National Science Foundation     |     Directorate for Engineering  (ENG)
Division of Chemical, Bioengineering, Environmental, & Transport Systems  (CBET)
CBET Award Achievements 
Notable Accomplishments from CBET Awards
Directing Neuronal Cells in 3-dimensions
Christine Schmidt  -  University of Texas at Austin

Simplified Description

Outcome or Accomplishment:  A team at the University of Texas at Austin has developed a novel system for studying and directing the behaviors of neurons and other neural cells in 3 dimensional (3D) materials.

Impact:  Current treatment strategies for nerve injuries, especially those involving the spinal cord, are rudimentary and in some cases non-existent.  The 3 dimensional material developed during this project provides a better model to investigate the requirements for nerve regeneration and will ultimately lead to new treatment strategies for nerve injuries.

Background the lay reader needs to understand the significance of this outcome:  Cells can recognize and respond to various chemical, mechanical, and surface roughness signals in their environment; however, differentiating one signal from another proves difficult.  The researchers developed a 3D structural support which allows them to control the spatial organization of cells in a material and attach chemical signals in precise locations without changing the mechanics of the material.  This gives researchers an opportunity to take a closer look at the chemical mechanisms that guide neural development and regeneration, and should lead to advances in treatment for nerve injury.

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Detailed Engineering Description

Background:  Cells can recognize and respond to various chemical, mechanical, and topographical cues in their environment; however, differentiating one cue from another proves difficult.  The researchers at the University of Texas at Austin, Schmidt and Shear, have developed novel technologies to rapidly manufacture 3 dimensional (3D) structural supports with spatially defined chemical, mechanical and geometric features that can be controlled independently.  These 3D supports will enable researchers to control cell location within precisely defined engineered environments.  The ability to design and build precisely controlled materials provides researchers an opportunity to examine the chemical and mechanical mechanisms that guide neural development and regeneration.

Results:  Schmidt and Shear have developed a novel method to direct-write three-dimensional (3-D) bioactive microstructures within hydrogel materials that mimic the composition and size scale of the native extracellular environment.  Precise control over material chemical and mechanical properties on submicron scales can be achieved using multiphoton-excited photopolymerization (MPP) to fabricate protein structures within hydrogels using a laser, which can be focused into a defined volume so that crosslinking only occurs within that volume (~1 fL).  Researchers have developed this technology for hyaluronic acid (HA)-based biomaterials because of the key role that HA plays in wound healing.
In order to rapidly prototype materials, the investigators have used a digital micro-mirror device composed of an array of 848x600 individually addressable mirrors with an area of 16 square microns that act as a dynamic photomask for the photopolymerization of the 3-D materials.  The orientation of this array of mirrors can be specified using a computer aided design program.  The PIs have developed chemistries to control chemical environment and hydrogel crosslinking that are all photoactive.  A laser beam is scanned across the surface of the array and by controlling the intensity of the duration of light exposure, geometry, mechanical stiffness, and chemical environment in the materials can be controlled.
Researchers have demonstrated that they can pattern complex 3D geometries of protein microstructures within HA Hydrogels with this technolgoy.  HA-based hydrogels patterned with extracellular matrix (ECM)-derived protein structures in three dimensions can spatially direct primary neuronal cell attachment, migration, and differentiation in vitro (Figure 1).
In the nervous system, neurite outgrowth and glial migration are particularly influenced by spatial organization of biomolecular cues into concentration gradients.  The mechanical environment resulting from the physical structure and composition of the ECM has also been shown to influence cell phenotype and gradients of these physical cues can guide cell migration.
Techniques for fabrication of microstructures presenting definable biomolecular and mechanical gradients will greatly facilitate research to elucidate mechanisms of cell-ECM interactions and exploit those mechanisms to control cell-biomaterial interactions and engineer materials and environments for regenerative medicine applications.

- 1 -  Seidlits, S.K., C.E. Schmidt, J.B. Shear (2009). High-Resolution Patterning of Hydrogels in Three Dimensions using Direct-Write Photofabrication for Cell Guidance.  Advanced Functional Materials.  19:3543-3551.
- 2 -  Seidlits, S.K., Z.Z. Khaing, R.R. Petersen*, J.D. Nickels, J.D. Vanscoy*, J.B. Shear, C.E. Schmidt (2010).  The effect of hyaluronic acid hydrogels with tunable mechanical properties on the differentiation of neural progenitor cells.  Biomaterials.  31: 3930 - 3940.

Christine Schmidt 1     Figure 1.  3D representation of the spiral biopolymer scaffold (labeled green) within a hydrogel and subsequent confocal montage of the scaffold with cells (stained blue) adhered and migrating down the spiral geometries into the hydrogel matrix.  Scale bar = 50 Ám.
Image Credit:  Stephanie Seidlits, University of Texas at Austin

Scientific Uniqueness:  The team has developed novel chemistries and tools for rapid manufacture of materials with spatially controlled chemical, mechanical and geometric environments to be used in regenerative medicine applications.  With this tool, investigators are creating defined 3-D materials that they are then using to investigate the role of different chemical and mechanical environments in control of migration and function of neural cells.

This project addresses the NSF Strategic Outcome Goals, as described in the NSF Strategic Plan 2006-2011, as follows:
- 1 Primary Strategic Outcome Goal:      (1) Discovery:  This research has lead to the development of new tools to rapidly manufacture spatially defined 3-D materials with controlled gradients in chemical and mechanical properties for tissue engineering applications.  In addition, the research has probed the role of chemical and mechanical characteristics of an engineered environment in neural engineering applications.
- 2 Secondary Strategic Outcome Goal:  (2) Learning:  Three graduate students and two undergraduate students are involved in this research, and have learned research methods in materials development, characterization, photochemistry, and tissue engineering.  In addition, the PIs have been active in outreach to many different community and K-12 organizations.

This Award Achievement represents Transformative Research.  The tools and technology developed by the investigators have the potential to lead to a paradigm shift in the way 3 dimensional materials are manufactured for tissue engineering and regenerative medicine applications.  The precise control of chemical and mechanical features of the material using the new technology will enable future researchers to ask new questions about how cells respond to engineered environments.

The Intellectual Merit of this research:  The intellectual merit of this project lies in the development of novel technology and chemistries for controlling the submicron scale the chemical and mechanical environment for cells in 3D engineered tissues.  This project is truly unique and will provide an important platform for developing scaffolds for regenerative medicine and for more physiological, 3D in vitro culture systems.  In addition, this research is particularly targeted for guiding axonal growth, which has potential implications for promoting regeneration in both the peripheral and central nervous systems.

The Broader Impacts of this research include:
- 1Benefits to Society:  This research will directly impact the field of regenerative medicine, providing powerful tools for developing new engineered tissues.  The PIs will apply this work to nerve regeneration.
- 2Broaden participation of underrepresented groups:  The investigators are active in outreach to underrepresented groups in the Austin community through College Forward and the Minority Introduction to Engineering Program.  The PI mentors both women faculty through the ADVANCE program, and women graduate and undergraduate students.
- 3Advance discovery and understanding while promoting teaching, training, and learning:  Three graduate and two undergraduate students participate in the research described.  In addition the PI incorporated ideas from research into the biomedical engineering and freshman engineering curriculum.
- 4Results will be disseminated broadly to enhance scientific and technological understanding:  PIs will continue to publish results of this work in high impact journals, and present work at national meetings.

Program Director:
Theresa Good
CBET Program Director - Biotechnology, Biochemical, and Biomass Engineering
NSF Award Number:   0829166
Award Title:   "Direct Write" Techniques to Create Submicron, Arbitrary Protein Structures within Hyaluronan Hydrogels
PI Name:   Christine Schmidt
Institution Name:   University of Texas at Austin
Program Element Code:   1491
CBET Award Achievement:

  FY 2011

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This Award Achievement was Updated on 15 March 2011.