The fluoroquinolones may positively affect tendon healing after surgical repair.

OBJECTIVES: This study aimed to evaluate the biomechanical and histological effects of fluoroquinolones on surgically repaired tendon healing. MATERIALS AND METHODS: The Achilles tendons of 40 Wistar rats (mean weight: 213.5 g; range 201 to 242 g) were bilaterally surgically cut and repaired. The rats were randomly divided into four groups: the first and third groups were designated as control groups and did not receive drug therapy, whereas the second and fourth groups received 300 mg/kg ciprofloxacin for a week after the surgical procedure. The first and second groups had both tendons dissected at the end of the first week, while the third and fourth groups were dissected at the end of the third week. The left tendons were examined biomechanically, while the right tendons were examined histologically. RESULTS: Statistical analysis revealed that the mean maximum tensile forces of tendons in the first and second groups were 5.2±1.84 N (range, 2.9 to 8.5 N) and 11.1±2.65 N (range, 7.3 to 13.9 N), respectively, which was found to be statistically significant (p< 0.05). At the end of the third week, mean maximum tensile forces of the third and fourth groups were determined to be 20.7±5.0 N (range, 22.1 to 29.8 N) and 28.7±4.6 N (range, 22.1 to 36.8 N), respectively, which was also statistically significant (p< 0.05). Histologically, our results were compatible. CONCLUSION: This study demonstrated that ciprofloxacin did not exhibit the expected adverse effects on surgically repaired tendon healing in the early stages but likely contributed to healing in the short term by affecting the inflammatory phase.

Galangin Promotes Tendon Repair Mediated by Tendon-Derived Stem Cells through Activating the TGF-ß1/Smad3 Signaling Pathway.

Tendon injury is a prevalent orthopedic disease that currently lacks effective treatment. Galangin (GLN) is a vital flavonoid found abundantly in galangal and is known for its natural activity. This study aimed to investigate the GLN-mediated molecular mechanism of tendon-derived stem cells (TDSCs) in tendon repair. The TDSCs were characterized using alkaline phosphatase staining, alizarin red S staining, oil red O staining, and flow cytometry. The effect of GLN treatment on collagen deposition was evaluated using Sirius red staining and quantitative (q)PCR, while a Western bot was used to assess protein levels and analyze pathways. Results showed that GLN treatment not only increased the collagen deposition but also elevated the mRNA expression and protein levels of multiple tendon markers like collagen type I alpha 1 (COL1A1), decorin (DCN) and tenomodulin (TNMD) in TDSCs. Moreover, GLN was also found to upregulate the protein levels of transforming growth factor ß1 (TGF-ß1) and p-Smad3 to activate the TGF-ß1/Smad3 signaling pathway, while GLN mediated collagen deposition in TDSCs was reversed by LY3200882, a TGF-ß receptor inhibitor. The study concluded that GLN-mediated TDSCs enhanced tendon repair by activating the TGF-ß1/Smad3 signaling pathway, suggesting a novel therapeutic option in treating tendon repair.

Dexamethasone treatment influences tendon healing through altered resolution and a direct effect on tendon cells.

Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between them. However, underlying mechanisms behind the effect of corticosteroids and the interaction with loading remain unclear. The aim of this study was to investigate the role of dexamethasone during tendon healing, including specific effects on tendon cells. Rats (n = 36) were randomized to heavy loading or mild loading, the Achilles tendon was transected, and animals were treated with dexamethasone or saline. Gene and protein analyses of the healing tendon were performed for extracellular matrix-, inflammation-, and tendon cell markers. We further tested specific effects of dexamethasone on tendon cells in vitro. Dexamethasone increased mRNA levels of S100A4 and decreased levels of ACTA2/α-SMA, irrespective of load level. Heavy loading + dexamethasone reduced mRNA levels of FN1 and TenC (p < 0.05), while resolution-related genes were unaltered (p > 0.05). In contrast, mild loading + dexamethasone increased mRNA levels of resolution-related genes ANXA1, MRC1, PDPN, and PTGES (p < 0.03). Altered protein levels were confirmed in tendons with mild loading. Dexamethasone treatment in vitro prevented tendon construct formation, increased mRNA levels of S100A4 and decreased levels of SCX and collagens. Dexamethasone during tendon healing appears to act through immunomodulation by promoting resolution, but also through an effect on tendon cells.

Pharmacological modulation of gp130 signalling enhances Achilles tendon repair by regulating tenocyte migration and collagen synthesis via SHP2-mediated crosstalk of the ERK/AKT pathway.

Tendon injuries typically display limited reparative capacity, often resulting in suboptimal outcomes and an elevated risk of recurrence or rupture. While cytokines of the IL-6 family are primarily recognised for their inflammatory properties, they also have multifaceted roles in tissue regeneration and repair. Despite this, studies examining the association between IL-6 family cytokines and tendon repair remained scarce. gp130, a type of glycoprotein, functions as a co-receptor for all cytokines in the IL-6 family. Its role is to assist in the transmission of signals following the binding of ligands to receptors. RCGD423 is a gp130 modulator. Phosphorylation of residue Y759 of gp130 recruits SHP2 and SOCS3 and inhibits activation of the STAT3 pathway. In our study, RCGD423 stimulated the formation of homologous dimers of gp130 and the phosphorylation of Y759 residues without the involvement of IL-6 and IL-6R. Subsequently, the phosphorylated residues recruited SHP2, activating the downstream ERK and AKT pathways. These mechanisms ultimately promoted the migration ability of tenocytes and matrix synthesis, especially collagen I. Moreover, RCGD423 also demonstrated significant improvements in collagen content, alignment of collagen fibres, and biological and biomechanical function in a rat Achilles tendon injury model. In summary, we demonstrated a promising gp130 modulator (RCGD423) that could potentially enhance tendon injury repair by redirecting downstream signalling of IL-6, suggesting its potential therapeutic application for tendon injuries.

Development of a nanoparticle-based tendon-targeting drug delivery system to pharmacologically modulate tendon healing.

Satisfactory healing following acute tendon injury is marred by fibrosis. Despite the high frequency of tendon injuries and poor outcomes, there are no pharmacological therapies in use to enhance the healing process. Moreover, systemic treatments demonstrate poor tendon homing, limiting the beneficial effects of potential tendon therapeutics. To address this unmet need, we leveraged our existing tendon healing spatial transcriptomics dataset and identified an area enriched for expression of Acp5 (TRAP) and subsequently demonstrated robust TRAP activity in the healing tendon. This unexpected finding allowed us to refine and apply our existing TRAP binding peptide (TBP) functionalized nanoparticle (NP) drug delivery system (DDS) to facilitate improved delivery of systemic treatments to the healing tendon. To demonstrate the translational potential of this DDS, we delivered niclosamide (NEN), an S100a4 inhibitor. While systemic delivery of free NEN did not alter healing, TBP-NPNEN enhanced both functional and mechanical recovery, demonstrating the translational potential of this approach to enhance the tendon healing process.

The effect of papaverine on tendon healing and adhesion in rats following Achilles tendon repair.

OBJECTIVES: The study aimed to examine the histopathological and biomechanical effects of papaverine administered intraperitoneally and locally on Achilles tendon healing in a rat model. MATERIALS AND METHODS: Forty-eight adult male Sprague-Dawley rats (range, 300 to 400 g) were used in this study conducted between October and November 2022. The rats were divided into three groups, with each group further subdivided into two for sacrifice on either the 15th (early period) or 30th (late period) day after surgery. The first (control) group received no treatment following Achilles tendon repair, while papaverine was intraperitoneally administered every other day for 10 days in the second group and locally in the third group after surgery. On the 15th and 30th days, the rats were sacrificed, and their Achilles tendons were subjected to biomechanical testing and histopathological evaluation. RESULTS: Histopathologically, there were no significant differences among the groups on the 15th day. However, on the 30th day, the locally applied papaverine group exhibited superior histopathological outcomes compared to the control group (p<0.05). Concerning the highest tensile strength values before rupture, the biomechanical assessment showed that the group receiving local papaverine treatment in the early period and both the group with systemic papaverine treatment and the one with local papaverine treatment in the late period displayed a statistically significant advantage compared to the control group (p<0.05). CONCLUSION: Locally administered papaverine has positive biomechanical effects in the early period and exhibits a positive correlation both histopathologically and biomechanically in the late period. Novel therapeutic options may be provided for patients through these findings.

Effect of cilostazol on healing of achilles tendon ruptures: an experimental study on rats.

PURPOSE: This study aimed to evaluate whether cilostazol (phosphodiesterase III inhibitor) could enhance the healing of Achilles tendon ruptures in rats. MATERIALS AND METHODS: The Achilles tendons of 24 healthy male adult rats were incised and repaired. The rats were randomly allocated to cilostazol and control groups. The cilostazol group received daily intragastric administration of 50 mg/kg cilostazol for 28 days, while the control group did not receive any medication. The rats were sacrificed on the 30th day, and the Achilles tendon was evaluated for biomechanical properties, histopathological characteristics, and immunohistochemical analysis. RESULTS: All rats completed the experiment. The Movin sum score of the control group was significantly higher (p = 0.008) than that of the cilostazol group, with means of 11 ± 0.63 and 7.50 ± 1.15, respectively. Similarly, the mean Bonar score was significantly higher (p = 0.026) in the control group compared to the cilostazol group (8.33 ± 1.50 vs. 5.5 ± 0.54, respectively). Moreover, the Type I/Type III Collagen ratio was notably higher (p = 0.016) in the cilostazol group (52.2 ± 8.4) than in the control group (34.6 ± 10.2). The load to failure was substantially higher in the cilostazol group than in the control group (p = 0.034), suggesting that the tendons in the cilostazol group were stronger and exhibited greater resistance to failure. CONCLUSIONS: The results of this study suggest that cilostazol treatment significantly improves the biomechanical and histopathological parameters of the healing Achilles tendon in rats. Cilostazol might be a valuable supplementary therapy in treating Achilles tendon ruptures in humans. Additional clinical studies are, however, required to verify these outcomes.

Investigation of the effects of pentoxifylline and alpha tocopherol treatment on recovery in rats with Achilles tendon rupture.

Although the Achilles tendon is the largest and strongest tendon in the body, healing of the Achilles tendon is the most common injury, and this process is difficult due to poor tendon circulation; moreover, the underlying mechanism has not been fully elucidated. In our study, we aimed to investigate the effects of pentoxifylline and alpha-tocopherol administered separately or in combination on rats with Achilles tendon injury. Forty-eight male Wistar rats weighing 230 ± 30 g were used in the study. The rats were randomly divided into eight groups of six animals each. Tendons were evaluated histopathologically and biomechanically. According to the statistical analysis, the vascularity density in the pentoxifylline group on day 14 was significantly greater than that in the other groups (p < 0.05). The collagen arrangement in the pentoxifylline and alpha-tocopherol groups on day 14 was found to be firmer and smoother than that in the control group (p < 0.05). The collagen arrangement in the pentoxifylline group on day 28 was greater than that in the other groups (p < 0.05). The biomechanical results were significantly greater in all groups (p < 0.05). Pentoxifylline contributed to tendon healing both through neovascularization in the early period and by improving collagen orientation in the late period, while alpha-tocopherol had a positive effect on collagen orientation in the early period. No beneficial effects were observed when pentoxifylline and alpha-tocopherol were used together. We believe that further research is needed to understand the effects of this combination therapy on tendon healing.

Prevented Cell Clusters' Migration Via Microdot Biomaterials for Inhibiting Scar Adhesion.

Cluster-like collective cell migration of fibroblasts is one of the main factors of adhesion in injured tissues. In this research, a microdot biomaterial system is constructed using α-helical polypeptide nanoparticles and anti-inflammatory micelles, which are prepared by ring-opening polymerization of α-amino acids-N-carboxylic anhydrides (NCAs) and lactide, respectively. The microdot biomaterial system slowly releases functionalized polypeptides targeting mitochondria and promoting the influx of extracellular calcium ions under the inflammatory environment, thus inhibiting the expression of N-cadherin mediating cell-cell interaction, and promoting apoptosis of cluster fibroblasts, synergistically inhibiting the migration of fibroblast clusters at the site of tendon injury. Meanwhile, the anti-inflammatory micelles are celecoxib (Cex) solubilized by PEG/polyester, which can improve the inflammatory microenvironment at the injury site for a long time. In vitro, the microdot biomaterial system can effectively inhibit the migration of the cluster fibroblasts by inhibiting the expression of N-cadherin between cell-cell and promoting apoptosis. In vivo, the microdot biomaterial system can promote apoptosis while achieving long-acting anti-inflammation effects, and reduce the expression of vimentin and α-smooth muscle actin (α-SMA) in fibroblasts. Thus, this microdot biomaterial system provides new ideas for the prevention and treatment of tendon adhesion by inhibiting the cluster migration of fibroblasts.

Blocking proteinase-activated receptor 2 signaling relieves pain, suppresses nerve sprouting, improves tissue repair, and enhances analgesic effect of B vitamins in rats with Achilles tendon injury.

ABSTRACT: Tendon injury produces intractable pain and disability in movement, but the medications for analgesia and restoring functional integrity of tendon are still limited. In this study, we report that proteinase-activated receptor 2 (PAR2) activation in dorsal root ganglion (DRG) neurons contributes to chronic pain and tendon histopathological changes produced by Achilles tendon partial transection injury (TTI). Tendon partial transection injury increases the expression of PAR2 protein in both somata of DRG neurons and their peripheral terminals within the injured Achilles tendon. Activation of PAR2 promotes the primary sensory neuron plasticity by activating downstream cAMP-PKA pathway, phosphorylation of PKC, CaMKII, and CREB. Blocking PAR2 signaling by PAR2 small-interference RNA or antagonistic peptide PIP delays the onset of TTI-induced pain, reverses the ongoing pain, as well as inhibits sensory nerve sprouting, and promotes structural remodeling of the injured tendon. Vitamin B complex (VBC), containing thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12), is effective to ameliorate TTI-induced pain, inhibit ectopic nerve sprouting, and accelerate tendon repair, through suppressing PAR2 activation. These findings reveal a critical role of PAR2 signaling in the development of chronic pain and histopathological alterations of injured tendon following Achilles tendon injury. This study suggests that the pharmaceuticals targeting PAR2, such as VBC, may be an effective approach for the treatment of tendon injury-induced pain and promoting tendon repair.

Curcumin Improves Functional Recovery of Ruptured Tendon by Promoting Tenogenesis via PI3K/Akt Signaling.

OBJECTIVE: In our previous study, we found that local release of curcumin from nanomicelles prevents peritendinous adhesion during Achilles tendon healing. The aim of this study is to further investigate the signaling integrated by curcumin to direct the tenogenetic program of tendon stem cells contributing to tendon healing. METHODS: A surgical model of tendon rupture and repair (TRR) was established in rats. Peritendinous adhesion and inflammation, biomechanical function, and expression of ß-catenin and epithelial cellular adhesion molecule (EpCAM) were determined. A dataset was analyzed to investigate differentially expressed genes and enriched genes related to the signaling pathways. Tendon stem cells were treated with curcumin to investigate the cellular and molecular events as well as the signaling pathway. RESULTS: In rat TRR model, curcumin treatment resulted in not only significantly decreased peritendinous inflammatory but also improved tendon functional recovery along with significantly increased expressions of EpCAM and ß-catenin. Analysis of the dataset indicated that the enriched genes were positively related to differentiation pathways but negatively related to proliferation pathways. In rat tendon stem cells, curcumin treatment inhibited proliferation but promoted differentiation. Curcumin's antioxidative activity was associated with tenogenesis. The upregulated expression of tendon lineage-specific markers was dependent on phosphatidylinositol 3'-kinase/Akt (PI3K/Akt) pathway which could be a potential mechanism of tenogenesis of curcumin treatment. CONCLUSION: Curcumin could improve tendon functional recovery via promoting tenogenesis in addition to its antioxidant and anti-inflammatory activities. Curcumin induced differentiation of tendon stem/progenitor cell into tenocytes via PI3K/Akt signaling pathway. This finding provided evidence for the application of curcumin to prevent adhesion during tendon repair.

A Combined Treatment of BMP2 and Soluble VEGFR1 for the Enhancement of Tendon-Bone Healing by Regulating Injury-Activated Skeletal Stem Cell Lineage.

BACKGROUND: Bone morphogenetic protein 2 (BMP2) is an appealing osteogenic and chondrogenic growth factor for promoting tendon-bone healing. Recently, it has been reported that soluble vascular endothelial growth factor (VEGF) receptor 1 (sVEGFR1) (a VEGF receptor antagonist) could enhance BMP2-induced bone repair and cartilage regeneration; thus, their combined application may represent a promising treatment to improve tendon-bone healing. Moreover, BMP2 could stimulate skeletal stem cell (SSC) expansion and formation, which is responsible for wounded tendon-bone interface repair. However, whether the codelivery of BMP2 and sVEGFR1 increases tendon enthesis injury-activated SSCs better than does BMP2 alone needs further research. PURPOSE: To study the effect of BMP2 combined with sVEGFR1 on tendon-bone healing and injury-activated SSC lineage. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 128 C57BL/6 mice that underwent unilateral supraspinatus tendon detachment and repair were randomly assigned to 4 groups: (1) untreated control group; (2) hydrogel group, which received a local injection of the blank hydrogel at the injured site; (3) BMP2 group, which received an injection of hydrogel with BMP2; and (4) BMP2 with sVEGFR1 group, which received an injection of hydrogel with BMP2 and sVEGFR1. Histology, micro-computed tomography, and biomechanical tests were conducted to evaluate tendon-bone healing at 4 and 8 weeks after surgery. In addition, flow cytometry was performed to detect the proportion of SSCs and their downstream differentiated subtypes, including bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors within supraspinatus tendon enthesis at 1 week postoperatively. RESULTS: The repaired interface in BMP2 with sVEGFR1 group showed a significantly improved collagen fiber continuity, increased fibrocartilage, greater newly formed bone, and elevated mechanical properties compared with the other 3 groups. There were more SSCs; bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors in the BMP2 with sVEGFR1 group than that in the other groups. CONCLUSION: Our study suggests that the combined delivery of BMP2 and sVEGFR1 could promote tendon-bone healing and stimulate the expansion of SSCs and their downstream progeny within the injured tendon-bone interface. CLINICAL RELEVANCE: Combining BMP2 with sVEGFR1 may be a good clinical treatment for wounded tendon enthesis healing.

The effect of Sildenafil, a phosphodiesterase-5 inhibitor, on tendon healing: an experimental study in rat model of achilles tendon injury.

INTRODUCTION: Sildenafil Citrate has various effects on the body, including widening blood vessels, inhibiting platelet aggregation, promoting the growth of blood vessels, stimulating apoptosis and adhesion of fibroblasts, and reducing inflammation. This research aims to explore how Sildenafil Citrate affects surgically treated Achilles tendons, both in terms of tissue structure and mechanical properties. MATERIALS AND METHODS: Forty-eight Wistar-albino rats weighing 350-400 g were randomly divided into groups, 6 in each group, as the study group was given Sildenafil Citrate and the control group given saline, respectively. The Achilles tendon rupture model was created under ketamine and xylazine anesthesia. During the entire experiment, rats were housed in eight separate cages, six of them each. The study group and control group of the first group were sacrificed at the end of 1 week, and Achilles tendon samples were taken. After that, Achilles tendon samples were taken after sacrificing the second group at 14 days, the third group at 21 days, and the fourth group at 28 days, respectively. Neovascularization, inflammation, fibrosis and fibroblastic activities of the harvested Achilles tendons were evaluated histopathologically. Biomechanically, stretching was applied to the Achilles tendons and continued until the tendon ruptured. the maximum force values at the moment of rupture were calculated. RESULTS: The mean maximum strength value of group T21, which was given sildenafil citrate for 21 days, was 31.1 ± 4.36 N, and the mean maximum strength value of group C21, which was the control group, was 20.56 ± 6.92 N. A significant difference was observed between the groups (p: 0.008). Group T28 (45.17 ± 5.54 N) also demonstrated greater strength than group C28 (34.62 ± 3.21 N) in the comparison (p: 0.004). The study also noted significant differences between the groups in neovascularization, in the first week, 1 mild, 3 moderate and 2 prominent neovascularization was observed in group T7, in group T28, moderate neovascularization was observed in 4 specimens and prominent neovascularization was observed in 2 specimens (p: 0.001). Furthermore, the groups showed significant differences in their levels of fibrosis, inflammation and fibroblastic proliferation (p: 0.017, p: 0.036, (p: 0.035) respectively). CONCLUSIONS: Study has demonstrated that sildenafil citrate can enhance the biomechanical and histopathological aspects of tendon healing, resulting in a stronger tendon.

Anti-Adhesive Resorbable Indomethacin/Bupivacaine-Eluting Nanofibers for Tendon Rupture Repair: In Vitro and In Vivo Studies.

The treatment and surgical repair of torn Achilles tendons seldom return the wounded tendon to its original elasticity and stiffness. This study explored the in vitro and in vivo simultaneous release of indomethacin and bupivacaine from electrospun polylactide-polyglycolide composite membranes for their capacity to repair torn Achilles tendons. These membranes were fabricated by mixing polylactide-polyglycolide/indomethacin, polylactide-polyglycolide/collagen, and polylactide-polyglycolide/bupivacaine with 1,1,1,3,3,3-hexafluoro-2-propanol into sandwich-structured composites. Subsequently, the in vitro pharmaceutic release rates over 30 days were determined, and the in vivo release behavior and effectiveness of the loaded drugs were assessed using an animal surgical model. High concentrations of indomethacin and bupivacaine were released for over four weeks. The released pharmaceutics resulted in complete recovery of rat tendons, and the nanofibrous composite membranes exhibited exceptional mechanical strength. Additionally, the anti-adhesion capacity of the developed membrane was confirmed. Using the electrospinning technique developed in this study, we plan on manufacturing degradable composite membranes for tendon healing, which can deliver sustained pharmaceutical release and provide a collagenous habitat.

The effect of caffeic acid on tendon healing in rats with an Achilles tendon injury model.

OBJECTIVES: This study aims to examine the effect of caffeic acid on tendon healing histopathologically and biomechanically in rats with an Achilles tendon injury model. MATERIALS AND METHODS: Twenty male Wistar-albino rats were used in this study. The rats were divided into two groups as the experimental group and control group. All rats underwent a bilateral achillotomy injury model and then surgical repair. Postoperatively, for four weeks, the experimental group was given intraperitoneal caffeic acid (100 mg/kg/day suspended in saline), while the control group was given only intraperitoneal saline. At the end of four weeks, after sacrificing each rat, right Achilles tendons were subjected to biomechanical analysis and the Achilles tendons were subjected to histopathological analysis. Bonar and Movin scores were used for histopathological analysis. In biomechanical analysis, tensile test was applied to Achilles tendons until rupture. For each tendon, failure load, displacement, cross-sectional area, maximum energy, total energy, length, stiffness, ultimate stress and strain parameters were recorded. RESULTS: According to Bonar and Movin scoring, the experimental group had lower scoring values than the control group (p=0.002 and p=0.002, respectively). Bonar scoring parameters were analyzed separately. Vascularity, collagen, and ground substance scores were lower in the experimental group compared to the control group (p=0.001, p=0.003, and p=0.047, respectively). No significant difference was found for tenocyte (p=0.064). In biomechanical analysis, failure load, displacement, ultimate stress, strain, and stiffness values were found to be higher in the experimental group compared to the control group (p=0.049, p=0.005, p=0.028, p=0.021, and p=0.049, respectively). CONCLUSION: The caffeic acid contributed positively to tendon healing histopathologically and biomechanically in rats with an Achilles tendon injury model.

Can pirfenidone prevent tendon adhesions? An experimental study in rats.

OBJECTIVES: In this experimental study, we aimed to investigate the effectiveness of oral pirfenidone (PFD) treatment on preventing tendon adhesion and tendon healing in rats. MATERIALS AND METHODS: A total of 21 rats were assigned into three groups including seven rats in each group. In Group 1 (sham group), no surgical procedure was performed. In Group 2 (control group), tendon repair was performed following right achillotomy. In Group 3 (treatment group), the rats also underwent tendon repair after right achillotomy. Additionally, 30 mg/kg of oral PFD was initiated from the postoperative Day 1 and administered via gavage for 28 days. At the end of the study, tendon healing and fibrosis levels in the tendon repair site were compared macroscopically, histopathologically, and immunohistochemically among the groups. RESULTS: Macroscopically, moderate and severe adhesions were observed in four and three rats, respectively in the control group, while no adhesion was found in four rats and filmy adhesions were observed in three rats in the treatment group (p<0.01). Microscopically, there was moderate adhesions in three rats and severe adhesions in four rats in the control group, while three rats had no adhesions and four rats had slight adhesions in the treatment group (p<0.01). Microscopically, tendon healing was good in six rats and fair in one rat in the control group, while five rats showed excellent tendon healing and two rats showed good tendon healing in the treatment group (p<0.01). Immunohistochemically, expressions of collagen I (p<0.01), collagen III (p<0.001), vascular endothelial growth factor (VEGF) (p<0.001), and proliferating cell nuclear antigen (PCNA) (p<0.001) significantly decreased in the treatment group compared to the control group. CONCLUSION: Our study results indicated that PFD decreased collagen synthesis and prevented the formation of peritendinous adhesion in rats; however, it did not impair tendon healing.

Bioactive and Elastic Emulsion Electrospun DegraPol Tubes Delivering IGF-1 for Tendon Rupture Repair.

Tendon injuries can result in two major drawbacks. Adhesions to the surrounding tissue may limit the range of motion, while fibrovascular scar formation can lead to poor biomechanical outcomes. Prosthetic devices may help to mitigate those problems. Emulsion electrospinning was used to develop a novel three-layer tube based on the polymer DegraPol (DP), with incorporated insulin-like growth factor-1 (IGF-1) in the middle layer. Scanning electron microscopy was utilized to assess the fiber diameter in IGF-1 containing pure DP meshes. Further characterization was performed with Fourier Transformed Infrared Spectroscopy, Differential Scanning Calorimetry, and water contact angle, as well as through the assessment of mechanical properties and release kinetics from ELISA, and the bioactivity of IGF-1 by qPCR of collagen I, ki67, and tenomodulin in rabbit Achilles tenocytes. The IGF-1-containing tubes exhibited a sustained release of the growth factor up to 4 days and showed bioactivity by significantly upregulated ki67 and tenomodulin gene expression. Moreover, they proved to be mechanically superior to pure DP tubes (significantly higher fracture strain, failure stress, and elastic modulus). The novel three-layer tubes intended to be applied over conventionally sutured tendons after a rupture may help accelerate the healing process. The release of IGF-1 stimulates proliferation and matrix synthesis of cells at the repair site. In addition, adhesion formation to surrounding tissue can be reduced due to the physical barrier.

Metformin suppressed tendon injury-induced adhesion via hydrogel-nanoparticle sustained-release system.

Tendon adhesion is one of the sequelae of tendon injury and can lead to disability in severe cases. Metformin is a commonly used antidiabetic drug. Some studies had shown that metformin could reduce tendon adhesion as well. Considering the characteristic of low absorption rate and short half-life, we established a sustained-release system, i.e., hydrogel-nanoparticle system to deliver metformin. In vitro, metformin could effectively suppress TGF-ß1-induced cell proliferation and accelerate cell apoptosis, according to cell counting kit-8, flow cytometry, and 5-ethynyl-2'-deoxyuridine (EdU) staining studies. In vivo, hydrogel-nanoparticle/metformin system could significantly lower adhesion scores and improve the gliding function of repaired flexor tendons, as well as decrease the expression of fibrotic proteins Col1a1, Col3a1, and α-smooth muscle actin (α-SMA). Histological staining revealed that the inflammation had subsided and that the gap between the tendon and the surrounding tissue was wider in the hydrogel-nanoparticle/metformin treatment group. Finally, we speculated that effect of metformin on reducing tendon adhesion might be achieved by regulating both Smad and MAPK-TGF-ß1 signaling pathways. In conclusion, metformin delivered through hydrogel-nanoparticle sustained-release system may be a promising strategy for coping with tendon adhesion.

Instantaneous self-healing and strongly adhesive self-adaptive hyaluronic acid-based hydrogel for controlled drug release to promote tendon wound healing.

The treatment of tendon injuries is an important healthcare challenge. Irregular wounds, hypocellularity, and prolonged inflammation impede the rate of healing for tendon injuries. To address these problems, a high-tenacity shape-adaptive, mussel-like hydrogel (PH/GMs@bFGF&PDA) was designed and constructed with polyvinyl alcohol (PVA) and hyaluronic acid grafted with phenylboronic acid (BA-HA) by encapsulating polydopamine and gelatin microspheres containing basic fibroblast growth factor (GMs@bFGF). The shape-adaptive PH/GMs@bFGF&PDA hydrogel can quickly adapt to irregular tendon wounds, and the strong adhesion (101.46 ± 10.88 kPa) can keep the hydrogel adhered to the wound at all times. In addition, the high tenacity and self-healing properties allow the hydrogel to move with the tendon without fracture. Additionally, even if fractured, it can quickly self-heal and continue to adhere to the tendon wound, while slowly releasing basic fibroblast growth factor during the inflammatory phase of the tendon repair process, promoting cell proliferation, migration and shortening the inflammatory phase. In acute tendon injury and chronic tendon injury models, PH/GMs@bFGF&PDA significantly alleviated inflammation and promoted collagen I secretion, enhancing wound healing through the synergistic effects of its shape-adaptive and high-adhesion properties.

Screening for autophagy/hypoxia/ferroptosis/pyroptosis-related genes of tendon injury and repair in a rat model after celecoxib and lactoferrin treatment.

BACKGROUND: Tendon injuries are among the most common musculoskeletal disorders. Celecoxib possesses an effective anti-inflammatory activity in the tendon injury treatment. Lactoferrin has a great potential for the tendon regeneration. However, the efficacy of celecoxib combined with lactoferrin in the treatment of tendon injury has not been reported. In this study, we aimed to investigate the effect of celecoxib and lactoferrin on tendon injury and repair, and screen for the crucial genes associated with the tendon injury and repair. METHODS: The rat tendon injury models were established and divided into four groups: normal control group (n = 10), tendon injury model group (n = 10), celecoxib treatment group (n = 10), and celecoxib + lactoferrin treatment group (n = 10). Then, RNA sequencing was performed to identify differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) in celecoxib treatment group and celecoxib + lactoferrin treatment group. Next, autophagy/hypoxia/ferroptosis/pyroptosis-related DEmRNAs were further identified. Subsequently, functional enrichment, protein-protein interaction (PPI) network and transcriptional regulatory network construction for these genes were performed. RESULTS: The animal study demonstrated that combinational administration of celecoxib with lactoferrin rescued the harmful effects caused by celecoxib in the treatment of tendon injury. Compared to tendon injury model group, 945 DEmRNAs, 7 DEmiRNAs and 34 DElncRNAs were obtained in celecoxib treatment group, and 493 DEmRNAs, 8 DEmiRNAs and 21 DElncRNAs were obtained in celecoxib + lactoferrin treatment group, respectively. Subsequently, 376 celecoxib + lactoferrin treatment group-specific DEmRNAs were determined. Then, 25 DEmRNAs associated with autophagy/hypoxia/ferroptosis/pyroptosis were identified. CONCLUSIONS: Several genes, such as, Ppp1r15a, Ddit4, Fos, Casp3, Tgfb3, Hspb1 and Hspa8, were identified to be associated with tendon injury and repair.