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.
Mesenchymal stem cells (MSCs) have the capability to differentiate into a variety of tissue types, including various musculoskeletal tissues. Potential uses of MSCs for orthopedic applications include treatment of damaged bone, cartilage, ligaments, tendons and intervertebral discs.
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. 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. In addition, 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.
Tissues such as muscle, cartilage, tendon, ligaments, and vertebral discs show limited capacity for endogenous repair. Therefore, tissue engineering techniques are being developed to improve the efficiency of repair or regeneration of damaged musculoskeletal tissues. Tissue engineering focuses on the integration of biomaterials with MSCs and/or bioactive molecules such as growth factors. 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.
The U.S. Food and Drug Administration (FDA) has stated:
“A major challenge posed by SC [stem-cell] therapy is the need to ensure their efficacy and safety. Cells manufactured in large quantities outside their natural environment in the human body can become ineffective or dangerous and produce significant adverse effects, such as tumors, severe immune reactions, or growth of unwanted tissue.”(1)
Concentrated autologous MSCs do not require approval by FDA.
Demineralized bone matrix (DBM), which is processed allograft bone, is considered minimally processed tissue and does not require FDA approval. At least 4 commercially available DBM products are reported to contain viable stem cells:
Other products contain DBM and are designed to be mixed with bone marrow aspirate. Some of the products that are currently available are:
Other commercially available products are intended to be mixed with bone marrow aspirate and have received 510(k) clearance, such as:
No products using engineered or expanded MSCs have been approved by FDA for orthopedic applications.
In 2008, FDA determined that the mesenchymal stem cells 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. (2) To date, no NDA or BLA has been approved by FDA for this product. As of 2013, the expanded stem-cell procedure is only offered in the Cayman Islands. Regenexx™ network facilities in the U.S. provide same-day stem-cell and blood platelet procedures, which do not require FDA approval. Available online at http://www.regenexx.com/common-questions/regenexx-fda-clarification\. (Last accessed May 8, 2014.)
Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
At the time this policy was created, the literature consisted almost entirely of review articles describing the potential of stem-cell therapy for orthopedic applications in humans, along with basic science experiments on sources of mesenchymal stem cells (MSCs), regulation of cell growth and differentiation, and development of scaffolds. (3) Authors of these reviews indicated that the technology was in an early stage of development. In literature searches of the MEDLINE database, use of cultured MSCs in humans was identified in only a few centers in the U.S., Europe, and Asia. Since the policy was created, the evidence base has been steadily increasing, although there is a lack of high-quality randomized controlled trials (RCTs) and nearly all of the studies to date have been performed outside of the U.S.
The source of MSCs may have an impact on outcomes, but this is not well understood and the available literature uses multiple different sources of MSC. Because of the uncertainty over whether these products are equivalent, the evidence will be grouped by source of MSC.
One systematic review was published in 2013 that included multiple sources of MSC. In 2013, Filardo et al. conducted a systematic review of mesenchymal stem cells for the treatment of cartilage lesions. (4) They identified 72 preclinical papers and 18 clinical reports. Of the 18 clinical reports, none were randomized, 5 were comparative, 6 were case series, and 7 were case reports. In 2 clinical studies, the source of MSCs was adipose tissue, in 5, bone marrow concentrate, and in 11, the source was bone marrow-derived. Following is a summary of the key literature to date, focusing on comparative studies.
Cartilage Defects: MSCs Expanded from Bone Marrow
In December 2013 (after the systematic review by Filardo et al. was published), Wong et al. reported an RCT of cultured MSCs in 56 patients with osteoarthritis who underwent medial opening-wedge high tibial osteotomy and microfracture of a cartilage lesion. (5) Bone marrow was harvested at the time of microfracture and the MSCs were isolated and cultured. After three weeks, the cells were assessed for viability and delivered to the clinic, where patients received an intra-articular injection of MSCs suspended in hyaluronic acid (HA), or for controls, intra-articular injection of HA alone. The primary outcome was the International Knee Documentation Committee (IKDC) score at six months, one year, and two years. Secondary outcomes were the Tegner and Lysholm scores through two years and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system by MRI at one year. All patients completed the two year follow-up. After adjusting for age, baseline scores, and time of evaluation, the group treated with MSCs showed significantly better scores on the IKDC (mean difference, 7.65 on 0-100 scale; p=0.001), Lysholm (mean difference, 7.61 on 0-100 scale; p=0.02), and Tegner (mean difference, 0.64 on a 0-10 scale; p=0.02). Blinded analysis of MRI results found higher MOCART scores in the MSC group. The group treated with MSCs had a higher proportion of patients who had complete cartilage coverage of their lesions (32% vs. 0%), greater than 50% cartilage cover (36% vs. 14%) and complete integration of the regenerated cartilage (61% vs. 14%). This study is ongoing and recruiting additional patients.
Wakitani et al. first reported use of expanded MSCs for repair of cartilage defects in 2002. (6) Cells from bone marrow aspirate of 12 patients with osteoarthritic knees were culture expanded, embedded in collagen gel, transplanted into the articular cartilage defect, and covered with autologous periosteum at the time of high tibial osteotomy. Clinical improvement was not found to be different between the experimental group and a group of 12 control patients who underwent high tibial osteotomy alone. Wakitani et al. have since published several cases of patients treated for isolated cartilage defects, with clinical improvement reported at up to 27 months. (7) However, most of the defects appear to have been filled with fibrocartilage. A 2011 report from Wakitani et al. was a follow-up safety study of 31 of the 41 patients (3 patients had died, 5 had undergone total knee arthroplasty) who had received MSCs for articular cartilage repair in their clinics between 1998 and 2008. (8) At a mean of 75 months (range, 5-137) since the index procedure, no tumors or infections were identified. Function was not reported.
Another study from Asia evaluated the efficacy of bone marrow-derived MSCs compared with autologous chondrocyte implantation (ACI) in 36 matched patient pairs. (9) Thirty-six consecutive patients with at least 1 symptomatic chondral lesion on the femoral condyle, trochlea, or patella were matched with 36 cases of ACI performed earlier, based on lesion sites and 10-year age intervals. Autologous MSCs were cultured from 30 mL of bone marrow from the iliac crest, tested to confirm that the cultured cells were MSCs, and implanted beneath a periosteal patch. Concomitant procedures included patella realignment, high -tibial osteotomy, partial meniscectomy, and anterior cruciate ligament reconstruction. Clinical outcomes, measured pre-operatively and at 3, 6, 12, 18, and 24 months after operation using the International Cartilage Repair Society Cartilage Injury Evaluation Package, showed improvement in patients’ scores over the 2-year follow-up in both groups, with no significant difference between groups for any of the outcome measures except for Physical Role Functioning on the 36-Item Short-Form Health Survey, which showed a greater improvement over time in the MSC group.
A 2010 publication from Centeno et al. of Regenerative Sciences describes the use of percutaneously injected culture-expanded MSCs from the iliac spine in 226 patients. (10) Following harvesting, cells were cultured with autologous platelet lysate and re-injected under fluoroscopic guidance into peripheral joints (n=213) or intervertebral discs (n=13). Follow-up for adverse events at a mean of 10.6 months showed 10 cases of probable procedure-related complications (injections or stem-cell related), all of which were considered to be self-limited or treated with simple therapeutic measures. Serial magnetic resonance imaging (MRIs) from a subset of patients showed no evidence of tumor formation at a median follow-up of 15 months. The efficacy of these procedures was not reported. This procedure is no longer offered in the U.S.
Cartilage Defects: MSCs Concentrated from Bone Marrow
In 2009, Giannini et al. reported a one-step procedure for transplanting bone marrow-derived cells for Type II (>1.5 cm2, <5 mm deep) osteochondral lesions of the talus in 48 patients. (11) A total of 60 -mL-bone marrow aspirate was collected from the iliac crest. The bone marrow-derived cells were concentrated in the operating room and implanted with a scaffold (collagen powder or HA membrane) and platelet gel. In a 2010 publication, Giannini et al. reported results of a retrospective analysis based on the evolution of the investigator’s technique at the time of treatment. Outcomes following arthroscopic application of the MSC concentrate (n=25) were similar to open (n=10) or arthroscopic (n=46) ACI. (12) ACI with a biodegradable scaffold is not commercially available in the U.S. (see Related Policies).
Cartilage Defects: Adipose-Derived MSCs
In 2013, Kim et al. reported a retrospective comparison of outcomes from 35 patients (37 ankles), who were older than 50 years of age, had focal osteochondral lesions of the talus, and were treated with microfracture alone between May 2008 and September 2010. (13) The comparison group was 30 patients (31 ankles) who received MSC injection along with marrow stimulation between October 2010 and December 2011. MSCs were harvested from the fat pad of the buttock of the patients 1 day before surgery, concentrated, and injected after the arthroscopic procedure. With an average 22 month follow-up (range, 12-44 months), patients treated with MSCs showed greater improvements in visual analog scale score, American Orthopaedic Foot and Ankle Society Ankle‒Hindfoot Scale, Tegner Activity Scale, and the Roles and Maudsley score .
The same group reported a retrospective analysis of the injection of adipose-derived MSCs from the infrapatellar fat pad and platelet-rich plasma (PRP) into arthroscopically-débrided knees of 25 patients with osteoarthritis of the knee. (14) Results were compared with a randomly selected group of patients who had previously undergone arthroscopic débridement and PRP injections without stem cells. Although there was a trend for greater improvement in the MSC group, at final follow-up, there was no significant difference between the MSC and control groups in clinical outcomes (Lysholm, Tegner, visual analog score). Use of PRP is discussed in a separate policy. (See Related Policies).
Cartilage Defects: MSCs from Peripheral Blood
A 2013 report from Asia described a small RCT with autologous peripheral blood MSCs for focal articular cartilage lesions. (15) Fifty patients with grade 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling followed by 5 weekly injections of HA. Half of the patients were randomly allocated to receive injections of peripheral blood stem cells or no further treatment. There were baseline differences in age between the groups, with a mean age of 38 years for the treatment group compared with 42 for the control group. The peripheral blood stem cells were harvested after stimulation with recombinant human granulocyte colony-stimulating factor, divided in vials, and cryopreserved. At 6 months after surgery, HA and MSCs were re-administered over 3 weekly injections. At 18 months after surgery, second look arthroscopy on 16 patients in each group showed significantly higher histological scores (by about 10%) for the MSC group (1,066 vs. 957 by independent observers) while blinded evaluation of MRI showed a higher morphologic score (9.9 vs. 8.5). There was no difference in IKDC scores between the 2 groups at 24 months after surgery. It is uncertain how differences in patient age at baseline may have affected the response to subchondral drilling.
The evidence base on MSCs for cartilage repair is increasing, although nearly all studies to date have been performed in Asia with a variety of methods of MSC preparation. Only 2 small randomized studies have been identified. Both of these studies reported an improvement in histological and morphologic outcomes. One of these studies also reported an improvement in functional outcomes. The method of preparation used in this positive study was to obtain MSCs from bone marrow at the time of microfracture, culture (expand) over a period of 3 weeks, and inject in the knee in a carrier of HA. The second randomized trial, using MSCs from peripheral blood, found improvement in histological and morphologic outcomes, but not functional outcomes, following stimulation with recombinant human granulocyte colony-stimulating factor. Other nonrandomized comparative studies reported no benefit compared with ACI, but have reported a benefit compared with microfracture alone.
Fusion and Non-union
There is limited evidence on the use of allografts with stem cells for fusion of the extremities or spine or for the treatment of non-union. One retrospective series from 2009 was identified on the use of Trinity Evolution Matrix MSC bone allograft for revision surgery of the foot and ankle. (16) Twenty-three patients were included who had undergone revision foot and/or ankle surgery for residual malunion, non-union, or significant segmental bone loss. Patients were followed to the point of radiographic and clinical union, which occurred at a median of 72.5 days for 21 of the 23 patients (91.3%).
In 2014, Vangsness et al. reported an industry-sponsored phase 1/2 randomized, double-blind, multicenter study (NCT00225095, NCT00702741) of cultured allogeneic MSCs (Chondrogen™, Osiris Therapeutics) injected into the knee after partial meniscectomy. (17) The 55 patients in this U.S. study were randomized to intra-articular injection of either 50x106 allogeneic MSCs, 150x106 allogeneic MSCs in HA, or HA vehicle control at seven to ten days after meniscectomy. The cultured MSCs were derived from bone-marrow aspirates from unrelated donors. At two year follow-up, 3 patients in the low-dose MSC group had significantly increased meniscal volume measured by MRI (with an a priori determined threshold of at least 15%) compared with none in the control group and none in the high-dose MSC group. There was no significant difference between the groups in the Lysholm Knee Scale. On subgroup analysis, patients with osteoarthritis who received MSCs had a significantly greater reduction in pain at two years compared with patients who received HA alone. This appears to be a post hoc analysis and should be considered preliminary. No serious adverse events were thought to be related to the investigational treatment.
Two randomized comparative trials from Asia have been identified that evaluated the use of MSCs for osteonecrosis of the femoral head.
Osteonecrosis: MSCs Expanded from Bone Marrow
In 2012, Zhao et al. reported a randomized trial that included 100 patients (104 hips) with early stage femoral head osteonecrosis treated with core decompression and expanded bone marrow MSCs versus core decompression alone. (18) At 60 months after surgery, 2 of the 53 hips (3.7%) treated with MSCs progressed and underwent vascularized bone grafting, compared with 10 of 44 hips (23%) in the decompression group who progressed and underwent either vascularized bone grafting (n=5) or total hip replacement (n=5). The MSC group also had improved Harris Hip Scores compared with the control group on independent evaluation (data presented graphically). The volume of the lesion was also reduced by treatment with MSCs.
Osteonecrosis: MSCs Concentrated from Bone Marrow
Another small trial randomized 40 patients (51 hips) with early stage femoral head osteonecrosis to core decompression plus concentrated bone marrow MSCs or core decompression alone. (19) Blinding of assessments in this small trial was not described. Harris Hip Score was significantly improved in the MSC group (scores of 83.65 and 82.42) compared with core decompression (scores of 76.68 and 77.39). Kaplan-Meier analysis showed improved hip survival in the MSC group (mean, 51.9 weeks) compared with the core decompression group (mean, 46.7 weeks). There were no significant differences between the groups in the radiographic assessment or MRI results.
Two small studies from Asia have compared core decompression alone versus core decompression with MSCs in patients with osteonecrosis of the femoral head. Both studies reported improvement in the Harris Hip Score in patients treated 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 larger with expanded MSCs compared with concentrated MSCs. Additional studies with a larger number of patients are needed to permit greater certainty regarding the effect of this treatment on health outcomes.
Ongoing and Unpublished Clinical Trials
A search of online site: ClinicalTrials.gov in March 2014 identified a number of trials on use of MSCs for orthopedic indications from both within and outside the U.S. The following is a sample of some of the larger studies:
The use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. Despite continued research into the methods of harvesting and delivering treatment, there are uncertainties regarding the optimal source of cells and the delivery method. Current available evidence on procedures using autologous bone-marrow-derived MSCs for orthopedic indications in humans consists of a few small randomized and non-randomized comparative trials with insufficient data to evaluate health outcomes. In addition, expanded MSCs for orthopedic applications are not Food and Drug Administration (FDA) approved (concentrated autologous MSCs do not require FDA approval). Due the lack of evidence that clinical outcomes are improved and the lack of regulatory approval, use of stem cells for orthopedic applications is considered investigational.
Practice Guidelines and Position Statements
The American Association of Orthopaedic Surgeons states that stem-cell procedures in orthopedics are still at an experimental stage; most musculoskeletal treatments using stem cells are performed at research centers as part of controlled, clinical trials, and results of studies in animal models provide proof-of-concept that in the future, similar methods could be used to treat osteoarthritis, nonunion of fractures, and bone defects in humans.(20)
In 2006, the Mesenchymal and Tissue Stem-Cell Committee of the International Society for Cellular Therapy proposed a minimal set of criteria to standardize the characterization of multipotent mesenchymal stem cells. (21) The proposed criteria for human MSCs included plastic-adherence when maintained in standard culture conditions; a phenotype of expression of CD105, CD73, and CD90 with a lack surface expression of CD45, CD34, CD14 or CD11b, CD79 alpha or CD19, and HLA-DR surface molecules; and the capability of differentiating into osteoblasts, adipocytes, and chondrocytes using standard in vitro tissue culture-differentiating conditions.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous
Bone marrow harvesting for transplantation
Bone marrow or blood-derived peripheral stem cell transplantation; autologous
New policy; add to Therapy section.Policy created with literature review through January 2011; considered investigational. ICD-10 codes included in policy.
Replace policy. Policy updated with literature review through February 2012; reference 6 added and references reordered; policy statement unchanged.
Update Related Policies: remove 7.01.48, it was archived.
Update Related Policies – add 2.02.18.
Update Coding Section – ICD-10 codes are now effective 10/01/2014.
Clarification only. Statement within the Benefit Application section stating, “Therefore, requests may be made for an out-of-network facility” was removed, as this conflicts with the FDA statements in the rest of the policy. No other changes.
Replace policy. New policy statement added that allograft bone containing viable stem cells is considered investigational. New policy guideline added that policy does not address unprocessed allograft bone. Regulatory status section updated regarding allograft bone. Rationale updated based on a literature review through March 2013. References 4, and 11-15 added; others renumbered or removed. Policy statement changed as noted.
Update Related Policies. Change title to 2.02.18.
Annual Review. Policy updated with literature review through March 3, 2014; references 5, 13, and 17 added; policy statements unchanged. ICD-10 codes removed in line with code mapping project and implementation delay.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).