The objective of this study is to improve the functional performance of an anterior cruciate ligament reconstruction (ACLR) by using a platelet hydrogel to enhance the early biologic incorporation of the graft. The current "standard of care" for an anterior cruciate ligament (ACL) tear is ACLR using autograft tendon. Despite short-term success of ACLR, temporal increases in joint laxity occur after surgery, which may place the knee at risk for subsequent damage and early arthritis. Thus, techniques to enhance graft healing to reduce early laxity, protect the joint, and preserve articular cartilage would provide better long-term outcome for the ACL injured patient. A platelet hydrogel was recently developed by the research team to enhance the healing response of the ACLR graft. Platelets are known to release various growth factors and cytokines that stimulate intra-articular ligament healing, and thus we hypothesize they will improve graft healing as well. A method has been developed to contain the platelets around the graft using a hydrogel.
Aim 1 is to define the effects of platelet concentration (5X vs 3X vs 0X) on the structural properties (failure load/linear stiffness) and histology (cellularity/vascularity) of the ACL graft after 12 weeks of healing when the graft is treated with the hydrogel at the time of surgery.
Aim 2 is to delineate the effects of the platelet hydrogel on knee joint laxity and the articular cartilage material properties after 12 weeks of healing. A translational model, which has been developed by this research team to study intra-articular ACL healing, will be used. The primary outcomes to address the study hypotheses will be the structural properties of the graft, graft histology, knee joint laxity and cartilage mechanics. Secondary outcome variables include the material properties of the graft, MRI assessments of vascularity and graft properties, meniscal status, and articular cartilage integrity via India ink staining and histology. If successful, these data will provide the foundation for a long-term translational study, and then subsequent clinical studies to further delineate the role of autologous platelets in improving graft healing and promoting long-term joint stability and articular cartilage health, thus reducing OA after ACLR.

Public Health Relevance

The use of autologous platelets to improve the functional healing of an ACL autograft (as evidenced by the faster return of graft strength and a reduction in knee laxity) could reduce rehabilitation time and promote a more stable knee, which in turn could reduce the risk of premature osteoarthritis for 200,000 ACLR patients annually. The results of this study will also stimulate entirely new fields of inquiry into cell-based therapies for intra-articular healing, and may result in a paradigm shift from use of a single growth factor toward the use of cells which can deliver multiple growth factors and cytokines over time as adjuncts to intra-articular healing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056834-04
Application #
8213690
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$330,055
Indirect Cost
$77,360
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
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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