(2cc) Excipient-Based Strategy for Engineering Stable Ultraconcentrated Insulin Formulation

Over the past several decades, protein therapeutics have seen a substantial increase in utilization, but the challenge of maintaining their stability during shelf-life in ambient conditions persists due to their inherent propensity to aggregate. In particular, the demand for insulin formulations resilient to room temperature and heat stress, essential for wearable insulin delivery devices such as pumps and patches and applications in countries where cold-chain delivery is not trivial, is paramount. Despite this need, such formulations are still inaccessible. In our study, we have successfully engineered a novel class of excipients based on fructan-type polysaccharides that facilitate ultra-concentrated insulin formulations (1000 units/ml) with enhanced solubility and stability. These excipients stabilized insulin without direct interactions, ensuring its structural and functional integrity for up to 6 months under stress aging conditions (37°C, continuous agitation). Our U-1000 insulin formulation boasts a concentration 10-fold higher than conventional U-100 insulin products (Novolog®, Fiasp®) available in the market. Conversely, U-100 formulations typically succumb to significant aggregation and undergo a marked decrease in efficacy (30-50 fold) within a month of stress aging. In vivo studies confirm the fully maintained efficacy of the insulin in our U-1000 formulation even after 6-month aging. Our novel drop-in excipient approach provides new insights into the mechanisms of protein aggregation and degradation. This research underscores the potential of excipient-based strategies to overcome key challenges associated with protein therapeutics, such as poor stability, aggregation, degradation, and suboptimal pharmacodynamics. It also paves a new avenue for enhancing therapeutic strategies for patients requiring insulin therapy.

Research Interests

I chose my academic and research training pathway to align with my career goal of becoming an independent investigator. Over the past 10 years, I have been continuously working in the field of engineering to address challenges in the biomedical field. My previous research career can be divided into two stages. During the initial stage, my focus was predominantly on materials research, wherein I endeavored to broaden the functional scope by integrating biomimetic properties. In the second stage, my research transitioned towards the biomedical field, specifically aimed at forging a connection between research breakthroughs and their applications in medicine. Throughout my postdoctoral training, I immersed myself in translational research, accruing invaluable experience and forging collaborations with experts across the fields of engineering, medicine, and pharmaceutical science. Building upon these previous research endeavors, my research interest now lies in leveraging synthetic macromolecules to facilitate the development of biologics.

In the ever-expanding field of biomolecular biology, we have witnessed the emergence of numerous biomolecule-based therapies. Natural biomolecule-based materials have gained significant attention as potential alternatives to synthetic polymers, thanks to their broader range of chemical and physical properties, enhanced biocompatibility, and biodegradability. However, they all face the challenge of limited accessibility, primarily due to stability issues that hinder their production and widespread application. Considering these challenges, my research will primarily focus on engineering synthetic or hybrid macromolecular platforms to preserve and amplify the functionality of biomolecules in non-native environments. By designing and fabricating innovative synthetic or hybrid systems, we aim to overcome stability limitations and optimize the performance of biomolecules for various applications.

First of all, macromolecules mimicking disordered biomolecules are expected to offer a versatile approach to the solubilization and stabilization of biomolecules. Rational design of chemical and architectural characteristics of macromolecular may be feasible to stabilize the surface hydration of biomolecules and prevent hydrophobic-driven misfolding without direct interaction between them. In addition, the physicochemical similarities between synthetic macromolecular and natural biomolecular systems bring new opportunities but have been rarely explored. For example, liquid-liquid phase separation is a well-known physicochemical phenomenon in polymer science that has recently emerged as a fundamental infrastructure governing various cellular process. Phase-separated biomolecular droplets exhibit various unique functions such as buffering of molecular concentrations, sensing of stimuli, compartmentalization, promotion of successive reactions, molecular filtration, and preservation. Taking the valuable functionality of phase separation in supporting biomolecule-related activity, constructing polymer-based liquid phase condensates would also be an intriguing method to host biomolecules and preserve desired functionality independently. Following the above-mentioned roadmaps, I envision my research expanding into elucidating the molecular grammar behind biomolecule-based behavior. For example, polymer-based phase behavior and the complex polymer–biomolecule condensates should be useful as models for pure biomolecule-based phase behavior. The design of hybrid networks formed through mixed molecular associations holds tremendous potential in areas such as chemical biology, drug delivery, and functional biomaterials. This represents long-term research interests that will allow me to use the knowledge of synthetic networks to mimic and support the functionality derived from biomolecular systems.

Teaching Interests

Chemical engineering is a field that intersects with various disciplines such as chemistry, physics, and biology, among others, to efficiently design, produce, and transform energy and materials. Therefore, it is crucial to create a nurturing environment where students can develop goal-oriented mindsets and explore a wide range of topics. In my teaching approach, I strive to challenge students to establish connections between different disciplines and cultivate problem-solving skills. To accomplish this objective, I consistently encourage students to delve deeper into the course material and engage in collaborative work with peers from diverse backgrounds. Additionally, I aim to adopt a reflective teaching strategy by allocating more time to students and incorporating feedback to continuously enhance my teaching methods.

I have gained valuable experience as a graduate teaching assistant for three consecutive semesters, where I had the opportunity to instruct key courses such as "Transport Phenomena," "Equilibrium Thermodynamics" (for undergraduate students), and "Classical Thermodynamics" (for graduate students). These courses encompassed both small classes, with around 10 students, as well as larger lectures with approximately 35 students. In addition to my classroom teaching, I have also served as a mentor for undergraduate students in their Project Management and Teamwork (PMT) course. This course holds significant importance in the development of well-rounded chemical engineers, as it focuses on enhancing crucial skills such as teamwork, communication, presentation, project management, and information technology proficiency. As part of the PMT course, students from various academic levels collaborate within a design team to address real-world chemical engineering problems. Furthermore, I am currently involved in the departmental internship program, where I serve as a mentor to high school students learning about science, medicine, and research. These experiences have equipped me with a wealth of knowledge and skills in effectively engaging students, particularly those with diverse backgrounds and distinct educational backgrounds.

Based on my teaching experience, I have observed that students benefit greatly from practical problem-solving, as evidenced by their engagement in the PMT project. I firmly believe that the main challenge in engaging students during lectures lies in their struggle to see the potential applications of what they are currently learning in their future careers, which often leads to a lack of self-motivation. Inspired by these teaching and mentoring experiences, I am motivated to expand the format of traditional didactic lectures to incorporate active case studies into my teaching methodology. My objectives are as follows: (i) Develop a troubleshooting-oriented engineering curriculum: By focusing on cultivating a problem-solving mindset, I aim to encourage students to critically analyze real-world engineering cases, pose questions, and guide them in finding answers with the aid of course materials. (ii) Emphasize cross-disciplinary concepts: I believe it is crucial for students to have a broader understanding of the engineering field. By incorporating cross-disciplinary concepts, students can deepen their comprehension of the subject matter and envision the possibilities in their future careers. (iii) Foster research-based learning in a supportive environment: I am interested in incorporating research or laboratory sessions to enable students to gain a better grasp of fundamental principles through independent critical thinking. Research or lab sessions are effective for students to better understand discipline fundamentals with independent critical thinking. Such research-based sessions will prioritize learning from feedback rather than solely focusing on grading, which can be a more encouraging and productive approach. Through these efforts, I aim to create a dynamic learning environment that nurtures students from diverse backgrounds, encourages their curiosity in science, and facilitates successful careers in engineering research.