Current Pharmaceutical Design - Volume 24, Issue 45, 2018

Current preclinical drug evaluation strategies that are explored to predict the pharmacological parameters, as well as toxicological issues, utilize traditional oversimplified cell cultures and animal models. However, these traditional approaches are time-consuming, and cannot reproduce the functions of the complex biological tissue architectures. On the other hand, the obtained data from animal models cannot be precisely extrapolated to humans because it sometimes results in the distinct safe starting doses for clinical trials due to vast differences in their genomes. To address these limitations, the microengineered, biomimetic organ-on-a-chip platforms fabricated using advanced materials that are interconnected using the microfluidic circuits, can stanchly reiterate or mimic the complex tissue-organ level structures including the cellular architecture and physiology, compartmentalization and interconnectivity of human organ platforms. These innovative and cost-effective systems potentially enable the prediction of the responses toward pharmaceutical compounds and remarkable advances in materials and microfluidics technology, which can rapidly progress the drug development process. In this review, we emphasize the integration of microfluidic models with the 3D simulations from tissue engineering to fabricate organ-on-a-chip platforms, which explicitly fulfill the demand of creating the robust models for preclinical testing of drugs. At first, we give a brief overview of the limitations associated with the current drug development pipeline that includes drug screening methods, in vitro molecular assays, cell culture platforms and in vivo models. Further, we discuss various organ-on-a-chip platforms, highlighting their benefits and performance in the preclinical stages. Next, we aim to emphasize their current applications toward pharmaceutical benefits including the drug screening as well as toxicity testing, and advances in personalized precision medicine as well as potential challenges for their commercialization. We finally recapitulate with the lessons learned and the outlook highlighting the future directions for accelerating the clinical translation of delivery systems.

The role of endovascular interventions has progressed rapidly over the past several decades. While animal models have long-served as the mainstay for the advancement of this field, the use of in vitro models has become increasingly widely adopted with recent advances in engineering technologies. Here, we review the strategies, mainly including bioprinting and microfabrication, which allow for fabrication of biomimetic vascular models that will potentially serve to supplement the conventional animal models for convenient investigations of endovascular interventions. Besides normal blood vessels, those in diseased states, such as thrombosis, may also be modeled by integrating cues that simulate the microenvironment of vascular disorders. These novel engineering strategies for the development of biomimetic in vitro vascular structures will possibly enable unconventional means of studying complex endovascular intervention problems that are otherwise hard to address using existing models.

Drug efficacy and toxicity are key factors of drug development. Conventional 2D cell models or animal models have their limitations for the efficacy or toxicity assessment in preclinical assays, which induce the failure of candidate drugs or withdrawal of approved drugs. Human organs-on-chips (OOCs) emerged to present human-specific properties based on their 3D bioinspired structures and functions in the recent decade. In this review, the basic definition and superiority of OOCs will be introduced. Moreover, a specific OOC, heart-on-achip (HOC) will be focused. We introduce HOC modeling in the sensor-free and sensor-based way and illustrate the advantages of sensor-based HOC in detail by taking examples of recent studies. We provide a new perspective on the integration of HOC technology and biosensing to develop a new sensor-based HOC platform.

Lung-on-a-chip is a micro device that combines the techniques of bioengineering, microbiology, polymer science and microfluidics disciplines in order to mimic physicochemical features and microenvironments, multicellular constructions, cell-cell interfaces of a human lung. Specifically, most novel lung on a chip designs consist of two micro-channeled outer parts, flexible and porous Polydimethylsiloxane (PDMS) membrane to create separation of air-blood chamber and subsidiary vacuum channels which enable stretching of the PDMS membrane to mimic movement mechanisms of the lung. Therefore, studies aim to emulate both tissue and organ functionality since it shall be creating great potential for advancing the studies about drug discovery, disease etiology and organ physiology compared with 2D (two dimensional) and 3D (three dimensional) cell culture models and current organoids. In this study, history of researches on lung anatomy and physiology, techniques of recreating lung functionality such as cell cultures in 2D and 3D models, organoids were covered and finally most advanced and recent state of the art technology product lung-on-a-chips’ construction steps, advantages compared with other techniques, usage in lung modeling and diseases, present and future offers were analyzed in detail.

Background: Tissue engineering (TE) is a promising solution for orthopaedic diseases such as bone or cartilage defects and bone metastasis. Cell culture in vitro and scaffold fabrication are two main parts of TE, but these two methods both have their own limitations. The static cell culture medium is unable to achieve multiple cell incubation or offer an optimal microenvironment for cells, while regularly arranged structures are unavailable in traditional cell-laden scaffolds, which results in low biocompatibility. To solve these problems, microfluidic techniques are combined with TE. By providing 3-D networks and interstitial fluid flows, microfluidic platforms manage to maintain phenotype and viability of osteocytic or chondrocytic cells, and the precise manipulation of liquid, gel and air flows in microfluidic devices leads to the highly organized construction of scaffolds. Methods: In this review, we focus on the recent advances of microfluidic techniques applied in the field of tissue engineering, especially in orthropaedics. An extensive literature search was done using PubMed. The introduction describes the properties of microfluidics and how it exploits the advantages to the full in the aspects of TE. Then we discuss the application of microfluidics on the cultivation of osteocytic cells and chondrocytes, and other extended researches carried out on this platform. The following section focuses on the fabrication of highly organized scaffolds and other biomaterials produced by microfluidic devices. Finally, the incubation and studying of bone metastasis models in microfluidic platforms are discussed. Conclusion: The combination of microfluidics and tissue engineering shows great potentials in the osteocytic cell culture and scaffold fabrication. Though there are several problems that still require further exploration, the future of microfluidics in TE is promising.

The oncology pharmaceutical research spent a shocking amount of money on target validation and drug optimization in preclinical models because many oncology drugs fail during clinical trial phase III. One of the most important reasons for oncology drug failures in clinical trials may due to the poor predictive tool of existing preclinical models. Therefore, in cancer research and personalized medicine field, it is critical to improve the effectiveness of preclinical predictions of the drug response of patients to therapies and to reduce costly failures in clinical trials. Three dimensional (3D) tumor models combine micro-manufacturing technologies mimic critical physiologic parameters present in vivo, including complex multicellular architecture with multicellular arrangement and extracellular matrix deposition, packed 3D structures with cell–cell interactions, such as tight junctions, barriers to mass transport of drugs, nutrients and other factors, which are similar to in vivo tumor tissues. These systems provide a solution to mimic the physiological environment for improving predictive accuracy in oncology drug discovery. This review gives an overview of the innovations, development and limitations of different types of tumor-like construction techniques such as self-assemble spheroid formation, spheroids formation by micro-manufacturing technologies, micro-dissected tumor tissues and tumor organoid. Combination of 3D tumor-like construction and microfluidic techniques to achieve tumor on a chip for in vitro tumor environment modeling and drug screening were all included. Eventually, developmental directions and technical challenges in the research field are also discussed. We believe tumor on chip models have provided better sufficient clinical predictive power and will bridge the gap between proof-of-concept studies and a wider implementation within the oncology drug development for pathophysiological applications.

Neurodegenerative disorders are related to the progressive functional loss of the brain, often connected to emotional and physical disability and, ultimately, to death. These disorders, strongly connected to the aging process, are becoming increasingly more relevant due to the increase of life expectancy. Current pharmaceutical treatments poorly tackle these diseases, mainly acting only on their symptomology. One of the main reasons of this is the current drug development process, which is not only expensive and time-consuming but, also, still strongly relies on animal models at the preclinical stage. Organ-on-a-chip platforms have the potential to strongly impact and improve the drug screening process by recreating in vitro the functionality of human organs. Patient-derived neurons from different regions of the brain can be directly grown and differentiated on a brain-on-a-chip device where the disease development, progression and pharmacological treatments can be studied and monitored in real time. The model reliability is strongly improved by using human-derived cells, more relevant than animal models for pharmacological screening and disease monitoring. The selected cells will be then capable of proliferating and organizing themselves in the in vivo environment thanks to the device architecture, materials selection and bio-chemical functionalization. In this review, we start by presenting the fundamental strategies adopted for brain-on-a-chip devices fabrication including e.g., photolithography, micromachining and 3D printing technology. Then, we discuss the state-of-theart of brain-on-a-chip platforms including their role in the study of the functional architecture of the brain e.g., blood-brain barrier, or of the most diffuse neurodegenerative diseases like Alzheimer’s and Parkinson’s. At last, the current limitations and future perspectives of this approach for the development of new drugs and neurodegenerative diseases modeling will be discussed.

The skin is the largest and most exposed organ in the human body. Not only it is involved in numerous biological processes essential for life but also it represents a significant endpoint for the application of pharmaceuticals. The area of in vitro skin tissue engineering has been progressing extensively in recent years. Advanced in vitro human skin models strongly impact the discovery of new drugs thanks to the enhanced screening efficiency and reliability. Nowadays, animal models are largely employed at the preclinical stage of new pharmaceutical compounds development for both risk assessment evaluation and pharmacokinetic studies. On the other hand, animal models often insufficiently foresee the human reaction due to the variations in skin immunity and physiology. Skin-on-chips devices offer innovative and state-of-the-art platforms essential to overcome these limitations. In the present review, we focus on the contribution of skin-on-chip platforms in fundamental research and applied medical research. In addition, we also highlighted the technical and practical difficulties that must be overcome to enhance skin-on-chip platforms, e.g. embedding electrical measurements, for improved modeling of human diseases as well as of new drug discovery and development.

In the last decades, bioengineers have developed myriad biomaterials for regenerative medicine. Development of screening techniques is essential for understanding complex behavior of cells in the biological microenvironments. Conventional approaches to the screening of cellular behavior in vitro have limitations in terms of accuracy, reusability, labor-intensive screening, and versatility. Thus, drug screening and toxicology test through in vitro screening platforms have been underwhelming. Recent advances in the high-throughput screening platforms somewhat overcome the limitations of in vitro screening platforms via repopulating human tissues’ biophysical and biomchemical microenvironments with the ability to continuous monitoring of miniaturized human tissue behavior. Herein, we review current trends in the screening platform in which a high-throughput system composed of engineered microarray devices is developed to investigate cell-biomaterial interaction. Furthermore, diverse methods to achieve continuous monitoring of cell behavior via developments of biosensor integrated high-throughput platforms, and future perspectives on high-throughput screening will be provided.

To reduce the required capital and time investment in the 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 develop 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 showing 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 the overall drug discovery process at a preclinical and clinical stage, as well as outline remaining challenges.