Hydrogels are hydrophilic polymeric matrices that can support cell and tissue growth in three-dimension. With careful design, hydrogels serve not only as a 3D platform for studying cell behaviors, but also as scaffolds for culturing and differentiating stem/progenitor cells.
We aim to develop a multifunctional hydrogel system that initially supports cell proliferation, but at a later stage can be "switched" into a microenvironment that promotes cell/tissue differentiation into a specific cell type. Our central hypothesis is that cell expansion and differentiation can be achieved in a single hydrogel matrix incorporated with dynamic biophysical and biochemical cues. We will test this hypothesis by developing a versatile hydrogel system using multiple cytocompatible thiol-ene "click" reactions. In the initial stage, we will design locally degradable thiol-ene gels to promote proliferation of PANC-1 cells (a pancreatic ductal epithelial cell line) (Aim 1). We will incorporate matrix metalloproteinase 2 (MMP-2) specific peptide substrates as hydrogel crosslinkers. This allows the gels to degrade locally (thus creating additional space for cell proliferation) by MMP-2 secreted from PANC-1 cells. The proliferation of encapsulated cells will be promoted by tuning cell-ECM and cell-cell interactions in hydrogels, as well as providing the encapsulated cells with diffusible soluble growth factors. Next, we will "switch" the cell-laden hydrogels from a "pro-proliferation" to a "pro-differentiation" microenvironment (Aim 2a). We will achieve this by performing a second thiol-ene click reaction to introduce pro-differentiation cues within the cell-laden hydrogels, thus promoting the formation of islet-like, insulin secreting cell clusters. The differentiation process will be a combinatorial result of using serum-free culture media, affinity-based recruitment of basic fibroblast growth factor (bFGF), and timely conjugation of glucagon-like peptide 1 (GLP-1). The differentiated cell clusters can be retrieved from the erodible gels (due to specific enzyme activity) for further characterization and biological/clinical applications (Aim 2b). The differentiated clusters are expected to form tight aggregates due to strong cell-cell interactions. Together, our strategies facilitate the formation of islet-like cell clusters with natural cell-cell interactions and normal insulin secretion profiles.

Public Health Relevance

This proposal aims to design biomaterial devices that incorporate signals to promote the proliferation of epithelial cells and to enhance the differentiation of these cells into insulin-producing cells. If successful, this strategy will provide alternative cell sources to benefit type 1 diabetic patients.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Exploratory/Developmental Grants (R21)
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Biomaterials and Biointerfaces Study Section (BMBI)
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Hunziker, Rosemarie
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Indiana University-Purdue University at Indianapolis
Biomedical Engineering
Schools of Engineering
United States
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Shih, Han; Mirmira, Raghavendra G; Lin, Chien-Chi (2015) Visible light-initiated interfacial thiol-norbornene photopolymerization for forming islet surface conformal coating. J Mater Chem B Mater Biol Med 3:170-175
Lin, Chien-Chi; Ki, Chang Seok; Shih, Han (2015) Thiol-norbornene photo-click hydrogels for tissue engineering applications. J Appl Polym Sci 132:
Hao, Yiting; Shih, Han; Munoz, Zachary et al. (2014) Visible light cured thiol-vinyl hydrogels with tunable degradation for 3D cell culture. Acta Biomater 10:104-14
Ki, Chang Seok; Lin, Tsai-Yu; Korc, Murray et al. (2014) Thiol-ene hydrogels as desmoplasia-mimetic matrices for modeling pancreatic cancer cell growth, invasion, and drug resistance. Biomaterials 35:9668-77
Shih, Han; Fraser, Andrew K; Lin, Chien-Chi (2013) Interfacial thiol-ene photoclick reactions for forming multilayer hydrogels. ACS Appl Mater Interfaces 5:1673-80
Raza, Asad; Lin, Chien-Chi (2013) The influence of matrix degradation and functionality on cell survival and morphogenesis in PEG-based hydrogels. Macromol Biosci 13:1048-58
Shih, Han; Lin, Chien-Chi (2013) Visible-light-mediated thiol-ene hydrogelation using eosin-Y as the only photoinitiator. Macromol Rapid Commun 34:269-73
Ki, Chang Seok; Shih, Han; Lin, Chien-Chi (2013) Facile preparation of photodegradable hydrogels by photopolymerization. Polymer (Guildf) 54:2115-2122
Raza, Asad; Ki, Chang Seok; Lin, Chien-Chi (2013) The influence of matrix properties on growth and morphogenesis of human pancreatic ductal epithelial cells in 3D. Biomaterials 34:5117-27
Raza, Asad; Lin, Chien-Chi (2012) Generation and recovery of β-cell spheroids from step-growth PEG-peptide hydrogels. J Vis Exp :e50081

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