Scaffolds and scaffold holders for tissue engineering

Abstract

Disclosed herein is a kit for manufacturing a scaffold for repairing tissue in a living being. The kit includes a structural reinforcing element. The structural reinforcing element is selected from i) at least one rod; or ii) a plurality of rods and brackets that are operative to be assembled into a cage. It comprises a plurality of module elements that can be assembled to form at least one module, where the module upon assembly contacts the structural reinforcing element. The module includes a plurality of curved ribs of different sizes that extend concentrically in a first direction when assembled. It also contains a spacing element that is operative to contact the plurality of curved ribs when assembled; where the spacing element extends in a second direction that is inclined at an angle to the first direction. The spacing element is operative to keep successive neighboring modules apart from one another.

Description

SCAFFOLDS AND SCAFFOLD HOLDERS FOR TISSUE ENGINEERINGCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application which claims priority to U.S. Provisional Patent Application No. 63 / 595,042 filed November 1, 2024, which is incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTION Field of the Invention

[0002] The invention disclosed herein relates to materials for biomedical applications, and in particular to scaffolds for tissue engineering. Description of the Related Art

[0003] Scaffolding in tissue engineering refers to the use of temporary structures to support the growth and differentiation of cells. These scaffolds serve as a framework on which cells attach and grow, mimicking the extracellular matrix found in natural tissues. The goal is to guide the formation of new functional tissues for medical applications, such as the replacement or repair of damaged body parts.

[0004] The emergence of scaffolding technology addresses the limitations and ethical concerns associated with traditional approaches for tissue repair, such as organ transplantation and artificial implants. Transplantation often faces issues of donor scarcity and immune rejection. Artificial implants do not usually integrate well with surrounding tissues. Scaffolding provides an alternative that leverages the body's natural ability to regenerate, offering the possibility of creating customized, biocompatible structures for in vitro and in vivo tissue repair.

[0005] Current scaffolding technologies primarily use materials such as biodegradable polymers, hydrogels, and decellularized tissues. These materials are designed to be biocompatible and to degrade over time, eventually leaving only the newly formed tissue. Advanced fabrication techniques like electrospinning and 3D printing are often used to create these scaffolds with high precision.

[0006] Despite advancements, existing scaffolding technologies face challenges. Biodegradability rates do not always align with the rates of tissue formation, leading to potential complications. Material properties like stiffness and porosity can also affect cellbehavior in unpredictable ways. The manufacturing processes are often complex, making it difficult to produce scaffolds that meet all the desired criteria for different tissue types.

[0007] For scaffolding technology to advance, a deeper understanding of the interaction between materials, cells, and the biological environment is desirable. Research should focus on developing new materials with tunable properties, as well as refining fabrication techniques for greater control over scaffold architecture. By addressing these issues, scaffolding could become a more versatile and effective tool in tissue engineering and regenerative medicine.

[0008] In addition, there are a variety of medical conditions where scaffold technology is well suited for patient therapy.SUMMARY

[0009] Disclosed herein is a kit for manufacturing a scaffold for repairing tissue in a living being, the kit comprising a structural reinforcing element; where the structural reinforcing element is selected from i) at least one rod; or ii) a plurality of rods and brackets that are operative to be assembled into a cage; a plurality of module elements that can be assembled to form at least one module; where the module upon assembly contacts the structural reinforcing element; wherein the plurality of module elements comprises a plurality of curved ribs of different sizes that extend concentrically in a first direction when assembled; where an outermost curved rib of the module is designed to communicate with the structural reinforcing element when assembled into the module; wherein an innermost curved rib is operative to be in a cantilevered arrangement with the outermost rib when assembled into the module; and wherein the innermost rib is operative to clamp the tissue being repaired; and a spacing element that is operative to contact the plurality of curved ribs when assembled; where the spacing element extends in a second direction that is inclined at an angle to the first direction, where the spacing element is operative to keep successive neighboring modules apart from one another.

[0010] Disclosed herein is a scaffold for repairing tissue in a living being, the scaffold comprising a structural reinforcing element; and at least one module adapted for use in operative communication with the structural reinforcing element; wherein the at least one module comprises curved ribs of different sizes that extend concentrically in a first direction when assembled; where an outermost curved rib of the module is in operative communication with the structural reinforcing element; wherein an innermost curved rib is operative to be in a cantilevered arrangement with the outermost rib; and wherein the innennost rib is operativeto clamp the tissue being repaired; and a spacing element that is operative to contact the plurality of curved ribs; where the spacing element extends in a second direction that is inclined at an angle to the first direction, where the spacing element is operative to keep successive neighboring modules apart from one another.

[0011] Disclosed herein is a method of repairing tissue in a living being, the method comprising selecting an element from a kit and assembling the elements to form a scaffold comprising, the kit comprising a structural reinforcing element; and at least one module adapted for use in operative communication with the structural reinforcing element; wherein the at least one module comprises a plurality of curved ribs that extend concentrically in a first direction when assembled; where an outermost curved rib of the module is in operative communication with the structural reinforcing element; wherein an innermost curved rib is operative to clamp the tissue being repaired; and a spacing element that is in operative communication with at least one of the plurality of curved ribs; where the spacing element extends in a second direction that is different from the first direction, where the spacing element is operative to keep successive neighboring modules of the plurality of modules apart from one another; and assembling the plurality of elements in the living being to effect a repair of the tissue.BRIEF DESCRIPTION OF THE FIGURES

[0012] FIGS. 1A - IE depict a scaffold and its constituent components;

[0013] FIGS. 2 A - 2E depict one method of assembling the scaffold and using it to assist in fixing a bone defect;

[0014] FIGS. 3A - 3C depict another exemplary module of the scaffold that can function as a bone graft containment system or a tissue containment system and that be used for repairing bone defects or damage as well as tissue damage;

[0015] FIG. 4 is a depiction of an exemplary rod holder that facilitates holding the module in position; and

[0016] FIG. 5 depicts one manner of using the scaffold of the FIG. 3C.DETAILED DESCRIPTION

[0017] Disclosed herein are methods and apparatus for tissue repair, regeneration and engineering. In an embodiment, the technology includes components of scaffolding useful as constructs for surgical procedures such as tissue grafting and biomaterial containments. Theconstructs are adaptable and scalable and provide for treatment of a variety of injuries of any size and shape. Generally, the technology is provided as a system that includes prefabricated units of varying forms with varying sizes and geometries. Surgical assembly of the prefabricated units provides for assembly of a lattice or scaffolding of any arrangement desired.

[0018] Disclosed herein are embodiments of a reversibly interlocking personalized resorbable implant (referred to herein as a “scaffold,” “cage” and by other similar terms). The implant provides for effective placement of bone grafts in large, segmental defects of the extremities such as humerus, femur, radius, ulna, patella, fibula, tibia, and other defects in pelvis, spine, and craniomaxillofacial bones. The implant is designed to retain grafts in the intended location(s) during healing. The intricate cage design facilitates graft packing, and versatile use with common rigid fixation devices (intramedullary nails, plates / screws, and / or external fixation devices). Generally, when disposed in-situ, each scaffold is a custom-built reversible aggregation of prefabricated units (also referred to as “elements” or “modules” or by another similar term). There are also conditions that scaffolds should be immobilized or contained in place using fixation devices to avoid their dislocation during the tissue regeneration and healing.

[0019] In an embodiment, the scaffold for repairing bone or tissue in a living being comprises a structural reinforcing element and a plurality of modules that are in operative communication with the structural reinforcing element. Each module of the plurality of modules comprises a plurality of curved ribs that lie in a first plane and that do not close on themselves. The outermost curved rib of each module is in direct or indirect communication with the structural reinforcing element, while the innermost curved rib is operative to secure the scaffold to the bone or tissue being repaired. In an embodiment, the innermost curved rib is operative to clamp the scaffold to the bone or tissue being repaired. The innermost curved rib functions like a snap ring. Disposed between each module of the plurality of modules is a spacing element that is in operative communication with at least one of the plurality of curved ribs. Each spacing elements extends in a second plane or in a second direction that is different from the direction of the first plane. The spacing element is operative to keep successive neighboring modules of the plurality of modules apart from one another.

[0020] In an embodiment, the scaffold may be available in the form of a kit that comprises a plurality of different elements that can be selected and assembled depending upon the features of the patient and features of the tissue being repaired. The kit comprises astructural reinforcing element that may be selected from i) at least one rod or ii) a plurality of rods and brackets that are operative to be assembled into a cage. The kit comprises module elements that may be used to assemble at least one module that can fit into the cage. Module elements are those components that are used to assemble the module.

[0021] The module elements comprise a plurality of curved ribs of different sizes that extend in a first direction when assembled to form the module. The outermost curved rib of module is designed to communicate with the structural reinforcing element when assembled into the module. The innermost curved rib lies inside the outermost curved rib and is operative to be in a cantilevered arrangement with the outermost rib when assembled into the module. The innermost rib is operative to clamp the tissue being repaired. In an embodiment, the kit may comprise a plurality of riblets that contact the outermost curved rib, the innermost curved rib and any intervening curved ribs.

[0022] In an embodiment, the kit may comprise elements that permit several modules to be manufactured and connected with one another. The kit comprises module elements that can form a plurality of modules, where the modules can be assembled to form a scaffold that provides for containment of a bone defect for up to 15 centimeters. The term containment implies that nutrients and other restorative materials (e.g., biologically active agents) can be held in position while the tissue regenerates.

[0023] The kit further comprises a spacing element that is operative to contact the plurality of curved ribs when assembled. The spacing element extends in a second direction that is inclined at an angle to the first direction. The spacing element is operative to keep successive neighboring modules apart from one another. In an embodiment, the spacing element comprises a circular ribs and linear ribs that are used to assemble a porous tubular clamp. The porous tubular clamp maintains a desired distance between successive modules.

[0024] In yet another embodiment, the kit comprises a plurality of rod holders that can be reversibly attached to an outer surface of the outermost curved rib. The rod holders have holes that accommodate rods. The rods function as structural reinforcing elements and extend in a second direction. The rod holders also accommodate a spacer that separates one module from its neighboring module and extend in the second direction.

[0025] The components for the kit are available in different sizes and are available in different materials that can be assembled at the site at which the patient is being treated. The elements used may depend upon the application. In an embodiment, the scaffold (or portions of the scaffold) manufactured from these kit elements may be used temporarily until a morepermanent scaffold can be constructed. During the course of treatment some elements from an existing scaffold can be removed and replaced with other temporary or other more permanent elements (of the same or different sizes and materials) that can be fused to the existing scaffold with adhesive.

[0026] In an embodiment, a method of repairing tissue in a living being includes selecting elements from a kit and assembling the elements to form a scaffold comprising. The kit comprises a structural reinforcing element and at least one module adapted for use in operative communication with the structural reinforcing element. The at least one module comprises a plurality of curved ribs that extend concentrically in a first direction when assembled. The outermost curved rib of the module is in operative communication with the structural reinforcing element. The innermost curved rib is operative to clamp the tissue being repaired. The kit further comprises a spacing element that is in operative communication with at least one of the plurality of curved ribs. The spacing element extends in a second direction that is different from the first direction, where the spacing element is operative to keep successive neighboring modules of the plurality of modules apart from one another. The plurality of elements from the kit are then assembled in the living to effect a repair of the tissue.

[0027] In an embodiment, the elements of the scaffold may be glued, welded, fused via use of a solvent or thermally fused together to bond them to one another to form the scaffold.

[0028] In yet another embodiment, the volume of the scaffold may be filled with another scaffold, a biodegradable material, a hydrogel, a bone graft material, a tissue piece, a minced tissue, a decellularized tissue, a decellularized extracellular matrix, a powdered bone, a synthetic graft, a cell, an organoid, a cell spheroid, a bio-ceramic powder, a bio-ceramic paste, or a combination thereof. In an embodiment, the volume of the scaffold may be filled up with proteins, biological factors, hormones, peptides, antibiotics, antibacterial compounds, bactericidal compounds, fungicides, antifungal drugs, or a combination thereof.

[0029] As used herein, the terms “anterior” and “posterior” are meant to define the positions of the openings to the base plate and the porous tubular clamp relative to the position of a viewer looking at a figure of the base plate and a porous tubular clamp. They are not meant to define the location of the openings when used in the body as a prosthetic.

[0030] As used herein, the term “arc” refers to a portion of any smooth curve. Arc can describe a part of the circumference of a circle or a part of the perimeter of an ellipse.

[0031] As used herein, a “snap ring” generally refers to a type of spring that expands circumferentially to fit over a shaft or within a groove but returns to its original circumference once in place.

[0032] As used herein, the term “direct” generally refers to a relationship between a first element and a second element without any substantial intervening elements. For example, it should be recognized that “direct contact” may include intermediate elements such as glue or adhesive to ensure retention of the relationship.

[0033] As used herein, the characteristic dimension of a particular shape generally refers to a specific measure that defines its shape and scale. For example, a characteristic dimension of a circle is its radius, a characteristic dimension of a parabola is its focal length; and a characteristic dimension of an ellipse is the semi-major axis and the semi-minor axis.

[0034] FIGs. 1A - 1C depict a scaffold 100 and its constituent components. The constituent components are also referred to herein as “elements.” The scaffold is manufactured from a kit, by selecting various items described herein such as rods, brackets, curved ribs, riblets, linear ribs, and the like, from the kit and assembling them to suit the characteristics of a particular patient that is being treated.

[0035] FIG. 1A depicts a semiflexible supporting cage 102 of inner diameter “d” into which is inserted a plurality of reversibly attachable modules 104A, 104B, 104C, . . .., (hereinafter modules 104A, 104B, 104C, ,) and so on to form the scaffold 100. FIG. IB depicts a single supporting cage 102. The supporting cage 102 supports and constrains the plurality of modules 104A, 104B, 104C, . . .., sequentially in position when the scaffold 100 is used to repair an injured part of the body, such as a bone or tissue. The cage 102 therefore functions as a structurally reinforcing element and holds each module 104A, 104B, 104C, , in position. Each of the plurality of modules 104A, 104B, 104C, , and so on, can be placed in position around an injured portion of the body (e.g., a bone or tissue) and the cage 102 can then be disposed around the plurality of modules to hold and support them in position during the process of regrowth.

[0036] The cage 102 also provides the scaffold 100 with the desired rigidity during the bone regrowth process. FIG. 1C depicts a plurality of modules 104A, 104B and 104C when they are separated from the scaffold 100. Both the cage and the respective modules can be attached and detached from each other (i.e., they are reversibly attachable) and can be manipulated at least by a single human hand (or at least by a pair of human hands) to be fitted around damaged bones and tissue during surgery. In short, there is no need for excessivemechanical force or for the use of mechanical implements during manipulation of the scaffold during surgery. Mechanical implements may be used, but the scaffold may be manipulated without them if desired.

[0037] FIG. ID depicts the supporting cage 102 and its constituent components. The constituent components (such as rods, brackets, curved ribs, linear ribs, riblets, and the like are also collectively referred to herein as “elements”). The cage 102 comprises a modular construction that can be assembled and disassembled and is manufactured from the rods 206 and brackets 208 as seen in the FIG. ID. The rod 206 constitutes the male member than can be inserted into receptacles 205 located in each of the bracket arms 208W, 208X, 208Y and / or 208Z. The receptacles 205 is sized to be in a clearance fit with the ends of the rod 206 so that they can be easily inserted and removed during assembly and disassembly respectively. While the FIG. ID depicts a bracket 208 with four arms that are at right angles to each other, the bracket may have more than four arms or less than four arms. FIG. ID depicts one bracket (enclosed in circle AA’) that has only three arms. Three- armed brackets preferably are used near the edge of the scaffold. Brackets having only two arms may also be used where greater flexibility in the structure is desired. The arms may have internal angles that vary from 15 degrees to 180 degrees, preferably 45 to 135 degrees.

[0038] FIG. ID depicts one section 102A of the assembled cage 102. In this section 102A of the assembled cage 102, rods 206A, 206B, 206C and 206D are inserted into receptacles in the brackets 204A, 204D (both of which have 4 arms) and brackets 208C and 208B (both of which have 3 arms) to form the section 102. The rods may be straight or curved and may be stiff or flexible. The resulting cage may have any cross-sectional shape (when viewed in a direction perpendicular to the direction in which the diameter “d” is measured) it may be circular, elliptical, square, rectangular, polygonal, or a combination thereof.

[0039] In a scaffold, some rods may be flexible or semi-flexible and may be straight or curved, while others may be stiff and either straight or curved.

[0040] FIG. IE depicts one module 104A (of the plurality of modules 104A, 104B, 104C, . . .., seen in the FIG. 1C). Each module comprises a base plate 306 that lies in a first plane and that contacts a porous tubular clamp 304 that extends in a second plane or second direction. The first plane generally extends in a first direction and the second plane or second direction is different from the first plane or first direction.

[0041] In an embodiment, the porous tubular clamp 304 protrudes at an angle 0 from the base plate 306. In other words, a longitudinal axis of the porous tubular clamp 304 extends at an angle 0 from a radial direction of the base plate 306. In an embodiment, the angle 0 varies from 70 to 110 degrees, preferably 85 to 95 degrees. The base plate 306 and the porous tubular clamp 304 together define central passage 350 which is used to support sections of bone or tissue that need growth, regrowth or development. An outer surface 312 of each base plate 306 of the plurality of modules 104A, 104B, 104C, . . .., contacts an inner surface of the cage 102 as seen in the FIG. 1 A. The base plate may have threads at its lower surface (not shown) that can mate with threads located at an upper surface of the tubular clamp 304 (not shown). When these threads interlock, one module 104A will be fixedly attached to an adjacent module 104B, and so on, thus providing some continuity to the scaffold 100. The base plate 306 thus serves as a locating element for each module 104A, 104B, 104C, and so on, within the cage 102. The base plate 306 further serves as a locating element for the porous tubular clamp 304. A plurality of modules can therefore be successively or intermittently lined up within the cage 102 such that each porous tubular clamp 304 is substantially concentric with an outer surface of the cage 102. This feature provides a substantially uni-directional support for any bone or tissue whose original growth or regrowth is desired.

[0042] The base plate 306 comprises a plurality of curved ribs 306A, 306B, 306C, 306D,. . .., 306n, and so on, that are spaced apart from each other and reinforced by riblets 306W, 306X, 306Y, 306Z, , and so on. Each of the curved ribs 306A, 306B, 306C, 306D,. . .., 306n, and so on are arc shaped. It is to be noted that n is an integer and may range from 1 to 20 and preferably 3 to 10. It is to be noted that the curved ribs may be part of a circle (e.g., arcs of a circle), part of a parabola (e.g., arc of a parabola), a part of an ellipse (e.g., arcs of an ellipse), or a combination thereof. Successive neighboring curved ribs may be concentric (i.e., they share a common center) or a common focal point.

[0043] The spacing of the curved ribs and the spacing of the riblets make the base plate 306 porous and permeable. In other words, there are open spaces between successive ribs and riblets. In an embodiment, the spacing of the curved ribs and the spacing of the riblets is periodic and hence the open spaces in the base plate may also be periodically spaced. The riblets 306W, 306X, 306Y, 306Z, , 306N and so on, generally extend perpendicular to a tangent to the curved ribs at any given point. It is to be noted that N is an integer and may range from 1 to 20 and preferably 3 to 10. End riblets 306P and 306Q(hereinafter end rods 306P and 306Q) form the first and last riblets on the base plate 306 and are located at the opposite ends of the base plate. They can also be used to spread apart the opposite ends of the base plate and the porous tubular clamp 304 along arrows A and B.

[0044] The number of curved ribs and the riblets are selected to provide each module with the desired flexibility or rigidity to facilitate providing structural support to the scaffold 100 to be extended around a damaged bone or tissue, to support the bone or tissue during growth and to enhance the rate of tissue growth. Each curved rib 306 A, 306B, 306C, 306D does not extend in a complete circle but has at least one opening 308 that permits each base plate to be expanded around a bone or tissue where support is desired. This will be detailed later.

[0045] In an embodiment, with reference to the top view of the FIG. IE, the outermost curved rib 306A has a single opening 308, while the successive inner curved ribs 306B, 306C, 306D, and so on, have at least two openings - a larger anterior opening 308 and a smaller posterior opening 310. In other words, the outermost curved rib 306A comprises a single arc with only one opening - the anterior opening 308, while the inner curved ribs 306B, 306C, 306D, and so on, each comprise two arcs. The curved ribs are of a progressively tighter characteristic dimension (e.g., radius or focal length) from the outermost curved rib 306A to the innermost curved rib 306D. The innermost curved rib 306D is of the smallest size (e.g., has the smallest radius or focal length), while the outermost curved rib 306A is of the largest size (e.g., has the smallest radius or focal length). The ribs 306B and 306D that lie between the outermost curved rib 306A and the innermost curved rib 306D have intermediate characteristic dimensions (e.g., radii of focal lengths) between those of the outermost and innermost curved ribs.

[0046] Each of the two arcs (of the inner curved ribs 306B, 306C, 306D, and so on) are separated by the larger anterior opening 308 and the smaller posterior opening 310. Stated another way, the curved ribs exhibit open spaces between the circumferential ends, thus, the curved ribs do not close on themselves to form a continuous structure. For example, with reference to the FIG. IE (top view), the ends 306P and 306Q of the outermost curved rib 306A are always apart from each other and never contact each other to form a closed structure (e.g., the never form a circle or an ellipse). The same applies to the ends of curved ribs 306B, 206C and 306D, which never close to form a circle or an ellipse.

[0047] The inner curved ribs (306B, 306C, 306D, and so on) are in a cantilevered relationship with the outermost curved rib 306A. In other words, the inner curved ribs((306B, 306C, 306D, and so on) are suspended from the outermost curved rib 306A via riblets 306W, 306X, 306Y, 306Z, . , 306N and so on.

[0048] This feature (the larger anterior opening 308 and the smaller posterior opening 310) permits each module 104A, 104B, 104C, and so on, to have the desired flexibility to be expanded in the radial direction so that it can circumscribe a portion of the bone or other tissue that it is meant to repair. While the FIG. IE depicts the outermost curved rib 306A as having the smallest number of openings, any of the other curved ribs or any plurality of ribs may have multiple openings so long as they provide the respective module with the flexibility to circumscribe the bone or tissue meant to be fixed.

[0049] Both openings, the larger anterior opening 308 and the smaller posterior opening 310 extend from the base plate to the porous tubular clamp 304 (as may be seen in the top and bottom view) of the FIG. IE. As noted above, the porous tubular clamp 304 extends at an angle 0 from the base plate 306. In an embodiment, the porous tubular clamp 304 generally extends in columnar fashion perpendicularly from the base plate 306. It can be fixedly attached to the base plate 306 (e.g., directly molded to the base plate 306) or reversibly attached to the base plate 306 (e.g., via screw treads, snap-fit joints, bayonet connectors, magnetic attachments, hook and loop fasteners, or a combination thereof).

[0050] The porous tubular clamp 304 (as seen in the bottom and side view of FIG. IE) comprises a number of circular ribs 304A, 304B, 304C, 304D, 304E, . , 304n, and so on, each of which have the anterior and posterior openings 310 and 308 respectively, that are stacked one atop another with a space between each successive pair or circular ribs. It is to be noted that n is an integer and may range from 1 to 20 and preferably 3 to 10. Linear ribs 304X, 304 Y, 304Z,. . .., 304N, and so on, that extend perpendicular to the circular ribs provide the porous tubular clamp with the desired structural strength while still permitting adjustment of the module by hand. It is to be noted that N is an integer and may range from 1 to 20 and preferably 3 to 10.

[0051] In an embodiment, the larger anterior opening 308 and the smaller posterior opening 310 of the porous tubular clamp 304 and the base plate 306 permit each module to be expanded radially outwards along arrows A and B, thus permitting the central opening 350 in each module to be expanded to accommodate a bone or tissue that needs to be repaired. By pulling apart the end rods 306P and 306Q, the posterior opening 310, the anterior opening 308 and the central opening 350 can be expanded to accommodate the solid portion of a bone or a fixation device (such as intramedullary rod or nail). In this manner, successively linkedmodules 104A, 104B, 104C, and so on, can each be expanded and disposed around a bone or tissue, till the entire plurality of successively linked modules 104A, 104B, 104C, and so on, are disposed around the bone or tissue that is to be repaired. The scaffold may be suturable (i.e., can be sutured) around a defective bone at a location proximate to the defect. In another embodiment, the scaffold may be stapled to the defective bone or affixed to the defective bone via a Velcro fixture.L0052 J In an embodiment, the various positions at which the curved ribs 306A, 306B, 306C, 306D,. . .., and the riblets 306W, 306X, 306Y, 306Z, , and / or the positions at which the circular ribs 304A, 304B, 204C, 304E, 304E of the porous tubular clamp contact the linear ribs 304X, 304 Y, 304Z,. . ., may be optionally welded together using a biodegradable adhesive. The points at which each successive module contacts the neighboring module may also be welded together. This will be discussed in detail later. This provides structural integrity to the entire scaffold.

[0053] The cage 102 can then be disposed around the plurality of successively linked modules 104A, 104B, 104C, , 104n, and so on, to form the prosthetic 100. The cage 102 can also be welded to the base plate of the each of the plurality of successively lined modules 104A, 104B, 104C, , 104n.

[0054] The diameter of each of the curved ribs 306A, 306B, 306C, 306D,. . .., the riblets 306W, 306X, 306Y, 306Z, , the circular ribs 304A, 304B, 304C, 304D, 304E, , and / or the linear ribs 304X, 304Y, 304Z,. . . , of the FIGs. 1 A through IE may vary from 1 to 4 millimeters. The diameters of the curved ribs, the riblets, the circular ribs, and / or the linear ribs can be the same or different. For example, the curved rib 306A may be manufactured from the same or different material as the curved rib 306B. The materials are discussed in detail later. Similarly, the curved rib 306A can have the same or different diameter as that used in the curved rib 306B.

[0055] The ability to use different sizes and different materials for each of the curved ribs 306A, 306B, 306C, 306D,. . .., the riblets 306W, 306X, 306Y, 306Z, , the circular ribs 304A, 304B, 304C, 304D, 304E, , and / or the linear ribs 304X, 304Y, 304Z,. . ., of the FIGs. 1 A through IE permits the respective modules and the surrounding cage to be made in different sizes so that they can accommodate different sized bones as well as defects present in the bones.

[0056] FIGs. 2A- 2E depict one method of assembling the scaffold 100 and using it to assist in fixing a bone defect. FIG. 2A depicts the modules 104A, 104B, 104C,. . . ,104nbeing assembled to form the plurality of modules 104. An adhesive gun 1000 deposits a biodegradable adhesive being applied to various points of contact in each of the modules and in between modules to provide a strong bonded structure to the scaffold. A scaffold containment layer 105 is applied to the outer surface of the modules as seen in the FIG. 2B. The scaffold containment layer 105 functions as a bone graft containment system or a tissue containment system and is designed to keep the bone graft material in place and support the healing process. They serve to hold the graft material and provide structural integrity while allowing for gradual resorption and replacement by natural bone. The scaffold containment layer not only secures the graft material within the defect site but also plays a role in controlling the release of nutrients and promoting cell attachment, migration, and proliferation. This structured support aids in creating an environment conducive to bone regeneration and successful graft integration.

[0057] This containment layer typically comprises a biocompatible polymer (e.g., poly lactic acid (PLA), poly glycolic acid (PGA), poly caprolactone (PCL), or a combination thereof), ceramics (e.g., calcium phosphate or hydroxyapatite), metals (e.g., magnesium), growth factors and bioactive molecules, antimicrobial agents, collagen, gelatin, or a combination thereof. The scaffold containment layer may be infused or coated with antimicrobial agents, or growth factors like bone morphogenetic proteins (BMPs) to promote cell differentiation and bone formation. Bioactive coatings or molecules may also be used to encourage cell proliferation and enhance healing. Other biologically active agents may also be included in the containment layer. These are detailed below.

[0058] FIG. 2C shows the cage 102 being applied to an outer surface of the scaffold containment layer 105. The cage 102 provides structural and mechanical support to the scaffold containment layer 105 and to plurality of modules 104 contained therein. FIG. 2D depicts a bone with a defect to which the aforementioned cage 102 (with the scaffold containment layer 105 and the plurality of modules 104 contained therein) is applied as seen in the FIG. 2E.

[0059] FIGs. 3A, 3B and 3C depict another exemplary module 502 of a scaffold 500 (see FIG. 3C) that can also function as a bone graft containment system or a tissue containment system and that be used for repairing bone defects or damage (e.g., via regeneration) as well as tissue damage. FIG. 3A is an isometric view of a single module 502 that may be used to construct the scaffold 500. FIG. 3B is a top view of a schematicdepiction of the single module 502. FIG. 3C depicts a plurality of modules that may be assembled to form the scaffold 500.

[0060] The constituent components of the FIGS. 3A, 3B and 3C are sometimes also referred to herein as “elements”. The module and scaffold of the FIGS. 3A, 3B and 3C are also manufactured from a kit, by selecting various items described herein such as curved ribs, rod holders, spacing elements, and the like, from the kit and assembling them to suit the characteristics of a particular patient that is being treated.

[0061] The scaffold 500 comprises a plurality of ribs - an outermost curved rib 502A and a pair of inner ribs 502B and 502C (also referred to herein as innermost curved ribs 502B and 502C) each of which are arc shaped. The innermost curved ribs 502B and 502C are opposed to each other and protrude from an inner surface of the outermost curved rib 502A into a central area circumscribed by the outermost curved rib 502A. The outermost curved rib 502A provides the mechanical support for the innermost curved ribs 502B and 502C and also supports a plurality of rod holders 509A, 509B, 509C, 509D, 509E and 509F that are disposed on its outer surface.

[0062] The outermost curved rib 502A is in the form of a single arc of a smooth curve (e.g., a portion of the circumference of a circle or a portion of the perimeter of an ellipse) and contains an anterior opening 508A. The opposing ends of the outermost curved rib 502A and the opposing ends of the innermost curved rib 502B and 502C do not contact each other (i.e., they do not close on themselves). Located opposite to the anterior opening 508A are a plurality of protrusions 504B and 504C (that protrude from an inner surface of the outer rib 502A) to which inner ribs 502B and 502C respectively are connected. Each inner rib 502B and 502C is arc shaped and has a characteristic dimension (e.g., a radius, focal length, or the like) that is smaller than a characteristic dimension (e.g., radius, focal length, or the like) of the arc that constitutes the outer rib 502A. In an embodiment, the outer rib 502A is parallel to the inner ribs 502B and 502C. In another embodiment, the outer rib 502A is concentric with the inner ribs 502B and 502C and share the same radial center. The inner ribs 502B and 502C are cantilevered from an inner surface of the outer rib 502A and define an opening 550, into which a bone or tissue that needs to be repaired is positioned. The opening is also intended to accommodate intramedullary nails or rods that may be used to support align broken bones. In an embodiment, the innermost rib is operative to clamp an intramedullary nail as a fixation system for segmental bone defects

[0063] With reference now to FIGS. 3 A and 3B, the inner ribs 502B and 502C are opposed to each other in a manner similar to opposing claws. The opposing claws define an anterior opening 508B. The inner ribs 502B and 502C have smaller posterior opening 510 that lies proximate to the point at which each inner rib contacts the protrusions 504B and 504C. The anterior opening 508 A is larger than the anterior opening 508B, which is larger than anterior opening 510.

[0064] The inner ribs 502B and 502C define the opening 550 and function as claws or clamps that lock onto bone or tissue that penetrates the opening 550. As noted, above, the opening accommodates intramedullary nails or rods that may be used to support align broken bones. In an embodiment, the inner ribs 502B and 502C function as snap rings that exert a compressive force that is directed to the center of opening 550. This compressive force secures at least one module 502 (of a plurality of modules that form the scaffold 500 of FIG. 3C) to the bone or tissue that needs to be repaired.

[0065] Located on the inner surface of the outer rib 502A are a plurality of stops 506A, 506B, 506C and 506D that protrude toward the center of opening 550. The stops 506 A, 506B, 506C and 506D may keep the bone graft from collapsing. They may also prevent the inner ribs 502B and 502C from expanding too far outwards in a radial direction.

[0066] Disposed on an outer surface of the outer rib 502A are a plurality of rod holders 509 A, 509B, 509C, 509D, 509E and 509F. The rod holders each accommodate a rod that secures and supports the plurality of modules 502 to form the scaffold 500 as seen in the FIG. 3C. In the scaffold 500, each rod holder 509A, 509B, 509C, 509D, 509E and 509F securely accommodates a rod 522A, 522B, 522C, 522D, 522E and 522F respectively that structurally interconnects and stabilizes the plurality of individual modules 502A, 502B, 502C,. . .., 502n, and so on, ensuring cohesion and alignment within the scaffold, where “n” is an integer that ranges from 1 to 20, preferably 3 to 10.

[0067] In reference to FIGs. 3A and 3B, each rod holder (509A, 509B, 509C, 509D, 509E, and 509F) includes a plug 511 with a through-hole 512 designed to accommodate a rod. FIG. 4 depicts the top view and two side views of one of these rod holders 509B. Side view M depicts the rod holder 509B with a portion of a rod 522A disposed within the hole. Each rod holder comprises a flat head 511 with a hole 512 disposed therein. The flat head 511 comprises a piece of biodegradable metal or plastic of thickness “t”. The hole 512 is designed to accommodate a rod (not shown) that structurally interconnects and stabilizes the plurality of individual modules. The rod holder 509B comprises a forward portion that has acurved surface 513 of radius Ri whose curvature is designed to correspond to that of the outer surface of outer rib 502A (see FIGs. 3A and 3B). In one embodiment, the curved surface 513 is configured to conform to and engage with the outer surface of the outer rib 502A.

[0068] Within each hole 512, one or more cantilevered elements 510A and 510B apply pressure to secure the rod in place. The cantilevered elements 510A and 51 OB may extend from the hole in at least one direction. In an embodiment, the cantilevered elements 510A and 510B may extend from the hole in two opposite directions. The cantilevered elements 510A and 51 OB (that extend for a height “h” from the hole in at least one direction) create a friction fit with a rod (e.g., rod 522 as seen in the FIG. 3C) that may be positioned in the through hole 512. The height “h” of the cantilevered elements may be selected depending upon the spacing desired between successive neighboring modules. The cantilevered elements 510A and 510B also function as spacing elements that keep neighboring successive modules spaced apart at a selected distance. The neighboring successive modules can be periodically spaced or aperiodically spaced.

[0069] In an embodiment, each rod holder may be affixed to an outer surface of the outer rib 502A via a reversible attachment 514 (located at surface 513) such as threaded couplings, a snap-fit connection, a twist-lock mechanism (e.g., which involves twisting one part to engage or disengage the plug form the rib), a press-fit connector (e.g., uses force to press parts together and allows them to be pulled apart with moderate force), a bayonet mount (e.g., uses a simple push-and-twist action to engage, found in camera lenses and lightbulbs), a dove tail joint ( e.g., a mechanical interlock where one piece slides into another with a tail and groove pattern) or an expandable plug fastener (e.g., when inserted into a hole, they expand to lock in place and can be removed by reversing the expansion).

[0070] In another embodiment, each rod holder may be affixed to an outer surface of the outer rib 502A via an adhesive bond. The adhesive bond typically includes a biodegradable adhesive.

[0071] As noted above, FIG. 3C depicts a scaffold 500 that contains a plurality of modules 501A, 502B, 502C,. . .., 502n, and so on, that are held in positions by a plurality of rods 522A, 522B, 522C, 522D, 522E, and 522F that penetrate rod holders 509A, 509B, 509C, 509D, 509E and 509F respectively. The various modules may then be bonded together using a biodegradable adhesive. The biodegradable adhesive prevents the modules from disassociating with each other during installation in the body of a living being around a bone (or other tissue) that may need repair.

[0072] The scaffold of the FIG. 3C may be suturable (can be sutured) around a defective bone at a location proximate to the defect. In another embodiment, the scaffold may be stapled to the defective bone or affixed to the defective bone via a Velcro fixture.

[0073] FIG. 5 depicts one manner of using the scaffold of the FIG. 3C. A bone 602 having a bone defect (e.g., a broken bone in two or more parts) is first aligned with an intramedullary rod 604 or intramedullary nail. This intramedullary rod 604 is inserted into the central cavity of the bone (the medullary canal) to stabilize and align the bone fragments thereby promoting proper healing. A scaffold 500 as seen in the FIG. 3C is then constructed. The rib sizes along with the sizes of the anterior and posterior openings may be selected depending upon the bone size and the bone defect of the particular patient.

[0074] In an embodiment, an adhesive gun (not shown in FIG. 5) may be used to deposit a biodegradable adhesive being applied to various points of contact in each of the modules and in between modules to provide a strong bonded structure to the scaffold. The scaffold 500 is then filled with an injectable biomaterial foam (not shown). After the foam is dried, the scaffold 500 may be disposed around the bone defect.

[0075] A scaffold containment layer 705 is applied to the outer surface of the modules as previously depicted in the FIG. 2B. The scaffold containment layer 705 (of the FIG. 5) functions as a bone graft containment system or a tissue containment system and is designed to keep the bone graft material in place and support the healing process. It serves to hold the graft material and provide structural integrity while allowing for gradual resorption and replacement by natural bone. The scaffold containment layer is detailed above and will not be discussed above in the interests of brevity.

[0076] Material composition for the elements and scaffolds and weld materials depends on the application of interest. Generally, the materials are biocompatible and biodegradable FDA approved polymers. They also may contain some ceramics or metal components incorporated with biologies such as growth factors or drugs such antimicrobial agents, biologically active agents, to help enhancement of the regeneration capacity. Additionally, due to the latticed design of the elements, they can be easily coated with different solutions to enhance tissue regeneration or reduce risk of infection and modify the surfaces as desired. A limitation for choosing the materials for the elements may be the compatibility of the material of choice with the fabrication method and the required resolution. Polycaprolactone, either alone or incorporated and coated with other materials is an example of a suitable base material for these structures.

[0077] The design of each element (rods, brackets, ribs, curved ribs, riblets, linear ribs, and the like disclosed herein) depends on the specific surgery intended. The elements are latticed, thus they will not prevent in-growth of tissue, in case of using them as the scaffolding material, and tissue integration, in case using them as cages for grafts or biomaterials. Generally, each element may have some features (male and female) to connect its adjacent units. Usually, for a given application, all elements have the same or similar overall shape with different dimensions. Yet, for some applications there may be a few different overall shapes. Assemble ability of the elements is an important feature of their design. Another important feature in the design of the elements is flexibility which is the result of design and materials selected. Flexibility is important as it enables necessary deformations to contain biomaterials properly. A degree of flexibility is chosen so as to not sacrifice the structural integrity of one individual element or a set of assembled elements. For example, elements for reconstruction of segmental large bone defects may have a circular shelve shape with an inner mesh, outer mesh and interstitial connecting mesh (please see the attached document for more details and illustrations on this example). The elements for craniomaxillofacial defect application may have some latticed curved plates with different curvature radius to be able to fit various defect contours and fill gaps of any size and shape. The elements selected for soft tissue regeneration applications may include small cylinders with a central canal for nerve conduct and scaffolding latticed space around them for soft tissue support, generally exhibiting more flexibility and connection features for dynamic attachment.

[0078] Connection mechanisms may be active or passive, static or dynamic or requiring some extra accessories. Passive connection between the elements may be a simple feature that makes connection without need of any other components. These connections may be simple male / female insertions or interlocking hooks, and the like. These connections may be weaker than the active ones but much faster, easier to use and also reversable. The active connection between elements may be provided in a way similar to welding. For example, after connecting the adjacent unit cells through a simple temporary passive connection, a handheld 3D printer / extruder device may be used to melt the same or a similar material used to construct the elements, in the connection site and fuse the adjacent -together. The presence of this welding spot in the connection makes it stronger and irreversible.

[0079] The static connection between the elements, are the connection (either passive or active) that does not let the adjacent elements to move relative to each other. This type ofconnection may be used mostly for bone related application. Dynamic connection between the unit cells, are the connections (usually passive) that provide some degree of freedom for relative movement between adjacent elements so the assembled structure will be easily deformable. This type of connection (for example spherical global joints) may be used mostly with soft tissue applications. Some accessories may be needed (mostly with the active connections) to connect the elements properly such as through use of the handheld 3D printer / extruder. These accessories depend on the application and may be temporary holders such that the elements can be placed on to get connected and stay next to each other while the fusing and permanent connection is forming.

[0080] In an embodiment, the ribs, brackets, and modules depicted in the FIGs. 1 A - 5 may have stiffnesses that vary that of an elastomer (e.g., having a Young's modulus or modulus of elasticity of 0.01 to 100 megapascals (MPa) when measured as per ASTM D412) to that of a biodegradable metal (e.g., which have an elastic modulus of 20 to 45 gigapascals (GPa) when measured as per ASTM E8 / E8M). Glassy biodegradable polymers (e.g., having a Young's modulus or modulus of elasticity of 1.8 to 2.4 GPa when measured at room temperature as per ASTM D638) may also be used in the rods, brackets and modules.

[0081] The rods and the brackets used in the cage 102 as well as in the ribs, rod holders and rods used in plurality of modules 104A, 104B, 104C, . . .., (See FIGs. 1A - IE) or in the plurality of modules 502A, 502B,. . .., 502n (See FIGs. 3A - 3C) are preferably manufactured from bioinert, biodegradable and / or biocompatible metals, ceramics, polymers, or a combination thereof. The rods and the brackets used in the cage 102 as well as in the plurality of modules 104A, 104B, 104C, . . .., (See FIGs. 1A - IE) or in the plurality of modules 502A, 502B,...., 502n (See FIGs. 3A - 3C) are preferably manufactured from biodegradable and biocompatible materials.

[0082] Examples of suitable biodegradable and biocompatible metals include titanium, magnesium, magnesium alloys that include zinc, calcium and / or rare earth metals; iron, iron alloys, zinc, zinc alloys, or a combination thereof. Examples of biodegradable and biocompatible ceramic materials include tricalcium phosphate, dicalcium phosphate, octacalcium phosphate, hydroxyapatite, carbonated apatite, or a combination thereof. Examples of suitable biodegradable and biocompatible polymers include naturally derived polymers (alginate, hyaluronic acid, chitosan, heparin, cellulose ethers (e.g. carboxymethyl cellulose, cellulose), elastin, gelatin, starch, carob gum, pectin, guar gum, carrageenan collagen, xanthan gum, fibronectin, elastin, albumin, lignin, glycosaminoglycans, chitin(including nanofibril form), and the like) and synthetic polymers polylactic-glycolic acid (PLGA), poly-caprolactone (PCL), copolymers of polylactic-glycolic acid and polycaprolactone (PCL-PLGA copolymer), polyhydroxy-butyrate-valerate (PHBV), polyorthoester (POE), polyethylene oxide-butylene terephthalate (PEO-PBTP), poly-D,L- lactic acid-p-dioxanone-polyethylene glycol block copolymer (PLA-DX-PEG), or a combination thereof. Hydrogels such as poly(2 -hydroxyethyl methacrylate) (pHEMA), poly- 2- hydroxyethylacrylate (polyHEA), PAAm, poly(N-isopropylacrylamide) (PNIPAAm), poly amines and polyethyleneimines, polyvinyl alcohol, polyacrylamides, polyacrylic acid, polymethacrylic acid, poly(glycerol) sebacate, poly(serinol sebacate), or a combination thereof may also be used.

[0083] In an embodiment, the material used in the ribs of the various cages and modules depicted in the FIGs. 1A - 3C may comprise a biodegradable metal that is coated with a biodegradable polymer or a biodegradable ceramic. In another embodiment, the material used may comprise a biodegradable polymer that is coated with a biodegradable metal or ceramic. By mixing or matching various with biodegradable polymers with biodegradable metals or ceramics the kinetics of degradation can be adjusted to provide for the proper structural support during bone or tissue regeneration.

[0084] In an embodiment, the biodegradable materials comprise ductile polymers, metals or ceramics that can be extended and deformed to accommodate fitting around a bone or around tissue during surgery, but that return back to their original dimensions upon removal of the deforming forces.

[0085] The kit can also contain biodegradable foam that may be used to fill up a volume of the scaffold during or after assembly. The kit can further contain another scaffold, a biodegradable material, a hydrogel, a bone graft material, a tissue piece, a minced tissue, a decellularized tissue, a decellularized extracellular matrix, a powdered bone, a synthetic graft, a cell, an organoid, a cell spheroid, a bio-ceramic powder, a bio-ceramic paste, or a combination thereof that can be used to fill up a volume of the scaffold. In another embodiment, the kit can contain proteins, biological factors, hormones, peptides, antibiotics, antibacterial compounds, bactericidal compounds, fungicides, antifungal drugs, or a combination thereof that may be used to fill up a volume of the scaffold. Some of these materials are detailed below.

[0086] The biodegradable foam used in the scaffold comprises one of the aforementioned biodegradable polymers, metals, ceramics, or a combination thereof.

[0087] Examples of materials suitable for use in fabrication of the scaffold (the adhesive materials and the prefabricated elements such as rods, brackets, ribs, rod holders, and the like) is provided in Table 1.Table 1Materials for Components of Scaffold

[0088] In an embodiment, the biodegradable compositions used in the elements (e.g., rods, brackets, ribs - such as curved ribs, linear ribs, riblets, and so on) disclosed herein may comprise a biodegradable polymer in an amount of 20 to 100 wt%, 30 to 80 wt%, preferably 50 to 70 wt%, based on the total weight of the biodegradable compositions. In an embodiment, the biodegradable compositions used in the elements disclosed herein may comprise a biodegradable ceramic or metal in an amount of 0 to 80 wt%, 20 to 70 wt%, preferably 30 to 50 wt%, based on the total weight of the biodegradable compositions. In an embodiment, the biodegradable polymer comprises polycaprolactone (PCL), while the biodegradable ceramic comprises hydroxyapatite, octacalcium phosphate, carbonated apatite, or a combination thereof.

[0089] In an embodiment, the biodegradable materials used in the module may be modified with suitable biologically active agents. Various types of biologically active agents may be used to coat or may be mixed in with the biodegradable materials. The coatings on the medical device may be used to deliver therapeutic and pharmaceutically biologically active agents including anti-analgesic agents, anti-arrhythmic agents, anti-microbial agents, antibiotics, anti-cholinergic agents, anti -coagulant agents, anti-convulsant agents, antidepressant agents, anti-diabetic agents, anti-diuretic agents, anti-fungal agents, antihypertensive agents, anti-inflammatory agents, anti-malarial agents, anti-neoplastic agents, anti-nootropic agents, anti-Parkinson agents, anti-retroviral agents, anti-tuberculosis agents, anti-tussive agents, anti-ulcerative agents, anti-viral agents, or the like, or a combination thereof.

[0090] Examples of other suitable therapeutic and pharmaceutically biologically active agents are anti-proliferative / antimitotic agents including natural products such as vincaalkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., dactinomycin, actinomycin D, daunorubicin, doxorubicin, penicillin V, penicillin G, ampicillin, amoxicillin, cephalosporin, tetracycline, doxycycline, minocycline, demeclocy cline, erythromycin, aminoglycoside antibiotics, polypeptide antibiotics, nystatin, griseofulvin, and idarubicin), an thracy clines, mitoxantrone, bleomycins, plicamycin, mithramycin and mitomycin, enzymes (L-asparaginase, which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine), antiplatelet agents such as G(GP) Ilb / IIIa inhibitors and vitronectin receptor antagonists, anti-proliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), alkyl sulfonates- busulfan, nitrosoureas (e.g., carmustine (BCNU) and analogs, streptozocin), trazenes— dacarbazinine (DTIC), anti-proliferative / antimitotic antimetabolites such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin and 2- chlorodeoxyadenosine {cladribine}), platinum coordination complexes (e.g., cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, hormones (e.g., estrogen), anti-coagulants (e.g., heparin, synthetic heparin salts and other inhibitors of thrombin), fibrinolytic agents (e.g., tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab, antimigratory, antisecretory (e.g., breveldin), anti-inflammatory: such as adrenocortical steroids (e.g., cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (e.g., salicylic acid derivatives such as aspirin, para- aminophenol derivatives such as acetominophen, indole and indene acetic acids (e.g., indomethacin, sulindac, etodalac), heteroaryl acetic acids (e.g., tolmetin, diclofenac, ketorolac), arylpropionic acids (e.g., ibuprofen and derivatives), anthranilic acids (e.g., mefenamic acid, meclofenamic acid), enolic acids (e.g., piroxicam, tenoxicam, phenylbutazone, oxyphenthatrazone), nabumetone, gold compounds (e.g., auranofin, aurothioglucose, gold sodium thiomalate), immunosuppressives (e.g., cyclosporine, tacrolimus (FK-506), sirolimus (e.g., rapamycin, azathioprine, my cophenolate mofetil), angiogenic agents such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiotensin receptor blockers, nitric oxide donors, anti-sense oligionucleotides and combinations thereof, cell cycle inhibitors, mTORinhibitors, and growth factor receptor signal transduction kinase inhibitors, retenoids, cyclin / CDK inhibitors, HMG co-enzyme reductase inhibitors (statins) or protease inhibitors.

[0091] The biologically active agents may also include cancer inhibitors. Suitable examples of cancer inhibitors are (-)-Ci-Cdpl, (-)-Ci-Cdp2, (-)-epigallocatechin gallate, (+)- Cbi-Cdpi2, (+)-Ci-Cdp2, 10-Deacetylbaccatin lii, 4-demethoxy daunorubicin, 5- azacytidine / 5-aza-2’-deoxycytidine, 5 -fluorouracil, 5 -iminodoxorubicin hydrochloride, 6- mercaptopurine, aclarubicin, acodazole, actinomycin D, adenine phosphate, adenosine, aderbasib, adozelesin; U-73,975, afeletecan, alemtuzumab, alitreninoin, alosetron HC1, alphitolic acid, altretamine, alvespimycin, ambazone, ametantrone, amifostine, aminoglutethimide, amsacrine HC1, amsilarotene, amygdalin, anagrelide, anastrozole, anaxirone, ancitabine, annomontacin, annomuricin A, (C19 / C20-Erythro), annomuricin B, (C10 / Cll,C19 / C20-Erythro), annomuricin C, (All Three) annomuricin E, annonacin, annonacin-10-One, annonacin-A-One, annonidin B, annonin VI, annosquamosin A, annosquamosin B, antramycin, apaziquone, argimesna, aristoforin, arsenic trioxide, artemisinin, ascomycin, asparaginase, atosiban, atrimustine, axitinib, azasetron HC1, azatepa, azathioprine, azotomycin, bafetinib, balamapimod, banoxantrone, batabulin, batimastat, Bbr- 34384, becatecarin, belotecan, benaxibine, bendamustine, benzodepa, berubicin, betulin, betulinic acid, betulinic aldehyde, bevacizumab, bexarotene, bicalutamide, bietaserpine, biricodar, bisantrene. bistramid A; bistratene A, bizelesin, bleomycin, bleomycin A2 [Sulfate], bleomycin A5, bleomycin Sulfate, bortezomib, bosentan, bosutinib, brequinar sodium, brequinar, bropirimine, brostallicin, budotitane, bullatacin, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, calusterone, camptothecin, canertinib, canfosfamide, cantharidin, capecitabine, caracemide, carbetimer, carboplatin, carboprost (carboprost tromethamine), carboquone, carfilzomib, carglumic acid, carmofur, carmustine, carzelesin, cedefingol, cemadotin, cetuximab, cevipabulin, chlorambucil, chlormethine (mechlorethamine), chlorotamoxifen, chlorotrianisene, cioteronel, cisplatin, cladribine, clanfenur, clofarabine, clofazimine, clomifene citrate, cordycepin, corosolic acid, crisnatol, curcumin, cyclocytidine, cyclophosphamide, cytarabine, cytidine, D-aminolevulinic acid, dacarbazine, damsin, daniquidone, danusertib, daporinad, darinaparsin, dasatinib, daunoblastin, daunorubicin / daunomycin, decitabine, deferasirox, deforolimus, demecolcine, denibulin, detorubicin, dexniguldipine, dexormaplatin, dezaguanine, dianhydrodulcitolum, dibrospidium chloride, dienogest, diflomotecan, dinalin, disermolide, docetaxel, dofequidar, dolasetron mesylate, dovitinib, doxifluridine, doxorubicin, dromostanolone, duazomycin,duocarmycin, dynemicin, ecomustine, edatrexate, edotecarin, edotreotide, eflornithine, elacridar, eacytarabine, elesclomol, elinafide, elomotecan, elsamitrucin, emitefur, enloplatin, enocitabine, enpromate, entecavir, entinostat, entricitabine, enzastaurin, epirubicin, eptaloprost, eribulin, erlotinib, Esorubicin, estramustine, etalocib, etanidazole, etoglucid, etoposide, exatecan, exemestane, exisulind, fadrozole, fazarabine, fiacitabine, floxuridine, fludarabine, fluoxymesterone, flurocitabine, flutamide, formestane, forodesine, fosfluridine tidoxil, fosquidone, fostriecin, fotemustine, fotretamine, fulvestrant, fumagillin, galarubicin, galocitabine, gefitinib, gemcitabine, gemtuzumab ozogamicin, geroquinol, gigantetronenin, gigantetroneninone, gimatecan, gimeracil, gloxazone, glufosfamide, goniothalamicin, goniothalamicinone, goserelin, granisetron HC1, gusperimus, hexarelin, homoharringtonine, hydrocamptothecine, hydroxycarbamide, hydroxyurea, hypericin, ibandronate sodium, ibandronic acid, idarubicin HC1, idronoxil, ifosfamide, ilmofosine, imatinib, imatinib mesylate, imexon, improsulfan, incadronate, indibulin, indisulam, inolitazone, inproquone, intiquinatine, intoplicine, iobenguane, irinotecan hydrochloride, irofulven, irsogladine, ispinesib, ixabepilone, ketotrexate, L-alanosine, laniquidar, lapatinib ditosylate, laromustine, larotaxel, ledoxantrone, lenalidomide, lentinan, lestaurtinib, letrozole, leuprolide acetate, leuprorelin, lexacalcitol, liarozole, lobaplatin, lomustine, lonafarnib, lonidamine, losoxantrone, Ly-83583, lysipressin, mafosfamide, mannomustine, mannosulfan, marimastat, marinomycin A, masitinib, maslinic acid, masoprocol, mechlorethamine, medorubicin, megestrol, mepitiostane, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, metomidate, metoprine, meturedepa, miboplatin, midostaurin, mifamurtide, milataxel, miproxifene, miriplatin, misonidazole, mitindomide, mitoflaxone, mitoguazone, mitomycin, mitonafide, mitoquidone, mitotane, mitoxantrone, mitozolomide, mivobulin, mizoribine, mofarotene, mopidamol, motesanib, motexafin, mubritinib, muricapentocin, muricatacin, mustine HC1, mycophenolate mofetil, mycophenolic acid, nedaplatin, nelzarabine, nemorubicin, neocuproine, neptamustine, neratinib, nigericin, nilotinib, nilutamide, nimustine, ninopterin, nitracrine, nogalamycin, nolatrexed, norcantharidine, nordihydroguaiaretic acid, nortopixantrone, novembichin, obatoclax, octreotide, olaparib, oleanolic aldehyde, omacetaxine mepesuccinate, ombrabulin, omtripolide, ondansetron HC1, ortataxel, oteracil, oteracil potassium, oxaliplatin, oxisuran, oxophenarsine, paclitaxel ceribate, palifosfamide, palonosetron, pamidronate disodium, pamidronic acid, panitumumab, panobinostat, patubilone, pazelliptine, pazopanib, pegaspargase, peldesine, pelitinib, pelitrexol, pemetrexed disodium, pentostatin, peplomycin, peretinoin, perfosfamide,perifosine, pibrozelesin hydrobromide, picoplatin, pinafide, piposulfan, pirarubicin, pirfenidone, piritrexim, piroxantrone, pixantrone, plevitrexed, plicamycin, plitidepsin, plomestane, podophyllotoxin, pomalidomide, porfimer sodium, pralatrexate, prinomastat, procarbazine HC1, propamidine, prospidium chloride, pumitepa, puromycin, pyrazofurin, ouarfloxin, raltegravir, raltitrexed, ramosetron HC1, ranimustine, retaspimycin, retelliptine, riboprine, ritrosulfan, rituximab, roflumilast, romidepsin, ropidoxuridine, roquinimex, rosabulin, rubitecan, sabarubicin, safingol, salirasib, sapacitabine, saracatinib, sardomozide, satraplatin, sebriplatin, seliciclib, semaxanib; SU-5416, semustine, sermorelin, simotaxel, simtrazene, sitagliptin, sizofiran, soblitodin, sobuzoxane, sodium phenylbutyrate, sorafenib, sparfosic acid, sparsomycin, spiroplatin, squalamine, squamocin, streptonigrin, streptovarycin, streptozocin, sufosfamide, sulofenur, sunitinib, swainsonine, tacedinaline, tafluposide, talabostat, talisomycin, tallimustine, talotrexin, taltobulin, tamoxifen citrate, tandutinib, tanespimycin, tariquidar, tasidotin, tasisulam, tauromustine, tegafur, tegafur- uracil, telantinib, teloxantrone, temozolomide, teniposide, tenuazonic acid, terameprocol, teriparatide, tesetaxel, testolactone, tezacitabine, thiamiprine, thioguanine, thiotepa, thymopoietin, tiazofurine, tilomisole, tilorone, timcodar, timonacic, tioguanine, tirapazamine, tocladesine, tomudex, topotecan hydrochloride, toremifene citrate, tosedostat, tositumomab, toxipantrone, trastuzumab, trenimon, tretinoin, triciribine, trilostane, trimetrexate, triplatin tetranitrate, triptolide, triptorelin, trofosfamide, tropisetron HC1, tubulozole, tylophorin, U- 67786, U-68415, U-71184, U-76074, U-78057, ubenimex, uramustine, uredepa, urethane, uridine, ursolic acid, ursolic aldehyde, vadimezan, valrubicin, valspodar, vandetanib, vapreotide, vatalanib; PTK-787, verteporfin, vildagliptin, vinblastine sulfate, vincristine, vindesine, vinepidine, vinflunine, vinformide, vinfosiltine, vinleucinol, vinleurosine, vinorelbine [base], vinorelbine tartrate, vintriptol, vinzolidine, voriconazole, vorinostat, vorozole, wilforlide A, xanthomycin A, zalcitabine, zeniplatin, zilascorb, zinostatin, zoledronic acid, zorubicin, zosuquidar, or the like, or a combination comprising at least one of the foregoing cancer inhibitors.

[0092] In some embodiments, in one method of using the scaffolds disclosed herein, a surgical team may be supplied with a series of prefabricated elements from which to choose. Accordingly, the surgical team may select from, for example, elements of varying diameters. The elements of varying diameters may be adapted for mating with similar elements of a greater or smaller diameter in order to accommodate changes in the physical profile of the native tissue.

[0093] A manufacturer may supply the series of elements as a custom kit. The custom kit may be developed by diagnostic data, such as initial imaging of the patient. The custom kit may include a limited set of elements such that likely adaptations as may be needed during a surgical procedure are easily accommodated.

[0094] Generally, the elements are fabricated remotely from the point-of care, then assembled during therapy. The elements may exhibit different geometries and may be used for fabrication of scaffolds that fixes or holds other scaffolding materials. The elements may have different compositions to enable the formation of different tissues and their interfaces or can be made from the same composition. The junction between elements can be firm and static to generate fixed structures or swivel and dynamic to generate flexible structures. The materials can be flexible or rigid to generate different physical properties. In the case of holder, the constructs can be used as a graft or biomaterial containment system. Such structures can be used on demand and in situ, for putting graft biomaterials for the treatment of different injuries with any size and shape. This system is composed of small pre-fabricated latticed units with different dimensions. The elements can be assembled to form graft cages of any desired height or size.

[0095] Users of the technology include surgeons, such as orthopedic or plastic surgeons. Use may be in-situ, during the surgery, either to contain grafts or biomaterials in place or as a standalone scaffolding material. The scaffold may act as a graft or biomaterials containment system, and may be used along with commercially available grafts, autografts or biomaterials.

[0096] Methods enable use of bone graft powders for segmental large bone defects without requiring multiple complex surgeries. The technology is designed be assembled into different shape and sizes (according to the defect) in situ during the surgery, as needed, so it bypasses the need for the length process of ordering, imaging, design, fabrication and delivery of other technologies, thus eliminating the risk of graft mismatch or damage since it is composed of pre-fabricated units and lots of them can be available in a kit in the surgery room.

[0097] Advantageously, the technology can be applied in the operating room without requiring any pre-imaging, design and fabrication, and provides optimal containment of grafts or biomaterials in place during the healing process, for defects of any shape and size. It provides patient-specific and complex scaffolding structures fitting any defect contour and is compatible with any defect shape and size without any lag time for design, and fabrication.It reduces the need for multiple complex surgeries for treatment of complex or large defects. It is composed of a biocompatible and biodegradable biomaterial so required no secondary surgery for removal. It can be used in conjunctions with standard of care and can be incorporated with any tissue specific biomaterials in its material that helps the process of regeneration, for example Ossteo inductive biomaterials. In case of bone defects, it can be used along with common fixation systems so will bear no mechanical loading and is only used to contain graft material in place. It is an assemble able system so the same kit of shelves can be use for defects with deferent size and shape (but the same type of surgery) and there is no need for ordering, imaging and design for every single use. It can be assembled in situ by surgeons into any shape and size; so, it provides patient-specific structures. It is composed of pre-fabricated latticed units, so it can be always ready to use as needed without requiring any wait time.

[0098] All statements herein reciting principles, aspects, and embodiments of the disclosure, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure.

[0099] Various other components may be included and called upon for providing for aspects of the teachings herein. For example, additional materials, combinations of materials and / or omission of materials may be used to provide for added embodiments that are within the scope of the teachings herein. Adequacy of any particular element for practice of the teachings herein is to be judged from the perspective of a designer, manufacturer, seller, user, system operator or other similarly interested party, and such limitations are to be perceived according to the standards of the interested party.

[0100] In the disclosure hereof any element expressed as a means for performing a specified function is intended to encompass any way of performing that function including, for example, a) a combination of circuit elements and associated hardware which perform that function or b) software in any form, including, therefore, firmware, microcode or the like as set forth herein, combined with appropriate circuitry for executing that software to perform the function. Applicants thus regard any means which can provide those functionalities as equivalent to those shown herein. No functional language used in claims appended herein is to be construed as invoking 35 U.S.C. § 112(f) interpretations as “means-plus-function”language unless specifically expressed as such by use of the words “means for” or “steps for” within the respective claim.

[0101] When introducing elements of the present invention or the embodiment(s) thereof, the articles “a,” “an,” and “the” are intended to mean that there are one or more of the elements. Similarly, the adjective “another,” when used to introduce an element, is intended to mean one or more elements. The terms “including” and “having” are intended to be inclusive such that there may be additional elements other than the listed elements. The term “exemplary” is not intended to be construed as a superlative example but merely one of many possible examples.

[0102] While the invention has been described with reference to some embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A kit for manufacturing a scaffold for repairing tissue in a living being, the kit comprising: a structural reinforcing element; where the structural reinforcing element is selected from i) at least one rod; or ii) a plurality of rods and brackets that are operative to be assembled into a cage; a plurality of module elements that can be assembled to form at least one module; where the module upon assembly contacts the structural reinforcing element; wherein the plurality of module elements comprises: a plurality of curved ribs of different sizes that extend concentrically in a first direction when assembled; where an outermost curved rib of the module is designed to communicate with the structural reinforcing element when assembled into the module; wherein an innermost curved rib is operative to be in a cantilevered arrangement with the outermost rib when assembled into the module; and wherein the innermost rib is operative to clamp the tissue being repaired; and a spacing element that is operative to contact the plurality of curved ribs when assembled; where the spacing element extends in a second direction that is inclined at an angle to the first direction, where the spacing element is operative to keep successive neighboring modules apart from one another.

2. The kit of Claim 1, where the kit comprises a plurality of module elements that are assembled to form a plurality of modules that forms a scaffold to provide support for a containment layer of up to 15 centimeters in length.

3. The kit of Claim 1, further comprising a rod holder that contacts an outer surface of the outermost curved rib when assembled; where the rod holder comprises a hole that accommodates the at least one rod.

4. The kit of Claim 1, where each rod holder comprises a spacing element that emanates from the hole and extends in the second direction from the rod holder.

5. The kit of Claim 1, further comprising a plurality of structural reinforcing elements, a plurality of module elements and a plurality of spacing elements, where at least some of the plurality of structural reinforcing elements, some of the plurality of module elements and some of the plurality of spacing elements are of different sizes and differentbiodegradable materials from the remainder of each of the pluralities and are tailorable to a patient’s needs.

6. The kit of Claim 1, where the first direction is inclined to the second direction at an angle of 70 to 110 degrees.

7. The kit of Claim 1, where the spacing element further comprises a circular rib and one or more linear ribs that form a porous tubular clamp when assembled and extends from the innermost curved rib.

8. The kit of Claim 1, where the innermost curved rib further comprises two opposing curved ribs each of which are operative to function as a snap ring.

9. The kit of Claim 1, where each curved rib of the plurality of curved ribs functions as a snap ring and where the innermost curved rib is in a cantilever arrangement with the outermost curved rib.

10. The kit of Claim 1, where at least one of the structural reinforcing element, the plurality of module elements and the spacing element comprise a biodegradable material.

11. The kit of Claim 10, where the biodegradable material comprises a biodegradable polymer, a biodegradable metal, a biodegradable ceramic, or a combination thereof.

12. The kit of Claim 10, where the biodegradable material comprises a biodegradable polymer in an amount of 20 to 100 wt%, and a biodegradable ceramic or biodegradable metal in an amount of 0 to 80 wt%, based on a total weight of the biodegradable material.

13. The kit of Claim 12, where the biodegradable polymer comprises poly caprolactone, and where biodegradable ceramic comprises hydroxyapatite, octacalcium phosphate, carbonated apatite, or a combination thereof.

14. The kit of Claim 10, where the biodegradable material further comprises antianalgesic agents, anti-arrhythmic agents, anti-microbial agents, antibiotics, anti-cholinergic agents, anti-coagulant agents, anti-convulsant agents, anti-depressant agents, anti-diabetic agents, anti-diuretic agents, anti-fungal agents, anti-hypertensive agents, anti-inflammatory agents, anti-malarial agents, anti-neoplastic agents, anti-nootropic agents, anti-Parkinson agents, anti-retroviral agents, anti-tuberculosis agents, anti-tussive agents, anti-ulcerative agents, anti-viral agents, or a combination thereof.

15. A scaffold for repairing tissue in a living being, the scaffold comprising: a structural reinforcing element; andat least one module adapted for use in operative communication with the structural reinforcing element; wherein the at least one module comprises: curved ribs of different sizes that extend concentrically in a first direction when assembled; where an outermost curved rib of the module is in operative communication with the structural reinforcing element; wherein an innermost curved rib is operative to be in a cantilevered arrangement with the outermost rib; and wherein the innermost rib is operative to clamp the tissue being repaired; and a spacing element that is operative to contact the plurality7of curved ribs; where the spacing element extends in a second direction that is inclined at an angle to the first direction, where the spacing element is operative to keep successive neighboring modules apart from one another.

16. A method of repairing tissue in a living being, the method comprising: selecting an element from a kit and assembling the elements to form a scaffold comprising, the kit comprising: a structural reinforcing element; and at least one module adapted for use in operative communication with the structural reinforcing element; wherein the at least one module comprises: a plurality of curved ribs that extend concentrically in a first direction when assembled; where an outermost curved rib of the module is in operative communication with the structural reinforcing element; wherein an innermost curved rib is operative to clamp the tissue being repaired; and a spacing element that is in operative communication with at least one of the plurality of curved ribs; where the spacing element extends in a second direction that is different from the first direction, where the spacing element is operative to keep successive neighboring modules of the plurality of modules apart from one another; and assembling the plurality of elements in the living being to effect a repair of the tissue.

17. The method of Claim 16, where further comprising disposing the structural reinforcing element in a rod holder that is located on an outer surface of the outermost curved rib; where the structural reinforcing element is a rod.

18. The method of Claim 16, further comprising adhesively bonding the at least one structural reinforcing element to the at least one module with a biodegradable adhesive.

19. The method of Claim 16, further comprising disposing a biodegradable foam between the outermost curved rib and the innermost curved rib.

20. The method of Claim 16, further comprising disposing a containment layer between the scaffold and a tissue that is to be repaired; where the scaffold is operative to provide support for a containment layer of up to 15 centimeters in length.

21. The method of Claim 16, further comprising filling up a volume of the scaffold with another scaffold, a biodegradable material, a hydrogel, a bone graft material, a tissue piece, a minced tissue, a decellularized tissue, a decellularized extracellular matrix, a powdered bone, a synthetic graft, a cell, an organoid, a cell spheroid, a bio-ceramic powder, a bio-ceramic paste, or a combination thereof.

22. The method of Claim 16, further comprising filling up a volume of the scaffold with proteins, biological factors, hormones, peptides, antibiotics, antibacterial compounds, bactericidal compounds, fungicides, antifungal drugs, or a combination thereof.

23. The method of Claim 16, further comprising gluing, welding, fusing via use of a solvent or thermally fusing together the elements to bond them to one another to form the scaffold.

24. The method of Claim 16, where the innermost rib is operative to clamp an intramedullary nail as a fixation system for segmental bone defects.

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