Editorial pubs.acs.org/molecularpharmaceutics
A Preface for Engineered Biomimetic Tissue Platforms for in Vitro Drug Evaluation
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neered models, microfluidic models, and recently developed stem cell based models are discussed respectively, updating our knowledge on approaches for efficient drug renal toxicity prediction. Meanwhile, Baker et al. overview utilization of redifferentiated normal human urothelial cells which are easy to dedifferentiate when cultured in vitro to simulate urothelium, another important tissue in the urinary system vulnerable to negative effects imposed by drugs in urine when they are excreted from the renal system. These human urothelial tissue models are valuable in terms of efficacy and toxicity assessments of bladder exposure to drugs which are very likely to produce harmful effects. Wilhelm et al. overview most recent and promising in vitro blood−brain barrier (BBB) models which are dependent on in vitro culture of brain endothelial cells and other relevant cells involved in the BBB for the development of a central nervous system drug that can successfully cross the BBB. Hume et al. summarize methods of defining mammary gland commitment in 3D structure, with mechanisms of mammary gland development and tumorigenesis being discussed in detail. Various biomimetic platforms that mimic different human tissues in vitro are developed for toxicity and efficacy evaluation of traditional drugs, such as bioactive molecules. Li et al. employ embryonic stem cell-derived human renal proximal tubular-like cells as in vitro model to test the nephrotoxicity of 41 compounds. They showed that high accuracy can be obtained when using this model to predict proximal tubular toxicity in humans. Täuber et al. utilize infected nail plate model to analyze the efficacy of various antifungal formulations. Peck et al. develop an osteoarthritis disease model through the coculture of macrophages with engineered living hyaline cartilage graft (LhCG) mimicking pure hyaline cartilage phenotype. Such a disease model mimics osteoarthritis cartilage and can be adopted as a useful platform for drug testing. Li et al. culture human umbilical vein endothelial cells inside the microchannel on chip under different pressures and shear stresses to develop an in vitro hypertensive model. A model drug is used to prove the suitability of such a microfluidic system as a platform for in vitro antihypertensive drug evaluation. Lam et al. generate a biomimetic 3D tissue stiffness interface for cancer cell migration and evaluate the response of cancer cells to chemotherapy under different tissue stiffness. Niu et al. coculture endothelial and cancer cells in their native three-dimensional morphology on a microfluidic device to mimic tumor microenvironment. Anticancer effects of 12 natural compounds are evaluated through this biomimetic model system, with three anticancer compounds being found. Costello et al. establish biomimetic in vitro intestinal models, which can be used as a platform to mimic the adhesion and
urrently, the developmental and approval process for a new drug is exceedingly long and often stretches over a decade, which is partially but substantially related to the proceeding of drug evaluation. Regardless of the numerous efforts that have been made to evaluate potential drug toxicity and efficacy by employing screening tools at the beginning of the development process, countless new drugs still fail in clinical trials especially during those late and more costly phases such as phases II and III. Therefore, research that intends to create more realistic in vitro living tissue or organ models by accurately mimicking human host responses may accelerate the drug screening process with the hopes of fast-tracking new and potentially life-saving treatments to commercial deployment. Successful implementation of this research is anticipated to shorten drug development times and lower costs, benefiting both pharmaceutical companies and patients at the receiving end. Traditionally, human or mammalian cells cultured in monolayer are extensively employed for in vitro drug evaluations upon the effectiveness and toxicity. However, in recent years there are increasing demands for more realistic and physiologically relevant 2D and 3D biomimetic tissue models that can fulfill the same role in drug testing. These attempts are aimed at mimicking and simulating human physiological responses to therapeutic administrations in vitro. One of the major driving factors behind this research is the fact that the toxicity of drug and bioactive compound constitute one of the most important health and drug development issues: it is estimated that only 8% of all drug candidates manage to enter the market and approximately 20% of all failures are caused by some form of toxicity. In the past two decades, the failure rates due to toxicity have not decreased, indicating the lack of comprehensive understanding of in vivo drug−host interactions and a dearth of suitable in vitro tissue models. On the other hand, animal experimentation always remains very costly and, more importantly, the data derived from animal models in preclinical trials often cannot be extrapolated directly to humans. For instance, animal models may fail to predict human responses to some pathogens that are species specific (such as hepatitis C). Therefore, such gaps in understanding could have dangerous or fatal results. In order to address this issue, there is an urgent need to create more realistic and accurate in vitro tissue models with the advent of tissue engineering, drug delivery, and molecular pharmaceutics so that one can envisage higher levels of biomimicry with tissue level platforms. In this theme issue, the focus is on engineering more realistic in vitro biomimetic tissues mimicking human organs or tissues for in vitro drug assessment. There are four reviews in this issue discussing the need for drug evaluation before clinical trial from the point of view of three different organ systems, that is, urinary, nervous, and reproductive systems. Tiong et al. review current methods of developing in vitro models for the prediction of nephrotoxicity. Three-dimensional (3D) engi© 2014 American Chemical Society
Special Issue: Engineered Biomimetic Tissue Platforms for in Vitro Drug Evaluation Published: July 7, 2014 1931
dx.doi.org/10.1021/mp500349x | Mol. Pharmaceutics 2014, 11, 1931−1932
Molecular Pharmaceutics
Editorial
corneal epithelial cell model, with no MRP2 protein expression or activity detected in three-dimensional human corneal epithelial cell model. Ferlin et al. set up a device consisting of a biomimetic scaffold cultured within a perfusion bioreactor to study effects of scaffold stiffness, material surface, shear force, and dynamic nutrient delivery on mesenchymal stem cell growth and maintenance. Guo et al. use magnetically labeled cells to form three-dimensional magnetic spheroids, which can be simply manipulated using magnetic field, and evaluation of impacts of a model drug on magnetic tumor spheroids based on this platform were successfully performed, demonstrating its suitability for high-throughput drug screening. Rajmohan et al. find that polylactide particles can self-assemble into membrane like structures at room temperature and show that such scaffolds fabricated from polylactide particles can support threedimensional growth of cells for regenerative medicine. Lin et al. employ a dual-chamber bioreactor to generate double layer osteochondral microtissue, with top layer human bone marrow stem cell undergoing chondrogenic differentiation and bottom layer human bone marrow stem cell undergoing osteogenic differentiation in respective tissue-specific media. They show that interleukin-1β application in either layer can induce strong degradative responses in both layers, mimicking osteoarthritis in vitro. In summary, these experts update us with the current status and future prospects of in vitro biomimetic tissues for efficient and high-throughput drug evaluation. We would like to thank all invited authors for their contributions made with great efforts and standards. Though the R&D area under this featured topic still remains in its infancy, we do believe that the contributions collected in this theme issue of Molecular Pharmaceutics would be an enormous asset to all our peers and readers working in this promising field.
invasion profiles of pathogen and assess the therapeutic potential of probiotics. Such a model is developed by culture of intestinal epithelial cells on scaffold with surface topography resembling that of the small intestine. Fong et al. encapsulated patient-derived xenograft tumor cells into hyaluronan-based hydrogel to develop a novel three-dimensional prostate cancer model, which can be used as a platform for rapid evaluation of patient-specific chemotherapeutic drug response. In addition to confirmation of suitability of in vitro biomimetic tissues as traditional drug evaluation model, novel drug like nanoparticles or gene therapies can also be tested based on recently developed in vitro biomimetic platforms. Huang et al. generate a 3D inflammatory bowel disease model consisting of human colonic epithelial cells and human monocytes for in vitro assessment of nanoparticle biodistribution. Li et al. encapsulate mesenchymal stem cells into poly(lactide-co-glycolide)/fibrin gel to develop a cartilagemimetic tissue that can be used as platform to deliver plasmid DNA encoding transforming growth factor-1 and enhance articular cartilage defect repair in vivo. Achilli et al. use a threedimensional multilayer cell spheroid as a quantitative model to study drug uptake and diffusion through efflux transporter Pglycoprotein and gap junction intercellular communication. Harrington et al. grow epithelial cells, fibroblasts, and dendritic cells on porous electrospun scaffolds to form an immunocompetent 3D model of airway epithelium and demonstrate that this model is a useful tool for drug discovery and delivery. In fact, various disease models that are impossible to reproduce using two-dimensional models or even animal models can be accurately recapitulated in vitro now through 3D biomimetic tissues under different pathogenic factor agent stimulation. Schlichting et al. describe the strategy of stimulating porcine chondrocyte micromass cultures with tumor necrosis factor alpha to model osteoarthritis in vitro. Ananthanarayanan et al. report the use of galactosylated cellulosic sponge with homogeneous macroporosity to construct human hepatocyte spheroid cultures for hepatitis C virus infection and replication. Wang et al. report successful construction of brain tumor model with poly(ethylene-glycol) (PEG)-based hydrogels to study the effects of matrix stiffness on glioblastoma cell behavior. Chong et al. seed prostate cancer cells into vascularized osseous constructs consisting of mesenchymal stem cells and endothelial cells, enabling the development of prostate metastatic model for drug screening. Tsao et al. describe the use of a thermoreversible poly(ethylene glycol)-g-chitosan hydrogel to develop an in vitro breast cancer model that supports a more malignant phenotype of breast cancer cells. In order to more accurately and realistically mimic various kinds of tissues in vivo, great effort have also been made to imitate fine-structure and natural microenvironment of in vivo tissues for better physiologically relevant tissue engineering, besides precise reappearance of disease in vitro. Donoghue et al. highlight the influences of gravity, topography, fluid flow, and scaffold dimension on cells involved in CNS repair using a tubular scaffold created by rolling up a microstructured membrane. Gurkan et al. develop an anisotropic biomimetic fibrocartilage via bioprinting nanoliter droplets containing human MSCs, bone morphogenetic protein 2, and transforming growth factor β1. Verstraelen et al. finds that there are different expression profiles of multidrug resistance-associated proteins (MRP1, 2, 4, and 5) between two-dimensional human corneal epithelial cell model and three-dimensional human
Dong-An Wang,*,† Guest Editor Ram I. Mahato,*,‡ Guest Editor
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† Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637457 ‡ Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38103, United States
AUTHOR INFORMATION
Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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dx.doi.org/10.1021/mp500349x | Mol. Pharmaceutics 2014, 11, 1931−1932
