Mechanobiology at the microscale : Organ-on-a-chip technology as a tool to boost preclinical model relevance

Abstract

Organ-on-a-chip technology provides precise control over vital biological, physical, and chemical parameters needed to recreate the physiological niche in vitro, thus fostering the establishment of organ models capable of recapitulating near-native tissue architectures and functions. These smallest functional units of human organs can now be subjected to dynamic (patho)physiological stimulation such as fluid flow, matrix stiffness, and nutrient diffusion. It is essential to highlight that any living tissue will react to changes in their respective environment, resulting in either maintaining healthy or displaying diseased phenotypes. Consequently, a deeper understanding of the cellular mechanisms that guide and regulate cell fate, including apoptosis, proliferation, differentiation, and migration in the presence of external biophysical stimuli, will ultimately open new insights into the onset, progression, and remission of diseases. This doctoral work clearly demonstrates that mechanobiological stimuli significantly improve physiologic relevance within vasculature-on-a-chip and cartilage-on-chip devices. The combinatorial effects of fluid perfusion, interstitial flow, and soluble compound delivery are instrumental in forming vasculature within large-sized vascularized tissue constructs and defining mechanisms in reciprocal signaling during vasculogenesis. This doctoral thesis also reports that directional interstitial fluid flow stimulation substantially contributes to establishing a blood-lymphatic capillary interface by initiating lymphatic sprout formation and guiding lymphatic vessel maturation. Similarly, replicating perichondral tissue elasticity and the directional nutrient gradient across cartilage tissue improved the redifferentiation capacity of primary chondrocytes on-chip. Chondrocytes cultivated under optimized conditions exhibited a striking similarity to native cartilage, including sphericalmorphology, synthesized cartilage matrix, and arranged into superficial and deep zone cartilage. The microphysiological systems developed within this thesis are expected to foster the identification of novel drug delivery routes into the lymphatic system and decipher deregulatory disease mechanisms in cartilage anabolism and catabolism, thus providing a tool to boost the discovery of novel drug candidates.