Biomimetic Nanofiber Scaffold Design for Tendon-to-Bone Interface Tissue Engineering

Soft tissues such as rotator cuff tendons integrate with subchondral bone through a direct insertion site, which is a multi-tissue interface that functions to minimize the formation of stress concentrations and enable the transfer of complex loads between tendon and bone. Current rotator cuff tendon repair techniques require the reattachment or fixation of the torn tendon to the bony footprint; however, the native multi- tissue tendon-to-bone interface is not regenerated following repair. Rather, the repaired tendon transitions to bone through a disorganized, fibrovascular tissue with weak mechanical properties, which renders the repair site prone to failure and compromises the stability and long-term clinical outcome. To address the challenge of biological fixation and integration of tendon-to-bone, the objective of this thesis is to design a biomimetic scaffold system that is able to promote the regeneration of the multi-tissue tendon-bone interface and support integration with tendon and bone. Biomimetic scaffold design parameters were established by first characterizing the structure-function relationship of direct insertion sites, which was determined by measuring the mechanical properties and evaluating the mineral distribution across the interface. Inspired by the collagen fiber organization and the controlled distribution of matrix and mineral of direct insertion sites, a bi-phasic nanofiber-based scaffold was designed, optimized and evaluated in vitro and in vivo. Each phase of the Bi-phasic scaffold was characterized and optimized for interface regeneration by evaluating the effect of nanofiber organization and mineral content on interface relevant cell populations. The optimized Bi-phasic scaffold supported the deposition of distinct yet continuous tissue regions that mimicked those of the tendon-bone interface and functionally integrated with bone. The results of this thesis demonstrate the potential of this biomimetic, nanofiber-based, Bi- phasic scaffold to facilitate functional and biological fixation of tendon-to-bone through interface regeneration and osteointegration. The knowledge gained with regard to the structure-function relationship of direct soft tissue-to-bone insertion sites and interface tissue regeneration on stratified nanofiber scaffolds will be highly significant for other musculoskeletal tissue engineering applications in which soft tissue-to-bone integration is critical. The findings described in this thesis will lead to the development of new orthopaedic devices for functional and biological fixation and will demonstrate the potential of nanotechnology for engineering complex tissue systems that can seamlessly integrate and function within the physiological environment.