Are leukocyte-poor or multiple injections of platelet-rich plasma more effective than hyaluronic acid for knee osteoarthritis? A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Platelet-rich plasma (PRP) has gained popularity as a treatment option for knee osteoarthritis; however, its efficacy remains controversial. The optimal leukocyte concentration and number of injections have not been well investigated. This study was, therefore, designed to provide clinical evidence on the leukocyte concentration and number of intra-articular injections of PRP via a meta-analysis of randomized controlled trials (RCTs). METHODS: The MEDLINE, Embase, Cochrane Library, CINAHL, and Scopus databases were searched and RCTs comparing PRP and hyaluronic acid (HA) for treating knee osteoarthritis were included. Clinical outcomes, including visual analog scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and adverse reactions, were evaluated. RESULTS: A total of 138 studies were screened, of which 21 level 1 RCTs (2086 knees; 1077 PRP and 1009 HA) were included. PRPs showed significant improvement in pain according to the VAS score compared to HA at 6 and 12 months, regardless of leukocyte concentration. Both single and multiple injections of PRP improved pain better than HA at 12 months. Regarding function, both single and multiple injections of leukocyte-poor PRP and leukocyte-rich PRP led to significantly better improvement in total WOMAC score compared with HA at 6 months. There was no significant difference in procedure-related knee pain or swelling between the PRP and HA groups. Leukocyte-rich PRP had a significantly higher odds ratio for procedure-related knee pain or swelling compared to HA (odds ratio, 3.3 [95% confidence interval, 1.1-10.2], P = .037). CONCLUSION: Based on evidence from Level 1 studies, intra-articular injection of PRP improves pain and function in patients with knee osteoarthritis for up to 12 months and is superior to HA, regardless of leukocyte concentration or number of injections. The findings of this study support the routine clinical use of intra-articular injections of PRP for the treatment of knee osteoarthritis, regardless of the type and frequency of PRP injection. LEVEL OF EVIDENCE: Meta-analysis of level I studies.

Cost Effectiveness of Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Patients with Knee Osteoarthritis.

OBJECTIVES: The aim of this study was to assess the cost effectiveness of allogeneic umbilical cord blood-derived mesenchymal stem cells with sodium hyaluronate (hUCB-MSC) compared with microfracture in patients with knee cartilage defects caused by osteoarthritis (OA) in South Korea. METHODS: A partitioned survival model approach was taken consisting of five mutually exclusive health states: excellent, good, fair, poor, and death over a 20-year time horizon. Utility values were obtained from a randomized clinical trial. Cost data were extracted from a database provided by the Health Insurance Review & Assessment Service, and the utilization of healthcare services was estimated from an expert panel of orthopedic surgeons using a structured questionnaire. The incremental cost-effectiveness ratio (ICER) in terms of quality-adjusted life-years (QALY) was calculated. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: In the base case, the incremental costs of US$14,410 for hUCB-MSC therapy along with its associated QALY gain of 0.857 resulted in an ICER of US$16,812 (₩18,790,773) per QALY (95% confidence interval [CI] US$13,408-US$20,828) when compared with microfracture treatment from a healthcare payer perspective. From a societal perspective, the ICER was US$268 (₩299,255) per QALY (95% CI -US$2915 to US$3784). When using a willingness-to-pay threshold of US$22,367/QALY, the probability of hUCB being cost effectiveness compared with microfracture was 99% from the healthcare payer perspective and 100% from the societal perspective. CONCLUSIONS: The study demonstrated that hUCB-MSC therapy was cost effective compared with microfracture when treating patients with knee OA. These findings should inform health policy decision makers about considerations for cost-effective therapy for treating knee OA to ultimately enhance population health.

Is it worth to perform initial non-operative treatment for patients with acute ACL injury?: a prospective cohort prognostic study.

PURPOSE: To evaluate the result of implementing an initial non-operative treatment program for an acute ACL injury and to find if the timing of initiating the non-operative treatment is significant. METHODS: This study included a prospective cohort of 85 consecutive patients with acute ACL injury who were treated according to the above strategy for the initial 3 months with 1-year follow-up. Clinical evaluations were made by Lysholm score, Tegner activity score, Lachman test (LT), pivot-shit test (PST), and the side to side difference (SSD) by KT-2000 arthrometer. The results were analyzed according to the timing of initiating the non-operative treatment. RESULTS: Initially, 84% of the patients showed LT and PST ≤ grade 1, and 16% with ≥grade 2. At 1-year follow-up, 77 patients (91%) with LT and PST ≤ grade 1 did not receive reconstruction as copers and 8 patients with LT or PST ≥ grade 2 required reconstruction (six patients received the operation and two refused). The patients with LT and PST ≤ grade 1 showed average Lysholm score 91.2, average SSD 2.5 mm, and mean Tegner score decreased from 6.9 (pre-injury) to 6.2. Patients who started the non-operative treatment within 2 weeks after injury revealed superior rates of grade 0 or 1 instability than those who commenced the treatment later than 2 weeks after injury (P = 0.043). CONCLUSIONS: Implementing a non-operative treatment with brace in acute phase of ACL injury appears to be an effective and viable option to achieve a reasonable clinical outcome. We recommend earlier initiation of the non-operative treatment to obtain a better result in patients with acute ACL injury.

Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cell Implantation Versus Microfracture for Large, Full-Thickness Cartilage Defects in Older Patients: A Multicenter Randomized Clinical Trial and Extended 5-Year Clinical Follow-up.

BACKGROUND: There is currently no optimal method for cartilage restoration in large, full-thickness cartilage defects in older patients. PURPOSE: To determine whether implantation of a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and 4% hyaluronate (UCB-MSC-HA) will result in reliable cartilage restoration in patients with large, full-thickness cartilage defects and whether any clinical improvements can be maintained up to 5 years postoperatively. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A randomized controlled phase 3 clinical trial was conducted for 48 weeks, and the participants then underwent extended 5-year observational follow-up. Enrolled were patients with large, full-thickness cartilage defects (International Cartilage Repair Society [ICRS] grade 4) in a single compartment of the knee joint, as confirmed by arthroscopy. The defect was treated either with UCB-MSC-HA implantation through mini-arthrotomy or with microfracture. The primary outcome was proportion of participants who improved by ≥1 grade on the ICRS Macroscopic Cartilage Repair Assessment (blinded evaluation) at 48-week arthroscopy. Secondary outcomes included histologic assessment; changes in pain visual analog scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) score from baseline; and adverse events. RESULTS: Among 114 randomized participants (mean age, 55.9 years; 67% female; body mass index, 26.2 kg/m2), 89 completed the phase 3 clinical trial and 73 were enrolled in the 5-year follow-up study. The mean defect size was 4.9 cm2 in the UCB-MSC-HA group and 4.0 cm2 in the microfracture group (P = .051). At 48 weeks, improvement by ≥1 ICRS grade was seen in 97.7% of the UCB-MSC-HA group versus 71.7% of the microfracture group (P = .001); the overall histologic assessment score was also superior in the UCB-MSC-HA group (P = .036). Improvement in VAS pain, WOMAC, and IKDC scores were not significantly different between the groups at 48 weeks, however the clinical results were significantly better in the UCB-MSC-HA group at 3- to 5-year follow-up (P < .05). There were no differences between the groups in adverse events. CONCLUSION: In older patients with symptomatic, large, full-thickness cartilage defects with or without osteoarthritis, UCB-MSC-HA implantation resulted in improved cartilage grade at second-look arthroscopy and provided more improvement in pain and function up to 5 years compared with microfracture. REGISTRATION: NCT01041001, NCT01626677 (ClinicalTrials.gov identifier).

A predictive model with radiographic signs can be a useful supplementary diagnostic tool for complete discoid lateral meniscus in adults.

PURPOSE: To investigate the diagnostic accuracy of radiographic signs for complete discoid lateral meniscus and whether a predictive model combining the radiographic signs can improve its diagnostic accuracy in adults. METHODS: A total of adult 119 knees with complete discoid lateral meniscus confirmed by arthroscopy and 119 age- and sex-matched knees with normal meniscus were included. The radiographic signs of lateral joint space, fibular head height, lateral tibial spine height, lateral tibial plateau obliquity, lateral femoral condyle squaring, lateral tibial plateau cupping, lateral femoral condyle notching, and the condylar cut-off sign were evaluated. The receiver-operating characteristic (ROC) curves and area under the curve (AUC) were evaluated for best accuracy. A prediction model was developed by multivariable regression with generalized estimating models, and was validated using data from 111 knees of children with complete discoid lateral meniscus and 111 normal controls. RESULTS: The fibular head height, lateral joint space, lateral tibial plateau obliquity, and the condylar cut-off sign were significantly different between the complete discoid lateral meniscus and the normal groups (p < 0.05). Among the four radiographic signs, the fibular head height showed the highest accuracy with 78.9% sensitivity and 57.3% specificity. The prediction models developed by logistic regression showed significantly improved accuracy for complete discoid lateral meniscus compared to the fibular head height (sensitivity: 69.8%, specificity: 82.9%, p = 0.001). For validation, the AUC of children seemed to be larger than that of adults, which indicated that the prediction models could be applied for children to detect complete discoid lateral meniscus. CONCLUSION: Among several radiographic signs, the fibular head height can be used as a screening tool for complete discoid lateral meniscus. The prediction models combined with lateral joint space, fibular head height, lateral tibial plateau obliquity, and/or the condylar cut-off sign yielded a much higher diagnostic value than each radiographic sign. Therefore, fibular head height and prediction models combined with radiographic signs can provide improved diagnostic value for complete discoid lateral meniscus. LEVEL OF EVIDENCE: III.

Underestimation and undertreatment of osteoporosis in patients awaiting primary total knee arthroplasty.

INTRODUCTION: Osteoporosis is generally regarded as a risk factor for periprosthetic fracture during or after primary total knee arthroplasty (TKA). Despite this, little is known about osteoporosis in patients undergoing elective primary TKA Therefore, we sought to investigate the prevalence of osteoporosis and rates of pharmacologic osteoporosis treatment prior to primary TKA. We hypothesized that preoperative osteoporosis is underestimated and undertreated in the primary TKA population. MATERIALS AND METHODS: This retrospective study included consecutive 1972 patients scheduled for elective primary TKA at a single tertiary hospital (age, 50-89 years). Charts were reviewed for patient demographics, prior pharmacologic osteoporosis treatment and Knee Society (KS) scoring system and WOMAC score. Dual energy X-ray absorptiometry (DEXA) measurement of the lumbar vertebrae and proximal femur was performed in all patients on the day before surgery. The associations of BMD with age, sex, body mass index (BMI), and clinical outcome were analyzed. RESULTS: The prevalence of osteoporosis was 50.0% (53.4% in women and 7.0% in men). Among patients with osteoporosis, only 15.1% (149/986) of patients (15.0% in women and 30.0% in men) had pharmacological osteoporosis treatment prior to primary TKA. Age, sex and WOMAC stiffness showed association with osteoporosis. Sex (odds ratio (OR): 20.83, p < 0.001) was the most significant factor associated with osteoporosis. CONCLUSION: Osteoporosis was highly prevalent in patients awaiting TKA, but the rates of diagnosis and pharmacologic osteoporosis treatment were low. Therefore, more attention needs to estimate and treat osteoporosis in patients awaiting primary TKA, especially in female patients.

Intra-articular Injection of Culture-Expanded Mesenchymal Stem Cells Without Adjuvant Surgery in Knee Osteoarthritis: A Systematic Review and Meta-analysis.

BACKGROUND: Although many clinical studies have assessed the efficacy of mesenchymal stem cells (MSCs) in knee osteoarthritis, evidence on their efficacy remains unclear owing to heterogeneity of cell entity and concomitant procedures. PURPOSE: To determine the efficacy of culture-expanded MSCs in knee osteoarthritis in terms of clinical outcome and cartilage repair via meta-analysis of randomized controlled trials (RCTs) without adjuvant surgery. STUDY DESIGN: Meta-analysis. METHODS: PubMed, Embase, the Cochrane Library, CINAHL, and Scopus were searched from inception to December 31, 2018. RCTs with culture-expanded MSCs for treating knee osteoarthritis were included. Studies with adjuvant surgery or cell concentrate were excluded. Quality was assessed by the Cochrane Collaboration risk-of-bias tool. For meta-analysis, data on clinical outcomes were measured using a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and data on cartilage repair were measured using the Whole-Organ Magnetic Resonance Imaging Score (WORMS); categorization related to improvement was extracted. RESULTS: Six RCTs (203 patients) were included. Two studies were deemed to have a low risk of bias. In pooled analysis, the only significant difference was in the VAS score (mean difference, -13.55; 95% CI, -22.19 to -4.9). In cumulative pain analysis with VAS and WOMAC pain scores, there was significant improvement after treatment (standardized mean difference, -0.54; 95% CI, -0.85 to -0.23). There was no significant difference in cartilage repair assessed by magnetic resonance imaging (standardized mean difference, 0.11; 95% CI, -0.51 to 0.73), WORMS (standardized mean difference, 1.68; 95% CI -14.84 to 18.21), or categorical results (odds ratio, 1.56; 95% CI, 0.32-7.59). CONCLUSION: Intra-articular injection of culture-expanded MSCs without adjuvant surgery can improve pain for patients experiencing knee osteoarthritis at short-term follow-up (6-12 months). However, evidence regarding function and cartilage repair remains limited.

Effect of platelet-rich plasma on the degenerative rotator cuff tendinopathy according to the compositions.

BACKGROUND: There are controversies about platelet-rich plasma (PRP) as an established treatment option for rotator cuff (RC) tendinopathy. The purpose of the study was to find the relation of cellular component with clinical efficacy in RC tendinopathy and to find the composition of PRP in treating RC tendinopathy. METHODS: A total 30 patients were recruited and divided into PRP and control groups. In the PRP group, 2 ml of PRP solution was injected to the hypoechoic lesion of degenerative supraspinatus via 22-gauge syringe with peppering technique. Patients in the control group were taught rotator cuff strengthening exercises. American Shoulder and Elbow Surgeons (ASES), Constant-Murley score, and numeric rating scale (NRS) were measured before, 6 weeks after, 12 weeks after, and 24 weeks after the procedure. PRP compositions were analyzed using the 1 ml of PRP solution. RESULTS: Linear regression analysis showed no significant difference of ASES and Constant-Murley scores between the groups at 6 weeks (P = 0.582 and 0.258) and at 12 weeks (P = 0.969 and 0.795) but showed a significant difference at 24 weeks (P = 0.050 and 0.048). Independent t test showed significant group difference of NRS at 6 weeks (P = 0.031) but not at 12 and 24 weeks (P = 0.147 and 0.935). 5.19 pg/ml in IL-1ß and 61.79 µg/ml in TGF-ß1 were acquired as cutoff values to predict meaningful improvement. The PRP subgroup above IL-1ß or TGF-ß1 cutoff value showed significant differences in all clinical outcomes compared with the exercise group while the PRP subgroup below the cutoff value showed no significant differences in linear regression analysis. CONCLUSIONS: Our study can help to find the optimal PRP condition and to enhance the effect of PRP on RC tendinopathy. TRIAL REGISTRATION: All the patients were registered in our Institutional Ethics Committee (approval number 2014-05-009).

Variability of the Composition of Growth Factors and Cytokines in Platelet-Rich Plasma From the Knee With Osteoarthritis.

PURPOSE: To investigate the composition and concentration of growth factors and cytokines in platelet-rich plasma (PRP) with knee osteoarthritis and to explore the association of the concentration of growth factors and cytokines with the platelet count of PRPs. METHODS: Patients who visited outpatient clinic with symptomatic knee osteoarthritis (Kellgren-Lawrence grades 1 to 3) and had no blood dyscrasia were enrolled from October 2014 to March 2015. PRPs were obtained using a commercial system. Concentrations of growth factors and cytokines were measured with an enzyme-linked immunosorbent assay. Anabolic factors (platelet-derived growth factor [PDGF]-AA, -BB, and -AB, transforming growth factor-ß, vascular endothelial growth factor [VEGF], epidermal growth factor [EGF], basic fibroblast growth factor [bFGF], and insulin-like growth factor 1), catabolic factors (interleukin [IL]-1ß and matrix metalloproteinase 13), and catabolic blockers (IL-1 receptor antagonist) were included. The degree of variation was determined by coefficient of variation (CoV). RESULTS: 105 patients were included. Growth factors and cytokines showed wide variation. bFGF showed the highest variation (CoV 78.45), and transforming growth factor-ß1 showed the lowest variation (CoV 5.30). Platelet count in PRP showed a positive correlation with PDGF-BB and -AB, and VEGF (r = 0.270, P = .005; r = 0.231, P = .018; and r = 0.200, P = .041, respectively) and was negatively correlated with IL-1ß (r = -0.220, P = .025). CONCLUSION: Growth factors and cytokines in PRPs obtained from patients with knee osteoarthritis show a wide variation; the highest variation was shown in bFGF. Platelet counts associated positively with PDGF-AB and -BB and VEGF and negatively with IL-1ß. CLINICAL RELEVANCE: This information leads to the concept that variation and association of specific factors needs to be taken into consideration for future investigations of PRPs in clinical application in patients with knee osteoarthritis.

Editorial Commentary: Considering Clinical Application of Bone Marrow Aspirate Concentrate for Restoration of Cartilage Defects in the Knee? Is It a Kind of Stem Cell Therapy?

The role of bone marrow aspirate concentrate (BMAC) is still inconclusive for restoration of chondral defects in lesions of the knee. More investigation is needed; thus, clinical application of BMAC for chondral defects should be considered cautiously. Correct nomenclature of the entity of cells used in various stem cell therapies for the treatment of cartilage lesions is critical to properly assess the efficacy and safety of various stem cell therapies. Constant effort is needed to prove the therapeutic potential of various novel therapeutic options such as BMAC or stem cell therapy under correct terminology for cartilage restoration before routine clinical application.

Antibiotic-impregnated articulating cement spacer maintained for 7 years in situ for two-stage primary total knee arthroplasty: a case report.

BACKGROUND: Antibiotic-impregnated articulating cement spacers can maintain interim joint motion with the potential to enhance functional status and improve patient satisfaction. Articular surfaces with cement against cement have raised concerns regarding mechanical complications and cement debris during knee motion. However, long-term clinical conditions regarding these concerns are not well addressed. CASE PRESENTATION: We report a case in which articulating cement spacers were maintained in situ for 7 years. The patient had severe left knee pain with an ankylosing knee and severe tricompartmental arthritis due to tuberculous infection. We planned to perform one- or two-stage primary total knee arthroplasty (TKA), depending on the presence of infection. Persistent osteomyelitis was found intraoperatively. The second-stage TKA was delayed on the patient's request. As the patient was satisfied with the improved knee function and pain relief after using articulating cement spacers. No symptom or sign that suggested recurrent infection or systemic toxicity was found during the 7-year follow-up. However, it seemed that the bone loss progressed insidiously. At the 7-year follow-up, a broken articulating cement spacer and medial femoral condylar fracture were found. The second-stage TKA was performed, and a considerable amount of bone loss surrounded by dense granulation tissue was observed intraoperatively. Excisional biopsy of the tissue revealed chronic foreign body reaction with infiltration of giant cells and macrophages. CONCLUSION: Although the articular spacers were maintained for 7 years without major complications, regular observation of the development and progress of bone loss was required. Surgeons should take considerable bone loss into account during conversion TKA in patients with a prolonged retention of articulating cement spacers.

Comparative analysis of differentially secreted proteins in serum-free and serum-containing media by using BONCAT and pulsed SILAC.

Despite the increased interest in secretomes associated with paracrine/autocrine mechanisms, the majority of mass spectrometric cell secretome studies have been performed using serum-free medium (SFM). On the other hand, serum-containing medium (SCM) is not recommended very much because the secretome obtained with SCM is easily contaminated with fetal bovine serum (FBS) proteins. In this study, through the combination of bioorthogonal non-canonical amino acid tagging (BONCAT) and pulsed-SILAC (pSILAC), we analyzed differentially secreted proteins between SFM and SCM in a cancer-derived human cell, U87MG, and a mesenchymal stem cell derived from human Wharton's jelly (hWJ-MSCs). In most cases, the bioinformatic tools predicted a protein to be truly secretory when the secretion level of the protein was more in SCM than in SFM. In the case of hWJ-MSCs, the amount of proteins secreted in SCM for 24 hours was larger than that of SFM (log2 fold change = 0.96), even considering different cell proliferation rates. hWJ-MSCs proteins secreted more in SCM included several positive markers of MSC paracrine factors implicated in angiogenesis, neurogenesis and osteogenesis, and upstream regulators of cell proliferation. Our study suggests the analysis of the secretome should be processed in SCM that promotes cell proliferation and secretion.

Intra-articular injection of mesenchymal stem cells for clinical outcomes and cartilage repair in osteoarthritis of the knee: a meta-analysis of randomized controlled trials.

INTRODUCTION: Mesenchymal stem cells (MSCs) have gained popularity for articular cartilage repair. However, efficacy of intra-articular MSCs in osteoarthritis remains unclear. In the setting of a meta-analysis of randomized controlled trials (RCTs), we aimed to investigate the efficacy of intra-articular MSCs on clinical outcomes and cartilage repair in patients with knee osteoarthritis. MATERIALS AND METHODS: PubMed, EMBASE, Cochrane Library, CINAHL, and Scopus were searched from inception to March 31, 2017. This study included RCTs using cell population containing MSCs for treatment of knee osteoarthritis. The quality was assessed by Cochrane Collaboration`s risk of bias tool. For meta-analysis, data on clinical outcomes measured by visual analog scale (VAS), Lysholm score, WOMAC and data on cartilage repair measured by MOCART and WORMS were extracted. In studies with several cell concentrations, outcomes of recommended concentration were used mainly to ensure robustness. RESULTS: A total of five RCTs (220 patients) were included. Two studies were deemed to have low risk of bias. In pooled analysis, there was significant difference in VAS score (mean difference [MD], - 9.2; 95% CI: - 17.21, - 1.20) and Lysholm score (MD, 8.70; 95% CI 0.06, 17.34), but not WOMAC (MD, - 7.44; 95% CI - 20.38, 5.50). In cumulative functional analysis using Lysholm score and WOMAC in recommended concentration, there was a significant improvement (standard mean difference [SMD], 0.53; 95% CI 0.13, 0.94) after treatment. In cartilage repair assessed by MRI, there was no significant difference (SMD, 0.53; 95% CI- 0.28, 1.34). CONCLUSIONS: This meta-analysis demonstrated that intra-articular MSCs have a limited evidence in pain relief and functional improvement in knee osteoarthritis. While MSCs may result in favorable clinical outcomes with a recommended concentration, use of concomitant treatment should be considered. In addition, current evidence does not support the use of intra-articular MSCs for improving cartilage repair in knee osteoarthritis. LEVEL OF EVIDENCE: Systematic review of Level-II studies.

Comparison of Undifferentiated Versus Chondrogenic Predifferentiated Mesenchymal Stem Cells Derived From Human Umbilical Cord Blood for Cartilage Repair in a Rat Model.

BACKGROUND: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have gained much interest as a promising cell source for regenerative medicine owing to the noninvasive collection, availability, high expansion capacity, and low immunogenicity. However, few in vivo studies have reported the use of hUCB-MSCs on cartilage repair. Moreover, little study has been conducted on the effects of chondrogenic predifferentiation of hUCB-MSCs on cartilage repair. PURPOSE: To compare the effectiveness of transplanting undifferentiated versus chondrogenic predifferentiated mesenchymal stem cells (MSCs) for treating osteochondral defects. STUDY DESIGN: Controlled laboratory study. METHODS: Critical-sized osteochondral defects were created in the trochlear grooves of rat femurs. In 20 rats, a composite of chondrogenic predifferentiated hUCB-MSCs (chondro-MSCs) and 4% hyaluronic acid (HA) hydrogel was transplanted into defects in the right knees, whereas undifferentiated hUCB-MSCs (undiff-MSCs) and 4% HA hydrogel were transplanted into the left knees. In the control groups, 4% HA hydrogel without MSCs was transplanted into defects in the right knees, and the defects in the left knees were left untreated in 20 rats. The cartilage repair was evaluated at 8 and 16 weeks after surgery. RESULTS: Transplanting undiff-MSCs resulted in overall superior cartilage repair as compared with chondro-MSCs, HA alone, or no treatment. The articular surfaces of the defect sites in the undiff-MSC group were relatively smoother than those of the other treatments. The undiff-MSC group showed cellular morphology and arrangement similar to surrounding normal articular cartilage tissue at 16 weeks, both of which were also better than those of the other groups. In addition, the undiff-MSC group showed coloration similar to surrounding normal articular cartilage tissue at 16 weeks in safranin O and type II collagen immunohistochemical staining. The histological scores also revealed that cartilage repair with undiff-MSCs was better than that with chondro-MSCs, HA alone, or no treatment ( P < .05 in all). CONCLUSION: This study demonstrated that treatment with undiff-MSCs resulted in more favorable cartilage repair than that with chondro-MSCs in a rat model. These findings indicate that chondrogenic predifferentiation of MSCs before transplantation does not enhance cartilage repair. CLINICAL RELEVANCE: The results of this study support the use of undifferentiated MSCs, rather than chondrogenic predifferentiated MSCs, as a stem cell therapy strategy for cartilage repair.

Comparable bone union progression after opening wedge high tibial osteotomy using allogenous bone chip or tri-calcium phosphate granule: a prospective randomized controlled trial.

PURPOSE: The purpose of this study is to compare the progression rate of bone union and clinical outcomes of opening wedge high tibial osteotomy (OWHTO) using allogenous bone chip or tri-calcium phosphate (TCP) granule as bone graft materials. The hypothesis was that the bone union progression in OWHTOs using TCP granule grafts would be comparable to that of OWHTOs using allogenous bone chip grafts. METHODS: Between 2011 and 2013, 54 patients who had undergone OWHTO for genu varum and osteoarthritis were randomized to one of the two groups at five centres. TCP granule was used to fill the defect in 27 patients and lyophilized allogenous bone chip was used in the other 27 patients. The degree of bone union was classified on a five-point scale and evaluated using plain radiographs of the knee at 6 weeks, 3 months, 6 months, and 12 months postoperatively. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, pain Visual Analogue Scale (VAS) score and complications were also evaluated. RESULTS: The highest degree of bone union observed at 6 and 12 months postoperatively was grade 4, and the number of cases of union progression at each time-point was not significantly different between the two groups (p > 0.05). WOMAC and pain VAS scores also showed no differences between the two groups. No complications were observed during the 12-month period following OWHTO in either group. CONCLUSION: OWHTO using TCP granule bone substitute showed similar bone union rates and clinical outcomes compared to allogenous bone chip grafts. TCP granule can be used as bone substitutes instead of allogenous bone chip grafts in OWHTO. LEVEL OF EVIDENCE: Level 1.

Intra-articular Mesenchymal Stem Cells in Osteoarthritis of the Knee: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair.

PURPOSE: To provide a systematic review of the clinical literature reporting the efficacy of mesenchymal stem cells (MSCs) in terms of clinical outcomes including pain and function and cartilage repair in patients with osteoarthritis. METHODS: We systematically reviewed any studies investigating clinical outcomes and cartilage repair after the clinical application of cell populations containing MSCs in human subjects with knee osteoarthritis through MEDLINE, EMBASE, the Cochrane Library, CINAHL, Web of Science, and Scopus. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies with a level of evidence of IV or V were excluded. Methodological quality was assessed using the Modified Coleman Methodology Score. Clinical outcomes were assessed using clinical scores, and cartilage repair was assessed using magnetic resonance imaging and second-look arthroscopy findings. RESULTS: A total of 17 studies that met the criteria of 50 full-text studies were included in this review, with 6 randomized controlled trials, 8 prospective observational studies, and 3 retrospective case-control studies. Among 17 studies, 8 studies used bone marrow-derived MSCs, 6 used adipose tissue-derived stromal vascular fraction, 2 used adipose tissue-derived MSCs, and 1 used umbilical cord blood-derived MSCs. All studies except 2 reported significantly better clinical outcomes in the MSC group or improved clinical outcomes at final follow-up. In terms of cartilage repair, 9 of 11 studies reported improvement of the cartilage state on magnetic resonance imaging, and 6 of 7 studies reported repaired tissue on second-look arthroscopy. The mean Modified Coleman Methodology Score was 55.5 ± 15.5 (range, 28-74). CONCLUSIONS: Intra-articular MSCs provide improvements in pain and function in knee osteoarthritis at short-term follow-up (<28 months) in many cases. Some efficacy has been shown of MSCs for cartilage repair in osteoarthritis; however, the evidence of efficacy of intra-articular MSCs on both clinical outcomes and cartilage repair remains limited. LEVEL OF EVIDENCE: Level III; systematic review of level I, II, and III studies.

Prediction Models to Improve the Diagnostic Value of Plain Radiographs in Children With Complete Discoid Lateral Meniscus.

PURPOSE: To develop prediction models to improve the diagnostic utility of plain radiographs for the diagnosis of complete discoid lateral meniscus by combining previously reported radiographic findings. METHODS: Patients ages 5 to 16 years with complete discoid lateral meniscus confirmed by arthroscopy or magnetic resonance imaging were included. Patients with insufficient radiographs were excluded. Normal control subjects were randomly sampled by age and sex matching. Subjects were divided into 2 groups considering skeletal maturation (5-9 and 10-16 years). Radiographic variables included were lateral joint space, height of the fibular head, height of the lateral tibial spine, obliquity and cupping of the lateral tibial plateau, condylar cutoff sign, and squaring and notching of the lateral femoral condyle. Prediction models were developed by regression analyses. The cutoff value (COV) for best accuracy was determined with its sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: A total of 162 knees (126 patients) with complete discoid lateral meniscus and 151 age- and sex-matched knees (151 subjects) with normal meniscus were included. In subjects 5 to 9 years old, the prediction model was risk score = [-20.08 * height of the fibular head/femoral interepicondylar distance (FIED)] + [-42.26 * height of the lateral tibial spine/FIED]. The COV of -8.47 showed the best accuracy (74.4%), with sensitivity of 85.9%; specificity, 60.4%; PPV, 72.4%; and NPV, 78.0%. In subjects 10 to 16 years old, the prediction model was risk score = [77.04 * lateral joint space/FIED] + [-34.55 * height of the fibular head/FIED] + [-56.58 * height of the lateral tibial spine/FIED] + [-16.44 * condylar cutoff sign]. The COV of -18.03 showed the best accuracy (85.4%), with sensitivity of 79.6%; specificity, 90.4%; PPV, 87.6%; and NPV, 83.9%. CONCLUSIONS: The prediction models combining the plain radiographic findings showed higher diagnostic values than the diagnostic values of the individual radiographic findings. The results of this study provide improved diagnostic utility of plain radiography for the detection of completed discoid lateral meniscus in children. LEVEL OF EVIDENCE: Level III, diagnostic study.

Stem Cell Therapy for Articular Cartilage Repair: Review of the Entity of Cell Populations Used and the Result of the Clinical Application of Each Entity.

BACKGROUND: Following successful preclinical studies, stem cell therapy is emerging as a candidate for the treatment of articular cartilage lesions. Because stem cell therapy for cartilage repair in humans is at an early phase, confusion and errors are found in the literature regarding use of the term stem cell therapy in this field. PURPOSE: To provide an overview of the outcomes of cartilage repair, elucidating the various cell populations used, and thus reduce confusion with regard to using the term stem cell therapy. STUDY DESIGN: Systematic review. METHODS: The authors systematically reviewed any studies on clinical application of mesenchymal stem cells (MSCs) in human subjects. A comprehensive search was performed in MEDLINE, EMBASE, the Cochrane Library, CINAHL, Web of Science, and Scopus for human studies that evaluated articular cartilage repair with cell populations containing MSCs. These studies were classified as using bone marrow-derived MSCs, adipose tissue-derived MSCs, peripheral blood-derived MSCs, synovium-derived MSCs, and umbilical cord blood-derived MSCs according to the entity of cell population used. RESULTS: Forty-six clinical studies were identified to focus on cartilage repair with MSCs: 20 studies with bone marrow-derived MSCs, 21 studies with adipose tissue-derived MSCs, 3 studies with peripheral blood-derived MSCs, 1 study with synovium-derived MSCs, and 1 study with umbilical cord blood-derived MSCs. All clinical studies reported that cartilage treated with MSCs showed favorable clinical outcomes in terms of clinical scores or cartilage repair evaluated by MRI. However, most studies were limited to case reports and case series. Among these 46 clinical studies, 18 studies erroneously referred to adipose tissue-derived stromal vascular fractions as "adipose-derived MSCs," 2 studies referred to peripheral blood-derived progenitor cells as "peripheral blood-derived MSCs," and 1 study referred to bone marrow aspirate concentrate as "bone marrow-derived MSCs." CONCLUSION: Limited evidence is available regarding clinical benefit of stem cell therapy for articular cartilage repair. Because the literature contains substantial errors in describing the therapeutic cells used, researchers need to be alert and observant of proper terms, especially regarding whether the cells used were stem cells or cell populations containing a small portion of stem cells, to prevent confusion in understanding the results of a given stem cell-based therapy.

Rapidly growing non-tuberculous mycobacteria infection of prosthetic knee joints: A report of two cases.

Non-tuberculous mycobacteria (NTM) cause prosthetic knee joint infections in rare cases. Infections with rapidly growing non-tuberculous mycobacteria (RGNTM) are difficult to treat due to their aggressive clinical behavior and resistance to antibiotics. Infections of a prosthetic knee joint by RGNTM have rarely been reported. A standard of treatment has not yet been established because of the rarity of the condition. In previous reports, diagnoses of RGNTM infections in prosthetic knee joints took a long time to reach because the condition was not suspected, due to its rarity. In addition, it is difficult to identify RGNTM in the lab because special identification tests are needed. In previous reports, after treatment for RGNTM prosthetic infections, knee prostheses could not be re-implanted in all cases but one, resulting in arthrodesis or resection arthroplasty; this was most likely due to the aggressiveness of these organisms. In the present report, two cases of prosthetic knee joint infection caused by RGNTM (Mycobacterium abscessus) are described that were successfully treated, and in which prosthetic joints were finally reimplanted in two-stage revision surgery.