Identification and Manipulation of a Novel Signaling Mechanism To Improve Articular Cartilage Restoration After Posttraumatic Joint Injury

Principal Investigator: EVSEENKO, DENIS A
Program: PRORP
Proposal Number: OR120161
Award Number: W81XWH-13-1-0465
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $748,140.00


Background: The advent of modern insurgency warfare and the prevalence of improvised explosive device (IED) inflicted injury has resulted in a high number of devastating extremity injuries in military personnel. These injuries often result in damage or loss of muscle, bone, and joint cartilage. While muscle and bone have an innate capacity for healing, joint cartilage does not heal spontaneously. Injury to the joint cartilage often results in pain, disability, and, in some cases, the development of joint degeneration and arthritis. Current treatment for cartilage loss either requires replacing the injured cartilage with donor cartilage or attempting to repair the cartilage with the warrior's own cells. However, these techniques are unsatisfactory in regard to the quality of the repair cartilage, cost, availability, and long-term outcome. Accordingly, an effective treatment for cartilage injury is a critical need for the Armed Forces and military Veterans.

Objective: Our objective is to develop a low-cost and practical method of improving the treatment of warriors with cartilage injuries. The aim of this proposal is to improve the quality of cartilage that is produced by the patient's body by preventing the formation of poor quality scar tissue by cartilage cells and stem cells at the location of the injury. Consequently, we aim to drive the patient's cells to produce high-quality, durable cartilage that will not be prone to arthritic degeneration.

Rationale: It is well established that cartilage has a poor capacity to heal spontaneously. When injured, the healing response in the area of cartilage loss is robust, but misdirected. Rather than forming durable cartilage, a scar is produced. This scar is of inferior quality that is prone to degeneration. In our laboratory's preliminary work, we have identified a specific cellular pathway that is responsible for driving this disorganized scar formation. In this proposal, we aim to block this pathway and, consequently, diminish the production of scar tissue formed at the area of cartilage injury. If this experiment proves successful, it may be possible, within approximately a 7-10 year time period, to use simple, low-cost, pharmacologic interventions to improve the warrior's repair of injured cartilage without the use of donor tissue or extensive surgical reconstruction. The current project is designed to develop and test a novel strategy preventing the formation of scar tissue in the injured joint using cell cultures applied to cartilage injury. The main risk of the current study is associated with the application of completely novel stem cell populations and chemical compounds previously not tested in cells for cartilage repair. If this current project is successful, the next step will be to initiate the process to obtain Food and Drug Administration approval.

Clinical Applicability: This approach to treating joint cartilage injury has high clinical applicability and feasibility. The aforementioned pathway can be modulated via pharmacologic agents either delivered systemically to the patient by mouth, through injection, or locally to the area of injury. This approach is attractive in that it can be an alternative to extensive reconstructive surgery, or may enhance the outcome of cartilage restoration procedures by encouraging the patient's own cells to generate high-quality cartilage tissue. This technology will benefit both wounded warriors and the civilian population, as joint cartilage injury and degeneration is a common orthopaedic condition. This approach has the clinical benefits of lower cost, lower surgical complications such as donor site morbidity, and possibly improved outcomes due to the improved mechanical properties of the reparative cartilage. Our research team consists of stem cell and cartilage cell researchers, orthopaedic surgeons, as well as tissue engineers, all of whom are well poised to guide the transition of this technology from the laboratory to patient care. This study will not only provide rapid and practical treatment of cartilage injuries to injured warriors, but change the paradigm of cartilage restoration and promote the engineering of "scarless" healing in musculoskeletal tissues.