Living Materials for Regenerative Medicine

Hydrogels are formed from hydrophilic polymer chains surrounded by a water-rich environment. They have widespread applications in various fields such as biomedicine, soft electronics, sensors, and actuators. Conventional hydrogels usually possess limited mechanical strength and are prone to permanent breakage. Further, the lack of dynamic cues and structural complexity within the hydrogels has limited their functions. Recent developments include engineering hydrogels that possess improved physicochemical properties, ranging from designs of innovative chemistries and compositions to integration of dynamic modulation and sophisticated architectures. We review major advances in designing and engineering hydrogels and strategies targeting precise manipulation of their properties across multiple scales.

Collagen is the primary component of the extracellular matrix in the human body. It has proved challenging to fabricate collagen scaffolds capable of replicating the structure and function of tissues and organs. We present a method to 3D-bioprint collagen using freeform reversible embedding of suspended hydrogels (FRESH) to engineer components of the human heart at various scales, from capillaries to the full organ. Control of pH-driven gelation provides 20-micrometer filament resolution, a porous microstructure that enables rapid cellular infiltration and microvascularization, and mechanical strength for fabrication and perfusion of multiscale vasculature and tri-leaflet valves. We found that FRESH 3D-bioprinted hearts accurately reproduce patient-specific anatomical structure as determined by micro–computed tomography. Cardiac ventricles printed with human cardiomyocytes showed synchronized contractions, directional action potential propagation, and wall thickening up to 14% during peak systole.

Significant research over the past two decades has established that extracellular matrix (ECM) elasticity, or stiffness, impacts fundamental cell processes including spreading, growth, proliferation, migration, differentiation, and organoid formation. Linearly elastic polyacrylamide hydrogels and polydimethylsiloxane (PDMS) elastomers coated with ECM proteins have become widely-used tools for assessing the role of stiffness, and results from these experiments are often assumed to reproduce the effect of the mechanical environment experienced by cells in vivo . However, tissues and ECMs are not linearly elastic materials – they in fact exhibit far more complex mechanical behaviors, including viscoelasticity, or a time-dependent response to loading or deformation, as well as mechanical plasticity and nonlinear elasticity. Recent work has revealed that matrix viscoelasticity regulates these same fundamental cell processes, and importantly can promote behaviors not observed with elastic hydrogels in both 2D and 3D culture microenvironments. These important findings have provided new insights into cell-matrix interactions and have given context as to how these interactions differentially modulate mechano-sensitive molecular pathways in cells. Moreover, these results indicate new design guidelines for the next generation of biomaterials that better match tissue and ECM mechanics for in vitro tissue models and applications in regenerative medicine.