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.

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.

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.

[The second dorsal metacarpal artery flap relaying the dorsal island flap of the index finger for the repair of soft tissue defect of thumb].

Objective: To investigate the effectiveness of the second dorsal metacarpal artery fascial vascular pedicle retrograde island flap relaying the dorsal island flap of the index finger in repairing skin and soft tissue defects of the thumb. Methods: The clinical data of 8 patients with skin and soft tissue defects of thumb between October 2019 and January 2021 were retrospectively analyzed. There were 3 males and 5 females with an average age of 35 years (range, 18-52 years). The causes of injury included machine injury in 2 cases, crush injury in 3 cases, and cutting injury in 3 cases. There were 2 cases of dorsal defect of the proximal part, 1 dorsal defect of the distal part, and 5 instances of the distal part defect. The skin and soft tissue defects ranged from 1.7 cm×1.4 cm to 3.0 cm×2.5 cm. The time from injury to flap repair was 7-21 days, with an average of 14 days. Firstly, the dorsal island flap of the index finger (dorsal side of the proximal part of the index finger) was used to repair the defect of the thumb. Then the second dorsal metacarpal artery fascia vascular pedicle retrograde island flap (near the radial side of the back of the hand) was used to repair the dorsal defect of the index finger; the donor site was sutured directly. Results: Vascular crisis of the flap occurred in 1 case within 48 hours after operation, and the flap was bloated and bruised in 1 case due to excessive suture tension, and all the flaps survived after symptomatic treatment; partial skin margin of the flap was necrotic in 1 case after operation, and the incision healed after dressing change; the other 5 flaps survived, and all the wounds in the donor and recipient sites healed by first intention. All the 8 patients were followed up 3-10 months, with an average of 6 months. One patient had mild scar; the other patients had no significant difference in the color of the flap and the surrounding skin, no adhesion of tendons, and little interference of index finger function, and there was no obvious pain and dysfunction in the donor and recipient sites of the flap. At last follow-up, the extension-flexion range of motion of the metacarpophalangeal joint of the thumb was 0°-55°, and that of the interphalangeal joint was 0°-75°; the extension-flexion range of motion of the metacarpophalangeal joint of the index finger was 0°-82°, that of the proximal interphalangeal joints was 0°-90°, and that of the distal interphalangeral joints was 0°-65°. Conclusion: The application of the second dorsal metacarpal artery fascial vascular pedicle retrograde island flap relaying the dorsal island flap of the index finger to repair skin and soft tissue defect wounds of thumb is a feasible treatment with reliable blood supply, less postoperative complications, no need for skin grafting, less interference to the function of the index finger, and satisfactory wound repair effect.

Outcomes of Eight-Plate Epiphysiodesis for Residual Clubfoot Deformities.

OBJECTIVE: The outcome of congenital clubfoot treatment is still challenging if the feet deformities are not completely corrected. Here we explore a minimal invasive procedure with an eight-plate implant to correct the residual forefoot adduction deformity after treatment of neglected or relapsed clubfoot. METHODS: We retrospectively reviewed patients with residual forefoot adduction deformity after clubfoot treatment between January 2013 and June 2016. The patients underwent temporary epiphysiodesis of the lateral column of the mid-foot, which in detail, an eight-plate was placed on each side of the calcaneocuboid joint. The foot deformities were recorded according to the weight-bearing radiographic measurements including talo-first metatarsal angle, calcaneo-fifth metatarsal angle and medial-to-lateral column length. RESULTS: A total of 13 patients (20 feet) with an average age of 7.8 years old were located with an average duration of 40.8 months follow-up (range, 28 to 54 months). The average talo-first metatarsal angle improved from 28.3° (range, 19° to 47°) preoperatively to 8.3° (range, 3° to 18°) and the calcaneo-fifth metatarsal angle improved from 29.1° (range, 19° to 40°) preoperatively to 8.4° (range, 0° to 21°) at final follow-up. The mean ratio of the medial-to-lateral column length improved from 1.14 ± 0.06 to 1.55 ± 0.09 with statistical significance (t = 3.566; P < 0.001). CONCLUSIONS: Eight-plate epiphysiodesis is an easy and effective method for the correction of residual forefoot adduction deformity after clubfoot treatment in growing children without the need of osteotomy.

Severe spaghetti wrist injury: Should we expand the terminology from wrist to proximal forearm?

OBJECTIVES: This study aims to point out the key principles for the management of multicomponent soft tissue injuries of the wrist and forearm to discuss whether we should expand the term "spaghetti" from the wrist to forearm in such terrifying cases. PATIENTS AND METHODS: Data from a total of 50 patients (44 males, 6 females; mean age: 48.5±25.7 years; range, 10 to 70 years) who were treated for multicomponent soft tissue injuries of the wrist and forearm, including at least one major artery and one major nerve, between February 2020 and December 2021 were retrospectively analyzed. The patients were divided into the wrist injury group (n=30) and forearm injury group (n=20) according to the location of laceration. Demographic characteristics, including age, sex ratio and mechanism and side of injury, total lacerated structures, and outcomes, including tendon function, opposition, intrinsic muscle function, deformities, sensation and grip strength were evaluated. RESULTS: In the wrist injury group, a mean of 12.27±3.53 structures at the volar side were injured. It took a mean time of 1.8±0.4 h for emergency surgical repair and, after a mean of 16.6±5.3 month follow-up, most patients received excellent/good outcomes in the six aspects. In the forearm injury group, a mean of 12.95±2.96 structures at the volar side were injured. It took an average time of 2.1±0.4 h for emergency surgical repair and, after a mean of 15.4±6.4 month follow-up, most patients received excellent/good outcomes and were satisfied with the functional recovery. Only surgical time (p=0.018) and final grip strength (p=0.023) between the two groups showed a statistically significant difference. CONCLUSION: We propose to merge the severe wrist and proximal forearm laceration of multiple tendons/muscles with at least one major artery and one major nerve as a whole, namely the spaghetti-ketchup injury, since the laceration of wrist and that of proximal forearm in this study share similar mechanisms and outcomes after primary repair or reconstruction.

Novel use of close-wedge osteotomy and monorail external fixator in the treatment of chronic Monteggia fracture.

OBJECTIVES: This study aims to evaluate the efficacy of close-wedge osteotomy and monorail external fixator in the treatment of chronic Monteggia fracture. PATIENTS AND METHODS: Between January 2014 and December 2021, data of a total of 22 patients (14 males, 8 females; mean age: 15.6±5.1 years; range, 6 to 25 years) who suffered from chronic Monteggia fractures were retrospectively reviewed. All the patients were treated for acute angulation of the ulna after osteotomy and gradual angulation for radial head reduction. Range of motion of the elbow and forearm, the angle between the longitudinal axis of proximal radius and the hypothesized Storen's line (RSA), Visual Analog Scale (VAS), and Mayo Elbow Performance Score (MEPS), as well as Disabilities of Arm, Shoulder and Hand (DASH) score were recorded preoperatively and at the final follow-up. RESULTS: Objective parameters were all significantly improved in the aspects of range of motions of the elbow and forearm, and RSA (21.4±4.5° preoperatively and 2.0±1.4° at the final follow-up, t=18.20, p<0.05). The level of pain due to the chronic injury was eliminated, as the mean VAS was significantly lower at the final follow-up compared to preoperative scoring (2.8±2.0 preoperatively and 0.5±0.9 at the final follow-up, t=4.86, p<0.05). The function of the elbow and upper limb was restored, which was indicated by improved MEPS (73.2±12.5 preoperatively and 96.6±6.4 at the final follow-up, t=7.70, p<0.05) and DASH (28.3±6.0 preoperatively and 4.1±2.0 at the final follow-up, t=19.35, p<0.05). No complication was observed. CONCLUSION: Close-wedge osteotomy and gradual lengthening with monorail external fixator in the treatment of chronic Monteggia fracture showed great efficacy. We also provided a specified osteotomy site aiming at PRUJ reconstruction.

Hinge positioning method of Ilizarov apparatus in correcting radial head luxation caused by multiple hereditary exostoses.

OBJECTIVES: In this study, we present a specified hinge positioning method to achieve satisfying and steerable lengthening and angulation to correct forearm multiple hereditary exostoses (MHE) combined with severe radiocapitellar joint dislocation using Ilizarov ring fixators. PATIENTS AND METHODS: Between January 2014 and December 2018, a total of 30 forearms of 23 patients (11 males, 12 females; mean age: 18.3±6.8 years; range, 8 to 35 years) who suffered from type IIa (n=2) or IIb (n=28) MHE with severe radiocapitellar joint luxation were retrospectively analyzed. All patients were treated with Ilizarov external fixators with our specified hinge positioning method. Range of motion of the elbow, forearm and wrist and Visual Analog Scale (VAS), as well as Disabilities of Arm, Shoulder, and Hand (DASH) score, and radiological parameters, including radial articular angle (RAA), ulnar variance (UV) and carpi slip (CS), were recorded preoperatively and at final follow-up and were compared. RESULTS: Clinical and radiological outcomes were evaluated. Range of motion of the elbow, forearm and wrist, VAS, DASH and radiological features, including RAA, CS, and UV were significantly improved, except for range of motion of the forearm supination. Temporary nail track infection was seen in two of the forearms and was controlled with oral antibiotics. None of the patients developed radial head dislocation again. CONCLUSION: Clinical and radiological outcomes of this novel hinge positioning method are satisfactory in treating MHE with severe radial head dislocation, and this method can be an alternative treatment for MHE by setting a milestone for accurate radiocapitellar joint reduction.

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.

Humeral lengthening and proximal deformity correction with monorail external fixator in young adults.

PURPOSE: Several humeral lengthening or simultaneous deformity corrections through one osteotomy using various external fixators were reported, while literature regarding correction of shortening and proximal varus deformity is scarce. This retrospective clinical study evaluated the results of preforming an acute correction and delayed lengthening in young adults through two osteotomies using monorail external fixator. METHODS: We report seven patients with various pathologies who underwent humeral proximal deformity correction and lengthening between 2009 and 2015. Pre-operative and post-operative clinical and radiographic data were collected. The mean follow-up time was 33.4 months (25-46 months). RESULTS: The humeral neck-shaft angle improved from 97.9° (85-110°) to 138.6° (135-145°). The magnitude of lengthening achieved was average 7.6 cm (range, 6-10 cm) at an average healing index of lengthening of 30.2 days/cm (range, 27.7-35.4 days/cm). There was a significant increase in range of shoulder abduction, and active abduction improved from pre-operative 136.4° (range, 95-160°) to post-operative 166.4° (range, 150-180°). The DASH score improved significance from 23.29 ± 8.36 to 6.57 ± 3.65 (t = 4.848; p < 0.001). CONCLUSION: Acute deformity correction and gradual lengthening with the monorail external fixator can be used for humeral shortening and proximal varus angular deformity. Functional improvement is expected after surgery and post-operative therapy.

RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis.

Peritendinous tissue fibrosis which leads to poor tendon function is a worldwide clinical problem; however, its mechanism remains unclear. Transcription factor RelA/p65, an important subunit in the NF-κB complex, is known to have a critical role in many fibrotic diseases. Here, we show that RelA/p65 functions as a core fibrogenic regulator in tendon adhesion and that its inhibition exerts an anti-fibrogenic effect on peritendinous adhesion. We detected the upregulation of the NF-κB pathway in human tendon adhesion using a gene chip microarray assay and revealed the overexpression of p65 and extracellular matrix (ECM) proteins Collagen I, Collagen III, and α-smooth muscle actin (α-SMA) in human fibrotic tissues by immunohistochemistry and western blotting. We also found that in a rat model of tendon injury, p65 expression correlated with tendon adhesion, whereas its inhibition by small interfering (si)RNA prevented fibrous tissue formation and inflammatory reaction as evidenced by macroscopic, biomechanical, histological, immunohistochemical, and western blotting analyses. Furthermore, in cultured fibroblasts, p65-siRNA, p65-specific inhibitor, Helenalin and JSH23 suppressed cell proliferation and promoted apoptosis, whereas inhibiting the mRNA and protein expression of ECM components and cyclo-oxygenase-2, an inflammatory factor involved in tendon adhesion. Our findings indicate that p65 has a critical role in peritendinous tissue fibrosis and suggest that p65 knockdown may be a promising therapeutic approach to prevent tendon adhesion.

miR-203 inhibits the traumatic heterotopic ossification by targeting Runx2.

Emerging evidence has indicated that dysregulated microRNAs (miRNAs) have an important role in bone formation. However, the pathophysiological role of miRNAs in traumatic heterotopic ossification (HO) remains to be elucidated. Using gene expression profile analyses and subsequent confirmation with real-time PCR assays, we identified the decreased expression of miRNA-203 (miR-203) and increased expression of Runx2 as responses to the development of traumatic HO. We found that miR-203 expression was markedly higher in primary and recurrent HO tissues than in normal bones. The upregulation of miR-203 significantly decreased the level of Runx2 expression, whereas miR-203 downregulation increased Runx2 expression. Mutation of the putative miR-203-binding sites in Runx2 mRNA abolished miR-203-mediated repression of Runx2 3'-untranslated region luciferase reporter activity, indicating that Runx2 is an important target of miR-203 in osteoblasts. We also found that miR-203 is negatively correlated with osteoblast differentiation. Furthermore, in vitro osteoblast activity and matrix mineralization were promoted by antagomir-203 and decreased by agomir-203. We showed that miR-203 suppresses osteoblast activity by inhibiting the ß-catenin and extracellular signal-regulated kinase pathways. Moreover, using a tenotomy mouse HO model, we found an inhibitory role of miR-203 in regulating HO in vivo; pretreatment with antagomiR-203 increased the development of HO. These data suggest that miR-203 has a crucial role in suppressing HO by directly targeting Runx2 and that the therapeutic overexpression of miR-203 may be a potential strategy for treating traumatic HO.

Ulnar neuritis after open elbow arthrolysis combined with ulnar nerve subcutaneous transposition for post-traumatic elbow stiffness: outcome and risk factors.

BACKGROUND: Ulnar neuritis (UN) is a common complication of open elbow arthrolysis for elbow stiffness. The purpose of this study was to evaluate the outcome of subcutaneous anterior transposition of the ulnar nerve during open elbow arthrolysis and to describe the risk factors for UN. METHODS: We retrospectively studied 260 patients with post-traumatic elbow stiffness who underwent routine ulnar nerve transposition during open elbow arthrolysis. Patient demographics, clinical characteristics, and incidence and reoperation rate of UN were recorded. UN was defined as new-onset ulnar nerve symptoms and no relief or worsening of pre-existing ulnar nerve symptoms during the period of postoperative rehabilitation. Factors affecting the development of UN were analyzed by univariate and multivariate analyses. RESULTS: A total of 9.2% of the patients had UN, 25% of whom required reoperation for progressive neuropathy. The Dellon grade of patients associated with UN at last follow-up improved significantly compared with that preoperatively. The mean arc of motion in patients with UN decreased during follow-up in a time-dependent manner. Univariate analysis showed that male sex, limited preoperative flexion and arc of motion, preoperative heterotopic ossification (HO), and preoperative ulnar nerve symptoms were significantly associated with the development of UN. Multivariate regression analysis revealed that preoperative HO was the only independent risk factor for the development of UN. CONCLUSIONS: UN is still an important complication, although ulnar nerve subcutaneous transposition was performed during open arthrolysis for post-traumatic elbow stiffness. Identified risk factors for UN, especially preoperative HO, should be taken into consideration before surgery.

The use of SHP-2 gene transduced bone marrow mesenchymal stem cells to promote osteogenic differentiation and bone defect repair in rat.

Bone tissue engineering is a promising approach for bone regeneration, in which growth factors play an important role. The tyrosine phosphatase Src-homology region 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by the PTPN11 gene, is essential for the differentiation, proliferation and metabolism of osteoblasts. However, SHP-2 has never been systematically studied for its effect in osteogenesis. We predicted that overexpression of SHP-2 could promote bone marrow-derived mesenchymal stem cell (BMSC)osteogenic differentiation and SHP-2 transduced BMSCs could enhance new bone formation, determined using the following study groups: (1) BMSCs transduced with SHP-2 and induced with osteoblast-inducing liquid (BMSCs/SHP-2/OL); (2) BMSCs transduced with SHP-2 (BMSCs/-SHP-2); (3) BMSCs induced with osteoblast-inducing liquid (BMSCs/OL) and (4) pure BMSCs. Cells were assessed for osteogenic differentiation by quantitative real-time polymerase chain reaction analysis, western blot analysis, alkaline phosphatase activity and alizarin red S staining. For in vivo assessment, cells were combined with beta-tricalcium phosphate scaffolds and transplanted into rat calvarial defects for 8 weeks. Following euthanasia, skull samples were explanted for osteogenic evaluation, including micro-computed tomography measurement, histology and immunohistochemistry staining. SHP-2 and upregulation of its gene promoted BMSC osteogenic differentiation and therefore represents a potential new therapeutic approach to bone repair. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1871-1881, 2016.

Release of celecoxib from a bi-layer biomimetic tendon sheath to prevent tissue adhesion.

Posttraumatic tendon adhesion limits the motion of the limbs greatly. Biomimetic tendon sheaths have been developed to promote tendon healing and gliding. However, after introduction of these biomaterials, the associated inflammatory responses can decrease the anti-adhesion effect. Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) that can decrease inflammation responses. We blended hyaluronic acid and poly(l-lactic acid)-polyethylene glycol (PELA) with microgel electrospinning technology to form an inner layer of a bi-layer biomimetic sheath using sequential electrospinning of an outer celecoxib-PELA layer. Electrospun bi-layer fibrous membranes were mechanically tested and characterized by morphology, surface wettability, and drug release. The tensile strength showed a decreased trend and water contact angles were 114.7 ± 3.9°, 103.6 ± 4.4°, 116.3 ± 5.1°, 122.8 ± 4.7°, and 126.5 ± 4.2° for the surface of PELA, hyaluronic acid-PELA, 2, 6, and 10% celecoxib-PELA electrospun fibrous membranes, respectively. In vitro drug release studies confirmed burst release and then sustained release from the fibrous membranes containing celecoxib for 20 days. In a chicken model of flexor digitorum profundus tendon surgery, the outer celecoxib/PELA layer offered advanced anti-adhesion roles compared to the outer PELA layer and the inner hyaluronic acid-loaded PELA layer still offered tendon healing and gliding. Thus, celecoxib-loaded anti-adhesive tendon sheaths can continuously offer bi-layer biomimetic tendon sheath effects with celecoxib release from the outer layer to prevent tendon adhesion.

[ROLE OF Smad4 ON FIBROSIS OF TENDON DERIVED FIBROBLASTS INDUCED BY TRANSFORMING GROWTH FACTOR ß1 BY TARGETED REGULATION OF miRNA219-5P].

OBJECTIVE: To investigate the effect of Smad4 on the fibrosis of tendon derived fibroblasts (TDFs) induced by transforming growth factor ß1(TGF-ß1) by targeted regulation of miRNA219-5P (miR219-5P). METHODS: The tendons donated by the volunteers were harvested to isolate and culture TDFs. The 3rd generation cells were used for experiment. Chemically synthesized miR219-5P mimics, miR219-5P inhibitor, and negative control sequences were transfected into TDFs. The gene expression of miR219-5P in TDFs was detected by real-time PCR, and the protein expression of Smad4 in TDFs was detected by Western blot at 48 hours after transfection. The combining sites of miR219-5P and Smad4 in 3'UTR district were predicted by informatics software. Wild type and mutant type reporter gene expression vectors were constructed and then targeted verification was carried out by the luciferase reporter gene test. Transfected TDFs were then induced by TGF-ß1. The proliferation activity of the cells were measured by the cell counting kit 8 after culturing for 24, 48, and 72 hours. The expressions of fibrosis related proteins in TDFs were detected by Western blot at 72 hours. RESULTS: After TDFs were transfected by miR219-5P mimics, miR219-5P expression was significantly up-regulated, but the expressions of Smad4 was decreased subsequently (P<0.05). Intracellular expression of miR219-5P was inhibited by miR219-5P mimics inhibitor, however, the protein expression of Smad4 was significantly increased (P<0.05). Luciferase reporter gene test showed that luciferase activities were significantly decreased in pGL3-WT-Smad4+mimics group, but were significantly increased in pGL3-WT-Smad4+inhibitor group when compared with pGL3-WT-Smad4 transfected group (P<0.05), but no significant difference was found between GL3-MT-Smad4+mimics and pGL3-MT-Smad4+inhibitor groups (P>0.05). Cell proliferation and the fibrosis related proteins were increased in TGF-ß1 induced TDFs, however, decreased in TGF-ß1 induced TDFs after transfected by miR219-5P inhibitor (P<0.01). CONCLUSIONS: miR219-5P can significantly inhibit fibrosis of TDFs induced by TGF-ß1 by down-regulating Smad4 expression.

The efficacy of celecoxib in preventing heterotopic ossification recurrence after open arthrolysis for post-traumatic elbow stiffness in adults.

BACKGROUND: Heterotopic ossification (HO) recurrence after joint surgery is always a disturbing problem for patients and surgeons. Our study was performed to assess the efficacy and safety of celecoxib in preventing the recurrence of HO after open arthrolysis for post-traumatic elbow stiffness. METHODS: We retrospectively studied 152 patients with stiff elbows caused by post-traumatic HO. After surgery, 77 patients received celecoxib (200 mg once daily) for 28 days, whereas 75 did not. Radiographic evaluation was performed at 3, 6, and 9 months postoperatively. Univariate and multivariate analyses were performed to determine which factors affected HO recurrence. RESULTS: HO was both more common and more severe in the no-celecoxib group than in the celecoxib group at 3, 6, and 9 months after surgery. A significant difference was observed between the 2 groups in terms of postoperative extension (P = .030), flexion (P = .008), and pronation (P = .005); however, no significant difference in postoperative supination was noted (P = .622). Logistic regression analysis showed that taking celecoxib was the protective factor for HO recurrence, whereas overweight (body mass index > 25) and male gender were the risk factors. CONCLUSIONS: A short course of celecoxib aids in the prevention of HO recurrence after open arthrolysis for elbow stiffness in adults and could be an effective and safe option.

The time point in surgical excision of heterotopic ossification of post-traumatic stiff elbow: recommendation for early excision followed by early exercise.

BACKGROUND: Post-traumatic heterotopic ossification (HO) around the elbow may severely impair joint function. Although surgical excision is effective at restoring range of motion (ROM), traditional surgical treatment is postponed for at least 1 year to prevent recurrence, which leads to secondary contracture of the elbow. Because the optimal timing of resection is controversial, our study was performed to compare recurrence and elbow function between early and late excision in our patients to determine whether the delay is necessary. METHODS: We retrospectively reviewed 164 patients during a 4-year period. In the control group (112 patients), HO was excised at an average of 23.0 months after initial injury (range, 9-204 months); in the early excision group (52 patients), resection was performed at an average of 6.1 months (range, 3-8 months). HO recurrence was assessed by the Hastings classification system. Final ROM and Mayo Elbow Performance Scores were also evaluated. RESULTS: Recurrent HO was observed in 30 of 112 patients (26.8%) in the control group and 15 of 52 (28.9%) in early excision group. No significant difference in HO recurrence was found between the 2 groups (P = .942). Moreover, there were no notable differences regarding ROM, Mayo Elbow Performance Scores, and complications postoperatively. CONCLUSIONS: Early excision associated with early exercise is effective for the treatment of HO aiming at a low recurrence rate and satisfactory function. The conventional surgical delay of more than 1 year may be shortened.

Limited Medial and Lateral Approaches to Treat Stiff Elbows.

Open arthrolysis is an effective way to treat elbow stiffness. However, previous approaches led to significant surgical trauma. The goal of the current study was to evaluate the outcome of open arthrolysis with limited medial and lateral approaches combined with hinged external fixation to treat elbow stiffness. A total of 18 patients (18 elbows) with elbow stiffness were retrospectively reviewed. The same inclusion and exclusion criteria were used for all patients. Preoperatively, the mean flexion arc was 43°±28° and the mean Mayo Elbow Performance Score was 62 points. Limited medial and lateral approaches were used to provide safe and complete arthrolysis. The other protocols included ulnar nerve transposition, medial epicondyle osteotomy, radial head resection, ligament repair, and hinged external fixation. Patients were encouraged to begin early rehabilitation 24 hours after surgery. At a mean follow-up of 20 months, the flexion arc improved to 130°±11° and the mean Mayo Elbow Performance Score was 97 points (15 excellent, 3 good). One patient had elbow instability, but function met the requirements of his daily life. Transient ulnar nerve palsy without infection occurred in 4 patients. With limited medial and lateral approaches, elbow stiffness can be treated effectively with open arthrolysis. This method is trauma controlled. Furthermore, a hinged external fixator can provide sufficient and safe rehabilitation. The use of open arthrolysis with limited medial and lateral approaches combined with hinged external fixation is an effective and safe method to treat elbow stiffness.