Evaluating Complexity in Orthopedic Tissue-on-a-Chip Systems

Orthopedic tissue-on-a-chip systems are rapidly emerging to model tissue homeostasis and disease, including to screen new therapeutics. These platforms range in complexity, related to the number of cells, materials, and other factors that are introduced into their design, which may influence their ability to mimic tissue physiology and the overall experimental throughput. To better understand current orthopedic tissue-on-a-chip platforms and their complexity, a systematic search is used to generate a library of publications. From this library, the device components (i.e., cells, materials, tissue structures, and external stimuli) and common applications are summarized, revealing that most devices are polydimethylsiloxane (PDMS)-based and include human cells, natural hydrogels, and limited tissue structures and stimuli. Next, a quantitative scoring system is developed and used to compare single versus multi tissue-on-a-chip systems across six criteria (i.e., assembly, cellular, fluidic, mechanical, structural, and readout complexity). The multi tissue-on-a-chip systems include more cell populations and materials, complicating device assembly. Additionally, total complexity negatively correlates with throughput, indicating that there is a tradeoff between the introduction of additional features and rapidly acquiring data. A clinically motivated evaluation and discussion concludes this review, which can be used to guide the development of future orthopedic tissue-on-a-chip systems.