Application of smart hydrogel materials in cartilage injury repair: A systematic review and meta-analysis.

OBJECTIVE: Cartilage injury is a common clinical condition, and treatment approaches have evolved over time from traditional conservative and surgical methods to regenerative repair. In this context, hydrogels, as widely used biomaterials in the field of cartilage repair, have garnered significant attention. Particularly, responsive hydrogels (also known as "smart hydrogels") have shown immense potential due to their ability to respond to various physicochemical properties and environmental changes. This paper aims to review the latest research developments of hydrogels in cartilage repair, utilizing a more systematic and comprehensive meta-analysis approach to evaluate the research status and application value of responsive hydrogels. The goal is to determine whether these materials demonstrate favorable therapeutic effects for subsequent clinical applications, thereby offering improved treatment methods for patients with cartilage injuries. METHOD: This study employed a systematic literature search method to summarize the research progress of responsive hydrogels by retrieving literature on the subject and review studies. The search terms included "hydrogel" and "cartilage," covering data from database inception up to October 2023. The quality of the literature was independently evaluated using Review Manager v5.4 software. Quantifiable data was statistically analyzed using the R language. RESULTS: A total of 7 articles were retrieved for further meta-analysis. In the quality assessment, the studies demonstrated reliability and accuracy. The results of the meta-analysis indicated that responsive hydrogels exhibit unique advantages and effective therapeutic outcomes in the field of cartilage repair. Subgroup analysis revealed potential influences of factors such as different types of hydrogels and animal models on treatment effects. CONCLUSION: Responsive hydrogels show significant therapeutic effects and substantial application potential in the field of cartilage repair. This study provides strong scientific evidence for their further clinical applications and research, with the hope of promoting advancements in the treatment of cartilage injuries.

Advanced Therapeutic Medicinal Products in Bone and Cartilage Defects.

The number of patients with functional loss of bone and cartilage tissue has shown an increasing trend. Insufficient or inappropriate conventional treatments applied for trauma, orthopedic diseases, or other bone and cartilage-related disorders can lead to bone and cartilage damage. This represents a worldwide public health issue and a significant economic burden. Advanced therapeutic medicinal products (ATMPs) proposed promising alternative therapeutic modalities by application of cell-based and tissue engineering approaches. Recently, several ATMPs have been developed to promote bone and cartilage tissue regeneration. Fifteen ATMPs, two related to bone and 13 related to cartilage, have received regulatory approval and marketing authorization. However, four ATMPs were withdrawn from the market for various reasons. However, ATMPs that are still on the market have demonstrated positive results, their broad application faced limitations. The development and standardization of methodologies will be a major challenge in the coming decades. Currently, the number of ATMPs in clinical trials using mesenchymal stromal cells or chondrocytes indicates a growing recognition that current ATMPs can be improved. Research on bone and cartilage tissue regeneration continues to expand. Cell-based therapies are likely to be clinically supported by the new ATMPs, innovative fabrication processes, and enhanced surgical approaches. In this study, we highlighted the available ATMPs that have been used in bone and cartilage defects and discussed their advantages and disadvantages in clinical applications.

Investigation of the efficacy of epidermal growth factor, boric acid and their combination in cartilage injury in rats: An experimental study.

OBJECTIVES: In this study, we aimed to determine the bioefficacy of epidermal growth factor (EGF), boric acid (BA), and their combination on cartilage injury in rats. MATERIALS AND METHODS: In in vitro setting, the cytotoxic effects of BA, EGF, and their combinations using mouse fibroblast cell (L929), human bone osteosarcoma cell (Saos-2), and human adipose derived mesenchymal stem cells (hAD-MSCs) were determined by applying MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] test. In in vivo setting, 72 rats were randomly divided into four groups. A standard chondral defect was created and microfracture was performed in all groups. Group A was determined as the control group. In addition to the standard procedure, Group B received 100 ng/mL of EGF, Group C received a combination of 100 ng/mL of EGF and 10 µg/mL of BA combination, and Group D 20 µg/mL of BA. RESULTS: The cytotoxic effect of the combinations of EGF dilutions (1, 5, 10, 25, 50, 100, 200 ng/mL) with BA (100, 300, 500 µg/mL) was observed only in the 72-h application period and in Saos-2. The cytotoxic effect of BA was reduced when combined with EGF. There was no significant difference in the histopathological scores among the groups (p=0.13). CONCLUSION: Our study showed that EGF and low-dose BA application had a positive effect on cartilage healing in rats. Significant decreases in recovery scores were observed in the other groups. The combination of EGF and BA promoted osteoblast growth. Detection of lytic lesions in the group treated with 20 µg/mL of BA indicates that BA may have a cytotoxic effect.

HMGB1 can activate cartilage progenitor cells in response to cartilage injury through the CXCL12/CXCR4 pathway.

INTRODUCTION: Recent studies have suggested that cartilage progenitor cells (CPCs) could be activated and differentiated into chondrocytes to produce matrix and to restore the integrity of damaged cartilage after injury. However, the mechanism involved in CPC activation upon damage is still unclear. This study aims to investigate the role of high mobility group box chromosomal protein 1 (HMGB1) in both activation and migration of CPCs during cartilage injury. MATERIAL AND METHODS: Explants harvested from mature bovine stifle joints were used for impact injury. The proliferation and migration of CPCs were examined via confocal imaging. Gene and protein expression of Hmbg1, Cxcl12, and Cxcr4 was also examined by quantitative polymerase chain reaction (qPCR), ELISA, and western blot. Each experiment was repeated 3 times. ANOVA and Student's t-test were performed for statistical analysis. RESULTS: HMGB1 released from dead and damaged chondrocytes after an impact injury could activate CPCs in the superficial zone of cartilage and promote their migration and proliferation to injury sites. However, the block of HMGB1 activation with its specific binding inhibitor glycyrrhizin inhibits the proliferation and migration of CPCs. Further investigations demonstrate that HMGB1 promotes CPCs migration through the pathway of C-X-C motif chemokine 12 (CXCL12) and its receptor CXCR4. Quantitative analysis of HMGB1 in cell culture medium also indicates that CPCs may have a self-activation property after the HMGB1 released from dead cells has been exhausted. CONCLUSION: HMGB1 is a pivotal factor that could enhance the migration and proliferation of CPCs through the CXCL12/CXCR4 pathway after cartilage injury, which could provide useful information for cartilage repair and osteoarthritis treatment.

Polyacrylamide hydrogel lubricates cartilage after biochemical degradation and mechanical injury.

Intra-articular injections of hyaluronic acid have been a mainstay of osteoarthritis treatment for decades. However, controversy surrounds the mechanism of action and efficacy of this therapy. As such, there has been recent interest in developing synthetic lubricants that lubricate cartilage. Recently, a synthetic 4 wt% polyacrylamide (pAAm) hydrogel was shown to effectively decrease lameness in horses. However, its mechanism of action and ability to lubricate cartilage is unknown. The goal of this study was to characterize the lubricating ability of this hydrogel and determine its efficacy for healthy and degraded cartilage. The study utilized previously established IL-1ß-induced biochemical degradation and mechanical impact injury models to degrade cartilage. The lubricating ability of the hydrogel was then characterized using a custom-built tribometer using a glass counterface and friction was evaluated using the Stribeck framework for articular cartilage. pAAm hydrogel was shown to significantly lower the friction coefficient of cartilage explants from both degradation models (30%-40% reduction in friction relative to controls). A striking finding from this study was the aggregation of the pAAm hydrogel at the articulating surface. The surface aggregation was observed in the histological sections of explants from all treatment groups after tribological evaluation. Using the Stribeck framework, the hydrogel was mapped to higher Sommerfeld numbers and was characterized as a viscous lubricant predominantly in the minimum friction mode. In summary, this study revealed that pAAm hydrogel lubricates native and degraded cartilage explants effectively and may have an affinity for the articulating surface of the cartilage.

Vomiting-induced costal cartilage fracture: a case report.

The use of ultrasonography as a first line imaging test in cases of possible costal cartilage fracture can be pivotal. In this case report, we present the case of a patient with a suspected atraumatic vomiting-induced costal cartilage fracture. The costal cartilage fracture was non-displaced and incomplete, thus not visible in a Computed Tomography scan. When Ultrasound imaging was employed at the area of tenderness, soft tissue edema and hematoma around the cartilage were visualized. High level of suspicion for a cartilage fracture in this case revealed a subtle osseous injury.

A smart injectable composite hydrogel with magnetic navigation and controlled glutathione release for promoting in situ chondrocyte array and self-healing in damaged cartilage tissue.

Injectable cell-based hydrogels allow surgical operation in a minimally invasive way for articular cartilage lesions but the chondrocytes in the injectable hydrogels are difficultly arrayed and fixed at the site of interest to repair the cartilage tissue. In this study, an injectable hyaluronic acid-polyacrylic acid (HA-pAA) hydrogel was first synthesized using hyaluronic acid-cyclodextrin (HA-CD) and polyacrylic acid-ferrocene (pAA-Fc) to provide cell-delivery and self-healing. To promote the cell fixation and alignment, porous poly(lactic-co-glycolic acid) (PLGA) magnetic microcapsules (PPMMs) with glutathione (GSH) loaded and iron oxide nanoparticles (IO) located in the shell were designed. The GSH-loaded PPMMs with layer-by-layer (LbL) assembly of hyaluronic acid (HA) and GSH (LbL-PPMMs) can provide a two-stage rapid and slow release of GSH to modulate the self-healing of the HA-pAA hydrogel at the injured site. Furthermore, the chondrocytes embedded in the HA-pAA hydrogel could be delivered through CD44 receptors on the HA polymer chains of LbL-PPMMs toward the surface of the damaged site by an internal magnetic force. The composite hydrogel system of chondrocytes/LbL-PPMMs/HA-pAA can provide the damaged cartilage with a more even and smooth surface than other groups in a rabbit model after 8 weeks of implantation. In addition, the chondrocytes in the deep zone tissue exhibit a columnar array, similar to the cell arrangement in normal cartilage tissue. Together with the cell navigation behavior and GSH release from the LbL-PPMM/HA-pAA hydrogel, a full closure of lesions on the cartilage tissue can be achieved. Our results demonstrate the highly promising potential of the injectable LbL-PPMM/HA-pAA system in cartilage tissue repair.

Microarray analysis of hub genes and pathways in damaged cartilage tissues of knee.

ABSTRACT: The aim of this study was to identify genes and functional pathways associated with damaged cartilage tissues of knee using microarray analysis.The gene expression profile GSE129147 including including 10 knee cartilage tissues from damaged side and 10 knee nonweight-bearing healthy cartilage was downloaded and bioinformatics analysis was made.A total of 182 differentially-expressed genes including 123 up-regulated and 59 down-regulated genes were identified from the GSE129147 dataset. Gene ontology and pathway enrichment analysis confirmed that extracellular matrix organization, collagen catabolic process, antigen processing and presentation of peptide or polysaccharide antigen, and endocytic vesicle membrane were strongly associated with cartilage injury. Furthermore, 10 hub differentially-expressed genes with a higher connectivity degree in protein-protein interactions network were found such as POSTN, FBN1, LOX, insulin-like growth factor binding proteins3, C3AR1, MMP2, ITGAM, CDKN2A, COL1A1, COL5A1.These hub genes and pathways provide a new perspective for revealing the potential pathological mechanisms and therapy strategy of cartilage injury.

Chitosan oligosaccharides packaged into rat adipose mesenchymal stem cells-derived extracellular vesicles facilitating cartilage injury repair and alleviating osteoarthritis.

OBJECTIVES: This study aimed to investigate the roles of adipose mesenchymal stem cell (AMSC)-derived extracellular vesicles (EVs) binding with chitosan oligosaccharides (COS) in cartilage injury, as well as the related mechanisms. RESULTS: IL-1ß treatment significantly inhibited the viability and migration of chondrocytes and enhanced cell apoptosis (P < 0.05), while chitosan oligosaccharides and extracellular vesicles-chitosan oligosaccharide conjugates (EVs-COS/EVs-COS conjugates) reversed the changes induced by IL-1ß (P < 0.05), and the effects of extracellular vesicles-chitosan oligosaccharide conjugates were better than those of chitosan oligosaccharides (P < 0.05). After cartilage damage, IL-1ß, OPN, and p53 were significantly upregulated, COL1A1, COL2A1, OCN, RUNX2, p-Akt/Akt, PI3K, c-Myc, and Bcl2 were markedly downregulated, and extracellular vesicles-chitosan oligosaccharide conjugates reversed the expression induced by cartilage injury. Through sequencing, 760 differentially expressed genes (DEGs) clustered into four expression patterns were associated with negative regulation of the canonical Wnt, PI3K-Akt, AMPK, and MAPK signaling pathways. CONCLUSION: Extracellular vesicles-chitosan oligosaccharide conjugates may serve as a new cell-free biomaterial to facilitate cartilage injury repair and improve osteoarthritis.

Meniscus Repair Techniques.

The menisci play a vital role in maintaining knee function and protecting the chondral surfaces. Acute and chronic tears are common injuries among both young athletes and older patients with early degenerative changes. The progression of physiological derangement and chondral injury after meniscus injury and meniscectomy have prompted interest in expanding meniscus repair techniques. Recent literature encourages an attempt at repair in tear patterns previously declared irreparable if the tissue quality allows. The orthopedic surgeon should understand the multitude of techniques available to them and be prepared to combine techniques to optimize the quality of their repair construct. While biological augmentation may show some promising early results, the quality of the current data precludes strong recommendations in their favor.

Acute Cartilage Injury Induced by Trans-Articular Sutures.

OBJECTIVE: To determine the extent of acute cartilage injury by using trans-articular sutures. METHODS: Five different absorbable sutures, monofilament polydioxanone (PDS) and braided polyglactin (Vicryl), were compared on viable human osteochondral explants. An atraumatic needle with 30 cm of thread was advanced through the cartilage with the final thread left in the tissue. A representative 300 µm transversal slice from the cartilage midportion was stained with Live/Dead probes, scanned under the confocal laser microscope, and analyzed for the diameters of (a) central "Black zone" without any cells, representing in situ thread thickness and (b) "Green zone," including the closest Live cells, representing the maximum injury to the tissue. The exact diameters of suture needles and threads were separately measured under an optical microscope. RESULTS: The diameters of the Black (from 144 to 219 µm) and the Green zones (from 282 to 487 µm) varied between the different sutures (P < 0.001). The Green/Black zone ratio remained relatively constant (from 1.9 to 2.2; P = 0.767). A positive correlation between thread diameters and PDS suturing material, toward the Black and Green zone, was established, but needle diameters did not reveal any influence on the zones. CONCLUSIONS: The width of acute cartilage injury induced by the trans-articular sutures is about twice the thread thickness inside of the tissue. Less compressible monofilament PDS induced wider tissue injury in comparison to a softer braided Vicryl. Needle diameter did not correlate to the extent of acute cartilage injury.

WNT3A-loaded exosomes enable cartilage repair.

Cartilage defects repair poorly. Recent genetic studies suggest that WNT3a may contribute to cartilage regeneration, however the dense, avascular cartilage extracellular matrix limits its penetration and signalling to chondrocytes. Extracellular vesicles actively penetrate intact cartilage. This study investigates the effect of delivering WNT3a into large cartilage defects in vivo using exosomes as a delivery vehicle. Exosomes were purified by ultracentrifugation from conditioned medium of either L-cells overexpressing WNT3a or control un-transduced L-cells, and characterized by electron microscopy, nanoparticle tracking analysis and marker profiling. WNT3a loaded on exosomes was quantified by western blotting and functionally characterized in vitro using the SUPER8TOPFlash reporter assay and other established readouts including proliferation and proteoglycan content. In vivo pathway activation was assessed using TCF/Lef:H2B-GFP reporter mice. Wnt3a loaded exosomes were injected into the knees of mice, in which large osteochondral defects were surgically generated. The degree of repair was histologically scored after 8 weeks. WNT3a was successfully loaded on exosomes and resulted in activation of WNT signalling in vitro. In vivo, recombinant WNT3a failed to activate WNT signalling in cartilage, whereas a single administration of WNT3a loaded exosomes activated canonical WNT signalling for at least one week, and eight weeks later, improved the repair of osteochondral defects. WNT3a assembled on exosomes, is efficiently delivered into cartilage and contributes to the healing of osteochondral defects.

Importance of detection of capitellar cartilage injuries concomitant with isolated radial head fractures: A retrospective clinical study.

OBJECTIVE: This study aimed to analyze the injury pattern and clinical importance of concomitant capitellar cartilage defects (CCDs) among patients treated surgically for radial head fracture (RHF). METHODS: A total of 74 patients who were treated surgically for isolated RHFs were retrospectively reviewed. Of these, 12 patients with CCDs (16.2%) were classified as Group I (10 men; mean age, 41.3±12.8 years) and the remaining 62 patients without CCD as Group II (control group) (48 men; mean age, 50.8±13 years). The mean follow-up was 21.3±3.2 months in Group I and 18.7±6.4 in Group II. In Group I, 11 patients underwent open reduction and internal fixation, whereas 1 patient was treated by radial head resection. The preoperative range of motion (ROM) was recorded; the severity of RHF was assessed using the Mason classification. The location, size, and thickness of CCD injuries at the time of surgery were also documented. At the final follow-up, radiological assessment was performed to determine the bone union, and clinical measurements, including ROM and the Mayo elbow performance score (MEPS), were performed. The clinical features of the 2 groups were statistically analyzed. RESULTS: In Group I, 10 patients showed limited forearm rotation. CCD was located posterolaterally in 11 patients and anterolaterally in 1 patient. At the final follow-up, 11 patients from Group I who underwent open reduction and internal fixation showed complete union of RHF and full recovery of pronation and supination. According to the MEPS, 9 patients exhibited excellent results, and 3 patients exhibited good results. In Group I, RHFs were classified as Mason type II in 7 patients (58.3%) and type III in 4 patients (58.3%). In Group II, RHFs were type II in 45 patients (72.6%) and type III in 17 patients (27.4%). In comparative analyses, there was a significant difference in age (41.3±12.8 versus 50.8±13.0, p=0.041) between the 2 groups. Preoperative pronation/supination was higher in Group II (131.7±36.2) than in Group I (106.3±31.6) (p=0.021). There were no significant differences in sex (p=0.097), follow-up period (p=0.326), Mason type (p=0.482), preoperative extension/flexion (102.3±43.3 [Group I] versus 107.6±44.9 [Group II]) (p=0.584), final follow-up extension/flexion (133.3±10.7 [Group I] versus 126.9±21.2 [Group II]) (p=0.384), pronation/supination (151.2±9.1 [Group I] versus 151.2±13.3 [Group II]) (p=0.558), and the MEPSs (92.9±6.6 [Group I] versus 93.3±7.5 [Group II]) (p=0.701). CONCLUSION: If a thorough physical examination of a patient with RHF reveals limited forearm rotation, effort must be made to identify the cause, and the possibility of CCD must be considered. Moreover, there is a need for careful observation during RHF surgery for not only fracture reduction or fixation but also possible CCD. LEVEL OF EVIDENCE: Level III, Therapeutic Study.

Evidence-based Treatment of Failed Primary Osteochondral Lesions of the Talus: A Systematic Review on Clinical Outcomes of Bone Marrow Stimulation.

OBJECTIVE: The purpose of this study is to systematically review the literature and to evaluate the outcomes following bone marrow stimulation (BMS) for nonprimary osteochondral lesions of the talus (OLT). DESIGN: A literature search was performed to identify studies published using PubMed (MEDLINE), EMBASE, CDSR, DARE, and CENTRAL. The review was performed according to the PRISMA guidelines. Two authors separately and independently screened the search results and conducted the quality assessment using the Methodological Index for Non-Randomized Studies (MINORS). Studies were pooled on clinical, sports, work, and imaging outcomes, as well as revision rates and complications. The primary outcome was clinical success rate. RESULTS: Five studies with 70 patients were included in whom nonprimary OLTs were treated with secondary BMS. The pooled clinical success rate was 61% (95% confidence interval [CI], 50-72). The rate of return to any level of sport was 83% (95% CI, 70-91), while the return to pre-injury level of sport was 55% (95% CI, 34-74). The rate of return to work was 92% (95% CI, 78-97), and the complication rate was assessed to be 10% (95% CI, 4-22). Imaging outcomes were heterogeneous in outcome assessment, though a depressed subchondral bone plate was observed in 91% of the patients. The revision rate was 27% (95% CI, 18-40). CONCLUSIONS: The overall success rate of arthroscopic BMS for nonprimary osteochondral lesions of the talus was 61%, including a revision rate of 27%. Return to sports, work, and complication outcomes yielded fair to good results.

Cartilaginous endplate avulsion is associated with modic changes and endplate defects, and residual back and leg pain following lumbar discectomy.

OBJECTIVE: While cartilaginous endplate (CEP) avulsion is a common finding in discectomy due to lumbar disc herniation, its roles in residual back and leg pain, associations with Modic changes (MCs) and endplate defects (EPD) remain unknown. DESIGN: Patients with a single-level lumbar disc herniation who underwent endoscopic discectomy were studied. On MR images, the adjacent endplates of the herniated disc were assessed for MCs and EPD. The presence of CEP avulsion was examined under endoscopic and visualized inspection. Back and leg pain were evaluated by a numeric rating scale (NRS) and the Oswestry Disability Index. Associations of CEP avulsion with adjacent MCs, EPD, and residual back and leg pain were examined. In addition, histological features of avulsed CEP were determined using gross staining and immunohistochemical methods. RESULTS: A total of 386 patients were included. CEP avulsion was found in 166 (43%) patients, and adjacent MCs and EPD were observed in 117 (30.3%) and 139 (36%) patients. The presence of CEP avulsion was associated with greater age, adjacent MCs (OR = 2.60, 95%CI [1.61-4.19]) and EPD (OR = 1.63, 95%CI [1.03-2.57]). Among the 187 patients with ≥2 years follow-up, CEP avulsion was associated with residual back pain (OR = 2.49, 95%CI [1.29-4.82]) and leg pain (OR = 2.25, 95%CI [1.04-4.84]). Histologically, the avulsed CEP was characterized by multiple defects, apparent inflammation, and nucleus invasion, as well as the upregulation of IL-1ß, caspase-1, and NLRP3 inflammasome. CONCLUSION: CEP avulsion was associated with MCs, EPD, and residual back and leg pain after discectomy, which may be attributed to NLRP3 inflammasome related inflammations.

Prevalence of Vitamin D Insufficiency and Deficiency in Young, Female Patients With Lower Extremity Musculoskeletal Complaints.

BACKGROUND: Low levels of vitamin D have well-known impacts on bone health, but vitamin D also has a more global role throughout many tissues, including skeletal muscle. The high prevalence of hypovitaminosis D and the vast physiological features of vitamin D have led researchers to examine the influence of vitamin D on physical performance and injury. Because of the critical role of vitamin D in maintaining musculoskeletal health and function, a high rate of hypovitaminosis D among female patients with a variety of musculoskeletal issues could be of high clinical relevance. HYPOTHESIS: There is a high prevalence of low vitamin D in female patients with both acute and overuse sports-related issues of both soft tissue and bone. STUDY DESIGN: Prospective cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: Female patients, aged 16 to 40 years, presenting with lower extremity injury diagnosed within the past 4 weeks, no use of multivitamin or vitamin D supplement, and no history of malabsorption syndrome met the inclusion criteria. Vitamin D levels were assessed and categorized as normal (≥32 ng/mL) and low, which includes insufficient (20.01-31.9 ng/mL) and deficient (≤20 ng/mL). RESULTS: Of the 105 patients enrolled, 65.7% had low vitamin D. Within the low vitamin D cohort, 40.6% were deficient and 59.4% were insufficient. Injuries were grouped into overuse or acute with 74 overuse injuries and 31 acute injuries, exhibiting low vitamin D prevalence of 60.8% and 77.4%, respectively. Patients with ligamentous/cartilaginous injuries exhibited the highest percentage of low vitamin D (76.5%), followed by those with patellofemoral-related complaints (71.0%), muscle/tendon injuries (54.6%), and bone stress injuries (45.5%). In univariable analysis, older age, non-White race, less physical activity, less high-intensity interval training days, less endurance training days, and more rest days showed an association with low vitamin D, but none showed an independent association in multivariable analysis. CONCLUSION: The prevalence of low vitamin D in female patients with various musculoskeletal complaints was high. Clinicians should evaluate for low vitamin D in both acute and overuse injuries. CLINICAL RELEVANCE: In addition to screening, this study suggests that clinicians should evaluate for low vitamin D levels beyond bone stress injuries in the setting of acute and overuse injuries.

Rapamycin-Induced Autophagy Promotes the Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells in the Temporomandibular Joint in Response to IL-1ß.

Cartilage defects in temporomandibular disorders (TMD) lead to chronic pain and seldom heal. Synovium-derived mesenchymal stem cells (SMSCs) exhibit superior chondrogenesis and have become promising seed cells for cartilage tissue engineering. However, local inflammatory conditions that affect the repair of articular cartilage by SMSCs present a challenge, and the specific mechanism through which the function remains unclear. Thus, it is important to explore the chondrogenesis of SMSCs under inflammatory conditions of TMD such that they can be used more effectively in clinical treatment. In this study, we obtained SMSCs from TMD patients with severe cartilage injuries. In response to stimulation with IL-1ß, which is well known as one of the most prevalent cytokines in TMD, MMP13 expression increased, while that of SOX9, aggrecan, and collagen II decreased during chondrogenic differentiation. At the same time, IL-1ß upregulated the expression of mTOR and decreased the ratio of LC3-II/LC3-I and the formation of autophagosomes. Further study revealed that rapamycin pretreatment promoted the migration of SMSCs and the expression of chondrogenesis-related markers in the presence of IL-1ß by inducing autophagy. 3-Benzyl-5-((2-nitrophenoxy)methyl)-dihydrofuran-2(3H)-one (3BDO), a new activator of mTOR, inhibited autophagy and increased the expression of p-GSK3ßser9 and ß-catenin, simulating the effect of IL-1ß stimulation. Furthermore, rapamycin reduced the expression of mTOR, whereas the promotion of LC3-II/LC3-I was blocked by the GSK3ß inhibitor TWS119. Taken together, these results indicate that rapamycin enhances the chondrogenesis of SMSCs by inducing autophagy, and GSK3ß may be an important regulator in the process of rapamycin-induced autophagy. Thus, inducing autophagy may be a useful approach in the chondrogenic differentiation of SMSCs in the inflammatory microenvironment and may represent a novel TMD treatment.

Machine learning to predict mesenchymal stem cell efficacy for cartilage repair.

Inconsistent therapeutic efficacy of mesenchymal stem cells (MSCs) in regenerative medicine has been documented in many clinical trials. Precise prediction on the therapeutic outcome of a MSC therapy based on the patient's conditions would provide valuable references for clinicians to decide the treatment strategies. In this article, we performed a meta-analysis on MSC therapies for cartilage repair using machine learning. A small database was generated from published in vivo and clinical studies. The unique features of our neural network model in handling missing data and calculating prediction uncertainty enabled precise prediction of post-treatment cartilage repair scores with coefficient of determination of 0.637 ± 0.005. From this model, we identified defect area percentage, defect depth percentage, implantation cell number, body weight, tissue source, and the type of cartilage damage as critical properties that significant impact cartilage repair. A dosage of 17 - 25 million MSCs was found to achieve optimal cartilage repair. Further, critical thresholds at 6% and 64% of cartilage damage in area, and 22% and 56% in depth were predicted to significantly compromise on the efficacy of MSC therapy. This study, for the first time, demonstrated machine learning of patient-specific cartilage repair post MSC therapy. This approach can be applied to identify and investigate more critical properties involved in MSC-induced cartilage repair, and adapted for other clinical indications.

Mesenchymal stem cell-derived extracellular matrix (mECM): a bioactive and versatile scaffold for musculoskeletal tissue engineering.

Mesenchymal stem cell-derived extracellular matrix (mECM) has received increased attention in the fields of tissue engineering and scaffold-assisted regeneration. mECM exhibits many unique characteristics, such as robust bioactivity, biocompatibility, ease of use, and the potential for autologous tissue engineering. As the use of mECM has increased in musculoskeletal tissue engineering, it should be noted that mECM generated from current methods has inherited insufficiencies, such as low mechanical properties and lack of internal architecture. In this review, we first summarize the development and use of mECM as a scaffold for musculoskeletal tissue regeneration and highlight our current progress on moving this technology toward clinical application. Then we review recent methods to improve the properties of mECM that will overcome current weaknesses. Lastly, we propose future studies that will pave the road for mECM application in regenerating tissues in humans.