Platelet-rich plasma augmentation in anterior cruciate ligament reconstruction: Evidence is still too scattered. A scoping review of randomised controlled trials.

PURPOSE: Platelet-rich plasma (PRP) augmentation has been proposed to improve the results of anterior cruciate ligament reconstruction (ACLR). The present study aims to quantify the available evidence to support the use of PRP as biological augmentation in ACLR surgery. METHODS: A systematic literature search was conducted on the PubMed, Cochrane, Web of Science and Embase databases on 10 March 2023. Inclusion criteria were randomised controlled trials (RCTs), written in English, addressing PRP augmentation in ACLR surgery, with no time limitation. A scoping review was performed to map the body of literature by examining the evidence related to specific aspects of patients' treatment and evaluation. Risk of bias evaluation was performed with the Cochrane risk-of-bias tool for randomised trials Version 2 (RoB 2), while the quality assessment was performed with the use of the Coleman Score. RESULTS: Out of 983 articles retrieved, 23 RCTs on 943 knees were included in this scoping review. PRP was administered in a liquid form in nine studies and clotted in 11 studies, while in three studies both liquid and clotted PRP were used. Hamstring auto/allografts were used in 14 studies, patellar tendon auto/allografts were used in eight studies and one study described ACLR with peroneus longus allografts. The map of the evidence documented high heterogeneity also in terms of surgical technique, objective and subjective outcome measures and radiological assessment, as well as follow-up times ranging from 1 day to 2 years, with virtually no overlapping data among studies neither in terms of treatments nor evaluations. Risk of bias evaluation showed an overall low quality of the included studies. CONCLUSIONS: The available literature addressing PRP augmentation in ACLR is largely scattered. PRP was produced and applied following different procedures, and high variability was detected across the included studies for every aspect of ACLR surgery and evaluation. Currently, a meaningful comparison of the available studies is not possible as the quantification of the literature results is biased by their heterogeneity. Future studies should provide more standardisation to investigate the benefits of biological augmentation in ACL surgery and confirm the promising yet weak evidence of PRP potential as well as the most suitable application modality, before routine use in clinical practice. LEVEL OF EVIDENCE: Levels I and II, scoping review.

Intra-articular corticosteroid injections provide a clinically relevant benefit compared to placebo only at short-term follow-up in patients with knee osteoarthritis: A systematic review and meta-analysis.

PURPOSE: To quantify the clinical relevance of intra-articular corticosteroid effects compared to placebo for the injective treatment of knee osteoarthritis (OA). METHODS: The PubMed, Cochrane Library and Web of Science databases were searched on May 3, 2023. This study was conducted in accordance with the PRISMA guidelines. The inclusion criteria were randomized controlled trials (RCTs), published in English, with no time limitation regarding publication date, comparing intra-articular corticosteroids and placebo injections for knee OA. The effects were quantified at short- (≤6 weeks), mid- (>6 weeks and ≤3 months), and long-term (≥6 months) follow-ups. The minimal clinically important difference (MCID) for the outcomes (visual analogue scale for pain - VAS: 1.4, Western Ontario and McMaster University Osteoarthritis Index - WOMAC: 9) was used to interpret the clinical improvement provided by intra-articular corticosteroid injections compared to placebo. The quality of each article was assessed using the Cochrane RoB 2 tool and the GRADE guidelines. RESULTS: Among the 1030 articles retrieved, 11 RCTs (842 patients) were included. A comparison of the two groups revealed statistically significant differences in the improvement of VAS and WOMAC scores in terms of the mean difference (MD); this difference was in favour of corticosteroids at short-term (p < 0.001, MD = -1.6 and p < 0.001, MD = -9.9, respectively) and mid-term follow-ups (p = 0.001, mean MD = -1.3 and p = 0.005, MD = -4.9, respectively). No difference was observed at the long-term follow-up. The MDs between the improvements in the two groups reached the MCID values for the VAS and WOMAC only at the short-term follow-up. The RoB 2 tool and the GRADE evaluations showed the presence of risk of bias and limited quality of evidence. CONCLUSION: This systematic review and meta-analysis demonstrated that intra-articular corticosteroid injections offer clinically perceivable pain relief and functional improvement higher than the placebo effect only at short-term follow-up in patients affected by knee OA, with benefits losing clinical relevance already after 6 weeks. These results, together with the low number and the limited quality of the RCTs comparing this treatment with placebo, question the indication for the use of corticosteroid injections in clinical practice for the treatment of knee OA. LEVEL OF EVIDENCE: Level I.

Cell-free biomimetic osteochondral scaffold for the treatment of knee articular surface lesions: Clinical outcomes differ based on patient and lesion characteristics.

PURPOSE: A cell-free biomimetic osteochondral scaffold was developed to treat cartilage knee lesions, with positive clinical results documented in small case series. However, clear evidence on patient and lesion characteristics that might affect the outcome is still lacking. The aim of this study is to analyse a large cohort of patients treated with this scaffold to investigate factors that could influence the clinical outcome. METHODS: Two hundred and three patients (mean age 30.7 ± 10.9 years) treated with this scaffold were prospectively evaluated at baseline, 6-, 12- and 24-month follow-up. The clinical outcome was analysed using the International Knee Documentation Committee (IKDC) score, and the activity level was assessed with the Tegner score. The influence of patient and lesion characteristics on clinical outcomes was analysed. RESULTS: Mild and severe adverse reactions were found in 39.0% and 1.5% of patients, respectively. The failure rate was 2.0%, increasing to 12.3% when including also clinical failures. The IKDC subjective score increased from 43.3 ± 15.9 to 61.0 ± 16.2 at 6 months, 68.3 ± 18.5 at 12 months and 73.8 ± 18.3 at 24 months (p < 0.0005). The Tegner improved from 2.5 ± 1.7 to 4.2 ± 1.7 at 24 months (p < 0.0005), without reaching the pre-injury level (6.0 ± 2.2) (p < 0.0005). The IKDC objective score changed from 68.5% normal and nearly normal knees before the treatment to 90.1% at 24 months. At 24 months, age showed a correlation with the IKDC subjective score (ρ = -0.247; p < 0.0005), women had a lower score (p < 0.0005), as well as patients with patellar lesions (p = 0.002). Previous surgery correlated with lower results (p = 0.003), while better results were found in osteochondritis dissecans (OCD) compared to degenerative lesions (p = 0.001). CONCLUSION: This cell-free biomimetic scaffold is a safe and effective treatment for cartilage knee lesions, offering positive clinical results at 2 years with a low failure rate. Better outcomes were observed in younger patients, in lesions of the femoral condyles and in OCD, while joints affected by patellar lesions, patients who underwent previous knee surgery, and women may expect lower results. LEVEL OF EVIDENCE: III, Cohort study.

Medial meniscal lesions increase antero-posterior laxity in knees with anterior cruciate ligament injury.

PURPOSE: The aim of this study was to quantify the impact of concomitant meniscal lesions on knee laxity using a triaxial accelerometer in a large population of patients affected by anterior cruciate ligament (ACL) injury. METHODS: A total of 326 consecutive patients (261 men and 65 women, mean age 31.3 ± 11.3) undergoing primary ACL reconstruction, were preoperatively evaluated through Lachman and pivot shift tests using a triaxial accelerometer to quantify knee laxity. An analysis based on the presence of meniscal tears assessed during surgery was performed to evaluate the impact of meniscal lesions on knee laxity. RESULTS: The anterior tibial translation (Lachman test) presented significantly higher values in patients with medial meniscal lesions (7.3 ± 1.7 mm, p = 0.049) and both medial and lateral meniscal lesions (7.7 ± 1.6 mm, p = 0.001) compared to patients without concomitant meniscal lesions (6.7 ± 1.3 mm). Moreover, patients with both medial and lateral meniscal lesions presented significantly higher values of anterior tibial translation compared to patients with lateral meniscal lesions (p = 0.049). No statistically significant differences were found between the groups in terms of tibial acceleration (pivot shift test). CONCLUSION: This study demonstrated that the contribution of concomitant meniscal lesions to knee laxity can be objectively quantified using a triaxial accelerometer in ACL-injured knees. In particular, medial meniscus lesions, alone or in association with lateral meniscus lesions, determine a significant increase of the anterior tibial translation compared to knees without meniscus tears. LEVEL OF EVIDENCE: Level IV.

Cell-based therapies have disease-modifying effects on osteoarthritis in animal models: A systematic review by the ESSKA Orthobiologic Initiative. Part 3: Umbilical cord, placenta, and other sources for cell-based injectable therapies.

PURPOSE: This systematic review aimed to investigate in animal models the presence of disease-modifying effects driven by non-bone marrow-derived and non-adipose-derived products, with a particular focus on umbilical cord and placenta-derived cell-based therapies for the intra-articular injective treatment of osteoarthritis (OA). METHODS: A systematic review was performed on three electronic databases (PubMed, Web of Science and Embase) according to PRISMA guidelines. The results were synthesised to investigate disease-modifying effects in preclinical animal studies comparing injectable umbilical cord, placenta, and other sources-derived products with OA controls. The risk of bias was assessed using the SYRCLE tool. RESULTS: A total of 80 studies were included (2314 animals). Cell therapies were most commonly obtained from the umbilical cord in 33 studies and placenta/amniotic tissue in 18. Cell products were xenogeneic in 61 studies and allogeneic in the remaining 19 studies. Overall, 25/27 (92.6%) of studies on umbilical cord-derived products documented better results compared to OA controls in at least one of the following outcomes: macroscopic, histological and/or immunohistochemical findings, with 19/22 of studies (83.4%) show positive results at the cartilage level and 4/6 of studies (66.7%) at the synovial level. Placenta-derived injectable products documented positive results in 13/16 (81.3%) of the studies, 12/15 (80.0%) at the cartilage level, and 2/4 (50.0%) at the synovial level, but 2/16 studies (12.5%) found overall worse results than OA controls. Other sources (embryonic, synovial, peripheral blood, dental pulp, cartilage, meniscus and muscle-derived products) were investigated in fewer preclinical studies. The risk of bias was low in 42% of items, unclear in 49%, and high in 9% of items. CONCLUSION: Interest in cell-based injectable therapies for OA treatment is soaring, particularly for alternatives to bone marrow and adipose tissue. While expanded umbilical cord mesenchymal stem cells reported auspicious disease-modifying effects in preventing OA progression in animal models, placenta/amniotic tissue also reported deleterious effects on OA joints. Lower evidence has been found for other cellular sources such as embryonic, synovial, peripheral blood, dental-pulp, cartilage, meniscus, and muscle-derived products. LEVEL OF EVIDENCE: Level II.

Corticosteroid injections for the treatment of osteoarthritis present a wide spectrum of effects ranging from detrimental to disease-modifying: A systematic review of preclinical evidence by the ESSKA Orthobiologic Initiative.

PURPOSE: Aim of this systematic review of preclinical evidence was to determine the effects of intra-articular corticosteroid (CS) injections in joints affected by osteoarthritis (OA). METHODS: A systematic review was performed on animal studies evaluating intra-articular CS injections for OA joints. The search was performed on PubMed, Cochrane, and Web of Science databases. A synthesis of the results was performed investigating CS effects by evaluating studies comparing CS with control groups. Morphological, histological, immunohistochemistry evaluations, clinical outcomes, biomarkers and imaging results were evaluated. The risk of bias was assessed according to the Systematic Review Centre for Laboratory Animal Experimentation's tool. RESULTS: Thirty-two articles analysing CS effects in OA animal models were included (1079 joints), 18 studies on small and 14 on large animals. CS injections showed overall positive effects in at least one of the outcomes in 68% of the studies, while 16% reported a deleterious effect. CS improved cartilage and synovial outcomes in 68% and 60% of the studies, but detrimental effects were documented in 11% and 20% of the studies, respectively. Clinical parameters evaluated in terms of pain, lameness or joint swelling improved in 63% of the studies but deteriorated in 13%. Evidence is limited on imaging and biomarkers results, as well as on the best CS type, dose, formulation and injection protocol. The risk of bias assessment revealed a 28% low and an 18% high risk of bias. CONCLUSION: Intra-articular CS injections induced a wide range of results on OA joints in experimental animal models, from disease-modifying and positive effects on pain and joint function at short-term evaluation to the lack of benefit or even negative effects. This underlines the need to identify more specific indications and treatment modalities to avoid possible detrimental effects while maximising the anti-inflammatory properties and the benefits of intra-articular CS in OA joints. LEVEL OF EVIDENCE: Level II.

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.

Platelet-rich plasma does not improve clinical results in patients with rotator cuff disorders but reduces the retear rate. A systematic review and meta-analysis.

PURPOSE: To assess whether the use of Platelet-rich plasma (PRP) produces a clinical benefit in patients with rotator cuff disorders, treated either conservatively or surgically. METHODS: A systematic review was performed according to PRISMA guidelines on three databases (PubMed, Cochrane Library, Web of Science) to identify randomised controlled trials (RCTs) on the use of PRP in patients with rotator cuff disorders, treated either conservatively or surgically. A meta-analysis was performed on articles reporting results for Constant, UCLA, VAS, SST scores and retear rate. The RoB 2.0 and the modified Coleman Methodology Score were used to assess methodological quality. RESULTS: A total of 36 RCTs (20 surgical, 16 conservative) were included, for a total of 2,443 patients. Conservative treatment showed high heterogeneity and no clear consensus in favour of PRP. The meta-analysis of the studies with surgical treatment showed no benefit in using PRP in any of the clinical outcomes, either at the short or medium/long-term follow-up. However, the retear rate was lower with PRP augmentation (p < 0.001). The overall quality of the studies was moderate to high, with the surgical studies presenting a lower risk of bias than the conservative studies. CONCLUSION: The use of PRP as augmentation in rotator cuff surgical repair significantly reduces the retear rate. However, no benefits were documented in terms of clinical outcomes. PRP application through injection in patients treated conservatively also failed to present any clear advantage. While there are many studies in the literature with several RCTs of moderate to high quality, the high heterogeneity of products and studies remains a significant limitation to fully understanding PRP potential in this field. LEVEL OF EVIDENCE: Level I.

Hyaluronic scaffold transplantation with bone marrow concentrate for the treatment of osteochondral lesions of the talus: durable results up to a minimum of 10 years.

PURPOSE: The aim of this study was to evaluate the long-term clinical results of the transplantation of a hyaluronic acid membrane augmented with bone marrow aspirate concentrate (BMAC) in an one-step technique for the treatment of patients affected by osteochondral lesions of the talus (OLT). METHODS: A total of 101 patients (64 men, 37 women, age 32.9 ± 10.9) were evaluated for a minimum of 10 years of follow-up (151.5 ± 18.4 months) The mean lesion size was 2.2 ± 1.4 cm2, the lesion had a post-traumatic origin in 73 patients, 15 patients previously had an ankle fracture, 22 patients had ankle osteoarthritis. All patients were clinically evaluated at baseline and at 2, 5, and a minimum of 10 years after treatment using the AOFAS score, the NRS for pain, and the Tegner score. A survival analysis was performed to check the survival to failure up to the last follow-up. RESULTS: The AOFAS score significantly improved from baseline (59.6 ± 13.9) to the final follow-up (82.3 ± 14.2) (p < 0.0005). A significant reduction in the AOFAS score was found from 2 to 10 years (p < 0.0005). The NRS for pain changed from 7.0 ± 1.3 at baseline to 3.9 ± 2.7 at the final follow-up (p < 0.0005). A significant worsening was documented between 5 years and the final follow-up (p < 0.0005). The Tegner score improved from the preoperative value of 2.0 (range 1-7) to 3.0 (range 1-7) at the final follow-up (p < 0.0005), although it remained lower as compared to the preinjury level of 4.0 (range 1-9) (p < 0.0005). Better results were documented in male and younger patients with smaller lesions, without the previous surgery, and without the previous ankle fractures or osteoarthritis. At the final follow-up, 85 patients considered their general health status "satisfactory" and 84 patients reported feeling "better" than the preoperative condition. Five patients were considered failures and underwent prosthetic ankle replacement or repeated the same surgery. CONCLUSION: This one-step technique showed to be an effective procedure for the treatment of OLT, providing a low failure rate and offering durable clinical improvements up to a minimum of 10 years of follow-up. However, this technique demonstrated a small yet significant decrease over the years in terms of pain and function and poor results in terms of sports activity level. LEVEL OF EVIDENCE: Level 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.

Bone marrow aspirate concentrate quality is affected by age and harvest site.

PURPOSE: To compare the number and properties of bone marrow stromal cells (BMSCs) collected from bone marrow aspirate concentrate (BMAC) obtained from different harvest sites and from patients of different ages. METHODS: BMAC was obtained from two groups of patients based on age (n = 10 per group): 19.0 ± 2.7 years for the younger and 56.8 ± 12.5 for the older group. In the latter, BMAC was obtained from both iliac crest and proximal tibia for a donor-matched analysis. Mononucleated cell count and CFU-F assay were performed, together with phenotype characterization of BMSCs from iliac crest and proximal tibia, the study of chondrogenic and osteogenic differentiation capacity, histological staining and spectrophotometric quantification, and the analysis of mRNAs expression. RESULTS: Cells derived from iliac crest and proximal tibia showed the same phenotypic pattern at flow cytometry, as well as similar chondrogenic and osteogenic potential. However, a significantly higher number of mononuclear cells per ml was observed in younger patients (3.8 ± 1.8 × 107) compared to older patients (1.2 ± 0.8 × 107) (p < 0.0005). The latter yield, obtained from the iliac crest, was significantly higher than resulting from the BMAC harvested from the proximal tibia in the same group of patients (0.3 ± 0.2 × 107, p < 0.0005). This result was confirmed by the CFU-F analysis at day 10 (15.9 ± 19.4 vs 0.6 ± 1.0, p = 0.001) and day-20 (21.7 ± 23.0 vs 2.9 ± 4.2, p = 0.006). CONCLUSION: Harvest site and age can affect the quality of BMAC. BMSCs obtained from iliac crest and proximal tibia present comparable mesenchymal markers expression as well as osteogenic and chondrogenic differentiation potential, but iliac crest BMAC presents a four times higher number of mononucleated cells with significantly higher clonogenic capacity compared to the tibia. BMAC of younger patients also had a three-time higher number of mononucleated cells. The identification of BMAC characteristics could help to optimize its preparation and to identify the most suitable indications for this orthobiologic treatment in the clinical practice.

Cell-based therapies have disease-modifying effects on osteoarthritis in animal models. A systematic review by the ESSKA Orthobiologic Initiative. Part 1: adipose tissue-derived cell-based injectable therapies.

PURPOSE: The aim of this systematic review was to determine if adipose tissue-derived cell-based injectable therapies can induce disease-modifying effects in joints affected by osteoarthritis (OA). METHODS: A systematic review was performed on three electronic databases (PubMed, Web of Science, Embase) according to PRISMA guidelines. A synthesis of the results was performed investigating disease-modifying effects in preclinical studies comparing injectable adipose-derived products with OA controls or other products, different formulations or injection intervals, and the combination with other products. The risk of bias was assessed according to the SYRCLE's tool. RESULTS: Seventy-one studies were included (2,086 animals) with an increasing publication trend over time. Expanded cells were used in 65 studies, 3 studies applied point of care products, and 3 studies investigated both approaches. Overall, 48 out of 51 studies (94%) reported better results with adipose-derived products compared to OA controls, with positive findings in 17 out of 20 studies (85%) in macroscopic, in 37 out of 40 studies (93%) in histological, and in 22 out of 23 studies (96%)  in immunohistochemical evaluations. Clinical and biomarker evaluations showed positive results in 14 studies out of 18 (78%) and 12 studies out of 14 (86%), while only 9 studies out of 17 (53%) of the imaging evaluations were able to detect differences versus controls. The risk of bias was low in 38% of items, unclear in 51%, and high in (11%). CONCLUSION: The current preclinical models document consistent evidence of disease-modifying effects of adipose-derived cell-based therapies for the treatment of OA. The high heterogeneity of the published studies highlights the need for further targeted research to provide recommendations on the optimal methodologies for a more effective application of these injective therapies for the treatment of OA in clinical practice. LEVEL OF EVIDENCE: II.

Cell-based therapies have disease-modifying effects on osteoarthritis in animal models. A systematic review by the ESSKA Orthobiologic Initiative. Part 2: bone marrow-derived cell-based injectable therapies.

PURPOSE: Aim of this systematic review was to determine if bone marrow-derived cell-based injectable therapies induce disease-modifying effects in joints affected by osteoarthritis (OA) in animal models. METHODS: A systematic review was performed on three electronic databases (PubMed, Web of Science, Embase) according to PRISMA guidelines. A synthesis of the results was performed investigating disease-modifying effects in preclinical animal studies comparing injectable bone marrow-derived products with OA controls or other products, different formulations or injection intervals, and the combination with other products. The risk of bias was assessed according to the SYRCLE's tool. RESULTS: Fifty-three studies were included (1819 animals) with an increasing publication trend over time. Expanded cells were used in 48 studies, point-of-care products in 3 studies, and both approaches were investigated in 2 studies. Among the 47 studies presenting results on the disease-modifying effects, 40 studies (85%) reported better results with bone marrow-derived products compared to OA controls, with positive findings evident in 14 out of 20 studies (70%) in macroscopic assessment, in 30 out of 41 studies (73%) in histological assessment, and in 10 out of 13 studies (77%) in immunohistochemical evaluations. Clinical evaluations showed positive results in 7 studies out of 9 (78%), positive imaging results in 11 studies out of 17 (65%), and positive biomarker results in 5 studies out of 10 (50%). While 36 out of 46 studies (78%) reported positive results at the cartilage level, only 3 out of 10 studies (30%) could detect positive changes at the synovial level. The risk of bias was low in 42% of items, unclear in 50%, and high in 8%. CONCLUSION: This systematic review of preclinical studies demonstrated that intra-articular injections of bone marrow-derived products can induce disease-modifying effects in the treatment of OA, slowing down the progression of cartilage damage with benefits at macroscopic, histological, and immunohistochemical levels. Positive results have been also observed in terms of clinical and imaging findings, as well as in the modulation of inflammatory and cartilage biomarkers, while poor effects have been described on the synovial membrane. These findings are important to understand the potential of bone marrow-derived products and to guide further research to optimise their use in the clinical practice. LEVEL OF EVIDENCE: II.

Infection Risk Increases After Total Hip Arthroplasty Within 3 Months Following Intra-Articular Corticosteroid Injection. A Meta-Analysis on Knee and Hip Arthroplasty.

BACKGROUND: Much debate continues regarding the risk of postoperative infection after intra-articular corticosteroid injection prior to total joint arthroplasty. The aim of this study was to evaluate the risk of periprosthetic joint infection (PJI) or other complications after joint arthroplasty in patients who received preoperative corticosteroids injections. METHODS: A literature search was performed on PubMed, Web of Science, and Cochrane Library through January 4, 2022. Of 4,596 studies, 28 studies on 480,532 patients were selected for qualitative analysis. Studies describing patients receiving corticosteroids injections before joint arthroplasty (hip, knee) were included in the systematic review. A meta-analysis was performed of studies focusing on corticosteroids injections and PJI. Assessment of risk of bias and quality of evidence was based on the "Downs and Black's Checklist for Measuring Quality". RESULTS: A significant association (odds ratio: 1.55, P = .001, 95% confidence interval: 1.357-1.772) between PJI and corticosteroids injections was found for total hip arthroplasty (THA). No association was found for knee arthroplasty procedures. The risk of PJI is statistically higher (odds ratio: 1.20, P = .045, 95% confidence interval: 1.058-1.347) if the injections are performed within 3 months preoperatively in THA patients. CONCLUSION: Patients undergoing THA who previously received intra-articular injections of corticosteroids may expect a statistically higher risk of developing PJI. On the contrary, no association between corticosteroids injections and PJI could be seen in total knee arthroplasty patients. In addition, injection timing plays an important role: surgeons should refrain from administering corticosteroids injections within 3 months before hip arthroplasty, as it appears to be less safe than waiting a 3-month interval.

Adipose Tissue-Derived Products May Present Inflammatory Properties That Affect Chondrocytes and Synoviocytes from Patients with Knee Osteoarthritis.

Adipose tissue-derived cell-based injectable therapies have been demonstrated to have disease-modifying effects on joint tissues in preclinical studies on animal osteoarthritis (OA) models, but clinical results are heterogeneous and not always satisfactory. The aim of this study was to investigate the influence of adipose tissue properties on the therapeutic effects of the adipose-derived product in an in vitro OA setting. Micro-fragmented adipose tissue (MF-AT) samples were obtained from 21 OA patients (mean age 51.7 ± 11.8 years, mean BMI 25.7 ± 4.1 kg/m2). The analysis of the MF-AT supernatant was performed to analyze the release of inflammatory factors. The effects of MF-AT inflammatory factors were investigated on chondrocytes and synoviocytes gene expression levels. Patients' characteristics were analyzed to explore their influence on MF-AT inflammatory molecules and on the MF-AT effects on the gene expression of chondrocytes and synoviocytes. The study results demonstrated that adipose tissue-derived products may present inflammatory properties that influence the therapeutic potential for OA treatment, with products with a higher pro-inflammatory profile stimulating a higher expression of genes related to a more inflamed and catabolic phenotype. A higher pro-inflammatory cytokine pattern and a higher pro-inflammatory effect were found in adipose tissue-derived products obtained from OA patients with higher BMI.

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.

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.

Platelet-rich plasma injections induce disease-modifying effects in the treatment of osteoarthritis in animal models.

PURPOSE: The mechanisms of action and disease-modifying potential of platelet-rich plasma (PRP) injection for osteoarthritis (OA) treatment are still not fully established. The aim of this systematic review of preclinical evidence was to determine if PRP injections can induce disease-modifying effects in OA joints. METHODS: A systematic review was performed on animal studies evaluating intra-articular PRP injections as treatment for OA joints. A synthesis of the results was performed investigating the disease-modifying effects of PRP by evaluating studies that compared PRP with OA controls or other injectable products, different PRP formulations or injection intervals, and the combination of PRP with other products. The risk of bias was assessed according to the SYRCLE's tool. RESULTS: Forty-four articles were included, for a total of 1251 animals. The publication trend remarkably increased over time. PRP injections showed clinical effects in 80% and disease-modifying effects in 68% of the studies, attenuating cartilage damage progression and reducing synovial inflammation, coupled with changes in biomarker levels. Evidence is limited on the best PRP formulation, injection intervals, and synergistic effect with other injectables. The risk of bias was low in 40%, unclear in 56%, and high in 4% of items. CONCLUSION: Intra-articular PRP injections showed disease-modifying effects in most studies, both at the cartilage and synovial level. These findings in animal OA models can play a crucial role in understanding mechanism of action and structural effects of this biological approach. Nevertheless, the overall low quality of the published studies warrants further preclinical studies to confirm the positive findings, as well as high-level human trials to demonstrate if these results translate into disease-modifying effects when PRP is used in the clinical practice to treat OA. LEVEL OF EVIDENCE: Level II.

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.