Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have failed to translate to OA. A lack of high-level evidence and methodological limitations hinder our understanding of so called ‘stem’ cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data is needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices, and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits new treatments must be carefully weighed against their costs and potential risks.

Background: Many clinical trials have investigated the use of platelet-rich plasma (PRP) to treat rotator cuff–related abnormalities. Several meta-analyses have been published, but none have focused exclusively on level 1 randomized controlled trials. Purpose: To assess the efficacy of PRP for rotator cuff–related abnormalities and evaluate how specific tendon involvement, the inclusion of leukocytes, and the use of gel/nongel formulations affect pain and functional outcomes. Study Design: Systematic review and meta-analysis. Methods: The literature was screened following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Baseline, short-term, and long-term data were extracted for the Constant score, University of California, Los Angeles (UCLA) score, visual analog scale (VAS) for pain, retear rate, Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) score. The 100-point modified Coleman Methodology Score (CMS) was used to assess methodological quality. Funnel plots and the Egger test were used to screen for publication bias, and sensitivity analysis was performed to evaluate the effect of potential outliers. Results: A total of 18 level 1 studies were included in this review, 17 (1116 patients) of which could be included in quantitative analysis. The mean modified CMS was 79.4 ± 10.39. The Constant scores of patients who received PRP were significantly better short term (weighted mean difference [WMD], 2.89 [95% CI, 0.89-4.90]; P < .01) and long term (WMD, 2.66 [95% CI, 1.13-4.19]; P < .01). The VAS scores were significantly improved short term (WMD, –0.45 [95% CI, –0.75 to −0.15]; P < .01). Sugaya grade IV and V retears in PRP-treated patients were significantly reduced long term (odds ratio [OR], 0.34 [95% CI, 0.20-0.57]; P < .01). In PRP-treated patients with multiple tendons torn, there were reduced odds of retears (OR, 0.28 [95% CI, 0.13-0.60]; P < .01). Patients who received leukocyte-rich PRP had significantly better Constant scores compared with the leukocyte-poor PRP group, but there was no difference in VAS scores. Patients receiving PRP gel reported higher Constant scores compared with the controls, whereas those receiving nongel PRP treatments did not, although there was no difference in VAS scores. Long-term odds of retears were decreased, regardless of leukocyte content (leukocyte-poor PRP: OR, 0.36 [95% CI, 0.16-0.82]; leukocyte-rich PRP: OR, 0.32 [95% CI, 0.16-0.65]; all P < .05) or usage of gel (nongel: OR, 0.42 [95% CI, 0.23-0.76]; gel: OR, 0.17 [95% CI, 0.05-0.51]; all P < .01). Conclusion: Long-term retear rates were significantly decreased in patients with rotator cuff–related abnormalities who received PRP. Significant improvements in PRP-treated patients were noted for multiple functional outcomes, but none reached their respective minimal clinically important differences. Overall, our results suggest that PRP may positively affect clinical outcomes, but limited data, study heterogeneity, and poor methodological quality hinder firm conclusions.

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The global PRP market is expected to grow to between 380 million and 4.5 billion (USD) over the next 5-10 years. The cost of a single treatment, which is not covered by most insurance, is roughly $500-$2500, with patients often returning for additional treatments. While PRP is not 'FDA-approved', it can be legally offered in the clinic 'off-label' in the USA for a myriad of musculoskeletal indications. Recently published meta-analyses have demonstrated statistically significant improvements that, in some cases, suggest that PRP may have clinically meaningful effects. However, given the fact that clearance is not synonymous with approval, PRP is a costly treatment not covered by insurance, and clinical trials have not demonstrated definitive efficacy, we recommend informing patients when providing PRP 'off-label'.

Aim: This study investigated the safety and clinical outcomes of expanded allogeneic human adipose-derived mesenchymal progenitor cells injected into patients with symptomatic, bilateral knee osteoarthritis. Design: In this single-site, randomized, double-blind, dose-ranging, Phase I study, patients were randomized to three treatment groups (low dose, 1 × 107 cells; medium dose, 2 × 107 cells; high dose, 5 × 107 cells). All patients received two bilateral intra-articular injections: week 0 (baseline) and week 3. The primary end point was adverse events within 48 weeks. Secondary end points were measured with Western Ontario and McMaster Universities Osteoarthritis index, visual analog scale, short form-36 at weeks 12, 24 and 48. Quantitative MRI measurements of cartilage volume were compared from baseline and week 48. Results: A total of 22 subjects were enrolled of which 19 (86%) completed the study. Adverse events were transient, including mild to moderate pain and swelling of injection site. Improvements from baseline were measured in the secondary end points. MRI assessments showed slight improvements in the low-dose group. Conclusion: Safety and improvements in pain and function after intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells into arthritic patients was demonstrated.