Medical Policies - Surgery


Orthopedic Applications of Stem-Cell Therapy

Number:SUR703.051

Effective Date:10-15-2017

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

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: This policy does not address unprocessed allograft bone.

Description:

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.

Background

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 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)

Regulatory Status

Concentrated autologous MSCs do not require approval by the 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:

AlloStem® (AlloSource) is 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) is 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.

Whether these products can be considered minimally manipulated tissue is debated. A product would not meet the criteria for FDA regulation part 1271.10 if it is dependent on the metabolic activity of living cells for its primary function. Otherwise, a product would be considered a biologic product and would need to demonstrate safety and efficacy for the product’s intended use with an investigational new drug and biologics license application (BLA).

Other products contain DBM and are designed to be mixed with bone marrow aspirate. Some products currently available are:

Fusion Flex™ (Wright Medical): a dehydrated moldable DBM scaffold that will absorb autologous bone marrow aspirate.

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

Other commercially available products are intended to be mixed with bone marrow aspirate and have been cleared by the FDA through the 510(k) process, such as:

CopiOs sponge or paste (Zimmer): synthetic bone graft material consisting of mineralized, lyophilized collagen.

Collage™ Putty (Orthofix): composed of type-1 bovine collagen and beta tricalcium phosphate.

Vitoss® (Stryker, developed by Orthovita): composed of beta tricalcium phosphate.

nanOss® Bioactive (rti surgical, developed by Pioneer Surgical): nanostructured hydroxyapatite and an open structured engineered collagen carrier.

FDA product code: MQV.

No products using engineered or expanded MSCs have been approved by the FDA for orthopedic applications.

In 2008, the FDA determined that the MSCs sold by Regenerative Sciences for use in the Regenexx™ procedure would be considered drugs or biological products and thus requires submission of a new drug application (NDA) or BLA to the FDA. (2) In 2014, a federal appellate court upheld the FDA’s power 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 is only offered in the Cayman Islands. Regenexx™ network facilities in the United States provide same-day stem-cell and blood platelet procedures, which do not require FDA approval.

Rationale:

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 April 2016.

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 review was created, the evidence base has been steadily increasing, although there is a lack of high-quality randomized controlled trials (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 different sources of MSCs. 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 MSCs for the treatment of cartilage lesions. (5) 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 adipose tissue in 2 clinical studies, bone marrow concentrate in 5, and in 11 studies, the source was bone marrow-derived. Many of these trials had been performed by the same research group in Asia. Following is a summary of the key literature to date, focusing on comparative studies.

MSCs Expanded from Bone Marrow

Autologous Bone Marrow

In 2013 (after the systematic review by Filardo 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. (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 and Lysholm Knee Scale scores through 2 years and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system 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 [MD], 7.65 on 0-100 scale; p=0.001), Lysholm (MD=7.61 on 0-100 scale; p=0.02), and Tegner (MD=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. (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 was not found to differ 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. (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. 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. (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. Concomitant procedures 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 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. (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. This procedure is no longer offered in the U.S.

Allogeneic Bone Marrow

In 2015, Vega et al. reported a small phase 1/2 RCT of 30 patients with osteoarthritis unresponsive to conventional treatments. (12) The MSC-treated group received 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 after injection. In the MSC-treated group, pain scores (Visual Analog Scale [VAS] and Western Ontario and McMasters 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 in the MSC group was supported by T2 MRI. Not reported was whether the patients or assessors were blinded to treatment in this trial. Additional study in a larger number of patients in a phase 3 trial with blinding of patients and assessors is needed.

MSCs Concentrated from Bone Marrow

In 2009, Giannini et al. reported 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. (13) 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. Outcomes following arthroscopic application of the MSC concentrate (n=25) were similar to open (n=10) or arthroscopic (n=46) ACI. (14) ACI with a biodegradable scaffold is not commercially available in the U.S.

Centeno et al. reported a multicenter registry of patients treated with autologous stem-cells, bone marrow concentrate, and platelet-rich plasma. (15) This report focused on 102 patients (115 shoulders) diagnosed with either osteoarthritis 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 prior to the bone marrow concentrate injection. The bone marrow concentrate injection included platelet-rich plasma and platelet lysate. Both Disabilities of the Arm, Shoulder, and Hand scores and numeric pain scale (NPS) scores decreased by about 50%, although the absolute decrease in the NPS score was a very modest 0.9. Interpretation of these results is limited by the lack of a placebo control and blinding, subjective outcome measures, and the multiple treatments used; although it is acknowledged that neither prolotherapy nor PRP appear to have efficacy on their own. Additional study with randomized and placebo-controlled trials is needed to evaluate this treatment protocol.

Adipose-Derived MSCs

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

In 2014, Koh et al. reported results of an RCT that evaluated cartilage healing after high tibial osteotomy (HTO) in 52 patients with osteoarthritis of the medial compartment. (16) Patients were randomly assigned via sealed envelopes to HTO with application of platelet-rich plasma (PRP) or HTO with application of PRP plus MSCs. MSCs from adipose tissue were obtained through liposuction from 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 Lysholm score (0-100 scale), and a VAS for pain (0-100 scale). There were statistically significant differences for PRP only versus PRP+MSC on 2 of 5 KOOS subscales: Pain (74±5.7 versus 81.2±6.9, p<0.001) and Symptoms (75.4±8.5 versus 82.8±7.2, p=0.006). There were also statistically significant differences on the final pain score for the PRP only versus PRP+MSC groups (16.2±4.6 versus 10.2±5.7, p<0.001), but the final Lysholm score did not differ significantly between the PRP only and PRP+MSC groups (80.6±13.5 versus 84.7±16.2, all respectively, 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. 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 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. (17) 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 VAS, American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale, Tegner, and the Roles and Maudsley scores. A 2014 retrospective review from this group reported clinical outcomes and MRI results from 49 patients who had undergone marrow stimulation with or without MSCs at their institution. (18) 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. (17) 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 a score of 49.4 for the conventional group and 62.1 for the MSC group (p=0.037).

Koh et al. also reported 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 osteoarthritis of the knee. (19) 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, VAS).

Another group reported a phase 1/2 trial of intra-articular injection of adipose-derived MSCs for the treatment of osteoarthritis of the knee. (20) The phase 1 was a dose-escalation study of 9 patients, and phase 2 assessed efficacy of the highest dose of 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 at 6 months after injection and a 45% improvement in VAS score. Arthroscopy showed a decrease in size of the cartilage defect and an increase in the volume of cartilage. Histology showed thick, hyaline-like cartilage regeneration. Additional study is needed with a larger sample size, sham-treated controls, and longer follow-up.

MSCs from Peripheral Blood

A 2013 report from Asia described a small RCT with autologous peripheral blood MSCs for focal articular cartilage lesions. (21) Fifty patients with grade 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling followed by 5 weekly injections of HA. Half 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 readministered 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 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 how differences in patient age at baseline may have affected the response to subchondral drilling.

MSCs from Synovial Tissue

Akgun et al. reported a small (N=14), though without major bias, investigator-blinded RCT that compared matrix-induced autologous MSCs from synovial tissue versus matrix-induced autologous chondrocyte implantation (MACI). (22) 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 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 the KOOS subscales and Tegner 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 Tegner. The results of this small pilot study do suggest that cartilage repair with matrix-induced MSCs from synovial tissue may result in outcomes that are at least as good as MACI, warranting additional study in a larger sample. It should also be noted that neither of these procedures 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 studies reported an improvement in histologic and morphologic outcomes. Three of these studies also reported an improvement in functional outcomes. 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 in the knee in a carrier of HA. Another randomized trial, using MSCs from peripheral blood, found improvement 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 on collagen resulted in outcomes that were at least as good as those following MACI.

The literature on adipose-derived MSCs includes a phase 1/2 study with cultured MSCs and 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 shows modest improvement in health outcomes that are of uncertain clinical significance. 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 study of cultured MSCs from adipose tissue shows promising results for this technology. Additional study in a larger sample of patients with longer follow-up is 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.

Meniscectomy

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. (23) 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 7 to 10 days after meniscectomy. The cultured MSCs were derived from bone marrow aspirates from unrelated donors. At 2-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 or in the high-dose MSC group. There was no significant difference between the groups in the Lysholm score. On subgroup analysis, patients with osteoarthritis who received MSCs had a significantly greater reduction in pain at 2 years than 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.

Spinal Fusion

There is limited evidence on the use of allografts with stem-cells for fusion of the extremities or spine or for the treatment of nonunion, although several large observational studies are ongoing (see Table 1). In 2014, Eastlack et al. reported outcomes from a series of 182 patients who were treated with anterior cervical discectomy and fusion using Osteocel Plus in a PEEK cage and anterior plating. (24) At 24 months, 74% of patients (180/249 levels treated) were available for follow-up. These patients had significant improvements in clinical outcomes; 87% of levels achieved solid bridging and 92% of levels had 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.

Osteonecrosis

Two randomized comparative trials from Asia have been identified that evaluated the use of MSCs for osteonecrosis of the femoral head.

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. (25) At 60 months after 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 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.

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. (26) 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 groups in radiographic assessment or MRI results.

Section Summary: Osteonecrosis

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 than with concentrated MSCs. Additional studies with a larger number of patients are needed to permit greater certainty on the effect of this treatment on health outcomes.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 1. A 2014 review on FDA regulations of adult stem-cell therapies for sports medicine identified over 45 ongoing clinical trials on this topic. (3) Many are observational studies with commercially available products (Cartistem®, AlloStem®, Trinity Evolution™, Osteocel® Plus).

Table 1. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01413061a

Study of Subtalar Arthrodesis Using AlloStem® Versus Autologous Bone Graft

140

Feb 2017

NCT00885729

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

50

Jul 2018

Unpublished

NCT00951938a

A Radiographic and Clinical Study Evaluating a Novel Allogeneic, Cancellous, Bone Matrix Containing Viable Stem Cells (Trinity Evolution™ Viable Cryopreserved Cellular Bone Matrix) in Patients Undergoing Anterior Cervical Discectomy and Fusion

200

Aug 2012

NCT0094853a

Osteocel® Plus in eXtreme Lateral Interbody Fusion (XLIF®): Evaluation of Radiographic and Patient Outcomes

104

Oct 2012

NCT00948831a

Osteocel® Plus in Anterior Lumbar Interbody Fusion (ALIF): Evaluation of Radiographic and Patient Outcomes

51

Oct 2012

NCT00988338a

A Radiographic and Clinical Study Evaluating a Novel Allogeneic, Cancellous, Bone Matrix Containing Viable Stem Cells (Trinity Evolution™ Matrix) in Subjects Undergoing Foot and Ankle Fusion

106

Jan 2013

NCT00965380a

A Radiographic and Clinical Study Evaluating a Novel Allogeneic, Cancellous, Bone Matrix Containing Viable Stem Cells (Trinity Evolution™ Viable Cryopreserved Cellular Bone Matrix) in Posterior Lumbar or Transforaminal Lumbar Interbody Fusion (PLIF or TLIF)

200

Jun 2014

NCT01626677/

NCT01041001a

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

104

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 AAOS 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. (27)

International Society for Cellular Therapy (ISCT)

In 2006, the ISCT proposed a minimal set of criteria to standardize the characterization of multipotent MSCs. (28) 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-DR surface molecules; and the capability of differentiating into osteoblasts, adipocytes, and chondrocytes using standard in vitro tissue culture-differentiating conditions.

Summary of Evidence

The evidence for stem-cell therapy in individuals who have various orthopedic conditions (cartilage defects, meniscectomy, spinal fusion procedures, and osteonecrosis) 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 is on 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. In addition, expanded MSCs for orthopedic applications are U.S. Food and Drug Administration (FDA)-approved (concentrated autologous MSCs do not require FDA 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.

Contract:

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.

Coding:

CODING:

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 vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

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

CPT Codes

38206, 38230, 38241

HCPCS Codes

None

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 <http://www.cms.hhs.gov>.

References:

1. U.S. Food and Drug Administration. Assuring safety and efficacy of stem-cell based products. Available online <http://www.fda.gov> accessed on February 2, 2016.

2. U.S. Food and Drug Administration. Untitled letter. Guidance, compliance, and regulatory information (Biologics) 2008. Available online <http://www.fda.gov> accessed on February 2, 2016.

3. 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

4. Deans TL, Elisseeff JH. Stem-cells in musculoskeletal engineered tissue. Curr Opin Biotechnol. 2009; 20(5):537-44. PMID 19879127

5. 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):1717-29. PMID 23306713

6. 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):2020-8. PMID 24286801

7. 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

8. 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):74-9. PMID 18038395

9. 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):146-50. PMID 20503892

10. Nejadnik H, Hui JH, Feng Choong EP, et al. Autologous bone marrow-derived mesenchymal stem-cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med. Jun 2010; 38(6):1110-6. PMID 20392971

11. Centeno CJ, Schultz JR, Cheever M, et al. Safety and Complications Reporting on the Re-implantation 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

12. 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):1681-90. PMID 25822648

13. 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):3307-20. PMID 19449082

14. 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

15. 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

16. 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

17. 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

18. 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

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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. American Academy of Orthopaedic Surgeons. Stem-cells and orthopaedics. Your Orthopaedic Connection 2007. Available online <http://orthoinfo.aaos.org> accessed on December 21, 2015.

28. 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. PMID 169230606

29. ECRI Institute. Transcatheter Left Atrial Appendage Occlusion (Watchman) for Preventing Stroke in Patients with Atrial Fibrillation. Plymouth Meeting (PA): ECRI Institute; 2013 May. 13 p. (Health Technology Forecast).

30. ECRI Institute. Core decompression plus autologous mesenchymal stem-cell transplantation for treating early-stage femoral head necrosis. Plymouth Meeting (PA): ECRI Institute; 2013 Jun. 28 p. (Emerging Technology Evidence Report).

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

32. ECRI Institute. What’s the promise of regenerative medicine? Plymouth Meeting (PA): ECRI Institute; 2012 Feb. (Health Technology Trends).

33. Orthopedic Applications of Stem-Cell Therapy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2016 January) Therapy 8.01.52.

Policy History:

DateReason
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.

Archived Document(s):

Back to Top