Ph.D., Brown University, 1993

Research in the Hoffman-Kim laboratory focuses on understanding axon guidance in complex environments and developing biomaterial and tissue engineering strategies for nerve guidance and repair. We apply engineering techniques to biological systems in vitro to challenge growing neurons with multiple guidance cues, including diffusible factors, substrate-bound molecules, electrical cues, and topographical surface features.

Project Summary: Axon Guidance by Permissive and Inhibitory Molecular Gradients
During development, correct guidance of growing axons is critical in order to establish the precise connections of the nervous system that are essential for proper brain function. Neurodevelopmental disorders that result from improper connections in the brain can lead to damaging disease states in humans. The interdisciplinary approaches of these studies, including microfluidics and chomophore-assisted laser inactivation, work toward a more quantitative understanding of axon growth decisions. We seek to assess how gradients of permissive and repulsive molecules guide axon decisions, giving particular attention to the complex situation of guidance by two contrasting molecules, a system that more closely approximates axon guidance conditions in vivo. We are testing the hypothesis that axons make growth decisions in multi-molecular gradients by integrating growth-promoting and growth-inhibitory factors—including extracellular gradient parameters, receptors, and intracellular signaling pathways. This work, to advance a more complete comprehension of the mechanisms underlying axon navigation, is critical for elucidating the basis of improper brain development.

Project Summary: Axon Guidance by Multiple Cues
Nerves fail to regenerate after injury, and current medical practice is unable to manipulate effectively the process of nerve regeneration. This project seeks to solve 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 accurate and effective nerve regeneration. Our 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 necessitates the fabrication of a new platform upon which to study neuronal growth. The platform (1) delivers a combination of cues in a controllable and quantifiable manner; and (2) provides a means by which to test their hierarchical and synergistic interactions. We are fabricating platforms with specific dimensions and spatial arrangements of multiple cues, to test how combinations of topographical and molecular guidance cues promote axon growth. Our objective is to correlate axon growth and direction to specific quantities and ratios of cues, thus establishing the basis for new strategies for nerve regeneration.

Project Summary: Neurite Bridging Across Micro-Patterned Grooves
During development and after injury, growing axons must navigate complex, three-dimensional microenvironments. Topographic guidance of neurite outgrowth has been demonstrated in vitro with culture substrates that contain micropatterned features on the nanometer-micron scales. We are characterizing the ability of microfabricated biomaterials to support neurite extension across micropatterned grooves with feature sizes on the order of tens of microns, a size relevant to the design of biomaterials and tissue engineering scaffolds. Neonatal rat dorsal root ganglion (DRG) neurons have been cultured on grooved substrates of poly(dimethyl siloxane) coated with poly-l-lysine and laminin. A subpopulation of DRG neurons displays an unusual capacity to extend neurites that span across the grooves, with no underlying solid support. Multiple parameters influence the formation of bridging neurites and underlying mechanisms are under investigation. These studies are of interest to understanding cytoskeletal dynamics and designing biomaterials for three-dimensional axon guidance.

Project Summary: Composite Biomaterials for Neurite Outgrowth in collaboration with Dr. Tayhas Palmore, Division of Engineering
Much of the previous research on biomaterial systems for nerve regeneration has examined the permissive capabilities of individual components or materials toward axon growth. These studies seek to quantify how composite biomaterials guide axon growth, giving particular attention to the complex problem of guidance by more than one component. Our working hypothesis is that composite biomaterials, presenting multiple growth-promoting cues, will enable axon growth to overcome a local environment that is inhibitory. Our long-term objective is twofold: to elucidate the cellular and molecular mechanisms that underlie axon guidance during development and after injury, and to develop biomaterial platforms to support and enhance axon growth. The important roles for glial cells, extracellular matrix molecules, and electrical stimulation in mediating axon growth have been established. How they interact and how they can be used in combination to direct axon growth is not well understood, however. This work combines microfabrication, electrochemistry, and primary cell cultures to generate a composite biomaterial substrate that is electrically conductive, embedded with growth-promoting proteins, and adheres supportive glial cells. Results from these studies will provide fundamental knowledge of how specific neural connections form during normal development and how they can be stimulated to regenerate following injury.

Project Summary: Nanoscale Biomimetic Materials for Nerve Regeneration
Successful nerve regeneration requires directed nerve growth. The goal of this project is to determine systematically the critical cues needed to guide nerves, thus providing essential information for new strategies for nerve regeneration. Dr. Diane Hoffman-Kim's group has developed a set of materials that are biomimetic and can replicate cellular shapes at the nanoscale. Significantly, the group can produce nanostructures "by design", where the design is motivated by and directly incorporates the biological structure. By systematically comparing Dr. Hoffman-Kim's biomimetic materials with the nanoscale, randomly patterned materials developed by the group of Dr. Thomas Webster, the team will elucidate the key pattern features required for nerve growth. By combining these materials with the cutting-edge drug delivery systems developed by the laboratory of Dr. Edith Mathiowitz, the research team will tailor materials to enhance nerve growth. In collaboration with Dr. Moses Goddard, a clinical and research surgeon, the team will evaluate the materials in vivo in a peripheral nerve injury model. This initial effort will ultimately result in an interdisciplinary research group with key areas of expertise that converge synergistically to develop and fabricate novel biomimetic biomaterial systems with drug delivery capabilities, to characterize these biomaterials in vitro, and to evaluate them in in vivo models of nerve injury, thus advancing work in the fields of regenerative medicine, tissue engineering, and nanomedicine.

Professor Hoffman-Kim teaches courses in the general field of biomedical engineering, including an upper-level undergraduate course, Tissue Engineering. Tissue engineering is an interdisciplinary field that incorporates progress in biology, materials science, and engineering, to work toward the goal of replacing or regenerating compromised tissue function. Using an integrative approach, BI0L 1140 examines tissue design and development, manipulation of the tissue microenvironment, and current strategies to reconstitute injured tissues. Ethical, legal, and regulatory issues that accompany current and emerging technologies are also discussed.

In her courses, Professor Hoffman-Kim also focuses on helping students develop the ability to explain scientific concepts to audiences with diverse backgrounds, a skill that is increasingly crucial in today's expanding and changing society. Facility at explanation is of particular importance in the fields of biotechnology and biomedical engineering, whose most exciting work is of great interest to the public, and often requires the participation of multiple diverse research groups to accomplish successful results. The goal is to improve oral communication skills of students at both the undergraduate and graduate levels, with a particular focus on translating information across disciplines -- between biologists and engineers, and from scientists to non-scientists.

Tissue Engineering (BIOL 1140)

• Li G and Hoffman-Kim D. Tissue engineered models of axon guidance. Tissue Engineering B 14(1), 2008.
• Li G, Liu J, and Hoffman-Kim D. Multi-molecular gradients of permissive and inhibitory cues direct neurite outgrowth. Annals of Biomedical Engineering 36(6): 889-904, 2008.
• Abe TK, Honda T, Takei K, Mikoshiba K, Hoffman-Kim D, Jay DG, and Kuwano R. Dynactin is essential for growth cone advance. Biochemical and Biophysical Research Communications 372: 418-422, 2008.
• Li GN and Hoffman-Kim D. Evaluation of neurite outgrowth using a novel application of circular analysis. J Neurosci Methods 174: 202-214, 2008.
• Kofron CM, Fong VJ, and Hoffman-Kim D. Neurite outgrowth at the interface of 2D and 3D growth environments. J Neural Engineering, in press, 2008.
• Li G, Livi LL, Gourd CM, Deweerd ES, and Hoffman-Kim D. Genomic and morphological changes of neuroblastoma cells in response to three-dimensional matrices. Tissue Engineering 13: 1035-1047, 2007. (Article featured in Genome Technology July/August 2007.)
• Bruder JM, Lee A, and Hoffman-Kim D. Biomimetic materials replicating Schwann cell topography enhance neuronal adhesion and neurite alignment in vitro. Journal of Biomaterials Science, Polymer Edition 18: 967-982, 2007. (Special issue on "Materials for Neural Engineering")
• Song HK, Toste B, Ahmann K, Hoffman-Kim D*, and Palmore GTR*. Micro-patterns of positive guidance cues anchored to polypyrrole doped with polyglutamic acid: a new platform for characterizing neurite extension in complex environments. Biomaterials 27(3): 473-484, 2006. [*Corresponding authors]
• Goldner JS, Bruder JM, Li G, Gazzola D, and Hoffman-Kim D. Neurite bridging across micropatterned grooves. Biomaterials 27(3): 460-472, 2006.
• Bruder JM, Monu N, Harrison M, and Hoffman-Kim D. Fabrication of polymer replicas of cell surfaces with nanoscale resolution. Langmuir 22(20): 8263-8265, 2006. Featured on the websites of Biocompare, The Engineer Online, Materials Research Society, Medical News Today, PhysOrg, Science Daily, and Scientific Frontline.
• Hoffman-Kim D, Maish MS, Krueger P, Lukoff H, Bert A, Hong T, and Hopkins RA. Comparison of three myofibroblast cell sources for tissue engineering cardiac valves. Tissue Engineering 11: 288-301, 2005.
• Maish MS, Hoffman-Kim D, Krueger P, Souza J, Harper J, and Hopkins RA. Tricuspid valve biopsy – a potential source of cardiac myofibroblast cells for tissue engineered cardiac valves. Journal of Heart Valve Disease, 12:264-269, 2003.
• Hoffman-Kim D, Kerner J, Chen A, Xu A, Wang T-F, and Jay DG. pp60c-src is a negative regulator of laminin-mediated neurite outgrowth in chick sensory neurons. Mol Cell Neurosci, 21(1): 81-93, 2002.
• Hong T, Maish MS, Cohen J, Fitzpatrick P, Bert AA, Harper J, Feng D, Hoffman-Kim D, and Hopkins RA. Reproducible echocardiography in juvenile sheep and its application in the evaluation of a pulmonary valve homograft implant. Contemporary Topics in Lab Animal Science 39:15-21, 2000.
• Hoffman-Kim D, Lander AD, and Jhaveri S. Regional differences in immunostaining for chondroitin sulfate in the developing tectum reflect differential GAG biosynthesis. Journal of Neuroscience 18: 5881-5890, 1998.
• Hoffman D, Breakefield XO, Short MP, and Aebischer P. Transplantation of a polymer encapsulated cell line genetically engineered to release NGF. Experimental Neurology 122: 100-106, 1993.
• Carstensen EL, Campbell DS, Hoffman D, Child SZ, and Ayme-Bellegarda EJ. Killing of drosophila larvae by the fields of an electrohydraulic lithotripter. Ultrasound in Medicine & Biology 16(7): 687-698, 1990.
• Hoffman D, Wahlberg L, and Aebischer P. NGF released from a polymer matrix prevents loss of ChAT expression in basal forebrain neurons following a fimbria-fornix lesion. Experimental Neurology 110: 39-44, 1990.
• Child SZ, Hoffman D, Strassner D, Carstensen EL, Gates AH, Cox C, and Miller MW. A test of I2T as a dose parameter for fetal weight reduction from exposure to ultrasound. Ultrasound in Medicine & Biology 15(1): 39-44, 1989.
• Miller MW, Azadniv M, Pettit SE, Church, Carstensen EL, and Hoffman D. Sister chromatid exchanges in chinese hamster ovary cells exposed to high intensity pulsed ultrasound: inability to confirm previous positive results. Ultrasound in Medicine & Biology 15(3): 255-262, 1989.