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Objective The aim of the present paper was to evaluate the results of one‐stage total hip arthroplasty (THA) for patients with bilateral Crowe type IV developmental dysplasia of the hip (DDH). Methods Data for 58 patients (116 hips) with bilateral Crowe type IV DDH who had one‐stage THA performed by the same surgeon during the period of April 2008 to February 2019 were retrospectively reviewed. The mean age of the patients was 37.3 years; 5 were men and 53 were women. All patients underwent THA through the posterolateral approach using the Pinnacle acetabular cup, a ceramic‐on‐ceramic bearing, and the modular S‐ROM stem. Subtrochanteric shortening osteotomy was performed on 86/116 hips. Intraoperative conditions were recorded. Radiographic and functional outcomes were evaluated, and complications were recorded. Results All patients were followed up for an average of 71.3 ± 37.6 months (range, 12–140). The mean operative time was 276.5 ± 57.9 min (range, 175–540). The mean intraoperative blood loss was 933.6 ± 400.8 mL (range, 300–2000). The mean transfusion requirement was 1778 ± 798.0 mL (range, 575–4550). The mean length of hospital stay was 8.6 ± 3.7 days (range, 5–22). At the final follow‐up, no loosening of acetabular and femoral components was observed. No osteolysis and heterotopic ossification occurred. The mean Harris hip scores were improved from 55.4 ± 14.3 preoperatively to 91.3 ± 4.2 postoperatively (P, The study demonstrates that one‐stage bilateral THA for bilateral Crowe type IV DDH is feasible and can effectively restore hip function.

Purpose The aim of this study was to investigate the location characteristics of cystic lesions in a three-dimensional context and discuss the mechanism of formation. Methods A total of 155 femoral head computed tomography images from 94 patients diagnosed with stage II and III osteonecrosis of the femoral head were retrospectively reviewed. Three-dimensional structures of the femoral head including the cystic lesions and necrotic area were reconstructed. We divided each femoral head into eight regions to observe the positional relationship of the cystic lesions, normal areas, and necrotic areas. Results The regional distribution revealed 14 (13%), 35 (32%), 9 (8%), 25 (23%), 6 (6%), 15 (14%), 4 (4%), and 0 (0%) cystic lesions in regions Ⅰ, Ⅱ, Ⅲ, Ⅳ, Ⅴ, Ⅵ, Ⅶ, and Ⅷ, respectively. The anteromedial zone, A (Ⅰ ​+ ​Ⅲ), contained 22% of the lesions, anterolateral zone, B (Ⅱ ​+ ​Ⅳ), contained 54%, posteromedial zone, C (Ⅴ +Ⅶ), contained 9% of the lesions, and posterolateral zone, D (Ⅵ ​+ ​Ⅷ), contained 15% of the lesions. Most of the cystic lesions (78%) were located between the normal and necrotic areas; 18% of cystic lesions were in the necrotic area ​and 4% were in the normal area. Conclusions Cystic lesions most often occur at the junction of the necrotic ​and normal areas and are most commonly located in the anterolateral femoral head, which is similar to the distribution of the stress concentration region. The translational potential of this article The study showed the location characteristics of cystic lesions in osteonecrosis of femoral head, which suggested that the formation of cystic lesions may be related to stress and could accelerate the collapse of femoral head. The results can support further research on cystic lesions and provide a reference for doctors' treatment strategies for patients with osteonecrosis of femoral head.

Osteonecrosis of the femoral head, an intractable but common disease that eventually triggers collapse of the femoral head, is characterized by increased osteoclast activity and markedly decreased osteoblast activity in the necrotic region of the femoral head. MicroRNA (miRNA)-214 (miR-214) may play important roles in vertebrate skeletal development by inhibiting osteoblast function by targeting activating transcription factor 4 (ATF4) and promoting osteoclast function via phosphatase and tensin homolog (PTEN). This study revealed significantly increased levels of miR-214 in necrotic regions, with commensurate changes in the numbers of its target cells (both osteoblasts and osteoclasts). To investigate whether targeting miR-214 could prevent femoral head collapse, we constructed an adeno-associated virus (AAV)-associated anti-miR-214 (AAV-anti-miR-214) and evaluated its function in vivo. AAV-anti-miR-214 promoted osteoblast activity and diminished osteoclast activity, effectively preventing collapse of the femoral head in a rat model of osteonecrosis. Keywords: miRNA-214, osteonecrosis of the femoral head, osteoblast activity, osteoclast activity

Objectives The incidence of acute Achilles tendon rupture appears to be increasing. The aim of this study was to summarize various therapies for acute Achilles tendon rupture and discuss their relative merits. Methods A PubMed search about the management of acute Achilles tendon rupture was performed. The search was open for original manuscripts and review papers limited to publication from January 2006 to July 2017. A total of 489 papers were identified initially and finally 323 articles were suitable for this review. Results The treatments of acute Achilles tendon rupture include operative and nonoperative treatments. Operative treatments mainly consist of open repair, percutaneous repair, mini-open repair, and augmentative repair. Traditional open repair has lower re-rupture rates with higher risks of complications. Percutaneous repair and mini-open repair show similar re-rupture rates but lower overall complication rates when compared with open repair. Percutaneous repair requires vigilance against nerve damage. Functional rehabilitation combining protected weight-bearing and early controlled motion can effectively reduce re-rupture rates with satisfactory outcomes. Biological adjuncts help accelerating tendon healing by adhering rupture ends or releasing highly complex pools of signalling factors. Conclusion The optimum treatment for complete rupture remains controversial. Both mini-open repair and functional protocols are attractive alternatives, while biotherapy is a potential future development. Cite this article: X. Yang, H. Meng, Q. Quan, J. Peng, S. Lu, A. Wang. Management of acute Achilles tendon ruptures: A review. Bone Joint Res 2018;7:561–569. DOI: 10.1302/2046-3758.710.BJR-2018-0004.R2.

Background Centrifugation is used to remove the color interference by erythrocytes in blood-synovial fluid samples before leukocyte esterase (LE) strip testing. However, the impact of centrifugation requires further study. Methods From April 2016 to October 2017, 133 (53 infected and 80 noninfected) patients were included in this study. One drop of synovial fluid was applied to LE strips before and after centrifugation in 110 cases. The other 23 cases could not be read without centrifugation due to the color disturbance caused by blood contamination. The results were recorded after approximately 3 minutes according to different color grades on a color chart, including grade 3 (++), grade 2 (+), and grade 1 (others). Results After centrifugation, almost every sample was lighter in color than before. Although most results changed inconspicuously and remained in the same grade, 18.6% (8/43) and 17.9% (12/67) of cases were downgraded in the periprosthetic joint infection and non-periprosthetic joint infection groups, respectively. Before centrifugation, when grade 3 (++) was used as the positive threshold, the sensitivity and specificity were 97.7% (86.2%-99.9%) and 100% (94.3%-100%), respectively. After centrifugation, when grades 2 and 3 (+ and ++, respectively) were used as the positive threshold, the sensitivity and specificity were 92.5% (80.9%-97.6%) and 100% (94.3%-100%), respectively. Conclusions The influence of centrifugation should be considered when interpreting the LE strip test results. For cases without centrifugation, we recommended using ++ as the positive threshold, while for cases using centrifugation, the threshold should be reduced to both ++ and +.

We explored the mechanism of early stage osteonecrotic femoral head collapse by analyzing and comparing different regions in human osteonecrotic femoral head samples. Eight osteonecrotic femoral heads (ARCO II-III) were obtained from patients undergoing total hip arthroplasty. Bone structure was observed and evaluated by micro-computed tomography (CT) scans and pathology. Osteoblast and osteoclast activities were detected by tartrate-resistant acid phosphatase, alkaline phosphatase, and immunofluorescent staining. Some trabeculae had microfractures in the subchondral bone and necrotic region, which had lower bone mineral density, as well as trabecular thickness and number, but greater osteoclast activity. A sclerotic band had already appeared in certain samples which had greater trabecular thickness and number, bone mineral density, and osteoblast activity. The appearance of the femoral head did not change significantly in the early stage of osteonecrosis of the femoral head. However, osteoblast and osteoclast activities had already changed in different regions of the osteonecrotic femoral head, which may lead to eventual collapse of the femoral head. Therefore, osteonecrosis of the femoral head must be treated during the early stage. In addition, osteoblast activity should be promoted and osteoclast activity inhibited as early as possible to prevent collapse of an osteonecrotic femoral head.

Background Spontaneous recovery from articular cartilage injury is difficult, and the ongoing progression of disease can eventually lead to osteoarthritis. Currently, there is no effective non-surgical treatment for articular cartilage injury. Arthroscopic debridement and microfracture surgery are performed for fibrocartilage repair. But fibrocartilage is different from normal articular cartilage, and functional recovery is not satisfactory. Therefore, it is necessary to develop more effective techniques for articular cartilage repair. Progress in material science, cell biology, biomechanics, and bioreactor technology has allowed the development of biomimetic, tissue-engineered osteochondral composites that have shown potential for the repair of damaged cartilage. We prepared biomimetic, tissue-engineered cartilage scaffolds optimized for biochemical composition and structural characteristics. Based on the experience of our pre-clinical studies on animals, a human articular cartilage acellular matrix scaffold was prepared and is in clinical use. The combination of autologous chondrocytes and scaffolds has shown satisfactory results in repairing cartilage defects in preliminary experiments. Methods This is a prospective randomized controlled trial. One hundred patients with full-thickness cartilage injury of the knee will be randomly divided into two groups to receive treatment with either tissue-engineered cartilage constructed using biomimetic cartilage extracellular-matrix-oriented scaffolds combined with autologous chondrocytes, or arthroscopic debridement and microfracture surgery. There will be five visiting time points: at baseline, then at 3, 6, 12, and 18 months postoperatively. The primary outcome will be therapeutic efficacy as assessed by the Lysholm score at 12 months postoperatively. The secondary outcomes will be the International Knee Documentation Committee score, Visual Analog Scale score, and cartilage injury and repair as assessed by magnetic resonance imaging as well as the incidence of postoperative adverse events. Discussion This trial will attempt to verify the use of tissue-engineered cartilage constructed using autologous chondrocytes combined with allogeneic, acellular cartilage matrix for the repair of cartilage defects, thereby providing favorable evidence for its use in clinical practice. Trial registration ClinicalTrials.gov, identifier: NCT02770209. Registered on 11 May 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2251-6) contains supplementary material, which is available to authorized users.

Background Knee osteoarthritis (KOA) is the most prevalent form of knee joint disease and characterized by the progressive degeneration of articular cartilage. Although pathology of KOA remains unknown, genetic factors are considered to be the major cause. Asporin is a group of biologically active components of extracellular matrix (ECM) in articular cartilage, and asporin gene (ASPN) D-repeat polymorphism was reported to be associated with KOA. Thus, our meta-analysis is aimed at investigation of the association between asporin D-repeat polymorphism and susceptibility of KOA. Methods We gathered data from MEDLINE, Embase, OVID, and ScienceDirect to search relevant published epidemiological studies through April 2017. Compared with previous studies, our meta-analysis is the first study to investigate the association of ASPN D15, D16, and D17 alleles and KOA susceptibility by ethnic- and sex-stratified subgroup analysis. Results We found no significant association between D15 allele and susceptibility to KOA (OR = 1.05, 95% CI 0.95–1.17) in overall population. The same results were observed in the analysis of D16 (OR = 1.01, 95% CI 0.80–1.28) and D17 alleles (OR = 1.28, 95% CI 0.91–1.80). The ethnic- and sex-subgroup analyses did not alter the ORs. However, significant association was detected in the sensitivity analysis of D17 in overall population (OR = 1.05, 95% CI 0.95–1.17) and Asian population (OR = 1.78, 95% CI 1.02–3.11, P

Freeze-dried and irradiated allograft bone (FIAB) is more easily impacted than fresh-frozen allograft bone (FAB), but has weaker incorporation efficiency. We combined FIAB with fresh autologous coagula to enhance donor-host incorporation after impaction during hip revision.Thirty adult male Sprague-Dawley (SD) rats were sacrificed for bone allograft harvesting, and nine male rats were subjected to ectopic bone allograft implantation. For each rat, the container on the left (study) side was filled with freeze-dried allograft bone powder and fresh autologous blood coagula, whereas the right (control) side was filled with freeze-dried allograft bone powder and physiological saline. The extent of angiogenesis (VEGFα) was investigated at postoperative weeks 1, 4, and 8. The deformability of the material was evaluated by performing a confined-impaction mechanical test.At postoperative weeks 4 and 8, angiogenesis within FIAB on the left side was more pronounced than that on the right side. At postoperative week 1, the left side showed significantly higher VEGFα expression than that on the right side. The delta ratios of compression of the allografts were found to be influenced by bone height and impaction frequency, but not by stiffness or elastic modulus (EM).Supplementation with fresh autologous coagula promoted angiogenesis within the FIABs. Moreover, FIABs were equivalent to FABs in terms of deformability.

Osteoarthritis (OA) is a type of chronic joint disease that is characterized by the degeneration and loss of articular cartilage and hyperplasia of the synovium and subchondral bone. There is reasonable knowledge about articular cartilage physiology, biochemistry, and chondrocyte metabolism. However, the etiology and pathogenesis of OA remain unclear and need urgent clarification to guide the early diagnosis and treatment of OA. Extracellular vesicles (EVs) are small membrane-linking particles that are released from cells. In recent decades, several special biological properties have been found in EV, especially in terms of cartilage. Autophagy plays a critical role in the regulation of cellular homeostasis. Likewise, more and more research has gradually focused on the effect of autophagy on chondrocyte proliferation and function in OA. The synthesis and release of EV are closely associated with autophagy. At the same time, both EV and autophagy play a role in OA development. Based on the mechanism of EV and autophagy in OA development, EV may be beneficial in the early diagnosis of OA; on the other hand, the combination of EV and autophagy-related regulatory drugs may provide insight into possible OA therapeutic strategies.

Gene therapy constitutes a promising strategy for the treatment of osteoarthritis (OA). We assessed the use of electroporation (EP) of non-viral gene vectors, and compared its efficacy with that of adeno-associated virus (AAV) vectors. EP- and AAV-mediated delivery of human interleukin-1 receptor antagonist (hIL-1Ra) was localized performed in the joints of rats following induction of OA. mRNA levels for hIL-1Ra, IL-1β, TNF-α, MMP-13 and ADAMTS-4 in the cartilage and synovial tissues were analyzed. Structural analyses of the subchondral bone at the medial femoral condyle were performed by Micro-CT after treatment. Knee joint specimens were staining with hematoxylin and eosin and Saffron O. Induction of hIL-1Ra by both EP and AAV inhibited inflammatory-induced sub-chondral bone reconstruction, and effectively suppressed IL-1β activity, as evidenced by decreased expression of MMP-13 and ADAMTS-4. Histological analyses revealed significant protection of cartilage, proteoglycan by EP and AAV. hIL-1Ra expression was similar in both the EP and AAV groups. Notably, this gene is not easier degraded transduced by EP compared with AAV. Taken together, these results show that EP offers transfection efficiency comparable to that of AAV, with the potential for longer gene expression, making EP a promising candidate for efficient non-viral delivery of OA gene therapy.

Osteonecrosis of the femoral head (ONFH) is a refractory disease that is associated with collapse of the femoral head, with a risk of hip arthroplasty in younger populations. Thus, there has been an increased focus on early interventions for ONFH that aim to preserve the native articulation. Stem cell therapy is a promising treatment, and an increasing number of recent studies have focused on this topic. Many clinical studies have reported positive outcomes of stem cell therapy for the treatment of ONFH. To improve the therapeutic effects of this approach, many related basic research studies have also been performed. However, some issues must be further explored, such as the appropriate patient selection procedure, the optimal stem cell selection protocol, the ideal injection number, and the safety of stem cell therapy. The purpose of this review is to summarize the available clinical studies and basic research related to stem cell therapy for ONFH.

Background Bone marrow is an important source of stem cells, which can promote bone fracture healing. Methods We investigated the optimal time to inject bone marrow mesenchymal stem cells (BMSCs) in a C57 murine unilateral, transverse, femur fracture model. BMSCs transfected with red fluorescent protein (RFP-BMSCs) were injected via the tail vein on day 1, 7, or 14 post-fracture. AMD3100 (inhibitor of stromal cell-derived factor 1 [SDF-1]) was also injected before RFP-BMSCs in one group for comparison; a control group received saline injections. RFP-BMSC migration and fracture healing were evaluated by in vivo fluorescence assay. Micro-CT was performed and mechanical testing and histological analysis. Chemokine levels were evaluated by quantitative real-time PCR and western blotting. Results Following injection on day 7 post-fracture, RFP-BMSCs more frequently homed to the fracture site and remained for a longer duration. Bone volume and bone mineral density were increased when BMSCs were injected on day 7 post-fracture (P

Background: Benefits of yoga practice in patients with knee osteoarthritis and rheumatoid arthritis remains controversial. This study performs a meta-analysis to quantify the efficiency of yoga exercise for patients pain reduction, functional recovery, and general wellbeing. Methods: A computerized search of PubMed and Embase was performed to identify relevant studies. The outcome measures were pain, stiffness, and physical function. Two investigators identified eligible studies and extracted data independently. The quality of citations was measured using Jadad score. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated for pain, musculoskeletal impairment, quality of life, general wellbeing, and mental wellbeing. Results: A total of 13 clinical trials involving 1557 patients with knee osteoarthritis and rheumatoid arthritis were included in final meta-analysis with the average Jadad score 2.8. The SMD was −0.98 (95% CI −1.18, −0.78, P

The meniscus plays a vital role in protecting the articular cartilage of the knee joint. The inner two-thirds of the meniscus are avascular, and injuries to this region often fail to heal without intervention. The use of tissue engineering and regenerative medicine techniques may offer novel and effective approaches to repairing meniscal injuries. Meniscal tissue engineering and regenerative medicine typically use one of two techniques, cell-based or cell-free. While numerous cell-based strategies have been applied to repair and regenerate meniscal defects, these techniques possess certain limitations including cellular contamination and an increased risk of disease transmission. Cell-free strategies attempt to repair and regenerate the injured tissues by recruiting endogenous stem/progenitor cells. Cell-free strategies avoid several of the disadvantages of cell-based techniques and, therefore, may have a wider clinical application. This review first compares cell-based to cell-free techniques. Next, it summarizes potential sources for endogenous stem/progenitor cells. Finally, it discusses important recruitment factors for meniscal repair and regeneration. In conclusion, cell-free techniques, which focus on the recruitment of endogenous stem and progenitor cells, are growing in efficacy and may play a critical role in the future of meniscal repair and regeneration.

Articular cartilage damage and osteoarthritis are the most common joint diseases. Joints are prone to damage caused by sports injuries or aging, and such damage regularly progresses to more serious joint disorders, including osteoarthritis, which is a degenerative disease characterized by the thinning and eventual wearing out of articular cartilage, ultimately leading to joint destruction. Osteoarthritis affects millions of people worldwide. Current approaches to repair of articular cartilage damage include mosaicplasty, microfracture, and injection of autologous chondrocytes. These treatments relieve pain and improve joint function, but the long-term results are unsatisfactory. The long-term success of cartilage repair depends on development of regenerative methodologies that restore articular cartilage to a near-native state. Two promising approaches are (i) implantation of engineered constructs of mesenchymal stem cell (MSC)-seeded scaffolds, and (ii) delivery of an appropriate population of MSCs by direct intra-articular injection. MSCs may be used as trophic producers of bioactive factors initiating regenerative activities in a defective joint. Current challenges in MSC therapy are the need to overcome current limitations in cartilage cell purity and to in vitro engineer tissue structures exhibiting the required biomechanical properties. This review outlines the current status of MSCs used in cartilage tissue engineering and in cell therapy seeking to repair articular cartilage defects and related problems. MSC-based technologies show promise when used to repair cartilage defects in joints.

Summary The top issue in tissue engineering is how to obtain more seed cells quickly and to preserve their characteristic morphology during in vitro expansion culture of cells. Microcarriers can help to amplify cell numbers and maintain the appropriate phenotype for tissue repair and restoration of function. In addition, microtissue with cell microcarriers can be used to repair diseased tissues or organs. This review introduces the materials used for, and classification of, microcarriers and the improvements in, and potential applications of, microtissues with cell microcarriers in tissue engineering.

Summary Objective As a novel and promising seed cell, human umbilical cord Wharton's jelly mesenchymal stem cells (hWJMSCs) are widely applied in tissue engineering. However, whether hWJMSCs can better repair and regenerate the articular cartilage in big animals than microfracture (MF, a predominant clinical treatment strategy for damaged cartilage) is unclear. Evaluation of the validity, and safety of hWJMSCs in a caprine model with a full-thickness femoral condyle articular cartilage defect, compared with MF is required. Methods After cultivation and identification, hWJMSCs were seeded in an acellular cartilage extracellular matrix (ACECM)-oriented scaffold to construct cell–scaffold complex. Six goats with full-thickness femoral condyle articular cartilage defects were randomized to MF (microfracture group, MFG) and cell–scaffold complexes (experimental group, EG). At 2 and 4 weeks, joint fluid was used to assess immuno-inflammatory responses. At 6 and 9 months, all goats were euthanized for assessment of morphology, and magnetic resonance imaging (MRI), histology staining, and evaluation of the elasticity modulus and glycosaminoglycan (GAG) contents of the repaired regions. Results There were no significant differences between the two groups in immuno-inflammatory parameters. MRI demonstrated higher-quality cartilage and complete subchondral bone at defect sites in the EG at 9 months. Histological staining showed that extracellular cartilage, cartilage lacuna and collagen type II levels were higher in the EG compared to the MFG, while the EG exhibited a higher elasticity modulus. Conclusions The hWJMSCs–ACECM scaffold complex achieved better quality repair and regeneration of hyaline cartilage without cartilage-inducing factor, while retaining the structure and functional integrity of the subchondral bone, compared with MF.

PurposeThe purpose of this study was to simulate and calculate the probability of iatrogenic perforation of the scaphoid cortical bone when internal fixation appeared to be safe on radiographs. The results will assist surgeons in determining proper screw placement.MethodsThirty scaphoids were reconstructed using computed tomography data and image-processing software. Different central axes were determined by the software to simulate the surgical views. The safe zone (SZ) and risk zone (RZ) were identified on the axial projection radiographs by comparing the scaphoid bone stenosis measured by the fluoroscopic radiographs with a three-dimensional reconstruction of the scaphoid stenosis. Each original axial projection radiograph was zoomed and compiled to match a calculated average image. The RZ, SZ, and probability of perforations in various quadrants were calculated.ResultsUsing a volar view (approach), the mean risks of cortical perforation were 25% with screws and 36% with k-wires. Using a dorsal view (approach), the mean risks of cortical perforation were 18% with screws and 30% with k-wires. A high risk of perforation was detected at the ulnar-dorsal zone.ConclusionSurgeons should be wary of screws that appear to lie close to the scaphoid cortex on both anteroposterior (AP) and lateral radiographs, particularly in the ulnar-dorsal and radial-dorsal quadrants, because such screws are likely to perforate the cortex. The position of the internal fixator should be assessed using a diagram outlining the various SZs. Therapeutic, Level III.

Background Traumatic vascular injury is caused by explosions and projectiles (bullets and shrapnel); it may affect the arteries and veins of the limbs, and is common in wartime, triggering bleeding, and ischemia. The increasing use of high-energy weapons in modern warfare is associated with severe vascular injuries. Methods To summarize the current evidence of diagnosis and treatment for traumatic vascular injury of limbs, for saving limbs and lives, and put forward some new insights, we comprehensively consulted literatures and analyzed progress in injury diagnosis and wound treatment, summarized the advanced treatments now available, especially in wartime, and explored the principal factors in play in an effort to optimize clinical outcomes. Results Extremity vascular trauma poses several difficult dilemmas in diagnosis and treatment. The increasing use of high-energy weapons in modern warfare is associated with severe vascular injuries. Any delay in treatment may lead to loss of limbs or death. The development of diagnose and treat vascular injury of extremities are the clinical significance to the tip of military medicine, such as the use of fast, cheap, low invasive diagnostic methods, repairing severe vascular injury as soon as possible, using related technologies actively (fasciotomy, etc). Conclusion We point out the frontier of the diagnosis and treatment of traumatic vascular injury, also with a new model of wartime injury treatment in American (forward surgical teams and combat support hospitals), French military surgeons regarding management of war-related vascular wounds and Chinese military ("3 districts and 7 grades" model). Many issues remain to be resolved by further experience and investigation.

The acellular nerve graft that can provide internal structure and extracellular matrix components of the nerve is an alternative for repair of peripheral nerve defects. However, results of the acellular nerve grafting for nerve repair still remain inconsistent. This study aimed to investigate if supplementing bone marrow mesenchymal stromal cells (MSCs) could improve the results of nerve repair with the acellular nerve graft in a 10-mm sciatic nerve defect model in mice. Eighteen mice were divided into three groups (n = 6 for each group) for nerve repairs with the nerve autograft, the acellular nerve graft, and the acellular nerve graft by supplemented with MSCs (5 × 105) fibrin glue around the graft. The mouse static sciatic index was evaluated by walking-track testing every 2 weeks. The weight preservation of the triceps surae muscles and histomorphometric assessment of triceps surae muscles and repaired nerves were examined at week 8. The results showed that the nerve repair by the nerve autografting obtained the best functional recovery of limb. The nerve repair with the acellular nerve graft supplemented with MSCs achieved better functional recovery and higher axon number than that with the acellular nerve graft alone at week 8 postoperatively. The results indicated that supplementing MSCs might help to improve nerve regeneration and functional recovery in repair of the nerve defect with the acellular nerve graft. © 2011 Wiley-Liss, Inc. Microsurgery, 2011.

This paper describes a clinical case study in which a chitosan/polyglycolic acid nerve guidance conduit (chitosan–PGA NGC) was utilized to repair a 30 mm long median nerve defect in the right distal forearm of a 55 year-old male patient. Thirty-six months after the nerve repair, the palm abduction of the thumb and the thumb–index digital opposition recovered, facilitating the patient to accomplish fine activities, such as handling chopsticks. Static two-point discrimination measured 14, 9 and 9 mm in the thumb, index and middle fingers of the right hand. Reproducible compound muscle action potentials were recorded on the right abductor pollicis. The ninhydrin test, a classical method for assessing sympathetic nerve function, showed partial recovery of the perspiration function of the injured thumb, index and middle fingers. This repair case suggested a possible strategy for the clinical reconstruction of extended defects in human peripheral nerve trunks by the implantation of chitosan–PGA NGCs. Copyright © 2011 John Wiley & Sons, Ltd.

NELL1 (NEL-like molecule-1; NEL [a protein strongly expressed in neural tissue encoding epidermal growth factor like domain]) is a cranisynostosis-associated molecule directly regulated by Runx2, the master molecule in controlling osteoblastic differentiation. NELL1 has exhibited potent osteoinductive activity for bone regeneration in several animal models. However, its capacity for promoting repair of long-bone defects remains unknown. In this study, we investigated the osteogenic effects of NELL1 on femoral distraction osteogenesis using adenoviral gene delivery and multiple approaches of in vivo analysis. Thirty Sprague-Dawley (SD) rats were randomly assigned to 3 groups for treatment (n=10 each): adenovirus-green fluorescent protein (Ad-GFP)-NELL1 or Ad-GFP at 1×10⁹ plaque-forming units/ml diluted in saline, or saline alone. The femoral distraction was at a speed of 0.25 mm every 12h for 14 days, and a single injection of Ad-GFP-NELL1 or Ad-GFP was given at the mid-distraction period. The effective NELL1 delivery in vivo after Ad-GFP-NELL1 injection was evaluated by optical imaging. The bone regeneration was assessed quantitatively at days 21, 28, 42, and 56 by live 3-D micro-computed tomography (micro-CT), and animals were sacrificed at day 56 for biomechanical testing and histological analysis. Exogenous NELL1 was expressed in the distracted gap for at least 14 days after Ad-GFP-NELL1 transfection. The bone union rate in the distracted gap was significantly higher with Ad-GFP-NELL1 than with Ad-GFP (9/9 vs. 4/9 rats) or saline alone (5/9 rats) at day 56. The serial 3-D micro-CT images and quantitation obtained with the development and application of radiolucent external fixators showed less callus but more mature cortical bones formed with Ad-GFP-NELL1 than with Ad-GFP transfection and saline administration during distraction osteogenesis. The biomechanical properties of femur samples with Ad-GFP-NELL1 transfection were better than samples with Ad-GFP transfection or saline treatment, and were similar with unoperated femurs. Histology revealed cartilaginous tissues in the middle of distraction gaps with Ad-GFP transfection and saline treatment but only bony bridges with Ad-GFP-NELL1 transfection at the final time point (day 56). Coincidently, the expression of Runx2, BMP2, and BMP7 did not differ among groups at day 56, whereas the expression of osteocalcin and osteopontin was slightly higher with Ad-GFP-NELL1 transfection. Thus, sustained Ad-NELL1 protein delivery into a local area of a rat femoral distraction osteogenesis model remarkably improved regeneration of good-quality bones and accelerated bone union at a high rate. Acquiring serial micro-CT data during rat femoral distraction osteogenesis and regional adenovirus delivery of NELL1 may facilitate future in vivo studies.

Autologous nerve grafting (ANG), the gold standard treatment for peripheral nerve defects, still has many restrictions. In this study, the acellular cauda equina allograft (ACEA), which consists of biodegradable chitin conduit and acellular cauda equina, is developed. The cauda equina is able to complete decellularization more quickly and efficiently than sciatic nerves under the same conditions, and it is able to reserve more basal lamina tube. In vitro, ACEA shows superior guidance capacity for the regeneration of axons and migration of Schwann cells compared to acellular sciatic nerve allograft (ASNA) in dorsal root ganglion culture. In vivo, ACEA is used to bridge 15 mm long-distance defects in rat sciatic nerves. On day 21 after transplantation, the regenerative distance of neurofilaments in the grafting segment is not significantly different between the ACEA and ANG groups. At week 12, ACEA group shows better sciatic nerve repair than chitin conduit only and ASNA groups, and the effect is similar to that in the ANG group as determined by gait analysis, neural electrophysiological, and histological analyses. The above results suggest that the ACEA has the potential to become a new biological material as a replacement for autografting in the treatment of long-distance nerve defects.

Previous studies have demonstrated the potential of growth factors in peripheral nerve regeneration. A method was developed for sustained delivery of nerve growth factor (NGF) for nerve repair with acellular nerve grafts to augment peripheral nerve regeneration. NGF-containing polymeric microspheres were fixed with fibrin glue around chemically extracted acellular nerve grafts for prolonged, site-specific delivery of NGF. A total of 52 Wistar rats were randomly divided into four groups for treatment: autografting, NGF-treated acellular grafting, acellular grafting alone, and acellular grafting with fibrin glue. The model of a 10-mm sciatic nerve with a 10-mm gap was used to assess nerve regeneration. At the 2nd week after nerve repair, the length of axonal regeneration was longer with NGF-treated acellular grafting than acellular grafting alone and acellular grafting with fibrin glue, but shorter than autografting (P < 0.05). Sixteen weeks after nerve repair, nerve regeneration was assessed functionally and histomorphometrically. The percentage tension of the triceps surae muscles in the autograft group was 85.33 +/- 5.59%, significantly higher than that of NGF-treated group, acellular graft group and fibrin-glue group, at 69.79 +/- 5.31%, 64.46 +/- 8.48%, and 63.35 +/- 6.40%, respectively (P < 0.05). The ratio of conserved muscle-mass was greater in the NGF-treated group (53.73 +/- 4.56%) than in the acellular graft (46.37 +/- 5.68%) and fibrin glue groups (45.78 +/- 7.14%) but lower than in the autograft group (62.54 +/- 8.25%) (P < 0.05). Image analysis on histological observation revealed axonal diameter, axon number, and myelin thickness better with NGF-treated acellular grafting than with acellular grafting alone and acellular grafting with fibrin glue (P < 0.05). There were no significant differences between NGF-treated acellular grafting and autografting. This method of sustained site-specific delivery of NGF can enhance peripheral nerve regeneration across short nerve gaps repaired with acellular nerve grafts.

The meniscus plays a crucial role in maintaining knee joint homoeostasis. Meniscal lesions are relatively common in the knee joint and are typically categorized into various types. However, it is difficult for inner avascular meniscal lesions to self-heal. Untreated meniscal lesions lead to meniscal extrusions in the long-term and gradually trigger the development of knee osteoarthritis (OA). The relationship between meniscal lesions and knee OA is complex. Partial meniscectomy, which is the primary method to treat a meniscal injury, only relieves short-term pain; however, it does not prevent the development of knee OA. Similarly, other current therapeutic strategies have intrinsic limitations in clinical practice. Tissue engineering technology will probably address this challenge by reconstructing a meniscus possessing an integrated configuration with competent biomechanical capacity. This review describes normal structure and biomechanical characteristics of the meniscus, discusses the relationship between meniscal lesions and knee OA, and summarizes the classifications and corresponding treatment strategies for meniscal lesions to understand meniscal regeneration from physiological and pathological perspectives. Last, we present current advances in meniscal scaffolds and provide a number of prospects that will potentially benefit the development of meniscal regeneration methods.

Osteoarthritis (OA) is a chronic disease and its etiology is complex. With increasing OA incidence, more and more people are facing heavy financial and social burdens from the disease. Genetics-related aspects of OA pathogenesis are not well understood. Recent reports have examined the molecular mechanisms and genes related to OA. It has been realized that genetic changes in articular cartilage and bone may contribute to OA’s development. Osteoclasts, osteoblasts, osteocytes, and chondrocytes in joints must express appropriate genes to achieve tissue homeostasis, and errors in this can cause OA. MicroRNAs (miRNAs) are small noncoding RNAs that have been discovered to be overarching regulators of gene expression. Their ability to repress many target genes and their target-binding specificity indicate a complex network of interactions, which is still being defined. Many studies have focused on the role of miRNAs in bone and cartilage and have identified numbers of miRNAs that play important roles in regulating bone and cartilage homeostasis. Those miRNAs may also be involved in the pathology of OA, which is the focus of this review. Future studies on the role of miRNAs in OA will provide important clues leading to a better understanding of the mechanism(s) of OA and, more particularly, to the development of therapeutic targets for OA.

SummaryCurrently, osteoarthritis (OA) is considered a disease of the entire joint, which is not simply a process of wear and tear but rather abnormal remodelling and joint failure of an organ. The bone–cartilage interface is therefore a functioning synergistic unit, with a close physical association between subchondral bone and cartilage suggesting the existence of biochemical and molecular crosstalk across the OA interface. The crosstalk at the bone–cartilage interface may be elevated in OA in vivo and in vitro. Increased vascularisation and formation of microcracks associated with abnormal bone remodelling in joints during OA facilitate molecular transport from cartilage to bone and vice versa. Recent reports suggest that several critical signalling pathways and biological factors are key regulators and activate cellular and molecular processes in crosstalk among joint compartments. Therapeutic interventions including angiogenesis inhibitors, agonists/antagonists of molecules and drugs targeting bone remodelling are potential candidates for this interaction. This review summarised the premise for the presence of crosstalk in bone–cartilage interface as well as the current knowledge of the major signalling pathways and molecular interactions that regulate OA progression. A better understanding of crosstalk in bone–cartilage interface may lead to development of more effective strategies for treating OA patients.

Osteonecrosis of the femoral head (ONFH), also known as femoral head avascular necrosis, is a pathological state with a number of possible etiologies including steroid administration, alcohol abuse, traumatic events, vascular injury and idiopathic origins. ONFH causes a reduction in the vascular supply to the subchondral bone of the femoral head, which results in osteocyte death and the collapse of the articular surface. Treatments for ONFH include non-weight-bearing therapy, physical support, the promotion of osteoclast apoptosis, and the reduction of osteoblast and osteocyte apoptosis. The aim of the present review was to summarize the treatments for ONFH by mechanism from a new perspective and to describe the condition with an emphasis on treatment options.

Osteoporosis is associated with delayed and/or reduced fracture healing. As cervus and cucumis are the traditional Chinese treatments for rheumatoid arthritis, we investigated the effect of supplementation of these peptides (CCP) on bone fracture healing in ovariectomized (OVX) osteoporotic ratsin vitroandin vivo. CCP enhanced osteoblast proliferation and increased alkaline phosphatase activity, matrix mineralization, and expression of runt-related transcription factor 2 (Runx2), bone morphogenetic protein 4 (BMP4), and osteopontin.In vivo, female Sprague-Dawley rats underwent ovariectomy and the right femora were fractured and fixed by intramedullary nailing 3 months later. Rats received intraperitoneal injections of either CCP (1.67 mg/kg) or physiological saline every day for 30 days. Fracture healing and callus formation were evaluated by radiography, micro-CT, biomechanical testing, and histology. At 12 weeks after fracture, calluses in CCP-treated bones showed significantly higher torsional strength and greater stiffness than control-treated bones. Bones in CCP-treated rats reunified and were thoroughly remodeled, while two saline-treated rats showed no bone union and incomplete remodeling. Taken together, these results indicate that use of CCP after fracture in osteoporotic rats accelerates mineralization and osteogenesis and improves fracture healing.

Bisphosphonates (BPs) have been widely used in clinical treatment of bone diseases with increased bone resorption because of their strong affinity for bone and their inhibition of bone resorption. Recently, there has been growing interest in their improvement of bone formation. However, the effect of local controlled delivery of BPs is unclear. We used polylactide acid-glycolic acid copolymer (PLGA) as a drug carrier to deliver various doses of the bisphosphonate zoledronate (Zol) into the distal femur of 8-week-old Sprague-Dawley rats. After 6 weeks, samples were harvested and analyzed by micro-CT and histology. The average bone mineral density and mineralized bone volume fraction were higher with medium- and high-dose PLGA-Zol (30 and 300 µg Zol, respectively) than control and low-dose Zol (3 µg PLGA-Zol; p

Mesenchymal stem cells (MSCs) are non-haematopoietic stromal stem cells that have many sources, such as bone marrow, periosteum, vessel walls, adipose, muscle, tendon, peripheral circulation, umbilical cord blood, skin and dental tissues. They are capable of self-replication and of differentiating into, and contributing to the regeneration of, mesenchymal tissues, such as bone, cartilage, ligament, tendon, muscle and adipose tissue. The homing of MSCs may play an important role in the repair of bone fractures. As a composite material, the formation and growth of bone tissue is a complex process, including molecular, cell and biochemical metabolic changes. The recruitment of factors with an adequate number of MSCs and the micro-environment around the fracture are effective for fracture repair. Several studies have investigated the functional expression of various chemokine receptors, trophic factors and adhesion molecules in human MSCs. Many external factors affect MSC homing. MSCs have been used as seed cells in building tissue-engineered bone grafts. Scaffolds seeded with MSCs are most often used in tissue engineering and include biotic and abiotic materials. This knowledge provides a platform for the development of novel therapies for bone regeneration with endogenous MSCs.

Acellular nerve grafting is often inferior as well as an inadequate alternative to autografting for the repair of long gaps in peripheral nerves. Moreover, the injection method is not perfect. During the injection of cells, the syringe can destroy the acellular nerve structure and the limited accumulation of seed cells. To resolve this problem, we constructed a nerve graft by acellular nerve grafting. Bone marrow-mesenchymal stromal cells (BM-MSCs) were affixed with fibrin glue and injected inside or around the graft, which was then used to repair a 15-mm nerve defect in rats. The acellular nerve graft maintained its structure and composition, and its tensile strength was decreased, as determined by two-photon microscopy and a tensile testing device. In vitro, MSCs embedded in fibrin glue survived and secreted growth factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). We repaired 15-mm Sprague–Dawley rat sciatic nerve defects using this nerve graft construction, and MSCs injected around the graft helped improve nerve regeneration and functional recovery of peripheral nerve lesions as determined by functional analysis and histology. Therefore, we conclude that supplying MSCs in fibrin glue around acellular nerves is successful in maintaining the nerve structure and can support nerve regeneration similar to the direct injection of MSCs into the acellular nerve for long nerve defects but may avoid destroying the nerve graft. The technique is simple and is another option for stem cell transplantation.

Chemical-extracted acellular nerve allografting, containing the natural nerve structure and elementary nerve extracellular matrix (ECM), has been used for peripheral nerve-defect treatment experimentally and clinically. However, functional outcome with acellular nerve allografting decreases with increased size of gap in nerve defects. Cell-based therapy is a good strategy for repairing long nerve defects. Bone-marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived mesenchymal stem cells (ADSCs) can be induced to differentiate into cells with Schwann cell-like properties (BMSC-SCs or ADSC-SCs), which have myelin-forming ability in vitro and secrete trophic nerve growth factors. Here, we aimed to determine whether BMSC-SCs or ADSC-SCs are a promising cell type for enriching acellular grafts in nerve repair. We evaluated axonal regeneration distance by immunofluorescence staining after 2-week implantation. We used functional and histomorphometric analysis to evaluate 3-month regeneration of the novel cell-supplemented tissue-engineered nerve graft used to bridge a 15-mm-long sciatic nerve gap in rats. Introducing BMSC-SCs or ADSC-SCs to the acellular nerve graft promoted sciatic nerve regeneration and functional recovery. Nerve regeneration with BMSC-SCs or ADSC-SCs was comparable to that with autografting and Schwann cells alone and better than that with acellular nerve allografting alone. Differentiated bone-marrow-or adipose-derived MSCs may be a promising cell source for tissue-engineered nerve grafts and promote functional recovery after peripheral nerve injury.

Osteonecrosis (ON) or avascular necrosis (AVN) is a common bone metabolic disorder, mostly affecting femoral head. Although many biological, biophysical, and surgical methods have been tested to preserve the femoral head with ON, none has been proven fully satisfactory. It lacks consensus on an optimal approach for treatment. This is due, at least in part, to the lack of ability to systematically compare treatment efficacy using an ideal animal model that mimics full-range osteonecrosis of femoral head (ONFH) in humans with high incidence of joint collapse accompanied by reparative reaction adjacent to the necrotic bone in a reproducible and accessible way. A number of preclinical animal ON models have been established for testing potential efficacy of various modalities developed for prevention and treatment of ON before introduction into clinics for potential applications. This paper describes a number of different methods for creating animal experimental ON models. Advantages and disadvantages of such models are also discussed as reference for future research in battle against this important medical condition.

Options for reconstructing peripheral nerve gaps after trauma are limited. The acellular nerve is a new kind of biomaterial used to reconstruct the peripheral nerve defect, but its use could be improved upon. We aimed to investigate the effect of adenoviral transfection with hepatocyte growth factor (HGF) on the functional recovery of transected sciatic nerves repaired by acellular nerve grafting. 30 Rats were divided into three groups (10/group) for autografting and acellular grafting, as well as acellular grafting with adenovirus transfection of HGF (1 x 10(8) pfu) injected in muscles around the proximal and distal allograft coapation. Sciatic functional index (SFI) was evaluated every 4 weeks to week 16 by measuring rat footprints on walking-track testing. The three groups presented initial complete functional loss, followed by slow but steady recovery, with final similar SFIs. Weight of the gastrocnemius and soleus muscles, histologic and morphometric study and neovascularization in the nerve grafts were evaluated at week 16. Autografting gave the best functional recovery, but HGF-treated acellular grafting gave better recovery than acellular grafting alone. Neovascularization was greater with HGF-treated acellular grafting than with autografting and acellular grafting alone. Axonal regeneration distance of autografting on the 20th postoperative day was the longest in the three groups,while that of acellular grafting alone was the smallest. Acellular nerve grafting may be useful for functional peripheral nerve regeneration, and with human HGF gene transfection may improve on acellular grafting alone in functional recovery.

It is now 40 years since bisphosphonates (BPs) were first used in the clinic. So, it is timely to provide a brief review of what we have learned about these agents in bone disease. BPs are bone-specific and have been classified into two major groups on the basis of their distinct molecular modes of action: amino-BPs and non-amino-BPs. The amino-BPs are more potent and they inhibit farnesyl pyrophosphate synthase (FPPS), a key enzyme of the mavalonate/cholesterol biosynthetic pathway, while the non-amino-BPs inhibit osteoclast activity, by incorporation into non-hydrolyzable analogs of ATP. Both amino-BPs and non-amino-BPs can protect osteoblasts and osteocytes against apoptosis. The BPs are widely used in the clinic to treat various diseases characterized by excessive bone resorption, including osteoporosis, myeloma, bone metastasis, Legg-Perthes disease, malignant hyperparathyroidism, and other conditions featuring bone fragility. This review provides insights into some of the adverse effects of BPs, such as gastric irritation, osteonecrosis of the jaw, atypical femoral fractures, esophageal cancer, atrial fibrillation, and ocular inflammation. In conclusion, this review covers the biochemical and molecular mechanisms of action of BPs in bone, particularly the discovery that BPs have direct anti-apoptotic effects on osteoblasts and osteocytes, and the current situation of BP use in the clinic.