Nanomedicines Promote Cartilage Regeneration in Osteoarthritis by Synergistically Enhancing Chondrogenesis of Mesenchymal Stem Cells and Regulating Inflammatory Environment.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-ß1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.

Meniscus heterogeneity and 3D-printed strategies for engineering anisotropic meniscus.

The meniscus is a fibrocartilaginous tissue of the knee joint that plays an important role in load transmission, shock absorption, joint stability maintenance, and contact stress reduction. Mild meniscal injuries can be treated with simple sutures, whereas severe injuries inevitably require meniscectomy. Meniscectomy destroys the mechanical microenvironment of the knee joint, leading to cartilage degeneration and osteoarthritis. Tissue engineering techniques, as a strategy with diverse sources and customizable and adjustable mechanical and biological properties, have emerged as promising approaches for the treatment of meniscal injuries and are represented by 3D printing. Notably, the heterogeneity of the meniscus, including its anatomical structure, cell phenotype, extracellular matrix, and biomechanical properties, is crucial for its normal function. Therefore, the construction of heterogeneous tissue-engineered menisci (TEM) has become a research hotspot in this field. In this review, we systematically summarize the heterogeneity of menisci and 3D-printed strategies for tissue-engineered anisotropic menisci. The manufacturing techniques, biomaterial combinations, surface functionalization, growth factors, and bioreactors related to 3D-printed strategies are introduced and a promising direction for the future research is proposed.

Effect of Arthroscopically Confirmed Syndesmotic Widening on Outcome Following Isolated Broström Operation for Chronic Lateral Ankle Instability.

BACKGROUND: Tibiofibular syndesmosis (TFS) widening sometimes is not evident on radiography but can be found under arthroscopy in chronic lateral ankle instability (CLAI). This study aimed to evaluate the effect of TFS widening severity on clinical outcomes and return to activities after isolated Broström operation in CLAI patients and to propose an indication for its surgical intervention. METHODS: A total of 118 CLAI patients undergoing diagnostic ankle arthroscopy and open Broström-Gould operation were included. Based on the middle width of TFS measured under arthroscopy, patients were divided into the TFS-2 group (≤2 mm, n = 44), the TFS-3 group (2-4 mm, n = 42), and the TFS-4 group (≥4 mm, n = 32). The time to return to recreational sport and work, Tegner activity score, and proportion of returning to preinjury sports at the final follow-up were evaluated and compared. Other subjective evaluations included the American Orthopaedic Foot & Ankle Society score, visual analog scale, and Karlsson-Peterson score. RESULTS: Among the 3 groups, the TFS-4 group demonstrated the longest mean time to return to work and recreational sports, with the lowest proportion returning to preinjury sports. The TFS-4 group showed a significantly higher rate of sprain recurrence (12.5%) than the other 2 groups (P =.021). All the other subjective scores significantly improved after the operation without differences among the 3 groups. CONCLUSION: Concomitant severe syndesmotic widening adversely affects the return to activities after Broström operation in CLAI cases. The CLAI patients with a middle TFS width ≥4 mm were associated with delayed return to work and sports, a lower proportion of returning to preinjury sports, and more sprain recurrence, which might require further surgical intervention for syndesmosis in addition to Broström surgery. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis.

Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, and its progression is closely related to imbalances in the M1/M2 synovial macrophages. A two-pronged strategy for the regulation of intracellular/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in "two-in-one" nanocarriers (NAHA-CaP/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (≈90%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro-chondrogenic TGF-ß1 mRNA (≈1.3-fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti-inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid-induced early and late OA mouse models and a surgical destabilization of medial meniscus-induced OA rat model. Therefore, the siCA9 and NO scavenger "two-in-one" delivery system is a potential and efficient strategy for progressive OA treatment.

Anatomic reconstruction using the autologous gracilis tendon achieved less sprain recurrence than the Broström-Gould procedure but delayed recovery in chronic lateral ankle instability.

PURPOSE: To compare the return-to-activity and long-term clinical outcomes between anatomic lateral ligament reconstruction using the autologous gracilis tendon and modified Broström-Gould (MBG) procedure in chronic lateral ankle instability (CLAI). It was hypothesised that there was no difference between the two techniques. METHODS: From 2013 to 2018, 30 CLAI patients with grade III joint instability confirmed by anterior drawer test underwent anatomic reconstruction of lateral ankle ligament with the autologous gracilis tendon (reconstruction group) in our institute. Another 30 patients undergoing MBG procedure (MBG group) were matched in a 1:1 ratio based on demographic parameters. The post-operative American Orthopaedic Foot and Ankle Society (AOFAS) score, visual analogue scale (VAS) pain score, Tegner activity score, Karlsson-Peterson score, surgical complications, return-to-activities and work were retrospectively evaluated and compared between the two groups. RESULTS: All subjective scores significantly improved after the operation (all with p < 0.001) without difference between the two groups (all n.s.). The MBG group showed a significantly higher proportion of postoperative sprain recurrence than the reconstruction group (26.7% vs. 0, p = 0.002). The reconstruction group showed a significantly longer period to start walking with full weight-bearing (10.5 ± 6.9 vs. 7.0 ± 3.1 weeks, p = 0.015), jogging (17.1 ± 8.9 vs. 12.7 ± 6.9 weeks, p = 0.043) and return-to-work (13.5 ± 12.6 vs. 8.0 ± 4.7 weeks, p = 0.039) than the MBG group. CONCLUSIONS: Both anatomic reconstruction using the autologous gracilis tendon and MBG procedure could equally achieved reliable long-term clinical outcomes and the tendon reconstruction showed a relatively lower incidence of postoperative sprain recurrence but delayed recovery to walking, jogging and return-to-work. The MBG procedure was still the first choice with rapid recovery but the tendon reconstruction was recommended for patients with higher strength demand. LEVEL OF EVIDENCE: III.

Simultaneous Treatment of Osteochondral Lesion Does Not Affect the Mid- to Long-Term Outcomes of Ligament Repair for Acute Ankle Sprain: A Retrospective Comparative Study with a 3-11-Year Follow-up.

Purpose: This study aims to evaluate the mid- to long-term outcome of concurrent arthroscopic treatment of osteochondral lesion (OCL) and open anatomical repair of lateral ankle ligaments for severe acute ankle sprain patients and compare them to the outcome of those without OCL. Methods: A total of 166 patients with grade III acute lateral ankle ligament injuries underwent concurrent ankle arthroscopy and open anatomic ligament repair. Forty-three patients (group A) with OCL underwent arthroscopic treatment followed by open ligament repair. A total of 105 patients (group B) without OCL were followed up as the control. The evaluation parameters included sports recovery, postoperative visual analog scale (VAS) pain score, American Orthopaedic Foot and Ankle Society (AOFAS) score, Tegner score, sprain recurrence, satisfaction, and range of motion. Patients in group A were then subgroup-analyzed according to age, sex, body mass index, injury side, OCL location, and stage (Ferkel and Cheng's staging system). Results: The postoperative exercise level of the two groups recovered to more than 90% of the normal level (91.2% ± 11.2% in group A and 90.9% ± 13.3% in group B, n.s.). The average time of group A and group B to return to preinjury sports activity was respectively 4.4 ± 1.0 months and 4.4 ± 1.2 months with no significant difference (p = 0.716). No significant differences were found in the preoperation VAS pain score, AOFAS score, and Tegner score between the two groups. The postoperative VAS pain score in group A was significantly higher than that in group B (0.8 ± 1.7 vs. 0.3 ± 0.8, p = 0.027), but the difference was not clinically important. The postoperative VAS pain score of patients with stage D-F lesions was significantly higher than that of patients with stage B-C lesions (1.3 ± 2.1 vs. 0.3 ± 0.9, p = 0.038). Conclusions: For the severe acute ankle sprain combined with OCL, the simultaneous arthroscopic treatment and open lateral ankle ligament repair achieved good mid- to long-term outcomes. Except that the pain was more pronounced than in the control group, there were no differences in other outcomes. Postoperative pain was positively correlated with the grade of OCL.

Advances in the Application of Three-dimensional Printing for the Clinical Treatment of Osteoarticular Defects.

As a promising manufacturing technology, three-dimensional (3D) printing technology is widely used in the medical field. In the treatment of osteoarticular defects, the emergence of 3D printing technology provides a new option for the reconstruction of functional articular surfaces. At present, 3D printing technology has been used in clinical applications such as models, patient-specific instruments (PSIs), and customized implants to treat joint defects caused by trauma, sports injury, and tumors. This review summarizes the application status of 3D printing technology in the treatment of osteoarticular defects and discusses its advantages, disadvantages, and possible future research strategies.

Integrated Analysis of lncRNA and mRNA Expression Profiles Indicates Age-Related Changes in Meniscus.

Little has been known about the role of long non-coding RNA (lncRNA) involves in change of aged meniscus. Microarray analyses were performed to identify lncRNAs and mRNAs expression profiles of meniscus in young and aging adults and apple bioinformatics methods to analyse their potential roles. The differentially expressed (DE) lncRNAs and mRNAs were confirmed by qRT-PCR. A total of 1608 DE lncRNAs and 1809 DE mRNAs were identified. Functional and pathway enrichment analyses of all DE mRNAs showed that DE mRNAs were mainly involved in the TGF-beta, Wnt, Hippo, PI3K-Akt signaling pathway. The expressions of TNFRSF11B and BMP2 were significantly upregulated in aging group. LASSO logistic regression analysis of the DE lncRNAs revealed four lncRNAs (AC124312.5, HCG11, POC1B-AS1, and AP001011.1) that were associated with meniscus degradation. CNC analysis demonstrated that AP001011 inhibited the expression of TNFRSF11B and AC1243125 upregulated the expression of TNFRSF11B. CeRNA analysis suggested that POC1B-AS1 regulates the expression of BMP2 by sponging miR 130a-3p, miR136-5p, miR 18a-3p, and miR 608. Furthermore, subcellular localization and m6A modification sites prediction analysis of these four lncRNAs was performed. These data lay a foundation for extensive studies on the role of lncRNAs in change of aged meniscus.

MicroRNA-210-3p Promotes Chondrogenic Differentiation and Inhibits Adipogenic Differentiation Correlated with HIF-3α Signalling in Bone Marrow Mesenchymal Stem Cells.

Cartilage injury of the knee joint is very common. Due to the limited self-healing ability of articular cartilage, osteoarthritis is very likely to occur if left untreated. Bone marrow mesenchymal stem cells (BMMSCs) are widely used in the study of cartilage injury due to their low immunity and good amplification ability, but they still have disadvantages, such as heterogeneous undifferentiated cells. MicroRNAs can regulate the chondrogenic differentiation ability of MSCs by inhibiting or promoting mRNA translation and degradation. In this research, we primarily investigated the effect of microRNA-210-3p (miR-210-3p) on chondrogenic and adipogenic differentiation of BMMSCs in vitro. Our results demonstrate that miR-210-3p promoted chondrogenic differentiation and inhibited adipogenic differentiation of rat BMMSCs, which was related to the HIF-3α signalling pathway. Additionally, miR-210-3p promotes mRNA and protein levels of the chondrogenic expression genes COLII and SOX9 and inhibits mRNA and protein levels of the adipogenic expression genes PPARγ and LPL. Thus, miR-210-3p combined with BMMSCs is a candidate for future clinical applications in cartilage regeneration and could represent a promising new therapeutic target for OA.

microRNA-141-3p fosters the growth, invasion, and tumorigenesis of cervical cancer cells by targeting FOXA2.

microRNA (miR)-141-3p has context-dependent effects on tumor progression. In this study, we attempted to explore the expression and function of miR-141-3p in cervical cancer. We found that miR-141-3p expression was significantly increased in cervical cancer specimens relative to normal cervical tissues. Moreover, miR-141-3p levels were associated with tumor size and lymph node metastasis status. Ectopic expression of miR-141-3p significantly increased cervical cancer cell proliferation, colony formation, invasion, and epithelial to mesenchymal transition, whereas depletion of miR-141-3p suppressed cervical cancer cell proliferation and invasion. FOXA2 was identified to be a target of miR-141-3p. Overexpression of miR-141-3p led to a marked inhibition of endogenous FOXA2 in cervical cancer cells. FOXA2 silencing phenocopied the effects of miR-141-3p overexpression on cervical cancer cell proliferation and invasion. Enforced expression of FOXA2 blocked the effects of miR-141-3p on cervical cancer cell proliferation and invasion. miR-141-3p overexpression significantly accelerated the growth of xenograft tumors, which was accompanied by a striking reduction in FOXA2 expression. miR-141-3p acts as an oncogene in cervical cancer largely through repression of FOXA2. Targeting miR-141-3p may represent a potential therapeutic strategy for cervical cancer.