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Hyaluronic Acid Gel-Based Scaffolds As Potential Carrier for Growth Factors: an in Vitro Bioassay on Its Osteogenic Potential

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Hyaluronic Acid Gel-Based Scaffolds As Potential Carrier for Growth Factors: an in Vitro Bioassay on Its Osteogenic Potential View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Bern Open Repository and Information System (BORIS) Journal of Clinical Medicine Article Hyaluronic Acid Gel-Based Scaffolds as Potential Carrier for Growth Factors: An In Vitro Bioassay on Its Osteogenic Potential Masako Fujioka-Kobayashi 1,2, Benoit Schaller 1, Eizaburo Kobayashi 1, Maria Hernandez 3, Yufeng Zhang 4 and Richard J. Miron 3,5,6,* 1 Department of Cranio-Maxillofacial Surgery, Inselspital, Bern University Hospital, Bern 3010, Switzerland; [email protected] (B.S.); [email protected] (E.K.) 2 Department of Oral Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8501, Japan; [email protected] 3 Department of Periodontology, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; [email protected] 4 Department of Oral Implantology, University of Wuhan, Wuhan 430079, China; [email protected] 5 Cell Therapy Institute, Center for Collaborative Research, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; [email protected] 6 Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, MI 48109-1078, USA; [email protected] * Correspondence: [email protected] Academic Editor: Hirohiko Okamura Received: 19 September 2016; Accepted: 24 November 2016; Published: 30 November 2016 Abstract: Hyaluronic acid (HA) has been utilized for a variety of regenerative medical procedures due to its widespread presence in connective tissue and perceived biocompatibility. The aim of the present study was to investigate HA in combination with recombinant human bone morphogenetic protein 9 (rhBMP9), one of the most osteogenic growth factors of the BMP family. HA was first combined with rhBMP9 and assessed for the adsorption and release of rhBMP9 over 10 days by ELISA. Thereafter, ST2 pre-osteoblasts were investigated by comparing (1) control tissue culture plastic, (2) HA alone, and (3) HA with rhBMP9 (100 ng/mL). Cellular proliferation was investigated by a MTS assay at one, three and five days and osteoblast differentiation was investigated by alkaline phosphatase (ALP) activity at seven days, alizarin red staining at 14 days and real-time PCR for osteoblast differentiation markers. The results demonstrated that rhBMP9 adsorbed within HA scaffolds and was released over a 10-day period in a controlled manner. While HA and rhBMP9 had little effect on cell proliferation, a marked and pronounced effect was observed for cell differentiation. rhBMP9 significantly induced ALP activity, mRNA levels of collagen1α2, and ALP and osteocalcin (OCN) at three or 14 days. HA also demonstrated some ability to induce osteoblast differentiation by increasing mRNA levels of OCN and increasing alizarin red staining at 14 days. In conclusion, the results from the present study demonstrate that (1) HA may serve as a potential carrier for various growth factors, and (2) rhBMP9 is a potent and promising inducer of osteoblast differentiation. Future animal studies are now necessary to investigate this combination approach in vivo. Keywords: osteoinduction; osteoinductive; guided bone regeneration; bone formation; bone induction; BMP; growth factor; dimensional changes; regenerative therapy; hard tissue regeneration 1. Introduction Bone morphogenetic proteins (BMPs) have played a pivotal role in modern medicine by directly influencing the commitment and differentiation of osteoprogenitor cells towards osteoblasts [1]. J. Clin. Med. 2016, 5, 112; doi:10.3390/jcm5120112 www.mdpi.com/journal/jcm J. Clin. Med. 2016, 5, 112 2 of 13 When combined with various tissue engineering strategies, they guide the induction of mesenchymal progenitor cells to differentiate towards bone-forming osteoblasts. As it relates to clinical practice, recombinant human (rh)BMP2 has been the most widely utilized BMP having been used for a variety of clinical procedures including spinal fusion, open tibial fractures and various bone augmentation procedures in regenerative dentistry [2–4]. Despite this, it remains surprising that of all the 15 BMPs, BMP2 is not necessarily the most osteoinductive of the BMP family [5]. Over a decade ago, two pioneering studies investigated and directly compared the regenerative potential of 14 BMPs via adenovirus transfection experiments (gene therapy) [5,6]. Cheng et al. demonstrated that alkaline phosphatase activity (a marker for osteoblast differentiation) was highest in BMP9 whereas Kang et al. reported that both BMP-6 and -9 had greater in vivo potential for ectopic bone formation [5,6]. Since those studies utilized adenovirus transfection experiments (an area of research still not approved by the food and drug administration (FDA) [7], translating these results into a clinical setting has not been attempted. BMP9 (also known as growth differentiation factor 2; GDF2) was first identified in 1995 in the developing mouse liver cDNA libraries [8]. Since then, BMP9 has been shown to play a role in many pathways including osteogenesis, angiogenesis and chondrogenesis [9–11]. One of the drawbacks of these few studies characterizing BMP9 were that they were only performed utilizing adenovirus transfections (gene therapy) with no information regarding its recombinant protein activity [5,6,10,11]. Recently our research group investigated for the first time the regenerative potential of a clinically viable recombinant source of human (rh)BMP9 [12,13]. In two separate studies, it was found that rhBMP9 demonstrated up to 10 times more osteopromotion in in vitro osteoblast differentiation when compared to rhBMP2 [12,13]. Critical to the success of tissue engineering strategies utilizing growth factors are their biomaterial carrier systems [14]. While the adsorption of BMPs to bone biomaterials has been a highly studied topic in recent years [15–18], additional strategies designed to facilitate the delivery of growth factors remain necessary. Hyaluronic acid (HA) has been utilized in recent years in various medical fields due to its natural constitution in human connective tissues. It is an anionic, non-sulfated glycosaminoglycan considered an optimal biomaterial for tissue engineering, with inherent biocompatible and bioresorbable properties [16]. It also plays a prominent role as a treatment agent for various medical conditions including chronic osteoarthritis, aesthetic surgery, dermatology, ophthalmology, oral maxilla-facial surgery, as well as for various tissue engineering applications [17–20]. HA is also available in cross-linked forms for various tissue engineering applications serving as a scaffold to further improve the overall mechanical properties of the scaffolding system [21–24]. Therefore, in light of the previous utilization of HA in its cross-linked format as a tissue engineering scaffold, the aim of the present study was to determine whether HA could also serve as a carrier for regenerative growth factors such as rhBMP9, one of the most osteogenic growth factors known to date. First, the growth factor release of rhBMP9 over time was investigated from a zero- to 10-day period within HA scaffolds. Thereafter, pre-osteoblasts were quantified for their ability to attach, proliferate and differentiate on HA scaffolds with/without rhBMP9. 2. Methods 2.1. Hyaluronic Acid and Recombinant Human BMP9 Recombinant human (rh)BMP9 was purchased from R&D systems Inc (Minneapolis, MM, USA). Hyaluronic acid (HA) was kindly provided by Regedent (Zürich, Switzerland) utilizing a carrier system including cross-linked HA (16 mg HA/mL—cross-linked at 1MDa; Hyadent BG, BioScience GmbH, Ransbach-Baumbach, Germany, crosslinked to butanediol diglycidyl ether (BDDE)). Figure1 demonstrates a scanning electron microscopy (SEM) image used to characterize surface shape and topography as previously described [25]. For all in vitro experiments, the following three J. Clin. Med. 2016, 5, 112 3 of 13 J. Clin. Med. 2016, 5, 112 3 of 12 groups were utilized: (1) control standard tissue culture plastic (TCP), (2) control HA alone and (3) HAwere with utilized:100 ng/mL (1) controlof rhBMP9. standard Undifferentiated tissue culture plastic mouse (TCP), cell-line (2) control ST2 HA was alone obtained and (3) from HA RIKENwith Cell100 Bank ng/mL (Tsukuba, of rhBMP9. Japan) Undifferentiated and therefore mouse no ethical cell‐line approval ST2 was was obtained necessary from for RIKEN the present Cell Bank study. Cells(Tsukuba, were cultured Japan) and in atherefore humidified no ethical atmosphere approval at was 37 ◦ Cnecessary in growth for mediumthe present consisting study. Cells of DMEMwere (Invitrogencultured in Corporation, a humidified Carlsbad, atmosphere CA, USA),at 37 °C 10% in fetalgrowth Bovine medium serum consisting (FBS; Invitrogen), of DMEM and (Invitrogen antibiotics (Invitrogen).Corporation, For Carlsbad,in vitro experiments,CA, USA), 10% cells fetal were Bovine seeded serum onto the (FBS; various Invitrogen), treatment and modalities antibiotics at a density(Invitrogen). of 10,000 For cells in vitro in 24 experiments, well culture cells plates were (Corning, seeded onto New the York, various NY, treatment USA) for cellmodalities proliferation at a density of 10,000 cells in 24 well culture plates (Corning, New York, NY, USA) for cell proliferation experiments and 50,000 cells per well in 24-well plates for real-time PCR, ALP assay and alizarin red experiments and 50,000 cells per well in 24‐well plates for real‐time PCR, ALP assay and alizarin red experiments. For experiments
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