Spatial Design Principles for Vascular Integration in Soft Tissue Repair and Ischemia

Abstract

Successful integration of engineered tissues depends on the timely establishment of a functional vascular supply. While many vascularization strategies aim to enhance angiogenesis through increased delivery of pro-angiogenic cues, clinical and experimental outcomes remain inconsistent, particularly in grafts and ischemic environments where vascular access is spatially constrained or severely compromised. This thesis advances the premise that vascularization is fundamentally governed by spatial accessibility rather than angiogenic magnitude alone.

In Chapter 2, spatial regulation of host-driven angiogenesis is investigated using bioprinted adipose tissue grafts as a clinically relevant model system. Both cellular angiogenic sources (adipose-derived stem cell spheroids) and acellular cues (platelet-rich plasma) are systematically engineered in size, dose, and spatial distribution. These studies demonstrate that precise spatial organization of angiogenic cues enhances host vessel infiltration, reduces fibrosis, and improves long-term graft preservation. However, despite optimized angiogenic stimulation, regions lacking early vascular access remain vulnerable to hypoxia-driven degeneration, revealing an intrinsic limitation of recruitment-based strategies.

Chapter 3 addresses regenerative contexts in which host angiogenesis is insufficient, such as ischemic tissue. Spatially engineered pre-vascularized constructs containing patterned microvascular architectures are developed to function as active vascular units capable of rapid anastomosis. In ischemic limb models, these constructs restore perfusion, enhance tissue survival, and promote functional recovery, with outcomes governed by architectural organization and alignment with the host microvasculature rather than angiogenic factor secretion.

Together, this work establishes a unified framework for vascular engineering based on spatial accessibility and perfusion dependency. By defining when angiogenic recruitment is sufficient and when vascular rescue through pre-organized microvascular support is required, this thesis provides design principles for engineering vascularized tissues across a spectrum of regenerative environments.