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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.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 ReviewAssessment 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.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.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.

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).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.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).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.Meta-analysis of level I studies.

Background: Meniscal deficiency from meniscectomy is a common situation in clinical practices. Regeneration of the deficient meniscal portion, however, is still not feasible. Purpose: To develop an injectable hydrogel system consisting of fibrin (Fb) and polyethylene oxide (PEO) and to estimate its clinical potential for treating a segmental defect of the meniscus in a rabbit meniscal defect model. Study Design: Controlled laboratory study. Methods: The Fb/PEO hydrogel was fabricated by extruding 100 mg·mL-1 of fibrinogen solution and 2,500 U·mL-1 of thrombin solution containing 100 mg·mL-1 of PEO through a dual-syringe system. The hydrogels were characterized by rheological analysis and biodegradation tests. The meniscal defects of New Zealand White male rabbits were generated by removing 60% of the medial meniscus from the anterior side. The removed portion included the central portion. The Fb/PEO hydrogel was injected into the meniscal defect of the experimental knee through the joint space between the femoral condyle and tibial plateau at the anterior knee without a skin incision. The entire medial menisci from both knees of each rabbit were collected and photographed before placement in formalin for histological processing. Hematoxylin and eosin, safranin O, and immunohistochemical staining for type II collagen was performed. The biomechanical property of the regenerated meniscus was evaluated using a universal tensile machine. Results: The Fb/PEO hydrogel was fabricated by an in situ gelation process, and the hydrogel displayed a semi-interpenetrating polymer network structure. We demonstrated that the mechanical properties of Fb-based hydrogels increased in a PEO-dependent manner. Furthermore, the addition of PEO delayed the biodegradation of the hydrogel. Our in vivo data demonstrated that, as compared with Fb hydrogel, Fb/PEO hydrogel injection into the meniscectomy model showed improved tissue regeneration. The regenerated meniscal tissue by Fb/PEO hydrogel showed enhanced tissue quality, which was supported by the histological and biomechanical properties. Conclusion: The Fb/PEO hydrogel had an effective tissue-regenerative ability through injection into the in vivo rabbit meniscal defect model. Clinical Relevance: This injectable hydrogel system can promote meniscal repair and be readily utilized in clinical application.

Background: Although platelet-rich plasma (PRP) has potential as a regenerative treatment for knee osteoarthritis, its efficacy varies. Compositional differences among types of PRP could affect clinical outcomes, but the biological characterization of PRP is lacking. Purpose: To assess the efficacy of intra-articular PRP injection in knee osteoarthritis as compared with hyaluronic acid (HA) injection and to determine whether the clinical efficacy of PRP is associated with its biological characteristics. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 110 patients with symptomatic knee osteoarthritis received a single injection of leukocyte-rich PRP (1 commercial kit) or HA. Clinical data were assessed at baseline and at 6 weeks and 3 and 6 months after injection. The primary endpoint was an improvement in the International Knee Documentation Committee (IKDC) subjective score at 6 months, and the secondary endpoints were improvements in scores based on the Patient Global Assessment, the visual analog scale (VAS) for pain, the Western Ontario and McMaster Universities Osteoarthritis Index, and the Samsung Medical Center patellofemoral score. Cell counts and concentrations of growth factors and cytokines in the injected PRP were assessed to determine their association with clinical outcomes. Results: PRP showed significantly improvement in IKDC subjective scores at 6 months (11.5 in the PRP group vs 6.3 in the HA group; P = .029). There were no significant differences between groups in other clinical outcomes. The Patient Global Assessment score at 6 months was better in the PRP group ( P = .035). The proportion of patients who scored above the minimal clinically important difference (MCID) for VAS at 6 months was significantly higher in the PRP group ( P = .044). Within the PRP group, the concentrations of platelet-derived growth factors were high in patients with a score above the MCID for VAS at 6 months. The incidence of adverse events did not differ between the groups ( P > .05). Conclusion: PRP had better clinical efficacy than HA. High concentrations of growth factors were observed in patients who scored above the MCID for clinical outcomes in the PRP group. These findings indicate that concentration of growth factors needs to be taken into consideration for future investigations of PRP in knee osteoarthritis. Registration: NCT02211521 (ClinicalTrials.gov identifier).

This study was a phase I/IIa, multicenter, randomized, double-blinded, parallel, placebo-controlled clinical trial that aimed to assess the efficacy and safety of a single intra-articular injection of YYD302, a novel high-molecular-weight hyaluronic acid with divinyl sulfone cross-linking. Thirty adults with knee osteoarthritis were randomized to receive a single 2 mL intra-articular injection of YYD302 (test group 1), 3 mL of YYD302 (test group 2), or 3 mL of the placebo (placebo group). We compared the changes from the baseline in the weight-bearing pain of 100 mm using the Visual Analog Scale (VAS), the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Rheumatology-Osteoarthritis Research Society International (OMERACT-OASRSI) responder rates, and the use of rescue analgesics to assess the safety of this novel drug. A total of 26 subjects (10 in test group 1, 10 in test group 2, and 6 in the placebo group) were included in the full analysis set. At 12 weeks, only test groups 1 and 2 showed significant changes in the weight-bearing pain VAS scores (p = 0.0015 and p = 0.0085), symptoms, and average daily KOOS values compared to the baseline (p < 0.001, p = 0.0124, and p = 0.0018, p = 0.0426, respectively). While the rate and frequency of consuming the rescue drug continued to increase in the placebo group until 12 weeks, there was no change in the test groups. Our findings showed that YYD302, especially 2 mL of YYD302, reduced pain and improved knee joint function compared to the placebo.

To date, the use of biomarkers for assessing individual severity of osteoarthritis (OA) is limited, and the correlation of histological scores with biomarkers for individual animals in the destabilization of the medial meniscus (DMM) model of OA has not been well investigated. Accordingly, this study investigated how well representative biomarkers in the DMM model reflected specific changes in individual animals. Rats were randomly divided into the OA group and the sham group. OA model was established by destabilization of the medial meniscus (DMM). After 2,4,6,8,10 and 12 weeks (n=14, each week), the concentrations of CTXII, COMP, C2C, and OC in serum were measured, and cartilage degeneration, osteophytes, and synovial membrane inflammation, typical of OA, were scored using Osteoarthritis Research Society International (OARSI) scoring system. Additionally, the correlation between each biomarker and the specific changes in osteoarthritis was analyzed for individual animals using the Generalized Estimating Equation (GEE). Statistical analysis showed a low correlation between CTXII and osteophyte score of the medial femur (coefficient = -0.0088, p= 0.0103), COMP and osteophyte score of the medial tibia (coefficient = -0.0911, p= 0.0003), and C2C and synovial membrane inflammation scores of the medial femoral (coefficient = 0.054, p= 0.0131). These results suggest that representative OA bio- markers in individual animals in the DMM model did not reflect histological scores well.

Injectable hydrogel systems are a facile approach to apply to the damaged meniscus in a minimally invasive way. We herein developed a clinically applicable and injectable semi-interpenetrated network (semi-IPN) hydrogel system based on fibrin (Fb), reinforced with Pluronic F127 (F127) and polymethyl methacrylate (PMMA), to improve the intrinsic weak mechanical properties. Through the dual-syringe device system, the hydrogel could form a gel state within about 50 s, and the increment of compressive modulus of Fb hydrogels was achieved by adding F127 from 3.0% (72.0 ± 4.3 kPa) to 10.0% (156.0 ± 9.8 kPa). The shear modulus was enhanced by adding PMMA microbeads (26.0 ± 1.1 kPa), which was higher than Fb (13.5 ± 0.5 kPa) and Fb/F127 (21.7 ± 0.8 kPa). Moreover, the addition of F127 and PMMA also delayed the rate of enzymatic biodegradation of Fb hydrogel. Finally, we confirmed that both Fb/F127 and Fb/F127/PMMA hydrogels showed accelerated tissue repair in the in vivo segmental defect of the rabbit meniscus model. In addition, the histological analysis showed that the quality of the regenerated tissues healed by Fb/F127 was particularly comparable to that of healthy tissue. The biomechanical strength of the regenerated tissues of Fb/F127 (3.50 ± 0.35 MPa) and Fb/F127/PMMA (3.59 ± 0.89 MPa) was much higher than that of Fb (0.82 ± 0.05 MPa) but inferior to that of healthy tissue (6.63 ± 1.12 MPa). These results suggest that the reinforcement of Fb hydrogel using FDA-approved synthetic biomaterials has great potential to be used clinically.

The diagnostic utility of radiographic signs of complete discoid lateral meniscus remains controversial. This study aimed to investigate the diagnostic accuracy and determine which sign is most reliably detects the presence of a complete discoid lateral meniscus in children. A total of 141 knees (age 7-16) with complete discoid lateral meniscus and 141 age- and sex-matched knees with normal meniscus were included. The following radiographic signs were evaluated: lateral joint (LJ) space, fibular head (FH) height, lateral tibial spine (LTS) height, lateral tibial plateau (LTP) obliquity, lateral femoral condyle (LFC) squaring, LTP cupping, LFC notching, and prominence ratio of the femoral condyle. Prediction models were constructed using logistic regressions, decision trees, and random forest analyses. Receiver operating characteristic curves and area under the curve (AUC) were estimated to compare the diagnostic accuracy of the radiographic signs and model fit. The random forest model yielded the best diagnostic accuracy (AUC: 0.909), with 86.5% sensitivity and 82.2% specificity. LJ space height, FH height, and prominence ratio showed statistically large AUC compared with LTS height and LTP obliquity (P .05 in all). The cut-off values for diagnosing discoid meniscus to be12.55 mm for FH height,0.804 for prominence ratio, and6.6 mm for LJ space height when using the random forest model. On the basis of the results of this study, in clinical practice, LJ space height, FH height and prominence ratio could be easily used as supplementary tools for complete discoid lateral meniscus in children.

We propose to use cRFP (common Repository of FBS Proteins) in the MS (mass spectrometry) raw data search of cell secretomes. cRFP is a small supplementary sequence list of highly abundant fetal bovine serum proteins added to the reference database in use. The aim behind using cRFP is to prevent the contaminant FBS proteins from being misidentified as other proteins in the reference database, just as we would use cRAP (common Repository of Adventitious Proteins) to prevent contaminant proteins present either by accident or through unavoidable contacts from being misidentified as other proteins. We expect it to be widely used in experiments where the proteins are obtained from serum-free media after thorough washing of the cells, or from a complex media such as SILAC, or from extracellular vesicles directly.

Hemostasis has critical significance during surgical procedures. Bone Wax has traditionally been commonly used for bone hemostasis despite well-documented undesirable side effects: hindering osteogenesis and induction of inflammatory reactions with consequent increase in infection rates. A later developed formulation, Ostene, offers an alternative to Bone Wax with lesser undesired effects. In this study, BoneStat, a newly developed bone hemostatic formulation comprising water-soluble alkylene oxide co-polymers, was evaluated for water solubility, hemostatic efficacy, ease of handling, bone healing efficacy, and inflammatory reactions compared with Bone Wax and Ostene in a rat calvarial defect model. More than 95% of BoneStat was dissolved in water within 48 h, as was Ostene, but not Bone Wax. The time to hemostasis using BoneStat was significantly faster than with Ostene or Bone Wax. BoneStat also improved ease of handling compared to Ostene or BoneWax. BoneStat- and Ostene-treated groups constantly showed better bone healing than with Bone Wax. The BoneStat and Ostene groups presented no evidence of chronic inflammation reaction contrary to Bone Wax. These results suggest improved hemostasis, ease of handling, non-hindering bone healing, and unnoticeable chronic inflammatory reactions with BoneStat. Thus, Bonestat is a useful and reliable formulation for mechanical hemostasis.

Purpose This double-blind, randomized, Phase III clinical trial was conducted to assess the efficacy and safety of the novel divinyl sulfone cross-linked hyaluronate (YYD302) compared with the 1,4-butanediol diglycidyl ether cross-linked hyaluronate (Synovian) in patients with knee osteoarthritis. Methods A total of 184 patients with osteoarthritis (Kellgren-Lawrence grade I–III) were randomized to 1 of 2 study groups (YYD302 group, n = 95; Synovian group, n = 89). A single injection of YYD302 or Synovian was given to both groups, and 182 participants completed the study (YYD302 group, n = 95; Synovian group, n = 87). The primary end point was the change in weight-bearing pain (WBP) at 12 weeks after the primary single injection. Secondary end points included the Knee Injury and Osteoarthritis Outcome Score; the Western Ontario and McMaster Universities Osteoarthritis Index score; the Patient Global Assessment and Investigator Global Assessment; the range of motion, swelling, and tenderness of the target knee; OMERACT-OARSI responder rate; WBP responder rate (the proportion of patients achieving at least 20 mm or 40% decrease in WBP); and rate of rescue medicine use and its total consumption at weeks 2, 4, and 12. Based on the efficacy results at week 12, the responders were administered an additional single injection of the same study drug at week 24, and safety and efficacy were additionally assessed at week 36. Findings Mean changes of WBP at 12 weeks after the primary injection were –31.76 mm with YYD302 and –29.74 mm with Synovian, proving noninferiority of the YYD302 group to the Synovian group as the lower bound of the 95% CI (–4.3 to 8.3) was well above the predefined margin (–10 mm). At week 2, the Knee Injury and Osteoarthritis Outcome Score (total, pain, activities of daily living, and sports/recreation) and Western Ontario and McMaster Universities Osteoarthritis Index scores (total, stiffness) were significantly better in the YYD302 group than in the Synovian group. There were no significant differences between the groups in all other end points. Local overall adverse events (pain, heat, erythema, or swelling) at the injection site were observed in 48.4% of the YYD302 group and in 47.7% of the Synovian group. No serious reactions were reported. There was no statistically significant difference between the 2 groups regarding re-injected patients (YYD302 group, n = 54; Synovian group, n = 46) in any of the efficacy outcomes at week 36. Implications The results of this study support that YYD302 is comparable to Synovian in terms of the efficacy and safety of the intra-articular injection treatment for osteoarthritis of the knee joint. Furthermore, YYD302 provided faster improvements in some efficacy assessments compared with Synovian. ClinicalTrials.gov identifier: NCT03561779.

Supplemental material, sj-pdf-1-ajs-10.1177_0363546521998021 for Injectable Fibrin/Polyethylene Oxide Semi-IPN Hydrogel for a Segmental Meniscal Defect Regeneration by Jin-A Kim, Young-Hyeon An, Hyun-Gu Yim, Woo-Jung Han, Yong-Beom Park, Hyun Jin Park, Man Young Kim, Jaewon Jang, Racheal H. Koh, Su-Hwan Kim, Nathaniel S. Hwang and Chul-Won Ha in The American Journal of Sports Medicine

Supplemental material, sj-pdf-1-ajs-10.1177_0363546520986867 for Clinical Efficacy of Platelet-Rich Plasma Injection and Its Association With Growth Factors in the Treatment of Mild to Moderate Knee Osteoarthritis: A Randomized Double-Blind Controlled Clinical Trial As Compared With Hyaluronic Acid by Yong-Beom Park, Jun-Ho Kim, Chul-Won Ha and Dong-Hyun Lee in The American Journal of Sports Medicine

Background: Platelet-rich plasma (PRP) has gained attention as a therapeutic option for knee osteoarthritis; however, its efficacy varies widely. Leukocytes in PRP raise the concern of aggravating proinflammatory activity. To date, PRP has rarely been investigated with regard to leukocyte concentration. Purpose: To provide clinical evidence of the intra-articular injection of PRPs containing different leukocyte concentrations. Study Design: Systematic review; Level of evidence, 4. Methods: We systematically searched the MEDLINE, Embase, Cochrane Library, CINAHL, and Scopus databases. PRP was classified into leukocyte-poor (LP-PRP) and leukocyte-rich (LR-PRP). Clinical outcomes including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale (VAS) for pain score, International Knee Documentation Committee (IKDC) subjective score, and adverse reactions were evaluated. The Methodological Index for Non-Randomized Studies criteria were used for quality assessment. Results: Included were 32 studies with an evidence level between 1 and 4. Both LP-PRP and LR-PRP showed improvements above the minimal clinically important difference (MCID) in VAS pain score. No significant intergroup difference was seen at 3, 6, or 12 months of follow-up. Regarding function, both LP-PRP and LR-PRP showed improvements above the MCID in the WOMAC and IKDC scores, with no significant difference between the groups. Adverse reactions for pain were significantly higher in LR-PRP than in LP-PRP (odds ratio, 1.64; 95% confidence interval, 1.29-2.10; P = .01). After intra-articular PRP injection, LR-PRP showed a significantly higher rate of swelling than LP-PRP (odds ratio, 1.56; 95% confidence interval, 1.22-1.99; P = .02). The mean Methodological Index for Non-Randomized Studies score of the included studies was 18.6 (range, 10-24). Conclusion: Intra-articular PRP injection resulted in improvements above the MCID in terms of pain and function in patients with knee osteoarthritis up to 12 months. The risk of local adverse reactions appeared to be increased after LR-PRP compared with LP-PRP injection. The findings of this review can support the potential use of intra-articular PRP injection for the treatment of knee osteoarthritis. In clinical application, clinicians need to consider selecting a specific type of PRP for knee osteoarthritis.

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.

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. 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. 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). 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. Systematic review of Level-II studies.

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. 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. 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. 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 1.

The aim of this study was to test the clinical efficacy of TissueGene-C (TG-C), a cell and gene therapeutic for osteoarthritis consisting of non-transformed and transduced chondrocytes (3:1) retrovirally transduced to overexpress transforming growth factor-β1. A total of 163 Kellgren-Lawrence grade 3 patients with knee osteoarthritis were randomly assigned to receive intra-articular TG-C or placebo. Primary efficacy measures included criteria for subjective assessment by International Knee Documentation Committee (IKDC) and pain severity by Visual Analog Scale (VAS) for 52 weeks. Secondary efficacy measures included IKDC and VAS at 26 and 39 weeks; pain, stiffness, and physical function by the Western Ontario and McMaster Universities Arthritis Index (WOMAC); and pain, symptoms, daily activities, function in sports and recreation, and quality of life by the Knee Injury and Osteoarthritis Outcome Score (KOOS), X-ray, magnetic resonance imaging, and soluble urine and blood biomarkers. TG-C was associated with statistically significant improvement over placebo in the total IKDC score and individual categories, and in the VAS score at 26, 39, and 52 weeks. WOMAC and KOOS scores also improved with TG-C over placebo. Patients treated with TG-C showed trends directed toward thicker cartilage and slower growing rates of subchondral bone surface area in the medial tibia, lateral tibia, lateral patella, and lateral patella femoral regions, although these were not statistically significant (p 0.05). Serum C-terminal telopeptide of type I collagen (CTX-I) and urine CTX-II levels were lower over 1 year in TG-C than placebo-treated patients, with CTX-I level reaching statistical significance. These tendencies supported TG-C as holding great potential as a disease-modifying osteoarthritis drug. The most frequent adverse events in the TG-C group were peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection site pain (5%). TG-C was associated with statistically significant improvements in function and pain in patients with knee osteoarthritis. The unexpected adverse events were not observed.

Background To assess the axial rotational change of distal tibia and posterior tibial slope (PTS) change after OWHTO in 3-D planes and to identify the causal relationship on the effect of variation in the posterior slope angle and rotational errors. Methods A total of 21 patients (23 knees) underwent OWHTO and were evaluated with 3D-CT before and after surgery. Medial proximal tibial angle in the coronal plane, PTS in the sagittal plane, and rotational axis in axial plane were evaluated and compared between pre- and post-operative 3D models constructed by applying reverse-engineering software. As a selective osteotomy parameter, hinge axis and gap ratio were measured in the postoperative 3D models Results The increasing tendency of internal rotation of the distal tibia after OWHTO was positively related to hinge axis (β=0.730, p=0.001, R 2 =0.546) and gap ratio (β=−0.283, p=0.001, R 2 =0.520), which also showed statistically significant linear correlations to PTS changes after multivariate regression analysis that controlled for the rotational change of the distal tibia (hinge axis: β=0.443, p=0.006; gap ratio: β=0.144, p=0.017). Conclusion Hinge axis more posterolaterally was related to a greater increase in internal rotation after biplane medial open-wedge HTO, and hinge axis and gap ratio were significant predictors of PTS change after rotational change was controlled for. Hinge axis has to be considered an important independent variable for limiting unintended axial rotation change as well as PTS change as secondary. Clinical relevance The relationship of the hinge axis with the rotational change and its influence to PTS change, acknowledged from by-product of the statistical analysis, might provide a deeper understanding of HTO, and should have constitutional effects on the development of HTO procedures and implants.

Background & Aim Increasing numbers of clinical studies have addressed the use of mesenchymal stem cells (MSCs) for the treatment of osteoarthritis. However, the clinical benefit of MSCs for cartilage repair in osteoarthritis remains unclear. Although some recent studies reported the clinical benefits of intra-articular MSCs in the treatment of osteoarthritis, the clinical efficacy of MSCs in cartilage repair or cartilage protection in osteoarthritis has not been established. In addition, there is little consensus as which cell source, type of cell population, or delivery method should be used. Hence, this study aimed to provide a systematic review of the clinical literature supporting the efficacy of MSCs in terms of clinical outcomes and cartilage repair in patients with osteoarthritis and to strictly differentiate the various cell sources, types of cell populations, and delivery methods that have been used. Methods, Results & Conclusion Methods We systematically reviewed any studies investigating 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. 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 MRI and second-look arthroscopy findings. Results A total of 17 studies that met the criteria were included in this review, with 6 randomized controlled trials, 8 prospective cohort 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 improvements in clinical outcomes. In terms of cartilage repair, 9 of 11 studies reported improvement of the cartilage state on MRI, 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). Conclusion Intra-articular MSCs seem to provide improvements in pain and function in knee osteoarthritis at short-term follow-up. However, the improvement was modest overall, and the effects of adjuvant treatment need to be clarified. Overall, evidence of the efficacy of MSCs for cartilage repair in osteoarthritis remains limited.

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.

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. 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. 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

The purpose of this study was to determine the utility of the radiographic ‘condylar cut-off sign’ to detect the presence of a complete discoid lateral meniscus in children and adolescents. The radiographs of 166 subjects younger than 17 with complete discoid lateral meniscus as well as 153 age- and sex-matched subjects with normal meniscus were reviewed. The condylar cut-off sign, judged by the prominence ratio of the medial and lateral femoral condyles in tunnel view radiographs, was assessed. The prominence ratio was compared between the complete discoid and the normal group. Subgroup analysis was performed by dividing the subjects into two groups: those younger than 10 and those between 10 and 16. When a significant difference was identified between the discoid and the normal group, the sensitivity, specificity and positive and negative predictive values (PPV and NPV) according to the best cut-off value for the prominence ratio was determined. The prominence ratio was significantly different between the complete discoid and normal groups in children and adolescents as a whole (p

Few methods are available to regenerate articular cartilage defects in patients with osteoarthritis. We aimed to assess the safety and efficacy of articular cartilage regeneration by a novel medicinal product composed of allogeneic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). Patients with Kellgren-Lawrence grade 3 osteoarthritis and International Cartilage Repair Society (ICRS) grade 4 cartilage defects were enrolled in this clinical trial. The stem cell-based medicinal product (a composite of culture-expanded allogeneic hUCB-MSCs and hyaluronic acid hydrogel [Cartistem]) was applied to the lesion site. Safety was assessed by the World Health Organization common toxicity criteria. The primary efficacy outcome was ICRS cartilage repair assessed by arthroscopy at 12 weeks. The secondary efficacy outcome was visual analog scale (VAS) score for pain on walking. During a 7-year extended follow-up, we evaluated safety, VAS score, International Knee Documentation Committee (IKDC) subjective score, magnetic resonance imaging (MRI) findings, and histological evaluations. Seven participants were enrolled. Maturing repair tissue was observed at the 12-week arthroscopic evaluation. The VAS and IKDC scores were improved at 24 weeks. The improved clinical outcomes were stable over 7 years of follow-up. The histological findings at 1 year showed hyaline-like cartilage. MRI at 3 years showed persistence of the regenerated cartilage. Only five mild to moderate treatment-emergent adverse events were observed. There were no cases of osteogenesis or tumorigenesis over 7 years. The application of this novel stem cell-based medicinal product appears to be safe and effective for the regeneration of durable articular cartilage in osteoarthritic knees.

The purpose of this study was to assess whether the use of a 10 mm-offset femoral tunnel guide with lateral rotation allows more anatomic placement of femoral tunnel compared to the conventional seven millimeters-offset guide in transtibial anterior cruciate ligament (ACL) reconstruction.Sixteen knees from eight cadavers were employed. Four guide pins were inserted using a seven millimeters- or 10mm-offset transtibial femoral tunnel guide with or without lateral rotation technique in each knee. The pin positions were assessed by the quadrant method. Femoral tunnels were then reamed along the guide pins inserted through the laterally rotated guides: seven millimeters-offset for right knees and 10 mm- offset for left knees. The percentages of the coverage of native ACL femoral footprints were analyzed.Lateral rotation of the seven millimeters-10mm-offset guides placed the pins more posteriorly (lower) by 15.7% and 24.5%, respectively (p0.001). Laterally rotated 10 mm-offset guides placed the guide pins more distally by 6.2% and more posteriorly by 6.6% than laterally rotated seven millimeters-offset guides. Laterally rotated seven millimeters-10 mm-offset guides resulted in average coverage of 52.3% and 61.8% of the native ACL femoral footprints, respectively (p0.001). The lengths of the tunnels were acceptable.Compared to the conventional seven millimeters-offset guide, the use of a 10mm-offset femoral tunnel guide with lateral rotation allows more anatomic placement of femoral tunnel in transtibial ACL reconstruction.Anatomic single bundle ACL reconstruction by transtibial technique seems feasible by using the technique described in this study.

Background As the possibility of developing complications after an "asymptomatic" venous thromboembolism (VTE) after total knee arthroplasty (TKA) has been reported very low, "symptomatic" VTEs seem to be the real concern among orthopedic surgeons. Therefore, the purpose of this study was to determine the incidence of "symptomatic" VTEs and the fate of "symptomatic" VTEs after anticoagulation therapy and assess whether routine pharmacologic prophylaxis is necessary in TKA patients. Methods We retrospectively reviewed 2891 consecutive TKAs in 1933 patients. Graduated compression stockings and intermittent pneumatic calf compression devices were used for VTE prophylaxis. The incidence of symptomatic VTE was investigated until 6 months postoperatively. Patients with VTE underwent anticoagulation therapy and followed up to evaluate range of motion, knee society score, Western Ontario and McMaster Universities index scores, and the presence of any complications (mean follow-up period, 3.6 years). Results Fifty-three (1.83%) of the 2891 TKAs had suggestive symptoms and/or sign of VTE. Of these 53 cases, 26 (0.90%) were diagnosed as symptomatic VTE, which comprised 10 (0.35%) symptomatic deep venous thromboses, 11 (0.38%) symptomatic pulmonary embolisms (PEs), 5 (0.17%) symptomatic deep venous thromboses combined with PEs, and no fatal PE. There was no significant difference in range of motion, knee society score, and Western Ontario and McMaster Universities index scores between the groups with or without symptomatic VTE. When treated properly after the diagnosis of symptomatic VTE, no specific complications were identified. Conclusion Symptomatic VTEs are rare in patients who undergo TKAs with mechanical prophylaxis only. Patients with symptomatic VTEs after TKA can be treated without significant sequelae once they are properly treated with anticoagulation after the diagnosis.

The pie-crusting method is popular in releasing lateral tightness during primary total knee arthroplasty (TKA) but is not well described for medial release. We established a selective medial release technique using the pie-crusting technique and investigated the effectiveness and safety of the technique during primary TKA.We retrospectively reviewed 729 primary TKAs with varus deformity between October 2009 and June 2012. Medial tightness in flexion was released by traditional subperiosteal stripping for the anterior portion of the medial collateral ligament (aMCL). Medial tightness in extension was released by the pie crusting for the tight fibers in the posterior portion of the MCL and/or posteromedial corner structures (pMCL/PMCS). Clinical outcomes were evaluated by Knee Society (KS) scores and the Western Ontario and McMaster Universities Osteoarthritis Index. Any complications, including late medial instability that may be related to our surgical technique, were carefully inspected.Among the 729 knees, 170 (23.3%) required subperiosteal stripping for balancing in flexion only, 186 (25.5%) required the pie-crusting for balancing in extension only and 142 (19.5%) required subperiosteal stripping and the pie-crusting for balancing in flexion and extension. The KS knee score was improved from 52.5 to 83.4, KS function score from 58.2 to 91.9, and Western Ontario and McMaster Universities Osteoarthritis Index from 42.7 to 21.8 (P.001, all). No specific complications related to our technique were identified.The selective medial release technique appears to be an effective and safe method to obtain a balanced mediolateral gap in primary TKA.

ObjectiveThe basic leucine zipper transcription factor, ATF-like (BATF), a member of the Activator protein-1 family, promotes transcriptional activation or repression, depending on the interacting partners (JUN-B or C-JUN). Here, we investigated whether the BATF/JUN complex exerts regulatory effects on catabolic and anabolic gene expression in chondrocytes and contributes to the pathogenesis of osteoarthritis (OA).MethodsPrimary cultured mouse chondrocytes were treated with proinflammatory cytokines (interleukin-1β, IL-6 or tumour necrosis factor-α) or infected with adenoviruses carrying the Batf gene (Ad-Batf). Expression of BATF and JUN was examined in human and mouse experimental OA cartilage samples. Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of Ad-Batf. The chromatin immunoprecipitation assay was used to examine the binding of BATF and JUN to the promoter regions of candidate genes.ResultsOverexpression of BATF, which forms a heterodimeric complex with JUN-B and C-JUN, induced upregulation of matrix-degrading enzymes and downregulation of cartilage matrix molecules in chondrocytes. BATF expression in mouse joint tissues promoted OA cartilage destruction, and conversely, knockout of Batf in mice suppressed experimental OA. Pharmacological inhibition of BATF/JUN transcriptional activity reduced the expression of matrix-degrading enzymes and protected against experimental OA in mice.ConclusionsBATF/JUN-B and BATF/C-JUN complexes play important roles in OA cartilage destruction through regulating anabolic and catabolic gene expression in chondrocytes. Our findings collectively support the utility of BATF as a therapeutic target for OA.

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).

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.

Background & Aim The placenta-derived mesenchymal stem cells have great interest as a promising cell source for regenerative medicine due to non-invasive collection, readily availability, high expansion capacity, and low immunogenicity. We investigated the feasibility of transplanting placenta-derived MSCs and a hyaluronic acid (HA) hydrogel composite to repair full-thickness articular cartilage defects and determine whether the transplantation of various concentrations of placenta-derived MSCs with 4% hyaluronic acid (HA) hydrogel promoted articular cartilage repair in a rabbit model. Methods, Results & Conclusion Methods Critical-sized osteochondral defects (5mm diameter × 5mm depth) were created in the center of the trochlear groove of femur. The Four experimental groups were as follows: group A, defect only (left knee)/ 4% HA hydrogel without placenta-MSCs (right knee), n=6; group B, 0.01 × 107 cells/ml with 4% HA hydrogel (left knee)/ 0.1 × 107 cells/ml with 4% HA hydrogel (right knee), n=8; group C, 0.1 × 107 cells/ml with 4% HA hydrogel (left knee)/ 0.5 × 107 cells/ml with 4% HA hydrogel (right knee), n=8; group D, 0.5 × 107 cells/ml with 4% HA hydrogel (left knee)/ 1 × 107 cells/ml with 4% HA hydrogel (right knee) were transplantation in a rabbit model. At 8 weeks after transplantation, the degree of cartilage repair was evaluated grossly and histologically using the International Cartilage Repair Society macroscopic score, the modified O'Driscoll score for histologic grading. Results Transplanting placenta-derived MSCs and a HA hydrogel composite resulted in overall superior cartilage repair tissue with better quality than no treatment and hyaluronic acid (HA) only treatment group. Interestingly, The 0.5 × 106 cells/ml group showed the highest cartilage repair at 8 weeks post transplantation. Conclusions The results of this study suggest that transplantation of the composite of placenta-derived MSCs and HA is promoting for cartilage repair. In addition, this study shows that optimal MSC concentration needs to be determined for better cartilage repair.

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.

Supplemental material, DS_10.1177_0363546519892278 for Intra-articular Injection of Culture-Expanded Mesenchymal Stem Cells Without Adjuvant Surgery in Knee Osteoarthritis: A Systematic Review and Meta-analysis by Seong Hwan Kim, Yoshi Pratama Djaja, Yong-Beom Park, Jung-Gwan Park, Young-Bong Ko and Chul-Won Ha in The American Journal of Sports Medicine

Background: Measuring the size of the anterior cruciate ligament (ACL) tibial footprint on magnetic resonance image (MRI) is common for preoperative planning of ACL reconstruction. However, the accuracy of such measurement has not been well documented. Purpose: To investigate whether the actual size of the ACL tibial footprint could be predicted by its measurement on MRI and to develop equations to improve the accuracy of predicting the actual size based on MRI measurement. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: A total of 164 patients with normal visualized ACL in gross evaluation and MRI were included (mean ± SD age, 67.3 ± 8.3 years). Cases with ACL tear, severe mucoid degeneration, osteophyte around the ACL tibial insertion, or intervals >12 months between MRI and actual measurement were excluded. The ACL tibial footprint was carefully dissected and measured during total knee arthroplasty. The length of the ACL tibial footprint on MRI was measured on a sagittal image, while the width was measured on an oblique coronal image. For the ACL tibial footprint, the association between measurement on MRI and actual measurement of length and width was analyzed via univariable and multivariable regression analyses. Reliability of measurements on MRI was also evaluated. Results: The length and width of the ACL tibial footprint as measured on MRI showed strong correlation with the actual length and width (coefficients: ρ = 0.904 and ρ = 0.808, respectively). There were differences between ACL size on MRI and its actual size: length, 12.4 mm (range, 9.7-15.3 mm) vs 13.8 (10.6-17.8) ( P < .001); width, 8.8 mm (range, 7.0-12.1 mm) vs 7.2 (5.8-10.4) ( P < .001). Based on sex, there were also differences between the size per MRI and the actual size ( P < .001 for all): length in men, 12.6 mm (range, 10.9-15.3 mm) vs 14.2 (12.3-17.8); length in women, 12.4 mm (range, 9.7-14.5 mm) vs 13.7 (10.6-15.8); width in men, 9.3 mm (range, 8.0-12.1 mm) vs 7.6 (5.8-10.4); width in women, 8.7 mm (range, 7.0-10.4 mm) vs 7.2 (5.8-9.7). The actual length of the ACL tibial footprint could be predicted by its length on MRI and sex ( R2 = 0.83, P < .001). Similarly, actual width could be predicted by the width on MRI and sex ( R2 = 0.75, P < .001). All intraclass correlation coefficients were >0.8, indicating good reliability. Conclusion: Measurements of the size of the ACL tibial footprint on MRI showed strong correlation with its actual size. Prediction equations showed good concordance correlation coefficients.

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.

ObjectiveThe zinc-ZIP8-MTF1 axis induces metallothionein (MT) expression and is a catabolic regulator of experimental osteoarthritis (OA) in mice. The main aim of the current study was to explore the roles and underlying molecular mechanisms of MTs in OA pathogenesis.MethodsExperimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of adenovirus carrying a target gene (Ad-Zip8, Ad-Mtf1, Ad-Epas1, Ad-Nampt, Ad-Mt1 or Ad-Mt2) into wild type, Zip8fl/fl; Col2a1-Cre, Mtf1fl/fl; Col2a1-Cre and Mt1/Mt2 double knockout mice. Primary cultured mouse chondrocytes were infected with Ad-Mt1 or Ad-Mt2, and gene expression profiles analysed via microarray and reverse transcription-PCR. Proteins in human and mouse OA cartilage were identified via immunostaining. Chondrocyte apoptosis in OA cartilage was determined using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL).ResultsMTs were highly expressed in human and mouse OA cartilage. Hypoxia-inducible factor 2α, nicotinamide phosphoribosyltransferase and several proinflammatory cytokine pathways, as well as the zinc-ZIP8-MTF1 axis were identified as upstream regulators of MT expression. Genetic deletion of Mt1 and Mt2 enhanced cartilage destruction through increasing chondrocyte apoptosis. Unexpectedly, aberrant overexpression of MT2, but not MT1, induced upregulation of matrix-degrading enzymes and downregulation of matrix molecules through nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activation, ultimately leading to OA.ConclusionsMTs play an antiapoptotic role in post-traumatic OA. However, aberrant and chronic upregulation of MT2 triggers an imbalance between chondrocyte anabolism and catabolism, consequently accelerating OA development. Our findings collectively highlight pleiotropic roles of MTs as regulators of chondrocyte apoptosis as well as catabolic and anabolic pathways during OA pathogenesis.

The cartilage regeneration potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with a hyaluronic acid (HA) hydrogel composite has shown remarkable results in rat and rabbit models. The purpose of the present study was to confirm the consistent regenerative potential in a pig model using three different cell lines. A full-thickness chondral injury was intentionally created in the trochlear groove of each knee in 6 minipigs. Three weeks later, an osteochondral defect, 5 mm wide by 10 mm deep, was created, followed by an 8-mm-wide and 5-mm-deep reaming. A mixture (1.5 ml) of hUCB-MSCs (0.5 × 107 cells per milliliter) and 4% HA hydrogel composite was then transplanted into the defect on the right knee. Each cell line was used in two minipigs. The osteochondral defect created in the same manner on the left knee was untreated to act as the control. At 12 weeks postoperatively, the pigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. The cellular characteristics (e.g., cellular proliferation and chondrogenic differentiation capacity) of the hUCB-MSCs influenced the degree of cartilage regeneration potential. This evidence of consistent cartilage regeneration using composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future. Significance To date, several studies have investigated the chondrogenic potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs); however, the preclinical studies are still limited in numbers with various results. In parallel, in the past several years, the cartilage regeneration potential of hUCB-MSCs with a hyaluronic acid (HA) hydrogel composite have been investigated and remarkable results in rat and rabbit models have been attained. (These experimental results are currently in preparation for publication.) Before applying the cartilage regeneration technique in a human clinical trial, it seemed necessary to confirm the consistent result in a larger animal model. At 12 weeks postoperatively, the minipigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. This evidence of consistent cartilage regeneration with composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future.

The aim of this study was to assess the effect of injecting genetically engineered chondrocytes expressing transforming growth factor beta 1 (TGF-β1) into the knees of patients with osteoarthritis. We assessed the resultant function, pain and quality of life.A total of 54 patients (20 men, 34 women) who had a mean age of 58 years (50 to 66) were blinded and randomised (1:1) to receive a single injection of the active treatment or a placebo. We assessed post-treatment function, pain severity, physical function, quality of life and the incidence of treatment-associated adverse events. Patients were followed at four, 12 and 24 weeks after injection.At final follow-up the treatment group had a significantly greater improvement in the mean International Knee Documentation Committee score than the placebo group (16 points; -18 to 49, vs 8 points; -4 to 37, respectively; p = 0.03). The treatment group also had a significantly improved mean visual analogue score at final follow-up (-25; -85 to 34, vs -11 points; -51 to 25, respectively; p = 0.032). Both cohorts showed an improvement in Western Ontario and McMaster Osteoarthritis Index and Knee Injury and Osteoarthritis Outcome Scores, but these differences were not statistically significant. One patient had an anaphylactic reaction to the preservation medium, but recovered within 24 hours. All other adverse events were localised and resolved without further action.This technique may result in improved clinical outcomes, with the aim of slowing the degenerative process, leading to improvements in pain and function. However, imaging and direct observational studies are needed to verify cartilage regeneration. Nevertheless, this study provided a sufficient basis to proceed to further clinical testing.Cite this article: Bone Joint J 2015;97-B:924–32.

This study was carried out to assess the feasibility of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in articular cartilage repair and to further determine a suitable delivering hydrogel in a rat model. Critical sized full thickness cartilage defects were created. The hUCB-MSCs and three different hydrogel composites (hydrogel A; 4% hyaluronic acid/30% pluronic (1:1, v/v), hydrogel B; 4% hyaluronic acid, and hydrogel C; 4% hyaluronic acid/30% pluronic/chitosan (1:1:2, v/v)) were implanted into the experimental knee (right knee) and hydrogels without hUCB-MSCs were implanted into the control knee (left knee). Defects were evaluated after 8 weeks. The hUCB-MSCs with hydrogels composites resulted in a better repair as seen by gross and histological evaluation compared with hydrogels without hUCB-MSCs. Among the three different hydrogels, the 4% hyaluronic acid hydrogel composite (hydrogel B) showed the best result in cartilage repair as seen by the histological evaluation compared with the other hydrogel composites (hydrogel A and C). The results of this study suggest that hUCB-MSCs may be a promising cell source in combination with 4% hyaluronic acid hydrogels in the in vivo repair of cartilage defects.

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.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.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).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 III; systematic review of level I, II, and III studies.

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.