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Release of the Non-Steroidal Anti-Inflammatory Drug Flufenamic materials Article Release of the Non-Steroidal Anti-Inflammatory Drug Flufenamic Acid by Multiparticulate Delivery Systems Promotes Adipogenic Differentiation of Adipose-Derived Stem Cells Andreea D. Lazăr 1 , Sorina Dinescu 1,2,* ,Mădălina G. Albu-Kaya 3, Sami Gharbia 4, Anca Hermenean 4 and Marieta Costache 1,2 1 Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania; [email protected] (A.D.L.); [email protected] (M.C.) 2 Research Institute of the University of Bucharest, 050663 Bucharest, Romania 3 Department of Collagen Research, Division of Leather and Footwear Research Institute, The National Research & Development Institute for Textiles and Leather, 031215 Bucharest, Romania; [email protected] 4 Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania; [email protected] (S.G.); [email protected] (A.H.) * Correspondence: [email protected] Received: 22 January 2020; Accepted: 25 March 2020; Published: 27 March 2020 Abstract: Engineered tissue-like structures often instigate an inflammatory response in the host that can inhibit wound healing and ultimately lead to the rejection of the implant. In our previous study, we have characterized the properties and biocompatibility of novel multiparticulate drug delivery systems (MDDS), based on collagen matrix with gradual release of anti-inflammatory drug flufenamic acid, we evaluated their anti-inflammatory potential and demonstrated their efficiency against burns and soft tissue lesions. In addition to these results, FA was previously described as a stimulant for adipogenesis, therefore we hypothesized that MDDS might also be appropriate for adipose tissue engineering. After the cell-scaffold constructs were obtained, cell morphology, adhesion and spreading on the systems were highlighted by scanning electron microscopy, immunostaining and confocal microscopy. The effect of FA-enriched materials on adipogenesis was evaluated at gene and protein level, by RT-qPCR, confocal microscopy and immunohistochemistry. Our current work indicates that flufenamic acid plays a beneficial role in adipocyte differentiation, with a direct effect upon the gene and protein expression of important early and late markers of adipogenesis, such as PPARγ2 and perilipin. Keywords: adipose tissue engineering; multiparticulate drug delivery systems; flufenamic acid; adipose-derived stem cells; adipogenic differentiation; PPARγ2; perilipin 1. Introduction The field of tissue engineering (TE) combines principles of engineering with notions from natural sciences in order to develop complex structures capable of mimicking natural tissue, in both aspect and function, fit for the purpose of regeneration [1]. Adipose tissue engineering (ATE) belongs to this interdisciplinary field and it aims to obtain a proper substitute for damaged adipose tissue, resulted for example, from tumor resection, burns or other types of wounds. In vitro an ATE construct can be generated by seeding a biomaterial, made out of natural/synthetic compounds or a combination of the two, with cells capable of differentiating in mature adipocytes in the presence of a proper differentiation Materials 2020, 13, 1550; doi:10.3390/ma13071550 www.mdpi.com/journal/materials Materials 2020, 13, 1550 2 of 13 media (adipogenic inducers). Once implanted at the lesion site, the construct should integrate with the normal tissue through in vivo remodeling [2,3]. The best choice for cellular component would seem to be human adipose-derived stem cells (hASCs), hypo-immunogenic cells suitable for designing biocompatible tissue constructs, which can be easily harvested in abundance from autologous fat tissue through minimal invasive procedures [4,5]. hASCs’ self-renewal ability is similar to bone marrow or umbilical cord stem cells, and they are capable of differentiating into cells of mesodermal or ectodermal lineages under the influence of a specific inducing microenvironment [6–11]. Moreover, hASCs release multiple growth factors that facilitate tissue regeneration, such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), fibroblast growth factor-2 (FGF-2), transforming growth factor (TGF), platelet-derived growth factor-b (PDGFB), angiopoietin-1 (Ang-1), Ang-2, stromal cell-derived factor-1 (SDF-1) and osteonectin [12]. Preclinical studies on the use of hASCs in vitro and in vivo have been performed, and their efficacy has been established in clinical trials [13–15]. The differentiation of hASCs involves a complex series of changes in the cellular gene and protein expression patterns. In vitro differentiation is characterized by growth arrest, the induction and expression of multiple adipogenic genes, and ultimately, triglyceride accumulation [16,17]. One of the key regulators of the process is peroxisome proliferating activated receptor gamma-2 (PPARγ2), a ligand-activated transcription factor that belongs to the nuclear receptor superfamily, which is selectively expressed in adipocytes and induced early (initial 24–48 h) during the course of differentiation [18,19]. After hormonal induction, PPARγ2 level significantly increases, thus initiating adipogenesis, and then gradually decreases as the process evolves. PPARγ2 also plays a role in maintenance of the differentiated state. If silenced, already differentiated 3T3-L1 preadipocytes express specific late markers, such as perilipin, at a lower level and the accumulated fat droplets diminish, thus dedifferentiating [20]. Perilipin is considered a late marker of adipogenesis because it coats the intracellular lipid droplets, which only form in the terminal stage of the process, acting as a protective barrier that restricts the access of cytosolic lipases. Its expression is mainly regulated by PPARγ2 [21,22]. In order to provide the cells with an in vivo-like structure, tridimensional (3D) scaffolds that resemble the natural extracellular matrix (ECM) in architecture and composition should be used, because they allow the cells to maintain their conformation, communicate and interact with one another, exert their native functions and better adhere to the material, thus facilitating the formation of a proper tissue construct [23]. Due to their high biocompatibility and similarity to the ECM, natural polymers are widely used for ATE purposes [24,25]. Collagen is prevalent in native adipose ECM, has low antigenicity, low inflammatory properties and good biocompatibility, promoting cell attachment and favorable adipose outcome [26–28]. Even more, it is approved for use in humans by the US Food and Drug Administration (FDA) [24]. However, pure collagen has a fast degradation rate in vivo; therefore, to enhance its mechanical strength and durability it needs to be cross-linked with other polymers (such as dextran) or fixatives (for example glutaraldehyde) [29]. To facilitate the future integration of the ATE construct into the lesion site, various drugs, natural plant extracts or growth factors can be incorporated into the biomaterials [16,30]. For example, Kimura et al. combined collagen sponges with gelatin microspheres containing basic fibroblast growth factor (bFGF) and implanted them in nude mice. Within 6 weeks, adipose tissue developed in the constructs and the extent of fat tissue formation was positively influenced by the bFGF concentration, presumably by promoting angiogenesis [31]. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as flufenamic acid (FA), modulate the immune response of the host, and diminish the excess inflammation that could occur as a result of implantation, a potential cause for construct rejection. NSAIDs are commonly used in the clinic for their anti-inflammatory, antipyretic and analgesic activity. Therapeutic actions are attributed to inhibition of cyclooxygenases (COX-1 and COX-2), enzymes that catalyze the first steps in conversion of arachidonic acid (AA) to prostaglandins (PGs) [32]. While the COX enzymes constitute major NSAID targets, there are also suggestions that some NSAIDs effects are mediated by PPAR members. High doses of certain NSAIDs concentrations can modulate PPARγ Materials 2020, 13, 1550 3 of 13 activation in vitro [33,34]. FA is a good candidate for ATE applications because in addition to its proven conventional role, a previous study reported that FA facilitates differentiation into fat tissue, acting as an adjuvant to the process in a similar, though less potent, manner to another class member, namely indomethacin, regularly used as a component in the adipocyte differentiation media [33,35]. As such, FA may contribute to the activation of PPARγ2, the main inducer of adipogenesis, in the first 1–2 days of differentiation [36]. To reduce the initial burst release effect and to provide a controlled drug release over time, our group previously proposed novel multiparticulate drug delivery systems (MDDS) for FA, based on collagen composite matrices with gelatin-alginate-carboxymethylcellulose microcapsules for drug encapsulation, that allowed the drug to be rapidly discharged in the first 60 min and then gradually released over the course of 48 h. Out of all the tested MDDS, the ones with the highest amount of FA, specifically M2 and M4 (systems with 30% FA microcapsules in their structure and additional FA in free form incorporated in the composite gel of M4) obtained the best results, the released FA percentage reaching 85.3% for M2 and 95.01% for M4. Moreover, these natural polymeric systems showed good biocompatibility, having a positive
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