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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AR056834-05A1
Application #
8701569
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
City
Providence
State
RI
Country
United States
Zip Code
02903
Chin, K E; Karamchedu, N P; Patel, T K et al. (2016) Comparison of micro-CT post-processing methods for evaluating the trabecular bone volume fraction in a rat ACL-transection model. J Biomech 49:3559-3563
Sieker, Jakob T; Ayturk, Ugur M; Proffen, Benedikt L et al. (2016) Immediate Administration of Intraarticular Triamcinolone Acetonide After Joint Injury Modulates Molecular Outcomes Associated With Early Synovitis. Arthritis Rheumatol 68:1637-47
Proffen, Benedikt L; Sieker, Jakob T; Murray, Martha M et al. (2016) Extracellular matrix-blood composite injection reduces post-traumatic osteoarthritis after anterior cruciate ligament injury in the rat. J Orthop Res 34:995-1003
Proffen, Benedikt L; Vavken, Patrick; Haslauer, Carla M et al. (2015) Addition of autologous mesenchymal stem cells to whole blood for bioenhanced ACL repair has no benefit in the porcine model. Am J Sports Med 43:320-30
Proffen, Benedikt L; Sieker, Jakob T; Murray, Martha M (2015) Bio-enhanced repair of the anterior cruciate ligament. Arthroscopy 31:990-7
Kiapour, Ata M; Fleming, Braden C; Murray, Martha M (2015) Biomechanical Outcomes of Bridge-enhanced Anterior Cruciate Ligament Repair Are Influenced by Sex in a Preclinical Model. Clin Orthop Relat Res 473:2599-608
Biercevicz, Alison M; Proffen, Benedikt L; Murray, Martha M et al. (2015) T2* relaxometry and volume predict semi-quantitative histological scoring of an ACL bridge-enhanced primary repair in a porcine model. J Orthop Res 33:1180-7
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
Proffen, Benedikt L; Perrone, Gabriel S; Fleming, Braden C et al. (2015) Effect of low-temperature ethylene oxide and electron beam sterilization on the in vitro and in vivo function of reconstituted extracellular matrix-derived scaffolds. J Biomater Appl 30:435-49
Proffen, Benedikt L; Perrone, Gabriel S; Fleming, Braden C et al. (2015) Electron beam sterilization does not have a detrimental effect on the ability of extracellular matrix scaffolds to support in vivo ligament healing. J Orthop Res 33:1015-23

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