The overall objective of this competitive renewal is to identify the key modulators of post-traumatic osteoarthritis (PTOA) using a novel large translational model of ACL injury and "bio-enhanced" ACL repair. In the last funding cycle we demonstrated with our experimental model that accelerated PTOA occurs following ACL injury and even after ACL reconstruction, the current standard of care in which the injured ligament is replaced by a tendon graft. We determined that our novel technique of "bio-enhanced" ACL repair, where the injured ligament is repaired using a bio-engineered scaffold to stimulate healing, not only effectively heals the ligament, but also prevents the onset of PTOA after ACL injury. The mechanisms behind this therapeutic effect on cartilage are unknown and the focus of the proposal. With the translational experimental model developed in the last funding cycle, we are now poised to use a differential systems biology approach to compare subjects that do not develop PTOA (i.e., those treated with bio-enhanced ACL repair) with those that do (i.e., those treated with conventional ACL reconstruction) to determine key biological, structural and biomechanical pathways that are different in knees which are developing PTOA from those that are not.
The specific aims of the study are: 1) to identify differences in cytokine, extracellular matrix (ECM)-associated protein profiles and asymmetries in gait in the joints of individuals undergoing ACL transection followed by bio-enhanced ACL repair compared to individuals undergoing ACL transection followed by conventional ACL reconstruction at 1, 4, 12, 26 and 52 weeks after injury, and 2) to define the source of cytokine and ECM-related protein expression within the synovial joint at 1, 4, and 52 weeks after injury.
Both aims will take advantage of our well- characterized experimental model of ACL transection, ACL reconstruction and bio-enhanced ACL repair. The primary outcome measures for Aim 1 (longitudinal assessments) are the concentrations of the cytokines, MMPs, and collagen and aggrecan fragments in synovial fluid, and the ratio of the peak ground reaction force during stance phase of gait. The primary outcome measures for Aim 2 (cross-sectional assessments) are the gene expression assays of cytokines in the synovium, ligament and articular cartilage and macroscopic (modified outerbridge score) and histological assessments of cartilage health. At the completion of this study we will better understand the chondroprotective effects of the bio-enhanced ACL repair, establish upstream targets for therapeutic intervention for other traumatic joint injuries, and be poised to transfer the bio-enhanced repair technology for clinical use.

Public Health Relevance

After a human joint sustains a significant injury, like a fracture or a tear of the anterior cruciate ligament, it typically starts to break down over time and ultimately develops premature osteoarthritis. This post-traumatic osteoarthritis has been estimated to affect over 5.6 million Americans each year, many of whom are young athletes at the time of injury. We have recently found a method to stop this post-traumatic osteoarthritis after an ACL injury, and in this study, we will determine why this works so we can translate it to the treatment of ACL injured patients and to extend the same cartilage protection to other traumatic joint injuries.

National Institute of Health (NIH)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
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Rhode Island Hospital
United States
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Fleming, Braden C; Proffen, Benedikt L; Vavken, Patrick et al. (2015) Increased platelet concentration does not improve functional graft healing in bio-enhanced ACL reconstruction. Knee Surg Sports Traumatol Arthrosc 23:1161-70
Kiapour, Ata M; Shalvoy, Matthew R; Murray, Martha M et al. (2015) Validation of porcine knee as a sex-specific model to study human anterior cruciate ligament disorders. Clin Orthop Relat Res 473:639-50
Yoshida, Ryu; Cheng, Mingyu; Murray, Martha M (2014) Increasing platelet concentration in platelet-rich plasma inhibits anterior cruciate ligament cell function in three-dimensional culture. J Orthop Res 32:291-5
Haslauer, Carla M; Proffen, Benedikt L; Johnson, Victor M et al. (2014) Expression of modulators of extracellular matrix structure after anterior cruciate ligament injury. Wound Repair Regen 22:103-10
Biercevicz, A M; Walsh, E G; Murray, M M et al. (2014) Improving the clinical efficiency of T2(*) mapping of ligament integrity. J Biomech 47:2522-5
Biercevicz, Alison M; Murray, Martha M; Walsh, Edward G et al. (2014) T2 * MR relaxometry and ligament volume are associated with the structural properties of the healing ACL. J Orthop Res 32:492-9
Vavken, Patrick; Proffen, Benedikt; Peterson, Chris et al. (2013) Effects of suture choice on biomechanics and physeal status after bioenhanced anterior cruciate ligament repair in skeletally immature patients: a large-animal study. Arthroscopy 29:122-32
Teeple, Erin; Jay, Gregory D; Elsaid, Khaled A et al. (2013) Animal models of osteoarthritis: challenges of model selection and analysis. AAPS J 15:438-46
Biercevicz, Alison M; Miranda, Daniel L; Machan, Jason T et al. (2013) In Situ, noninvasive, T2*-weighted MRI-derived parameters predict ex vivo structural properties of an anterior cruciate ligament reconstruction or bioenhanced primary repair in a porcine model. Am J Sports Med 41:560-6
Haslauer, C M; Elsaid, K A; Fleming, B C et al. (2013) Loss of extracellular matrix from articular cartilage is mediated by the synovium and ligament after anterior cruciate ligament injury. Osteoarthritis Cartilage 21:1950-7

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