{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:46:37Z","timestamp":1785415597413,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["SFB 1270\/2\u2014299150580"],"award-info":[{"award-number":["SFB 1270\/2\u2014299150580"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"award":["SFB 1270\/2\u2014299150580"],"award-info":[{"award-number":["SFB 1270\/2\u2014299150580"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Osteochondral defects, involving both articular cartilage and subchondral bone, can lead to joint degeneration and osteoarthritis. Recent advances in 3D-printed biphasic scaffolds offer promising opportunities to recreate physiological microenvironments for tissue regeneration. In tissue engineering, these scaffolds can be mechanically stimulated to promote targeted cartilage and bone formation. While computational models have been widely used to study mechanically induced cellular responses in monophasic scaffolds, time-dependent modelling of biphasic osteochondral systems remains relatively scarce. In this study, a fluid\u2013structure interaction (FSI) framework coupled with a mechanoregulatory algorithm was developed to predict mechanically induced early-stage mesenchymal stem cell (MSC) differentiation in biphasic open-porous osteochondral scaffolds comprising chondral and bone layers designed for direct ink writing (DIW). In a second model, an interfacial barrier layer representing the native osteochondral interface was integrated. Dynamic compressive loading (1 Hz, 2.5% strain) was applied. The simulations predicted region-specific differentiation patterns in both the chondral and subchondral bone regions. In the scaffold without a barrier layer, approximately 68.9% of MSCs in the chondral layer and 93.4% of MSCs in the bone layer underwent chondrogenic and osteogenic differentiation, respectively. Incorporation of the barrier layer caused only minor changes, reducing predicted cartilage and bone differentiation by approximately 1.5% and 3.9%, respectively. Overall, this study highlights the capability of computational modelling to predict mechanobiological responses in complex osteochondral systems and support scaffold design and effective mechanical stimulation protocols.<\/jats:p>","DOI":"10.3390\/bioengineering13070809","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:08:34Z","timestamp":1784189314000},"page":"809","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Predicting Cell Differentiation in Mechanically Stimulated Biphasic Osteochondral Scaffolds Using Fluid\u2013Structure Interaction Modelling"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3671-271X","authenticated-orcid":false,"given":"Pedram","family":"Azizi","sequence":"first","affiliation":[{"name":"Chair of Microfluidics, Faculty of Mechanical Engineering and Marine Technology, University of Rostock, 18059 Rostock, Germany"},{"name":"Chair of Electromagnetic Field Theory, Faculty of Computer Science and Electrical Engineering, Institute of General Electrical Engineering, University of Rostock, 18059 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1042-2058","authenticated-orcid":false,"given":"Ursula","family":"van Rienen","sequence":"additional","affiliation":[{"name":"Chair of Electromagnetic Field Theory, Faculty of Computer Science and Electrical Engineering, Institute of General Electrical Engineering, University of Rostock, 18059 Rostock, Germany"},{"name":"Department of Life, Light and Matter, University of Rostock, 18059 Rostock, Germany"},{"name":"Department of Ageing of Individuals and Society, Interdisciplinary Faculty, University of Rostock, 18059 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3401-0090","authenticated-orcid":false,"given":"Hermann","family":"Seitz","sequence":"additional","affiliation":[{"name":"Chair of Microfluidics, Faculty of Mechanical Engineering and Marine Technology, University of Rostock, 18059 Rostock, Germany"},{"name":"Department of Life, Light and Matter, University of Rostock, 18059 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11370","DOI":"10.1039\/D5RA09529H","article-title":"The Osteochondral Regeneration Paradox: Why Biomimetic Scaffolds Are Biologically Superior but Injectable Systems Dominate the Clinic","volume":"16","author":"Gubert","year":"2026","journal-title":"RSC Adv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101834","DOI":"10.1016\/j.mtbio.2025.101834","article-title":"3D Bioprinted Scaffolds for Osteochondral Regeneration: Advancements and Applications","volume":"32","author":"Lu","year":"2025","journal-title":"Mater. Today Bio"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"743","DOI":"10.2217\/17460751.3.5.743","article-title":"Biomechanics and Mechanobiology in Osteochondral Tissues","volume":"3","author":"McMahon","year":"2008","journal-title":"Regen. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Jacob, G., Shimomura, K., and Nakamura, N. (2020). Osteochondral Injury, Management and Tissue Engineering Approaches. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.580868"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"165273","DOI":"10.1016\/j.cej.2025.165273","article-title":"3D Printing of Scaffolds for Articular Cartilage\/Osteochondral Regeneration: Design, Performance, and Applications","volume":"519","author":"Li","year":"2025","journal-title":"Chem. Eng. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1007\/s10439-024-03516-x","article-title":"Controlled Mechanical Property Gradients Within a Digital Light Processing Printed Hydrogel-Composite Osteochondral Scaffold","volume":"52","author":"Eckstein","year":"2024","journal-title":"Ann. Biomed. Eng."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8277","DOI":"10.1038\/s41598-020-65050-9","article-title":"3D Bioprinting of Osteochondral Tissue Substitutes\u2014In Vitro-Chondrogenesis in Multi-Layered Mineralized Constructs","volume":"10","author":"Kilian","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2108855","DOI":"10.1002\/adma.202108855","article-title":"Direct Ink Writing: A 3D Printing Technology for Diverse Materials","volume":"34","author":"Saadi","year":"2022","journal-title":"Adv. Mater."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2415507","DOI":"10.1002\/adfm.202415507","article-title":"Direct Ink Writing of Conductive Hydrogels","volume":"35","author":"Ho","year":"2025","journal-title":"Adv. Funct. Mater."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.actbio.2024.02.012","article-title":"Toughening 3D Printed Biomimetic Hydroxyapatite Scaffolds: Polycaprolactone-based Self-Hardening Inks","volume":"177","author":"Johansson","year":"2024","journal-title":"Acta Biomater."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e00609","DOI":"10.1002\/admi.202500609","article-title":"3D-Printed Functional Biphasic Scaffolds with Nanocomposites for Osteochondral Regeneration: A Step Toward Bioengineered Cartilage and Bone Integration","volume":"12","author":"Khoshnood","year":"2025","journal-title":"Adv. Mater. Interfaces"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"035025","DOI":"10.1088\/1758-5090\/ade8a9","article-title":"3D Printed Osteochondral Lineage-Specific Biphasic Scaffolds for Functional Repair of Full-Thickness Articular Cartilage Defects in Weight-Bearing Area","volume":"17","author":"Qin","year":"2025","journal-title":"Biofabrication"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ntousi, O., Roumpi, M., Siogkas, P.K., Polyzos, D., Kakkos, I., Matsopoulos, G.K., and Fotiadis, D.I. (2025). Advances in Computational Modeling of Scaffolds for Bone Tissue Engineering: A Narrative Review of the Current Approaches and Challenges. Biomechanics, 5.","DOI":"10.3390\/biomechanics5040076"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105822","DOI":"10.1016\/j.jmbbm.2023.105822","article-title":"Prediction of the Mechanical Response of a 3D (Bio)Printed Hybrid Scaffold for Improving Bone Tissue Regeneration by Structural Finite Element Analysis","volume":"142","author":"Scocozza","year":"2023","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1089\/ten.tea.2023.0217","article-title":"Designing Biomimetic 3D-Printed Osteochondral Scaffolds for Enhanced Load-Bearing Capacity","volume":"30","author":"Choe","year":"2024","journal-title":"Tissue Eng. Part A"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Shahid, M.N., Shahid, M.U., Rasheed, S., Irfan, M., and Obeidi, M.A. (2024). Computational Investigation of the Fluidic Properties of Triply Periodic Minimal Surface (TPMS) Structures in Tissue Engineering. Designs, 8.","DOI":"10.3390\/designs8040069"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"106055","DOI":"10.1016\/j.cmpb.2021.106055","article-title":"Design and Research of Bone Repair Scaffold Based on Two-Way Fluid-Structure Interaction","volume":"204","author":"Fu","year":"2021","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.medengphy.2016.04.016","article-title":"Modeling the Fluid-Dynamics and Oxygen Consumption in a Porous Scaffold Stimulated by Cyclic Squeeze Pressure","volume":"38","author":"Ferroni","year":"2016","journal-title":"Med. Eng. Phys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e3342","DOI":"10.1002\/cnm.3342","article-title":"Fluid Flow-Induced Cell Stimulation in Bone Tissue Engineering Changes Due to Interstitial Tissue Formation in Vitro","volume":"36","author":"Zhao","year":"2020","journal-title":"Int. J. Numer. Methods Biomed. Eng."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e3821","DOI":"10.1002\/cnm.3821","article-title":"Comparing the Bone Regeneration Potential between a Trabecular Bone and a Porous Scaffold through Osteoblast Migration and Differentiation: A Multiscale Approach","volume":"40","author":"Majumder","year":"2024","journal-title":"Int. J. Numer. Methods Biomed. Eng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100394","DOI":"10.1016\/j.rsurfi.2024.100394","article-title":"Evaluating the Mechanical Responses on a Cell under Fluid Perfusion: A Multiscale Computational Method","volume":"18","author":"Samanta","year":"2025","journal-title":"Results Surf. Interfaces"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Berni, M., Marchiori, G., Baleani, M., Giavaresi, G., and Lopomo, N.F. (2024). Biomechanics of the Human Osteochondral Unit: A Systematic Review. Materials, 17.","DOI":"10.3390\/ma17071698"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Silva, B., Domingos, M., Amado, S., Dias, J.R., Pascoal-Faria, P., Maur\u00edcio, A.C., and Alves, N. (2025). Toward Integrative Biomechanical Models of Osteochondral Tissues: A Multilayered Perspective. Bioengineering, 12.","DOI":"10.3390\/bioengineering12060649"},{"key":"ref_24","first-page":"317","article-title":"Enhanced Osteochondral Regeneration with a 3D-Printed Biomimetic Scaffold Featuring a Calcified Interfacial Layer","volume":"36","author":"Wu","year":"2024","journal-title":"Bioact. Mater."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1007\/s10237-025-01976-1","article-title":"Numerical Study of the Structural Design Influence on Cartilage Cell Differentiation in Mechanically Stimulated Hydrogel Scaffolds Using an FSI-based Model","volume":"24","author":"Azizi","year":"2025","journal-title":"Biomech. Model. Mechanobiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gorro\u00f1ogoitia, I., Urtaza, U., Zubiarrain-Laserna, A., Alonso-Varona, A., and Zaldua, A.M. (2022). A Study of the Printability of Alginate-Based Bioinks by 3D Bioprinting for Articular Cartilage Tissue Engineering. Polymers, 14.","DOI":"10.3390\/polym14020354"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ege, D., and Boccaccini, A.R. (2024). Investigating the Effect of Processing and Material Parameters of Alginate Dialdehyde-Gelatin (ADA-GEL)-Based Hydrogels on Stiffness by XGB Machine Learning Model. Bioengineering, 11.","DOI":"10.3390\/bioengineering11050415"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5964","DOI":"10.36922\/ijb.5964","article-title":"3D Printing of Microstructured Piezoelectric and Bioactive PCL-composite Scaffolds for Bone Regeneration","volume":"11","author":"Barkow","year":"2024","journal-title":"Int. J. Bioprint."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Gharibshahian, M., Salehi, M., Beheshtizadeh, N., Kamalabadi-Farahani, M., Atashi, A., Nourbakhsh, M.S., and Alizadeh, M. (2023). Recent Advances on 3D-printed PCL-based Composite Scaffolds for Bone Tissue Engineering. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1168504"},{"key":"ref_30","first-page":"264","article-title":"Osteoarthritis Animal Models for Biomaterial-Assisted Osteochondral Regeneration","volume":"3","author":"Wang","year":"2022","journal-title":"Biomater. Transl."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s42242-021-00177-w","article-title":"In Vivo Evaluation of Additively Manufactured Multi-Layered Scaffold for the Repair of Large Osteochondral Defects","volume":"5","author":"Tamaddon","year":"2022","journal-title":"Bio-Des. Manuf."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Azizi, P., Drobek, C., Budday, S., and Seitz, H. (2023). Simulating the Mechanical Stimulation of Cells on a Porous Hydrogel Scaffold Using an FSI Model to Predict Cell Differentiation. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1249867"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1089\/ten.teb.2018.0006","article-title":"A Guide for Using Mechanical Stimulation to Enhance Tissue-Engineered Articular Cartilage Properties","volume":"24","author":"Salinas","year":"2018","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1039\/D0BM02117B","article-title":"Mechanical Properties of Cell- and Microgel Bead-Laden Oxidized Alginate-Gelatin Hydrogels","volume":"9","author":"Distler","year":"2021","journal-title":"Biomater. Sci."},{"key":"ref_35","unstructured":"Ansys Academic Research Mechanical (2024). Release 2024 R2, Help System, Mechanical APDL Theory Reference, ANSYS Inc.. Software Documentation."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3138","DOI":"10.1016\/j.actbio.2012.04.022","article-title":"Micromechanical Finite-Element Modeling and Experimental Characterization of the Compressive Mechanical Properties of Polycaprolactone\u2013Hydroxyapatite Composite Scaffolds Prepared by Selective Laser Sintering for Bone Tissue Engineering","volume":"8","author":"Eshraghi","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0021-9290(96)00140-6","article-title":"Biophysical Stimuli on Cells during Tissue Differentiation at Implant Interfaces","volume":"30","author":"Prendergast","year":"1997","journal-title":"J. Biomech."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6142","DOI":"10.1016\/j.biomaterials.2009.07.041","article-title":"Finite Element Study of Scaffold Architecture Design and Culture Conditions for Tissue Engineering","volume":"30","author":"Olivares","year":"2009","journal-title":"Biomaterials"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"De, S., Guilak, F., and Mohammad Mofrad, R.K. (2010). Computational Models of Tissue Differentiation. Computational Modeling in Biomechanics, Springer.","DOI":"10.1007\/978-90-481-3575-2"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"104919","DOI":"10.1016\/j.jmbbm.2021.104919","article-title":"BEM Evaluation of Surface Octahedral Strains and Internal Strain Gradients in 3D-printed Scaffolds Used for Bone Tissue Regeneration","volume":"125","author":"Gortsas","year":"2022","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hendrikson, W.J., Deegan, A.J., Yang, Y., van Blitterswijk, C.A., Verdonschot, N., Moroni, L., and Rouwkema, J. (2017). Influence of Additive Manufactured Scaffold Architecture on the Distribution of Surface Strains and Fluid Flow Shear Stresses and Expected Osteochondral Cell Differentiation. Front. Bioeng. Biotechnol., 5.","DOI":"10.3389\/fbioe.2017.00006"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9697","DOI":"10.1039\/C9TB02127B","article-title":"A Modular Programmed Biphasic Dual-Delivery System on 3D Ceramic Scaffolds for Osteogenesis in Vitro and in Vivo","volume":"8","author":"Chen","year":"2020","journal-title":"J. Mater. Chem. B"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.icheatmasstransfer.2018.05.014","article-title":"Modeling the Flow and Mass Transport in a Mechanically Stimulated Parametric Porous Scaffold under Fluid-Structure Interaction Approach","volume":"96","author":"Bergstrom","year":"2018","journal-title":"Int. Commun. Heat Mass Transf."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100153","DOI":"10.1016\/j.bea.2025.100153","article-title":"Determining the Optimal Design Parameters for Gyroids Using Computational Fluid Dynamics Analysis under a Non-Newtonian Perfusion System","volume":"9","author":"Gupta","year":"2025","journal-title":"Biomed. Eng. Adv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1177\/03635465221114412","article-title":"A Slotted Decellularized Osteochondral Scaffold With Layer-Specific Release of Stem Cell Differentiation Stimulators Enhances Cartilage and Bone Regeneration in Osteochondral Defects in a Rabbit Model","volume":"50","author":"Deng","year":"2022","journal-title":"Am. J. Sports Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.msec.2016.08.027","article-title":"A New Bi-Layered Scaffold for Osteochondral Tissue Regeneration: In Vitro and In Vivo Preclinical Investigations","volume":"70","author":"Sartori","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"105618","DOI":"10.1016\/j.jmbbm.2022.105618","article-title":"Time-Dependent Hyper-Viscoelastic Parameter Identification of Human Articular Cartilage and Substitute Materials","volume":"138","author":"Weizel","year":"2023","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Abroug, N., Sch\u00f6bel, L., Boccaccini, A.R., and Seitz, H. (2024). Quantitative Macromolecular Modeling Assay of Biopolymer-Based Hydrogels. Gels, 10.","DOI":"10.3390\/gels10110676"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1007\/s10237-024-01817-7","article-title":"An Explainable Machine Learning-Based Probabilistic Framework for the Design of Scaffolds in Bone Tissue Engineering","volume":"23","author":"Drakoulas","year":"2024","journal-title":"Biomech. Model. Mechanobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"114992","DOI":"10.1016\/j.mtcomm.2026.114992","article-title":"A Hybrid CFD\u2013Machine Learning Framework for Efficient Permeability Prediction in 3D-printed Bone Scaffold Design","volume":"52","author":"Amirpour","year":"2026","journal-title":"Mater. Today Commun."}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/13\/7\/809\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:20:29Z","timestamp":1784262029000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/13\/7\/809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["bioengineering13070809"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering13070809","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,15]]}}}