Mitigation of Posttraumatic Osteoarthritis via Augmented Immunomodulation of Endogenous Marrow-Derived Stem Cells
Abstract
Post-traumatic osteoarthritis (PTOA), the progressive destruction of the cartilage surface of the joint, is directly attributable to a traumatic injury to the joint. PTOA resulting from battlefield injuries is the leading source of disability in U.S. Warriors. The treatment of musculoskeletal injuries accounts for $600 million to $750 million in direct healthcare spending, with additional cost related to wages for lost duty days. In combat-wounded Warriors, over 90% of knee injuries lead to PTOA, translating into an increased risk of PTOA in military personnel compared to the general public. One of the most common causes of PTOA of the knee is rupture of the anterior cruciate ligament (ACL), an important stabilizing structure of the joint. This injury occurs in both combat and non-combat scenarios and leads to destabilization of the knee, resulting in abnormal joint motion and accelerated loss of cartilage. Because of the significant pain and loss of function associated with traumatic ACL ruptures, both civilian and military personnel frequently elect for surgical reconstruction of the ligament. Advances in surgical techniques and instrumentation have led to significant improvements in the restoration of normal joint motion and loading following ACL reconstruction. Despite returning the mechanical function of the knee to near pre-injury status, over half of all surgically reconstructed patients will go on to develop PTOA. This suggests that non-mechanical factors, present in the acute phase following ACL injury, play a role in the development of joint degeneration. Currently, definitive treatment of end-stage PTOA is total joint replacement. In military personnel undergoing total knee arthroplasty for a diagnosis of PTOA, a history of ACL rupture is the most common injury mechanism. The young age and high activity level of military personnel with PTOA-inducing injuries, coupled with the limited lifespan of materials used in total joint replacement, leads to a cycle of multiple surgical procedures resulting in long-term disability and increased healthcare cost. Stem cell-based techniques have shown promise for the treatment of PTOA, primarily due to the cells’ ability to modulate the immune environment in their surroundings by secretion of biomolecules like indoleamine 2,3-dioxygenase (IDO). Numerous technical and regulatory hurdles restrict the widespread adoption of traditional stem cell techniques, but our group has discovered the ability of a Food and Drug Administration (FDA)-approved drug (AMD3100) to allow native, marrow-derived stem cells to enter the joint after ACL injury. We hypothesize that promoting the entry of the native, marrow-derived stem cells inside the knee joint after ACL injury will allow the cells to exert immunomodulatory effects, primarily related to the secretion of IDO, to control the initial inflammatory response to injury. It is further hypothesized that we can enhance the immunomodulatory effects of the stem cells by injecting the knee joint with additional IDO after the cells have been recruited. Ultimately, we propose that augmenting the response of native, marrow-derived stem cells to ACL injury via IDO injections will mitigate the onset of new PTOA, and may reverse the degenerative cascade in established PTOA. Innovation: Our group developed and fully characterized a new rat model of non-surgical ACL injury, which closely mimics both the mechanics of injury and the cascade of joint degeneration. Most recently, we were the first to demonstrate that, following ACL injury, marrow-derived MSCs are mobilized into peripheral blood, and subsequently migrate towards the injured knee. Notably, we found that the responding MSCs are not able to enter the knee joint, and instead are trapped in a structure surrounding the knee joint called the synovium. This severely limits the ability of a patient’s own stem cells to efficiently respond to a knee injury. Interestingly, we have
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810565
Entities
People
- Kevin C Baker
Organizations
- Beaumont Health
- United States Army