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Biomaterials. 2018 Feb;154:34-47. doi: 10.1016/j.biomaterials.2017.10.051. Epub 2017 Oct 31.

Guiding morphogenesis in cell-instructive microgels for therapeutic angiogenesis.

Author information

1
i3S - Instituto de Inovação e Investigação em Saúde, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
2
i3S - Instituto de Inovação e Investigação em Saúde, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
3
i3S - Instituto de Inovação e Investigação em Saúde, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto Patologia e Imunologia Molecular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
4
Department of Biomedical Engineering, University of California - Davis, One Shields Avenue, Davis, CA 95616, USA. Electronic address: esilva@ucdavis.edu.
5
i3S - Instituto de Inovação e Investigação em Saúde, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. Electronic address: ccbarrias@ineb.up.pt.

Abstract

Efficient cell delivery strategies are urgently needed to improve the outcome of cell-based pro-angiogenic therapies. This study describes the design of an injectable cell delivery platform, based on biomaterial-guided morphogenesis principles. Soft high-mannuronic acid alginate microgels, oxidized and functionalized with integrin-binding peptides, provided adequate biochemical/biomechanical cues for the co-assembly of mesenchymal stem cells and outgrowth endothelial cells (OEC) into pre-vascularized microtissues. In vitro priming conditions regulated OEC tubulogenesis, which only occurred under normoxia (+O2) in the presence of angiogenic factors (+GF) and, importantly, did not revert in an ischemic-like environment. Primed (+O2+GF) microgel-entrapped cells secreted a large variety of angiogenesis-related proteins and produced endogenous extracellular-matrix, rich in fibronectin and collagen type I, fostering cell-cell/cell-matrix interactions and establishing a stable angiogenic niche. Extending the pre-culture time resulted in higher cell outward migration and in vivo angiogenic potential. Microgels partially disintegrated upon implantation in chick embryos, promoting interaction between pre-vascularized microtissues and the host. Preserved human vascular structures were still detected in vivo, and human cells showed the ability to migrate and integrate with the chick vasculature. Our results suggest that an integrated approach combining pro-angiogenic cells, cell-instructive microgels and adequate in vitro priming may provide the basis for successful therapeutic angiogenesis.

KEYWORDS:

Cell therapy; Cell-instructive; Injectable biomaterial; Microtissue; Pre-vascularization

[Indexed for MEDLINE]

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