WO2023220041A1 - Greffe composite comprenant un composant dérivé de tissu biostimulateur et ses procédés de fabrication et d'utilisation - Google Patents

Greffe composite comprenant un composant dérivé de tissu biostimulateur et ses procédés de fabrication et d'utilisation Download PDF

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Publication number
WO2023220041A1
WO2023220041A1 PCT/US2023/021505 US2023021505W WO2023220041A1 WO 2023220041 A1 WO2023220041 A1 WO 2023220041A1 US 2023021505 W US2023021505 W US 2023021505W WO 2023220041 A1 WO2023220041 A1 WO 2023220041A1
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WIPO (PCT)
Prior art keywords
tissue
biostimulative
composite graft
graft
composite
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PCT/US2023/021505
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English (en)
Inventor
Eric J. Semler
Jeffrey Cartmell
Subha BHATTACHARYYA
Marc Long
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Musculoskeletal Transplant Foundation
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Application filed by Musculoskeletal Transplant Foundation filed Critical Musculoskeletal Transplant Foundation
Publication of WO2023220041A1 publication Critical patent/WO2023220041A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/005—Ingredients of undetermined constitution or reaction products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking

Definitions

  • the present invention relates to composite implants which include a biostimulative tissue derived component combined with a mechanical reinforcement component.
  • Methods for producing the composite grafts include reformative manufacturing processes such as molding, reforming, reshaping, additive manufacturing, coating, filling, and combinations thereof.
  • Reformative manufacturing processes such as, for example, molding, reforming, reshaping, additive manufacturing, coating, filling, and combinations thereof, enable controlled formation of specific shapes, textures, and geometries, to be created from reduced size bulk materials in the form of particulates, fibers, granules, powder, and combinations thereof.
  • Such processes can be advantageous when applied to reduced size tissue derived materials to produce tissue derived grafts (or implants) having a selected geometry (e.g., size, shape, configuration, or some combination thereof) that may not otherwise be possible due to limitations imposed by natural anatomy and variability of donor tissue samples.
  • grafts which are successfully produced from tissue derived materials using such reformative manufacturing processes and having a desired, selected geometry may lack sufficient acute mechanical reinforcement (e g., mechanical strength, support, elasticity, etc.) for the intended clinical application.
  • acute mechanical reinforcement e g., mechanical strength, support, elasticity, etc.
  • grafts comprise biological materials (i.e., tissue derived materials)
  • they will be at least partially remodeled, and even completely resorbed into tissue, over time, in the recipient’s body, in which case long-term mechanical reinforcement may also be necessary to maintain the mechanical function of the graft and allow appropriate healing following implantation.
  • additive manufacturing i.e., three-dimensional, 3D, or 3-D, printing
  • an appropriate “bioink” may be a useful fabrication method to create grafts of specific geometries, or components thereof, from biostimulative tissue derived materials by utilizing a biostimulative tissue derived material in a reduced size form and incorporating it into the bioink that also comprises a biocompatible polymer that acts as a binder.
  • additive manufacturing processes using bioink comprising a biocompatible polymer binder and a reduced size tissue derived material may allow for the creation of detailed selected surface geometries and textures on grafts or components thereof.
  • Bioinks may also contain other particulate or dissolved biostimulative ingredients such as ceramics, peptides recombinant growth factors, proteins, cells, exosomes, etc.
  • biostimulative ingredients such as ceramics, peptides recombinant growth factors, proteins, cells, exosomes, etc.
  • performing additive manufacturing processes using such a bioink alone is not likely to produce a graft or components thereof having sufficient mechanical reinforcement or strength for use in load bearing clinical applications such as, for example, structural spine grafts or segmental bone repair.
  • a composite graft which comprises: (A) at least one mechanical reinforcement component (“MRC”) and (B) at least one biostimulative tissue derived component (“BTC”), wherein the composite graft has a desired selected geometry (e.g., size, shape, configuration, or some combination thereof), with or without desired selected surface geometries and/or textures thereon, and provides desired bioactivity capable of facilitating or enhancing healing, as well as having sufficient mechanical strength for use in load bearing grafts and applications.
  • MRC mechanical reinforcement component
  • BTC biostimulative tissue derived component
  • Methods for producing the aforesaid composite graft comprise performing one or more reformative manufacturing processes such as, without limitation, molding, reforming, reshaping, additive manufacturing (three dimensional or 3-D printing), coating, filling, and combinations thereof, thereby combining the BTC with, on, around, or within the MTC and forming the composite graft or a component thereof which has a desired selected geometry.
  • reformative manufacturing processes such as, without limitation, molding, reforming, reshaping, additive manufacturing (three dimensional or 3-D printing), coating, filling, and combinations thereof.
  • a composite interbody spacer comprising a biostimulative tissue derived component and at least one structural (mechanical) reinforcement component, is produced partially or entirely by performing additive manufacturing process (e.g., 3-D printing), using a bioink comprising a particulate tissue derived material, at room temperature to minimize or avoid degradation of the tissue derived material.
  • additive manufacturing process e.g., 3-D printing
  • the invention described and contemplated herein incorporates the addition of a durable mechanical reinforcement component to a biostimulative tissue derived component to create a composite graft having biostimulative materials which facilitate or enhance tissue healing and regeneration as well as being capable of withstanding mechanical forces (e.g., compressive, torsional, tensile, gravity, etc.) that may be applied to the graft initially and over a period of time at least necessary for sufficient healing to occur.
  • mechanical forces e.g., compressive, torsional, tensile, gravity, etc.
  • the benefits of this design include the ability to create specific and precise geometric configurations from a reduced size biostimulative tissue derived component without being limited by natural anatomical dimensions, allowing better or more extensive cell infiltration, attachment, migration, remodeling, etc., while maintaining the necessary mechanical strength and support requirements for the graft over time post-implantation.
  • the composite grafts described and contemplated herein are structurally enhanced composite grafts which include a mechanical reinforcement component (“MRC”) and a biostimulative tissue derived component (“BTC”), and possess increased mechanical strength.
  • the structurally enhanced composite grafts include both “load bearing” composite grafts and “shape retaining” composite grafts.
  • load bearing composite grafts are grafts that possess improved mechanical strength for supporting compressive loads, as well as resisting torsional forces, which is useful for repairing or reconstructing load bearing body features such as knees, hips, spine, etc.
  • shape retaining composite grafts are grafts that possess improved strength and physical integrity which, after implanting in a patient, resist one or more of positional movement and shifting, orientational shifting, as well as reshaping, such as sagging, drooping, bending, rippling, twisting, puckering, wrinkling, bulging, receding, collapsing, creep deformation, fatigue strength, fatigue failure, fracturing, other acute and long-term failure, and other loss of desired contour or shape of the body feature being treated.
  • structurally enhanced shape retaining composite grafts possess one or more of increased tensile or torsional strength (e g., suitable for use in composite grafts sized and shaped for replacement or repair of tendons and ligaments, and enthesis regions of such body features), and mechanical integrity capable of resisting radial pressure forces (e g., suitable for use in composite grafts sized and shaped as stents, heart valves, conduits or circulatory vessels, and other devices useful for repair, reinforcement, and reconstruction of cardiovascular body features).
  • increased tensile or torsional strength e g., suitable for use in composite grafts sized and shaped for replacement or repair of tendons and ligaments, and enthesis regions of such body features
  • mechanical integrity capable of resisting radial pressure forces e g., suitable for use in composite grafts sized and shaped as stents, heart valves, conduits or circulatory vessels, and other devices useful for repair, reinforcement, and reconstruction of cardiovascular body features.
  • the composite implant described and contemplated herein is formed either entirely or partially by performing one or more reformative manufacturing processes.
  • Reformative manufacturing processes include, for example without limitation: molding, reforming, reshaping, additive manufacturing (i.e., three dimensional or 3-D printing), coating, filling, etc., a reduced size, particulate biostimulative tissue derived material into a biostimulative tissue derived component of a composite graft that has a specific, desired geometry.
  • a desired selected geometry is a size, shape, configuration, surface texture, etc., or combination thereof which has been selected and is desirable based on the intended use of the composite graft, such as the nature of the implant site (size, tissue type, kind of damage or disease to be treated, etc.) and the desired outcome of the treatment procedure.
  • a reformative manufacturing process may include dehydration or not.
  • a reformative manufacturing process may include terminal sterilization or not.
  • a reformative manufacturing process may include providing a biostimulative tissue derived material already in a reduced size bulk form and ready to be molded, shaped, reformed, 3- D printed, etc.
  • a reformative manufacturing process may include producing a reduced size bulk biostimulative tissue derived material by processing one or more tissue samples, with chemical techniques, physical techniques, or both, to produce the biostimulative tissue derived material in reduced size bulk form which may then be subjected to molding, reshaping, additive manufacturing, etc., as described above.
  • Chemical and physical processing techniques for producing a biostimulative tissue derived material from one or more tissue sample include, for example without limitation, one or more of: recovering, isolating, cleaning, disinfecting, decellularizing, delipidizing, digesting, demineralizing, remineralizing, precipitating, disrupting, resizing, cutting, slicing, pulverizing, grinding, milling, freezing, refrigerating, preserving (e.g., by cryopreserving, lyophilizing, contacting with a preserving agent, storing with a preserving agent, storing in a basal media, at least partially dehydrating, etc.), dehydrating, and sterilizing a tissue sample.
  • preserving e.g., by cryopreserving, lyophilizing, contacting with a preserving agent, storing with a preserving agent, storing in a basal media, at least partially dehydrating, etc.
  • the reformative manufacturing process may further include measuring, imaging, or otherwise determining and saving information regarding the shape and dimensions of a body feature or region thereof of a particular patient that is to be treated using a composite graft described and contemplated herein. That information would then be used and applied to produce a composite graft (MTC and BTC added thereto) which has the patient-specific shape and dimensions of the particular body feature or region thereof to be treated with the composite graft.
  • a biostimulative tissue derived graft by additive manufacturing using a bioink which comprises a particulate biostimulative tissue derived material will not likely provide sufficient mechanical strength for use in load bearing grafts such as structural spine grafts.
  • the composite graft described and contemplated herein incorporate a mechanical reinforcement component to provide the necessary mechanical strength properties of a load bearing graft, while still offering biostimulative properties provided by a biostimulative tissue derived component by performing additive manufacturing (3-D printing) using the aforesaid bioink, thereby combining the particulate biostimulative tissue derived material on the surface of, or around or within, the mechanical reinforcement component (e.g., where voids exist in the MRC).
  • additive manufacturing additive manufacturing
  • the invention described and contemplated herein provides a composite graft having a multicomponent structure which comprises: (A) one or more mechanical reinforcement components (“MRCs”), and (B) at least one biostimulative tissue derived components (“BTCs”) which is combined with the MRC to form the composite graft.
  • the composite graft may, for example, have a roughened surface similar to titanium in order to improve biocompatibility and incorporation upon implantation.
  • the composite graft may, for example, have an engineered or desired porosity, which may be uniform throughout or engineered to be non- uniform, which is conducive to host cell infdtration and attachment for promoting or accelerating bone healing.
  • Each MRC (A) is comprised of any structural material which is biocompatible and capable of providing durable mechanical support following implantation in a recipient’s body.
  • Suitable structural materials include, for example without limitation, surgical grade metals (e.g., titanium, cobalt, chrome, stainless steel, etc., and combinations or alloys thereof), ceramics, biocompatible polymers (e.g., polyether ether ketone or “PEEK”, polyethylene, poly(methyl methacrylate) or “PMMA”), structural allograft materials (e.g., either or both of allograft cortical and cancellous bone), and other similar materials (e.g., pryocarbon, bioglass).
  • surgical grade metals e.g., titanium, cobalt, chrome, stainless steel, etc., and combinations or alloys thereof
  • ceramics e.g., ceramics, ceramics, biocompatible polymers (e.g., polyether ether ketone or “PEEK”, polyethylene, poly(methyl methacrylate) or “P
  • An MRC may be produced by any effective method or process including, without limitation, in part or entirely, by one or more reformative manufacturing processes.
  • the MRC may be configured, shaped, arranged or assembled in any of a variety of different ways, depending on the desired mechanical support that is required.
  • the MRC may have a single geometry or shape, multiple components of the same geometry, multiple components of different geometries, a symmetrical configuration, an asymmetrical configuration, or any combination thereof.
  • a composite graft may comprise two or more MRCs, which may be the same or different from one another and each of which may, independently of the others, be configured, shaped, arranged, or assembled as described above.
  • the MRC may comprise two or more vertical columns or pillars which would be vertically oriented upon implantation to provide compression resistance, as well as possibly torsional resistance.
  • Such a configuration might be suitable, for example, for an interbody spinal spacer graft, and would help to maintain the target disc height at the implanted level after implantation.
  • columns or pillars may be arranged so as to not provide focused loads on the vertebral endplates, but rather to share the load as much as possible in order to avoid graft subsidence.
  • the MRC may be configured or arranged as a frame or rebar in the composite graft so that the graft does not lose its original (i.e., intended, pre-implantation) geometry as remodeling occurs in the body post-implantation.
  • Such embodiments are analogous to clay sculpture techniques in which a frame or rebar structure is created, and clay pieces are added thereon and shaped.
  • the composite graft may be configured in an elongated strip shape with MRC component(s) embedded within the composite graft and aligned in the direction of the long axis or in both long and short axes of the strip shape.
  • the MRC may be configured or arranged having a cage structure, with one or more interior cavities, each of which is in communication with an external environment such as a recipient host’s tissues, through a plurality of openings through an outer wall or lattice structure of the MRC.
  • the MRC may be configured or arranged having a honeycomb structure with interconnected cavities throughout.
  • the (B) BTC comprises a biostimulative tissue derived material which is in a reduced size bulk form such as, without limitation, particulate, fiber, granule, powder, or a combination thereof, prior to being subjected to one or more reformative manufacturing processes (as previously described above) to form the BTC in combination with the MRC.
  • a composite graft as described and contemplated herein comprises a BTC which is attached, applied, or otherwise connected to or around, adsorbed, coated, layered, filled, dispersed, or otherwise deposited on or within one or more MRCs, after performing the one or more reformative manufacturing processes.
  • the biostimulative tissue derived material should be flowable, moldable, or otherwise reshapable.
  • the biostimulative tissue derived material may be combined or formulated with another biocompatible material or carrier to provide a flowable, moldable, or otherwise reshapable reduced size bulk biostimulative tissue derived material.
  • Such reduced size bulk biostimulative tissue derived material is useful to surround, coat, penetrate, fdl, adsorb on or be otherwise combined with an MRC to produce the composite graft.
  • the BTC may be at least partially dehydrated after combination with an MRC by one or more reformative manufacturing processes.
  • the BTC may be fully or completely dehydrated to about 10 % or less water, by weight, based on the total weight of the BTC, after combination with an MRC by one or more reformative manufacturing processes.
  • the biostimulative tissue derived material may be derived from one or more types of autogeneic, allogeneic or xenogenic tissue samples which have been subjected to physical processing techniques, chemical processing techniques, or combinations thereof.
  • the biostimulative tissue derived material may comprise at least partially decellularized extracellular matrix.
  • the biostimulative-tissue derived material may comprise at least partially demineralized extracellular matrix.
  • the biostimulative tissue derived material may comprise at least partially delipidized extracellular matrix.
  • the biostimulative tissue derived material may comprise bioinorganic precipitate.
  • the BTC (B) may comprise biostimulative tissue derived material that is derived from two or more types of tissues.
  • the biostimulative tissue derived material may be combined with one or more bioresorbable materials, such as biodegradable polymers, ceramics, synthetic materials, or combinations thereof.
  • the reformed biostimulative tissue component i.e., the BTC, whether comprised of one or more biostimulative tissue derived materials, and whether or not combined with other biostimulative or therapeutic compounds, imparts a biostimulative response (upon implantation) and is ultimately either (1) resorbed and replaced by host tissue, or (2) allows for, or even facilitates, host tissue to incorporate into the composite implant.
  • the BTC when the composite graft is implanted in a recipient subject, the BTC is capable of facilitating graft incorporation, remodeling, and integration, due to the nature of its composition (e.g., extracellular matrix components, viable and nonviable cells, endogenous growth factors and cytokines), density, porosity and other characteristics (e.g., surface charge, wettability, roughness, nanostructure, etc.).
  • the BTC can further elicit guided tissue regeneration from different tissue types (e.g., bone and cartilage or bone, cartilage and vasculature, etc.).
  • MRC e.g., dense cortical bone, PEEK polymer, metal, ceramic, etc.
  • MRC e.g., dense cortical bone, PEEK polymer, metal, ceramic, etc.
  • Tissue samples of any tissue type may be the source for the reduced size biostimulative tissue derived material and BTC for therefrom. Accordingly, although several exemplary embodiments will be described herein as including or using bone tissue sample or comprising biostimulative bone derived material or BTC, the tissue type is not particularly limited.
  • Suitable tissue types include, without limitation, one or more of: adipose, amnion, artery, breast, bone, cartilage, chorion, colon, dental, dermal, duodenal, endothelial, epithelial, fascial, gastrointestinal, growth plate, intervertebral disc, intestinal mucosa, intestinal serosa, ligament, liver, lung, mammary, meniscal, muscle, nerve, ovarian, parenchymal organ, pericardial, periosteal, peritoneal, placental, skin, spleen, stomach, synovial, tendon, testes, umbilical cord, urological, vascular, vein.
  • the tissue derived component may be prepared as a flowable mixture, slurry, paste or putty comprising one or more reduced size biostimulative tissue derived materials. This step may be important in order to allow the BTC to surround, penetrate or coat the MRC of the composite graft.
  • the biostimulative tissue derived material is prepared as a fine powder that is combined, for example, with polylactic/polyglycolic acid copolymers that act as a binder and then a solvent is added to create a flowable ink. This bioink can then be 3-D printed around the MRC to form the composite graft.
  • the biostimulative tissue derived materials used to form the BTC may each be derived from more than one type of tissue.
  • the BTC may also be formed by combining two or more biostimulative tissue derived materials, each of which may be derived from one or more types of tissues.
  • Additional exemplary binders which are suitable for producing bioink in combination with one or more BTCs include, without limitation, other biodegradable synthetic polymers such as poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), poly (glycolic acid) (PGA), polyurethane (PU), polycaprolactone (PCL), polyethylene glycol (PEG), as well as water soluble natural polymers capable of forming aqueous solutions and/or hydrogels such as collagen, gelatin, alginate, fibrinogen, hyaluronan, silk, agarose, chitosan, and natural and processed (or synthetic) extracellular matrix proteins such as laminin, fibronectin, and MATRIGEL® (commercially available from Coming Life Sciences, of Tewksbury, Massachusetts, U.S.A.).
  • PLGA poly(lactic-co-glycolic acid)
  • PLA polylactic acid
  • PGA poly (glycolic acid)
  • PU polyurethane
  • Hydrogels are water-insoluble, three-dimensional networks of polymer chains capable of holding large amounts of water.
  • combinations of two or more of the exemplary binders listed above may be used as binders for producing bioink with BTCs described and contemplated herein.
  • the powder tissue derived material may comprise processed allograft bone tissue.
  • Any bone type can be used (e.g., cortical, cancellous, lamellar, combination of any, etc.), and the bone can be in mineralized, partially demineralized or fully demineralized form.
  • Tissue derived bioinorganic e.g., ceramic, non-collagenous protein, etc.
  • precipitate powder may also be incorporated to increase the in vivo biostimulative response which can include osteoinduction, angiogenesis and osteoimmunomodulation.
  • 3-D printing of the bioink will allow for the creation of intricate geometries, specific porosity and surface characteristics that should provide one or more of improved cell recruitment, attachment, infiltration, proliferation, differentiation (e g., osteoinduction, angiogenesis, adipogenesis, etc.), cell bioactivity, immunomodulation, as well as tissue remodeling, tissue integration, and new tissue formation, etc.
  • the tissue derived portion of the bioink may be derived from hyaline cartilage (e.g., articular, auricular or costal), fibrocartilage (e.g., meniscus, intervertebral disc) or other soft or connective tissues (e.g., tendon, ligament, fascia, periosteum, pericardium, peritoneum, adipose, dermis, muscle, nerve, vessels, valves, trachea, lung or placenta).
  • hyaline cartilage e.g., articular, auricular or costal
  • fibrocartilage e.g., meniscus, intervertebral disc
  • other soft or connective tissues e.g., tendon, ligament, fascia, periosteum, pericardium, peritoneum, adipose, dermis, muscle, nerve, vessels, valves, trachea, lung or placenta.
  • methods for making the composite grafts comprise performing one or more reformative manufacturing processes such as, for example, molding, reforming, reshaping, additive manufacturing, coating, fdling, and combinations thereof, because they enable controlled formation of MRCs, BTCs, or both, each having a desired specific geometry.
  • reformative manufacturing processes may generally be applied to produce one or more of the MRCs, BTCs, and composite graft comprising both, from reduced size bulk materials, whether structural materials (for the MRC) or biostimulative tissue derived materials (for the BTC).
  • Such processes can be advantageous when applied to particulate tissue derived materials to produce tissue derived grafts (or implants) having a desired selected geometry (e g., size, shape, configuration, or some combination thereof) that may not otherwise be possible due to limitations imposed by natural anatomy and variability of donor tissue samples.
  • the one or more MRCs (A) can be constructed using any methods currently utilized for these devices, such as molding, casting, cutting, constituent assembly, as well as entirely or in part by reformative manufacturing processes (e.g., 3-D printing, extruding, coating, filling, etc.). The design may be unique to this application.
  • the one or more MRCs (A) can be separate, non-attached pieces.
  • the one or more MRCs (A) can be coupled, linked, or otherwise connected to one another to form a mechanical support structure.
  • the one or more MRCs (A) can be an entire open construct in one piece.
  • Each of one or more BTCs (B) is formed by providing or obtaining a reduced size biostimulative tissue derived material (e.g., in the form of particulates, fibers, granules, powder, or combinations thereof) and subjecting it to a reformative manufacturing process which combines the tissue derived material with the MRC and forms the composite graft, as previously described.
  • the reduced size biostimulative tissue derived material may comprise one or more processed tissue samples which may be the same or different tissue types from one another.
  • the method for making the composite graft may comprise a reformative manufacturing process which comprises producing a reduced size bulk biostimulative tissue derived material by processing one or more tissue samples, with chemical techniques, physical techniques, or both, as also described above, followed by subjecting the reduced size bulk biostimulative tissue derived material to one or more of: molding, reshaping, reforming, coating, additive manufacturing, etc., as described above, to produce the BTC.
  • the method may comprise, prior to molding, reshaping, reforming, coating, additive manufacturing, etc., combining one or more additional materials such as, without limitation, other biostimulative or therapeutic compounds, biocompatible carriers, etc., with the reduced size bulk biostimulative tissue derived material.
  • the BTC may comprise one or more biostimulative tissue derived materials. Where there are two or more biostimulative tissue derived materials, they may, or may not, differ from one another in any one or more of several characteristics, including but not limited to: shape (particles, fiber, irregular particles, etc ), size, type of tissue, number of types of tissue, proportions of different types of tissue, viscosity, types or amounts of additional materials included with the one or more types of tissue, degree of demineralization, degree of decellularization, degree of delipidation, disinfected or not, sterilized or not, preserved or not, etc. [00036] Furthermore, one or more biostimulative tissue derived materials may be formulated into one or more bioinks.
  • each bioink may include one or more biostimulative tissue derived materials, each of which may differ from the others as described above.
  • a bioink may contain two or more biostimulative tissue derived materials, each of which is derived from a different type of tissue.
  • two or more bioinks are used to form a BTC by 3-D printing, wherein each bioink differs from the others in any of one or more characteristics, including but not limited to: types of binder, types of solvent(s), types of tissue contained in the biostimulative tissue derived materials, proportion of different biostimulative tissue derived materials, viscosity, proportions of several components (e.g., biostimulative tissue derived material(s), binder, solvent, etc.), types and amounts of other components, etc.
  • characteristics including but not limited to: types of binder, types of solvent(s), types of tissue contained in the biostimulative tissue derived materials, proportion of different biostimulative tissue derived materials, viscosity, proportions of several components (e.g., biostimulative tissue derived material(s), binder, solvent, etc.), types and amounts of other components, etc.
  • the BTC is applied using any one or more effective reformative manufacturing processes.
  • the reduced size bulk biostimulative tissue derived material would be applied to an MRC via 3-D printing (after formulation into a bioink) or a molding/reforming process to form the BTC of the composite graft.
  • performing one or more reformative manufacturing processes such as 3-D printing, molding, etc., to combine one or more BTCs with one or more MRCs can produce composite grafts having a specific internal structure (i.e., having both MRC and BTC materials).
  • a bioink comprising a first biostimulative tissue derived material derived from a first type of tissue may be 3-D printed through one or more ink nozzles to form a BTC.
  • a bioink comprising two or more biostimulative tissue derived materials each of which is derived from a different type of tissue, may be 3-D printed through one or more ink nozzles to form a BTC. Where two or more ink nozzles are used, they may be operated or activated to deliver bioink at least partially concurrently, fully concurrently, or sequentially, with one another, or combinations thereof.
  • a BTC may be formed by 3-D printing using two or more ink nozzles, wherein at least one nozzle delivers a first bioink comprising a first biostimulative tissue derived material derived from at least two different types of tissue, and at least a second nozzle delivers a second bioink comprising a second biostimulative tissue derived material derived from one or more types of tissue which are different from the at least two different tissue types of the first bioink.
  • the reduced size bulk biostimulative tissue derived material used to form the BTC may comprise bone particles, which are preferably partially or substantially demineralized and may be combined with other materials such as biodegradable polymers, ceramics, cells, growth factors, bioinorganics, etc. or additional materials such as may be necessary to create a bioink for 3D printing.
  • substantially demineralized bone tissue contains about 10 % or less, such as about 8% or less, by weight, residual calcium, based on the total weight of the substantially demineralized bone tissue.
  • bioink may be produced by combining a binder, such as PLGA or other biodegradable polymer and compositions described above as suitable binders, and an organic solvent (e.g., acetone, acetonitrile, anisole, chloroform, dichloromethane, dimethylformamide, dimethylsulfoxide, ethyl acetate, and dioxane), along with the reduced size bulk biostimulative tissue derived material.
  • a binder such as PLGA or other biodegradable polymer and compositions described above as suitable binders
  • an organic solvent e.g., acetone, acetonitrile, anisole, chloroform, dichloromethane, dimethylformamide, dimethylsulfoxide, ethyl acetate, and dioxane
  • suitable binders for bioinks include, without limitation, one or more reactive polymer or prepolymer compounds with one or more of a suitable accelerator, crosslinking agent, or catalyst, depending upon the nature and structure of the reactive polymer or prepolymer, as is determinable by persons of ordinary skill in the relevant art.
  • a suitable bioink should be a free-flowing liquid at the time of 3-D printing or molding. During 3-D printing, the constituent particles, fibers, granules, powder, etc.
  • the biostimulative tissue derived material should be small enough to be printed through a fine nozzle such as are included in 3-D printing devices (the finer the nozzle the higher the resolution of the 3-D printed construct, e.g., BTC).
  • the solvent is expected to evaporate, resulting in setting (i.e., hardening, curing, crosslinking, etc.) of the binder due to the drying action of the solvent from the printed structure, which leaves behind the mineralized bone matrix (“DBM”) particles and the binder that holds them together as the BTC of the composite graft.
  • DBM mineralized bone matrix
  • the MRC would be manufactured first, and then the BTC would be 3-D printed on, around or within the MRC, thus forming a composite graft having a solid, yet porous, structure.
  • the BTC could, alternatively, be formed by performing a molding/reforming process, to form the composite graft.
  • the entire composite graft could be 3-D printed, i.e., with the MRC 3-D printed using a first ink and the BTC 3-D printed using a different second bioink.
  • the MRC and BTC can be printed simultaneously through one or more ink nozzles instead of sequentially.
  • the setting or curing is due to the drying action of the solvent.
  • a two or more isocyanate based biodegradable prepolymers which are polymerizable once mixed and injected, may be used as a polymer binder in bioink to form biodegradable polyurethanes suitable for formation a 3-D printed or molded
  • a prepolymer can be included in bioink as a binder and, after 3-D printing, polymerized, and crosslinked by exposure to heat, or electromagnetic energy such as microwave, ultraviolet light, or visible light.
  • the prepolymer mix may need to include or otherwise be contacted with an appropriate accelerator/catalyst.
  • the BTC could be formed first, such as by 3-D printing, and then the MRC could be molded or otherwise formed around or on the BTC, thus adding structure and/or a filler to the 3-D printed BTC to form a reinforced composite graft.
  • composite graft may be formed by a method comprising more traditional coating techniques in which at least a portion of an exterior or interior surface of an MRC is covered or coated with a BTC, wherein the coating is performed by any effective process including, but not limited to, dipping, coating, casting, or spraying, a reduced size bulk tissue derived material on the MRC.
  • One embodiment consists of currently known structural allograft bone spacers for interbody fusion used as the MRC with DBM, or a bioink containing DBM, that is formed by reformative manufacturing on the surface and/or in the lumen of the spacers used as the BTC.
  • the composition, density, porosity and other features of the biostimulative component enable acute host cell infiltration and attachment and more rapid and more complete remodeling into bone compared to standard allograft bone spacers.
  • Such composite grafts would be useful as load bearing composite grafts in the surgical repair or reconstruction of the spine.
  • Another embodiment consists of a truss-like titanium structure as the MRC with DBM that is formed in the void space of the composite implant and/or on its surface as the BTC.
  • the DBM is formed using reformative manufacturing and configured in such a way to enable faster or more complete cell infiltration, attachment, or both, and bone healing, fusion, or both, as compared to just manually packing the spacer with DBM.
  • Such configuration could, for example without limitation, 3-D printing the BTC having a modified degree of porosity, as it is combined with the MRC, rather than just 3-D printing solid sections of DBM particulate containing bioink within an MRC spacer. Modified porosity would allow formore immediate cell infiltration and provide more surface area for cell attachment.
  • the porosity may, for example, include interconnected or noninterconnected channels or pores in the BTC, or the BTC may be a lattice-like structure.
  • Another load bearing embodiment consists of a design that has several parallel posts as the MRC to provide resistance to compressive loading, torsional force, or even both.
  • DBM is formed around the posts and the formation of the DBM can effectively hold the composite implant together such that it can be implanted as a single unit.
  • These posts may be separate structures prior to printing or may be linked or connected after formation to produce an open structural lattice.
  • Such embodiments of the structurally enhanced composite grafts would be useful for either or both of load bearing and shape retaining composite grafts.
  • Yet another embodiment consists of a design where multiple BTC formulations are layered to construct a composite tissue type mimicking the natural architecture of tissue.
  • the structure can have different or gradients of biologic or physical properties in different parts of the device including osteoinductivity, angiogenicity, osteoimmunomodulation and porosity.
  • these kinds of composite grafts can be entheses or an osteochondral grafts. It can also be an osteochondral graft with blood vessels. It can also be soft tissue grafts such nerve conduits with suitable bioink derived from soft tissue particulates.
  • the foregoing composite grafts would generally be considered shape retaining composite grafts.
  • biostimulative bone powder ink onto the surface and/or within the volume of a structural support element.
  • the bone powder ink is optimally demineralized so that osteoinductivity is imparted to the composite implant; however, mineralized bone powder can be used as well.
  • demineralized and mineralized bone can be mixed in the ink to calibrate the level of desired osteoinductive response.
  • Growth factors e.g., BMP2, PDGF, etc.
  • peptides, bioinorganics and synthetic bone graft materials e.g., HA, b-TCP, biostimulative glass
  • this bioink can be made by precipitating natural bioinorganics from the tissue which will allow the endogenous proteins and cytokines to be preserved in the final construct.
  • Suitable natural bioinorganics could be derived from bone tissue samples during demineralization processing, along with endogenous proteins, and then both may be precipitated back onto the reduced size bulk biostimulative DBM particulate material prior to formulation into a bioink with a suitable solvent and binder.
  • residual demineralization solution generated during demineralization processing may be lyophilized into a powder and then combined with DBM particles, binder and solvent into the bio-ink.
  • suitable bioinks may, without limitation, comprise one or more of: reduced size DBM material, reduced size mineralized bone-derived material, bone-derived material which is at least partially demineralized, bioinorganics, and combinations thereof.
  • Such embodiments of the structurally enhanced composite grafts would be useful for either or both of load bearing and shape retaining composite grafts.
  • the bioink When applied to the surface of an MRC, the bioink can be printed so as to create a roughened or textured surface pattern.
  • roughened surfaces are known to enhance biocompatibility .
  • the porosity of the BTC can be controlled in the reformative manufacturing so that cell attachment and infiltration can be optimized.
  • the printed surface can also be controlled to have patterns conducive to elicit immunomodulatory responses.
  • Such roughened or textured surfaces may be advantageously applied to either types of composite grafts (i.e., either load bearing or shape maintaining).
  • Increased levels of surface roughness or texture, on a micro- or nano-scale, may be produced on the BTC using 3-D printing techniques which are believed to be beneficial to the bone healing process compared to smooth surfaces.
  • rough or textured surfaces may influence the ability of precursor cells to adhere and differentiate into boneforming cells and/or by modulating the immune response of macrophages that affect the inflammatory cascade during bone repair.
  • a load bearing composite graft may comprise a spinal spacer with at least one mechanical reinforcement component (MRC) combined with a biostimulative tissue component (preferably demineralized bone matrix-derived bioink) that is applied (either onto, around and in between the MRC) via a reformative manufacturing process.
  • the bone component can be either mineralized or demineralized cortical bone, but demineralized bone imparts osteoinductive properties to the implant. Cancellous bone can also be used. Growth factors or other biostimulative components can also be included in the surface coating (BTC).
  • the MRC can be comprised of a cortical bone top and bottom shell, said shells being square, and the four corners of the top and bottom shells connected by cortical bone struts (i.e., pillars).
  • the middle could initially be empty or have titanium included for strength.
  • the open structure and the exposed surface can then have the BTC added, such as via 3-D printing. These would generally be considered load bearing composite grafts.
  • current allograft cortical or cortical-cancellous spacer designs could have a layer of demineralized bone bioink (i.e., the biostimulative component) applied via 3-D printing onto the exposed surfaces.
  • demineralized bone bioink i.e., the biostimulative component
  • the 3-D printed biostimulative component can have a density gradient to (lower density at the surface; higher in the interior) to facilitate ingress of fluids, cells, etc. This may allow for absorption of fluids, growth factor and other additional biostimulative components either during surgical preparation or in situ in the patient during the healing response.
  • density gradient may be advantageously included in the BTC of either types of composite grafts (i.e., either load bearing or shape maintaining).
  • the method for producing the composite grafts may comprise performing bioinorganic precipitation processes to include osteoconductive synthetic materials (HA, biostimulative glass, b-TCP, etc.) or ceramic precipitate from bone tissue samples back into the bioink.
  • osteoconductive synthetic materials HA, biostimulative glass, b-TCP, etc.
  • ceramic precipitate from bone tissue samples back into the bioink.
  • 3-D printing will allow engineering of specific features (e.g., porosity, texture patterns, grooves, roughness, etc.) into and onto the final composite graft to improve one or more of cell attachment, infiltration, integration, and remodeling.
  • 3-D printing techniques are also able to produce composite grafts (load bearing and shape retaining) which are configured to have geometries which approximate or closely conform to the geometry or anatomy of a particular recipient.
  • therapeutic compounds e.g., anti-infectives, anti -mi cr obi al s, bacteriostatic agents, concentrated growth factors, etc.
  • the same inventive concepts can be used for “solid” bone grafts used in other surgical procedures such as long-bone trauma, smallbone reconstruction, acetabulum (hip) reconstruction, cranio-maxillofacial, mandibular, and cranial reconstruction.
  • Such procedures may, for example, utilize composite grafts as described and contemplated herein which have been configured in the form of other bone spacer devices, bone void filling devices, acetabular shells, wedges, custom shaped or 3-d printed geometries, etc.
  • Such embodiments would generally be considered load bearing composite grafts, but could also be useful as shape retaining composite grafts.
  • Initial contemplated uses would be for use in load bearing grafts such as interbody spinal fusion typically with concomitant spinal fixation (i.e., instrumentation) to provide initial support post-operatively.
  • the BTC for this design would include at least some portion of autogeneic, allogeneic or xenogenic bone. The goal is to provide restoration of disc height, relief from nerve impingement and prevention of further disc degenerative diseases.
  • the spinal instrumentation could be omitted.
  • the composite graft may be configured to interface with a cervical plate and with insertion tools that allow it to be placed in its desired location in the spine.
  • Another potential application can be in producing devices for hip reconstruction, such as in acetabular cup construction, with the distal portion of the titanium or other metallic cup rendered biostimulative by 3D printing the surface of the cup.
  • Another potential application would be to create pre-shaped structural grafts for cosmetic surgeries involving one or more of recontouring, replacement, augmentation, reshaping, etc. of a particular body feature, such as the nose (e.g., by rhinoplasty), breast, a muscle or muscle group (e.g., abdominal, gluteal, calf, bicep, tricep, etc.), cheeks, or chin, as well as reconstructive surgeries involving restoration of one or more of mass, volume, shape, contour to a body feature or defect, such as a tumor resection site, a biopsy site, a debridement site, diseased tissue, trauma damage site, and a combination thereof.
  • a body feature such as the nose (e.g., by rhinoplasty), breast, a muscle or muscle group (e.g., abdominal, gluteal, calf, bicep, tricep, etc.), cheeks, or chin, as well as reconstructive surgeries involving restoration of one or more of
  • Such pre-shaped grafts would be reinforced to optimally retain their original shape, implant orientation, and implant location, over time such that the desired contour of the treated body feature (e.g., nose, face, breast, etc.) would be substantially maintained (i.e., recognizable as an average naturally shaped and contoured body feature).
  • This Graft configurations could include those for use as a columellar strut, spreader graft or dorsal on-lay graft.
  • the BTC for this design would include at least some portion of cartilage, preferably costal cartilage.
  • Additional contemplated uses would be for use in lumbar or thoracic interbody fusion with concomitant spinal fixation (i.e., instrumentation). Once again, the goal is to provide restoration of disc height, relief from nerve impingement, and prevention of further disc degenerative diseases.
  • Such embodiments of the structurally enhanced composite grafts would generally be considered load bearing composite grafts.
  • the technology can be applied to any implant (graft) where mechanical support with a biostimulative tissue (e.g., bone) layer is desired.
  • implants for trauma acetabular cups, femoral hip stems, total / partial joint replacement implants (e.g., knees, shoulders, elbows, distal digits), long bone segments (to replace large allografts), short bone segments (to replace digits, facets, etc.) and others as may be recognized and contemplated by persons of ordinary skill in the relevant art.
  • total / partial joint replacement implants e.g., knees, shoulders, elbows, distal digits
  • long bone segments to replace large allografts
  • short bone segments to replace digits, facets, etc.
  • the load bearing component When combined as a structural spine spacer (i.e., as a BTC within/on a load bearing MRC) and implanted between two vertebral bodies, the load bearing component will bear the structural load (i.e., reinforcing the structures mechanical properties and providing strength).
  • This allows the biostimulative component (BTC) to facilitate bony integration from the vertebral endplates into the spine spacer.
  • the bony integration will replace the biostimulative component with the patient’s own tissue, while the MRC remains intact. It should be noted that for current allograft spine spacers, the surface of the bone may become incorporated with the bone on the vertebral endplates, but integration and bony replacement does not appear to occur.
  • this composite graft design may allow a spinal spacer to be created that can maximize the incorporation of the biologic tissue component and also provide optimal porosity, density and surface properties for the BTC to generate a spacer that facilities faster or more complete fusion.
  • Most spacers currently available are limited to the addition of biologically active material only in a central lumen of their designs. This leaves a large footprint that cannot be remodeled and incorporated over time.
  • the composite graft described herein will allow for more direct endplate contact with the BTC due to increased surface area and also allow for a greater spatial volume in which the fusion mass can be formed. These features may lead to a more rapid and more thorough fusion with better patient outcomes and lower revision rates.
  • the BTC can be added on the top and bottom surfaces to further facilitate integration between those surfaces and the respective vertebral body endplates.
  • the MRC can form a skeleton support into which (i.e., on and around) the biostimulative component can be printed.
  • the skeleton could be a truss-like structure or one or more of vertical columns or pillars.
  • the resulting bone material (of the BTC) will have a porosity as high as about 70% - 80%. This would provide a basic skeleton structure to allow for 3D printing the biostimulative around and/or within to produce a load bearing composite graft.

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Abstract

L'invention concerne un greffon composite structurellement amélioré qui comprend : au moins un composant de renforcement mécanique (« MRC ») et au moins un composant dérivé de tissu biostimulateur (« BTC »). La greffe composite peut avoir une géométrie sélectionnée souhaitée correspondant à la caractéristique corporelle ou à une partie de celle-ci à traiter. Le BTC fournit une biostimulation permettant de faciliter ou d'améliorer la cicatrisation, et le remodelage tissulaire endogène ou la nouvelle formation. Le MRC fournit une résistance mécanique accrue pour des greffes de support de charge et des applications, une résistance mécanique accrue pour des greffes de retenue de forme utiles dans la reconstruction et la réparation. Les procédés de production comprennent un ou plusieurs processus de fabrication reformatifs tels que, sans limitation, le moulage, le reformage, le remodelage, la fabrication additive (impression tridimensionnelle ou 3D), le revêtement et le remplissage, combinant ainsi le BTC avec, sur, autour, ou à l'intérieur du MRC. Dans un mode de réalisation donné à titre d'exemple, un espaceur intersomatique composite comprenant au moins un MRC est produit par impression 3D à l'aide d'une bioencre comprenant un matériau dérivé de tissu biostimulateur en vrac de taille réduite.
PCT/US2023/021505 2022-05-09 2023-05-09 Greffe composite comprenant un composant dérivé de tissu biostimulateur et ses procédés de fabrication et d'utilisation WO2023220041A1 (fr)

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DRISCOLL J. ADAM ET AL: "3D-Printed Ceramic-Demineralized Bone Matrix Hyperelastic Bone Composite Scaffolds for Spinal Fusion", TISSUE ENGINEERING PART A, vol. 26, no. 3-4, 1 February 2020 (2020-02-01), US, pages 157 - 166, XP093071398, ISSN: 1937-3341, DOI: 10.1089/ten.tea.2019.0166 *
MATTHEW T. WOLF ET AL: "Polypropylene surgical mesh coated with extracellular matrix mitigates the host foreign body response : Polypropylene Surgical Mesh Coated With ECM", JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A, vol. 102, no. 1, 19 July 2013 (2013-07-19), US, pages 234 - 246, XP055711713, ISSN: 1549-3296, DOI: 10.1002/jbm.a.34671 *
THALGOTT JOHN S ET AL: "Anterior lumbar interbody fusion with titanium mesh cages, coralline hydroxyapatite, and demineralized bone matrix as part of a circumferential fusion", THE SPINE JOURNAL, vol. 2, no. 1, 1 January 2002 (2002-01-01), AMSTERDAM, NL, pages 63 - 69, XP093071394, ISSN: 1529-9430, DOI: 10.1016/S1529-9430(01)00155-3 *
ZHANG XIAO ET AL: "3D Bioprinting of Biomimetic Bilayered Scaffold Consisting of Decellularized Extracellular Matrix and Silk Fibroin for Osteochondral Repair", INTERNATIONAL JOURNAL OF BIOPRINTING, vol. 7, no. 4, 14 September 2021 (2021-09-14), pages 401, XP093071692, ISSN: 2424-7723, Retrieved from the Internet <URL:https://ijb.whioce.com/index.php/int-j-bioprinting/article/viewFile/401/pdf_1> [retrieved on 20230807], DOI: 10.18063/ijb.v7i4.401 *

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