Intellectual Merit: Nerves fail to reconnect properly after injury and current medical practice is unable to successfully control the process of nerve regeneration. The proposed research seeks to attend to this problem by quantifying how guidance cues, both individually and in combination, promote axon growth. This knowledge is central to understanding nerve development and promoting nerve regeneration. The working hypothesis is that directed axon growth requires multiple cues, which must be well-defined and coordinated at the level of the local cellular environment. To test this hypothesis will necessitate the fabrication of new platforms upon which to study neuronal growth. These platforms will (1) deliver combinations of cues in a controllable and quantifiable manner; and (2) provide a means by which to test their hierarchical and cooperative interactions, specifically at the level of cellular traction forces. With interdisciplinary expertise in nerve development, regeneration, biomaterials, and microfabrication, the group has designed a set of such platforms, and has shown with preliminary data that they have the capability to deliver biochemical and topographical guidance cues to neurons. These platforms make possible innovative experiments that will test how combinations of cell-topographical and biochemical guidance cues promote neurite growth, and how neurites exert traction forces during growth. The objective is to correlate directed axon growth to specific quantities and ratios of cues, thus transforming the understanding of how the precise connections of the nervous system form as well as strategies to rewire these connections after injury.

Investigations will determine which cellular topographical features encode critical guidance information to a navigating neuron, and subsequently, how topographical and biochemical guidance cues interact to influence neurite growth, testing on both cooperative and competitive platforms. Further, neuronal traction forces will be determined during nerve guidance by multiple cues. Neurite growth will be characterized on patterned materials with custom designed image analysis approaches, and time-lapse microscopy with phase contrast and laser scanning confocal optics. Conditions will be determined by which contact with topographical features limits the set of angles over which growing neurites can orient. The overarching goal is to develop methods by which axons can be guided following injury to the nervous system. The proposed multidisciplinary experiments quantify how growing axons respond to specific topographical and biochemical stimuli, and as such they will provide critical information with which to develop new conduits, scaffolds, and general biomaterial-based strategies to regenerate nerve tissue.

Broader Impacts: This project will have multiple Broader Impacts. It will provide to the larger engineering and scientific communities, in particular the Biomedical Engineering, Neurobiology and Cell Biology communities, a set of versatile, tailorable platforms with which to test a wide variety of types of information of relevance to multiple cell and tissue types, including mechanical, topographical and biochemical cues. It will also generate new frameworks with which to conceptualize cell behaviors in the local cellular environment, where the environment can be deconstructed and reassembled to advance understanding.

Through this project, the numbers of female undergraduate and graduate students involved in Biomedical Engineering research will be increased as the PI has a strong record of training female biomedical engineers. Further, this project includes an Outreach Program to enhance the exposure of middle school students in the Providence Public Schools to biomedical engineering research. There is an urgent need to improve middle school science performance, and this infusion of technology, engineering, and inquiry-based learning provides an ideal strategy to address this challenge. Video conferencing will allow large numbers of middle school students to interact in real time with experiments in otherwise inaccessible environments, following a series of curriculum-integrated classroom modules by trained graduate students as well as teacher-laboratory visits. This intensive program will augment the middle school science curriculum, train biomedical engineering students to explain science and engineering concepts to audiences with diverse backgrounds, provide teachers with internship opportunities, and inspire middle school students, at critical points in their education, to consider science and engineering careers.

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Brown University
United States
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