Organs-on-chip (OoC), often referred to as microphysiological systems (MPS), are advanced in vitro tools able to replicate essential functions of human organs. Owing to their unprecedented ability to recapitulate key features of the native cellular environments, they represent promising tools for tissue engineering and drug screening applications. The achievement of proper functionalities within OoC is crucial; to this purpose, several parameters (e.g., chemical, physical) need to be assessed. Currently, most approaches rely on off-chip analysis and imaging techniques. However, the urgent demand for continuous, noninvasive, and real-time monitoring of tissue constructs requires the direct integration of biosensors. In this review, we focus on recent strategies to miniaturize and embed biosensing systems into organs-on-chip platforms. Biosensors for monitoring biological models with metabolic activities, models with tissue barrier functions, as well as models with electromechanical properties will be described and critically evaluated. In addition, multisensor integration within multiorgan platforms will be further reviewed and discussed.

Friedreich’s ataxia (FRDA) is an autosomal-recessive neurodegenerative and cardiac disorder which occurs when transcription of the FXN gene is silenced due to an excessive expansion of GAA repeats into its first intron. Herein, we generate dorsal root ganglia organoids (DRG organoids) by in vitro differentiation of human iPSCs. Bulk and single-cell RNA sequencing show that DRG organoids present a transcriptional signature similar to native DRGs and display the main peripheral sensory neuronal and glial cell subtypes. Furthermore, when co-cultured with human intrafusal muscle fibers, DRG organoid sensory neurons contact their peripheral targets and reconstitute the muscle spindle proprioceptive receptors. FRDA DRG organoids model some molecular and cellular deficits of the disease that are rescued when the entire FXN intron 1 is removed, and not with the excision of the expanded GAA tract. These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.

Current treatments for osteoarthritis (OA) often fail to address the underlying pathophysiology and may have systemic side effects, particularly associated with long‐term use of non‐steroidal anti‐inflammatory drugs (NSAIDs). Thus, researchers are currently directing their efforts toward innovative polymer‐drug combinations, such as mixtures of hyaluronic acid viscoelastic hydrogels and NSAIDs like diclofenac, to ensure sustained release of the NSAID within the joint following intra‐articular injection. However, the progress of novel injectable therapies for OA is hindered by the absence of preclinical models that accurately represent the pathology of the disease. The uBeat® MultiCompress platform is here presented as a novel approach for studying anti‐OA injectable therapeutics on human mechanically‐damaged OA cartilage microtissues, in a physiologically relevant environment. This platform can accommodate injectable therapeutic formulations and is successfully tested with SYN321, a novel diclofenac‐sodium hyaluronate conjugate under development as a treatment for knee OA. Results indicate the platform's effectiveness in evaluating therapeutic potential, showing downregulation of inflammatory markers and reduction in matrix degradation in OA cartilage micro‐tissues treated with SYN321. The uBeat® MultiCompress platform thus represents a valuable tool for OA research, offering a bridge between traditional in vitro studies and potential clinical applications, with implications for future drug discovery.

Osteoarthritis (OA) is a joint disorder causing pain and disability, yet effective treatments are limited due to incomplete understanding of pathogenic mechanisms involving complex tissue interactions. Articular cartilage degradation is a hallmark, resulting from an imbalance in extracellular matrix turnover, influenced by mechanical and biochemical signals. The synovium also plays a central role in joint inflammation, with macrophages and fibroblasts releasing pro‐inflammatory cytokines and degradative enzymes. However, understanding cartilage‐synovium interactions in OA pathogenesis remains challenging. Here, a compartmentalized joint‐on‐chip (JoC) model that enables independent culture of 3D human cartilage and synovium constructs, allowing spatio‐temporal control over their communication, is presented. The JoC platform supports induction of OA characteristics in both tissues, by applying hyper‐physiological compression to cartilage constructs to mimic mechanical damage and by treating synovium constructs with TNFα and IFNγ to simulate inflammation. Moreover, the platform enables exploration of paracrine signaling between these tissues under pathophysiological conditions, showing that inflamed synovium constructs induce early cartilage degradation, while mechanically damaged cartilage promotes macrophage activation and inflammatory responses in the synovium. These findings support a bidirectional relationship in OA onset and underscore the JoC model as a tool for studying joint tissue interactions.

The dysregulation of the immune system plays a crucial role in the pathogenesis of manyfold diseases, among which we find rheumatoid arthritis (RA), an autoimmune disease characterized by chronic inflammation in synovial joints, leading to pain and disability. Immune cells such as pro-inflammatory macrophages and T helper 1 (Th1) cells drive the inflammatory cascade. Thus, including immune system in in vitro models is pivotal to recapitulate and better understand the complex interactions between these immune cell subsets and their secreted mediators. Here, a compartmentalized microfluidic platform is presented, for precise confinement of circulating immune cells in organs-on-chip. The integration of innovative normally-closed sieving valves allows, through minimal waste of biological material, to co-culture different immune cell types (e.g. macrophages and Th1). Moreover, the platform allows to stimulate cell subsets separately, and to assess their cross-talk at desired time points. Functional validation of the platform demonstrates its ability to create stable chemotactic gradients, allowing for induction and evaluation of Th1 cells migration. In a proof-of-concept study, the platform allowed to assess Th1 T cells migration towards pro-inflammatory macrophages, thus replicating a characteristic interaction among immune cells triggered during RA onset. These results thus support the suitability of the platform to study immune cells cross-talk and migration phenomena, being potentially applicable to a manyfold immune cell mechanisms, both involved in RA progression and in different immune-mediated pathologies.

Both emerging viruses and well-known viral pathogens endowed with neurotropism can either directly impair neuronal functions or induce physio-pathological changes by diffusing from the periphery through neurosensory–epithelial connections. However, developing a reliable and reproducible in vitro system modeling the connectivity between the different human sensory neurons and peripheral tissues is still a challenge and precludes the deepest comprehension of viral latency and reactivation at the cellular and molecular levels. This study shows a stable topographic neurosensory–epithelial connection on a chip using human stem cell-derived dorsal root ganglia (DRG) organoids. Bulk and single-cell transcriptomics showed that different combinations of key receptors for herpes simplex virus 1 (HSV-1) are expressed by each sensory neuronal cell type. This neuronal–epithelial circuitry enabled a detailed analysis of HSV infectivity, faithfully modeling its dynamics and cell type specificity. The reconstitution of an organized connectivity between human sensory neurons and keratinocytes into microfluidic chips provides a powerful in vitro platform for modeling viral latency and reactivation of human viral pathogens.