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Aims Autologous chondrocyte implantation (ACI) is a promising treatment for articular cartilage degeneration and injury; however, it requires a large number of human hyaline chondrocytes, which often undergo dedifferentiation during in vitro expansion. This study aimed to investigate the effect of suramin on chondrocyte differentiation and its underlying mechanism. Methods Porcine chondrocytes were treated with vehicle or various doses of suramin. The expression of collagen, type II, alpha 1 (COL2A1), aggrecan (ACAN); COL1A1; COL10A1; SRY-box transcription factor 9 (SOX9); nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX); interleukin (IL)-1β; tumour necrosis factor alpha (TNFα); IL-8; and matrix metallopeptidase 13 (MMP-13) in chondrocytes at both messenger RNA (mRNA) and protein levels was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot. In addition, the supplementation of suramin to redifferentiation medium for the culture of expanded chondrocytes in 3D pellets was evaluated. Glycosaminoglycan (GAG) and collagen production were evaluated by biochemical analyses and immunofluorescence, as well as by immunohistochemistry. The expression of reactive oxygen species (ROS) and NOX activity were assessed by luciferase reporter gene assay, immunofluorescence analysis, and flow cytometry. Mutagenesis analysis, Alcian blue staining, reverse transcriptase polymerase chain reaction (RT-PCR), and western blot assay were used to determine whether p67phox was involved in suramin-enhanced chondrocyte phenotype maintenance. Results Suramin enhanced the COL2A1 and ACAN expression and lowered COL1A1 synthesis. Also, in 3D pellet culture GAG and COL2A1 production was significantly higher in pellets consisting of chondrocytes expanded with suramin compared to controls. Surprisingly, suramin also increased ROS generation, which is largely caused by enhanced NOX (p67phox) activity and membrane translocation. Overexpression of p67phox but not p67phoxAD (deleting amino acid (a.a) 199 to 212) mutant, which does not support ROS production in chondrocytes, significantly enhanced chondrocyte phenotype maintenance, SOX9 expression, and AKT (S473) phosphorylation. Knockdown of p67phox with its specific short hairpin (sh) RNA (shRNA) abolished the suramin-induced effects. Moreover, when these cells were treated with the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) inhibitor LY294002 or shRNA of AKT1, p67phox-induced COL2A1 and ACAN expression was significantly inhibited. Conclusion Suramin could redifferentiate dedifferentiated chondrocytes dependent on p67phox activation, which is mediated by the PI3K/AKT/SOX9 signalling pathway. Cite this article: Bone Joint Res 2022;11(10):723–738.

Aims Interleukin (IL)-1β is one of the major pathogenic regulators during the pathological development of intervertebral disc degeneration (IDD). However, effective treatment options for IDD are limited. Suramin is used to treat African sleeping sickness. This study aimed to investigate the pharmacological effects of suramin on mitigating IDD and to characterize the underlying mechanism. Methods Porcine nucleus pulposus (NP) cells were treated with vehicle, 10 ng/ml IL-1β, 10 μM suramin, or 10 μM suramin plus IL-1β. The expression levels of catabolic and anabolic proteins, proinflammatory cytokines, mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-κB-related signalling molecules were assessed by Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence analysis. Flow cytometry was applied to detect apoptotic cells. The ex vivo effects of suramin were examined using IDD organ culture and differentiation was analyzed by Safranin O-Fast green and Alcian blue staining. Results Suramin inhibited IL-1β-induced apoptosis, downregulated matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5, and upregulated collagen 2A (Col2a1) and aggrecan in IL-1β-treated NP cells. IL-1β-induced inflammation, assessed by IL-1β, IL-8, and tumour necrosis factor α (TNF-α) upregulation, was alleviated by suramin treatment. Suramin suppressed IL-1β-mediated proteoglycan depletion and the induction of MMP-3, ADAMTS-4, and pro-inflammatory gene expression in ex vivo experiments. Conclusion Suramin administration represents a novel and effectively therapeutic approach, which could potentially alleviate IDD by reducing extracellular matrix (ECM) deposition and inhibiting apoptosis and inflammatory responses in the NP cells. Cite this article: Bone Joint Res 2021;10(8):498–513.

Objective Shockwave application is a potential treatment for osteoarthritis (OA), but the underlying mechanism remains unknown. Oxidative stress and a counterbalancing antioxidant system might be the key to understanding this mechanism. We hypothesized that reactive oxygen species (ROS) and the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2),which is an important regulator of cellular redox homeostasis, are plausible elements. Design Porcine chondrocytes were cultured in a 3-dimensional pellet model and subjected to shockwaves. The effects of shockwaves with various energy-flux densities on optimal extracellular matrix (ECM) synthesis were assessed. ROS, mitogen-activated protein kinase (MAPK) signaling, and the redox activity of Nrf2 were measured. To investigate the signaling mechanism involved in the shockwave treatment in chondrocytes, specific inhibitors of ROS, MAPK signaling, and Nrf2 activity were targeted. Results Shockwaves increased ECM synthesis without affecting cell viability or proliferation. Furthermore, they induced transient ROS production mainly through xanthine oxidase. The phosphorylation of ERK1/2 and p38 and the nuclear translocation of Nrf2 were activated by shockwaves. By contrast, suppression of ROS signaling mitigated shockwave-induced MAPK phosphorylation, Nrf2 nuclear translocation, and ECM synthesis. Pretreatment of chondrocytes with the specific inhibitors of MEK1/2 and p38, respectively, mitigated the shockwave-induced nuclear translocation of Nrf2 and ECM synthesis. Nrf2 inhibition by both small hairpin RNA knockdown and brusatol reduced the shockwave-enhanced ECM synthesis. Conclusions Shockwaves activated Nrf2 activity through the induction of transient ROS signaling and subsequently enhanced ECM synthesis in chondrocytes. This study provided fundamental evidence confirming the potential of shockwaves for OA management.

Objective: To compare the efficacy of various strategies in the treatment of trigger finger. Data sources: A systematic literature search for randomized controlled trials to compare treatments for trigger finger was conducted through three online databases, Pubmed, Embase and Cochrane Library, from their inception dates to 22 May 2020. Methods: Relative risk (RR) with 95% confidence interval (CI) was used to evaluate the effect sizes in success rate for included articles. Results: Sixteen articles ( n = 1185) were included in our meta-analysis. The results showed that the efficacy of steroid injection was significantly better than the placebo group at short-term follow-ups (RR = 19.00, 95% CI = 1.17–309.77 for one-week; RR = 3.70, 95% CI = 3.70, 95% CI = 1.61–8.53 for one-month), and then became non-significant at four months (RR = 3.21, 95% CI = 0.88–11.79). There was no significant difference in success rate between steroid injection and nonsteroidal anti-inflammatory drug injection, and between open surgery and percutaneous release at all the follow-ups. Only surgical treatment had significantly better efficacy in success rate than steroid injection at all follow-ups (RR = 0.48, 95% CI = 0.34–0.66 for one-month; RR = 0.87, 95% CI = 0.80–0.96 for three-month; RR = 0.58, 95% CI = 0.48–0.68 for six-month; RR = 0.38, 95% CI = 0.20–0.72 for 12-month). Conclusion: There were no differences in efficacy between steroid injection and shockwave or nonsteroidal anti-inflammatory drug injection. The surgical treatments had the best efficacy among these treatments.

Introduction Rapamycin has been considered as a potential treatment for osteoarthritis (OA). Drug carriers fabricated from liposomes can prolong the effects of drugs and reduce side effects of drugs. Low-intensity pulsed ultrasound (LIPUS) has been found to possess anti-OA effects. Materials and methods The anti-osteoarthritic effects of liposome-encapsulated rapamycin (L-rapa) combined with LIPUS were examined by culture of normal and OA chondrocytes in alginate beads and further validated in OA prone Dunkin-Hartley guinea pigs. Results L-rapa with LIPUS largely up-regulated aggrecan and type II collagen mRNA in human OA chondrocytes (HOACs). L-rapa with LIPUS caused significant enhancement in proteoglycan and type II collagen production in HOACs. Large decreases in both MMP-13 and IL-6 proteins were found in the HOACs exposed to L-rapa with LIPUS. Intra-articular injection of 40 μL L-rapa at both 5 μM and 50 μM twice a week combined with LIPUS thrice a week for 8 weeks significantly increased GAGs and type II collagen in the cartilage of knee. Results on OARSI score showed that intra-articular injection of 5 μM L-rapa with LIPUS displayed the greatest anti-OA effects. Immunohistochemistry revealed that L-rapa with or without LIPUS predominantly reduced MMP-13 in vivo. The values of complete blood count and serum biochemical examinations remained in the normal ranges after the injections with or without LIPUS. These data indicated that intra-articular injection of L-rapa collaborated with LIPUS is not only effective against OA but a safe OA therapy. Conclusion Taken together, L-rapa combined with LIPUS possessed the most consistently and effectively anabolic and anti-catabolic effects in HOACs and the spontaneous OA guinea pigs. This study evidently revealed that liposome-encapsulation collaborated with LIPUS is able to reduce the effective dose and administration frequency of rapamycin and further stably reinforce its therapeutic actions against OA.

Study Design: This was a single-center, retrospective study. Objective: The objective of this study was to assess the risk factors for deformity progression after scoliosis correction surgery in spinal muscular atrophy (SMA) patients. Summary of Background Data: Moderate residual postoperative scoliosis curve is common in SMA populations; however, the acceptable postoperative scoliosis curve for preventing deformity progression remains uncertain. Materials and Methods: Twenty-nine SMA patients undergoing scoliosis correction surgery were included. Scoliosis progression was defined as an increase of 10 degrees in the major curve of Cobb angle (MCCA); pelvic obliquity (PO) or concave-side hip progression was arbitrarily defined as an increase of ≥1 grade after surgery. Risk factors for deformity progression were examined using Cox proportional hazard models. The cumulative incidence rate of deformity progression was performed by the Kaplan-Meier survival analysis Results: The mean age at surgery was 13.3 years (range: 8–25 y) and the mean follow-up time was 7 years (range: 2–22.9 y). The mean MCCA was corrected from 69 to 34.6 degrees at initial follow-up and 42.2 degrees at the final follow-up. Postoperative MCCA (P=0.002) and PO (P=0.004) at initial follow-up were the risk factors for scoliosis progression. Postoperative MCCA at initial follow-up (P=0.007) and age at the time of surgery (P=0.017) were the risk factors for PO progression. Different cutoff points of postoperative MCCA at initial follow-up were compared for predicting deformity progression. We found the patient with postoperative MCCA of

The cell sheet technique is a promising approach for tissue engineering, and the present study is aimed to determine a better configuration of cell sheets for cartilage repair. For stratified chondrocyte sheets (S-CS), articular chondrocytes isolated from superficial, middle, and deep zones were stacked accordingly. Heterogeneous chondrocyte sheets (H-CS) were obtained by mixing zonal chondrocytes. The expressions of chondrocytes, cytokine markers, and glycosaminoglycan (GAG) production were assessed in an in vitro assay. The curative effect was investigated in an in vivo porcine osteochondral defect model. The S-CS showed a higher cell viability, proliferation rate, expression of chondrogenic markers, secretion of tissue inhibitor of metalloproteinase, and GAG production level than the H-CS group. The expressions of ECM destruction enzyme and proinflammatory cytokines were lower in the S-CS group. In the mini-pigs articular cartilage defect model, the S-CS group had a higher International Cartilage Repair Society (ICRS) macroscopic score and displayed a zonal structure that more closely resembled the native cartilage than those implanted with the H-CS. Our study demonstrated that the application of the S-CS increased the hyaline cartilage formation and improved the surgical outcome of chondrocyte implication, offering a better tissue engineering strategy for treating articular cartilage defects.

Background Early versions of spinal muscular atrophy (SMA) scoliosis correction surgery often involved sublaminar devices. Recently, the utilization of pedicle screws has gained much popularity. Pedicle screws are generally believed to provide additional deformity correction, but pedicle size and rotational deformity limit their application in the thoracic spine, resulting in a hybrid construct involving pedicle screws and sublaminar wire. Studies of the efficacy of hybrid instrumentation in SMA scoliosis are often limited by the scarcity of the disease itself. In this study, we aimed to compare the surgical outcomes between hybrid constructs involving pedicle screws and sublaminar wire and sublaminar wire alone in patients with SMA scoliosis. Methods We retrospectively reviewed the clinical records and radiographic assessments of patients with SMA scoliosis who underwent corrective surgery between 1993 and 2017. The radiographic assessments included deformity correction and progressive changes in the major curve angle, pelvic tilt (PT) and coronal balance (CB). The correction of deformities was observed postoperatively and at the patient’s 2-year follow-up to test the efficacy of each type of construct. Results Thirty-three patients were included in this study. There were 14 and 19 patients in the wiring and hybrid construct groups, respectively. The hybrid construct group demonstrated a higher major curve angle correction (50.5° ± 11.2° vs. 36.4° ± 8.4°, p p p p = 0.002). Conclusion This study demonstrated that hybrid instrumentation can provide a greater magnitude of correction in major curve and apical rotation as well as less major curve progression than sublaminar wire instrumentation alone in patients with SMA scoliosis. Level of evidence III

Cell-based therapy is an ideal way of repairing defective cartilage. At present, the articular chondrocytes (ACs) is the cell source for cartilage repair. Problematically, in serial culture, the de...

Flexible flatfoot is the most common condition seen in pediatric orthopedic practice and generalized joint hypermobility is widely regarded as one of the predisposing factors. However, in previous studies, the flatfoot was defined by observers' subjective evaluation of the eversion of the bare foot in the standing position; and the joint hypermobility was defined by the Beighton score. The objective of this study is to evaluate the correlation between preschool-age flexible flatfoot and joint hypermobility in preschool-age children objectively. Footprints were measured on a Harris and Beath footprint mat. Flatfoot flexibility was assessed by Staheli Plantar Arch Index (PAI). Other than the Beighton score, 2 new measurement methods, the thumb-to-forearm test and the thumb-thrust test were developed to evaluate joint hypermobility. Of the 291 preschool children from 4 different kindergarten schools included in this study, 156 were boys and 135 were girls. The mean age was 64.18 ± 9.33 months (range 35-88 months). Pearson correlation analysis demonstrated PAI was not associated with the Beighton score (R = 0.020, P = .735), thumb-to-forearm grade (R = 0.109, P = .066), and thumb-thrust grade (R = 0.027, P = .642). Two-sample t-test results showed that the normal and flatfoot groups did not differ significantly in the Beighton score (P = .404), thumb-to-forearm grade (P = .063), and thumb-thrust grade (P = .449). The results demonstrated no correlation between joint hypermobility and preschool-age flexible flatfoot when flatfoot was defined with Staheli PAI and joint hypermobility with the Beighton score. Even with 2 new methods, the thumb-to-forearm test and thumb-thrust test, to define joint hypermobility, we still found no correlation between preschool-age flexible flatfoot and joint hypermobility.

Radiofrequency ablation (RFA) was first introduced for treating knee osteoarthritis (OA) in 2010 and has emerged as a minimally invasive treatment option. Three RFA techniques have been adopted for treating knee OA, including conventional, pulsed, and cooled RFA. However, the efficacy among different RFA techniques in the treatment of knee OA is still unclear. Three electronic databases were systematically searched for relevant articles, including PubMed, Embase, and Cochrane Library. A meta-analysis of articles that investigated the use of RFA techniques in the treatment of knee OA was conducted to pool the effect size in pain before and after treatment. A total of 20 eligible articles (including 605 patients) were included for our meta-analysis. After treatment, the patients had significant improvements in pain for all three RFA techniques when compared with the baseline level for the 1, 3-, and 6-month follow-ups (p &lt, 0.00001). However, there were no significant differences in the efficacy among the three RFA techniques for all follow-up visits (p &gt, 0.05). The three RFA techniques demonstrated a significant improvement in pain for up to 6 months after treatment. Comparing the efficacy of the three RFA techniques in the treatment of knee OA, our results showed that no significant differences in pain relief among the three RFA techniques were observed at the 1-, 3-, 6, and 12-month follow-up visits.

Graft cell repopulation and tendon-bone tunnel healing are important after allograft anterior cruciate ligament reconstruction (ACLR). Freshly isolated bone marrow mononuclear cells (BMMNCs) have the advantage of short isolation time during surgery and may enhance tissue regeneration. Thus, we hypothesized that the effect of intra-articular BMMNCs in post-allograft ACLR treatment is comparable to that of cultured bone marrow stromal cells (BMSCs). A rabbit model of hamstring allograft ACLR was used in this study. Animals were randomly assigned to the BMMNC, BMSC, and control groups. Fresh BMMNCs isolated from the iliac crest during surgery and cultured BMSCs at passage four were used in this study. A total of 1 × 107 BMMNCs or BMSCs in 100 µL phosphate-buffered saline were injected into the knee joint immediately after ACLR. The control group was not injected with cells. At two and six weeks post operation, we assessed graft cell repopulation with histological and cell tracking staining (PKH26), and tendon-bone healing with histological micro-computed tomography and immunohistochemical analyses for collagen I and monocyte chemoattractant protein-1 (MCP1). At two weeks post operation, there was no significant difference in the total cell population within the allograft among the three groups. However, the control group showed significantly higher cell population within the allograft than that of BM cell groups at six weeks. Histological examination of proximal tibia revealed that the intra-articular delivered cells infiltrated into the tendon-bone interface. Compared to the control group, the BM cell groups showed broader gaps with interfacial fibrocartilage healing, similar collagen I level, and higher MCP1 expression in the early stage. Micro-CT did not reveal any significant difference among the three groups. BMMNCs and BMSCs had comparable effects on cell repopulation and interfacial allograft-bone healing. Intra-articular BM cells delivery had limited benefits on graft cell repopulation and caused higher inflammation than that in the control group in the early stage, with fibrocartilage formation in the tendon-bone interface after allograft ACLR.

Rapamycin has been considered as a potential treatment for osteoarthritis (OA). Drug carriers fabricated from liposomes can prolong the effects of drugs and reduce side effects of drugs. Low-intensity pulsed ultrasound (LIPUS) has been found to possess anti-OA effects.The anti-osteoarthritic effects of liposome-encapsulated rapamycin (L-rapa) combined with LIPUS were examined by culture of normal and OA chondrocytes in alginate beads and further validated in OA prone Dunkin-Hartley guinea pigs.L-rapa with LIPUS largely up-regulated aggrecan and type II collagen mRNA in human OA chondrocytes (HOACs). L-rapa with LIPUS caused significant enhancement in proteoglycan and type II collagen production in HOACs. Large decreases in both MMP-13 and IL-6 proteins were found in the HOACs exposed to L-rapa with LIPUS. Intra-articular injection of 40 μL L-rapa at both 5 μM and 50 μM twice a week combined with LIPUS thrice a week for 8 weeks significantly increased GAGs and type II collagen in the cartilage of knee. Results on OARSI score showed that intra-articular injection of 5 μM L-rapa with LIPUS displayed the greatest anti-OA effects. Immunohistochemistry revealed that L-rapa with or without LIPUS predominantly reduced MMP-13 in vivo. The values of complete blood count and serum biochemical examinations remained in the normal ranges after the injections with or without LIPUS. These data indicated that intra-articular injection of L-rapa collaborated with LIPUS is not only effective against OA but a safe OA therapy.Taken together, L-rapa combined with LIPUS possessed the most consistently and effectively anabolic and anti-catabolic effects in HOACs and the spontaneous OA guinea pigs. This study evidently revealed that liposome-encapsulation collaborated with LIPUS is able to reduce the effective dose and administration frequency of rapamycin and further stably reinforce its therapeutic actions against OA.

Aims Proliferation, migration, and differentiation of anterior cruciate ligament (ACL) remnant and surrounding cells are fundamental processes for ACL reconstruction; however, the interaction between ACL remnant and surrounding cells is unclear. We hypothesized that ACL remnant cells preserve the capability to regulate the surrounding cells’ activity, collagen gene expression, and tenogenic differentiation. Moreover, extracorporeal shock wave (ESW) would not only promote activity of ACL remnant cells, but also enhance their paracrine regulation of surrounding cells. Methods Cell viability, proliferation, migration, and expression levels of Collagen-I (COL-I) A1, transforming growth factor beta (TGF-β), and vascular endothelial growth factor (VEGF) were compared between ACL remnant cells untreated and treated with ESW (0.15 mJ/mm2, 1,000 impulses, 4 Hz). To evaluate the subsequent effects on the surrounding cells, bone marrow stromal cells (BMSCs)’ viability, proliferation, migration, and levels of Type I Collagen, Type III Collagen, and tenogenic gene ( Scx, TNC) expression were investigated using coculture system. Results ESW-treated ACL remnant cells presented higher cell viability, proliferation, migration, and increased expression of COL-I A1, TGF-β, and VEGF. BMSC proliferation and migration rate significantly increased after coculture with ACL remnant cells with and without ESW stimulation compared to the BMSCs alone group. Furthermore, ESW significantly enhanced ACL remnant cells’ capability to upregulate the collagen gene expression and tenogenic differentiation of BMSCs, without affecting cell viability, TGF-β, and VEGF expression. Conclusion ACL remnant cells modulated activity and differentiation of surrounding cells. The results indicated that ESW enhanced ACL remnant cells viability, proliferation, migration, and expression of collagen, TGF-β, VEGF, and paracrine regulation of BMSC proliferation, migration, collagen expression, and tenogenesis. Cite this article: Bone Joint Res 2020;9(8):457–467.

Preventive effects of two traditional Chinese medicines, Chia-wei-hsiao-yao-san and Kuei-lu-erh-hsien-chiao, on the bone loss induced by ovariectomy in Long-Evans rats were investigated. The rats were divided randomly into five groups. The first group was given a sham operation with administration of distilled water, whereas the second, third and fourth groups were ovariectomized with administration of distilled water, Kuei-lu-erh-hsien-chiao and Chia-wei-hsiao-yao-san, respectively. The rats of the fifth group were embedded by intraperitoneal with a silicon tube containing 17 β-estradiol (10% in cholesterol) at a dose of 10μg/kg. Eight weeks later, the mean differences of spinal bone mineral density (BMD) in groups 1, 4 and 5 were significantly higher than that in group 2. The mean differences of plasma alkaline phosphatase (ALP) in groups 1 and 5 were significantly lower than those in group 2, but there were no significant differences between groups 1 and 5. In histologic analysis, the cross sections from lower third of the tibial shaft in group 3 showed more mucopolysaccharide accumulation than those in groups 4 and 5. The urinary N-telopeptide of type I collagen (NTx) levels did not differ significantly among groups 1, 2, 3, 4 and 5. Nevertheless, the mean differences of urinary deoxypyridinoline (Dpd) levels in group 5 were significantly higher than those in group 2. 17 β-estradiol and Chia-wei-hsiao-yao-san showed inure profound effect than Kuei-lu-erh-hsien-chiao in the prevention of bone loss in the ovariectomized (OVX) rats. Although 17 β-estradiol exerted more profound effect, Chia-wei-hsiao-yao-san showed good compliance and safety for relief of climacteric symptoms for postmenopausal women in a previous study. Therefore, Chia-wei-hsiao-yao-san might be an alternative for preventing bone loss.

Background: Shockwaves are acoustic pulses that have been widely used in the management of musculoskeletal disease. In current study, we investigated the biological effect of shockwaves on articular chondrocytes and clarified the mechanism by which chondrocytes sense and respond to the mechanical stimulation of shockwave treatment. Methods: Porcine articular chondrocytes and human osteoarthritis (OA) chondrocytes were cultured in a three-dimensional pellet culture model and subjected to shockwaves. Then alamarBlue assay, Hoechest DNA assay, fluorescence-activated cell sorter, real-time polymerase chain reaction immunofluorescence staining, and western blotting were used to determine biological function and signaling transduction of chondrocytes after shockwaves.Results: Shockwaves increased the sulfated glycosaminoglycan (GAG), Col2a1, and Acan production of chondrocytes without affecting cell viability and proliferation. Furthermore, shockwaves increased transient reactive oxygen species (ROS) production primarily through the action of xanthine oxidase and subsequently through phosphorylation of Erk1/2 and p38. Shockwaves also activated the nuclear translocation of Nrf2 and the Nrf2-related downstream gene expression of Ho-1 and Nqo-1. We suppressed the xanthine oxidase activity by allopurinol or specific siRNA, which significantly abrogated shockwave-induced mitogen-activated protein kinase (MAPK) phosphorylation, Nrf2 nuclear translocation, and extracellular matrix (ECM) synthesis. U0126 and SB203580, the specific inhibitors of MAPKs MEK1/2 and p38, respectively, significantly abolished shockwave-induced Nrf2 nuclear translocation and ECM synthesis. Inhibition of Nrf2 by both shRNA knockdown and brusatol reduced the shockwave-increased GAG, Col2a1, and Acan production. Conclusions: Maintaining the homeostasis of the ECM of the articular cartilage is crucial for preventing the development OA. Our data indicate that shockwaves enhanced the ECM synthesis of chondrocytes through the activation of the ROS/MAPK/Nrf2 signaling axis. This study demonstrates that shockwaves holds promising therapeutic potential for OA and provides fundamental evidence for developing an optimal therapeutic strategy.

Background: Low back pain may inhibit patients’ spinal range of motion during radiography. Little is known about the dynamic changes of measurement variables and diagnosis of unstable segments in flexion/extension radiographs before and after analgesic injections. We hypothesise that pain control with intramuscular (IM) ketorolac could reveal more radiographic instability segments currently masked by low back pain. Methods: One hundred patients with symptomatic spondylolisthesis from outpatient clinics were recruited. Standing flexion-extension radiographs before and after analgesic injections (IM ketorolac 30 mg) were examined. The visual analog scale (VAS) score and the parameters of segmental instability, including dynamic lumbar lordosis (º; DL), dynamic segmental angulation (º; DA), dynamic segmental translation (mm; DT), and slip percentage (dynamic translation divided with vertebral body width; SP) (%), before and after ketorolac injection were measured. In addition, newly diagnosed unstable segments by different instability criteria were recorded. Pre-post changes between the two groups were analysed using paired t-tests.Results: The VAS score decreased significantly after analgesic injections (66.9 ± 0.97 vs. 32.2 ± 13.1 mm, P < 0.001). DL, DA, DT, and SP were significantly increased (P < 0.001) after providing analgesia compared to pre-analgesia. More unstable segments were found from radiography after ketorolac injection.Conclusion: Ketorolac 30 mg injections provided effective analgesia. The radiographic change and diagnosis of instability segments, which might be masked by back pain, significantly changed after IM Ketorolac in patients with symptomatic spondylolisthesis.

Objective To compare the efficacy of different radiofrequency techniques (thermal, pulsed, and cooled radiofrequency) for treating lumbar facet joint (LFJ) or sacroiliac joint (SIJ) pain. Patients and methods The inclusion criteria were as follows: (1) age > 18 years; (2) patients suffering from LFJ or SIJ pain; and (3) patients receiving radiofrequency treatments. Four electronic databases, including Pubmed, Embase, Cochrane Library, and ISI Web of Knowledge were systematically searched from inception until December 2019 for relevant articles. The search was conducted on 2 January 2020. When the outcomes among articles showed heterogeneity, then a random-effects model was adopted to calculate the effect size; otherwise, a fixed-effects model was adopted. Results All the three techniques showed significant improvements in LFJ or SIJ pain for up to 12 months compared with the baseline level. However, no significant differences among the three techniques were observed at any follow-up visits except for possibly a trend for variance in efficacy. For treating LFJ pain, cooled radiofrequency was the most effective, followed by thermal radiofrequency and then pulsed radiofrequency as the least respectively for the follow-up visit at 6 months. No serious complications were reported after receiving treatment using the three techniques. Conclusion Sequentially, cooled radiofrequency followed by thermal radiofrequency and then pulsed radiofrequency for treating LFJ pain were identified as most to least effective at the 6-month follow-up.

ObjectiveThe aim of this study is to evaluate the efficacy of intra-articular injection with HYAJOINT Plus, a biofermentation-derived, high-molecular hyaluronic acid (HA), on the progression of structural changes of cartilage in patients with knee osteoarthritis (OA) by using objectively promised ultrasonography (US) evaluation.DesignIn this prospective clinical trial, 56 OA patients completed the study. One single dose of injection of HYAJOINT Plus into the knee cavity was performed. The primary efficacy outcome measure for structural change of knee joint was evaluated by US using a semiquantitative grading system. Secondary efficacy outcome measures included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total and subscale scores. All efficacy outcomes were measured at baseline and at first, third, and sixth month following treatment.ResultsThere were significant US grade-improvement changes of cartilage between baseline and follow-up visits over medial femoral condyle and transverse overall evaluation at 3- and 6-month follow-ups, and over lateral femoral condyle, intercondylar notch, and medial longitudinal area at 6-month follow-up. The improved score change of WOMAC from baseline was significant at 1- and 3-month follow-ups in pain subscale, whereas score change from baseline was significant at 6-month follow-up in total score and all 3 subscale scores.ConclusionsIt was determined that significant improvement was found on cartilage by US after intra-articular injection with high-molecular weight, biological fermentation–derived HYAJOINT Plus. The semiquantitative grading system by US is a promising tool to identify the efficacy on cartilage band after interventions.

Supplemental material, Supplyment_material_revision3 for Comparative effectiveness of various treatment strategies for trigger finger by pairwise meta-analysis by Po-Chih Shen, Shih-Hsiang Chou, Cheng-Chang Lu, Yin-Chih Fu, Chun-Kuan Lu, Wen-Chih Liu, Peng-Ju Huang, Yin-Chun Tien and Chia-Lung Shih in Clinical Rehabilitation

Appendix 2. Methodological quality checklist. (DOCX 13 kb)

Appendix 1. Data extraction form. (DOCX 15 kb)

Background We investigated whether, in the emergency department (ED), educational video-assisted informed consent is superior to the conventional consent process, to inform trauma patients undergoing surgery about the procedure, benefits, risks, alternatives, and postoperative care. Methods We conducted a prospective randomized controlled trial, with superiority study design. All trauma patients scheduled to receive trauma-related debridement surgery in the ED of Kaohsiung Medical University Hospital were included. Patients were assigned to one of two education protocols. Participants in the intervention group watched an educational video illustrating informed consent information, whereas those in the control group read an informed consent document. The primary outcome was knowledge scores and the secondary outcome was assessment of patient satisfaction. A multivariable regression model, with predefined covariates, was used to analyze differences in knowledge scores and patient satisfaction levels between the groups. Results A total of 142 patients were enrolled, with 70 and 72 assigned to the intervention and control groups, respectively. Mean knowledge scores were higher in the intervention (72.57 ± 16.21 (SD)) than in the control (61.67 ± 18.39) group. By multivariate analysis, the intervention group had significantly greater differences in knowledge scores (coefficient: 7.646, 95% CI: 3.381–11.911). Age, injury severity score, and baseline knowledge score significantly affected the differences in knowledge scores. Significant improvements were observed in patients’ perception of statements addressing comprehension of the information provided, helpfulness of the supplied information for decision making, and satisfaction with the informed consent process. Multivariate analysis showed significant correlations between video education and patient satisfaction. Conclusions Both the educational approach and severity of injury may have an impact on patient understanding during the informed consent process in an emergency environment. Video-assisted informed consent may improve the understanding of surgery and satisfaction with the informed consent process for trauma patients in the ED. Institutions should develop structured methods and other strategies to better inform trauma patients, facilitate treatment decisions, and improve patient satisfaction. Trial registration The ClinicalTrials.gov Identifier is NCT01338480. The date of registration was April 18, 2011 (retrospectively registered). Electronic supplementary material The online version of this article (10.1186/s12910-018-0264-7) contains supplementary material, which is available to authorized users.

This study has two purposes: (1) to compare the clinical results between the Titanium Elastic Nail (TEN) and plate fixation of the displaced midshaft clavicle fracture; and (2) to demonstrate the relationship between length shortening and functional outcome after TEN fixation, especially in the comminuted fracture pattern. A retrospective, case-controlled study was conducted and 55 patients were included in our study: 25 in the TEN fixation group (TEN group) and 30 in the plate fixation group (plate group). All patients were classified into four subgroups: simple fracture in the TEN group (ST; n = 13), simple fracture in the plate group (SP; n = 15), comminuted fracture in the TEN group (CT; n = 12), and comminuted fracture in the plate group (CP; n = 15). Wound size was significantly smaller in the TEN group (p

Table S1. Comparisons of satisfaction between control and intervention subgroups. (DOCX 29 kb)

Appendix. Knowledge measurement questionnaire. (DOCX 15 kb)

Background Ensuring adequate informed consent for surgery in a trauma setting is challenging. We developed and pilot tested an educational video containing information regarding the informed consent process for surgery in trauma patients and a knowledge measure instrument and evaluated whether the audiovisual presentation improved the patients’ knowledge regarding their procedure and aftercare and their satisfaction with the informed consent process. Methods A modified Delphi technique in which a panel of experts participated in successive rounds of shared scoring of items to forecast outcomes was applied to reach a consensus among the experts. The resulting consensus was used to develop the video content and questions for measuring the understanding of the informed consent for debridement surgery in limb trauma patients. The expert panel included experienced patients. The participants in this pilot study were enrolled as a convenience sample of adult trauma patients scheduled to receive surgery. Results The modified Delphi technique comprised three rounds over a 4-month period. The items given higher scores by the experts in several categories were chosen for the subsequent rounds until consensus was reached. The experts reached a consensus on each item after the three-round process. The final knowledge measure comprising 10 questions was developed and validated. Thirty eligible trauma patients presenting to the Emergency Department (ED) were approached and completed the questionnaires in this pilot study. The participants exhibited significantly higher mean knowledge and satisfaction scores after watching the educational video than before watching the video. Conclusions Our process is promising for developing procedure-specific informed consent and audiovisual aids in medical and surgical specialties. The educational video was developed using a scientific method that integrated the opinions of different stakeholders, particularly patients. This video is a useful tool for improving the knowledge and satisfaction of trauma patients in the ED. The modified Delphi technique is an effective method for collecting experts’ opinions and reaching a consensus on the content of educational materials for informed consent. Institutions should prioritize patient-centered health care and develop a structured informed consent process to improve the quality of care. Trial registration The ClinicalTrials.gov Identifier is NCT01338480 . The date of registration was April 18, 2011 (retrospectively registered).

Pediatric humeral medial condyle fracture (HMCF) is a rare condition and is difficult to detect, especially in young children. The management of late presentation of HMCF is challenging and lacks consensus. Herein, we reported four cases of HMCF nonunion received open reduction and internal fixation (ORIF) or supracondyle osteotomy from our institution. In addition, 12 cases of ORIF and 4 cases of osteotomy reported in the previous studies were also reviewed. The HMCF nonunion can heal after ORIF, but the indication and the optimal techniques need to be clarified. Supracondylar osteotomy alone is an effective and safe treatment option to improve the functional and cosmetic outcomes of HMCF nonunion.

In this study, a calcium phosphate cement was developed using tetracalcium phosphate and surface-modified dicalcium phosphate anhydrous (DCPA). This developed injectable bone graft substitute can be molded to the shape of the bone cavity and set in situ through the piping system that has an adequate mechanical strength, non-dispersibility, and biocompatibility. The materials were based on the modified DCPA compositions of calcium phosphate cement (CPC), where the phase ratio of the surface-modified DCPA is higher than that of the conventional CPC for forming dicalcium phosphate (DCP)-rich cement. The composition and morphology of several calcium phosphate cement specimens during setting were analyzed via X-ray diffractometry and transmission electron microscopy coupled with an energy dispersive spectroscopy system. The compressive strength of DCP-rich CPCs was greater than 30MPa after 24h of immersion in vitro. The reaction of the CPCs produced steady final biphasic products of DCPs with apatite. The composites of calcium phosphate cements derived from tetracalcium phosphate mixed with surface-modified DCPA exhibited excellent mechanical properties, injectability, and interlocking forces between particles, and they also featured nondispersive behavior when immersed in a physiological solution.

Calcium phosphate cement (CPC) is a widely used bone substitute. However, CPC application is limited by poor bioresorption, which is attributed to apatite, the stable product. This study aims to systematically survey the biological performance of dicalcium phosphate (DCP)-rich CPC. DCP-rich CPC exhibited a twofold, surface-modified DCP anhydrous (DCPA)-to-tetracalcium phosphate (TTCP) molar ratio, whereas conventional CPC (c-CPC) showed a onefold, surface unmodified DCPA-to-TTCP molar ratio. Cell adhesion, morphology, viability, and alkaline phosphatase (ALP) activity in the two CPCs were examined with bone cell progenitor D1 cultured in vitro. Microcomputed tomography and histological observation were conducted after CPC implantation in vivo to analyze the residual implant ratio and new bone formation rate. D1 cells cultured on DCP-rich CPC surfaces exhibited higher cell viability, ALP activity, and ALP quantity than c-CPC. Histological evaluation indicated that DCP-rich CPC showed lesser residual implant and higher new bone formation rate than c-CPC. Therefore, DCP-rich CPC can improve bioresorption. The newly developed DCP-rich CPC exhibited potential therapeutic applications for bone reconstruction.

Favorable results have been reported for tibialis posterior tendon transfers, which can effectively restore the dorsiflexion of the ankle and normal heel-to-toe gait. However, the commonly used methods for anchoring the transplanted tendon have some drawbacks. Therefore, we developed a new tendon-anchoring method to improve fixation of the transferred tendon and reduce the related complications. The new method entails tying the anchoring suture to the navicular bone instead of the button on the plantar foot to avoid wound complications. It requires no additional skin incisions or special equipment. We retrospectively evaluated 24 feet of 19 pediatric patients (13 [68.4%] females and 6 [31.6%] males) who had undergone anterior transfer of the tibialis posterior tendon with our new method from 2000 to 2013. All patients were clinically followed up. At the final follow-up visit, they were evaluated while standing and walking, and the range of motion of the foot was evaluated. The mean age at surgery was 7.8 (range 2 to 16) years. At the longest follow-up point, all the patients exhibited improved gait, except for 1 patient who required a secondary procedure. All the transferred tibialis posterior tendons could be palpated with certainty during active dorsiflexion or withdrawal of the foot. No tendon displacements, wound infections, or postoperative complications were observed. Fixation of a transferred tibialis posterior tendon by tying the suture to the navicular bone is simple and reliable. This technique can efficiently prevent the plantar ulcers that can develop with the traditional pull-out button method and provides a solution when appropriate-size bioabsorbable interference screws are unavailable.

The purpose of this study was to evaluate the osteointegration of a titanium (Ti) implant with the calcium phosphate cement (CPC) and autograft prostheses by pull-out test and histological examination. Stems of sixty Ti cylinders were bilaterally inserted into femoral medullary canals in 30 rabbits at the 1st, 4th, 12th, 26th and 70th postoperative weeks. The bone autograft and CPC were filled into the pre-trimmed bone marrow cavity with a polymethyl methacrylate retarder in the distal end, and then a Ti cylinder was inserted into femurs. The CPC group was significantly (p

Removing a bent femoral intramedullary nail is challenging and usually requires special equipment to weaken or transect the nail. We have developed a novel technique with simple devices including one dynamic compression plate and two bone-holding forceps to straighten a bent nail. The results showed that one can use this method for bent nail removal effectively and easily.

Cerium oxide nanocrystallites were synthesized by a co-precipitation process at a relatively low temperature, using cerium (III) nitrate as the starting material in a water solution with pH in the range of 8–9. The effect of calcination temperature on the crystallite growth of cerium oxide nano-powders was investigated by X-ray diffraction, transmission electron microscopy and electron diffraction. The crystallization temperature of the cerium oxide powders was estimated to be about 273 K, by XRD analysis. When calcined at temperatures from 473 to 1273 K, face-centered cubic phase crystallization was observed by XRD. The crystallite size of the cerium oxide increased from 12.0 to 48 nm as the calcining temperature increased from 473 to 1273 K, in the pH range 8–9. The activation energy for the growth of cerium oxide nanoparticles was found to have very low values of 17.5 kJ/mol for pH = 8 and 16.0 kJ/mol for pH = 9.

This study reports the development of a non-dispersive calcium phosphate cement (nd-CPC) paste containing tetracalcium phosphate and anhydrous dicalcium phosphate that can be used as a filling material in dental and orthopedic applications. The nd-CPC bone cement is compared with two commercial materials, OsteoSet ® and Collagraft ® bone grafts. Gross examination of retrieved implants/bone composite samples indicated that none of the implants in this study evoked an inflammatory response. The OsteoSet ® (calcium sulfate) implant was resorbed too quickly to allow for osteo-remodeling, and it led to the formation of fibrous connective tissue in the fracture site, which remained even 24 weeks after implantation. Histological examination revealed that nd-CPC and Collagraft ® (hydroxyapatite/tricalcium phosphate/collagen) had greater remodeling and osteoconductive activity than OsteoSet ® at both 12 and 24 weeks after implantation. Greater remodeling activities were found with nd-CPC cement than with the other materials at 12 weeks after implantation, and the Fourier transform infrared absorption band of carbonate or cellulose derivatives grew from 6 weeks to 24 weeks after implantation in nd-CPC cement. These findings show that nd-CPC compares favorably to commercial bone remodeling materials, and the fact that it is in a paste formulation makes it an ideal material to fill regeneration defects.

Surgery for Baker's cysts in children is plagued by high recurrent rate after the operation. In this study, a modified surgical method is developed to avoid the recurrence. Between 1995 and 2002, nine symptomatic Baker's cysts were excised in nine children, including six boys and three girls with a mean age of 5.7 years, were reviewed retrospectively. The diagnosis and follow-up were confirmed by clinical and ultrasound investigation. The modified surgical technique features a step in which the orifice of the posterior joint capsule is closed tightly by the application of one purse-string non-absorbable suture, and augmented by the suturing of the gastronomies tendon onto the closed orifice of the knee-joint capsule. Then the affected knee is immobilized with long leg cast for 2 weeks. After a mean follow-up of 8.3 years (ranged from 5.6 years to 12.1 years), none of the cysts recurred. All the patients were free of symptoms and none complained of any cosmetic problems. While comparing the affected and the unaffected knee, neither limitation of motion nor difference of muscle power was found. From the results, the modified surgical method is considered effective to treat the symptomatic Baker's cyst in children and to avoid its recurrence.

Type IV-D duplicated thumb has the most complex anomalies and difficulties for treatment among polydatyly. Double osteotomy is usually recommended to gain the best cosmetic and functional outcome. However, 4 cases of type IV-D duplicated thumb were treated only by soft tissue procedure in this study. At operation, a conjoined A2 pulley was routinely identified, and the flexor pollicis longus (FPL) was found bifurcated distal to the conjoined pulley in every of these cases. Instead of double osteotomy, a soft tissue procedure that included centralization of FPL and A2 pulley reconstruction was pursued to correct these special anomalies. The overall clinical results were evaluated by a modification of the Tada scoring system based on the range of motion, joint stability, alignment of the remaining thumb, and subjective opinion regarding the reconstructed thumb after an average follow-up of 3.3 years (range, 2.5-4.7 years). According to the scoring system, the results were rated as good in 3 cases and fair in 1 case. From the results, the A2 pulley reconstruction and FPL centralization could prove to be an effective method for the treatment of type IV-D duplicated thumb and could efficiently avoid the residual angular deformities. Therefore, we recommend this soft tissue procedure as an alternative surgical technique to the double-osteotomy procedure for treating a type IV-D duplicated thumb in a very young child, whose bone is still not mature enough for holding the fixing pins.

The prognosis of type II floating knee injuries was not as good as that of type I. Our purpose is to clarify the factors affecting the outcome of type II floating knee injuries. Thirty-five patients (36 limbs) with type II floating knee injury were studied with a mean follow-up of 52 months (26-96). Blake and McBryde had classified these injuries into type I for pure diaphyseal (true type) fracture and type II if the intra-articular involvements are one or more including hip, knee and ankle joints (variant type). According to this classification, we divided these patients into two groups depending on whether their knees were involved or not. Those cases with intra-articular knee involvement were classified as type IIA, while those without intra-articular knee involvement were classified as type IIB. Of the 36 cases, 21 were classified as type IIA and 15 were type IIB. The functional outcomes of these injuries were evaluated by using the criteria of Karlström and Olerud and analyzed with multivariate analysis. After multivariate analysis with logistic regression, we show the following results: first, the poor functional outcome of type II floating knee is contributed by type IIA. Second, the type IIA group has severer femoral open fracture grading (P = 0.027) and poorer functional outcome (P = 0.009) than type IIB. Third, the significant contributing factors to final outcome are the group (P = 0.013) and the fixation time after injury in femur (P = 0.015). Intra-articular knee involvement is the most important factor contributing to poor outcome of type II floating knee. The treatment of floating knee injuries with intra-articular knee involvement is still difficult. Further efforts to search better methods of treatment are required for these complex injuries in the future.

Various results of the previous literature related to surgical effect on pulmonary function of spinal muscular atrophy (SMA) patients might be due to different SMA type, different fusion level and technique. The aim of this study was to determine the value of scoliosis surgery for SMA type II patients with regard to pulmonary function, under the same fusion level, fusion technique and average long-term follow-up. Ten SMA II patients who underwent spinal correction procedures from 1993 to 2010 were identified. Data on clinical features and pulmonary function, including forced vital capacity (FVC) and forced expiratory volume in 1st second (FEV1), were collected. The data on pulmonary function were divided into preoperative, postoperative short-term (0–5 years), mid-term (5–10 years), and long-term (>10 years). Statistical comparisons were made using the Wilcoxon test for pulmonary function and body weight analysis. Questions were answered by parents on how surgery influenced the frequency of respiratory infection and the ability to sit at school. The average length of postoperative pulmonary function follow-up was 12.3 years (range 4.9–15.9 years). There was no significant difference in FVC or FEV1 between preoperative and each postoperative period. However, a significant decline from mid-term to long-term was observed (p = 0.028). Body weight increased significantly in all postoperative periods and was moderately correlated to pulmonary function (r = 0.526 for FVC). The answers to the questionnaire revealed that 80% of the patients had obvious improvement in the frequency of respiratory infection and 100% were tolerable sitting at school. Surgical correction for scoliosis in SMA II patients results in pulmonary function being maintained during long-term follow-up. In addition, the advantages of surgery also include body weight gain, better sitting tolerance, and reduced frequency of respiratory infection.

Background Open reduction, autogenous bone-grafting, and internal fixation for the treatment of established nonunion of the lateral condyle associated with a cubitus valgus deformity has a high rate of complications. As a consequence, we developed a new technique that includes in situ compression fixation of the lateral condylar nonunion and a dome-shaped supracondylar osteotomy of the distal aspect of the humerus through a single posterior incision. Methods Eight consecutive patients were treated with the new surgical technique between 1994 and 2000. The mean age at the time of surgery was 8.6 years. The mean interval between the lateral condylar fracture and surgery was 4.9 years. The mean preoperative radiographic humerus-ulna angle was 31 degrees of valgus. The postoperative results were classified with a modification of the scoring system described by Dhillon et al., which assesses pain, weakness, range of motion, the humerus-ulna angle, and prominence of the medial epicondyle on a 12-point scale. Results All eight lateral condylar nonunions achieved union within three months postoperatively. The mean postoperative humerus-ulna angle was 5.5 degrees of valgus. All of the supracondylar dome osteotomies healed uneventfully, and there was no loss of correction postoperatively. The mean duration of follow-up was 4.5 years. The overall results were excellent in two patients, good in four patients, and fair in two patients. Conclusions With better exposure of the lateral condylar nonunion through a posterior approach, we can effectively stabilize the lateral condylar nonunion and avoid postoperative loss of motion and osteonecrosis of the condyle. With a dome-shaped supracondylar osteotomy, we can correct the cubitus valgus deformity and avoid the development of a medial epicondylar prominence. With careful selection of patients, this new technique can be an effective method to treat this clinically challenging problem.