Ingenious Synergy of a Pathology-Specific Biomimetic Multifunctional Nanoplatform for Targeted Therapy in Rheumatoid Arthritis.

Based on the pathological characteristics of rheumatoid arthritis, including the overproduction of reactive oxygen species (ROS), inflammatory responses, and osteoclast differentiation, a biomimetic multifunctional nanomedicine (M-M@I) is designed. Iguratimod (IGU) is loaded, which inhibits inflammatory responses and osteoclast differentiation, into mesoporous polydopamine (MPDA), which scavenges ROS. Subsequently, the nanoparticles are coated with a cell membrane of macrophages to achieve actively targeted delivery of the nanoparticles to inflamed joints. It is shown that the M-M@I nanoparticles are taken up well by lipopolysaccharide-induced RAW 264.7 macrophages or bone marrow-derived macrophages (BMDMs). In vitro, the M-M@I nanoparticles effectively scavenge ROS, downregulate genes related to inflammation promotion and osteoclast differentiation, and reduce the proinflammatory cytokines and osteoclast-related enzymes. They also reduce the polarization of macrophages to a pro-inflammatory M1 phenotype and inhibit differentiation into osteoclasts. In mice with collagen-induced arthritis, the M-M@I nanoparticles accumulate at arthritic sites and circulate longer, significantly mitigating arthritis symptoms and bone destruction. These results suggest that the pathology-specific biomimetic multifunctional nanoparticles are effective against rheumatoid arthritis, and they validate the approach of developing multifunctional therapies that target various pathological processes simultaneously.

DLP Fabrication of Multiple Hierarchical Biomimetic GelMA/SilMA/HAp Scaffolds for Enhancing Bone Regeneration.

Severe bone defects resulting from trauma and diseases remain a persistent clinical challenge. In this study, a hierarchical biomimetic microporous hydrogel composite scaffold was constructed by mimicking the hierarchical structure of bone. Initially, gelatin methacrylamide (GelMA) and methacrylic anhydride silk fibroin (SilMA) were synthesized, and GelMA/SilMA inks with suitable rheological and mechanical properties were prepared. Biomimetic micropores were then generated by using an aqueous two-phase emulsification method. Subsequently, biomimetic microporous GelMA/SilMA was mixed with hydroxyapatite (HAp) to prepare biomimetic microporous GelMA/SilMA/HAp ink. Hierarchical biomimetic microporous GelMA/SilMA/HAp (M-GSH) scaffolds were then fabricated through digital light processing (DLP) 3D printing. Finally, in vitro experiments were conducted to investigate cell adhesion, proliferation, and inward migration as well as osteogenic differentiation and vascular regeneration effects. In vivo experiments indicated that the biomimetic microporous scaffold significantly promoted tissue integration and bone regeneration after 12 weeks of implantation, achieving 42.39% bone volume fraction regeneration. In summary, this hierarchical biomimetic microporous scaffold provides a promising strategy for the repair and treatment of bone defects.

Cocktail of Ropivacaine, Morphine, and Diprospan Reduces Pain and Prolongs Analgesic Effects after Total Knee Arthroplasty: A Prospective Randomized Controlled Trial.

Background: Local infiltration analgesia (LIA) provides postoperative analgesia for total knee arthroplasty (TKA). The purpose of this study was to evaluate the analgesic effect of a cocktail of ropivacaine, morphine, and Diprospan for TKA. Methods: A total of 100 patients from September 2018 to February 2019 were randomized into 2 groups. Group A (control group, 50 patients) received LIA of ropivacaine alone (80 ml, 0.25% ropivacaine). Group B (LIA group, 50 patients) received an LIA cocktail of ropivacaine, morphine, and Diprospan (80 ml, 0.25% ropivacaine, 0.125 mg/ml morphine, and 62.5 µg/ml compound betamethasone). The primary outcomes were the levels of inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6), pain visual analog scale (VAS) scores, opioid consumption, range of motion (ROM), functional tests, and sleeping quality. The secondary outcomes were adverse events, satisfaction rates, HSS scores, and SF-12 scores. The longest follow-up was 2 years. Results: The two groups showed no differences in terms of characteristics (P > 0.05). Group B had lower resting VAS pain scores (1.54 ± 0.60, 95% CI = 1.37 to 1.70 vs. 2.00 ± 0.63, 95% CI = 2.05 to 2.34) and active VAS pain scores (2.64 ± 0.62, 95% CI = 2.46 to 2.81 vs. 3.16 ± 0.75, 95% CI = 2.95 to 3.36) within 48 h postoperatively than Group A (P < 0.001), while none of the pain differences exceeded the minimal clinically important difference (MCID). Group B had significantly lower CRP levels (59.49 ± 13.01, 95% CI = 55.88 to 63.09 vs. 65.95 ± 14.41, 95% CI = 61.95 to 69.94) and IL-6 levels (44.11 ± 13.67, 95% CI = 40.32 to 47.89 vs. 60.72 ± 15.49, 95% CI = 56.42 to 65.01), lower opioid consumption (7.60 ± 11.10, 95% CI = 4.52 to 10.67 vs. 13.80 ± 14.68, 95% CI = 9.73 to 17.86), better ROM (110.20 ± 10.46, 95% CI = 107.30 to 113.09 vs. 105.30 ± 10.02, 95% CI = 102.52 to 108.07), better sleep quality (3.40 ± 1.03, 95% CI = 3.11 to 3.68 vs. 4.20 ± 1.06, 95% CI = 3.90 to 4.49), and higher satisfaction rates than Group A within 48 h postoperatively (P < 0.05). Adverse events, HSS scores, and SF-12 scores were not significantly different within 2 years postoperatively. Conclusions: A cocktail of ropivacaine, morphine, and Diprospan prolongs the analgesic effect up to 48 h postoperatively. Although the small statistical benefit may not result in MCID, the LIA cocktail still reduces opioid consumption, results in better sleeping quality and faster rehabilitation, and does not increase adverse events. Therefore, cocktails of ropivacaine, morphine, and Diprospan have good application value for pain control in TKA. This trial is registered with ChiCTR1800018372.

Effects of Dexamethasone on Postoperative Glycemic Control in Patients After Primary Total Joint Arthroplasty: A Randomized Double-Blind Controlled Trial.

BACKGROUND: In patients undergoing total joint arthroplasty, the use of dexamethasone (DEX) may cause perioperative blood glucose (BG) disorders, leading to complications even in patients who do not have diabetes. We aimed to evaluate the effects of different DEX doses on perioperative BG levels. METHODS: A total of 135 patients who do not have diabetes were randomized into three groups: preoperative intravenous (IV) injection of normal saline (Group A, the placebo group), preoperative IV injection of 10 mg DEX (Group B), and preoperative IV injection of 20 mg DEX (Group C). Postoperative fasting BG (FBG) levels were designated as the primary outcome, while postoperative postprandial BG (PBG) levels were assigned as the secondary outcome. The incidence of complications was recorded. We also investigated the risk factors for FBG ≥ 140 mg/dL and PBG ≥ 180 mg/dL. RESULTS: The FBG levels were higher in Groups B and C than in Group A on postoperative days (PODs) 0 and 1. The PBG levels were lower for Groups A and B compared to Group C on POD 1. No differences in FBG or PBG were detected beyond POD 1. Elevated preoperative glycosylated hemoglobin A1c levels increased the risk of FBG ≥ 140 mg/dL and PBG ≥ 180 mg/dL, respectively. However, preoperative IV injection of DEX was not associated with FBG ≥ 140 mg/dL or PBG ≥ 180 mg/dL. No differences were found in postoperative complications among the three groups. CONCLUSIONS: The preoperative IV administration of 10 or 20 mg DEX in patients who do not have diabetes showed transient effects on postoperative BG after total joint arthroplasty. The preoperative glycosylated hemoglobin A1c level threshold (regardless of the administration or dosage of DEX) that increased the risk for the occurrence of FBG ≥ 140 mg/dL and PBG ≥ 180 mg/dL was 5.75 and 5.85%, respectively.

Adductor canal block combined with local infiltration analgesia with morphine and betamethasone show superior analgesic effect than local infiltration analgesia alone for total knee arthroplasty: a prospective randomized controlled trial.

BACKGROUND: Local infiltration analgesia (LIA) and adductor canal block (ACB) provide postoperative analgesia for total knee arthroplasty (TKA). ACB blocks the saphenous nerve and has smaller impacts on quadriceps muscle weakness. ACB theoretically does not have enough analgesic effects on posterior sensory nerves. LIA may increase its analgesic effects on the posterolateral knee. The purpose of this study was to evaluate whether ACB combined with a LIA cocktail of ropivacaine, morphine, and betamethasone has superior analgesic effect than LIA for TKA. METHODS: A total of 86 patients were assessed for eligibility from February 2019 to May 2019. 26 of those were excluded, and 60 patients were divided into 2 groups by computer-generated random number. Group A (LIA group) received LIA cocktail of ropivacaine, morphine and betamethasone. Group B (LIA+ ACB group) received ultrasound-guided ACB and LIA cocktail of ropivacaine, morphine and betamethasone. Postoperative visual analogue scale (VAS) resting or active pain scores, opioid consumption, range of motion (ROM), functional tests, complications and satisfaction rates were measured. The longest follow-up was 2 years. RESULTS: Two groups have no differences in terms of characteristics, preoperative pain or function (P > 0.05). ACB combined with LIA had significantly lower resting and active VAS pain scores, better ROM, better sleeping quality and higher satisfaction rates than LIA alone within 72 h postoperatively (P < 0.05). Complications, or adverse events and HSS score, SF-12 score were observed no significant differences within 2 years postoperatively. CONCLUSIONS: Adductor canal block combined with Local infiltration analgesia provide better early pain control. Although the small statistical benefit may not result in minimal clinically important difference, Adductor canal block combined with Local infiltration analgesia also reduce opioid requirements, improve sleeping quality, and do not increase the complication rate. Therefore, Adductor canal block combined with Local infiltration analgesia still have good application prospects as an effective pain management for total knee arthroplasty. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900021385 , 18/02/2019.

Adductor Canal Block Combined With IPACK Block for Postoperative Analgesia and Function Recovery Following Total Knee Arthroplasty: A Prospective, Double-Blind, Randomized Controlled Study.

BACKGROUND: This study aimed to explore the analgesic effect among adductor canal block (ACB) combined with infiltration between the popliteal artery and the capsule of the posterior knee (IPACK) block, ACB, and IPACK block following total knee arthroplasty (TKA). METHODS: One hundred twenty patients were randomly allocated into 3 groups including group A (ACB + IPACK block), group B (ACB), and group C (IPACK block). The primary outcome was postoperative pain score. The secondary outcome was opioid consumption. Other outcomes included functional evaluation and postoperative complications. RESULTS: Group A showed the lowest pain scores within 8 hours at rest and with knee maximum flexion (P < .001). From 12 to 24 hours, group C showed the highest pain scores, while no significant difference was found between group A and group B. No significant difference was found among the 3 groups 24 hours postoperatively. Group C showed the most opioid consumption within the first 24 hours and during the hospitalization, while no significant difference was found between group A and group B. No significant difference was found among the 3 groups including function evaluation and postoperative complications. CONCLUSION: ACB + IPACK block can improve early analgesia when compared with ACB. However, the small statistical benefit to the addition of IPACK block to ACB may be unlikely to be clinically significant. Further studies may focus on patient selection and how to prolong the effect of IPACK block.

[Preliminary Study on the Effect of Whole-Process Case Management Based on Service Process Design on the Function and Satisfaction of Patients Undergoing Total Knee Arthroplasty].

Objective: To investigate the effect of whole-process case management based on service process design on patients undergoing total knee arthroplasty (TKA) in areas including pain, function, satisfaction, and complications. Methods: A total of 204 patients who underwent unilateral TKA between April 2021 and March 2022 at the Department of Orthopedics, West China Hospital, Sichuan University were enrolled. By using a random number table, the patients were randomly assigned to two groups, 102 in the general case management group (group G) and 102 in the whole-process case management group (group W). Patients in group G received traditional perioperative case management, while those in the whole-process case management group received integrated case management optimized on the basis of the service process design. The two groups of patients were studied through comparison of their general data, Visual Analogue Scale (VAS) pain score, knee flexion and range of motion, Hospital for Special Surgery (HSS) knee score, the 18-item Patient Satisfaction Questionnaire Short Form (PSQ-18), ability to climb stairs, and complications at 3 days and 3, 8, and 12 weeks after TKA. Results: There was no significant difference between the two groups in patient general information or baseline data collected at the time of enrollment ( P>0.05). There was no significant difference in HSS score, joint range of motion, and VAS pain score between the two groups before the surgery and 3 days after the surgery ( P>0.05). However, the HSS score, joint range of motion, and VAS pain scores of group W were significantly superior to those of group G at 3, 8 and 12 weeks after the surgery (all P<0.05). In addition, group W demonstrated significantly better ability to climb up and down stairs than that of group G at 12 weeks after the surgery ( P< 0.001). In terms of satisfaction, patients in group W were significantly more satisfied than those in group G at 3 days, and 3, 8, and 12 weeks after the surgery ( P<0.001). Conclusion: Whole-process case management based on service process design has a positive effect of relieving pain, increasing range of motion, improving function, increasing satisfaction, and reducing complications in patients undergoing TKA.

Mitochondria-targeting graphene oxide nanocomposites for fluorescence imaging-guided synergistic phototherapy of drug-resistant osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor occurring in children and young adults. Drug-resistant osteosarcoma often results in chemotherapy failure. Therefore, new treatments aimed at novel therapeutic targets are urgently needed for the treatment of drug-resistant osteosarcoma. Mitochondria-targeted phototherapy, i.e., synergistic photodynamic/photothermal therapy, has emerged as a highly promising strategy for treating drug-resistant tumors. This study proposed a new nano-drug delivery system based on near-infrared imaging and multifunctional graphene, which can target mitochondria and show synergistic phototherapy, with preferential accumulation in tumors. METHODS AND RESULTS: Based on our previous study, (4-carboxybutyl) triphenyl phosphonium bromide (TPP), a mitochondria-targeting ligand, was conjugated to indocyanine green (ICG)-loaded, polyethylenimine-modified PEGylated nanographene oxide sheets (TPP-PPG@ICG) to promote mitochondrial accumulation after cellular internalization. Thereafter, exposure to a single dose of near-infrared irradiation enabled synergistic photodynamic and photothermal therapy, which simultaneously inhibited adenosine triphosphate synthesis and mitochondrial function. Induction of intrinsic apoptosis assisted in surmounting drug resistance and caused tumor cell death. After fluorescence imaging-guided synergistic phototherapy, the mitochondria-targeting, multifunctional graphene-based, drug-delivery system showed highly selective anticancer efficiency in vitro and in vivo, resulting in marked inhibition of tumor progression without noticeable toxicity in mice bearing doxorubicin-resistant MG63 tumor cells. CONCLUSION: The mitochondria-targeting TPP-PPG@ICG nanocomposite constitutes a new class of nanomedicine for fluorescence imaging-guided synergistic phototherapy and shows promise for treating drug-resistant osteosarcoma.

Mid-long-term results of total knee arthroplasty followed by ipsilateral total hip arthroplasty versus total hip arthroplasty subsequent to ipsilateral total knee arthroplasty: a case-control analysis.

BACKGROUND: The aim of the present study was to compare the outcomes of patients who underwent different sequences of ipsilateral total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: We retrospectively identified 47 patients who underwent TKA followed by ipsilateral THA (THA-TKA) and 36 patients who received THA subsequent to ipsilateral TKA (TKA-THA) for rheumatoid arthritis or osteoarthritis between January 2008 and April 2014. Twenty-eight patients were selected for each group after case-control matching with preoperative demographics and protheses of THA. Clinical scores, radiographic results, complication rates, and survivorship were compared. The median duration of follow-up was 110 (range 80-149) months. RESULTS: Both groups showed significant improvement in Harris Hip Scores, Knee Society Score, and Short Form-12 at the last follow-up compared to baseline (p < .001). At the last follow-up, all clinical scores were actually lower in the THA-TKA group, but those differences were not statistically significant. Otherwise, there was no significant difference in radiological alignment or complication rates. The survivorship of THA and TKA in the THA-TKA group was 94.7 and 95.7%, respectively, compared with 92.4 and 100.0% in the TKA-THA group at 8 years (log rank, p = .939 and .187). CONCLUSIONS: Patients who underwent ipsilateral THA and TKA with different sequences achieved similar favorable outcomes. Total joint arthroplasty can be performed safely with excellent outcomes in patients with a history of prior ipsilateral THA or TKA. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry ( ChiCTR2000035147 ) dated 2 August 2020.

Multiple drilling is not effective in reducing the rate of conversion to Total hip Arthroplasty in early-stage nontraumatic osteonecrosis of the femoral head: a case-control comparative study with a natural course.

BACKGROUND: To determine whether multiple drilling is effective in postponing the need for total hip arthroplasty (THA) in early-stage nontraumatic osteonecrosis of the femoral head (ONFH). METHODS: We identified 514 patients who were diagnosed with early-stage ONFH between January 2008 and December 2018. One hundred ninety-six patients underwent multiple drilling, and 318 patients had a natural course of progression. One hundred fifty-nine patients were selected for each group after case-control matching for preoperative demographics and modified Ficat and Arlet stage. The rates of THA conversion were compared. We also performed Cox regression to identify risk factors associated with THA conversion in patients who underwent multiple drilling. RESULTS: Kaplan-Meier survivorship with an endpoint of THA for nontraumatic reasons were not significantly different between the multiple drilling group (75.6, 95% confidence interval 67.8-83.4%) and the natural course group (72.2, 95% confidence interval 64.8-79.6%) at 5 years (log-rank, P = .191). In the Cox regression model, a larger extent of necrotic lesion, bone marrow edema (BME), and higher postoperative work intensity significantly increased the risk of THA conversion (P < .05). Among patients treated with autogenous bone grafting, there was a lower risk of failure in patients with necrotic lesion less than 15% (P < .05). CONCLUSIONS: Multiple drilling is not effective in reducing the rate of THA conversion in early-stage nontraumatic ONFH. The risk of conversion to THA after multiple drilling is increased by a larger extent of necrotic lesion, presence of BME, and higher postoperative work intensity in patients with early-stage ONFH. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry ( ChiCTR2000035180 ) dated 2 August 2020.

Duloxetine reduces pain after Total hip arthroplasty: a prospective, randomized controlled study.

BACKGROUND: Previous studies have demonstrated the efficacy of duloxetine in reducing postoperative pain and opioid consumption. However, the effect of duloxetine on total hip arthroplasty (THA) remains unclear. The objective of this study was to assess the efficacy of oral duloxetine in THA. METHODS: We enrolled 96 patients in this randomized controlled trial. These patients were randomized (1,1) to either the duloxetine group or the placebo group and received daily doses of 60 mg duloxetine or placebo, respectively, from 2 d pre-operation to 14 d after surgery. The primary outcome was pain severity upon movement measured by a visual analogue scale (VAS). The secondary outcomes included VAS scores for resting pain, morphine consumption, Harris Hip Score, patient satisfaction at discharge, length of postoperative hospital stay, and adverse events. RESULTS: Patients in the duloxetine group had significantly lower pain severity scores upon movement within 3 postoperative weeks (p < 0.05) while none of the differences met the minimum clinically important difference (MCID). Moreover, patients in the duloxetine group performed better in terms of resting pain (in 3 weeks after surgery), morphine requirements, and satisfaction level at discharge (all p < 0.05). There was no difference between groups in the prevalence of adverse events. CONCLUSIONS: Although it did not result in a clinically meaning reduction in pain after total hip arthroplasty, perioperative administration of 60 mg of duloxetine daily significantly alleviated pain in the postoperative 3 weeks and morphine requirements during the postoperative 48 h. Therefore, duloxetine still shows promise in optimizing the multimodal pain-management protocols in total hip arthroplasty. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000033606 , 06/06/2020.

Midterm Results of Total Hip Arthroplasty in Patients With High Hip Dislocation After Suppurative Hip Arthritis.

BACKGROUND: Total hip arthroplasty (THA) is technically challenging in patients with high dislocation of the hip secondary to suppurative arthritis. The technical difficulty is attributable to the complex hip anatomy and the potential risk of recurrent infection in these patients. This study investigated the midterm results of THA in patients with Crowe type III and IV high dislocation of the hip secondary to suppurative arthritis. METHODS: This study retrospectively reviewed 45 patients (45 hips) who underwent cementless THA with a mean quiescent infection period of 34.2 years. This study included 23 men and 22 women (mean age, 45.9 years) at the time of operation. The mean follow-up was 6.4 years. Clinical and radiographic outcomes and complications were evaluated. RESULTS: The mean Harris hip score significantly improved from 48.1 to 87.6. The modified Merle d'Aubigné-Postel, Western Ontario and McMaster Universities Arthritis Index, low back pain visual analog scale, and the 12-item short-form health survey scores also improved significantly. The mean limb length discrepancy was reduced from 38.9 mm to 6.4 mm. Postoperative dislocation occurred in 2, temporary sciatic nerve paralysis in 3, and intraoperative fracture in 2 patients. Infection and femoral stem loosening necessitated hip revision surgery in 1 patient each. CONCLUSION: THA could provide good joint function and significantly improve quality of life at the time of midterm follow-up in patients undergoing high hip dislocation secondary to suppurative arthritis. However, a relatively high incidence of complications occurred which can be treated.

Long-Term Results of Cementless Total Hip Arthroplasty for Patients With High Hip Dislocation After Childhood Pyogenic Infection.

BACKGROUND: The purpose of this study is to analyze the 10-year outcomes of cementless, modular total hip arthroplasty (THA) in adult patients who had high dislocation secondary to childhood pyogenic arthritis. METHODS: We retrospectively followed 56 consecutive patients who underwent cementless, modular THA for the late sequelae of childhood septic arthritis of the hip from 2001 to 2011. There were 23 men and 33 women with a mean age of 47 years (24 to 68). Of the 56 hips, 25 were classified as Crowe type III and 31 as type IV. Mean follow-up was 10.7 years. RESULTS: One hip with a quiescent period of 23 years had recurrence of infection. Revision surgery was performed in 2 patients because of loosening and breakage of femoral stem and new infection with no correlation with childhood sepsis, respectively. The mean Harris hip scores improved from 44.2 points preoperatively to 87.5 points at final follow-up. Similarly, the Hip dysfunction and Osteoarthritis Outcome Score and hip pain also significantly improved at the latest follow-up. The mean acetabular cup abduction was 40.8° and the mean anteversion 27.8°, respectively. There were 5 cases of transient nerve palsy and 5 cases of intraoperative fracture. CONCLUSION: THA can reliably restore the abnormal anatomy and provide good results in these young and active patients who had high hip dislocation secondary to childhood pyogenic arthritis with a relatively high incidence of complications. However, these complications can be treated.

Psychometric properties of the symptom check list 90 (SCL-90) for Chinese undergraduate students.

BACKGROUND: Despite the widespread application of the Chinese version of Symptom Check List 90 (SCL-90) amongst undergraduate students, researchers have not thoroughly evaluated its psychometric features with representative samples of Chinese undergraduate students. AIM: To evaluate its psychometric properties based on a large, representative sample of Chinese undergraduate students. METHODS: A total of 4456 Chinese undergraduate students (age range = 17-25 years) completed the SCL-90. Correlation analysis, confirmatory factor analysis and structural equation modeling were used to evaluate its reliability and validity. RESULTS: The evidence for item-total correlations, internal consistency reliability, intraclass correlation coefficients and composite reliability, and the hypothesized factor structure was satisfactory. The evidence for convergent validity was acceptable; however, the evidence for discriminant validity was not satisfactory. CONCLUSION: Based on a large, representative sample of Chinese undergraduate students, the Chinese version of the SCL-90 revealed both strengths and limitations, suggesting the need for further research.

Gender differences in Chinese adolescents' subjective well-being: the mediating role of self-efficacy.

Although gender differences in self-efficacy and subjective well-being have been reported in previous studies, little published research has investigated the interrelationships between these variables in adolescents. 648 Chinese adolescents were administered a series of questionnaires to test the hypothesis that self-efficacy mediates the relationship between gender and subjective well-being. The results indicated that adolescent girls had lower general self-efficacy than adolescent boys, which explained girls' lower subjective well-being. The theoretical and practical implications may help parents and educators to strengthen adolescents' happiness.

M2 macrophage-derived exosome-functionalized topological scaffolds regulate the foreign body response and the coupling of angio/osteoclasto/osteogenesis.

Designing scaffolds that can regulate the innate immune response and promote vascularized bone regeneration holds promise for bone tissue engineering. Herein, electrospun scaffolds that combined physical and biological cues were fabricated by anchoring reparative M2 macrophage-derived exosomes onto topological pore structured nanofibrous scaffolds. The topological pore structure of the fiber and the immobilization of exosomes increased the nanoscale roughness and hydrophilicity of the fibrous scaffold. In vitro cell experiments showed that exosomes could be internalized by target cells to promote cell migration, tube formation, osteogenic differentiation, and anti-inflammatory macrophage polarization. The activation of fibrosis, angiogenesis, and macrophage was elucidated during the exosome-functionalized fibrous scaffold-mediated foreign body response (FBR) in subcutaneous implantation in mice. The exosome-functionalized nanofibrous scaffolds also enhanced vascularized bone formation in a critical-sized rat cranial bone defect model. Importantly, histological analysis revealed that the biofunctional scaffolds regulated the coupling effect of angiogenesis, osteoclastogenesis, and osteogenesis by stimulating type H vessel formation. This study elaborated on the complex processes within the cell microenvironment niche during fibrous scaffold-mediated FBR and vascularized bone regeneration to guide the design of implants or devices used in orthopedics and maxillofacial surgery. STATEMENT OF SIGNIFICANCE: How to design scaffold materials that can regulate the local immune niche and truly achieve functional vascularized bone regeneration still remain an open question. Here, combining physical and biological cues, we proposed new insight to cell-free and growth factor-free therapy, anchoring reparative M2 macrophage-derived exosomes onto topological pore structured nanofibrous scaffolds. The exosomes functionalized-scaffold system mitigated foreign body response, including excessive fibrosis, tumor-like vascularization, and macrophage activation. Importantly, the biofunctional scaffolds regulated the coupling effect of angiogenesis, osteoclastogenesis, and osteogenesis by stimulating type H vessel formation.

A Composite Hydrogel Functionalized by Borosilicate Bioactive Glasses and VEGF for Critical-Size Bone Regeneration.

Critical-size bone defects pose a formidable challenge in clinical treatment, prompting extensive research efforts to address this problem. In this study, an inorganic-organic multifunctional composite hydrogel denoted as PLG-g-TA/VEGF/Sr-BGNPs is developed, engineered for the synergistic management of bone defects. The composite hydrogel demonstrated the capacity for mineralization, hydroxyapatite formation, and gradual release of essential functional ions and vascular endothelial growth factor (VEGF) and also maintained an alkaline microenvironment. The composite hydrogel promoted the proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs), as indicated by increased expression of osteogenesis-related genes and proteins in vitro. Moreover, the composite hydrogel significantly enhanced the tube-forming capability of human umbilical vein endothelial cells (HUVECs) and effectively inhibited the process of osteoblastic differentiation of nuclear factor kappa-B ligand (RANKL)-induced Raw264.7 cells and osteoclast bone resorption. After the implantation of the composite hydrogel into rat cranial bone defects, the expression of osteogenic and angiogenic biomarkers increased, substantiating its efficacy in promoting bone defect repair in vivo. The commendable attributes of the multifunctional composite hydrogel underscore its pivotal role in expediting hydrogel-associated bone growth and repairing critical bone defects, positioning it as a promising adjuvant therapy candidate for large-segment bone defects.

The effect of a split-dose intravenous dexamethasone and a single high-dose on postoperative blood glucose after total joint arthroplasty: a randomized double-blind placebo-controlled trial.

BACKGROUND: In patients undergoing total joint arthroplasty (TJA), the administration of dexamethasone may contribute to perioperative blood glucose (BG) disturbances, potentially resulting in complications, even in patients without diabetes. This study aimed to demonstrate the impact of different administration regimens of dexamethasone in postoperative BG levels. METHODS: In this randomized, controlled, double-blind trial, 136 patients without diabetes scheduled for TJA were randomly assigned to three groups: two perioperative saline injections (Group A, placebo); a single preoperative injection of 20 mg dexamethasone and a postoperative saline injection (Group B), and two perioperative injections of 10 mg dexamethasone (Group C). Primary outcomes were the postoperative fasting blood glucose (FBG) levels. Secondary outcome parameters were the postoperative postprandial blood glucose (PBG) levels. Postoperative complications within 90 days were also recorded. Risk factors for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl were investigated. RESULTS: Compared to Group A, there were transient increases in FBG and PBG on postoperative days (PODs) 0 and 1 in Groups B and C. Statistical differences in FBG and PBG among the three groups were nearly absent from POD 1 onward. Both dexamethasone regimens did not increase the risk for postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl. Elevated preoperative HbA1c levels may increase the risk of postoperative FBG ≥ 140 mg/dl or PBG ≥ 180 mg/dl, respectively. CONCLUSION: Perioperative intravenous high-dose dexamethasone to patients without diabetes has transient effects on increasing BG levels after TJA. However, no differences were found between the split-dose and single high-dose regimens. The elevated preoperative HbA1c, but not the dexamethasone regimens were the risk factor for FBG ≥ 140 mg/dl and PBG ≥ 180 mg/dl. TRIAL REGISTRATION: Chinese Clinical Trail Registry, ChiCTR2300069473. Registered 17 March 2023, https://www.chictr.org.cn/showproj.html?proj=186760 .

Engineered Microchannel Scaffolds with Instructive Niches Reinforce Endogenous Bone Regeneration by Regulating CSF-1/CSF-1R Pathway.

Structural and physiological cues provide guidance for the directional migration and spatial organization of endogenous cells. Here, a microchannel scaffold with instructive niches is developed using a circumferential freeze-casting technique with an alkaline salting-out strategy. Thereinto, polydopamine-coated nano-hydroxyapatite is employed as a functional inorganic linker to participate in the entanglement and crystallization of chitosan molecules. This scaffold orchestrates the advantage of an oriented porous structure for rapid cell infiltration and satisfactory immunomodulatory capacity to promote stem cell recruitment, retention, and subsequent osteogenic differentiation. Transcriptomic analysis as well as its in vitro and in vivo verification demonstrates that essential colony-stimulating factor-1 (CSF-1) factor is induced by this scaffold, and effectively bound to the target colony-stimulating factor-1 receptor (CSF-1R) on the macrophage surface to activate the M2 phenotype, achieving substantial endogenous bone regeneration. This strategy provides a simple and efficient approach for engineering inducible bone regenerative biomaterials.

Molecular co-assembled strategy tuning protein conformation for cartilage regeneration.

The assembly of oligopeptide and polypeptide molecules can reconstruct various ordered advanced structures through intermolecular interactions to achieve protein-like biofunction. Here, we develop a "molecular velcro"-inspired peptide and gelatin co-assembly strategy, in which amphiphilic supramolecular tripeptides are attached to the molecular chain of gelatin methacryloyl via intra-/intermolecular interactions. We perform molecular docking and dynamics simulations to demonstrate the feasibility of this strategy and reveal the advanced structural transition of the co-assembled hydrogel, which brings more ordered ß-sheet content and 10-fold or more compressive strength improvement. We conduct transcriptome analysis to reveal the role of co-assembled hydrogel in promoting cell proliferation and chondrogenic differentiation. Subcutaneous implantation evaluation confirms considerably reduced inflammatory responses and immunogenicity in comparison with type I collagen. We demonstrate that bone mesenchymal stem cells-laden co-assembled hydrogel can be stably fixed in rabbit knee joint defects by photocuring, which significantly facilitates hyaline cartilage regeneration after three months. This co-assembly strategy provides an approach for developing cartilage regenerative biomaterials.