Platelet-rich Plasma and Knee Osteoarthritis Clinical Trials or Studies: Metaanalyses

In a level I systematic review and metaanalysis performed by Chang and colleagues in 2014, the effectiveness of PRP in treating cartilage degenerative pathology in knee joints was explored. For this metaanalysis, the investigators included single-arm prospective studies, quasiexperimental studies, and randomized controlled trials that used PRP to treat knee chondral degenerative lesions. Eight single-arm studies, 3 quasiexperimental studies, and 5 randomized controlled trials were identified, comprising 1543 participants. PRP injections in patients with knee degenerative pathology showed continual efficacy for 12 months compared with their pretreatment condition. The effectiveness of PRP was likely better and more prolonged than that of hyaluronic acid (HA). Patients with less severe OA achieved superior outcomes as opposed to those with advanced OA.

In another level I metaanalysis of PRP use in knee OA using LR or LP products performed by Riboh and colleagues in 2015, clinical outcomes and rates of adverse reactions between LP-PRP and LR-PRP preparations were compared. For this metaanalysis, the MEDLINE, EMBASE, and Cochrane databases were reviewed. The primary outcome was the incidence of local adverse reactions. Secondary outcomes were the changes in International Knee Documentation Committee (IKDC) subjective score and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score between baseline and final follow-up measurements. Included in the analysis were 6 randomized controlled trials (evidence level 1) and 3 prospective comparative studies (evidence level 2) with a total of 1055 patients. Injection of LP-PRP resulted in significantly better WOMAC scores than did injection of HA (mean difference, −21.14; 95% CI, −39.63 to −2.65) or placebo (mean difference, −17.84; 95% CI, −34.95 to −0.73). No such difference was observed with LR-PRP (mean difference, −14.28; 95% CI, −44.80 to 16.25). All treatment groups resulted in equivalent IKDC subjective scores. Subsequent analysis showed that LP-PRP was the highest ranked treatment for both measures of clinical efficacy (WOMAC and IKDC). Finally, PRP injections resulted in a higher incidence of adverse reactions than HA (odds ratio, 5.63; 95% CI, 1.38–22.90), but there was no difference between LR-PRP and LP-PRP (odds ratio, 0.78; 95% CI, 0.05–11.93). These reactions were nearly always local swelling and pain, with a single study reporting medical side effects including syncope, dizziness, headache, gastritis, and tachycardia (17 of 1055 total patients).

Meheux and colleagues performed a level I systematic review of level I studies in 2015. Studies were evaluated to determine (1) whether PRP injection significantly improves validated patient-reported outcomes in patients with symptomatic knee OA at 6 and 12 months after injection, (2) differences in outcomes between PRP and corticosteroid injections or viscosupplementation or placebo injections at 6 and 12 months after injection, (3) and similarities and differences in outcomes based on the PRP formulations used in the analyzed studies. In this review, a quality assessment of all articles was performed using the Modified Coleman Methodology Score (average, 83.3/100), and outcomes were analyzed using 2-proportion z -tests. Six articles (739 patients, 817 knees, 39% males, mean age of 59.9 years, with 38 weeks average follow-up) were analyzed. All studies met minimal clinically important difference criteria and showed significant improvements in statistical and clinical outcomes, including pain, physical function, and stiffness, with PRP. All but 1 study showed significant differences in clinical outcomes between PRP and HA or PRP and placebo in pain and function. Average pretreatment WOMAC scores were 52.36 and 52.05 for the PRP and HA groups, respectively ( P = .420). Mean posttreatment WOMAC scores for PRP were significantly better than for HA at 3 to 6 months (28.5 and 43.4, respectively; P = .0008) and at 6 to 12 months (22.8 and 38.1, respectively; P = .0062). None of the included studies used corticosteroids. This review suggests that, in patients with symptomatic knee OA, PRP injections result in significant clinical improvements up to 12 months after injection. There is limited evidence for comparing LR-PRP versus LP-PRP or PRP versus steroids per this review. The authors were therefore unable to evaluate the third stated objective as noted.

Autologous Conditioned Plasma and Knee Osteoarthritis Clinical Trials or Studies

In a level I RCT study published by Smith in 2016, ACP proved to be an efficacious treatment for knee OA in a small group of patients studied. This was a US Food and Drug Administration–sanctioned, double-blind, randomized, controlled trial designed to determine the safety and efficacy of LP-ACP for knee OA treatment. The study was designed as a feasibility trial regulated by the US Food and Drug Administration. Thirty patients were included in the study. These patients were randomized to receive either ACP (n = 15) or saline placebo (n = 15) for a series of 3 weekly injections. WOMAC scores served as the primary efficacy outcome measure. Patients were followed for 1 year. Results showed no adverse events for ACP administration. Furthermore, the results demonstrated no difference in baseline WOMAC scores between the 2 groups. However, in the ACP group, WOMAC scores at 1 week were decreased significantly compared with baseline scores, and the scores for this group remained significantly lower throughout the study duration. At the study conclusion (12 months), subjects in the ACP group had improved their overall WOMAC scores by 78% from their baseline score, compared with 7% for the placebo group (Smith PA ; ACP LP –heme –mtx). In another small randomized, controlled trial study performed by Cerza and associates in 2013, a total of 120 patients affected by clinically and radiographically documented knee OA were evaluated. OA scores were graded using the Kellgren–Lawrence radiographic classification scale. The 120 patients were randomized into 2 study groups: 60 patients received 4 intraarticular injections of PRP (ACP LP –heme –mtx) and 60 patients received 4 intraarticular injections of HA. All patients were evaluated with the WOMAC score before the infiltration and at 4, 12, and 24 weeks after the first injection. Results showed that treatment with a local injection of ACP had a significant effect shortly after the final infiltration with a continuously improving sustained effect up to 24 weeks (WOMAC score, 65.1 and 36.5 in the HA and ACP groups, respectively; P <.001). In the HA group, the worst results were obtained for grade III knee OA, whereas the clinical results obtained in the ACP group did not show any difference in terms of the grade of knee arthrosis. The mean WOMAC scores for grade III knee OA were 74.85 in the HA group and 41.20 in the ACP group ( P <.001; ACP LP –heme –mtx).

In a level IV small case series reported by Filardo and colleagues in 2014, ACP use for the treatment of knee OA was studied. The aim of the study was to describe the clinical results obtained after intraarticular injection of an ACP preparation for the treatment of knee OA. In this study, 45 patients (mean age, 59 years; mean body mass index, 27 kg/m ² ) were included and treated with a cycle of 3 weekly injections of ACP. Six patients were affected by bilateral symptomatic OA; therefore, 51 knees in total were treated. The patients were divided into 2 groups: those affected by early to moderate OA and those affected by severe OA. The patients were submitted to baseline evaluation, and evaluation after a mean follow-up of 14.5 months (range, 6–24). Outcome measures used included IKDC-subjective, the EuroQual Visual Analog Scale, Tegner, and Knee Injury and Osteoarthritis Outcome (KOOS) scores. The overall clinical outcome was positive and the treatment proved to be safe. In the early or moderate OA group, the IKDC-subjective score increased from 36.4 at the baseline evaluation to 57.3 at the follow-up ( P <.0005) and a similar trend was shown by the EuroQual Visual Analog Scale, and Tegner and KOOS scores. Although an improvement was also recorded in the severe OA group, the clinical outcome of the patients in this group was significantly poorer, and they reported less benefit. In the early to moderate OA group, body mass index and longer symptom duration before treatment were found to be correlated with clinical outcome (ACP LP –heme –mtx).

Platelet-rich Plasma and Knee Osteoarthritis Clinical Trials or Studies: Randomized Controlled Trials or Case Series

In a small level I randomized, controlled trial performed by Sanchez and colleagues in 2012, 176 patients were randomized to receive PRP or HA in 3 weekly injections with pain and function scores followed to 24 weeks. Of patients receiving PRP, 38% had a 50% decrease in WOMAC pain score at 24 weeks compared with 24% of patients receiving HA ( P value 0.044; unknown platelet or leukocyte concentrations -mtx). Another study performed by Vaquerizo and colleagues, 2013 compared the efficacy and safety of 3 injections of PRP versus 1 single intraarticular injection of HA as a treatment for reducing symptoms in patients with knee OA. Ninety-six patients with symptomatic knee OA were randomly assigned to receive PRP (3 injections on a weekly basis) or 1 infiltration with Durolane HA (Bioventus, Hoofddorp, The Netherlands). The primary outcome measures were a 30% decrease and a 50% decrease in the summed score for pain, physical function, and stiffness subscales of the WOMAC and Lequesne scores from baseline to weeks 24 and 48, respectively. Treatment with PRP was significantly more efficient than treatment with HA in reducing knee pain and stiffness and improving physical function in patients with knee OA. The rate of response to PRP was significantly higher than the rate of response to HA for all the scores including pain, stiffness, and physical function in patients at 24 and 48 weeks. Adverse events were mild and evenly distributed between the groups (unknown platelet or leukocyte concentration −mtx).

Bone Marrow Concentrate and Human Mesenchymal Stem Cell Clinical Studies

In a prospective case series published in July 2015, Oliver and colleagues evaluated the clinical efficacy of autologous intraarticular BMC with autologous lipoaspirate as a treatment option for knee OA. Additionally, BMC samples from a patient population subset were sent for outside laboratory analysis. Seventy patients diagnosed with Kellgren-Lawrence stage 2 to 4 knee OA were analyzed. Data regarding adverse events and KOOS metrics were obtained at baseline, 90 days, and 180 days. Samples of BMC from 11 patients were sent to an outside source for laboratory analysis. Adverse events were limited to transient pain and swelling of the treated joint. The mean reported KOOS changes from before the procedure to 180 days after the procedure were as follows: pain, +18.1; activities of daily living, +15.6; symptoms, +17.3; quality of life, +20.3; and sports/recreation +18.1. Laboratory analysis of the samples demonstrated statistically significant increases in concentration of platelets, interleukin-1 receptor antagonist (IL-1Rra and IL-1β). This ratio of IL-1ra to IL-β has been shown to alleviate the degenerative effects of IL-1. The increase in the IL-1ra/IL-1β ratio was statistically significant at 193.54 when processed with a 2% hematocrit setting, and 720.62 when processed with a 15% hematocrit. The group concluded that intraarticular injection of autologous BMC and lipoaspirate in patients diagnosed with knee OA demonstrates encouraging results for positive outcomes in pain and function without complication, in addition to showing elevations of antiinflammatory levels of IL-1ra (BMC LP ± heme + mtx).

Vangsness and colleagues in 2014 published a randomized, double-blind, controlled study using adult human MSCs delivered via intraarticular injection to the knee after partial medial meniscectomy. In this study, 55 patients from 7 institutions underwent partial medial meniscectomy. A single superolateral knee injection was given within 7 to 10 days after the meniscectomy. Patients were then randomized to 1 of 3 treatment groups: group A, in which patients received an injection of 50 × 10 ⁶ allogeneic MSCs; group B, 150 × 10 ⁶ allogeneic MSCs; and the control group, a sodium hyaluronate (HA/hyaluronan) vehicle control. Patients were followed to evaluate safety, meniscus regeneration, the overall condition of the knee joint, and clinical outcomes at intervals through 2 years. Evaluations included sequential MRI scans. The results showed no ectopic tissue or safety issues. Significantly increased meniscal volume (defined a priori as a 15% threshold) determined by quantitative MRI was noted in 24% of patients in group A and 6% in group B at 12 months after meniscectomy ( P = .022). No patients in the control group met the 15% threshold for increased meniscal volume. Overall, patients with osteoarthritic changes who received MSCs experienced a significant reduction in pain compared with those who received the control, on the basis of assessments by visual analog scale (MSC unknown leuk, -heme –mtx).

In a level II, randomized controlled trial published by Saw and colleagues in 2013, histologic and MRI evaluation of articular cartilage regeneration in patients with chondral lesions treated by arthroscopic subchondral drilling followed by postoperative intraarticular injections of HA with and without peripheral blood stem cells (PBSC) was evaluated. The PBSC were harvested through apheresis after filgrastim (recombinant human granulocyte colony-stimulating factor) stimulation. Fifty patients ages 18 to 50 years with International Cartilage Repair Society (ICRS) grade 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling. Twenty-five patients each were randomized to the control (HA) and the intervention (PBSC plus HA) groups. Both groups received 5 weekly injections commencing 1 week after surgery. Three additional injections of either HA or PBSC plus HA were given at weekly intervals 6 months after surgery. Subjective IKDC scores and MRI scans were obtained preoperatively and postoperatively at serial visits. Second-look arthroscopy and biopsy was performed at 18 months on 16 patients in each group. Biopsy specimens using 14 components of the ICRS Visual Assessment Scale II (ICRS II) were graded and a total score was obtained. MRI scans at 18 months were assessed with a morphologic scoring system. The total ICRS II histologic scores for the control group averaged 957, whereas the intervention group averaged 1066 ( P = .022). On evaluation of the MRI morphologic scores, the control group averaged 8.5 and the intervention group averaged 9.9 ( P = .013). The mean 24-month IKDC scores for the control and intervention groups were 71.1 and 74.8, respectively ( P = .844). There were no notable adverse events. The authors concluded that arthroscopic subchondral drilling into grades 3 and 4 chondral lesions with postoperative intraarticular injections of autologous PBSC in combination with HA resulted in an improvement of the quality of articular cartilage repair over the same treatment without PBSC as shown by histologic and MRI evaluation (MSC unknown leuk –heme + mtx).

Autologous Conditioned Plasma Laboratory Studies

One study done by Sundman and colleagues was designed to look at the effects of PRP or high molecular weight HA on the expression of anabolic and catabolic genes as well as the secretion of nociceptive and inflammatory mediators in knee OA. This controlled laboratory study used synovium and cartilage harvested from patients undergoing total knee arthroplasty that were cocultured with media of PRP or HA. The results showed that inflammatory cytokines and interleukins and matrix metalloproteinases such as tumor necrosis factor-α, IL-6, and matrix metalloproteinase-13 concentrations decreased in ACP and HA preparations compared with control cultures. Neither platelet nor leukocyte concentration had a significant effect on outcome measurements (gene or protein expression data) in cartilage or synoviocytes in this model. These results indicated that PRP acts to stimulate endogenous HA production and decrease cartilage catabolism (ACP LP -mtx for the PRP-labeled cohort).

In another study of ACP for use in cartilage growth, Sakata and colleagues in 2015 performed a controlled laboratory study, which evaluated superficial zone protein (SZP) production after use of ACP. SZP is known as a boundary lubricant in articular cartilage, plays a role in reducing friction and wear, and is involved with cartilage homeostasis. In using cells isolated from articular cartilage, synovium, and the anterior cruciate ligament (ACL) from 12 patients undergoing ACL reconstruction, they found that PRP stimulated proliferation of SZP cells derived from articular cartilage, synovium, and the ACL. It also significantly enhanced SZP secretion from synovium and cartilage-derived cells while reducing the friction coefficient compared with saline or HA. An unexpected finding was the presence of SZP in the PRP preparation (ACP LP allograft cells).

Adipose Orthobiologic Clinical Studies

In 2016, Koh and colleagues published a level II prospective randomized comparative study evaluating Ad-MSC with microfracture (group 1) versus microfracture alone (group 2) with a 2-year follow-up. This study used Ad-MSCs with fibrin glue and microfracture in 40 patients versus microfracture alone in 40 patients with symptomatic knee ICRS grade III or IV cartilage defects. Preoperative MRI and quantitative and qualitative assessments of the repair tissue were carried out at 24 months by using the magnetic resonance observation of cartilage repair tissue scoring system with follow-up MRI. Clinical results were evaluated using the Lysholm score, the KOOS, and a 10-point visual analog score preoperatively and postoperatively at 3 months, 12 months, and the last follow-up visit. Group 1 included 26 patients (65%) who had complete cartilage coverage of the lesion at follow-up compared with 18 patients (45%) in group 2. Significantly better signal intensity was observed for the repair tissue in group 1, with 32 patients (80%) having normal or nearly normal signal intensity (ie, complete cartilage coverage of the lesion) compared with 28 patients (72.5%) in group 2. The mean clinical follow-up period was 27.4 months (range, 26–30). The improvements in the mean KOOS pain and symptom subscores were significantly greater at follow-up in group 1 than in group 2 (pain, 36.6 ± 11.9 in group 1 and 30.1 ± 14.7 in group 2 [ P = .034]; symptoms, 32.3 ± 7.2 in group 1 and 27.8 ± 6.8 in group 2 [ P = .005]). However, the improvements in the other subscores were not different between groups 1 and 2 (activities of daily living, 38.5 ± 12.8 and 37.6 ± 12.9, respectively [ P = .767]; sports and recreation, 33.9 ± 10.3 and 31.6 ± 11.0, respectively [ P = .338]; and quality of life, 38.4 ± 13.1 and 37.8 ± 12.0, respectively [ P = .650]). Among the 80 patients, second-look arthroscopies were performed in 57 knees (30 in group 1 and 27 in group 2), and biopsy procedures were performed during these arthroscopies for 18 patients in group 1 and 16 patients in group 2. The second-look arthroscopies showed good repair tissue quality with slightly better safranin O and collagen II staining in group 1, although no intergroup difference was observed. Age, lesion size, duration of symptoms before surgery, mechanism of injury, and combined procedures were not correlated with clinical results (Ad-MSC + heme + mtx).

In a multicenter case control study published in 2015 by Michalek and colleagues, the authors studied the use of SVF cells in a single injection in 1128 patients with OA of multiple joint structures. The design of the study was to evaluate the safety and clinical efficacy of freshly isolated autologous SVF cells in a case control study. Patients with grade 2 to 4 degenerative OA were selected. A total of 1128 patients underwent standard liposuction under local anesthesia and SVF cells were isolated and prepared for application into 1 to 4 large joints. A total of 1856 joints, mainly knee and hip joints, were treated with a single dose of SVF cells. These were processed using Cellthera Kit I or II from the Czech Republic containing good manufacturing practices-grade collagenase. Grafts were assessed for total nucleated cell counts, although a portion was culture expanded for colony-forming unit evaluation. Overall, 1114 patients were followed for 12.1 to 54.3 months (median 17.2 months) for safety and efficacy. Modified KOOS/HOOS Clinical Scores were used to evaluate clinical effect and was based on pain, nonsteroid analgesic usage, limping, extent of joint movement, and stiffness evaluation before and at 3, 6, and 12 months after treatment. No serious side effects, systemic infection, or cancer was associated with SVF cell therapy. Reportedly most patients gradually improved 3 to 12 months after the treatment. At least 75% score improvement was noticed in 63% of patients, and at least 50% score improvement was documented in 91% of patients 12 months after SVF cell therapy. Obesity and a higher grade of OA were associated with slower healing (Ad-MSC LP –heme –mtx).

In 2014, Vilar and colleagues published a veterinary study entitled Assessment of the effect of Intraarticular Injection of Autologous Adipose-Derived Mesenchymal Stem Cells in Osteoarthritic Dogs Using a Double-blinded Force Platform Analysis. In this study, 10 lame dogs suffering from severe hip OA were enrolled as the active treatment group with 5 other animals for the control group. Outcomes were based on force platform analysis because this has been consistently used to verify and quantify the efficacy of different therapeutic strategies for the treatment of OA in dogs, including MSC associated with plasma rich in growth factors, but never with Ad-MSC alone. In the study, a biopsy of 20 g of subcutaneous fat tissue (4–5 cm ³ ) was collected from the animal along with 120 mL of blood for preparation in a commercial kit. Immediately after sample collection, fat biopsy and blood (in an anticoagulant container) were sent at 4°C for cell isolation and to the Fat-Stem Laboratory used for processing. The fat was processed with collagenase and by centrifugation, and 30 million Ad-MSCs were subsequently administered in a single injection. Results were analyzed to detect a significant increase in peak vertical force and vertical impulse (from force plate measurements) in treated dogs. Mean values of peak vertical force and vertical impulse were improved significantly within the first 3 months after treatment in the OA group, increasing 9% and 2.5% body weight, respectively, at day 30. After this, the effect seemed to decrease, reaching initial values and tapering off over the ensuing 60 days (reportedly a 90 day effect; Vilar JM and colleagues ; Ad-MSC LP –heme –mtx).

In another animal model using rabbit knees, Mehrabani and colleagues in 2015 used Ad-MSCs to evaluate treatment of full-thickness femoral articular cartilage defects. In this study, 2 Million cells suspended in culture medium (DMEM) were supplemented with 10% fetal bovine serum and transplanted using a single injection into the articular cartilage defect of the femoral articular cartilage. The cells were injected into the knee joint of 6 rabbits with 6 rabbits used as controls. Findings on subsequent dissection showed that, in the cell therapy group after transplantation, no abnormal gross findings were noticed. Neoformed tissues in cell-treated groups were translucent with a smooth and intact surface and less irregularity. In cell-treated group after 8 weeks after transplantation, the overall healing score of experimental knees were superior when compared with other groups (Ad-MSC unk leuk –heme + mtx).