Incorporation of Human-Platelet-Derived Growth Factor-BB Encapsulated Poly(lactic-co-glycolic acid) Microspheres into 3D CORAGRAF Enhances Osteogenic Differentiation of Mesenchymal Stromal Cells Saktiswaren Mohan, † Hanumantharao Balaji Raghavendran,* ,† Puvanan Karunanithi, † Malliga Raman Murali, † Sangeetha Vasudevaraj Naveen, † Sepehr Talebian, ‡ Mohammad Mehrali, § Mehdi Mehrali, ∥ Elango Natarajan, ⊥ Chee Ken Chan, † and Tunku Kamarul* ,† † Tissue Engineering Group (TEG), National Orthopaedic Centre of Excellence in Research and Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia ‡ Intelligent Polymer Research Institute, ARC Centre of Excellence for Electromaterials Science, University of Wollongong, Wollongong, New South Wales 2522, Australia § Process and Energy Department, Delft University of Technology, Leeghwaterstraat 39, Delft 2628 CB, The Netherlands ∥ DTU Nanotech, Department of Micro- and Nanotechnology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Kongens Lyngby 2800, Denmark ⊥ Mechanical Engineering Department, Faculty of Engineering, UCSI University, Technology and Built Environment, Kuala Lumpur 506000, Malaysia ABSTRACT: Tissue engineering aims to generate or facilitate regrowth or healing of damaged tissues by applying a combination of biomaterials, cells, and bioactive signaling molecules. In this regard, growth factors clearly play important roles in regulating cellular fate. However, uncontrolled release of growth factors has been demonstrated to produce severe side effects on the surrounding tissues. In this study, poly(lactic-co-glycolic acid) (PLGA) micro- spheres (MS) incorporated three-dimensional (3D) CORAGRAF scaffolds were engineered to achieve controlled release of platelet- derived growth factor-BB (PDGF-BB) for the differentiation of stem cells within the 3D polymer network. Fourier transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, scanning electron microscopy, and microtomography were applied to characterize the fabricated scaffolds. In vitro study revealed that the CORAGRAF-PLGA-PDGF-BB scaffold system enhanced the release of PDGF-BB for the regulation of cell behavior. Stromal cell attachment, viability, release of osteogenic differentiation markers such as osteocalcin, and upregulation of osteogenic gene expression exhibited positive response. Overall, the developed scaffold system was noted to support rapid cell expansion and differentiation of stromal cells into osteogenic cells in vitro for bone tissue engineering applications. KEYWORDS: CORAGRAF, PLGA, microsphere, stromal cell, platelet-derived growth factor, osteogenic ■ INTRODUCTION Calcium phosphate (CaP) scaffolds composed of beta- tricalcium phosphate, 1 hydroxyapatite, chitosan, 2 and their composites 3 are ideal for bone repair because of their biocompatibility, adjustable degradation rates, and excellent bioactivity. 4−6 However, they are not osteoinductive in nature, and materials such as chitosan are brittle and exhibit poor cell attachment. 7−9 Although scaffolding materials are critical for tissue regeneration, researchers have found that growth factor stimulation, both in vitro and in vivo, is also vital. Reports have shown that the overall functional bioactivity of scaffolds, including bone or cartilage healing, improved following incorporation of growth factors, such as transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and bone morphogenetic proteins (BMPs), into the biomaterial scaffolds. 10 Among the various well-known growth factors, platelet-derived growth factor-BB (PDGF-BB) is a potent mitogen that can induce angiogenesis and direct cell migration, and is involved in vessel maturation and stabilization. 11 In recent times, although increasing numbers of drug-loaded scaffolds have been designed using different structures and materials, the undesirable drug burst release phenomenon associated with rapid drug diffusion from these scaffolds has reduced the effectiveness of the drugs, thus Received: October 23, 2016 Accepted: February 22, 2017 Published: March 7, 2017 Research Article www.acsami.org © 2017 American Chemical Society 9291 DOI: 10.1021/acsami.6b13422 ACS Appl. Mater. Interfaces 2017, 9, 9291−9303