"Development and Validation of an Advanced Mechatronic Perfusion Platfo" by David Dellal

Development and Validation of an Advanced Mechatronic Perfusion Platform

Date of Award

Spring 2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering (ENAS)

First Advisor

Sestan, Nenad

Abstract

In the United States alone, there are over 105,000 people who are critical ill and need an organ transplant. While organ transplantation is one of the most successful forms of treatment offered by modern medicine, with 1-year survival rates greater than 90%, 17 people die per day since they are unable to access this life-saving intervention. Yet, while there is a dearth of organs available for transplant, there are more than 13 donor organs that are discarded daily in the United States. These organs are not transplanted since there are limited interventions to revitalize marginalized organs. There is a significant clinical and research need for novel solutions that are capable of recovering and preserving organs. The BrainEx technology, developed in the Sestan Lab at the Yale School of Medicine, first demonstrated that an advanced perfusion platform could restore circulation, reverse ischemic damage, and recover some cellular functions several hours post-mortem in an ex-vivo large mammalian brain, the organ most susceptible to ischemic injury. The perfusion system, however, had several key limitations that hindered its usage for new models and applications. Here, we describe the development of OrganEx, an advanced mechatronic perfusion platform that is capable of artificially replicating normal physiological conditions to promote organ recovery and preservation. It was designed as a modular system that could be applied to both ex vivo and in vivo settings across a number of organs. Several artificial physiological systems were created, namely cardiovascular, respiratory, and reno-hepatic, that can be leveraged to maintain homeostasis and organ viability. The platform leverages both advanced monitoring systems, capable of real-time analysis of the organ’s condition, and compensatory mechanisms that can execute dynamic adjustments to ensure the stability of the organ. Following the iterative development of the OrganEx platform, the technology was successfully validated in three studies across distinct models. These sought to evaluate OrganEx’s core capabilities and how they could be utilized for improved organ recovery and preservation. The investigation with the first model, namely the ex-vivo isolated porcine brain, found that the system was capable of promoting improved restoration and extended preservation. The study also established that OrganEx is able to serve as a platform technology for novel research applications, which was first validated through connectome tracing. The second model, namely in the ex-vivo isolated porcine kidney, validated the system’s modular design and its ability to support the physiological needs of another organ beyond the brain in an isolated ex-vivo setting. Lastly, the third study was conducted in a whole-body swine model and validated the platform’s ability to restore systemic circulation and some metabolic homeostasis, as well as cellular and tissue recovery, across multiple organs. The OrganEx technology has been developed and established across several models as an advanced, modular mechatronic perfusion system. It offers the possibility to expand improved perfusion studies across numerous organs. OrganEx holds the potential to serve as a platform technology that numerous research and clinical applications can be built upon to support scientific advancements and address critical patient needs.

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