Verteporfin attenuates trauma-induced heterotopic ossification of Achilles tendon by inhibiting osteogenesis and angiogenesis involving YAP/ß-catenin signaling.

Heterotopic ossification occurs as a pathological ossification condition characterized by ectopic bone formation within soft tissues following trauma. Vascularization has long been established to fuel skeletal ossification during tissue development and regeneration. However, the feasibility of vascularization as a target of heterotopic ossification prevention remained to be further clarified. Here, we aimed to identify whether verteporfin as a widely used FDA-approved anti-vascularization drug could effectively inhibit trauma-induced heterotopic ossification formation. In the current study, we found that verteporfin not only dose dependently inhibited the angiogenic activity of human umbilical vein endothelial cells (HUVECs) but also the osteogenic differentiation of tendon stem cells (TDSCs). Moreover, YAP/ß-catenin signaling axis was downregulated by the verteporfin. Application of lithium chloride, an agonist of ß-catenin, recovered TDSCs osteogenesis and HUVECs angiogenesis that was inhibited by verteporfin. In vivo, verteporfin attenuated heterotopic ossification formation by decelerating osteogenesis and the vessels densely associated with osteoprogenitors formation, which could also be readily reversed by lithium chloride, as revealed by histological analysis and Micro-CT scan in a murine burn/tenotomy model. Collectively, this study confirmed the therapeutic effect of verteporfin on angiogenesis and osteogenesis in trauma-induced heterotopic ossification. Our study sheds light on the anti-vascularization strategy with verteporfin as a candidate treatment for heterotopic ossification prevention.

Endocrine modulation of brain-skeleton axis driven by neural stem cell-derived perilipin 5 in the lipid metabolism homeostasis for bone regeneration.

Factors released from the nervous system always play crucial roles in modulating bone metabolism and regeneration. How the brain-driven endocrine axes maintain bone homeostasis, especially under metabolic disorders, remains obscure. Here, we found that neural stem cells (NSCs) residing in the subventricular zone participated in lipid metabolism homeostasis of regenerative bone through exosomal perilipin 5 (PLIN5). Fluorescence-labeled exosomes tracing and histological detection identified that NSC-derived exosomes (NSC-Exo) could travel from the lateral ventricle into bone injury sites. Homocysteine (Hcy) led to osteogenic and angiogenic impairment, whereas the NSC-Exo were confirmed to restore it. Mecobalamin, a clinically used neurotrophic drug, further enhanced the protective effects of NSC-Exo through increased PLIN5 expression. Mechanistically, NSC-derived PLIN5 reversed excessive Hcy-induced lipid metabolic imbalance and aberrant lipid droplet accumulation through lipophagy-dependent intracellular lipolysis. Intracerebroventricular administration of mecobalamin and/or AAV-shPlin5 confirmed the effects of PLIN5-driven endocrine modulations on new bone formation and vascular reconstruction in hyperhomocysteinemic and high-fat diet models. This study uncovered a novel brain-skeleton axis that NSCs in the mammalian brain modulated bone regeneration through PLIN5-driven lipid metabolism modulation, providing evidence for lipid- or bone-targeted medicine development.

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

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

Hypoxia and Matrix Metalloproteinase 13-Responsive Hydrogel Microspheres Alleviate Osteoarthritis Progression In Vivo.

The occurrence of osteoarthritis (OA) is highly associated with the inflammatory hypoxic microenvironment. Yet currently no attention has been paid to fabricating hypoxia-responsive platforms for OA treatment. Herein, an injectable hydrogel microsphere system (HAM-SA@HCQ) focusing on the hypoxic inflamed joint is prepared with methacrylate-modified sulfonated azocalix[4]arene (SAC4A-MA), methacrylated hyaluronic acid (HA-MA), and dithiol-terminated matrix metalloproteinase 13 (MMP-13) sensitive peptide via a microfluidic device and photo crosslinking technique, followed by encapsulation of the anti-inflammatory drug hydroxychloroquine (HCQ) through host-guest interaction. Owing to the hydrophobic deep cavity, phenolic units, and azo bonds of SAC4A-MA, the hydrogel microspheres show strong drug loading capacity, prominent reactive oxygen species (ROS) scavenging capability, and specific hypoxia-responsive drug release ability. In the OA tissue microenvironment, the hydrogel microspheres undergo degradation by excessive MMP-13 and release HCQ under the hypoxia condition, which synergizes with the ROS-scavenging calixarene to inhibit the inflammatory response of macrophages. After being injected into the OA-inflamed joint, the HAM-SA@HCQ can significantly attenuate the oxidative stress, downregulate the expression of hypoxia-induced factor-1α and inflammatory cytokines, and prevent the cartilage from being destroyed.

Glycolipotoxicity conferred tendinopathy through ferroptosis dictation of tendon-derived stem cells by YAP activation.

Tendinopathy is a condition characterized by chronic, complex, and multidimensional pathological changes in the tendons. The etiology of tendinopathy is the combination of several factors, and diabetes mellitus (DM) is a risk factor. Increasing evidence has shown that the diabetic microenvironment plays an important role in tendinopathy. However, the mechanism causing tendinopathy in patients with DM remains unclear. Our study found that ferroptosis played an important role in tendinopathy in patients with DM. In vitro, high glucose and high fat treatment was used to simulate the DM microenvironment. Results showed that such a mechanism significantly increased ferroptosis, which was characterized by mass cell death, lipid peroxide accumulation, mitochondrial morphological changes, mitochondrial membrane potential decline, iron overload, and the activation of ferroptosis-related genes, in tendon-derived stem cells cultured in vitro. In the animal studies, db/db mice were used in the DM model, and the db mice had severe tendon injury and high ACSL4 and TfR1 expressions. These phenomena could be alleviated by the ferroptosis inhibitor ferrostatin-1. In conclusion, ferroptosis is associated with tendinopathy in patients with DM, and ferroptosis targeting may be a novel approach for treating diabetic tendinopathy. Our results can provide a new strategy for managing tendinopathy clinically in patients with DM.

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

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

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

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

Human osteoprogenitor cells obtained from traumatic heterotopic ossification samples showed enhanced osteogenic differentiation potential and ERK/hedgehog signaling than that from normal bone.

Traumatic heterotopic ossification (HO) refers to the abnormal ectopic osteogenesis following trauma, causing limb dysfunction and seriously lowering the life quality of patients. Aberrant osteogenic behavior of progenitor cells that ectopically accumulated within the soft tissues are believed to be responsible for HO formation. However, the detailed mechanism still remained to be clarified. Here in this study, we successfully isolated osteoprogenitors from human heterotopic ossification tissues (HO-ops) and identified their stemness and multi-directional differentiation potential. Using alkaline phosphatase staining together with alizarin red staining, we confirmed that the HO-ops in the heterotopic ossified tissues gained greater osteogenic potential than the normal human bone marrow mesenchymal stem cells (HBMSCs). RT-qPCR also indicated that HO-ops obtained more gene transcriptions of critical osteogenic determinators than HBMSCs. In addition, through Western blot, we proved that ERK signaling pathway and hedgehog signaling pathway were significantly activated in the HO-ops. When U0126 and cyclopamine were used to inhibit ERK signaling and hedgehog signaling respectively, the osteogenic potential of HO-ops decreased significantly. The hedgehog signaling and ERK signaling also showed cross-talk in HO-ops during osteogenic differentiation in HO-ops during osteogenic differentiation. The elevated ERK signaling and hedgehog signaling were further confirmed in the human traumatic HO sample sections by immunohistochemical staining. In sum, our results showed that the activation of ERK and hedgehog signaling pathway jointly enhanced the osteogenic potential of HO-ops to induce the formation of traumatic HO, which provides novel insights into the molecular basis of HO formation and offers promising targets for future therapeutic strategy.

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

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

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

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

Inhibition of IL-17 prevents the progression of traumatic heterotopic ossification.

Traumatic heterotopic ossification (HO) is the abnormal formation of bone in soft tissues as a consequence of injury. However, the pathological mechanisms leading to traumatic HO remain unknown. Here, we report that aberrant expression of IL-17 promotes traumatic HO formation by activating ß-catenin signalling in mouse model. We found that elevated IL-17 and ß-catenin levels are correlated with a high degree of HO formation in specimens from patients and HO animals. We also show that IL-17 initiates and promotes HO progression in mice. Local injection of an IL-17 neutralizing antibody attenuates ectopic bone formation in a traumatic mouse model. IL-17 enhances the osteoblastic differentiation of mesenchymal stem cells (MSCs) by activating ß-catenin signalling. Moreover, inhibition of IL-17R or ß-catenin signalling by neutralizing antibodies or drugs prevents the osteogenic differentiation of isolated MSCs and decreases HO formation in mouse models. Together, our study identifies a novel role for active IL-17 as the inducer and promoter of ectopic bone formation and suggests that IL-17 inhibition might be a potential therapeutic target in traumatic HO.

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

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

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

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

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

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

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

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

Mechano-Informed Biomimetic Polymer Scaffolds by Incorporating Self-Powered Zinc Oxide Nanogenerators Enhance Motor Recovery and Neural Function.

Piezoelectric materials can produce electrical power from the mechanical stimulation and thus, they may accelerate electroactive tissue healing as a promising treatment for traumatic peripheral nerve injuries. In this study, a piezoelectric zinc oxide nanogenerator scaffold is manufactured by 3D injectable multilayer biofabrication. The piezoelectric polymeric scaffold displays desirable mechanical and physical characteristics, such as aligned porosity, high elasticity, scaffold stiffness, surface energy, and excellent shear behavior. In addition, its biocompatibility supplies Schwann cells with an adhesive, proliferative, and angiogenic interface, as is reflected by higher expression of functional proteins including nerve growth factor (NGF) and vascular endothelial growth factor (VEGF). In vivo mechanical stimuli by treadmill practice contribute to the comprehensive reparative therapy. The piezoelectric conduit accelerates nerve conducting velocity, promotes axonal remyelination, and restores motor function by recovering endplate muscles. Moreover, the piezoelectric nanogenerator scaffold creates biomimetic electrically conductive microenvironment without causing noticeable toxicity to functioning organs and improves peripheral nerve restoration by the multifunctional characteristics. Therefore, the mechano-informed biomimetic piezoelectric scaffold may have enormous potential in the neuroengineering for regenerative medicine.

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

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

Effect of hyperuricemia on functional outcomes and complications in patients with elbow stiffness after open arthrolysis combined with hinged external fixation: a retrospective study.

BACKGROUND: Hyperuricemia is considered a risk factor for increased postoperative complications and adverse functional outcomes in a variety of orthopedic surgeries. The purpose of this retrospective study was to investigate the clinical efficacy of patients with different uric acid levels after elbow arthrolysis. METHODS: The study included 131 patients with post-traumatic elbow stiffness who underwent arthrolysis between March 2014 and March 2016. All patients were divided into 4 groups based on the preoperative serum level of uric acid (UA). The quartile method was used for grouping patients, including 33 in Q1 (UA <293 µmol/L), 34 in Q2 (293-348 µmol/L), 32 in Q3 (348-441 µmol/L), and 32 in Q4 (441-710 µmol/L). At baseline and each time point of follow-up, functional performance, Mayo Elbow Performance Score, visual analog scale for pain, and complications were evaluated. RESULTS: Preoperative data were not significantly different among the 4 groups (Q1, Q2, Q3, and Q4). At the final follow-up, the following data showed significant differences among the 4 groups: extension (P = .031), flexion (P = .008), range of motion (P = .003), Mayo Elbow Performance Score (P = .011), and visual analog scale (P = .032). Interestingly, patients in the Q4 group had the poorest clinical outcomes. However, no significant differences were found among the 4 groups in new onset or exacerbation of nerve symptoms (P = .919), reduced muscle strength (P = .536), instability (P = .567), or infection (P = .374) at the last follow-up. CONCLUSION: This study confirms that in patients with post-traumatic elbow stiffness, abnormal serum uric acid metabolism was a risk factor for poor performance and postoperative pain after arthrolysis. Therefore, detecting the preoperative serum uric acid levels of the patients would be helpful for evaluating the postoperative outcomes.

Concentrically Integrative Bioassembly of a Three-Dimensional Black Phosphorus Nanoscaffold for Restoring Neurogenesis, Angiogenesis, and Immune Homeostasis.

Black phosphorus is well known for its excellent electromechanical properties. Although it has previously been used for therapeutic drug delivery in cancer, it has never been applied as an electroactive polymer for post-trauma tissue regeneration (e.g., in cardiac muscles and neurons). The major concern currently preventing such applications is its controversial biosafety profile in vivo. Here, we demonstrate the production of a concentrically integrative layer-by-layer bioassembled black phosphorus nanoscaffold. This scaffold has remarkable electrical conductivity, permitting smooth release into the surrounding microenvironment. We confirmed that, under mild oxidative stress, our black phosphorus nanoscaffold induced angiogenesis and neurogenesis and stimulated calcium-dependent axon regrowth and remyelination. Long-term in vivo implantation of this nanoscaffold during severe neurological defect regeneration induced negligible toxicity levels. These results provide new insight into the regenerative capability of manufactured 3D scaffolds using neuroengineered 2D black phosphorus nanomaterials.

Hydroxycamptothecin Prevents Fibrotic Pathways in Fibroblasts In Vitro.

Peritendinous fibrosis, which leads to impaired tendon function, is a clinical problem worldwide, and it is urgent to explore potential ways to reduce the formation of peritendinous adhesion. Several studies have demonstrated the biological roles of hydroxycamptothecin (HCPT) in inhibiting fibrosis in different tissues. In this study, we investigated whether HCPT could inhibit tendon fibrosis in vitro. Our results revealed that HCPT inhibited transforming growth factor (TGF)-ß1-induced cell viability of human fibroblasts, decreased excessive cell hyperproliferation and promoted fibroblasts apoptosis. In addition, HCPT treatment also inhibited expression of fibrosis genes COL3A1 and α-smooth muscle actin (α-SMA). In terms of mechanism, we pretreated fibroblasts with the endoplasmic reticulum stress (ER) inhibitor salubrinal and RNA-dependent protein kinase-like ER kinase (PERK) short hairpin RNA, these treatments abolished the inhibitory effects of HCPT on fibrosis, thereby suggesting that HCPT's inhibition of TGF-ß1-induced tendon fibrosis might be mediated by the PERK signaling pathway in vitro. In conclusion, our results suggested that HCPT had protective effects on peritendinous tissue fibrosis and might be promising in future clinical applications. © 2019 IUBMB Life, 71(5):653-662, 2019.