The increasing prevalence and incidence urge efficient treatment of osteoarthritis (OA). In contrast, a single modality is hard to combat OA's complicated pathogenesis and achieve comprehensive chondroprotective function. Through RNA sequencing, we identified bone marrow mesenchymal stromal cell-derived exosomes (BMSC-Exo) and cartilage progenitor cell-derived exosomes (CPC-Exo) have distinct enrichment of miRNA contents, emphasizing macrophage and chondrocyte modulation, respectively. Thus, inspiring us to develop a bi-exosome combination strategy, which combines anti-inflammatory BMSC-Exo and anti-catabolic CPC-Exo, to alleviate osteoarthritis progression via simultaneous regulation of macrophage polarization and chondrocyte phenotype. Once delivered into the rat knee joint cavity by hyaluronic acid methacryloyl microspheres, the bi-exosome combination remarkably postponed OA progression via combating the joint inflammatory and catabolic environment, in which the dominant interventive pathways (i.e., miR-708-5p/NRP-1, miR-431/BRCA-1/PLK-1, and miR-7a-5p/NOTCH-3) were further revealed. This work presents the tailoring of exosome compositions to modulate multitargeting, thereby creating a potential for OA treatment.

Starch-based gels represent promising bioinks for 3D-printed cell scaffolds due to their biosafety, biocompatibility, and biodegradability. However, their widespread adoption has been hindered by inadequate formability and poor self-supporting properties. Here, we introduce an innovative starch-dominated hydrogel system achieved through dual methacrylation of normal corn starch and chitosan, enabling the fabrication of biodegradable cell scaffolds. While methacrylated starch alone (substitution degree: 0.013) exhibited insufficient printing accuracy even with UV assistance, the optimized 10:1 (starch/chitosan, w/w) blend of methacrylated chitosan (substitution degree: 0.27) demonstrated dramatically enhanced 3D printing formability and precision when combined with UV crosslinking. Rheological analysis demonstrated that blending methacrylated starch with methacrylated chitosan reduced flow stress (τf), improving printability while retaining shear-thinning behavior. Incorporation of 10 % glycerol enhanced biomacromolecular compatibility, as evidenced by rheological results and homogenous microstructures in SEM, enabling high-fidelity printing of intricate architectures. UV-cured scaffolds exhibited tunable compressive strength (150-200 kPa) and deformation rate (50-60 %), balancing mechanical compliance with tissue safety. The material's hydrophilic surface (contact angle: 30-60°) supported robust cell adhesion, while in vitro assays confirmed exceptional biocompatibility (96 % cell viability) and controlled biodegradation in α-amylase/lysozyme solutions. This work establishes starch as a primary matrix for bioinks, advancing sustainable, high-precision 3D printing in biomedicine.

ABSTRACT Objective: Tibial plateau fractures are common intra-articular fractures that pose classification and treatment challenges for orthopedic surgeons. Objective: This study examines the value of 3D printing for classifying and planning surgery for complex tibial plateau fractures. Methods: We reviewed 54 complex tibial plateau fractures treated at our hospital from January 2017 to January 2019. Patients underwent preoperative spiral CT scans, with DICOM data processed using Mimics software. 3D printing technology created accurate 1:1 scale models of the fractures. These models helped subdivide the fractures into seven types based on the tibial plateau's geometric planes. Surgical approaches and simulated operations, including fracture reduction and plate placement, were planned using these models. Results: The 3D models accurately depicted the direction and extent of fracture displacement and plateau collapse. They facilitated the preoperative planning, allowing for precise reconstruction strategies and matching intraoperative details with the pre-printed models. Post-surgery, the anatomical structure of the tibial plateau was significantly improved in all 54 cases. Conclusion: 3D printing effectively aids in the classification and preoperative planning of complex tibial plateau fractures, enhancing surgical outcomes and anatomical restoration. Level of Evidence IV, Prospective Study.

Microtubules are recognized as an appealing target for cancer treatment. We designed and synthesized of novel tubulin colchicine binding site inhibitors based on millepachine. Biological evaluation revealed compound 5h exhibited significant antiproliferative activity against osteosarcoma cell U2OS and MG-63. And compound 5h also remarkably inhibited tubulin polymerization. Further investigations indicated compound 5h not only arrest U2OS cells cycle at the G2/M phases, but also induced U2OS cells apoptosis in dose-dependent manners. Moreover, compound 5h was verified to inhibit cell migration and angiogenesis of HUVECs, induce mitochondrial membrane potential decreased and promoted the elevation of ROS levels. Furthermore, compound 5h exhibited remarkable effects on tumor growth in vivo, and the TGI rate was up to 84.94 % at a dose of 20 mg/kg without obvious toxicity. These results indicated that 5h may be an appealing tubulin inhibitor for treatment of osteosarcoma.

With the increasing incidence of osteoarthritis (OA) in elderly patients and the challenges posed by its multifaceted pathogenesis in developing effective treatments, this study explores the effective protein loading mode of Progranulin (PGRN) and its therapeutic potential for treating OA. GelMA hydrogels prepared with different concentrations of PGRN, employing AC-PEG-NHS as a crosslinking agent for drug encapsulation, were used to test the sustained release effect of the composite hydrogel drug delivery system. Additionally, we conducted in vitro assays to investigate the regulatory effects on rat bone marrow mesenchymal atromal cells (BMSCs), chondrocytes, and mouse macrophages - focusing on cell proliferation, and differentiation. For in vivo studies, histological staining techniques were utilized to assess inflammatory cell polarization and cartilage repair in a rat knee injury model. The results demonstrated that PGRN-loaded hydrogels significantly accelerated cell proliferation, enhance differentiation of BMSCs into chondrocytes, maintained a healthy chondrocyte phenotype, and induce M2-type polarization while inhibiting M1-type polarization in macrophages. Histological analyses also showed markedly improved tissue repair in the group treated with GelMA-NHS-PGRN hydrogels. As a result, these GelMA-NHS-PGRN hydrogels present a promising therapeutic approach for OA, potentially mitigating chronic inflammation and facilitating cartilage repair through controlled release of PGRN.Key worldPGRN, Osteoarthritis, Anti-inflammatory hydrogels, Cartilage regeneration.

目的 观察Cox迷宫Ⅳ手术联合二尖瓣成形术治疗心房颤动(AF)合并继发性二尖瓣关闭不全的临床疗效.方法 AF合并继发性二尖瓣关闭不全患者12例行Cox迷宫Ⅳ手术联合二尖瓣成形术治疗,观察术前和术后的超声心动图相关指标和临床指标.结果 本组12例患者手术顺利,无术后早期死亡.术后入ICU即刻心电图全部显示无AF发作,均顺利转入普通病房,AF转复10例.围术期所有患者血流动力学稳定,术后顺利出院.术后1周左心房内径、左心室舒张末期内径和左心室收缩末期内径分别为(45.8±6.1)mm、(51.6±3.6)mm和(34.9±2.7)mm,均低于术前的(55.6±6.5)mm、(54.6±4.9)mm 和(38.0±4.3)mm(P＜0.05).结论 Cox 迷宫 Ⅳ手术联合二尖瓣成形术治疗AF合并继发性二尖瓣关闭不全患者,能够降低围术期并发症,优化左心房及左心室的重构,提高患者窦性心律的转复和维持率,有效改善和提高患者预后生存质量.

Stem cell therapy using mesenchymal stem/stromal cells (MSCs) represents a novel approach to treating severe diseases, including osteoarthritis. However, the therapeutic benefit of MSCs is highly dependent on their differentiation state, which can be regulated by many factors. Herein, three-dimensional (3D) magnetic scaffolds were successfully fabricated by incorporating magnetic nanoparticles (MNPs) into electrospun gelatin nanofibers. When positioned near a rotating magnet (f= 0.5 Hz), the magnetic scaffolds with the embedded MSCs were driven upward/downward in the culture container, which induced mechanical stimulation to MSCs due to spatial confinement and fluid flow. The extracellular matrix-mimicking scaffold and the alternating magnetic field significantly enhanced chondrogenesis instead of osteogenesis. Furthermore, the fiber topography could be tuned with different compositions of the coating layer on MNPs, and the topography had a significant impact on MSC differentiation. Selective up-regulation of chondrogenesis-related genes (COL2A1andACAN) was found for the magnetic scaffolds with citric acid-coated MNPs (CAG). In contrast, osteogenesis-related genes (RUNX2andSPARC) were selectively and significantly up-regulated for the magnetic scaffolds with polyvinylpyrrolidone-coated MNPs. Prior to implantationin vivo, chondrogenic preconditioning of MSCs within the CAG scaffolds under a dynamic magnetic field resulted in superior osteochondral repair. Hence, the magnetic scaffolds together with an in-house rotating magnet device could be a novel platform to initiate multiple stimuli on stem cell differentiation for effective repair of osteochondral defects.

Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells. Little is known about the molecular mechanisms that regulate the output and maintenance of the cells that give rise to mature cartilage. Here we demonstrate that postnatal chondrocyte-specific deletion of a transcription factor Stat3 results in severely reduced proliferation coupled with increased hypertrophy, growth plate fusion, stunting and signs of progressive dysfunction of the articular cartilage. This effect is dimorphic, with females more strongly affected than males. Chondrocyte-specific deletion of the IL-6 family cytokine receptor gp130, which activates Stat3, phenocopied Stat3-deletion; deletion of Lifr, one of many co-receptors that signals through gp130, resulted in a milder phenotype. These data define a molecular circuit that regulates chondrogenic cell maintenance and output and reveals a pivotal positive function of IL-6 family cytokines in the skeletal system with direct implications for skeletal development and regeneration.

先天性心脏病是先天性畸形中最常见的一类,约占各种先天畸形的28％,是胚胎在发育时期由于心脏及大血管的形成障碍或发育异常而引起的解剖结构异常,或出生后应自动关闭的通道未能闭合的情形. 先天性心脏病发病率不容小视,在我国每年出生的婴儿中约占7‰～10‰,给家庭和社会带来巨大不幸和沉重负担.

Abstract Background Enhanced recovery after surgery (ERAS) protocols were rapidly adopted in many surgeries such as fast-track arthroplasty. The study aimed to investigate the impact of ERAS protocols on the clinical effect of total knee arthroplasty (TKA) via the midvastus approach. Methods A total of 69 patients who underwent primary unilateral TKA via the midvastus approach from October 2018 to June 2019 were enrolled and randomly divided into two groups: ERAS group and Control group. The ERAS protocols were adopted for the ERAS group and consisted of pure juice drinking 2 h before the surgery, optimization of the preoperative anesthesia plan, phased use of tourniquets, and the use of tranexamic acid as well as a drug cocktail. The operative time, first postoperative walking time, first straight leg elevation time, postoperative hospitalization time, visual analogue scale score (VAS score), Hospital for Special Surgery score (HSS score), conventional Knee Society score (KSS), and knee range of motion (ROM) were used to assess the clinical effects in the two groups. All the included patients were followed up for 12 months. Results There were no significant differences in the basic demographic information and operation time between the ERAS and Control groups (P > 0.05). The first postoperative walking time (2.11 ± 0.11 h) and first postoperative straight leg elevation time (6.14 ± 1.73 h) in the ERAS group were significantly earlier than those in the Control group (P < 0.001) and the postoperative hospitalization time was significantly shorter (3.11 ± 0.32 days). The postoperative mean VAS scores in both groups were significantly reduced compared with those before surgery (P < 0.001). The VAS scores for the ERAS group were significantly lower than those for the Control group at 1, 2, and 7 days after surgery (P < 0.001). The mean HSS scores, KSS, and knee ROM were significantly increased in both the ERAS and Control groups at 1, 3, 6, and 12 months after surgery (P < 0.001). In addition, the HSS scores, KSS, and knee ROM in the ERAS group were significantly higher than those in the Control group at 1 month after surgery (P < 0.001). Conclusions ERAS protocols improved the clinical effects of TKA via the midvastus approach, facilitating early out-of-bed activity and comfortable postoperative rehabilitation exercise, and further increasing patient satisfaction. Trial registration ClinicalTrials.gov Identifier: NCT04873544.

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.

3D-printed scaffolds have been developed as potential therapeutic strategies in bone tissue engineering. Mg/PCL biomaterials have been attracted much attention owing to biocompatibility, biodegradability as well as tunable mechanical properties. In this work, we developed 3D-printed customized Mg/PCL composite scaffolds with enhanced osteogenesis and biomineralization. Mg microparticles embedded in PCL-based scaffolds took a positive role in the improvement of biocompatibility, biomineralization, and biodegradable abilities. When incorporated with 3 wt% Mg, PCL-based scaffolds exhibited the optimal bone repairing ability in vitro and in vivo. The in vitro experiments indicated that 3 Mg/PCL scaffolds had improved mechanical properties, good biocompatibility, enhanced osteogenic and angiogenic activities. Besides, the in vivo studies demonstrated that Mg/PCL scaffolds promoted tissue ingrowth and new bone formation. In sum, these findings indicated that 3D-printed cell-free Mg/PCL scaffolds are promising strategies for bone healing application.

目的 探讨中度功能性二尖瓣反流(FMR)在重度主动脉瓣关闭不全患者中的处理原则及其近中期疗效.方法 分析2019年10月至2020年10月南京医科大学附属南京医院心胸血管外科16例重度主动脉瓣关闭不全合并中度功能性二尖瓣反流患者经手术治疗的临床资料.结果 所有术后患者围手术期无死亡,术后超声心动图示FMR程度与术前相比有所减轻,同时左心房内径(LAD)[(55.0±8.5)mm比(45.0±4.8)mm,P=0.01]、左心室舒张末期内径(LVEDD)[(68.0±11.9)mm比(57.0±9.8)mm,P=0.025]及左心室收缩末期内径(LVESD)[(51.0±12.3)mm比(43.0±9.5)mm,P=0.045]明显缩小,左心室射血分数(LVEF)较术前有所下降[(51.0±10.9)％比(50.0±9.4)％],但差异无统计学意义(P=0.259).术后3～6个月随访,所有患者无复发,无需再次手术,复查超声心动图与术前比较LAD(P=0.022)、LVEDD(P=0.006)、LVESD(P=0.043)呈进行性缩小,接近正常水平,EF较术前相比明显改善,有显著统计学差异(P=0.029),且FMR同步明显减轻.截至最后一次随访,5例二尖瓣无反流,7例微量反流,4例少量反流,手术成形效果满意.结论 重度主动脉瓣关闭不全合并中度的FMR建议积极行二尖瓣成形术处理,能够保留二尖瓣瓣膜的持久性和功能性,可获得较满意的近中期疗效.

Objective: To examine the clinical experience and outcomes of coronary artery bypass grafting (CABG) using radial artery as the second arterial graft. Methods: Totally 585 patients in whom both left internal thoracic artery and radial artery as arterial conduits were used in CABG in Department of Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University from April 2008 to August 2019 were consecutively enrolled. There were 436 males and 149 females, aging (63±10) years (range: 36 to 86 years). There were 40.7%(238/585) of patients had diabetes and 75.6%(442/585) of them had multivessel disease (two-vessel or three-vessel diseases). From January 2017, transit time flow measurement was performed on every patient. Demographic and perioperative data were retrospectively collected, as well as follow-up data for patients who underwent CABG from January 2014 to August 2019. Analysis were made on their early and late outcomes. Results: Most patients(81.9%(479/585)) in this cohort received on-pump CABG and 11 patients had intraoperative intro-aortic balloon counterpulsation (prior to CABG) support. Forty-three patients had concomitant valve procedures. The number of distal anastomosis was 3.6±0.9 (range: 2 to 6) and number of arterial distal anastomosis was 2.1±0.3(range:2 to 5). Radial artery was anastomosed to left obtuse marginal artery in 95.8%(560/585) patients. All target vessels for radial artery conduit had significant proximal stenosis (>70%) and 72.5%(424/585) patients' target vessels had proximal stenosis which was >90%. Intraoperative transit-time flow measurement of 151 cases showed that radial artery conduits had a flow of (29.8±10.2) ml/minutes (range: 10 to 150 ml/minutes), and a pulsatility index of 2.5±1.4 (range: 0.7 to 5.0). There was no operative death. Two in-hospital deaths occurred more than 30 days after index surgery. There was no perioperative myocardial infarction. There were 188 patients who received CABG from January 2014 to August 2019 followed-up for a median duration of 3.2 years. There were 2 noncardiac deaths. No patient had myocardial infarction or myocardial revascularization. Conclusions: Radial artery as the second arterial conduit is a safe and effective strategy for CABG. Good selection of target vessel and intraoperative transit-time flow measurement may help achieve good patency, as well as the short and mid-term outcome.

OBJECTIVE:Inhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease-modifying activity in OA.METHODS:Primary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy (PMM) model of knee OA in rats was used. A novel automated 3-dimensional indentation tester (Mach-1) was used to quantify the thickness and stiffness properties of the articular cartilage.RESULTS:Inhibition of HH signaling through KOR activation was achieved with a selective peptide agonist, JT09, which reduced HH signaling via the cAMP/CREB pathway in OA human articular chondrocytes (P = 0.002 for treated versus untreated OA chondrocytes). Moreover, JT09 markedly decreased matrix degeneration induced by an HH agonist, SAG, in pig articular chondrocytes and cartilage explants (P = 0.026 versus untreated controls). In vivo application of JT09 via intraarticular injection into the rat knee joint after PMM surgery significantly attenuated articular cartilage degeneration (60% improvement in the tibial plateau; P = 0.021 versus vehicle-treated controls). In JT09-treated rats, cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% (P = 0.005 versus vehicle-treated controls).CONCLUSION:The results of this study define a novel mechanism for the role of KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in disease processes and features involving opioid and HH signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with OA.

Inhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease-modifying activity in OA. Primary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy (PMM) model of knee OA in rats was used. A novel automated 3-dimensional indentation tester (Mach-1) was used to quantify the thickness and stiffness properties of the articular cartilage. Inhibition of HH signaling through KOR activation was achieved with a selective peptide agonist, JT09, which reduced HH signaling via the cAMP/CREB pathway in OA human articular chondrocytes ( P = 0.002 for treated versus untreated OA chondrocytes). Moreover, JT09 markedly decreased matrix degeneration induced by an HH agonist, SAG, in pig articular chondrocytes and cartilage explants ( P = 0.026 versus untreated controls). In vivo application of JT09 via intraarticular injection into the rat knee joint after PMM surgery significantly attenuated articular cartilage degeneration (60% improvement in the tibial plateau; P = 0.021 versus vehicle-treated controls). In JT09-treated rats, cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% ( P = 0.005 versus vehicle-treated controls). The results of this study define a novel mechanism for the role of KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in disease processes and features involving opioid and HH signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with OA.

The authors have withdrawn this preprint due to author disagreement.