Coverage Policy Manual
Policy #: 2010023
Category: Medicine
Initiated: April 2010
Last Review: August 2018
  Orthopedic Applications of Stem Cell Therapy

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.
 
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. Stimulation of endogenous MSCs is the basis of procedures such as bone marrow stimulation (e.g., microfracture) and harvesting/grafting of autologous bone for fusion. Bone marrow aspirate is considered to be the most accessible source and thus the most common place to isolate MSCs for treatment of musculoskeletal disease. However, harvesting MSCs from bone marrow requires an additional procedure that may result in donor site morbidity. In addition, the number of MSCs in bone marrow is low, and the number and differentiation capacity of bone marrow derived MSCs decreases with age, limiting their efficiency when isolated from older patients.
 
Tissues such as muscle, cartilage, tendon, ligaments, and vertebral discs show limited capacity for endogenous repair. Therefore, tissue engineering techniques are being developed to improve the efficiency of repair or regeneration of damaged musculoskeletal tissues. Tissue engineering focuses on the integration of biomaterials with MSCs and/or bioactive molecules such as growth factors. In vivo, the fate of stem cells is regulated by signals in the local 3-dimensional microenvironment from the extracellular matrix and neighboring cells. It is believed that the success of tissue engineering with MSCs will also require an appropriate 3-dimensional scaffold or matrix, culture conditions for tissue specific induction, and implantation techniques that provide appropriate biomechanical forces and mechanical stimulation. The ability to induce cell division and differentiation without adverse effects, such as the formation of neoplasms, remains a significant concern. Given that each tissue type requires different culture conditions, induction factors (signaling proteins, cytokines, growth factors, etc.) and implantation techniques, each preparation must be individually examined.
 
The U.S. Food and Drug Administration (FDA) has stated that “cell-based therapies are one of the most rapidly advancing approaches intended to repair, replace, restore, or regenerate cells, tissues and organs. They can be applied to damage caused by disease, injury, or aging. Many cell-based therapies use immature cells (stem cells) that are expanded outside of the body. The expanded cells are sometimes used in their immature state, but they are often manufactured into more mature cells before they are given to a patient. The resulting cells are intended to repair cell or tissue damage (efficacy) without unintended serious consequences such as tumors, severe immune reactions, or unwanted tissue development (safety). Manufacturing of large numbers of cells outside the natural environment of the human body may lead to ineffective or dangerous cells, so it is important to understand and carefully control the production process and to define measures that reliably predict safety and efficacy of the cell-based products.”  
 
Regulatory Status
Concentrated autologous MSCs do not require approval by the U.S. Food and Drug Administration (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): partially demineralized allograft bone seeded with adipose-derived MSCs
    • Map3™ (rti surgical) contains cortical cancellous bone chips, DBM, and multipotent adult progenitor cells
    • Osteocel Plus® (NuVasive): DBM combined with viable MSCs that have been isolated from allogeneic bone marrow
    • Trinity Evolution Matrix™ (Orthofix) DBM combined with viable MSCs that have been isolated from allogeneic bone marrow
 
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 upon 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 (IND) and Biologics License Application (BLA).
Other products contain DBM and are designed to be mixed with bone marrow aspirate. Some of the products that are 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 received 510(k) clearance, such as:
 
    • 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.
 
No products using engineered or expanded MSCs have been approved by FDA for orthopedic applications.
 
In 2008, FDA determined that the MSCs sold by Regenerative Sciences for use in the Regenexx-C™ procedure would be considered drugs or biologic products and thus require submission of a new drug application or biologic license application to FDA\l " (FDA, 2008) The Regenexx-C™ 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 FDA authority to regulate adult stem cells as drugs and biologics and ruled that the Regenexx cell product fell within FDA’s authority to regulate HCT/Ps. To date, no new drug application or biologic license application has been approved by FDA for this product. As of 2015, the expanded stem cell procedure is only offered in the Cayman Islands. Regenexx® Stem Cell Procedure is offered through a network of facilities in the United States 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\l " (Regenexx, 2017).
    
Related Policies
2009049 - Platelet-Rich Plasma (Autologous Growth Factors)_Orthopedic Applications
 
There are no specific CPT or HCPCS codes that describe all the services included in the orthopedic application of mesenchymal stem cell therapy.
 

Policy/
Coverage:
Effective August 2017
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of stem cell therapy in the treatment of avascular necrosis (AVN) of the femoral head, or the use of mesenchymal stem cell therapy for any orthopedic application, does not meet primary coverage criteria for effectiveness. This technology is currently being studied in ongoing clinical trials.
 
For contracts without primary coverage criteria the use of stem cell therapy in the treatment of avascular necrosis (AVN) of the femoral head, or the use of mesenchymal stem cell therapy for any orthopedic application is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
The use of allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix with stem cells, does not meet primary coverage criteria for effectiveness.
 
For contracts without primary coverage criteria, use of allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix with stem cells, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
The use of allograft or synthetic bone graft substitutes that must be combined with autologous blood or bone marrow does not meet primary coverage criteria for effectiveness. This technology is currently being studied in ongoing clinical trials.
 
For contracts without primary coverage criteria, the use of allograft or synthetic bone graft substitutes that must be combined with autologous blood or bone marrow is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to August 2017:
 
The use of stem cell therapy in the treatment of avascular necrosis (AVN) of the femoral head, or the use of mesenchymal stem cell therapy for any orthopedic application, does not meet primary coverage criteria for effectiveness. This technology is currently being studied in ongoing clinical trials.
 
For contracts without primary coverage criteria the use of stem cell therapy in the treatment of avascular necrosis (AVN) of the femoral head, or the use of mesenchymal stem cell therapy for any orthopedic application is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to August 2016
The use of mesenchymal stem cell therapy for any orthopedic application does not meet primary coverage criteria for effectiveness.  This technology is currently being studied in ongoing clinical trials.  
 
For contracts without primary coverage criteria the use of mesenchymal stem cell therapy for any orthopedic application is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DBM) with stem cells, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DBM) with stem cells is considered investigational for all orthopedic applications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to April 2013
The use of mesenchymal stem cell therapy for any orthopedic application does not meet primary coverage criteria for effectiveness.  This technology is currently being studied in ongoing clinical trials.  
 
For contracts without primary coverage criteria the use of mesenchymal stem cell therapy for any orthopedic application is considered investigational.  Investigational services are an exclusion in the member benefit certificate.  

Rationale:
At this time, the literature consists 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 (Deans, 2009).  Authors of these reviews indicate that the technology is in an early stage of development. In a literature search of the MEDLINE database in March 2010, use of cultured MSCs in humans was identified in only a few centers (U.S. and Asia).
 
Wakitani and colleagues (2002) first reported use of expanded MSCs for repair of cartilage defects.  Cells from bone marrow aspirate of 12 patients with osteoarthritic knees were culture expanded, embedded in collagen gel, transplanted into the articular cartilage defect and covered with autologous periosteum at the time of high tibial osteotomy. Clinical improvement was not found to be different between the experimental group and a group of 12 control patients who underwent high tibial osteotomy alone. Wakitani (2007) has since published several cases of patients treated for isolated cartilage defects, with clinical improvement reported at up to 27 months.  However, most of the defects appear to have been filled with fibrocartilage, and in the absence of controlled studies, the benefit of this procedure in comparison with established alternatives such as microfracture is unclear.
 
A 2010 article from Centeno et al. describes the use of percutaneously injected culture-expanded MSCs from the iliac spine in 226 patients.  Following harvesting, cells were cultured with autologous platelet lysate and re-injected under fluoroscopic guidance into peripheral joints (n=213) or intervertebral discs (n=13). Follow-up for adverse events at a mean of 10.6 months showed 10 cases of probable procedure-related complications (injections or stem cell related), all of which were considered to be self-limited or treated with simple therapeutic measures. Serial 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.
 
A search of ClinicalTrials.gov in March 2010 identified a number of trials on use of MSCs for orthopedic indications from both within and outside the U.S. The following is a sample of some of the larger studies:
 
A Phase I/II randomized, placebo controlled, double blind study of 2 doses of Chondrogen™ (Osiris Therapeutics) or a placebo intra-articular injection following meniscectomy in 60 patients is listed as completed in 2008 (NCT00225095). Chondrogen™ is a preparation of adult MSCs in a solution containing hyaluronic acid. Three-year follow-up of Chondrogen™ versus placebo injections is listed as a separate study (NCT00702741).
 
Medipost is sponsoring a randomized, open-label, multi-center phase III clinical trial to compare the efficacy and safety of Cartistem® and microfracture in patients with knee articular cartilage injury or defect (NCT01041001). MSCs will be isolated from umbilical cord blood and cultured, mixed with semi-solid polymer, and administered in the cartilage tissue lesion by orthopedic surgery. The study has an estimated enrollment of 104 patients with completion in 2011.
 
Orthofix is sponsoring a radiographic and clinical study evaluating a novel allogeneic, cancellous, bone matrix containing viable stem cell (Trinity Evolution Matrix,) in subjects undergoing tibiotalar arthrodesis with or without hind foot fusion (NCT00988338). The study has an estimated enrollment of 100 patients with completion in 2012.
 
NCT00885729 is a phase I randomized, single blind, active control trial of MSCs compared with chondrocytes to heal articular cartilage defects in 50 patients. The study is sponsored by an academic medical center in Norway. Both MSCs and chondrocytes will be delivered in a commercially available scaffold (not described). The estimated study completion date is 2018.
 
The American Association of Orthopaedic Surgeons (AAOS) states that stem cell procedures in orthopaedics 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.
 
Overall, the literature suggests a technology that is at a very early stage of development, with the vast majority of studies focused on development of methods for tissue engineering along with preliminary testing in animal models. A number of clinical trials are in progress, but are not expected to be completed for several years. Current evidence on procedures using autologous bone marrow derived MSCs for orthopedic indications in humans consists of several case reports/case series, with insufficient data to evaluate health outcomes.
 
2012 Update
This policy is being updated with a literature search through July 2012.  There was no new information identified that would prompt a change in the coverage statement. A summary of the relevant literature is as follows.
 
A 2011 report from Wakitani et al. was a follow-up safety study of 31 of the 41 patients (3 patients had died and 5 had undergone total knee arthroplasty) who had received MSCs for articular cartilage repair in their clinics between 1998 and 2008 (Wakitani, 2011). Patients who could not return to clinic were interviewed by telephone to determine if there were any abnormalities in the operated joints. At a mean of 75 months (range, 5 to 137) since the index procedure, no tumors or infections were identified. Function was not reported. In the absence of controlled studies, the benefit of this procedure in comparison with established alternatives such as microfracture is unclear.
 
Another study from Asia compared the efficacy of bone marrow-derived MSCs and autologous chondrocyte implantation (ACI) in 36 matched patient pairs (Nejadnik, 2010). 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. At baseline, the MSC group had a slightly (non-significantly) greater lesion size (4.6 cm2 vs. 3.6 cm2, respectively). The grade of the lesion was comparable for the 2 groups (30-33% grade 4). Autologous MSCs were cultured from 30 mL of bone marrow from the iliac crest and tested to confirm that the cultured cells were MSCs. The cultured chondrocytes or MSCs were implanted beneath a periosteal patch. Concomitant procedures included patella realignment, high-tibial osteotomy, partial meniscectomy, and anterior cruciate ligament reconstruction. Clinical outcomes were measured pre-operatively and at 3, 6, 12, 18, and 24 months’ after operation using the International Cartilage Repair Society (ICRS) Cartilage Injury Evaluation Package. The Evaluation Package included questions from the Short-Form-36 (SF-36) Health Survey, International Knee Documentation Committee (IKDC) subjective knee evaluation form, Lysholm knee scale, and Tegner activity level scale. Both treatments improved patients’ scores over the 2-year follow-up by mixed effect models. There was no significant difference between groups for any of the measures except for Physical Role Functioning on the SF-36, which showed a greater improvement over time in the MSC group. Although scatter plots were provided, neither the absolute improvement nor the proportion of patients with clinically significant improvement was reported. This study is also limited by the small number of patients.
In 2009, Giannini et al. reported a one-step procedure for transplanting bone marrow-derived cells for Type II (>1.5 cm2, <5 mm deep) osteochondral lesions of the talus in 48 patients (Giannini, 2009).  The mean age of the patients was 29 years. Fifteen of the patients had been previously treated by microfracture (n=8), debridement (n=5), or autologous chondrocyte transplantation (n=2). A total of 60 mL-bone marrow aspirate was collected from the iliac crest. The bone marrow-derived cells were concentrated in the operating room and implanted with a scaffold (collagen powder or hyaluronic acid membrane) and platelet gel. Twenty-two patients underwent associated surgical procedures (osteophytectomy, synovectomy, loose body extraction, or calcaneal osteotomy). Active and passive ankle motions were advised beginning the day after surgery; no weight bearing was recommended for 6 weeks. Patients were evaluated at 6, 12, 18, and 24 months after surgery with standard radiographs and magnetic resonance imaging (MRI). At 24-month follow-up, the mean American Orthopaedic Foot and Ankle Society (AOFAS) score had changed from 64.4 to 91.4, representing a meaningful improvement. The AOFAS score at follow-up was affected by the area of the lesion and previous surgeries. MRI showed newly formed tissue at the lesion site in all patients. Histologic evaluation in the first 3 patients (asymptomatic) showed regenerated tissue in various degrees of remodeling, although none showed entirely hyaline cartilage. Two additional patients were reoperated due to hypertrophic regenerated tissue. Integration with the healthy cartilage was reported to be complete in all 5 patients with a smooth transition zone.
 
The use of mesenchymal stem cell therapy for orthopedic applications continues to be studied in the following clinical trials:
    • A Phase I/II randomized, placebo controlled, double blind study of 2 doses of Chondrogen™ (Osiris Therapeutics) or a placebo intra-articular injection following meniscectomy in 60 patients is listed as completed in 2008 (NCT00225095). Chondrogen™ is a preparation of adult MSCs in a solution containing hyaluronic acid. Three-year follow-up of Chondrogen™ versus placebo injections is listed as a separate study (NCT00702741).
    • Medipost is sponsoring a randomized, open-label, multicenter Phase III clinical trial to compare the efficacy and safety of Cartistem® and microfracture in patients with knee articular cartilage injury or defect (NCT01041001). MSCs will be isolated from umbilical cord blood and cultured, mixed with semi-solid polymer, and administered in the cartilage tissue lesion by orthopedic surgery. The study has an estimated enrollment of 104 patients with completion in 2011. Preliminary results of this study were presented at the annual meeting of the American Academy of Orthopaedic Surgeons in February 2012.
    • Orthofix is sponsoring a radiographic and clinical study evaluating a novel allogeneic, cancellous, bone matrix containing viable stem cells (Trinity Evolution Matrix) in subjects undergoing tibiotalar arthrodesis with or without hind-foot fusion (NCT00988338). The study has an estimated enrollment of 100 patients with completion in 2012.
    • NCT00885729 is a Phase I randomized, single-blind, active control trial of MSCs compared with chondrocytes to heal articular cartilage defects in 50 patients. The study is sponsored by an academic medical center in Norway. Both MSCs and chondrocytes will be delivered in a commercially available scaffold (not described). The estimated study completion date is 2018.
    • The National University of Malaysia is sponsoring a randomized controlled trial of intra-articular MSC injection versus hyaluronic acid in patients with osteoarthritis (NCT01459640). The study has an estimated enrollment of 50 patients with completion in 2014.
 
2013 Update
This policy is being updated with a literature review through March 2013. The following is a summary of the key literature identified.
 
Cartilage Defects
 
Caritilage Defects: Adipose-derived MSCs
In 2012, Koh et al. reported a retrospective analysis of the injection of adipose-derived MSCs and platelet-rich plasma (PRP) into arthroscopically-debrided knees of 25 patients with osteoarthritis (Koh, 2012). Results were compared with a randomly selected group of patients who had previously undergone arthroscopic debridement and PRP injections without stem cells. Although there was a trend for greater improvement in the MSC group, at final follow-up there was no significant difference between the MSC and control groups in clinical outcomes (Lysholm, Tegner, visual analog score). Use of PRP is discussed separately in policy No 2009049.
 
Caritilage Defects: MSCs from Peripheral Blood
A 2013 report from Asia described a small randomized controlled trial with autologous peripheral blood MSCs for focal articular cartilage lesions (Saw, 2013). Fifty patients with grade 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling followed by 5 weekly injections of hyaluronic acid. Half of the patients were randomly allocated to receive injections of peripheral blood stem cells or no further treatment. There were baseline differences in age between the groups, with a mean age of 38 years for the treatment group compared to 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, hyaluronic acid and MSC were re-administered over 3 weekly injections. At 18 months after surgery, second look arthroscopy on 16 patients in each group showed significantly higher histological scores (by about 10%) for the MSC group (1,066 vs. 957 by independent observers) while blinded evaluation of magnetic resonance imaging (MRI) showed a higher morphologic score (9.9 vs. 8.5). There was no difference in International Knee Documentation Committee (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.
 
Conclusions-The evidence base on MSCs for cartilage repair is increasing, although as of March 2013 only one study was identified that was randomized. This small randomized study, which is limited by group differences in age at baseline, is also the only comparative study to show an improvement in histological and morphologic outcomes. No study to date has shown an improvement in functional outcomes following treatment with MSCs for cartilage repair.
 
Fusion and Non-union
There is limited evidence on the use of allografts with stem cells for fusion of the extremities or spine or for the treatment of non-union. One retrospective series from 2009 was identified on the use of Trinity Evolution Matrix MSC bone allograft for revision surgery of the foot and ankle (Rush, 2009). Twenty-three patients were included who had undergone revision foot and/or ankle surgery for residual malunion, non-union, or significant segmental bone loss. Patients were followed to the point of radiographic and clinical union, which occurred at a median of 72.5 days for 21 of the 23 patients (91.3%).
 
Osteonecrosis
Two randomized comparative trials from Asia have been identified that evaluated the use of MSCs for osteonecrosis of the femoral head.
 
Osteonecrosis: MSCs Expanded from Bone Marrow
In 2012, Zhao et al. reported a randomized trial that included 100 patients (104 hips) with early stage femoral head osteonecrosis treated with core decompression and expanded bone marrow MSCs versus core decompression alone (Zhao, 2012)  At 60 months after surgery, 2 of the 53 hips (3.7%) treated with MSCs progressed and underwent vascularized bone grafting, compared with 10 of 44 hips (23%) in the decompression group who progressed and underwent either vascularized bone grafting (n=5) or total hip replacement (n=5). The MSC group also had improved Harris Hip Scores compared with the control group on independent evaluation (data presented graphically). The volume of the lesion was also reduced by treatment with MSCs.
 
Osteonecrosis: MSCs Concentrated from Bone Marrow
Another small trial randomized 40 patients (51 hips) with early stage femoral head osteonecrosis to core decompression plus concentrated bone marrow MSCs or core decompression alone (Sen, 2012).  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 of 51.9 weeks) compared to the core decompression group (mean of 46.7 weeks). There were no significant differences between the groups in the radiographic assessment or MRI results.
 
Conclusions-Two small studies from Asia have compared core decompression alone versus core decompression with MSCs in patients with osteonecrosis of the femoral head. Both studies reported improvement in the Harris Hip Score in patients treated with MSCs, although it was not reported whether the patients or investigators were blinded to the treatment group. Hip survival was significantly improved following treatment with either expanded or concentrated MSCs. The effect appears to be larger with expanded MSCs compared to concentrated MSCs. Additional studies with a larger number of patients are needed to permit greater certainty regarding the effect of this treatment on health outcomes.
 
Ongoing Clinical Trials
A search of online site: ClinicalTrials.gov in March 2013 identified a number of trials on use of MSCs for orthopedic indications from both within and outside the U.S. The following is a sample of some of the larger studies:
    • A Phase I/II randomized, placebo controlled, double blind study of 2 doses of Chondrogen™ (Osiris Therapeutics) or a placebo intra-articular injection following meniscectomy in 60 patients is listed as completed in 2008 (NCT00225095). Chondrogen™ is a preparation of adult MSCs in a solution containing hyaluronic acid. Three-year follow-up of Chondrogen™ versus placebo injections is listed as a separate study (NCT00702741). The status of this trial is unknown.
    • Medipost is sponsoring a randomized, open-label, multicenter Phase III clinical trial to compare the efficacy and safety of Cartistem® and microfracture in patients with knee articular cartilage injury or defect (NCT01041001). MSCs will be isolated from umbilical cord blood and cultured, mixed with semi-solid polymer, and administered in the cartilage tissue lesion by orthopedic surgery. The study is listed as completed as of April 2012 with an enrollment of 104 patients. Preliminary results of this study were presented at the annual meeting of the American Academy of Orthopaedic Surgeons in February 2012. As of March 2013, no peer-reviewed publications from this trial have been identified.
    • Medipost is sponsoring a 60-month follow-up study (NCT01626677) of the patients who participated in the Phase III trial of Cartistem® (NCT01041001). The study has an estimated enrollment of 103 patients with completion in May 2015.
    • NCT00885729 is a Phase I randomized, single-blind, active control trial of MSCs compared with chondrocytes to heal articular cartilage defects in 50 patients. The study is sponsored by an academic medical center in Norway. Both MSCs and chondrocytes will be delivered in a commercially available scaffold (not described). The estimated study completion date is 2018.
    • The National University of Malaysia is sponsoring a randomized controlled trial of intra-articular MSC injection versus hyaluronic acid in patients with osteoarthritis (NCT01459640). The study has an estimated enrollment of 50 patients with completion in 2014.
    • Three series are listed with Trinity Evolution Matrix for foot and ankle surgery, anterior cervical discectomy and fusion (ACDF), and posterior or transforaminal lumbar interbody fusion (PLIF or TLIF). All 3 studies are listed as ongoing but not recruiting subjects.
 
2014 Update
A search of the MEDLINE database conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
In December 2013 (after the systematic review by Filardo et al was published), Wong et al reported an RCT of cultured MSCs in 56 patients with osteoarthritis who underwent medial opening-wedge high tibial osteotomy and microfracture of a cartilage lesion (Wong, 2013). 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 and Lysholm scores through 2 years and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system by 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), Lysholm (mean difference 7.61 on 0-100 scale, p=0.02), and Tegner (mean difference 0.64 on a 0-10 scale, p=0.02). Blinded analysis of MRI results found higher MOCART scores in the MSC group. The group treated with MSCs had a higher proportion of patients who had complete cartilage coverage of their lesions (32% vs 0%), greater than 50% cartilage cover (36% vs 14%) and complete integration of the regenerated cartilage (61% vs 14%). This study is ongoing and recruiting additional patients.
 
In 2014, Vangsness et al reported an industry-sponsored Phase I/II randomized, double-blind, multicenter study (NCT00225095, NCT00702741) of cultured allogeneic MSCs (Chondrogen™, Osiris Therapeutics) injected into the knee after partial meniscectomy (Vangsness, 2014). The 55 patients in this U.S. study were randomized to intra-articular injection of either 50 x 106 allogeneic MSCs, 150 x 106 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 and none in the high-dose MSC group. There was no significant difference between the groups in the Lysholm Knee Scale. On subgroup analysis, patients with osteoarthritis who received MSCs had a significantly greater reduction in pain at 2 years compared with patients who received HA alone. This appears to be a posthoc analysis and should be considered preliminary. No serious adverse events were thought to be related to the investigational treatment.
 
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov in March 2014 identified a number of trials on use of MSCs for orthopedic indications from both within and outside the U.S. The following is a sample of some of the larger studies:
 
    • Medipost is sponsoring a randomized, open-label, multicenter Phase III clinical trial to compare the efficacy and safety of Cartistem® and microfracture in patients with knee articular cartilage injury or defect (NCT01041001). MSCs will be isolated from umbilical cord blood and cultured, mixed with semisolid polymer, and administered in the cartilage tissue lesion by orthopedic surgery. The study is listed as completed as of April 2012 with an enrollment of 104 patients. Preliminary results of this study were presented at the annual meeting of the American Academy of Orthopaedic Surgeons in February 2012. As of March 2014, no peer-reviewed publications from this trial have been identified.
    • Medipost is sponsoring a 60-month follow-up study (NCT01626677) of the patients who participated in the Phase III trial of Cartistem® (NCT01041001). The study has an estimated enrollment of 103 patients with completion in May 2015.
    • NCT00885729 is a Phase I randomized, single-blind, active control trial of MSCs compared with chondrocytes to heal articular cartilage defects in 50 patients. The study is sponsored by an academic medical center in Norway. Both MSCs and chondrocytes will be delivered in a commercially available scaffold (not described). The estimated study completion date is 2018.
    • The National University of Malaysia is sponsoring an RCT of intra-articular MSC injection versus HA in patients with osteoarthritis (NCT01459640). The study has an estimated enrollment of 50 patients with completion in 2014. The status of this study is unknown.
    • Three large series are listed with Trinity Evolution Matrix (Orthofix) for foot and ankle surgery, anterior cervical discectomy and fusion, and posterior or transforaminal lumbar interbody fusion. All 3 studies are listed as ongoing but not recruiting subjects.
    • NCT01413061 is a randomized comparative trial of Allostem® (AlloSource) versus autologous bone marrow aspirate in subtalar arthrodesis procedures. The study has an estimated enrollment of 136 patients with completion expected in 2016.
    • Five large multicenter series are posted for Osteocel® Plus (NuVasive) covering 5 different approaches to lumbar and cervical spinal fusion (ie, transformaminal, anterior, posterior, lateral). All 5 studies are listed as completed. No publications from these trials have been identified and no results have been posted.
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Adipose-Derived MSCs
The literature on adipose-derived MSCs for articular cartilage repair comes from 2 different research groups in Korea. One of the groups 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 and colleagues reported results of an RCT that evaluated cartilage healing after high tibial osteotomy (HTO) in 52 patients with osteoarthritis of the medial compartment (Koh, 2014). Patients were randomly assigned via sealed envelopes to HTO with application of platelet-rich plasma (PRP) or HTO with application of PRP plus MSCs. (Use of PRP is considered investigational, see Policy No. 2.01.16 for further information.) 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-up. The primary outcomes were the Knee Injury and Osteoarthritis Outcome Score (KOOS, five subscales with 0-100 scale), the Lysholm score (0-100 scale), and a VAS pain scale (0-100 scale). There were statistically significant differences for PRP only versus PRP+MSC on 2/5 KOOS subscales; pain (74±5.7 vs. 81.2±6.9, p<0.001) and symptoms (75.4±8.5 vs. 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 vs. 10.2±5.7, p<0.001), but the final Lysholm score was not significantly different between the PRP only and PRP+MSC groups (80.6±13.5 vs. 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. There are a number of limitations of this study, including the small sample size the short duration of follow-up, and significant improvements on only some of the outcomes. All of the significant differences in outcomes were modest in magnitude, and as a result there is uncertainty regarding the clinical significance of the findings.
 
A 2014 retrospective review from Kim and colleagues reported clinical outcomes and MRI results from 49 patients who had undergone marrow stimulation with or without MSCs at their institution (Kim, 2014). The 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 publication above (Koh, 2014). This analysis also found modest but statistically significant improvements in clinical outcomes for the MSC group compared to microfracture alone. Blinded ratings with the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scale resulted in a score of 49.4 for the conventional group and 62.1 for the MSC group (p=0.037).
 
Another group reported a Phase I/II trial of intra-articular injection of adipose-derived MSCs for the treatment of osteoarthritis of the knee (Jo, 2014). Phase I was a dose escalation study in 9 patients and Phase II assessed efficacy of the highest dose in 9 patients. The study of 18 patients was approved by the Korean Food and Drug Administration. Procedures included liposuction, arthroscopy of the knee one week later with MSC injection through the portal, MRI at 3 and 6 months, and second-look arthroscopy with punch biopsy at 6 months. Intent-to-treat analysis showed a 39% improvement in WOMAC at 6 months after injection and a 45% improvement in VAS. 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 Synovial Tissue
Akgun and colleagues 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) (Akgun, 2015). 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 (CPM) 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 activity score 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.
 
In summary, a 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 I/II study with cultured MSCs and an RCT from a separate group in Asia that have 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 non-blinded use of a novel procedure on subjective outcome measures is also a limitation of these studies. The Phase I/II 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. FDA approval for this method has also not been obtained.
 
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 and colleagues 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 (Eastlack, 2014). At 24 months, 74% of patients (180 out of 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.
 
Ongoing and Unpublished Clinical Trials
A 2014 review on FDA regulations of adult stem cell therapies for sports medicine identified over 45 ongoing clinical trials on this topic (Chirba, 2015). Some of the currently ongoing and unpublished trials that might influence this policy are listed in below. Many are observational studies with commercially available products (Cartistem®, AlloStem®, Trinity Evolution™, and Osteocel® Plus).
 
Ongoing
  • (NCT01626677 / NCT01041001a) Randomized, Open-Label Multi-Center and Phase 3 Clinicl 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; planned enrollment 104; completion date May 2015.
  • (NCT00885729) Mesenchymal Stem Cells in a Clinical Trial to Heal Articular Cartilage Defects; planned enrollment 50; completion date 2018.
  • (NCT01413061a) Study of Subtalar Arthrodesis Using AlloStem® Versus Autologous Bone Graft; planned enrollment 140; completion date February
 
Unpublished
  • (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); planned enrollment 200; completion date June 2014.
  • (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; planned enrollment 106; completion date January 2013.
  • (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; planned enrollment 200; completion date August 2012.
  • (NCT0094853a) Osteocel® Plus in extreme Lateral Interbody Fusion (XLIF®): Evaluation of Radiographic and Patient Outcomes; planned enrollment 104; completion date October 2012.
  • (NCT00948831a) Osteocel® Plus in Anterior Lumbar Interbody Fusion (ALIF): Evaluation of Radiographic and Patient Outcomes
  
2016 Update
A literature search conducted through July 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Allogeneic Bone Marrow
In 2015, Vega and colleagues reported a small phase I/II RCT of 30 patients with osteoarthritis unresponsive to conventional treatments (Vega, 2015). 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 hyaluronic acid (HA). Follow-up using standard outcome measures was performed at 3, 6, and 12 months after injection. In the MSC-treated group, pain scores (VAS and WOMAC [Western Ontario and McMasters Universities Arthritis Index]) 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 magnetic resonance imaging (MRI). It was not reported if the patients or assessors were blinded to treatment in this phase I/II study. Additional study in a larger number of patients in a phase III trial with blinding of patients and assessors is needed.
 
Centeno and colleagues reported a multi-center registry of patients treated with autologous stem cells, bone marrow concentrate, and platelet-rich plasma (Centeno, 2015).  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 DASH (disabilities of the arm, shoulder, and hand score) and numeric pain scores (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 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.
 
Lu and colleagues published a systemic review on stem cell therapy for the treatment of early stage avascular necrosis of the femoral head (Lau, 2014). Avascular necrosis (AVN) of the femoral head (FH) is believed to be caused by a multitude of etiologic factors and is associated with significant morbidity in younger populations. Eventually, the disease progresses and results in FH collapse. A key focus is on early disease management aimed at joint preservation by preventing or delaying progression. The use of stem cells (SC) for the treatment of AVN of the FH has been proposed. We undertook a systematic review of the medical literature examining the use of SC for the treatment of early stage (precollapse) AVN of the FH, in both pre-clinical and clinical studies. Data collected included: Pre-clinical studies - model of AVN, variety and dosage of SC, histologic and imaging analyses. Clinical studies - study design, classification and etiology of AVN, SC dosage and treatment protocol, incidence of disease progression, patient reported outcomes, volume of necrotic lesion and hip survivorship. In pre-clinical studies, the use of SC uniformly demonstrated improvements in osteogenesis and angiogenesis, yet source of implanted SC was variable. In clinical studies, groups treated with SC showed significant improvements in patient reported outcomes; however hip survivorship was not affected. Discrepancies regarding dose of SC, AVN etiology and disease severity were present. Routine use of this treatment method will first require further research into dose and quality optimization as well as confirmed improvements in hip survivorship.
 
2017 Update
A literature search conducted through July 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Shapiro and colleagues reported on the results of a prospective, single-blind, placebo-controlled trial assessing 25 patients with bilateral knee pain from bilateral osteoarthritis (Shapiro, 2017). 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 an injection into the arthritic knee and was compared with a saline injection into the contralateral knee, thereby using each patient as his or her own control. Safety outcomes, pain relief, and function as measured by Osteoarthritis Research Society International (OARSI) measures and a visual analog scale (VAS) score were tracked initially at 1 week, 3 months, and 6 months postprocedure. 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 on effectiveness of HA in the treatment of degenerative joint disease in knee joints, reported that no conclusions can be drawn from available literature on avoidance or delay of total knee replacement with the use of HA (Newberry, 2015). Guideline updates on viscosupplementation are included in that section of this evidence review.
 
Whitehouse and colleagues published a report on techniques of in vitro expansion of autologous-derived MSCs and a case series of first-in-human implantation to treat meniscal defects in 5 patients (Whitehouse, 2017). 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 postprocedure, 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 month had repeat arthroscopic procedures with meniscectomy.
 
A prospective, clinical, and radiographic 12-month outcomes study 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 comparison to historical controls (Vanichkachorn, 2016).
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 endpoints included function as assessed by Neck Disability Index 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 postprocedure. 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 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 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 (Peppers, 2017). 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 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 Neck Disability Index 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 the surgeons preferred technique (Jones, 2015). A total of 103 subjects were prospectively enrolled at 10 participating sites. No restrictions were placed on the diagnosis, which included arthritis (primary osteoarthritis, posttraumatic osteoarthritis, and rheumatoid), deformity, neuropathy (Charcot and diabetic), revision surgery, and degenerative joint disease, 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 computed tomography scans and standard radiographs by an independent radiology consultant. At 6 months fusion rate was 68.5% in 81.1% of joints. American Orthopaedic Foot and Ankle Society Hindfoot Scale scores for disability improved over time.
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in July 2017 did not identify any ongoing or unpublished trials that would likely influence this review.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
MSCs Expanded From Bone Marrow
 
Autologous Bone Marrow for Treatment of Osteoarthritis
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 (ie, studies using chondrogenic cellular therapy as control were not included) (Borakati, 2017). 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.
 
Adipose-Derived MSCs
In 2014, another group reported a phase 1/2 trial of intra-articular injection of adipose-derived MSCs for the treatment of osteoarthritis of the knee (Jo, 2014). 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 Western Ontario and McMaster Universities Arthritis Index score and a 45% improvement in VAS score at 6 months postinjection. 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 Western Ontario and McMaster Universities Osteoarthritis Index, 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 (Jo, 2017). In the high-dose group, the Western Ontario and McMaster Universities Osteoarthritis Index 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 (eg, 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.

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