MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling.

BACKGROUND: Exosomes are extracellular vesicles of nano-structures and represent an emerging nano-scale acellular therapy in recent years. Tendon regeneration is a sophisticated process in the field of microsurgery due to its poor natural healing ability. To date, no successful long-term solution has been provided for the healing of tendon injuries. Functional recovery requires advanced treatment strategies. Human umbilical cord mesenchymal stem cell-derived exosomes (HUMSC-Exos) are considered as promising cell-free therapeutic agents. However, few studies reported their potential in the tendon repair previously. In this study, we explored the roles and underlying mechanisms of HUMSC-Exos in the tendon regeneration. RESULTS: Expression of tendon-specific markers in, and collagen deposition by, tendon-derived stem cells (TDSCs) treated with HUMSC-Exos increased in vitro. In a rat Achilles tendon injury model, treatment with HUMSC-Exos improved the histological structure, enhanced tendon-specific matrix components, and optimized biomechanical properties of the Achilles tendon. Findings in miRNA sequencing indicated a significant increase in miR-29a-3p in HUMSC-Exo-treated Achilles tendons. Next, luciferase assay in combination with western blot identified phosphatase and tensin homolog (PTEN) as the specific target of miR-29a-3p. Furthermore, we applied a miR-29a-3p-specific agonist to engineer HUMSC-Exos. These HUMSC-Exos overexpressing miR-29a-3p amplified the gain effects of HUMSC-Exos on tendon healing in vivo. To explore the underlying mechanisms, a transforming growth factor-ß1 (TGF-ß1) inhibitor (SB-431542), mTOR inhibitor (rapamycin), and engineered HUMSC-Exos were employed. The results showed that TGF-ß1 and mTOR signaling were involved in the beneficial effects of HUMSC-Exos on tendon regeneration. CONCLUSION: The findings in our study suggest that PTEN/mTOR/TGF-ß1 signaling cascades may be a potential pathway for HUMSC-Exos to deliver miR-29a-3p for tendon healing and implicate a novel therapeutic strategy for tendon regeneration via engineered stem cell-derived exosomes.

How effective is periarticular multimodal drug injection in open elbow arthrolysis? A prospective double-blind randomized controlled trial.

BACKGROUND: Evidence on the efficacy and safety of periarticular multimodal drug injection (PMDI) in open elbow arthrolysis (OEA) is limited. This study aimed to investigate differences in postoperative pain, blood loss, and range of motion (ROM) between PMDI vs. no injection among patients undergoing OEA, and the presence of PMDI-related complications. METHODS: This prospective, double-blind randomized controlled trial included 59 patients who underwent OEA. Patients randomly received PMDI (ropivacaine, epinephrine, ketoprofen) before wound closure or no injection. The primary outcomes were elbow pain over the first postoperative week at rest and during motion, measured using the visual analog scale (VAS). VAS scores were compared to attain the 20-mm threshold values for a minimum clinically important difference. Parecoxib consumption on OEA night and postoperative days (PODs) 1-3 and total consumption during the first postoperative week were recorded. Blood loss was recorded every 24 hours until POD 3. ROM during rehabilitation was measured daily from day 1 to day 7 after surgery, as well as at 3-month follow-up. Medication-related side effects were recorded prospectively. RESULTS: The mean VAS score showed clinically important differences between PMDI and control groups at rest on OEA night (mean difference [MD], 25 mm; P < .001) and first 3 PODs with motion (POD 1: MD, 28 mm, P < .001; POD 2: MD, 21 mm, P < .001; POD 3: MD, 21 mm, P < .001) but not in other postoperative assessments. Parecoxib consumption was lower in the PMDI group on OEA night and PODs 1-3. Total parecoxib consumption during the first postoperative week was lower in the PMDI group vs. the control group (MD, 148 mg; P < .001). Blood drainage was less in the PMDI group vs. the control group on POD 1 (MD, 38 mL; P = .016) but not on POD 2 (P = .950), POD 3 (P = .259), or total (P = .184). The PMDI group exhibited significantly better ROM during the first 4 PODs than the control group, whereas there was no difference at 3-month follow-up. No medication-related side effects were noted in the PMDI group. CONCLUSION: PMDI effectively relieves pain and reduces analgesic consumption for OEA patients, without an apparent increase in risks.

Intravenous tranexamic acid reduce postoperative drainage and pain after open elbow arthrolysis: a randomized controlled trial.

BACKGROUND: Open elbow arthrolysis (OEA), which has become an established treatment for post-traumatic elbow stiffness (PTES), requires complete release of contracture tissue and wide excision of ectopic bone, which results in extensive bleeding. The aim of the present study is to evaluate the efficacy of intravenous tranexamic acid (TXA) on postoperative drainage, calculated blood loss, and early clinical outcomes in patients undergoing OEA. METHODS: A double-blind, randomized, placebo-controlled trial including 96 patients undergoing OEA was undertaken. Patients received intravenously either 100 mL saline (placebo group, n = 48), or 100 mL saline plus 1 g TXA (TXA group, n = 48) before skin incision. The primary outcome was the drainage volume on postoperative days (PODs) 1-3. Secondary outcomes included the calculated blood loss, elbow pain score measured by visual analog scale (VAS), elbow function valued by Mayo Elbow Performance Score (MEPS), and rate of complications after OEA. RESULTS: Mean total postoperative drainage volume (TXA group: 182 mL vs. placebo group: 214 mL, P = .003) and mean calculated total blood loss (TXA group: 582 mL vs. placebo group: 657 mL, P = .004) were significantly lower in the TXA group. No transfusions were necessary in either group. Mean VAS pain scores in elbow motion showed marked differences between both groups on POD 1 (TXA: 5 vs. placebo: 6, P = .003) and POD 2 (TXA: 4 vs. placebo: 5, P = .023) but not in other postoperative time points. No differences were detected in complications, such as pin-related infection, hematoma, new or exacerbation of ulnar nerve symptoms, and recurrent heterotopic ossification. At the 6-month follow-up, no statistical differences were found between the 2 groups with respect to the elbow functions including range of motion, VAS score, and MEPS. CONCLUSION: Intravenous administration of TXA significantly decreased the postoperative drainage volume and the total estimated blood loss and alleviated the elbow pain with motion during early postoperative days in patients undergoing OEA.

Midterm Outcomes After Open Arthrolysis for Posttraumatic Elbow Stiffness in Children and Adolescents.

BACKGROUND: Open arthrolysis is used for treating elbow stiffness in adults. This study evaluated the midterm outcomes after open arthrolysis in children and adolescents with posttraumatic elbow stiffness. METHODS: Data of 31 children and adolescents with posttraumatic elbow stiffness following open arthrolysis with or without hinged external fixation from 2010 to 2014 were retrospectively analyzed. Their mean age was 15 (range: 6 to 19) years. At baseline and the follow-up (>4 y), we evaluated the outcomes (range of motion and Mayo Elbow Performance Index) and postoperative complications (pain, ulnar nerve symptoms, infections, and instability) and analyzed the association between outcomes and clinical variables. RESULTS: The Mayo Elbow Performance Index improved from 67.9 (range: 35 to 95 points) to 93.7 points (range: 65 to 100 points; P<0.001). The elbow active flexion/extension arc increased significantly from 49 degrees (range: 0 to 120 degrees) to 108 degrees (range: 0 to 120 degrees; P<0.001), with a mean flexion of 123 degrees (range: 70 to 140 degrees; P<0.001) and mean extension of 15 degrees (range: 0 to 85 degrees; P<0.001) postoperatively. The increasing age at surgery was associated with improved elbow motions (P=0.004). Patients with increased preoperative serum alkaline phosphatase level demonstrated decreased arc of motion (P=0.015). Patients with extra-articular fractures had better outcomes than the other patients. At the final follow-up, 8 patients experienced recurrent contracture in the flexion arc with heterotopic ossification. Two patients had postoperative pain, 1 elbow instability, and 1 ulnar neuropathy. CONCLUSIONS: Most patients showed satisfactory functional outcomes after arthrolysis, indicating that open release with or without hinged external fixation is an effective and maintained technique for children and adolescents with posttraumatic elbow stiffness. The age at surgery, preoperative alkaline phosphatase level, and injury type should be considered to achieve good outcomes. LEVEL OF EVIDENCE: Therapeutic level III.

A new pathologic classification for elbow stiffness based on our experience in 216 patients.

BACKGROUND: Elbow stiffness commonly causes functional impairment and upper-limb disability. This study aimed to develop a new pathologic classification to further understand and standardize elbow arthrolysis from a new perspective, as well as to determine clinical outcomes. METHODS: Extension-flexion dysfunction was classified into 4 types: EFI, tethers alone; EFII, tethers with blocks; EFIII, articular malformation; and EFIV, bony ankylosis. Forearm rotation dysfunction was classified into 3 types: FRI, contracture alone; FRII, radial head malunion or nonunion; and FRIII, proximal radioulnar bony ankylosis. A total of 216 patients with elbow stiffness were prospectively included and categorized preoperatively. All surgical procedures were performed by the same chief surgeon; different types underwent specific procedures. Patient data, elbow motion, and functional scores were analyzed. RESULTS: Mean range of motion (ROM) increased from 40° preoperatively to 118° at final follow-up; 88% of patients regained ROM of 100° or greater. The forearm rotation arc (FRA) with forearm rotation dysfunction increased from a preoperative mean of 76° to 128°; 82% of patients regained an FRA of 100° or greater. The mean Mayo Elbow Performance Index (MEPI) increased from 63 to 91 points; the proportion of patients with good or excellent results was 95%. EFI patients had the best ROM (129°) and MEPI (93 points) and EFIV patients achieved the most-changed ROM (116°), whereas EFIII patients had the worst ROM (104°) and MEPI (84 points) and the least-changed ROM (64°). The FRA was best in FRI patients (142°), followed by FRII patients (118°), and worst in FRIII patients (82°); in contrast, the changed FRA was greatest in FRIII patients (82°), followed by FRII patients (64°), and least in FRI patients (37°). CONCLUSION: This study suggests that the proposed pathologic classification provides a new perspective on the understanding and standardization of elbow arthrolysis, providing satisfactory clinical outcomes.

What Range of Motion and Functional Results Can Be Expected After Open Arthrolysis with Hinged External Fixation For Severe Posttraumatic Elbow Stiffness?

BACKGROUND: The elbow is more susceptible to loss of motion after trauma than any other joint. Open arthrolysis often is performed for posttraumatic elbow stiffness if the stiffness does not improve with nonsurgical treatment, but the midterm results of this procedure and factors that may limit recovery have not been widely studied. QUESTIONS/PURPOSES: We reviewed patients who had undergone open arthrolysis with hinged external fixator for severe posttraumatic elbow stiffness (ROM ≤ 60°) with a minimum of 5 years followup to (1) analyze ROM gains; (2) assess functional improvement with the Mayo Elbow Performance Index (MEPI) and DASH, quality of life with the SF-36, pain with VAS, and ulnar nerve function with the Amadio rating scale and Dellon classification; and (3) identify complications and risk factors that might hinder mid-term elbow motion recovery after this procedure. METHODS: Between March 2011 and December 2012, we generally offered patients with elbow stiffness an open arthrolysis procedure when function did not improve with 6 months of nonoperative therapy, and no contraindications such as immature heterotopic ossification or complete destruction of articular cartilage were present. During that time, 161 patients underwent open arthrolysis for posttraumatic elbow stiffness at our institution; 49 of them satisfied the study inclusion criteria (adults with elbow ROM ≤ 60° as a result of trauma) and exclusion criteria (stiffness caused by burns or central nervous system injuries, causative trauma associated with nonunion or malunion of the elbow, severe articular damage that would have necessitated joint arthroplasty, or prior elbow release). In general, a combined medial-lateral approach to the elbow was performed to address the soft tissue tethers and any blocks to elbow motion, and a hinged external fixator was applied for 6 weeks to maintain elbow stability and improve the efficacy of postoperative rehabilitation. These patients were evaluated retrospectively at a mean followup period of 69 months (range, 62-83 months), and demographics, disease characteristics, arthrolysis details, pre- and postoutcome measures as noted, and complications were recorded via an electronic database. Multivariate regression analysis was performed to identify factors associated with ROM recovery. RESULTS: At final followup, total ROM increased from a preoperative mean of 27 ± 20° to a postoperative mean of 131 ± 11° (mean difference, 104°; 95% CI, 98°-111°; p < 0.001), and 98% (48 of 49) of patients achieved a functional ROM of 30° to 130°. Improvements were also found in functional scores (MEPI: 54 ± 12 to 95 ± 7, mean difference, 41 points; DASH: 48 ± 17 to 8 ± 8, mean difference, 40 points; both p < 0.001), life quality (physical SF-36: 46 ± 11 to 81 ± 12, mean difference, 35 points; mental SF-36: 43 ± 14 to 80 ± 9, mean difference, 37 points; both p < .001), pain (VAS: 2.5 ± 2.4 to 0.4 ± 0.8; mean difference, 2.0 points; p < 0.001), and ulnar nerve function (Amadio score: 7.8 ± 1.9 to 8.4 ± 0.8; mean difference, 0.6 points; p = 0.004). A total of 18% (nine of 49 patients) developed complications, including new-onset or exacerbated nerve symptoms (four patients), recurrent heterotopic ossification (two patients), and pin-related infections (three patients). No patients underwent subsequent surgery for any of the above complications. Lastly, the medium-term ROM was divided into ROM ≤ 120° (n = 9) and ROM > 120° (n = 40). After controlling for potential confounding variables such as duration of stiffness and tobacco use, we found that tobacco use was the only independent risk factor examined (odds ratio, 9; 95% CI, 2-47; p = 0.009) associated with recovery of ROM. CONCLUSIONS: Satisfactory medium-term results were found for open arthrolysis with hinged external fixation with our protocol in patients who had severe posttraumatic elbow stiffness. Appropriate and sufficient releases of tethered soft tissues and correction of any blocks that affect elbow motion intraoperatively, a dedicated team approach, and an aggressive and systematic postoperative rehabilitation program are the core steps for this procedure. Additionally, the importance of preoperative discontinuation of tobacco use should be emphasized. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Determining the effective timing of an open arthrolysis for post-traumatic elbow stiffness: a retrospective cohort study.

BACKGROUND: Following trauma, the elbow is the most susceptible to restricted motion among all joints. Open arthrolysis is often performed for post-traumatic elbow stiffness if that stiffness does not improve with non-operative management. However, the optimal timing for performing an open arthrolysis remains controversial. The purpose of this study was to compare the outcome (elbow motion and function) and the rate of complications among patients who had undergone early, median and late release procedures to establish an optimal time interval following the injury, after which, an effective open arthrolysis can be performed. METHODS: In this retrospective cohort study, we included total 133 patients, who had undergone open arthrolysis for post-traumatic elbow stiffness. The subjects were divided into 3 groups, with 31 patients in the early release group (arthrolysis performed at 6-10 months after injury), 78 patients in the median release group (at 11-20 months), and 24 patients in the late release group (at > 20 months). The release procedure in all patients was performed by the same surgeon, using the same technique. The general data, functional performance, and complications, if any, were retrospectively documented for all patients and statistically analysed. RESULTS: The demographic data and disease characteristics of all patients were comparable at baseline. Postoperatively, no significant differences were found among the three groups with respect to the range of motion (p = 0.067), Mayo Elbow Performance Score (p = 0.350) and its ratings (p = 0.329), visual analog scale score for pain (p = 0.227), Dellon classification for ulnar nerve symptoms (p = 0.497), and each discrete complication (all p values > 0.05). CONCLUSIONS: At the final follow-up, our results showed no significant difference in the postoperative elbow motion capacities, functional scores and the rates of complications among patients who had undergone an early, median, and late release. Therefore, we have recommended that an early arthrolysis would be preferable due to its multiple advantages, and the conventionally observed interval of > 1 year after the injury, could be shortened. LEVEL OF EVIDENCE: Level III; Retrospective Cohort Design; Therapeutic Study.

Management of elbow dysfunction associated with giant cell tumor of the distal humerus: achieving oncologic safety and good function by a combined reconstruction.

BACKGROUND: The purpose of our study was to evaluate the functional outcomes and oncologic results of elbow salvage surgery using arthrolysis combined with ligament repair and external fixation for reconstruction of the elbow after tumor excision and autografting. METHODS: We retrospectively reviewed 6 patients with elbow dysfunction associated with giant cell tumor of the distal humerus. All patients were treated with our combined protocol. We assessed the Musculoskeletal Tumor Society system score, range of motion, Mayo Elbow Performance Score, recurrence, and complications for each patient. RESULTS: The mean follow-up period was 48 months (range, 36-60 months). There were no cases of postoperative fracture, infection, elbow dislocation, elbow stiffness, or local recurrence. The average Musculoskeletal Tumor Society score was 28 of 30 points (93%; range, 87%-100%). The Mayo Elbow Performance Score improved from a mean of 61 points to 93 points, with mean flexion of 135° and mean extension of 3°. CONCLUSIONS: Local tumor resection, autografting, and elbow reconstruction by arthrolysis combined with ligament repair and external fixation can be performed with oncologic safety and provide satisfactory functional outcomes with low complication rates.

Management of elbow stiffness after postoperative treatment of terrible triad elbow injury: maintaining mobility and stability using a combined protocol.

PURPOSES: The purpose of this study was to evaluate the results of our protocol that include the restoration of mobility using open release combined with external fixation and stability using ligament repair, to determine the optimal timing of surgery, and to investigate whether resection and replacement of the radial head are associated with different outcomes. METHODS: Twenty-six patients with elbow stiffness after operation of terrible triad injury of the elbow were treated with our protocol. We assessed the optimal timing of the operation by comparing outcomes between the early treatment group and the delayed treatment group. The comparison was performed to investigate whether the results differed between resection and replacement of the radial head. Stability of the elbow, range of motion (ROM), Mayo Elbow Performance Score (MEPS), and complications were assessed for each patient. RESULTS: The mean interval from the initial surgery to the index procedure was 13 months, and the mean follow-up period was 29 months. The MEPS increased from a mean of 65 points to 94 points. Twenty-five of 26 patients achieved stability of the elbow, and all patients achieved functional ROM. There were no significant differences between the two subgroups with respect to ROM and stability of the elbow. CONCLUSION: Our protocol can restore mobility and stability. Resection and replacement of the radial head are both feasible using this protocol. Lastly, the timing of the surgery was not very rigorous, and the surgical delay may be insignificant. LEVEL OF EVIDENCE: Level IV; Case Series; Treatment Study.

Endogenous hydrogen sulfide accelerated trauma-induced heterotopic ossification through the Ca2+/ERK pathway-enhanced aberrant osteogenic activity.

Unveiling of the mechanism involved in the occurrence and development of trauma-induced heterotopic ossification (tHO) is highly demanding due to current ineffective clinical treatment for it. Previous studies proposed that hydrogen sulfide (H2S) was vital for fate determination of stem cells, suggesting a potential role in the regulation of tHO development. In the current study, We found that expression of metabolic enzyme within sulfur conversion pathway was enhanced after tendon injury, leading to H2S accumulation within the tHO region. Increased production of endogenous H2S was shown to promote aberrant osteogenic activity of tendon-derived stem cells (TDSCs), which accelerated tHO formation. The inhibition of metabolic enzyme of H2S production or directly absorption of H2S could abolished osteogenic induction of TDSCs and the formation of tHO. Mechanistically, through RNA sequencing combined with rescue experiments, we demonstrated that activation of Ca2+/ERK pathway was the downstream molecular event of H2S-induced osteogenic commitment of TDSCs and tHO. For treatment strategy exploration, zine oxide nanoparticles (ZnO) as an effective H2S elimination material was validated to ideally halt the tHO formation in this study. Furthermore, in terms of chirality of nanoparticles, D-ZnO or L-ZnO nanoparticles showed superiority over R-ZnO nanoparticles in both clearing of H2S and inhibition of tHO. Our study not only revealed the mechanism of tHO through the endogenous gas signaling event from a new perspective, but also presented a applicable platform for elimination of the inordinate gas production, thus aiding the development of clinical treatment for tHO.

Decellularized diseased tissues: current state-of-the-art and future directions.

Decellularized matrices derived from diseased tissues/organs have evolved in the most recent years, providing novel research perspectives for understanding disease occurrence and progression and providing accurate pseudo models for developing new disease treatments. Although decellularized matrix maintaining the native composition, ultrastructure, and biomechanical characteristics of extracellular matrix (ECM), alongside intact and perfusable vascular compartments, facilitates the construction of bioengineered organ explants in vitro and promotes angiogenesis and tissue/organ regeneration in vivo, the availability of healthy tissues and organs for the preparation of decellularized ECM materials is limited. In this paper, we review the research advancements in decellularized diseased matrices. Considering that current research focuses on the matrices derived from cancers and fibrotic organs (mainly fibrotic kidney, lungs, and liver), the pathological characterizations and the applications of these diseased matrices are mainly discussed. Additionally, a contrastive analysis between the decellularized diseased matrices and decellularized healthy matrices, along with the development in vitro 3D models, is discussed in this paper. And last, we have provided the challenges and future directions in this review. Deep and comprehensive research on decellularized diseased tissues and organs will promote in-depth exploration of source materials in tissue engineering field, thus providing new ideas for clinical transformation.

Surgical resection outcomes of post-traumatic elbow heterotopic ossification: multicenter case series at a minimum 5-year follow-up.

BACKGROUND: Heterotopic ossification (HO), a common complication after elbow trauma, causes severe limb disability, Surgical resection is usually performed for post-traumatic elbow HO (PTEHO) to regain mobility. Though it was heavily reported, there has been no long-term (minimum 5-year) follow-up. PATIENTS AND METHODS: 173 patients who underwent PTEHO resection were followed up for minimum 5 years in 4 hospitals between January/2015 and August/2016. Demographics, disease characteristics, preoperative and minimum 5-year assessments were collected. After controlling for potential variables when dividing long-term ROM into <120° and ≥120°, risk factors for ROM recovery to modern functional arc were identified through multivariable regression analysis. RESULTS: Clinically important improvements in ROM of 39°â†’124° were obtained at final follow-up, and 74.6% achieved modern functional arc (≥120°). Mayo Elbow Performance Index (MEPI) had clinically important increases of 69→93 points at final follow-up, and 96.5% reported excellent-to-good. Pain (Numerical Rating Scale, 1.9→0.6 points) and ulnar nerve symptoms were improved. Total complication rate was 15.6%, including new-onset ulnar nerve symptoms (5.8%), HO recurrence with clinical symptoms (6.9%), elbow instability (1.7%), and joint infection (1.2%). Previously reported high body mass index (BMI, p=0.002) and long disease duration (p=0.033) were equally identified as risk factors for not achieving modern functional arc, meanwhile tobacco use (p=0.024) and ankylosed HO (p<0.001) were found to be new risk factors. CONCLUSION: Surgical resection yields satisfactory outcomes for PTEHO at long-term of minimum 5 years. High BMI, tobacco use, long disease duration, and ankylosed HO would negatively affect ROM recovery to modern functional arc (≥120°). LEVEL OF EVIDENCE: Level IV, therapeutic study.

NLRP3-Dependent Crosstalk between Pyroptotic Macrophage and Senescent Cell Orchestrates Trauma-Induced Heterotopic Ossification During Aberrant Wound Healing.

Heterotopic ossification (HO) represents an unwanted ossific wound healing response to the soft tissue injury which caused catastrophic limb dysfunction. Recent studies established the involvement of inflammation and cellular senescence in the tissue healing process, though their role in HO still remained to be clarified. Here, a novel crosstalk where the pyroptotic macrophages aroused tendon-derived stem cells (TDSCs) senescence is revealed to encourage osteogenic healing during trauma-induced HO formation. Macrophage pyroptosis blockade reduces the senescent cell burden and HO formation in NLRP3 knockout mice. Pyroptosis-driven IL-1ß and extracellular vesicles (EVs) secretion from macrophages are determined to motivate TDSCs senescence and resultant osteogenesis. Mechanistically, pyroptosis in macrophages enhances the exosomal release of high mobility group protein 1 (HMGB1), which directly bounds TLR9 in TDSCs to trigger morbid signaling. NF-κB signaling is confirmed to be the converging downstream pathway of TDSCs in response to HMGB1-containing EVs and IL-1ß. This study adds insights into aberrant regeneration-based theory for HO formation and boosts therapeutic strategy development.

Tranexamic acid in patients with post-traumatic elbow stiffness: protocol for a randomised, double-blind, placebo-controlled trial investigating the effectiveness of tranexamic acid at reducing the recurrence of heterotopic ossification after open elbow arthrolysis.

INTRODUCTION: Exaggerated inflammatory response is one of the main mechanisms underlying heterotopic ossification (HO). It has been suggested that the antifibrinolytic drug tranexamic acid (TXA) can exert a significant anti-inflammatory effect during orthopaedic surgery. However, no prospective studies have yet investigated the effects of TXA on HO recurrence in patients following open elbow arthrolysis (OEA). METHODS AND ANALYSIS: Here, we present a protocol for a single-centre, randomised, double-blind, placebo-controlled trial to investigate the effectiveness of TXA on HO recurrence after OEA in a single hospital. A minimum sample size of 138 eligible and consenting participants randomised into treatment and control groups in a 1:1 manner will be included. Patients will receive 2 g of intravenous TXA (experimental group) or placebo (normal saline, control group) administered before skin incision. The primary outcome is HO recurrence rate within 12 months after surgery. The secondary outcomes are the serum immune-inflammatory cytokines including erythrocyte sedimentation rate, C reactive protein, interleukin (IL)-6, IL-1ß, IL-13 at the first and third day postoperatively, and elbow range of motion and functional score at 1.5, 6, 9 and 12 months after surgery. After completion of the trial, the results will be reported in accordance with the extensions of the Consolidated Standards of Reporting Trials Statement for trials. The results of this study should determine whether TXA can reduce the rates of HO occurrence after OEA. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Medical Ethics Committee of the Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (reference number 2022-123-(1)). The results of this study will be disseminated through presentations at academic conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2300068106.

Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult.

Heterotopic ossification (HO) is one of the most intractable disorders following musculoskeletal injury and is characterized by the ectopic presence of bone tissue in the soft tissue leading to severe loss of function in the extremities. Recent studies have indicated that immune cell infiltration and inflammation are involved in aberrant bone formation. In this study, we found increased monocyte/macrophage and mast cell accumulation during early HO progression. Macrophage depletion by clodronate liposomes and mast cell stabilization by cromolyn sodium significantly impeded HO formation. Therefore, we proposed that the dietary phytochemical quercetin could also suppress immune cell recruitment and related inflammatory responses to prevent HO. As expected, quercetin inhibited the monocyte-to-macrophage transition, macrophage polarization, and mast cell activation in vitro in a dose-dependent manner. Using a murine burn/tenotomy model, we also demonstrated that quercetin attenuated inflammatory responses and HO in vivo. Furthermore, elevated SIRT1 and decreased acetylated NFκB p65 expression were responsible for the mechanism of quercetin, and the beneficial effects of quercetin were reversed by the SIRT1 antagonist EX527 and mimicked by the SIRT agonist SRT1720. The findings in this study suggest that targeting monocyte/macrophage and mast cell activities may represent an attractive approach for therapeutic intervention of HO and that quercetin may serve as a promising therapeutic candidate for the treatment of trauma-induced HO by modulating SIRT1/NFκB signaling.

Intra-Aortic Balloon Occlusion Decreases Blood Loss During Open Reduction and Internal Fixation for Delayed Acetabular Fractures: A Retrospective Study of 43 Patients.

Aim: It is difficult to treat delayed acetabular fractures due to massive blood loss during operation. Temporary balloon occlusion of the abdominal aorta was introduced into sacral tumor surgery to reduce intraoperative hemorrhage. The aim of this study was to investigate the effect of this method on reduction of intraoperative blood loss and analyze the complications of this technique in the treatment of delayed acetabular fracture. Methods: We retrospectively reviewed 43 patients with delayed acetabular fracture who were surgically treated through combined approaches. Nineteen patients underwent temporary balloon occlusion of the abdominal aorta; 10 patients had type B fracture and 9 patients had type C fracture according to the Müller AO classification. The remaining 24 patients were classified into a control group; 14 patients had type B fracture and 10 patients had type C fracture. Surgical time, intraoperative blood loss, blood transfusion, satisfactory reduction rate, and functional recovery were recorded and compared between two groups. Merle d'Aubigné and Postel scoring was applied to evaluate the patients. Results: The patients treated with intra-aortic balloon occlusion had a shorter surgical time (p = 0.008), less intraoperative blood loss (p = 0.005), and less transfused blood units (p = 0.001). No complications caused by balloon occlusion. No significant difference were observed in the outcomes and the complications related to acetabular fractures between two groups. Conclusions: Temporary balloon occlusion of the abdominal aorta is a reliable technique to control bleeding for the surgery of delayed acetabular fracture.

Effectiveness of three-dimensional printed and virtual reality models in learning the morphology of craniovertebral junction deformities: a multicentre, randomised controlled study.

OBJECTIVES: To compare the effectiveness of three-dimensional printed (3DP), virtual reality (VR) and conventional normal physical (NP) models in clinical education regarding the morphology of craniovertebral junction (CVJ) deformities. DESIGN: Prospective, multicentre, randomised controlled study. SETTING: Three teaching hospitals in China. PARTICIPANTS: One hundred and fifty-three participants in their first year of a 3-year medical residency programme. INTERVENTIONS: All participants were randomised to one of the three groups to learn the morphology of CVJ deformities using 3DP, VR or NP models. PRIMARY OUTCOME MEASURES: The objective outcomes were evaluated using three-level objective testing. In the first-level test, the participants were required to identify 15 anatomical landmarks on radiographs without CVJ deformities. In the second-level test, all participants were asked to identify the same 15 landmarks on radiographs showing classic CVJ deformities. In the third-level test, the participants were required to describe the key features of three classic cases of CVJ deformities depicted on radiographs. Each participant was also asked to answer four subjective questions to evaluate the importance and usefulness of the educational materials. RESULTS: In the first-level test, the 3DP, VR and NP groups achieved similar correct rates. In the second-level test, the correct rate was higher in the 3DP group (82.1%±13.6%) than the VR and NP groups (76.9%±16.9% and 69.9%±20.0%, p=0.002). In the third-level test, the 3DP group achieved better correct rates regarding the description of key CVJ deformities features (66.2%±20.0%, p=0.049) than the other groups. The subjective tests showed that the 3DP model method was considered the most valuable approach for learning CVJ deformities. CONCLUSIONS: The objective and subjective results show that the 3DP model is more effective teaching instrument than the NP model for learning the pathomorphology of CVJ deformities. The VR model also showed great efficacy, second to 3DP model, in improving participants' understanding of CVJ deformities.

Human nail bed extracellular matrix facilitates bone regeneration via macrophage polarization mediated by the JAK2/STAT3 pathway.

Critical-sized bone defects caused by trauma, tumor resection or serious infection represent one of the most challenging problems faced by orthopedic surgeons. However, the construction of bone grafts with good osteointegration and osteoinductivity is a clinical challenge. It has been elaborated that the nail bed tissue is an essential element for digit tip regeneration, suggesting that the nail bed may serve as a new material to manipulate bone regeneration. Herein, it was found that human nail bed extracellular matrix derived from amputated patients stimulates macrophage polarization toward a pro-healing phenotype and the expression of BMP2, to facilitate the osteogenic differentiation of bone marrow stromal cells (BMSCs) in vitro. The in vivo osteogenic capacity of decellularized nail bed scaffolds was then confirmed using a rat model of critical-sized calvarial defects. The in-depth analysis of immune responses to implanted scaffolds revealed that macrophage polarization toward the pro-regenerative M2 phenotype directs osteogenesis, as confirmed by macrophage depletion. A combination of proteomics analysis and RNA interference verified that the JAK2/STAT3 pathway is the positive regulator of macrophage polarization initiated by the decellularized nail bed during the promoted osteogenesis process. Thus, the decellularized human nail bed scaffold developed in this work is a promising biomaterial for bone regeneration.

Extracellular vesicles from hydroxycamptothecin primed umbilical cord stem cells enhance anti-adhesion potential for treatment of tendon injury.

BACKGROUND: Peritendinous fibrosis represents a fibrotic healing process that usually occurs after tendon injury or surgery. This worldwide challenge hampers the functional rehabilitation and the mobility of extremities. However, effective treatment is still lacking at present. The aim of our study was to explore the effect of extracellular vesicles derived from hydroxycamptothecin primed human umbilical cord stem cells (HCPT-EVs) on post-traumatic tendon adhesion. METHODS: Extracellular vesicles derived from unprimed human umbilical cord mesenchymal stem cells (Unprimed EVs) or HCPT-EVs were isolated and characterized. A rat model of Achilles tendon injury was used to confirm the anti-adhesion effect of HCPT-EVs and compared with that of Unprimed EVs in vivo. In vitro, the inhibitory effects of HCPT-EVs on fibroblast proliferation, viability, and myofibroblast differentiation upon TGF-ß1 stimulation were compared with the effects of Unprimed EVs. For mechanistic analysis, the expression of endoplasmic reticulum stress (ERS)-associated proteins was examined among the effector cargos of HCPT-EVs and Unprimed EVs. The ERS antagonist salubrinal was used to determine the ERS dependence of the anti-adhesion effects of HCPT-EVs. RESULTS: There were no obvious differences between Unprimed EVs and HCPT-EVs in terms of morphology, particle size, characteristic protein expression, and cellular uptake. HCPT-EVs exhibited a fortified anti-adhesion effect after Achilles tendon injury compared with Unprimed EVs. Fibroblast proliferation and viability and myofibroblast differentiation were all inhibited by HCPT-EVs. These properties were superior for HCPT-EVs relative to Unprimed EVs. Mechanistically, HCPT-EVs contained more ERS-associated protein than Unprimed EVs and activated the ERS pathway in fibroblast to counteract myofibroblast differentiation. CONCLUSION: This study demonstrates that HCPT-EVs show high anti-adhesion potential for the treatment of tendon injury by provoking ERS in fibroblasts. HCPT-EVs represent a promising strategy for clinical use in treating adhesion-related diseases.

Progress in developing decellularized bioscaffolds for enhancing skin construction.

The skin is the largest organ in the human body, and skin defects are very common. Skin flap transplantation is the best treatment for serious wound defects, and donor site tissues are always sacrificed during this process. Decellularized biomaterials, derived mainly from various nonautologous organs and tissues, have promising applications in tissue engineering and repair of wound defects. To date, decellularized mesothelium, intestine, amniotic membrane, dermis, and skin flaps have been developed and applied for skin coverage in animal models and clinical practice. In this review, we discuss recent advances in decellularized biomaterials for skin substitutes and future perspectives. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1849-1859, 2019.