(2fn) Developing Materials-Based Biointeractive Therapeutics and Technologies

My research interest is leveraging biomaterials and fabrication methods to develop creative solutions for unmet therapeutic needs in the biomedical field. Therapeutic agents have expanded rapidly beyond small molecules to include peptides, proteins, antibodies and even live-cells. However, their potential has remained limited due to the fundamental differences in how molecule, biologics, and cell-based therapies function. Therefore, delivery strategies and technologies should be developed accordingly to adapt to reflect changing drug delivery needs.

My research vision combines engineering and an understanding of biological processes to develop technologies that can fulfill their therapeutic potentials. Effective strategies to reach this goal will require the integration of expertise in engineering, biology, material science, drug delivery and medicine. My work during my PhD at UCLA and post-doc at the Brigham and Women’s Hospital/Harvard Medical School has provided a strong background for this proposed research. During my PhD at Dino Di Carlo Lab, I focused on engineering biomaterials and developing fabrication methods for different biomedical applications, including 3D bioprinting of the native heart (Figure 1A) and single-cell-based diagnostics and therapy using microfluidic technologies (Figure 1B). Since I joined the Karp and Joshi Labs at BWH, I have expanded the scope of my research even further by developing ultra-long acting injectables and nanoparticles as drug delivery platforms (Figure 1C and 1D).

While I have a broad interest in developing materials-based biointeractive therapeutics and technologies, my initial research will focus on applications in biomaterials that expand the potential of emerging technologies in the field of biomedicine, specifically in areas like 3D bioprinting, single-cell studies, and precision medicine to leverage my experience from my PhD and postdoctoral work. My research group will combine expertise in micro/nano-fabrication and polymer biomaterials to address challenges in biopharmaceutical delivery using 1) 3D bioprinting, 2) Single-cell analysis, and 3) Stimuli-responsive local delivery.

1. 3D bioprinting of soft complex tissues

The main challenge in tissue engineering is the difficulties of recreating the exquisite microarchitectural features of biological organs, such as the heart, lung and vascular networks. 3D bioprinting has potential to revolutionize the next generation of tissue engineering, as it can interfere and manipulate the interactions between materials and biological systems in microscale. However, there are several drawbacks of current bioinks and printing methodologies that limit the ability to print elastic and complex tissues. The demanding nature of the design criteria for ideal bioinks limits the available options, requiring extensive study on material properties including mechanical and rheological characteristics, reaction kinetics, and biocompatibility. Therefore, my initial research will focus on developing novel printable biomaterials that can create complex soft tissues. To meet these criteria, my research group will develop smart materials that shift their mechanical, rheological, and reactive properties upon temperature, pH or ionic changes. Also, I will utilize multiple extruders, gel-in-gel printing technique, and sacrificial templating techniques to maximize the resolution and complexity of the printed structures. My 3D bioprinting and tissue engineering background will be critical to optimize the printability of the materials while keeping physiologically relevant conditions during printing.

2. Single-cell analysis for therapeutic applications

The progress made in biotechnology has revolutionized our understanding of living cells over the past decades. Cells, which used to be regarded as simple organisms, can now serve as therapeutic factories producing monoclonal antibodies, or can be utilized directly as living drugs, as exemplified by CAR T cell therapies. While collective cell behaviors heavily rely on cellular interactions regulated through secretions from neighboring cells, the accurate detection and quantification of these chemicals is a huge challenge. As a result, there remains a limited understanding of the intricate dynamics underlying such signaling processes. Therefore, my research group will focus on developing multiplexing single-cell technologies that are compatible with downstream applications. I believe the single-cell assay platform should be easily accessible and affordable so that many researchers can take advantage of the technology. I will incorporate fluorophore conjugated antibodies as detection probes for the secretions to develop a versatile platform compatible with common instruments such as microscope and FACS which are easy to be found in any research institute. I will exploit sandwich assay and reversible antibody immobilization to achieve high resolution and enhance the multiplexing capabilities. The success of this project hinges on the capacity to capture and confine small quantities of secretory molecules produced by individual cells within picoliter to nanoliter volumes. My experience during PhD in developing a nanoreactor based single cell assay platform will be invaluable resource for the proposed study.

3. Stimuli-responsive local delivery of biologics

Antibody therapies have shifted the treatment landscape for inflammatory diseases, enabling long-term remission for patients. Antibodies are typically administered through intravenous infusion, which can be time-consuming and require specialized medical facilities or personnel. Moreover, systemic exposure increases the risk of opportunistic infection from suppression of the inflammatory response throughout the entire body, as well as the risk of developing anti-drug antibodies. Thus, technologies that enable targeted delivery of antibodies directly to the target organ would reduce systemic exposure, lower required doses, and potentially increase the duration of effective therapy. My strategy for local delivery exploits the design of biomaterials responding to the distinct physiological environment in inflamed regions. Inflammatory processes can result in the release of various ions and molecules, including protons, cytokines, and chemokines. These substances can alter the local ion concentrations and pH levels at the inflamed area depending on the type and severity of the inflammation. I will tailor my materials to be responsive to abnormal surge in charge or chemicals accumulation in inflamed region to trigger the effective release of the therapeutics at target area. The delivery platforms will be fabricated in nano/micro-particles or injectable implants depending on the target diseases. The expertise I earned during my postdoc research in using polymers and affinity-directed dynamics to modulate protein pharmacokinetics will be critical to tune the release of biologics in response to changes in physiological environment. As this technology matures, it can be used to deliver combination therapies with controlled pharmacokinetics and increased treatment synergy.

Teaching Interests

The driving motivation for my career goals is to make a difference in the lives of others. Beyond helping people through my research, my other motivation for obtaining a faculty position is to have the opportunity to closely train and mentor the next generation of scientists. At each phase of my education, I have had opportunities, support and role models that were necessary for me to succeed. I believe that I owe my responsibility to provide my support, expertise, and mentorship to the scientific community.

Both my teaching and mentorship philosophies center around designing experiences that will help students develop skills towards maximizing learning and helping to define and achieve career goals. I aim to design learning experiences that empower students to become independent thinkers, by building their scientific toolbox, developing critical thinking skills, encouraging curiosity and creativity, and providing the support required for these experiences to be positive, both in the classroom and lab. To achieve this goal, I believe it is important 1) to cultivate an inclusive learning environment, 2) to stimulate student engagement, and 3) to foster self-directed learning.

1. Inclusive learning environment

I recognize that students come to courses with different backgrounds, goals, and interests. In creating an inclusive classroom environment, I want to foster an environment of open communication to solicit student feedback, invite questions and define course norms - such as the purpose of office hours. Asking and answering questions stimulates the learning process, but there are occasions when students, myself included, feel reluctant to ask questions or attend office hours because they believe they do not know enough to ask a good question. I hope to implement methods to reduce these barriers by encouraging students to come to office hours even if they just want to listen to the questions of others and providing a way for students to ask questions anonymously.

2. Student engagement

Maximizing student engagement in the classroom is critical, especially with the many sources of distraction available. Courses that promote active student participation in classes are more engaging than lecture-based classes and encourage students to come to class prepared. I plan to create opportunities for students to think independently about class materials as well as the opportunity to share and learn with their classmates in think-pair-share and small group-based discussions or activities.

3. Project-based learning

It is also my experience that self-directed learning provides students the opportunity to apply course concepts to topics of interest to them. Project-based learning enables the instructor to have the flexibility to use different evaluation mediums to accommodate different learning styles, and promotes student exploration, allowing them to take a deeper dive into course topics. The opportunity to apply and extend course content to the real world results in a learning opportunity that may hit multiple levels on Bloom’s Taxonomy, resulting in a deeper understanding and better long-term retention of course content. I will implement formative assessments for students to check their understanding and receive feedback in a low-stakes environment before they receive summative assessments.