Constructing 3D voxelated tissues with molecular architecture encoded modular biomaterials to understand and control stem cell function

PROJECT SUMMARY Most biological tissues are not simply static materials but active living composites. They are composed of living cells dispersed in nonliving polymers known as extracellular matrix. Decades of research in biomaterials have demonstrated a multitude of ways in which polymeric materials can influence cells, and cells can modify

polymeric materials. Thus, recent advances in biomaterials design have shifted from pure elastic to viscoelastic polymeric biomaterials featuring time-dependent mechanical properties. However, existing biomaterial design largely relies on flexible linear polymers; such a simple molecular architecture intrinsically limits using linear

polymers to create biomaterials with nonlinear elasticity and relaxation dynamics matching the complexity and variations in tissue-specific mechanics for dissecting intricate cell-matrix interactions. Moreover, there remains a grand challenge in assembling cells and soft, viscoelastic biomaterials to create tightly organized structures

matching that of three-dimensional (3D) tissues for probing and exploiting cell-cell interactions. Trained as a theoretical polymer physicist but later switched to experimental soft (bio)materials and bioengineering, I have identified compelling opportunities for me to uniquely help address these challenges. Leveraging our expertise

in polymer physics, polymer chemistry, and bioengineering, I will develop platform technologies for constructing voxelated 3D tissues with molecular architecture encoded modular biomaterials to understand and control stem cell function. This is based on two research areas that I have been pioneering: (1) bottlebrush polymers and

networks and (2) voxelated bioprinting. In Thrust 1, I will develop modular bottlebrush gels to understand and control cell-matrix interactions. This thrust is built on my lab's recent breakthrough in discovering a new way to control the relaxation time without altering the shape of viscoelastic spectra of polymer networks. Leveraging my

expertise in theoretical polymer physics and soft matter, and based on how cells interact with matrix, I will introduce two new sets of parameters to provide a more complete description of matrix strain-stiffening and viscoelasticity. Further, I will develop general strategies for independently encoding stiffness, strain-stiffening,

relaxation time, and the shape of relaxation profile into the molecular architecture of bottlebrush gels. Using these modular bottlebrush gels, I will dissect the impact of each parameter on the behavior of stem cells. Recently, my lab proposed and showed the concept of voxelated bioprinting, a technology that enables precise

manipulation and assembly of highly viscoelastic spheric bio-ink droplets in 3D space. In Thrust 2, I will advance our voxelated bioprinting technology to print multiple material voxels in which are encapsulated different types of cells. I hypothesize that pre-defining the specific location and cell-cell interactions of different cell types

enables highly functional 3D tissues. Leveraging voxelated bioprinting and modular bottlebrush bio-inks, I will test this hypothesis in the context of engineering a 3D stem cell niche.