Translational Models for Advancement of Regenerative Medicine and Tissue Engineering

At the root of each regenerative medicine or tissue engineering breakthrough is a simple goal, to improve quality of healing, thus improving a patient’s quality of life. Each tissue presents its own complexities and limitations to healing, whether it is the scarring nature of tendon healing or the mechanical complexity driving bone regeneration. Preclinical, translational models aim to reflect these complexities and limitations, allowing for effective development and refinement of tissue engineered therapeutics for human use. The following body of work explores several of these translational models, both utilizing them for tissue regenerative therapy development and evaluating the benefits and complications incurred with each model. This work begins with a discussion of the complexity of bone healing and how dysfunction in the mechanical, surgical, and systemic fracture environment can lead to delayed healing and nonunion. A comprehensive review of the advances in preventative and corrective therapeutics for bone nonunion is included next, with specific focuses on mechanical and tissue-engineered technology. Then, this work presents a tissue-engineered application of mesenchymal stem cells in acute tendon injury, highlighting experimentation in cell fate direction in vitro and intralesional mesenchymal stem cell implantation in vivo. Next, this work presents a series of experiments that evaluated and refined a commonly utilized preclinical model of delayed bone healing, the caprine segmental tibial defect stabilized using single locking plate fixation. First, the biomechanical stability of the model was evaluated in vivo using plantar-pressure analysis of gait. Then, the surgical technique was refined through a retrospective analysis of the effects of plate length and position on fixation stability in vitro and in vivo. Finally, the comorbidities of this preclinical model were explored via an analysis of the effect of long-term tibial locking plate fixation on cortical dimensions and density.