Multicomponent hydrogels for the formation of vascularized bone-like constructs in vitro

Burak Derkus; Babatunde O Okesola; David W Barrett; Matteo D'Este; Tina T Chowdhury; David Eglin; Alvaro Mata

doi:10.1016/j.actbio.2020.03.025

Multicomponent hydrogels for the formation of vascularized bone-like constructs in vitro

Acta Biomater. 2020 Jun:109:82-94. doi: 10.1016/j.actbio.2020.03.025. Epub 2020 Apr 18.

Authors

Burak Derkus¹, Babatunde O Okesola², David W Barrett², Matteo D'Este³, Tina T Chowdhury², David Eglin³, Alvaro Mata⁴

Affiliations

¹ Institute of Bioengineering, Queen Mary University of London, E1 4NS London, UK; School of Engineering and Materials Science, Queen Mary University of London, E1 4NS London, UK; Biomedical Engineering Department, Faculty of Engineering, Eskisehir Osmangazi University, 26480 Eskisehir, Turkey; Department of Chemistry, Faculty of Science, Ankara University, 06560 Ankara, Turkey.
² Institute of Bioengineering, Queen Mary University of London, E1 4NS London, UK; School of Engineering and Materials Science, Queen Mary University of London, E1 4NS London, UK.
³ AO Research Institute Davos, Clavadelerstrasse 8, Davos Platz 7270, Switzerland.
⁴ Institute of Bioengineering, Queen Mary University of London, E1 4NS London, UK; School of Engineering and Materials Science, Queen Mary University of London, E1 4NS London, UK; School of Pharmacy, University of Nottingham, NG7 2RD Nottingham, UK; Department of Chemical and Environmental Engineering, University of Nottingham, NG7 2RD Nottingham, UK; Biodiscovery Institute, University of Nottingham, NG7 2RD Nottingham, UK. Electronic address: a.mata@nottingham.ac.uk.

PMID: 32311533
DOI: 10.1016/j.actbio.2020.03.025

Abstract

The native extracellular matrix (ECM) is a complex gel-like system with a broad range of structural features and biomolecular signals. Hydrogel platforms that can recapitulate the complexity and signaling properties of this ECM would have enormous impact in fields ranging from tissue engineering to drug discovery. Here, we report on the design, synthesis, and proof-of-concept validation of a microporous and nanofibrous hydrogel exhibiting multiple bioactive epitopes designed to recreate key features of the bone ECM. The material platform integrates self-assembly with orthogonal enzymatic cross-linking to create a supramolecular environment comprising hyaluronic acid modified with tyramine (HA-Tyr) and peptides amphiphiles (PAs) designed to promote cell adhesion (RGDS-PA), osteogenesis (Osteo-PA), and angiogenesis (Angio-PA). Through individual and co-cultures of human adipose derived mesenchymal stem cells (hAMSCs) and human umbilical vascular endothelial cells (HUVECs), we confirmed the capacity of the HA-Tyr/RGDS-PA/Osteo-PA/Angio-PA hydrogel to promote cell adhesion as well as osteogenic and angiogenic differentiation in both 2D and 3D setups. Furthermore, using immunofluorescent staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), we demonstrated co-differentiation and organization of hAMSCs and HUVECs into 3D aggregates resembling vascularized bone-like constructs. STATEMENT OF SIGNIFICANCE: This body of work presents a new approach to develop more complex, yet functional, in vitro environments for cell culture while enabling a high level of control, tuneability, and reproducibility. The multicomponent self-assembling bioactive 2D and 3D hydrogels with nanofibrous architecture designed to recreate key molecular and macromolecular features of the native bone ECM and promote both osteogenesis and angiogenesis. The materials induce endothelial cells towards large vascular lumens and MSCs into bone cells on/within the same platform and form vascularized-bone like construct in vitro. This strategy looks encouraging for lifelike bone tissue engineering in vitro and bone tissue regeneration in vivo.

Keywords: 3D cell culture; Angiogenesis; Bone tissue engineering; Peptide nanofiber; Self-assembly.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / cytology
Biomimetic Materials / chemical synthesis
Biomimetic Materials / chemistry*
Cell Adhesion / drug effects
Cell Differentiation / drug effects
Cell Proliferation / drug effects
Coculture Techniques / methods*
Elastic Modulus
Extracellular Matrix / chemistry
Human Umbilical Vein Endothelial Cells
Humans
Hyaluronic Acid / chemistry
Hydrogels / chemical synthesis
Hydrogels / chemistry*
Mesenchymal Stem Cells / drug effects
Mesenchymal Stem Cells / metabolism
Neovascularization, Physiologic / drug effects*
Osteogenesis / drug effects*
Peptides / chemical synthesis
Peptides / chemistry
Porosity
Proof of Concept Study
Tyramine / chemistry

Substances

Hydrogels
Peptides
Hyaluronic Acid
Tyramine

Grants and funding

MR/R015651/1/MRC_/Medical Research Council/United Kingdom