CAREER: Programming Vascularization by Design in Porous Composites

University Of Texas At San Antonio, San Antonio TX

Investigators

Abstract

Understanding how blood vessels grow is crucial to advancing many fields, including tissue engineering and cancer research. Many factors influence the growth of new blood vessels, including how much oxygen is available, the chemical signals present and the matrix (environment) through which these vessels are growing. Of these factors, the exact influence of the matrix is the least understood. Studying the influence of factors such as the stiffness and softness of the material, the size and organization of the pores and how these inter-related variables interact to guide vessel growth will enable a better-informed design of suitable porous materials and advance the field of tissue engineering. This Faculty Early Career Development Program (CAREER) project seeks to evaluate the growth of vessels in three dimensions within a variety of materials to map out the design space. A validated computer model will be developed to predict how vessels might grow in as yet untested porous materials. These outcomes will both accelerate the design of new tissue engineering solutions and potentially reduce the cost of their development by enabling rapid screening. Understanding how branching structures grow in nature and how things move through highly porous structures is critical to a variety of fields, including plant root growth in farming, tumors in cancer, natural gas extraction and chemical processing on catalysts. The project's complementary education plan is designed to engage underserved students in science and technical education and instill scientific curiosity in middle school students through hands-on experiments. Research community outreach will be achieved through the development of visualization workshops that will enable researchers to track particle movement through highly porous structures. The overarching goal of this project is to generate a predictive rubric that enables the improved design of porous materials for tissue regeneration optimized for rapid vascularization. Models that determine vessel network patterns based on fluid mass transport are an invaluable first approximation, however their significant deviation from the randomness of natural vessel tree networks indicates that the impact of material/matrix mechanics needs to be further incorporated. This project's Research Plan is designed to test the hypothesis that local matrix compliance affects vascular sprouting, while regional architecture affects growth, and global material compliance affects maintenance and inosculation (joining) of vascular networks. The information gained can be used to design biomaterials that can coax an angiogenic response instead of overwhelming the system with chemical stimuli. The research methodology will involve developing composite materials, using imaging modalities to develop 3D architectural maps and using structural metrics and local mechanical properties as inputs to model vascularization outcomes. The Research Plan is organized under three objectives. The FIRST OBJECTIVE is to measure the specific impact of hydrogel compliance, density, crosslinking and temporal degradation on the vascularization of homogenous hydrogel systems. Studies are designed to test the hypotheses that there is an optimal hydrogel compliance for any hydrogel system that best supports vascularization, that variation of molecular weight, fiber length, gel density and crosslinking can all independently modulate the compliance of the system and that vascular network formation is only possible when the time scale of vascularization is comparable to the time scale of degradation, i.e., when instantaneous regional matrix compliance meets the requirements needed to support vascularization. The SECOND OBJECTIVE is to quantify the effect of scaffold pore size, stiffness and stromal cell seeding on vascularization responses within biphasic scaffold-hydrogel systems. Studies are designed to test the hypotheses that larger pore interconnections are better for enhanced vascularization, and that soft porous scaffolds will allow vascularization with longer segment lengths than rigid scaffolds and that the presence of stromal cells might impact vascularization interdependently with scaffold pore size since greater pore surface areas would result in greater stromal cell number and consequently a stronger vascularization signal. The THIRD OBJECTIVE is to develop and validate a computational mechanics-based model to simulate vascular network formation in biphasic materials comprising a porous material with variable architecture and infiltrated with a hydrogel material permitting vascularization within the pores using both deterministic and probabilistic approaches. Studies are designed to test the hypotheses that development of vascularization over time in hydrogels is affected primarily by material density and global boundary conditions, while the vascularization of porous scaffolds containing hydrogels is significantly affected not only by the scaffold pore size (regional boundary), but also by the elastic modulus of the scaffold material. The novelty of the project's approach lies in adding a mechanical perspective to existing knowledge on chemical and biological processes to understand mechanisms of vascularization and aid in the rapid exploration of any porous biomaterial for architectures suitable for tissue grafts. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.