No abstract

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.

Developing biomimetic cartilaginous tissues that support locomotion while maintaining chondrogenic behavior is a major challenge in the tissue engineering field. Specifically, while locomotive forces demand tissues with strong mechanical properties, chondrogenesis requires a soft microenvironment. To address this challenge, 3D cartilage-like tissue is fabricated using two biomaterials with different mechanical properties: a hard biomaterial to reflect the macromechanical properties of native cartilage, and a soft biomaterial to create a chondrogenic microenvironment. To this end, a bath composed of an interpenetrating polymer network (IPN) of polyethylene glycol (PEG) and alginate hydrogel (MPa order compressive modulus) is developed as an extracellular matrix (ECM) with self-healing properties. Within this bath supplemented with thrombin, human mesenchymal stem cell (hMSC) spheroids embedded in fibrinogen are 3D bioprinted, creating a soft microenvironment composed of fibrin (kPa order compressive modulus) that simulate cartilage's pericellular matrix and allow a fast diffusion of nutrients. The bioprinted hMSC spheroids present high viability and chondrogenic-like behavior without adversely affecting the macromechanical properties of the tissue. Therefore, the ability to locally bioprint a soft and cell stimulating biomaterial inside of a mechanically robust hydrogel is demonstrated, thereby uncoupling the micro-and macromechanical properties of the 3D printed tissues such as cartilage.