Core-shell microparticles for protein sequestration and controlled release of a protein-laden core

• Type of Material: Article
• Authors: Torri E. Rinker, Georgia Institute of Technology; Brandon D. Philbrick, Georgia Institute of Technology; Johnna Sue Temenoff, Emory University
• Language: English
• Date: 2017-07-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Acta Materialia Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.actbio.2016.12.042
• Title of Journal or Parent Work: Acta Biomaterialia
• ISSN: 1742-7061
• Volume: 56
• Start Page: 91
• End Page: 101
• Grant/Funding Information: This study was supported with funding from the National Science Foundation (NSF) Graduate Research Fellowship (DGE-1148903) to TER, the Georgia Tech Petit Scholar Program to BDP, NSF (DMR 1207045), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01AR063692.
• Keywords: MESENCHYMAL STEM-CELLS; MICROSPHERES; HYDROGELS; DESIGN; Materials Science, Biomaterials; Hydrolytically degradable; Engineering, Biomedical; DIFFERENTIATION; HEPARIN DESULFATION; Protein delivery; Controlled release; Materials Science; FABRICATION; FIBROBLAST-GROWTH-FACTOR; Technology; Engineering; BONE MORPHOGENETIC PROTEIN-2; DELIVERY-SYSTEM; Core-shell microparticles; Science & Technology; Heparin
• Research Categories: Engineering, Biomedical

Abstract

Development of multifunctional biomaterials that sequester, isolate, and redeliver cell-secreted proteins at a specific timepoint may be required to achieve the level of temporal control needed to more fully regulate tissue regeneration and repair. In response, we fabricated core-shell heparin-poly(ethylene-glycol) (PEG) microparticles (MPs) with a degradable PEG-based shell that can temporally control delivery of protein-laden heparin MPs. Core-shell MPs were fabricated via a re-emulsification technique and the number of heparin MPs per PEG-based shell could be tuned by varying the mass of heparin MPs in the precursor PEG phase. When heparin MPs were loaded with bone morphogenetic protein-2 (BMP-2) and then encapsulated into core-shell MPs, degradable core-shell MPs initiated similar C2C12 cell alkaline phosphatase (ALP) activity as the soluble control, while non-degradable core-shell MPs initiated a significantly lower response (85 + 19% vs. 9.0 + 4.8% of the soluble control, respectively). Similarly, when degradable core-shell MPs were formed and then loaded with BMP-2, they induced a ∼7-fold higher C2C12 ALP activity than the soluble control. As C2C12 ALP activity was enhanced by BMP-2, these studies indicated that degradable core-shell MPs were able to deliver a bioactive, BMP-2-laden heparin MP core. Overall, these dynamic core-shell MPs have the potential to sequester, isolate, and then redeliver proteins attached to a heparin core to initiate a cell response, which could be of great benefit to tissue regeneration applications requiring tight temporal control over protein presentation. Statement of Significance Tissue repair requires temporally controlled presentation of potent proteins. Recently, biomaterial-mediated binding (sequestration) of cell-secreted proteins has emerged as a strategy to harness the regenerative potential of naturally produced proteins, but this strategy currently only allows immediate amplification and re-delivery of these signals. The multifunctional, dynamic core-shell heparin-PEG microparticles presented here overcome this limitation by sequestering proteins through a PEG-based shell onto a protein-protective heparin core, temporarily isolating bound proteins from the cellular microenvironment, and re-delivering proteins only after degradation of the PEG-based shell. Thus, these core-shell microparticles have potential to be a novel tool to harness and isolate proteins produced in the cellular environment and then control when proteins are re-introduced for the most effective tissue regeneration and repair.