Medical Policy: 08.01.22
Original Effective Date: June 2014
Reviewed: May 2015
Revised: May 2015
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.
Mesenchymal stem cells (MSCs) have the capability to differentiate into a variety of tissue types, including various musculoskeletal tissues. Potential uses of MSCs for orthopedic applications include treatment of damaged bone, cartilage, ligaments, tendons and intervertebral discs.
MSCs are multipotent cells (also called stromal multipotent cells) that possess the ability to differentiate into various tissues including organs, trabecular bone, tendon, articular cartilage, ligaments, muscle, and fat. MSCs are associated with the blood vessels within bone marrow, synovium, fat, and muscle, where they can be mobilized for endogenous repair as occurs with healing of bone fractures. Bone-marrow aspirate is considered to be the most accessible source and, thus, the most common place to isolate MSCs for treatment of musculoskeletal disease. However, harvesting MSCs from bone marrow requires an additional procedure that may result in donor-site morbidity. In addition, the number of MSCs in bone marrow is low, and the number and differentiation capacity of bone marrow-derived MSCs decreases with age, limiting their efficiency when isolated from older patients.
Tissues such as muscle, cartilage, tendon, ligaments, and vertebral discs show limited capacity for endogenous repair. Therefore, tissue engineering techniques are being developed to improve the efficiency of repair or regeneration of damaged musculoskeletal tissues. Tissue engineering focuses on the integration of biomaterials with MSCs and/or bioactive molecules such as growth factors. In vivo, the fate of stem cells is regulated by signals in the local 3-dimensional microenvironment from the extracellular matrix and neighboring cells. It is believed that the success of tissue engineering with MSCs will also require an appropriate 3-dimensional scaffold or matrix, culture conditions for tissue-specific induction, and implantation techniques that provide appropriate biomechanical forces and mechanical stimulation. The ability to induce cell division and differentiation without adverse effects, such as the formation of neoplasms, remains a significant concern. Given that each tissue type requires different culture conditions, induction factors (signaling proteins, cytokines, growth factors), and implantation techniques, each preparation must be individually examined.
Mesenchymal Stem Cell Procedure
Regenexx Stem Cell Procedure
Stem cells act as the repairman of the body and as people age and get injuries there are not enough of these critical repair cells getting to the injured area. The Regenexx Procedures help solve this problem by amplifying the body’s natural repair cells. This is accomplished by harvesting cells from the areas known to be rich in mesenchymal stem cells and then concentrating those cells in a lab before precisely re-injecting them into the damaged area in need of repair.
Regenexx Same Day (Regenexx - SD)/Regenexx Same Day Plus (Regenexx - SD+)
The procedure begins in the morning when the doctor performs a bone marrow aspiration by thoroughly numbing the back of the hip (PSIS) and takes a small bone marrow sample through a needle. In addition, some blood is also taken from the patient’s vein in their arm. These samples are sent to the lab which is part of the medical practice and processed.
The mesenchymal stem cells are isolated from the bone marrow sample, while some practices add platelet rich plasma (PRP) to their stem cell concentration, for this procedure a “super platelet” mix is utilized. By mixing lab prepared PRP (slow release growth factors) and platelet lysate (immediately available growth factors), adult stem cells grow many times more than with just PRP or platelet lysate alone. The goal is to deliver much greater numbers of stem cells to the injured area than the body would deliver on its own.
The patient will return in the afternoon and the cells are re-injected into the injured area using either fluoroscopy or musculoskeletal ultrasound. Re-injections can be as soon as 6 weeks and it is recommended that most patients will need 2-4 injection cycles.
Regenexx Same Day or Same Day Plus (Regenexx - SD+) 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
Regenexx C (Cultured) – Only Offered by RegenexxCayman
RegenexxCayman is an independently owned and operated medical service provider operating exclusively in the Cayman Islands and is not affiliated with any U.S. Regenexx network provider. The Regenexx-C procedure is licensed by RegenexxCayman and is not approved by the U.S. FDA for use in the United States.
Regenexx-C starts with harvesting the patient’s bone marrow stem cells. The stem cells are cultured and grow over two weeks using a proprietary platelet lysate lab technique. After the cells have been grown to between 100-1,000 times more than initially harvested, they are tested by the lab for quality assurance and then re-injected back into the precise area of injury using imaging guidance.
The results should become apparent over 1-3 months, but sometimes can take as long as 6-9 months. Also, some patients may require a second or even third procedure. Usual protocol involves 1-3 injection cycles. Most patients get a single procedure. Patients are asked to use a home infra-red unit or another type of ultrasound unit to help with cell growth.
Regenexx - C Common Conditions Treated:
- Individuals with joint arthritis, avascular necrosis and other degenerative diseases (knee, hip, ankle, shoulder, small joints)
- Tendon and ligament tears (such as rotator cuff, hip and shoulder labral tears, Achilles tendon, ACL, MCL, and ankle tendons and ligaments)
- Knee meniscus and cartilage damage
- Non-healing fractures
The use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. Despite continued research into the methods of harvesting and delivering treatment, there are uncertainties regarding the optimal source of cells and the delivery method. Current available evidence on procedures using autologous bone marrow derived MSCs for orthopedic indications in humans consist of a few small randomized and nonrandomized comparative trials with insufficient data to evaluate health outcomes. Comparative prospective randomized clinical trials are needed to adequately compare MSC based therapies to standard treatment modalities. In addition, expanded MSCs for orthopedic applications are not Food and Drug Administration (FDA) approved (concentrated autologous MSCs do not require FDA approval). Due to the lack of evidence that clinical outcomes are improved and the lack of regulatory approval, use of stem cells for orthopedic applications is considered investigational.
Mesenchymal Stem Cells (MSCs) with Demineralized Bone Matrix (DBM)
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.
Practice Guidelines and Position Statements
American Academy of Orthopedic Surgeons (AAOS)
The American Academy of Orthopedic Surgeons (AAOS) states the following: “Stem cell procedures are being developed to treat bone fractures and nonunions, regenerate articular cartilage in arthritic joints, and heal ligaments and tendons. Stem cell procedures in orthopedics are still in the experimental stage and most musculoskeletal treatments using stem cells are performed in research centers as part of controlled clinical trials.”
The U.S. Food and Drug Administration (FDA) has stated:
“A major challenge posed by SC [stem-cell] therapy is the need to ensure their efficacy and safety. Cells manufactured in large quantities outside their natural environment in the human body can become ineffective or dangerous and produce significant adverse effects, such as tumors, severe immune reactions, or growth of unwanted tissue.”
Concentrated autologous MSCs do not require approval by FDA.
Demineralized bone matrix (DBM), which is processed allograft bone, is considered minimally processed tissue and does not require FDA approval. At least 4 commercially available DBM products are reported to contain viable stem cells:
- 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 and Biologics License Application (BLA).
No products using engineered or expanded MSCs have been approved by FDA for orthopedic applications.
In 2008, FDA determined that the mesenchymal stem cells sold by Regenerative Sciences for use in the Regenexx™ procedure would be considered drugs or biological products and thus require submission of a New Drug Application (NDA) or Biologics Licensing Application (BLA) to FDA.(2) To date, no NDA or BLA has been approved by FDA for this product. As of 2013, the expanded stem-cell procedure is only offered in the Cayman Islands. Regenexx™ network facilities in the U.S. provide same-day stem-cell and blood platelet procedures, which do not require FDA approval.
Prior approval is recommended. Submit a prior approval now .
Mesenchymal stem cell therapy (including but not limited to Regenexx Procedure), is considered investigational for all orthopaedic applications, including use in repair or regeneration of musculoskeletal tissue.
The use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. Despite continued research into the methods of harvesting and delivering treatment, there are uncertainties regarding the optimal source of cells and the delivery method. Current available evidence on procedures using mesenchymal stem cells (MSCs) for orthopedic indications in humans consists of a few small randomized and nonrandomized comparative trials with insufficient data to evaluate health outcomes. Comparative prospective randomized clinical trials are needed to adequately compare MSC based therapies to standard treatment modalities. In addition, expanded MSCs for orthopedic applications are not Food and Drug Administration (FDA) approved (concentrated autologous MSCs do not require FDA approval). Due to the lack of evidence that clinical outcomes are improved and the lack of regulatory approval, use of stem cells for orthopedic applications is considered investigational.
Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DBM) with stem cells, is considered investigational for all orthopaedic applications, due to a lack of evidence supporting safety and efficacy.
Note: See regulatory information above for demineralized bone matrix (DMB) products 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 ICD-9-CM diagnostic 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
- U.S. Food and Drug Administration. Ensuring Safety and Efficacy of Stem Cell Based Products. Available on line at: http//:www.fda.gov/BiologicsBloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm127182.htm. 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: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/UntitledLetter. Accessed May 14, 2014
- American Academy of Orthopaedic Surgeons (AAOS), OrthoInfo, Your connection to expert orthopaedic information, Stem Cells and Orthopaedics. Available on line at: http//:orthoinfo.aaos.org Accessed May 2, 2014
- American Academy of Orthopaedic Surgeons (AAOS), OrthoInfo, Your connection to expert orthopaedic information, Frequently Asked Questions about Stem Cells. Available on line at: http//:orthoinfo.aaos.org Accessed May 2, 2014
- International Congress for Joint Reconstruction (ICJR). Reports, Looking Toward the Future of Stem Cells in Orthopaedics. Available on line at: http:/icjr.net/report146stemcells.htm 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. Also available on line at: www.futuremedicine.com
- 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. www.medscape.com/viewarticle/575067
- ECRI Institute. Nanotechnology May Help Speed Bone Healing. Published 2/6/2009. www.ecri.org
- ECRI Institute. Health Technology Forecast. Autologous and Allogeneic Mesenchymal Stem Cell Therapy for Treating Osteoarthritis. November 2012. www.ecri.org
- ECRI Institute. Emerging Technology Evidence Report. Autologous Mesenchymal Stem Cells for Treating Knee Osteoarthritis. June 2013. www.ecri.org
- ECRI Institute. Product Brief. AlloStem Stem Cell Bone Growth Substitute (AlloSource) for Orthopedic procedures. August 2013. www.ecri.org
- PubMed. 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
- PubMed. 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. Also available at www.StemCellsTM.com
- 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. Also available at http://www.biomedcentral.com/1471-2474/15/156
- 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
- PubMed. Mesenchymal Stem Cells for the Treatment of Cartilage Lesions: From Preclinical Findings to Clinical Application in Orthopaedics, Filardo G, Madry H, et. al. 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. Also available at www.orthofix.com
- Allosource Allostem Cellular Bone Allograft. Also available at ww.allosource.org
- RTIX Map3 Cellular Allogeneic Bone Graft. Also available at www.rtix.com
- Nuvasive Osteocel Plus Bone Grafting. Also available at www.nuvasive.com
Date Reason Action
June 2014 New Policy
March 2015 Interim review Policy revised
May 2015 Annual review Policy revised
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.