Nanoceria Can Act as the Cues for Angiogenesis in Tissue- Engineering Scaffolds: Toward Next-Generation in Situ Tissue Engineering Robin Augustine,* ,† Yogesh B. Dalvi, ‡ Pan Dan, § Nebu George, ‡ Debora Helle, § Ruby Varghese, ‡ Sabu Thomas, ∥ Patrick Menu, § and Neelakandapillai Sandhyarani † † Nanoscience Research Laboratory, School of Nano Science and Technology, National Institute of Technology Calicut, Kozhikode, Kerala 673601, India ‡ Pushpagiri Research Centre, Pushpagiri Institute of Medical Sciences, Tiruvalla, Kerala 689101, India § UMR 7365 CNRS - Université de Lorraine, Ingé nierie Molé culaire et Physiopathologie Articulaire, Vandoeuvre-lè s Nancy, F54500, France ∥ International and Inter University Centre for Nanoscience and Nanotechnology, Mahatma Gandhi University, Kottayam, Kerala 686560, India * S Supporting Information ABSTRACT: Next-generation tissue engineering exploits the body’s own regenerative capacity by providing an optimal niche via a scaffold for the migration and subsequent proliferation of endogenous cells to the site of injury, enhancing regeneration and healing and bypassing laborious in vitro cell-culturing procedures. Such systems are also required to have a sufficient angiogenic capacity for the subsequent patency of implanted scaffolds. The exploitation of redox properties of nanodimensional ceria (nCeO 2 ) in in situ tissue engineering to promote cell adhesion and angiogenesis is poorly investigated. As a novel strategy, electrospun polycaprolactone based tissue-engineering scaffolds loaded with nCeO 2 were developed and evaluated for morphological and physicomechanical features. In addition, in vitro and in vivo studies were performed to show the ability of nCeO 2 - containing scaffolds to enhance cell adhesion and angiogenesis. These studies confirmed that nCeO 2 -containing scaffolds supported cell adhesion and angiogenesis better than bare scaffolds. Gene-expression studies had shown that angiogenesis- related factors such as HIF1α and VEGF were up-regulated. Overall results show that incorporation of nCeO 2 plays a key role in scaffolds for the enhancement of angiogenesis, cell adhesion, and cell proliferation and can produce a successful outcome in in situ tissue engineering. KEYWORDS: nanoceria, in situ tissue engineering, angiogenesis, polycaprolactone ■ INTRODUCTION The field of tissue engineering has produced many achieve- ments in producing novel tools and translating various biomaterial approaches toward the development of functional tissue-engineered products. Although the conventional tissue- engineering approaches, which are based on the use of autologous cells and preseeded scaffolds for implantation at the injury, have been well-established, they are time-consuming and laborious. 1 The commercialization of such products are limited due to the difficulty with transport and storage that make them less convenient and clinically less viable. To bypass the bottlenecks of cell-based tissue engineering, a new concept referred to as in situ tissue engineering that utilizes the body’s own regenerating capacity was proposed. 2 This method exploits target-specific tissue engineering scaffolds that can effectively control the microenvironment at the implantation site and attract, mobilize, and facilitate the proliferation of host stem and progenitor cells to the desired tissues. 3 Rapid development of an adequate vasculature is a major prerequisite for the survival of the engineered construct after their implantation and during long-term function. In conven- tional tissue engineering, pre-vascularization has been recog- nized as a promising approach focusing on the generation of a preformed microvasculature in tissue-engineered constructs prior to their application. 4 However, this approach is not feasible in in situ tissue engineering. Although the incorpo- Received: September 13, 2018 Accepted: October 22, 2018 Published: October 22, 2018 Article pubs.acs.org/journal/abseba Cite This: ACS Biomater. Sci. Eng. 2018, 4, 4338-4353 © 2018 American Chemical Society 4338 DOI: 10.1021/acsbiomaterials.8b01102 ACS Biomater. Sci. Eng. 2018, 4, 4338−4353 Downloaded via UNIV OF QATAR on December 27, 2018 at 09:27:59 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.