Citrate-based constructs for the repair of osteochondral defects

Abstract

The present disclosure provides a citrate-based structure for use in the repair of osteochondral defects. The structure generally includes (i) a citrate component, (ii) a diol component, (iii) a polyol, and (iv) a particulate inorganic material. The scaffold may take the form of a 50-90% porous scaffold and may form a polymer network. The scaffold may be immersed in a hyaluronic acid solution and lyophilized to generate a porous structure within the pores of the scaffold. The scaffold may be biphasic, containing a porous portion for regenerating subchondral bone tissue and a citrate-based polymer hydrogel for regenerating cartilage tissue. The scaffold may form an implant, and the implant may include a porous core within a biphasic core-shell structure.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 435,375, filed December 27, 2022, and entitled "Citrate-Based Constructs for Repair of Osteochondral Defects." The entire contents of the prior U.S. provisional application are incorporated herein by reference.

[0002] background 1.Technical Field The present disclosure refers to citrate-based structures for use in the repair of osteochondral defects. [Background technology]

[0003] 2.Background technology Joint surface lesions (JSLs) involving articular cartilage and subchondral bone are clinically significant in orthopedic surgery, affecting approximately 600,000 patients annually, accounting for approximately 20% of all reported arthroscopic procedures. JSLs can be superficial, partial-thickness cartilage defects, or full-thickness lesions, respectively, spanning the osteochondral junction without affecting the subchondral bone. JSLs remain a major clinical challenge due to the poor self-healing ability of articular cartilage. If left untreated, JSLs can lead to secondary osteoarthritis (OA). Therefore, symptomatic chronic full-thickness defects in the knee joint surface require intervention to alleviate symptoms and potentially prevent progression to OA.

[0004] A study on the natural history and outcome of JSL in advanced OA joints documented cartilage damage in a cohort of patients with osteoarthritis, in which cartilage damage worsened in 81% of cases and improved in only 4% over a 2-year period (Davies-Tuck, M. L., Wluka, A. E., Wang, Y., Teichtahl, A. J., Jones, G., Ding, C., Cicuttini, F. M., The natural history of cartilage defects in people with knee osteoarthritis, Osteoarthritis and Cartilage, Vol. 16, No. 3, 2007, pp. 337-342). In a similar prospective study, the presence of cartilage defects in patients with advanced symptomatic OA was associated with disease severity and was a predictor of joint replacement within 4 years (Wluka, A.E., Ding, C., Jones, G., Cicuttini, F.M. The clinical correlates of articular cartilage defects in symptomatic knee osteoarthritis: A prospective study, Rheumatology, Vol. 44, No. 10, 2005, pp. 1311-1316). Summary of the Invention [Problem to be solved by the invention]

[0005] In summary, JSL can exacerbate and accelerate the progression of OA. Therefore, treating JSL can be of significant benefit to patients, and there is a need for effective treatment modalities. [Means for solving the problem]

[0006] The present disclosure refers to synthetic implants / constructs designed to treat articular surface damage. The disclosed biodegradable constructs comprise citrate-based biomaterials that advantageously promote the regeneration of articular cartilage and subchondral bone tissue.

[0007] Citrate is an essential molecule in bone anatomy and physiology, playing an essential role in mineral formation and bone metabolism regulation. In biomaterial design, the functional groups of citrate-based polymers present chemical functional groups for bioceramic interactions, can be reacted according to the present disclosure to extend release rates, can be used as conjugation sites for peptide addition, and cross-linking sites to create elastomeric properties that enhance tissue regeneration.

[0008] Additional properties, features, and advantages of the disclosed scaffolds may become apparent from the following description. [Brief explanation of the drawings]

[0009] To assist those skilled in the art in making and using the subject matter of the present disclosure, reference is made to the accompanying drawings. [Figure 1] Figure 1 shows the pH of Dulbecco's Modified Eagle's Medium (DMEM) extracts after 72 hours of leaching of poly(octamethylene citrate) (POC) containing bioglass according to the ISO 10993 standard. [Figure 2] FIG. 2 depicts the proliferation of primary chondrocytes on poly(octamethylene citrate) (POC) scaffolds containing bioglass compared to tissue culture plate controls. [Figure 3] FIG. 3 depicts a graphical representation of a porous citrate-based scaffold being immersed in a hyaluronic acid solution. [Figure 4] FIG. 4 shows a scanning electron microscope image of porous hyaluronic acid structures within the pores of a citrate-based scaffold after freeze-drying. [Figure 5A]5A-C show graphical representations of porous citrate-based scaffolds inserted into solid citrate-based composite cores with 30-70% fenestration to form core-shell structures. [Figure 5B] 5A-C show graphical representations of porous citrate-based scaffolds inserted into solid citrate-based composite cores with 30-70% fenestration to form core-shell structures. [Figure 5C] 5A-C show graphical representations of porous citrate-based scaffolds inserted into solid citrate-based composite cores with 30-70% fenestration to form core-shell structures. [Figure 6A] 6A-B show a graphical representation of a porous citrate-based mesh on the cartilage side of a core-shell construct. [Figure 6B] 6A-B show a graphical representation of a porous citrate-based mesh on the cartilage side of a core-shell construct. [Figure 7A] 7A-C depict graphical representations of solid citrate-based composite structures with variable diameter geometries. [Figure 7B] 7A-C depict graphical representations of solid citrate-based composite structures with variable diameter geometries. [Figure 7C] 7A-C depict graphical representations of solid citrate-based composite structures with variable diameter geometries. [Figure 8] FIG. 8 depicts the proliferation of primary bovine chondrocytes on poly(octamethylene xylitol citrate) (POXC) scaffolds containing 60 wt% tricalcium phosphate (TCP) and increasing concentrations of bioglass compared to tissue culture plate controls. [Figure 9] FIG. 9 depicts a biphasic citrate-based construct containing a porous citrate-based scaffold portion for subchondral bone tissue regeneration and a citrate-based hydrogel for cartilage tissue regeneration. [Figure 10]FIG. 10 depicts peptides conjugated to the surface of a porous citrate-based scaffold. [Figure 11A] 11A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 11B] 11A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 11C] 11A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 12A] 12A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 12B] 12A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 12C] 12A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 13A] 13A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 13B] 13A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 13C] 13A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 14A] 14A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 14B] 14A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 14C] 14A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 15A] 15A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 15B] 15A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 15C] 15A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 16A] 16A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 16B] 16A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 16C] 16A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 17A] 17A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 17B] 17A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 17C] 17A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 18A] 18A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 18B] 18A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. [Figure 18C] 18A-C depict graphical representations of solid citrate-based composite structures with alternative variable diameter geometries. DETAILED DESCRIPTION OF THE INVENTION

[0010] Description of Exemplary Embodiments The present disclosure provides advantageous citrate-based structures for use in the repair of osteochondral defects. According to exemplary embodiments, the disclosed structures include (i) a citrate component, (ii) a diol component, (iii) a polyol, and (iv) a particulate inorganic material. In exemplary embodiments, the citrate component may be selected from the group consisting of citric acid, citrate salts, and / or esters of citric acid. In exemplary embodiments, the diol may include butanediol, hexanediol, octanediol, or polyethyleneglycerol. In exemplary embodiments, the polyol may include glycerol, β-glycerol phosphate, and / or xylitol. In forming the disclosed structures, the citrate, diol, and polyol components may form a polymer. Particulate inorganic materials may be added to create composite structures. In exemplary embodiments, the structures may be fabricated into porous scaffolds to facilitate cell migration, nutrient delivery, and waste removal for tissue regeneration.

[0011] The disclosed structures can include particulate inorganic material in an amount of 0-60% by weight. In exemplary embodiments, the particulate inorganic material can include one or more of hydroxyapatite, tricalcium phosphate, biphasic calcium phosphate, and bioglass (BG). BG45S5 is one bioceramic that can be utilized in accordance with the present disclosure to increase primary chondrocyte cell proliferation, glycosaminoglycan production, and scaffold resorption. BG is composed of 43-47% silica, 22.5-26.5% calcium oxide, 5-7% diphosphorus pentoxide, and 22.5-26.5% sodium oxide (Safety Data Sheet - mo-SCI Corporation (n.d.). Retrieved May 13, 2022, from mo-sci.com / wp-content / uploads / product-docs / biomaterials / GL0811-SDS.pdf).

[0012] To evaluate the properties and benefits of the disclosed constructs, citrate-based polymers (including poly(octamethylene citrate) (POC)) were combined with 0-40 wt% BG and 92 wt% sodium chloride to form porous scaffolds. BG can exchange its anions with hydrogen ions in solution, thereby increasing the pH of the surrounding solution and buffering the acidity of the POC polymer in solution. As shown in Figure 1, increasing the BG concentration in the POC scaffolds increased the alkalinity of the cell culture extraction medium.

[0013] Increasing BG concentration has been shown to increase primary chondrocyte proliferation. Figure 2 shows the proliferation of primary bovine chondrocytes on POC scaffolds composited with 0-40 wt% BG over a 7-day period. POC scaffolds containing 20 wt% or more BG enabled significantly greater chondrocyte proliferation at day 7 compared to tissue culture plate controls.

[0014] The bioceramic may also be micro- or nano-sized. In an exemplary embodiment, the bioceramic may be rod-shaped.

[0015] In the exemplary embodiment, the scaffold 11 defines a biodegradable scaffold. The scaffold 11 may be immersed in a hyaluronic acid solution 13, for example, as depicted schematically in FIG.

[0016] In an exemplary embodiment, the scaffold soaked in hyaluronic acid can be freeze-dried to produce a porous hyaluronic acid structure within the pores of the scaffold, as depicted, for example, in the scanning electron microscope image of FIG.

[0017] The disclosed structures may advantageously define a porous inner core scaffold 11 of a biphasic core-shell structure 10, for example, as depicted schematically in Figure 5A. As seen in Figures 5A-C, the outer shell 15 may be perforated by circular perforations 17, elongated slots 19, and / or other shaped holes to allow access to the porous inner core scaffold 11 or to provide properties to support the ingrowth of individual cells.

[0018] In an exemplary embodiment, the outer shell 15 may be open at one end, for example, as depicted schematically in FIG. 5A. In further exemplary embodiments, the outer shell 15 may completely enclose a porous inner core scaffold 11, for example, as depicted schematically in FIGS. 5B-C, and / or may be made of two or more pieces, for example, as depicted schematically in FIG. 5C. The outer shell 15 may include a first portion 21 and a second portion 23 connected by a seam 25. In an exemplary embodiment, a circular perforation 17, elongated slot 19, or other hole may span the seam 25 in the outer shell 15, for example, as depicted schematically in FIG. 5C.

[0019] 5A-C, the disclosed structures may also advantageously define a porous inner core scaffold of a biphasic core-shell structure, as illustrated, for example, in FIG. 6A, and a porous mesh 31 on the cartilage side of the shell structure. The porous mesh 31 on the cartilage side may be fabricated using particulate leaching or 3D printing techniques. It is understood that the porous mesh 31 may be used in addition to any of the shell structures disclosed herein.

[0020] The porous mesh 31 may be made from multiple fibers or layers of fibers such that the porous mesh 31 is generally porous, for example, 50-90% porous. Each fiber that makes up the porous mesh 31 is itself porous, which can increase the porosity (porosity) of the porous mesh 31 or allow the fibers to be closer together without decreasing the porosity of the porous mesh 31.

[0021] In an exemplary embodiment, porous mesh 31 may be used in place of, or in addition to, circular perforations 17, elongated slots 19, or other holes on outer shell 15 to promote chondrocyte infiltration and growth factor binding. Porous mesh 31 may be soaked in a hyaluronic acid solution.

[0022] In an exemplary embodiment, the porous mesh 31 may be used independently, for example, as depicted schematically in Figure 6B. The porous mesh 31 may be initially connected to the surface of the subchondral bone tissue via, but not limited to, fibrin glue, sutures, chemical bonding, or other conditions or adhesive substances without breaching the bone surface.

[0023] The disclosed structures can take a variety of solid forms, e.g., forms / shapes other than a single-diameter cylinder. For example, the disclosed structure 40 can feature regions defining different diameters 41, 43, 45, 47, e.g., structures with decreasing diameters moving away from the articular surface 49. These through-shafts of subchondral bone tissue can be fenestrated to allow for the integration of new bone growth. These fenestrations can take various forms, e.g., holes and / or slots 51, and can vary in size, e.g., from 0.5 mm to 2.0 mm.

[0024] For example, as depicted in Figures 5-7, the shell structure can comprise, for example, 40-65 wt% bioceramic, or a citrate-based composite containing, for example, 50-65 wt% bioceramic. To evaluate the benefits of this embodiment of the disclosed device, citrate-based polymers (including POC with xylitol additive (POXC)) were combined with additives of 60 wt% β-tricalcium phosphate (TCP) and 0-15 wt% BG. The proliferation of primary bovine chondrocytes was evaluated on these composite formulations. As depicted in Figure 8, the proliferation of these cells increased with increasing amounts of BG.

[0025] In an exemplary embodiment, the disclosed scaffold 90 may be biphasic, containing a porous portion 91 for regenerating subchondral bone tissue and a citrate-based hydrogel 93 for regenerating cartilage tissue, as depicted in Figure 9. Additionally, the citrate-based hydrogel 93 may be blended with, for example, hyaluronic acid 95.

[0026] Peptides 105 may be conjugated to the surface 103 of the citrate-based scaffold 101. In an exemplary embodiment, a heparin-binding peptide or a mimetic peptide of transforming growth factor beta may be conjugated to the surface 103 of the citrate-based scaffold 101, for example, as depicted schematically in Figure 10. A solution of growth factors may also be absorbed into the citrate-based scaffold 101.

[0027] Referring now to Figures 11-18, eight exemplary embodiments of solid citrate-based composite structures having alternative shapes are depicted. The citrate-based composite structure 100 may be machined, extruded, molded, or printed using 3D printing techniques, but is not limited to these. The composite structure 100 may have a head 101 having a cartilage-facing side 103. The head 101 may be a single-diameter cylinder or may have other shapes, such as, but not limited to, an ellipse, an oval, or a truncated cone. In exemplary embodiments, the head 101 may be tapered along its axial length such that the cartilage-facing side 103 is larger than the opposing side of the head 101, for example, as depicted in Figures 11-15 and 17-18. This taper may allow for a press seal that fits the user, thereby forcing the tapered head 101 into a void in the user's bone. In one embodiment, the head 101 may taper at an angle of 6-10 degrees. In an alternative embodiment, the head 101 may taper at an angle of 0-15 degrees.

[0028] The cartilage-facing side 103 can be horizontal, convex, or concave. In an exemplary embodiment, the cartilage-facing side 103 can be convex to match the surrounding cartilage structure, for example, as depicted in Figures 17A-C. In further exemplary embodiments, the cartilage-facing side 103 can be horizontal or concave and can include additional structures, such as, but not limited to, a porous mesh 31 or a citrate-based hydrogel 93.

[0029] The composite structure 100 may also have a post or pin 105 extending from the head 101 opposite the cartilage-contacting side 103. The pin 105 may be supported by a plurality of fins 107. In an exemplary embodiment, there may be three or four fins 107, although it will be appreciated that any number of fins 107 (including zero) suitable for supporting the pin 105 and / or providing additional contact surface area for the composite structure 100 may be present.

[0030] In the exemplary embodiments illustrated in FIGS. 11-18 , pins 105 and fins 107 of various diameters, shapes, numbers, and orientations are depicted. It is understood that any element or configuration of each pin 105 and fin 107 illustrated in FIGS. 11-18 may alternatively and / or additionally be used with any other element or configuration to achieve various desired effects, including, but not limited to, those described above. For example, pins 105 with smaller diameters may be desired because they may require only a small amount of the user's bone to be removed to insert the composite structure 100. Alternatively, pins 105 with larger diameters may be desired because they may provide greater structural stability. As a further example, more or fewer fins 107 with various shapes may be desired to support pins 105 of different diameters and / or to provide larger or smaller contact surface areas.

[0031] Additionally, the edges and joints of the composite structure 100 may be, but are not limited to, straight cut, rounded, chamfered, or beveled. These edges may provide a better fit of the composite structure 100 in the user or may be used to increase manufacturing efficiency / reduce costs. For example, a particular edge finish on the fins 107 may tend to be more or less milled depending on the shape of the fins 107 or the radial angle between adjacent fins 107.

[0032] In an exemplary embodiment, the pins 105 or fins 107 may include notches 109, as shown, for example, in Figures 18A-C. The notches 109 may be filled with or coated with a growth factor solution to promote ingrowth and adhesion between the composite structure 100 and the user's bone.

[0033] An additional consideration is that composite structure 100, including certain head 101, cartilage-facing side 103, pins 105, fins 107, and incisions 109 configurations, may be inefficient or expensive to manufacture or may be difficult or impossible to achieve using certain manufacturing processes, i.e., machining or 3D printing. For example, pins 105 with smaller diameters are more likely to break during the manufacturing process, and the addition of additional fins 107 reduces the radius angle between adjacent fins 107, making machining more difficult.

[0034] 11-18 are solid, it is understood that the composite structure 100 may be hollow and may include scaffolds or other structures similar to those discussed with respect to Figures 3, 5, 9, and 10. Additionally, the cartilage-facing side 103, pins 105, and fins 107 may have circular perforations, elongated slots, and / or other shaped holes to allow access to internal structures or to provide properties that support the ingrowth of individual cells.

[0035] The disclosed scaffolds are generally porous, e.g., 50-90% porous. The scaffolds may contain / define a gradient or biphasic porosity structure with two different pore size ranges. The disclosed scaffolds may be conformable and, in exemplary embodiments, may be cut in an operating room.

[0036] The disclosed scaffolds can swell in liquid, for example, the disclosed scaffolds can swell up to 500%-1500% in liquid. The disclosed scaffolds generally fully degrade within 6-15 months.

[0037] It is understood that the various exemplary embodiments and components thereof discussed herein may be used in combination, alternatively, and / or additionally with other exemplary embodiments and components thereof, respectively.

[0038] While the present disclosure has been described with reference to exemplary embodiments and implementations, the present disclosure is not limited by or to such exemplary embodiments / implementations.

[0039] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. It can be further understood that the terms "comprise" and / or "comprising," when used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0040] While the present disclosure has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various modifications may be made and equivalents may be substituted for elements thereof without departing from the scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the present disclosure without departing from the essential scope of the present disclosure. Therefore, it is intended that the present disclosure not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this disclosure, but that the present disclosure may include all embodiments falling within the scope of the appended claims.

Claims

1. a. Citrate component, b. a diol component; c. polyol, and d. Granular inorganic material 1. A construct for use in repairing osteochondral defects, comprising:

2. 10. The method of claim 1, wherein the citrate component is selected from the group consisting of citric acid, citrate salts, or esters of citric acid.

3. 10. The structure of claim 1, wherein the diol comprises butanediol, hexanediol, octanediol, or polyethyleneglycerol.

4. 10. The method of claim 1, wherein the polyol comprises glycerol, β-glycerol phosphate, or xylitol.

5. 10. The structure of claim 1, wherein the particulate inorganic material comprises one or more of hydroxyapatite, tricalcium phosphate, biphasic calcium phosphate, and bioglass.

6. 6. The structure of claim 5, wherein the bioceramic is in the form of a rod.

7. 10. The structure of claim 1, wherein the citrate, diol, and polyol components form a polymer.

8. A scaffold formed from the structure of any one of claims 1 to 7.

9. 9. The scaffold of claim 8, wherein the scaffold is a 50-90% porous scaffold.

10. 10. The scaffold of claim 8, wherein the scaffold is a polymer network.

11. 10. The scaffold of claim 8, wherein the scaffold comprises a biodegradable scaffold.

12. 9. The scaffold of claim 8, wherein the scaffold is immersed in a hyaluronic acid solution.

13. 10. The scaffold of claim 8, wherein the scaffold is freeze-dried to create a porous structure within the pores of the scaffold.

14. 9. The scaffold of claim 8, wherein the bioceramic is present in an amount of 10 to 50 weight percent.

15. 9. The scaffold of claim 8, wherein the bioceramic is micro- or nano-sized.

16. 9. The scaffold of claim 8, wherein a peptide is conjugated to the surface of the citrate-based scaffold.

17. 10. The scaffold of claim 8, wherein a growth factor solution is absorbed onto the citrate-based scaffold.

18. 9. The scaffold of claim 8, wherein the scaffold is biphasic, containing a porous portion for regenerating subchondral bone tissue and a hydrogel of a citrate-based polymer for regenerating cartilage tissue.

19. 20. The scaffold of claim 18, wherein the citrate-based hydrogel is blended with hyaluronic acid.

20. 9. The scaffold of claim 8, wherein a heparin-binding peptide is conjugated to the surface of the citrate-based hydrogel.

21. 9. The scaffold of claim 8, wherein a transforming growth factor beta mimetic peptide is conjugated to the surface of the citrate-based hydrogel.

22. 10. The scaffold of claim 8, wherein the scaffold comprises a gradient porosity structure.

23. 10. The scaffold of claim 8, wherein the scaffold is malleable.

24. 10. The scaffold of claim 8, wherein the scaffold is cuttable in an operating room.

25. 9. The scaffold of claim 8, wherein the scaffold is capable of expanding in a liquid by 500 to 1500%.

26. 9. The scaffold of claim 8, wherein the scaffold completely degrades between 6 and 15 months.

27. An implant formed from the structure of any one of claims 1 to 7.

28. 28. The implant of claim 27, wherein the implant comprises an inner porous core of a biphasic core-shell structure.

29. 29. The implant of claim 28, wherein the shell structure comprises a citrate-based composite containing 40-65% by weight bioceramic or 50-65% by weight bioceramic.

30. 28. The implant of claim 27, wherein the implant comprises an inner porous core, a solid outer shell, and a porous component on the cartilage side of the implant.

31. 28. The implant of claim 27, wherein the implant comprises a solid component for the subchondral side and a porous component on the cartilage side of the implant.

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