Research Overview

The macroscopic properties of materials are largely determined by their microstructure, which often cannot be changed once made; and this limitation applies to most ‘hard’ materials. By contrast, soft biological materials such as proteins and tissues respond to external stimuli by changing the structure of constituent components and thus properties, which yield adaptive function often inaccessible by manmade materials. Underpinning this contrast is the basic component of biological materials – biomacromolecules with sequentially arranged monomers of prescribed physical and chemical properties. This points toward an opportunity for materials scientists: Can we design sequence-controlled polymers and exploit their self-assembly to create adaptive soft materials and use them to build devices with melded, adaptive function?

This research integrates three core aspects: (i) molecular design and synthesis, (ii) self-assembly and microstructure, and (iii) macroscopic nonlinear (mechanical, electric, magnetic, and optical) properties. Integrating polymer chemistry, polymer physics, molecular theory, advanced characterization, and multi-scale modeling, we are establishing molecule-structure-property-function relations for new classes of adaptive soft materials. Using 3D printing, we transform these materials to functional architectures for applications including soft electronics, soft robotics, optical materials, and tissue engineering.

Current research projects include:

• Bottlebrush polymers and networks
• Associative polymers
• Additive manufacturing of soft/inorganic matter for soft robotics and catalysis

Biological tissues are not a random assembly of cells but a hierarchical and tightly controlled three-dimensional (3D) organization of various cell types. Current systems for modeling human biology, however, are predominantly based on the two-dimensional (2D) culture of human cells and animal models of tissue and organ function. As a crucial complement to these systems, 3D cell assemblies are increasingly being used in modeling tissue development and diseases, for in vitro drug screening, and as in vivo replacements for damaged tissues and organs. Yet most 3D cell culture systems start with clusters or a random assembly of cells with the assumption that the originally random cells can appropriately self-organize over time. However, this premise has been recognized to be questionable.

The overarching goal of this research is to engineer functional 3D tissue mimics through programmable cell assembly. Our approach is inspired by Minecraft, a popular video game that uses individual 3D cubes as voxels to create a virtual world. We use cell-encapsulated hydrogel particles as voxels, assemble the voxels to create hierarchical and organized 3D structures, and exploit biophysical and biochemical cues to program the assemblies to functional tissues. The central hypothesis is that such programmable cell assembly allows for precisely delineated cell phenotypes and thus highly functional tissues. The vision of this research integrates three aspects: (i) voxelated bioprinting, (ii) modular biomaterials, and (iii) functional tissue mimics. This research will provide a suite of tools for programmable engineering of 3D tissue mimics for basic and applied biomedicine.

Current research directions include:

• Development of voxel bioprinting platform
• Modular biomaterials with tailored biophysical and biochemical properties to direct cell interaction and behavior
• Engineering functional tissue mimics for basic and applied biomedicine

Current biomaterial design largely relies on flexible linear polymers. This simple molecular architecture intrinsically limits the creation of biomaterials with nonlinear elasticity and relaxation dynamics matching the complexity and variations in tissue-specific mechanics. Moreover, chemical modification is needed to allow polymeric biomaterials to engage with cells. However, this chemical modification may change the polymer physics parameters and the biophysical properties of linear polymers. 

We are encoding biophysical and biochemical complexity into the molecular architecture of bottlebrush polymeric biomaterials, an emerging area in which we have been one of the pioneers. Using a combination of controlled chemical synthesis, theoretical modeling, in vitro cell culture models, and in vivo animal models, we are investigating the interactions between modular bottlebrush biomaterials and proteins, cells, or tissues. Based on this understanding, we apply the developed biomaterials for therapeutic delivery. 

Currently, we focus on three application areas:

• Mucosal drug delivery
• Delivery of therapeutic proteins to treat diabetic foot ulcer
• Delivery of therapeutic cells to reverse type 1 diabetes

As we are alive, we must breathe. This process of breathing brings bacterial, viral, and environmental particulates into our lungs. How can the lungs fight against them? Biologists have discovered that, in the airway, particles are trapped by mucus and cleared out from the lung by coordinated cilia beating of airway epithelia, a process that is reminiscent of transporting people on an escalator. The clearance of mucus is the primary innate defense mechanism that protects the lung from inhaled pathogens. It remains a mystery, however, how and why mucus can be transported from the lower to the upper airway against gravity. This active transport phenomenon is ubiquitous among animals ranging from mice to giraffes, which possess radically different airway lengths. Importantly, the failure of this upward transport associates with mucus obstructive lung diseases, including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis (CF), and the emerging COVID-19. This research aims to understand and restore the active transport of mucus in the lung.

Our approach to studying mucus transport started with engineering a micro-human airway model mimicking the conditions in vivo. Existing studies rely on a closed circular cell culture model, where the beating of cilia must adapt the circular geometry; this inevitably results in a swirl-like motion of mucus. By contrast, in the airway, the mucus is directionally transported. To this end, guided by fluid dynamics and using additive manufacturing, in recent months we had developed a prototype mucus clearance device that successfully captures the geometric and biological features of human airway. This device is inspired by a recently developed technique “lung-on-a-chip,” but different in that it allows a continuous and directional mucus flow, a dynamic exchange of foreign particulates, and the application of pathological triggers. We are exploiting this micro-human airway device to study mucus transport. Integrating soft matter physics, engineering, molecular biology, bioinformatics, and systems biology, we are investigating the interactions between mucus and three indispensable components of the microenvironment: cilia, cells, and bacteria.

We seek to answer three fundamental questions:

• What are the kinds of mucus-cilia interactions required for efficient mucus transport?
• Whether and how mucus-cell interactions induce human airway remodeling?
• How do mucus-bacteria interactions impact mucus transport?