Avidity-controlled hydrogels for injectable co-delivery of induced pluripotent stem cell-derived endothelial cells and growth factors

JOURNAL OF CONTROLLED RELEASE

卷:191

Article; Proceedings Paper

Mulyasasmita, Widya¹  Cai, Lei^2,3  Dewi, Ruby E.²  Jha, Arshi^3,4  Ullmann, Sabrina D.⁵  Luong, Richard H.⁶  Huang, Ngan F.^3,4,7  Heilshom, Sarah C.^1,2,3 

[1] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Mat Sci & Engn, Stanford, CA 94305 USA

[3] Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA

[4] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA

[5] RWIH Aachen Univ, Dept Chem, Aachen, Germany

[6] Stanford Univ, Dept Comparat Med, Stanford, CA 94305 USA

[7] Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA

关键词: iPSC;    Hydrogel;    Protein engineering;    VEGF;    Endothelial cell;   

DOI  :  10.1016/j.jconrel.2014.05.015

来源: Elsevier

【 摘 要 】

To translate recent advances in induced pluripotent stem cell biology to clinical regenerative medicine therapies, new strategies to control the co-delivery of cells and growth factors are needed. Building on our previous work designing Mixing-Induced Two-Component Hydrogels (MITCHs) from engineered proteins, here we develop protein-polyethylene glycol (PEG) hybrid hydrogels, MITCH-PEG, which form physical gels upon mixing for cell and growth factor co-delivery. MITCH-PEG is a mixture of C7, which is a linear, engineered protein containing seven repeats of the CC43 WW peptide domain (C), and 8-arm star-shaped PEG conjugated with either one or two repeats of a proline-rich peptide to each arm (P1 or P2, respectively). Both 20 kDa and 40 kDa star-shaped PEG variants were investigated, and all four PEG-peptide variants were able to undergo a sol-gel phase transition when mixed with the linear C7 protein at constant physiological conditions due to noncovalent hetero-dimerization between the C and P domains. Due to the dynamic nature of the C-P physical crosslinks, all four gels were observed to be reversibly shear-thinning and self-healing. The P2 variants exhibited higher storage moduli than the P1 variants, demonstrating the ability to tune the hydrogel bulk properties through a biomimetic peptide-avidity strategy. The 20 kDa PEG variants exhibited slower release of encapsulated vascular endothelial growth factor (VEGF), due to a decrease in hydrogel mesh size relative to the 40 kDa variants. Human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) adopted a well-spread morphology within three-dimensional MITCH-PEG cultures, and MITCH-PEG provided significant protection from cell damage during ejection through a fine-gauge syringe needle. In a mouse hindlimb ischemia model of peripheral arterial disease, MITCH-PEG co-delivery of hiPSC-ECs and VEGF was found to reduce inflammation and promote muscle tissue regeneration compared to a saline control. (C) 2014 Elsevier B.V. All rights reserved.

【 授权许可】

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