Small extracellular vesicles from mesenchymal stromal cells: the next therapeutic paradigm for musculoskeletal disorders.

Musculoskeletal disorders are one of the biggest contributors to morbidity and place an enormous burden on the health care system in an aging population. Owing to their immunomodulatory and regenerative properties, mesenchymal stromal/stem cells (MSCs) have demonstrated therapeutic efficacy for treatment of a wide variety of conditions, including musculoskeletal disorders. Although MSCs were originally thought to differentiate and replace injured/diseased tissues, it is now accepted that MSCs mediate tissue repair through secretion of trophic factors, particularly extracellular vesicles (EVs). Endowed with a diverse cargo of bioactive lipids, proteins, nucleic acids and metabolites, MSC-EVs have been shown to elicit diverse cellular responses and interact with many cell types needed in tissue repair. The present review aims to summarize the latest advances in the use of native MSC-EVs for musculoskeletal regeneration, examine the cargo molecules and mechanisms underlying their therapeutic effects, and discuss the progress and challenges in their translation to the clinic.

A systematic review and meta-analysis on the incidence of osteoporosis and fractures after liver transplant.

Following liver transplant (LT), osteoporosis is a severe complication that causes morbidity. However, the incidence and risk factors of osteoporosis and fractures have not been well described. Single-arm meta-analysis of studies reporting osteopenia, osteoporosis, and fractures post-LT was performed with meta-regression for study period. Dichotomous variables, continuous variables and time-to-event variables were pooled in odds ratio, weighted mean difference and hazard ratio, respectively. For risk factors with limited data, a systematic review of literature was conducted. There was a significant increase in both osteoporosis and fractures compared to non-LT patients. Osteopenia, osteoporosis and incident fractures were newly diagnosed in 34.53% (CI: 0.17-0.56, n = 301), 11.68% (CI: 0.05-0.24, n = 1251) and 20.40% (CI: 0.13-0.30, n = 4322) of LT patients, respectively. Female gender (P = 0.017) increased risks of osteoporosis but not older age and BMI. Older age, lower pre-LT bone mineral density (BMD), presence of bone disease pre-LT were significant risk factors for fractures but not female gender, post-menopausal state, BMI, smoking and alcohol. There is a high incidence of skeletal complications post-LT. Older age, lower pre-LT BMD and presence of bone disease pre-LT are significant risk factors that are associated with incident fractures physicians should be cognisant of in liver transplant recipients.

Bisphosphonate therapy after liver transplant improves bone mineral density and reduces fracture rates: an updated systematic review and meta-analysis.

To investigate the efficacy of bisphosphonates and compare oral and IV formulations on bone mineral density (BMD) and fracture incidence in post-orthotopic liver transplant (OLT) patients. Electronic databases were searched, and six RCTs and three cohort studies were included out of 711 articles. Main outcomes included post-OLT BMD changes, fracture incidence, and treatment adverse reactions. Pairwise meta-analysis was conducted for binary and continuous outcomes, while pooled fracture incidence utilized single-arm meta-analysis. Post-OLT fracture incidence was reported in nine studies (n = 591). Total fracture incidence was 6.6% (CI: 3.4-12.4%) in bisphosphonate group and 19.1% (CI: 14.3-25.1%) in calcium and vitamin D group. Total fractures were significantly lower in patients on bisphosphonate, compared to calcium and vitamin D (n = 591; OR = 0.037; CI: 0.18-0.77; P = 0.008). Overall fractures were significantly lower in the oral group (n = 263; OR = 0.26; CI: 0.08-0.85; P = 0.02) but not in the IV group (n = 328; OR = 0.45; CI: 0.16-1.26; P = 0.129). Both oral and IV bisphosphonates are effective in reducing fracture incidence post-OLT compared to calcium and vitamin D. Oral formulations may also have an advantage over IV in reducing bone loss and fracture incidence post-OLT.

All-Cause Failure Rates Increase With Time Following Meniscal Repair Despite Favorable Outcomes: A Systematic Review and Meta-analysis.

PURPOSE: The purpose of this review is to perform a meta-analysis of studies reporting meniscus repair outcomes. Pooled analyses of such studies will provide an accurate estimate of the outcomes that can be expected following meniscal repair at various postoperative time points. METHODS: A meta-analysis of meniscal repair failure (defined as persistent symptoms, lack of healing on magnetic resonance imaging or revision surgery) and other clinical outcomes was performed following meniscal repair. Patients included had traumatic, nondegenerative meniscal tears, were skeletally mature, and had specific time-points after surgery. Repairs included were performed either in isolation, or with concomitant ACL reconstruction. Because of the inherent heterogeneity of single-arm meta-analyses, pooled analyses were performed using a random-effects model. RESULTS: Rates of all-cause meniscal repair failure was pooled to be 12% at 0-1 years (95% CI: .09-.16), 15% at 2-3 years (95% CI: .11-.20), and 19% at 4-6 years (95% CI: .13-.24). Sensitivity analysis for studies performing meniscal repair entirely on patients with concomitant ACL reconstruction (ACLR) showed comparable rates of failure at similar time intervals. Development of osteoarthritis, in patients with knees previously free from articular pathologies, was 4% at 2-3 years (95% CI: .02-.07), and 10% at 4-6 years (95% CI: .03-.25). CONCLUSION: Meniscus repair for traumatic injuries have an all-cause failure rate that increases from 12% to 19% through a time period ranging from 1-6 years following surgery. The failure rates were comparable for patients with meniscal repairs performed with concomitant ACLRs. LEVEL OF EVIDENCE: IV; Systematic Review of Level II-IV Studies.

Epidemiology of patients with anterior cruciate ligament injuries undergoing reconstruction surgery in a multi-ethnic Asian population.

We conducted an epidemiological study to identify the demographics and pre-operative characteristics of patients undergoing primary anterior cruciate ligament (ACL) reconstruction in a multi-ethnic Asian population. A retrospective study was performed on 696 patients who registered in our ACL reconstruction registry from January 2013 to August 2016. Important inter-ethnic differences were found. Indian patients were significantly older compared to Malay and Chinese patients. Malay and Indian patients were more likely to be male, overweight, and obese compared to Chinese patients. Soccer was the predominant sport involved, although ethnic predominance in specific sports exists. Novel findings from this study include increased prevalence of concomitant chondral injuries in the Chinese population compared to Malays and Indians, and significantly higher rates of concomitant intra-articular injuries in soccer and basketball compared to netball. Identification of these high-risk subgroups would serve useful in guiding the formulation of prevention strategies within our multi-ethnic community.

Intra-Articular Injections of Mesenchymal Stem Cell Exosomes and Hyaluronic Acid Improve Structural and Mechanical Properties of Repaired Cartilage in a Rabbit Model.

PURPOSE: To compare the efficacy of mesenchymal stem cell (MSC) exosomes with hyaluronic acid (HA) against HA alone for functional cartilage regeneration in a rabbit osteochondral defect model. METHODS: Critical-size osteochondral defects (4.5-mm diameter and 1.5-mm depth) were created on the trochlear grooves in the knees of 18 rabbits and were randomly allocated to 2 treatment groups: (1) exosomes and HA combination and (2) HA alone. Three 1-mL injections of either exosomes and HA or HA alone were administered intra-articularly immediately after surgery and thereafter at 7 and 14 days after surgery. At 6 and 12 weeks, gross evaluation, histologic and immunohistochemical analysis, and scoring were performed. The functional biomechanical competence of the repaired cartilage also was evaluated. RESULTS: Compared with defects treated with HA, defects treated with exosomes and HA showed significant improvements in macroscopic scores (P = .032; P = .001) and histologic scores (P = .005; P < .001) at 6 and 12 weeks, respectively. Defects treated with exosomes and HA also demonstrated improvements in mechanical properties compared with HA-treated defects, with significantly greater Young's moduli (P < .05) and stiffness (P < .05) at 6 and 12 weeks. By 12 weeks, the newly-repaired tissues in defects treated with exosomes and HA composed mainly of hyaline cartilage that are mechanically and structurally superior to that of HA-treated defects and demonstrated mechanical properties that approximated that of adjacent native cartilage (P > .05). In contrast, HA-treated defects showed some repair at 6 weeks, but this was not sustained, as evidenced by significant deterioration of histologic scores (P = .002) and a plateau in mechanical properties from 6 to 12 weeks. CONCLUSIONS: This study shows that the combination of MSC exosomes and HA administered at a clinically acceptable frequency of 3 intra-articular injections can promote sustained and functional cartilage repair in a rabbit post-traumatic cartilage defect model, when compared with HA alone. CLINICAL RELEVANCE: Human MSC exosomes and HA administered in combination promote functional cartilage repair and may represent a promising cell-free therapy for cartilage repair in patients.

Chemoprophylaxis in addition to mechanical prophylaxis after total knee arthroplasty surgery does not reduce the incidence of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) of the lower limbs is an important complication post total knee arthroplasty (TKA). Current guidelines recommend routine chemical prophylaxis to all patients undergoing this procedure but this is rarely done in Asia as it is believed that Asians have a lower risk of VTE. However, recent evidence suggests otherwise. AIMS: We evaluated the incidence of DVT after TKA in a multi-ethnic Asian population with and without pharmacological prophylaxis, as well as the management and outcome of patients with post-operative DVTs. METHODS: We conducted a retrospective study of consecutive patients who underwent TKA in our hospital from 1st January 2004 to 30th December 2014. All patients were on mechanical thromboprophylaxis via calf pumps after TKA with a postoperative day 3 to 5 doppler ultrasound (DUS) of bilateral lower limbs. 2258 (80.7%) patients did not receive additional chemoprophylaxis, while 540 (19.3%) received chemoprophylaxis on top of mechanical thromboprophylaxis. All patients who received chemoprophylaxis were administered the drug until they were ambulating, with a median administration duration of 6 days. Patients were followed up for a period of 3 months for recurrence of DVTs and 24 months for postoperative outcome scores. RESULTS: Two thousand nine hundred seventy-eight patients had DUS of the lower limbs with 134 diagnosed with DVT giving an incidence of 4.5%. Six of these patients had concurrent PEs. There were 26 (19.4%) proximal DVTs and 108 (80.6%) distal DVTs. After 3 months of follow up, no additional VTE occurred. None of the DVTs or PEs progressed.All DVTs with accompanying PE were proximal. 102 out of 2200 patients (4.6%) without chemoprophylaxis developed DVT as compared to 32 out of 540 patients (5.9%) with chemoprophylaxis, which was not statistically significant (p = 0.13). 19 (0.8%) proximal and 83 (3.8%) distal DVT developed in the patient group without chemoprophylaxis while 4 (0.7%) proximal and 28 (5.2%) distal DVT developed in the patient group with (p = 0.62). Comparison of the incidence of PEs between the two groups, revealed a similar incidence with 5 out of 2200 patients (0.2%) without chemoprophylaxis developing PE as compared to 1 out of 540 patients (0.2%) with chemoprophylaxis (p = 0.87).In addition, patients with chemoprophylaxis showed an association with higher post-operative outcome scores such as post op 6 months SF36 (PCS), post op 12 months SF36 (PCS), post op 12 months SF36 (MCS), post op 24 months SF36 (MCS) and post op 24 months WOMAC. CONCLUSION: In one of the largest Asian studies specifically investigating the incidence of DVT after TKA, we found that the incidence is low at 4.5%. This is in contrast to recent studies that showed higher post-operative VTE rates similar to Western populations. In addition, patients who were administered chemoprophylaxis did not have a statistically significant difference in incidence of VTE although it did show a correlation with higher post-operative outcome scores which may indicate better function. This was seen in functional outcome scores such as post op 6 months SF36 (PCS), post op 12 months SF36 (PCS), post op 12 months SF36 (MCS), post op 24 months SF36 (MCS) and post op 24 months WOMAC.

The presence of concomitant intra-articular injuries and bone bruise does not affect pre-operative knee pain and symptoms in patients undergoing anterior cruciate ligament reconstruction.

PURPOSE: Increased knee pain at the time of anterior cruciate ligament (ACL) reconstruction may predict increased pain post-operatively, a prolonged recovery and a more difficult rehabilitation. The main objective of our study was to identify preoperative factors, such as concomitant intra-articular injuries and bone bruises, that may be associated with increased knee pain and symptoms in patients undergoing ACL reconstruction. METHODS: Patient data was queried from our institution's prospectively maintained ACL reconstruction registry. Two-hundred and seventy patients who underwent primary ACL reconstruction within 3 months of injury were included in the study. Predictors such as demographic characteristics (age, body mass index and gender) and injury characteristics (mechanism of injury, meniscal injury, chondral injury and bone bruise) were recorded. The association between the pre-operative knee injury and Osteoarthritis Outcome Score (KOOS) pain and symptom subscales and the Short Form-36 (SF-36) bodily pain subscale, and the predictors were assessed using logistic regression for categorical variables and linear regression for continuous variables. RESULTS: The mean age of our patient group was 25.4 years with 211 out of 270 (78%) being males. Bone bruise was present in 243 patients (90%), meniscal injury in 165 (61%) patients and chondral injury in 40 (15%) patients. The presence of bone bruise, meniscal injury or chondral injury was not significantly associated with worse preoperative KOOS pain and symptom and SF-36 bodily pain scores. Other factors that were not associated were demographic characteristics (age, BMI and gender) and mechanism of injury. CONCLUSION: The presence of bone bruise and concomitant intra-articular injuries does not affect pre-operative knee pain and symptoms in patients undergoing ACL reconstruction within 3 months of injury. This knowledge would aid the surgeon in pre-operative counselling, and prognostication of post-operative pain and rehabilitation after ACL reconstruction.

Anterior cruciate ligament reconstruction performed within 12 months of the index injury is associated with a lower rate of medial meniscus tears.

PURPOSE: To verify the correlation of time to surgery with the prevalence of concomitant intra-articular injuries detected on arthroscopy during anterior cruciate ligament (ACL) reconstruction. METHODS: The medical records of 653 patients who underwent ACL reconstruction surgery were retrospectively analyzed. Univariate and multivariate logistic regression analysis was performed to identify factors that were associated with the presence of at least one intra-articular injury, medial meniscus tears, lateral meniscus tears and chondral injuries at the time of surgery. Further univariate analysis was conducted to determine the earliest time-point for surgery, after which the rate of concomitant injuries was significantly higher. RESULTS: Longer time to surgery (OR 1.019 95% CI 1.010, 1.028, p = 0.000), male sex (OR 1.695 95% CI 1.074, 2.675 p = 0.023), and higher BMI (OR 1.050 95% CI 1.006, 1.097 p = 0.025) were correlated with a higher prevalence of medial meniscus tears. There was an increased prevalence of medial meniscus tears when surgery was carried out more than 12 months after the index injury (OR 2.274 95% CI 1.469, 3.522, p = 0.000). The correlation between longer time to surgery and chondral injuries approached statistical significance (OR 1.006 95% CI 0.999, 1.012, p = 0.073). However, a longer time to surgery was not associated with an increased prevalence of lateral meniscus tears (OR 1.003 95% CI 0.998, 1.009, p = n.s.). CONCLUSIONS: Longer time to surgery is associated with an increased prevalence of medial meniscus tears in ACL reconstruction. Surgery performed within 12 months of the index injury reduces the prevalence of medial meniscus tears. Prioritizing males and overweight patients for counselling and early intervention can be considered. LEVEL OF EVIDENCE: Therapeutic level III retrospective cohort study.

Delayed lymphocele formation following lateral lumbar interbody fusion of the spine.

PURPOSE: This paper aims to describe the rare post-operative complication of a lymphocele formation after lateral lumbar interbody fusion. METHODS: The patient in this case was a 76-year-old lady with a 10 year history of low back pain and neurogenic claudication. She had previously underwent multiple spine surgeries for her condition. She presented to our institution for a recurrence of her low back pain and right anterior thigh pain. She then underwent surgery in two stages; first, a mini-open lateral interbody fusion at L3/4 and L4/5; second, posterior instrumentation of T3 to S1 with sagittal spinal deformity correction. RESULTS: The patient recovered uneventfully in the initial post op period and was discharged within 8 days. However, she developed abdominal distension and discomfort 6 months after surgery. MRI and CT scan of her abdomen showed a retroperitoneal fluid collection compressing her left ureter, resulting in hydroureter and hydronephrosis. She was managed with a CT-guided drainage of the fluid collection. Fluid analysis was consistent with a lymphocele. Since the procedure, the patient has been asymptomatic for 2 years. CONCLUSIONS: Delayed lymphocele formation is a potential complication of lateral lumbar interbody fusion. When present, it can be managed conservatively with good results. This case suggests that surgeons should have a low threshold to investigate for a lymphocele development post-anterior or lateral lumbar spine surgery. The authors recommend the placement of a post surgical retroperitoneal drain, as it might assist in the early detection of a lymphocele formation.

Impact of Centrifugation Parameters on Platelet-Rich Plasma Injection for Patella Tendinopathy: A Systematic Review and Meta-Analysis.

Patellar tendinopathy (PT) is a chronic, degenerative form of tendinitis commonly affecting young, active individuals. Numerous nonsurgical treatments exist, of which platelet-rich plasma (PRP) is a frontrunner. However, heterogeneity among various PRP preparation techniques results in a large variation in treatment efficacy. This review and meta-analysis aims to investigate the effect of PRP centrifugation factors, specifically centrifuge speed and duration, on functional outcomes in patients with PT. A systematic search of the literature was performed in April 2024 on Medline and Embase. Articles involving the use of PRP in the treatment of PT were included. The risk of bias was assessed using the Risk of Bias 2 (RoB 2; the Cochrane Collaboration, England, UK) and Risk of Bias in Non-randomised Studies of Intervention (ROBINS-I; the Cochrane Collaboration, England, UK) tools. Comparative meta-analysis between the different centrifugation speeds and the different centrifugation durations was performed on articles reporting Victorian Institute of Sports Assessment - Patellar tendon (VISA-P) and visual analogue scale (VAS) scores for PT. Seventeen studies consisting of 360 participants were included in the analysis. The mean follow-up duration was 13.2 months (95% CI: 8.81 to 17.7). The mean VAS reduction was 3.85 (95% CI: -4.63 to -3.08; P < 0.01). VISA-P scores improved by 32.03 (95% CI: 24.29 to 39.78; P < 0.01). There were no significant differences between centrifuge speeds for VAS (P = 0.17) and VISA-P (P = 0.18) and between centrifuge durations for VAS (P = 0.25) and VISA-P (P = 0.27). Centrifuge speed and duration and number of centrifuge cycles did not show any significant differences in patient outcomes. There were no significant differences observed in outcomes for the different preparations of PRP. There remains a need for further high-quality RCTs using standardized PRP preparations with long-term follow-up for the development of a consensus method of PRP preparation for the treatment of PT.

Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up.

PURPOSE: To analyze the results of the use of intra-articular cultured autologous bone marrow-derived mesenchymal stem cell (MSC) injections in conjunction with microfracture and medial opening-wedge high tibial osteotomy (HTO). METHODS: Fifty-six knees in 56 patients with unicompartmental osteoarthritic knees and genu varum were randomly allocated to the cell-recipient group (n = 28) or control group (n = 28). Patients who had a joint line congruity angle of more than 2°, malalignment of the knee from femoral causes, a fixed flexion deformity, or age older than 55 years were excluded. All patients underwent HTO and microfracture. The cell-recipient group received intra-articular injection of cultured MSCs with hyaluronic acid 3 weeks after surgery, whereas the control group only received hyaluronic acid. The primary outcome measure was the International Knee Documentation Committee (IKDC) score at intervals of 6 months, 1 year, and 2 years postoperatively. Secondary outcome measures were Tegner and Lysholm clinical scores and 1-year postoperative Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores. RESULTS: The median age of the patients was 51 years, with a mean body mass index of 23.85. Both treatment arms achieved improvements in Tegner, Lysholm, and IKDC scores. After adjustment for age, baseline scores, and time of evaluation, the cell-recipient group showed significantly better scores. The effect of treatment showed an added improvement of 7.65 (95% confidence interval [CI], 3.04 to 12.26; P = .001) for IKDC scores, 7.61 (95% CI, 1.44 to 13.79; P = .016) for Lysholm scores, and 0.64 (95% CI, 0.10 to 1.19; P = .021) for Tegner scores. Magnetic resonance imaging scans performed 1 year after surgical intervention showed significantly better MOCART scores for the cell-recipient group. The age-adjusted mean difference in MOCART score was 19.6 (95% CI, 10.5 to 28.6; P < .001). CONCLUSIONS: Intra-articular injection of cultured MSCs is effective in improving both short-term clinical and MOCART outcomes in patients undergoing HTO and microfracture for varus knees with cartilage defects. LEVEL OF EVIDENCE: Level II, randomized controlled trial.

Single-Stage Arthroscopic Cartilage Repair With Chondrectomy and Implantation of a Templated Membrane Collagen Scaffold With Bone Marrow Aspirate Concentrate Augmentation (AMIC Plus).

Single-staged cartilage repair techniques have shown great clinical efficacy in the treatment of articular cartilage defects of the knee, particularly when using bilayered acellular scaffolds augmented with bone marrow aspirate concentrate. We describe an all-arthroscopic approach to the single-staged cartilage repair procedure using a porcine-derived collagen I/III bilayered scaffold that is templated arthroscopically and augmented with bone marrow aspirate concentrate, in the treatment of critically sized articular defects of the knee.

Does the Choice of Acellular Scaffold and Augmentation With Bone Marrow Aspirate Concentrate Affect Short-term Outcomes in Cartilage Repair? A Systematic Review and Meta-analysis.

BACKGROUND: Matrix-induced chondrogenesis (MIC) is a promising treatment option for critical-size cartilage lesions of the knee; however, there exists substantial heterogeneity in the choice of acellular scaffold matrix for MIC cartilage repairs. HYPOTHESIS: The choice of acellular matrix will not affect patient outcomes after MIC cartilage repair procedures, and the addition of concentrated bone marrow aspirate (cBMA) will improve short-term patient outcomes regardless of matrix choice. STUDY DESIGN: Meta-analysis; Level of evidence, 4. METHODS: Studies were stratified by matrix type: multilayered, single layered, and gel based. Continuous outcomes were analyzed with pairwise meta-analysis using the inverse variance model with random effects applied. Binary outcomes were analyzed as pooled proportions in a single-arm fashion; after which, reconstruction of relative risks (RRs) with confidence intervals was performed using the Katz logarithmic method. RESULTS: A total of 876 patients were included: 469 received multilayered bioscaffolds; 238, gel-based scaffolds; and 169, single-layered scaffolds. The mean age of patients was 36.2 years (95% CI, 33.9 to 38.4), while the mean lesion size was 3.91 cm2 (95% CI, 3.40 to 4.42). The weighted mean follow-up was 23.8 months (95% CI, 20.1 to 27.6). Multilayered bioscaffolds were most effective at improving visual analog scale scores (P = .03; weighted mean difference [WMD], -4.44 [95% CI, -4.83 to -4.06]; P < .001). There were significantly lower risks of incomplete defect filling for gel-based scaffolds when compared with multilayered scaffolds (RR, 0.78 [95% CI, 0.69 to 0.88]; P < .001) and single-layered scaffolds (RR, 0.58 [95% CI, 0.41 to 0.81]; P = .001). Augmentation with cBMA further improved clinical scores across all scaffolds, with significant improvements in Tegner score (P = .02), while decreasing incomplete defect filling rates as well. There was significantly greater improvement in visual analog scale scores (P = .01) for single-layered scaffolds with cBMA augmentation (WMD, -4.88 [95% CI, -5.38 to -4.37]; P < .001) as compared with single-layered scaffolds without cBMA augmentation (WMD, -4.08 [95% CI, -4.46 to -3.71]; P < .001). All significant improvements were below their respective minimum clinically important differences. CONCLUSION: While cartilage repair with acellular scaffolds provides significant improvements in pain and function for patients, there is insufficient clinical evidence to suggest which scaffold material is the most superior in influencing such improvements. The enhancement of cartilage repair procedures with cBMA may provide further functional improvements and improve defect filling; however, more long-term evidence is required to evaluate the effects.

Biomaterials for meniscus and cartilage in knee surgery: state of the art.

Meniscus and cartilage injuries of the knee joint lead to cartilage degeneration and osteoarthritis (OA). The research on biomaterials and artificial implants as substitutes in reconstruction and regeneration has become a main international focus in order to solve clinical problems such as irreparable meniscus injury, postmeniscectomy syndrome, osteochondral lesions and generalised chronic OA. In this review, we provide a summary of biomaterials currently used in clinical practice as well as state-of-the-art tissue engineering strategies and technologies that are developed for articular cartilage and meniscus repair and regeneration. The literature was reviewed over the last 5 years on clinically used meniscus and cartilage repair biomaterials, such as Collagen Meniscal Implant, Actifit, NUsurface, TruFit, Agili-C and MaioRegen. There are clinical advantages for these biomaterials and the application of these treatment options should be considered individually. Standardised evaluation protocols are needed for biological and mechanical assessment and comparison between different scaffolds, and long-term randomised independent clinical trials with large study numbers are needed to provide more insight into the use of these biomaterials. Surgeons should become familiar and stay up to date with evolving repair options to improve their armamentarium for meniscal and cartilage defects.

Mesenchymal Stem Cell Exosomes Promote Growth Plate Repair and Reduce Limb-Length Discrepancy in Young Rats.

BACKGROUND: The objective of this study was to examine the therapeutic effects of human mesenchymal stromal/stem cell (MSC) exosomes in a rat model of growth plate injury. METHODS: A growth plate defect was surgically created on the distal part of the right femur of 40 female Sprague-Dawley rats. A single intra-articular injection of 100 µg of MSC exosomes in 100 µL of phosphate-buffered saline solution (PBS), or an equivalent volume of PBS alone, was administered to the right knee immediately after surgery. At 4 and 8 weeks post-treatment, limb length was measured with micro-CT, and tissue repair was assessed with histological, immunohistochemical, and histomorphometric analyses. RESULTS: A single injection of MSC exosomes significantly increased limb length from 3.29 ± 0.07 cm at 4 weeks to 3.37 ± 0.11 cm at 8 weeks (p = 0.047). However, no improvement in limb length was observed in the PBS control group. The limb-length discrepancy between the involved limb and the contralateral limb in the exosome-treated group was significantly less than the discrepancy in the PBS-treated group at both 4 weeks (2.52% ± 1.30% versus 4.11% ± 0.93%; p = 0.006) and 8 weeks (5.27% ± 2.11% versus 8.06% ± 2.56%; p = 0.016). Consistent with the reduced limb-length discrepancy, the exosome-treated defects displayed significantly more chondrocytes (p < 0.05) and a higher area percentage with deposition of sulphated glycosaminoglycan (p < 0.05) and collagen II (p < 0.05) than PBS-treated defects at 8 weeks. However, bone bridge formation was not inhibited in either group. CONCLUSIONS: A single intra-articular injection of MSC exosomes significantly enhanced physeal repair and reduced limb-length discrepancy but did not inhibit bone-bridge formation. CLINICAL RELEVANCE: This proof-of-concept study demonstrates for the first time the potential use of MSC exosomes as a minimally invasive cell-free therapeutic to promote physeal repair and reduce limb-length discrepancy following growth plate injuries.

Mesenchymal Stem Cell Exosomes Promote Functional Osteochondral Repair in a Clinically Relevant Porcine Model.

BACKGROUND: Previous studies have reported the efficacy of human mesenchymal stem cell (MSC) exosomes for the repair of osteochondral defects in rats and rabbits. However, the safety and efficacy of MSC exosomes remain to be validated in a clinically relevant large animal model. PURPOSE: To validate the safety and efficacy of human MSC exosomes for osteochondral repair in a clinically relevant micropig model. STUDY DESIGN: Controlled laboratory study. METHODS: Bilateral osteochondral defects (6-mm diameter and 1-mm depth) were surgically created in the medial femoral condyles in knees of 12 micropigs. The pigs then received 2-mL intra-articular injections of MSC exosomes and hyaluronic acid (HA) (Exosome+HA) or HA alone after surgery and thereafter at 8 and 15 days. Osteochondral repair was assessed by magnetic resonance imaging (MRI) at 15 days and at 2 and 4 months after surgery as well as by macroscopic, histological, biomechanical, and micro-computed tomography (micro-CT) analyses at 4 months after surgery. RESULTS: Exosome+HA-treated defects demonstrated significantly better MRI scores than HA-treated defects at 15 days and at 2 and 4 months. Additionally, Exosome+HA-treated defects demonstrated functional cartilage and subchondral bone repair, with significantly better macroscopic and histological scores and biomechanical properties (Young modulus and stiffness) than HA-treated defects at 4 months. Micro-CT further showed significantly higher bone volume and trabecular thickness in the subchondral bone of Exosome+HA-treated defects than that of HA-treated defects. Importantly, no adverse response or major systemic alteration was observed in any of the animals. CONCLUSION: This study shows that the combination of MSC exosomes and HA administered at a clinically acceptable frequency of 3 weekly intra-articular injections can promote functional cartilage and subchondral bone repair, with significantly improved morphological, histological, and biomechanical outcomes in a clinically relevant porcine model. CLINICAL RELEVANCE: Our findings provide a robust scientific rationale to support a phase 1/2 clinical trial to test MSC exosomes in patients with osteochondral lesions.

Securing Transplanted Meniscal Allografts Using Bone Plugs Results in Lower Risks of Graft Failure and Reoperations: A Meta-analysis.

BACKGROUND: Meniscal allograft transplant (MAT) is an important treatment option for young patients with deficient menisci; however, there is a lack of consensus on the optimal method of allograft fixation. HYPOTHESIS: The various methods of MAT fixation have measurable and significant differences in outcomes. STUDY DESIGN: Meta-analysis; Level of evidence, 4. METHODS: A single-arm meta-analysis of studies reporting graft failure, reoperations, and other clinical outcomes after MAT was performed. Studies were stratified by suture-only, bone plug, and bone bridge fixation methods. Proportionate rates of failure and reoperation for each fixation technique were pooled with a mixed-effects model, after which reconstruction of relative risks with confidence intervals was performed using the Katz logarithmic method. RESULTS: A total of 2604 patients underwent MAT. Weighted mean follow-up was 4.3 years (95% CI, 3.2-5.6 years). During this follow-up period, graft failure rates were 6.2% (95% CI, 3.2%-11.6%) for bone plug fixation, 6.9% (95% CI, 4.5%-10.3%) for suture-only fixation, and 9.3% (95% CI, 6.2%-13.9%) for bone bridge fixation. Transplanted menisci secured using bone plugs displayed a lower risk of failure compared with menisci secured via bone bridges (RR = 0.97; 95% CI, 0.94-0.99; P = .02). Risks of failure were not significantly different when comparing suture fixation to bone bridge (RR = 1.02; 95% CI, 0.99-1.06; P = .12) and bone plugs (RR = 0.99; 95% CI, 0.96-1.02; P = .64). Allografts secured using bone plugs were at a lower risk of requiring reoperations compared with those secured using sutures (RR = 0.91; 95% CI, 0.87-0.95; P < .001), whereas allografts secured using bone bridges had a higher risk of reoperation when compared with those secured using either sutures (RR = 1.28; 95% CI, 1.19-1.38; P < .001) or bone plugs (RR = 1.41; 95% CI, 1.32-1.51; P < .001). Improvements in Lysholm and International Knee Documentation Committee scores were comparable among the different groups. CONCLUSION: This meta-analysis demonstrates that bone plug fixation of transplanted meniscal allografts carries a lower risk of failure than the bone bridge method and has a lower risk of requiring subsequent operations than both suture-only and bone bridge methods of fixation. This suggests that the technique used in the fixation of a transplanted meniscal allograft is an important factor in the clinical outcomes of patients receiving MATs.

Radiographic Outcomes Following the Suture Fixation of Mid-pole Patellar Fractures.

Background Mid-pole patellar fractures are typically fixed with metal implants in the conventional "11-8" tension band construct. However, this technique is fraught with numerous implant-related complications. The aim of this study is to evaluate the union rate following "all-suture" fixation of mid-pole patellar fractures. Methods We retrospectively evaluated a consecutive case series of patients with displaced mid-pole patella fractures treated with "all-suture" fixation in our institution. Fifteen cases were available for this study. The average age was 61.5 years. Clinical and radiological outcomes were evaluated. Union time, complications, and revision rate were recorded. The minimum follow-up was one year. Results There were eight males and seven females, with a mean age of 61.5 ± 13.3 years. Fourteen out of 15 cases (93.3%) achieved radiographic union at 12 weeks postoperatively. The average time to radiographic union was 8.0 ± 2.7 weeks. Five cases (33.3%) had an increase in the fracture gap (>2 mm) at around four to six weeks postoperatively. Four of these cases had an eventual union, whereas one patient had fibrous non-union. There was one case of superficial surgical site infection and one case of infected hematoma. None of the patients required revision surgery. Conclusion "All-suture" fixation of mid-pole transverse patellar fractures is a safe and viable alternative to the conventional "11-8" tension band constructs with metal implants, with good union time, rates, and added benefits of not requiring additional surgery for implant removal.

Mesenchymal Stem Cell Exosomes for Cartilage Regeneration: A Systematic Review of Preclinical In Vivo Studies.

Clinical and animal studies have demonstrated efficacy of mesenchymal stem/stromal cells (MSCs) in cartilage repair. Although MSCs were originally predicated to mediate tissue repair through cellular differentiation and cell replacement, it is now recognized that MSCs exert most of their paracrine effects on tissue repair through the release of extracellular vesicles (EVs). In particular, 50-200 nm small EVs that also include exosomes carry a rich cargo of lipids, nucleic acids, and proteins, and have been reported to be therapeutically efficacious in various disease indications, including osteochondral injuries and osteoarthritis (OA). This systematic review aimed to assess the preclinical studies that used MSC exosomes for cartilage repair. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, PubMed and Cochrane Library databases were searched for relevant controlled preclinical animal studies. A total of 13 studies were identified, with the total sample size being 434. This included 378 (87.1%) mice or rats and 56 (12.9%) rabbits. According to Systematic Review Centre for Laboratory Animal Experimentation risk of bias assessment, all the studies presented with unclear-to-low risk in bias. In general, MSC exosomes were found to be efficacious in promoting repair and regeneration of osteochondral defects and alleviating OA degeneration. In most studies, exosome-treated animals displayed increased cellular proliferation, enhanced matrix deposition, and improved histological scores. Having assessed the relevant preclinical animal studies reported to date, this systematic review shows the therapeutic benefit of MSC exosome therapy in cartilage repair. Standardization of animal models and outcome measurements would be needed to facilitate more robust analysis and improve the validity of the results in future studies.