Medical Policy: 08.01.22
Original Effective Date: June 2014
Reviewed: February 2018
Revised: August 2018
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Mesenchymal stem cells (MSCs) are being investigated as a regenerative biologic agent because of their ability to differentiate into multiple tissue types and to self-renew. MSCs can be derived from a variety of sources, including adipose tissue, bone marrow, peripheral blood and synovial tissue, however, bone marrow is currently the primary source of mesenchymal stem cell procurement. MSC therapy has been proposed as a treatment option for orthopedic indications that include but are not limited to the following:
Mesenchymal stem cells (MSCs) are multipotent cells (also called stromal multipotent cells) that possess the ability to differentiate into various tissues including organs, trabecular bone, tendon, articular cartilage, ligaments, muscle, and fat. MSCs are associated with the blood vessels within bone marrow, synovium, fat, and muscle, where they can be mobilized for endogenous repair as occurs with healing of bone fractures. Tissues, such as muscle, cartilage, tendon, ligaments, and vertebral discs, show limited capacity for endogenous repair because of the limited presence of the triad of functional tissue components: vasculature, nerves and lymphatics. Orthobiologics is a term introduced to describe interventions using cells and biomaterials to support healing and repair. Cell therapy is the application of MSCs directly to a musculoskeletal site. Tissue engineering techniques use MSCs and/or bioactive molecules such as growth factors and scaffold combinations to improve the efficiency of repair or regeneration of damaged musculoskeletal tissues.
Bone-marrow aspirate is considered to be the most accessible source and, thus, the most common place to isolate MSCs for treatment of musculoskeletal disease. However, harvesting MSCs from bone marrow requires an additional procedure that may result in donor-site morbidity. Also, the number of MSCs in bone marrow is low, and the number and differentiation capacity of bone marrow-derived MSCs decreases with age, limiting their efficiency when isolated from older patients.
In vivo, the fate of stem cells is regulated by signals in the local 3-dimensional microenvironment from the extracellular matrix and neighboring cells. It is believed that the success of tissue engineering with MSCs will also require an appropriate 3-dimensional scaffold or matrix, culture conditions for tissue-specific induction, and implantation techniques that provide appropriate biomechanical forces and mechanical stimulation. The ability to induce cell division and differentiation without adverse effects, such as the formation of neoplasms, remains a significant concern. Given that each tissue type requires different culture conditions, induction factors (signaling proteins, cytokines, growth factors), and implantation techniques, each preparation must be individually examined.
Stem cells act as the repairman of the body and as people age and get injuries there are sometimes not enough of these critical repair cells getting to the injured area. The Regenexx™ procedures help solve this problem by greatly increasing the body’s natural repair cells and promote healing. This is accomplished by harvesting cells from the areas known to be rich in mesenchymal stem cells and then concentrating those cells in a lab before precisely re-injecting them into the damaged area in need of repair.
The Regenexx™ Same-Day Stem Cell Protocol is called a same-day procedure because the stem cells are harvested and reinjected in the same day. However, for most patients the complete protocol is actually a series of injections that happen over the course of about a week, depending on the individual’s situation. These injections include a pre-injection, the same day stem cell extraction and reinjection procedure, followed by a post-injection of multiple proprietary platelet mixes a few days later.
On the day of the procedure, blood is drawn from the patient’s vein from their arm. This will be processed in the lab along with the stem cell sample. The first step of the procedure is the bone marrow aspiration, the doctor will thoroughly numb the back of the hip and take a small bone marrow sample through a needle. These samples are sent to the lab which is part of the medical practice and processed.
The mesenchymal stem cells are isolated from the bone marrow sample, while some practices add platelet rich plasma (PRP) to their stem cell concentration, for this procedure a “super platelet” mix is utilized. By mixing lab prepared PRP (slow release growth factors) and platelet lysate (immediately available growth factors), adult stem cells grow many times more than with just PRP or platelet lysate alone (Regenexx™ Super Concentrated Platelet Rich Plasma). The goal is to deliver much greater numbers of stem cells to the injured area than the body would deliver on its own.
Once the cells are processed the patient will return and the stem cells and natural growth factors from the blood platelets are re-injected into the injured area using either real time fluoroscopy or musculoskeletal ultrasound, which allows the physician to pinpoint the exact location of the injection into the injured area as well as the dispersion of the cells into the tissues. Re-injections can be as soon as 6 weeks and it is recommended that most patients will need 2-4 injection cycles.
Regenexx™ is a national network of musculoskeletal doctors specializing in advanced regenerative medicine protocols, developed and patented by Regenexx™. These physicians practice “Interventional Orthopedics” by providing non-surgical biologic therapies delivered with high accuracy through a needle. Regenexx™ network providers are board certified musculoskeletal medicine specialists that have joined this exclusive network. Joining this network involves extensive training in addition to having the ability to perform in depth, complex musculoskeletal exam lasting more than 25-30 minutes of hands on time with the patient is required or must be learned. This includes the ability to quantify problems of stability, nerves, muscles, joints and body symmetry.
A systematic review in 2013 by Filardo et. al. examined the available clinical evidence in the literature to support mesenchymal stem cell (MSC) treatment strategies in cartilage lesions/defects. The systematic research showed an increasing number of published studies on this topic over time and identified 72 preclinical papers and 18 clinical trials. Among the 18 clinical trials identified focusing on cartilage regeneration, none were randomized, five were comparative, six were case series, and seven were case reports. Two concerned the use of adipose-derived MSC, five the use of BMAC (bone marrow aspirate concentrate), and 11 the use of bone marrow derived MSCs. The authors concluded, despite the growing interest in this biological approach for cartilage regeneration, knowledge on this topic is still preliminary, as shown by the prevalence of preclinical studies and the presence of low quality clinical studies. Many aspects have to be optimized, and randomized controlled trials are needed to support the potential of this biological treatment for cartilage repair and to evaluate advantages and disadvantages with respect to the available treatments.
In 2017, Goldberg et. al. conducted a systematic review on the use of mesenchymal stem cells for cartilage repair and regeneration. There were 2880 studies identified of which 252 studies were included for analysis: 100 articles were in vitro studies; 111 studies for animal studies; and 31 studies for human studies). There was a huge variance in cell source in preclinical studies both of terms of animal used, location of harvest (fat, marrow, blood or synovium) and allogeneicity. The use of scaffolds, growth factors, number of cell passages and number of cells used was hugely heterogeneous (different). This systematic review is the first of its kind to explore the full spectrum of evidence from in vitro studies, through animal studies to human clinical trials and yet, little evidence of connectivity was found between in vitro, animal and human work. In fact they did not find a single group that had carried out and reported studies in all three categories. There is an increasing interest in allogeneic cells to avoid donor site morbidity and to reduce cost. However, the preclinical data with regards to allogeneic cells is conflicting. Another area of huge controversy is the actual dose of cells that should be used. It remains unclear what the most appropriate cell dose should be, with some groups reporting that a higher cell number leads to a better repair, but Zhao et. al. highlighted the limitation to cell saturation and survival, and thus, there may be a top limit to cell number that can be used to aid repair. It is clear that the relationship between cell passage, cell dose, the use of scaffolds and growth factors and the efficacy of mesenchymal stem cell treatment is still to be established. The authors concluded, this review is a comprehensive assessment of the evidence base to date behind the translation of basic science to the clinical practice of cartilage repair. We have revealed a lack of connectivity between the in vitro, preclinical and human data and a patchwork quilt of synergistic evidence. It appears that the drivers for progress in this space are largely driven by patient demand, surgeon inquisition, and regulatory framework that is learning at the same pace as new developments take place. We strongly recommend funding body commission studies that have a clear translational purpose in order to drive the science towards patient benefit.
In 2015, Centro et. al. completed a prospective multi-site registry study of a specific protocol of autologous bone marrow concentrate for the treatment of shoulder rotator cuff tears and osteoarthritis. A total of 115 shoulders in 102 patients were treated with autologous bone marrow concentrate (BMC) injections for symptomatic osteoarthritis (OA) at the glenohumeral joint and/or rotator cuff tears. Data was collected for factors potentially influencing outcome, including age, sex, body mass index, and the type of condition treated (i.e. OA or rotator cuff tear). Clinical outcomes were assessed serially over time using the disabilities of the arm, shoulder and hand score (DASH), the numeric pain scale (NPS), and a subjective improvement rating scale. Baseline scores were compared to the most recent outcome scores at the time of the analysis and adjusted for demographic differences. Reported comparisons of pre and post treatment scores, the differences between osteoarthritis and rotator cuff groups, and the predictive effects on the clinical outcomes. At the most current follow-up assessment after treatment, the average DASH score decreased (improved) from 36.1 to 17.1 ((P<0.001) and the average numeric pain scale value decreased (improved from 4.3 to 2.4 (P<0.001). These changes were associated with an average improvement of 48.8%. No differences were observed between outcomes among the shoulders treated for OA versus rotator cuff tears, nor did age, sex, body mass index influence pain or functional outcomes. There were not significant treatment related adverse events reported. The authors concluded the use of BMC to treat symptomatic rotator cuff tears and glenohumeral OA is promising, and in an uncontrolled treatment registry population, effective at both reducing pain and improving function. Randomized clinical trials are required to confirm the efficacy of BMC injections for treatment of shoulder OA and rotator cuff tears.
In 2015, Vega et. al. reported on randomized trial of 30 patients with chronic knee pain unresponsive to conservative treatments and showing radiological evidence of osteoarthritis into 2 groups of 15 patients. The test group was treated with allogeneic bone marrow mesenchymal stem cells (MSCs) by intra-articular injection of 40 x 10 (6) cells. The control group receive intra-articular hyaluronic acid (60 mg, single dose). Clinical outcomes were followed for 1 year and included evaluations of pain, disability, and quality of life. Articular cartilage quality was assessed by quantitative magnetic resonance imaging T2 mapping. Feasibility and safety were confirmed and indications of clinical efficacy were identified. The MSC treated patients displayed significant improvement in algofunctional indices versus the active controls treated with hyaluronic acid. Quantification of cartilage quality by T2 relaxation measurements showed a significant decrease in poor cartilage areas, with cartilage quality improvements in MSC treated patients. Not reported was whether the patients or assessors were blinded to treatment. The authors concluded allogeneic MSC therapy may be a valid alternative for the treatment of chronic knee osteoarthritis that is more logistically conventional that autologous MSC treatment. The intervention is simple, does not require surgery, provides pain relief, and significantly improves cartilage quality.
In 2017, Shapiro et. al. reported on the results of a prospective, single blind, placebo controlled trial assessing 25 patients with bilateral knee pain from bilateral osteoarthritis. Patients were randomized to receive bone marrow aspirate concentrate (BMAC) into one knee and saline placebo into the other. Fifty-two millimeters of bone marrow as aspirated from the iliac crests and concentrated in an automated centrifuge. The resulting BMAC was combined with platelet-poor plasma for an injection into the arthritic knee and was compared with a saline injection into the contralateral knee, thereby utilizing each patient as his or her own control. Safety outcomes, pain relief, and function as measured by Osteoarthritis Research Society International (OARS) measures and the visual analog scale (VAS) score were tracked initially at 1 week, 3 months, and 6 months after the procedure. There were no serious adverse events from the BMAC procedure. OARSI Intermittent and Constant Osteoarthritis Pain and VAS pain scores in both knees decreased significantly from baseline at 1 week, 3 months and 6 months (P< 0.19 for all). Pain relief, although dramatic, did not differ significantly between treated knees (P>0.9 for all). The authors concluded early results show that BMAC is safe to use and is reliable and viable cellular product. Study patients experiences a similar relief of pain in both BMAC and saline treated arthritic knees. Further studies are required to determine the mechanisms of action, duration of efficacy, optimal frequency of treatments and regenerative potential.
In 2017, a systematic review and meta-analysis by Borakati et. al. included 13 studies that assessed patients with osteoarthritis (OA) who were treated with mesenchymal stem cells (MSCs) to regenerate cartilage damage in OA. Pain assessment results were noted for each of the controlled studies, resulting a pooled standardized mean difference of -1.27 (95% confidence intervals, -1.95 to -0.58) in favor of the group treated with MSCs. Reviewers reported a Z-statistic effect size of 3.62 again in favor of the group treated with MSCs (P<0.001); although they noted the data was extremely heterogeneous with I2=95%, this may be attributed to differing therapies across controlled studies. There were no severe adverse outcomes found across all studies that could be attributed to MSCs implying their safety. The authors concluded that MSCs have significant potential for the treatment of OA, however, larger more consistent trials are needed for conclusive analysis.
Adipose derived stem cells are multi-potential mesenchymal cells that can be harvested from multiple anatomic locations and with greater ease than bone marrow – derived mesenchymal stem cells (MSCs).
In 2013, Kim et. al. compared clinical outcomes of mesenchymal stem cell (MSC) injection with arthroscopic treatment in older patients with osteochondral lesions of the talus. The ideal treatment for osteochondral lesions of the talus (OLTs) is still controversial, especially in older patients. Recently mesenchymal stem cells (MSCs) have been suggested for use in the cell-based treatment of cartilage lesions. Among 107 patients with OLTs treated arthroscopically, only the patients older than 50 years (65 patients) were included in this study. Patients were divided into 2 groups: 35 patients (37 ankles) treated with arthroscopic marrow stimulation treatment alone (group A) and 30 patients (31 ankles) who underwent MSC injection along with arthroscopic marrow stimulation treatment (group B). MSCs were harvested from the fat pad of the buttock of the patients 1 day before surgery, concentrated and injected after the arthroscopic procedure. Clinical outcomes were evaluated according to the visual analog scale (VAS) for pain, the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale, and the Roles and Maudsly score. The Tenger activity scale was used to determine outcomes in activity levels. The mean VAS score in each group was significantly improved (P < .05) from 7.2 ± 1.1 to 4.0 ± 0.7 in group A and from 7.1 ± 1.0 to 3.2 ± 0.9 in group B. The mean AOFAS score in each group was also significantly improved (P < .05) from 68.0 ± 5.5 to 77.2 ± 4.8 in group A and from 68.1 ± 5.6 to 82.6 ± 6.4 in group B. There were significant differences in mean VAS and AOFAS scores between the groups at final follow-up (mean, 21.8 months; range, 12-44 months) (P < .001). The Roles and Maudsley score showed significantly greater improvement in group B than in group A after surgery (P = .040). The Tegner activity scale score was significantly improved in group B (from 3.5 ± 0.7 to 3.8 ± 0.7; P = .041) but not in group A (from 3.5 ± 0.8 to 3.6 ± 0.6; P = .645). Large lesion size (≥109 mm2) and the existence of subchondral cysts were significant predictors of unsatisfactory clinical outcomes in group A (P = .04 and .03, respectively). These correlations were not observed in group B. The authors concluded injection of MSCs with marrow stimulation treatment was encouraging in patients older than 50 years compared with patients treated with marrow stimulation treatment alone, especially when the lesion size was larger than 109 mm2 or a subchondral cyst existed. Although still in the early stages of application, MSC may have great potential in the treatment of OLTs in patients older than 50 years, and more evaluation of its effect should be performed.
In 2014, Koh et. al. reported on results of a prospective study comparing outcomes of open-wedge high tibial osteotomy (HTO) with platelet rich plasma (PRP) alone or in combination with mesenchymal stem cell treatment in patients with osteoarthritis of the medial compartment. MSCs from adipose tissue were obtained through liposuction of the buttocks. The tissue was centrifuged and the stromal vascular fraction mixed with PRP for injection. The patients were divided into 2 groups: HTO with platelet-rich plasma (PRP) injection only (n = 23) or HTO in conjunction with MSC therapy and PRP injection (n = 21). Prospective evaluations of both groups were performed using the Lysholm score, Knee Injury and Osteoarthritis Outcome Score (KOOS), and a visual analog scale (VAS) score for pain. Second-look arthroscopy was carried out in all patients at the time of metal removal. The patients in the MSC-PRP group showed significantly greater improvements in the KOOS subscales for pain (PRP only, 74.0 ± 5.7; MSC-PRP, 81.2 ± 6.9; P < .001) and symptoms (PRP only, 75.4 ± 8.5; MSC-PRP, 82.8 ± 7.2; P = .006) relative to the PRP-only group. Although the mean Lysholm score was similarly improved in both groups (PRP only, 80.6 ± 13.5; MSC-PRP, 84.7 ± 16.2; P = .357), the MSC-PRP group showed a significantly greater improvement in the VAS pain score (PRP only, 16.2 ± 4.6; MSC-PRP, 10.2 ± 5.7; P < .001). There were no differences in the preoperative (PRP only, varus 2.8° ± 1.7°; MSC-PRP, varus 3.4° ± 3.0°; P = .719) and postoperative (PRP only, valgus 9.8° ± 2.4°; MSC-PRP, valgus 8.7° ± 2.3°; P = .678) femorotibial angles or weight-bearing lines between the groups. Arthroscopic evaluation, at plate removal, showed that partial or even fibrocartilage coverage was achieved in 50% of the MSC-PRP group patients but in only 10% of the patients in the PRP-only group (P < .001); the blinding of this measure is unclear. Study design and results were flawed (small sample size, short duration of follow-up, and significant improvements only on some outcomes. Also, all significant differences were modest in magnitude and, as a result, there is uncertainty about the clinical significance of the findings.
In 2014, Jo et. al. reported on a proof-of-concept trial assessing the safety and efficacy of intra-articular injection of autologous adipose tissue derived mesenchymal stem cells (AD-MSCs) for osteoarthritis of the knee. Eighteen patients with osteoarthritis of the knee were enrolled and injected with AD-MSCs into the knee. The phase I study consisted of three dose-escalation cohorts; the low-dose (1.0 × 10(7) cells), mid-dose (5.0 × 10(7)), and high-dose (1.0 × 10(8)) group with three patients each. The phase II included nine patients receiving the high-dose. The primary outcomes were the safety and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 6 months. Secondary outcomes included clinical, radiological, arthroscopic, and histological evaluations. There was no treatment-related adverse event. The WOMAC score improved at 6 months after injection in the high-dose group. The size of cartilage defect decreased while the volume of cartilage increased in the medial femoral and tibial condyles of the high-dose group. Arthroscopy showed that the size of cartilage defect decreased in the medial femoral and medial tibial condyles of the high-dose group. Histology demonstrated thick, hyaline-like cartilage regeneration. These results showed that intra-articular injection of 1.0 × 10(8) AD-MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline-like articular cartilage.
A two year follow up of the above trial was published by Jo et. al. in 2017. Eighteen patients with OA of the knee were enrolled (3 male, 15 female; mean age, 61.8 ± 6.6 years [range, 52-72 years]). Patients in the low-, medium-, and high-dose groups received an intra-articular injection of 1.0 × 107, 5.0 × 107, and 1.0 × 108 AD MSCs into the knee, respectively. Clinical and structural evaluations were performed with widely used methodologies including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and measurements of the size and depth of the cartilage defect, signal intensity of regenerated cartilage, and cartilage volume using magnetic resonance imaging (MRI). There were no treatment-related adverse events during the 2-year period. An intra-articular injection of autologous AD MSCs improved knee function, as measured with the WOMAC, Knee Society clinical rating system (KSS), and Knee injury and Osteoarthritis Outcome Score (KOOS), and reduced knee pain, as measured with the visual analog scale (VAS), for up to 2 years regardless of the cell dosage. However, statistical significance was found mainly in the high-dose group. Clinical outcomes tended to deteriorate after 1 year in the low- and medium-dose groups, whereas those in the high-dose group plateaued until 2 years. The structural outcomes evaluated with MRI also showed similar trends. The authors concluded this study identified the safety and efficacy of the intra-articular injection of AD-MSCs into the OA knee over 2 years, encouraging a larger randomized clinical trial. However, this study also showed potential concerns about the durability of clinical and structural outcomes, suggesting the need for further studies.
In 2013, Saw et. al. reported on a randomized controlled trial assessing articular cartilage regeneration in patients with chondral lesions treated with arthroscopic subchondral lesions followed by postoperative intra-articular injections of hyaluronic acid (HA) with and without autologous peripheral blood mesenchymal stem cells (MSCs). Fifty patients aged 18 to 50 years with International Cartilage Repair Society (ICRS) grade 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling; 25 patients each were randomized to the control (HA) and the intervention (autologous peripheral blood MSCs plus HA) groups. Both groups received 5 weekly injections commencing 1 week after surgery. Three additional injections of either HA or autologous peripheral blood MSCs 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. A second-look arthroscopy and biopsy was performed at 18 months on 16 patients in each group. They graded biopsy specimens using 14 components of the International Cartilage Repair Society Visual Assessment Scale II (ICRS II) 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 and they averaged 1,066 for the intervention group (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). One patient was lost to follow-up. There were no notable adverse events. The authors concluded after arthroscopic subchondral drilling into grade 3 and 4 chondral lesions, postoperative intra-articular injections of autologous peripheral blood MSCs 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.
In 2015, Akgun et. al. reported on a two year randomized, prospective, single-site, single-blind study comparing matrix induced autologous mesenchymal stem cells (MSCs) from synovial tissue with matrix induced autologous chondrocyte implantation (M-ACI) for the treatment of isolated chondral defects of the knee. Both chondrocytes from cartilage and MSCs from synovia were harvested in an arthroscopic procedure, expanded in culture, and then cultured on a collagen membrane for 2 days. Implantation was performed with the construct trimmed to the size and shape of the defect and placed with the cells facing the subchondral bone. Clinical evaluations revealed that improvement from pre-operation to 24 months post-operation occurred in both groups (p < 0.05). At all follow-up intervals, m-AMI demonstrated significantly better functional outcomes (motion deficit and straight leg raise strength) than did m-ACI (p < 0.05). At all follow-up intervals, m-AMI demonstrated significantly better subjective sub-scale scores for pain, symptoms, activities of daily living and sport and recreation of the knee injury and osteoarthritis outcome score (KOOS) than did m-ACI (p < 0.05). Additionally, m-AMI demonstrated significantly better (p < 0.05) scores than m-ACI for the quality of life sub-scale of the KOOS and visual analog scale (VAS) severity at the 6-month follow-up. The Tegner activity score and VAS frequency were not significantly different between the two groups. Graft failure was not observed on magnetic resonance imaging at the 24-month follow-up. m-AMI and m-ACI demonstrated very good-to-excellent and good-to-very good infill, respectively, with no adverse effects from the implant, regardless of the treatment. The authors concluded results of this small study would suggest that cartilage repair with matrix-induced MSCs from synovial tissue might provider outcomes at least as good as matrix-induced autologous chondrocyte implantation. A larger patient cohort and follow-up supported by histological analyses are necessary to determine long-term outcomes.
Damage to the meniscal cartilage in the knee is very common orthopedic injury and predisposes to the development of osteoarthritis. The tissue is relatively avascular and does not spontaneously heal well. Standard treatment is the arthroscopic removal of damaged tissue to relieve symptoms of pain.
In 2014, Vangsness et. al. reported on an industry-sponsored phase 1/2 randomized, double-blind, multi-center, controlled study (NCT00225095, NCT00702741) of cultured allogeneic mesenchymal stem cells (Chondrogen; Osiris Therapeutics) injected into the knee after partial meniscectomy. A total of fifty-five patients at seven institutions underwent a partial medial meniscectomy. A single superolateral knee injection was given within seven to ten days after the meniscectomy. Patients were randomized to one of three treatment groups: Group A, in which patients received an injection of 50 × 10â¶ allogeneic mesenchymal stem cells; Group B, 150 × 10â¶ allogeneic mesenchymal stem cells; and the control group, a sodium hyaluronate (hyaluronic acid/hyaluronan) vehicle control. Patients were followed to evaluate safety, meniscus regeneration, the overall condition of the knee joint, and clinical outcomes at intervals through two years. Evaluations included sequential magnetic resonance imaging (MRI). No ectopic tissue formation or clinically important safety issues were identified. There was significantly increased meniscal volume (defined a priori as a 15% threshold) determined by quantitative MRI in 24% of patients in Group A and 6% in Group B at twelve months post meniscectomy (p = 0.022). No patients in the control group met the 15% threshold for increased meniscal volume. Patients with osteoarthritic changes who received mesenchymal stem cells experienced a significant reduction in pain compared with those who received the control, on the basis of visual analog scale assessments. The authors concluded there was evidence of meniscus regeneration and improvement in knee pain following treatment with allogeneic human mesenchymal stem cells (MSCs). These results support the study of human mesenchymal stem cells (MSCs) for the apparent knee-tissue regeneration and protective effects.
In 2017, Whitehouse et. al. reported on a single center, prospective, open-label first-in-human study of patients with avascular meniscal tear. Autologous mesenchymal stem cells (MSCs) were isolated from an iliac crest bone marrow biopsy, expanded and seeded into the collagen scaffold. The resulting human-MSC/collagen scaffold implant was placed into the meniscal tear prior to the repair with vertical mattress sutures and the patients were followed for 2 years. Five patients were treated and there was significant clinical improvement on repeated measures analysis. Three were asymptomatic at 24 months with no magnetic resonance imaging evidence of recurrent tear and clinical improvement in knee function scores. Two required subsequent meniscectomy due to retear or nonhealing of the meniscal tear at approximately 15 months after implantation. No other adverse events occurred.
The evidence on the use of mesenchymal stem cells (MSCs) to repair or regenerate damaged meniscal tissue consists of preclinical animal studies, first-in-human uncontrolled implantation of expanded autologous MSCs into the meniscal tears, and an early-phase randomized trial of cultured allogeneic MSCs injected into the site of partial meniscectomy. Results are preliminary.
In 2012, Sen et. al. in a small randomized controlled trial of 51 osteonecrotic hips in 40 patients were randomly divided into two treatment groups. Patients in group A (25 hips) were treated with core decompression, and those in group B (26 hips) received autologous bone marrow mononuclear cell instillation into the core tract after core decompression. Blinding of assessments in this trial was not described. Outcome between the 2 groups were compared clinically (Harris Hip score), radiographically (x-ray and magnetic resonance imaging), and by Kaplan-Meier hip survival analysis after 12 and 24 months of surgical intervention. The clinical score and mean hip survival were significantly better in group B than in group A (P < .05). Patients with adverse prognostic features at initial presentation, that is, poor Harris Hip score, x-ray changes, edema, and/or effusion on magnetic resonance imaging had significantly better clinical outcome and hip survival in group B than in group A.
In 2012, Zhao et. al. reported on a randomized trial that included 100 patients (104 hips) with early stage femoral head osteonecrosis treated with core decompression and expanded bone marrow mesenchymal stem cells (BMMSCs) or with core decompression alone. Each BMMSC-treated hip received femoral head (FH) implantation of 2×10(6) autologous subtrochanteric bone marrow-derived and ex vivo expanded BMMSCs. The radiographic stage of ONFH according to the Association Research Circulation Osseous classification, Harris hip score (HHS), and the volume of the necrotic lesion or the low signal intensity zone (LowSIZ) in the FH were assessed before and 6, 12, 24, and 60 months after the initial operation. Sixty months after the operation, only 2 of the 53 BMMSC-treated hips progressed and underwent vascularized bone grafting. In CD group, 7 hips lost follow-up, and 10 of the rest 44 hips progressed and underwent vascularized bone grafting (5 hips) or total hip replacement (5 hips). Compared with the CD group, BMMSC treatment significantly improved the HHS as well as decreased the volume of femoral head LowSIZ of the hips preoperatively classified at stage IC, IIB, and IIC (P<0.05, respectively; stage IIA, P=0.06, respectively). No complication was observed in both treatment groups.
Two small studies have compared core decompression alone with core decompression plus MSCs in patients with osteonecrosis of the femoral head. Both reported improvement in the Harris Hip Score in patients with MSCs, although it was not reported whether the patients or investigators were blinded to the treatment group. Hip survival was significantly improved following treatment with either expanded or concentrated MSCs. The effect appears to be large with expanded MSCs than with concentrated MSCs. Additional studies with larger number of patients are needed to permit greater certainty on the efficacy of this treatment for osteonecrosis.
Demineralized bone matrix (DBM) is a type of allograft. It is produced through a process that involves the decalcification of cortical bone; substantially decreasing the structural strength. However, it is more osteoinductive than ordinary allograft. Although the reason for this is not completely understood, it has been speculated that the osteoinductive growth factors contained in the extracellular bone matrix are easily accessed once the mineral phase of the bone has been removed.
Cell Based: Bone graft substitutes that are cell based use cells to generate new tissue either alone or seeded onto a support matrix (e.g. in combination with allograft material). Support matrix may include xenograft (i.e. bovine) or human type I collagen. Cell based substitutes that are available include mesenchymal and other cell based products.
There is limited evidence on the use of allografts with stem cells for bone fusion of the extremities of spine or the treatment of nonunion. The results of several industry sponsored, early phase trials are available.
In 2014, Eastlack et. al. reported on outcomes from a prospective multicenter study of 182 patients treated with anterior cervical discectomy and fusion using Osteocel Plus in a polyetheretherketone cage and anterior plating at 1 or 2 consecutive levels. Clinical outcomes included visual analogue scale for neck and arm pain, neck disability index, and SF-12 physical and mental component scores. Computed tomography and plain film radiographic measures included assessment of bridging bone, disc height, disc angle, and segmental range of motion. At 24 months, 74% of patients (180/249 levels treated) were available for follow-up. These patients had significant improvements in clinical outcomes, with 87% of levels achieved solid bridging, and 92% of levels had a range of motion less than 3 degrees. With 26% loss to follow up at 24 months and lack of standard care control group, interpretation of these results is limited.
In 2015, Jones et. al. reported on a prospective, multicenter, open-label clinical trial using allogeneic bone matrix containing viable osteogenic cells (Trinity Evolution) in foot and/or ankle arthrodesis. A total of 103 subjects were prospectively enrolled at 10 participating sites. No restrictions were placed on the diagnosis, which included arthritis (primary osteoarthritis, post-traumatic osteoarthritis, and rheumatoid), deformity, neuropathy (Charcot and diabetic), revision surgery and degenerative joint disease, and arthrodesis was performed on 171 joints. The per protocol population consisted of 92 patients at 6 months and 76 patients at 12 months, with 153 and 129 total arthrodeses, respectively. At 6 weeks and at 3, 6, and 12 months, imaging was performed and the subject's pain, function, and quality of life (QOL) status (Visual Analog Scale, American Orthopaedic Foot & Ankle Society Hindfoot Scale, and the Short Form 36) were recorded. At 6 months, fusion rates were 68.5% for all patients and 81.1% for all joints; at 12 months, rates were 71.1% and 86.8%, respectively. Certain high-risk subjects (eg, with diabetes or obesity) had fusion rates comparable to those of normal patients. Statistically significant improvements in pain, function, and QOL were observed, and fusion correlated with both function and QOL outcomes at 6 and 12 months. There were no adverse events attributable to CBA. The authors concluded fusion rates using CBA were higher than or comparable to fusion rates with autograft that have been reported in the recent literature, and CBA fusion rates were not adversely affected by several high risk patient factors. CBA was a safe and effective graft material to achieve fusion in patients with compromised bone healing and may provide an effectively autograft replacement for foot and/or ankle arthrodeses.
A prospective, clinical, and radiographic 12-month outcomes study (2016 Vanichkachorn et.al) of patients undergoing single level anterior cervical discectomy and fusion (ACDF) for symptomatic cervical degenerative disc disease utilizing a novel viable allogeneic stem cell and cancellous bone matrix (Trinity Evolution) was reported using historical controls as the comparator. The ACDF procedure was performed using the polyetheretherketone interbody spacer and bone graft substitute (Trinity Evolution) in 31 patients at multiple clinical sites. At 6 and 12 months, radiographic fusion was evaluated as determined by independent radiographic review of angular motion (≤4°) from flexion/extension X-rays combined with presence of bridging bone across the adjacent endplates on thin cut CT scans. In addition other metrics were measured including function as assessed by the Neck Disability Index (NDI), and neck and arm pain as assessed by individual Visual Analog Scales (VAS). The fusion rate for patients using a PEEK interbody spacer in combination with TE was 78.6 % at 6 months and 93.5 % at 12 months. When considering high risk factors, 6-month fusion rates for patients that were current or former smokers, diabetic, overweight or obese/extremely obese were 70 % (7/10), 100 % (1/1), 70 % (7/10), and 82 % (9/11), respectively. At 12 months, the fusion rates were 100 % (12/12), 100 % (2/2), 100 % (11/11) and 85 % (11/13), respectively. Neck function, and neck/arm pain were found to significantly improve at both time points. Reported adverse events included carpal tunnel syndrome, minor pain, numbness, permanent and/or unresolved pain and swelling. Independent medical adjudication of the 26 adverse events occurring in 31 patients found that no adverse events were definitely or probably related to Trinity Evolution, However, 5 adverse events were found to be possibly related to Trinity Evolution with 3 events of mild severity and 2 of moderate severity.
In 2017, Peppers et. al. reported on a prospective, radiographic evaluation, multicenter study of allogeneic bone matrix containing stem cells (Trinity Evolution) in patients undergoing two-level anterior cervical discectomy and fusion. This study involved 40 patients that presented with symptomatic cervical degeneration at two adjacent vertebral levels and underwent instrumented anterior cervical discectomy and fusion (ACDF) using Trinity Evolution (TE) autograft substitute in a polyetherethereketone (PEEK) cage. At 12 months, radiographic fusion status was evaluated by dynamic motion plain radiographs and thin cut CT with multi-planar reconstruction by a panel that was blinded to clinical outcome. Fusion success was defined by angular motion (≤4°) and the presence of bridging bone across the adjacent vertebral endplates. Clinical pain and function assessments included the Neck Disability Index (NDI), neck and arm pain as evaluated by visual analog scales (VAS), and SF-36 at both 6 and 12 months. At both 6 and 12 months, all clinical outcome scores (SF-36, NDI, and VAS pain) improved significantly (p < 0.05) compared to baseline values. There were no adverse events or infections that were attributed to the graft material, no subjects that required revisions, and no significant decreases to mean neurological evaluations at any time as compared to baseline. At 12 months, the per subject and per level fusion rate was 89.4 and 93.4%, respectively. Subgroup analysis of subjects with risk factors for pseudoarthrosis (current or former smokers, diabetic, or obese/extremely obese) compared to those without risk factors demonstrated no significant differences in fusion rates. Limitations to this study include a lack of a control group and thus TE treatment was not directly compared to autograft or non-cellular autograft treatments. Additionally, since the surgeons were not restricted with their use of operative approaches or fixation, either or both may have impacted outcomes. The impact of these factors on the outcome was not evaluated. Lastly there was no sample size estimation in the protocol because there were no formal statistical hypotheses. The authors concluded, subjects who received Trinity Evolution in combination with PEEK interbody device during a two-level ACDF procedure had a high rate of fusion success both overall and when stratified into high risk groups, while having no serious adverse events related to the graft material.
The use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. For individuals who have cartilage defects, meniscal defects, joint fusion procedures, or osteonecrosis who receive mesenchymal stem cell (MSC) therapy (from bone marrow, adipose tissue, peripheral blood and synovial tissue), the evidence includes preclinical studies, case series, and small randomized and nonrandomized comparative studies and systematic reviews, which may suggest that MSC therapy may improve regeneration of bone or tissue in orthopedic indications. However, the lack of validated, comparable scoring, robust sample sizes and long term follow-up data, preclude definitive conclusions regarding the net health benefit of MSC therapy. While the results of early trials have been promising a number of questions remain. The available data has not yet established that MSCs when infused or transplanted into an area can: 1) truly regenerate by incorporating themselves into the native tissue, surviving and differentiating; or 2) promote the preservation of injured tissue and tissue remodeling. In addition, the optimal source of MSCs has not been clearly identified. Further studies are needed to determine the mechanism of action, duration of efficacy, optimal frequency of treatment and regenerative potential. The evidence is insufficient to determine the effects on net health outcomes.
In 2017, the American Academy of Orthopaedic Surgeons (AAOS) issued a position statement on use of emerging biologic therapies. This new position statement applies to the use of stem cell and other biologic treatments for musculoskeletal joint conditions. The position statement states the following:
The increasing shift to therapeutic biologic products for restoring structure and function presents new questions of safety and effectiveness. No longer reserved for treatment trauma and soft tissue injuries, biologic therapies are now explored as options for osteoarthritis. As we note in the statement “Innovation and New Technologies in Orthopaedic Surgery,” surgeons must be aware of the scientific basis for the different treatment options offered to their patients, including benefits and risks. The varying regulatory pathways by which biologic therapies come to market require the additional burden for surgeons to become familiar with the Food and Drug Administration’s current thinking with respect to the source, retrieval and/or manufacturing methods, processing, storage, and use of these products, whether alone or as part of combination products.
The American Academy of Orthopaedic Surgeons (AAOS) believes that surgeons should be cognizant of the risks, benefit, regulatory status and labeled indications of the products they use. Unlike devices, the effects of these products may not be limited to the duration of their implantation. Autogenous products may be subject to regulatory review.
Emerging biologic therapies may lack the demonstrated safety and effectiveness profiles of many traditional orthopaedic treatments. Patient education is needed for informed consent. The core concepts outlined in the statement “Orthopaedic Surgical Consent” provide guidance to surgeons as they prepare to discuss the risk and benefits of procedures and products with patients.
The AAOS Standards of Professionalism state “An orthopaedic surgeon, or his or her qualified designee, shall present pertinent medical facts and recommendations to, and obtain informed consent from, the patient or the person responsible for the patient.” The mandatory standard obligates surgeons to disclose any products that may be used during the episode of care and engage in frank discussion regarding the risk and benefits of biologics.
Orthopaedic surgeons and their organizations/facilities should support and participate in orthopaedic registries and other data collection systems. Through voluntary reporting of key patient and orthopaedic treatment information to local, state and national repositories, both patient care and safety will be improved. Documentation and reporting are critical to establishing the body of evidence needed to demonstrate the safety and effectiveness of emerging biologics.
In 2014, the American Association of Neurological Surgeons (AANS) issued a guideline on fusion procedures for degenerative disease of the lumbar spine that states “The use of demineralized bone matrix (DBM) as a bone graft extender is an option for 1 and 2 level instrumented posterolateral fusions. Demineralized Bone Matrix: Grade C (poor level of evidence).”
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, title 21, parts 1270 and 1271.
Concentrated autologous mesenchymal stem cells (MSCs) do not require approval by the U.S. Food and Drug Administration (FDA). No products using engineered or expanded MSCs have been approved by the FDA for orthopedic applications
The following products are examples of commercialized demineralized bone matrix (DBM). They are marketed as containing viable stem cells. In some instances, manufacturers have received communications and inquiries from the FDA related to the appropriateness of their marketing products that are dependent on living cells for their function.
In 2008, FDA determined that the mesenchymal stem cells (MSCs) sold by Regenerative Sciences for use in the Regenexx™ procedure would be considered drugs or biological products and thus require submission of a New Drug Application (NDA) or Biologics Licensing Application (BLA) to FDA. The Regenexx™ procedure originally used stem cells derived from bone marrow or synovial fluid and cultured the cells with autologous platelet lysate in a separate laboratory. Other compounds such as antibiotics were added before the material was returned to the patient in a separate orthopedic procedure. Regenerative Sciences asserted that the procedure was the practice of medicine and not subject to FDA regulation. In 2014, a federal appellate court upheld FDA authority to regulate human cells, tissues, and cellular and tissue-based products. To date, no new drug application (NDA) or biologic license application (BLA) has been approved by FDA for this product. As of 2015, the expanded stem-cell procedure (now termed Regenexx-C™) is only offered in the Cayman Islands. The current Regenexx™ Stem Cell Procedure is offered through a network facilities in the United States that provide same-day stem-cell and blood platelet procedures, which do not require FDA approval. These procedures, along with Regenexx™ Super Concentrated Platelet Rich Plasma, are marketed as treatments for arthritis and injuries of the knee, hip, shoulder, spine, hand and wrist, foot and ankle and elbow.
Prior approval is recommended.
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Mesenchymal stem cell (MSC) therapy from bone marrow, adipose tissue, peripheral blood or synovial tissue alone or in combination with platelet-derived products (e.g. platelet-rich plaxma, lysate) is considered investigational for all orthopedic applications, including use in repair or regeneration of musculoskeletal tissue.
Mesenchymal stem cell (MSC) therapy may include, but are not limited to the following:
The use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. The evidence includes preclinical studies, case series, and small randomized and nonrandomized comparative studies and systematic reviews, which may suggest that mesenchymal stem cells (MSCs) therapy may improve regeneration of bone or tissue in orthopedic indications. However, the lack of validated, comparable scoring, robust sample sizes and long term follow-up data, preclude definitive conclusions regarding the net health benefit of mesenchymal stem cells (MSCs) therapy. While the results of early trials have been promising a number of questions remain. The available data has not yet established that mesenchymal stem cells (MSCs) when infused or transplanted into an area can: 1) truly regenerate by incorporating themselves into the native tissue, surviving and differentiating; or 2) promote the preservation of injured tissue and tissue remodeling. In addition, the optimal source of mesenchymal stem cells (MSCs) has not been clearly identified. Further studies are needed to determine the mechanism of action, duration of efficacy, optimal frequency of treatment and regenerative potential. The evidence is insufficient to determine the effects on net health outcomes.
Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DMB) with stem cells used alone, added to ther biomaterials for grafting or seeded onto scaffolds is considered investigational for all orthopedic applications. There is insufficient evidence to support a conclusion concerning the net health outcomes or benefits associated with this procedure.
Demineralized bone matrix (DBM) with viable stem cells (mesenchymal stem cells) including but not limited to the following:
Note: See regulatory information above for additional information regarding demineralized bone matrix (DBM) product(s) containing viable stem cells.
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Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc. They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.
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