Root Repair Has Superior Radiological and Clinical Outcomes Than Partial Meniscectomy and Nonoperative Treatment in the Management of Meniscus Root Tears: A Systematic Review.

PURPOSE: To compile and analyze structural and clinical outcomes after meniscus root tear treatment as currently described in the literature. METHODS: A review was conducted to identify studies published since 2011 on efficacy of repair, meniscectomy, and nonoperative management in the treatment of meniscus root tears. Patient cohorts were grouped into treatment categories, with medial and lateral root tears analyzed separately; data were collected on patient demographics, structural outcomes including joint space width, degree of medial meniscal extrusion, progression to total knee arthroplasty, and patient-reported outcome measures. Risk of bias was assessed using the MINORS (methodological index for non-randomized studies) criteria. Heterogeneity was measured using the I-statistic, and outcomes were summarized using forest plots without pooled means. RESULTS: The 56 included studies comprised a total of 3,191 patients. Mean age among the included studies ranged from 24.6 to 65.6 years, whereas mean follow-up ranged from 12 to 125.9 months. Heterogeneity analysis identified significant differences between studies. Change in joint space width ranged from -2.4 to -0.6 mm (i.e., decreased space) after meniscectomy (n = 186) and -0.9 to -0.1 mm after root repair (n = 209); change in medial meniscal extrusion ranged from -0.6 to 6.5 mm after root repair (n = 521) and 0.2 to 4.2 mm after meniscectomy (n = 66); and event rate for total knee arthroplasty ranged from 0.00 to 0.22 after root repair (n = 205), 0.35 to 0.60 after meniscectomy (n = 53), and 0.27 to 0.35 after nonoperative treatment (n = 93). Root repair produced the greatest numerical increase in International Knee Documentation Committee and Lysholm scores of the 3 treatment arms. In addition, root repair improvements in Knee Injury and Osteoarthritis Outcome Score Pain (range: 22-32), Sports and Recreational Activities (range: 23-36), Quality of Life (range: 22-42), and Symptoms subscales (range: 10-19), in studies with low risk of bias. CONCLUSIONS: The literature reporting on the treatment of meniscus root tears is heterogenous and largely limited to Level III and IV studies. Current evidence suggests root repair may be the most effective treatment strategy in lessening joint space narrowing of the knee and producing improvements in patient-reported outcomes. LEVEL OF EVIDENCE: Level IV, systematic review of Level II-IV studies.

High incidence of medial meniscus root/radial tears and extrusion in 253 patients with subchondral insufficiency fractures of the knee.

PURPOSE: The demographic and radiological risk factors of subchondral insufficiency fractures of the knee (SIFK) continue to be a subject of debate. The purpose of this study was to associate patient-specific factors with SIFK in a large cohort of patients. METHODS: Inclusion criteria consisted of patients with SIFK as verified on magnetic resonance imaging (MRI). All radiographs and MRIs were reviewed to assess characteristics such as meniscus tear presence and type, subchondral oedema presence and location, location of SIFK, mechanical limb alignment, osteoarthritis as assessed by Kellgren-Lawrence grade and ligamentous injury. A total of 253 patients (253 knees) were included, with 171 being female. The average body mass index (BMI) was 32.1 ± 7.0 kg/m2. RESULTS: SIFK was more common in patients with medial meniscus tears (77.1%, 195/253) rather than tears of the lateral meniscus (14.6%, 37/253) (p < 0.001). Medial meniscus root and radial tears of the posterior horn were present in 71.1% (180/253) of patients. Ninety-one percent (164/180) of medial meniscus posterior root and radial tears had an extrusion ≥3.0 mm. Eighty-one percent (119/147) of patients with SIFK on the medial femoral condyle and 86.8% (105/121) of patients with SIFK on the medial tibial plateau had a medial meniscus tear. Varus knees had a significantly increased rate of SIFK on the medial femoral condyle in comparison to valgus knees (p = 0.016). CONCLUSION: In this large cohort of patients with SIFK, there was a high association with medial meniscus root and radial tears of the posterior horn, meniscus extrusion ≥3.0 mm as well as higher age, female gender and higher BMI. Additionally, there was a particularly strong association of medial compartment SIFK with medial meniscus tears. As SIFK is frequently undiagnosed, identifying patient-specific demographic and radiological risk factors will help achieve a prompt diagnosis. LEVEL OF EVIDENCE: Level IV.

Risk factors for secondary meniscus tears can be accurately predicted through machine learning, creating a resource for patient education and intervention.

PURPOSE: This study sought to develop and internally validate a machine learning model to identify risk factors and quantify overall risk of secondary meniscus injury in a longitudinal cohort after primary ACL reconstruction (ACLR). METHODS: Patients with new ACL injury between 1990 and 2016 with minimum 2-year follow-up were identified. Records were extensively reviewed to extract demographic, treatment, and diagnosis of new meniscus injury following ACLR. Four candidate machine learning algorithms were evaluated to predict secondary meniscus tears. Performance was assessed through discrimination using area under the receiver operating characteristics curve (AUROC), calibration, and decision curve analysis; interpretability was enhanced utilizing global variable importance plots and partial dependence curves. RESULTS: A total of 1187 patients underwent ACLR; 139 (11.7%) experienced a secondary meniscus tear at a mean time of 65 months post-op. The best performing model for predicting secondary meniscus tear was the random forest (AUROC = 0.790, 95% CI: 0.785-0.795; calibration intercept = 0.006, 95% CI: 0.005-0.007, calibration slope = 0.961 95% CI: 0.956-0.965, Brier's score = 0.10 95% CI: 0.09-0.12), and all four machine learning algorithms outperformed traditional logistic regression. The following risk factors were identified: shorter time to return to sport (RTS), lower VAS at injury, increased time from injury to surgery, older age at injury, and proximal ACL tear. CONCLUSION: Machine learning models outperformed traditional prediction models and identified multiple risk factors for secondary meniscus tears after ACLR. Following careful external validation, these models can be deployed to provide real-time quantifiable risk for counseling and timely intervention to help guide patient expectations and possibly improve clinical outcomes. LEVEL OF EVIDENCE: III.

Hamstring Autograft Anterior Cruciate Ligament Reconstruction Using an All-Inside Technique With and Without Independent Suture Tape Reinforcement.

PURPOSE: To compare the (1) rates of complications and reoperations, (2) rate of anterior cruciate ligament (ACL) graft failure, and (3) patient-reported outcomes (PROs) among patients after hamstring autograft ACL reconstruction (ACLR) with and without independent suture tape reinforcement at a minimum 2-year clinical follow-up. METHODS: We performed a 1:2 matched-cohort comparison of patients who underwent hamstring autograft ACLR with and without independent suture tape reinforcement between July 2011 and July 2017. Patients were matched according to age, sex, body mass index, preinjury Tegner activity score, and concomitant meniscal injury. Medical records were reviewed for demographic characteristics, additional injuries, and concomitant procedures. PRO scores (including Tegner activity, Lysholm, and International Knee Documentation Committee scores) and physical examination findings were collected both preoperatively and at a minimum of 2 years postoperatively. RESULTS: Overall, 108 patients who underwent ACLR were included: 36 patients (mean age, 25.3 years; range, 13-44 years) with independent suture tape reinforcement and 72 patients (mean age, 24.9 years; range, 13-54 years) without suture tape reinforcement. Overall, 5 of 36 suture tape patients (14%) and 10 of 72 control patients (14%) underwent reoperations. At an average follow-up of 26.1 months in the suture tape cohort and 31.3 months in the control cohort, 1 patient in the suture tape cohort and 4 patients in the control cohort experienced graft failure. There were no statistically significant differences between the suture tape and control groups regarding return-to-sport rate (89% and 88%, respectively), postoperative International Knee Documentation Committee score (94.4 and 93.8, respectively), and postoperative Lysholm score (95.6 and 94, respectively). There was a statistically significant difference between the suture tape and control groups in postoperative Tegner activity score, at 7.1 (95% confidence interval, 6.5-7.6) and 6.4 (95% confidence interval, 6.2-6.6), respectively (P = .026). CONCLUSIONS: ACLR with hamstring autograft and independent suture tape reinforcement was performed safely with low rates of complications, graft failure, and reoperations with similar PROs, function, and return-to-sport rates when compared with hamstring autograft ACLR without suture tape reinforcement at a minimum 2-year follow-up. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

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

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

Post-arthroscopic Subchondral Insufficiency Fractures of the Knee Yield High Rate of Conversion to Arthroplasty.

PURPOSE: To evaluate both the potential causes and resultant outcomes in patients in whom subchondral insufficiency fracture of the knee (SIFK) develops after arthroscopy. METHODS: We performed a retrospective review of all patients with a magnetic resonance imaging diagnosis of SIFK after arthroscopic meniscectomy and chondroplasty over a 12-year period. RESULTS: A total of 28 patients were included, with a mean age of 61 years and mean follow-up period of 5.7 years. SIFK showed a predilection for the medial compartment (n = 25, 89%), specifically the medial femoral condyle (n = 21, 75%). In 7 patients (25%), SIFK developed in both the femoral condyle and tibial plateau in the ipsilateral compartment. Fifteen patients (54%) went on to conversion to arthroplasty at a mean of 0.72 years. The rate of survival free of conversion to arthroplasty was 57%, 45%, and 40% at 1 year, 2 years, and 5 years, respectively. Furthermore, 63% of patients with a meniscal tear and SIFK in the same compartment went on to arthroplasty (P = .04). There was an increased risk of conversion to arthroplasty if SIFK was present in both the femur and tibia in the same compartment (P = .04). A higher Kellgren-Lawrence grade at the time of the SIFK diagnosis increased the likelihood of eventual arthroplasty (P = .03). The presence of SIFK in both the femur and tibia in the ipsilateral compartment, an increased Kellgren-Lawrence grade, and a meniscal tear or prior meniscectomy in the same compartment as SIFK were associated with an increased risk of eventual arthroplasty. CONCLUSIONS: Post-arthroscopic SIFK most commonly occurs in the medial compartment, particularly in patients who underwent a prior meniscectomy. The presence of meniscal root and radial tears in these patients is notable (75%). Ultimately, there is a high rate of progression of arthrosis (33%) and eventual conversion to arthroplasty. LEVEL OF EVIDENCE: Level IV, case series.

Arthritic progression secondary to meniscus root tear treated with knee arthroplasty demonstrates similar outcomes to primary osteoarthritis: a matched case-control comparison.

PURPOSE: There is limited data comparing the outcomes of knee arthroplasty for arthritis secondary to meniscus root tear versus primary osteoarthritis. The aim of this 2:1 matched case control series was to compare outcomes in patients who underwent arthroplasty for arthritis following a meniscus root tear (root tear cohort-"RTC") with a control group of patients with primary osteoarthritis (primary osteoarthritis-"controls"). The authors hypothesized that the meniscus root tear patients would have similar clinical outcomes, return to activity, complication and reoperation rates as their matched controls. METHODS: A consecutive series of patients who had a clinically and radiographically confirmed meniscus root tear between 2002 and 2017 at a mean 4.8 year follow-up that developed secondary arthritis were matched 2:1 by laterality, surgery, age at surgery, date of surgery, sex, and surgeon to a control group of patients with primary osteoarthritis, without a root tear, who underwent arthroplasty. No patients were lost to follow-up. Patient demographics, Kellgren-Lawrence grades at the time of surgery, pre- and post-operative Knee Society Score pain and function scores, Tegner score, complications, and survival free of reoperation were analyzed between groups. RESULTS: A total of 225 subjects were identified, including 75 root tear cohort patients (13 UKA, 62 TKA) and 150 control patients. The root tear cohort had significantly lower Kellgren-Lawrence grades than the control group at the time of arthroplasty (p ≤ 0.001), but similar baseline pre-operative Knee Society Score pain, Knee Society Score function, and Tegner activity scale score. Post-operatively, Knee Society Score pain scores were comparable, and root tear cohort Knee Society Score function scores statistically significantly improved (p ≤ 0.007). Complication rates and survival free of reoperation at final follow-up were not statistically significantly different between groups. CONCLUSION: Patients treated with arthroplasty for secondary arthritis after a meniscus root tear demonstrated less severe radiographic arthritis, but similar pre-operative pain levels compared to matched controls with primary osteoarthritis. The root tear cohort patients demonstrated improved outcomes with respect to function, and similar outcomes with respect to pain, activity level, complication rates, and reoperation rates. The authors conclude that arthroplasty can be a reliable option for selected patients with an irreparable root tear and ongoing pain and dysfunction refractory to non-operative management, even in the setting of less advanced osteoarthritis on X-ray. LEVEL OF EVIDENCE: III.

Selection of Highly Proliferative and Multipotent Meniscus Progenitors through Differential Adhesion to Fibronectin: A Novel Approach in Meniscus Tissue Engineering.

Meniscus injuries can be highly debilitating and lead to knee osteoarthritis. Progenitor cells from the meniscus could be a superior cell type for meniscus repair and tissue-engineering. The purpose of this study is to characterize meniscus progenitor cells isolated by differential adhesion to fibronectin (FN-prog). Human osteoarthritic menisci were digested, and FN-prog were selected by differential adhesion to fibronectin. Multilineage differentiation, population doubling time, colony formation, and MSC surface markers were assessed in the FN-prog and the total meniscus population (Men). Colony formation was compared between outer and inner zone meniscus digest. Chondrogenic pellet cultures were performed for redifferentiation. FN-prog demonstrated multipotency. The outer zone FN-prog formed more colonies than the inner zone FN-prog. FN-prog displayed more colony formation and a higher proliferation rate than Men. FN-prog redifferentiated in pellet culture and mostly adhered to the MSC surface marker profile, except for HLA-DR receptor expression. This is the first study that demonstrates differential adhesion to fibronectin for the isolation of a progenitor-like population from the meniscus. The high proliferation rates and ability to form meniscus extracellular matrix upon redifferentiation, together with the broad availability of osteoarthritis meniscus tissue, make FN-prog a promising cell type for clinical translation in meniscus tissue-engineering.

Potential of Melt Electrowritten Scaffolds Seeded with Meniscus Cells and Mesenchymal Stromal Cells.

Meniscus injury and meniscectomy are strongly related to osteoarthritis, thus there is a clinical need for meniscus replacement. The purpose of this study is to create a meniscus scaffold with micro-scale circumferential and radial fibres suitable for a one-stage cell-based treatment. Poly-caprolactone-based scaffolds with three different architectures were made using melt electrowriting (MEW) technology and their in vitro performance was compared with scaffolds made using fused-deposition modelling (FDM) and with the clinically used Collagen Meniscus Implants® (CMI®). The scaffolds were seeded with meniscus and mesenchymal stromal cells (MSCs) in fibrin gel and cultured for 28 d. A basal level of proteoglycan production was demonstrated in MEW scaffolds, the CMI®, and fibrin gel control, yet within the FDM scaffolds less proteoglycan production was observed. Compressive properties were assessed under uniaxial confined compression after 1 and 28 d of culture. The MEW scaffolds showed a higher Young's modulus when compared to the CMI® scaffolds and a higher yield point compared to FDM scaffolds. This study demonstrates the feasibility of creating a wedge-shaped meniscus scaffold with MEW using medical-grade materials and seeding the scaffold with a clinically-feasible cell number and -type for potential translation as a one-stage treatment.

How do the costs of physical therapy and arthroscopic partial meniscectomy compare? A trial-based economic evaluation of two treatments in patients with meniscal tears alongside the ESCAPE study.

OBJECTIVES: To examine whether physical therapy (PT) is cost-effective compared with arthroscopic partial meniscectomy (APM) in patients with a non-obstructive meniscal tear, we performed a full trial-based economic evaluation from a societal perspective. In a secondary analysis-this paper-we examined whether PT is non-inferior to APM. METHODS: We recruited patients aged 45-70 years with a non-obstructive meniscal tear in nine Dutch hospitals. Resource use was measured using web-based questionnaires. Measures of effectiveness included knee function using the International Knee Documentation Committee (IKDC) and quality-adjusted life-years (QALYs). Follow-up was 24 months. Uncertainty was assessed using bootstrapping techniques. The non-inferiority margins for societal costs, the IKDC and QALYs, were €670, 8 points and 0.057 points, respectively. RESULTS: We randomly assigned 321 patients to PT (n=162) or APM (n=159). PT was associated with significantly lower costs after 24 months compared with APM (-€1803; 95% CI -€3008 to -€838). The probability of PT being cost-effective compared with APM was 1.00 at a willingness to pay of €0/unit of effect for the IKDC (knee function) and QALYs (quality of life) and decreased with increasing values of willingness to pay. The probability that PT is non-inferior to APM was 0.97 for all non-inferiority margins for the IKDC and 0.89 for QALYs. CONCLUSIONS: The probability of PT being cost-effective compared with APM was relatively high at reasonable values of willingness to pay for the IKDC and QALYs. Also, PT had a relatively high probability of being non-inferior to APM for both outcomes. This warrants further deimplementation of APM in patients with non-obstructive meniscal tears. TRIAL REGISTRATION NUMBERS: NCT01850719 and NTR3908.

The SIFK score: a validated predictive model for arthroplasty progression after subchondral insufficiency fractures of the knee.

PURPOSE: The purpose of this study was to create a predictive model utilizing baseline demographic and radiographic characteristics for the likelihood that a patient with subchondral insufficiency fracture of the knee will progress to knee arthroplasty with emphasis on clinical interpretability and usability. METHODS: A retrospective review of baseline and final radiographs in addition to MRIs were reviewed for evaluation of insufficiency fractures and associated injuries. Patient and radiographic factors were used in building predictive models for progression to arthroplasty with Train: Validation: Test subsets. Multiple models were compared with emphasis on clinical utility. RESULTS: Total of 249 patients with a mean age of 64.6 (SD 10.5) years were included. Knee arthroplasty rate was 27% at mean of 4 years of follow-up. Lasso Regression was non-inferior to other models and was chosen for ease of interpretability. In order of importance, predictors for progression to arthroplasty included lateral meniscus extrusion, Kellgren-Lawrence Grade 4, SIFK on MFC, lateral meniscus root tear, and medial meniscus extrusion. The final SIFK Score stratified patients into low-, medium-, and high-risk categories with arthroplasty rates of 8.8%, 40.4%, and 78.9% (p < 0.001) and an area under the curve of 82.5%. CONCLUSION: In this validated model, lateral meniscus extrusion, K-L Grade 4, SIFK on MFC, lateral meniscus root tear, and medial meniscus extrusion were the most important factors in predicting progression to arthroplasty (in that order). This model assists in patient treatment and counseling in providing prognostic information based on patient-specific risk factors by classifying them into a low-, medium-, and high-risk categories. This model can be used both by medical professionals treating musculoskeletal injuries in guiding patient decision making. LEVEL OF EVIDENCE: Level III.

Intra-articular injection with Autologous Conditioned Plasma does not lead to a clinically relevant improvement of knee osteoarthritis: a prospective case series of 140 patients with 1-year follow-up.

Background and purpose - Platelet-rich plasma (PRP) is broadly used in the treatment of knee osteoarthritis, but clinical outcomes are highly variable. We evaluated the effectiveness of intra-articular injections with Autologous Conditioned Plasma (ACP), a commercially available form of platelet-rich plasma, in a tertiary referral center. Second, we aimed to identify which patient factors are associated with clinical outcome. Patients and methods - 140 patients (158 knees) with knee osteoarthritis (Kellgren and Lawrence grade 0-4) were treated with 3 intra-articular injections of ACP. The Knee Injury and Osteoarthritis Outcome Score (KOOS), pain (Numeric Rating Scale; NRS), and general health (EuroQol 5 Dimensions; EQ5D) were assessed at baseline and 3, 6, and 12 months' follow-up. The effect of sex, age, BMI, Kellgren and Lawrence grade, history of knee trauma, and baseline KOOS on clinical outcome at 6 and 12 months was determined using linear regression. Results - Mean KOOS increased from 37 at baseline to 44 at 3 months, 45 at 6 months, and 43 at 12 months' follow-up. Mean NRS-pain decreased from 6.2 at baseline to 5.3 at 3 months, 5.2 at 6 months, and 5.3 at 12 months. EQ5D did not change significantly. There were no predictors of clinical outcome. Interpretation - ACP does not lead to a clinically relevant improvement (exceeding the minimal clinically important difference) in patients suffering from knee osteoarthritis. None of the investigated factors predicts clinical outcome.

Does Internal Fixation for Unstable Osteochondritis Dissecans of the Skeletally Mature Knee Work? A Systematic Review.

PURPOSE: To report the rate of radiographic union, patient-reported outcomes, complications, and reoperations after internal fixation of unstable osteochondritis dissecans (OCD) in the skeletally mature knee. METHODS: A literature search was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Patients were included if they were skeletally mature and underwent internal fixation of an unstable OCD lesion of the knee. Risk of bias assessment was performed using the Methodological Index for Non-randomized Studies scoring system. Surgical technique, rate of union, patient-reported outcomes, complications, and reoperations were collected. RESULTS: Thirteen studies resulted in 148 patients (150 knees) for inclusion. Patient age ranged from 14 to 45 years. Numerous fixation procedures were used, including biodegradable devices (rods, pins, nails, and screws), metal screws, Kirschner wire, and autologous bone sticks. Overall, reported outcome measures were heterogeneous in nature. The rate of radiographic healing ranged from 67% to 100% across 6 studies. Improved subjective results and Hughston criteria on final follow-up ranged from 83% to 100% across 4 studies each. Mean postoperative Lysholm scores ranged from 42 to 98 in studies that reported them. Both complication and reoperation rates ranged from 0% to 44%. The most commonly performed reoperations were loose body excision and cartilage resurfacing procedures. CONCLUSIONS: A variety of surgical techniques are available for treatment of unstable OCD lesions in the skeletally mature knee. In this systematic review, internal fixation of the native fragment showed acceptable rates of radiographic union and improved patient-reported outcomes relative to other techniques. LEVEL OF EVIDENCE: Level IV, systematic review of level III-IV studies.

Nanoparticle Enhancement Cascade for Sensitive Multiplex Measurements of Biomarkers in Complex Fluids with Surface Plasmon Resonance Imaging.

There is a large unmet need for reliable biomarker measurement systems for clinical application. Such systems should meet challenging requirements for large scale use, including a large dynamic detection range, multiplexing capacity, and both high specificity and sensitivity. More importantly, these requirements need to apply to complex biological samples, which require extensive quality control. In this paper, we present the development of an enhancement detection cascade for surface plasmon resonance imaging (SPRi). The cascade applies an antibody sandwich assay, followed by neutravidin and a gold nanoparticle enhancement for quantitative biomarker measurements in small volumes of complex fluids. We present a feasibility study both in simple buffers and in spiked equine synovial fluid with four cytokines, IL-1ß, IL-6, IFN-γ, and TNF-α. Our enhancement cascade leads to an antibody dependent improvement in sensitivity up to 40 000 times, resulting in a limit of detection as low as 50 fg/mL and a dynamic detection range of more than 7 logs. Additionally, measurements at these low concentrations are highly reliable with intra- and interassay CVs between 2% and 20%. We subsequently showed this assay is suitable for multiplex measurements with good specificity and limited cross-reactivity. Moreover, we demonstrated robust detection of IL-6 and IL-1ß in spiked undiluted equine synovial fluid with small variation compared to buffer controls. In addition, the availability of real time measurements provides extensive quality control opportunities, essential for clinical applications. Therefore, we consider this method is suitable for broad application in SPRi for multiplex biomarker detection in both research and clinical settings.

Allogeneic MSCs and Recycled Autologous Chondrons Mixed in a One-Stage Cartilage Cell Transplantion: A First-in-Man Trial in 35 Patients.

MSCs are known as multipotent mesenchymal stem cells that have been found capable of differentiating into various lineages including cartilage. However, recent studies suggest MSCs are pericytes that stimulate tissue repair through trophic signaling. Aimed at articular cartilage repair in a one-stage cell transplantation, this study provides first clinical evidence that MSCs stimulate autologous cartilage repair in the knee without engrafting in the host tissue. A phase I (first-in-man) clinical trial studied the one-stage application of allogeneic MSCs mixed with 10% or 20% recycled defect derived autologous chondrons for the treatment of cartilage defects in 35 patients. No treatment-related serious adverse events were found and statistically significant improvement in clinical outcome shown. Magnetic resonance imaging and second-look arthroscopies showed consistent newly formed cartilage tissue. A biopsy taken from the center of the repair tissue was found to have hyaline-like features with a high concentration of proteoglycans and type II collagen. DNA short tandem repeat analysis delivered unique proof that the regenerated tissue contained patient-DNA only. These findings support the hypothesis that allogeneic MSCs stimulate a regenerative host response. This first-in-man trial supports a paradigm shift in which MSCs are applied as augmentations or "signaling cells" rather than differentiating stem cells and opens doors for other applications. Stem Cells 2017;35:1984-1993.

Allogeneic Mesenchymal Stem Cells Stimulate Cartilage Regeneration and Are Safe for Single-Stage Cartilage Repair in Humans upon Mixture with Recycled Autologous Chondrons.

Traditionally, mesenchymal stem cells (MSCs) isolated from adult bone marrow were described as being capable of differentiating to various lineages including cartilage. Despite increasing interest in these MSCs, concerns regarding their safety, in vivo behavior and clinical effectiveness have restrained their clinical application. We hypothesized that MSCs have trophic effects that stimulate recycled chondrons (chondrocytes with their native pericellular matrix) to regenerate cartilage. Searching for a proof of principle, this phase I (first-in-man) clinical trial applied allogeneic MSCs mixed with either 10% or 20% recycled autologous cartilage-derived cells (chondrons) for treatment of cartilage defects in the knee in symptomatic cartilage defect patients. This unique first in man series demonstrated no treatment-related adverse events up to one year postoperatively. At 12 months, all patients showed statistically significant improvement in clinical outcome compared to baseline. Magnetic resonance imaging and second-look arthroscopies showed completely filled defects with regenerative cartilage tissue. Histological analysis on biopsies of the grafts indicated hyaline-like regeneration with a high concentration of proteoglycans and type II collagen. Short tandem repeat analysis showed the regenerative tissue only contained patient-own DNA. These findings support the novel insight that the use of allogeneic MSCs is safe and opens opportunities for other applications. Stem cell-induced paracrine mechanisms may play an important role in the chondrogenesis and successful tissue regeneration found. Stem Cells 2017;35:256-264.

Detection of early cartilage damage: feasibility and potential of gagCEST imaging at 7T.

OBJECTIVES: The purpose was to implement a fast 3D glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) sequence at 7 T, test stability and reproducibility in cartilage in the knee in healthy volunteers, and evaluate clinical applicability in cartilage repair patients. METHODS: Experiments were carried out on a 7-T scanner using a volume transmit coil and a 32-channel receiver wrap-around knee coil. The 3D gagCEST measurement had an acquisition time of 7 min. Signal stability and reproducibility of the GAG effect were assessed in eight healthy volunteers. Clinical applicability of the method was demonstrated in five patients before cartilage repair surgery. RESULTS: Coefficient of variation of the gagCEST signal was 1.9%. The reproducibility of the GAG effect measurements was good in the medial condyle (ICC = 0.87) and excellent in the lateral condyle (ICC = 0.97). GAG effect measurements in healthy cartilage ranged from 2.6%-12.4% compared with 1.3%-5.1% in damaged cartilage. Difference in GAG measurement between healthy cartilage and damaged cartilage was significant (p < 0.05). CONCLUSIONS: A fast 3D gagCEST sequence was applied at 7 T for use in cartilage in the knee, acquired within a clinically feasible scan time of 7 min. We demonstrated that the method has high stability, reproducibility and clinical applicability. KEY POINTS: • gagCEST measurements are stable and reproducible • A non-invasive GAG measurement with gagCEST can be acquired in 7 min • gagCEST is able to discriminate between healthy and damaged cartilage.

Effect of Early Surgery vs Physical Therapy on Knee Function Among Patients With Nonobstructive Meniscal Tears: The ESCAPE Randomized Clinical Trial.

Importance: Despite recent studies suggesting arthroscopic partial meniscectomy (APM) is not more effective than physical therapy (PT), the procedure is still frequently performed in patients with meniscal tears. Objective: To assess whether PT is noninferior to APM for improving patient-reported knee function in patients with meniscal tears. Design, Setting, and Participants: Noninferiority, multicenter, randomized clinical trial conducted in 9 hospitals in the Netherlands. Participants were aged 45 to 70 years with nonobstructive meniscal tears (ie, no locking of the knee joint). Patients with knee instability, severe osteoarthritis, and body mass index greater than 35 were excluded. Recruitment took place between July 17, 2013, and November 4, 2015. Participants were followed up for 24 months (final participant follow-up, October 11, 2017). Interventions: Three hundred twenty-one participants were randomly assigned to APM (n = 159) or a predefined PT protocol (n = 162). The PT protocol consisted of 16 sessions of exercise therapy over 8 weeks focused on coordination and closed kinetic chain strength exercises. Main Outcomes and Measures: The primary outcome was change in patient-reported knee function on the International Knee Documentation Committee Subjective Knee Form (range, 0 to 100; from worse to best) from baseline over a 24-month follow-up period. The noninferiority margin was defined as a difference between treatment groups of 8 points and was assessed with a 1-sided α of .025. The primary analysis followed the intention-to-treat principle. Results: Among 321 patients who were randomized (mean [SD] age, 58 [6.6] years; 161 women [50%]), 289 (90%) completed the trial (161 women and 158 men). In the PT group, 47 participants (29%) had APM during the 24-month follow-up period, and 8 participants randomized to APM (5%) did not have APM. Over a 24-month follow-up period, knee function improved in the APM group by 26.2 points (from 44.8 to 71.5) and in the PT group by 20.4 points (from 46.5 to 67.7). The overall between-group difference was 3.6 points (97.5% CI, -∞ to 6.5; P value for noninferiority = .001). Adverse events occurred in 18 participants in the APM group and 12 in the PT group. Repeat surgery (3 in the APM group and 1 in the PT group) and additional outpatient visits for knee pain (6 in the APM group and 2 in the PT group) were the most frequent adverse events. Conclusions and Relevance: Among patients with nonobstructive meniscal tears, PT was noninferior to APM for improving patient-reported knee function over a 24-month follow-up period. Based on these results, PT may be considered an alternative to surgery for patients with nonobstructive meniscal tears. Trial Registration: ClinicalTrials.gov Identifier: NCT01850719.

Cross-Talk Between Human Tenocytes and Bone Marrow Stromal Cells Potentiates Extracellular Matrix Remodeling In Vitro.

Tendon and ligament (T/L) pathologies account for a significant portion of musculoskeletal injuries and disorders. Tissue engineering has emerged as a promising solution in the regeneration of both tissues. Specifically, the use of multipotent human mesenchymal stromal cells (hMSC) has shown great promise to serve as both a suitable cell source for tenogenic regeneration and a source of trophic factors to induce tenogenesis. Using four donor sets, we investigated the bidirectional paracrine tenogenic response between human hamstring tenocytes (hHT) and bone marrow-derived hMSC. Cell metabolic assays showed that only one hHT donor experienced sustained notable increases in cell metabolic activity during co-culture. Histological staining confirmed that co-culture induced elevated collagen protein levels in both cell types at varying time-points in two of four donor sets assessed. Gene expression analysis using qPCR showed the varied up-regulation of anabolic and catabolic markers involved in extracellular matrix maintenance for hMSC and hHT. Furthermore, analysis of hMSC/hHT co-culture secretome using a reporter cell line for TGF-ß, a potent inducer of tenogenesis, revealed a trend of higher TGF-ß bioactivity in hMSC secretome compared to hHT. Finally, hHT cytoskeletal immunostaining confirmed that both cell types released soluble factors capable of inducing favorable tenogenic morphology, comparable to control levels of soluble TGF-ß1. These results suggest a potential for TGF-ß-mediated signaling mechanism that is involved during the paracrine interplay between the two cell types that is reminiscent of T/L matrix remodeling/turnover. These findings have significant implications in the clinical use of hMSC for common T/L pathologies.

Means of enhancing bone fracture healing: optimal cell source, isolation methods and acoustic stimulation.

BACKGROUND: The human body has an extensive capacity to regenerate bone tissue after trauma. However large defects such as long bone fractures of the lower limbs cannot be restored without intervention and often lead to nonunion. Therefore, the aim of the present study was to assess the pool and biological functions of human mesenchymal stromal cells (hMSCs) isolated from different bone marrow locations of the lower limbs and to identify novel strategies to prime the cells prior to their use in bone fracture healing. Following, bone marrow from the ilium, proximal femur, distal femur and proximal tibia was aspirated and the hMSCs isolated. Bone marrow type, volume, number of mononuclear cells/hMSCs and their self-renewal, multilineage potential, extracellular matrix (ECM) production and surface marker profiling were analyzed. Additionally, the cells were primed to accelerate bone fracture healing either by using acoustic stimulation or varying the initial hMSCs isolation conditions. RESULTS: We found that the more proximal the bone marrow aspiration location, the larger the bone marrow volume was, the higher the content in mononuclear cells/hMSCs and the higher the self-renewal and osteogenic differentiation potential of the isolated hMSCs were. Acoustic stimulation of bone marrow, as well as the isolation of hMSCs in the absence of fetal bovine serum, increased the osteogenic and ECM production potential of the cells, respectively. CONCLUSION: We showed that bone marrow properties change with the aspiration location, potentially explaining the differences in bone fracture healing between the tibia and the femur. Furthermore, we showed two new priming methods capable of enhancing bone fracture healing.