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To address these limitations, we developed and characterized three chitosan-based hydrogels with distinct physicochemical and mechanical properties as tunable three-dimensional (3D) platforms for DLBCL culture. U2932 lymphoma cells were encapsulated either alone or in co-culture with WPMY-1 stromal cells to investigate the effects of matrix stiffness and stromal support on lymphoma growth. Furthermore, co-culture with stromal cells promoted rapid spheroid formation and generated larger cellular aggregates than mono-cultures, with the most pronounced effect observed in the 2% chitosan hydrogel. Live\/dead assays demonstrated high cell viability within the selected culture condition. Overall, the 2% chitosan formulation provided the most suitable microenvironment for supporting DLBCL growth and organization, highlighting its potential as a physiologically relevant 3D in vitro model for investigating lymphoma biology and evaluating novel therapeutic strategies.<\/jats:p>","DOI":"10.3390\/gels12080705","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T09:24:53Z","timestamp":1786353893000},"page":"705","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Matrix Stiffness Regulates Diffuse Large B-Cell Lymphoma (DLBCL) Spheroid Formation in a Tunable 3D Chitosan Hydrogel Model"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9928-7405","authenticated-orcid":false,"given":"Gaia","family":"Corallo","sequence":"first","affiliation":[{"name":"Dipartimento di Matematica e Fisica E. de Giorgi, Universit\u00e0 del Salento, c\/o Campus Ecotekne, 73100 Lecce, Italy"},{"name":"Institute of Nanotechnology, National Research Council (CNR-NANOTEC), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"},{"name":"Tecnomed Puglia\u2014Technopole for Precision Medicine (Biotech Lecce Hub), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carmela","family":"Vegliante","sequence":"additional","affiliation":[{"name":"Hematology and Cell Therapy Unit, IRCCS-Istituto Tumori \u2018Giovanni Paolo II\u2019, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna Anita","family":"Pappagallo","sequence":"additional","affiliation":[{"name":"Hematology and Cell Therapy Unit, IRCCS-Istituto Tumori \u2018Giovanni Paolo II\u2019, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Stanzione","sequence":"additional","affiliation":[{"name":"Institute of Nanotechnology, National Research Council (CNR-NANOTEC), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1686-6736","authenticated-orcid":false,"given":"Francesca","family":"Scalera","sequence":"additional","affiliation":[{"name":"Institute of Nanotechnology, National Research Council (CNR-NANOTEC), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"},{"name":"Tecnomed Puglia\u2014Technopole for Precision Medicine (Biotech Lecce Hub), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Gigli","sequence":"additional","affiliation":[{"name":"Institute of Nanotechnology, National Research Council (CNR-NANOTEC), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"},{"name":"Tecnomed Puglia\u2014Technopole for Precision Medicine (Biotech Lecce Hub), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"},{"name":"Dipartimento di Medicina Sperimentale, Universit\u00e0 del Salento, c\/o Campus Ecotekne, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Pastore","sequence":"additional","affiliation":[{"name":"Hematology and Cell Therapy Unit, IRCCS-Istituto Tumori \u2018Giovanni Paolo II\u2019, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabino","family":"Ciavarella","sequence":"additional","affiliation":[{"name":"Hematology and Cell Therapy Unit, IRCCS-Istituto Tumori \u2018Giovanni Paolo II\u2019, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8644-1653","authenticated-orcid":false,"given":"Francesca","family":"Gervaso","sequence":"additional","affiliation":[{"name":"Institute of Nanotechnology, National Research Council (CNR-NANOTEC), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"},{"name":"Tecnomed Puglia\u2014Technopole for Precision Medicine (Biotech Lecce Hub), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3188-983X","authenticated-orcid":false,"given":"Alessandro","family":"Polini","sequence":"additional","affiliation":[{"name":"Institute of Nanotechnology, National Research Council (CNR-NANOTEC), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"},{"name":"Tecnomed Puglia\u2014Technopole for Precision Medicine (Biotech Lecce Hub), c\/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.1007\/s00277-024-05880-z","article-title":"Advances in Biology, Diagnosis and Treatment of DLBCL","volume":"103","author":"Shi","year":"2024","journal-title":"Ann. 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