Dynamic assembly of ultrasoft colloidal networks enables cell invasion within restrictive fibrillar polymers

• Type of Material: Article
• Authors: Alison M. Douglas, Emory University; Alexandros A. Fragkopoulos, Georgia Institute of Technology; Michelle K. Gaines, Emory University; L. Andrew Lyon, Chapman University; Alberto Fernandez-Nieves, Georgia Institute of Technology; Thomas Barker, Emory University
• Language: English
• Date: 2017-01-31
• Publisher: United States National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2017 National Academy of Sciences.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1607350114
• Title of Journal or Parent Work: PNAS
• Volume: 114
• Issue: 5
• Start Page: 885
• End Page: 890
• Grant/Funding Information: We thank the Parker H. Petit Institute for Bioengineering and Bioscience and Georgia Tech/Children's Healthcare of Atlanta (GT/CHOA) Center for Pediatric Nanomedicine for additional funding for this project.; We also acknowledge the American Heart Association for support of A.M.D. through a Predoctoral Fellowship and the National Science Foundation (NSF) Stem Cell Biomanufacturing training grant (NSF DGE 0965945, to A.M.D.).; We acknowledge funding from the Department of Defense (Award W81XWH-15-1-0485), the National Institutes of Health (Grant R01HL130918), and the National Science Foundation (Grant DMR-1609841).
• Keywords: Fibrin; NIH 3T3 Cells; Hydrogels; microgels; porosity; Biocompatible Materials; Cell Movement; cell migration; Animals; Regenerative Medicine; fibrin; Mice; Polymers; Colloids; Thrombin; colloidal assemblies

Abstract

In regenerative medicine, natural protein-based polymers offer enhanced endogenous bioactivity and potential for seamless integration with tissue, yet form weak hydrogels that lack the physical robustness required for surgical manipulation, making them difficult to apply in practice. The use of higher concentrations of protein, exogenous cross-linkers, and blending synthetic polymers has all been applied to form more mechanically robust networks. Each relies on generating a smaller network mesh size, which increases the elastic modulus and robustness, but critically inhibits cell spreading and migration, hampering tissue regeneration. Here we report two unique observations; first, that colloidal suspensions, at sufficiently high volume fraction (φ), dynamically assemble into a fully percolated 3D network within high-concentration protein polymers. Second, cells appear capable of leveraging these unique domains for highly efficient cell migration throughout the composite construct. In contrast to porogens, the particles in our system remain embedded within the bulk polymer, creating a network of particle-filled tunnels. Whereas this would normally physically restrict cell motility, when the particulate network is created using ultralow cross-linked microgels, the colloidal suspension displays viscous behavior on the same timescale as cell spreading and migration and thus enables efficient cell infiltration of the construct through the colloidal-filled tunnels.