An exciting finding in the first funding cycle of this grant is that skeletally immature animals have a functionally successful repair response to ACL injury, whereas adolescent and adult animals do not. We postulate that the impaired ACL healing noted in adolescents and adults could be improved if the fundamental biologic processes of increased cellular migration and proliferation found with immature ACL cells and repair tissue could be recapitulated in the adolescent animals using our novel "enhanced ACL repair" strategy. In this competitive renewal, we will determine if the impaired healing potential of adolescent ACL tears can be improved in vivo by using an enhanced repair strategy in which a scaffold stimulates increased cellular density of the repair tissue by facilitating fibroblast migration and proliferation within the wound site. We propose to study the effects of these additives in both the ideal acute repair situation, and in the more clinically relevant case in which the repair is delayed by 2, 4 or 6 weeks in the following two Specific Aims:
Aim 1 : Evaluate the effect of increasing the cellular density of the ACL repair tissue on functional healing after an immediate repair of a ruptured adolescent ACL. Hypothesis 1a: Tissue engineered scaffolds that increase the cellular density of the ACL repair tissue will have a higher yield load and linear stiffness and lower AP knee laxity after 15 weeks of healing than repairs using scaffolds which impede cellular population of the wound site. Hypothesis 1b: An increase in cell density is related to an increase in yield load and stiffness and a decrease in AP knee laxity. Hypothesis 1C: The repairs augmented with a tissue engineered scaffold containing platelets or erythrocytes will have a higher yield load and linear stiffness and lower AP knee laxity than repairs with collagen alone or ACL reconstruction.
Aim 2 : Establish the effect delaying repair on the functional healing of the ACL. Hypothesis 2a: The delay of primary repair by 2, 4 or 6 weeks will result in changes in the yield load and linear stiffness of an enhanced ACL repair relative to the acute condition. Hypothesis 2b: A greater degree of cartilage and meniscal damage will be present in knees undergoing repair at 6 weeks as compared to the immediate repair situation. For both Aims our well-characterized adolescent mini pig model of ACL injury and repair will be utilized. The primary outcome measures will include biomechanics (AP knee laxity, ligament structural properties) and histology (cellular density and vascular density). Secondary outcome measures include cartilage injury (India ink staining and histology of the menisci and articular cartilage) and the material properties of the repair. The studies in the proposal are designed to determine whether the impaired ACL healing noted in adolescents and adults could be improved if the repair tissue in these populations could be made to more closely resemble the repair tissue in immature animals using our novel "enhanced ACL repair" strategy. Success in this endeavor could improve the care of hundreds of thousands of adolescent and adult patients with ACL tears each year.

Public Health Relevance

An estimated 300,000 to 500,000 patient each year in the US sustain a tear of the anterior cruciate ligament (ACL). Even with current surgical treatments for this injury, the risk of premature osteoarthritis in these patients approaches 80% at only 14 years out from the injury. For the hundreds of thousands of adolescents this injury affects, that is a troubling statistic. Our work focuses on improving the repairs of these injuries. In our previous grant period, we discovered that young animals heal ligament injuries better than adolescent or adult animals. In this next study, we propose to find out if the impaired ACL healing noted in adolescents and adults could be improved if the repair tissue in these populations could be made to more closely resemble the repair tissue in immature animals if the repairs are supplemented with a scaffold designed to deliver the right growth factors to the ACL tear. Success in this endeavor could improve the care of hundreds of thousands of adolescent and adult patients with ACL tears each year.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054099-06
Application #
8296050
Study Section
Special Emphasis Panel (ZRG1-MOSS-F (02))
Program Officer
Wang, Fei
Project Start
2006-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$558,303
Indirect Cost
$109,410
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
Bennike, Tue; Ayturk, Ugur; Haslauer, Carla M et al. (2014) A normative study of the synovial fluid proteome from healthy porcine knee joints. J Proteome Res 13:4377-87
Kiapour, A M; Murray, M M (2014) Basic science of anterior cruciate ligament injury and repair. Bone Joint Res 3:20-31
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
Proffen, Benedikt L; Nielson, Jason H; Zurakowski, David et al. (2014) The Effect of Perioperative Ketorolac on the Clinical Failure Rate of Meniscal Repair. Orthop J Sports Med 2:
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
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

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