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Wednesday, August 22

Drug development is a time and money consuming process. Stem cell and 3D models that capture both the organization and multicellular complexity of the target provide the most powerful tools for screening the effects of therapeutic candidates. 
The development of functional screening models has:

• Reduced cost and time to identify new drug candidates 
• Drove more selective/predictive screens for selection of compounds 
• Reduced animal testing 
• Yielded more predictive data 
• Improved efficiency 
• Decreased time to market 

CHI’s Fourth Annual Stem Cell and 3D Models for Therapeutic Screening weaves together tissue engineers who are developing the 3D tissue models with biologists who are studying healthy vs. diseased states and pharmacologists who are utilizing high-throughput screening assays. As with any model, each specialty provides insight into the complete system.

Scientific Advisory Committee:

Jonathan Garlick, Ph.D., DDS, Professor, Division of Cancer Biology and Tissue Engineering, Tufts University

David Kaplan, Ph.D., Professor and Chair, Department of Biomedical Engineering, Science and Technology Center, Tufts University School of Engineering

Melvin Schindler, Ph.D., President, Nanoculture LLC 

8:00 am Registration and Morning Coffee

8:30 Chairperson’s Remarks

9:05 Potential Applications of Stem Cells in the Pharmaceutical Industry
Huseyin Mehmet, Ph.D., Director, Apoptosis Research, Merck Research Laboratories 
Stem cells can differentiate into numerous types of cells with specific functions. It is well documented that stem cells might be of therapeutic value in the direct treatment of diseases including Parkinson’s, Alzheimer’s, diabetes, cancer, heart disease, spinal cord injury, and multiple sclerosis, as well as in organ transplantation and wound healing. However, stem cells are also a valuable source of material in drug discovery, where they can provide model systems for understanding disease mechanisms, for high-content screening assays, and in toxicology studies. In this presentation, I will discuss some of the non-therapeutic applications of the use of stem cells.

9:35 Therapeutic Targeting of a Stem Cell Niche
David T. Scadden, Ph.D., Professor of Medicine, Center for Regenerative Medicine & Technology, Mass General Hospital (invited)

10:05 Human Embryonic Stem Cells: Bridging Animal Models and Cell-Based Preclinical Safety Assessment of Chemicals 
Gabriela Cezar, DVM, Ph.D., Assistant Professor, Stem Cell Safety Sciences, Department of Animal Sciences, University of Wisconsin, Madison 

10:35 Technology Spotlight (Sponsorship Available)

10:50 Coffee Break, Poster and Exhibit Viewing

11:30 Using Embryonic Stem Cells for Drug Discovery 
Amy Sinor, Ph.D., Assay Development Scientist, Harvard Stem Cell Institute, Harvard University
Embryonic Stem (ES) cells can be used as a valuable tool in drug discovery. We currently use ES cells to generate cultures that are highly enriched for motor neurons. This provides us with a unique opportunity to perform high throughput screening experiments because we are able to generate large quantities of motor neurons. Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) are two diseases in which motor neurons are the cell type that is affected. In SMA, although the SMN protein is ubiquitously expressed, its deficiency in motor neurons is directly linked to disease severity and progression. Previously, fibroblasts from patients afflicted with SMA were utilized in drug screening efforts. We have devised a novel approach that involves using motor neurons derived from mouse ES cells to screen for small molecules that may increase either motor neuron survival or SMN protein levels. As these cultures represent the actual cell type that is affected during the progression of SMA, we believe this is a more straightforward and relevant background with which to perform screening experiments. Since ES cells have the ability to differentiate into many different neuronal cell types, we expect this model system will be valuable for screening drugs for many other neurodegenerative diseases. 

12:00 pm Stem Cells and Biomaterials
Karen J.L. Burg, Ph.D., Hunter Endowed Chair and Professor of Bioengineering, Clemson University 
Three dimensional biomaterials systems have been used for the rapid expansion of cells and as the template or scaffold in tissue engineering systems. The scaffold material design is crucial as it affects cellular attachment, proliferation, and differentiation and may be used as a tool with which to "tune" cellular behaviors. Microfabrication techniques such as cellular printing provide tools with which to precisely position and explore the interactions of anchorage-dependent cells with their in vitro environment, where spatial control of the substrate chemistry, pattern, and mechanical properties can provide new insights into fundamental aspects of stem cell-surface interactions. 

12:30 Luncheon Technology Workshop	Sponsored by
Optimization of Stem Cell Growth and Scaffold Selection for 3-D Constructs Paul J. Price, Ph.D., Chief Scientific Officer, D-Finitive Cell Technologies The cell culture medium and the physical environment play key roles in the optimization of cell growth and function in either 2D or 3D formats. This seminar will cover the basics of the cell culture medium, factors for optimal viability and media performance and the selection of the proper scaffold or matrix for the desired outcome.

2:00 Chairperson’s Remarks

2:35 Taking Cancer Biology to the Third Dimension
Keiran Smalley, Ph.D., Senior Scientist, Program of Molecular Oncogenesis, The Wistar Institute 
It is becoming more apparent that the responses of cancer cells to novel targeted therapies are determined by their interaction with neighboring tumor cells and the extracellular matrix. Recent work from our laboratory has demonstrated that culture of tumor cells under 3D spheroid and organotypic culture conditions dramatically alters both cell phenotype and drug response. I will discuss the practical application of these techniques to cancer biology and drug discovery, and show how these methods are more predictive of anti-cancer drug activity in vivo.

3:05 Tissue Engineering and 3-D Cell Culture Using Hyaluronan-Based Hydrogels Anna Scott, Ph.D., Director of Operations, Glycosan BioSystems 
We have recently developed a novel approach to the creation of a fully synthetic, covalently crosslinked extracellular matrix known as Extracel. Extracel can be crosslinked under ambient, physiological conditions in situ in the presence of cells to provide an injectable cell-seeded hydrogel for tissue repair in vivo or three-dimensional (3-D) cell culture in vitro. The hydrogel is composed of thiol-modified hyaluronan, thiol-modified gelatin (denatured collagen), and polyethylene glycol diacrylate (biocompatible, polyvalent electrophile that reacts with the thiol residues to crosslink the hydrogel). Extracel hydrogels and sponges (lyophilized hydrogels) support in vivo growth of healthy, cellularized tissues and in vitro growth of primary human hepatocytes, human dermal fibroblasts, mesenchymal stem cells and many other primary cells and cell lines. For tissue engineering, Extracel impregnated with cells dramatically improves repair of bone and cartilage defects and aids in the regeneration of functional liver tissue.

3:20 Refreshment Break, Poster and Exhibit Viewing

4:00 Tissue Architecture Linked to Epigenetic Control of Therapeutic Response
Kelvin K.C. Tsai, Ph.D., Postdoctoral Fellow, Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco 
Using three-dimensional tissue culture as a model system, we report that tissue organization is associated with profound resistance to multiple death inducers, which is functionally-linked to transcriptional reprogramming of cellular pro-apoptotic/anti-apoptotic pathways by the nuclear receptor corepressor SMRT (silencing mediator of retinoic acid and thyroid hormone receptor). The SMRT-mediated death resistance was found to be functionally-linked to chromatin remodelling-mediated transcriptional regulation through activation of the histone deacetylase-3, and is usurped by malignant tumor cells during their phenotypic evolution of multi-drug resistance. Our findings provide a novel example in which tissue architecture and microenvironmental heterogenecity is tied to in vivo selection of drug resistance.

4:30 3D Scaffolds with Inverted Colloidal Crystal Geometry for ex vivo Drug Screening Assays
Nicholas Kotov, Professor, Chemical Engineering, University of Michigan
Efficacy of in-vitro testing can be significantly improved provided that better ex vivo models for different organs and tissues are developed. A large body of research indicates that cultured cells organized in three-dimensions (3D) behave a lot more closely to the original tissues and retain more natural functions than the cells in 2D cultures. However the currently available 3D scaffolds have either poor optical properties or impair cellular migration. Both of these factors are detrimental for scaffold utilization for rapid drug screening currently used in industry. A new type of scaffold was developed based on inverted colloidal crystal (ICC) topology, which can resolve these issues and result in adequate ex vivo models with 3D cellular organization resembling that of original organs. Additionally, the ICC scaffolds can be standardized exceptionally well, which is critical for reproducibility of the drug screening assays. The ex vivo replicas of liver and bone marrow made in well plate format adaptable for drug screening will be demonstrated.

5:00 Panel of Experts

5:30 Close of Day