Computational Model-Driven Design of Organ Scale Vasculature for Biomanufactured Tissues

About This Grant

PROJECT SUMMARY Biomanufactured tissues hold enormous promise for repairing and restoring cardiac function in patients with cardiac disease and failure, and ultimately for whole organ replacement. There is a particularly pressing need for bespoke design of tissues to repair complex congenital heart defects (CHD) which present with highly vari- able anatomies. For example, in patients with large ventricular septal defects (VSDs), surgeons currently implant an inert patch which can impair overall cardiac function and cause electrophysiological issues. Creating and implanting contractile, conducting, functional tissue, matched to the patient-specific defect, would enhance car- diac function and could increase transplant free survival in CHD patients. However, a major barrier to creating large-scale functional tissues is the need for adequate perfusion and oxygen delivery via vascular networks. Prior methods have relied on either diffusion (at scales below 20µm) or simplified lattice designs which have been shown to leave large pockets of tissue at risk for poor perfusion and necrosis. Our team recently developed a fast algorithm capable of generating space-filling vascular trees in complex geometries to support the design of bioprinted tissues. We demonstrated that these trees vastly outperform prior lattice designs and produced water-tight printable designs that could achieve baseline cell viability. As a next step, computational models of biofabricated tissue should incorporate functional deficits in the event of inadequate perfusion. Such predictive modeling would greatly accelerate the engineering design of functional tissues. Herein, we propose to develop and validate a multi-physics solver to predict the function of vascularized bioprinted tissue and to use this solver to guide the design of a contractile cardiac patch that will be implanted in a porcine model of CHD. To achieve these objectives, we propose three specific aims. In Aim 1, we will experimentally probe permeability constraints to inform a computational model of vascularized tissue perfusion. We will validate our model in a cell viability study using cardiac orgonoids. In Aim 2, we will add key functionality to our multi-physics solver which will couple perfusion, cell metabolism, and myocardial contraction to assess function of bioprinted tissue. We will carry out targeted experiments to inform and validate model components, allowing for iterative improvement. Importantly this model will reveal functional impairment in the event of perfusion deficit, a feature that is lacking in current modeling approaches. In Aim 3, we will deploy the simulator to design and print a functional cardiac tissue patch for a VSD. We will demonstrate viability and contractile function via in vivo surgical implantation in a porcine model of CHD. This proposal brings together an interdisciplinary team comprising experts in computational mod- eling of cardiovascular biomechanics, biofabrication of living tissues and 3D printing technology, vascular biology and regenerative medicine, and pediatric cardiac surgery. Our ultimate goal is to improve cardiac function and long-term outcomes for CHD patients by producing bespoke functional tissues for cardiac repair.