Responsive hydrogels for 4D cell culture and controlled drug delivery
Mark W. Tibbitt and Robert Langer, Massachusetts Institute of Technology
Interactions between mammalian cells and the surrounding extracellular matrix (ECM) are critical in the regulation of stem cell differentiation, cell migration, tissue morphogenesis, and disease progression. Cell decisions are often made by integrating these complex interactions, which are dynamic in 4D: three-dimensional space and time. Synthetic polymer-based hydrogels have emerged as an attractive cell culture platform to investigate the influence of these cell-matrix interactions on cell function in a systematic manner. Hydrogels are appealing mimics of the ECM on account of their high water content, tissue-like elasticity, and facile transport of nutrients, waste, and soluble factors. Furthermore, poly(ethylene glycol) (PEG) hydrogels can be formed under mild, cytocompatible conditions and are easily modified to present various biochemical and mechanical signals to cells during culture.
While cell-laden PEG hydrogel constructs have been employed for regenerative medicine and fundamental biological applications, there is still a lack of materials that allow the user to recapitulate the spatially heterogeneous and dynamic environment that cells interact with in vivo. My Ph.D. research has focused on the development, characterization, and application of photoresponsive PEG-based hydrogels that afford the user control of the mechanical and biochemical properties of the scaffold in both 3D space and time. This class of materials facilitates experiments that probe the relationship between spatially heterogeneous and dynamic signals from the ECM and cell function in a well-defined environment to study the fundamentals of the cell-material interactions, stem cell differentiation and plasticity, as well as the cellular response to local changes in soluble factor concentration.
Specifically, we have developed photoresponsive materials for the dynamic modulation of the ECM during 2D and 3D culture. These materials have been used to investigate stem cell response to dynamic changes in elasticity and the plasticity of stem cells during microenvironmental mechanotransduction. Importantly, we uncovered fundamental information about mechanical dosing and memory in mesenchymal stem cells that is regulated by YAP/TAZ signaling. Further, we have utilized photoresponsive hydrogels to develop photodegradable microspheres for the targeted delivery of soluble factors to study tissue morphogenesis and chemotaxis. Thin films of photodegradable hydrogel have been employed for the selective capture and release of cells for diagnostic application.
In my Postdoctoral research, we have developed responsive hydrogels for controlled delivery of therapeutics to intervene during disease progression. Specifically, we have developed a class of shear-thinning and self-healing hydrogels based on specific and reversible polymer-nanoparticle (PNP) interactions. These materials are facile to fabricate, scalable, and amenable to a broad range of biomedical and industrial applications. As the PNP hydrogels can be formed from biocompatible materials, they have been leveraged for local injection and dual-stage therapeutic release as well as cell carriers. Additional efforts are exploring the use of PNP gels for local cell recruitment within the body.
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