(2mo) Design of Advanced Functional Materials for Cardiovascular engineering

Executive Summary: The long-term goal of my research group is to address cardiovascular engineering challenges using chemistry strategies to develop materials that are sustainable, scalable, and clinically relevant. Our materials approach will combine the molecular design creativity of chemists with the application-oriented mindset of biomaterial scientists to create comprehensive solutions to cardiovascular challenges. In bridging these disciplines, my research program will leverage dynamic chemistries to develop injectable materials that can be seamlessly translated into laboratory and clinical practice. By using sustainably sourced polymers that are cost-effective and readily accessible, our goal is to expand the use of these materials for human health applications in a manner that is environmentally and economically responsible. These user-friendly materials will be designed as 1) Catheter-injectable gels for local drug-delivery, 2) 3D-printed cardiovascular tissues for personalized drug screening, and 3) In situ gelling biopolymers for aneurysm therapy. In each of these projects, I will use a holistic approach that combines my technical expertise and scientific creativity in materials development with a thorough understanding of the unmet medical need. My interdisciplinary approach positions me to guide a preeminent research group that will develop cardiovascular disease therapies to advance sustainable engineering practices and impact patient health.

Catheter-Injectable Gel for Drug Delivery to the Beating Heart: Cardiovascular therapies after a myocardial infarction (aka heart attack) often rely on systemic delivery that requires multiple injections and doses that present off-target concerns, thereby significantly limiting their clinical translation.1-9 Furthermore, many therapies have a short lifespan due to rapid clearing,10,11 diffusion away from the affected area,12-14 and degradation.15,16 To mitigate these effects, several gels have been explored for use in heart therapy, however, none to date have demonstrated a statistically significant improvement in cargo delivery while still being clinically relevant in a surgical setting.3,17-19 To overcome this, my laboratory will develop an injectable nanoparticle (NP) crosslinked therapy-eluting hydrogel that solves two critical challenges in myocardial drug delivery: (1) rapid diffusion away from the infarct zone due to the mechanically active heart and (2) delivery of a sustained therapeutic dosage that maintains its bioactivity. We will achieve this by integrating NPs as crosslinkers to anchor them to the gel, resulting in the delivery of a reservoir of therapeutics, and limiting off-target effects.

3D-Bioprinted Cardiovascular Tissue Models for Rapid Drug Screening: Drug-induced cardiotoxicity is the primary reason drugs are removed from clinical use.20-27 As the FDA Modernization Act 2.0, no longer mandates animal testing during drug development,28-30 it is essential to implement new user-friendly, cost-effective, and scalable models to assess the risk of cardiotoxicity. 3D bioprinting is an innovative technique that can enable the rapid fabrication of in vitro cardiovascular models to evaluate emerging therapies.31-37 Nevertheless, the use of 3D bioprinting has been limited, in part due to a lack of bioink materials that can be both printable and promote tissue growth.38 While hydrogels are ideal tissue culture materials,39- 43 traditional hydrogel crosslinking chemistries aren't well-suited for 3D bioprinting.32 Statically crosslinked hydrogels suffer from poor extrudability, while physically crosslinked gels have limited stability. 44-48 To address these limitations, my group will develop a hydrogel platform that uses both transient and static crosslinking strategies, enabling ideal printability while improving post-printing stability and maintaining cellular support. The static bonds will act as anchors, while the dynamic bonds will impart bulk mechanical properties, resulting in a shear-thinning, viscoelastic hydrogel that mimics the cardiovascular matrix in composition and mechanical properties. The bioink will support the scalability of 3D bioprinted cardiovascular models, enabling cardiotoxicity testing of diverse cell lines that account for individual variations in sex and ethnicity for more comprehensive and inclusive representation.

In situ gelling polymers for abdominal aortic aneurysm: Abdominal aortic aneurysm (AAA) is a cardiovascular disease that affects our aging population.49-51 While the pathophysiology of AAA is not completely understood, saccular AAAs are the most concerning.50,52 As the disease progresses, the abdominal aorta starts to develop outpouching due to the degradation of the ECM, allowing blood to enter the vulnerable pouch and increasing the risk of rupture. 53-55 There are limited treatment options for AAA. Early intervention is aimed at managing symptoms, while late-stage intervention involves exchanging the damaged vessel with a synthetic replacement, which does not promote regeneration and may fail over time.56-58 To provide an early therapeutic strategy that regenerates the damaged tissue, my group will develop an in-situ gelling copolymer that can be delivered via a minimally invasive catheter as a liquid to fill the pouch. Upon contact with biomolecules present at the aneurysm site, it can then rapidly crosslink to form a robust gel. The copolymer is designed to crosslink with aminecontaining biomolecules at the aneurysm site, without the need for light, catalysts, or external reactive motifs. The resulting gel will fill the aneurysm with a densely packed network, preventing rapid blood flow into the pouch and reducing the risk of rupture. Lastly, we will deliver therapeutics to aid in neovascularization.

2. Previous Research

I am a polymer chemist, biomaterial scientist, and cardiovascular bioengineer. My graduate work, under the mentorship of Prof. Peter X. Ma, focused on broadening the use of sustainable tissue engineering platforms by developing polymers with chemical functionality that can be easily and rapidly fashioned into biomimetic physical constructs and activated with regulatory signals (i.e. biomolecules, peptides, and growth factors). Specifically, I developed novel polymer synthesis methods that are cost-effective and facile to ease the path toward clinical translation. By developing practical and easily tunable materials that limit the upfront investment necessary to implement these powerful tools, we can increase the accessibility and usage by clinicians who do not traditionally employ synthetic biomaterial platforms for regenerative medicine. As a postdoctoral researcher, I have worked toward my long-term goal of developing sustainable materials for cardiovascular medicine. During this training, I have been a member of an interdisciplinary team mentored by Prof. Sarah Heilshorn (Materials Science and Engineering) and Prof. Joseph Wu (Stanford Cardiovascular Institute) as an American Heart Association Postdoctoral Fellow and currently as an NIH K99 Maximizing Opportunities for Scientific and Academic Independent Careers Postdoctoral Researcher. Under their guidance, I am tackling the pressing challenge of delivering a therapeutic agent to the beating heart tissue to provide sustained therapeutic effects in vivo. This work has broadened my expertise in biopolymers, injectable materials, the use of animal models for in vivo experiments, and cardiovascular biology. This unique interdisciplinary training has positioned me to succeed in leading a research program that uses creative, sustainable chemistry to solve unmet clinical needs.

3. Teaching Interest

I have a multidisciplinary background in chemistry, bioengineering, and chemical engineering, which makes me qualified to teach the core and interdisciplinary courses in these departments. In addition to the fundamental topics of Engineering Design, Intro to Materials, Intro. to Chemical Engineering Thermodynamics, and Intro. to Biomolecular/Biochemical Engineering, I am particularly interested in developing elective courses in Biomaterials for Drug Delivery, Colloids and Biointerfaces, and Hydrogel Design. My approach to curriculum development for electives is to balance the teaching of fundamental chemistry and engineering topics with exciting applications that highlight current research themes. Beyond the technical curriculum, I look forward to partnering with experts within the university and externally who study URM experience in higher education to identify areas to improve introductory engineering courses to retain URM students in engineering through more inclusive educational practice.

Teaching Experience:

Stanford University

Guest Lecturer: Adapted and presented lecture content

MATSCI 81N: Bioengineering of Materials to Heal the Body

Biomaterials Techniques, Spring 2023

Biomaterials for Gene Therapy, Spring 2023

Guest Lecturer: Adapted and presented lecture content

MATSCI/BIOE 381/361: Materials for Regenerative Medicine

Introduction to Protein-Engineered Biomaterials, Spring 2021

Introduction to Protein-Engineered Biomaterials, Spring 2022

University of Michigan

Teaching Assistant: Developed and presented lecture content and weekly quizzes CHEM 125: General Chemistry Laboratory, Fall 2015 & Spring 2016

Texas State University – San Marcos

Teaching Assistant: Developed and presented lecture content and weekly quizzes CHEM 1341: General Chemistry Laboratory, Spring 2013 - Fall 2014