{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T17:31:56Z","timestamp":1772386316549,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Center (Poland) \u201cPreludium 19\u201d","award":["2020\/37\/N\/NZ7\/02553"],"award-info":[{"award-number":["2020\/37\/N\/NZ7\/02553"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Introduction: Many orally administered drugs are either unstable in the acidic environment of the stomach or cause moderate to severe side effects in the upper gastrointestinal tract (GIT). These limitations can reduce therapeutic efficacy, discourage patient compliance, worsen the disease, and even contribute to the risk of cancer development. To overcome these issues, drug release often needs to be modified and targeted to the distal parts of the GIT. This is typically achieved through the use of pH-sensitive polymer coatings or incorporation into polymeric delivery systems. With this in mind, the aim of this project was to design, develop, and characterize gellan gum-based beads for colon-specific prolonged release of mesalazine, with potential application in the chemoprevention and treatment of bowel diseases. Materials and Methods: The dehydrated capsules were characterized using Raman spectroscopy and scanning electron microscopy. The crosslinked gellan gum was additionally evaluated for cytotoxicity. Key parameters such as pH-dependent swelling behavior, drug content, encapsulation efficiency, and drug release in simulated gastrointestinal fluids were also assessed. Furthermore, the behavior of the capsules in the gastrointestinal tract was studied in a rat model to evaluate their in vivo performance. Results: Significant differences in drug release profiles were observed between formulations crosslinked solely with calcium ions and those additionally crosslinked with glutaraldehyde (GA). The incorporation of GA effectively prolonged the release of mesalazine. These findings were further supported by in vivo studies conducted on Wistar rats, where the GA-crosslinked formulation demonstrated a markedly extended release compared to the formulation prepared using only ionotropic gelation. Conclusions: The combination of ionotropic gelation and glutaraldehyde crosslinking in gellan gum-based beads appears to be a promising strategy for achieving colon-specific prolonged release of mesalazine, facilitating targeted delivery to the distal regions of the gastrointestinal tract.<\/jats:p>","DOI":"10.3390\/pharmaceutics17050569","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T08:57:47Z","timestamp":1745571467000},"page":"569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ionotropic Gelation and Chemical Crosslinking as Tools to Obtain Gellan Gum-Based Beads with Mesalazine"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7577-7410","authenticated-orcid":false,"given":"Piotr","family":"Gadzi\u0144ski","sequence":"first","affiliation":[{"name":"Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, 3 Rokietnicka Street, 60-806 Pozna\u0144, Poland"},{"name":"Doctoral School, Poznan University of Medical Sciences, 70 Bukowska Street, 60-812 Pozna\u0144, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3452-8754","authenticated-orcid":false,"given":"Agnieszka","family":"Skotnicka","sequence":"additional","affiliation":[{"name":"Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, 3 Rokietnicka Street, 60-806 Pozna\u0144, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Lisiak","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 3 Rokietnicka Street, 60-806 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7602-1604","authenticated-orcid":false,"given":"Ewa","family":"Toto\u0144","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 3 Rokietnicka Street, 60-806 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1730-0176","authenticated-orcid":false,"given":"B\u0142a\u017cej","family":"Rubi\u015b","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 3 Rokietnicka Street, 60-806 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2689-3009","authenticated-orcid":false,"given":"Ewa","family":"Florek","sequence":"additional","affiliation":[{"name":"Laboratory of Environmental Research, Department of Toxicology, Poznan University of Medical Sciences, 3 Rokietnicka Street, 60-806 Pozna\u0144, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3583-0752","authenticated-orcid":false,"given":"Dariusz T.","family":"Mlynarczyk","sequence":"additional","affiliation":[{"name":"Chair and Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8933-571X","authenticated-orcid":false,"given":"Miros\u0142aw","family":"Szybowicz","sequence":"additional","affiliation":[{"name":"Institute of Materials Research and Quantum Engineering, Faculty of Materials Engineering and Technical Physics, Pozna\u0144 University of Technology, Piotrowo 3, 60-965 Pozna\u0144, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0744-5486","authenticated-orcid":false,"given":"Ewelina","family":"Nowak","sequence":"additional","affiliation":[{"name":"Institute of Materials Research and Quantum Engineering, Faculty of Materials Engineering and Technical Physics, Pozna\u0144 University of Technology, Piotrowo 3, 60-965 Pozna\u0144, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6939-2888","authenticated-orcid":false,"given":"Tomasz","family":"Osma\u0142ek","sequence":"additional","affiliation":[{"name":"Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, 3 Rokietnicka Street, 60-806 Pozna\u0144, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s13346-022-01179-6","article-title":"Impact of gastric and bowel surgery on gastrointestinal drug delivery","volume":"13","author":"Hua","year":"2023","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/s41575-021-00539-w","article-title":"Foundations of gastrointestinal-based drug delivery and future developments","volume":"19","author":"Chu","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ijpharm.2015.02.051","article-title":"Gastrointestinal release behaviour of modified-release drug products: Dynamic dissolution testing of mesalazine formulations","volume":"484","author":"Goyanes","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_4","first-page":"319","article-title":"Encapsulation of Roxithromycin into Gellan Gum Matrices and the Impact of Other Natural Polymers on Drug Release","volume":"77","author":"Gadzinski","year":"2020","journal-title":"Acta Pol. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1007\/s10787-021-00856-1","article-title":"A review of the biological and pharmacological activities of mesalazine or 5-aminosalicylic acid (5-ASA): An anti-ulcer and anti-oxidant drug","volume":"29","author":"Beiranvand","year":"2021","journal-title":"Inflammopharmacology"},{"key":"ref_6","first-page":"215","article-title":"NSAIDs, gastrointestinal toxicity and inflammatory bowel disease","volume":"45","author":"Sostres","year":"2022","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1016\/j.apsb.2021.04.001","article-title":"Oral delivery of proteins and peptides: Challenges, status quo and future perspectives","volume":"11","author":"Zhu","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4757","DOI":"10.2147\/IJGM.S326929","article-title":"Enteric-Coated Aspirin and the Risk of Gastrointestinal Side Effects: A Systematic Review","volume":"14","author":"Kedir","year":"2021","journal-title":"Int. J. Gen. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.2147\/IJN.S157566","article-title":"Colon-targeted delivery of cyclosporine A using dual-functional Eudragit\u00ae FS30D\/PLGA nanoparticles ameliorates murine experimental colitis","volume":"13","author":"Naeem","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Coban, O., Aytac, Z., Yildiz, Z.I., and Uyar, T. (2021). Colon targeted delivery of niclosamide from \u03b2-cyclodextrin inclusion complex incorporated electrospun Eudragit\u00ae L100 nanofibers. Colloids Surf. B Biointerfaces, 197.","DOI":"10.1016\/j.colsurfb.2020.111391"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ijbiomac.2016.12.087","article-title":"Pectin-zinc-chitosan-polyethylene glycol colloidal nano-suspension as a food grade carrier for colon targeted delivery of resveratrol","volume":"97","author":"Andishmand","year":"2017","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Najm, A., Niculescu, A.G., Bolocan, A., R\u0103dulescu, M., Grumezescu, A.M., Beuran, M., and Gaspar, B.S. (2023). Chitosan and Cyclodextrins-Versatile Materials Used to Create Drug Delivery Systems for Gastrointestinal Cancers. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16010043"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1080\/02652048.2017.1390005","article-title":"Microencapsulation of probiotics by efficient vibration technology","volume":"34","author":"Olivares","year":"2017","journal-title":"J. Microencapsul."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1177\/0885328218779705","article-title":"Gellan gum macrobeads loaded with naproxen: The impact of various naturally derived polymers on pH-dependent behavior","volume":"33","author":"Froelich","year":"2018","journal-title":"J. Biomater. Appl."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1080\/03639045.2017.1318896","article-title":"Design and characteristics of gellan gum beads for modified release of meloxicam","volume":"43","author":"Milanowski","year":"2017","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.tibtech.2015.03.008","article-title":"Crosslinking biopolymers for biomedical applications","volume":"33","author":"Reddy","year":"2015","journal-title":"Trends Biotechnol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1208\/s12249-010-9384-1","article-title":"Stomach-Specific Controlled Release Gellan Beads of Acid-Soluble Drug Prepared by Ionotropic Gelation Method","volume":"11","author":"Narkar","year":"2010","journal-title":"AAPS PharmSciTech"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1080\/03602559.2018.1447126","article-title":"Design, Synthesis, Characterization, Swelling and in Vitro Drug Release Behavior of Composite Hydrogel Beads Based on Methotrexate and Chitosan Incorporating Antipyrine Moiety","volume":"57","author":"Harmal","year":"2018","journal-title":"Polym.-Plast. Technol. Eng."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.carbpol.2011.02.010","article-title":"Al+3 ion cross-linked and acetalated gellan hydrogel network beads for prolonged release of glipizide","volume":"85","author":"Maiti","year":"2011","journal-title":"Carbohydr. Polym."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1177\/08853282211052755","article-title":"Rheological and textural analysis as tools for investigation of drug-polymer and polymer-polymer interactions on the example of low-acyl gellan gum and mesalazine","volume":"36","author":"Froelich","year":"2022","journal-title":"J. Biomater. Appl."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.ijbiomac.2017.11.099","article-title":"Recent trends on gellan gum blends with natural and synthetic polymers: A review","volume":"109","author":"Zia","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Satar, R., Jafri, M.A., Rasool, M., and Ansari, S.A. (2018). Role of Glutaraldehyde in Imparting Stability to Immobilized \u03b2-Galactosidase Systems. Braz. Arch. Biol. Technol., 60.","DOI":"10.1590\/1678-4324-2017160311"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/jphp.12332","article-title":"Dissolution of mesalazine modified release tablets under standard and bio-relevant test conditions","volume":"67","author":"Garbacz","year":"2015","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1517\/14656566.2013.808622","article-title":"Mesalazine for the treatment of inflammatory bowel disease","volume":"14","author":"Criscuoli","year":"2013","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wegrzynowska-Drzymalska, K., Grebicka, P., Mlynarczyk, D.T., Chelminiak-Dudkiewicz, D., Kaczmarek, H., Goslinski, T., and Ziegler-Borowska, M. (2020). Crosslinking of Chitosan with Dialdehyde Chitosan as a New Approach for Biomedical Applications. Materials, 13.","DOI":"10.3390\/ma13153413"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Budzianowska, A., Toto\u0144, E., Romaniuk-Drapa\u0142a, A., Kikowska, M., and Budzianowski, J. (2023). Cytotoxic Effect of Phenylethanoid Glycosides Isolated from Plantago lanceolata L. Life, 13.","DOI":"10.3390\/life13020556"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Prezotti, F.G., Boni, F.I., Ferreira, N.N., Silva Dde Se Campana-Filho, S.P., Almeida, A., Vasconcelos, T., Gremi\u00e3o, M.P.D., Cury, B.S.F., and Sarmento, B. (2018). Gellan Gum\/Pectin Beads Are Safe and Efficient for the Targeted Colonic Delivery of Resveratrol. Polymers, 10.","DOI":"10.3390\/polym10010050"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"36","DOI":"10.2174\/156720110790396445","article-title":"Formulation of Controlled Release Gellan Gum Macro Beads of Amoxicillin","volume":"7","author":"Babu","year":"2010","journal-title":"Curr. Drug Deliv."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nagpal, S., Dubey, S.K., Rapalli, V.K., and Singhvi, G. (2019). Pharmaceutical Applications of Gellan Gum. Natural Polymers for Pharmaceutical Applications, Apple Academic Press.","DOI":"10.1201\/9780429328299-4"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.foodhyd.2008.01.001","article-title":"Effect of temperature and cross-linking density on rheology of chemical cross-linked guar gum at the gel point","volume":"23","author":"Sandolo","year":"2009","journal-title":"Food Hydrocoll."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1111\/jtxs.12684","article-title":"Mechanical properties of gellan gum beads prepared with potassium or calcium ions","volume":"53","author":"Vilela","year":"2022","journal-title":"J. Texture Stud."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhang, F., Wang, X., Guo, N., Dai, H., Wang, Y., Sun, Y., and Zhu, G. (2023). Influence of Different pH Values on Gels Produced from Tea Polyphenols and Low Acyl Gellan Gum. Gels, 9.","DOI":"10.3390\/gels9050368"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Adrover, A., Paolicelli, P., Petralito, S., Di Muzio, L., Trilli, J., Cesa, S., Tho, I., and Casadei, M.A. (2019). Gellan Gum\/Laponite Beads for the Modified Release of Drugs: Experimental and Modeling Study of Gastrointestinal Release. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11040187"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1163\/156856208783227640","article-title":"Ionically cross-linked carrageenan-alginate hydrogel beads","volume":"19","author":"Mohamadnia","year":"2008","journal-title":"J. Biomater. Sci. Polym. Ed."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3126\/sw.v17i17.66417","article-title":"Frontier molecular orbitals, MEP, NBO, and vibrational spectra of Mesalamine: A first principle study from DFT and molecular docking approaches","volume":"17","author":"Chaudhary","year":"2024","journal-title":"Sci. World"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"119751","DOI":"10.1016\/j.ijheatmasstransfer.2020.119751","article-title":"Raman-based Nanoscale Thermal Transport Characterization: A Critical Review","volume":"154","author":"Xu","year":"2020","journal-title":"Int. J. Heat Mass Transf."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1364\/OE.412852","article-title":"Quantum theory of Rayleigh scattering","volume":"29","author":"Vinogradov","year":"2021","journal-title":"Opt. Express"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Stachowiak, N., Kowalonek, J., Kozlowska, J., and Burkowska-But, A. (2023). Stability Studies, Biodegradation Tests, and Mechanical Properties of Sodium Alginate and Gellan Gum Beads Containing Surfactant. Polymers, 15.","DOI":"10.3390\/polym15112568"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"117794","DOI":"10.1016\/j.carbpol.2021.117794","article-title":"Preparation, physicochemical characterization and in vitro release behavior of resveratrol-loaded oxidized gellan gum\/resistant starch hydrogel beads","volume":"260","author":"Wang","year":"2021","journal-title":"Carbohydr. Polym."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3832","DOI":"10.1021\/acsbiomaterials.1c00685","article-title":"Fabrication Methods and Form Factors of Gellan Gum-Based Materials for Drug Delivery and Anti-Cancer Applications","volume":"9","author":"Coburn","year":"2023","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jcmgh.2021.09.005","article-title":"Gastric Organoids: Progress and Remaining Challenges","volume":"13","author":"Pang","year":"2022","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"F\u00fcl\u00f6pov\u00e1, N., Pavlokov\u00e1, S., DeBono, I., Vetch\u00fd, D., and Franc, A. (2022). Development and Comparison of Various Coated Hard Capsules Suitable for Enteric Administration to Small Patient Cohorts. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14081577"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"102393","DOI":"10.1016\/j.jddst.2021.102393","article-title":"Development and characterization of enteric coated pectin pellets containing mesalamine and Saccharomyces boulardii for specific inflamed colon: In vitro and in vivo evaluation","volume":"62","author":"Singh","year":"2021","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Alharbi, H.Y., Alnoman, R.B., Aljohani, M.S., Al-Anazia, M., and Monier, M. (2024). Synthesis and characterization of gellan gum-based hydrogels for drug delivery applications. Int. J. Biol. Macromol., 258.","DOI":"10.1016\/j.ijbiomac.2023.128828"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9423","DOI":"10.1002\/jsfa.13765","article-title":"Novel pH-sensitive gellan gum-\u03b5-polylysine hydrogel microspheres for sulforaphene delivery","volume":"104","author":"Qu","year":"2024","journal-title":"J. Sci. Food Agric."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S0380-1330(03)70458-4","article-title":"Assessing the Potential Efficacy of Glutaraldehyde for Biocide Treatment of Un-ballasted Transoceanic Vessels","volume":"29","author":"Sano","year":"2003","journal-title":"J. Great Lakes Res."},{"key":"ref_47","first-page":"2021","article-title":"A novel pH-enzyme-dependent mesalamine colon-specific delivery system","volume":"10","author":"Jin","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"122981","DOI":"10.1016\/j.ijpharm.2023.122981","article-title":"Comparison of 5-ASA layered or matrix pellets coated with a combination of ethylcellulose and eudragits L and s in the treatment of ulcerative colitis in rats","volume":"640","author":"Sardou","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0939-6411(01)00134-5","article-title":"A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis","volume":"51","author":"Rudolph","year":"2001","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"De Marco, P., Henriques, A.C., Azevedo, R., S\u00e1, S.I., Cardoso, A., Fonseca, B., Barbosa, J., and Leal, S. (2021). Gut Microbiome Composition and Metabolic Status Are Differently Affected by Early Exposure to Unhealthy Diets in a Rat Model. Nutrients, 13.","DOI":"10.3390\/nu13093236"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Nagpal, R., Wang, S., Solberg Woods, L.C., Seshie, O., Chung, S.T., Shively, C.A., Register, T.C., Craft, S., McClain, D.A., and Yadav, H. (2018). Comparative Microbiome Signatures and Short-Chain Fatty Acids in Mouse, Rat, Non-human Primate, and Human Feces. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.02897"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1007\/s11095-006-9041-2","article-title":"Why is it Challenging to Predict Intestinal Drug Absorption and Oral Bioavailability in Human Using Rat Model","volume":"23","author":"Cao","year":"2006","journal-title":"Pharm. Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Weersma, R.K., Zhernakova, A., and Fu, J. (2025, April 06). Interaction Between Drugs and the Gut Microbiome. 1 August 2020. Available online: https:\/\/gut.bmj.com\/content\/69\/8\/1510.","DOI":"10.1136\/gutjnl-2019-320204"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Vieira, S., Strymecka, P., Stanaszek, L., Silva-Correia, J., Drela, K., Fiedorowicz, M., Malysz-Cymborska, I., Janowski, M., Reis, R.L., and \u0141ukomska, B. (2023). Mn-Based Methacrylated Gellan Gum Hydrogels for MRI-Guided Cell Delivery and Imaging. Bioengineering, 10.","DOI":"10.3390\/bioengineering10040427"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/5\/569\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:21:38Z","timestamp":1760030498000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/5\/569"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,25]]},"references-count":54,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["pharmaceutics17050569"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17050569","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,25]]}}}