Pending Policies - Surgery

Orthopedic Applications of Stem-Cell Therapy


Effective Date:08-15-2018



Mesenchymal stem-cell (MSC) therapy, including but not limited to bone-marrow aspirate concentrate (BMAC), is considered experimental, investigational and/or unproven for all orthopedic applications, including use in repair or regeneration of musculoskeletal tissue.

Allograft bone products containing viable stem-cells, including but not limited to demineralized bone matrix (DBM) with stem-cells, is considered experimental, investigational and/or unproven for all orthopedic applications.

Allograft or synthetic bone graft substitutes combined with autologous blood or bone marrow are considered experimental, investigational and/or unproven for all orthopedic applications.

NOTE 1: This policy does not address unprocessed allograft bone.


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 multipotent stromal cells) that can differentiate into various tissues including organs, trabecular bone, tendon, articular cartilage, ligaments, muscle, and fat. MSCs are associated with the blood vessels within the bone marrow, synovium, fat, and muscle, where they can be mobilized for endogenous repair as occurs with the healing of bone fractures. Tissues, such as muscle, cartilage, tendon, ligaments, and vertebral discs, show limited capacity for endogenous repair because of the limited presence of the triad of functional tissue components: vasculature, nerves, and lymphatics. Orthobiologics is a term introduced to describe interventions using cells and biomaterials to support healing and repair. Cell therapy is the application of MSCs directly to a musculoskeletal site. Tissue engineering techniques use MSCs and/or bioactive molecules such as growth factors and scaffold combinations to improve the efficiency of repair or regeneration of damaged musculoskeletal tissues. (1)

Bone-marrow aspirate is considered 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 a procedure that may result in donor-site morbidity. Also, the number of MSCs in bone marrow is low, and the number and differentiation capacity of bone marrow-derived MSCs decreases with age, limiting their efficiency when isolated from older patients.

In vivo, the fate of stem-cells is regulated by signals in the local 3-dimensional (3-D) 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-D 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.

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. MSCs are included in these regulations.

The regulatory status of the stem-cell or stem-cell-containing products addressed in this policy are summarized below.

Concentrated autologous MSCs do not require approval by 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) products, which is processed allograft bone. 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. The following descriptions are from the product literature:

AlloStem® (AlloSource) is a partially demineralized allograft bone seeded with adipose-derived MSCs.

Map3® (RTI Surgical) contains cortical cancellous bone chips, DBM, and cryopreserved multipotent adult progenitor cells (MAPC®).

Osteocel Plus® (NuVasive) is a DBM combined with viable MSCs isolated from allogeneic bone marrow.

Trinity Evolution Matrix™ (Orthofix) is a DBM combined with viable MSCs isolated from allogeneic bone marrow.

Other products contain DBM alone and are designed to be mixed with bone marrow aspirate:

o Fusion Flex™ (Wright Medical) is a dehydrated moldable DBM scaffold (strips and cubes) that will absorb autologous bone marrow aspirate;

o Ignite® (Wright Medical) is an injectable graft with DBM that can be combined with autologous bone marrow aspirate.

A number of DBM combination products have been cleared for marketing by the FDA through the 510(k) process. FDA product code: MQV.

Table 1 provides a representative sample of these products; some of which are specifically labeled for mixing with bone marrow aspirate.

Table 1. Demineralized Bone Matrix Products Cleared by the FDA


Matrix Type

Mix With Autologous MSCs

Manufacturer or Sponsor

Date Cleared

510(k) No.

Vitoss® Bioactive Foam Bone Graft Substitute

Type I bovine collagen



Nov 2008


NanOss BVF-E

Nanocrystalline hydroxyapatite

Pioneer Surgical

Aug 2008

OrthoBlast® II Demineralized bone matrix putty and paste

Human cancellous bone chips


Sep 2007


CopiOs® Bone Void Filler (sponge and powder disc)

Type I bovine dermal collagen


Kensey Nash

May 2007


DBX® Demineralized bone matrix putty, paste and mix

Processed human bone and sodium hyaluronate


Musculoskeletal Transplant Foundation

Dec 2006


Integra MOZAIK™ Osteoconductive Scaffold-Putty

Human cancellous bone


IsoTis OrthoBiologics

Dec 2006


Formagraft™ Collagen Bone Graft Matrix

Bovine fibrillary collagen


R and L Medical

May 2005


DynaGraft® II Gel and Putty

Processed human bone particles

IsoTis Orthobiologics

Mar 2005


Table Key:

FDA: Food and Drug Administration;

MSCs: mesenchymal stem-cells;

No: number.

In 2008, the FDA determined that the MSCs sold by Regenerative Sciences for use in the Regenexx™ procedure would be considered drugs or biologic products and thus would require submission of a new drug application (NDA) or biologic license application (BLA) to the FDA. (2) 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 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 the FDA’s authority to regulate adult stem-cells as drugs and biologics and ruled that the Regenexx™ cell product fell within the FDA’s authority to regulate human cells, tissues, and cellular and tissue-based products. (3) To date, no NDA or BLA has been approved by the 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 of facilities in the U.S. that provide same-day stem-cell and blood platelet procedures that do not require FDA approval. These procedures, along with the 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. (4)


This policy was created in 2014, based on peer-reviewed scientific literature, and has been updated using the MedLine database. The most recent literature update was performed through July 2018.

Medical policies assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

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. (4) 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 this medical policy was created, the evidence base has been steadily increasing, although there is a lack of high-quality RCTs, and nearly all studies to date have been performed outside of the U.S.

Cartilage Defects

The source of MSCs may have an impact on outcomes, but this is not well-understood, and the available literature uses multiple sources of MSCs. Because of the uncertainty over whether these products are equivalent, the evidence will be grouped by the source of MSC.

One 2013 systematic review included multiple sources of MSC. (5) In it, Filardo et al. assessed MSCs for the treatment of cartilage lesions. They identified 72 preclinical and 18 clinical reports. Of the 18 clinical reports, none was randomized, 5 were comparative, 6 were case series, and 7 were case reports. The source of MSCs was derived from bone marrow in 11 clinical studies, bone marrow aspirate concentrate (BMAC) in 5 studies, and adipose tissue in 2 studies. Many of these trials had been performed by the same research group in Asia. The following is a summary of the key literature to date, focusing on comparative studies.

MSCs Expanded from Bone Marrow

Autologous Bone Marrow for the Treatment of Osteoarthritis (OA)

In 2013 (after the Filardo review was published), Wong et al. reported on an RCT of cultured MSCs in 56 patients with OA who underwent medial opening-wedge high tibial osteotomy and microfracture of a cartilage lesion. (6) Bone marrow was harvested at the time of microfracture, and the MSCs were isolated and cultured. After 3 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 6 months, 1 year, and 2 years. Secondary outcomes were the Tegner Activity Scale (TAS) and Lysholm Knee Scale (LKS) scores through 2 years and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system (0-100 points, where higher scores indicate better cartilage repair) by magnetic resonance imaging (MRI) at 1 year. All patients completed the 2-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), LKS (mean difference, 7.61 on 0-100 scale; p=0.02), and TAS (mean difference, 0.64 on a 0-10 scale; p=0.02) scores. 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% versus 0%), greater than 50% cartilage cover (36% versus 14%), and complete integration of the regenerated cartilage (61% versus 14%).

Wakitani et al. first reported on the use of expanded MSCs for repair of cartilage defects in 2002. (7) 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 did not differ between the experimental group and a group of 12 control patients who underwent high tibial osteotomy alone. Wakitani et al. (2007) have since published several cases of patients treated for isolated cartilage defects, with clinical improvement reported at up to 27 months. (8) 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. (9) At a mean of 75 months (range, 5-137 months) since the index procedure, no tumors or infections were identified. Functional outcomes were not reported.

Another study (2010) from Asia compared the efficacy of bone marrow-derived MSCs with autologous chondrocyte implantation (ACI) in 36 matched patient pairs. (10) 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. There were mixed indications based on the concomitant procedures, which included patella realignment, high-tibial osteotomy, partial meniscectomy, and anterior cruciate ligament reconstruction. Clinical outcomes, measured preoperatively and at 3, 6, 12, 18, and 24 months after operation using the International Cartilage Repair Society Cartilage Injury Evaluation Package, showed improvements 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 scale 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 has described the use of percutaneously injected culture-expanded MSCs obtained from the iliac spine in 226 patients. (11) Following harvesting, cells were cultured with autologous platelet lysate and reinjected 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 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 and indications for the injections varied. This procedure is no longer offered in the U.S.

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 OA. (12) Patients were randomized to BMAC into 1 knee and to saline placebo into the other. Fifty-two milliliters of bone marrow was aspirated from the iliac crests and concentrated in an automated centrifuge. The resulting BMAC was combined with platelet-poor plasma for injection into the arthritic knee and was compared with a saline injection into the contralateral knee, thereby using each patient as his or her control. Safety outcomes, pain relief, and function as measured by Osteoarthritis Research Society International measures and a visual analog scale (VAS) score were tracked initially at 1 week, 3 months, and 6 months post-procedure. Study patients experienced a similar relief of pain in both BMAC- and saline-treated arthritic knees. This trial is important because some previously reported studies have used injection of high-molecular weight HA derivatives as an active comparator. HA derivatives have been used for viscosupplementation in arthritic knee joints. However, a systematic review, prepared for the Agency for Healthcare Research and Quality (AHRQ) on the effectiveness of HA in the treatment of degenerative joint disease in knee joints, reported that no conclusions could be drawn from available literature on avoidance or delay of total knee replacement with the use of HA. (13) Guideline updates on viscosupplementation are included in that section of this medical policy.

A 2017 systematic review by Borakati et al. included 13 studies assessed patients with osteoarthritis who were treated with MSCs or with a control treatment that was identical other than the inclusion of MSCs (i.e., studies using chondrogenic cellular therapy as control were not included). (14) Pain assessment results were noted for each of the controlled studies, resulting in a pooled standardized mean difference of -1.27 (95% confidence interval, -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 groups treated with MSCs (p<0.001); although they noted high heterogeneity across controlled studies (I2=92%). Additionally, 34 uncontrolled studies (n=737 patients) were summarized and evaluated qualitatively: reviewers noted consistent cartilage regrowth and reduction of pain following treatment with MSCs in these studies; however, because pain medication was often given concurrently, interpretation of the latter outcome is limited.

Allogeneic Bone Marrow for the Treatment of OA

In 2015, Vega et al. reported on a small phase 1/2 RCT of 30 patients with OA unresponsive to conventional treatments. (15) The MSC-treated group received an intra-articular injection of expanded allogeneic bone marrow MSCs from healthy donors, and the control group received an intra-articular injection of HA. Follow-up using standard outcome measures was performed at 3, 6, and 12 months post-injection. In the MSC-treated group, pain scores (Visual Analog Scale [VAS] and Western Ontario and McMaster Universities Arthritis Index [WOMAC]) decreased significantly between baseline and the 12-month follow-up, whereas pain scores in the control group did not improve significantly. A significant improvement in cartilage quality in the MSC group was supported by T2 MRI. Not reported was whether the patients or assessors were blinded to treatment.

MSCs Concentrated from BMAC

In 2009, Giannini et al. reported on a 1-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. (16) A total of 60-mL bone marrow aspirate was collected from the iliac crest. The bone marrow-derived cells were concentrated 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. (17) Outcomes following arthroscopic application of the MSC concentrate (n=25) were similar to open (n=10) or arthroscopic (n=46) autologous chondrocyte implantation. Both studies treated posttraumatic lesions. ACI with a biodegradable scaffold is not commercially available in the U.S.

Centeno et al. (2015) reported on a multicenter registry of patients treated with autologous stem-cells, BMAC, and platelet rich plasma (PRP). (18) This study focused on 102 patients (115 shoulders) diagnosed with OA of the shoulder or rotator cuff tears. Patients were treated with a protocol that included a hypertonic dextrose solution (prolotherapy) injection to create an inflammatory response several days before the BMAC injection. The BMAC injection included PRP and platelet lysate. Both Disabilities of the Arm, Shoulder, and Hand questionnaire and numeric rating scale (NPS) decreased by about 50%, although the absolute decrease in the NPS was a very modest 0.9. Interpretation of these results is limited by the lack of placebo control and blinding, subjective outcome measures, and the multiple treatments used. Moreover, as a comparator, although it is not established whether prolotherapy or PRP have efficacy on its own (use of PRP has insufficient evidence to demonstrate improved net health outcome).

Adipose-Derived MSCs

Adipose-derived stem-cells are multipotential mesenchymal cells that can be harvested from multiple anatomic locations and with greater ease than bone marrow-derived MSCs.

The literature on adipose-derived MSCs for articular cartilage repair comes from 2 research groups in Korea. One group appears to have been providing this treatment as an option for patients for a number of years. They compared outcomes of this new add-on treatment with those for patients who only received other cartilage repair procedures.

In 2014, Koh et al. reported on results of an RCT that evaluated cartilage healing after high tibial osteotomy (HTO) in 52 patients with OA of the medial compartment. (19) Patients were randomized via sealed envelopes to HTO with the application of PRP or to HTO with the application of PRP plus MSCs. 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. A total of 44 patients completed second-look arthroscopy and 1- and 2-year clinical follow-ups. The primary outcomes were the Knee Injury and Osteoarthritis Outcome Score (KOOS; 5 subscales with 0-100 scale), the LKS score (0-100 scale), and a VAS for pain (0-100 scale). There were statistically significant differences between PRP only and PRP plus MSC on 2 of 5 KOOS subscales: pain (74 versus 81.2, p<0.001) and symptoms (75.4 versus 82.8, p=0.006), all respectively. There were also statistically significant differences on the final pain score between the PRP only (16.2) and PRP plus MSC groups (10.2; p<0.001), but the final LKS score did not differ significantly between the PRP only (80.6) and PRP plus MSC groups (84.7; p=0.36). Articular cartilage healing was rated as improved with MSCs following video review of second-look arthroscopy; 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 in outcomes were modest in magnitude and, as a result, there is uncertainty about the clinical significance of the findings.

A 2013 publication from this Korean group retrospectively compared 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 2008 and 2010. (20) The comparison group was 30 patients (31 ankles) who received MSC injection along with marrow stimulation between 2010 and 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 VAS, American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale, TAS, and the Roles and Maudsley scores. A 2014 retrospective review from this group reported on clinical outcomes and MRI results from 49 patients who had undergone marrow stimulation with or without MSCs at their institution. (21) Use of MSCs in addition to microfracture was determined by patient choice, and there was an overlap of 26 patients between this report and their 2013 previously discussed publication. (20) This analysis also found modest but statistically significant improvements in clinical outcomes for the MSC group compared with microfracture alone. Blinded ratings with the MOCART scale resulted in scores that suggested greater improvement in the MSC group (62.1) than in the conventional group (49.4; p=0.037).

Koh et al. (2012) also reported on a retrospective analysis of the injection of adipose-derived MSCs from the infrapatellar fat pad and PRP into arthroscopically débrided knees of 25 patients with OA of the knee. (22) 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 statistical trend toward greater improvement in the MSC group, at final follow-up, there was no significant difference between the MSC and control groups in clinical outcomes (LKS, TAS, VAS).

In 2014, another group reported a phase 1/2 trial of intra-articular injection of adipose-derived MSCs for the treatment of OA of the knee. (23) Phase 1 was a dose-escalation study of 9 patients and phase 2 assessed efficacy of the highest dose in another 9 patients. The study of 18 patients was approved by the Korean Food and Drug Administration. Procedures included liposuction, arthroscopy of the knee 1 week later with MSC injection through the portal, MRI at 3 and 6 months, and second-look arthroscopy with punch biopsy at 6 months. Intention-to-treat analysis showed a 39% improvement in WOMAC score and a 45% improvement in VAS score at 6 months post-injection. The knee section of the Knee Society clinical rating system showed significant increases in the low-dose group (91%) and in the high-dose group (50%), compared with baseline (p=0.025 and p<0.001, respectively). The function section of Knee Society clinical rating System was also significantly improved for the low-dose group (39%; p=0.020). Arthroscopy showed a significant decrease in the size of the cartilage defect: in four of the domains assessed (medial femoral and tibial condyles and lateral femoral and tibial condyles), decreases in defect ranged from 40% to 51%. There was also an increase in the volume of cartilage in the medial femoral condyle for both high- and low-dose groups, although this change was only significant in the low-dose patients, who showed a 27% increase (p=0.26). For the high-dose group and other domains, changes in cartilage volume was insignificant over 6 months. Histology showed thick, hyaline-like cartilage regeneration. The results of 2-year follow-up are reported below, as are the limitations of both phases of the trial.

The 2-year follow-up of this phase 1/2 trial was published by Jo et al. in 2017; functional outcomes were assessed by WOMAC, Knee Society clinical rating System, KOOS, and VAS; almost exclusively, the high-dose group showed significantly improved scores at 2 years compared with baseline and 1-year follow-up, while the medium- and low-dose groups showed insignificant changes or deterioration from 1-year to 2-year follow-up. (24) In the high-dose group, the WOMAC score decreased from baseline 54.2 to 16.0 at 1-year follow-up; after 2 years, the score was 19.0, which reflected the tendency of high-dose patients to improve early in treatment and remain at a stable level of improvement. Those in the medium- and low-dose groups, on the other hand, were more likely to show signs of deterioration after 2 years, a finding supported by structural measures (e.g., no significant changes in cartilage defects were reported for these patients, as assessed by MRI). In the high-dose group, measurement of the medial femoral defect showed a 49.4% decrease after 2 years (p=0.005), and measurement of lateral tibial condyles defect showed a 64.4% decrease (p=0.037); additionally, no adverse events were reported, prompting investigators to call for more randomized trials of the treatment. Among the trial’s limitations were a lack of a control group and the absence of data at 1 year for both MRI results and patients receiving a medium stem-cell dose. Another factor potentially influencing results was the use of arthroscopic exploration with lavage.

MSCs from Peripheral Blood

A 2013 report from Asia has described a small RCT assessing the use of autologous peripheral blood MSCs for focal articular cartilage lesions. (25) Fifty patients with grade 3 or 4 lesions of the knee joint underwent arthroscopic subchondral drilling followed by 5 weekly injections of HA. Half the patients were randomized to 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 and a mean of 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 postsurgery, second-look arthroscopy on 16 patients in each group showed significantly higher histologic scores (»10%) for the MSC group (1066 versus 957 by independent observers) while blinded evaluation of MRI scans showed a higher morphologic score (9.9 versus 8.5). There was no difference in IKDC scores between the 2 groups at 24 months after surgery. It is uncertain whether differences in patient age at baseline affected the response to subchondral drilling.

MSCs from Synovial Tissue

Akgun et al. (2015) reported on a small (n=14), though without major bias, investigator-blinded RCT that compared matrix-induced autologous MSCs from synovial tissue with matrix-induced ACI (MACI). (26) 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. Rehabilitation was the same for the 2 groups, with a continuous passive motion for at least 1 hour daily and non-weight bearing for the first 6 weeks. The 2 groups were similar at baseline, and all patients completed the evaluations through 24 months. Outcomes on KOOS subscales and TAS were statistically better in the MSC group, although it is not clear if the difference observed would be considered clinically significant, with differences of around 6 on the 100-point KOOS subscales and 0.6 on the 10-point TAS. The results of this small pilot study would suggest that cartilage repair with matrix-induced MSCs from synovial tissue might provide outcomes at least as good as MACI, warranting additional study in a larger sample. Neither procedure is approved for use in the U.S.

Section Summary: Cartilage Defects

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. Four randomized trials have reported improvements in histologic and morphologic outcomes. Three of them also reported improvements in functional outcomes. A meta-analysis of 13 studies found a consistent reduction of pain in groups treated with MSCs, although the studies included were highly heterogeneous and did not consistently distinguish between improvements due to MSCs and those due to pain medication. The method of preparation used in 1 positive study was to obtain MSCs from bone marrow at the time of microfracture, culture (expand) over a period of 3 weeks, and inject into the knee in HA. Another randomized trial, using MSCs from peripheral blood, found improvements in histologic and morphologic outcomes, but not functional outcomes, following stimulation with recombinant human granulocyte colony-stimulating factor. A third small RCT found that MSCs from synovial tissue and cultured in collagen resulted in outcomes at least as good as those following MACI.

The literature on adipose-derived MSCs includes a phase 1/2 trial with cultured MSCs and follow-up results after 2 years, as well as an RCT from a separate group in Asia that has been using uncultured MSCs as an adjunctive procedure in clinical practice. Comparisons between patients who have and have not received uncultured adipose-derived MSCs have shown modest improvements in health outcomes of uncertain clinical significance. The potential for bias from nonblinded use of a novel procedure on subjective outcome measures is also a limitation of these studies. The phase 1/2 trial of cultured MSCs from adipose tissue showed promising results for this technology. Additional study in a larger sample of patients with longer follow-up would be needed to evaluate the long-term efficacy and safety of the procedure. U.S. Food and Drug Administration (FDA) approval for this method has also not been obtained.

Meniscal Defects

Damage to the meniscal cartilage in the knee is a very common orthopedic injury and predisposes to the development of OA. The tissue is relatively avascular and does not spontaneously heal well. Standard treatment is the arthroscopic removal of damaged tissue to relieve symptoms of pain.

In 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. (27) The regulatory framework in the U.K. 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.

In 2014, Vangsness et al. reported on 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. (28) 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 an HA vehicle control at 7 to 10 days after meniscectomy. The cultured MSCs were derived from BMAC of unrelated donors. At 2-year follow-up, 3 patients in the low-dose MSC group had significantly increased meniscal volume measured by MRI (with a prior determined threshold of at least 15%) compared with none in the control group or the high-dose MSC group. There was no significant difference between the groups in LKS scores. On subgroup analysis, patients with OA who received MSCs had a significantly greater reduction in pain at 2 years than patients who received HA alone. This trial appears to have been a post hoc analysis and, hence, should be considered preliminary. No serious adverse events were reported as related to the investigational treatment.

Section Summary: Meniscal Defects

The evidence on the use of MSCs to repair or regenerate damaged meniscal tissue consists of preclinical animal studies, first-in-human uncontrolled implantation of expanded autologous MSCs into meniscal tears, and an early-phase randomized trial of cultured allogeneic MSCs injected into the site of partial meniscectomy. Results are preliminary.

Joint Fusion Procedures

There is limited evidence on the use of allografts with stem-cells for bone fusion of the extremities or spine or the treatment of nonunion. The results of several industry-sponsored, early-phase trials are available.

A prospective, clinical, and radiographic 12-month outcomes study (2016) of patients undergoing single-level anterior cervical discectomy and fusion (ACDF) for symptomatic cervical degenerative disc disease using a novel viable allogeneic stem-cell and cancellous bone matrix (Trinity Evolution™) was reported using historical controls as the comparator. (29) The ACDF procedure was performed using the polyetheretherketone (PEEK) interbody spacer and bone graft substitute (Trinity Evolution™) in 31 patients at multiple clinical sites. At 6 and 12 months, the primary end point of radiographic fusion was evaluated as determined by independent radiographic review and the fusion rate was 78.6% at 6 months and 93.5% at 12 months. Secondary end points included a function as assessed by Neck Disability Index (NDI) scores, and neck and arm pain as assessed by individual VAS scores. Neck function and neck and arm pain were reported as significantly improved at both 6 and 12 months post-procedure. 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.

A similar study (2017) involving several of the same investigators and clinical sites reported on the clinical and radiographic evaluation of an allogeneic bone matrix containing stem-cells (Trinity Evolution™ Viable Cellular Bone Matrix) in patients undergoing 2-level ACDF. (30) This study involved 40 patients exposed to the ACDF and bone graft substitute procedure at 2 adjacent disc levels. A panel blinded to clinical outcomes reviewed 12-month dynamic motion plain radiographs and thin-cut computed tomography (CT) with multiplanar reconstruction. At 12 months, the per-subject and per-level fusion rates were 89.4% and 93.4%, respectively. The clinical function assessments using NDI and VAS scores were reported to have improved from baseline.

A 2015 prospective, multicenter, open-label clinical trial using a cryopreserved, donor mesenchymal cell scaffold (Trinity Evolution™) was performed in subjects undergoing foot and/or ankle arthrodesis with surgeons’ preferred technique. (31) A total of 103 subjects were prospectively enrolled at 10 participating sites. No restrictions were placed on the diagnosis, which included arthritis (primary OA, post-traumatic OA, and rheumatoid), deformity, neuropathy (Charcot and diabetic), revision surgery, and degenerative joint disease (DJD), and arthrodesis was performed in 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. The primary end point was fusion at 6 months, as assessed from CT scans and standard radiographs by an independent radiology consultant. At 6 months, the fusion rate for all patients was 68.5% and 81.1% for all joints. American Orthopaedic Foot and Ankle Society Hindfoot Scale scores for disability improved over time.

In 2014, Eastlack et al. reported on outcomes from a series of 182 patients treated with ACDF using Osteocel® Plus in a PEEK cage and anterior plating. (32) 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 3o. With 26% loss to follow-up at 24 months and lack of a standard of care control group, interpretation of these results is limited.

Section Summary: Joint Fusion Procedures

The evidence on the use of MSCs as a component of joint fusion procedures primarily comes from industry-sponsored, prospective, open-label procedures. Outcomes included radiologic assessments of fusion, sometimes made independently, and patient-reported measures (e.g., VAS scores). The MSCs used were cryopreserved allogeneic in origin. Presumptive benefits of allogeneic MSCs are that patients undergoing an orthopedic intervention procedure do not need another graft harvesting procedure and that dose of stem-cells can be managed.


At least 2 randomized comparative trials from Asia have evaluated the use of MSCs for osteonecrosis of the femoral head.

MSCs Concentrated from BMAC

Another small trial (2012) randomized 40 patients (51 hips) with early-stage femoral head osteonecrosis to core decompression plus concentrated bone marrow MSCs or core decompression alone. (33) Blinding of assessments in this small trial was not described. Harris Hip Score (HHS) was significantly improved in the core decompression plus MSC group compared with the core decompression alone group at 12 months (scores, 83.65 versus 76.68, p<0.016) but not at 24 months (scores, 82.42 versus 77.39; p=0.09), all respectively. 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 groups in radiographic assessment or MRI results.

MSCs Expanded from BMAC

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 MSCs or with core decompression alone. (34) At 60 months post-surgery, 2 (3.7%) of the 53 hips treated with MSCs progressed and underwent vascularized bone grafting compared with 10 (23%) of 44 hips 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 HHS compared with the control group on independent evaluation (data presented graphically). Lesion volume was also reduced by treatment with MSCs.

Section Summary: Osteonecrosis

Two small studies from Asia have compared core decompression alone with core decompression plus MSCs in patients with osteonecrosis of the femoral head. Both reported improvement in the HHS 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 than with concentrated MSCs. Additional studies with a larger number of patients are needed to permit greater certainty on the efficacy of this treatment for osteonecrosis.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this medical policy are listed in Table 2. Many are observational studies with commercially available products (e.g., Cartistem®, AlloStem®, Trinity Evolution™, Osteocel® Plus).

Table 2. Summary of Key Trials


Trial Name

Planned Enrollment

Completion Date



Study of Subtalar Arthrodesis Using AlloStem® Versus Autologous Bone Graft


Sep 2017



Mesenchymal Stem-Cells in a Clinical Trial to Heal Articular Cartilage Defects


Jul 2018




Randomized, Open-Label, Multi-Center and Phase 3 Clinical Trial to Compare the Efficacy and Safety of Cartistem® and Microfracture in Patients With Knee Articular Cartilage Injury or Defect/ Long Term Follow-Up Study of CARTISTEM® Versus Microfracture


May 2015


Table Key:

NCT: national clinical trial.

a: Denotes industry-sponsored or cosponsored trial.

Practice Guidelines and Position Statements

American Association of Orthopaedic Surgeons (AAOS)

The 2013 and 2014 AAOS guidelines on the treatment of glenohumeral joint OA have indicated that:

Treatment using allograft, autograft, biologic, and interpositional grafts in patients with glenohumeral joint OA is inconclusive (35); and

Treatment using growth factor injections and/or platelet rich plasma for patients with symptomatic OA of the knee is inconclusive. (36)

American Association of Neurological Surgeons (AANS)

The AANS 2014 guidelines on fusion procedures for degenerative disease of the lumbar spine relevant to this medical policy have indicated that “The use of demineralized bone matrix (DBM) as a bone graft extender is an option for 1- and 2-level instrumented posterolateral fusions. DBM: Grade C (poor level of evidence).” (37)

International Society for Cellular Therapy (ISCT)

In 2006, the ISCT proposed a minimum set of criteria to standardize the characterization of multipotent MSCs. (38) 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 human leukocyte antigen-antigen D related surface molecules; and the capability of differentiating into osteoblasts, adipocytes, and chondrocytes using standard in vitro tissue culture-differentiating conditions.

Summary of Evidence

For individuals who have cartilage defects, meniscal defects, joint fusion procedures, or osteonecrosis who receive stem-cell therapy, the evidence includes small randomized controlled trials (RCTs) and nonrandomized comparative trials. Relevant outcomes are symptoms, morbid events, functional outcomes, quality of life, and treatment-related morbidity. 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. Studies have included MSCs from bone marrow, adipose tissue, peripheral blood, and synovial tissue. The largest body of evidence has evaluated the use of autologous MSCs, either concentrated or expanded in culture, for cartilage repair. This evidence includes small randomized and nonrandomized comparative trials with insufficient data to evaluate health outcomes. Also, expanded MSCs for orthopedic applications are not U.S. Food and Drug Administration?approved (concentrated autologous MSCs do not require agency approval). Overall, there is a lack of evidence that clinical outcomes are improved. The evidence is insufficient to determine the effects of the technology on health outcomes.


Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.



Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage versus. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.


The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

38206, 38230, 38232, 38241, 0263T, 0264T, 0265T



ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual

Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <>.


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17. 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):1196-203. PMID 20934692

18. 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; 8:269-76. PMID 26089699

19. 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):1453-60. PMID 25108907

20. 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):1090-9. PMID 23460335

21. 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):2424-34. PMID 25106781

22. Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem-cell therapy for knee osteoarthritis. Knee. Dec 2012; 19(6):902-7. PMID 22583627

23. 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):1254-66. PMID 24449146

24. 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):2774-83. PMID 28746812

25. 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):684-94. PMID 23380230

26. 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):251-63. PMID 25548122

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28. 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):90-8. PMID 24430407

29. 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):2233-8. PMID 26849141

30. 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

31. 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):1129-37. PMID 25976919

32. 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. Oct 15 2014; 39(22):E1331-7. PMID 25188591

33. 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):679-86. PMID 22000577

34. 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):325-30. PMID 22094904

35. American Academy of Orthopaedic Surgeons (AAOS). American Academy of Orthopaedic Surgeons clinical practice guideline on the treatment of glenohumeral joint osteoarthritis. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2009 (affirmed 2014).

36. American Academy of Orthopaedic Surgeons (AAOS). American Academy of Orthopaedic Surgeons clinical practice guideline on treatment of osteoarthritis of the knee. 2nd ed. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2013.

37. Kaiser MG, Groff MW, Watters WC, 3rd, 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; 21(1):106-32. PMID 24980593

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41. ECRI Institute. Autologous mesenchymal stem-cells for treating knee osteoarthritis. Plymouth Meeting (PA): ECRI Institute; 2013 Jun. 27 p. (Emerging Technology Evidence Report).

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43. Orthopedic Applications of Stem-Cell Therapy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 January) Therapy 8.01.52.

Policy History:

Date Reason
8/15/2018 Document updated with literature review. Coverage unchanged. References 1, 4, 12-14, 24, 27, and 29-31 were added, with several references removed.
10/15/2017 Reviewed. No changes.
11/1/2016 Document updated with literature review. The following coverage statement was added: “Allograft or synthetic bone graft substitutes that must be combined with autologous blood or bone marrow are considered experimental, investigational and/or unproven for all orthopedic applications.”
8/15/2015 Reviewed. No changes.
8/15/2014 New medical document. Mesenchymal stem-cell (MSC) therapy, including but not limited to bone-marrow aspirate concentrate (BMAC), is considered experimental, investigational and/or unproven for all orthopedic applications, including use in repair or regeneration of musculoskeletal tissue. Allograft bone products containing viable stem-cells, including but not limited to demineralized bone matrix (DBM) with stem-cells, is considered experimental, investigational and/or unproven for all orthopedic applications. NOTE: This policy does not address unprocessed allograft bone.

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