figures

[0071] Reference is made below to exemplary embodiments, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers are used in the drawings to designate the same or similar parts. The drawings are not necessarily to scale.

[0072] Figure 1 A shows in perspective a preferred embodiment of a universal biological prosthesis made of Acellular Dermal Matrix (ADM) for a breast application, the peripheral edge of which is sutured.

[0073] Figure 1B shows the universal biological prosthesis of Figure 1A in cross-section, showing a first layer of ADM forming a volume to be filled, the ADM grinding material of fibrous paste consistency constituting the internal filling of said prosthesis, and a second layer of ADM bonded with a biological adhesive and sutured to the edges of the two layers forming a rim which produces the closure of the ADM prosthesis.

[0074] Figure 2A shows in perspective a preferred embodiment of a universal biological prosthesis in Acellular Dermal Matrix (ADM) for application on the buttocks, without suture on the peripheral rim.

[0075] Figure 2B shows the universal biological prosthesis of Figure 2A in cross-section, showing a first layer of ADM forming a volume to be filled, the fibrous, paste-like ADM grinding material constituting the inner filling of the ADM prosthesis, and a second layer of ADM bonded with biological adhesive to the edges of the two layers forming a rim which produces the closure of the ADM prosthesis.

[0076] Figure 3A shows in perspective a preferred embodiment of a universal biological prosthesis made of Acellular Dermal Matrix (ADM) for application on heels, particularly for diabetic patients, with a suture on the edge at the periphery.

[0077] Figure 3B shows the universal biological prosthesis of Figure 3A in longitudinal section, with a first layer of ADM forming a volume to be filled, the ADM grinding material with the consistency of a fibrous paste constituting the internal filling of said prosthesis, and a second layer d'ADM glued with a biological adhesive and sutured on the edges of the two layers, forming a rim which produces the closure of the d'ADM prosthesis.

[0078] Figure 3C shows the universal biological prosthesis of figure 3A in cross-section.

[0079] Figure 4A shows in perspective a preferred embodiment of a universal biological prosthesis in Acellular Dermal Matrix (ADM) for breast or buttock lift, without suture on the peripheral rim.

[0080] Figure 4B shows the universal biological prosthesis of Figure 5A in longitudinal section, showing a first layer of ADM forming a volume to be filled, the ADM grinding material with the consistency of a fibrous paste constituting the internal filling of said prosthesis, and a second layer of ADM bonded with a biological adhesive on the edges of the two layers forming a rim which produces the closure of the ADM prosthesis.

[0081] Figure 4C shows the universal biological prosthesis of Figure 5A in cross-section.

[0082] Figure 5A shows in perspective a preferred embodiment of a universal biological prosthesis in Acellular Dermal Matrix (ADM) for filling the chin, upper or lower jaw, whether in soft tissue or in bone, without suture at the edge at the periphery.

[0083] Figure 5B shows the universal biological prosthesis of Figure 5A in longitudinal section, showing a first layer of ADM forming a volume to be filled, the ADM grinding material with the consistency of a fibrous paste constituting the internal filling of said prosthesis, and a second layer of ADM bonded with a biological adhesive on the edges of the two layers forming a rim which produces the closure of the ADM prosthesis.

[0084] Figure 5C shows the universal biological prosthesis of Figure 5A in cross-section.

[0085] Figure 6A shows in perspective a preferred embodiment of a universal biological prosthesis in Acellular Dermal Matrix (ADM) for application to the buttock, cheekbones or pectorals, without suture on the peripheral rim.

[0086] Figure 6B shows the universal biological prosthesis of Figure 6A in longitudinal section, showing a first layer of ADM forming a volume to be filled, the ADM grinding material with the consistency of a fibrous paste constituting the internal filling of said prosthesis, and a second layer of ADM bonded with a biological adhesive on the edges of the two layers forming a rim which produces the closure of the ADM prosthesis.

[0087] Figure 6C shows the universal biological prosthesis of Figure 6A in cross-section.

[0088] Detailed description of the invention

[0089] Tissue engineering combines engineering methods with principles from the life sciences, enabling an understanding of the structural and functional relationships of normal and pathological mammalian tissues. The goal of tissue engineering is the development and application of biological substitutes to restore, maintain, and enhance tissue function.

[0090] Collagen is the body's main structural protein and makes up about one-third of the body's total protein. It comprises most of the organic matter in skin, tendons, bones, and teeth, and is present as fibrous inclusions in most other body structures.

[0091] Among the properties of collagen are its high tensile strength, its low antigenicity, due in particular to the masking of possible antigenic determinants by the helical structure, as well as its low extensibility, semi-permeability and solubility.

[0092] Furthermore, collagen is a natural substance for cell adhesion. Collagen-based materials are capable of bioremodeling provided they are mechanically and chemically treated in a suitable manner to preserve their bioremodeling properties, unlike synthetic materials, for which the lack of bioremodeling is a disadvantage. These properties, along with others, make collagen a suitable material for tissue engineering and for the manufacture of biocompatible implantable substitutes and bioremodeling prostheses.

[0093] Methods for obtaining collagen tissue and tissue structures from explanted mammalian tissues, and processes for constructing prostheses from this tissue, have been extensively studied for surgical repair or for the replacement of tissues or organs. One of the ongoing goals of researchers is to develop prostheses that can be successfully used to replace or repair mammalian tissues.

[0094] Collagen-based materials and prostheses are necessary for use in procedures involving human breast tissue. In recent years, the rate of plastic surgery procedures has increased, and many women are choosing to undergo surgery to alter the size, shape, and position of their breasts.

[0095] On the other hand, the rate of breast reconstruction surgeries after mastectomy has increased thanks to improved methods of cancer detection and the fact that many women have become more vigilant regarding their breast health.

[0096] Traditionally, autologous tissue grafts and synthetic materials have been used in reconstructive surgery, but each has its disadvantages. With autologous tissue grafts, the morbidity associated with the donor's second surgical site and the more painful recovery period for patients were significant problems. As for synthetic materials, they always carry a risk of infection. Thus, reconstructive surgery always requires a suitable material.

[0097] Acellular Dermal Matrix (ADM) is a biological graft containing neither cellular nor antigenic components to avoid immunogenicity. It has therefore been recognized as a good substitute material for plastic and reconstructive surgeries. ADM can be obtained from human, bovine, caprine, and porcine tissues, among others. ADM is composed of collagen fibers, fibronectin, elastin, laminin, glycosaminoglycans, and hyaluronic acid. It serves as a scaffold that the vascularized host gradually fills with cells. ADM is used in cosmetic and reconstructive surgeries of the nasal and oral cavities, breasts, and walls. abdominal. It is also used for burns and diabetic wounds.

[0098] It is important to note that ADM (artificial dermal grafting) should not replace a full layer of skin tissue due to the absence of an epidermis. When using ADM, instead of a full-thickness skin graft, only a thin layer of skin graft is required, resulting in less scarring in the donor area. The surgeon decides whether or not to use a thin layer of skin graft.

[0099] Several studies have shown favorable results with ADM in breast reconstruction with implants, with low complication rates. Furthermore, some research has demonstrated faster healing of diabetic foot ulcers with ADM than with standard treatment. Several studies have also evaluated the results of biological mesh, i.e., ADM, compared to synthetic mesh in abdominal hernia repair.

[0100] Universal 3D bioprostheses capable of delivering a large volume of filler material to different parts of the human body have never been tested before. These universal bioprostheses (1) of the invention provide a structure or scaffold for the recipient body to reconstruct the affected area by modifying the prosthesis with its own elements, changing the fibers one after another. The ADM comprises long fibers that function as a scaffold that does not disintegrate in the moist environment of the body.

[0101] Breasts

[0102] Breast cancer is the most common cancer among women worldwide and leads to numerous social and psychological problems. Several surgical options are used for breast reconstruction. The use of implant-supported mammography (ASM) in breast reconstruction with implants after mastectomy has recently garnered significant interest. The advantages of ASM in implant-based breast surgery include implant stabilization, improved aesthetic outcomes, and reduced risks of capsular contracture, donor-site morbidity, and postoperative pain.

[0103] Mastopexy, or breast lift, is a procedure designed to improve the appearance of sagging breasts or those affected by breast ptosis. The goal of the procedure is to improve the shape and position of the breasts, that is, to lift them while minimizing visible scarring. To achieve this result, numerous procedures and countless modifications of mastopexy have been developed.

[0104] After a mastectomy, breast reconstruction with implants is a very popular option. However, one of the risks of this technique is capsular contracture. Previous research has suggested that breast implants coated with ADM are less likely to develop capsular contracture. Stump et al. decided to compare the rate of capsular contracture in breast implants with and without ADM in primates. They found that ADM-coated breast implants significantly reduced the rate of capsular contracture. Coating the implant in ADM prevents the immune system from recognizing the implant and forming a fibrous capsule around it.

[0105] Universal biological prosthesis

[0106] The use of porcine-derived DNA (DMA) dates back to 1990, and since then, it has led to a better understanding of how this material functions when placed in the human body. A DMA is a decellularized matrix structure obtained through mechanical and enzymatic debridement to eliminate unwanted elements.

[0107] Firstly, it has been established that ADMs integrate into the organism, providing their three-dimensional architecture for the construction of new tissue.

[0108] These matrices are invaded by blood vessels from the bed, which invade the scaffold formed by the ADM with the patient's cells; this is the natural replacement of the structure, as well as the recomposition of the aqueous matrix.

[0109] In this way, the patient manufactures their own tissue, the scaffold does not generate immune rejection, and the matrices are not all the same, but at least they are similar.

[0110] Faced with the current problem of synthetic implants, a biological prosthesis (1) of universal type composed of Acellular Dermal Matrices (ADM) of human, porcine, bovine or caprine cadaveric origin has been developed.

[0111] Preferably, porcine-derived MDAs are used.

[0112] To this end, the present invention relates to a universal biological prosthesis (1) for use in body reconstruction processes, comprising:

[0113] a first layer (2) of biologically sourced ADM arranged inferiorly to delimit a cavity (3) with a lower edge (4);

[0114] a filling material (5) disposed in the cavity (3) surrounded by the first layer (2) of ADM consisting of a ground ADM having the consistency of a fibrous paste; and a second layer (6) of ADM of biological origin arranged on the upper part covering the filling material (5) and whose upper edge (7) rests peripherally on the lower edge (4) of the first layer (2) of ADM, thus defining a peripheral rim (8);

[0115] where the first layer (2) of ADM and the second layer (6) of ADM are joined by careful overlapping along the upper edge (7) of the first layer (2) of ADM with the lower edge (4) of the rim in the periphery (8) using a biocompatible adhesive; where the first layer (2) of ADM, the second layer (2) of ADM and the filling material (5) of ADM are not immunogenic; and where the ADM comprises collagen fibers, fibronectin, elastin, laminin, glycosaminoglycans and hyaluronic acid.

[0116] The universal biological prosthesis (1) of the present invention, based on ADM, determines a three-dimensional (3D) volume which produces a filling of body cavities by offering solutions of continuity to the surrounding tissues and generating high-quality scars through cellular colonization and vascularization obtained throughout the implanted volume.

[0117] Placement of a biological prosthesis in patients with dermal flap circulation disorders after mastectomies

[0118] Currently, the practice of wrapping breast implants with ADM is widespread in international literature. There are studies dating back to 2000 with very good results.

[0119] However, in recent years, cases of collagen disease or rheumatic disease, also known as ASIA syndrome, have become increasingly evident. These are immunological, autoimmune, autoinflammatory diseases induced by implants such as silicone prostheses. As part of the treatment, implant removal has been necessary, after which ASIA syndrome resolves. In response to the increasing number of reports in the international literature on ASIA syndrome, where silicone breast implants are suspected of being one of the causes, a universal biological prosthesis (1) made entirely from biologics with DNA of cadaveric or animal origin, such as bovine, porcine, or caprine, is being proposed.

[0120] The universal biological prosthesis (1) of the present invention provides the body with a material that the body recognizes as its own, collagen, so that it can then rebuild a volume vascularized by the body itself by generating the development of new cells that fill the space left by removed tissue or a removed silicone prosthesis.

[0121] Furthermore, not all DMAs are created equal. For example, one DMA used was PELCUPRON, a matrix that preserves the body's natural architecture for cellular self-regeneration in environments where the body cannot rebuild this missing tissue. Synthetic matrices produced in the laboratory do not possess the natural structure of a dermis; examples include INTEGRA, MATRIDERM, ALLODERM, etc.

[0122] This problem is solved thanks to the universal biological prosthesis (1) based on the use of ADMs such as the one described, which is not only intended for breast application, but can be adapted to any other part of the human body desired or necessary.

[0123] Evaluation of the results obtained

[0124] When filling a cavity, for example one created after the resection of a sacral pressure ulcer, with an Acellular Dermal Matrix (ADM), we observe firstly, that these expand rapidly when rehydrated with organic fluids and that they become vascularized; secondly, if no excess material is placed, integration is generally complete and the resulting filling tissue is granulation tissue contained within a connective tissue structure which gives it structure and differentiates it from common granulation tissue because it does not bleed easily and reassembles a scaffold which fills the defect.

[0125] Occasionally, some of the material may be lost due to insufficient vascularization; however, it can be replenished with other materials to complete the filling. This result does not suggest, nor does it lead a person skilled in the art to conclude, that much larger 3D volumes would allow for effective implants using the universal biological prostheses of the present invention. Knowledge of the state of the art for implant placement in general, and breast implant placement in particular, provides no indication of the differences in the placement of large-volume implants of this type of material.

[0126] In a preferred embodiment, the method for implanting a universal biological prosthesis (1) in Acellular Dermal Matrix (ADM) according to the present invention, for example of porcine origin, comprises the following steps: a) making an incision, preferably using the anterior primary incision; b) dissecting the skin and cellular planes by creating a pocket large enough to accommodate the biological prosthesis (1), avoiding excessive dissection; c) placing a biological prosthesis (1) in the pocket created in step (b); d) fixing the edge (8) of the biological prosthesis (1) to the bed to the deep plane by means of sutures; e) optionally, placing a drain if necessary; and f) closing the planes and placing an elastic splint which will be maintained during the post-surgical period, preferably until the biological prosthesis (1) is incorporated into the patient's body.

[0127] The implanted universal biological prosthesis (1) adapts by incorporating water from the recipient body in a natural biological remodeling behavior, resulting in high-quality healing with cellular colonization and vascularization of the entire implanted volume.

[0128] Biological breast implant

[0129] When implanting a volume, for example of about 100 g, it must be taken into account that this initial volume will increase, that is to say it expands by about 45% to 55%.

[0130] It has also been noted that it is not necessary to make the patient's pocket larger than the biological prosthesis (1) to be implanted.

[0131] Beyond the size of the biological prosthesis (1), for example its diameter in the case of a breast prosthesis, there is a rim on the periphery (8) which borders the biological prosthesis (1) and which allows it to be sutured for its fixation.

[0132] Furthermore, the biological prosthesis (1) of the invention is flexible, allowing it to be folded in half and placed through smaller incisions. If necessary, volume can be easily added using additional filling material in the quadrant that needs to be augmented.

[0133] After implantation, seromas are to be expected during the first week, which may justify drainage during the first 48 hours.

[0134] In the event of wound dehiscence, the removal of biological prostheses (1) is not necessary because the prostheses are fixed and their edges (4, 7) are sealed, and the closure of the wound is done in the same way as a sacral pressure ulcer repair with a matrix.

[0135] The evolution of the universal bioprosthesis (1) after implantation allows observation of the shape and volume achieved after three months, and if necessary, the volume can be augmented by injecting fibrous paste ADM, alone or mixed with the patient's fat, using a trocar. Normally, a bioprosthesis (1) is implanted with a volume smaller than that required to achieve the aesthetic correction, taking advantage of the fact that the increase in prosthesis volume (1) due to hydration corrects the deficiency, or it is supplemented in a way that additionally with fibrous paste-like ADM material. The graft matrix gradually becomes a new tissue, similar to natural adipose tissue.

[0136] The goal is to ultimately obtain a fatty breast that doesn't function like a natural breast but provides a substitute volume. The collagen base of the implant allows for lipotransfer, which is not a graft since it gradually disappears.

[0137] Preferably, the implant of the reconstructive biological prosthesis (1) is placed after the ablation and said prosthesis (1) is refractory to subsequent oncological treatments.

[0138] Construction of a universal biological prosthesis (1) from Acellular Dermal Matrix (ADM)

[0139] Another object of the present invention is a method for manufacturing a universal biological prosthesis (1) made of Acellular Dermal Matrix (ADM) for use in the body reconstruction processes of patients who require it, comprising the following steps: a) providing a mold with a cavity that defines the external shape of the prosthesis (1) to be manufactured; b) molding a first layer (2) of ADM onto the cavity of the mold that gives shape to the biological prosthesis (1) by adhering it to its surface to form a cavity (3); c) filling the interior of the cavity (3) with a filling material (5) consisting of ADM granules of fibrous paste consistency by distributing it within the cavity; d) covering the filling material (5) from the interior of the cavity (3) with a second layer (6) of ADM, carefully overlapping the upper edge (7) and the lower edge (4) to form a rim around the periphery (8) and eliminate air pockets;e) connect the first layer (2) of ADM to the second layer (6) of ADM along said upper (7) and lower (4) edges of the rim using a biocompatible glue or by means of a resorbable suture; f) insert the product obtained at point e) into a mold of the shape of the prosthesis (1) in order to preserve its format; g) introduce the product obtained at point f) into a primary polyethylene package and vacuum-seal; h) introduce the product obtained at point g) into a secondary polyethylene package and vacuum-seal; i) sterilize the product obtained at point h) by gamma radiation; and j) package the product obtained at point i) into a commercial tertiary package.

[0140] The first (2) and second (6) ADM layers have a thickness between 300 microns and 1 mm.

[0141] In a preferred embodiment, a first layer (2) of ADM, for example with a diameter of about 9 cm, is placed in a mold with a concave cavity which will give the external shape to the biological prosthesis (1) for breast application in particular, or in general for different parts of a patient's body.

[0142] Integrity is checked and the first layer (2) of ADM is molded so that it remains stuck to a surface belonging to the concave cavity of the mold.

[0143] Next, the interior of the generated cavity (3) is filled with a filling material (5) consisting of a ground ADM with the consistency of a fibrous, plastic, and malleable paste. When the very hard ADM fiber passes through the knives of a mill, it becomes a plastic fibrous paste. The filling material (5) of the biological prosthesis (1) is therefore an irregular fibrous paste obtained by grinding ADM.

[0144] The layers (2, 6) of ADM, preferably of human, porcine, bovine or caprine cadaveric origin, are obtained by decellularization of human cadaveric material or of leather from the back of an already laminated and cut animal, by means of an enzymatic process.

[0145] For example, about 100 g of ADM powder can be used as filling material (5), the quantity or weight required ultimately depending on the size of the biological prosthesis (1).

[0146] This ADM mold is housed and distributed inside the cavity (3) and is covered by a second layer (6) of ADM that is also essentially circular for a biological prosthesis (1) for breast application, overlapping the upper edge (7) with the lower edge (4) carefully, joining the lower part with the upper part along these edges (4, 7) with a biocompatible glue forming a perimeter rim (8), or suturing with a resorbable thread.

[0147] Biocompatible adhesives such as poly(methyl methacrylate) (PMMA), methyl-, ethyl-, N-butyl-, hexyl- and octyl-2-cyanoacrylates (Eastman 910, Krazy GlueMR, IndermilMR, TrufillMR, HistoacrylMR, HistoacrylMR, DermabondMR, Histoacryl MR) are used as biocompatible adhesives; fibrin-based adhesives that combine fibrinogen and thrombin to form a clot (such as TissucolMR (Baxter), CryosealMR (Thermogenesis) and Vivos-tatMR (Vivolution A / S)); adhesives based on polyphenolic proteins obtained from the mollusc Mytilus edulis; adhesives based on polymers derived from resorcinol and gelatin activated by formaldehyde or glutaraldehyde; adhesives based on hydrogels formed by polyethylene glycol polymeric networks; polymers derived from ethylene vinyl alcohol, dimethyl sulfoxide and tantalum;adhesives based on polycaprolactone (PCL, a biodegradable low-melting-point polymer) with four arms modified by N-hydroxy succinimide (star-PCL-NHS); adhesives based on a hydrogel composed of chitosan (CS) and star-shaped polycaprolactone (stPCL), and the like, alone or in combination with cream collagen and / or absorbable suture (9), for example thread obtained from braided filaments based on polyglycolic acid.;

[0148] In this way, the edges (4, 7) form a rim around the periphery (8) with a width of about 0.8 to 1.2 cm all around, allowing the suturing of universal biological prostheses (1) for their attachment to the internal fascia of the cavities to be filled, such as the breasts.

[0149] In addition, the same technique can be used for the production of filler material for buttocks, heels, which is particularly interesting for diabetic patients, cheekbones, chin, ears, menisci, bone parts, and the like.

[0150] Once assembled, the product is placed in a mold shaped like the biological prosthesis (1) to preserve its dimensions and is then placed in a primary polyethylene package approximately 80 to 100 microns thick and vacuum-sealed. It is then placed in another polyethylene package of approximately 80 to 100 microns thick, and this secondary package is vacuum-sealed again.

[0151] The product thus obtained is kept cold at a temperature of about 3.5 °C to 4.5 °C until it is sterilized by gamma radiation, after which the universal biological prosthesis (1) thus obtained is packaged in its final commercial packaging.

[0152] Références bibliographiques - Gao Z. R.: Porcine dermal collagen as wound dressing for skin donor sites and deep partial skin thickness burns. Burns (1992) 18, (6), 492-496. - Gustafson C. and col.: Cultured autologous kératinocytes on a cell-free dermis in the treatment of full-thickness wounds. Burns, Vol. 25, 331 -335, June 1999. - Harrison, M. R., Adzik Net al: ‘Successful repair in utero of fetal diaphragmatic hernia after removal of hernated viscera from the left thorax”, N. Engl. J. Med., 322;1582; 1990. - Langaker M. and Adzick N.: “The biology of fetal wound healing a review” Plast. Recon str. Surg, Vol. 87,788. 1991. - Lorenz C., Petracic A., Hohl H. P., Wessel L., Waag K. L.: Early wound closure and early reconstruction. Experience with a dermal substitute in a child with 60 per cent surface area burn. Burns. 1997 Sep; 23(6):505-508. - Mohammad M. Al-Qattan, Jeffrey C. Posnick, Kant Y. Lin, and Paul Thorner: Fetal Tendon Healing: development of an Experimental Model. Plast. Reconstr. Surg, Vol. 92, N Q 6: page. 1155-1159, Nov. 1993. - Munster A. and col.: Acellular allograft derma matrix: immediate or delayed epidermal coverage?. Burns 27 (2001 ) 150-153. - Ou L. F. and col.: Use of Biobrane in pediatric scald burns - experience in 106 children. Burns 24 (1998) 49 - 53. - Puma S. K., Babu M.: Collagen based dressings - a review. Burns, 2000 Feb; 26(1 ):54-62. - Siebert, J. et al: “Fetal Wound healing a biochemical study of scarless healing”, Plast. Reconstr. Surg., 85:495, 1990. - Chih-chun Y., Tsi-siang S., Wei-shia X.: A Chinese concept of treatment of extensive third-degree burns. Plast Reconstr Surg. 1982 Aug; 70(2):238-54. doi: 10.1097 / 00006534-198208000-00025. PMID: 7048371. - Wainwright D. J.: Use of an acellular allograft dermal matrix (AlloDerm) in the management of full-thickness burns. Burns. 1995 Jun; 21 (4):243-248. - Breuing K. H., Warren S. M.: Immediate bilateral breast reconstruction with implants and inferolateral alloderm slings. Ann Plast Surg, 2005; 55:232-9. - Salzberg C. A., Ashikari A. Y., Koch R. M., Chabner-Thompson E.: An 8-year experience of direct-to-implant immediate breast reconstruction using human acellular dermal matrix (AlloDerm). Plast Reconstruct Surg 201 1 ;127:514-24. - Ibrahim A. M. S., Shuster M., Koolen P. G. L., et al.: Analysis of the National Surgical Quality Improvement Program database in 19,100 patients undergoing implant-based breast reconstruction: complication rates with acellular dermal matrix. Plast Reconstr Surg 2013; 132:1057-66. - Davila A. A., Seth A. K., Wang E., et al.: Human acellular dermis versus submuscular tissue expander breast reconstruction: a multivariate analysis of short-term complications. Arch Plast Surg 2013; 40:19-27. - Kocak E., Nagel T. W., Hulsen J. H., et al.: Biologic matrices in oncologic breast reconstruction after mastectomy. Expert Rev Med Devices 2014; 1 1 :65-75. - Melman L., Jenkins E. D., Hamilton N. A., et al. Early biocompatibility of crosslinked and non-crosslinked biologic meshes in a porcine model of ventral hernia repair. Hernia 201 1 ; 15:157-64. - Cheng A., Saint-Cyr M.: Comparison of different ADM materials in breast surgery. Clin Plast Surg 2012; 39:167-75. - Carruthers C. A., Dearth C. L., Reing J. E., et al.: Histologic characterization of acellular dermal matrices in a porcine model of tissue expander breast reconstruction. Tissue Eng Part A 2014:21 . DOI: 0.1089 / ten.tea.2014.0095. - Sandor M., Singh D., Silverman R. P., et al.: Comparative host response of 2 human acellular dermal matrices in a primate implant model. Eplasty 2014;14:52- 64. - Jansen LA, De Caigny P, Guay NA, et al.: The evidence base for the acellular dermal matrix AlloDerm: a systematic review. Ann Plast Surg 2013;70:587-94. - Simon Skovsted Yde, Mette Eline Brunbjerg & Tine Engberg Damsgaard (2016): Acellular dermal matrices in breast reconstructions - a literature review, Journal of Plastic Surgery and Hand Surgery, DOI: 10.3109 / 2000656X. 2016. 1140053. - Mohammadyari F., Parvin S., Khorvash M., Amini A., Behzadi A., Haj Ebrahimi R., Kasaei F. and Olangian-Tehrani S. (2023): Acellular dermal matrix in reconstructive surgery: Applications, benefits, and cost. Front. Transplant. 2:1133806. doi: 10.3389 / frtra. 2023. 1133806.

Claims

Demands

1. A universal biological prosthesis of Acellular Dermal Matrix (ADM) intended for use in body reconstruction processes, characterized in that it comprises: a first layer of biologically derived ADM disposed inferiorly and delimiting a cavity with a lower edge; a filling material disposed in the cavity surrounded by the first layer of ADM consisting of an ADM powder having the consistency of a fibrous paste; and a second layer of biologically derived ADM arranged on the upper part covering the filling material and the upper edge of which rests peripherally on the lower edge of the first layer of ADM, thus defining a rim; wherein the first layer of ADM and the second layer of ADM are joined by careful superimposition along the upper edge of the first layer of ADM with the lower edge of the rim peripherally using a biocompatible adhesive, or by suture with absorbable thread;where the first layer of ADM, the second layer of ADM and the ADM filling material are not immunogenic; and where the ADM comprises collagen fibers, fibronectin, elastin, laminin, glycosaminoglycans and hyaluronic acid.;

2. The universal biological prosthesis of claim 1, characterized in that the ADM is of cadaveric human, porcine, bovine or caprine origin.

3. The universal biological prosthesis of claim 2, characterized in that the ADM is preferably of porcine origin.

4. The universal biological prosthesis according to any one of the preceding claims, characterized in that the first and second layers of ADM have a thickness between 300 microns and 1 mm.

5. The universal biological prosthesis of claim 1, characterized in that the biocompatible adhesive is selected from poly(methyl methacrylate) (PMMA); methyl-, ethyl-, N-butyl-, hexyl- and octyl-2-cyanoacrylates; fibrin-based adhesives combining fibrinogen and thrombin to form a clot; adhesives based on polyphenolic proteins obtained from the mollusc Mytilus edulis; adhesives based on polymers derived from resorcinol and gelatin activated by formaldehyde or glutaraldehyde; adhesives based on hydrogels formed by polymeric networks of polyethylene glycol, polymers derived from ethylene vinyl alcohol, dimethyl sulfoxide and tantalum; adhesives based on four-arm polycaprolactone (PCL, a biodegradable low-melting-point polymer) modified by N-hydroxy succinimide (star-PCL-NHS); adhesives based on a hydrogel composed of chitosan (CS) and star-shaped polycaprolactone (stPCL).

6. The universal biological prosthesis of claim 1, characterized in that it comprises a collagen cream combined with biocompatible glue.

7. The universal biological prosthesis of claim 1, characterized in that it comprises a suture made of absorbable thread combined with biocompatible glue.

8. The universal biological prosthesis of claim 1, characterized in that the rim has a width of approximately 0.8 to 1.2 cm around the entire contour, allowing a suture for its attachment to the internal fascia of the cavities to be filled.

9. The universal biological prosthesis of claim 1, characterized in that it constitutes an implant of breast, buttocks, heels, cheekbones, chins, ears, menisci or parts of bone.

10. The universal biological prosthesis of claim 1, characterized in that it is configured so that its volume is capable of expanding approximately 45% to 55% with tissue fluids. [Claim 1 1] The universal biological prosthesis of claim 1, characterized in that it is flexible and configured to be folded in half.

12. A body reconstruction product comprising a universal biological prosthesis, characterized in that the universal biological prosthesis is according to claim 1, and in that it comprises a mold of the shape of the prosthesis to preserve the shape in which the prosthesis universal biological is inserted and in that it comprises a primary polyethylene package into which the universal biological prosthesis inserted in the mold is inserted under vacuum.

13. The body reconstruction product of claim 12, characterized in that it comprises a secondary polyethylene package in which the universal biological prosthesis inserted into the mold and into the primary package is vacuum-sealed.

14. The body reconstruction product of claim 12 or 13, characterized in that the polyethylene is about 80 to 100 microns thick.

15. The body reconstruction product of claim 12 or 13, characterized in that it is sterilized by gamma radiation.

16. A method of manufacturing a universal biological prosthesis of Acellular Dermal Matrix (ADM) for use in body reconstruction processes for patients who require it, according to any one of claims 1 to 15, characterized in that it comprises the steps of: a) providing a mold with a cavity that defines the external shape of the prosthesis to be manufactured; b) molding a first layer of ADM onto the cavity of the mold that gives shape to the biological prosthesis by adhering it to its surface to form a cavity; c) filling the interior of the cavity with a filling material consisting of ADM granules of the consistency of a fibrous paste by distributing it within the cavity; d) covering the filling material inside the cavity with a second layer of ADM, carefully overlapping the upper and lower edges to form a rim at the periphery and eliminate air pockets;e) connect the first layer of ADM to the second layer of ADM along said upper and lower edges of the rim using a biocompatible glue or by absorbable suture or a combination of both; f) insert the product obtained at point e) into a mold of the shape of the prosthesis in order to preserve its format; g) introduce the product obtained at point f) into a primary polyethylene package and vacuum-seal; h) introduce the product obtained at point g) into a secondary polyethylene package and vacuum-seal; i) sterilize the product obtained at point h) by gamma radiation; and j) package the product obtained at point i) into a commercial tertiary package.

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