Animal models of impaired long bone healing and tissue engineering- and cell-based in vivo interventions

Bone healing after injury typically follows a systematic process and occurs spontaneously under appropriate physiological conditions. However, impaired long bone healing is still quite common and may require surgical intervention. Various complications can result in different forms of impaired bone healing including nonunion, critical-size defects, or stress fractures. While a nonunion may occur due to impaired biological signaling and/or mechanical instability, a critical-size defect exhibits extensive bone loss that will not spontaneously heal. Comparatively, a stress fracture occurs from repetitive forces and results in a non-healing crack or break in the bone. Clinical standards of treatment vary between these bone defects due to their pathological differences. The use of appropriate animal models for modeling healing defects is critical to improve current treatment methods and develop novel rescue therapies. This review provides an overview of these clinical bone healing impairments and current animal models available to study the defects in vivo. The techniques used to create these models are compared, along with the outcomes, to clarify limitations and future objectives. Finally, rescue techniques focused on tissue engineering and cell-based therapies currently applied in animal models are specifically discussed to analyze their ability to initiate healing at the defect site, providing information regarding potential future therapies. In summary, this review focuses on the current animal models of nonunion, critical-size defects, and stress fractures, as well as interventions that have been tested in vivo to provide an overview of the clinical potential and future directions for improving bone healing.