Contents lists available at ScienceDirect Materials Science & Engineering C journal homepage: www.elsevier.com/locate/msec Microfibrous scaffolds from poly(L-lactide-co-ε-caprolactone) blended with xeno-free collagen/hyaluronic acid for improvement of vascularization in tissue engineering applications Halime Kenar a,b,c, ⁎ , Candan Yilmaz Ozdogan a,d , Cansu Dumlu b , Emek Doger e , Gamze Torun Kose c,f , Vasif Hasirci c,g a Experimental and Clinical Research Center, Diabetes and Obesity Research Laboratory, Kocaeli University, Turkey b Polymer Science and Technology Dept., Graduate School of Natural and Applied Sciences, Kocaeli University, Turkey c BIOMATEN, METU Center of Excellence in Biomaterials and Tissue Engineering, Ankara, Turkey d Department of Biology, Graduate School of Natural and Applied Sciences, Kocaeli University, Turkey e Department of Gynecology and Obstetrics, Kocaeli University, Turkey f Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey g Department of Biological Sciences, Middle East Technical University (METU), Ankara, Turkey ARTICLE INFO Keywords: Electrospinning Xeno-free scaffold Human umbilical cord Collagen Hyaluronic acid Vascularization ABSTRACT Success of 3D tissue substitutes in clinical applications depends on the presence of vascular networks in their structure. Accordingly, research in tissue engineering is focused on the stimulation of angiogenesis or generation of a vascular network in the scaffolds prior to implantation. A novel, xeno-free, collagen/hyaluronic acid-based poly(L-lactide-co-ε-caprolactone) (PLC/COL/HA) (20/9.5/0.5 w/w/w) microfibrous scaffold was produced by electrospinning. Collagen types I and III, and hyaluronic acid were isolated from human umbilical cords and blended with the GMP grade PLC. When compared with PLC scaffolds the PLC/COL/HA had higher water uptake capacity (103% vs 66%) which may have contributed to the decrease in its Young's Modulus (from 1.31 to 0.89 MPa). The PLC/COL/HA better supported adipose tissue-derived mesenchymal stem cell (AT MSC) adhe- sion; within 24 h the cell number on the PLC/COL/HA scaffolds was 3 fold higher. Co-culture of human umbilical vein endothelial cells and AT MSCs induced capillary formation on both scaffold types, but the PLC/COL/HA led to formation of interconnected vessels whose total length was 1.6 fold of the total vessel length on PLC. Clinical use of this scaffold would eliminate the immune response triggered by xenogeneic collagen and transmission of animal-borne diseases while promoting a better vascular network formation. 1. Introduction Tissue engineering is a promising solution for the treatment of tissue defects and restoring organ function [1,2]. This approach is mainly developing biological substitutes that mimic natural tissues. Natural tissues and organs exhibit a three-dimensional architecture which harbors interactions between the cells themselves and between the cells and the extracellular matrix (ECM). Survival of large 3D tissue sub- stitutes depends on the presence of vascular networks providing oxygen and nutrients after implantation [1–10]. In vitro studies carried out under static conditions showed that tissue substitutes thicker than ap- proximately 150 μm resulted in hypoxia and inadequate supply of oxygen and nutrients leading to cell death [11–14]. One of the existing approaches to aid vascular network formation and fluid transport is the use of porous scaffolds. Various manufacturing methodologies have been developed to form three-dimensional scaf- folds, such as vacuum freeze drying, particle leaching, microsphere sintering, gas foaming, and 3D printing. Despite the advantages of these approaches, most of them have some limitations like uncontrolled pore interconnectivity, and pore-forming agent's residue [15]. Moreover, the cells adhere better to fibers having the size of ECM fibrous components, a property that cannot be provided to the scaffolds by the aforemen- tioned techniques. Electrospinning, a method commonly used in tissue engineering, enables the production of fibrous scaffolds that can mimic and replace the natural ECM until the seeded cells proliferate and produce their own. Electrospinning is a simple, versatile, and a cost- effective system to generate fibrous mats from natural and synthetic polymers. Additionally, fiber diameter can be easily modified from https://doi.org/10.1016/j.msec.2018.12.011 Received 30 May 2018; Received in revised form 3 November 2018; Accepted 5 December 2018 ⁎ Corresponding author at: Experimental and Clinical Research Center, Diabetes and Obesity Research Laboratory, Kocaeli University, Turkey. E-mail address: halime.kenar@kocaeli.edu.tr (H. Kenar). Materials Science & Engineering C 97 (2019) 31–44 Available online 06 December 2018 0928-4931/ © 2018 Elsevier B.V. All rights reserved. T