Combating Posttraumatic Osteoarthritis via Enhanced Intra-Articular Recruitment of Stem Cells and Targeted Delivery of a Chondrogenic Agent
Abstract
Post-traumatic osteoarthritis (PTOA) is the progressive destruction of the cartilage surface of the joint, which is directly attributable to a traumatic injury to the joint. PTOA as a result of battlefield injuries is the leading source of disability in U.S. Warriors. The treatment of musculoskeletal injuries accounts for $600-$750 million in annual spending, and additional dollars are attributed to wages for lost duty days caused by injury. In combat-wounded Warriors, over 90% of knee injuries lead to PTOA, demonstrating that military personnel are at an increased risk for the development of PTOA when 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 -- which occurs in both combat and non-combat scenarios. This painful injury 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 opt 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 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. 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; however, numerous technical and regulatory hurdles restrict the widespread adoption of these techniques. To overcome the obstacles associated with the use of stem cells in the treatment of PTOA, a technique is proposed which mimics the body s native response to significant trauma. We hypothesize that, following traumatic ACL rupture, PTOA can be mitigated using a novel three-step in situ regenerative medicine (ISRM) approach that involves mobilizing, homing, and signaling native stem cells to populate and repair the damaged joint by (1) mobilizing marrow-derived stem cells via systemic administration of a Food and Drug Administration-approved drug (AMD3100), (2) directing the migration of mobilized stem cells to the injured knee via local injections of a biomolecule that stimulates the recruitment of stem cells (SDF-1beta), and (3) signaling the stem cells recruited to the knee to protect cartilage via intra-cellular delivery of a potent anti-inflammatory agent attached to a nanoparticle. In Situ Regenerative Medicine -- a synchronized approach to mitigate PTOA: Mobilizing: --Egressing stem cells rapidly from bone marrow to peripheral blood --AMD3100 Homing: --Guiding mobilized stem cells to site of trauma (knee) --SDF-1beta Signaling: --Reducing inflammation and enhancing cartilage protection in the local environment --Dexamethasone PAMAM dendrimer Specific Aim 1: Increase the concentration of native marrow-derived mesenchymal stem cells (MSCs) within the injured knee joint following traumatic rupture of the ACL via mobilization and chemokine-directed homing. Specific Aim 2: Evaluate the effects of acute phase implementation of the ISRM technique on the onset and progression of PTOA following ACL rupture with and without surgical reconstruction. Innovation: AMD3100, liposome-encapsulated SDF-1beta, and PAMAM-dendrimer-conjugated dexamethasone have never been combined
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510186
Entities
People
- Kevin C Baker
Organizations
- Beaumont Health
- United States Army