(4ip) Multiscale Approches for Mechano-Immunomodulation: From Molecular Design to Soft Materials

Immunomodulation that regulates various components of immune systems to achieve effective therapeutic outcomes are promising strategies to resolve health problems, such as immunotherapy and regenerative medicine, and often engages different cell populations at different periods throughout the process. For example, various types of immune cells with different phenotypes and functions are involved in tissue repair at different phases to promote the regeneration processes. Biomaterials that mimic the complex environment of biological systems and deliver biochemical and mechanical cues to the surroundings serve as artificial scaffolds to regulate immune cells for immunomodulation. Signals from the mechanical properties of local microenvironment are sensed by cells and translated into changes in immune cell function. However, material systems that can actively deliver and respond to mechanical forces to regulate immune response temporarily are underexplored. Leveraging my diverse backgrounds in biomaterials, chemistry, tissue regeneration and immunotherapy, my future research will focus on molecular designs of developing the next generation of hydrogel-based soft materials that can actively exert force on surrounding immune systems and adapt their functions in response to mechanical force generated by cells or tissues in a spatiotemporal controlled manner for mechano-immunomodulation. Specifically, three research thrusts will be pursued (Figure attached).

Thrust 1: Modulating Material Mechanics for Activating Regulatory T Cells

Regulatory T cells that infiltrate the tissue to suppress inflammation in later phases of tissue repair play important roles in facilitating tissue regeneration. However, it is unclear how temporally delivering biochemical and physical cues affect their productions. In this thrust, we will fabricate microgels with spatiotemporal control over various mechanical and biochemical properties using photochemistry (Aim 1). We will then combine high throughput experimental approaches with machine learning to optimize the production of regulatory T cells in vitro in response to different properties of microgels (Aim 2). We will further exploit granular hydrogels, microporous scaffolds assembled from microgels, with optimized features to in situ recruit and generate regulatory T cells and examine their therapeutic outcome for bone and muscle regeneration (Aim 3). This study will provide understanding of the fundamental mechanisms to regulate regulatory T cell activity for effective manufacture and control over their functions for therapeutics in regenerative medicine.

Thrust 2: Mechanically Responsive Soft Materials for Tissue Regeneration

Controlled degradation of hydrogel is a key factor in regulating tissue replacement and drug release for tissue regeneration. Although mechanical force is widely existing in the biological system with deep tissue penetration and high precision at desired locations and time, materials systems that undergo degradation triggered by mechanical forces are underexplored. I will investigate force-sensitive molecular motifs known as mechanophores and self-destructive polymers that can be activated by physiological or clinical-relevant force when incorporated in the hydrogel network and tailor profile of the hydrogel degradation and release of immunomodulator in vitro (Aim 1). We will next evaluate hydrogel degradation and release of immunomodulator triggered by mechanical force in vivo when applied for tissue regeneration (Aim 2) and explore their use as mechanically activated drug depot to release drugs for immunomodulation in response to mechanical damage for muscle and bone regeneration (Aim 3). Development of mechanically activated hydrogels will open up exciting new avenues in converting mechanical stimuli into therapeutic functions in tissue regeneration.

Thrust 3: Mechanically Actuated Microgels for Immunotherapy

For adoptive cell therapy for cancer treatment, modulating isolated T cell expansion and functions ex vivo are critical for clinical success. Biomaterials have served as aAPCs by locally providing the required stimulatory cues for T cell activation. Previous studies have demonstrated that the mechanical properties of aAPCs have profound effects on T activity. However, how T cells respond to actively applied mechanical forces is still underexplored. To achieve this goal, I will develop mechanically active, optically powered and controlled microgel actuators that can undergo different motions in a wavelength dependent manner (Aim 1). We will investigate how mechanical actuation can modulate T cell phenotype and functions and elucidate the underlying biophysical mechanisms (Aim 2). Generated T cells will be reinfused to examine the therapeutic efficacy against tumors in vivo (Aim 3). This technology will create a new system to manufacture T cells with desired phenotype and function for T cell immunotherapy and provide mechanistic insight in T cell regulation.

Teaching Interests

One of my key motivations in academic is the opportunity to teach and mentor students. I believe teaching is more than simply delivering knowledge; rather, it is a comprehensive process of inspiring the next generation of scholars. During my time as a graduate student and postdoctoral scholar, I’ve been privileged to both teach and mentor young scientists in STEM fields. While in graduate school at Stanford University, I served as a teaching assistant for an undergraduate/graduate-level course MSE 190/210 Organic and Biological Materials, and was responsible for leading discussion sections, grading coursework, hosting office hours, and invigilating exams. I was also engaged in Stanford Splash Program to give lectures about polymers to students in grades 8-12 from the bay area. Subsequently as a postdoc at Harvard University, I had the opportunity to give guest lectures about biomaterials for BE 125 Tissue Engineering. Stimulating students’ engagement and enthusiasm in learning science has been my chief teaching goal. Through my extensive coursework and teaching experience in chemistry, materials science, chemical engineering and bioengineering, I have developed a solid background to teach courses in the Department of Chemical Engineering. I am flexible and open to teaching a wide range of courses, particularly involving those subjects, such as Thermodynamics, Kinetics, Polymer Science and Bioengineering.