Method of producing FABP4 inhibitor-loaded biomaterial and application for the treatment of tendon and ligament injuries

Abstract

Provided are methods of inhibiting FABP4 and treating and retarding the progression of degenerative tendon lesions of chronic tendinopathy and promoting surgical repair, after, tendon and ligament rupture in a subject. Provided are methods of producing a FABP4 inhibitor- loaded biomaterial and application of FABP4 inhibitor and / or FABP4 inhibitor- loaded biomaterial for the treatment of tendon and ligament injury of a subject.

Description

[0001]1 CUHK.212XC1PCT DESCRIPTION TITLE METHOD OF PRODUCING FABP4 INHIBITOR-LOADED BIOMATERIAL AND APPLICATION FOR THE TREATMENT OF TENDON AND LIGAMENT INJURIES CROSS-REFERENCE TO RELATED APPLICATION The present application claims the benefit of U.S. Provisional Application Serial No.63 / 512,322, filed July 7, 2023, which is hereby incorporated by reference herein in its entirety, including any figures, tables, nucleic acid sequences, amino acid sequences, or drawings. REFERENCE TO SEQUENCE LISTING The Sequence Listing for this application is labeled “CUHK-212XC1PCT-SeqList- 28Jun24.xml” which was created on June 28, 2024, and is 2,803 bytes. The entire content of the sequence listing is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The disclosed invention is in the fields of musculoskeletal medicine, pharmaceuticals, tendon and ligament injuries, especially in chronic tendinopathy. BACKGROUND OF THE INVENTION Chronic tendinopathy is a serious medical condition that affects the tendons of the body, causing activity-related tendon pain, tenderness, and localized swelling.1Tendinopathy can be diagnosed using imaging techniques such as ultrasound (US) and magnetic resonance imaging (MRI). In chronic tendinopathy, US may reveal hypoechogenic regions, increased tendon thickness and loss of imaging signals typical of well-aligned collagen fibres, while MRI may show tendon enlargement, heterogeneity and focal high T1 and T2 signals. Tissue metaplasia in the tendon proper may exist in tendinopathy. Tendinopathy causes tendon degeneration and may predispose the tendon to rupture. It may or may not be presented with tendon rupture in the clinical setting. Chronic tendinopathy is common. It accounts for 30-50% of all sports-related injuries,2and almost half of all occupational illnesses in the United States,3costing billions of healthcare J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 2 CUHK.212XC1PCT dollars each year. In the United States, managing shoulder tendon injuries alone can cost over $3 billion per year.4Addressing chronic tendinopathy is critical to reducing the financial burden of healthcare systems and improving patient outcomes. Common sites of chronic tendinopathy include rotator cuff, extensor Carpi radialis brevis and medial common flexor tendon of the elbow, patellar tendon, Achilles tendon, plantar fascia and flexor tendon of finger. Rotator cuff tendinopathy, affecting the supraspinatus tendon, is a common cause of shoulder pain, with an estimated prevalence of 30% in the general population.5The rotator cuff tendons, especially the supraspinatus tendon, degenerates and finally ruptures. Lateral elbow tendinopathy is also a highly prevalent tendon disorder, affecting not only tennis players but also the general population. The prevalence of lateral elbow tendinopathy in the general population and manual workers is around 1-3% and 7%, respectively.6Its annual incidence in the general practice is between 4 and 7 per 1000 people.7The prevalence of patellar tendinopathy in the athletic population varies depending on the sports. It has been reported that the prevalence of patellar tendinopathy in volleyball players was as high as 45%, while in basketball players it was 32%.8Achilles tendinopathy is especially prevalent among runners, especially elite long-distance runners, who have up to a 52% risk of suffering an Achilles tendon injury.9In soccer players, the incidence rate of Achilles tendinopathy is around 3%, and the recurrence rate is 27%.10The etio-pathogenesis of chronic tendinopathy is multi-factorial and remains unclear, though change of mechanical loading such as overuse is an important risk factor. Other risk factors such as environmental factors, metabolic diseases, genetics, demographics, and drug use modify the risk of development and prognosis of overuse-induced tendinopathy. The prevalence of chronic tendinopathy increases with age and severely limits the physical activity of the aging population. Age is an important risk factor for the development of tendinopathy, particularly for rotator cuff tears. Approximately 30% of adults aged over 60 have a rotator cuff tear and the prevalence increases to 62% in adults aged over 80. With the aging of the population and the promotion of an active lifestyle, the incidence of aging- and overuse- associated tendinopathy is increasing. The management of chronic tendinopathy is challenging and there is still a lack of effective and evidence-based interventions. Non-surgical interventions, such as rest, physical therapy, Kinesio taping, shockwave, non-steroid anti-inflammatory drugs (NSAIDs) and corticosteroids have been found to have a low to very low certainty of evidence to support their use. Conservative treatment for patellar tendinopathy is not significantly more effective than minimal intervention or other invasive treatments on improving short-term pain and function.11J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 3 CUHK.212XC1PCT Similarly, there is no robust basis for the use of conservative treatments for the management of chronic tendinopathy.12-15Surgery is often considered if non-surgical treatments fail. Debridement, tendon insertion repairs, or reconstruction are performed depending on the injury condition. However, the success of these procedures can be mixed, with a high risk of complications. Recurrent pain after surgery is common. Tendon-to-bone healing is challenging, and the failure of rotator cuff repair is high as it requires the healing of two materials of different stiffness (bone and tendon). The high failure rate of rotator cuff repair (20%-94%) is an unsolved problem.16-17Surgery for patellar tendinopathy is not significantly more effective than eccentric exercise or sclerosing injections.18Therefore, there is a pressing need for the development of more effective treatments for chronic tendinopathy. BRIEF SUMMARY OF THE INVENTION The present invention relates to treating or retarding the progression of tendinopathy as well as promoting surgical repair after tendon rupture by inhibiting the functions of fatty acid- binding protein 4 (FABP4). Tendon overuse triggers an inflammatory response that causes a decrease in tenogenic markers and an increase in non-tenogenic markers in tendon-derived stem / progenitor cells (TDSCs), resulting in tissue metaplasia. The present invention discloses the upregulation of FABP4 and its pro-inflammatory and non-tenogenic effects in the clinical samples and animal models of collagenase-induced (CI) inflammatory degenerative tendon injuries. The erroneous differentiation of TDSCs to non-tenocytes in the presence of increased amount of FABP4 reduces their ability to participate in tendon healing, leading to failed healing and calcification. FABP4 is therefore a target for the treatment of tendinopathy and inflammatory degenerative tendon and ligament injuries. In certain embodiments, the subject invention can suppress inflammation, inhibit, and / or reverse the erroneous differentiation of TDSCs, and / or enhance the regeneration of degenerative tendons by preserving the pool of TDSCs available for tenogenesis. In certain embodiments, the subject methods comprise the administration of a FABP4 inhibitor to a subject. In certain embodiments, the subject methods alleviate CI tendon damages, promote tendon healing by reducing inflammation and oxidative stress, promoting self-renewal and tenogenic activity of TDSCs. In certain embodiments, a biomaterial is used to administer the FABP4 inhibitor. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 4 CUHK.212XC1PCT In certain embodiments, a FABP4 inhibitor, such as, for example BMS309403, is loaded into a biomaterial, such as, for example, a GelMA hydrogel. In certain embodiments, the FABP4 inhibitor or a FABP4 inhibitor-loaded GelMA hydrogel can be used in methods of promoting healing after inflammatory degenerative tendon and ligament injuries and / or tendinopathy. In certain embodiments, the FABP4 inhibitor is BMS309403, which is a selective and potent biphenyl azole inhibitor of FABP4 (Ki: <2nM; IC50: 0.71μM). In certain embodiments, a biological scaffold can be used for the local delivery and slow release of a FABP4 inhibitor to the injured tendon in tendinopathy patients. In certain embodiments, the loading of a FABP4 inhibitor in GelMA pre-polymers followed by injection of the mixture after UV and / or blue light cross-linking of GelMA pre-polymers can support local administration to the injured tendons and slow release of FABP4 inhibitors, as the GelMA slowly dissolves. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIGs. 1A-1D (FIG. 1A) Photomicrographs showing immunohistochemistry (IHC) staining of FABP4 in healthy hamstring tendon samples, healthy patellar tendon samples, and patellar tendinopathy samples. Scale bar = 100 µm, yellow arrow: blood vessel; red arrow: hypercellular area; CR: calcified region. (FIG. 1B) Boxplot showing IOD / mm2of FABP4 signal. n=6 / group; ** p<0.01; *** p<0.001 (FIG. 1C) Photomicrographs showing IHC staining of FABP4 in healthy human hamstring tendon samples and human rotator cuff tendinopathy samples. Scale bar = 100 µm, yellow arrow: blood vessels; red arrow: hypercellular area; CR: calcified region. (FIG. 1D) Boxplot showing IOD / mm2of FABP4 signal. n=5 / group; ** p<0.01 FIG.2. Photomicrographs showing the co-localization of FABP4 with IL-1β or TNF- α in healthy tendon samples and human rotator cuff tendinopathy samples. Scale bar = 50 µm; n=5 / group; white arrows: co-localized signal in tendon cells; red arrows: co-localized signal in blood vessels. FIGs. 3A-3B. (FIG. 3A) Photomicrographs showing IHC staining of FABP4, IL-1β, TNF-α, IL-6, and IL-10 in representative samples of mouse Achilles tendons at at (A) week 2 and week 8 after saline or collagenase injection. Scale bar = 100 µm (insert 25 µm); red arrow: J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 5 CUHK.212XC1PCT hypercellular area; green arrow: small, nucleated cells; *: chondrocyte-like cells; CR: calcified region; black arrow: immunopositive cells; (FIG.3B) Boxplots showing the IOD / mm2of target markers. n=5 / group; ** p<0.01; *** p<0.001. FIGs. 4A-4C. (FIG. 4A) (Ai) Photomicrographs showing H&E staining and corresponding polarized images of representative samples of mouse Achilles tendons at week 2 and week 8 after saline or FABP4 (0.5 µg) injection. Scale bar = 100 µm (insert 25 µm); CR: calcified region; *: chondrocyte-like cells; (Aii) Histopathological scoring of H&E images. n=5 / group; *** p<0.001. (FIG.4B) (Bi) microCT images showing ectopic calcification inside Achilles tendons at week 8 after saline or FABP4 (0.5 µg) injection. Scale bar = 50 µm; white arrow: ectopic bone; (Bii) Boxplot showing the bone volume (BV) inside tendon in different groups. n=6 / group; * p<0.05. (FIG.4C) (Ci) Photomicrographs showing the IHC staining of IL-1β, TNF-α, IL-6, and IL-10 in representative samples of mouse Achilles tendons at week 2 and week 8 after saline or FABP4 (0.5 µg) injection. Scale bar = 100 µm (insert 25 µm); red arrow: hypercellular area; *: chondrocyte-like cells; black arrow: immunopositive cells; (Cii) Boxplots showing the IOD / mm2of L-1β, TNF-α, IL-6, and IL-10 at week 2 and week 8 after saline or FABP4 (0.5 µg) injection. n=5 / group; * p<0.05; ** p<0.01; *** p<0.001. FIGs.5A-5B. Boxplots showing (FIG.5A) the expressions of IL1b, IL6, and TNFa in human TDSCs and; (FIG.5B) the expressions of Il1b, Il6, and Il10 in mouse TDSCs after the addition of FABP4 (120 ng / mL) for 24 h. *p<0.05; **p<0.01; ***p<0.001; n=4 / group. FIGs.6A-6C. (FIG.6A) Photomicrographs showing protein expression of FABP4 in human rotator cuff tendinopathy TDSCs compared to healthy hamstring tendon TDSCs; Scale bar: 100 µm; n=4. The cell nucleus was stained by DAPI. (FIG. 6B) Photomicrographs showing protein expression of FABP4 in mouse TDSCs treated with IL-1β (10 ng / mL) for 48 h; Scale bar: 100 µm; n=6. The cell nucleus was stained by DAPI. (FIG.6C) Boxplot showing mRNA expression of Fabp4. *p<0.05; n=4-5 / group. FIGs.7A-7C. (FIG.7A) Photomicrographs showing H&E staining and corresponding polarized images of Achilles tendons in WT and FABP4 KO mice at week 2 and week 8 after saline or collagenase injection. Stain: hematoxylin & eosin; n=5 / group; Scale bar: 50 µm (insert 200 µm); yellow arrow: blood vessel; red arrow: hypercellular area; green arrow: small, nucleated cells; white arrow: collagen birefringence; *: chondrocyte-like cells. (FIG. 7B) (i) microCT images showing the Achilles tendons of WT and FABP4 KO (Fabp4- / -) groups at week 8 after saline or collagenase injection. (ii) Boxplot showing the bone volume (BV) inside tendons in different groups. n=6 / group; Scale bar: 50 µm; white arrow: ectopic bone; **p<0.01. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 6 CUHK.212XC1PCT (FIG. 7C) Photomicrographs showing IHC staining of IL-1β in the Achilles tendons of WT and FABP4 KO mice at week 2 and week 8 after saline or collagenase injection. n=5 / group; Scale bar: 50 µm (insert 200 µm); black arrow: immunopositive cells. FIG.8. Photomicrographs showing H&E staining and corresponding polarized images of representative samples of WT mouse Achilles tendons at week 2 after repeated injection of vehicle or BMS309403 in the CI tendon injury model. n=4 / group; scale bar = 100 µm (insert 25 µm); red arrow: hypercellular area; green arrow: small, nucleated cells. FIG.9. Photomicrographs showing IHC staining of IL-1β, IL-6, and TNF-α of mouse Achilles tendons at week 2 after repeated injection of vehicle or BMS309403 in the CI tendon injury model. n=4 / group; scale bar = 100 µm (insert 25 µm); red arrow: immunopositive cells. FIGs.10A-10B. (FIG.10A) Photographs showing the procedures for (i) mixing LAP, F127 and GelMA pre-polymers with BMS309403, (ii) loading into a syringe and cross-linking with blue light at 405 nm and (iii) injection into the Achilles tendon. The ability of the mixture to eject from the syringe after cross-linking with blue light for different times was shown. (FIG. 10B) Gross morphology (i, ii) and SEM images (iii-vi) showing surface morphology of GelMA hydrogel without and with loading of BMS309403. Panels (v-vi) are higher magnification of Panels (iii-iv). n=3 / group; scale bars: 100 µm (iii-iv); 10 µm (v-vi); arrows: BMS309403. FIGs. 11A-11D. (FIG. 11A) Photomicrographs showing H&E staining and corresponding polarized images of representative samples of WT mouse Achilles tendons at week 2, week 4, and week 8 after single injection of saline, GelMA-only (‘GelMA’) or BMS309403-loaded GelMA hydrogel (‘Gel-BMS’) in the CI tendon injury model. The contralateral uninjured Achilles tendons of the saline group without injury or injection were used as normal controls (‘Normal’). n=6 / group; scale bar = 50 µm (insert: 200 µm); yellow arrow: blood vessels; red arrow: hypercellular area; green arrow: small, nucleated cells; CR: calcified regions; *: chondrocyte-like cells. (FIG. 11B) Photomicrographs showing IHC staining of FABP4 and IL-1β of representative samples of WT mouse Achilles tendons at week 2, week 4, and week 8 after single injection of saline, GelMA-only (‘GelMA’) or BMS309403- loaded GelMA hydrogel (‘Gel-BMS’) in the CI tendon injury model. The contralateral uninjured Achilles tendons of the saline group without injury or injection were used as normal controls (‘Normal’). n=5 / group; Scale bar = 100 µm; red arrow: immunopositive cells. (FIG. 11C) i. microCT images showing ectopic mineralized tissue inside the WT mouse Achilles tendons after single injection of saline (‘Saline’), GelMA-only (‘GelMA’) or BMS309403- loaded GelMA hydrogel (‘Gel-BMS’) in the CI tendon injury model at week 8 after treatment. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 7 CUHK.212XC1PCT The contralateral uninjured Achilles tendons of the saline group without injury or injection were used as normal controls (‘Normal’). n=6 / group; Scale bar = 50 µm; white arrow: ectopic mineralized tissue. ii. Boxplot showing the BV inside tendons in the saline group (‘Saline’), GelMA-only group (‘GelMA’) and BMS309403-loaded GelMA group (‘GEL-BMS’) in the CI tendon injury model at week 8 after treatment. The contralateral uninjured Achilles tendons of the saline group without injury or injection were used as normal controls (‘Normal’). n=6 / group; * p<0.05. (FIG.11D) Boxplots showing the gait parameters of mice in different groups at week 2 and week 8 after treatment. n=8 / group; *p<0.05; **p<0.01; ***p<0.001. FIGs.12A-12B. (FIG.12A) Photomicrographs showing the colony-forming unit (CFU) and individual colonies untreated or treated with FABP4 or BMS309403; stain: crystal violet; scale bar = 100 μm. (FIG.12B) Boxplot showing the CFU of different groups. *p<0.05; n=4- 5 / group. FIG.13. Boxplots showing the effect of FABP4 on the mRNA expression of ER stress marker (Chop), osteogenic marker (Bglap) and tenogenic marker (Col1a1) in inflamed TDSCs after treatment for 48 h. n=4-6 / group; *p<0.05. FIG.14. Boxplots showing the effect of BMS309403 on the mRNA expression of pro- inflammatory marker (Tnfa), ER stress marker (Chop, Grp78), tenogenic makers (Tnmd, Scx) and osteogenic marker (Runx2) in inflamed TDSCs after treatment for 48 h. n=4-6 / group; *p<0.05. BRIEF DESCRIPTION OF THE SEQUENCES SEQ ID NO: 1: FABP4 shRNA inhibitor SEQ ID NO: 2: FABP4 shRNA inhibitor DETAILED DISCLOSURE OF THE INVENTION Selected Definitions 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. Furthermore, to the extent that the terms “including”, “includes”, “having”, “has”, “with”, or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising”. The transitional terms / phrases (and any grammatical variations thereof) “comprising”, “comprises”, “comprise”, “consisting essentially of”, “consists essentially of”, “consisting” and “consists” can be used interchangeably. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 8 CUHK.212XC1PCT The phrases “consisting essentially of” or “consists essentially of” indicate that the claim encompasses embodiments containing the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claim. The term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured, i.e., the limitations of the measurement system. In the context of compositions containing amounts of ingredients where the term “about” is used, these compositions contain the stated amount of the ingredient with a variation (error range) of 0-10% around the value (X ± 10%). In other contexts, the term “about” is used provides a variation (error range) of 0-10% around a given value (X ± 10%). As is apparent, this variation represents a range that is up to 10% above or below a given value, for example, X ± 1%, X ± 2%, X ± 3%, X ± 4%, X ± 5%, X ± 6%, X ± 7%, X ± 8%, X ± 9%, or X ± 10%. In the present disclosure, ranges are stated in shorthand to avoid having to set out at length and describe each and every value within the range. Any appropriate value within the range can be selected, where appropriate, as the upper value, lower value, or the terminus of the range. For example, a range of 0.1-1.0 represents the terminal values of 0.1 and 1.0, as well as the intermediate values of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges encompassed within 0.1-1.0, such as 0.2-0.5, 0.2-0.8, 0.7-1.0, etc. Values having at least two significant digits within a range are envisioned, for example, a range of 5-10 indicates all the values between 5.0 and 10.0 as well as between 5.00 and 10.00 including the terminal values. When ranges are used herein, combinations and subcombinations of ranges (e.g., subranges within the disclosed range) and specific embodiments therein are explicitly included. “Treatment”, “treating”, “palliating” and “ameliorating” (and grammatical variants of these terms), as used herein, are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit. A therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease or symptom thereof or injury such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the injury, disease or symptom thereof. The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease or injury treatment. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject and disease condition J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 9 CUHK.212XC1PCT being treated, e.g., the weight and age of the subject, the severity of the disease or injury condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response, e.g., retarding the progression of chronic tendinopathy or promoting healing after inflammatory degenerative tendon tear and surgical repair. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. In some embodiments of the invention, the method comprises administration of one or multiple doses of the compositions of the subject invention. The method may comprise administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or more therapeutically effective doses of a composition of the subject invention as described herein. In some embodiments, doses may be administered over the course of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 21 days, 30 days, about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 26 weeks, or more than 26 weeks. In some embodiments, doses may be administered daily, every other day, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 10 days, once every 14 days, once every 21 days, once every 30 days, once every about 4 weeks, once every about 6 weeks, once every about 8 weeks, once every about 12 weeks, once every about 16 weeks, once every about 20 weeks, once every about 24 weeks, or once every about 26 weeks. Moreover, treatment of a subject with a therapeutically effective amount of the compositions of the invention can include a single treatment or can include a series of treatments. It will also be appreciated that the effective dosage of a composition used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of imaging techniques for detecting, for example, injuries to tendons and / or ligaments, which is well-known in the art. As used herein, the term “subject” refers to an animal, needing or desiring delivery of the benefits provided by a therapeutic composition. The animal may be, for example, a mammal, including, humans, pigs, horses, goats, cats, mice, rats, dogs, apes, chimpanzees, orangutans, guinea pigs, hamsters, cows, and sheep. These benefits can include, but are not limited to, the treatment of a health condition, disease or disorder; prevention of a health condition, disease or disorder; enhancement of the function of tendons and / or ligaments, in the body. The subject can be of any age or stage of development, including infant, toddler, J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 10 CUHK.212XC1PCT adolescent, teenager, adult, or senior. The terms “subject” and “patient” can be used interchangeably. As used herein the terms “scaffold”, “bio-scaffold”, “construct”, “bio-construct”, “composite”, “bio-composite”, might be used interchangeably. As used herein, a “scaffold” refers to a temporary structure used as a support system to aid in drug delivery to the damaged or diseased areas. By “reduces” or “retards” is meant a negative alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%. By “increases” is meant as a positive alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. All references cited herein are hereby incorporated by reference. Compositions In certain embodiments, the compositions according to the subject invention utilize a FABP4 inhibitor, including, for example, BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, and other triazolopyrimidine derivatives (e.g., compounds 1-58, as disclosed in Floresta G, Patamia V, Zagni C, Rescifina A. Adipocyte fatty acid binding protein 4 (FABP4) inhibitors. An update from 2017 to early 2022. Eur J Med Chem.2022 Oct 5;240:114604, which is hereby incorporated by reference), short hairpin (shRNA) (e.g., 5’ CCGGTCAGAGAGTACTTTT 3’ (SEQ ID NO: 1), and RNA interference (RNAi) (e.g., 5′-CACCGAGATTTCCTTCAAA-3′ (SEQ ID NO: 2)) targeting FABP4 expression, benzbromarone (a uricosuric agent), polyclonal and monoclonal FABP4 neutralizing antibodies, such as, for example, CA33 (see commercially available CA33 at worldwide website: creativebiolabs.net / Anti-FABP4-Recombinant-Antibody-clone-CA33- 22932.htm) and 2E4. In preferred embodiments, the FABP4 inhibitor is BMS309403. In certain J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 11 CUHK.212XC1PCT embodiments, to create a short hairpin RNA (shRNA), a nine-nucleotide loop (5′- TTCAAGAGA-3′) was placed to separate the sense and antisense sequences for RNAi. In certain embodiments, the FABP4 inhibitor can be present in a biomaterial at a concentration of about 0.01 mg / mL to about 1000 mg / mL, about 0.1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 75 mg / mL, or about 50 mg / mL. In certain embodiments, the FABP4 inhibitor can be administered without the use of a biomaterial to a subject at a dose of about 0.01 mg / kg to about 1000 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 75 mg / kg, or about 20 mg / kg. In certain embodiments, the FABP4 inhibitor can be incorporated into a composite scaffold composed of synthetic and / or natural polymers. In certain embodiments, the synthetic polymers include, for example, to poly-ɛ-caprolactone (PCL), poly-L-lactide (PLLA), and poly (lactin-co-glycolic acid) (PLGA). In certain embodiments, natural polymers include, for example, type I collagen, alginate, chitosan, gelatin and decellularized tendon matrix. Gelatin is a natural hydrophilic polymer produced by hydrolysis and denaturation of collagen under high temperature. Gelatin shows good biocompatibility, solubility and degradability as well as lower antigenicity compared to collagen. However, the thermostability of gelatin is poor and chemical cross-linking of gelatin may affect its biocompatibility as some cross-linking agents are poisonousness. In preferred embodiments, the polymer is Gelatin methacryloyl (GelMA), which is produced by modifying gelatin with methacrylic anhydride (MA). In certain embodiments, a solution of pre-polymers, such as, for example, a GelMA pre-polymer, comprising the FABP4 inhibitor crosslink under UV and / or blue light when a photoinitiator is added, resulting in a hydrogel with good thermostability, biocompatibility and degradation properties. In certain embodiments, a FABP4 inhibitor can be mixed with a polymer, such as, for example, a GelMA pre-polymer, and a photoinitiator, a thermosensitive poloxamer, or a combination thereof. In certain embodiments, the photoinitiator is lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP) or 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl- 1-propanone (Irgacure-2959), and the thermosensitive poloxamer is poloxamer 407 (e.g., Pluronic™ F-127 (BASF, Ludwigshafen, Germany)). In certain embodiments, the photoinitiator LAP is at a concentration of about 0.001% to about 10%, about 0.01% to about 5%, about 0.01% to about 1%, or about 0.25%. In certain embodiments, the thermosensitive poloxamer 407 is at a concentration about 0.001% to about 10%, about 0.01% to about 5%, about 0.1% to about 1%, or about 0.1% relative to amount of the photoinitiator in the J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 12 CUHK.212XC1PCT composition. In certain embodiments, the polymer GelMA pre-polymer is at a concentration of about 0.01% w / v to about 50% w / v, about 0.1% w / v to about 10% w / v, or about 5% w / v. In certain embodiments, the mixture can be cross-linked by UV or blue light before application of the composition to the subject. In certain embodiments, the UV light is at a wavelength of about 320 nm to about 390 nm and the blue light is at a wavelength of about 405 nm. In certain embodiments, the cross-linking of the said mixture can occur for about 1 second to about 1 minute. In preferred embodiments, BMS309403 is mixed with GelMA pre-polymers, LAP (0.25% in PBS (phosphate buffered saline)) and F127 thermosensitive poloxamer (0.1% of LAP) and cross-linked with blue light at 405 mm for about 1 second to about 1 minute or about 14 seconds and applied to the injured tendon and / or ligament. In one embodiment, the subject compositions are formulated as an orally-consumable product, such as, for example a food item, capsule, pill, or drinkable liquid. An orally deliverable pharmaceutical is any physiologically active substance delivered via initial absorption in the gastrointestinal tract or into the mucus membranes of the mouth. The topic compositions can also be formulated as a solution that can be administered via, for example, injection, which includes intravenously, intraperitoneally, intramuscularly, subcutaneously or topically. The subject composition can further comprise one or more pharmaceutically acceptable carriers, and / or excipients, and can be formulated into preparations, for example, solid, semi- solid, liquid, forms, such as tablets, capsules, powders, granules, solutions, suppositories, injections, spray, cream, pellets, caplets, troches, lozenges, dispersions, aqueous solution, non- aqueous solution, oil-in-water emulsion, or water-in-oil liquid emulsion. The term “pharmaceutically acceptable” as used herein means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof. Carriers and / or excipients according the subject invention can include any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffers), oil-in-water or water-in-oil emulsions, aqueous compositions with or without inclusion of organic co-solvents suitable for, e.g., IV use, solubilizers (e.g., Polysorbate 65, Polysorbate 80), colloids, dispersion media, vehicles, fillers, chelating agents (e.g., EDTA or glutathione), amino acids (e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavorings, aromatizers, thickeners (e.g. carbomer, gelatin, or sodium alginate), coatings, preservatives (e.g., Thimerosal, benzyl alcohol, polyquaterium), antioxidants (e.g., ascorbic acid, sodium J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 13 CUHK.212XC1PCT metabisulfite), tonicity controlling agents, absorption delaying agents, adjuvants, bulking agents (e.g., lactose, mannitol) and the like. The use of carriers and / or excipients in the field of drugs and supplements is well known. Except for any conventional media or agent that is incompatible with the target health-promoting substance or with the composition, carrier or excipient use in the subject compositions may be contemplated. In one embodiment, the compositions of the subject invention can be formulated for administration via injection, for example, as a solution or suspension. The solution or suspension can comprise suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, phosphate buffered saline (PBS), Dimethylsulfoxide (DMSO), polyethylene glycol, or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, non-irritant, fixed oils, including synthetic mono- or diglycerides. Methods of Treating Tendon and / or Ligament Injury In certain embodiments, a FABP4 inhibitor and / or a FABP4 inhibitor-loaded biomaterial, such as, for example, GelMA, can be used for the treatment of tendon and / or ligament injuries, chronic tendinopathy, and for the promotion of healing after inflammatory degenerative tendon and ligament injuries. Tendons and ligaments that may develop tendinopathy due to change of loading, such as, for example, overuse in the Achilles tendon, patellar tendon, rotator cuff, extensor Carpi radialis brevis and medial common flexor tendon of the elbow, plantar fascia, and the flexor tendon of finger. In certain embodiments, the affected tendon and ligament can be presented with pain and swelling without and with tear. In certain embodiments, for painful tendinopathy not requiring surgical operation, a FABP4 inhibitor and / or a FABP4 inhibitor-loaded biomaterial can be applied to the painful and / or injured tendon or ligament by, for example, local injection. In certain embodiments, for tendinopathy presented with tendon tear requiring surgical repair, a FABP4 inhibitor and / or a FABP4 inhibitor-loaded biomaterial can be applied during or after surgical repair by, for example, injection after surgery or direct application of the FABP4 inhibitor and / or FABP4 inhibitor-loaded biomaterial to the surgically repaired tendon and / or ligament during surgery. In certain embodiments, FABP4 inhibitor and / or a FABP4 inhibitor-loaded biomaterial can be used for enhancing tissue repair, particularly tendon and / or ligament tissue. In certain embodiments, the FABP4 inhibitor and / or FABP4 inhibitor-loaded biomaterial can be used to promote tendon or ligament regeneration. In certain embodiments, the FABP4 inhibitor and / or J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 14 CUHK.212XC1PCT FABP4 inhibitor-loaded biomaterial can be used in forms of putty, scaffolds, or injectable hydrogel. In certain embodiments, the administration of a FABP4 inhibitor and / or FABP4 inhibitor-loaded biomaterial alleviates tendon damages, reduces ectopic bone formation, reduced walking pain. In certain embodiments, the administration of a FABP4 inhibitor and / or FABP4 inhibitor-loaded biomaterial reduces the expression of inflammatory cytokines, such as, for example, IL-1β, IL-6, and TNF-α. In certain embodiments, the administration of a FABP4 inhibitor restores natural tendon healing by promoting the self-renewal ability of TDSCs. In certain embodiments, the administration of a FABP4 inhibitor enhances anti-inflammatory and anti-oxidative effects of inflammatory TDSCs, as indicated by the reduced expression of inflammatory cytokine (Tnfa) and ER stress markers (Chop, Grp78). In certain embodiments, the administration of a FABP4 inhibitor redirects the cell fate of inflammatory TDSCs towards tenocyte lineage by promoting the expression of tenogenic markers (Tnmd, Scx) and reducing the expression of osteogenic marker (Runx2) in inflammatory TDSCs. In certain embodiments, the present invention discloses the method of producing FABP4 inhibitors-loaded biomaterials and the use of FABP4 inhibitors and / or FABP4 inhibitors-loaded biomaterials for treating or retarding the progression of chronic tendinopathy as well as promotion of healing after inflammatory degenerative tendon tear and surgical repair. In certain embodiments, the present invention provides methods for treating chronic tendinopathy in a patient with a FABP4 inhibitor and / or a FABP4 inhibitor-loaded biomaterial. In certain embodiments, the symptoms, and pathological changes of tendons in a patient with tendinopathy are reversed after local administration of a FABP4 inhibitor and / or a FABP4 inhibitor-loaded biomaterial. In certain embodiments, the progression of tendinopathy is retarded after local administration of FABP4 inhibitor and / or a FABP4 inhibitor-loaded biomaterial. In certain embodiments, the development of tendinopathy is prevented after local administration of FABP4 inhibitor and / or a FABP4 inhibitor-loaded biomaterial. In certain embodiments, healing after degenerative tendon tear and surgical repair is improved after local administration of FABP4 inhibitor and / or a FABP4 inhibitor-loaded biomaterial. All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 15 CUHK.212XC1PCT Following are examples that illustrate procedures for practicing the invention. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted. EXAMPLE 1—UPREGULATION OF FABP4 IN PATELLAR TENDINOPATHY AND ROTATOR CUFF TENDINOPATHY Adult patients with tendinopathy at the patellar tendons and rotator cuff tendons as verified by ultrasound (US) or magnetic resonance imaging (MRI), tendon pain or weakness prior to surgery and unsatisfactory physiotherapy treatment were recruited. Guided by clinical findings and US or MRI scans, the pathological tendon tissue was excised. The control groups shared similar subject inclusion and exclusion criteria except that they had no history or current clinical signs of tendon injury and tendon pain. Healthy tendons were obtained from the remnant of hamstring tendon autograft or patellar tendon autograft during anterior cruciate ligament reconstruction (ACLR). The tendon tissues were fixed, dehydrated and paraffinized in tissue blocks for storage. For immunohistochemistry (IHC) staining, 5-μm-thick sections were cut and mounted on coated slides. After deparaffination, the sections were rehydrated, decalcified, quenched of endogenous peroxidase activity, and treated with 10 mM citrate buffer at 65oC for 20 min for antigen retrieval. After blocking with 1% goat serum, the sections were incubated with specific antibodies against FABP4 (1:200) at 4oC overnight. The primary antibodies were replaced with blocking solution in the controls. HRP-conjugated goat anti- rabbit secondary antibody (1:500) was used and the immunopositivity was visualized using the DAB substrate kit according to the manufacturer’s protocol. After counterstaining with hematoxylin, the sections were dehydrated with graded ethanol and xylene, mounted with p- xylene-bis-pyridinium bromide (DPX) permount (SigmaAldrich, St Louis, MO) and examined under light microscopy (DM5500; Leica Microsystems Wetzlar GmbH, Wetzlar, Germany). A positive signal was shown as brown color. All the incubation times and conditions were strictly controlled. The pathological and healthy tendons were stained in the same batch. Representative images were presented. Image analysis was done using the Image Pro Plus software (MediaCybernetics). The immunopositive signal was measured and presented as integrated optical density (IOD / mm2) of area of interest. There was an upregulation of FABP4, with significantly higher IOD / mm2of FABP4 signal, in the human patellar tendinopathy samples and rotator cuff tendinopathy samples J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 16 CUHK.212XC1PCT compared to the healthy hamstring tendons and healthy patellar tendons, supporting the association of FABP4 expression with the disease pathogenesis (FIGs.1A-1D). EXAMPLE 2—CO-LOCALIZATION OF FABP4 WITH INFLAMMATORY CYTOKINES IN HUMAN ROTATOR CUFF TENDINOPATHY Co-immunofluorescent staining of FABP4 with IL-1β and TNF-α in healthy tendon samples and rotator cuff tendinopathy samples collected as described above was done. The sections were stained with primary antibodies against FABP4 (1:200), washed and stained with primary antibodies against IL-1β (1:200) or primary antibodies against TNF-α (1:200). After washing, the sections were stained with anti-rabbit Alexa Fluor® 488 (1:500) and anti-goat Alexa Fluor® 555 (1:500). The sections were washed and counterstained with 4′-6-diamidino- 2-phenylindole (DAPI) before examination with a fluorescent microscope (FIG.2). The results showed that the expression of IL-1β and TNF-α increased in rotator cuff tendinopathy samples and the expression of FABP4 co-localized with the expression of IL-1β and TNF-α, particularly at the blood vessels and tendon cells, supporting interaction of FABP4 and inflammatory cytokines in the pathogenesis of tendinopathy. EXAMPLE 3—UPREGULATION OF FABP4 AND INFLAMMATORY CYTOKINES IN THE MOUSE CI ANIMAL MODEL After anesthesia, 20 μl of 1% bacterial collagenase I (0.1 mg) or saline was injected in the mid-substance of one Achilles tendon of each mouse. At week 2 and week 8 after saline or collagenase injection (CI model), the Achilles tendon was harvested for IHC staining of FABP4, pro- inflammatory cytokines (IL-1β, IL-6, TNF-α) and anti-inflammatory cytokine (IL-10). The IHC staining protocol was similar to the one described in Example 1. Primary antibodies against FABP4 (1:200) and IL-1β (1:200), IL-6 (1:100), TNF-α (1:200), IL-10 (1:200) and HRP-conjugated secondary antibody (1:500) were used (FIG.3). There was concurrent upregulation of FABP4, pro-inflammatory and anti- inflammatory cytokines in the mouse’s Achilles tendon after CI tendon injury. The results suggested that FABP4 upregulation was associated with inflammation and tendon damages in the CI model. The upregulation of FABP4 in both patellar tendinopathy and rotator cuff tendinopathy as well as in the CI animal model of Achilles tendinopathy supported the universal involvement of FABP4 in the disease pathogenesis. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 17 CUHK.212XC1PCT EXAMPLE 4—FABP4 INJECTION INDUCED DAMAGES, ECTOPIC BONE AND INFLAMMATION IN MOUSE ACHILLES TENDONS RESEMBLING HUMAN TENDINOPATHY After anaesthesia, 20 µl of saline or FABP4 (0.5 µg) was injected into one Achilles tendon of each mouse. The tendon samples were collected at week 2 and week 8 for histology with haemtoxylin and eosin (H&E) staining and IHC staining of pro-inflammatory cytokines (IL-1-β, TNF-α, IL-6) and anti-inflammatory cytokine (IL-10). Ectopic bone formation in tendon was also examined at week 8 after injection by microCT imaging. The Achilles tendons were harvested and prepared for histology. The tendon samples were stained with H&E after sectioning, deparaffinization, and rehydration. The H&E-stained slides were dehydrated, mounted, and visualized under light and polarization microscopy (DM5500; Leica Microsystems Wetzlar GmbH, Wetzlar, Germany). Ectopic bone formation in tendons was examined using a cone-beam microCT system (Bruker Skyscan 1276 in vivo microCT system). The Achilles tendons were scanned with the calf muscle and the calcaneus bone as the landmarks. The images were then 3D-reconstructed after thresholding, using the built-in software. The Achilles tendon-only region was selected as the region of interest (ROI). The bone volume (BV) of ectopic mineralization inside the Achilles tendon was measured. The IHC staining protocol was similar to the one described in Example 1 (FIG.4). FABP4 injection induced damages, chondrocyte-like cells, ectopic bone, fat accumulation, loss of collagen fiber alignment, and inflammation in mouse Achilles tendons resembling human tendinopathy. EXAMPLE 5—FABP4 INCREASED THE MRNA EXPRESSION OF INFLAMMATORY CYTOKINES Human and mice TDSCs were treated with FABP4 (120 ng / mL) with serum starvation for 24 h. The mRNA expressions of inflammatory cytokines were examined by quantitative real-time-polymerase chain reaction (qRT-PCR) (FIG.5). The addition of FABP4 significantly increased the expressions of inflammatory cytokines in both human and mouse TDSCs, suggesting that FABP4 is a pro-inflammatory adipokine. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 18 CUHK.212XC1PCT EXAMPLE 6—HIGHER EXPRESSION OF FABP4 IN THE INFLAMMATORY HUMAN ROTATOR CUFF TENDINOPATHY TDSCS AND MOUSE TDSCS AFTER IL-1Β TREATMENT TDSCs were isolated from healthy human hamstring tendons, human rotator cuff tendinopathy tendons and mouse Achilles tendons. Mouse TDSCs were treated with or without IL-1β (10 ng / mL) under serum starvation (2% FBS for immunofluorescent staining and 1% FBS for qRT-PCR) for 48 h. The cells were stained with anti-primary antibodies against FABP4 (1:200) and anti-rabbit Alexa Fluor® 555 (1:500). Afterwards, the cells were washed and counterstained with DAPI before examination with a fluorescent microscope. The expression of Fabp4 in mouse TDSCs with or without IL-1β treatment was also examined by qRT-PCR (FIG.6). There was higher expression of FABP4 in human rotator cuff tendinopathy TDSCs compared to healthy hamstring tendon TDSCs. Treatment of mouse TDSCs with IL-1β increased the protein and mRNA expressions of FABP4. The results suggested that the reciprocal interaction of FABP4 and inflammatory cytokines can lead to the destructive cycle of inflammation and pain in tendinopathy. EXAMPLE 7—FABP4 KO PROTECTED TENDON FROM CI TENDON INJURY FABP4 wild type (WT) and knockout (KO) mice on C57BL / 6J background (Fabp4- / -) were injected with collagenase (20 μl of 1% bacterial collagenase I (0.1 mg)) or saline. At week 2 and week 8 after CI tendon injury, the Achilles tendons were harvested and prepared for H&E histology, microCT imaging of ectopic bone, and IHC staining of pro-inflammatory cytokine (IL-1β). The protocols for histology, microCT imaging and IHC staining were similar to the ones described in Example 1 and Example 4 (FIG.7). Genetic deletion of FABP4 protected tendon from collagenase-induced tendon injury as indicated by lower infiltration of inflammatory cells, lower cellularity, lower vascularity, higher collagen birefringence, absence of chondrocyte-like cells, lower ectopic bone and lower expression of IL-1β compared to the injured WT tendons. EXAMPLE 8—PHARMACOLOGICAL INHIBITION OF FABP4 WITH REPEATED INJECTIONS OF BMS309403 PROMOTED TENDON HEALING IN THE CI ANIMAL MODEL J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 19 CUHK.212XC1PCT CI tendon injury was induced by injecting collagenase into the mid-substances of mouse Achilles tendon. At week 1 after CI injury, the animals were randomized into two groups. Vehicles or BMS309403 (20 mg / kg) was injected in the Achilles tendon every 3 days for 4 times in the control and treatment groups, respectively. About 0.4 mg was therefore injected into each mouse for each injection. At week 2 after vehicle or BMS309403 treatment, the Achilles tendons were harvested for histology as described in Example 4 (FIG.8). BMS309403 promoted better tendon healing with improved tendon histological organization and collagen birefringence compared to the vehicle group. More small, nucleated cells were observed at the peripheral region in the CI tendons in the vehicle group (dotted rectangle), compared to that in the BMS309403 group at week 2 after treatment. EXAMPLE 9—PHARMACOLOGICAL INHIBITION OF FABP4 WITH REPEATED INJECTIONS OF BMS309403 PROMOTED TENDON HEALING PARTIALLY VIA SUPPRESSION OF INFLAMMATION IN THE CI ANIMAL MODEL. The CI tendon injury model and BMS309403 treatment were the same as that described in Example 8. The tendon samples were subjected to IHC staining of inflammatory cytokines IL-1β, IL-6, and TNF-α. The IHC staining protocol was similar to the one described in Example 1. Primary antibodies against IL-1β (1:500), IL-6 (1:50), TNF-α (1:100) and HRP- conjugated secondary antibody (1:500) were used (FIG.9). BMS309403 promoted tendon healing after CI tendon injury partly via suppression of inflammatory cytokines. EXAMPLE 10—OPTIMIZATION OF PROTOCOL FOR THE PREPARATION OF BMS309403-LOADED GELMA HYDROGEL COMPLEX FOR LOCAL DELIVERY TO THE ACHILLES TENDON Photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) (0.25% in PBS) at 200 µL was mixed with 0.2 mg F127 thermosensitive poloxamer (final 0.1% of LAP) and 10 mg GelMA pre-polymers (final 5% w / v). The mixture was filtered and 200 µL of the mixture was then mixed without or with 10 mg BMS309403. Twenty microliters of mixture was drawn into a syringe, irradiated with blue light at 405 nm for 15 s, 20 s, 25 s or 30 s. The ability of the mixture to eject from the syringe was observed. The incorporation of BMS309403 into GelMA hydrogel was examined by scanning electron microscopy (SEM). Twenty J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 20 CUHK.212XC1PCT microliters of the optimized preparation containing 50 mg / mL BMS309403 was injected into the Achilles tendon of each mice before polymerization (i.e., 1 mg of BMS309403 / mouse) (FIGs.10A-10B). The results showed that cross-linking the mixture with blue light for 25 s and 30 s resulted in BMS309403-loaded GelMA complexes that polymerized too quickly and hence were not suitable for injection into the Achilles tendon. GelMA hydrogel loaded with BMS309403 appeared milky white. The GelMA hydrogel surface was smooth under SEM. The successful loading of BMS309403 into GelMA hydrogel was confirmed by the presence of small particles on the surface of GelMA hydrogel. EXAMPLE 11—PHARMACOLOGICAL INHIBITION OF FABP4 WITH SINGLE INJECTION OF BMS309403-LOADED GELMA HYDROGEL COMPLEX PROMOTED TENDON HEALING IN THE CI ANIMAL MODEL GelMA loaded with 50 mg / mL BMS309403 was prepared according to the optimized protocol described in Example 10. CI tendon injury was induced by injecting collagenase into the mid-substances of Achilles tendon. At week 1 after CI tendon injury, the animals were randomly divided into three groups. The injured tendons were injected either with saline, GelMA-only, or BMS309403-loaded GelMA hydrogel once. At week 2, week 4, and week 8 after treatment, the Achilles tendons were harvested for histology, IHC staining, and microCT imaging. The contralateral uninjured Achilles tendons of the saline group without injury or injection were used as normal controls. The animals were also subjected to gait analysis at week 2 and week 8 after treatment, before sacrifice. Healthy, uninjured animals were used as controls for the gait analysis. Histology was done as described in Example 4. The IHC staining protocol was similar to the one described in Example 1. Primary antibodies against FABP4 (1:200), IL-1β (1:200) and HRP-conjugated secondary antibody (1:500) were used. The microCT imaging protocol was similar to the one described in Example 4. Gait analysis was performed at week 2 and week 8 after treatment before sacrifice using the Catwalk XT 9.0 system (Noldus Information Technology, Wageningen, The Netherlands). The mouse was guided to run in a 1.5-m transparent acyclic plastic track in both directions to record the sagittal view of both hind limbs by a high-speed CCD camera (JVC 9600) at 100 Hz. Video clip with 3 consecutive strides and with walking speed <30% variation was considered as a successful trial. Three successful trials were done for each side of the mouse, and the trial with median speed was taken for further analysis. Stand time (s), swing time (s), J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 21 CUHK.212XC1PCT mean foot loading intensity, print area (cm2) and swing speed (cm / s) were calculated from the middle stride using the built-in motion analysis software. The gait parameters of the injured / treated limb were normalized by the values of the contralateral uninjured limb of each animal. Eight uninjured mice were used as uninjured controls (‘Control’ (FIGs.11A-11D) The results showed that CI induced histopathological changes in tendon including hypercellularity, hypervascularity, cell rounding, infiltration of inflammatory cells, loss of collagen birefringence, and ectopic bone formation. Local injection of GelMA hydrogel into the Achilles tendon did not affect the histology and microCT images of Achilles tendon. Local injection of BMS309403-loaded GelMA hydrogel promoted tendon healing as shown by reduced infiltration of small, nucleated cells, reduced hypercellularity, hypervascularity, cell rounding and increased collagen fiber alignment from week 2 to week 8. The expression of FABP4 and IL-1β in the injured Achilles tendons remained high at week 2 to week 8 after treatment in the Saline group and GelMA group. However, the expression of FABP4 and IL- 1β in the Achilles tendons was reduced at week 8 after treatment with BMS309403-loaded GelMA hydrogel. BMS309403-loaded GelMA hydrogel suppressed the formation of ectopic bone after CI tendon injury at week 8 after treatment (6 / 6 samples in the Saline group and GelMA group vs.0 / 6 samples in the Gel-BMS group). There was significant lower BV in tendons in the Gel- BMS group compared to the Saline group and GelMA group at week 8 after treatment (p<0.05). CI tendon injury reduced the normalized stand time, print area and swing speed as well as increased the normalized swing time in the injured limb at week 2 and week 8 after treatment in the Saline group compared to the Control group. There was no significant change in the normalized mean foot loading intensity in the Saline group compared to the Control group. Similar results were observed in the GelMA group. Treatment of injured tendons with BMS309403-loaded GelMA hydrogel reversed the gait parameters and there were no significant difference in the gait parameters in the BMS309403-loaded GelMA group compared to the Control group at week 2 and week 8 after treatment. Single injection of BMS309403-loaded GelMA at a lower cumulative dose, therefore, promoted tendon healing in the CI tendon injury model with improvement in tendon histology, ectopic bone formation, and walking pain, and reduced expression of inflammatory cytokine. BMS309403-loaded GelMA therefore can be used as a novel treatment of inflammatory degenerative tendon and ligament injuries as well as tendinopathy. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 22 CUHK.212XC1PCT EXAMPLE 12—BMS309403 INCREASED THE COLONY-FORMING ABILITY OF TENDON-DERIVED STEM / PROGENITOR CELLS (TDSCs) TDSCs were isolated from mouse Achilles tendons and seeded at 1000 cells / well in 6- well culture plate overnight. The cells were untreated or treated with FABP4 (120 ng / mL) or BMS309403 (10 μg / mL) in 10% fetal bovine serum (FBS) and incubated for 10 days. At day 10 after treatment, the cells were stained with crystal violet and the numbers of colony-forming unit (CFU) were counted (FIGs.12A-12B). The results showed that FABP4 reduced the CFU, while BMS309403 increased the CFU. More single cells that were unable to form colonies were observed in the FABP4 group (insert). FABP4 inhibition with BMS309403 therefore improved the self-renewal ability of TDSCs, which can help to promote tendon repair after injury. EXAMPLE 13—FABP4 INCREASED ER STRESS, ENHANCED OSTEOGENESIS AND REDUCED TENOGENESIS OF INFLAMMATORY TDSCS Mouse TDSCs were seeded in 12-well culture plates overnight and treated with FABP4 (120 ng / mL) in the presence of IL-1β (10 ng / mL) in 1% FBS for 48 h. The mRNA expression of ER stress marker (Chop), osteogenic marker (Bglap) and tenogenic marker (Col1a1) were assessed by qRT-PCR (FIG.13). The results showed that there were significantly higher expressions of Chop and Bglap, but lower expression of Col1a1 after treatment of inflammatory TDSCs with FABP4. The results might explain higher oxidative stress and altered fate of TDSCs in tendinopathy. EXAMPLE 14—BMS309403 REDUCED INFLAMMATION, ER STRESS, OSTEOGENESIS AND PROMOTED TENOGENESIS OF INFLAMMATORY TDSCS Mouse TDSCs were seeded in 12-well culture plates overnight and treated with BMS309403 (10 μM) in the presence of IL-1β (10 ng / mL) at 1% FBS for 48 h. The mRNA expressions of pro-inflammatory marker (Tnfa), ER stress marker (Chop, Grp78), tenogenic makers (Tnmd, Scx) and osteogenic marker (Runx2) were assessed by qRT-PCR (FIG.14). The results showed that there was significantly lower mRNA expression of Tnfa, Chop, Grp78, and Runx2, but higher expression of Tnmd and Scx in inflammatory TDSCs after treatment with BMS309403. FABP4 inhibitors such as BMS309403, therefore, might promote tendon healing in tendinopathy by suppressing inflammation and oxidative stress and promoting tenogenesis of inflammatory TDSCs. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 23 CUHK.212XC1PCT EXEMPLARY EMBODIMENTS Embodiment 1. A method of treating an injury to a tendon or ligament in a subject, the method comprising administering to the subject a composition comprising an effective dose of a fatty acid-binding protein 4 (FABP4) inhibitor. Embodiment 2. The method of embodiment 1, wherein the FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, a triazolopyrimidine derivative, a short hairpin RNA (shRNA) that targets FABP4 expression, RNA interference (RNAi) that targets FABP4 expression, benzbromarone, a polyclonal FABP4 neutralizing antibody, a monoclonal FABP4 neutralizing antibody, or any combination thereof. Embodiment 3. The method of embodiment 1 or 2, wherein the FABP4 inhibitor is BMS309403. Embodiment 4. The method of any preceding embodiment, wherein the monoclonal neutralizing antibody is CA33 or 2E4. Embodiment 5. The method of any preceding embodiment, wherein the composition further comprises a polymer. Embodiment 6. The method of embodiment 5, wherein the polymer is gelatin methacryloyl (GelMA), poly-ɛ-caprolactone (PCL), poly-L-lactide (PLLA), poly (lactin-co- glycolic acid) (PLGA), type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof. Embodiment 7. The method of any preceding embodiment, wherein the composition further comprises a photoinitiator and a thermosensitive poloxamer. Embodiment 8. The method of embodiment 7, wherein the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) and the thermosensitive poloxamer is poloxamer 407. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 24 CUHK.212XC1PCT Embodiment 9. The method of embodiment 7 or 8, further comprising cross- linking the composition before administration of the composition to the subject. Embodiment 10. The method of embodiment 9, wherein the cross-linking comprises applying ultraviolet or blue light to the composition for about 1 second to about 1 minute. Embodiment 11. The method of any preceding embodiment, wherein the administration of the composition comprises injecting the composition into the subject or direct application of the composition to the injured tendon and / or ligament. Embodiment 12. The method of any preceding embodiment, wherein the administering to the subject comprises injecting the composition into the subject or oral administration of the composition to the subject. Embodiment 13. The method of any preceding embodiment, wherein the FABP4 inhibitor is at a concentration of about 50 mg / mL in the composition. Embodiment 14. A composition comprising a fatty acid-binding protein 4 (FABP4) inhibitor, and a polymer. Embodiment 15. The composition of embodiment 14, wherein the FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, a triazolopyrimidine derivative, a short hairpin RNA (shRNA) that targets FABP4 expression, RNA interference (RNAi) that targets FABP4 expression, benzbromarone, a polyclonal FABP4 neutralizing antibody, a monoclonal FABP4 neutralizing antibody, or any combination thereof. Embodiment 16. The composition of embodiment 14 or 15, wherein the FABP4 inhibitor is BMS309403. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 25 CUHK.212XC1PCT Embodiment 17. The composition of any of embodiments 14-16, wherein the monoclonal neutralizing antibody is CA33 or 2E4. Embodiment 18. The composition of any of embodiments 14-17, wherein the polymer is GelMA, PCL, PLLA, PLGA, type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof. Embodiment 19. The composition of any of embodiments 14-18, wherein the composition further comprises a photoinitiator and a thermosensitive poloxamer. Embodiment 20. The composition of embodiment 19, wherein the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP). Embodiment 21. The composition of embodiment 19 or 20, wherein the thermosensitive poloxamer is poloxamer 407. Embodiment 22. The composition of any of embodiments 14-21, wherein the FABP4 inhibitor is at a concentration of about 50 mg / mL. It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application. In addition, any elements or limitations of any invention or embodiment thereof disclosed herein can be combined with any and / or all other elements or limitations (individually or in any combination) or any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated with the scope of the invention without limitation thereto. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 26 CUHK.212XC1PCT REFERENCES 1. Lui PP, Maffulli N, Rolf C, Smith RK. What are the validated animal models for tendinopathy? Scand J Med Sci Sports 2011; 21(1): 3-17. 2. Kannus P. Tendons: a source of major concern in competitive and recreational athletes. Scand. J Med Sci Sports 1997; 7: 53-4. 3. U.S. Bureau of Labor Statistics. Occupational injuries and illnesses – counts, rates and characteristics. Washington, DC: Bureau of Labor Statistics, 1995. 4. Scott A, Ashe MC. Common tendinopathies in the upper and lower extremities. Curr Sports Med Rep 2006; 5(5): 233-41. 5. Alqunaee M, Galvin R, Fahey T. Diagnostic accuracy of clinical tests for subacromial impingement syndrome: a systematic review and meta-analysis. Arch Phys Med Rehabil 2012; 93(2): 229-36. 6. Gregory BP, Wysocki RW, Cohen MS. Controversies in Surgical Management of Recalcitrant Enthesopathy of the Extensor Carpi Radialis Brevis. J Hand Surg Am 2016; 41(8): 856-9. 7. Buchbinder R, Green SE, Struijs P. Tennis elbow. BMJ Clin Evid 2008; 28: 2008. 8. Lian OB, Engebretsen L, Bahr R. Prevalence of jumper’s knee among elite athletes from different sports: a cross-sectional study. Am J Sports Med 2005; 33(4): 561–7. 9. Kujala UM, Sarna S, Kaprio J. Cumulative incidence of achilles tendon rupture and tendinopathy in male former elite athletes. Clin J Sport Med 2005; 15(3): 133–5. 10. Gajhede-Knudsen M, Ekstrand J, Magnusson H, Maffulli N. Recurrence of Achilles tendon injuries in elite male football players is more common after early return to play: an 11-year follow-up of the UEFA Champions League injury study. Br J Sports Med 2013; 47(13): 856. 11. Mendonça LM, Leite HR, Zwerver J, Henschke N, Branco G, Oliveira VC. How strong is the evidence that conservative treatment reduces pain and improves function in individuals with patellar tendinopathy? A systematic review of randomised controlled trials including GRADE recommendations. Br J Sports Med 2020; 54(2): 87-93. 12. Kearney RS, Parsons N, Metcalfe D, Costa ML. Injection therapies for Achilles tendinopathy. Cochrane Database of Systematic Reviews 2015, Issue 5. Art. No.: CD010960. DOI: 10.1002 / 14651858.CD010960.pub2 J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 27 CUHK.212XC1PCT 13. Cumpston M, Johnston RV, Wengier L, Buchbinder R. Topical glyceryl trinitrate for rotator cuff disease. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006355. DOI: 10.1002 / 14651858.CD006355.pub2 14. Gianola S, Iannicelli V, Fascio E, Andreano A, Li LC, Valsecchi MG, et al. Kinesio taping for rotator cuff disease. Cochrane Database of Systematic Reviews 2021, Issue 8. Art. No.: CD012720. DOI: 10.1002 / 14651858.CD012720.pub2. 15. Moraes VY, Lenza M, Tamaoki M, Faloppa F, Belloti J. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD010071. DOI: 10.1002 / 14651858.CD010071.pub3 16. Harryman DT 2nd, Mack LA, Wang KY, Jackins SE, Richardson ML, Matsen FA 3rd. Repairs of the rotator cuff. Correlation of functional results with integrity of the cuff. J Bone Joint Surg Am 1991; 73(7): 982-9. 17. Galatz LM, Ball CM, Teefey SA, Middleton WD, Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears. J Bone Joint Surg Am 2004; 86(2): 219-24. 18. Dan M, Phillips A, Johnston RV, Harris IA. Surgery for patellar tendinopathy (jumper’s knee). Cochrane Database of Systematic Reviews 2019, Issue 9. Art. No.: CD013034. DOI: 10.1002 / 14651858.CD013034.pub2 19. Rees JD, Stride M, Scott A. Tendons - time to revisit inflammation. Br J Sports Med 2014; 48(21): 1553-1557. 20. Challoumas D, Biddle M, Millar NL. Recent advances in tendinopathy. Fac Rev 2020; 9: 16. 21. Chang W, Callan KT, Dragoo JL. The Behavior of Tendon Progenitor Cells from Tendinopathic Tendons: Implications for Treatment. Tissue Eng Part A 2020; 26(1-2): 38-46. 22. Rui YF, Lui PP, Wong YM, Tan Q, Chan KM. Altered fate of tendon-derived stem cells isolated from a failed tendon-healing animal model of tendinopathy. Stem Cells Dev 2013; 22(7): 1076-85. 23. Furuhashi M, Saitoh S, Shimamoto K, Miura T. Fatty Acid-Binding Protein 4 (FABP4): Pathophysiological Insights and Potent Clinical Biomarker of Metabolic and Cardiovascular Diseases. Clin Med Insights Cardiol 2015; 8(Suppl 3): 23-33. 24. Furuhashi M. Fatty Acid-Binding Protein 4 in Cardiovascular and Metabolic Diseases. J Atheroscler Thromb 2019; 26(3): 216-32. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 28 CUHK.212XC1PCT 25. Xu A, Wang Y, Xu JY, Stejskal D, Tam S, Zhang J, et al. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem 2006; 52(3):405-13. 26. Xu A, Tso AW, Cheung BM, Wang Y, Wat NM, Fong CH, et al. Circulating adipocyte- fatty acid binding protein levels predict the development of the metabolic syndrome: a 5-year prospective study. Circulation 2007; 115(12): 1537-43. 27. Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH, et al. Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort. Diabetes Care 2007; 30(10): 2667-72. 28. Ota H, Furuhashi M, Ishimura S, Koyama M, Okazaki Y, Mita T, et al. Elevation of fatty acid-binding protein 4 is predisposed by family history of hypertension and contributes to blood pressure elevation. Am J Hypertens 2012; 25(10): 1124-30. 29. Fuseya T, Furuhashi M, Yuda S, Muranaka A, Kawamukai M, Mita T, et al. Elevation of circulating fatty acid-binding protein 4 is independently associated with left ventricular diastolic dysfunction in a general population. Cardiovasc Diabetol 2014; 13: 126. 30. Yeung DC, Xu A, Cheung CW, Wat NM, Yau MH, Fong CH, et al. Serum adipocyte fatty acid-binding protein levels were independently associated with carotid atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27(8): 1796-802. 31. Tu WJ, Zeng XW, Deng A, Zhao SJ, Luo DZ, Ma GZ, et al. Circulating FABP4 (Fatty Acid-Binding Protein 4) Is a Novel Prognostic Biomarker in Patients With Acute Ischemic Stroke. Stroke 2017; 48(6): 1531-8. 32. Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M, Ince TA, et al. Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB J 2009; 23(11): 3865-73. 33. Iso T, Maeda K, Hanaoka H, Suga T, Goto K, Syamsunarno MR, et al. Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle. Arterioscler Thromb Vasc Biol 2013; 33(11): 2549-57. 34. Lee MY, Li H, Xiao Y, Zhou Z, Xu A, Vanhoutte PM. Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells. Br J Pharmacol 2011; 162(7): 1564-76. 35. Han Q, Yeung SC, Ip MSM, Mak JCW. Effects of intermittent hypoxia on A- / E-FABP expression in human aortic endothelial cells. Int J Cardiol 2010; 145(2): 396-8. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 29 CUHK.212XC1PCT 36. Tanaka M, Furuhashi M, Okazaki Y, Mita T, Fuseya T, Ohno K,. Ectopic expression of fatty acid-binding protein 4 in the glomerulus is associated with proteinuria and renal dysfunction. Nephron Clin Pract 2014; 128(3-4): 345-51. 37. Shum BO, Mackay CR, Gorgun CZ, Frost MJ, Kumar RK, Hotamisligil GS, et al. The adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation. J Clin Invest 2006; 116(8): 2183-92. 38. Hu W, Qiao J. Expression and regulation of adipocyte fatty acid binding protein in granulosa cells and its relation with clinical characteristics of polycystic ovary syndrome. Endocrine 2011; 40(2): 196-202. 39. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011; 17(11): 1498-503. 40. Cataltepe O, Arikan MC, Ghelfi E, Karaaslan C, Ozsurekci Y, Dresser K, et al. Fatty acid binding protein 4 is expressed in distinct endothelial and non-endothelial cell populations in glioblastoma. Neuropathol Appl Neurobiol 2012; 38(5): 400-10. 41. Fuseya T, Furuhashi M, Matsumoto M, Watanabe Y, Hoshina K, Mita T, et al. Ectopic Fatty Acid-Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury. J Am Heart Assoc 2017; 6(9): e006377. 42. Licero J, Illan MS, Descorbeth M, Cordero K, Figueroa JD, De Leon M. Fatty acid- binding protein 4 (FABP4) inhibition promotes locomotor and autonomic recovery in rats following spinal cord injury. J Neurotrauma 2022 Mar 17. doi: 10.1089 / neu.2021.0346. 43. Yang XL, Mi JH, Dong Q. FABP4 alleviates endoplasmic reticulum stress-mediated ischemia-reperfusion injury in PC12 cells via regulation of PPARγ. Exp Ther Med 2021; 21(3): 181. 44. Zhang C, Chiu KY, Chan BPM, Li T, Wen C, Xu A, et al. Knocking out or pharmaceutical inhibition of fatty acid binding protein 4 (FABP4) alleviates osteoarthritis induced by high-fat diet in mice. Osteoarthritis Cartilage 2018; 26(6): 824-33. 45. Look C, Morano I, Ehrhart-Bornstein M, Bornstein SR, Lamounier-Zepter V. BMS309403 directly suppresses cardiac contractile function. Naunyn Schmiedebergs Arch Pharmacol 2011; 384(3): 255-63. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 30 CUHK.212XC1PCT 46. Lin W, Huang X, Zhang L, Chen D, Wang D, Peng Q, et al. BMS309403 stimulates glucose uptake in myotubes through activation of AMP-activated protein kinase. PLoS One 2012; 7(8): e44570. 47. Bosquet A, Girona J, Guaita-Esteruelas S, Heras M, Saavedra-García P, Martínez- Micaelo N, et al. FABP4 inhibitor BMS309403 decreases saturated-fatty-acid-induced endoplasmic reticulum stress-associated inflammation in skeletal muscle by reducing p38 MAPK activation. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863(6): 604-13. 48. Yao F, Jiang DD, Guo WH, Guo LS, Gao MM, Bai Y, et al. FABP4 inhibitor attenuates inflammation and endoplasmic reticulum stress of islet in leptin receptor knockout rats. Eur Rev Med Pharmacol Sci 2020; 24(24): 12808-20. 49. Fan X, Xu M, Ren Q, Fan Y, Liu B, Chen J, et al. Downregulation of fatty acid binding protein 4 alleviates lipid peroxidation and oxidative stress in diabetic retinopathy by regulating peroxisome proliferator-activated receptor γ-mediated ferroptosis. Bioengineered 2022; 13(4):10540-51. 50. Shi M, Guo F, Liao D, Huang R, Feng Y, Zeng X, et al. Pharmacological inhibition of fatty acid-binding protein 4 alleviated kidney inflammation and fibrosis in hyperuricemic nephropathy. Eur J Pharmacol 2020; 887: 173570. 51. Sun M, Sun X, Wang Z, Guo S, Yu G, Yang H. Synthesis and Properties of Gelatin Methacryloyl (GelMA) Hydrogels and Their Recent Applications in Load-Bearing Tissue. Polymers (Basel) 2018; 10(11): 1290. 52. Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008; 7(6): 489-503. 53. Lan H, Cheng CC, Kowalski TJ, Pang L, Shan L, Chuang CC, et al. Small-molecule inhibitors of FABP4 / 5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity. J Lipid Res 2011; 52(4): 646-56. 54. Hertzel AV, Hellberg K, Reynolds JM, Kruse AC, Juhlmann BE, Smith AJ, et al. Identification and characterization of a small molecule inhibitor of Fatty Acid binding proteins. J Med Chem 2009; 52(19): 6024-31. 55. Wang Y, Law WK, Hu JS, Lin HQ, Ip TM, Wan DC. Discovery of FDA-approved drugs as inhibitors of fatty acid binding protein 4 using molecular docking screening. J Chem Inf Model 2014; 54(11): 3046-50. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb 31 CUHK.212XC1PCT 56. Won YW, Adhikary PP, Lim KS, Kim HJ, Kim JK, Kim YH. Oligopeptide complex for targeted non-viral gene delivery to adipocytes. Nat Mater 2014; 13(12): 1157-64 57. Yang R, Castriota G, Chen Y, Cleary MA, Ellsworth K, Shin MK, Tran JL, Vogt TF, Wu M, Xu S, Yang X, Zhang BB, Berger JP, Qureshi SA. RNAi-mediated germline knockdown of FABP4 increases body weight but does not improve the deranged nutrient metabolism of diet-induced obese mice. Int J Obes (Lond) 2011; 35(2): 217- 25. 58. Cai HY, Wang T, Zhao JC, Sun P, Yan GR, Ding HP, et al. Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db / db mice. Acta Pharmacol Sin 2013; 34(11): 1397-402. 59. Cao H, Sekiya M, Ertunc ME, Burak MF, Mayers JR, White A, et al. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab 2013; 17(5): 768-78. 60. Burak MF, Inouye KE, White A, Lee A, Tuncman G, Calay ES, Sekiya M, Tirosh A, Eguchi K, Birrane G, Lightwood D, Howells L, Odede G, Hailu H, West S, Garlish R, Neale H, Doyle C, Moore A, Hotamisligil GS. Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes. Sci Transl Med 2015; 7(319): 319ra205. 61. Miao X, Wang Y, Wang W, Lv X, Wang M, Yin H. The mAb against adipocyte fatty acid-binding protein 2E4 attenuates the inflammation in the mouse model of high-fat diet-induced obesity via toll-like receptor 4 pathway. Mol Cell Endocrinol 2015; 403: 1-9. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb

Claims

32 CUHK.212XC1PCT CLAIMS We claim:

1. A method of treating an injury to a tendon or ligament in a subject, the method comprising administering to the subject a composition comprising an effective dose of a fatty acid-binding protein 4 (FABP4) inhibitor.

2. The method of claim 1, wherein the FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, a triazolopyrimidine derivative, a short hairpin RNA (shRNA) that targets FABP4 expression, RNA interference (RNAi) that targets FABP4 expression, benzbromarone, a polyclonal FABP4 neutralizing antibody, a monoclonal FABP4 neutralizing antibody, or any combination thereof.

3. The method of claim 2, wherein the FABP4 inhibitor is BMS309403.

4. The method of claim 2, wherein the monoclonal neutralizing antibody is CA33 or 2E4.

5. The method of claim 1, wherein the composition further comprises a polymer.

6. The method of claim 5, wherein the polymer is gelatin methacryloyl (GelMA), poly-ɛ-caprolactone (PCL), poly-L-lactide (PLLA), poly (lactin-co-glycolic acid) (PLGA), type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof.

7. The method of claim 5, wherein the composition further comprises a photoinitiator and a thermosensitive poloxamer.

8. The method of claim 7, wherein the photoinitiator is lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP) and the thermosensitive poloxamer is poloxamer 407. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb33 CUHK.212XC1PCT 9. The method of claim 8, further comprising cross-linking the composition before administration of the composition to the subject.

10. The method of claim 9, wherein the cross-linking comprises applying ultraviolet or blue light to the composition for about 1 second to about 1 minute.

11. The method of claim 9, wherein the administration of the composition comprises injecting the composition into the subject or direct application of the composition to the injured tendon and / or ligament.

12. The method of claim 1, wherein the administering to the subject comprises injecting the composition into the subject or oral administration of the composition to the subject.

13. The method of claim 1, wherein the FABP4 inhibitor is at a concentration of about 50 mg / mL in the composition.

14. A composition comprising a fatty acid-binding protein 4 (FABP4) inhibitor, and a polymer.

15. The composition of claim 14, wherein the FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, a triazolopyrimidine derivative, a short hairpin RNA (shRNA) that targets FABP4 expression, RNA interference (RNAi) that targets FABP4 expression, benzbromarone, a polyclonal FABP4 neutralizing antibody, a monoclonal FABP4 neutralizing antibody, or any combination thereof.

16. The composition of claim 15, wherein the FABP4 inhibitor is BMS309403.

17. The composition of claim 15, wherein the monoclonal neutralizing antibody is CA33 or 2E4. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb34 CUHK.212XC1PCT 18. The composition of claim 14, wherein the polymer is GelMA, PCL, PLLA, PLGA, type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof.

19. The composition of claim 14, wherein the composition further comprises a photoinitiator and a thermosensitive poloxamer.

20. The composition of claim 19, wherein the photoinitiator is lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP).

21. The composition of claim 19, wherein the thermosensitive poloxamer is poloxamer 407.

22. The composition of claim 14, wherein the FABP4 inhibitor is at a concentration of about 50 mg / mL. J:\CUHK\212XC1PCT\Application\CUHK-212XC1PCT-Application.docx / brb

Images