The myth of a flat world was dispelled long ago, yet to this day the notion that the human body can be studied by culturing cells on planar surfaces remains. Can the flat cell teach us what we need to know about human health and disease? Evidence and intuition suggest that cells behave differently when they are isolated from the complex architecture of their native tissues and constrained to petri dishes with unnaturally high stiffness, polarity, and surface-to-volume ratio. In living organisms, each cell is surrounded by a unique three-dimensional environment that is pliable and inhomogeneous. This tissue support structure, composed of extracellular matrix, presents a situation-specific milieu of soluble and insoluble factors to the resident cell population. Although an individual cell lacks eyes and ears, a sophisticated biochemical and biophysical language ensures that a community of cells can see and hear the world around them. With increasing awareness that a cell's physical context is an important determinant of its responses, three-dimensional platforms for cell culture are needed to translate new findings in cellular biology into clinical advances.
Our group is interested in synthesizing biomaterial niches, custom three-dimensional cellular microenvironments, that present cells with informative chemical, biological, and physical cues. Our goals are twofold: (1) to provide better in vitro models to study disease and development and (2) to enable the regeneration of functional tissues for clinical applications. To date, we have designed a repertoire of materials that combine the advantages of synthetic polymers with those of natural biomacromolecules. Specifically, we develop highly characterized synthetic niches modified with biomimetic cues to create physiologically relevant cell-material interactions in a defined experimental space. Unique to our approach is the use of light and photoinitiated reactions to fabricate our biomaterial cell scaffolds. This allows us to synthesize biomaterials in seconds to minutes, under physiological conditions, and in the presence of tissues or cells. Furthermore, we can turn the process on and off by shuttering the light source, and we use focused laser beams to control spatial patterning.
We use this spatial and temporal control to selectively decorate our scaffolds with biological signaling molecules in patterns that mimic the environment that cells encounter in vivo (e.g., during wound healing or development). We incorporate oligopeptides to promote cell adhesion or tether growth factors that can be released by proteases secreted by cells. Through these approaches, we seek to better understand how physiological processes are guided by interactions between cells and their extracellular matrix, and how to exploit this knowledge in the design of our biomaterial niches that promote tissue regeneration.
Three applications are of recent interest to us: (1) creating chondrocyte carriers that permit the regeneration of cartilaginous tissue, (2) synthesizing gel niches that present valvular interstitial cells with a local environment similar to that found during heart valve development, and (3) creating matrices laden with soluble and tethered biological signals that promote the differentiation of progenitor cells. These applications require scaffolds of increasing sophistication—from relatively inert scaffolds that the cells only "see" and "touch" to ones that "talk" to the cells and remodel themselves in response to cellular feedback. For example, neuroprogenitor cells encapsulated in three-dimensional synthetic biomaterials with localized trophic factors recapitulate the intricate three-dimensional web of processes seen in the natural architecture of neural tissue. This differs strikingly from cell behavior on two-dimensional polymer surfaces. Cartilage regeneration is spatially and temporally controlled when chondrocytes are encapsulated in scaffolds with varying degradation properties, and gels for heart valve tissue engineering can be tuned to release signals that trigger valvular interstitial cell proliferation, migration, and/or extracellular matrix production. In all of these approaches, we apply single- and multiphoton imaging tools to visualize and explore cell behavior noninvasively and directly in these complex three-dimensional biomaterials.
Grants from the National Institutes of Health provide support for the work on cartilage tissue engineering, the design of osteogenic scaffolds for mesenchymal stem cells, the synthesis of niches for the regeneration of heart valves, and the development of functionalized gels to facilitate islet function and suppress deleterious effects of the immune system. Beyond these targeted applications, fundamental research related to material development is supported by the National Science Foundation.
As of May 30, 2012