The Therapeutic Effect of iMSC-Derived Small Extracellular Vesicles on Tendinopathy Related Pain Through Alleviating Inflammation: An in vivo and in vitro Study.

Background: Tendinopathy is a common cause of tendon pain. However, there is a lack of effective therapies for managing tendinopathy pain, despite the pain being the most common complaint of patients. This study aimed to evaluate the therapeutic effect of small extracellular vesicles released from induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) on tendinopathy pain and explore the underlying mechanisms. Methods: Rat tendinopathy model was established and underwent the injection of iMSC-sEVs to the quadriceps tendon one week after modeling. Pain-related behaviors were measured for the following four weeks. Tendon histology was assessed four weeks after the injection. To further investigate the potential mechanism, tenocytes were stimulated with IL-1ß to mimic tendinopathy in vitro. The effect of iMSC-sEVs on tenocyte proliferation and the expression of proinflammatory cytokines were measured by CCK-8, RT-qPCR, and ELISA. RNA-seq was further performed to systematically analyze the related global changes and underlying mechanisms. Results: Local injection of iMSC-sEVs was effective in alleviating pain in the tendinopathy rats compared with the vehicle group. Tendon histology showed ameliorated tendinopathy characteristics. Upon iMSC-sEVs treatment, significantly increased tenocyte proliferation and less expression of proinflammatory cytokines were observed. Transcriptome analysis revealed that iMSC-sEVs treatment upregulated the expression of genes involved in cell proliferation and downregulated the expression of genes involved in inflammation and collagen degeneration. Conclusion: Collectively, this study demonstrated iMSC-sEVs protect tenocytes from inflammatory stimulation and promote cell proliferation as well as collagen synthesis, thereby relieving pain derived from tendinopathy. As a cell-free regenerative treatment, iMSC-sEVs might be a promising therapeutic candidate for tendinopathy.

Small extracellular vesicles from iPSC-derived mesenchymal stem cells ameliorate tendinopathy pain by inhibiting mast cell activation.

Aim: This study aimed to explore the effect of small extracellular vesicles from induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) on acute pain and investigate the underlying mechanisms. Materials & methods: The pathology of tendons was accessed by hematoxylin and eosin staining, immunohistochemical and immunofluorescent staining. The pain degree was measured by pain-related behaviors. In vitro, we performed ß-hexosaminidase release assay, RT-qPCR, toluidine blue staining, ELISA and RNA sequencing. Results: iMSC-sEVs effectively alleviated acute pain in tendinopathy as well as inhibiting activated mast cell infiltration and interactions with nerve fibers in vivo. In vitro, iMSC-sEVs reduced the degranulation of mast cells and the expression of proinflammatory cytokines and genes involved in the HIF-1 signaling pathway. Conclusion: This study demonstrated that iMSC-sEVs relieved tendinopathy-related pain through inhibiting mast cell activation via the HIF-1 signaling pathway.

Reversing the surface charge of MSC-derived small extracellular vesicles by εPL-PEG-DSPE for enhanced osteoarthritis treatment.

Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) possess a great therapeutical potential for osteoarthritis (OA) treatment. However, the steric and electrostatic hindrance of cartilage matrix leads to very limited distribution of MSC-sEVs in cartilage and low bioavailability of MSC-sEVs after intra-articular injection. To overcome this, a strategy to reverse the surface charge of MSC-sEVs by modifying the MSC-sEVs with a novel cationic amphiphilic macromolecule namely ε-polylysine-polyethylene-distearyl phosphatidylethanolamine (PPD) was developed in this study. Through incubation with 100 µg/ml PPD, positively charged MSC-sEVs (PPD-sEVs) were obtained, and the modification process showed nearly no disturbance to the integrity and contents of sEVs and exhibited good stability under the interference of anionic macromolecules. A more effective cellular uptake and homeostasis modulation ability of PPD-sEVs than unmodified MSC-sEVs to chondrocytes was demonstrated. More importantly, PPD-sEVs demonstrated significantly enhanced cartilage uptake, cartilage penetration, and joint retention capacity as compared to MSC-sEVs. Intra-articular injection of PPD-sEVs into a mouse OA model showed significantly improved bioavailability than MSC-sEVs, which resulted in enhanced therapeutic efficacy with reduced injection frequency. In general, this study provides a facile and effective strategy to improve the intra-articular bioavailability of MSC-sEVs and has a great potential to accelerate the clinical practice of MSC-sEVs based OA therapy.

[Mid-term effectiveness of periacetabular osteotomy through modified ilioinguinal approach for acetabular dysplasia in adults].

OBJECTIVE: To investigate the mid-term effectiveness of periacetabular osteotomy (PAO) through modified ilioinguinal approach for acetabular dysplasia in adults. METHODS: Between January 2016 and December 2018, 39 patients (43 hips) with acetabular dysplasia who met the selection criteria were enrolled in the study and their clinical data were retrospectively analyzed. All patients were treated with PAO via modified ilioinguinal approach (firstly, the skin and superficial facia were cut via the traditional ilioinguinal approach, and the deep tissues were cut via the modified iliac-femoral approach). There were 3 males (3 hips) and 36 females (40 hips) with an average age of 36 years (range, 18-51 years). Among them, 35 cases of lesions involved single hip and 4 cases of lesions involved bilateral hips. The disease duration ranged from 4 to 96 months, with a median of 18 months. According to the modified Tönnis grading for osteoarthritis, 35 hips were classified as grade 0, 6 hips as grade Ⅰ, and 2 hips as grade Ⅱ. All patients had different degrees of hip pain. The preoperative visual analogue scale (VAS) score of pain was 4.7±0.8, and the modified Harris hip score was 78.5±8.6. The lateral centre-edge angle (LCEA) was (10.52±10.83)°, and the acetabular index (AI) was (26.89±9.07) °. The operation time, intraoperative blood loss, and the incidence of complications were recorded. LCEA, AI, and the progression of osteoarthritis were reviewed by X-ray films. The function and pain of hip joint were evaluated by modified Harris hip score and VAS score. RESULTS: All operations were successfully completed. The operation time was 90-150 minutes, with an average of 130 minutes. The volume of intraoperative blood loss was 350-600 mL, with an average of 500.6 mL. All patients were followed up 17-52 months, with an average of 32.7 months. Postoperative numbness of the lateral femoral cutaneous nerve occurred in 3 cases, and no other complications occurred. At last follow-up, the modified Harris hip score was 97.7±3.7 and VAS score was 0.9±1.1, both of which were better than those before operation ( P<0.05). At 1 year after operation, X-ray films showed that the all osteotomies healed. In term of the modified Tönnis grading for osteoarthritis, 1 hip downgraded from grade 1 to grade 0, while the remaining hips stayed unchanged. At last follow-up, LCEA and AI were (27.54±8.49) ° and (11.30±5.53) °, respectively, which were significantly different from those before operation ( P<0.05). CONCLUSION: PAO through modified ilioinguinal approach is effective in relieving pain and restoring hip function in adults with acetabular dysplasia, which can overcome the disadvantages of the traditional ilioinguinal approach, and may delay the development of osteoarthritis.

Controlled release of MSC-derived small extracellular vesicles by an injectable Diels-Alder crosslinked hyaluronic acid/PEG hydrogel for osteoarthritis improvement.

Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) show great therapeutic potential for osteoarthritis (OA). However, their low bioavailability through intraarticular injection inhibits the process of clinical application. In the present study, an injectable Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel was developed as an intraarticular delivery platform for MSC-sEVs. Our results showed that the DAHP hydrogel could be prepared easily and that its gelation properties were suitable for intraarticular administration. In vitro studies demonstrated that the DAHP hydrogel could achieve sustained release of MSC-sEVs mainly by degradation control and preserve the therapeutic functions of sEVs. An in vivo experiment revealed that the DAHP hydrogel could enhance the efficacy of MSC-sEVs for OA improvement. This study provides a suitable delivery platform for MSC-sEVs-based OA therapy. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) have shown a high potential as a cell-free therapeutic factor for treating osteoarthritis (OA). The sustained release of these MSC-sEVs in the joint space is essential for their clinical application. Herein, an injectable Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel was developed for intraarticular release of MSC-sEVs. The properties of the DAHP hydrogel, namely gelation features, cytocompatibility, sustained release, and functional maintenance of MSC-sEVs, make it suitable for intraarticular injection and delivery of sEVs. The efficacy of MSC-sEVs was enhanced by the intraarticularly injected DAHP hydrogel. Our present study provides a promising sustained delivery platform for MSC-sEVs for treating OA.

Low Back Pain Caused by Iliopsoas Tendinopathy Treated with Ultrasound-Guided Local Injection of Anesthetic and Steroid: A Retrospective Study.

BACKGROUND: Low back pain is a prevalent symptom that occurs in all age of people, whereas the pathogenesis is unknown. Iliopsoas tendinopathy is an increasingly recognized hip disorder that may contribute to low back pain. Our purpose is to evaluate the effect of ultrasound-guided local injection of anesthetic and steroid into the trigger point of iliopsoas tendon in treating low back pain caused by iliopsoas tendinopathy. MATERIALS AND METHODS: This retrospective study reviewed 45 patients diagnosed with iliopsoas tendinopathy treated by B-ultrasound guided injection of 2 mL 2% lidocaine and 1 mL (5 mg) triamcinolone acetonide into the trigger point of iliopsoas tendon from March 2016 to June 2016. Medical records were collected to analyze the clinical presentation. Numerical Rating Scale (NRS) measuring low back pain and Harris Hip score (HHS) measuring hip pain and function were administered to determine patient outcomes. Telephone follow-up was conducted, and the mean follow-up was 11 months. RESULTS: We observed that most patients with iliopsoas tendinopathy also complain about chronic low back pain except for groin pain. After injection of anesthetic and corticosteroid into the iliopsoas tendon, the NRS of patients with low back pain fell from 7.68±1.31 to 2.58±1.16 immediately after the injection and 0.75±0.73 at follow-up. The HHS improved from 43.02±16.81 to 98.15±2.56 at follow-up. Statistically significant difference (P<0.001) was observed. All patients returned to their original level of function, and only five patients presented with mild low back pain at the follow-up. CONCLUSION: Low back pain is a prevalent presentation for iliopsoas tendinopathy. Diagnosis of iliopsoas tendinopathy should be considered in patients with low back pain with tenderness over the iliopsoas tendon. Ultrasound-guided local injection of anesthetic and steroid lead to satisfactory effect in relieving low back and groin pain and improving joint function.