Platelet-rich plasma injections for the management of knee osteoarthritis: The ESSKA-ICRS consensus. Recommendations using the RAND/UCLA appropriateness method for different clinical scenarios.

PURPOSE: The aim of this consensus was to develop evidence- and expert-based patient-focused recommendations on the appropriateness of intra-articular platelet-rich plasma (PRP) injections in different clinical scenarios of patients with knee osteoarthritis (OA). METHODS: The RAND/UCLA Appropriateness Method was used by the European Society of Sports Traumatology, Knee Surgery, and Arthroscopy (ESSKA), as well as the International Cartilage Regeneration and Joint Preservation Society (ICRS) to reach a consensus and produce recommendations for specific patient categories combining best available scientific evidence with the collective judgement of a panel of experts. RESULTS: Scenarios were defined based on first treatment vs first injective treatment vs second injective treatment, age (<50/50-65/66-80/>80), tibiofemoral vs patellofemoral involvement, OA level (Kellgren-Lawrence/KL 0-I/II-III/IV), and joint effusion (dry knee, minor-mild or major effusion). Out of 216 scenarios, in 84 (38.9%) the indication was considered appropriate, in 9 (4.2%) inappropriate and in 123 (56.9%) uncertain. The parameters associated with the highest consensus were PRP use after failed injective treatments (62.5%), followed by PRP after failed conservative treatments and KL 0-III scenarios (58.3%), while the highest uncertainty was found for PRP use as first treatment and KL IV OA (91.7% and 87.5% of uncertain scenarios, respectively). CONCLUSION: This ESSKA-ICRS consensus established recommendations on the appropriateness or inappropriateness of PRP injections for the treatment of knee OA, providing a useful reference for clinical practice. PRP injections are considered appropriate in patients aged ≤80 years with knee KL 0-III OA grade after failed conservative non-injective or injective treatments, while they are not considered appropriate as first treatment nor in KL IV OA grade. LEVEL OF EVIDENCE: Level I.

Chitosan-based scaffold augmentation to microfractures: Stable results at mid-term follow-up in patients with patellar cartilage lesions.

Purpose: Patellar cartilage lesions are a frequent and challenging finding in orthopaedic clinical practice. This study aimed to evaluate a chitosan-based scaffold's mid-term clinical and imaging results patients with patellar cartilage lesions. Methods: Thirteen patients (nine men, four women, 31.3 ± 12.7 years old) were clinically evaluated prospectively at baseline, 12, 24 and at a final minimum follow-up of 60 months (80.2 ± 14.7) with International Knee Documentation Committee (IKDC) subjective, Knee Injury and Osteoarthritis Outcome Score and Tegner scores. A magnetic resonance analysis was performed at the last follow-up using the Magnetic resonance Observation of CArtilage Repair Tissue (MOCART) 2.0 score. Results: An overall significant clinical improvement in the scores was observed from baseline to all follow-ups, with stable clinical results from 24 months to the mid-term evaluation. The IKDC subjective score passed from 46.3 ± 20.0 at baseline to 70.1 ± 21.5 at the last follow-up (p = 0.029). Symptoms' duration before surgery negatively correlated with the clinical improvement from baseline to the final follow-up (p = 0.013) and sex influenced the improvement of activity level from the preoperative evaluation to the final follow-up, with better results in men (p = 0.049). In line with the clinical findings, positive results were documented in terms of cartilage repair quality with a mean MOCART 2.0 score of 72.4 ± 12.5. Conclusions: Overall, the use of this chitosan-based scaffold provided satisfactory results with a stable clinical improvement up to mid-term follow-up, which should be confirmed by further high-level studies to be considered a suitable surgical option to treat patients affected by patellar cartilage lesions. Level of Evidence: Level IV, prospective case series.

Unicompartmental osteoarthritis: High survival rate with a combined mechanical and biological salvage approach as alternative to metal resurfacing: Results at minimum 10 years of follow-up.

PURPOSE: The aim of this study was to prospectively evaluate the long-term clinical results and failure rate of patients treated with complex salvage procedures using a combined mechanical and biological approach to address unicompartmental knee osteoarthritis (OA) and postpone the need for joint replacement. METHODS: Thirty-nine patients (40.3 ± 10.9 years old) affected by unicompartmental OA (Kellgren-Lawrence 3) in stable joints underwent a personalized surgical treatment depending on the specific requirements of the affected compartment, including high tibial osteotomy, osteochondral scaffold, meniscal scaffold and meniscal allograft transplantation. Patients were evaluated with the International Knee Documentation Committee (IKDC), Visual Analogue Scale (VAS) and Tegner scores before surgery, at 3 years and a minimum of 10 years of follow-up. RESULTS: A significant improvement was observed over time in all scores but worsened at the final follow-up. The IKDC subjective score improved from 46.9 ± 16.2 to 79.8 ± 16.4 at 3 years (p < 0.0005) and then decreased to 64.5 ± 21.4 (p = 0.001) at 12 years. A similar trend was confirmed for VAS and Tegner scores. Only two patients subsequently underwent knee arthroplasty, and nine more patients were considered clinical failure, for a cumulative surgical and clinical failure rate of 28.2% at the final follow-up. CONCLUSION: A personalized, joint-preserving, combined mechanical and biological approach, addressing alignment as well as meniscal and cartilage lesions, is safe and effective, providing a clinical benefit and delaying the need for arthroplasty in young patients affected by unicompartmental knee OA. At the final evaluation, the clinical improvement decreased, but more than two-thirds of the patients still benefited from this treatment at a long-term follow-up. LEVEL OF EVIDENCE: Level IV case series.

Chitosan based scaffold applied in patellar cartilage lesions showed positive clinical and MRI results at minimum 2 years of follow up.

PURPOSE: New scaffold-based cartilage regeneration techniques have been developed to improve the results of microfractures also in complex locations like the patello-femoral joint. The aim of this study was to analyse the results obtained in patellar lesions treated with a bioscaffold,  a mixture composed by a chitosan solution, a buffer, and the patient's whole blood  which forms a stable clot into the lesion. METHODS: Fifteen patients with ICRS grade 3-4 cartilage lesions of the patellar surface were treated with a chitosan bioscaffold. Fourteen patients were clinically and radiologically evaluated prospectively for a minimum follow-up of 2 years with IKDC, KOOS, Tegner score, and MRI. The mean age of patients at the time of surgery was 31.8 ± 11.9 and nine patients presented degenerative aetiology, four patients with previous trauma, and 1 patient with osteochondritis dissecans.  RESULTS: The IKDC subjective score improved from 46.2 ± 19.3 preoperatively to 69.5 ± 20.3 (p < 0.05) and 74.1 ± 23.2 (p < 0.05) at 12 and 24 months, respectively. Also KOOS Pain, KOOS Sport/Rec and KOOS QOL showed a significant improvement from baseline to 12 months and to the final follow-up. MRI evaluation showed a complete filling of the cartilage defect at the final follow-up in 70% of the lesions, obtaining a total MOCART 2.0 score of 71.5 ± 13.6 at 24 months after surgery. CONCLUSION: Chondral patellar lesions represent a complex pathology, with lower results compared to other sites. This bioscaffold represents a safe surgical treatment providing a significant clinical improvement at 24 months in the treatment of patellar cartilage lesions. LEVEL OF EVIDENCE: IV.

Combined subchondral and intra-articular injections of bone marrow aspirate concentrate provide stable results up to 24 months.

PURPOSE: The aim of this study was to evaluate the clinical and imaging findings up to 24 months of follow-up in patients treated with combined subchondral and intra-articular bone marrow aspirate concentrate (BMAC) injections for the treatment of knee osteoarthritis (OA). METHODS: Thirty consecutive patients (19 males, 11 females) aged between 40 and 75 years (mean age 56.4 ± 8.1 years) with unilateral symptomatic knee OA (Kellgren-Lawrence 2-3) were included in the study. Patients were treated with combined intra-articular and subchondral bone BMAC injections (total 9 ml) under fluoroscopic control. IKDC subjective score, VAS for pain, KOOS, and EQ-VAS were prospectively evaluated up to 24 months. Radiographs were performed at baseline and at 24 months after the procedure. MRI was evaluated with the WORMS score at baseline, 6-12 months, and 24 months of follow-up. The statistical analysis was performed using SPSS v.19.0 and for all tests p < 0.05 was considered significant. RESULTS: No major complications and a 13% failure rate were reported. The IKDC subjective score remained stable from 62.6 ± 19.4 at 12 months to 63.4 ± 17.1 at 24 months (both p < 0.0005 compared to baseline, 40.5 ± 12.5). Similar improvements were reported for all KOOS subscales, while EQ-VAS did not report any significant improvement. VAS pain worsened from 3.0 ± 1.9 at 12 months to 4.4 ± 1.8 at the final follow-up (p = 0.0001), although remaining lower compared to the baseline value of 6.3 ± 1.8 (p = 0.002). The radiographic evaluation did not reveal signs of improvement or deterioration of the OA grade. The MRI findings showed a worsening in marginal osteophytes and synovitis, but a significant reduction of bone marrow edema at 24 months (p < 0.0005). CONCLUSION: Combined intra-articular and subchondral BMAC injections provided clinical and imaging benefits up to 24 months for the treatment of symptomatic knee OA, with durable clinical results, a low failure rate, and a significant reduction of bone marrow edema.

Prospective double-blind randomised controlled trial protocol comparing bone marrow aspirate concentrate intra-articular injection combined with subchondral injection versus intra-articular injection alone for the treatment of symptomatic knee osteoarthritis.

INTRODUCTION: Subchondral and intra-articular injections of bone marrow aspirate concentrate (BMAC) showed promising results for knee osteoarthritis (OA) patients. To date, there is no evidence to demonstrate whether the combination of these treatments provides higher benefits than the intra-articular injection alone. METHODS AND ANALYSIS: Eighty-six patients with symptomatic knee OA (aged between 40 and 70 years) are randomised to BMAC intra-articular injection combined with subchondral BMAC injection or BMAC intra-articular injection alone in a ratio of 1:1. The primary outcome is the total Western Ontario and McMaster Universities Osteoarthritis Index, the secondary outcomes are the International Knee Documentation Committee Subjective and Objective Knee Evaluation Form, the Tegner activity scale, the EuroQol-Visual Analogue Scale, and the health questionnaire European Quality of Life Five Dimension score. Additional CT and MRI evaluations are performed at the baseline assessment and at the final 12-month follow-up. The hypothesis is that the combined injections provide higher knee pain and function improvement compared with BMAC intra-articular injection alone. The primary analysis follows an intention to treat principle. ETHICS AND DISSEMINATION: The study protocol has been approved by the Emilia Wide Area Ethical Committee of the Emilia-Romagna Region (CE-AVEC), Bologna, Italy. Written informed consent is obtained from all the participants. Findings of this study will be disseminated through peer-reviewed publications and conference presentations. PROTOCOL VERSION: Version 1 (14 May 2018). TRIAL REGISTRATION NUMBER: NCT03876795.

Union, complication, reintervention and failure rates of surgical techniques for large diaphyseal defects: a systematic review and meta-analysis.

To understand the potential and limitations of the different available surgical techniques used to treat large, long-bone diaphyseal defects by focusing on union, complication, re-intervention, and failure rates, summarizing the pros and cons of each technique. A literature search was performed on PubMed, Web of Science, and Cochrane databases up to March 16th, 2022; Inclusion criteria were clinical studies written in English, of any level of evidence, with more than five patients, describing the treatment of diaphyseal bone defects. The primary outcome was the analysis of results in terms of primary union, complication, reintervention, and failure rate of the four major groups of techniques: bone allograft and autograft, bone transport, vascularized and non-vascularized fibular graft, and endoprosthesis. The statistical analysis was carried out according to Neyeloff et al., and the Mantel-Haenszel method was used to provide pooled rates across the studies. The influence of the various techniques on union rates, complication rates, and reintervention rates was assessed by a z test on the pooled rates with their corresponding 95% CIs. Assessment of risk of bias and quality of evidence was based on Downs and Black's "Checklist for Measuring Quality" and Rob 2.0 tool. Certainty of yielded evidence was evaluated with the GRADE system. Seventy-four articles were included on 1781 patients treated for the reconstruction of diaphyseal bone defects, 1496 cases in the inferior limb, and 285 in the upper limb, with trauma being the main cause of bone defect. The meta-analysis identified different outcomes in terms of results and risks. Primary union, complications, and reinterventions were 75%, 26% and 23% for bone allografts and autografts, 91%, 62% and 19% for the bone transport group, and 78%, 38% and 23% for fibular grafts; mean time to union was between 7.8 and 8.9 months in all these groups. Results varied according to the different aetiologies, endoprosthesis was the best solution for tumour, although with a 22% failure rate, while trauma presented a more composite outcome, with fibular grafts providing a faster time to union (6.9 months), while cancellous and cortical-cancellous grafts caused less complications, reinterventions, and failures. The literature about this topic has overall limited quality. However, important conclusions can be made: Many options are available to treat critical-size defects of the diaphysis, but no one appears to be an optimal solution in terms of a safe, satisfactory, and long-lasting outcome. Regardless of the bone defect cause, bone transport techniques showed a better primary union rate, but bone allograft and autograft had fewer complication, reintervention, and failure rates than the other techniques. The specific lesion aetiology represents a critical aspect influencing potential and limitations and therefore the choice of the most suitable technique to address the challenging large diaphyseal defects.

The 50 most-cited clinical articles in cartilage surgery research: a bibliometric analysis.

PURPOSE: Articular cartilage lesions remain a challenge for orthopedic surgeons. The identification of the most important articles can help identifying the most influential techniques of the past, the current prevalent focus, and emerging strategies. The aim of this study was to identify milestones and trends in cartilage research. METHODS: This study is a bibliometric analysis based on published articles. All citation count data included in the "Scopus database" were used to identify eligible studies up to December 2020. The 50 most-cited articles on cartilage surgery were ranked based on the citation count and analyzed regarding citation density and quality (Coleman score and RoB 2.0 tool). A further search was performed to identify the most promising clinical studies among the latest publications on cartilage surgery. RESULTS: Different kinds of cartilage treatments were investigated in the 50 most-cited clinical articles. Regenerative techniques with chondrocytes were the most reported with a total of 23 articles, followed by microfracture technique in 17 articles and mosaicplasty or osteochondral autograft transplantation (OAT) in 11. Forty-five articles focused on the knee. A higher citation density was found in the most recent articles (p = 0.004). The study of the most promising landmarks of the most recent articles showed new cell-free or tissue engineering-based procedures and an overall increasing quality of the published studies. CONCLUSION: This bibliometric analysis documented an increasing interest in cartilage surgery, with efforts toward high-quality studies. Over the years, the focus switched from reconstructive toward regenerative techniques, with emerging options including cell-free and tissue-engineering strategies to restore the cartilage surface. LEVEL OF EVIDENCE: IV.

Bone marrow aspirate concentrate injections provide similar results versus viscosupplementation up to 24 months of follow-up in patients with symptomatic knee osteoarthritis. A randomized controlled trial.

PURPOSE: The purpose of this double-blind randomized controlled trial (RCT) was to compare clinical improvement and radiographic findings up to 2 years of follow-up of a single intra-articular injection of bone marrow aspirate concentrate (BMAC) versus hyaluronic acid (HA) for the treatment of knee osteoarthritis (OA). The hypothesis was that BMAC injection could lead to better clinical and radiographic results compared to viscosupplementation. METHODS: Patients with bilateral knee OA were randomized to one intra-articular injection of tibial-derived BMAC in one knee and one HA injection in the contralateral knee. Sixty patients were enrolled, and 56 were studied up to the final follow-up (35 men, 21 women, mean age 57.8 ± 8.9 years), for a total of 112 knees. Patients were evaluated before the injection and at 1, 3, 6, 12, and 24 months with the IKDC subjective score, VAS for pain, and the KOOS score. Minimal clinically important difference (MCID), patient treatment judgement, and adverse events were documented, as well as bilateral X-Rays (Rosenberg view) before and after treatment. RESULTS: No severe adverse events nor differences were reported in terms of mild adverse events (7.1% vs 5.4%, p = ns) and treatment failures (10.7% vs 12.5%, p = ns) in BMAC and HA groups, respectively. The IKDC subjective score improved from baseline to all follow-ups for BMAC (p < 0.0005), while it improved up to 12 months (p < 0.0005) and then decreased at 24 months (p = 0.030) for HA. Compared to HA, BMAC showed a higher improvement for VAS pain at 12 (2.2 ± 2.6 vs 1.7 ± 2.5, p = 0.041) and 24 months (2.2 ± 2.6 vs 1.4 ± 2.8, p = 0.002). The analysis based on OA severity confirmed this difference only in Kellgren-Lawrence 1-2 knees, while comparable results were observed in moderate/severe OA. Radiographic evaluation did not show knee OA deterioration for both treatment groups, without intergroup differences. CONCLUSION: BMAC did not demonstrate a clinically significant superiority at short-term compared to viscosupplementation, reporting overall comparable results in terms of clinical scores, failures, adverse events, radiographic evaluation, MCID achievement, and patient treatment judgment. However, while HA results decreased over time, BMAC presented more durable results in mild OA knees. LEVEL OF EVIDENCE: Level I.

A taper-fit junction to improve long bone reconstruction: A parametric In Silico model.

PURPOSE: Critical size long bone defects represent a clinical challenge in orthopaedic surgery. Various grafting techniques have been developed through the years, but they all present several downsides. A key requirement of all grafting techniques is the achievement of a continuous interface between host bone and graft to enhance both biological processes and mechanical stability. This study used a parametric in silico model to quantify the biomechanical effect of the inaccuracies inherent to current osteotomy techniques, and to test a new concept of accurate taper-fit junction that may improve the biomechanical parameters of the reconstruction under load. METHODS: A population-based in-silico 3D model of the reconstruction of a long bone defect was built to represent a defect of the femoral mid-diaphysis. To fix the reconstruction a titanium plate was placed on the lateral aspect of the reconstruction. The model was modified to (i) quantify the biomechanical consequences of actual inaccuracies in the realization of a flat host-graft interface, (ii) compare the contact behaviour and bone strains among different taper angles of the new design and the current host-graft flat interface, (iii) evaluate the robustness of the taper-fit design to inter-subject variability in bone geometry and defect length. RESULTS: The influence of 2° single-plane misalignments of the host-graft interface is highly dependent on the misalignment orientation with respect to the metal plate. For some misalignment orientations, tangential micromotions of contact interfaces exceeded alert thresholds. When the angle of the taper-fit host-graft junction is changed from 10° to 30° and the results obtained are compared with the planar case, the overall stiffness is almost preserved, the bone strains are almost unchanged with safety factors higher than five, and full contact closure around the host-graft junction is achieved at 20°. Similarly, contact pressures decrease almost linearly with a 20% decrease at 30°. The host-graft micro motions are almost unchanged in both value and distribution up to 20° and never exceed the warning threshold of 50 µm. CONCLUSIONS: The present in silico study developed quantitative biomechanical evidence that an osteotomy performed with attention to the perpendicularity of the cut planes is needed to reduce the risk of mismatch and possible complications of long bone reconstructions, and that a new concept of a taper-fit junction may improve the biomechanical environment of the interface between the graft and the host bone. The optimal taper-fit configuration is suggested to be around a 20° taper angle. These results will serve as an input to conduct exvivo experiments to further corroborate the proposed taper-fit junction concept and to refine its surgical implementation.

Cell-Free Biomimetic Osteochondral Scaffold for the Treatment of Knee Lesions: Clinical and Imaging Results at 10-Year Follow-up.

BACKGROUND: Cell-free devices have been introduced to restore osteochondral defects, avoiding the limitations of cell-based procedures. Among these, an osteochondral scaffold made of type I collagen and hydroxyapatite has been investigated with promising results up to medium-term follow-up. However, the clinical and imaging results over time still need to be documented. PURPOSE: To evaluate the clinical outcome and tissue maturation at long-term follow-up after the implantation of the osteochondral scaffold. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 24 patients (7 women, 17 men; age, 36 ± 9.5 years) underwent surgical implantation of the osteochondral scaffold and were prospectively evaluated before surgery, at 2-, 5-, and 10-year follow-up. The mean defect size was 2.9 ± 1.4 cm2. Patients were evaluated using the International Knee Documentation Committee (IKDC) subjective and objective scores, and the activity level was documented with the Tegner score. Magnetic resonance imaging (MRI) evaluation involved the use of the magnetic resonance observation of cartilage repair tissue score combined with 5 more variables focused on the bone layer. RESULTS: A statistically significant improvement of all clinical scores was documented from the baseline to the final evaluation. The IKDC subjective score improved from the preoperative level to 2 years (41 ± 13.2 and 77.1 ± 14.6, respectively) (P < .0005), with stable results up to 10 years (77.4 ± 19.4). The IKDC objective score changed from 52% of normal and nearly normal knees before the treatment to 84% at 10 years (P < .0005). Tegner sports activity at the final evaluation (3.8 ± 1.7) was higher compared with the preoperative level (1.6 ± 1.1; P < .05), but it remained significantly lower compared with the preinjury level (5.5 ± 2.6; P < .05). Treatment failed in 1 patient. Persisting graft alterations were observed on MRI scans, although without correlating with the clinical outcome. CONCLUSION: The regenerative potential of this scaffold is limited, as demonstrated by the signal alterations persisting over time on MRI scans. On the other hand, the clinical improvement was significant and stable over time both in terms of subjective and objective outcomes, including activity level, with overall good results.

Subchondral and intra-articular injections of bone marrow concentrate are a safe and effective treatment for knee osteoarthritis: a prospective, multi-center pilot study.

PURPOSE: Subchondral bone is becoming a treatment target for knee OA patients, with promising early findings on the use of bone marrow aspirate concentrate (BMAC). The aim of this prospective, multi-centric pilot study was to evaluate safety as well as clinical and MRI outcomes of a combined approach of intra-articular and subchondral BMAC injections. METHODS: Thirty patients (19 men, 11 women, 56.4 ± 8.1 years) with symptomatic knee OA were treated with a combination of an intra-articular and two subchondral BMAC injections (femoral condyle and tibial plateau). Patients were evaluated at baseline and at 1-3-6-12 months of follow-up with the IKDC subjective, VAS, KOOS, and EQ-VAS scores. The MRI evaluation was performed with the WORMS score. RESULTS: No major complications were reported and only two patients were considered treatment failures, requiring a new injective or surgical treatment. The IKDC subjective score improved significantly from 40.5 ± 12.5 to 59.9 ± 16.1 at 3 months, 59.1 ± 12.2 at 6 months, and 62.6 ± 19.4 at 12 months (p < 0.0005). A similar improvement was reported for VAS pain and all KOOS subscales at all follow-ups, while EQ-VAS did not show any significant improvement. The MRI analysis showed a significant bone marrow edema reduction (p = 0.003), while the remaining WORMS parameters did not show any significant changes. CONCLUSION: The pilot evaluation of this combined BMAC injective treatment showed safety and positive outcome up to 12 months of follow-up in patients with symptomatic knee OA associated with subchondral bone alterations. These findings suggest that targeting both subchondral bone and joint environment can provide promising results, and that BMAC can be a valid option for this combined approach to treat knee OA.

Small Extracellular Vesicles from adipose derived stromal cells significantly attenuate in vitro the NF-κB dependent inflammatory/catabolic environment of osteoarthritis.

The therapeutic ability of Mesenchymal Stem/Stromal Cells to address osteoarthritis (OA) is mainly related to the secretion of biologically active factors, which can be found within their secreted Extracellular Vesicles including small Extracellular Vesicles (sEV). Aim of this study was to investigate the effects of sEV from adipose derived stromal cells (ADSC) on both chondrocytes and synoviocytes, in order to gain insights into the mechanisms modulating the inflammatory/catabolic OA environment. sEV, obtained by a combined precipitation and size exclusion chromatography method, were quantified and characterized, and administered to chondrocytes and synoviocytes stimulated with IL-1ß. Cellular uptake of sEV was evaluated from 1 to 12 h. Gene expression and protein release of cytokines/chemokines, catabolic and inflammatory molecules were analyzed at 4 and 15 h, when p65 nuclear translocation was investigated to study NF-κB pathway. This study underlined the potential of ADSC derived sEV to affect gene expression and protein release of both chondrocytes and synoviocytes, counteracting IL-1ß induced inflammatory effects, and provided insights into their mechanisms of action. sEV uptake was faster in synoviocytes, where it also elicited stronger effects, especially in terms of cytokine and chemokine modulation. The inflammatory/catabolic environment mediated by NF-κB pathway was significantly attenuated by sEV, which hold promise as new therapeutic strategy to address OA.

Cell-Free Scaffolds in Cartilage Knee Surgery: A Systematic Review and Meta-Analysis of Clinical Evidence.

OBJECTIVE: To evaluate current evidence and results of cell-free scaffold techniques for knee chondral lesions. DESIGN: A systematic review was conducted on 3 medical electronic databases according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines, and the methodological quality was assessed with a modified Coleman Methodology Score. A meta-analysis was performed on the articles reporting results for visual analogue scale (VAS), Lysholm, and International Knee Documentation Committee (IKDC) scores. In order to investigate the clinical results improvement over time of cell-free cartilage scaffold implantation, all scores were reported and analyzed as improvement from basal scores at 1, 2, and ≥3 years' follow-up. RESULTS: A total of 23 studies involving 521 patients were included in the qualitative data synthesis. The Coleman score showed an overall poor study quality with the majority of studies reporting results at short-/mid-term follow-up. Sixteen studies were included in the meta-analysis, showing a significant improvement from basal score at 1, 2, and ≥3 years' follow-up. The improvement reached at 1 year remained stable up to the last follow-up for all scores. CONCLUSIONS: The current literature suggests that cell-free scaffolds may provide good clinical short-/mid-term results; however, the low evidence of the published studies and their short mean follow-up demand further evidence before more definitive conclusions can be drawn on their real potential over time and on their advantages and disadvantages compared to the cell-based strategies for the treatment of cartilage lesions.

Matrix-assisted chondrocyte transplantation with bone grafting for knee osteochondritis dissecans: stable results at 12 years.

PURPOSE: To document clinical and radiological results of arthroscopic matrix-assisted autologous chondrocyte transplantation (MACT) combined with bone grafting for the treatment of knee osteochondritis dissecans (OCD) at long-term follow-up. METHODS: Thirty-one knees in 29 patients (20.4 ± 5.7 years) were treated for symptomatic unfixable OCD lesions (2.6 ± 1.1 cm2) and prospectively evaluated at 2, 5, and 12 years (average, minimum 10 years). Patients were evaluated over time with IKDC subjective score, EQ-VAS, and Tegner scores. Failures were also documented. At the final follow-up, MRI evaluation was performed in 14 knees with the MOCART 2.0 score. RESULTS: Beside 4 early failures, an overall clinical improvement was documented: the IKDC subjective score improved from 39.9 ± 16.8 to 82.1 ± 17.0 and 84.8 ± 17.2 at 2 and 5 years, respectively (p < 0.0005), and remained stable for up to 12 years (85.0 ± 20.2). EQ-VAS and Tegner scores presented similar trends, but patients did not reach their original activity level. Worse results were obtained for lesions bigger than 4 cm2. At MRI evaluation, subchondral bone abnormalities were detected in over 85% of knees at long-term follow-up. CONCLUSIONS: Arthroscopic bone grafting followed by MACT for unfixable knee OCD can offer a promising and stable clinical outcome over time in lesions smaller than 4 cm2, with a low failure rate of 13%. Persistent subchondral alterations were documented at long-term MRI evaluation, suggesting the limits of this approach to regenerate the osteochondral unit in patients affected by knee OCD. LEVEL OF EVIDENCE: IV.

Long-term Results of Arthroscopic Matrix-Assisted Autologous Chondrocyte Transplantation: A Prospective Follow-up at 15 Years.

BACKGROUND: Matrix-assisted autologous chondrocyte transplantation (MACT) procedures have been developed to overcome some of the limits of first-generation autologous chondrocyte implantation. However, while good autologous chondrocyte implantation results have been documented over time, data are scarce on the long-term MACT results. PURPOSE: To evaluate long-term clinical results of a large cohort of patients treated with hyaluronic acid-based MACT for articular cartilage defects of the knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A long-term evaluation of 113 patients was performed (91 men, 22 women; mean ± SD age, 29.0 ± 10.6 years) for 115 knees affected by chondral and osteochondral lesions of the femoral condyles and trochlea. Of these, 61 knees had undergone previous surgery, while other procedures were combined during the same operation in 48 knees. These patients were prospectively evaluated before surgery and at 2, 5, and 10 years after surgery, as well as at a final mean follow-up of 15 years (range, 12-18 years), with various clinical scores: International Knee Documentation Committee (IKDC), EuroQol visual analog scale (EQ-VAS), and Tegner. Both surgical and clinical failures were documented. RESULTS: The IKDC subjective score increased from the basal level of 39.9 ± 14.6 (mean ± SD) to 77.3 ± 20.5 (P < .0005) at 2 years; results remained stable up to the 15-year follow-up (76.9 ± 20.5). EQ-VAS and Tegner scores showed a statistically significant improvement up to 10 years, with a further significant improvement at the final follow-up. A failure rate of 15.0% was documented, which increased to 21.7% when clinical failures were also considered. A worse outcome was found for older age (P < .0005), female sex (P = .002), degenerative lesions (P < .0005), longer duration of symptoms (P = .005), and previous surgery (P < .0005). CONCLUSION: Arthroscopic MACT offered good and long-lasting results that were stable over time and resulted in a limited number of failures and reinterventions for up to 15 years of follow-up. Several factors were identified as having a prognostic value: a worse outcome could be expected in older patients, female patients, those affected by lesions with a degenerative cause, those having a longer duration of symptoms, and patients who underwent previous surgery.

Skeletal Muscle Gene Expression in Long-Term Endurance and Resistance Trained Elderly.

Physical exercise is deemed the most efficient way of counteracting the age-related decline of skeletal muscle. Here we report a transcriptional study by next-generation sequencing of vastus lateralis biopsies from elderly with a life-long high-level training practice (n = 9) and from age-matched sedentary subjects (n = 5). Unsupervised mixture distribution analysis was able to correctly categorize trained and untrained subjects, whereas it failed to discriminate between individuals who underwent a prevalent endurance (n = 5) or a prevalent resistance (n = 4) training, thus showing that the training mode was not relevant for sarcopenia prevention. KEGG analysis of transcripts showed that physical exercise affected a high number of metabolic and signaling pathways, in particular those related to energy handling and mitochondrial biogenesis, where AMPK and AKT-mTOR signaling pathways are both active and balance each other, concurring to the establishment of an insulin-sensitive phenotype and to the maintenance of a functional muscle mass. Other pathways affected by exercise training increased the efficiency of the proteostatic mechanisms, consolidated the cytoskeletal organization, lowered the inflammation level, and contrasted cellular senescence. This study on extraordinary individuals who trained at high level for at least thirty years suggests that aging processes and exercise training travel the same paths in the opposite direction.

Long-term Results of Matrix-assisted Autologous Chondrocyte Transplantation Combined With Autologous Bone Grafting for the Treatment of Juvenile Osteochondritis Dissecans.

BACKGROUND: Osteochondritis dissecans is a pathology affecting young patients that involves the entire osteochondral unit. In the case of unfixable fragments, regenerative cartilage treatments are a viable solution, but little is known about the use of these procedures for the treatment of juvenile osteochondritis dissecans (JOCD). The aim of this study was to evaluate the long-term results offered by matrix-assisted autologous chondrocyte transplantation combined with autologous bone grafting for the treatment of JOCD. METHODS: Nineteen patients have been enrolled. The mean age at the time of treatment was 16.8±1.5 years, with a mean body mass index of 22.9±2.7. The average size of the defects was 2.8±1.2 cm. All patients were evaluated prospectively before surgery and at 12, 24, 60, and at a final follow-up of 120 months with International Knee Documentation Committee scores, EuroQol-Visual Analogue Scale, and the Tegner Score. RESULTS: A statistically significant improvement in all clinical scores was observed from baseline evaluation to 120 months of final follow-up. In particular, the International Knee Documentation Committee subjective score improved from the preoperative evaluation of 38.7±17.3 to 74.0±21.8 at 12 months (P<0.0005), with scores remaining stable for up to 120 months (83.8±20.7), with all follow-ups showing a statistically significant improvement compared with the basal value (P<0.0005). Three patients failed at 12 months, for a failure rate of 16% at 10 years of follow-up. Lesions >3.5 cm obtained worse subjective results. In addition, lesion size and female sex were significantly associated with failures. CONCLUSIONS: The matrix-assisted autologous chondrocyte transplantation technique with autologous bone grafting is a valid treatment option for JOCD in case of unfixable fragments. The clinical improvement obtained is significant and stable, with good results maintained for up to 10 years of follow-up and an overall low failure rate. Lesion size and sex could influence the clinical outcome and should be considered in the treatment choice. LEVEL OF EVIDENCE: Level IV-case series.

Cereblon (CRBN) gene polymorphisms predict clinical response and progression-free survival in relapsed/refractory multiple myeloma patients treated with lenalidomide: a pharmacogenetic study from the IMMEnSE consortium.

Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the CRBN gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the CRBN gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67; p = .0055, Bonferroni corrected p = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65; p = .0063, Bonferroni corrected p = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74, p = .0054, Bonferroni corrected p = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM.

Cell-Free Osteochondral Scaffold for the Treatment of Focal Articular Cartilage Defects in Early Knee OA: 5 Years' Follow-Up Results.

The purpose of this study was to investigate the clinical results at five years' follow-up of a tri-layered nanostructured biomimetic osteochondral scaffold used for focal articular cartilage defects in patients meeting the criteria of early osteoarthritis (EOA). The study population comprised 22 patients (mean age: 39 years), prospectively assessed before surgery, at 24 and 60 months' follow-up. Inclusion criteria were: at least two episodes of knee pain for more than 10 days in the last year, Kellgren-Lawrence OA grade 0, I or II and arthroscopic or MRI findings according to the European Society of Sports Traumatology, Knee Surgery & Arthroscopy (ESSKA) criteria. Clinical results demonstrated significant improvement in International Knee Documentation Committee (IKDC) subjective and objective scores and in Tegner score, although activity level never reached the pre-injury level. The complication rate of this study was 8.3%. Two patients underwent re-operation (8.3%), while a comprehensive definition of failure (including both surgical and clinical criteria) identified four failed patients (16.6%) at this mid-term follow-up evaluation. The use of a free-cell osteochondral scaffold represented a safe and valid alternative for the treatment of focal articular cartilage defects in the setting of an EOA, and was able to permit a significant clinical improvement and stable outcome with low complication and failure rates.