To reduce required capital and time investment in development of new pharmaceutical agents, there is an urgent need for preclinical drug testing models that are predictive of drug response in human tissues or organs. Despite tremendous advancements and rigorous multistage screening of drug candidates involving computational models, traditional cell culture platforms, animal models and most recently humanized animals, there is still a large deficit in our ability to predict drug response in patient groups and overall attrition rates from phase 1 through phase 4 of clinical studies remain well above 90%. Organ-on-a-chip (OOC) platforms have proven potential in providing tremendous flexibility and robustness in drug screening and development by employing engineering techniques and materials. More importantly, in recent years there is a clear upward trend in studies that utilize human-induced pluripotent stem cell (hiPSC) to developed personalized tissue or organ models. Additionally, integrated multiple organs on the single chip with increasingly more sophisticated representation of absorption, distribution, metabolism, excretion and toxicity (ADMET) process are being utilized to better understand drug interaction mechanisms in the human body and thus show great potential to better predict drug efficacy and safety. In this review, we summarize these advances, highlighting studies that took the next step to clinical trials and research areas with the utmost potential and discuss the role of the OOCs in overall drug discovery process at preclinical and clinical stage, as well as outline remaining challenges.
Biologically active materials from marine sources have been receiving increasing attention as they are free from the transmissible diseases and religious restrictions associated with the use of mammalian resources. Among various other biomaterials from marine sources, alginate and fish gelatin (f-gelatin), with their inherent bioactivity and physicochemical tunability, have been studied extensively and applied in various biomedical fields such as regenerative medicine, tissue engineering, and pharmaceutical products. In this study, by using alginate and f-gelatin’s chemical derivatives, we developed a marine-based interpenetrating polymer network (IPN) hydrogel consisting of alginate and f-gelatin methacryloyl (f-GelMA) networks via physical and chemical crosslinking methods, respectively. We then evaluated their physical properties (mechanical strength, swelling degree, and degradation rate) and cell behavior in hydrogels. Our results showed that the alginate/f-GelMA hydrogel displayed unique physical properties compared to when alginate and f-GelMA were used separately. These properties included high mechanical strength, low swelling and degradation rate, and an increase in cell adhesive ability. Moreover, for the first time, we introduced and optimized the application of alginate/f-GelMA hydrogel in a three-dimensional (3D) bioprinting system with high cell viability, which breaks the restriction of their utilization in tissue engineering applications and suggests that alginate/f-GelMA can be utilized as a novel bioink to broaden the uses of marine products in biomedical fields.
Bioink based 3D bioprinting is a promising new technology that enables fabrication of complex tissue structures with living cells. The printability of the bioink depends on the physical properties such as viscosity. However, the high viscosity bioink puts shear stress on the cells and low viscosity bioink cannot maintain complex tissue structure firmly after the printing. In this work, we applied dual crosslinkable bioink using Kappa-carrageenan (κ-CA) to overcome existing shortcomings. κ-CA has properties such as biocompatibility, biodegradability, shear-thinning and ionic gelation but the difficulty of controlling gelation properties makes it unsuitable for application in 3D bioprinting. This problem was solved by synthesizing methacrylated Kappa-carrageenan (MA-κ-CA), which can be dual crosslinked through ionic and UV (Ultraviolet) crosslinking to form hydrogel using NIH-3T3 cells. Through MA substitutions, the rheological properties of the gel could be controlled to reduce the shear stress. Moreover, bioprinting using the cell-laden MA-κ-CA showed cell compatibility with enhanced shape retention capability. The potential to control the physical properties through dual crosslinking of MA-κ-CA hydrogel is expected to be widely applied in 3D bioprinting applications.
To overcome the drawbacks of conventional drug delivery system, nanoemulsion have been developed as an advanced form for improving the delivery of active ingredients. However, safety evaluation is crucial during the development stage before the commercialization. Therefore, the aim of this study was to evaluate the cytotoxicity of two types of newly developed nanoemulsions. Turmeric extract-loaded nanoemulsion powder-10.6 (TE-NEP-10.6, high content of artificial surfactant Tween 80), which forms the optimal nanoemulsion, and the TE-NEP-8.6 made by increasing the content of natural emulsifier (lecithin) to reduce the potential toxicity of nanoemulsion were cultured with various cells (NIH3T3, H9C2, HepG2, hCPC, and hEPC) and the changes of each cell were observed followed by nanoemulsion treatment. As a result, the two nanoemulsions (TE-NEP-10.6 and TE-NEP-8.6) did not show significant difference in cell viability. In the case of cell line (NIH3T3, H9C2, and HepG2), toxicity was not observed at an experimental concentration of less than 1 mg/mL, however, the cell survival rate decreased in a concentration dependent manner in the case of primary cultured cells. These results from our study can be used as a basic data to confirm the cell type dependent toxicity of nanoemulsion.
Citrons have been widely used for medicinal purposes for a long time, but the application of citron in the food industry is still restricted. The extensive advantages of nanotechnology in the food industry have greatly broadened the application of foods. In this study, by employing nanotechnology, we prepared citron-extract nanoparticle with an average size of 174.11 ± 3.89 nm, containing protein peptide and/or liposome. In order to evaluate the toxicity of nanoparticles and to ensure food safety, biological cytotoxicity at the cell and genomic levels was also identified to examine the toxicity of citron extracts by using an in vitro system. Our results demonstrated that the cytotoxicity of citronliposome was dependent on cell type in high concentrations (1 and 5 mg/mL), selectively against primary human cardiac progenitor cells (hCPCs), and human endothelial progenitor cells (hEPCs) in MTT and lactate dehydrogenase (LDH) assays. Interestingly, for the NIH-3T3 and H9C2 cell lines, cell cytotoxicity was observed with slight genotoxicity, especially from citronpeptide extract for both cell lines. Taken together, our study provides cytotoxicity data on nanoengineered citron extracts according to different cell type as is crucial for further applications.
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