Sprouting Angiogenesis: A Numerical Approach with Experimental Validation

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Annals of Biomedical Engineering (Ó 2020) https://doi.org/10.1007/s10439-020-02622-w

Original Article

Sprouting Angiogenesis: A Numerical Approach with Experimental Validation ANA GUERRA ,1 JORGE BELINHA,2 NASIDE MANGIR,3,4 SHEILA MACNEIL,3 and RENATO NATAL JORGE 5,6 1

Institute of Science and Innovation in Mechanical and Industrial Engineering (INEGI), Rua Dr. Roberto Frias, 400, 4200465 Porto, Portugal; 2Mechanical Engineering Department, School of Engineering, Polytechnic of Porto (ISEP), Rua Dr. Anto´nio Bernardino de Almeida, 431, 4249-015 Porto, Portugal; 3Kroto Research Institute, Department of Material Science and Engineering, University of Sheffield, North Campus, Broad Lane, Sheffield S3 7HQ, UK; 4Department of Urology, Royal Hallamshire Hospital, Glossop Rd, Sheffield S10 2JF, UK; 5Associated Laboratory for Energy, Transports and Aeronautics (LAETA – INEGI), Rua Dr. Roberto Frias, 400, 4200-465 Porto, Portugal; and 6Mechanical Engineering Department, Faculty of Engineering of the University of Porto (FEUP), Rua Dr. Roberto Frias, 4200-465 Porto, Portugal (Received 8 April 2020; accepted 14 September 2020) Associate Editor Estefanı´ a Pen˜a oversaw the review of this article.

Abstract—A functional vascular network is essential to the correct wound healing. In sprouting angiogenesis, vascular endothelial growth factor (VEGF) regulates the formation of new capillaries from pre-existing vessels. This is a very complex process and mathematical formulation permits to study angiogenesis using less time-consuming, reproducible and cheaper methodologies. This study aimed to mimic the chemoattractant effect of VEGF in stimulating sprouting angiogenesis. We developed a numerical model in which endothelial cells migrate according to a diffusion-reaction equation for VEGF. A chick chorioallantoic membrane (CAM) bioassay was used to obtain some important parameters to implement in the model and also to validate the numerical results. We verified that endothelial cells migrate following the highest VEGF concentration. We compared the parameters—total branching number, total vessel length and branching angle—that were obtained in the in silico and the in vivo methodologies and similar results were achieved (p-value smaller than 0.5; n = 6). For the difference between the total capillary volume fractions assessed using both methodologies values smaller than 15% were obtained. In this study we simulated, for the first time, the capillary network obtained during the CAM assay with a realistic morphology and structure. Keywords—Vascular endothelial growth factor, Capillary network, Chick chorioallantoic membrane assay, Radial point interpolation method.

Address correspondence to Renato Natal Jorge, Associated Laboratory for Energy, Transports and Aeronautics (LAETA – INEGI), Rua Dr. Roberto Frias, 400, 4200-465 Porto, Portugal. Electronic mail: [email protected]

INTRODUCTION The failure of some wounds to heal becomes a social and economic issue. The NHS spends every year between £4.5bn and £5.1bn on the treatment of acute an