The overall goal of this multidisciplinary research project, supported by the National Science Foundation - Frontiers of Integrative Biological Research program, is to further advance our understanding of self-assembly during the organization of cells and tissues into functional organ modules.

Forgacs The two developmental processes, with common and distinct features to be investigated in detail in the project: fusion of cardiac cushions during the formation of cardiac chambers (left) and the appearance of limb buds the precursors of the limbs (right). (The images refer to chicken embryos.)

The strategy of our multidisciplinary approach for addressing this fundamental biological problem of tremendous complexity is based on the recognition that although morphogenetic processes are under strict genetic control, genes do not create shapes and forms: physical mechanisms and processes do. Our efforts to reveal the principles of cellular organization will focus on two specific, apparently similar developmental phenomena: the formation of cardiac cushions and limb buds. The major biophysical framework within which these processes will be studied is tissue liquidity, the in vitro- and in vivo-demonstrated concept according to which embryonic tissues mimic the behavior of liquids. The molecular basis of this behavior will be investigated through genetic manipulations, and the interplay between biomolecular and biophysical determinants will be explored by the combination of experimental and modeling techniques. The knowledge gained from these studies will serve as biological validation for new methods for building three-dimensional living structures of specific geometries. The proposed research will thus have both basic and applied science components. The former will be based on key scientific concepts underlying early development, cell-extracellular matrix (ECM) interactions, epithelial-mesenchymal transformation and physical mechanisms of morphogenesis. The latter will rely on the technology of bioprinting, specifically, our custom-built bioprinters operating with "bioink" particles composed of spheroidal cell aggregates and "biopaper" made of biocompatible ECM-containing hydrogels.

Schematics of building a tubular organ module by bioprinting. The blue sheets represent the biopaper or scaffold gel. The gel and the histotypical spherical bioink particles are deposited/printed layer-by-layer.

The outlined program will be carried out by the integration of developmental, cell and molecular biology with the physical and engineering sciences, modeling with experiments, and research with education.

In the course of this project we anticipate that we will discover new principles of multicellular self-organization (morphogenesis, organogenesis), which in turn will enable us to develop functional biological structures for basic science purposes (e.g., in vitro studies of mechanisms of development and tumor formation), and applications such as targeted drug testing and delivery, and organ (module) replacement.

Due to its strongly cross-disciplinary character, our research program will provide excellent training grounds for students who will be facing challenges awaiting educators and scientists in the life sciences entering the 21st century workplace. Our educational activity will be centered on five major components: curriculum development, student research programs, student/educator forums, special summer programs and outreach.