Medical Policy: 08.01.22 

Original Effective Date: June 2014 

Reviewed: February 2021 

Revised: February 2021 

 

Notice:

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

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

This policy addresses stem cell therapy for orthopaedic applications, in particular mesenchymal stem cells (MSCs). MSCs have been proposed as a type of regenerative therapy. Regenerative therapy is considered an emerging field of medicine focusing on repair, replacement, or regeneration of cells and tissues. MSCs are found in a variety of tissues and have the ability to rapidly proliferate and differentiate to musculoskeletal tissue, including bone and cartilage.

 

Stem cell transplantation using hematopoietic stem cells for treatment of blood cancer, non-cancer conditions and solid tumors are not in scope of this policy. Refer to medical policy 07.03.11 Hematopoietic Stem Cell Transplantation (Bone Marrow Transplant) Autologous and Allogeneic*. 

 

Mesenchymal stem cells (MSCs)

Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells that can differentiate into a variety of cell types. MSCs have immunomodulatory properties and secrete cytokines. MSCs can be derived from a variety of sources, including adipose tissue (adipose tissue-derived mesenchymal stem cells (AD-MSCs), bone marrow (bone marrow derived mesenchymal stem cells (BM-MSCs), peripheral blood and synovial tissue/Synovium-derived mesenchymal stem cells (S-MSCs), however, bone marrow is currently the primary source of mesenchymal stem cell procurement. MSC therapy has been proposed as a treatment option for orthopedic indications that include but are not limited to the following:

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

 

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

 

Optimal materials or grafts that promote bone growth and healing require the following properties:

  • Osteogenic:  contains osteoprogenitor cells that can lay down a new bone matrix
  • Osteoinductive:  provides signals required to induce differentiation of MSCs into mature osteoblasts
  • Osteoconductive:  passive scaffolding to promote vascular invasion and bone apposition on the surface for new bone formulation

 

The proposed benefits of MSC therapy are improved healing and possible avoidance of surgical procedures with protracted recovery times. MSCs are used as a stand-alone therapy in the form of an injection or in combination with scaffolds

 

Cartistem

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

 

Lipogem

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

 

Regenexx Stem Cell Procedure

Regenexx “regenerative” procedures e.g. RegenexxSD (Same Day Stem Cell Procedure), RegenexxAD (Adipose Derived Stem Cell Procedure) have been recommended for treatment of musculoskeletal trauma, overuse injuries, and degenerative issues. During Regenexx procedures, cells of various derivatives, often from bone, are injected to locally diseased joint areas with the expectation that they will seek out and repair diseased cartilage bone, ligaments and tendons. According to the manufacturer, the Regenexx- Same Day (SD)/Regenexx-SD Plus procedure involves the injection of a highly concentrated stem cell mixture combined with autologous platelet-derived growth factors, referred to as SCP (Super Concentrated Platelets). It has been proposed for a variety of orthopaedic applications including but not limited to repair or regeneration of musculoskeletal tissue, spinal fusion, and bone repair. 

 

Common Conditions Treated:

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

 

In addition, Regenexx describes a licensed culture-expansion site, Regenexx Cayman that provides Regenexx-C (cultured stem cell treatment) and Regenexx Cryopreservation (stem cell storage). The manufacturer asserts these techniques are reported to yield up to 1,000 times more stem cells. Regenexx-C is stated to be ideal for patients with more severe orthopaedic injuries or conditions, patients who want to treat multiple joints, or patients who want to store their stem cells for future treatment.

 

Osteoarthritis (OA) is a degenerative joint disease characterized by loss of cartilage, osteophyte formation, and periarticular bone change, resulting in disability. Mesenchymal stem cells (MSCs) are emerging as an attractive option for osteoarthritis (OA) of the knee joint, due to their marked disease-modifying ability and chondrogenic potential.

 

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

 

Summary

MSCs are the hottest topic in recent stem cell research. The application of stem cells in cartilage regeneration has been tried a lot, but so far, the effect of cartilage regeneration is not consistent from one study to another. Moreover, the most appropriate cell source is still controversial. Further research is needed to determine which tissue-derived stem cells, which usage and dose will be ideal. 

 

The use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. Despite continued research into the methods of harvesting and delivering treatment, there are uncertainties regarding the optimal source of cells and the delivery method and safety. The quality of evidence is low and there is a possibility of publication bias. Overall, there is a lack of evidence that clinical outcomes are improved with Regenexx procedures. Additional studies in a larger sample of patients with longer follow-up would be needed to evaluate the long-term efficacy and safety to include avoidance of surgical procedures. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Clinical Issues for Application of Mesenchymal Stem Cells

  • There is no consensus on the optimal dose or cell number to achieve the utmost effect of stem cells. The optimal dose of MSC implantation for cartilage regeneration has not yet been established.
  • Treatment strategies for clinical application may also be one of the issues faced by clinicians. Injective treatment is relatively efficient because it is easy to apply and does not require hospitalization, but precise delivery to target site may be difficult.
  • Potential risks of MSCs in clinical use, such as tumorigenesis, immune response, and heterotrophic calcification are also considerable issues. Therefore, it should be recognized that such risk of MSC-mediated abnormal reactions might occur in some cases and mandating a careful assessment of the patient's condition. Further research is also needed to guarantee the safety of MSCs.

 

Summary of Evidence

A treatment option for orthopedic indications including but not limited to the following:

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

 

using mesenchymal stem cell therapy (derived from a variety of sources, including adipose tissue [adipose tissue-derived mesenchymal stem cells (AD-MSCs)] bone marrow [bone marrow derived mesenchymal stem cells (BM-MSCs)], peripheral blood and synovial tissue/synovium-derived mesenchymal stem cells [S-MSC]), the evidence includes small randomized controlled trials (RCTs) and nonrandomized comparative trials. Use of 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 and safety. Studies have included MSCs from bone marrow, adipose tissue, peripheral blood. Overall, the quality of evidence is low and there is a possibility of publication bias. The strongest evidence to date is on MSCs expanded from bone marrow, which includes several phase 1/2 RCTs. Limitations in these initial trials preclude reaching conclusions, but the results to date do support future study in phase 3 trials. Alternative methods of obtaining MSCs have been reported in a smaller number of trials and with mixed results. Additional studies in a larger sample of patients with longer follow-up would be needed to evaluate the long-term efficacy and safety to include avoidance of surgical procedures. Also, expanded MSCs for orthopedic applications are not U.S. Food and Drug Administration‒approved (concentrated autologous MSCs do not require agency approval). Overall, there is a lack of evidence that clinical outcomes are improved. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Joint Fusion Procedures

Clinical Context and Therapy Purpose

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

 

Patients

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

 

Interventions

The therapy being considered is stem cell therapy.

 

Comparators

Comparators of interest include iliac crest bone graft.

 

Outcomes

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

 

Demineralized bone matrix (DBM) is a type of allograft. It is produced through a process that involves the decalcification of cortical bone; substantially decreasing the structural strength. However, it is more osteoinductive than ordinary allograft. Although the reason for this is not completely understood, it has been speculated that the osteoinductive growth factors contained in the extracellular bone matrix are easily accessed once the mineral phase of the bone has been removed.

 

Cell Based: Bone graft substitutes that are cell-based use cells to generate new tissue either alone or seeded onto a support matrix (e.g. in combination with allograft material). Support matrix may include xenograft (i.e. bovine) or human type I collagen. Cell based substitutes that are available include mesenchymal and other cell-based products.

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

 

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

 

In 2014, Eastlack et. al. reported on outcomes from a prospective multicenter study of 182 patients treated with anterior cervical discectomy and fusion using Osteocel Plus in a polyetheretherketone cage and anterior plating at 1 or 2 consecutive levels. Clinical outcomes included visual analogue scale for neck and arm pain, neck disability index, and SF-12 physical and mental component scores. Computed tomography and plain film radiographic measures included assessment of bridging bone, disc height, disc angle, and segmental range of motion. At 24 months, 74% of patients (180/249 levels treated) were available for follow-up. These patients had significant improvements in clinical outcomes, with 87% of levels achieved solid bridging, and 92% of levels had a range of motion less than 3 degrees. With 26% loss to follow up at 24 months and lack of standard care control group, interpretation of these results is limited.

 

In 2015, Jones et. al. reported on a prospective, multicenter, open-label clinical trial using allogeneic bone matrix containing viable osteogenic cells (Trinity Evolution) in foot and/or ankle arthrodesis. A total of 103 subjects were prospectively enrolled at 10 participating sites. No restrictions were placed on the diagnosis, which included arthritis (primary osteoarthritis, post-traumatic osteoarthritis, and rheumatoid), deformity, neuropathy (Charcot and diabetic), revision surgery and degenerative joint disease, and arthrodesis was performed on 171 joints. The per protocol population consisted of 92 patients at 6 months and 76 patients at 12 months, with 153 and 129 total arthrodeses, respectively. At 6 weeks and at 3, 6, and 12 months, imaging was performed and the subject's pain, function, and quality of life (QOL) status (Visual Analog Scale, American Orthopaedic Foot & Ankle Society Hindfoot Scale, and the Short Form 36) were recorded. At 6 months, fusion rates were 68.5% for all patients and 81.1% for all joints; at 12 months, rates were 71.1% and 86.8%, respectively. Certain high-risk subjects (eg, with diabetes or obesity) had fusion rates comparable to those of normal patients. Statistically significant improvements in pain, function, and QOL were observed, and fusion correlated with both function and QOL outcomes at 6 and 12 months. There were no adverse events attributable to CBA. The authors concluded fusion rates using CBA were higher than or comparable to fusion rates with autograft that have been reported in the recent literature, and CBA fusion rates were not adversely affected by several high risk patient factors. CBA was a safe and effective graft material to achieve fusion in patients with compromised bone healing and may provide an effectively autograft replacement for foot and/or ankle arthrodeses.

 

A prospective, clinical, and radiographic 12-month outcomes study (2016 Vanichkachorn et.al) of patients undergoing single level anterior cervical discectomy and fusion (ACDF) for symptomatic cervical degenerative disc disease utilizing a novel viable allogeneic stem cell and cancellous bone matrix (Trinity Evolution) was reported using historical controls as the comparator. The ACDF procedure was performed using the polyetheretherketone interbody spacer and bone graft substitute (Trinity Evolution) in 31 patients at multiple clinical sites. At 6 and 12 months, radiographic fusion was evaluated as determined by independent radiographic review of angular motion (≤4°) from flexion/extension X-rays combined with presence of bridging bone across the adjacent endplates on thin cut CT scans. In addition other metrics were measured including function as assessed by the Neck Disability Index (NDI), and neck and arm pain as assessed by individual Visual Analog Scales (VAS). The fusion rate for patients using a PEEK interbody spacer in combination with TE was 78.6 % at 6 months and 93.5 % at 12 months. When considering high risk factors, 6-month fusion rates for patients that were current or former smokers, diabetic, overweight or obese/extremely obese were 70 % (7/10), 100 % (1/1), 70 % (7/10), and 82 % (9/11), respectively. At 12 months, the fusion rates were 100 % (12/12), 100 % (2/2), 100 % (11/11) and 85 % (11/13), respectively. Neck function, and neck/arm pain were found to significantly improve at both time points. Reported adverse events included carpal tunnel syndrome, minor pain, numbness, permanent and/or unresolved pain and swelling. Independent medical adjudication of the 26 adverse events occurring in 31 patients found that no adverse events were definitely or probably related to Trinity Evolution, However, 5 adverse events were found to be possibly related to Trinity Evolution with 3 events of mild severity and 2 of moderate severity.

 

In 2017, Peppers et. al. reported on a prospective, radiographic evaluation, multicenter study of allogeneic bone matrix containing stem cells (Trinity Evolution) in patients undergoing two-level anterior cervical discectomy and fusion. This study involved 40 patients that presented with symptomatic cervical degeneration at two adjacent vertebral levels and underwent instrumented anterior cervical discectomy and fusion (ACDF) using Trinity Evolution (TE) autograft substitute in a polyetherethereketone (PEEK) cage. At 12 months, radiographic fusion status was evaluated by dynamic motion plain radiographs and thin cut CT with multi-planar reconstruction by a panel that was blinded to clinical outcome. Fusion success was defined by angular motion (≤4°) and the presence of bridging bone across the adjacent vertebral endplates. Clinical pain and function assessments included the Neck Disability Index (NDI), neck and arm pain as evaluated by visual analog scales (VAS), and SF-36 at both 6 and 12 months. At both 6 and 12 months, all clinical outcome scores (SF-36, NDI, and VAS pain) improved significantly (p < 0.05) compared to baseline values. There were no adverse events or infections that were attributed to the graft material, no subjects that required revisions, and no significant decreases to mean neurological evaluations at any time as compared to baseline. At 12 months, the per subject and per level fusion rate was 89.4 and 93.4%, respectively. Subgroup analysis of subjects with risk factors for pseudoarthrosis (current or former smokers, diabetic, or obese/extremely obese) compared to those without risk factors demonstrated no significant differences in fusion rates. Limitations to this study include a lack of a control group and thus TE treatment was not directly compared to autograft or non-cellular autograft treatments. Additionally, since the surgeons were not restricted with their use of operative approaches or fixation, either or both may have impacted outcomes. The impact of these factors on the outcome was not evaluated. Lastly there was no sample size estimation in the protocol because there were no formal statistical hypotheses. The authors concluded, subjects who received Trinity Evolution in combination with PEEK interbody device during a two-level ACDF procedure had a high rate of fusion success both overall and when stratified into high risk groups, while having no serious adverse events related to the graft material.

 

Summary of Evidence

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

 

Practice Guidelines and Position Statements

The International Society of Stem Cell Research (ISSCR)

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

 

American Academy of Orthopaedic Surgeons (AAOS)

In 2020, the American Academy of Orthopaedic Surgeons (AAOS) updated their position statement on the use of emerging biologic therapies. This updated position statement applies to the use of stem cell and other biologic treatments for musculoskeletal joint conditions. The position statement states the following:

 

The increasing use of biologics to try to improve outcomes for orthopaedic patients presents new questions of safety and effectiveness for those products. As noted in the statement “Innovation and New Technologies in Orthopaedic Surgery,” surgeons must be aware of the scientific basis for the different treatment options available to their patients, including the benefits and risks. Biologic therapies vary widely with regard to the requirements for evidence of safety and effectiveness needed for clearance by regulatory bodies, including the FDA. Not all biologic products require extensive FDA regulation, and in some cases, the FDA has primarily focused on safety concerns and has ceded responsibility for determining the efficacy of these products to the clinician.

 

AAOS believes that surgeons should be cognizant of the risks, benefits, regulatory status, and labeled indications of the products they use.

 

For all products, but particularly those for which the FDA does not critically evaluate effectiveness data, clinicians bear a greater responsibility to independently weigh that evidence. This responsibility also extends to off-label use of FDA-regulated products and cases where the devices used to create or deliver the biologic product, rather than the product itself, are what has been approved by the FDA. It also applies to cases where a manufacturer believes they are exempt from certain FDA regulations without formal review of exemption, such as the so-called 361 exemption for human cell and tissue products. In all of these examples, the clinicians using these biologic products need to be particularly careful to weigh the available evidence and conduct shared decision making with the patient in the informed consent process.

 

The AAOS Standards of Professionalism state, “An orthopaedic surgeon, or his or her qualified designee, shall present pertinent medical facts and recommendations to, and obtain informed consent from, the patient or the person responsible for the patient.” The mandatory standard obligates surgeons to disclose any products that may be used during the episode of care and engage in frank discussion regarding the risks and benefits of biologics when they are part of that episode of care.

 

For any product, but in particular for biologic products where information on efficacy may be limited, orthopaedic surgeons and their organizations/facilities should support and participate in orthopaedic randomized, controlled trials; registries; and other data collection systems. Through voluntary reporting of key patient and orthopaedic treatment information to local, state, and national repositories, patient outcomes will be improved. Documentation and reporting are critical to establishing the body of evidence needed to demonstrate the safety and effectiveness of emerging biologics.

 

AAOS champions the interests of patients by improving treatment options through education and research and by fostering a culture of safety and evidence-based treatment.

 

American Association of Neurological Surgeons

In 2014, the American Association of Neurological Surgeons (AANS) issued a guideline on fusion procedures for degenerative disease of the lumbar spine that states “The use of demineralized bone matrix (DBM) as a bone graft extender is an option for 1 and 2 level instrumented posterolateral fusions. Demineralized Bone Matrix: Grade C (poor level of evidence).”

 

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, title 21, parts 1270 and 1271.

 

Concentrated autologous mesenchymal stem cells (MSCs) do not require approval by the U.S. Food and Drug Administration (FDA). No products using engineered or expanded MSCs have been approved by the FDA for orthopedic applications

 

The following products are examples of commercialized demineralized bone matrix (DBM). They are marketed as containing viable stem cells (MSCs). In some instances, manufacturers have received communications and inquiries from the FDA related to the appropriateness of their marketing products that are dependent on living cells for their function.

  • Allostem (AlloSource): partially demineralized allograft bone seeded with adipose-derived MSCs
  • Map3 (rti surgical) contains cortical cancellous bone chips, DBM, and multipotent adult progenitor cells
  • Osteocel Plus (NuVasive): DBM combined with viable MSCs that have been isolated from allogeneic bone marrow
  • Trinity Evolution Matrix (Orthofix) DBM combined with viable MSCs that have been isolated from allogeneic bone marrow
  • Vitoss Bioactive Foam Bone Graft Substitute (Stryker): Type I bovine collagen mixed with autologous mesenchymal stem cells (MSCs)
  • Copios Bone void filler (sponge and powder disc) (Kensey Nash): Type I bovine dermal collagen mixed with autologous mesenchymal stem cells (MSCs)
  • DBX demineralized bone matrix putty, paste and mix (Musculoskeletal Transplant Foundation): processed human bone and sodium hyaluronate mixed with autologous mesenchymal stem cells (MSCs)

 

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

 

In 2020, the FDA updated their guidance on "Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use."2,

 

Human cells, tissues, and cellular and tissue-based products (HCT/P) are defined as human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. If an HCT/P does not meet the criteria below and does not qualify for any of the stated exceptions, the HCT/P will be regulated as a drug, device, and/or biological product and applicable regulations and premarket review will be required.

 

An HCT/P is regulated solely under section 361 of the PHS Act and 21 CFR Part 1271 if it meets all of the following criteria:

"1) The HCT/P is minimally manipulated;
2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;
3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and
4) Either:
i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or
ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and: a) Is for autologous use; b) Is for allogeneic use in a first-degree or second-degree blood relative; or c) Is for reproductive use."

 

The FDA does not consider the use of stem cells for orthopedic procedures to be homologous use.

 

Prior Approval:

Prior approval is recommended.

 

Policy:

See Related Medical Policies:

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

 

Mesenchymal Stem Cell (MSC) Therapy

Mesenchymal stem cell (MSC) therapy from bone marrow (bone marrow derived mesenchymal stem cells [BM-MSCs]), adipose tissue (adipose tissue-derived mesenchymal stem cells [AD-MSCs]), peripheral blood or synovial tissue/synovium-derived mesenchymal stem cells (S-MSC) alone or in combination with platelet-derived products (e.g. platelet-rich plasma, lysate) as treatment for orthopaedic and/or musculoskelatal conditions is considered investigational for all indications including but not limited to the following:

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

 

The use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. Despite continued research into the methods of harvesting and delivering treatment, there are uncertainties regarding the optimal source of cells and the delivery method and safety. Studies have included mesenchymal stem cells (MSCs) from bone marrow, adipose tissue, peripheral blood. Overall, the quality of evidence is low and there is a possibility of publication bias. Additional studies in a larger sample of patients with longer follow-up would be needed to evaluate the long-term efficacy and safety to include avoidance of surgical procedures. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Regenexx 

Mesenchymal stem cell (MSC) therapy alone or in combination with platelet-derived products (e.g. platelet-rich plasma, lysate) as treatment of orthopaedic and/or musculoskeletal conditions, including but not limited the following:

  • Regenexx
  • Regenexx Stem Cell Same Day Procedure (RegenexxSD)
  • Regenexx Super Concentrated Platelet Rich Plasma (Regenexx-SD Plus)
  • Regenexx Adipose Derived Stem Cell Procedure (RegenexxAD);  

 

is considered investigational for all indications including but not limited to the following:  

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

 

The use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. Despite continued research into the methods of harvesting and delivering treatment, there are uncertainties regarding the optimal source of cells and the delivery method and safety. The quality of evidence is low and there is a possibility of publication bias. Overall, there is a lack of evidence that clinical outcomes are improved with Regenexx procedures. Additional studies in a larger sample of patients with longer follow-up would be needed to evaluate the long-term efficacy and safety to include avoidance of surgical procedures. The evidence is insufficient to determine the effects of the technology on health outcomes.
xAD);  

 

Alloraft Bone Products with Viable Stem Cells

Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DMB) with stem cells used alone, added to their biomaterials for grafting or seeded onto scaffolds is considered investigational for all orthopedic applications. There is insufficient evidence to support a conclusion concerning the net health outcomes or benefits associated with this procedure.

 

Demineralized bone matrix (DBM) with viable stem cells (mesenchymal stem cells) including but not limited to the following:

  • Allostem (Allosource)
  • Map3 (RTI Surgical)
  • Osteocel Plus (NuVasive)
  • Trinity Evolution Matrix (Orthofix)
  • Vitoss Bioactive Foam Bone Graft Substitute (Stryker)
  • CopiOs Bone voice filler (sponge and powder disc) (Kensey Nash)
  • DBX demineralized bone matrix putty, paste and mix (Musculoskeletal Transplant Foundation)

 

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

 

Procedure Codes and Billing Guidelines:

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

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

 

Selected References:

  • U.S. Food and Drug Administration. Ensuring Safety and Efficacy of Stem Cell Based Products Accessed May 14, 2014
  • U.S. Food and Drug Administration. Untitled Letters (Biologics), Regenerative Sciences, Inc. Guidance, Compliance and Regulatory Information (Biologics) 2008 Available online at: Accessed May 14, 2014
  • American Academy of Orthopaedic Surgeons (AAOS) OrthoInfo, Your connection to expert orthopaedic information, Stem Cells and Orthopaedics. Accessed May 2, 2014
  • American Academy of Orthopaedic Surgeons (AAOS) OrthoInfo, Your connection to expert orthopaedic information, Frequently Asked Questions about Stem Cells. Accessed May 2, 2014
  • International Congress for Joint Reconstruction (ICJR). Reports, Looking Toward the Future of Stem Cells in Orthopaedics Accessed May 15, 2014
  • International Society for Cellular Therapy (ISCT), Position Paper, Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy Position Statement. Cryotherapy (2006)Vol. 8, No.4, 315-317.
  • Sally Roberts, et al. Prospects of Stem Cell Therapy in Osteoarthritis. Regen.Med (2011) 6(3), 351-366.
  • Shaul Beyth, Josh Schroeder and Meir Liebergall, Stem Cells in Bone Diseases: Current Clinical Practice. British Medical Bulletin 2011; 99:199-210
  • Christopher J. Centeno and Stephen J. Faulkner, Chapter 21, The Use of Mesenchymal Stem Cells in Orthopedics. M.A. Hayat (ed), Stem Cells and Cancer Stem Cells, Volume 1, DOI 10.1007/978-94-007-1709-1-21.
  • Medscape. Technology Insight: Adult Mesenchymal Stem Cells for Osteoarthritis Therapy.
  • ECRI Institute. Nanotechnology May Help Speed Bone Healing. Published 2/6/2009.
  • ECRI Institute. Health Technology Forecast. Autologous and Allogeneic Mesenchymal Stem Cell Therapy for Treating Osteoarthritis. November 2012.
  • ECRI Institute. Emerging Technology Evidence Report. Autologous Mesenchymal Stem Cells for Treating Knee Osteoarthritis. June 2013.
  • ECRI Institute Product Brief. AlloStem Stem Cell Bone Growth Substitute (AlloSource) for Orthopedic procedures. August 2013.
  • Dominici M, Le Blanc K, Mueller I, et. al. Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy Position Statement. Cytotherapy 2006;8(4):315-7
  • Rush SM, Hamilton GA, Ackerson LM, Mesenchymal Stem Cell Allograft in Revision Foot and Ankle Surgery: A clinical and Radiographic Analysis. J Foot Ankle Surg 2009; 48(2):163-9
  • Centeno CJ, Schultz JR, Cheever M, et. al. Safety and Compliations Reporting on Re-Implantation of Culture Expanded Mesenchymal Stem Cells Using Autologous Platelet Lysate Technique, Curr Stem Cell Rews Ther, 2011, 6, 368-378
  • Andre F. Steinert, Lars Rackwitz, et. al. Concise Review: The Clinical Application of Mesenchymal Stem Cells for Musculoskeletal Regeneration: Current States and Perspectives, Stem Cells Translational Medicine 2012;1:237-247.
  • Rick L Lau, Anthony V. Perruccio, et. al. Stem Cell Therapy for the Treatment of Early Stage Avascular Necrosis of the Femoral Head: A Systematic Review, BMC Musculoskeletal Disorders 2014, 15:156.
  • Jonathan I. Dawson, Janos Kanczler, et. al. Concise Review: Bridging the Gap: Bone Regeneration Using Skeletal Stem Cell-Based Strategies-Where Are We Now?, Stem Cells Volume 32, Issue 1 January 2014
  • Filardo G, Madry H, et. al. Mesenchymal Stem Cells for the Treatment of Cartilage Lesions: From Preclinical Findings to Clinical Application in Orthopaedics. Knee Surg Sports Traumatol Arthrosc 2013 aug;21(8):1717-29
  • Wong KL, Lee KB, Tai BC et. al. Injectable Cultured Bone Marrow-Derived Mesenchymal Stem Cells in Varus Knees with Cartilage Defects Undergoing High Tibial Osteotomy: A Prospective, Randomized Controlled Clinical Trial with 2 Years Follow Up. Arthroscopy 2013; 29(12):2020-8
  • Hana Yu, Adetola B Adesida and Nadr M Jomha, Meniscus Repair Using Mesenchymal Stem Cells – A Comprehensive Review. Stem Cell Research & Therapy 2015 6:86
  • Orthofix Trinity Evolution Matrix Allograft with Viable Cells.
  • Allosource  Allostem Cellular Bone Allograft.
  • RTIX Map3 Cellular Allogeneic Bone Graft.
  • Nuvasive Osteocel Plus Bone Grafting.
  • Centeno Christopher, Pitts John, et. al. Efficacy and Safety of Bone Marrow Concentrate for Osteoarthritis of the Hip: Treatment Registry Results of 196 Patients, Journal Stem Cell Research and Therapy 2014, Volume 4 Issue 10
  • Centeno Christopher, Pitts John, et. al. Efficacy of Autologous Bone Marrow Concentrate for Knee Osteoarthritis with and without Adipose Graft, BioMed Research International September 2014
  • Veronesi F, Giavaresi G, et. al. Clinical Use of Bone Marrow, Bone Marrow Concentrate, and Expanded Bone Marrow Mesenchymal Stem Cells in Cartilage Disease, Stem Cells Dev. 2013 Jan 15;22(2):181-92
  • Hernigou P, Flouzat Lachaniette CH, et. al. Biologic Augmentation of Rotator Cuff Repair with Mesenchymal Stem Cells During Arthroscopy Improves Healing and Prevents Further Tears: A Case-Controlled Study, Int Orthop 2014 Sep;38(9):1811-8
  • Centeno CJ, Busse D, et. al. Regeneration of Meniscus Cartilage in a Knee Treated with Percutaneously Implanted Autologous Mesenchymal Stem Cells, Med Hyptheses 2008 Dec; 71(6):900-8
  • PubMed: Bashir J, Sherman A., et. al. Mesenchymal Stem Cell Therapies in the Treatment of Musculoskeletal Diseases, Physical Medicine and Rehabilitation 2014 Jan;6(1):61-9
  • Houdek Matthew, Wyle Cody, et. al. Stem Cell Treatment for Avascular Necrosis of the Femoral Head: Current Perspectives, Stem Cells and Cloning: Advances and Applications 2014:7 65-70
  • Carpenter RS, Goodrich LR, Frisbie DD, Kisiday JD, Carbone B, Mcllwraith, CJ Centeno, and C Hidaka, Osteoblastic Differentiation of Human and Equine Adult Bone Marrow-Derived Mesenchymal Stem Cells when BMP-2 or BMP-7 Homodimer Genetic Modification is Compared to BMP-2/7 Heterodimer Genetic Modification in the Presence and Absence of Dexamethasone, J Orthop Res. 2010 October; 28(10): 1130-1337
  • Peters C.M.M., Leijs M.J.C., et. al. Safety of Intra-Articular Cell-Therapy with Culture Expanded Stem Cells in Humans: A Systemic Literature Review, Osteoarthritis Research Society International June 2013,
  • Centeno CJ, Freeman MD, Percutaneous Injection of Autologous, Culture Expanded Mesenchymal Stem Cells into Carpometacarpal Hand Joints: A Case Series with an Untreated Comparison Group, Wien Med Wochenschr 2014 Mar;164(5-6):83-7
  • Centeno Christopher, Schultz John, et. al. A Case Series of Percutaneous Treatment of Non-Union Fractures with Autologous, Culture Expanded, Bone Marrow Derived, Mesenchymal Stem Cells and Platelet Lysate, Bioengineering and Biomedical Science
  • Chirba MA, Sweetapple B, Hannon CP, et al. FDA regulation of adult stem cell therapies as used in sports medicine. J Knee Surg. Feb 2015;28(1):55-62. PMID 25603042
  • Filardo G, Madry H, Jelic M, et al. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. Aug 2013;21(8):1717-1729. PMID 23306713
  • Wong KL, Lee KB, Tai BC, et al. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up. Arthroscopy. Dec 2013;29(12):2020-2028. PMID 24286801
  • Wakitani S, Imoto K, Yamamoto T, et al. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage. Mar 2002;10(3):199-206. PMID 11869080
  • Wakitani S, Nawata M, Tensho K, et al. Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees. J Tissue Eng Regen Med. Jan-Feb 2007;1(1):74-79. PMID 18038395
  • Wakitani S, Okabe T, Horibe S, et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. Feb 2011;5(2):146-150. PMID 20603892
  • 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):1110-1116. PMID 20392971
  • Vega A, Martin-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. Aug 2015;99(8):1681-1690. PMID 25822648
  • Giannini S, Buda R, Vannini F, et al. One-step bone marrow-derived cell transplantation in talar osteochondral lesions. Clin Orthop Relat Res. Dec 2009;467(12):3307-3320. PMID 19449082
  • Giannini S, Buda R, Cavallo M, et al. Cartilage repair evolution in post-traumatic osteochondral lesions of the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation. Injury. Nov 2010;41(11):1196-1203. PMID 20934692
  • Centeno CJ, Al-Sayegh H, Bashir J, et al. A prospective multi-site registry study of a specific protocol of autologous bone marrow concentrate for the treatment of shoulder rotator cuff tears and osteoarthritis. J Pain Res. 2015;8:269-276. PMID 26089699
  • Koh YG, Kwon OR, Kim YS, et al. Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study. Arthroscopy. Nov 2014;30(11):1453-1460. PMID 25108907
  • Kim YS, Park EH, Kim YC, et al. Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus. Am J Sports Med. May 2013;41(5):1090-1099. PMID 23460335
  • Kim YS, Lee HJ, Choi YJ, et al. Does an injection of a stromal vascular fraction containing adipose-derived mesenchymal stem cells influence the outcomes of marrow stimulation in osteochondral lesions of the talus? A clinical and magnetic resonance imaging study. Am J Sports Med. Oct 2014;42(10):2424-2434. PMID 25106781
  • Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. Dec 2012;19(6):902-907. PMID 22583627
  • Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. May 2014;32(5):1254-1266. PMID 24449146
  • Saw KY, Anz A, Siew-Yoke Jee C, et al. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial. Arthroscopy. Apr 2013;29(4):684-694. PMID 23380230
  • Akgun I, Unlu MC, Erdal OA, et al. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Arch Orthop Trauma Surg. Feb 2015;135(2):251-263. PMID 25548122
  • Vangsness CT, Jr., Farr J, 2nd, Boyd J, et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. Jan 15 2014;96(2):90-98. PMID 24430407
  • Eastlack RK, Garfin SR, Brown CR, et al. Osteocel plus cellular allograft in anterior cervical discectomy and fusion: evaluation of clinical and radiographic outcomes from a prospective multicenter study. Spine (Phila Pa 1976). Oct 15 2014;39(22):E1331-1337. PMID 25188591
  • Zhao D, Cui D, Wang B, et al. Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone. Jan 2012;50(1):325-330. PMID 22094904
  • Sen RK, Tripathy SK, Aggarwal S, et al. Early results of core decompression and autologous bone marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J Arthroplasty. May 2012;27(5):679-686. PMID 22000577
  • Centeno C, Al-Sayegh H, Freeman M, et. al. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. International Orthopaedics (SICOT) 2016 40:1755-1765
  • Centeno CJ, Schultz JR, Cheever M, et. al. Safety and complications reporting on the reimplantation of culture expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther Dec 2, 2010;5(1):81-93. PMID 19951252 
  • Goldberg A, Mitchell K, Soans J, et al. The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. Mar 09 2017;12(1):39. PMID 28279182
  • Shapiro SA, Kazmerchak SE, Heckman MG, et al. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. Jan 2017;45(1):82-90. PMID 27566242
  • Borakati A, Mafi R, Mafi P, et al. A systematic review and meta-analysis of clinical trials of mesenchymal stem cell therapy for cartilage repair. Curr Stem Cell Res Ther. Sep 15 2017. PMID 28914207
  • Jo CH, Chai JW, Jeong EC, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study. Am J Sports Med. Oct 2017;45(12):2774-2783. PMID 28746812
  • Whitehouse MR, Howells NR, Parry MC, et al. Repair of torn avascular meniscal cartilage using undifferentiated autologous mesenchymal stem cells: from in vitro optimization to a first-in-human study. Stem Cells Transl Med. Apr 2017;6(4):1237-1248. PMID 28186682
  • Vanichkachorn J, Peppers T, Bullard D, et al. A prospective clinical and radiographic 12-month outcome study of patients undergoing single-level anterior cervical discectomy and fusion for symptomatic cervical degenerative disc disease utilizing a novel viable allogeneic, cancellous, bone matrix (trinity evolution) with a comparison to historical controls. Eur Spine J. Jul 2016;25(7):2233-2238. PMID 26849141
  • Peppers TA, Bullard DE, Vanichkachorn JS, et al. Prospective clinical and radiographic evaluation of an allogeneic bone matrix containing stem cells (Trinity Evolution(R) Viable Cellular Bone Matrix) in patients undergoing two-level anterior cervical discectomy and fusion. J Orthop Surg Res. Apr 26 2017;12(1):67. PMID 28446192
  • Jones CP, Loveland J, Atkinson BL, et al. Prospective, multicenter evaluation of allogeneic bone matrix containing viable osteogenic cells in foot and/or ankle arthrodesis. Foot Ankle Int. Oct 2015;36(10):1129-1137. PMID 25976919
  • Kaiser MG, Groff MW, Watters WC, et. al. Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 16: bone graft extenders and substitutes as an adjunct for lumbar fusion. J Neurosurg Spine Jul 2014;2191):106-132. PMID 24980593
  • Lee KB, Wang VT, Chan YH, et. al. A novel, minimally-invasive technique of cartilage repair in the human knee using arthroscopic microfracture and injections of mesenchymal stem cells and hyaluronic acid-a prospective comparative study on safety and short-term efficacy. Ann Acad Med Singapore 2012 Nov:41(11):511-7. PMID 23235728
  • Liebergall M, Schroeder J, Mosheiff R, et. al. Stem call based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol Ther 2013 Aug;21(8):1631-8.    
  • Piccirilli M, Delfinis CP, Santoro A, et. al. Mesenchymal stem cells in lumbar spine surgery: a single institution experience about red bone marrow and fat tissue derived MSCs. J Neurosurg Sci 2017 Apr;61(2):124-133. PMID 26082381
  • Shao J, Zhang W, Yang T. Using mesenchymal stem cells as therapy for bone regeneration and repairing. Biol Res 2015;48:62. PMID 26530042
  • Vigano M, Sansone V, et. al. Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders. Journal of Orthopaedic Surgery and Research 2016 11:163
  • American Academy of Orthopaedic Surgeons (AAOS) Position statement on the use of emerging biologic therapies. 2017.
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines: Anterior Cruciate Ligament Injuries. 
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines: Glenohumeral Joint Arthritis.
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines: Osteoarthritis of the Hip. 
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines: Osteoarthritis of the knee (Non-Arthroplasty). 
  • American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines Rotator Cuff Problems.    
  • Akpancar S, Tatar O, Turgut H, et. al. The current perspectives of stem cell therapy in orthopedic surgery. Arch Trauma Res 2016 December 5(4):E37976
  • Giuseppe Usuelli F, D’Ambrosi R, Maccario C, et. al. Adipose-derived stem cells in orthopaedic pathologies. British Medical Bulletin 2017 124:31-54
  • UpToDate. Management of Rotator Cuff Tears. Scott David Martin M.D., Tamara L. Martin M.D.. Topic last updated March 29, 2017.  
  • Burke J, Hunter M, Kolhe R, Isales C, Hamrick M, Fulzele S. Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis. Clin Transl Med. 2016 Dec;5(1):27 
  • Centeno CJ, Al-Sayegh H, Freeman MD ,et al. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. Int Orthop. 2016 Aug;40(8):1755-1765 
  • Centeno C, Sheinkop M, Dodson D, et al. A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2 year follow-up. J Trans Med. 2018b; 16:355 
  • Chew E, Prakash R, Khan W. Mesenchymal stem cells in human meniscal regeneration: A systematic review. Ann Med Surg (Lond). 2017 Oct 5;24:3-7 
  • Delanois RE, Etcheson JI, Sodhi N, Henn RF 3rd, Gwam CU, George NE, Mont MA. Biologic Therapies for the Treatment of Knee Osteoarthritis. J Arthroplasty. 2019 Apr;34(4):801-813 
  • Di Matteo B, El Araby MM, D'Angelo A, et al. Adipose-Derived Stem Cell Treatments and Formulations. Clin Sports Med. 2019 Jan;38(1):61-78 
  • Di Matteo B, Vandenbulcke F Vitale ND, et al. Minimally Manipulated Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Systematic Review of Clinical Evidence. Stem Cells Int. 2019 Aug 14;2019:1735242 
  • Emadedin M, Labibzadeh N, Liastani MG, et al. Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Cytotherapy. 2018 Oct;20(10):1238-1246 
  • Ha CW, Park YB, Kim SH, Lee HJ. Intra-articular Mesenchymal Stem Cells in Osteoarthritis of the Knee: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair. Arthroscopy. 2019 Jan;35(1):277-288.e2 
  • Hurley ET, Yasui Y, Gianakos AL, et al. Limited evidence for adipose-derived stem cell therapy on the treatment of osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2018 Nov;26(11):3499-3507 
  • International Society for Stem Cell Research. Types of stem cells. © 2019 International Society of Stem Cell Research. Accessed October 25, 2019. 
  • Kehoe O, Cartwright A, Askari A, El Haj AJ, Middleton J. Intra-articular injection of mesenchymal stem cells leads to reduced inflammation and cartilage damage in murine antigen-induced arthritis. J Transl Med. 2014 Jun 3;12:157 
  • Khan S, Mafi P, Mafi R, Khan W. A Systematic Review of Mesenchymal Stem Cells in Spinal Cord Injury, Intervertebral Disc Repair and Spinal Fusion. Curr Stem Cell Res Ther. 2018;13(4):316-323 
  • Lee WY, Wang B. Cartilage repair by mesenchymal stem cells: Clinical trial update and perspectives. J Orthop Translat. 2017 Apr 9;9:76-88 
  • Lin KM, Wang D, Dines JS. Injection therapies for rotator cuff disease. Orthop Clin N Am 49 (2018) 231–239 
  • Marks PW, Witten CM, Califf RM. Clarifying Stem-Cell Therapy's Benefits and Risks. N Engl J Med. 2017 Mar 16;376(11):1007-1009 
  • Migliorini F, Rath B, Colarossi G, et al. Improved outcomes after mesenchymal stem cells injections for knee osteoarthritis: results at 12-months follow-up: a systematic review of the literature. Arch Orthop Trauma Surg. 2019 Aug 27 
  • Pak J. Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: a case series. J Med Case Rep. 2011 Jul 7;5:296 
  • Pak J, Lee JH, Pak N, et al. Cartilage Regeneration in Humans with Adipose Tissue-Derived Stem Cells and Adipose Stromal Vascular Fraction Cells: Updated Status. Int J Mol Sci. 2018 Jul 23;19(7) 
  • Panchal J, Malanga G, Sheinkop M. Safety and Efficacy of Percutaneous Injection of Lipogems Micro-Fractured Adipose Tissue for Osteoarthritic Knees. Am J Orthop (Belle Mead NJ). 2018 Nov;47(11) 
  • Park YB, Ha CW, Rhim JH, Lee HJ. Stem Cell Therapy for Articular Cartilage Repair: Review of the Entity of Cell Populations Used and the Result of the Clinical Application of Each Entity. Am J Sports Med. 2018 Aug;46(10):2540-2552 
  • Pas HI, Winters M, Haisma HJ, Koenis MJ, Tol JL, Moen MH. Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br J Sports Med. 2017a Aug;51(15):1125-1133 
  • Pas HIMFL, Moen MH, Haisma HJ, Winters M. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Br J Sports Med. 2017b Jul;51(13):996-1002 
  • Roffi A, Nakamura N, Sanchez M, Cucchiarini M, Filardo G. Injectable Systems for Intra-Articular Delivery of Mesenchymal Stromal Cells for Cartilage Treatment: A Systematic Review of Preclinical and Clinical Evidence. Int J Mol Sci. 2018 Oct 25;19(11) 
  • Tremolada C, Colombo V, Ventura C. Adipose Tissue and Mesenchymal Stem Cells: State of the Art and Lipogems® Technology Development. Curr Stem Cell Rep. 2016;2:304-312 
  • United States Food and drug Administration. Lipogems system. 510(k) approval (K161636). September 2016. Accessed October 11, 2019.  
  • Uth K, Trifonov D. Stem cell application for osteoarthritis in the knee joint: A minireview. World J Stem Cells. 2014 Nov 26;6(5):629-36 
  • Vadalà G, Russo F, Ambrosio L, Loppini M, Denaro V. Stem cells sources for intervertebral disc regeneration. World J Stem Cells. 2016 May 26;8(5):185-201 
  • Vannabouathong C, Del Fabbro G, Sales B, Intra-articular Injections in the Treatment of Symptoms from Ankle Arthritis: A Systematic Review. Foot Ankle Int. 2018 Oct;39(10):1141-1150
  • Wang M, Yuan Q, Xie L. Mesenchymal Stem Cell-Based Immunomodulation: Properties and Clinical Application. Stem Cells Int. 2018 Jun 14;2018:3057624 
  • Wang Y, Han ZB, Song YP, Han ZC. Safety of mesenchymal stem cells for clinical application. Stem Cells Int. 2012;2012:652034       
  • Szabo L/Kaiser Health News Employers are Steering Workers Toward Controversial Stem Cell Therapies. Time Health June 19, 2019.
  • AAOS Releases Position Statement on the Use of Emerging Biologic Therapies. December 2020 Position Statement 1187
  • Kim GB and Shon OJ. Current perspectives in stem cell therapies for osteoarthritis of the knee. Yeungnam University Journal of Medicine 2020;37(3):149-158

 

Policy History:

  • February 2021 - Annual review, Policy Revised
  • February 2020 - Annual review, Policy Revised
  • February 2019 - Annual review, Policy Renewed
  • August 2018 - Interim review, Policy Revised
  • February 2018 - Annual review, Policy Revised
  • April 2017 - Annual review, Policy Revised
  • April 2016 - Annual review, Policy Renewed
  • May 2015 - Annual review, Policy Revised
  • March 2015 - Interim review, Policy Revised
  • June 2014 - New Policy 

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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