Tendon-on-a-chip: A biomimetic tendinopathy model

Projektleitung an der Vetmeduni

Jenner, Florien

Geldgeber

FWF Österreichischer Wissenschaftsfonds

Laufzeit

04.09.2023 - 04.09.2026

Abstract

Wider research context/theoretical framework: Tendinopathy is a leading cause of disability with a commensurate socioeconomic burden. Although the annually increasing prevalence is fuelling research efforts, scientific and clinical advances are hindered by the lack of suitable models of human tendon disease. Hypothesis1) Multiaxial overloading results in higher Piezo1 upregulation and subsequent Piezo1-dependent release of TFGb1 than uniaxial loading at equal magnitudes of strain.2) Tensile overloading of tenocytes induces CCL2-mediated recruitment and proinflammatory polarization of macrophages3) Tensile overloading of tenocytes induces IL1α-mediated upregulation of Piezo1 in cocultured synoviocytes Objectives: We aim to replace and reduce animal models of tendinopathy by developing a humanized tendon on a chip with the capacity to mimic multiaxial mechanical overload and the associated inflammatory response in both extra- and intrasynovial tendons. We will develop a microfluidic model of 1) extrasynovial energy-storing tendons (e.g. Achilles tendon) and 2) intrasynovial tendons (e.g. rotator cuff); and 3) Validate the microfluidic models by drug screening and benchmarking against legacy data.Approach/methods: Our microfluidic tendon-on-a-chip combines tissue-relevant fluid-flow, mechanical stimulation and heterotypic 3D co-culture (tenocytes, macrophages, +/- synoviocytes) with state-of-the-art molecular and microscopic analysis to model overload-induced tendinopathy, pathophysiological immune cell stimuli and the influence thereof in extra- and intrasynovial tendon niches.Level of originality/innovation: Our tendon-on-a-chip will be the first biomechanically challenged 3D model of stromal and immune cell crosstalk in tendon pathophysiology. Our highly innovative biomimetic approach allows the dynamic manipulation of the cellular microenvironment at high spatiotemporal resolution and emulates the pathophysiology of both extra- and intrasynovial tendon disorders by recapitulating in vivo multiaxial mechanical cues and cellular crosstalk. It will be uniquely suited to investigate the mechanobiology and short-term inflammatory cascades of tendinopathy and will be able to replace a broad range of large and small animal models. We will pursue a multi-species validation strategy to ensure that legacy data across the disease spectrum are available for benchmarking and validation as there are insufficient human data from early disease stages for validation. The multi-species approach will also improve our understanding of interspecies differences, facilitating the selection of the most appropriate animal model and thereby further contributing to the reduction and replacement of the use of animals in tendon research.