Development and Validation of a Deep-Learning Model to Predict Total Hip Replacement on Radiographs: The Total Hip Replacement Prediction (THREP) Model.

BACKGROUND: There are few methods for accurately assessing the risk of total hip arthroplasty (THA) in patients with osteoarthritis. A novel and reliable method that could play a substantial role in research and clinical routine should be investigated. The purpose of the present study was to develop a deep-learning model that can reliably predict the risk of THA with use of radiographic images and clinical symptom data. METHODS: This retrospective, multicenter, case-control study assessed hip joints on weighted-bearing anteroposterior pelvic radiographs obtained from Osteoarthritis Initiative (OAI) participants. Participants who underwent THA were matched to controls according to age, sex, body mass index, and ethnicity. Cases and controls were uniformly split into training, validation, and testing data sets at proportions of 72% (n = 528), 14% (n = 104), and 14% (n = 104), respectively. Images and clinical symptom data were passed through a detection model and a deep convolutional neural network (DCNN) model to predict the probability of THA within 9 years as well as the most likely time period for THA (0 to 2 years, 3 to 5 years, 6 to 9 years). Model performance was assessed with use of the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity in the testing set. RESULTS: A total of 736 participants were evaluated, including 184 cases and 552 controls. The prediction model achieved an overall accuracy, sensitivity, and specificity of 91.35%, 92.59% and 86.96%, respectively, with an AUC of 0.944, for THA within 9 years. The AUC of the DCNN model for assessing the most likely time period was 0.907 for 0 to 2 years, 0.916 for 3 to 5 years, and 0.841 for 6 to 9 years. Gradient-weighted class activation mapping closely corresponded to regions affecting the prediction of the DCNN model. CONCLUSIONS: The proposed DCNN model is a reliable and valid method to predict the probability of THA-within limitations. It could assist clinicians in patient counseling and decision-making regarding the timing of the intervention. In the future, by increasing the size of the data set, enhancing the ethnic and socioeconomic diversity of the participants, and improving the follow-up rate, the quality of the conclusions can be further improved. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

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.

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.

Association Between Tranexamic Acid Use and Heterotopic Ossification Prevalence After Elbow Trauma Surgery: A Propensity-Score-Matched Cohort Study.

BACKGROUND: Heterotopic ossification (HO) is a common complication of elbow trauma that can affect limb mobility. Inflammation is an initiating factor for HO formation. Tranexamic acid (TXA) can reduce the inflammatory response after orthopaedic surgery. However, evidence regarding the effectiveness of TXA use for HO prevention after elbow trauma surgery is lacking. METHODS: This retrospective observational propensity-score-matched (PSM) cohort study was conducted from July 1, 2019, to June 30, 2021, at the National Orthopedics Clinical Medical Center, Shanghai, People's Republic of China. A total of 640 patients who underwent surgery following elbow trauma were evaluated. The present study excluded patients with an age of <18 years; those with a history of elbow fracture; those with a central nervous system injury, spinal cord injury, burn injury, or destructive injury; and those who had been lost to follow-up. After 1:1 matching on the basis of sex, age, dominant arm, injury type, open injury, comminuted fracture, ipsilateral trauma, time from injury to surgery, and nonsteroidal anti-inflammatory drug use, the TXA group and the no-TXA group comprised 241 patients each. RESULTS: In the PSM population, the prevalence of HO was 8.71% in the TXA group and 16.18% in the no-TXA group (with rates of 2.07% and 5.80% for clinically important HO, respectively). Logistic regression analyses showed that TXA use was associated with a lower rate of HO (odds ratio [OR], 0.49; 95% CI, 0.28 to 0.86; p = 0.014) than no TXA use, as well as with a lower rate of clinically important HO (OR, 0.34; 95% CI, 0.11 to 0.91; p = 0.044). None of the baseline covariates significantly affected the relationship between TXA use and HO rate (p > 0.05 for all). Sensitivity analyses supported these findings. CONCLUSIONS: TXA prophylaxis may be an appropriate method for the prevention of HO following elbow trauma. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

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.

STING contributes to trauma-induced heterotopic ossification through NLRP3-dependent macrophage pyroptosis.

Trauma-induced heterotopic ossification (HO) is featured by aberrant bone formation at extra-skeletal site. STING is a master adaptor protein linking cellular damage to immune responses, while its role in HO remains elusive. A murine burn/tenotomy model was used to mimic trauma-induced HO in vivo. We demonstrated elevated STING expression in macrophages in inflammatory stage after burn/tenotomy, and STING inhibition significantly alleviated HO formation. Activated NLRP3-dependent macrophage pyroptosis was also found in inflammatory stage after burn/tenotomy. Either STING or NLRP3 suppression reduced mature HO by weakening macrophage pyroptotic inflammation, while protective effects of STING were abolished by NLRP3 overexpression. Further, in vitro, we also found a prominent STING level in pyroptotic BMDMs. STING suppression relieved macrophage pyroptotic inflammation, while abolished by NLRP3 overexpression. Our results reveal that STING poses regulatory effects on trauma-induced HO formation, via modulating NLRP3-dependent macrophage pyroptosis. Targeting STING-NLRP3 axis represents an attractive approach for trauma-induced HO prevention.

Macrophage-Derived TGF-ß and VEGF Promote the Progression of Trauma-Induced Heterotopic Ossification.

Heterotopic ossification (HO) is a pathological bone formation process caused by musculoskeletal trauma. HO is characterized by aberrant endochondral ossification and angiogenesis. Our previous studies have indicated that macrophage inflammation is involved in traumatic HO formation. In this study, we found that macrophage infiltration and TGF-ß signaling activation are presented in human HO. Depletion of macrophages effectively suppressed traumatic HO formation in a HO mice model, and macrophage depletion significantly inhibited the activation of TGF-ß/Smad2/3 signaling. In addition, the TGF-ß blockade created by a neutralizing antibody impeded ectopic bone formation in vivo. Notably, endochondral ossification and angiogenesis are attenuated following macrophage depletion or TGF-ß inhibition. Furthermore, our observations on macrophage polarization revealed that M2 macrophages, rather than M1 macrophages, play a critical role in supporting HO development by enhancing the osteogenic and chondrogenic differentiation of mesenchymal stem cells. Our findings on ectopic bone formation in HO patients and the mice model indicate that M2 macrophages are an important contributor for HO development, and that inhibition of M2 polarization or TGF-ß activity may be a potential method of therapy for traumatic HO.

PDGF-loaded microneedles promote tendon healing through p38/cyclin D1 pathway mediated angiogenesis.

Tendon injury is one of the most serious orthopedic diseases often leading to disability of patients. Major shortages of tendon healing are due to its multiple comorbidities, uncertainty of therapeutic efficacy and insufficient of angiogenesis. With a deeper understanding of angiogenic mechanism of tendon healing, we investigated an innovative microneedle patch loaded with platelet derived growth factor (PDGF) to achieve a constant systemic administration of PDGF to enhance topical tendon healing. Rat achilles tendon injury model was performed as in vivo animal models. Histological staining showed an enhancement of tendon healing quality, especially angiogenesis. Biomechanical studies demonstrated an increase of tendon stiffness, maximum load and maximum stress with treatment of PDGF-loaded microneedles. Furthermore, MAPK/p38/Cyclin D1 pathway and angiogenesis were found to play an important role in tendon healing process by using a biological high throughput RNA-sequence method and bioinformatic analysis. The high throughput RNA-seq tendon healing results were confirmed by histochemical staining and western blot. These results suggest the novel therapeutic potential of PDGF-loaded microneedle patch in tendon surgery.

Identification of CKD, bedridden history and cancer as higher-risk comorbidities and their impact on prognosis of hospitalized Omicron patients: a multi-centre cohort study.

To further describe the effect of the "fragile population" and their "higher-risk" comorbidities on prognosis among hospitalized Omicron patients, this observational cohort study enrolled hospitalized patients confirmed with SARS-CoV-2 during the 2022 Omicron wave in Shanghai, China. The primary outcome was progression to severe or critical cases. The secondary outcome was viral shedding time from the first positive SARS-CoV-2 detection. A total of 847 participants were enrolled, most of whom featured as advanced age (>70 years old: 30.34%), not fully vaccinated (55.84%), combined with at least 1 comorbidity (65.41%). Multivariate cox regression suggested age >70 years old (aHR[95%CI] 0.78[0.61-0.99]), chronic kidney disease (CKD) stage 4-5 (aHR[95%CI] 0.61[0.46-0.80]), heart conditions (aHR[95%CI] 0.76[0.60-0.97]) would elongate viral shedding time and fully/booster vaccination (aHR[95%CI] 1.4 [1.14-1.72]) would shorten this duration. Multivariate logistic regression suggested CKD stage 4-5 (aHR[95%CI] 3.21[1.45-7.27]), cancer (aHR[95%CI] 9.52[4.19-22.61]), and long-term bedridden status (aHR[95%CI] 4.94[2.36-10.44]) were the "higher" risk factor compared with the elderly, heart conditions, metabolic disorders, isolated hypertension, etc. for severity while female (aHR[95%CI] 0.34[0.16-0.68]) and fully/booster Vaccination (aHR[95%CI] 0.35[0.12-0.87]) could provide protection from illness progression. CKD stage 4-5, cancer and long-term bedridden history were "higher-risk" factors among hospitalized Omicron patients for severity progression while full vaccination could provide protection from illness progression.

Simultaneous reconstruction of septic composite defects in lower extremities: Combination of fasciocutaneous perforator flap and Masquelet technique.

Background: Management of composite defects with deep infection is a challenge to reconstructive surgeons. This study aimed to demonstrate the versatility, safety, and complications of simultaneous reconstruction of infectious composite defects with fasciocutaneous perforator flap combined with the Masquelet technique. Methods: This study presents 10 patients in whom a fasciocutaneous perforator flap combined with the Masquelet technique was used to restore soft tissue and bone defects of the lower extremity, and were admitted in two level 1 trauma centers in Shanghai. The first stage included debridement of necrotic bone and infected tissues, implantation of a polymethylmethacrylate cement spacer to cover the void; bridging fixation of the osseous defect using external or internal fixators, and soft-tissue reconstruction with a fasciocutaneous perforator flap. The second stage included cement spacer removal with membrane preservation, refreshing bone edges, and grafting the cavity with bone morphogenetic proteins and autologous iliac bone graft. Results: The mean follow-up duration after autologous bone graft was 17.5 months. The average bony defects and average flap dimensions were 7.1 cm and 44.9 cm2, respectively. All flaps survived uneventfully. No recurrence of infection was detected in either the second stage of surgery or follow-up period. The mean duration of bone consolidation was 31.9 weeks. One patient had a 2 cm leg length discrepancy, and one patient had mild foot drop. No residual deformity requiring a secondary procedure occurred. Conclusion: Fasciocutaneous perforator flap combined with Masquelet technique provides a reliable and versatile alternative for patients with composite defects resulting from lower extremity infection.

A new prognostic nomogram for heterotopic ossification formation after elbow trauma : the Shanghai post-Traumatic Elbow Heterotopic Ossification Prediction (STEHOP) model.

AIMS: Heterotopic ossification (HO) is a common complication after elbow trauma and can cause severe upper limb disability. Although multiple prognostic factors have been reported to be associated with the development of post-traumatic HO, no model has yet been able to combine these predictors more succinctly to convey prognostic information and medical measures to patients. Therefore, this study aimed to identify prognostic factors leading to the formation of HO after surgery for elbow trauma, and to establish and validate a nomogram to predict the probability of HO formation in such particular injuries. METHODS: This multicentre case-control study comprised 200 patients with post-traumatic elbow HO and 229 patients who had elbow trauma but without HO formation between July 2019 and December 2020. Features possibly associated with HO formation were obtained. The least absolute shrinkage and selection operator regression model was used to optimize feature selection. Multivariable logistic regression analysis was applied to build the new nomogram: the Shanghai post-Traumatic Elbow Heterotopic Ossification Prediction model (STEHOP). STEHOP was validated by concordance index (C-index) and calibration plot. Internal validation was conducted using bootstrapping validation. RESULTS: Male sex, obesity, open wound, dislocations, late definitive surgical treatment, and lack of use of non-steroidal anti-inflammatory drugs were identified as adverse predictors and incorporated to construct the STEHOP model. It displayed good discrimination with a C-index of 0.80 (95% confidence interval 0.75 to 0.84). A high C-index value of 0.77 could still be reached in the internal validation. The calibration plot showed good agreement between nomogram prediction and observed outcomes. CONCLUSION: The newly developed STEHOP model is a valid and convenient instrument to predict HO formation after surgery for elbow trauma. It could assist clinicians in counselling patients regarding treatment expectations and therapeutic choices. Cite this article: Bone Joint J 2022;104-B(8):963-971.

Biodegradable Hollow-Structured Nanozymes Modulate Phenotypic Polarization of Macrophages and Relieve Hypoxia for Treatment of Osteoarthritis.

Nanozymes are widely applied for treating various major diseases, including neurological diseases and tumors. However, the biodegradability of nanozymes remains a great challenge, which hinders their further clinical translation. Based on the microenvironment of osteoarthritis (OA), a representative pH-responsive biodegradable hollow-structured manganese Prussian blue nanozyme (HMPBzyme) is designed and applied for treatment of OA. HMPBzyme with good pH-responsive biodegradability, biocompatibility, and multi-enzyme activities is constructed by bovine serum albumin bubbles as a template-mediated biomineralization strategy. HMPBzyme suppresses hypoxia-inducible factor-1α (HIF-1α) expression and decreases reactive oxygen species (ROS) level in the in vitro experiment. Furthermore, HMPBzyme markedly suppresses the expression of ROS and alleviates the degeneration of cartilage in OA rat models. The results indicate that the biodegradable HMPBzyme inhibits oxidative damage and relieves hypoxia synergistically to suppress inflammation and promote the anabolism of cartilage extracellular matrix by protecting mitochondrial function and down-regulating the expression of HIF-1α, which modulates the phenotypic conversion of macrophages from pro-inflammatory M1 subtype to anti-inflammatory M2 subtype for OA treatment. This research lays a solid foundation for the design, construction, and biomedical application of biodegradable nanozymes and promotes the application of nanozymes in biomedicine.

MiR-20a-5p facilitates cartilage repair in osteoarthritis via suppressing mitogen-activated protein kinase kinase kinase 2.

Bone marrow mesenchymal stem cell (BMSC) chondrogenic differentiation contributes to the treatment of osteoarthritis (OA). Numerous studies have indicated that microRNAs (miRNAs) regulate the pathogenesis and development of multiple disorders, including OA. Nevertheless, the role of miR-20a-5p in OA remains obscure. Forty male C57BL/6 mice were divided into four groups and were surgically induced OA or underwent sham surgery in the presence or absence of miR-20a-5p. Flow cytometry was implemented to detect surface markers of BMSCs. Reverse transcription quantitative polymerase chain reaction revealed the upregulation of miR-20a-5p during BMSC chondrogenic differentiation. Western blotting displayed that miR-20a-5p inhibition decreased protein levels of cartilage matrix markers but enhanced those of catabolic and hypertrophic chondrocyte markers in BMSCs. Alcian blue staining, hematoxylin­eosin staining and micro-CT revealed that miR-20a-5p inhibition restrained chondrogenic differentiation and miR-20a-5p overexpression promoted the repair of damaged cartilage and subchondral bone, respectively. Luciferase reporter assay identified that mitogen activated protein kinase kinase kinase 2 (Map3k2) was a target of miR-20a-5p in BMSCs. Moreover, the expression of miR-20a-5p and Map3k2 was negatively correlated in murine cartilage tissues. Knocking down Map3k2 could rescue the suppressive influence of miR-20a-5p inhibition on chondrogenic differentiation of BMSCs. In conclusion, miR-20a-5p facilitates BMSC chondrogenic differentiation and contributes to cartilage repair in OA by suppressing Map3k2.

Clinical results of a 10-year follow-up of surgical treatment for elbow stiffness in rheumatoid arthritis: A case series.

BACKGROUND: Rheumatoid arthritis commonly causes transient limitation of joint motion, but the treatment of persistent stiffness in the rheumatoid elbow has rarely been reported. The purpose of this study was to evaluate the long-term clinical results of surgical treatment of rheumatoid elbow stiffness. METHODS: Surgical treatment, including open arthrolysis with hinged external fixation, total synovectomy, and ulnar nerve release and anteriorization, was performed in 48 elbows in 43 patients with rheumatoid arthritis and early joint destruction. Mobility (flexion-extension and pronation-supination), Mayo Elbow Performance Score (MEPS), visual analog scale (VAS) score, muscle strength, nerve symptoms, postoperative complications, and recurrent synovitis were evaluated 9-11 years (average, 9.88 years) postoperatively. RESULTS: The mobility of the elbow was significantly improved over the preoperative period either in extension, flexion, protonation, supination (P < .001, P < .001, P < .001, P = .002). The mean MEPS was significantly improved from 56.25 points (range, 30-90) to 87.40 points (range, 40-100) (P < .001). The pain was relieved, and the mean VAS score was reduced from 3.56 (range, 0-8) to 1.08 (range, 0-5) points (P < .001). Preoperative ulnar nerve symptoms were observed in 17 patients and relieved in 10 (59%) patients, and the mean Amadio score was raised from 6.9 (range, 3-9) to 7.96 (range, 4-9) points (P < .001). Through surgical treatment and postoperative rehabilitation, the mean grip strength of the patients was significantly improved from an average of 9.01 (range, 3.4-18.5) to 17.56 kg (range, 3.9-40.2) (P < .001). Five elbows developed recurrent synovitis, and one underwent total elbow arthroplasty. Postoperative complications were uncommon and not severe. CONCLUSION: Surgical treatment is a reliable procedure for rheumatoid elbow stiffness and can be effective in improving elbow mobility, function, muscle strength, pain relief, and relief of nerve symptoms.

Self-Healing Hydrogel Embodied with Macrophage-Regulation and Responsive-Gene-Silencing Properties for Synergistic Prevention of Peritendinous Adhesion.

Antiadhesion barriers such as films and hydrogels used to wrap repaired tendons are important for preventing the formation of adhesion tissue after tendon surgery. However, sliding of the tendon can compress the adjacent hydrogel barrier and cause it to rupture, which may then lead to unexpected inflammation. Here, a self-healing and deformable hyaluronic acid (HA) hydrogel is constructed as a peritendinous antiadhesion barrier. Matrix metalloproteinase-2 (MMP-2)-degradable gelatin-methacryloyl (GelMA) microspheres (MSs) encapsulated with Smad3-siRNA nanoparticles are entrapped within the HA hydrogel to inhibit fibroblast proliferation and prevent peritendinous adhesion. GelMA MSs are responsively degraded by upregulation of MMP-2, achieving on-demand release of siRNA nanoparticles. Silencing effect of Smad3-siRNA nanoparticles is around 75% toward targeted gene. Furthermore, the self-healing hydrogel shows relatively attenuated inflammation compared to non-healing hydrogel. The mean adhesion scores of composite barrier group are 1.67 ± 0.51 and 2.17 ± 0.75 by macroscopic and histological evaluation, respectively. The proposed self-healing hydrogel antiadhesion barrier with MMP-2-responsive drug release behavior is highly effective for decreasing inflammation and inhibiting tendon adhesion. Therefore, this research provides a new strategy for the development of safe and effective antiadhesion barriers.

Macrophage Polarization Modulated by NF-κB in Polylactide Membranes-Treated Peritendinous Adhesion.

Foreign body reactions (FBR) to implants seriously impair tissue-implant integration and postoperative adhesion. The macrophage, owing to its phenotypic plasticity, is a major regulator in the formation of the inflammatory microenvironment; NF-κB signaling also plays a vital role in the process. It is hypothesized that NF-κB phosphorylation exerts a proinflammatory regulator in FBR to polylactide membranes (PLA-M) and adhesion. First, in vitro and in vivo experiments show that PLA-M induces NF-κB phosphorylation in macrophages, leading to M1 polarization and release of inflammatory factors. The inflammatory microenvironment formed due to PLA-M accelerates myofibroblast differentiation and release of collagen III and MMP2, jointly resulting in peritendinous adhesion. Therefore, JSH-23 (a selective NF-κB inhibitor)-loaded PLA membrane (JSH-23/PLA-M) is fabricated by blend electrospinning to regulate the associated M1 polarization for peritendinous anti-adhesion. JSH-23/PLA-M specifically inhibits NF-κB phosphorylation in macrophages and exhibits anti-inflammatory and anti-adhesion properties. The findings demonstrate that NF-κB phosphorylation has a critical role in PLA-induced M1 polarization and aggravating FBR to PLA-M. Additionally, JSH-23/PLA-M precisely targets modulation of NF-κB phosphorylation in FBR to break the vicious cycle in peritendinous adhesion therapy.

What are the prevalence of and factors independently associated with depression and anxiety among patients with posttraumatic elbow stiffness? A cross-sectional, multicenter study.

BACKGROUND: Joint stiffness is a common complication after articular-related trauma in the elbow, resulting in significant limb disability, psychological stress, and a negative impact on daily life. No previous study has reported the impact of post-traumatic elbow stiffness (PTES) on psychological health. This study aims to (1) investigate the depression and anxiety levels and (2) identify factors independently associated with depression and anxiety symptoms in patients with PTES. METHODS: A total of 108 patients with PTES presenting to 4 collaborative municipal hospitals were consecutively enrolled from September to December 2020. Sociodemographic and clinical characteristics were collected through questionnaires and medical records. The Depression Anxiety Stress Scale-21 was used to assess depression and anxiety status. Ordinal logistic regression analysis was performed to identify factors independently associated with depression and anxiety symptoms. RESULTS: The detection rates of mild-to-moderate depression and anxiety are 40.7% and 27.8%, and severe-to-extremely severe levels are 23.1% and 25.9%, respectively. Regression results show that factors independently associated with depression include elbow flexion (odds ratio [OR]per 1° loss = 1.021, 95% confidence interval [CI]: 1.001-1.041, P = .035), elbow pain on movement (ORper 1 point increase = 1.236, 95% CI: 1.029-1.484, P = .023), family relationship (ORless close/very close = 10.059, 95% CI: 2.170-46.633, P = .003), and self-care ability (ORunable/able = 3.858, 95% CI: 1.244-11.961, P = .019). Factors independently associated with anxiety are elbow flexion (ORper 1° loss = 1.031, 95% CI: 1.009-1.052, P = .005), elbow pain on movement (ORper 1 point increase = 1.212, 95% CI: 1.003-1.465, P = .047), and clinically significant heterotopic ossification around elbow (ORyes/no = 2.344, 95% CI: 1.048-5.243, P = .038). CONCLUSION: Patients with PTES exhibit significant depression and anxiety symptoms. Several sociodemographic and clinical characteristics are independently associated with depression and anxiety levels. Identifying and addressing these factors may be of particular benefit during PTES management. Future research might address whether depression and anxiety affect the outcome after stiff elbow surgery.

Long-term outcomes of open arthrolysis combined with radial head arthroplasty for post-traumatic elbow stiffness: results are durable over 8 years.

BACKGROUND: Post-trauma elbow stiffness (PTES) is a common complication after elbow trauma that causes severe upper limb disability. Open elbow arthrolysis (OEA) with radial head arthroplasty (RHA) is an effective method to treat PTES with rotation limitation, or persistent pain/instability after radial head resection. However, no long-term results have been reported for this technique. This study aimed to show the clinical and radiographic outcomes of OEA with RHA over 8 years and compare its efficacy at 3 years (short-term). METHODS: Patients with PTES treated by OEA with RHA between September 2010 and December 2012 were retrospectively reviewed. Seventeen patients were followed up over 8 years (range, 100-106 months). A bipolar prosthesis of RHA was performed during OEA. Preoperative, 3-year, and 8-year elbow and forearm motion, upper limb function, radiographic outcomes, and complications were recorded. RESULTS: Clinically important improvements in elbow motion and forearm rotation were obtained, from 34° and 58° preoperatively, to 109° and 135° at 3 years, which were maintained over 8 years, to 113° (P = .262) and 134° (P = .489). The Mayo Elbow Performance Index had clinically important increases from the preoperative level of 58 to 94 points at 3 years, and was maintained over 8 years (95 points, P = .422), with 100% reporting excellent to good outcomes. Pain and nerve symptoms were also improved. Complications consisted of new-onset ulnar nerve symptoms in 1 patient, nonclinically significant heterotopic ossification recurrence in 3, humeroulnar arthritis exacerbation in 4, and periprosthetic lucency in 8. CONCLUSIONS: OEA with RHA yielded satisfactory short-term outcomes for PTES at 3 years, with substantial improvements in elbow mobility and function, and the results were durable over the long term (8 years).

Pharmacological activation of SIRT1 by metformin prevented trauma-induced heterotopic ossification through inhibiting macrophage mediated inflammation.

Trauma-induced heterotopic ossification (HO) is the aberrant extra-skeletal bone formation that severely incapacitates patient's daily life. Inflammation is the first stage of this progression, becoming an appealing target of early therapeutic intervention. Metformin, a widely used antidiabetic drug, also poses the therapeutic potential to modulate various inflammatory-related diseases. Therefore, this study aimed to investigate the preventive effect of metformin on trauma-induced HO progression, and unveil the underlying molecular mechanisms. A murine burn/tenotomy model was established to mimic trauma-induced HO in vivo. The anti-inflammation and anti-ossification effects of metformin were evaluated by histological staining and micro-CT. The inhibitory effects of metformin on macrophages activation in vitro were examined by ELISA and qRT-PCR. The underlying molecular mechanisms were further explored by immunofluorescence staining and western-blotting in vivo. Increased macrophages infiltration and inflammatory responses were found at early stage during HO progression. However, metformin dose-dependently attenuated the macrophage-mediated inflammatory responses both in vivo and vitro, which might account for the inhibitory effect of metformin on chondrogenesis and HO formation after trauma. Furthermore, elevated SIRT1 expression and decreased NF-κB p65 acetylation were found in the beneficial effects of metformin. Moreover, similar preventive effects were also found in SRT1720 HCI, a specific SIRT1 activator, while were remarkably reversed after the administration of EX527 (a specific SIRT1 inhibitor) with metformin. Taken together, our results provide a novel evidence that metformin can effectively attenuate trauma-induced HO by mitigating macrophage inflammatory responses through inhibiting NF-κB signaling via SIRT1-dependent mechanisms, which favors future therapeutic investigations for trauma-related disease.

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.