DESCRIPTION (provided by applicant): Tissue vascularization is one of the most critical components of the natural or assisted regenerative response. Typically, such areas of regeneration are characterized by the presence of nascent vascular structures moving across an interface of normal tissue to healing areas of likely different mechanical properties. Though the molecular and cellular nature of such angiogenic processes are well investigated, not much is known about the mechanical forces that influence the vasculature. It is well established, especially in the musculoskeletal system, that an effective and early vascularization response is central to functional regeneration, a delay or disruption of which can be deleterious to the regenerative process. Our early studies have shown that timing of the mechanical loading is equally important in healing bone tissue and its vascularity. It is thus clear that the mechanical environment exquisitely regulates the vascular networks. 3D constructs examined in tensile loading and luminal fluid shear studies form the bulk of our knowledge base on the interactions of microvessels with their microenvironment. In vivo, especially in musculoskeletal tissue, compression and shear - both bulk and interfacial - are the predominant modes of loading. We believe that external mechanical loading will influence the growth and remodeling of microvasculature by virtue of the direct compressive loads as well as by shear at the interface of the mechanically loaded and unloaded tissue. This proposal examines these questions first in an in vitro model, which is a simplistic recapitulation of the in vivo loading scenario. These studies will inform an in vivo loading model of microvascular growth and mineralization where in addition to the external forces, mineralization induced change in local stiffness is likely to playa role. In parallel, in silico studies, based on an already well-established computational framework for modeling microvascular growth, will be modified to reflect the needs of the current approach. The validated computational model will then allow examination of these mechanical interactions with vascular growth and remodeling in greater detail and more importantly establish a predictive framework based on this relationship that may ultimately guide post-traumatic rehabilitation programs or even the design of engineered vascularized scaffolds.