Medical Policy: 08.01.22 

Original Effective Date: June 2014 

Reviewed: February 2020 

Revised: February 2020 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

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.

 

Description:

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:

  • Knee: Arthritis, meniscus tears, tendon and ligament tears, overuse injuries and other conditions
  • Hip: Injuries, arthritis, bursitis and other degenerative conditions
  • Shoulder: Arthritis, rotator cuff tears, and other shoulder conditions
  • Spine and cervical conditions: Back pain, pain from bulging or herniated discs, degenerated disc or pain from an extruded or torn disc
  • Elbow: Injuries, overuse conditions and arthritis (tendon and ligament issues)
  • Hand/Wrist: Arthritis and other conditions
  • Foot/Ankle: Ligament tears, sprains and instability of the ankle joint, an alternative to fusion or replacement surgery of the ankle
  • Non-union fractures

 

Mesenchymal stem cells (MSCs) are multipotent cells (also called multipotent stromal cells) that express a variety of different cell surface proteins and can differentiate into various lineages, such adipogenic (fat cells), osteogenic (bone cells) and chondrogenic (cartilage cells). If MSCs are placed within normal healthy bone, cartilage or adipose tissue, the stem cells differentiate into that particular tissue. In theory, this property applies to all mesenchymal tissues, including muscle, tendon, and fibrous tissues.

 

Mesenchymal stem cells (MSCs) are immunosuppressive and as such do not result in host rejection. One of the proposed advantages of autologous MSCs is the ability to isolate them, expand them in vitro and deliver them as autologous therapy. Nevertheless both autologous and allogenic MSCs are being used as therapy to treat various orthopaedic conditions. Although processing techniques vary, and the optimal number of MSCs to be transplanted/seeded has yet to be established, MSCs can be concentrated for direct injection, or they can be cultured and incubated. Once cultured MSCs can be mixed with other materials such as gels or pastes, or they can be seeded onto scaffolds and used as a support matrix for implantation. Seeded scaffolds have been investigated as a tissue-engineering method within the musculoskeletal system for bone and cartilage repair. However, stem cells may undergo malignant transformation and there is some concern that autologous MSCs may induce tumors by changing the action of cancer cells and accelerating tumor growth, and that allogeneic MSCs may accelerate infectious risk.

 

The steps involved in processing MSCs include harvesting the cells from bone marrow or lipoaspirate, isolation of the cells, followed by proliferation in a culture medium (i.e., culture expanded). Following proliferation the MSCs are stored using cryopreservation. Other manufacturing procedures can be done that avoid cellular isolation and proliferation (i.e., nonexpanded cells) although the resulting number of stem cells within these products are unknown.

 

Treatment modalities for orthopaedic and/or musculoskeletal conditions proven safe and effective in the peer-reviewed medical literature include the use of pharmaceutical agents, weight loss, physical therapy and exercise, acupuncture, chiropractic care, and surgical repair when all other treatment options have failed. Stem cell therapy is an emerging technology that authors assert may be considered an alternative treatment modality and that may for some individuals avoid future surgical procedures (e.g., knee arthroplasty).

 

Regenexx™ Stem Cell Procedure

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.

 

Common Conditions Treated:

  • Osteoarthritis of the knee, hip, ankle, shoulder, hands
  • Patients with non-healing bone fractures
  • Certain types of injuries to the meniscus, hip labrum, shoulder labrum, shoulder SLAP lesions
  • Tendon injuries such a partial rotator cuff or other partial muscle-tendon tears
  • Avascular necrosis of the hip, shoulder, knee, ankle

 

Centeno, et al. (2018) evaluated Regenexx therapy for knee osteoarthritis (OA). This study included patients with symptomatic knee osteoarthritis (n=48) who were assigned to either an exercise therapy control group (n=22) or treatment group with image-guided injection of autologous bone marrow concentrate (BMC) and platelet products (n=26). At three months subjects were allowed to crossover to the bone marrow treatment group. Measured outcomes included the Knee Society Score (KSS), Pain Visual Analogue Scale, Short Form-12 Scales (SF-12), and Lower Extremity Activity Scale (LEAS). Follow-up for clinical outcomes occurred at 6-weeks, 3, 6, 12 and 24 months. A total of 14 patients were lost to follow-up. All 22 patients in the control group crossed over to BMC treatment after three months. Patients who received a specific protocol of BMC and platelet products improved significantly in activity levels, as well as pain, range of motion and stability, compared to patients who underwent a home exercise therapy program for 3 months. Pain decreased for both the exercise therapy and the BMC groups, and function increased for the BMC group, although did not differ significantly between the 2 groups. Exercise therapy provided significant improvements in ROM and activity levels at 3-months compared to baseline. No serious adverse events were reported. Limitations of this RCT included the small sample size and the allowance of those in the exercise group to crossover at three months and receive BMC. Additional controlled studies with larger sample sizes evaluating Regenexx processes/procedures/products are needed to support safety and effectiveness.

 

The overall body of evidence indicates that safety and efficacy of Regenexx procedures, including BMC with platelet rich plasma and other lysate preparations, are currently unproven. Although the body of evidence is emerging, concerns regarding quality and oversight, preparation, application/procedure, safety, clinical utility, and durability have been reported among authors.

 

Cartisem®

Cartistem® is a combination of human umbilical cord blood-derived mesenchymal stem cells and sodium hyaluronate, and is intended to be used as a single-dose therapeutic agent for cartilage regeneration in humans with cartilage defects of the knee as a result of aging, trauma, or degenerative diseases (National Institute of Health, Clinicaltrials.gov NCT01733186). Although results have not yet been published, according to Clinical Trials.gov a study is underway evaluating the efficacy and safety of Cartistem®.

 

Lipogem

Lipogem® Microfragmented Adipose Tissue Transplant System (Lipogem, Norcross, GA) is an adipose-derived regenerative cell therapy described by the manufacturer as closed circuit processing system used to remove adipose tissue from the body and transfer it via injection into a patients injured joint or diseases soft tissue. It is asserted Lipogems preserves the structural properties and microarchitecture of the original tissue: the scaffold (the adipose tissue and the stromal structure), the cells (endothelium, pericytes / MSCs), and the growth factors (cytokines and chemokines).

 

Panchal et. al. (2017) reported on 17 subjects with osteoarthritis of the knee who underwent Lipogem injection intra-articularly under ultrasound guidance. Pre and post treatment outcomes were collected at six weeks, six months and 12 months following therapy using NPRS (numerical pain rating scale), the 100-point Knee Society Score (KSS) and lower extremity activity scale (LEAS). Although the authors reported significant improvements in MPRS, mean KSS at 12 months the study is limited by small sample population, lack of control, and short-term outcomes.

 

An evidence analysis evaluating the use of autologous micro-fragmented adipose tissue (MFAT) injection for treatment of degenerative joint disease (DJD) included nine abstracts, including 1 randomized controlled trial (RCT), 3 prospective uncontrolled studies, 3 reports of 2 retrospective uncontrolled studies, and 2 commentaries. The Lipogems system was used in one study, others did not report the source of MFAT. The overall findings are conflicting for improvement of health outcomes, and conclusions regarding the safety and effectiveness could not be made. Additional studies are underway, however at present there is insufficient evidence in the peer reviewed scientific literature to support safety and efficacy of Lipogems for treatment of knee osteoarthritis or other orthopaedic /musculoskeletal conditions.

 

Adipose Derived Mesenchymal Stem Cells (MSCs)

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.

 

Mesenchymal Stem Cells (MSCs) from Peripheral Blood

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.

 

Mesenchymal Stem Cells (MSCs) from Synovial Tissue

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.

 

Cartilage Defects

Clinical Context and Therapy Purpose

The purpose of stem cell therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with osteoarthritis (OA) or focal cartilage defects.

 

Patients

The relevant population of interest is individuals with OA or focal cartilage defects.

 

Interventions

The therapy being considered is treatment with mesenchymal stem cells (MSCs)

 

Comparators

Comparators of interest include conservative management with medication or hyaluronic acid injection, microfracture, and autologous chondrocyte implantation.

 

Outcomes

The general outcomes of interest are symptoms, functional outcomes, quality of life (QOL) and treatment related morbidity (TRM). Specific scales may include the following:

  • Knee Injury and Osteoarthritis Outcome Score (KOOS; 5 subscales with 0-100 scales)
  • Lysolm Knee Scale (LKS) score (0-100)
  • Tegner Activity Score (TAS); a visual analog scale (VAS) for pain (0-100 mm or 0-10 cm scale)
  • Western Ontario and McMaster Universities Arthritis Index (WOMAC) which as 3 subscores: pain which includes 5 items; stiffness, with 2 items; and physical function with 17 items
  • WOMAC response criteria is an improvement of 20% in at least 2 items together with an improvement of 10 points in the overall scale
  • Cartilage is evaluated with the Magnetic Resonance observation of Cartilage Repair Tissue (MOCART, 0-100 points, where higher scores indicate better cartilage repair)

 

Follow-up over months to years is of interest for relevant outcomes.

 

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 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.

 

Meniscal Defects

Clinical Context and Therapy Purpose

The purpose of stem cell therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with meniscal defects.

 

Patients

The relevant population of interest is individuals with meniscal defects.

 

Interventions

The therapy being considered is mesenchymal stem cell therapy.

 

Comparators

Comparators of interest include conservative management.

 

Outcomes

The general outcomes of interest are symptoms, functional outcomes, quality of life (QOL) and treatment related morbidity (TRM).

 

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 × 106 allogeneic mesenchymal stem cells; Group B, 150 × 106 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. This trial appears to have been a post hoc analysis and should be considered preliminary.

 

In 2017, Whitehouse et. al. published a report on techniques of in vitro expansion of autologous-derived MSCs and a case series of the first-in-human implantation to treat meniscal defects in 5 patients. The regulatory framework in the United Kingdom allows cell manipulation and requires immunohistochemical documentation of the presence and volume of mesenchymal cells. Over the first 12 months post-procedure, 3 of the 5 patients were reported to have clinical symptom relief, which persisted through 24 months. MRI scans showing lack of meniscal displacement were the only other postoperative assessment. The 2 patients who failed to obtain symptom relief at 6 and 12 months had to repeat arthroscopic procedures with meniscectomy.

 

Summary

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.

 

Muscle, Tendon and Ligament Repair

Stem cell therapy as treatment of tendon and ligament disorders is also an emerging field. Similar to other musculoskeletal tissues tendons and ligaments possess poor regenerative capability. There is a paucity of studies evaluating the efficacy of stem cell therapy for tendon/ligament healing. A systematic review evaluating the evidence for the use of stem cell therapy for tendon disorders was published by Pas, et al., 2017(b). A total of four published trials and three unpublished/pending trials were included in the review (n=79). Two of the trials evaluated bone marrow stem cells injected for treatment of rotator cuff repair, one trial used allogenic adipose derived stem cells for treatment of epicondylar tendinopathy and one trial evaluated bone marrow derived stem cells for treatment patellar tendinopathy. According to the authors all trials were high risk of bias and level four evidence. Absence of controls limited interpretation regarding any benefit. With the exception of the trial using adipose derived stem cells none of the trials using bone marrow MSCs performed cell culturing or cell typing. In epidcondylar tendinopathy, patellar tendinopathy and rotator cuff repairs improved healing, functional outcomes and pain scores were reported compared with baseline. Re-rupture of repaired rotator cuffs treated with stem cells preoperatively were reduced in comparison with historical controls or other literature. Only one trial reported adverse events, safety concerns remain. Reporting of cell analysis was inconsistent among trials and it is unknown what if any effect cell dose had. The authors concluded the evidence was insufficient to support the use of stem cell therapy for treatment of tendon disorders.

 

Because of their multipotent potential and ability to exert paracrine effects and potential to improve blood flow mesenchymal stem cells have been studied as a treatment of rotator cuff disease (Lin, et al, 2017). Rotator cuff repairs occur most commonly at the tendon-bone interface. During repair, reattaching the tendon to the bone is challenging due to various physiological reasons, often resulting in frequent failure. Nevertheless, there is a paucity of evidence evaluating the effect of MSC therapy for rotator cuff disease and outcomes demonstrating improved healing are inconsistent.

 

Osteonecrosis

Clinical Context and Therapy Purpose

The purpose of stem cell therapy is to provide treatment option that is an alternative to or an improvement on existing therapies in patients with osteonecrosis.

 

Patients

The relevant population of interest is individuals with osteonecrosis.

 

Interventions

The therapy being considered is therapy with mesenchymal stem cells.

 

Comparators

Comparators of interest include core decompression.

 

Outcomes

The general outcomes of interest are symptoms, functional outcomes, quality of life (QOL) and treatment related morbidity (TRM).

 

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.

 

Summary

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.

 

Joint Fusion Procedures

Clinical Context and Therapy Purpose

The purpose of stem cell therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with joint fusion procedures. 

 

Patients

The relevant population of interest is individuals with joint fusion procedures.

 

Interventions

The therapy being considered is stem cell therapy.

 

Comparators

Comparators of interest include iliac crest bone graft.

 

Outcomes

The general outcomes of interest are symptoms, functional outcomes, quality of life (QOL) and treatment related morbidity (TRM).

 

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.

  • Mesenchymal stem cells (MSCs) may also be administered by combining the cells with demineralized bone matrix (DBM). DBM is considered minimally processed tissue and does not require FDA approval. MSCs are multipotent stem cells that express a variety of different cell surface proteins and can differentiate into a variety of cell types. Obtained from bone marrow they have shown to differentiate into osteoblasts, chondrocytes, myocytes, adipocytes and neuronal cells.
  • The use of demineralized bone matrix (DBM) with MSCs has been and continues to be investigated for various procedures, including spinal fusion and for intervertebral disc regeneration. Although currently under investigation, data published in the medical literature evaluating cell based substitutes is in preliminary stages and mainly in the form of nonhuman trials or case reports; data supporting safety and efficacy are lacking. Therefore, the use of allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DBM) with stem cells, is considered investigational for all orthopedic applications, due to the lack of evidence supporting safety and efficacy.

 

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.

 

Summary

They use of mesenchymal stem cell (MSCSs) based bone graft substitutes has been and continues to be investigated for various procedures, including spinal fusion, intervertebral disc regeneration and other orthopedic procedures. Although currently under investigation data supporting safety and efficacy of these indications is lacking.

 

Summary of Evidence

Treatment modalities for orthopaedic and/or musculoskeletal conditions proven safe and effective in the peer-reviewed medical literature include the use of pharmaceutical agents, weight loss, physical therapy and exercise, acupuncture, chiropractic care, and surgical repair when all other treatment options have failed. Mesenchymal stem cell therapy is an emerging technology that authors assert may be considered an alternative treatment modality and that may for some individuals avoid future surgical procedures.

 

The use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research including but not limited to regeneration and/or repair of musculoskeletal tissue, of muscle, ligament, tendon, meniscus repair; treatment of joint disease including cartilage lesions, osteoarthritis of knee, hip, ankle and shoulder; epicondylitis; fracture including nonunion; and various spinal conditions such as spinal fusion and intervertebral disc repair. For individuals who receive mesenchymal stem cell (MSC) therapy from bone marrow, adipose tissue, peripheral blood and synovial tissue, the evidence in the published peer reviewed literature evaluating MSCs for the treatment of these conditions is mainly in the form of case series/case reports, nonrandomized comparative studies, a number of systematic reviews/meta-analyses and few randomized trials. The type/source of stem cell used and methods of extraction vary across studies, sample populations are small, reported outcomes are < two years in most studies, and injections include use of other components in some studies, such as hyaluronan or platelet rich plasma making it difficult to attribute the sole effect of MSCs as a treatment response. Regeneration and tissue remodeling has not been firmly established in well-designed, controlled studies and extraction and concentration methods, infusion procedures, indications for use are not standardized, and the optimal source of MSC including the quantity of cells to inject have not been firmly established. Additional RCTs evaluating long term outcomes are needed to firmly establish safety and efficacy of MSCs used for treatment of orthopaedic and /or musculoskeletal conditions. It is not yet proven that a clinical benefit outweighs potential harm that may be associated with MSC therapies. The evidence is insufficient to determine the effects on net health outcomes.

 

Information available on the National Institutes of Health website regarding clinical trials indicates that several registered trials of MSCs for the treatment of osteoarthritis, tendon regeneration and other orthopaedic conditions are being conducted and few have been completed. The cells used within these trials include both expanded and nonexpanded MSCs for the treatment of a variety of orthopaedic and/or musculoskeletal conditions.

 

Practice Guidelines and Position Statements

The International Society of Stem Cell Research (ISSCR)

In 2019, the International Society of Stem Cell Research (ISSCR) published information regarding stem cell types and uses and asserts there is little evidence they are beneficial. MSC therapy remains in early experimental stages. According to ISSCR, mesenchymal stem cells are cells that originate from stroma, the connective tissue surrounding tissues and organs. Although various MSCs are thought to have stem cell and immunomodulatory properties as treatment for various disorders. Scientists do not fully understand whether these cells are actually stem cells or what types of cells they are capable of generating. They do agree that not all MSCs are the same, and that their characteristics depend on where in the body they come from and how they are isolated and grown. Some types of stem cells are capable of migration after transplantation, meaning there is a risk of off-target effects and inappropriate integration.

 

American Academy of Orthopaedic Surgeons (AAOS)

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.

 

American Association of Neurological Surgeons

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).”

 

Regulatory Status

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.

  • Allostem® (AlloSource): partially demineralized allograft bone seeded with adipose-derived MSCs
  • Map3™ (rti surgical) contains cortical cancellous bone chips, DBM, and multipotent adult progenitor cells
  • Osteocel Plus® (NuVasive): DBM combined with viable MSCs that have been isolated from allogeneic bone marrow
  • Trinity Evolution Matrix™ (Orthofix) DBM combined with viable MSCs that have been isolated from allogeneic bone marrow

 

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.

 

Lipogems received FDA 5109k) approval in 2016 as a suction lipoplasty system. It is noted with the 510(k) approval the device is intended for use in the following surgical specialties when the transfer of harvested adipose tissue is desired: orthopaedic surgery, arthroscopic surgery, neurosurgery, gastrointestinal and affiliated organ surgery, urological surgery, general surgery, gynecological surgery, thoracic surgery, laparoscopic surgery, and plastic and reconstructive surgery when aesthetic body contouring is desired (FDA, K161636).

 

Prior Approval:

Prior approval is recommended.

 

Policy:

See Related Medical Policies:

  • 02.01.32 Platelet-Rich Plasma and Autologous Protein Solution for Orthopedic Applications
  • 02.01.18 Prolotherapy

 

Mesenchymal Stem Cell (MSC) Therapy

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 plasma, lysate) as treatment for orthopaedic and/or musculoskelatal conditions is considered investigational for all indications including but not limited to the following:

  • Regeneration and/or repair of musculoskeletal tissue (e.g. ligament, tendon, and/or meniscus repair, muscle sprain, tendonitis, epicondylitis) 
  • Treatment of joint disease (e.g., articular cartilage repair, joint capsular injury) 
  • Degenerative disc disease (e.g., intervertebral disc repair) 
  • Osteoarthritis (e.g., knee, hip, ankle, shoulder) 
  • Fracture repair, including nonunion of long bone 
  • Osteonecrosis repair

 

Mesenchymal stem cell (MSC) therapy may be referred to as one of the following:

  • Regenexx™
  • Regenexx™ Stem Cell Same Day Procedure
  • Regenexx™ Super Concentrated Platelet Rich Plasma
  • Bone marrow aspirate concentrate (BMAC)

 

Based on review of the peer reviewed medical literature the type/source of stem cells used and methods of extraction vary across studies, sample populations are small, reported outcomes are < two years in most studies, and injections include use of other components in some studies, such as hyaluronan or platelet rich plasma making it difficult to attribute the sole effect of mesenchymal stem cells (MSCs) as a treatment response. Regeneration and tissue remodeling have not been firmly established in well-designed, controlled studies and extraction and concentration methods, infusion procedures, indications for use are not standardized. Also, the optimal source of mesenchymal stem cells (MSCs) including the quantity of cells to inject have not been firmly established. Additional randomized controlled trials (RCTs) evaluating long term outcomes are needed to firmly establish safety and efficacy of mesenchymal stem cells (MSCs) used for treatment of orthopaedic and /or musculoskeletal conditions. It is not yet proven that a clinical benefit outweighs potential harm (autologous MSCs may induce tumors by changing the action of cancer cells and accelerate growth; allogeneic MSCs may accelerate infectious risk) that may be associated with mesenchymal stem cell (MSC) therapies. The evidence is insufficient to determine the effects on net health outcomes.

 

Alloraft Bone Products with Viable Stem Cells

Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DMB) with stem cells used alone, added to their 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:

  • Allostem (Allosource)
  • Map3 (RTI Surgical)
  • Osteocel Plus (NuVasive)
  • Trinity Evolution Matrix (Orthofix).

 

Note: See regulatory information above for additional information regarding demineralized bone matrix (DBM) product(s) containing viable stem cells.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • 20999 unlisted musculoskeletal procedure
  • 38205 blood derived hematopoietic progenitor cell harvesting for transplantation, per collection allogeneic
  • 38206 blood derived hematopoietic progenitor cell harvesting for transplantation, autologous
  • 38212 transplant preparation of hematopoietic progenitor cells; red blood cell removal
  • 38215 transplant preparation of hematopoietic progenitor cells; cell concentration in plasma, mononuclear or buffy coat layer
  • 38230 bone marrow harvesting for transplantation allogeneic
  • 38232 bone marrow harvesting for transplantation autologous
  • 38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
  • 38241 Hematopoietic progenitor cell (HPC); autologous transplantation
  • 0232T injection(s), platelet-rich plasma, any tissue, including image guidance, harvesting and preparation when performed
  • 0565T Autologous cellular implant derived from adipose tissue for the treatment of osteoarthritis of the knees; tissue harvesting and cellular implant creation
  • 0566T Autologous cellular implant derived from adipose tissue for the treatment of osteoarthritis of the knees; injection of cellular implant into knee joint including ultrasound guidance, unilateral

 

Selected References:

  • U.S. Food and Drug Administration. Ensuring Safety and Efficacy of Stem Cell Based Products Accessed May 14, 2014
  • U.S. Food and Drug Administration. Untitled Letters (Biologics), Regenerative Sciences, Inc. Guidance, Compliance and Regulatory Information (Biologics) 2008 Available online at: Accessed May 14, 2014
  • American Academy of Orthopaedic Surgeons (AAOS) OrthoInfo, Your connection to expert orthopaedic information, Stem Cells and Orthopaedics. Accessed May 2, 2014
  • American Academy of Orthopaedic Surgeons (AAOS) OrthoInfo, Your connection to expert orthopaedic information, Frequently Asked Questions about Stem Cells. Accessed May 2, 2014
  • International Congress for Joint Reconstruction (ICJR). Reports, Looking Toward the Future of Stem Cells in Orthopaedics Accessed May 15, 2014
  • International Society for Cellular Therapy (ISCT), Position Paper, Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy Position Statement. Cryotherapy (2006)Vol. 8, No.4, 315-317.
  • Sally Roberts, et al. Prospects of Stem Cell Therapy in Osteoarthritis. Regen.Med (2011) 6(3), 351-366.
  • Shaul Beyth, Josh Schroeder and Meir Liebergall, Stem Cells in Bone Diseases: Current Clinical Practice. British Medical Bulletin 2011; 99:199-210
  • Christopher J. Centeno and Stephen J. Faulkner, Chapter 21, The Use of Mesenchymal Stem Cells in Orthopedics. M.A. Hayat (ed), Stem Cells and Cancer Stem Cells, Volume 1, DOI 10.1007/978-94-007-1709-1-21.
  • Medscape. Technology Insight: Adult Mesenchymal Stem Cells for Osteoarthritis Therapy.
  • ECRI Institute. Nanotechnology May Help Speed Bone Healing. Published 2/6/2009.
  • ECRI Institute. Health Technology Forecast. Autologous and Allogeneic Mesenchymal Stem Cell Therapy for Treating Osteoarthritis. November 2012.
  • ECRI Institute. Emerging Technology Evidence Report. Autologous Mesenchymal Stem Cells for Treating Knee Osteoarthritis. June 2013.
  • ECRI Institute Product Brief. AlloStem Stem Cell Bone Growth Substitute (AlloSource) for Orthopedic procedures. August 2013.
  • Dominici M, Le Blanc K, Mueller I, et. al. Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy Position Statement. Cytotherapy 2006;8(4):315-7
  • Rush SM, Hamilton GA, Ackerson LM, Mesenchymal Stem Cell Allograft in Revision Foot and Ankle Surgery: A clinical and Radiographic Analysis. J Foot Ankle Surg 2009; 48(2):163-9
  • Centeno CJ, Schultz JR, Cheever M, et. al. Safety and Compliations Reporting on Re-Implantation of Culture Expanded Mesenchymal Stem Cells Using Autologous Platelet Lysate Technique, Curr Stem Cell Rews Ther, 2011, 6, 368-378
  • Andre F. Steinert, Lars Rackwitz, et. al. Concise Review: The Clinical Application of Mesenchymal Stem Cells for Musculoskeletal Regeneration: Current States and Perspectives, Stem Cells Translational Medicine 2012;1:237-247.
  • Rick L Lau, Anthony V. Perruccio, et. al. Stem Cell Therapy for the Treatment of Early Stage Avascular Necrosis of the Femoral Head: A Systematic Review, BMC Musculoskeletal Disorders 2014, 15:156.
  • Jonathan I. Dawson, Janos Kanczler, et. al. Concise Review: Bridging the Gap: Bone Regeneration Using Skeletal Stem Cell-Based Strategies-Where Are We Now?, Stem Cells Volume 32, Issue 1 January 2014
  • Filardo G, Madry H, et. al. Mesenchymal Stem Cells for the Treatment of Cartilage Lesions: From Preclinical Findings to Clinical Application in Orthopaedics. Knee Surg Sports Traumatol Arthrosc 2013 aug;21(8):1717-29
  • Wong KL, Lee KB, Tai BC et. al. Injectable Cultured Bone Marrow-Derived Mesenchymal Stem Cells in Varus Knees with Cartilage Defects Undergoing High Tibial Osteotomy: A Prospective, Randomized Controlled Clinical Trial with 2 Years Follow Up. Arthroscopy 2013; 29(12):2020-8
  • Hana Yu, Adetola B Adesida and Nadr M Jomha, Meniscus Repair Using Mesenchymal Stem Cells – A Comprehensive Review. Stem Cell Research & Therapy 2015 6:86
  • Orthofix Trinity Evolution Matrix Allograft with Viable Cells.
  • Allosource  Allostem Cellular Bone Allograft.
  • RTIX Map3 Cellular Allogeneic Bone Graft.
  • Nuvasive Osteocel Plus Bone Grafting.
  • Centeno Christopher, Pitts John, et. al. Efficacy and Safety of Bone Marrow Concentrate for Osteoarthritis of the Hip: Treatment Registry Results of 196 Patients, Journal Stem Cell Research and Therapy 2014, Volume 4 Issue 10
  • Centeno Christopher, Pitts John, et. al. Efficacy of Autologous Bone Marrow Concentrate for Knee Osteoarthritis with and without Adipose Graft, BioMed Research International September 2014
  • Veronesi F, Giavaresi G, et. al. Clinical Use of Bone Marrow, Bone Marrow Concentrate, and Expanded Bone Marrow Mesenchymal Stem Cells in Cartilage Disease, Stem Cells Dev. 2013 Jan 15;22(2):181-92
  • Hernigou P, Flouzat Lachaniette CH, et. al. Biologic Augmentation of Rotator Cuff Repair with Mesenchymal Stem Cells During Arthroscopy Improves Healing and Prevents Further Tears: A Case-Controlled Study, Int Orthop 2014 Sep;38(9):1811-8
  • Centeno CJ, Busse D, et. al. Regeneration of Meniscus Cartilage in a Knee Treated with Percutaneously Implanted Autologous Mesenchymal Stem Cells, Med Hyptheses 2008 Dec; 71(6):900-8
  • PubMed: Bashir J, Sherman A., et. al. Mesenchymal Stem Cell Therapies in the Treatment of Musculoskeletal Diseases, Physical Medicine and Rehabilitation 2014 Jan;6(1):61-9
  • Houdek Matthew, Wyle Cody, et. al. Stem Cell Treatment for Avascular Necrosis of the Femoral Head: Current Perspectives, Stem Cells and Cloning: Advances and Applications 2014:7 65-70
  • Carpenter RS, Goodrich LR, Frisbie DD, Kisiday JD, Carbone B, Mcllwraith, CJ Centeno, and C Hidaka, Osteoblastic Differentiation of Human and Equine Adult Bone Marrow-Derived Mesenchymal Stem Cells when BMP-2 or BMP-7 Homodimer Genetic Modification is Compared to BMP-2/7 Heterodimer Genetic Modification in the Presence and Absence of Dexamethasone, J Orthop Res. 2010 October; 28(10): 1130-1337
  • Peters C.M.M., Leijs M.J.C., et. al. Safety of Intra-Articular Cell-Therapy with Culture Expanded Stem Cells in Humans: A Systemic Literature Review, Osteoarthritis Research Society International June 2013,
  • Centeno CJ, Freeman MD, Percutaneous Injection of Autologous, Culture Expanded Mesenchymal Stem Cells into Carpometacarpal Hand Joints: A Case Series with an Untreated Comparison Group, Wien Med Wochenschr 2014 Mar;164(5-6):83-7
  • Centeno Christopher, Schultz John, et. al. A Case Series of Percutaneous Treatment of Non-Union Fractures with Autologous, Culture Expanded, Bone Marrow Derived, Mesenchymal Stem Cells and Platelet Lysate, Bioengineering and Biomedical Science
  • Chirba MA, Sweetapple B, Hannon CP, et al. FDA regulation of adult stem cell therapies as used in sports medicine. J Knee Surg. Feb 2015;28(1):55-62. PMID 25603042
  • Filardo G, Madry H, Jelic M, et al. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. Aug 2013;21(8):1717-1729. PMID 23306713
  • Wong KL, Lee KB, Tai BC, et al. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up. Arthroscopy. Dec 2013;29(12):2020-2028. PMID 24286801
  • Wakitani S, Imoto K, Yamamoto T, et al. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage. Mar 2002;10(3):199-206. PMID 11869080
  • Wakitani S, Nawata M, Tensho K, et al. Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees. J Tissue Eng Regen Med. Jan-Feb 2007;1(1):74-79. PMID 18038395
  • Wakitani S, Okabe T, Horibe S, et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. Feb 2011;5(2):146-150. PMID 20603892
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  • Vega A, Martin-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. Aug 2015;99(8):1681-1690. PMID 25822648
  • Giannini S, Buda R, Vannini F, et al. One-step bone marrow-derived cell transplantation in talar osteochondral lesions. Clin Orthop Relat Res. Dec 2009;467(12):3307-3320. PMID 19449082
  • Giannini S, Buda R, Cavallo M, et al. Cartilage repair evolution in post-traumatic osteochondral lesions of the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation. Injury. Nov 2010;41(11):1196-1203. PMID 20934692
  • Centeno CJ, Al-Sayegh H, Bashir J, et al. 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. J Pain Res. 2015;8:269-276. PMID 26089699
  • Koh YG, Kwon OR, Kim YS, et al. Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study. Arthroscopy. Nov 2014;30(11):1453-1460. PMID 25108907
  • Kim YS, Park EH, Kim YC, et al. Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus. Am J Sports Med. May 2013;41(5):1090-1099. PMID 23460335
  • Kim YS, Lee HJ, Choi YJ, et al. Does an injection of a stromal vascular fraction containing adipose-derived mesenchymal stem cells influence the outcomes of marrow stimulation in osteochondral lesions of the talus? A clinical and magnetic resonance imaging study. Am J Sports Med. Oct 2014;42(10):2424-2434. PMID 25106781
  • Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. Dec 2012;19(6):902-907. PMID 22583627
  • Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. May 2014;32(5):1254-1266. PMID 24449146
  • Saw KY, Anz A, Siew-Yoke Jee C, et al. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial. Arthroscopy. Apr 2013;29(4):684-694. PMID 23380230
  • Akgun I, Unlu MC, Erdal OA, et al. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Arch Orthop Trauma Surg. Feb 2015;135(2):251-263. PMID 25548122
  • Vangsness CT, Jr., Farr J, 2nd, Boyd J, et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. Jan 15 2014;96(2):90-98. PMID 24430407
  • Eastlack RK, Garfin SR, Brown CR, et al. Osteocel plus cellular allograft in anterior cervical discectomy and fusion: evaluation of clinical and radiographic outcomes from a prospective multicenter study. Spine (Phila Pa 1976). Oct 15 2014;39(22):E1331-1337. PMID 25188591
  • Zhao D, Cui D, Wang B, et al. Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone. Jan 2012;50(1):325-330. PMID 22094904
  • Sen RK, Tripathy SK, Aggarwal S, et al. Early results of core decompression and autologous bone marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J Arthroplasty. May 2012;27(5):679-686. PMID 22000577
  • Centeno C, Al-Sayegh H, Freeman M, et. al. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. International Orthopaedics (SICOT) 2016 40:1755-1765
  • Centeno CJ, Schultz JR, Cheever M, et. al. Safety and complications reporting on the reimplantation of culture expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther Dec 2, 2010;5(1):81-93. PMID 19951252 
  • Goldberg A, Mitchell K, Soans J, et al. The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. Mar 09 2017;12(1):39. PMID 28279182
  • Shapiro SA, Kazmerchak SE, Heckman MG, et al. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. Jan 2017;45(1):82-90. PMID 27566242
  • Borakati A, Mafi R, Mafi P, et al. A systematic review and meta-analysis of clinical trials of mesenchymal stem cell therapy for cartilage repair. Curr Stem Cell Res Ther. Sep 15 2017. PMID 28914207
  • Jo CH, Chai JW, Jeong EC, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study. Am J Sports Med. Oct 2017;45(12):2774-2783. PMID 28746812
  • Whitehouse MR, Howells NR, Parry MC, et al. Repair of torn avascular meniscal cartilage using undifferentiated autologous mesenchymal stem cells: from in vitro optimization to a first-in-human study. Stem Cells Transl Med. Apr 2017;6(4):1237-1248. PMID 28186682
  • Vanichkachorn J, Peppers T, Bullard D, et al. A prospective clinical and radiographic 12-month outcome study of patients undergoing single-level anterior cervical discectomy and fusion for symptomatic cervical degenerative disc disease utilizing a novel viable allogeneic, cancellous, bone matrix (trinity evolution) with a comparison to historical controls. Eur Spine J. Jul 2016;25(7):2233-2238. PMID 26849141
  • Peppers TA, Bullard DE, Vanichkachorn JS, et al. Prospective clinical and radiographic evaluation of an allogeneic bone matrix containing stem cells (Trinity Evolution(R) Viable Cellular Bone Matrix) in patients undergoing two-level anterior cervical discectomy and fusion. J Orthop Surg Res. Apr 26 2017;12(1):67. PMID 28446192
  • Jones CP, Loveland J, Atkinson BL, et al. Prospective, multicenter evaluation of allogeneic bone matrix containing viable osteogenic cells in foot and/or ankle arthrodesis. Foot Ankle Int. Oct 2015;36(10):1129-1137. PMID 25976919
  • Kaiser MG, Groff MW, Watters WC, et. al. Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 16: bone graft extenders and substitutes as an adjunct for lumbar fusion. J Neurosurg Spine Jul 2014;2191):106-132. PMID 24980593
  • Lee KB, Wang VT, Chan YH, et. al. A novel, minimally-invasive technique of cartilage repair in the human knee using arthroscopic microfracture and injections of mesenchymal stem cells and hyaluronic acid-a prospective comparative study on safety and short-term efficacy. Ann Acad Med Singapore 2012 Nov:41(11):511-7. PMID 23235728
  • Liebergall M, Schroeder J, Mosheiff R, et. al. Stem call based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol Ther 2013 Aug;21(8):1631-8.    
  • Piccirilli M, Delfinis CP, Santoro A, et. al. Mesenchymal stem cells in lumbar spine surgery: a single institution experience about red bone marrow and fat tissue derived MSCs. J Neurosurg Sci 2017 Apr;61(2):124-133. PMID 26082381
  • Shao J, Zhang W, Yang T. Using mesenchymal stem cells as therapy for bone regeneration and repairing. Biol Res 2015;48:62. PMID 26530042
  • Vigano M, Sansone V, et. al. Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders. Journal of Orthopaedic Surgery and Research 2016 11:163
  • American Academy of Orthopaedic Surgeons (AAOS) Position statement on the use of emerging biologic therapies. 2017.
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines: Anterior Cruciate Ligament Injuries. 
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines: Glenohumeral Joint Arthritis.
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines: Osteoarthritis of the Hip. 
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines: Osteoarthritis of the knee (Non-Arthroplasty). 
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines Rotator Cuff Problems.    
  • Akpancar S, Tatar O, Turgut H, et. al. The current perspectives of stem cell therapy in orthopedic surgery. Arch Trauma Res 2016 December 5(4):E37976
  • Giuseppe Usuelli F, D’Ambrosi R, Maccario C, et. al. Adipose-derived stem cells in orthopaedic pathologies. British Medical Bulletin 2017 124:31-54
  • UpToDate. Management of Rotator Cuff Tears. Scott David Martin M.D., Tamara L. Martin M.D.. Topic last updated March 29, 2017.  
  • Burke J, Hunter M, Kolhe R, Isales C, Hamrick M, Fulzele S. Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis. Clin Transl Med. 2016 Dec;5(1):27 
  • Centeno CJ, Al-Sayegh H, Freeman MD ,et al. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. Int Orthop. 2016 Aug;40(8):1755-1765 
  • Centeno C, Sheinkop M, Dodson D, et al. A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2 year follow-up. J Trans Med. 2018b; 16:355 
  • Chew E, Prakash R, Khan W. Mesenchymal stem cells in human meniscal regeneration: A systematic review. Ann Med Surg (Lond). 2017 Oct 5;24:3-7 
  • Delanois RE, Etcheson JI, Sodhi N, Henn RF 3rd, Gwam CU, George NE, Mont MA. Biologic Therapies for the Treatment of Knee Osteoarthritis. J Arthroplasty. 2019 Apr;34(4):801-813 
  • Di Matteo B, El Araby MM, D'Angelo A, et al. Adipose-Derived Stem Cell Treatments and Formulations. Clin Sports Med. 2019 Jan;38(1):61-78 
  • Di Matteo B, Vandenbulcke F Vitale ND, et al. Minimally Manipulated Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Systematic Review of Clinical Evidence. Stem Cells Int. 2019 Aug 14;2019:1735242 
  • Emadedin M, Labibzadeh N, Liastani MG, et al. Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Cytotherapy. 2018 Oct;20(10):1238-1246 
  • Ha CW, Park YB, Kim SH, Lee HJ. Intra-articular Mesenchymal Stem Cells in Osteoarthritis of the Knee: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair. Arthroscopy. 2019 Jan;35(1):277-288.e2 
  • Hurley ET, Yasui Y, Gianakos AL, et al. Limited evidence for adipose-derived stem cell therapy on the treatment of osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2018 Nov;26(11):3499-3507 
  • International Society for Stem Cell Research. Types of stem cells. © 2019 International Society of Stem Cell Research. Accessed October 25, 2019. 
  • Kehoe O, Cartwright A, Askari A, El Haj AJ, Middleton J. Intra-articular injection of mesenchymal stem cells leads to reduced inflammation and cartilage damage in murine antigen-induced arthritis. J Transl Med. 2014 Jun 3;12:157 
  • Khan S, Mafi P, Mafi R, Khan W. A Systematic Review of Mesenchymal Stem Cells in Spinal Cord Injury, Intervertebral Disc Repair and Spinal Fusion. Curr Stem Cell Res Ther. 2018;13(4):316-323 
  • Lee WY, Wang B. Cartilage repair by mesenchymal stem cells: Clinical trial update and perspectives. J Orthop Translat. 2017 Apr 9;9:76-88 
  • Lin KM, Wang D, Dines JS. Injection therapies for rotator cuff disease. Orthop Clin N Am 49 (2018) 231–239 
  • Marks PW, Witten CM, Califf RM. Clarifying Stem-Cell Therapy's Benefits and Risks. N Engl J Med. 2017 Mar 16;376(11):1007-1009 
  • Migliorini F, Rath B, Colarossi G, et al. Improved outcomes after mesenchymal stem cells injections for knee osteoarthritis: results at 12-months follow-up: a systematic review of the literature. Arch Orthop Trauma Surg. 2019 Aug 27 
  • Pak J. Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: a case series. J Med Case Rep. 2011 Jul 7;5:296 
  • Pak J, Lee JH, Pak N, et al. Cartilage Regeneration in Humans with Adipose Tissue-Derived Stem Cells and Adipose Stromal Vascular Fraction Cells: Updated Status. Int J Mol Sci. 2018 Jul 23;19(7) 
  • Panchal J, Malanga G, Sheinkop M. Safety and Efficacy of Percutaneous Injection of Lipogems Micro-Fractured Adipose Tissue for Osteoarthritic Knees. Am J Orthop (Belle Mead NJ). 2018 Nov;47(11) 
  • Park YB, Ha CW, Rhim JH, Lee HJ. Stem Cell Therapy for Articular Cartilage Repair: Review of the Entity of Cell Populations Used and the Result of the Clinical Application of Each Entity. Am J Sports Med. 2018 Aug;46(10):2540-2552 
  • Pas HI, Winters M, Haisma HJ, Koenis MJ, Tol JL, Moen MH. Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br J Sports Med. 2017a Aug;51(15):1125-1133 
  • Pas HIMFL, Moen MH, Haisma HJ, Winters M. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Br J Sports Med. 2017b Jul;51(13):996-1002 
  • Roffi A, Nakamura N, Sanchez M, Cucchiarini M, Filardo G. Injectable Systems for Intra-Articular Delivery of Mesenchymal Stromal Cells for Cartilage Treatment: A Systematic Review of Preclinical and Clinical Evidence. Int J Mol Sci. 2018 Oct 25;19(11) 
  • Tremolada C, Colombo V, Ventura C. Adipose Tissue and Mesenchymal Stem Cells: State of the Art and Lipogems® Technology Development. Curr Stem Cell Rep. 2016;2:304-312 
  • United States Food and drug Administration. Lipogems system. 510(k) approval (K161636). September 2016. Accessed October 11, 2019.  
  • Uth K, Trifonov D. Stem cell application for osteoarthritis in the knee joint: A minireview. World J Stem Cells. 2014 Nov 26;6(5):629-36 
  • Vadalà G, Russo F, Ambrosio L, Loppini M, Denaro V. Stem cells sources for intervertebral disc regeneration. World J Stem Cells. 2016 May 26;8(5):185-201 
  • Vannabouathong C, Del Fabbro G, Sales B, Intra-articular Injections in the Treatment of Symptoms from Ankle Arthritis: A Systematic Review. Foot Ankle Int. 2018 Oct;39(10):1141-1150
  • Wang M, Yuan Q, Xie L. Mesenchymal Stem Cell-Based Immunomodulation: Properties and Clinical Application. Stem Cells Int. 2018 Jun 14;2018:3057624 
  • Wang Y, Han ZB, Song YP, Han ZC. Safety of mesenchymal stem cells for clinical application. Stem Cells Int. 2012;2012:652034       
  • Szabo L/Kaiser Health News Employers are Steering Workers Toward Controversial Stem Cell Therapies. Time Health June 19, 2019.

 

Policy History:

  • February 2020 - Annual review, Policy Revised
  • February 2019 - Annual review, Policy Renewed
  • August 2018 - Interim review, Policy Revised
  • February 2018 - Annual review, Policy Revised
  • April 2017 - Annual review, Policy Revised
  • April 2016 - Annual review, Policy Renewed
  • May 2015 - Annual review, Policy Revised
  • March 2015 - Interim review, Policy Revised
  • June 2014 - New Policy 

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.

 

*CPT® is a registered trademark of the American Medical Association.