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.

A Multicenter, Randomized, Double-Blinded, Parallel-Group, Placebo-Controlled Phase I/IIa Study to Evaluate the Efficacy and Safety of a Single Intra-Articular Injection of YYD302 in Patients with Knee Osteoarthritis.

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.

Meniscus regeneration with injectable Pluronic/PMMA-reinforced fibrin hydrogels in a rabbit segmental meniscectomy model.

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.

Intra-Articular Injection of a Novel DVS Cross-Linked Hyaluronic Acid Manufactured by Biological Fermentation (YYD302) in Patients With Knee Osteoarthritis: A Double-Blind, Randomized, Multicenter, Noninferiority Study.

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.

Efficacy and safety of a novel hemostatic material, BoneStat, compared with Ostene and Bone Wax in a rat calvarial defect model.

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.

Adverse Reactions and Clinical Outcomes for Leukocyte-Poor Versus Leukocyte-Rich Platelet-Rich Plasma in Knee Osteoarthritis: A Systematic Review and Meta-analysis.

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.

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.

Injectable Fibrin/Polyethylene Oxide Semi-IPN Hydrogel for a Segmental Meniscal Defect Regeneration.

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.

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.

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).

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).

Associations between biomarkers and histological assessment in individual animals in a destabilization of the medial meniscus (DMM) model of osteoarthritis (OA).

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.

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.

Predictive validity of radiographic signs of complete discoid lateral meniscus in children using machine learning techniques.

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 be <12.55 mm for FH height, <0.804 for prominence ratio, and >6.6 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.

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.

Common Repository of FBS Proteins (cRFP) To Be Added to a Search Database for Mass Spectrometric Analysis of Cell Secretome.

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.