Adult stem cells have the ability repair a variety of tissues. Mesenchymal stem cells (MSCs) can differentiate into osteoblasts, chondrocytes, adipocytes, neurocytes and hepatocytes to repair bone, cartilage, connective tissue, nerves and liver tissue. This article discusses clinical applications of bone marrow aspirate concentrate (BMAC), the basic science of MSCs from BMAC and the differences between “amniotic stem cells” and BMAC.¹
Researchers have experimented with various types of stem cell therapy, including stem cells derived from adipose tissue, allogeneic stem cells or “amniotic stem cells” and autologous MSCs harvested from bone marrow. Researchers have examined the therapeutic effects of MSCs from bone marrow for orthopedic conditions like knee and hip osteoarthritis, neurological conditions like multiple sclerosis, and cardiovascular conditions like critical limb ischemia. Researchers have found BMAC procedures to be safe and improve patient outcomes without adverse effects.
Orthobiologic Applications of BMAC
Clinical trials have shown BMAC to be effective in many orthopedic applications including chondral lesions, bony defects and tendon injuries.² Clinical evidence is available for the use of BMAC for chondral defects such as hip and knee osteoarthritis. BMAC is commonly used to improve wound healing as an adjunct therapy to tendon or bone surgeries. Bone marrow aspirate concentrate allows for the precise application of MSCs which can differentiate into a variety of tissues while delivering growth factors to the wound site. MSCs, growth factors and biologic scaffold are the three key components required for cell regeneration and renewal. Thus, the addition of MSCs biologically enhances the body’s ability to rebuild tissues.³
BMAC and Osteochondral Lesions of the Knee
The application of BMAC has been widely studied in patients with osteochondral lesions of the knee. Osteochondral lesion are normally treated with a chondrocyte transplantation and bone graft. One study compared cultured BMAC to cultured chondrocyte transplant and found favorable results with BMAC. The BMAC procedure was more economical, less invasive and had less donor-site morbidity. The cultured BMAC increased proliferation and migration of chondrocytes, the specialized joint cells which regulate the production of collagen and proteoglycans. (Though researchers have found great results with cultured stem cells, these procedures are not available to the general public in the United States because of FDA safety regulations.) Additional studies have found positive outcomes by utilizing BMAC as an adjunct to arthroscopic knee surgery⁴ and high tibial osteotomy⁵ with microfracture in patients with degenerative knee arthritis.
BMAC and Hip Osteoarthritis
In 2014, researchers at the Oregon Health and Sciences University released registry results from 216 BMAC procedures on patients with hip osteoarthritis. Each patient received an intra-articular injectate consisting of BMAC, platelet rich plasma (PRP) and platelet lysate (PL). The therapy benefited patients by reducing pain according to the numeric pain scale (p value <0.001) and improving function according to Oxford Hip Score (p value <0.001). The therapy is most advantageous when applied to treat early stages of avascular necrosis in patients under 55.⁶
Multiple Sclerosis and BMAC
In addition to orthopedic applications, researchers have designed studies aimed at evaluating the application of BMAC in patients with multiple sclerosis (MS) and critical limb ischemia. A phase I clinical trial published in 2018 from researchers at the Tisch Multiple Sclerosis Research Center of New York was designed to assess the safety of MSCs cultured ex vivo into MSC-Neural Progenitors (MSC-NPs). The treatment was found to be safe and well tolerated with positive recovery trends. Results were assessed according to the Expanded Disability Status Scale (EDSS), muscle strength, urodynamic testing, and a times 25 ft walk. Though the study was not designed to assess efficacy, the researchers found EDSS scores were reduced in 40% of participants, 50% of patients showed improved bladder function, and 70% of patients showed improved muscle strength.⁷
BMAC and Critical Limb Ischemia
Critical limb ischemia (CLI) is a life threatening vascular condition with a 1-year mortality of 25% and often leads to amputation. CLI affects patients with a history of cardiovascular disease, diabetes, smoking, arterial plaque, and obesity. Some patients may be eligible for endovascular procedures to reroute blood flow and circumvent blockages, but 40% of patients with CLI are not eligible for surgical revascularization, ‘no-option’ patients. A 2011 randomized controlled trial from researchers at the New England Society for Vascular Surgery found BMAC to be a safe and effective procedure for patients with ‘no-option’ CLI. Researchers concentrated 120ml of bone marrow aspirate from the iliac crest into 40 ml of BMAC. Patients in the treatment group received 40 1-ml injections along the popliteal, tibial, and/or pedal arteries each spaced 1-2 cm apart. Researchers found positive trends for patients in the treatment group including a decrease in major amputations, pain, and increase in distal circulation according to the ankle brachial index.⁸
How does stem cell therapy work?
Bone marrow actually contains two types of stem cells; hematopoietic stem cells which produce red blood cells at a rate of 500 billion per day and MSCs which are found in almost all tissues. MSCs are pericytes meaning that they surround capillaries and blood vessels, poised for quick release into the bloodstream in response to injury.
Adult mesenchymal stem cells have multi-lineage differentiation potential or the ability to differentiate into a variety of tissues including osteoblasts, chondrocytes, adipocytes, neurocytes and hepatocytes. Researchers have investigated several signalling pathways and transcription factors that initiate the differentiation process and have found that transforming growth factor-β and bone morphogenetic protein signaling pathways facilitate MSC differentiation into cartilage and bone. Additionally, growth factors contained in BMAC increase cell regeneration and scaffolding to repair damaged tissues at an increased rate.⁹
MSCs act as a sensors by assessing and responding the local environment. MSCs travel throughout the body seeking inflamed and damaged tissues to regenerate damaged cells. In a 2017 study researchers showed that MSCs are able to donate mitochondria to sick cells by secreting vesicles containing healthy mitochondria.¹⁰
What are “Amniotic Stem Cells”?
As discussed previously, most scientific research examines the use of BMAC while allogeneic or “amniotic stem cell” are some of the most widely available procedures. A simple web search for ‘stem cell clinics’ will populate your browser with providers offering amniotic stem cells therapy to treat arthritis and soft tissue conditions, but the safety and efficacy of these procedures has not been cleared by the FDA.
Allogeneic stem cells originate from another patient and are often sold as amniotic stem cells, cord blood, wharton’s jelly or placenta stem cells. Because these products are allogeneic, and not autologous they come with increased risk of adverse events and allergic reaction. Stem cells from another person are known to benefit patients with blood and immune disorders such as leukemia. For these treatments to be effective, the donor must be a match and the cells must be living.
Amniotic products are often illegally marketed as ‘live stem cells’, but the thawing and processing methods are known to damage viable tissues. The process of shock thawing the product from a freeze-dried state damages cell membranes and renders the cells nonviable. Businesses claiming to sell “living stem cells” are misrepresenting a product, which is illegal according to FDCA code.
All living tissue products are currently regulated by the FDA as drugs. As such, the FDA requires rigorous clinical trials to demonstrate the product’s safety and efficacy for one specific application. Taking a drug to trial is multi-year multi-million dollar process designed to keep the public safe. If the cell drug is proven to be safe and effective, it’s classified as a 351 drug. Many “amniotic stem cell” products currently on the market are 361 registered tissues, not 351 drugs. The tissue registration process is a simple online form which requires no clinical testing.
MSCs, BMAC, and Orthobiologics
The injection of mesenchymal stem cells from concentrated bone marrow has been shown to be safe, well-tolerated and effective for several orthopedic applications including knee and hip osteoarthritis. Patients with critical limb ischemia and multiple sclerosis could also benefit from the therapeutic properties of MSCs according to recent research.
References
- Holton J, Imam M, Ward J, Snow M. The Basic Science of Bone Marrow Aspirate Concentrate in Chondral Injuries. Orthopedic Reviews. 2016;8(3):6659. doi:10.4081/or.2016.6659.[ncbi]
- Gianakos AL, Sun L, Patel JN, Adams DM, Liporace FA. Clinical application of concentrated bone marrow aspirate in orthopaedics: A systematic review. World Journal of Orthopedics. 2017;8(6):491-506. doi:10.5312/wjo.v8.i6.491.[ncbi]
- Henning Madry, Liang Gao, Hermann Eichler, Patrick Orth, and Magali Cucchiarini, “Bone Marrow Aspirate Concentrate-Enhanced Marrow Stimulation of Chondral Defects,” Stem Cells International, vol. 2017, Article ID 1609685, 13 pages, 2017. doi:10.1155/2017/1609685 [ncbi]
- Kim JD, Lee GW, Jung GH, et al. Clinical outcome of autologous bone marrow aspirates concentrate (BMAC) injection in degenerative arthritis of the knee. Eur J Orthop Surg Traumatol. 2014;24(8):1505-11.[ncbi]
- Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH. 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.[ncbi]
- Centeno CJ, Pitts JA, Al-Sayegh H, Freeman MD (2014) Efficacy and Safety of Bone Marrow Concentrate for Osteoarthritis of the Hip; Treatment Registry Results for 196 Patients. J Stem Cell Res Ther 4:242. doi:10.4172/2157-7633.1000242.[ncbi]
- Harris VK, Stark J, Vyshkina T, et al. Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural Progenitors in Progressive Multiple Sclerosis. EBioMedicine. 2018.[ncbi]
- Iafrati, Mark D., MD, Hallett, John W., MD, et al. Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia. J of Vascular Surg. Dec 2011;54(6):1650-1658.[ncbi]
- Augello A, De bari C. The regulation of differentiation in mesenchymal stem cells. Hum Gene Ther. 2010;21(10):1226-38.[ncbi]
- Mahrouf-Yorgov, Meriem, et al. “Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties.” Cell death and differentiation 24.7 (2017): 1224.[ncbi]
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