Method for preparing biological material loaded with FABP4 inhibitor and application of biological material in treatment of tendon and ligament injury

Abstract

The present disclosure relates to methods of inhibiting FABP4, treating and delaying the progression of degenerative tendinopathy of chronic tendinopathy, and promoting surgical repair after tendon and ligament rupture in a subject. The present disclosure also relates to methods of making the FABP4 inhibitor loaded biomaterials, and the use of the FABP4 inhibitor and / or the FABP4 inhibitor loaded biomaterials in the treatment of tendon and ligament injury in a subject.

Description

[0001] Cross-reference to related applications This application claims the benefit of U.S. Provisional Application Serial No. 63 / 512,322, filed July 7, 2023, the entire contents of which, including any figures, tables, nucleic acid sequences, amino acid sequences or diagrams, are incorporated herein by reference in their entirety.

[0002] References to sequence lists The sequence list of this application is marked "CUHK-212XC1PCT-SeqList-28Jun24.xml", which was created on June 28, 2024, and has a size of 2,803 bytes. The entire contents of this sequence list are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the fields of musculoskeletal medicine, pharmacy, tendon and ligament injuries, and particularly to chronic tendinopathy. Background Technology

[0004] Chronic tendinopathy is a serious medical condition that affects the tendons in the body, causing activity-related tendon pain, tenderness, and localized pain. Tendinopathy can be diagnosed using imaging techniques such as ultrasound (US) and magnetic resonance imaging (MRI). In chronic tendinopathy, ultrasound may show hypoechoic areas, increased tendon thickness, and loss of signal characteristic of well-aligned collagen fibers, while MRI may show tendon enlargement, heterogeneity, and focal high T1 and T2 signals. Metaplasia of the tendon body may be present in tendinopathy. Tendinopathy leads to tendon degeneration and may make the tendon prone to rupture. Clinically, it may or may not be accompanied by tendon rupture.

[0005] Chronic tendinopathy is very common. It accounts for a significant portion of all sports-related injuries. Nearly 10% of all occupational diseases in the United States This results in billions of dollars in healthcare costs annually. In the United States alone, the cost of treating shoulder tendon injuries may exceed $3 billion per year. Addressing chronic tendinopathy is crucial for alleviating the financial burden on the healthcare system and improving patient outcomes. Common sites of chronic tendinopathy include the rotator cuff, the extensor carpi radialis brevis and flexor carpi medialis tendons at the elbow, the patellar tendon, the Achilles tendon, the plantar fascia, and the finger flexor tendons. Rotator cuff tendinopathy affecting the supraspinatus tendon is a common cause of shoulder pain, with an estimated prevalence of [percentage missing] in the general population. Rotator cuff tendons, especially the supraspinatus tendon, can degenerate and eventually rupture. Lateral elbow tendinopathy is also a common tendon disorder, affecting not only tennis players but also the general population. The prevalence of lateral elbow tendinopathy in the general population and manual laborers is approximately 1-3% and [missing data - likely related to prevalence]. Its annual incidence rate in general practice is 4 to 7 per 1000 people. 7 The prevalence of patellar tendinitis in athletes varies depending on the sport. It has been reported that the prevalence is as high as 45% among volleyball players, while it is lower among basketball players. Achilles tendinitis is particularly common among runners, especially elite long-distance runners, who are at high risk of Achilles tendon injury. The incidence of Achilles tendinitis among football players is approximately 3%, with a recurrence rate of [missing information]. .

[0006] The etiology and pathogenesis of chronic tendinopathy are multifactorial and not yet fully understood, but changes in mechanical load, such as overuse, are important risk factors. Other risk factors, such as environmental factors, metabolic diseases, genetics, demographic characteristics, and drug use, can alter the risk and prognosis of overuse-induced tendinopathy.

[0007] The prevalence of chronic tendinopathy increases with age and severely limits physical activity in an aging population. Age is a significant risk factor for tendinopathy, particularly rotator cuff tears. Approximately 30% of adults over 60 years of age have rotator cuff tears, while this prevalence increases to 62% in adults over 80 years of age. With an aging population and the promotion of active lifestyles, the incidence of age-related and overuse-related tendinopathy is increasing.

[0008] Treatment of chronic tendinopathy is challenging, and effective, evidence-based interventions are currently lacking. The evidence supporting non-surgical interventions, such as rest, physical therapy, kinesiology tape, shockwave therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids, is low to very low. For patellar tendinopathy, conservative treatment is not significantly superior to minimally invasive or other invasive interventions in improving short-term pain and function. Similarly, there is no conclusive evidence to support the use of conservative treatment. .

[0009] If non-surgical treatment fails, surgery is usually considered. Depending on the extent of the injury, debridement, tendon insertion repair, or reconstruction may be performed. However, the success rates of these surgeries can vary, and the risk of complications is high. Postoperative recurrent pain is common. Healing of the tendon and bone is challenging, and rotator cuff repair has a high failure rate because it requires the healing of two materials with different stiffnesses (bone and tendon). The high failure rate (20%–94%) of rotator cuff repair remains unresolved. For patellar tendinopathy, surgery is no more effective than eccentric exercise or sclerotherapy. Therefore, there is an urgent need to develop more effective treatments for chronic tendinopathy. Summary of the Invention

[0010] This disclosure relates to treating or delaying the progression of tendinopathy and promoting surgical repair after tendon rupture by inhibiting the function of fatty acid-binding protein 4 (FABP4). Tendon overuse triggers an inflammatory response, leading to a decrease in tenogenic markers and an increase in non-tendinogenic markers in tendon-derived stem / progenitor cells (TDSCs), thereby causing tissue metaplasia. This disclosure presents the upregulation of FABP4 and its pro-inflammatory and non-tendinogenic effects in clinical samples and in a collagenase-induced (CI) animal model of inflammatory degenerative tendon injury. With increased FABP4 levels, the misdifferentiation of TDSCs into non-tendinogenic cells reduces their ability to participate in tendon healing, leading to healing failure and calcification. Therefore, FABP4 is a target for the treatment of tendinopathy and inflammatory degenerative tendon and ligament injuries.

[0011] In some embodiments, this disclosure can inhibit inflammation, suppress and / or reverse misdifferentiation of TDSCs by retention, and increase the pool of TDSCs available for tendinogenic differentiation to enhance the regeneration of degenerative tendons. In some embodiments, the method of this disclosure includes administering a FABP4 inhibitor to a subject. In some embodiments, the method of this disclosure alleviates CI tendon injury and promotes tendon healing by reducing inflammation and oxidative stress, promoting self-renewal and tendinogenic activity of TDSCs. In some embodiments, biological materials are used to administer the FABP4 inhibitor.

[0012] In some embodiments, a FABP4 inhibitor (e.g., BMS309403) is loaded into a biomaterial (e.g., methacrylamide gelatin (GelMA) hydrogel). In some embodiments, the FABP4 inhibitor or the GelMA hydrogel loaded with the FABP4 inhibitor can be used in methods to promote the healing of inflammatory degenerative tendon and ligament injuries and / or tendinopathy.

[0013] In some embodiments, the FABP4 inhibitor is BMS309403, which is a selective and potent bifonazole FABP4 inhibitor (Ki: <2 nM; IC50: 0.71). In some embodiments, a biological scaffold can be used to locally deliver the FABP4 inhibitor to the injured tendon in a tendinopathy patient, achieving slow release. In some embodiments, the FABP4 inhibitor is loaded into a GelMA prepolymer, and the mixture is then injected after the GelMA prepolymer is crosslinked with ultraviolet light and / or blue light. This approach supports local application to the injured tendon and achieves slow release of the FABP4 inhibitor as the GelMA slowly dissolves. Attached Figure Description

[0014] The patent or application documents include at least one color drawing. Upon request and payment of the necessary fees, the patent office will provide a copy of the patent or application publication with color drawings.

[0015] Figures 1A-1D :( Figure 1A This image shows immunohistochemical (IHC) staining micrographs of FABP4 in healthy hamstring tendon samples, healthy patellar tendon samples, and patellar tendinopathy samples. Scale bar = 100µm, yellow arrow: blood vessels; red arrow: areas of cell proliferation; CR: calcification areas. Figure 1B Displaying the FABP4 signal Box plots. n=6 / group; p < 0.01; p < 0.001. Figure 1C This image shows IHC staining micrographs of FABP4 in hamstring tendon samples from healthy individuals and rotator cuff tendinopathy samples. Scale bar = 100µm, yellow arrow: blood vessels; red arrow: areas of cell proliferation; CR: areas of calcification. Figure 1D Displaying the FABP4 signal Box plots. n=5 / group; p < 0.01.

[0016] Figure 2 Photomicrographs showing the colocalization of FABP4 with IL-1β or TNF-α in healthy tendon samples and human rotator cuff tendinopathy samples. Scale bar = 50µm; n = 5 / group; white arrow: colocalization signal in tendon cells; red arrow: colocalization signal in blood vessels.

[0017] Figures 3A-3B :( Figure 3A (Image showing IHC staining of FABP4, IL-1β, TNF-α, IL-6, and IL-10 in representative mouse Achilles tendon samples at weeks 2 and 8 after saline or collagenase injection. Scale bar = 100µm (inset: 25µm); red arrows: areas of cell proliferation; green arrows: small nucleated cells;) : Chondrocytes; CR: Calcified area; Black arrow: Immunopositive cells; Figure 3B Display target markers Box plots. n=5 / group; p < 0.01; p < 0.001.

[0018] Figures 4A-4C :( Figure 4A(Ai) Photomicrographs showing H&E staining and corresponding polarized light images of representative mouse Achilles tendon samples at weeks 2 and 8 after injection of saline or FABP4 (0.5 µg). Scale bar = 100 µm (inset: 25 µm); CR: calcified area; : Chondroid cells; (Aii) Histopathological score of H&E images. n=5 / group; p < 0.001. Figure 4B (Bi) MicroCT images show ectopic calcification within the Achilles tendon at week 8 following saline or FABP4 (0.5µg) injection. Scale bar = 50µm; white arrows: ectopic bone; (Bii) Box plots showing bone volume (BV) within the tendon in different groups. n = 6 / group; p < 0.05. Figure 4C (Ci) Photomicrographs showing IHC staining of IL-1β, TNF-α, IL-6, and IL-10 in representative mouse Achilles tendon samples at weeks 2 and 8 after injection of saline or FABP4 (0.5 µg). Scale bar = 100 µm (inset: 25 µm); red arrows: areas of cell proliferation; : Chondrocytes; Black arrow: Immunopositive cells; (Cii) Showing levels of IL-1β, TNF-α, IL-6, and IL-10 at weeks 2 and 8 following saline or FABP4 (0.5 µg) injection. Box plot. n=5 / group; p<0.05; p < 0.01; p < 0.001.

[0019] Figures 5A-5B Box plot shows ( Figure 5A In human TDSCs and ( Figure 5B In mouse TDSCs, the expression of IL1b, IL6, TNFα (for human TDSCs) and Il1b, Il6, Il10 (for mouse TDSCs) was measured 24 hours after the addition of FABP4 (120 ng / mL). p < 0.05; p < 0.01; p < 0.001; n = 4 / group.

[0020] Figures 6A-6C :( Figure 6A Micrographs show the protein expression of FABP4 in human rotator cuff tendinopathy TDSCs compared to healthy hamstring tendon TDSCs; scale bar: 100µm; n=4. Cell nuclei were stained with DAPI. Figure 6BMicrographs show FABP4 protein expression in mouse TDSCs after treatment with IL-1β (10 ng / mL) for 48 hours; scale bar: 100 µm; n=6. Cell nuclei were stained with DAPI. Figure 6C The box plot shows the expression of Fap4 mRNA. p < 0.05; n = 4~5 / group.

[0021] Figures 7A-7C :( Figure 7A Photomicrographs showing H&E staining and corresponding polarized light images of the Achilles tendon in WT and FABP4 KO mice at weeks 2 and 8 after saline or collagenase injection. Staining: Hematoxylin-eosin; n=5 / group; Scale bar: 50µm (inset: 200µm); Yellow arrow: blood vessels; Red arrow: area of ​​cell proliferation; Green arrow: small nucleated cells; White arrow: collagen birefringence; Chondrocytes. Figure 7B (i) MicroCT images show WT and FABP4 KO (Fabp4) at week 8 following saline or collagenase injection. - / - (ii) Box plots showing the bone volume (BV) within the tendon in different groups. n=6 / group; scale bar: 50µm; white arrows: ectopic bone; p < 0.01. Figure 7C (Image showing IHC staining of IL-1β in the Achilles tendon of WT and FABP4 KO mice at weeks 2 and 8 after saline or collagenase injection. n=5 / group; scale bar: 50µm (inset: 200µm); black arrows: immunopositive cells.)

[0022] Figure 8 Micrographs show H&E staining and corresponding polarized light images of representative Achilles tendon samples from WT mice at week 2 after repeated injections of the vector or BMS309403 in the CI tendon injury model. n=4 / group; scale bar=100µm (inset: 25µm); red arrow: cell proliferation area; green arrow: small nucleated cells.

[0023] Figure 9 Micrographs show IHC staining of IL-1β, IL-6, and TNF-α in the Achilles tendon of mice in a CI tendon injury model at week 2 after repeated injections of the vector or BMS309403. n=4 / group; scale bar=100µm (inset: 25µm); red arrows: immunopositive cells.

[0024] Figures 10A-10B :( Figure 10AThe photograph shows the following steps: (i) mixing LAP, F127, and GelMA prepolymers with BMS309403, (ii) loading the mixture into a syringe and crosslinking it with 405nm blue light, and (iii) injecting it into the Achilles tendon. The ability of the mixture to be ejected from the syringe after different crosslinking times with blue light is shown. Figure 10B The gross morphology (i, ii) and SEM images (iii~vi) show the surface morphology of GelMA hydrogels with and without BMS309403. Figures (v~vi) are higher magnification images of figures (iii~iv). n=3 / group; scale bar: 100µm (iii~iv); 10µm (v~vi); arrow: BMS309403.

[0025] Figures 11A-11D :( Figure 11A Micrographs show H&E staining and corresponding polarized light images of representative Achilles tendon samples from WT mice at weeks 2, 4, and 8 after a single injection of saline, GelMA-only ('GelMA'), or GelMA hydrogel loaded with BMS309403 ('Gel-BMS') in the CI tendon injury model. Uninjured or uninjected contralateral Achilles tendons from the saline group were used as normal controls ('Normal'). n=6 / group; scale bar=50µm (inset: 200µm); yellow arrow: blood vessels; red arrow: area of ​​cell proliferation; green arrow: small nucleated cells; CR: calcification area; Chondrocytes. Figure 11B Micrographs show IHC staining of FABP4 and IL-1β in representative Achilles tendon samples from WT mice at weeks 2, 4, and 8 after a single injection of saline, GelMA-only ('GelMA'), or GelMA hydrogel loaded with BMS309403 ('Gel-BMS') in a CI tendon injury model. Uninjured or undamaged contralateral Achilles tendons from the saline group served as normal controls ('Normal'). n=5 / group; scale bar=100µm; red arrows: immunopositive cells. Figure 11Ci. MicroCT images show ectopic mineralization within the Achilles tendon of WT mice after a single injection of saline ('Saline'), GelMA-only ('GelMA'), or GelMA hydrogel loaded with BMS309403 ('Gel-BMS') at week 8 post-treatment in the CI tendon injury model. The uninjured or uninjected contralateral Achilles tendon in the saline group served as a normal control ('Normal'). n=6 / group; scale bar=50µm; white arrow: ectopic mineralization. ii. Box plots show the bone volume (BV) within the tendon in the saline ('Saline'), GelMA-only ('GelMA'), and GelMA-loaded with BMS309403 ('Gel-BMS') groups at week 8 post-treatment in the CI tendon injury model. The uninjured or uninjected contralateral Achilles tendon in the saline group served as a normal control ('Normal'). n=6 / group; p<0.05. ( Figure 11D Box plots show gait parameters of mice in different groups at weeks 2 and 8 after treatment. n=8 / group; p < 0.05; p < 0.01; p < 0.001.

[0026] Figures 12A-12B :( Figure 12A Photomicrographs showing untreated or treated colony-forming units (CFUs) and individual colonies with FABP4 or BMS309403; staining: crystal violet; scale bar = 100µm. Figure 12B Box plots show different groups of CFUs. p < 0.05; n = 4~5 / group.

[0027] Figure 13 Box plots show the effect of FABP4 on the mRNA expression of endoplasmic reticulum stress markers (Chop), osteogenic markers (Bglap), and tendonogenic markers (Col1a1) in inflammatory TDSCs 48 hours after treatment. n=4-6 / group; p < 0.05.

[0028] Figure 14 Box plots show the effects of BMS309403 on the mRNA expression of pro-inflammatory markers (Tnfa), endoplasmic reticulum stress markers (Chop, Grp78), tendonogenic markers (Tnmd, Scx), and osteogenic markers (Runx2) in inflammatory TDSCs after 48 hours of treatment. n=4-6 / group; p < 0.05.

[0029] Brief description of sequence lists Sequence Listing ID: 1: FABP4 shRNA Inhibitor Sequence Listing ID: 2: FABP4 shRNA Inhibitor Detailed Implementation Specific definition The singular forms “a,” “an,” and “the” used herein are intended to also include the plural forms, unless the context clearly indicates otherwise. Furthermore, when the terms “including,” “includes,” “having,” “has,” “with,” or variations thereof are used in the detailed description and / or claims, these 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” are used interchangeably.

[0030] The phrase "consistently composed of" or "consistently composed of" indicates that the claim covers embodiments that include the specified materials or steps, as well as those embodiments that do not substantially affect the basic and novel features of the claim.

[0031] The term "about" refers to an acceptable margin of error for a specific value, as determined by a person skilled in the art, which depends in part on how the value is measured, i.e., the limitations of the measurement system. When used in the context of compositions containing a specified amount of an ingredient, these compositions contain an amount of the ingredient with a variation of 0 to 10% (error range) (X±10%) above and below that value. In other contexts, the term "about" provides a variation of 0 to 10% (error range) (X±10%) above and below a given value. Clearly, this variation represents a range that can be up to 10% higher or lower than the 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%.

[0032] In this disclosure, to avoid having to elaborate and describe every value within a range in detail, ranges are stated in abbreviated form. Any appropriate value within a range may be chosen as the upper limit, lower limit, or endpoint of the range where appropriate. For example, the range 0.1 to 1.0 represents the endpoint values ​​0.1 and 1.0, and the intermediate values ​​0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges included within 0.1 to 1.0, such as 0.2 to 0.5, 0.2 to 0.8, 0.7 to 1.0, etc. A range containing at least two significant digits is envisioned; for example, the range 5 to 10 represents all values ​​between 5.0 and 10.0 and between 5.00 and 10.00, including endpoint values. When ranges are used herein, combinations and sub-combinations of ranges (e.g., sub-ranges within the scope of the disclosure) and specific embodiments thereof are explicitly included.

[0033] The terms “treatment,” “treating,” “palliating,” and “ameliorating” (and grammatical variations thereof) used in this article are used interchangeably. These terms refer to methods employed to achieve a beneficial or desired outcome, including but not limited to therapeutic benefits. A therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with an underlying disease or its symptoms or lesions, resulting in an improvement observed in the patient, even if the patient may still be troubled by the lesion, disease, or its symptoms.

[0034] The term "effective amount" or "therapeutically effective amount" refers to the amount of a compound described herein sufficient to affect the intended application, including but not limited to the treatment of a disease or injury. Therapeuticly effective amounts may vary depending on the intended application (in vitro or in vivo) or the subject being treated and the condition of the disease, such as the subject's weight and age, the severity of the disease or injury, the method of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to doses that induce a specific response, such as delaying the progression of chronic tendinopathy or promoting healing of inflammatory degenerative tendon tears and surgical repairs. A specific dose will depend on the specific compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.

[0035] In some embodiments of this disclosure, the method includes administering one or more doses of a composition of the subject matter of this disclosure. The method may include administering 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 matter of this disclosure described herein. In some embodiments, the dose may be administered over a period 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, the dosage may be administered daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 10 days, every 14 days, every 21 days, every 30 days, approximately every 4 weeks, approximately every 6 weeks, approximately every 8 weeks, approximately every 12 weeks, approximately every 16 weeks, approximately every 20 weeks, approximately every 24 weeks, or approximately every 26 weeks. Furthermore, treatment of a subject with a therapeutically effective amount of the composition disclosed herein may include a single treatment or a series of treatments. It should also be understood that the effective dose of the composition used for treatment may increase or decrease during a particular treatment. Dosage variations may arise and become apparent from the results of imaging techniques used to detect, for example, tendon and / or ligament injuries, as is well known in the art.

[0036] As used herein, the term "subject" refers to an animal that needs or expects to receive the benefits provided by the therapeutic composition. This animal can be, for example, a mammal, including humans, pigs, horses, goats, cats, mice, rats, dogs, apes, chimpanzees, orangutans, guinea pigs, hamsters, cattle, and sheep. These benefits may include, but are not limited to, treating a health condition, disease, or disorder; preventing a health condition, disease, or disorder; and enhancing the function of tendons and / or ligaments in the body. Subjects can be of any age or developmental stage, including infants, toddlers, adolescents, teenagers, adults, or the elderly. The terms "subject" and "patient" are used interchangeably.

[0037] The terms “scaffold”, “bio-scaffold”, “construct”, “bio-construct”, “composite”, and “bio-composite” used in this article are interchangeable.

[0038] The term "scaffold" as used in this article refers to a temporary structure used as a support system to assist in drug delivery to damaged or diseased areas.

[0039] "Reduces" or "retards" refers to a negative change of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.

[0040] "Increases" means a positive change of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.

[0041] References to any list of chemical groups for a variable in this document include the definition of that variable as any single group or combination of the listed groups. References to embodiments of a variable or aspect in this document include that embodiment as any single embodiment or as an embodiment in combination with any other embodiment or part thereof.

[0042] Any composition or method provided herein may be combined with one or more of any other compositions and methods provided herein.

[0043] Other features and advantages of this disclosure will be apparent from the following description of its preferred embodiments and from the claims. All references cited herein are incorporated herein by reference in their entirety.

[0044] Composition In some embodiments, the compositions according to the subject matter of this disclosure utilize FABP4 inhibitors, including, for example, BMS309403, HM50316, HTS01037, cobimetinib, dafinaracin, fosaprepitant, paliperidone, risperidone, pimozide, and other triazolopyrimidine derivatives (e.g., compounds 1-58 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 incorporated herein by reference), and short hairpin RNAs (shRNAs) targeting FABP4 expression (e.g., 5'CCGGTCAGAGAGTACTTTT). 3' (Sequence Listing ID: 1) and RNA interference (RNAi) (e.g., 5'-CACCGAGATTTCCTTCAAA-3' (Sequence Listing ID: 2)), benzbromarone (a uricosuric agent), polyclonal and monoclonal FABP4 neutralizing antibodies, such as CA33 (see commercially available CA33 at creativebiolabs.net / Anti-FABP4-Recombinant-Antibody-clone-CA33-22932.htm) and 2E4. In a preferred embodiment, the FABP4 inhibitor is BMS309403. In some embodiments, to create short hairpin RNA (shRNA), a nine-nucleotide loop (5'-TTCAAGAGA-3') is placed to separate the sense and antisense sequences used for RNAi.

[0045] In some embodiments, the concentration of the FABP4 inhibitor in the biological material may be from about 0.01 mg / mL to about 1000 mg / mL, from about 0.1 mg / mL to about 100 mg / mL, from about 1 mg / mL to about 75 mg / mL, or about 50 mg / mL. In some embodiments, without the use of biological materials, the FABP4 inhibitor may be administered to the subject at a dose of from about 0.01 mg / kg to about 1000 mg / kg, from about 0.1 mg / kg to about 100 mg / kg, from about 1 mg / kg to about 75 mg / kg, or about 20 mg / kg.

[0046] In some embodiments, the FABP4 inhibitor can be integrated into a composite scaffold composed of synthetic and / or natural polymers. In some embodiments, synthetic polymers include, for example, poly-ε-caprolactone (PCL), poly-L-lactide (PLLA), and polylactic-co-glycolic acid copolymer (PLGA). In some embodiments, natural polymers include, for example, type I collagen, alginate, chitosan, gelatin, and decellularized tendon matrix. Gelatin is a natural hydrophilic polymer produced by the hydrolysis and denaturation of collagen at high temperatures. Compared to collagen, gelatin exhibits good biocompatibility, solubility, and degradability, as well as lower antigenicity. However, gelatin has poor thermal stability, and chemical crosslinking of gelatin can affect its biocompatibility because some crosslinking agents are toxic. In a preferred embodiment, the polymer is methacrylamide gelatin (GelMA), which is produced by modifying gelatin with methacrylic anhydride (MA). In some embodiments, when a photoinitiator is added, a prepolymer solution including a FABP4 inhibitor, such as a GelMA prepolymer, crosslinks under ultraviolet and / or blue light to form a hydrogel with good thermal stability, biocompatibility and degradation properties.

[0047] In some embodiments, the FABP4 inhibitor can be mixed with a polymer (e.g., GelMA prepolymer) and a photoinitiator, a thermosensitive poloxamer, or a combination thereof. In some embodiments, the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphine (LAP) or 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure-2959), while the thermosensitive poloxamer is poloxamer 407 (e.g., F-127 (BASF, Ludwigshafen, Germany). In some embodiments, the concentration of the photoinitiator LAP is about 0.001% to about 10%, about 0.01% to about 5%, about 0.01% to about 1%, or about 0.25%. In some embodiments, the concentration of the thermosensitive poloxamer 407 is about 0.001% to about 10%, about 0.01% to about 5%, about 0.1% to about 1%, or about 0.1%, relative to the amount of photoinitiator in the composition. In some embodiments, the concentration of the polymer GelMA prepolymer is 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 some embodiments, the mixture may be crosslinked by ultraviolet or blue light prior to application of the composition to a subject. In some embodiments, the wavelength of the ultraviolet light is about 320 nm to about 390 nm, and the wavelength of the blue light is about 405 nm. In some embodiments, the crosslinking of the mixture can be carried out for about 1 second to about 1 minute. In a preferred embodiment, BMS309403 is mixed with GelMA prepolymer, LAP (0.25% in PBS (phosphate-buffered saline)) and F127 thermosensitive poloxamer (0.1% of LAP), and crosslinked with blue light at 405 nm for about 1 second to about 1 minute or about 14 seconds, and then applied to the injured tendon and / or ligament.

[0048] In one embodiment, the compositions of this disclosure are formulated into products that can be consumed orally, such as food, capsules, pills, or drinkable liquids. Orally deliverable drugs are any physiologically active substances delivered through initial absorption in the gastrointestinal tract or oral mucosa. These subject compositions can also be formulated into solutions that can be administered, for example, by injection, including intravenous, intraperitoneal, intramuscular, subcutaneous, or local injection.

[0049] The compositions disclosed herein may further include one or more pharmaceutically acceptable carriers and / or excipients, and may be formulated into formulations in solid, semi-solid, or liquid forms, such as tablets, capsules, powders, granules, solutions, suppositories, injections, sprays, creams, pellets, pods, lozenges, dispersants, aqueous solutions, non-aqueous solutions, oil-in-water emulsions, or water-in-oil liquid emulsions.

[0050] As used in this article, the term "pharmaceutically acceptable" means compatible with other components of a pharmaceutical composition and harmless to the recipient.

[0051] Carriers and / or excipients according to the subject matter of this disclosure may include any and all solvents, diluents, buffers (e.g., neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffer), oil-in-water or water-in-oil emulsions, aqueous compositions including or excluding organic cosolvents suitable for intravenous use, solubilizers (e.g., polysorbate 65, polysorbate 80), colloids, dispersion media, carriers, fillers, chelating agents (e.g., EDTA or glutathione), amino acids (e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, aromas, thickeners (e.g., carbomer, gelatin or sodium alginate), coatings, preservatives (e.g., thimerosal, benzyl alcohol, polyquaternium), antioxidants (e.g., ascorbic acid, sodium metabisulfite), tension modifiers, absorption delay agents, adjuvants, fillers (e.g., lactose, mannitol), etc. The use of carriers and / or excipients is well known in the pharmaceutical and supplement fields. The use of carriers or excipients in the compositions of this disclosure may be considered, except for any conventional media or reagents incompatible with the target health-promoting substance or the composition.

[0052] In one embodiment, the compositions of the subject matter of this disclosure can be formulated for administration by injection, for example, as a solution or suspension. The solution or suspension may include suitable non-toxic, parenteral-acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, phosphate-buffered saline (PBS), dimethyl sulfoxide (DMSO), polyethylene glycol, or isotonic sodium chloride solution, or suitable dispersants or wetting agents and suspending agents such as sterile, non-irritating fixed oils, including synthetic monoglycerides or diglycerides.

[0053] Treatment methods for tendon and / or ligament injuries In some embodiments, FABP4 inhibitors and / or biomaterials carrying FABP4 inhibitors (e.g., GelMA) can be used to treat tendon and / or ligament injuries, chronic tendinopathy, and to promote healing following inflammatory degenerative tendon and ligament injuries. Tendons and ligaments that may develop tendinopathy due to load changes (e.g., overuse) include the Achilles tendon, patellar tendon, rotator cuff, extensor carpi radialis brevis and flexor carpi medialis tendons of the elbow, plantar fascia, and flexor tendons of the fingers. In some embodiments, the affected tendons and ligaments may present with pain and swelling, with or without tearing. In some embodiments, for painful tendinopathy that does not require surgery, FABP4 inhibitors and / or biomaterials carrying FABP4 inhibitors can be applied, for example, by local injection to the painful and / or injured tendon or ligament. In some implementations, for tendinopathy presenting as tendon tears requiring surgical repair, FABP4 inhibitors and / or biomaterials carrying FABP4 inhibitors may be applied during or after surgical repair, for example by postoperative injection or by direct application of FABP4 inhibitors and / or biomaterials carrying FABP4 inhibitors to the surgically repaired tendon and / or ligament during surgery.

[0054] In some embodiments, FABP4 inhibitors and / or biomaterials carrying FABP4 inhibitors can be used to enhance tissue repair, particularly tendon and / or ligament tissue. In some embodiments, FABP4 inhibitors and / or biomaterials carrying FABP4 inhibitors can be used to promote tendon or ligament regeneration. In some embodiments, FABP4 inhibitors and / or biomaterials carrying FABP4 inhibitors can be used in the form of putty, scaffold, or injectable hydrogel.

[0055] In some embodiments, administration of a FABP4 inhibitor and / or a biomaterial carrying a FABP4 inhibitor can reduce tendon injury, decrease ectopic bone formation, and alleviate walking pain. In some embodiments, administration of a FABP4 inhibitor and / or a biomaterial carrying a FABP4 inhibitor can reduce the expression of inflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α).

[0056] In some embodiments, administration of a FABP4 inhibitor can restore natural tendon healing by promoting the self-renewal capacity of TDSCs. In some embodiments, administration of a FABP4 inhibitor can enhance the anti-inflammatory and antioxidant effects of inflammatory TDSCs, manifested by decreased expression of inflammatory cytokines (Tnfa) and endoplasmic reticulum stress markers (Chop, Grp78). In some embodiments, administration of a FABP4 inhibitor can redirect the cell fate of inflammatory TDSCs towards the tendon cell lineage by promoting the expression of tenogenic markers (Tnmd, Scx) and reducing the expression of osteogenic markers (Runx2) in inflammatory TDSCs.

[0057] In some embodiments, this disclosure discloses methods for producing biomaterials carrying FABP4 inhibitors, and methods for treating or delaying the progression of chronic tendinopathy and promoting healing of inflammatory degenerative tendon tears and surgical repairs using FABP4 inhibitors and / or biomaterials carrying FABP4 inhibitors.

[0058] In some embodiments, this disclosure provides a method for treating chronic tendinopathy in patients with FABP4 inhibitors and / or biomaterials containing FABP4 inhibitors. In some embodiments, tendon symptoms and pathological changes in patients with tendinopathy are reversed after topical application of FABP4 inhibitors and / or biomaterials containing FABP4 inhibitors. In some embodiments, the progression of tendinopathy is slowed after topical application of FABP4 inhibitors and / or biomaterials containing FABP4 inhibitors. In some embodiments, the occurrence of tendinopathy is prevented after topical application of FABP4 inhibitors and / or biomaterials containing FABP4 inhibitors. In some embodiments, degenerative tendon tears and post-operative healing are improved after topical application of FABP4 inhibitors and / or biomaterials containing FABP4 inhibitors.

[0059] All patents, patent applications, provisional applications and publications cited or referenced herein are incorporated in their entirety by reference, including all figures and tables, to the extent that they do not conflict with the express teachings of this specification.

[0060] The following are examples illustrating the procedures of this disclosure. These examples should not be construed as limiting. Unless otherwise stated, all percentages are by weight and all solvent mixture ratios are by volume.

[0061] Example 1—Upregulation of FABP4 in patellar tendinopathy and rotator cuff tendinopathy Adult patients with patellar tendinopathy and rotator cuff tendinopathy confirmed by ultrasound (US) or magnetic resonance imaging (MRI) who had preoperative tendon pain or weakness and poor response to physical therapy were recruited. Pathological tendon tissue was excised based on clinical findings and US or MRI scan results. The control group had similar inclusion and exclusion criteria, except that they had no history of tendon injury and tendon pain or current clinical signs. Healthy tendons were harvested from autologous hamstring tendon grafts or remnants of autologous patellar tendon grafts from anterior cruciate ligament reconstruction (ACLR). These tendon tissues were fixed, dehydrated, and embedded in paraffin to form tissue blocks for storage. For immunohistochemical (IHC) staining, the tissue blocks were cut into 5-micrometer-thick sections and mounted on coated glass slides. After dewaxing, the sections were rehydrated, decalcified, and endogenous peroxidase activity was quenched, and then treated with 10 mM citrate buffer at 65°C for 20 minutes for antigen retrieval. After blocking with 1% goat serum, sections were incubated overnight at 4°C with a specific antibody against FABP4 (1:200). In the control group, blocking solution was used instead of the primary antibody. Immunopositive signals were developed using HRP-conjugated goat anti-rabbit secondary antibody (1:500) and a DAB substrate kit according to the manufacturer's instructions. After counterstaining with hematoxylin, sections were dehydrated with gradient ethanol and xylene, mounted with p-xylene-bis-pyridine bromide (DPX) mounting medium (SigmaAldrich, St Louis, MO), and examined under an optical microscope (DM5500; Leica Microsystems Wetzlar GmbH, Wetzlar, Germany). Positive signals appeared as brown. All incubation times and conditions were strictly controlled. Pathological and healthy tendons were stained in the same batch. Representative images are shown. Image analysis was performed using Image Pro Plus software (MediaCybernetics). Immunopositive signals were measured and expressed as integrated optical density of the region of interest (IOP). )express.

[0062] Compared to healthy hamstring tendons and healthy patellar tendons, FABP4 was upregulated in human patellar tendinopathy and rotator cuff tendinopathy samples, with FABP4 signaling... Significantly higher levels of FABP4 expression support the association between FABP4 expression and disease pathogenesis. Figures 1A-1D ).

[0063] Example 2—Colocalization of FABP4 and inflammatory cytokines in human rotator cuff tendinopathy The healthy tendon samples and rotator cuff tendinopathy samples collected above were subjected to immunofluorescence co-staining with FABP4, IL-1β, and TNF-α. The sections were stained with anti-FABP4 primary antibody (1:200), washed, and then stained with either anti-IL-1β primary antibody (1:200) or anti-TNF-α primary antibody (1:200). After washing, the sections were stained with anti-rabbit Alexa Fluor® 488 (1:500) and anti-goat Alexa Fluor® 555 (1:500). Before examination with a fluorescence microscope, the sections were washed and counterstained with 4'-6-diamidinyl-2-phenylindole (DAPI). Figure 2 ).

[0064] The results showed that the expression of IL-1β and TNF-α was increased in rotator cuff tendinopathy samples, and the expression of FABP4 was colocalized with the expression of IL-1β and TNF-α, especially in blood vessels and tendon cells, which supports the interaction between FABP4 and inflammatory cytokines in the pathogenesis of tendinopathy.

[0065] Example 3—Upregulation of FABP4 and inflammatory cytokines in a mouse collagenase-induced (CI) animal model After anesthesia, 20 mg of the drug was injected into the middle of one side of the Achilles tendon of each mouse. 1% bacterial collagenase I (0.1 mg) or saline was used. At weeks 2 and 8 following saline or collagenase injection (CI model), Achilles tendons were harvested for IHC staining of FABP4, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and anti-inflammatory cytokines (IL-10). The IHC staining protocol was similar to that described in Example 1. Primary antibodies against FABP4 (1:200) and against IL-1β (1:200), IL-6 (1:100), TNF-α (1:200), and IL-10 (1:200), along with HRP-conjugated secondary antibodies (1:500), were used (Figure 3).

[0066] Following Achilles tendon injury (CI), FABP4, pro-inflammatory cytokines, and anti-inflammatory cytokines were simultaneously upregulated in the Achilles tendon of mice. These results indicate that the upregulation of FABP4 in the CI model is associated with inflammation and tendon injury.

[0067] FABP4 was upregulated in collagenase-induced (CI) animal models of patellar tendinopathy, rotator cuff tendinopathy, and Achilles tendinopathy, supporting the broad involvement of FABP4 in the pathogenesis of these diseases.

[0068] Example 4—Injection of FABP4 induced tendon injury, ectopic bone, and inflammation similar to those in human tendinopathy in the Achilles tendon of mice. After anesthesia, 20 mg of the drug was injected into one side of the Achilles tendon of each mouse. Saline or FABP4 (0.5 µg) was administered. Tendon samples were collected at weeks 2 and 8 for histological examination with hematoxylin and eosin (H&E) staining, and for IHC staining of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and anti-inflammatory cytokines (IL-10). Ectopic bone formation in the tendon was also examined by microCT imaging at week 8 post-injection. The Achilles tendon was harvested and prepared for histological examination. Tendon samples were sectioned, dewaxed, and rehydrated before being stained with H&E. H&E-stained slides were dehydrated, mounted, and observed under an optical and polarizing microscope (DM5500; Leica Microsystems Wetzlar GmbH, Wetzlar, Germany). Ectopic bone formation in the tendon was examined using a cone-beam microCT system (Bruker Skyscan 1276 in vivo microCT system). The Achilles tendon was scanned using the gastrocnemius muscle and calcaneus as landmarks. Then, using the built-in software, three-dimensional reconstruction of the images was performed after setting a threshold. The region containing only the Achilles tendon was selected as the region of interest (ROI). The bone volume (BV) of ectopic mineralization within the Achilles tendon was measured. The IHC staining protocol was similar to that described in Example 1 (Figure 4).

[0069] Injection of FABP4 induced damage, chondrocyte-like cells, ectopic bone, fat accumulation, loss of collagen fiber arrangement, and inflammation in the Achilles tendon of mice, features similar to those of human tendinopathy.

[0070] Example 5—FABP4 increased the mRNA expression of inflammatory cytokines Human and mouse TDSCs were treated with FABP4 (120 ng / mL) for 24 hours under serum starvation conditions. The mRNA expression of inflammatory cytokines was examined by quantitative real-time polymerase chain reaction (qRT-PCR) (Figure 5).

[0071] The addition of FABP4 significantly increased the expression of inflammatory cytokines in human and mouse TDSCs, indicating that FABP4 is a pro-inflammatory adipokine.

[0072] Example 6—FABP4 expression was higher in inflammatory human rotator cuff tendinopathy TDSCs and IL-1β-treated mouse TDSCs. TDSCs were isolated from healthy human hamstring tendons, human rotator cuff tendonopathy tendons, and mouse Achilles tendons. Mouse TDSCs were treated with or without IL-1β (10 ng / mL) for 48 hours under serum starvation conditions (2% FBS for immunofluorescence staining, 1% FBS for qRT-PCR). Cells were stained with primary antibody against FABP4 (1:200) and anti-rabbit Alexa Fluor® 555 (1:500). Cells were then washed and counterstained with DAPI before examination under a fluorescence microscope. The expression of Fabp4 in mouse TDSCs treated or untreated with IL-1β was also examined by qRT-PCR (Figure 6).

[0073] Compared with healthy hamstring tendon TDSCs, human rotator cuff tendinopathy TDSCs showed higher expression of FABP4. Treatment of mouse TDSCs with IL-1β increased both protein and mRNA expression of FABP4. These results indicate that the interaction between FABP4 and inflammatory cytokines can lead to a disruptive cycle of inflammation and pain in tendinopathy.

[0074] Example 7—FABP4 gene knockout (KO) protects tendons from CI tendon injury FABP4 wild-type (WT) and knockout (KO) mice with C57BL / 6J background (Fabp4) - / - Injecting collagenase (20) 1% bacterial collagenase I (0.1 mg) or saline was used. The Achilles tendon was harvested at weeks 2 and 8 following CI tendon injury and prepared for H&E histological examination, microCT imaging of ectopic bone, and IHC staining for pro-inflammatory cytokines (IL-1β). The protocols for histological examination, microCT imaging, and IHC staining were similar to those described in Examples 1 and 4 (Figure 7).

[0075] Compared to injured WT tendons, FABP4 gene knockout protects tendons from collagenase-induced tendon damage, characterized by less inflammatory cell infiltration, lower cell density, less vascularization, stronger collagen birefringence, absence of chondrocytes, less ectopic bone, and lower IL-1β expression.

[0076] Example 8—Repeated injections of BMS309403 to pharmacologically inhibit FABP4 promote tendon healing in a collagenase-induced (CI) animal model. CI tendon injury was induced in mice by injecting collagenase into the mid-segment of the Achilles tendon. One week after CI injury, animals were randomly assigned to two groups. In the control and treatment groups, the Achilles tendon was injected with either the carrier or BMS309403 (20 mg / kg) every 3 days for a total of 4 injections. Therefore, each injection administered approximately 0.4 mg per mouse. Two weeks after carrier or BMS309403 treatment, the Achilles tendon was harvested and subjected to histological examination as described in Example 4. Figure 8 ).

[0077] Compared to the vector group, BMS309403 promoted better tendon healing and improved tendon histology and collagen birefringence. At week 2 post-treatment, more small nucleated cells were observed in the peripheral region of the CI tendon (dashed rectangle) in the vector group compared to the BMS309403 group.

[0078] Example 9—Repeated injection of BMS309403 pharmacologically inhibits FABP4 by promoting tendon healing in a collagenase-induced (CI) animal model by inhibiting inflammation. The CI tendon injury model and BMS309403 treatment were the same as described in Example 8. Tendon samples were stained with IHC for inflammatory cytokines IL-1β, IL-6, and TNF-α. The IHC staining protocol was similar to that described in Example 1.

[0079] Primary antibodies against IL-1β (1:500), IL-6 (1:50), and TNF-α (1:100) and secondary antibodies conjugated with HRP (1:500) were used. Figure 9 ).

[0080] BMS309403 partially promotes tendon healing after CI tendon injury by inhibiting inflammatory cytokines.

[0081] Example 10—Optimization of the preparation method for a BMS309403-loaded GelMA hydrogel complex for local delivery to the Achilles tendon 200 Photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphine (LAP) (0.25% in PBS) was mixed with 0.2 mg F127 thermosensitive poloxamer (finally 0.1% of LAP) and 10 mg GelMA prepolymer (finally 5% w / v). The mixture was filtered, and then 200 This mixture may or may not be mixed with 10 mg BMS309403. 20 The mixture was drawn into a syringe and irradiated with 405 nm blue light for 15, 20, 25, or 30 seconds. The ability of the mixture to be ejected from the syringe was observed. The incorporation of BMS309403 into the GelMA hydrogel was examined using scanning electron microscopy (SEM). Before polymerization, 20... An optimized formulation containing 50 mg / mL BMS309403 was injected into the Achilles tendon of each mouse (i.e., 1 mg BMS309403 / mouse). Figures 10A-10B ).

[0082] The results showed that using blue light to crosslink the mixture for 25 seconds and 30 seconds caused the GelMA complex carrying BMS309403 to polymerize too quickly, making it unsuitable for injection into the Achilles tendon.

[0083] The GelMA hydrogel containing BMS309403 was milky white. Under SEM, the surface of the GelMA hydrogel was smooth. The presence of small particles on the surface of the GelMA hydrogel confirmed the successful incorporation of BMS309403.

[0084] Example 11—A single injection of a BMS309403-loaded GelMA hydrogel complex pharmacologically inhibited FABP4, promoting tendon healing in a collagenase-induced (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-segment of the Achilles tendon. At week 1 post-injury, animals were randomly assigned to three groups. The injured tendon was injected once with saline, a preparation containing only GelMA, or a GelMA hydrogel loaded with BMS309403. At weeks 2, 4, and 8 post-treatment, the Achilles tendons were harvested for histological examination, IHC staining, and microCT imaging. Uninjured or uninjected contralateral Achilles tendons from the saline group served as normal controls. Gait analysis was also performed on the animals at weeks 2 and 8 post-treatment before sacrifice. Healthy, uninjured animals served as controls for gait analysis. Histological examination was performed according to the method described in Example 4. The IHC staining protocol was similar to that described in Example 1. Primary antibodies against FABP4 (1:200) and IL-1β (1:200) and HRP-conjugated secondary antibodies (1:500) were used. The microCT imaging protocol is similar to that described in Example 4.

[0085] Gait analysis was performed on mice at 2 and 8 weeks post-treatment using a Catwalk XT 9.0 system (Noldus Information Technology, Wageningen, The Netherlands). Mice were guided to run bidirectionally on a 1.5-meter-long transparent acrylic track, and sagittal views of both hind limbs were recorded at 100 Hz using a high-speed CCD camera (JVC 9600). A successful trial was defined as a video segment comprising three consecutive strides with a walking speed variation of <30%. Three successful trials were performed on each side of the mice, and the trials with the median speed were used for further analysis. The built-in motion analysis software was used to calculate the standing time (s), swing time (s), mean foot load intensity, and footprint area (cm²) from the median stride. 2 Gait parameters (cm / s) and swing speed were normalized to the values ​​of the contralateral uninjured limb for each animal. Eight uninjured mice were used as uninjured controls. Figures 11A-11D ).

[0086] The results showed that CI induced histopathological changes in the tendon, including hypercellularity, excessive angiogenesis, cell rounding, inflammatory cell infiltration, loss of collagen birefringence, and ectopic bone formation. Local injection of GelMA hydrogel into the Achilles tendon did not affect the histological and microCT images of the tendon. Local injection of BMS309403-loaded GelMA hydrogel promoted tendon healing, manifested from week 2 to week 8 by reduced small nucleated cell infiltration, hypercellularity, excessive angiogenesis, reduced cell rounding, and increased collagen fiber arrangement. In both the saline and GelMA groups, FABP4 and IL-1β expression remained high in the injured Achilles tendon from week 2 to week 8 post-treatment. However, at week 8 post-treatment with BMS309403-loaded GelMA hydrogel, FABP4 and IL-1β expression in the Achilles tendon decreased.

[0087] GelMA hydrogel loaded with BMS309403 inhibited ectopic bone formation following CI tendon injury at week 8 post-treatment (6 / 6 samples in the saline and GelMA groups, and 0 / 6 samples in the Gel-BMS group). At week 8 post-treatment, the bone volume (BV) in the tendon was significantly lower in the Gel-BMS group compared to the saline and GelMA groups (p < 0.05).

[0088] Compared to the control group, in the saline group, CI tendon injury showed reduced normalized standing time, footprint area, and swing speed of the injured limb at weeks 2 and 8 post-treatment, and increased normalized swing time. Normalized mean foot load intensity did not change significantly 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 gait parameters, and at weeks 2 and 8 post-treatment, gait parameters in the BMS309403-loaded GelMA group were not significantly different from the control group.

[0089] Therefore, a single injection of BMS309403-loaded GelMA at a low cumulative dose promoted tendon healing in a CI tendon injury model, improved tendon histology, ectopic bone formation, and gait pain, and reduced the expression of inflammatory cytokines. Thus, BMS309403-loaded GelMA could be used as a novel therapy for treating inflammatory degenerative tendon and ligament injuries and tendinopathy.

[0090] Example 12—BMS309403 enhances the colony-forming ability of tendon-derived stem / progenitor cells (TDSCs). Mouse TDSCs were isolated from the Achilles tendon and seeded overnight in 6-well plates at a density of 1000 cells per well. Cells were either left untreated or treated with FABP4 (120 ng / mL) or BMS309403 (10 µg / mL) in medium containing 10% fetal bovine serum (FBS) for 10 days. On day 10 post-treatment, cells were stained with crystal violet and the number of colony-forming units (CFUs) was counted. Figures 12A-12B ).

[0091] The results showed that FABP4 reduced CFU, while BMS309403 increased CFU. More single cells that failed to form colonies were observed in the FABP4 group (inset). Therefore, inhibition of FABP4 with BMS309403 improved the self-renewal capacity of TDSCs, which helps promote tendon repair after injury.

[0092] Example 13—FABP4 exacerbated endoplasmic reticulum stress in inflammatory TDSCs, enhanced osteogenic differentiation, and reduced tendinogenic differentiation. Mouse TDSCs were seeded in 12-well plates overnight and treated with FABP4 (120 ng / mL) for 48 h in the presence of 1% FBS and IL-1β (10 ng / mL). The mRNA expression of endoplasmic reticulum stress markers (Chop), osteogenic markers (Bglap), and tendonogenic markers (Col1a1) was assessed by qRT-PCR. Figure 13 ).

[0093] The results showed that treatment of inflammatory TDSCs with FABP4 significantly increased the expression of Chop and Bglap, while decreasing the expression of Col1a1. These results may explain the increased oxidative stress and altered fate of TDSCs in tendinopathy.

[0094] Example 14—BMS309403 reduced inflammation, endoplasmic reticulum stress, and osteogenic differentiation in inflammatory TDSCs and promoted tendonogenic differentiation. Mouse TDSCs were seeded in 12-well culture plates overnight and, in the presence of 1% FBS and IL-1β (10 ng / mL), were administered BMS309403 (10 Treatment lasted 48 hours. The mRNA expression of pro-inflammatory markers (Tnfa), endoplasmic reticulum stress markers (Chop, Grp78), tendinogenic markers (Tnmd, Scx), and osteogenic markers (Runx2) was assessed by qRT-PCR. Figure 14 ).

[0095] The results showed that treatment with BMS309403 significantly reduced the mRNA expression of Tnfa, Chop, Grp78, and Runx2 in inflamed TDSCs, while increasing the expression of Tnmd and Scx. Therefore, FABP4 inhibitors such as BMS309403 may promote tendon healing in tendinopathy by inhibiting inflammation and oxidative stress in inflammatory TDSCs and promoting their tendinogenic differentiation.

[0096] Exemplary implementation method Implementation Method 1: A method for treating tendon or ligament injury in a subject, the method comprising administering to the subject a composition comprising an effective dose of a FABP4 inhibitor (fatty acid binding protein 4 inhibitor).

[0097] Implementation Method 2: The method of Implementation Method 1, wherein the FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, triazolopyrimidine derivatives, short hairpin RNA (shRNA) targeting FABP4 expression, RNA interference (RNAi) targeting FABP4 expression, benzbromarone, polyclonal FABP4 neutralizing antibody, monoclonal FABP4 neutralizing antibody, or any combination thereof.

[0098] Implementation method 3: The method of implementation method 1 or 2, wherein the FABP4 inhibitor is BMS309403.

[0099] Implementation Method 4: The method of any of the foregoing embodiments, wherein the monoclonal neutralizing antibody is CA33 or 2E4.

[0100] Embodiment 5: The method of any of the foregoing embodiments, wherein the composition further comprises a polymer.

[0101] Embodiment 6: The method of Embodiment 5, wherein the polymer is methacrylamide gelatin (GelMA), poly-ε-caprolactone (PCL), poly-L-lactide (PLLA), polylactic-co-glycolic acid copolymer (PLGA), type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof.

[0102] Implementation Method 7: The method of any of the foregoing embodiments, wherein the composition further comprises a photoinitiator and a thermosensitive poloxamer.

[0103] Implementation Method 8: The method of Implementation Method 7, wherein the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphine (LAP), and the thermosensitive poloxamer is poloxamer 407.

[0104] Implementation 9: The method of Implementation 7 or 8 further includes: crosslinking the composition before administering the composition to the subject.

[0105] Implementation Method 10: The method of Implementation Method 9, wherein the crosslinking includes: applying ultraviolet or blue light to the composition for about 1 second to about 1 minute.

[0106] Implementation Method 11: The method of any of the foregoing embodiments, wherein the application of the composition comprises: injecting the composition into the subject, or applying the composition directly to the injured tendon and / or ligament.

[0107] Implementation Method 12: The method of any of the foregoing embodiments, wherein administration to the subject includes injecting the composition into the subject or administering the composition orally to the subject.

[0108] Implementation Method 13: The method of any of the foregoing embodiments, wherein the concentration of the FABP4 inhibitor in the composition is about 50 mg / mL.

[0109] Implementation Method 14: A composition comprising a FABP4 inhibitor (fatty acid binding protein 4 inhibitor) and a polymer.

[0110] Example 15: The composition of Example 14, wherein the FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, triazolopyrimidine derivatives, short hairpin RNA (shRNA) targeting FABP4 expression, RNA interference (RNAi) targeting FABP4 expression, benzbromarone, polyclonal FABP4 neutralizing antibody, monoclonal FABP4 neutralizing antibody, or any combination thereof.

[0111] Embodiment 16: The composition of Embodiment 14 or 15, wherein the FABP4 inhibitor is BMS309403.

[0112] Embodiment 17: A composition of any one of Embodiments 14 to 16, wherein the monoclonal neutralizing antibody is CA33 or 2E4.

[0113] Embodiment 18: A composition of any one of Embodiments 14 to 17, wherein the polymer is methacrylamide gelatin (GelMA), poly-ε-caprolactone (PCL), poly-L-lactide (PLLA), polylactic acid-glycolic acid copolymer (PLGA), type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof.

[0114] Embodiment 19: A composition of any one of Embodiments 14 to 18, wherein the composition further comprises a photoinitiator and a thermosensitive poloxamer.

[0115] Example 20: The composition of Example 19, wherein the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP).

[0116] Implementation Method 21: The composition of Implementation Method 19 or 20, wherein the thermosensitive poloxamer is poloxamer 407.

[0117] Embodiment 22: The composition of any one of Embodiments 14 to 21, wherein the concentration of the FABP4 inhibitor is about 50 mg / mL.

[0118] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and any modifications or alterations made to those skilled in the art based thereon should be included within the spirit and scope of this application. Furthermore, any element or limitation of any invention or implementation thereof disclosed herein may be combined with any and / or all other elements or limitations (alone or in any combination) of any other invention or implementation thereof disclosed herein, and all such combinations are contemplated without limitation within the scope of this disclosure.

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Claims

1. A method for treating tendon or ligament injuries in a subject, characterized in that, include: The composition comprising an effective dose of a FABP4 inhibitor (fatty acid binding protein 4 inhibitor) was administered to the subject.

2. The method according to claim 1, characterized in that, in, The FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, triazolopyrimidine derivatives, short hairpin RNA (shRNA) targeting FABP4 expression, RNA interference (RNAi) targeting FABP4 expression, benzbromarone, polyclonal FABP4 neutralizing antibody, monoclonal FABP4 neutralizing antibody, or any combination thereof.

3. The method according to claim 2, characterized in that, in, The FABP4 inhibitor is BMS309403.

4. The method according to claim 2, characterized in that, in, The monoclonal neutralizing antibody is CA33 or 2E4.

5. The method according to claim 1, characterized in that, in, The composition also includes a polymer.

6. The method according to claim 5, characterized in that, in, The polymer is methacrylamide gelatin (GelMA), poly-ε-caprolactone (PCL), poly-L-lactide (PLLA), polylactic-co-glycolic acid copolymer (PLGA), type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof.

7. The method according to claim 5, characterized in that, in, The composition also includes a photoinitiator and a thermosensitive poloxamer.

8. The method according to claim 7, characterized in that, in, The photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphine (LAP), and the thermosensitive poloxamer is poloxamer 407.

9. The method according to claim 8, characterized in that, Also includes: The composition is crosslinked prior to administration to the subject.

10. The method according to claim 9, characterized in that, in, The crosslinking includes applying ultraviolet or blue light to the composition for about 1 second to about 1 minute.

11. The method according to claim 9, characterized in that, in, The application of the composition includes: injecting the composition into the subject, or applying the composition directly to the injured tendon and / or ligament.

12. The method according to claim 1, characterized in that, in, Administration to the subject includes: injecting the composition into the subject, or administering the composition orally to the subject.

13. The method according to claim 1, characterized in that, in, The concentration of the FABP4 inhibitor in the composition is approximately 50 mg / mL.

14. A composition, characterized in that, include: FABP4 inhibitors (fatty acid binding protein 4 inhibitors) and polymers.

15. The composition according to claim 14, characterized in that, in, The FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, triazolopyrimidine derivatives, short hairpin RNA (shRNA) targeting FABP4 expression, RNA interference (RNAi) targeting FABP4 expression, benzbromarone, polyclonal FABP4 neutralizing antibody, monoclonal FABP4 neutralizing antibody, or any combination thereof.

16. The composition according to claim 15, characterized in that, in, The FABP4 inhibitor is BMS309403.

17. The composition according to claim 15, characterized in that, in, The monoclonal neutralizing antibody is CA33 or 2E4.

18. The composition according to claim 14, characterized in that, in, The polymer is methacrylamide gelatin (GelMA), poly-ε-caprolactone (PCL), poly-L-lactide (PLLA), polylactic-co-glycolic acid copolymer (PLGA), type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof.

19. The composition according to claim 14, characterized in that, in, The composition also includes a photoinitiator and a thermosensitive poloxamer.

20. The composition according to claim 19, characterized in that, in, The photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid (LAP).

21. The composition according to claim 19, characterized in that, in, The thermosensitive poloxamer is poloxamer 407.

22. The composition according to claim 14, characterized in that, in, The concentration of the FABP4 inhibitor is approximately 50 mg / mL.

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