Background: Orthopedic injuries represent a significant challenge to both military and civilian medical capabilities. Repair of these injuries is associated with difficult and specialized surgical techniques, long rehabilitation and recovery cycles, and reduced total function following completed recovery. Anterior cruciate ligament (ACL) reconstruction is currently one of the most common orthopedic procedures; being performed more than 100,000 times annually in the United States. Although numerous graft alternatives, autologous, allogeneic, and synthetic, have been used with some success, an ideal graft that exhibits all desired restorative characteristics does not exist. Autologous tissues are associated with donor site morbidity while synthetic prostheses have universally failed to provide long-term function. The ideal graft for ACL reconstruction should reproduce the complex anatomy of the ACL, provide the same biomechanical properties as native ACL, permit strong and secure fixation, and promote rapid biologic incorporation.

Objective/Hypothesis: The objective of this proposal is to develop an off-the-shelf ACL graft compatible with military medical capabilities, thereby solving the significant problems associated with current and previously developed repair technologies and reconstruction procedures. To accomplish the stated development goal and overcome current technical limitations to ACL repair, we will jointly leverage the properties of an acellular regenerative tissue matrix (RTM) and the strength of a biocompatible, bioresorbable polymeric construct. The resulting hybrid product will be a truly regenerative ACL graft providing both strength and function during ligament regeneration.

Specific Aims: The five specific aims of this proposal are: (1) design and manufacture three to four unique polymeric constructs that bracket a number of possible design characteristics; (2) establish the mechanical, physico-chemical, and kinematic properties of the basic polymer filament, the polymeric constructs, and the full tissue/polymer hybrid grafts and select viable constructs relative to established design specifications; (3) establish effective methods to preserve, ship, and store the final graft product; (4) establish in vivo feasibility of graft function and regeneration using an appropriate model of ACL reconstruction surgery, and (5) deliver a developmental and clinical project plan.

Study Design: The specific aims of this proposal were developed to provide a logical progression through the discrete steps of graft design. The polymeric construct design phase will address a variety of potential design characteristics based on abilities of textile fabrication methods. Mechanical properties, ability to marry RTM to the polymeric construct, and hybrid graft fixation methods will be addressed as part of the prototype design phase. Prototypes will be assessed using mechanical and physico-chemical testing methods and compared to prospective design specifications for viable prototype selection. Testing methods will minimally measure breaking strength, yield strength, ultimate strain, elongation, and modulus. Selected constructs will be used to produce prototype hybrid grafts for kinematic mechanical analysis to measure abrasion resistance, fatigue failure of the graft, and load failure of fixation methods. Finally, prototype grafts, selected based on acceptable kinematic results, will be tested for in vivo efficacy in a model of ACL reconstruction comparable in size, mechanics, and loads to the human condition. In addition to graft maintenance and differential joint laxity, grafts will be monitored for ligament regeneration, bone formation in the bone tunnel, and acceptable polymeric bioresorption characteristics. Simultaneously, methods of preservation for storage and delivery of the hybrid graft will be developed by leveraging proprietary strengths in cell and tissue preservation. Finally, a development and clinical plan will be developed to fast-track hybrid graft(s) that meet acceptable in vivo functional and regenerative criteria into clinical evaluation. This plan will establish operating procedures, including terminal sterilization, meet design control requirements, and establish control over generation of the Device Master Record necessary for regulatory filing.

Relevance: The proposed project directly addresses the use of acellular regenerative tissue matrices for repair and regeneration of orthopedic tissues. Successful completion of this research program will establish the preclinical in vivo feasibility and development criteria for an off-the-shelf, truly regenerative ACL graft compatible with military medical capabilities. This hybrid graft will have direct impact on ACL reconstruction for both military and civilian patients in that it will address the significant disadvantages of all current graft selection options. Moreover, successful implementation of the proposed method for ACL regeneration through directed RTM transition, both in the presence and absence of polymeric strength components, will serve as a platform for application to regeneration of other orthopedic tissues, thereby addressing significant unmet medical needs for both military and civilian trauma care.