|STEM-CELL THERAPY FOR ORTHOPEDIC APPLICATIONS|
Mesenchymal stem cells (MSCs) are multipotent stem cells (also referred to as stromal multipotent cells) that are able to differentiate into a variety of tissue types, including organs, trabecular bones, tendons, articular cartilages, ligaments, muscles, fats, and various musculoskeletal tissues. MSCs have possible orthopedic applications, which include the treatment of damaged bones, cartilages, ligaments, tendons, and intervertebral discs.
MSCs decrease as people age, and acute and chronic illnesses and diseases can tax stem-cell reserves. MSCs can be increased and stem-cell reserves replenished by treatment with drugs such as filgrastim injection (Neupogen®) and plerixafor injection (Mozobil®) to mobilize stem cells, or by autologous stem-cell transplantation. Although MSCs can be harvested from the bone marrow, harvesting requires an additional procedure that may result in donor site morbidity.
Tissues such as muscle, cartilage, tendon, ligaments, and vertebral discs show limited capacity for endogenous repair (i.e., the repair of cells within their own structures). Therefore, tissue engineering techniques have been developed to improve the efficiency of repair or regeneration of damaged musculoskeletal tissues. Using an engineered process to induce cell division and differentiation, without adverse effects such as the formation of neoplasms, remains a challenge.
According to the US Food and Drug Administration (FDA), "...Cell-based therapy is one of the most rapidly advancing approaches intended to repair, replace, restore, or regenerate cells, tissues, and organs. The cell-based therapies use immature stem cells that are expanded outside the body. The expanded cells are sometimes used in their immature state, but are often manufactured into mature cells before being used. Manufacturing a large number of cells outside the natural environment of the body may lead to ineffective or dangerous cells. It is important to control the production process and to define measures that reliably predict safety and efficacy of the cell-based products."
No products using engineered MSCs have been approved by the FDA for orthopedic applications. The FDA has determined that MSCs sold by Regenerative Sciences for use in the RegenexxTM Procedure (Regenerative Sciences, Colorado) would be considered drugs or biological products and thus require submission for a New Drug Application (NDA) or a Biologics Licensing Application (BLA) to the FDA. These procedures by Regenexx TM have platelet-derived components as well.
The literature overall suggests that this technology is in the early stages of development. Preliminary testing of tissue engineering has focused on animal models. Several clinical trials are in progress but are not expected to be completed for several years. Current information on procedures using autologous bone marrow derived from MSCs for orthopedic applications in humans consists mainly of case reports or case series with insufficient data to evaluate health outcomes. Therefore, the use of stem cells for orthopedic applications remains under investigation.
The American Association of Orthopaedic Surgeons (AAOS) states that stem-cell procedures in orthopedics are still at an experimental stage; most musculoskeletal treatments using stem cells are performed at research centers as part of controlled clinical trials.
AUTOLOGOUS PLATELET-DERIVED GROWTH FACTORS (PDGFs)/PLATELET-RICH PLASMAS (PRPs)
Impaired wound healing may be caused by venous stasis, peripheral neuropathy, ischemia, or a poor healing response related to local trauma. These clinical conditions are often present in individuals with diabetes. Current treatment of chronic, non-healing wounds includes debridement, management of infection, limitation of weight-bearing activities, and revascularization of the affected area.
The science of wound healing is advancing rapidly due to new therapeutic approaches such as the use of growth factors. Several growth factors contribute to wound healing, including platelet-derived growth factors (PDGFs)/platelet-rich plasmas (PRPs), epidermal growth factors, fibroblast growth factors, transforming growth factors, and insulin-like growth factors. Topically applied PDGFs/PRPs have been evaluated as primary clinical agents to help promote wound healing.
PDGFs/PRPs have also been proposed for conditions such as epicondylitis (tennis elbow) and plantar fasciitis (an inflammatory condition that causes intense heel pain), and have been investigated as adjuncts to periodontal, reconstructive, and orthopedic surgical procedures.
PDGFs/PRPs are autologous platelet concentrations suspended in plasma and can be prepared from samples of centrifuged autologous blood. Exposure to solutions of thrombin and calcium chloride degranulates platelets, causing the release of the growth factors, which results in a polymerization of fibrin from fibrinogen and the creation of a platelet gel. Because autologous PDGFs/PRPs originate from the individual's own blood, they are not regulated by the US FDA.
Procuren ® (Cytomedix Inc.), a type of PDGF/PRP, has not been marketed since 2002. AutoloGel ™ (Cytomedix Inc.) and SafeBlood ® (SafeBlood Technologies) are similar, yet distinct, autologous PDGF/PRP products that are currently marketed for wound healing. Both products centrifuge blood samples from an individual to create PDGF/PRP, which is then activated by various reagents. The resultant gel-like substance (AutoloGel™) or semi-solid graft (SafeBlood®) can then be immediately applied to a wound or used as an adjunct to surgery to promote hemostasis and accelerate healing. Unlike Procuren®, which requires processing at a specialty laboratory, AutoloGel™ and SafeBlood® can be prepared on-site using proprietary portable centrifuges and may therefore be used in wound care clinics, home settings, skilled nursing facilities, and acute care facilities.
The Magellan ®, Autologous Platelet Separator System (Arteriocyte Medical Systems) is a portable centrifuge approved by the FDA in June 2003. The Magellan® system can be used in the clinical laboratory or intraoperatively for rapid preparation of platelet-poor plasma and platelet concentrate (PDGF/PRP). The PDGF/PRP is prepared from a very small amount of blood that is mixed with autograft and/or allograft bone before its application to an orthopedic site.
At present, there is insufficient published medical literature to support the clinical safety and/or effectiveness of autologous platelet-derived products to promote the healing of chronic, non-healing wounds, or for use with other miscellaneous conditions.
The possible benefit of using PDGF/PRP is of considerable interest. There is limited but rapidly developing literature on the safety and effectiveness of PRP, in addition to an increasing number of routine clinical trials in progress involving various conditions. However, clear evidence of PRP benefit is still lacking, and the safety and effectiveness of PDGF/PRP for treatment of acute or chronic wounds, or as an adjunct to surgical procedures, remain to be proven.