Citric acid-based constructs for osteochondral defect repair

Abstract

The present disclosure provides citric acid-based constructs for repairing osteochondral defects. The constructs generally include (i) a citric acid 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 soaked in a hyaluronic acid solution and may be freeze-dried to create a porous construct within the pores of the scaffold. The scaffold may be biphasic containing a porous portion for subchondral bone regeneration and a citric acid-based polymer hydrogel for cartilage regeneration. The scaffold may form an implant, and the implant may include an internal porous core of a biphasic core-shell construct.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63 / 435,375, entitled “Citrate-Based Constructs for Osteochondral Defect Repair,” filed on December 27, 2022. The entire contents of the aforementioned U.S. Provisional Application are incorporated herein by reference. background Technical Field

[0003] The present disclosure relates to citrate-based constructs for repairing osteochondral defects. Background Art

[0004] Articular surface lesions (JSLs), involving articular cartilage and subchondral bone, are reported to be very common in orthopedic clinics, affecting nearly 600,000 patients each year in approximately 20% of arthroscopic surgeries. JSLs can be superficial partial-thickness cartilage defects or full-thickness injuries, which do not involve subchondral bone and transosteocartilage connections, respectively. Due to the poor self-healing ability of articular cartilage, JSLs remain a major clinical challenge. If left untreated, JSLs can lead to secondary osteoarthritis (OA). Therefore, symptomatic chronic full-thickness defects of the knee joint surface require intervention to relieve symptoms and prevent possible progression to OA.

[0005] An investigation of the natural history and consequences of JSL in established OA joints in a group of osteoarthritis patients documented cartilage damage. In this group, cartilage damage worsened in 81% of cases, with only 4% improving over two years [Davies-Tuck, ML, Wluka, AE, Wang, Y., Teichtahl, AJ, Jones, G., Ding, C., Cicuttini, FM, 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 established 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 kneeosteoarthritis: A prospective study, Rheumatology, Vol. 44, No. 10, 2005, pp. 1311–1316].

[0006] Conclusions: JSL complicates and accelerates the progression of OA. Therefore, treatment of JSL may have functional benefits for patients, and effective treatment modalities are needed. Summary of the Invention

[0007] The present disclosure relates to synthetic implants / constructs designed for treating joint surface injuries. The disclosed biodegradable constructs comprise citric acid-based biomaterials that advantageously promote articular cartilage regeneration and subchondral bone regeneration.

[0008] Citric acid is an intrinsic molecule in bone anatomy and physiology that plays an important role in regulating mineral formation and bone metabolism. In biomaterial design, citrate-based polymer functional groups represent chemical functional groups for bioceramic interactions that can be reacted according to the present disclosure to extend release rates, serve as binding sites for peptide attachment, and act as cross-linking sites to generate elastic properties that enhance tissue regeneration.

[0009] Other features, functions, and benefits of the disclosed stent will become apparent from the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] 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, in which:

[0011] Figure 1 Shown is the pH of Dubelco's modified Eagle's medium (DMEM) extract after 72 hours of leaching into poly(octamethylene citrate) (POC) containing bioglass according to ISO 10993.

[0012] Figure 2 Shown are primary chondrocyte proliferation on poly(octamethylene citrate) (POC) scaffolds containing bioglass compared to tissue culture plate controls.

[0013] Figure 3 A schematic representation of a porous citric acid-based scaffold soaked in a hyaluronic acid solution is shown.

[0014] Figure 4 Scanning electron microscopy images of porous hyaluronic acid constructs within the pores of a citric acid-based scaffold after freeze-drying are shown.

[0015] Figure 5A -C shows a schematic representation of a porous citric acid-based scaffold inserted into the core of a solid citric acid-based composite material with 30-70% fenestrations to form a core-shell construct.

[0016] Figure 6A -B shows a schematic representation of the porous citrate-based network on the cartilage side of the core-shell construct.

[0017] Figure 7A -C shows a schematic representation of a solid citric acid-based composite construct with variable diameter geometry.

[0018] Figure 8 Shown is 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.

[0019] Figure 9 Shown is a biphasic citric acid-based construct containing a porous citric acid-based scaffold portion for subchondral bone regeneration and a citric acid-based hydrogel for cartilage regeneration.

[0020] Figure 10 Peptides are shown bound to the surface of a porous citric acid-based scaffold.

[0021] Figure 11A -C shows a schematic representation of a solid citric acid-based composite construct with an alternative variable diameter geometry.

[0022] Figure 12A -C shows a schematic representation of a solid citric acid-based composite construct with an alternative variable diameter geometry.

[0023] Figure 13A -C shows a schematic representation of a solid citric acid-based composite construct with an alternative variable diameter geometry.

[0024] Figure 14A -C shows a schematic representation of a solid citric acid-based composite construct with an alternative variable diameter geometry.

[0025] Figure 15A -C shows a schematic representation of a solid citric acid-based composite construct with an alternative variable diameter geometry.

[0026] Figure 16A -C shows a schematic representation of a solid citric acid-based composite construct with an alternative variable diameter geometry.

[0027] Figure 17A -C shows a schematic representation of a solid citric acid-based composite construct with an alternative variable diameter geometry.

[0028] Figure 18A -C shows a schematic representation of a solid citric acid-based composite construct with an alternative variable diameter geometry. DETAILED DESCRIPTION

[0029] The present disclosure provides a favorable citric acid-based construct for repairing osteochondral defects. According to an exemplary embodiment, the disclosed construct comprises (i) a citric acid component, (ii) a diol component, (iii) a polyol, and (iv) a granular inorganic material. In an exemplary embodiment, the citric acid component can be selected from the group consisting of: citric acid, citrate and / or a citrate ester. In an exemplary embodiment, the diol can include butanediol, hexylene glycol, octanediol or polyethylene glycol. In an exemplary embodiment, the polyol can include glycerol, β-glycerophosphate and / or xylitol. When forming the disclosed construct, the citric acid, diol and polyol components can form a polymer. Granular inorganic material can be added to produce a composite material construct. In an exemplary embodiment, the construct can be made into a porous scaffold to promote cell migration, nutrient delivery and waste removal for tissue regeneration.

[0030] The disclosed constructs may include a particulate inorganic material in an amount of 0 to 60 wt.%. In exemplary embodiments, the particulate inorganic material may include one or more of hydroxyapatite, tricalcium phosphate, biphasic calcium phosphate, and bioglass (BG). BG 45S5 is a bioceramic that can be used according to the present disclosure to increase primary chondrocyte proliferation, glycosaminoglycan production, and scaffold resorption. BG is composed of 43-47% silicon dioxide, 22.5-26.5% calcium oxide, 5-7% phosphorus pentoxide, and 22.5-26.5% sodium oxide [Safety Data Sheet - mo-SCI corporation Mo-SCI Corporation. (nd). Retrieved on May 13, 2022, from mo-sci.com / wp-content / uploads / product-docs / biomaterials / GL0811-SDS.pdf].

[0031] To evaluate the features and benefits of the disclosed constructs, citric acid-based polymers, including poly(octamethylene citrate) (POC), were combined with 0-40 wt.-% BG and 92 wt.-% sodium chloride to form a porous scaffold. BG can exchange its anions with hydrogen ions in solution, thereby increasing the pH of the surrounding solution to buffer the acidity of the POC polymer in solution. Figure 1 As shown, increasing BG concentration in the POC scaffolds increased the alkalinity of the cell culture extract medium.

[0032] Increasing BG concentrations were shown to increase primary chondrocyte proliferation. Figure 2 Proliferation of primary bovine chondrocytes over seven days on POC scaffolds compounded with 0-40 wt.-% BG is shown. POC scaffolds containing 20 wt.-% BG had significantly higher chondrocyte proliferation at day 7 compared to tissue culture plate controls.

[0033] The bioceramic may also be micron-sized or nano-sized. In an exemplary embodiment, the bioceramic may be rod-shaped.

[0034] In an exemplary embodiment, the scaffold 11 is defined as a biodegradable scaffold. The scaffold 11 can be soaked in a hyaluronic acid solution 13, e.g. Figure 3 Depicted schematically.

[0035] In an exemplary embodiment, the hyaluronic acid impregnated scaffold can be freeze-dried to produce porous hyaluronic acid constructs within the pores of the scaffold, e.g., Figure 4 Scanning electron microscope image shown.

[0036] The disclosed constructs can be advantageously defined as a porous core scaffold 11 of a dual phase core-shell construct 10, e.g. Figure 5A As shown in the schematic depiction. Figure 5A As shown in FIG. 1C , the shell 15 may be perforated with circular perforations 17 , elongated slots 19 , and / or holes of other shapes to allow access to the porous inner core scaffold 11 or to provide features that facilitate ingrowth of corresponding cells.

[0037] In an exemplary embodiment, the housing 15 may be open at one end, e.g. Figure 5A In another exemplary embodiment, the shell 15 can completely surround the porous core scaffold 11 (e.g., Figure 5B - schematically depicted in C) and / or may be made of two or more parts, e.g. Figure 5C The housing 15 may include a first portion 21 and a second portion 23 connected at a seam 25. In an exemplary embodiment, the circular perforations 17, elongated slots 19, or other apertures may span the seam 25 of the housing 15, e.g., as shown in FIG. Figure 5C Depicted schematically.

[0038] Apart from Figure 5A In addition to the configuration described in -C, the disclosed constructs can also be advantageously defined as a porous core scaffold of a dual-phase core-shell construct and a porous mesh 31 on the cartilage side of the shell construct, for example, Figure 6A The porous mesh 31 on the cartilage surface can be manufactured using particle leaching or 3D printing technology. It should be understood that the porous mesh 31 can be used in addition to any shell construct disclosed herein.

[0039] The porous web 31 can be made of a variety of fibers or fiber layers so that the porous web 31 is generally porous, for example, 50-90% porous. The individual fibers that make up the porous web 31 can themselves be porous, thereby increasing the porosity of the porous web 31 or allowing the fibers to be packed closer together without reducing the porosity of the porous web 31.

[0040] In an exemplary embodiment, the porous mesh 31 can be used to replace or supplement the circular perforations 17, elongated slots 19, or other holes on the shell 15 to promote chondrocyte infiltration and growth factor binding. The porous mesh 31 can be soaked in a hyaluronic acid solution.

[0041] In an exemplary embodiment, the porous mesh 31 can be used independently, for example, Figure 6B The porous mesh 31 can be initially attached to the subchondral bone surface without disrupting the bone surface by, but not limited to, fibrin glue, sutures, chemical bonding, or another setting or adhesive substance.

[0042] The disclosed constructs can take a variety of solid forms, for example, forms / shapes other than a single diameter cylinder. For example, the disclosed construct 40 can have features defining regions of varying diameters 41, 43, 45, 47, for example, a construct in which the diameter decreases in a direction away from the articular surface 49. These subchondral bone penetrating shafts can be perforated to allow for integration of new bone growth. These perforations can take a variety of forms, such as holes and / or slots 51, and can vary in size, for example, from 0.5 mm to 2.0 mm.

[0043] For example, the shell constructs shown in Figures 5-7 can include a citric acid-based composite material containing, for example, 40-65 wt.-% bioceramic, or, for example, 50-65 wt.-% bioceramic. To evaluate the benefits of the disclosed devices in this regard, a citric acid-based polymer, including POC with added xylitol (POXC), was combined with 60 wt.-% beta-tricalcium phosphate (TCP) and 0-15 wt.-% added BG. The proliferation of primary bovine chondrocytes was evaluated on these composite formulations. Figure 8 As shown, the proliferation of these cells increased with increasing BG amount.

[0044] In an exemplary embodiment, the disclosed scaffold 90 may be biphasic, containing a porous portion 91 for subchondral bone regeneration and a citric acid-based hydrogel 93 for cartilage regeneration, e.g. Figure 9 Furthermore, the citric acid-based hydrogel 93 may be mixed with, for example, hyaluronic acid 95.

[0045] Peptide 105 can be bound to surface 103 of citrate-based scaffold 101. In an exemplary embodiment, a heparin-binding peptide or a transforming growth factor-β mimetic peptide can be bound to surface 103 of citrate-based scaffold 101, e.g., Figure 10 Growth factor solutions can also be absorbed into the citrate-based scaffold 101 as schematically depicted in FIG.

[0046] Referring now to Figures 11-18, eight exemplary embodiments of solid citric acid-based composite constructs having alternative geometries are shown. The citric acid-based composite construct 100 can be machined, extruded, molded, or printed using 3D printing technology, but is not limited thereto. The composite construct 100 can have a head 101 having a cartilage-facing surface 103. The head 101 can be a cylinder of a single diameter or can have another shape, such as, but not limited to, an elliptical, oval, or truncated cone. In an exemplary embodiment, the head 101 can taper along its axial length such that the cartilage-facing surface 103 is larger than the opposing surface of the head 101, for example, as shown in Figures 11-15 and 17-18. This tapered shape allows for a press-fit fit within the user's body, whereby the tapered head 101 is wedged into a cavity in the user's bone. In one embodiment, the head 101 can taper at an angle of 6 to 10 degrees. In an alternative embodiment, the head 101 can taper at an angle of 0 to 15 degrees.

[0047] The cartilage-facing surface 103 can be flat, convex, or concave. In an exemplary embodiment, the cartilage-facing surface 103 can be convex, which matches the surrounding cartilage structure, for example, Figure 17A - C. In another exemplary embodiment, the cartilage-facing surface 103 may be planar or concave and may accommodate additional structures, such as, but not limited to, a porous mesh 31 or a citric acid-based hydrogel 93.

[0048] The composite construct 100 may also have a post or pin 105 extending from the head 101 opposite the cartilage-facing surface 103. The pin 105 may be supported by a plurality of fins 107. In exemplary embodiments, there may be three or four fins 107; however, it should be understood that there may be any number of fins 107 (including no fins) suitable for supporting the pin 105 and / or providing additional contact surface area for the composite construct 100.

[0049] In the exemplary embodiments shown in Figures 11-18, pegs 105 and wings 107 of different diameters, geometries, numbers, and orientations are shown. It should be understood that any element or configuration of the various pegs 105 and wings 107 shown in Figures 11-18 can be used alternatively and / or supplemented with any other element or configuration, but is not limited thereto, to achieve a variety of desired effects. For example, a peg 105 with a smaller diameter may be ideal because it may require less bone to be cut away from the user to be inserted into the composite construct 100. Alternatively, a peg 105 with a larger diameter may be ideal because it may provide greater structural stability. By way of another example, more or fewer wings 107 of various geometries may be ideal to support pegs 105 of different diameters and / or provide more / less contact surface area.

[0050] Furthermore, the edges and connections of the composite construct 100 may be straight-cut, rounded, chamfered, or beveled, but are not limited thereto. These edges may provide a better fit of the composite construct 100 to the user or may be used to improve manufacturing efficiency / reduce costs. For example, depending on the geometry of the fins 107 or the radial angles between adjacent fins 107, certain edge finishes on the fins 107 may be more or less prone to cracking.

[0051] In an exemplary embodiment, the peg 105 or fin 107 may include a cutout 109, e.g. Figure 18A - C. The cutout 109 may be filled or coated with a growth factor solution to promote ingrowth and adhesion between the composite construct 100 and the user's bone.

[0052] An additional consideration is that the composite construct 100 (including the configuration of the particular head 101, cartilage-facing surface 103, plug 105, fins 107, and cutouts 109) may be inefficient or costly to manufacture, or may be difficult or impossible to manufacture using certain manufacturing methods (i.e., machining versus 3D printing). For example, a plug 105 having a smaller diameter may be more susceptible to breakage during manufacturing, and the addition of additional fins 107 reduces the radial angle between adjacent fins 107, making machining more difficult.

[0053] While the embodiment shown in Figures 11-18 is solid, it should be understood that the composite construct 100 can be hollow and can accommodate similar Figure 3 , 5, 9 and 10. In addition, the cartilage-facing surface 103, the plug 105 and the wing 107 can have circular perforations, elongated slots and / or holes of other shapes to allow access to internal structures or provide features that facilitate ingrowth of corresponding cells.

[0054] The disclosed scaffolds are generally porous, for example, 50-90% porous. The scaffolds may contain / define a gradient or biphasic porous structure with two different pore size ranges. The disclosed scaffolds may be conformable and, in exemplary embodiments, may be cut in the operating room.

[0055] The disclosed stents can expand in liquid, for example, the disclosed stents can expand in liquid by up to 500% to 1500%. The disclosed stents typically completely degrade in 6-15 months.

[0056] It should be understood that the various exemplary embodiments and components thereof discussed herein may be used in conjunction with, in lieu of, and / or in addition to each of the other exemplary embodiments and components thereof.

[0057] Although the present disclosure has been described with reference to exemplary embodiments and implementations, the present disclosure is not limited to such exemplary embodiments / implementations.

[0058] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the present disclosure. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will also be understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or parts, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, parts, and / or combinations thereof.

[0059] Although the present disclosure has been described with reference to one or more exemplary 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 present disclosure. In addition, many modifications may be made to adapt specific situations or materials to the teachings of the present disclosure without departing from the basic scope of the present disclosure. Therefore, the present disclosure is not intended to be limited to the specific embodiments disclosed as the best mode for carrying out the present disclosure, but rather the present disclosure will include all embodiments falling within the scope of the claims.

Claims

1. A construct for repairing osteochondral defects, comprising: a. Citric acid component, b. diol component, c. polyols, and d. Granular inorganic materials.

2. The construct of claim 1, wherein the citric acid component is selected from the group consisting of: citric acid, citrate, or a citrate ester.

3. The construct of claim 1, wherein the diol comprises butanediol, hexanediol, octanediol, or polyethylene glycol.

4. The construct of claim 1, wherein the polyol comprises glycerol, β-glycerophosphate, or xylitol.

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

6. The construct of claim 5, wherein the bioglass is rod-shaped.

7. The construct of claim 1, wherein the citric acid, diol, and polyol components form a polymer.

8. A scaffold formed from a construct according to any one of the preceding claims.

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

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

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

12. The stent according to claim 8, wherein the stent is soaked in a hyaluronic acid solution.

13. The scaffold of claim 8, wherein the scaffold is freeze-dried to produce a porous construct within the pores of the scaffold.

14. The scaffold according to claim 8, wherein the bioceramic is present in an amount between 10 and 50 wt.-%.

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

16. The scaffold of claim 8, wherein the peptide is bound to the surface of the citric acid-based scaffold.

17. The scaffold of claim 8, wherein the growth factor solution is absorbed onto the citric acid based scaffold.

18. The scaffold of claim 8, wherein the scaffold is biphasic comprising a porous portion for subchondral bone regeneration and a citric acid-based polymer hydrogel for cartilage regeneration.

19. The stent of claim 18, wherein the citric acid-based hydrogel is mixed with hyaluronic acid.

20. The stent of claim 8, wherein the heparin-binding peptide is bound to the surface of the citric acid-based hydrogel.

21. The scaffold of claim 8, wherein the transforming growth factor β-mimetic peptide is bound to the surface of the citric acid-based hydrogel.

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

23. The stent of claim 8, wherein the stent is conformable.

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

25. The stent of claim 8, wherein the stent can expand 500-1500% in liquid. The stent according to claim 8 , wherein the stent completely degrades within 6-15 months.

27. An implant formed from a construct according to any one of claims 1 to 7.

28. The implant of claim 27, wherein the implant comprises an inner porous core of a dual-phase core-shell construct.

29. The implant according to claim 28, wherein the shell construct comprises a citric acid-based composite material comprising 40-65 wt.-% bioceramic or 50-65 wt.-% bioceramic.

30. 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. The implant of claim 27, wherein the implant comprises a solid component for underlying the cartilage and a porous component on the cartilaginous side of the implant.

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