National Science Foundation     |     Directorate for Engineering  (ENG)
Division of Chemical, Bioengineering, Environmental, & Transport Systems  (CBET)
 
CBET Award Achievements  (Formerly "CBET Nuggets")
Notable Accomplishments from CBET Awards
 
 
Engineering of Embryonic Stem Cell (ESC) Microenvironments via Biomaterials
 
Todd McDevitt  -  Georgia Institute of TechnologyAtlanta, GA

Background:  Embryonic stem cells (ESCs) are characterized by their well known ability to differentiate into any cell type in the body.  However, obstacles remain to realizing the potential of ESCs for clinical use, including producing large quantities of homogeneous populations of differentiated cell types.  Currently, ESC differentiation as a single layer of cells can be directed down select lineages through the addition of biological factors to the medium in which the cells are grown.  Large-scale, batch differentiation of ESCs can be achieved through the formation of spheroids grown in suspension termed embryoid bodies (EBs).  EB culture promotes differentiation of cells to all three cell types; however, this process is difficult to efficiently control through media manipulation alone.  As EBs differentiate, barriers to diffusion progressively restrict the interior of the EB from being influenced by the external environment, thus necessitating new strategies to control the local microenvironment of cells within EBs.
 
The aim of this NSF sponsored research conducted by Dr. Todd McDevitt's stem cell engineering lab at the Georgia Institute of Technology in Atlanta, GA is to efficiently differentiate ESCs into homogeneous populations of cells by incorporating engineered biomaterial microparticles within EBs to uniformly deliver soluble morphogenic factors (potential substances that would govern the pattern of tissue development).  The results of this work provide an improved approach to more efficiently direct stem cell differentiation in suspension culture conditions that can be directly integrated into stem cell biomanufacturing practices and more directly and accurately assess the effects of morphogenic factors and biomaterials on stem cell differentiation.  It should be possible as a result of this work to engineer biomaterial properties to better control stem cell behavior and phenotype and thus transform the potential of stem cells into viable commercial technologies.

Results:  Recent results from the McDevitt lab indicate that the incorporation of microparticles into EBs can be readily achieved and controlled by parameters such as microparticle-to-cell-ratio, rotational mixing speed, and microparticle size.  When retinoic acid, a vitamin A derivative commonly used in ESC differentiation studies, was delivered from microparticles incorporated within EBs, uniquely cystic spheroids reminiscent of an early stage of mouse development were produced efficiently and reproducibly.  Additionally, the acquisition of this unique morphology was found to be dependent on microsphere size, as smaller microspheres induced accelerated and more pronounced formation of cystic spheroids.  This work demonstrated that biomaterials embedded within EBs can be used to safely and effectively deliver biological factors to direct differentiation of ESCs.  The ability to more efficiently differentiate EBs in an inherently scalable manner makes these developments directly relevant to the translation of stem cell technologies for regenerative medicine and diagnostic applications.

Todd McDevitt 1a     Figure 1aSoluble delivery of differentiation factors to EBs is limited by matrix-dense, shell-like exterior.
 
 
Todd McDevitt 1b
    Figure 1bMicrosphere-mediated delivery circumvents the barrier illustrated in Figure 1a and is able to present molecules throughout the EBs interior.
 
 
Todd McDevitt 1c
    Figure 1cThe degree of microsphere incorporation within EBs can be modulated via microparticle size, microparticle to cell mixing ratio, and orbital mixing speed.
 
Credit for Images 1a, 1b, 1c & 2c:  Todd McDevitt; Georgia Institute of Technology
 
Todd McDevitt 2a
    Figure 2aDelivery of retinoic acid to EBs using microspheres results in cystic EB formation
 
 
Todd McDevitt 2b
    Figure 2bDelivery of retinoic acid to EBs using microspheres results in cystic EB formation (Figure 1a), with uniform expression of Oct4 in the interior cells (green dye).
 
Credit for Images 2a & 2b:  Todd McDevitt; Georgia Institute of Technology; Adapted from images published in Biomaterials 30(13) 2507-2515
 
Todd McDevitt 2c
    Figure 2cThe degree of microsphere incorporation within EBs can be modulated via microparticle size, microparticle to cell mixing ratio, and orbital mixing speed.

Scientific Uniqueness:  The integration of biomaterials science with stem cell biology provides a unique approach and opportunity to translate the potential of stem cells into viable regenerative medicine and diagnostic technologies.

This project addresses the NSF Strategic Outcome Goals, as described in the NSF Strategic Plan 2006-2011, as follows:
 
Primary Strategic Outcome Goal:      (1) Discovery:  The incorporation of biomaterial delivery vehicles directly within 3D stem cell microenvironments enables spatiotemporally controlled presentation of morphogenic factors that can not be achieved simply by soluble treatment regimens.  The engineering of stem cell microenvironments in this manner yields more homogeneous differentiation of pluripotent stem cells in suspension culture conditions.
 
                                                                   (1) Discovery Categories:
                                                                           -  Biology
                                                                           -  Engineering

 
Secondary Strategic Outcome Goal:  (2) Learning:  This project has provided unique training experiences for undergraduate and graduate students to learn how to apply principles of biomaterials science to new discoveries in stem cell biology.  Two Ph.D. students and eight undergraduate students have contributed to various aspects of this project.  Through discussions with public groups, such as teachers and K-12 students, and laboratory tours to students and parents, we have had several opportunities to share our work and its potential impact on society.

 
                                                                   (2) Learning Categories:
                                                                           -  Undergraduate Education and Undergraduate Student Research
                                                                           -  Graduate Education and Graduate Student Research
                                                                           -  Public Understanding of Science and Lifelong Learning


This Award Achievement represents Transformative Research.  The principle of using engineered biomaterial properties to better control stem cell behavior and phenotype could transform the potential of stem cells into viable commercial technologies.

The Intellectual Merit of this research:  The results of this work provide an improved approach to more efficiently direct stem cell differentiation in suspension culture conditions that can be directly integrated into stem cell biomanufacturing practices and more directly and accurately assess the effects of morphogenic factors and biomaterials on stem cell differentiation.

The Broader Impacts of this research include:
 
(1Benefits to Society:  Enhancing the development of stem cell technologies which can be used for a broad variety of unmet clinical needs and thereby significantly improve the quality of health care.
 
(2Dissemination of Research Results:  The results of this work have already been disseminated in the form of peer-reviewed publications, international conference proceedings and public presentations to inform various audiences about the integration of biomaterials and stem cell science.

Areas of Emphasis (Themes) for FY 2010 Highlights included in this research project:
 
(1)  Is interdisciplinary, high-risk, and potentially transformative
 
(2Speeds the translation of promising fundamental research into innovations that can be commercialized
 
(3Enhances health and quality of life
 
(4Advances new materials and devices, such as silicon microelectronics, that exploit properties at the quantum level required to realize computing capacity beyond the limits suggested by Moore's Law (SEBML)
 
(5Nurtures a world-class engineering workforce and a technically literate population


 
Program Director:
 
 
 
Semahat Demir
CBET Program Director - Biomedical Engineering
     
NSF Award Number:   0651739
     
Award Title:   Engineering Control of Embryonic Stem Cell Microenvironments during Differentiation via Integration of Degradable Biomaterials
     
PI Name:   Todd McDevitt
     
Institution Name:   Georgia Institute of Technology;  Atlanta, GA
     
Program Element Code:   5345
     
CBET Award Achievement:

  FY 2010


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This Award Achievement was Updated on 17 August 2010.