CAREER: Phase-Shift Microbubbles for Intravenous Oxygenation

Columbia University, New York NY

Investigators

Abstract

0952681 Borden Biologically inspired colloids (biocolloids) are increasingly being employed to detect and treat human disease, but the field lacks cohesion and integration within university curricula. An integrative plan is proposed to build a career on (i) research that develops potentially transformative biocolloid technology, (ii) teaching that collects and disseminates principles in biocolloid engineering and creates adaptive expertise within the research group, and (iii) service that integrates local underrepresented and under-resourced youth directly into the research and educational activities and provides an avenue for professional development. The primary research goal is to develop biocolloids (specifically microbubbles) as a method for intravenous delivery of oxygen (IVO2), which would have an immediate and profound impact on the treatment of patients presenting acute and sub-acute hypoxia, e.g., owing to airway obstruction (20 million incidents/yr), cardiac arrest (1.3 million incidents/yr), traumatic brain injury (1.4 million incidents/yr), or organ transplantation (28,000 incidents/yr). IVO2 would supplement current treatment, including ventilation and extracorporeal membrane oxygenation, by providing lifesaving oxygen where these technologies are inadequate or injurious. IVO2 is superior because it does not exacerbate airway problems or require blood to exit and reenter the body. The approach taken here is to disperse oxygen gas into trillions of micron-scale bubbles (small enough to traverse capillaries), each stabilized by a nano-scale bioresorbable phospholipid shell and suspended in saline. While efficient oxygen encapsulation and stability are paramount outside the body, the microbubbles must rapidly disintegrate to release oxygen to unsaturated hemoglobin and oxygen-starved tissue once injected into blood. To address this paradox, the proposed microbubble design employs a monolayer shell that undergoes a thermotropic phase transition as the suspension heats up to body temperature. The rational design of temperature-sensitive IVO2 microbubbles requires empirical data and modeling parameters relating shell composition to biomedical performance. Aim 1 focuses on the experimental exploration of microbubble shell phase behavior. Aim 2 parameterizes this physicochemical knowledge into the model-based design of an IVO2 formulation. Aim 3 involves in vitro testing and optimization to prove feasibility and provide feedback for future design. The primary deliverable of the education plan is a biocolloid engineering track that serves graduate and undergraduate students and underrepresented and under-resourced minority elementary and high school students in the surrounding community. An approach is taken to integrate the research and education goals, facilitate knowledge transfer and promote meta-cognitive skills. Ultimately, the work seeks to promote higher education, develop critical thinking skills and establish a robust philosophical approach to biocolloid design. The intellectual merit of this work is that it will establish a framework for optimizing phase-shift microbubbles by determining quantitative interrelationships between composition, temperature and stability. The concept of phase-shift microbubbles, in which a thermotropic transition in the lipid shell induces rapid and irreversible dissolution of the oxygen core, is novel. The work will reveal fundamental insights into lipid membrane behavior. The proposed IVO2 technology is transformative and may improve the outcome of critical care patients who require a rapid, direct infusion of oxygen. The broader impact of this work is that it will advance a novel therapy for acute hypoxemia while developing pedagogical tools for biocolloid engineering. A novel course sequence, textbook and symposia series will be created to expose undergraduate and graduate students to the science and application of biocolloids. The work will impact science and engineering education beyond the university through outreach activities geared to K-12 students. Talented and motivated minorities will be recruited from these programs to participate in the research and educational activities.