RU2785894C2 - Intervertebral disc prostheses and their manufacturing methods - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to the field of intervertebral disc prostheses and their manufacturing methods. A biologically compatible supporting structure for an intervertebral disc prosthesis contains an annular element of biologically compatible material. At the same time, the specified annular element contains an inner surface of a wall, an outer surface of the wall, the first flat surface, and the second flat surface opposite to the first flat surface. The specified biologically compatible material is present in amount from 1% to 100 wt.% of the biologically compatible supporting structure. The specified annular element has at least one hole passing through from the outer surface of the wall to the inner surface of the wall and having an average size from 10±10% mcm to 10,000±10% mcm. A method for the manufacture of a biologically compatible supporting structure for an intervertebral disc prosthesis, a composition of an intervertebral disc prothesis, as well as a method for the manufacture of a composition of an intervertebral disc prosthesis are also disclosed.

EFFECT: obtainment of an intervertebral disc prothesis.

29 cl, 9 dwg

Description

Cross reference to related patent applications

This application claims priority over U.S. Provisional Application No. 62/737,915 filed September 27, 2018, which is hereby incorporated by reference in its entirety.

The technical field to which the invention belongs

The proposed technology relates, in general, to prostheses of intervertebral discs and methods for their manufacture. More specifically, this technology relates to intervertebral disc prostheses having a biocompatible supporting structure and tissue engineering design, as well as manufacturing methods using 3D printing or injection molding.

State of the art

Intervertebral discs can be damaged due to herniation, protrusion, dystrophy or trauma, and they do not heal on their own. Modern surgical options for repairing intervertebral disc injuries include synthetic discs, cages, or vertebral fixation. When using fully synthetic discs, the problem is that they remain in place and grow into the body, which can lead to further operations. Fixation of the vertebrae limits the patient's range of motion and does not restore quality of life. This technology is aimed at overcoming these and other disadvantages. In addition, intervertebral disc prostheses using this technology retain the structural integrity of tissue-engineered structures, for example, tissue-engineered intervertebral discs.

Disclosure of invention

In one aspect, this technology provides an intervertebral disc prosthesis composition that includes a biocompatible support that includes one or more of: an annular element, a first plate, or a second plate in a biocompatible material structure, and a tissue-engineered construct that includes a bioink, wherein the annular the element includes an inner surface, an outer surface, a first flat surface, and a second flat surface, and the biocompatible material is present in an amount of from about 1% to about 100% by weight of the biocompatible supporting structure.

In another aspect, the present technology provides a biocompatible support structure that includes one or more of: an annular element, a first plate, or a second plate of biocompatible material; moreover, the annular element includes the inner surface of the wall, the outer surface of the wall, the first flat surface and the second flat surface; and the biocompatible material is present in an amount of from about 1% to about 100% by weight of the biocompatible support structure.

In a related aspect, this technology provides a method of manufacturing a biocompatible support structure, described in this document in any of the embodiments of the invention, while this method includes applying a biocompatible material to a substrate; optionally, crosslinking the applied biocompatible material; and optionally repeating the steps of applying and optionally crosslinking to form a biocompatible support structure; moreover, the biologically compatible supporting structure includes one or more of: an annular element, a first plate or a second plate of a biologically compatible material, and the specified annular element includes an inner wall surface, an outer wall surface, a first flat surface and a second flat surface; and the biocompatible material is present in an amount of from about 1% to about 100% by weight of the biocompatible support structure.

In yet another related aspect, this technology provides a method of manufacturing a prosthesis of the intervertebral disc, which includes the manufacture of a biocompatible supporting structure, described herein in any of the embodiments of the invention, including: applying a biocompatible material to a substrate; optionally, crosslinking the applied biocompatible material; and optionally repeating the steps of applying and optionally crosslinking to form a biocompatible support structure; fabrication of a tissue engineering construct described herein in any of the embodiments of the invention, including: applying the bioink described herein in any of the embodiments of the invention to or around a biocompatible supporting structure; crosslinking the bioink, and optionally repeating the application and crosslinking steps to form a tissue engineered construct; curing the composition of the intervertebral disc prosthesis; moreover, the biologically compatible supporting structure includes one or more of: an annular element, a first plate or a second plate of a biologically compatible material, the specified annular element includes an inner wall surface, an outer wall surface, a first flat surface and a second flat surface; and the biocompatible material is present in an amount of from about 1% to about 100% by weight of the biocompatible support structure.

Brief description of the drawings

In FIG. 1A is a perspective view of a biocompatible support structure having an annular element in accordance with an embodiment of the invention.

In FIG. 1B illustrates a top view, a cross-sectional view and a side view of a biocompatible support structure having an annular element in accordance with an embodiment of the invention.

In FIG. 1C illustrates a side view of a biocompatible support structure having an annular element in accordance with an embodiment of the invention.

In FIG. 2 illustrates a top and side view of a biocompatible support structure having an annular element in accordance with an embodiment of the invention.

In FIG. 3 illustrates a top and side view of a biocompatible support structure having a first (or second) plate, in accordance with an embodiment of the invention.

In FIG. 4 illustrates a top and side view of a biocompatible support structure having a first (or second) plate in accordance with an embodiment of the invention.

In FIG. 5 illustrates a top, perspective, and side view of a biocompatible support structure having a first (or second) plate and one or more protrusions, in accordance with an embodiment of the invention.

In FIG. 6 illustrates a top view, side view, and perspective view of a biocompatible support structure having a first lamina and a second lamina having protrusions (i.e., struts) connecting the flat surface of the first lamina and the second lamina, in accordance with an embodiment of the invention.

In FIG. 7 illustrates a top view, a side view and a perspective view of an intervertebral disc prosthesis in accordance with an embodiment of the invention.

In FIG. 8 illustrates a top view, a side view, and a perspective view of a tissue engineered construct in accordance with an embodiment of the invention.

In FIG. 9 is a flow chart illustrating a typical method for fabricating a biocompatible support structure and tissue engineered intervertebral disc prosthesis.

Implementation of the invention

In this document, various embodiments of the invention are described below. It should be noted that specific embodiments of the invention are not intended to exhaustively describe or limit the broader aspects discussed in this document. One aspect described in conjunction with a particular embodiment of the invention is not necessarily limited to this embodiment, and may be practiced with any(s) other(s) embodiment(s) of the invention.

In the context of this document, the term "about" will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If there are uses of said term that are not clear to those skilled in the art, given the context in which it is used, the term "about" will mean up to plus or minus 10% of the specific meaning.

The use of terms in the singular and similar references in the context of the description of the elements (in particular, in the context of the following claims) should be construed as covering both the singular and the plural, unless otherwise indicated in this document or otherwise clearly contrary to the context. The listing of ranges of values in this document is simply intended to be used as a shorthand way of referring to each individual value falling within that range, unless otherwise noted in this document, and each individual value is included in the description as if it were set forth in this document. separately. All methods described herein may be carried out in any suitable order, unless otherwise specified herein or otherwise clearly contradicts the context. The use of any and all examples or a pre-example word (eg, "such as") provided herein is merely intended to better illuminate embodiments of the invention and is not meant to limit the scope of the claims, unless otherwise indicated. Nothing in the description should be construed as indicating any non-declared elements as essential.

In the context of this document, the term "intervertebral disc" refers to the discs that separate the vertebrae from each other and act as natural shock absorbers by dampening shock and absorbing stress and strain transmitted to the spine. The tissues of the intervertebral disc are mainly composed of three regions: the endplates, the annulus fibrosus, and the nucleus pulposus. The annulus fibrosus is a strong structure of collagen fibers that has an outer rim of type I collagen fibers surrounding less dense fibrous cartilage and the transition zone. These collagen fibers are structured in cylindrical layers. In each layer, the fibers are parallel to each other; however, the orientation of the fibers between layers varies from 30 to 60 degrees. This structure provides support for twisting, bending and compressive loads on the spine. The endplates, which are found on the upper and lower surfaces of the disc, work together with the annulus fibrosus to hold the gel-like matrix of the nucleus pulposus within the intervertebral disc. The nucleus pulposus consists of a soft matrix of proteoglycans and randomly oriented type II collagen fibers in water. The highest content of proteoglycan and water is in the center of the disc and it decreases towards the periphery of the disc. Fabrics that mimic these structures effectively can be made according to the methods described herein. These collagen fibers are structured in cylindrical layers.

The term "biocompatible material" refers to a material derived from a natural or synthetic source that is capable of performing its desired function in a subject's body without causing any undesirable local or systemic effects. As used herein, biocompatible materials may also refer to materials that under physiological conditions are biodegradable, bioabsorbable, bioresorbable, or a combination of two or more of these. The term "biodegradable" refers to a material that can be broken down into basic substances as a result of normal processes due to environmental conditions, and/or under the action of living things, such as microorganisms. The term "bioabsorbable" refers to a material capable of being absorbed into living tissues. The term bioresorbable refers to a material that, when placed inside the human body, begins to dissolve (resorb) and is slowly replaced by growing tissue. In the context of this document, in any of the embodiments of the invention, the terms "biodegradable", "bioabsorbable" and "bioresorbable" are used interchangeably.

In the context of this document, "subject" or "patient" is a mammal, as described in this document. The terms "subject" and "patient" may be used interchangeably. As used herein, the term mammal includes, but is not limited to, a cat, dog, rodent, or primate. For example, in any of the embodiments herein, the mammal is a human.

The term "hydrogel" or "gel" refers to a substance that is formed when an organic polymer (natural or synthetic) solidifies into a three-dimensional open lattice structure that traps water or other solution molecules to form a gel. Solidification may occur, for example, through aggregation, coagulation, hydrophobic interactions or crosslinking. Hydrogels can be cellular (ie containing cells) or acellular (ie not containing cells). Hydrogels containing cells can quickly solidify so that the cells remain evenly suspended in the mold (or around or within another solidified gel) until the gel solidifies. Hydrogels can also be biocompatible, eg non-toxic to the cells suspended in the hydrogel.

In the context of this document, the term "collagen" refers to the main connective tissue protein with high tensile strength and found in most multicellular organisms. Collagen is the main fibrillar protein and also the non-fibrillar basement membrane protein. It contains large amounts of glycine, proline, hydroxyproline and hydroxylysine. Collagen is found throughout the body and comes in at least 12 types (types I-XII).

Intervertebral disc prosthesis using this technology

In one aspect, this technology provides an intervertebral disc prosthesis that includes a biocompatible support structure that includes one or more of: an annular element, a first plate, or a second plate of a biocompatible material, and a tissue-engineered structure that includes a bioink, the annular element including an internal a surface, an outer surface, a first planar surface, and a second planar surface, and the biocompatible material is present in an amount of from about 1% to about 100% by weight of the biocompatible support structure.

In FIG. 1A illustrates a perspective view of a biocompatible support structure 100 in accordance with an embodiment of the invention that includes an annular element 110, wherein the annular element has an inner wall surface 120, an outer wall surface 130, a first planar surface 140, and a second planar surface 150. the structure 100 further illustrates one or more apertures 160 extending through the outer surface of the wall 130 to the inner surface of the wall 120, in fluid communication with the external physiological environment of the annular element 110 to the internal cavity 170 of the annular element 110. In FIG. 1B and 1C illustrate top, sectional, and side views of a biocompatible support structure 100.

In FIG. 2 illustrates a top and side view of a biocompatible structure 200 in accordance with an embodiment of the invention that includes an annular member 210, wherein the annular member has an inner wall surface 220, an outer wall surface 230, a first planar surface 240, and a second planar surface 250. The compatible support structure 200 is further illustrated with one or more apertures 260 extending through from the outer surface of the wall 230 to the inner surface of the wall 220, in fluid communication with the external physiological environment of the annular element 210 to the internal cavity 270 of the annular element.

In FIG. 3 illustrates a top and side view of a biocompatible support structure 300 in accordance with an embodiment of the invention that includes a first (or second) lamina 310, the lamella having a first flat surface 320 and a second flat surface 330. The first (or second) lamina 310 includes one or more holes 340 passing through from the first flat surface to the second flat surface. In FIG. 4 illustrates a top and side view of a biocompatible support structure 400 in accordance with an embodiment of the invention that includes a first (or second) lamella 410, the lamella having a first flat surface 420 and a second flat surface 430. The first (or second) lamina 410 includes one or more holes 440 passing through from the first flat surface to the second flat surface. The first (or second) plate further includes one or more protruding elements 450 attached to the first flat surface 420 and extending away from it. In FIG. 5 illustrates a top and side view of a biocompatible support structure 500 in accordance with an embodiment of the invention that includes a first (or second) lamina, the lamella having a first flat surface 510 and a second flat surface 520. The first (or second) lamina includes one or more holes 540 extending from the first flat surface to the second flat surface. The first (or second) plate further includes one or more protruding elements (ie, spikes) 530 attached to the second flat surface 520 and extending away from it.

In FIG. 6 illustrates a top, perspective, and side view of a biocompatible support structure 600 in accordance with an embodiment of the invention that includes a first plate 610 and a second plate 620. The first (or second) plate includes one or more holes 640 passing through. The first and/or second plate further includes one or more protrusions (i.e. posts) 630 connecting the flat surface of the first plate 610 to the second plate 620.

In FIG. 7 illustrates a top, perspective, and side view of an intervertebral disc prosthesis 700 according to an embodiment of the invention, which includes an annular member 710. The annular member 710 includes an inner wall 720, an outer wall 730, a first flat surface 740, and a second flat surface 750. the element further includes one or more apertures 760 extending through to the tissue engineered construct 780 to provide fluid communication between the external physiological environment and the tissue engineered construct.

In FIG. 8 illustrates a top, perspective, and side view of a tissue engineered construct 800 in accordance with an embodiment of the invention having an annular (similar to the shape of an intervertebral disc (IVD)) shape.

Biocompatible support structure

In one aspect, the present technology provides a biocompatible support structure that includes one or more of: an annular element, a first plate, or a second plate of a biocompatible material. In the context of this document, "ring-shaped element" refers to an annular or hoop-shaped form, which can be made in a round, egg-shaped or oval shape. For example, in any of the embodiments of the invention herein, the annular or hoop shape may include a cavity (i.e., an opening) passing through the interior of the annular element to allow the flow of materials (e.g., nutrients, biological waste, cellular and tissue materials and similar materials or combinations thereof). In any of the embodiments of the invention herein, the annular element may have an annular shape of the intervertebral disc (IVD) of the subject. For example, in any of the embodiments of the invention herein, one or more parts of the annular element may have a profile that may be flat, concave, convex, or a combination thereof. In FIG. 1A-1C illustrate an embodiment of the claimed biocompatible support 100 that includes an annular element 110, with one or more parts of the annular element 110 having a concave and convex profile.

The annular element may include an inner wall surface, an outer wall surface, a first flat surface, and a second flat surface. In the context of this document, the "inner surface of the wall" refers to the surface of the annular element along any point facing the internal cavity of the annular element. In the context of this document, "outer wall surface" refers to the surface of the annular element along any point facing the outside or opposite side of the inside of the annular element. In the context of this document, "flat surface" refers to surfaces that are generally recognized as flat or can be laid in a plane-parallel manner. For example, in any of the embodiments of the invention herein, a generally flat surface may include undulations, deviations, or texture elements (eg, inclusions, spikes, depressions, or the like, or combinations thereof). For example, in the embodiment of the invention in FIG. 1A illustrates a perspective view of a biocompatible support structure 100 that includes an annular member 110, the annular member having an inner wall surface 120, an outer wall surface 130, a first planar surface 140, and a second planar surface 150. FIG. 2 illustrates a top and side view of a biocompatible structure 200 in accordance with an embodiment of the invention that includes an annular member 210, wherein the annular member has an inner wall surface 220, an outer wall surface 230, a first planar surface 240, and a second planar surface 250.

Without being limited by theory, it can be assumed that the annular element enhances the axial rigidity of the tissue engineered structure due to the radial compression of the tissue engineered structure by the annular element. The radial compression applied by the annulus prevents or reduces the amount of bulging of the tissue engineered structure in response to the compressive force, improving the axial stiffness of the tissue engineered structure. In any of the embodiments herein, the annular biocompatible support structure increases the axial stiffness of the tissue engineered construct from its 5-fold stiffness to about 10,000-fold stiffness. For example, in any of the embodiments herein, the axial stiffness can be increased by about 5 times, about 10 times, about 20 times, about 30 times, about 40 times, about 50 times, about 60 times. times, approximately 70 times, approximately 80 times, approximately 90 times, approximately 100 times, approximately 200 times, approximately 300 times, approximately 400 times, approximately 500 times, approximately 1000 times, approximately 5000 times times, approximately 10,000 times, or any range including and/or between any two of the preceding values.

In any of the embodiments of the invention herein, the first flat surface and the second flat surface of the annular element are opposed to each other and the annular element has an average thickness perpendicular to the flat surfaces. For example, in any of the embodiments of the invention herein, the annular element has an average thickness of from about 100 microns to about 6000 microns. Suitable average thicknesses include, but are not limited to, about 100 µm, about 150 µm, about 200 µm, about 250 µm, about 300 µm, about 350 µm, about 400 µm, about 450 µm, about 500 µm, about 550 µm , approx. 600 µm, approx. 650 µm, approx. 700 µm, approx. 750 µm, approx. 800 µm, approx. 850 µm, approx. 900 µm, approx. 2000 µm, approx. 2250 µm, approx. 2500 µm, approx. 2750 µm, approx. 3000 µm, approx. 3250 µm, approx. , about 5250 µm, about 5500 µm, about 5750 µm, about 6000 µm, or are in the range including and/or between the two previous values. For example, in any of the embodiments of the invention herein, the average thickness may be from about 100 µm to about 6000 µm, from about 1000 µm to about 6000 µm, from about 3000 µm to about 6000 µm, from about 4000 µm to about 6000 µm or is in the range including and/or between any two of the preceding values.

In any of the embodiments of the invention herein, the annular element may have a transverse thickness perpendicular to the inner and outer wall surfaces. For example, in any of the embodiments of the invention herein, the annular element has a transverse thickness from about 100 microns to about 2000 microns. Suitable transverse thicknesses include, but are not limited to, about 100 µm, about 150 µm, about 200 µm, about 250 µm, about 300 µm, about 350 µm, about 400 µm, about 450 µm, about 500 µm, about 550 µm , approx. 600 µm, approx. 650 µm, approx. 700 µm, approx. 750 µm, approx. 800 µm, approx. 850 µm, approx. 900 µm, approx. 1400 µm, about 1500 µm, about 1600 µm, about 1700 µm, about 1800 µm, about 1900 µm, about 2000 µm, or within a range including and/or between the two preceding values. For example, in any of the embodiments herein, the average thickness may be from about 100 µm to about 2000 µm, from about 300 µm to about 1500 µm, from about 500 µm to about 1000 µm, from about 700 µm to about 1000 µm, from about 500 µm to about 750 µm, or is in the range including and/or between any two of the preceding values. In any of the embodiments of the invention herein, the inner surface or the outer surface of the peripheral wall can be made flat, concave, convex, or a combination of the above.

In any of the embodiments of the invention herein, the annular element may include one or more holes extending through from the outer surface of the wall to the inner surface of the wall of the annular element, allowing the flow of materials (for example, nutrients, biological waste, cellular and tissue materials and similar materials or combinations thereof). The one or more holes may have an average size in the range of about 10 microns to about 10,000 microns. In FIG. 1A illustrates an embodiment of the invention of a biocompatible support structure 100 having one or more apertures 160 extending through from the outer surface of the wall 130 to the inner surface of the wall 120, in fluid communication with the external physiological environment of the annular element 110 to the internal cavity 170 of the annular element 110. B in any of the embodiments herein, the average size of one or more apertures may include, but is not limited to, about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 70 µm, approx. 80 µm, approx. 90 µm, approx. 100 µm, approx. 200 µm, approx. 300 µm, approx. 400 µm, approx. µm, approx. 2000 µm, approx. 2500 µm, approx. 3000 µm, approx. 3500 µm, approx. 4000 µm, approx. about 7500 µm, about 8000 µm, about 8500 µm, about 9000 µm, about 9500 µm, about 10000 µm, or is in any range including and/or between any two of the preceding values. Suitable ranges include about 10 µm to about 10000 µm, about 500 µm to about 7500 µm, about 1000 µm to about 7000 µm, about 2000 µm to about 5000 µm, about 3500 µm to about 6500 µm, or within a range including and/or between any two of the preceding values. One or more holes may be of any shape; for example, the shape of one or more holes may be round, egg-shaped, oval, polygonal, or the like, or combinations thereof. In any of the embodiments of the invention herein, the first flat surface or the second flat surface may include one or more protruding elements attached to and extending away from the first flat surface and/or the second flat surface of the annular element. For example, in any of the embodiments of the invention herein, the protruding elements may include, but are not limited to, spikes, inclusions, bulges, posts, protrusions, or the like, or combinations thereof.

In any of the embodiments of the invention herein, the annular element can withstand hoop stress from about 1 MPa to about 100 MPa. For example, in any of the embodiments of the invention herein, the annular element can withstand a hoop stress of about 1 MPa, about 2 MPa, about 3 MPa, about 4 MPa, about 5 MPa, about 6 MPa, about 7 MPa, about 8 MPa, about 9 MPa, about 10 MPa, about 15 MPa, about 20 MPa, about 30 MPa, about 40 MPa, about 50 MPa, about 60 MPa, about 70 MPa, about 80 MPa, about 90 MPa, about 100 MPa or any range , including and/or between any two of the preceding values.

In any of the embodiments herein, the first lamina and the second lamina may have a generally flat configuration, including two generally flat surfaces opposite each other, and a thickness generally perpendicular to the flat surfaces. For example, in any of the embodiments of the invention herein, the planar surfaces of the first plate and the second plate may include undulations, deviations, or texture elements (eg, inclusions, spikes, depressions, or the like, or combinations thereof). For example, in the embodiment of the invention in FIG. 3 illustrates a top and side view of a biocompatible support structure 300 that includes a first (or second) lamina 310, the lamella having a first flat surface 320 and a second flat surface 330. In any of the embodiments herein, the first lamina and the second lamina may have a thickness of from about 100 microns to about 1200 microns. For example, in any of the embodiments herein, the first plate and the second plate may have a thickness of about 100 µm, about 150 µm, about 200 µm, about 250 µm, about 300 µm, about 350 µm, about 400 µm, about 450 µm , approx. 500 µm¸ approx. 550 µm, approx. 600 µm, approx. 650 µm, approx. 1100 µm, about 1150 µm, about 1200 µm, or any range including and/or between any of the preceding values. Suitable thicknesses include, but are not limited to, about 100 µm to about 600 µm, about 200 µm to about 600 µm, about 400 µm to about 600 µm, about 100 µm to about 300 µm, or in the range, including and/or between any of the preceding values.

The first plate and the second plate may include one or more holes passing through, allowing the flow of materials (eg, nutrients, biological waste, cellular and tissue materials and similar materials, or combinations thereof). The one or more holes may have an average size in the range of about 10 microns to about 10,000 microns, as described herein in any of the embodiments of the invention. For example, suitable ranges include about 10 µm to about 10,000 µm, about 500 µm to about 7500 µm, about 1000 µm to about 7000 µm, about 3500 µm to about 6500 µm, or within a range including and/or between any two of the previous values. One or more holes may be of any shape; for example, the shape of one or more holes may be round, egg-shaped, oval, polygonal, or the like, or combinations thereof. For example, in FIG. 3 and 4 illustrate a plan view of a first (or second) plate 310, 410 that includes one or more holes 340, 440 extending through from the first flat surface 320, 420 to the second flat surface 330, 430. In any of the embodiments of the invention, in herein, the flat surface of the first plate or second plate may include one or more protrusions attached to and extending away from the flat surface of the first plate or second plate. For example, in any of the embodiments of the invention herein, the protruding elements may include, but are not limited to, spikes, inclusions, bulges, posts, protrusions, or the like, or combinations thereof. In any of the embodiments of the invention herein, one or more protruding elements can connect the first plate to the second plate. In FIG. 4 illustrates a biocompatible support structure that includes a first (or second) plate 410 that includes one or more protrusions 450 attached to and extending away from the first flat surface 420.

In any of the embodiments of the invention herein, the first plate, the second plate, or a combination thereof may increase the axial ultimate load of the tissue engineered structure by from about 1% to about 10,000%. For example, in any of the embodiments herein, the axial ultimate load of the tissue engineered structure may be increased by about 1% to about 10000%, about 1% to about 1000%, about 1% to about 100%, about 1 % up to about 10% or any range including and/or between any two of the preceding values. Suitable axial ultimate load increases may include, but are not limited to, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 30%, about 40 %, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, about 1000%, about 2000%, about 3000%, about 4000%, about 5000%, about 6000%, about 7000%, about 8000%, about 9000%, about 10000% or are in any range including and/or between any two of the preceding values. Without being limited by theory, it can be assumed that the first plate and/or the second plate distribute the axial load of the tissue engineered structure in response to a compressive force.

In any of the embodiments of the invention herein, the biocompatible support structure may include any combination of an annular element, a first plate, or a second plate. For example, a biocompatible support structure may include only the annular element described herein in any of the embodiments of the invention. Biocompatible support, in any of the embodiments of the invention herein, may include only the first plate. In any of the embodiments of the invention herein, the biocompatible support structure may include an annular element and a first plate, with the flat surface of the first plate in contact with the first or second flat surface of the annular element. For example, the first plate may be attached to the first or second flat surface of the annular element, such that the first plate completely or partially covers the internal cavity on one side of the annular element. In any of the embodiments of the invention herein, the biocompatible support structure may include an annular element, a first plate, and a second plate. For example, the flat surface of the first plate may be in contact with the first flat surface of the annular element, and the flat surface of the second plate may be in contact with the second flat surface of the annular element, thus, the first and second plates completely or partially cover the internal cavity of the annular element on both sides. In any of the embodiments of the invention herein, the first plate and/or the second plate may be included as a flat surface adjacent to the border of the first and/or second flat surfaces of the annular element. In any of the embodiments of the invention herein, the biocompatible support structure may include a first plate and a second plate, with the flat surface of the first plate and the second plate in contact with the tissue engineered structure.

The biocompatible support structure may include one or more connecting elements. For example, in any of the embodiments of the invention herein, one or more connecting elements may include rods, posts, beams, or similar elements, or combinations thereof. In any of the embodiments of the invention herein, the tie elements can connect the cross-sectional area of the annular element from one point of contact of the inner surface of the wall to another point of contact of the inner surface of the wall. In any of the embodiments of the invention herein, the connecting elements can connect the flat surface of the first plate to the flat surface of the second plate. One or more connecting elements may be configured to form a truss-like structure within the annular element or between the first plate and the second plate. For example, in any of the embodiments herein, the truss-like structure may include a Warren truss, an octet truss, a Pratt truss, a diagonal arch truss, a kingpost truss, a fish truss, a Towne truss truss, a Wierendel truss, or similar trusses, or a combination of two or more of them. In any of the embodiments of the invention herein, the truss-like structure may be 2-dimensional in the formation of one or more internal surfaces or one or more external surfaces. In any of the embodiments herein, the truss structure may be a 3-dimensional structure to provide continuous support. In addition, one or more connecting elements can be combined, so that the flat surfaces of the first plate or the second plate can be connected or several concentric annular elements can be used.

The biocompatible support structure may include a biocompatible material. For example, in any of the embodiments of the invention herein, the biocompatible material may include, but is not limited to, polysaccharides, biocompatible polymers, rubber, silicon, biocompatible metals (e.g., steel, cobalt-chromium alloys, titanium, titanium alloys, magnesium, magnesium alloys, zinc, zinc alloys, iron alloys or similar metals or combinations thereof), biocompatible ceramics, polyethylene glycol, polypropylene glycol, polyamino acids, natural and biopolymers (e.g. glycosaminoglycans, cellulose, chitosan, chitin, dextrans, gelatin, collagen, lignins, polyamino acids , glycoproteins, eslastin, laminins) or combinations of two or more of them. In any of the embodiments of the invention, the biocompatible material may include biocompatible polymers; for example, in any of the embodiments herein, biocompatible polymers can include polylactides (PLA), polyglycolic acid (PGA), poly(lactide-co-glycolide) (PLGA), polydioxanone (PDO), polycaprolactones, and combinations thereof. In any of the embodiments of the invention herein, the biocompatible polymer may have a melting point in the range from about 50°C to about 290°C. For example, in any of the embodiments herein, the biocompatible polymer may have a melting point of about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80° C, about 85°C, about 90°C, about 95°C, about 100°C, about 110°C, about 120°C, about 130°C, about 140°C, about 150°C, about 160° C, about 170°C, about 180°C, about 190°C, about 200°C, about 210°C, about 220°C, about 230°C, about 240°C, about 250°C, about 260° C, about 270°C, about 280°C, about 290°C, or any range including and/or between any two of the preceding values.

In any of the embodiments of the invention herein, the biocompatible material may further include one or more additives. For example, one or more additives may include, but are not limited to, cross-linking agents.

The biocompatible material may be biodegradable, bioabsorbable, and bioresorbable, or a combination thereof. For example, in any of the embodiments of the invention herein, the biocompatible material may be degraded, absorbed, or resorbed under physiological conditions at a rate of from about 1 month to about 7 years. Suitable disintegration, absorption or resorption rates may include, but are not limited to, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months , about 10 months, about 11 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 5.5 years, about 6 years, about 6.5 years, about 7 years, or within a range including and/or between any two of the preceding values. For example, in any of the embodiments herein, the rate of disintegration, absorption, or resorption may include from about 1 month to about 7 years, from about 1 month to about 5 years, from about 1 month to about 3 years, from about 1 month up to about 1 year, from about 1 month to about 6 months, from about 1 month to about 3 months. Suitable biodegradable, bioabsorbable and/or bioresorbable materials include, but are not limited to, PLA, PGA, PLGA, PDO, polycaprolactones, bioresorbable metal alloys, and combinations thereof.

The biocompatible material may have a density from about 1500 mg/mL to about 2500 mg/mL. For example, in any of the embodiments herein, the biocompatible material may have a density of about 1500 mg/mL, about 1600 mg/mL, about 1700 mg/mL, about 1800 mg/mL, about 1900 mg/mL, about 2000 mg /ml, about 2100 mg/ml, about 2200 mg/ml, about 2300 mg/ml, about 2400 mg/ml, about 2500 mg/ml, or any range including and/or between any two of the preceding values. In any of the embodiments of the invention herein, the biocompatible material may have a density of from about 1500 mg/ml to about 2500 mg/ml, from about 1750 mg/ml to about 2200 mg/ml, from about 2000 mg/ml to about 2300 mg/ml or in any range including and/or between any two of the preceding values.

The biocompatible material may be present in the biocompatible support structure in an amount of from about 1% wt. up to 100% wt. biocompatible support structure. For example, in any of the embodiments herein, the amount of biocompatible material present by weight in a biocompatible support structure may be about 1%, about 5%, about 10%, about 15%, about 20%, about 25%. , about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or any range including and/or between any two of the preceding values. Suitable amounts of biocompatible material in a biocompatible support include, but are not limited to, about 5% to about 100%, 10% to about 100%, about 50% to about 100%, about 5% to about 20% , from about 90% to about 100%, or any range including and/or between any two of the preceding values.

The biocompatible material may be present in the biocompatible support structure in an amount of from about 1% wt. up to 100% wt. biocompatible support structure. For example, in any of the embodiments herein, the amount of biocompatible material present by weight in a biocompatible support structure may be about 1%, about 5%, about 10%, about 15%, about 20%, about 25%. , about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or any range including and/or between any two of the preceding values. Suitable amounts of biocompatible material in a biocompatible support include, but are not limited to, about 5% to about 100%, 10% to about 100%, about 50% to about 100%, about 5% to about 20% , from about 90% to about 100%, or any range including and/or between any two of the preceding values.

The biocompatible support structure has mechanical properties to improve the mechanical properties of the tissue engineered structure. In any of the embodiments herein, the biocompatible support structure may have one or more of: a flexural modulus of about 0.2 GPa to about 100 GPa, a buckling modulus of about 0.02 GPa to about 100 GPa, or a strength at a break from about 1 MPa to about 1000 MPa.

In any of the embodiments herein, the biocompatible support structure may have a flexural modulus of about 0.2 GPa to about 100 GPa. For example, in any of the embodiments herein, the biocompatible support structure may have a flexural modulus of about 0.2 GPa, about 0.3 GPa, about 0.4 GPa, about 0.5 GPa, about 0.6 GPa. , about 0.7 GPa, about 0.8 GPa, about 0.9 GPa, about 1 GPa, about 2 GPa, about 3 GPa, about 4 GPa, about 5 GPa, about 6 GPa, about 7 GPa, about 8 GPa , about 9 GPa, about 10 GPa, about 11 GPa, about 12 GPa, about 13 GPa, about 14 GPa, about 15 GPa, about 16 GPa, about 17 GPa, about 18 GPa, about 19 GPa, about 20 GPa, about 25 GPa, about 30 GPa, about 35 GPa, about 40 GPa, about 45 GPa, about 50 GPa, about 55 GPa, about 60 GPa, about 65 GPa, about 70 GPa, about 75 GPa, about 80 GPa, about 85 GPa , about 90 GPa, about 95 GPa, about 100 GPa, or any range including and/or between any two of the preceding values. Suitable flexural modulus values may include, but are not limited to, about 0.2 GPa to about 100 GPa, about 0.2 GPa to about 50 GPa, about 0.2 GPa to about 25 GPa, about 0 .2 GPa to about 15 GPa, about 1 GPa to about 15 GPa, about 5 GPa to about 15 GPa, or a range including and/or between any two of these values.

In any of the embodiments herein, the biocompatible support structure may have a modulus of elasticity from about 0.02 GPa to about 100 GPa. For example, in any of the embodiments herein, the biocompatible support structure may have a modulus of elasticity of about 0.02 GPa, 0.04 GPa, about 0.06 GPa, about 0.08 GPa, about 0.1 GPa, about 0.2 GPa, about 0.3 GPa, about 0.4 GPa, about 0.5 GPa, about 0.6 GPa, about 0.7 GPa, about 0.8 GPa, about 0.9 GPa, about 1 GPa , about 2 GPa, about 3 GPa, about 4 GPa, about 5 GPa, about 6 GPa, about 7 GPa, about 8 GPa, about 9 GPa, about 10 GPa, about 11 GPa, about 12 GPa, about 13 GPa, about 14 GPa, about 15 GPa, about 16 GPa, about 17 GPa, about 18 GPa, about 19 GPa, about 20 GPa, about 25 GPa, about 30 GPa, about 35 GPa, about 40 GPa, about 45 GPa, about 50 GPa , about 55 GPa, about 60 GPa, about 65 GPa, about 70 GPa, about 75 GPa, about 80 GPa, about 85 GPa, about 90 GPa, about 95 GPa, about 100 GPa, or any range including and/or between any two of the previous values. Suitable values for modulus of elasticity may include, but are not limited to, about 0.2 GPa to about 100 GPa, about 0.2 GPa to about 50 GPa, about 0.2 GPa to about 25 GPa, about 0, 2 GPa to about 15 GPa, about 1 GPa to about 15 GPa, about 5 GPa to about 15 GPa, or a range including and/or between any two of these values.

In any of the embodiments of the invention herein, the biocompatible support structure may have a tensile strength of from about 1 MPa to about 1000 MPa. For example, in any of the embodiments herein, the biocompatible support structure may have a tensile strength of about 1 MPa, about 2 MPa, about 3 MPa, about 4 MPa, about 5 MPa, about 6 MPa, about 7 MPa, about 8 MPa, about 9MPa, about 10MPa, about 20MPa, about 25MPa, about 30MPa, about 35MPa, about 40MPa, about 45MPa, about 50MPa, about 55MPa, about 60MPa, about 65MPa, about 70 MPa, about 75 MPa, about 80 MPa, about 85 MPa, about 90 MPa, about 95 MPa, about 100 MPa, about 150 MPa, about 200 MPa, about 250 MPa, about 300 MPa, about 350 MPa, about 400 MPa, approx. 450 MPa, approx. 500 MPa, approx. 550 MPa, approx. 600 MPa, approx. 650 MPa, approx. 700 MPa, approx. 750 MPa, approx. 800 MPa, approx. is in the range including and/or between any two of the preceding values.

Tissue engineering design

An intervertebral disc prosthesis using this technology includes a tissue-engineered structure that includes bioink. In any of the embodiments of the invention herein, the tissue engineered construct can be made in any shape or size. For example, in any of the embodiments herein, the tissue engineered construct may be circular, egg-shaped, oval, or polygonal in shape. In any of the embodiments of the invention herein, the tissue engineered construct may be in the form of an intervertebral disc (IVD). For example, the tissue-engineered design of an IVD shape may be a standard tissue-engineered design. In any of the embodiments of the invention herein, the tissue-engineered design of the IVD shape may include an annulus structure and a nucleus pulposus structure, with the annulus structure located circumferentially around the nucleus pulposus. In any of the embodiments of the invention herein, the tissue-engineered design of the IVD form may include an annulus structure, a nucleus pulposus structure, and an endplate structure, with the annulus structure located circumferentially around the nucleus pulposus. In any of the embodiments of the invention, the tissue-engineered construct according to this technology may be in the form of the IVD of the subject. In any of the embodiments of the invention, the tissue engineered construct may be in the form of a negative space between the subject's vertebrae (eg, between the vertebrae as seen on an MRI or CT scan).

The tissue engineered construct can be configured such that the size of the tissue engineered construct is larger than the size of the biocompatible support structure, wherein the tissue engineered construct is partially or completely in contact with the biocompatible support structure. For example, in any of the embodiments of the invention herein, the tissue engineered construct can be configured such that the biocompatible support structure is fully or partially encapsulated within the tissue engineered construct.

In any of the embodiments of the invention herein, the tissue engineered construct can be configured so that the size of the tissue engineered construct is smaller than the size of the biocompatible support, while the tissue engineered construct is enclosed in and does not come into contact with the biocompatible support structure. For example, in any of the embodiments of the invention herein, the tissue engineered construct may be enclosed within the annular element of the biocompatible support structure such that the tissue engineered structure does not come into contact with the surface of the inner wall of the annular element.

In any of the embodiments of the invention herein, the tissue engineered construct can be sized such that said tissue engineered construct is partially or completely enclosed within a biocompatible support structure and is in contact with one or more of its surfaces. For example, in any of the embodiments of the invention herein, the tissue engineered structure can be sized so that the tissue engineered structure is in contact with the surface of the inner wall of the annular element, with the flat surface of the first and/or second plate, or a combination of them. In any of the embodiments of the invention herein, the tissue-engineered construct may be sized to exceed the capacity of the biocompatible support structure, such that the tissue-engineered construct extends (or protrudes) beyond the average thickness or transverse thickness of the annulus or circumference of the first plate and/or second plates. For example, in any of the embodiments of the invention herein, the tissue engineered construct may pass through (or protrude from) one or more of the annulus holes, the first plate, and/or the second plate of the biocompatible support structure. In any of the embodiments of the invention herein, the tissue engineered structure may extend (or protrude) through the internal cavity of the annular element beyond the first and/or second flat surface of the annular element, and the biologically compatible supporting structure may include a first plate and/or a second plate, which may rest on the surface of the tissue engineered construct or may be encapsulated in the tissue engineered construct without contacting the annular element. In any of the embodiments of the invention herein, the tissue engineered construct may be configured to encapsulate one or more compounds of a biologically compatible support structure.

Without being limited by theory, it can be assumed that if the tissue engineered structure is made in such a way that it is enclosed in a biologically compatible support and comes into contact with it in such a way that the tissue engineered structure passes (or protrudes) through one or more openings of one or more of: , the first lamina or the second lamina, this creates friction between the biocompatible support structure and the tissue-engineered construct. In this respect, the resulting friction prevents the tissue engineered structure from slipping off, so it remains within the biocompatible support. In addition, it is also believed that the protruding portions of the tissue engineered structure create friction between the intervertebral disc prosthesis and the vertebral endplates, which may also prevent slippage of the intervertebral disc prosthesis.

In any of the embodiments of the invention herein, the tissue engineered construct may include a unique set of mechanical properties to ensure its proper functioning. For example, in any of the embodiments herein, the tissue engineered construct may have one or more of: an equilibrium modulus of about 2 MPa to about 15 MPa, an instantaneous modulus of about 5 kPa to about 2000 kPa, and a hydraulic permeability of about 1×10 ^{- 16} m ² /Pa⋅s to about 1×10 ^-8 m ² /Pa⋅s. In any of the embodiments herein, the tissue engineered construct may have an equilibrium modulus of about 2 MPa to about 15 MPa, about 2 MPa to about 12 MPa, about 2 MPa to about 10 MPa, about 2 MPa to about 8 MPa , from about 2 MPa to about 6 MPa, from about 2 MPa to about 4 MPa, or in any range including and/or between any two of the preceding values. For example, in any of the embodiments herein, the equilibrium modulus may be 2 MPa, about 2.5 MPa, about 3 MPa, about 3.5 MPa, about 4 MPa, about 4.5 MPa, about 5 MPa, about 5 .5 MPa, about 6 MPa, about 6.5 MPa, about 7 MPa, about 7.5 MPa, about 8 MPa, about 8.5 MPa, about 9 MPa, about 9.5 MPa, about 10 MPa, about 11 MPa, about 12 MPa, about 13 MPa, about 14 MPa, about 15 MPa, or any range including and/or between any two of the preceding values.

In any of the embodiments herein, the tissue engineered construct may have an instantaneous modulus of about 5 kPa to about 2000 kPa, 5 kPa to about 1500 kPa, about 5 kPa to about 1000 kPa, about 5 kPa to about 500 kPa, from about 5 kPa to about 100 kPa, from about 5 kPa to about 40 kPa, or any range including and/or between any two of the preceding values. For example, in any of the embodiments herein, the tissue engineered construct may have an instantaneous modulus of about 5 kPa, about 6 kPa, about 7 kPa, about 8 kPa, about 9 kPa, about 10 kPa, about 12 kPa, about 14 kPa, about 16 kPa, approx. 18 kPa, approx. 20 kPa, approx. 22 kPa, approx. 24 kPa, approx. kPa, approx. 26 kPa, approx. 28 kPa, approx. 40 kPa, approx. 60 kPa, approx. 80 kPa, approx. 100 kPa, approx. 200 kPa, approx. 300 kPa, approx. 400 kPa, approx. 500 kPa, approx. 600 kPa, approx. , about 1100 kPa, about 1200 kPa, about 1300 kPa, about 1400 kPa, about 1500 kPa, about 1600 kPa, about 1700 kPa, about 1800 kPa, about 1900 kPa, about 2000 kPa or any range including and/or between any two of the previous values. In any of the embodiments of the invention herein, the tissue engineered structure may have a hydraulic permeability from about 1×10 ^-16 m ² /Pa s to about 1×10 ^-8 m ² /Pa s, from about 1×10 ^-13 m ² /Pa⋅s to about 9×10 ^-10 m ² /Pa⋅s, from about 1×10 ^-12 m ² /Pa⋅s to about 6×10 ^-10 , from about 1×10 ^-11 m ² / Pa⋅s up to about 3×10 ^-10 m ² /Pa⋅s or any range including and/or between any two of the preceding values.

The tissue engineered construct may include bioink. The term "bio-ink" refers to an ink derived from a biomaterial. For example, in any of the embodiments of the invention herein, the bioink may include, but is not limited to, hydrogel (e.g., alginate hydrogel), agarose, collagen, chitosan, fibrin, hyaluronic acid, carrageenan, polyethylene oxide, polypropylene oxide, copolymer of polyethylene oxide and polypropylene oxide, hydroxypropyl methylcellulose, poly(propylene fumarate-co-ethylene glycol), poly(ethylene glycol)-co-poly(lactic acid), poly(vinyl alcohol), KDLl 2 oligopeptides, poly(n-isopropylacrylamide), or a combination of two or more of these. The bioink can have a controlled crosslinking rate by adjusting environmental variables including, but not limited to, temperature, pH, ionic strength, heat, light, or the addition of chemical crosslinkers, e.g., calcium, magnesium, barium, chondroitin, sulfate, carbodiimides, ribose, riboflavin and thrombin. Suitable hydrogels for use in tissue engineered bioinks are described in U.S. Patent No. 9,044,335 entitled "COMPOSITE TISSUE-ENGINEERED INTERVERTEBRAL DISC WITH SELF-ASSEMBLED ANNULAR ALIGNMENT" filed May 5, 2010, the contents of which are hereby incorporated by reference in their entirety.

In any of the embodiments of the invention herein, the bioink of the tissue engineered construct may include an alginate hydrogel. For example, in any of the embodiments herein, the alginate hydrogel may be present in an amount of from about 0.5% (w/v) to about 10% (w/v). For example, in any of the embodiments herein, the alginate hydrogel may be present in an amount of about 0.5% (w/v), about 0.6% (w/v), about 0.7% (w/v). ./v), about 0.8% (w/v), about 0.9% (w/v), about 1.0% (w/v), about 1.5% (w/v), about 2.0% (w/v), about 2.5% (w/v), about 3.0% (w/v), about 3, 5% (w/v), about 4.0% (w/v), about 4.5% (w/v), about 5.0% (w/v), about 5.0% (w/v), about 5.5% (w/v), about 6.0% (w/v), about 6.5% (w/v) , about 7.0% (w/v), about 7.5% (w/v), about 8.0% (w/v), about 8.5% (w/v .), about 9.0% (w/v), about 9.5% (w/v), about 10.0% (w/v), or any range including and/or between any two of the preceding values.

In any of the embodiments of the invention herein, the bioink of the tissue engineered construct may include collagen. Collagen-based materials are preferred for use in tissue engineering constructs. Methods for harvesting collagen for use in biogel formulations, methods for generating 3D structures using biogel formulations, and methods for preparing biogel formulations for use in 3D printing systems are described in PCT Application Serial No. PCT/US2017/034582 entitled "3D PRINTABLE BIO GEL AND METHOD OF USE, filed May 25, 2017, with Patent Registry Number 113066-0104, the contents of which are incorporated herein in their entirety by reference for additional information, and the methods.

In any of the embodiments herein, the bioink of the tissue engineered construct may include more than about 5 mg/mL of collagen. Suitable amounts of collagen in the bioink may include, but are not limited to, from about 5 mg/mL to about 200 mg/mL. For example, in any of the embodiments of the invention herein, collagen may be present in an amount of about 5 mg/ml, about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml. ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, about 75 mg/ml, about 80 mg/ml, about 85 mg/ml, about 90 mg/ml, about 95 mg/ml, about 100 mg/ml, about 105 mg/ml, about 110 mg/ml, about 115 mg/ml, about 120 mg/ml, about 125 mg/ml, about 130 mg/ml, about 135 mg/ml, about 140 mg/ml, about 145 mg/ml, about 150 mg/ml, about 155 mg/ml ml, about 160 mg/ml, about 165 mg/ml, about 170 mg/ml, about 175 mg/ml, about 180 mg/ml, about 185 mg/ml, about 190 mg/ml, about 195 mg/ml, about 200 mg/ml, or in any range including and/or between any two of the preceding values.

In any of the embodiments of the invention herein, the tissue engineered construct may include a bioink having type I collagen, type II collagen, or a combination thereof. For example, in any of the embodiments herein, if the tissue engineered construct includes an annulus structure and a nucleus pulposus structure, then the annulus structure may include type I collagen and the nucleus pulposus structure may include type II collagen.

In any of the embodiments of the invention herein, the bioink of the tissue engineered construct may further include a neutralizer and cellular material, as described herein in any of the embodiments of the invention. Suitable neutralizers may include, but are not limited to, for example, formulations containing a weak acid. In any of the embodiments of the invention herein, the tissue engineered construct may be cellular or acellular. For example, in any of the embodiments of the invention herein, the tissue-engineered bioink may include cellular material containing a population of cells, which may include, but is not limited to, living cells obtained and/or isolated from intervertebral disc tissue, for example, nucleus pulposus or fibrous ring. The cellular material may further include other living cells; for example, in any of the embodiments of the invention herein, the bioink may include epidermal cells, chondrocytes and other cells that form mesenchymal stem cells, IVD stem cells, cartilage, macrophages, adipocytes, dermal cells, muscle cells, hair follicles, fibroblasts, cells organs, osteoblasts, osteocytes and other bone-forming cells, endothelial cells, mucosal cells, pleura cells, ear canal cells, tympanic membrane cells, peritoneal cells, Schwann cells, corneal epithelial cells, gingival cells, neural stem cells of the central nervous system, tracheal epithelial cells; or combinations of two or more of the above. In any of the embodiments of the invention herein, the tissue-engineered bioink can be cell-free when the bioink does not contain living cells. In any of the embodiments herein, the tissue engineered construct may be configured such that said tissue engineered construct has areas or components (eg, annulus fibrosus, nucleus pulposus, or endplate) that may be acellular or cellular.

In any of the embodiments of the invention herein, the cell population may be present in an amount from about 1.0×10 ⁵ cells/ml to about 5.0×10 ⁷ cells/ml. For example, in any of the embodiments herein, the number of cells present in the bioink of the tissue engineered construct may include about 1.0×10 ⁵ cells/mL, about 2.0×10 ⁵ cells/mL, about 3.0×10 ⁵ cells/ml, about 4.0×10 ⁵ cells/ml, about 5.0×10 ⁵ cells/ml, about 6.0×10 ⁵ cells/ml, about 7.0×10 ⁵ cells/ml, about 8 .0×10 ⁵ cells/ml, about 9.0×10 ⁵ cells/ml, about 1.0×10 ⁶ cells/ml, about 2.0×10 ⁶ cells/ml, about 3.0×10 ⁶ cells /ml, about 4.0×10 ⁶ cells/ml, about 5.0×10 ⁶ cells/ml, about 6.0×10 ⁶ cells/ml, about 7.0×10 ⁶ cells/ml, about 8, 0×10 ⁶ cells/ml, about 9.0×10 ⁶ cells/ml, about 1.0×10 ⁷ cells/ml, about 2.0×10 ⁷ cells/ml, about 3.0×10 ⁷ cells/ ml, about 4.0×10 ⁷ cells/ml, about 5.0×10 ⁷ cells/ml, or is in any range including and/or between any two of the preceding values. Suitable amounts of cells present in the tissue engineered bioink include, but are not limited to, from about 1.0×10 ⁵ cells/ml to about 5.0×10 ⁷ cells/ml, from about 1.0×10 ⁵ cells/ml up to about 1.0×10 ⁷ cells/ml, from about 1.0×10 ⁵ cells/ml to about 5.0×10 ⁶ cells/ml, from about 1.0×10 ⁵ cells/ml to about 5, 0×10 ⁶ cells/ml or any range including and/or between any two of the preceding values.

In any of the embodiments of the invention herein, the tissue-engineered bioink may further include carriers or additives. Suitable carriers may include, but are not limited to, water, aqueous ionic salt solutions (e.g., sodium hydroxide), phosphate buffered saline (PBS), cell material, fetal calf serum (FBS), Dulbecco's Modified Eagle's Minimal Medium (DMEM) , fibroblast growth factor (bFGF) or similar carriers or combinations of the above. Suitable additives include, but are not limited to, growth factors and cross-linking agents. Suitable crosslinkers include, but are not limited to, riboflavin, ribose, polyethylene glycol (PEG), glutaraldehyde, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, genipin, chitosan, or similar crosslinkers or combinations of the foregoing.

The composition of the intervertebral disc prosthesis includes a tissue-engineered design along with a biocompatible support structure in any configuration disclosed herein, and has improved mechanical properties (ie, strength). An intervertebral disc prosthesis, in any of the embodiments herein, can withstand an axial compression of about 1 kN to about 10,000 kN and a shear force of about 0.2 kN to about 1,000 kN. For example, in any of the embodiments of the invention herein, a prosthesis of the intervertebral disc according to this technology can withstand axial compression of about 1 kN, 2 kN, about 3 kN, about 4 kN, about 5 kN, about 6 kN, about 7 kN, about 8 kN, about 9 kN, about 10 kN, about 20 kN, about 30 kN, about 40 kN, about 50 kN, about 60 kN, about 70 kN, about 80 kN, about 90 kN, about 100 kN, about 200 kN, approx. 300 kN, approx. 400 kN, approx. 500 kN, approx. 600 kN, approx. 700 kN, approx. 800 kN, approx. 900 kN, approx. 1000 kN, approx. kN, approx. 4000 kN, approx. 4500 kN, approx. 5000 kN, approx. 5500 kN, approx. 6000 kN, approx. 6500 kN, approx. 7000 kN, approx. about 10,000 kN or in a range including and/or between any two of the preceding values. Suitable axial compression may include, but is not limited to, about 1 kN to about 10,000 kN, about 1 kN to about 5,000 kN, about 1 kN to about 1,000 kN, about 1 kN to about 500 kN, about 1 kN to about 15 kN, from about 4 kN to about 10 kN, or within a range including and/or between any two of the preceding values.

In any of the embodiments herein, an intervertebral disc prosthesis of this technology can withstand a shear force of about 0.2 kN to about 1000 kN. For example, in any of the embodiments of the invention herein, a prosthesis of the intervertebral disc according to this technology can withstand a shear force, which can be about 0.2 kN, about 0.3 kN, about 0.4 kN, about 0.5 kN, about 0.6 kN, approx. 0.7 kN, approx. 0.8 kN, approx. 0.9 kN, approx. 1.0 kN, approx. 10 kN, approx. 50 kN, approx. 100 kN, approx. 250 kN, approx. 300 kN, approx. 350 kN, approx. 400 kN, approx. 450 kN, approx. 500 kN, approx. 550 kN, approx. 600 kN, approx. 650 kN, approx. 700 kN, approx. , about 900 kN, about 950 kN, about 1000 kN, or is in the range including and/or between any two of the preceding values. Suitable shear force ranges include, but are not limited to, about 0.2 kN to about 1000 kN, about 1 kN to about 500 kN, about 10 kN to about 100 kN, about 0.2 kN to about 0, 9 kN or are in the range including and/or between any two of the preceding values.

Ways

In a related aspect, this technology provides a method of manufacturing a biocompatible support structure, described in this document in any of the embodiments of the invention, and this method includes applying a biocompatible material to a substrate; optionally, crosslinking the applied biocompatible material; and optionally repeating the steps of applying and optionally crosslinking to form a biocompatible support structure; moreover, the biologically compatible supporting structure includes one or more of: an annular element, a first plate or a second plate of a biologically compatible material, while the specified annular element includes an inner wall surface, an outer wall surface, a first flat surface and a second flat surface; and the biocompatible material is present in an amount of from about 1% to about 100% by weight of the biocompatible support structure.

A method for manufacturing a biocompatible support structure may include one or more manufacturing systems or methods, including, but not limited to, injection molding, rotational molding, positive moulds, negative moulds, subtractive machining, milling and machining, and three-dimensional ( 3D) printing. For example, in any of the embodiments of the invention herein, the manufacturing method may include 3D printing. Suitable 3D printing techniques may include, but are not limited to, inkjet printing, layer-by-layer printing, extrusion printing, and bioprinting. For example, in any of the embodiments of the invention herein, the application may include the application of one or more layers of biocompatible material. For example, in any of the embodiments of the invention herein, 3D printing may include: applying one or more layers of a biocompatible material to a substrate; optionally, crosslinking the applied biocompatible material; and optionally repeating the steps of applying and optionally crosslinking to form a biocompatible support structure; moreover, the biologically compatible supporting structure includes one or more of: an annular element, a first plate or a second plate of a biologically compatible material, and the specified annular element includes an inner wall surface, an outer wall surface, a first flat surface and a second flat surface; and the biocompatible material is present in an amount of from about 1% to about 100% by weight of the biocompatible support structure.

In any of the embodiments of the invention herein, a biocompatible support structure can be manufactured using biocompatible materials, as described herein in any of the embodiments of the invention, using 3D printing systems described in the PCT application with serial number PCT / 2018/034457 entitled "ASEPTIC PRINTER SYSTEM INCLUDING DUAL ARM-MECHANISM", filed on May 24, 2018 and bearing Patent Registry Number 113066-0107, the contents of which are incorporated herein in their entirety by reference for additional information, and set forth herein ways.

In any of the embodiments of the invention herein, a method for manufacturing a biocompatible support structure may include injection molding. For example, in any of the embodiments of the invention herein, the application of a biocompatible material may include injection molding. In any of the embodiments of the invention herein, application may include applying a biocompatible material in the form of a biocompatible support structure; optionally crosslinking the biocompatible material in the mold and optionally repeating the application and optional crosslinking steps; and removing the biocompatible support structure from the mould.

In any of the embodiments herein, the substrate may include a 3D printer surface (eg, a 3D printer desktop). In any of the embodiments of the invention herein, the substrate may include a form suitable for use in one or more of: injection molding, rotational molding, positive moulds, negative moulds, or similar methods. In any of the embodiments of the invention herein, the substrate may include the surface of a manufacturing device suitable for performing subtractive processing, milling and machining, or a similar device.

In any of the embodiments of the invention herein, the biocompatible material is crosslinked. For example, in any of the embodiments herein, the biocompatible material may be subjected to crosslinking conditions to form a crosslinked or polymerized biocompatible material. Suitable crosslinking conditions may include, but are not limited to, UV irradiation. In any of the embodiments of the invention herein, the biocompatible material may not include crosslinking. For example, in any of the embodiments of the invention, after application, said biomaterial may include a cooling step, a melting step, and similar steps, or combinations thereof.

In the method according to this technology, the specified method of manufacturing a biocompatible support structure may include applying one or more layers of biocompatible material so that the annular element has an average thickness of from about 100 microns to about 6000 microns and a transverse thickness of from about 100 microns to about 1000 microns , as described herein in any of the embodiments of the invention, and that the first plate and the second plate have a thickness of from about 100 microns to about 600 microns, as described herein in any of the embodiments of the invention.

In any of the embodiments of the invention herein, a method for making a biocompatible support structure may include applying one or more layers of a biocompatible material such that the biocompatible support structure has an annular MPD shape. For example, in any of the embodiments of the invention, a biocompatible support structure may have an annular shape IVD of the subject. Typically, the subject or patient is human and preferably requires implants to replace and/or regenerate IVD tissue.

In the method of this technology, the biocompatible material may include the biocompatible material described herein in any of the embodiments of the invention. For example, in any of the embodiments of the invention herein, the biocompatible material may include, but is not limited to, polysaccharides, biocompatible polymers, rubber, silicon, biocompatible metals (e.g., steel, cobalt-chromium alloys, titanium, titanium alloys, magnesium, magnesium alloys, zinc, zinc alloys, iron alloys or similar metals or combinations thereof), biocompatible ceramics, polyethylene glycol, polypropylene glycol, polyamino acids, natural and biopolymers (e.g. glycosaminoglycans, cellulose, chitosan, chitin, dextrans, gelatin, collagen, lignins, polyamino acids , glycoproteins, eslastin, laminins) or combinations of two or more of the above. In any of the embodiments of the invention, the biocompatible material may include biocompatible polymers; for example, in any of the embodiments herein, biocompatible polymers can include polylactides (PLA), polyglycolic acid (PGA), poly(lactide-co-glycolide) (PLGA), polydioxanone (PDO), polycaprolactones, and combinations thereof. In any of the embodiments of the invention herein, the biocompatible polymer may have a melting point in the range from about 50°C to about 290°C. For example, in any of the embodiments herein, the biocompatible polymer may have a melting point of about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80° C, about 85°C, about 90°C, about 95°C, about 100°C, about 110°C, about 120°C, about 130°C, about 140°C, about 150°C, about 160° C, about 170°C, about 180°C, about 190°C, about 200°C, about 210°C, about 220°C, about 230°C, about 240°C, about 250°C, about 260° C, about 270°C, about 280°C, about 290°C, or any range including and/or between any two of the preceding values.

In any of the embodiments of the invention herein, a biocompatible support structure obtained by this method of manufacture may have one or more of: a flexural modulus of from about 0.2 GPa to about 100 GPa, a modulus of elasticity from about 0.2 GPa up to about 100 GPa or tensile strength from about 1 MPa to about 1000 MPa, as described herein in any of the embodiments of the invention.

In any of the embodiments of the invention herein, said method may further comprise sterilizing the biocompatible support structure. For example, in any of the embodiments herein, sterilization may include, but is not limited to, gamma irradiation, peracid incubation, autoclaving, UV irradiation, peroxide sterilization, supercritical fluid treatment, and similar methods, or combinations thereof.

In another related aspect, this technology provides a method of manufacturing a prosthetic intervertebral disc, which includes manufacturing a biocompatible support structure, as described herein in any of the embodiments of the invention, including: applying a biocompatible material to a substrate; optionally, crosslinking the applied biocompatible material; and optionally repeating the steps of applying and optionally crosslinking to form a biocompatible support structure; fabrication of a tissue engineered construct described herein in any of the embodiments of the invention, including: application of bioink, as described herein in any of the embodiments of the invention, in or around a biocompatible supporting structure; crosslinking the bioink, and optionally repeating the application and crosslinking steps to form a tissue engineered construct; and curing the composition of the intervertebral disc prosthesis; moreover, the biologically compatible supporting structure includes one or more of: an annular element, a first plate or a second plate of a biologically compatible material, while the specified annular element includes an inner wall surface, an outer wall surface, a first flat surface and a second flat surface; and the biocompatible material is present in an amount of from about 1% to about 100% by weight of the biocompatible support structure.

A method for making a biocompatible support structure may include the methods described herein in any of the embodiments of the invention. For example, in any of the embodiments of the invention herein, one or more manufacturing systems or methods may include, but are not limited to, injection molding, rotational molding, positive moulds, negative moulds, subtractive machining, milling and machining, and as well as three-dimensional (3D) printing. In any of the embodiments of the invention herein, the manufacturing method may include 3D printing, as described herein in any of the embodiments of the invention. In any of the embodiments of the invention herein, a method for manufacturing a biocompatible support structure may include injection molding, as described herein in any of the embodiments of the invention. In any of the embodiments of the invention herein, said method may include cross-linking a biocompatible material as described herein in any of the embodiments of the invention.

Fabrication of a tissue engineered construct involves the application of one or more layers of bioink as described herein in any of the embodiments of the invention. In any of the embodiments of the invention herein, the fabrication of a tissue engineered construct may include one or more fabrication systems or methods; for example, in any of the embodiments herein, one or more manufacturing systems or methods may include injection molding, rotational molding, positive molds, negative molds, subtractive machining, milling and machining, and three-dimensional (3D) printing. . In any of the embodiments of the invention herein, the manufacturing method may include 3D printing, as described herein in any of the embodiments of the invention. For example, in any of the embodiments herein, application may include applying one or more layers of bioink to or around a biocompatible support structure using a 3D printer; cross-linking the bio-ink and optionally repeating the application and cross-linking steps to obtain a tissue-engineered construct; and curing of an intervertebral disc prosthesis.

In any of the embodiments of the invention herein, the fabrication of the tissue engineered structure may include injection molding. For example, in any of the embodiments of the invention herein, application may include applying the bioink to a form containing a biocompatible support structure; cross-linking the bio-ink in a mold and optionally repeating the application and cross-linking steps to obtain a tissue-engineered construct; and curing the intervertebral disc prosthesis, wherein the mold can be removed before or after the curing step. In any of the embodiments of the invention herein, said method may include demoulding after the intervertebral disc prosthesis has cured. In any of the embodiments of the invention herein, said method may include demoulding prior to curing of the intervertebral disc prosthesis.

The method may include fabricating a tissue engineered construct having an annulus structure and a nucleus pulposus structure as described herein in any of the embodiments of the invention. In any of the embodiments of the invention, the manufacturing method may include applying the bioink to form the annulus structure and applying the bioink to form the nucleus pulposus structure. For example, in any of the embodiments of the invention herein, the specified method may include the application of bioink for the simultaneous or sequential formation of the structure of the annulus and the structure of the nucleus pulposus. In some embodiments of the invention, the application may include the sequential formation of the structure of the fibrous ring and the structure of the nucleus pulposus. In any of the embodiments of the invention herein, the application may include the simultaneous formation of the structure of the fibrous ring and the structure of the nucleus pulposus.

In any of the embodiments of the invention herein, the bioink is crosslinked. For example, in any of the embodiments of the invention herein, the bioink can be subjected to crosslinking conditions to obtain crosslinked or polymerized bioink. For example, in any of the embodiments herein, crosslinking may include UV irradiation, addition of salts, pH neutralization, thermal crosslinking, and similar methods, or combinations thereof.

The intervertebral disc prosthesis undergoes a curing stage after suturing. In any of the embodiments of the invention herein, the specified method includes curing the intervertebral disc prosthesis at a temperature of from about 34°C to about 37°C. Suitable cure temperatures may include, but are not limited to, about 34°C to about 37°C, about 35°C to about 37°C, about 36°C to about 37°C, and any range including and/ or between any two of the preceding values. In any of the embodiments of the invention herein, the intervertebral disc prosthesis can be placed in a buffer solution or cellular material during the curing step. In any of the embodiments of the invention herein, suitable buffer solutions include, but are not limited to, phosphate buffered saline, sodium chloride solution, phosphates, and phosphate buffer solution. Suitable cellular material may include, but is not limited to, serum, serum-free medium, HEPES, DMEM, bFGF, FBS, and similar media, or combinations thereof. In any of the embodiments of the invention herein, the specified method may include curing the intervertebral disc prosthesis in a buffer solution or cellular material. In any of the embodiments herein, the curing period may be from about 3 hours to about 24 hours. For example, in any of the embodiments herein, the curing period may be from about 3 hours, about 4 hours, about 5 hours. , about 6 a.m., about 7 a.m., about 8 a.m., about 9 a.m., about 10 a.m., about 11 a.m., about 12 a.m., about 1 p.m., about 2 p.m., about 3 p.m., about 4 p.m., about 5 p.m., about 18:00, about 19:00, about 20:00, about 21:00, about 22:00, about 23:00, about 24:00, or any range including and/or between any two of the preceding values.

In any of the embodiments herein, the bioink may include, but is not limited to, alginate, agarose, collagen, chitosan, fibrin, hyaluronic acid, carrageenan, polyethylene oxide, polypropylene oxide, polyethylene oxide-polypropylene oxide copolymer, hydroxypropyl methylcellulose, poly(propylene fumarate-co- ethylene glycol), poly(ethylene glycol)-co-poly(lactic acid), poly(vinyl alcohol), KDLl 2 oligopeptides, poly(n-isopropylacrylamide), or a combination of two or more of these. The bioink can have a controlled crosslinking rate by adjusting environmental variables including, but not limited to, temperature, pH, ionic strength, heat, light, or the addition of chemical crosslinkers such as calcium, magnesium, barium, chondroitin, sulfate, and thrombin. Suitable hydrogels for use in tissue engineered bioinks are described in U.S. Patent No. 9,044,335 entitled "COMPOSITE TISSUE-ENGINEERED INTERVERTEBRAL DISC WITH SELF-ASSEMBLED ANNULAR ALIGNMENT" filed May 5, 2010, the contents of which are hereby incorporated by reference in their entirety.

In any of the embodiments herein, the bioink may include an alginate hydrogel as described herein in any of the embodiments of the invention. For example, in any of the embodiments herein, the alginate hydrogel may be present in an amount of from about 0.5% (w/v) to about 10% (w/v). In any of the embodiments herein, the bioink may include collagen as described herein in any of the embodiments of the invention. For example, in any of the embodiments herein, the bioink may include more than about 5 mg/mL of collagen. In any of the embodiments herein, the bioink may include type I collagen, type II collagen, or a combination thereof. For example, in any of the embodiments of the invention herein, a method for making a tissue engineered construct may include applying one or more layers of bioink that includes type I collagen to form an annulus structure and applying one or more layers of bioink that includes type II collagen to the formation of the nucleus pulposus structure.

In any of the embodiments of the invention herein, the bioink may further include a neutralizer and cellular material, as described herein in any of the embodiments of the invention. Suitable neutralizers may include, but are not limited to, for example, formulations containing a weak acid. In any of the embodiments of the invention herein, the bioink can be cellular or acellular. For example, in any of the embodiments of the invention herein, the bioink may include cellular material containing living cells, which may include, but are not limited to, cells obtained and/or isolated from intervertebral disc tissue, for example, nucleus pulposus or annulus fibrosus. The cellular material may further include other living cells; for example, in any of the embodiments of the invention herein, the bioink may include epidermal cells, chondrocytes and other cells that form mesenchymal stem cells, IVD stem cells, cartilage, macrophages, adipocytes, dermal cells, muscle cells, hair follicles, fibroblasts, cells organs, osteoblasts, osteocytes and other bone-forming cells, endothelial cells, mucosal cells, pleura cells, ear canal cells, tympanic membrane cells, peritoneal cells, Schwann cells, corneal epithelial cells, gingival cells, neural stem cells of the central nervous system, tracheal epithelial cells; or combinations of two or more of the above. In any of the embodiments of the invention herein, the bioink can be cell-free if the bioink does not contain living cells.

In any of the embodiments of the invention herein, the bioink may further include carriers or additives. Suitable carriers may include, but are not limited to, water, aqueous ionic salts (e.g., sodium hydroxide), phosphate buffered saline (PBS), cell material, fetal calf serum (FBS), Dulbecco's Modified Eagle's Minimal Medium (DMEM) , fibroblast growth factor (bFGF) or similar carriers or combinations of the above. Suitable additives include, but are not limited to, cross-linking agents. Suitable crosslinkers include, but are not limited to, riboflavin, ribose, polyethylene glycol (PEG), glutaraldehyde, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, genipin, chitosan, or similar crosslinkers or combinations of the foregoing.

In any of the embodiments of the invention herein, the bioink is crosslinked. For example, in any of the embodiments herein, the bioink can be subjected to crosslinking conditions to form a crosslinked or polymerized bioink material.

In any of the embodiments of the invention herein, a method for manufacturing a biocompatible support structure may include applying one or more layers of biocompatible material so that the biocompatible support structure has an annular MPD shape. For example, in any of the embodiments of the invention, a biocompatible support structure may have an annular shape IVD of the subject. Typically, the subject or patient is human and preferably needs implants to replace and/or regenerate IVD tissue.

In any of the embodiments of the invention herein, the intervertebral disc prosthesis can withstand one or more of: axial compression from about 1 kN to about 10,000 kN or shear force from about 0.2 kN to about 1000 kN, as described herein in any of the embodiments of the invention.

In at least one embodiment of the invention, the method for manufacturing an intervertebral disc prosthesis according to this technology is a method in accordance with the steps illustrated in FIG. nine.

Thus, the present invention, described as a whole, will be more easily understood with reference to the following examples, which are provided by way of illustration and are not intended to limit the present invention.

While certain embodiments of the invention have been illustrated and described, it should be understood that changes and modifications may be made in accordance with ordinary skill in the art without deviating from the technology in its broader aspects as defined in the following claims.

Embodiments of the invention illustratively described herein may be properly practiced in the absence of any element or elements, limitation or limitations not specifically disclosed in this document. Thus, for example, the terms "comprising", "including", etc. should be interpreted broadly and without limitation. In addition, the terms and expressions used herein are used as terms of description and not limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described, or parts thereof, but it is recognized that various modifications are possible. within the scope of the declared technology. In addition, the phrase "essentially consisting of" will be understood to include those elements specifically listed and those additional elements that do not materially affect the core and novel features of the claimed technology. The phrase "consisting of" excludes any unspecified element.

This disclosure should not be limited to the specific embodiments of the invention described in this application. Many modifications and variations can be made without departing from the spirit and scope of the invention, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, other than those listed herein, will be apparent to those skilled in the art from the foregoing description. It is intended that such modifications and variations fall within the scope of the appended claims. This disclosure is to be limited only by the terms of the appended claims together with the full scope of equivalents to which such claims are entitled. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, or compositions, which, of course, may vary. It should also be understood that the terminology used herein is only intended to describe specific embodiments of the invention and is not intended to be limiting.

Furthermore, if features or aspects of a disclosure are described in the context of Markush groups, then those skilled in the art will appreciate that said disclosure is thus also described in the context of any individual member or subgroup of members of a Markush group.

As will be appreciated by one of skill in the art, for any and all purposes, particularly in the context of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations thereof. Any given range can be readily recognized as being sufficiently descriptive and allowing the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, and so on. As a non-limiting example, each range discussed herein can be easily broken down into lower third, middle third, upper third, and so on. It will also be appreciated by one of ordinary skill in the art that all expressions such as "up to", "at least", "more than", "less than" and similar expressions include the number listed and refer to ranges that can be further subdivided. into subranges as discussed above. Finally, one of ordinary skill in the art will appreciate that the range includes each individual member.

Although this description contains many implementation specific details, they should not be considered as limiting the scope of the claimed requirements, but rather as a description of features specific to a particular implementation. Some of the features described herein in the context of separate embodiments may also be implemented in combination in one embodiment. Conversely, the various features described in the context of a single embodiment may also be implemented in multiple embodiments individually or in any suitable subcombination. In addition, although the features may be described above as operating in certain combinations and even originally claimed as such, one or more features of the claimed combination may in some cases be excluded from the combination, and the claimed combination may be directed to a subcombination or variation of the subcombination.

The terms "connected", "attached" and similar terms in the context of this document means the direct or indirect connection of two components to each other. Such a connection may be fixed (eg, permanent) or movable (eg, removable or detachable). Such a connection can be achieved with two components or two components and any additional intermediate components integral with each other, or with two components or two components and any additional intermediate components attached to each other.

The terms "in fluid communication", "in fluid communication" and similar terms as used herein mean that two components or objects have a path formed between the two components or objects through which a fluid such as water, air, etc. .d. can proceed in the presence of intermediate components or objects or without them. Examples of fluid connections or configurations for fluid communication may include tubes, conduits, or any other suitable components for allowing fluid flow from one component or object to another.

All publications, patent applications, granted patents, and other documents referred to in this specification are incorporated herein by reference as if each individual publication, patent application, patent granted, or other document were specifically and separately identified for inclusion in its entirety. volume by reference. Definitions that are contained in the text incorporated by reference are excluded to the extent that they conflict with the definitions in this disclosure.

Other embodiments of the invention are set forth in the following claims.

Claims (53)

1. A biocompatible support structure for an intervertebral disc prosthesis, comprising: an annular element made of a biologically compatible material, while: the specified annular element contains the inner surface of the wall, the outer surface of the wall, the first flat surface and the second flat surface, opposite the first flat surface; and the specified biocompatible material is present in an amount of from 1% to 100 wt.% biocompatible supporting structures; and said annular element has at least one hole passing through from the outer surface of the wall to the inner surface of the wall and having an average size of 10±10% µm to 10,000±10% µm. 2. Support structure according to claim 1, further comprising at least one of the first plate and the second plate of a biologically compatible material, wherein the first plate is different from the second plate, and the first plate and the second plate are in a substantially parallel position with respect to each other friend. 3. The supporting structure according to claim 1 or 2, characterized in that the annular element has an average thickness of 100±10% µm to 6000±10% µm and a transverse thickness of 100±10% µm to 2000±10% µm. 4. The supporting structure according to claim 1, characterized in that said supporting structure has at least one of: a flexural modulus of 0.2±10% GPa to 100±10% GPa; modulus of longitudinal elasticity from 0.02±10% GPa to 100±10% GPa; and tensile strength from 1± MPa to 1000±10% MPa. 5. Support structure according to claim 1, characterized in that the biocompatible material is selected from the group consisting of polysaccharides, biocompatible polymers, rubber, silicon, biocompatible metals, biocompatible ceramics, polyethylene glycol, polypropylene glycol, polyamino acids, natural and biopolymers, or combinations of two or more of them. 6. Supporting structure according to claim 5, characterized in that: the biocompatible material is selected from the group consisting of PLA, PGA, PLGA, PDO, polycaprolactones, bioresorbable metal alloys, and combinations thereof; and biocompatible material decomposes, is absorbed or resorbed at a rate of 1 ± 10% of the month to 7 ± 10% of the years. 7. Support structure according to claim 1, characterized in that the annular element is made in the form of an intervertebral disc of the subject. 8. Support structure according to claim 1, characterized in that the annular element has at least one hole having an average size of 2.000±10% µm to 5.000±10% µm. 9. The supporting structure according to claim 2, characterized in that said supporting structure further comprises at least one protruding element attached to and extending away from the first flat surface or the second flat surface of the annular element or the flat surface of the first plate or the second plate . 10. The supporting structure according to claim 2, characterized in that said supporting structure further comprises at least one connecting element connecting the cross section of the annular element from the first section of the inner surface of the wall to the second section of the inner surface of the wall, different from the first section of the inner surface of the wall , or connecting the flat surface of the first plate with the flat surface of the second plate. 11. A method of manufacturing a biocompatible supporting structure for an intervertebral disc prosthesis according to any one of paragraphs. 1-10, and the specified method of manufacture includes: applying at least one layer of biocompatible material to the substrate; and cross-linking said biocompatible material to form a biocompatible support structure. 12. The method of claim. 11, characterized in that said method of manufacture includes at least one of: injection molding, rotational molding, molding using positive moulds, molding using negative moulds, subtractive processing, milling and machining , as well as three-dimensional (3D) printing. 13. The method according to claim 12, characterized in that: application includes 3D printing at least one layer of biocompatible material; and 3D printing is selected from the group consisting of: inkjet printing, layer printing, extrusion printing and bioprinting. 14. The method according to claim 12, characterized in that said manufacturing method includes injection molding, wherein said injection molding includes: depositing at least one layer of a biocompatible material on a support, said support being a form of a biocompatible support structure; cross-linking the biocompatible material in said form; and extracting a biologically compatible support structure from said form. 15. The method according to claim 11, characterized in that the biocompatible material is a biocompatible polymer having a melting point from 50±10% °C to 250±10% °C. 16. The method according to any one of paragraphs. 11-15, further comprising repeating the application and crosslinking steps to obtain a biocompatible support structure. 17. The composition of the prosthesis of the intervertebral disc, containing: a biocompatible support structure for an intervertebral disc prosthesis according to any one of paragraphs. 1-10; and tissue engineering construct containing bioink. 18. The composition of the intervertebral disc prosthesis according to claim 17, characterized in that the bioink contains at least one of: hydrogel, agarose, collagen, chitosan, fibrin, hyaluronic acid, carrageenan, polyethylene oxide, polypropylene oxide, a copolymer of polyethylene oxide and polypropylene oxide, hydroxypropyl methylcellulose, poly (propylene fumarate-co-ethylene glycol), poly(ethylene glycol)-co-poly(lactic acid), poly(vinyl alcohol), KDLl 2 oligopeptides, poly(n-isopropylacrylamide), or combinations of two or more of them. 19. The composition of the intervertebral disc prosthesis according to claim 18, characterized in that the bioink contains an alginate hydrogel present in an amount of from 0.5% (w/v) to 10% (w/v). 20. The composition of the intervertebral disc prosthesis according to claim 17, characterized in that the bioink contains from 5±10% mg/ml to 200±10% mg/ml of collagen. 21. The composition of the intervertebral disc prosthesis according to claim 20, characterized in that the collagen is selected from type I collagen, type II collagen, or a combination thereof. 22. The composition of the intervertebral disc prosthesis according to claim 17, characterized in that the tissue-engineered structure contains a nucleus pulposus structure containing type II collagen and an annulus fibrosus structure containing type I collagen, while the annulus fibrosus structure is aligned circumferentially around the nucleus pulposus structure. 23. The composition of the intervertebral disc prosthesis according to claim 17, characterized in that the tissue engineering structure additionally contains a population of cells present at a concentration of 1.0×10 ⁵ ±10% cells/ml to 5.0×10 ⁷ ±10% cells/ ml. 24. The composition of the intervertebral disc prosthesis according to any one of paragraphs. 17-23, characterized in that: an annular element of a biologically compatible supporting structure increases the axial stiffness of the tissue engineered structure from about 5±10% times stiffness to about 10,000±10% times stiffness; and/or the first plate or the second plate of the biologically compatible supporting structure increases the axial ultimate load of the tissue-engineered structure by 1% - 10000%; and/or said composition withstands axial compression from 1±10% kN to 10,000±10% kN, shear force from 0.2±10% kN to 1000±10% kN, or a combination thereof. 25. A method of manufacturing the composition of the prosthesis of the intervertebral disc according to any one of paragraphs. 17-24, including: production of a biologically compatible supporting structure, including: applying a biocompatible material to a substrate to form a biocompatible support structure; fabrication of a tissue engineering structure, including: applying the bioink to or around the biocompatible support structure; crosslinking said bioink to form a tissue engineering construct; and curing the composition of the prosthesis of the intervertebral disc. 26. The method of claim. 25, characterized in that the curing of the intervertebral disc prosthesis composition is carried out at a temperature of from 34±10% °C to about 37±10% °C. 27. The method of claim 25, further comprising, after applying the biocompatible material to the support, crosslinking said biocompatible material to form a biocompatible support structure. 28. The method of claim 27, further comprising repeating the steps of applying and crosslinking said biocompatible material to form a biocompatible support structure. 29. The method of claim 25, further comprising repeating the steps of applying and suturing to form a tissue engineered construct.

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