Endogenous Osteocyte-Osteoclast Signaling Enables Bone Remodeling, Drug Response, and Cancer Invasion in a Nanoscale Calcified Bone-on-a-Chip Model

Endogenous Osteocyte-Osteoclast Signaling Enables Bone Remodeling, Drug Response, and Cancer Invasion in a Nanoscale Calcified Bone-on-a-Chip Model | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Endogenous Osteocyte-Osteoclast Signaling Enables Bone Remodeling, Drug Response, and Cancer Invasion in a Nanoscale Calcified Bone-on-a-Chip Model Luiz Bertassoni, Mauricio Sousa, Avathamsa Athirasala, Daniela Roth, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8970234/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Bone homeostasis depends on spatially orchestrated interactions among osteoclasts, osteoblasts, and osteocytes that are embedded within a unique extracellular matrix that is mineralized on the nanoscale. Reconstructing these interactions to enable autonomous cell differentiation and tissue remodeling has remained a significant challenge towards mimicking adequate bone physiology and disease in-vitro. Here, we present an engineered model that spatially defines the paracrine communication of heterogeneous cell populations within bone tissue that supports the rapid maturation of primary osteoblasts into osteocytes, the differentiation of immune cells into osteoclasts, and calcified tissue resorption within a mineralized cell-laden bone-like tissue. We demonstrate that nanoscale mineralization of cell-laden collagen hydrogels on-a-chip enhances osteoblast to osteocyte differentiation, whereas osteocytes in the matrix accelerate osteoclastogenesis and remodeling in a spatially defined manner without the need for exogenous growth factors. Osteocyte-dependent osteoclastogenesis on-a-chip outperformed conventional stimulation with RANKL and M-CSF, reproduced the clinical response of anti-resorptive drugs, and mimicked established tumor-bone interactions observed in invasive oral cancer. By replicating essential aspects of bone composition and function, this system provides a robust, self-regulated microphysiologic model to investigate bone remodeling, cancer-bone crosstalk, and therapeutic interventions. Biological sciences/Biotechnology/Tissue engineering Physical sciences/Materials science/Biomaterials/Tissues bone-on-a-chip osteocytes osteoclastogenesis biomimetic bone Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Table1GenedatasetSousaetall.csv Dataset1 SupportingInformation.pdf Supporting Information Supplementaryvideo2.mp4 Supplementary video 2 Supplementaryvideo1.mp4 Supplementary video 1 Supplementaryvideo3.mp4 Supplementary video 3 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8970234","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":600603148,"identity":"01c876e1-dd1f-4154-a03a-f07e592ba1f7","order_by":0,"name":"Luiz 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