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Conventional in vitro models of isolated renal cell types lack this complexity and native extracellular matrix (ECM) support, limiting their translational relevance. To address these limitations, we developed a composite hydrogel comprising hydroxypropyl methylcellulose (HPMC), chitosan, and collagen for encapsulating rat kidney slices, combining ECM-like mechanical cues with preserved tissue heterogeneity. Thirteen formulations were evaluated for chemical composition, rheological properties, swelling, degradation, and cytocompatibility. Also, the Design of Experiments (DoE) approach was employed to analyze the role of various components in hydrogel properties. Two optimal candidates were identified: H10C30 (1:1 HPMC:chitosan\/collagen, 10% citric acid, 30% \u03b2-glycerophosphate) and H20C50 (7:3 ratio, 20% citric acid, 50% \u03b2-glycerophosphate). Both supported renal architecture for 14 days, with H10C30 demonstrating superior preservation of glomerular and tubular structures. The platform enabled oxidative stress modeling via lipopolysaccharide\/interferon-\u03b3\u2212induced reactive oxygen species and demonstrated structural recovery following mesenchymal stromal cell treatment. This cost-effective, tunable system bridges the gap between 2D cultures and native tissue, providing a physiologically relevant ex vivo platform for drug screening, disease modeling, and regenerative therapy evaluation.<\/jats:p>","DOI":"10.1021\/acsabm.5c01628","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T14:53:47Z","timestamp":1784732027000},"page":"6821-6838","source":"Crossref","is-referenced-by-count":0,"title":["Design and Optimization of a Bioactive Composite Hydrogel for Sustained Ex Vivo Maintenance of Kidney Slices in Preclinical Applications"],"prefix":"10.1021","volume":"9","author":[{"given":"Amal","family":"Kassab","sequence":"first","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1257-9465","authenticated-orcid":true,"given":"Ahmed","family":"Abosalha","sequence":"additional","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]},{"name":"Tanta University , , Tanta Al-Geish St. , The Medical Campus, , ,","place":["Tanta, Egypt, 31527"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Makhlouf","sequence":"additional","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paromita","family":"Islam","sequence":"additional","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Editha","family":"Renesteen","sequence":"additional","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline L","family":"Boyajian","sequence":"additional","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Santos","sequence":"additional","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Chen","sequence":"additional","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedrique","family":"Shum-Tim","sequence":"additional","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"Al Asmakh","sequence":"additional","affiliation":[{"name":"Qatar University , , ,","place":["Doha, Qatar, 2713"]},{"name":"Qatar University, QU-Health , , , ,","place":["Doha, Qatar, 2713"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4902-2353","authenticated-orcid":true,"given":"Satya","family":"Prakash","sequence":"additional","affiliation":[{"name":"McGill University , , , , ,","place":["Montr\u00e9al, Quebec, Canada, H3A 2B4"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"issue":"1","key":"2026080308064301100_cit1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/J.KISU.2021.11.003","article-title":"Epidemiology of Chronic Kidney Disease: An Update 2022","volume":"12","author":"Kovesdy","year":"2022","journal-title":"Kidney Int. 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