Marissa Ruehle

PhD Proposal Presentation

Date: Thursday, June 8th 

Time: 10:30 AM

Location: EBB CHOA seminar room

Advisors:

Dr. Robert Guldberg

Dr. Nick Willett

Thesis Committee:

Dr. Joel Boerckel 

Dr. Andres Garcia

Dr. Jay Hoying

Dr. Rebecca Levit 

Title: Cell-Based Vascular Therapeutics for Enhanced Bone Regeneration

Abstract:

Bone is a highly vascularized tissue, and adequate vascularity is an essential requirement for proper bone healing. Vascularity is a challenge in critical-sized defects, especially those with concomitant muscle damage typical of traumatic injury. The Gustilo Classification system scores open fractures from I to IIIC in order of increasing severity, increasing complication rate, and increasing patient morbidity. The hallmark of the most severe class IIIC injuries is the presence of vascular damage. These patients heal slowly and exhibit higher rates of infection and non-union, underscoring the critical importance of vasculature to bone healing. Additionally, the bone defect environment is a complex niche, involving mechanical cues in addition to a host of chemical signals. It is well known that mechanical loading affects bone growth and remodeling, and while flow-mediated mechanics influence the vasculature, effects of bulk matrix deformation are not well understood. To most effectively leverage the use of a vascular therapeutic in this space, we must better understand the effect of the relevant mechanical loading environment on the vasculature. Microvascular fragments (MVF), multicellular structures derived from mature vasculature, form networks in vitro and anastamose with the host vasculature when implanted in vivo. As such, they are a useful in vitro model of mature vasculature and may be a viable therapeutic candidate. Stromal vascular fraction (SVF) is a single cell digestion of mature vasculature that also forms networks in vitro and has been used as an in vivo therapeutic. The overall objective of this thesis is to increase understanding of mechanical effects on vascular growth in order to engineer a cell-based vascular therapeutic for enhanced bone regeneration. The overarching hypothesis is that cell source, material delivery vehicle, and mechanical environment each influence the efficacy of a vascular therapeutic for critical-sized bone defects.