{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T23:30:55Z","timestamp":1790465455063,"version":"4.1.0"},"reference-count":130,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,25]],"date-time":"2024-12-25T00:00:00Z","timestamp":1735084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000266","name":"K Engineering and Physical Sciences Research Council Doctoral Training Partnership","doi-asserted-by":"publisher","award":["2442338"],"award-info":[{"award-number":["2442338"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>Chitosan is widely explored in the field of biomedicine due to its abundance and reported properties, including biocompatibility, biodegradability, non-toxicity, mucoadhesion, and anti-microbial activity. Although our understanding of the immune response to chitosan has evolved, confusion remains regarding whether chitosan is a pro- or anti-inflammatory biomaterial. Tackling this knowledge gap is essential for the translation of chitosan-based biomaterials to clinical use. Herein, we provide an overview of the immune responses to chitosan, exploring the roles of endotoxin contamination and physiochemical properties in immunomodulation. Ultimately, this literature review concludes that various physiochemical properties, including molecular weight, degree of deacetylation and polydispersity, endotoxin contamination, and cellular environment, interplay in the complex process of chitosan immunomodulation, which can lead to both pro- and anti-inflammatory effects.<\/jats:p>","DOI":"10.3390\/polym17010019","type":"journal-article","created":{"date-parts":[[2024,12,25]],"date-time":"2024-12-25T19:19:32Z","timestamp":1735154372000},"page":"19","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The Paradoxical Immunomodulatory Effects of Chitosan in Biomedicine"],"prefix":"10.3390","volume":"17","author":[{"given":"Sophie L.","family":"Reay","sequence":"first","affiliation":[{"name":"School of Engineering, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7728-1619","authenticated-orcid":false,"given":"Ana","family":"Marina Ferreira","sequence":"additional","affiliation":[{"name":"School of Engineering, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharien M. U.","family":"Hilkens","sequence":"additional","affiliation":[{"name":"Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3763-2696","authenticated-orcid":false,"given":"Katarina","family":"Novakovic","sequence":"additional","affiliation":[{"name":"School of Engineering, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,25]]},"reference":[{"key":"ref_1","unstructured":"Ibrahim, H.M., and Zairy, E.M.R.E. (2015). Concepts, Compounds and the Alternatives of Antibacterials, IntechOpen Limited."},{"key":"ref_2","first-page":"411","article-title":"Chitin and Chitosan: Production and Application of Versatile Biomedical Nanomaterials","volume":"4","author":"Hamblin","year":"2016","journal-title":"Int. J. Adv. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1080\/02652040500100139","article-title":"Preparation of cross-linked chitosan microspheres by spray drying: Effect of cross-linking agent on the properties of spray dried microspheres","volume":"22","author":"Desai","year":"2005","journal-title":"J. Microencapsul."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/raq.12610","article-title":"Review of shell waste reutilization to promote sustainable shellfish aquaculture","volume":"14","author":"Zhan","year":"2022","journal-title":"Rev. Aquac."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1381-5148(00)00038-9","article-title":"A review of chitin and chitosan applications","volume":"46","author":"Kumar","year":"2000","journal-title":"React. Funct. Polym."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.progpolymsci.2018.04.001","article-title":"Recent advances in chitin based materials constructed via physical methods","volume":"82","author":"Duan","year":"2018","journal-title":"Prog. Polym. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1007\/s10924-016-0865-5","article-title":"Chitin and Chitosan: Structure. Properties and Applications in Biomedical Engineering","volume":"25","author":"Islam","year":"2017","journal-title":"J. Polym. Environ."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11254","DOI":"10.1016\/j.matpr.2021.02.656","article-title":"Chitin as bio-based nanomaterial in packaging: A review","volume":"46","author":"Bose","year":"2021","journal-title":"Mater. Today Proc."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Desai, N., Rana, D., Salave, S., Gupta, R., Patel, P., Karunakaran, B., Sharma, A., Giri, J., Benival, D., and Kommineni, N. (2023). Chitosan: A Potential Biopolymer in Drug Delivery and Biomedical Applications. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15041313"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1039\/C7GC00089H","article-title":"Base-catalysed, one-step mechanochemical conversion of chitin and shrimp shells into low molecular weight chitosan","volume":"19","author":"Chen","year":"2017","journal-title":"Green Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"119132","DOI":"10.1016\/j.carbpol.2022.119132","article-title":"Chitosan: A review of molecular structure. bioactivities and interactions with the human body and micro-organisms","volume":"282","author":"Kou","year":"2022","journal-title":"Carbohydr. Polym."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3390\/jfb3030615","article-title":"Biocompatibility of Chitosan Carriers with Application in Drug Delivery","volume":"3","author":"Rodrigues","year":"2012","journal-title":"J. Funct. Biomater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1023\/B:JPOL.0000031080.70010.0b","article-title":"Chitosan as Scaffold Materials: Effects of Molecular Weight and Degree of Deacetylation","volume":"11","author":"Hsu","year":"2004","journal-title":"J. Polym. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.foodcont.2018.10.014","article-title":"Effect of deacetylation degree on properties of Chitosan films using electrostatic spraying technique","volume":"97","author":"Zhuang","year":"2019","journal-title":"Food Control"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wang, W., Meng, Q., Li, Q., Liu, J., Zhou, M., Jin, Z., and Zhao, K. (2020). Chitosan Derivatives and Their Application in Biomedicine. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020487"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/12_2021_90","article-title":"Chitosan for Biomaterials III","volume":"287","author":"Wang","year":"2021","journal-title":"Adv. Polym. Sci."},{"key":"ref_17","first-page":"100033","article-title":"A systematic review of physical techniques for chitosan degradation","volume":"2","author":"Pandit","year":"2021","journal-title":"Carbohydr. Polym. Technol. Appl."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/0009-8981(84)90097-4","article-title":"Determination of lysozyme in serum, urine, cerebrospinal fluid and feces by enzyme immunoassay","volume":"142","author":"Brouwer","year":"1984","journal-title":"Clin. Chim. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1172\/JCI115407","article-title":"Killing of gram-negative bacteria by lactoferrin and lysozyme","volume":"88","author":"Ellison","year":"1991","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Oliver, W.T., and Wells, J.E. (2015). Lysozyme as an alternative to growth promoting antibiotics in swine production. J. Anim. Sci. Biotechnol., 6.","DOI":"10.1186\/s40104-015-0034-z"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1046\/j.1432-1327.1998.2510335.x","article-title":"The interactions between highly de-N-acetylated chitosans and lysozyme from chicken egg white studied by 1H-NMR spectroscopy","volume":"251","author":"Kristiansen","year":"1998","journal-title":"Eur. J. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/0006-3002(57)90098-7","article-title":"The \u03b2-glucosaminidase activity of egg-white lysozyme","volume":"26","author":"Berger","year":"1957","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/0144-8617(94)90187-2","article-title":"Degradation of fully water-soluble. partially N-acetylated chitosans with lysozyme","volume":"23","author":"Nordtveit","year":"1994","journal-title":"Carbohydr. Polym."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/jbm.b.30573","article-title":"Chitosan scaffolds for in vitro buffalo embryonic stem-like cell culture: An approach to tissue engineering","volume":"80B","author":"Kitiyanant","year":"2007","journal-title":"J. Biomed. Mater. Res. Part B Appl. Biomater."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1016\/j.carres.2005.07.022","article-title":"The enzymatic degradation and swelling properties of chitosan matrices with different degrees of N-acetylation","volume":"340","author":"Ren","year":"2005","journal-title":"Carbohydr. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.ijbiomac.2021.12.129","article-title":"Recent advances on chitosan as an adjuvant for vaccine delivery","volume":"200","author":"Dmour","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Aranaz, I., Alc\u00e1ntara, A.R., Civera, M.C., Arias, C., Elorza, B., Caballero, A.H., and Acosta, N. (2021). Chitosan: An Overview of Its Properties and Applications. Polymers, 13.","DOI":"10.3390\/polym13193256"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.addr.2009.07.019","article-title":"Chitosan-based hydrogels for controlled, localized drug delivery","volume":"62","author":"Bhattarai","year":"2010","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.drudis.2015.03.002","article-title":"The design of pH-sensitive chitosan-based formulations for gastrointestinal delivery","volume":"20","author":"Du","year":"2015","journal-title":"Drug Discov. Today"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gong, X., Gao, Y., Shu, J., Zhang, C., and Zhao, K. (2022). Chitosan-Based Nanomaterial as Immune Adjuvant and Delivery Carrier for Vaccines. Vaccines, 10.","DOI":"10.3390\/vaccines10111906"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7533","DOI":"10.1039\/C7RA13510F","article-title":"A functional chitosan-based hydrogel as a wound dressing and drug delivery system in the treatment of wound healing","volume":"8","author":"Liu","year":"2018","journal-title":"RSC Adv."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1007\/s00253-018-9550-z","article-title":"Chitosan and its derivatives: Synthesis, biotechnological applications, and future challenges","volume":"103","author":"Rajoka","year":"2019","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_33","unstructured":"Roy, B.K., Tahmid, I., and Rashid, T.U. (2021). Engineering Materials for Stem Cell Regeneration, Springer."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.msec.2018.12.026","article-title":"Chitosan based polymer\/bioglass composites for tissue engineering applications","volume":"96","author":"Vukajlovic","year":"2019","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5897","DOI":"10.1016\/j.biomaterials.2009.07.027","article-title":"On the nature of biomaterials","volume":"30","author":"Williams","year":"2009","journal-title":"Biomaterials"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1097\/01.shk.0000228797.41044.08","article-title":"Emerging Paradigm","volume":"26","author":"Mollen","year":"2006","journal-title":"Shock"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.smim.2007.10.013","article-title":"Interaction of dendritic cells with biomaterials","volume":"20","author":"Babensee","year":"2008","journal-title":"Semin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1084\/jem.137.5.1142","article-title":"Identification of a novel cell type in peripheral lymphoid organs of mice","volume":"137","author":"Steinman","year":"1973","journal-title":"J. Exp. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1189\/jlb.1104664","article-title":"Maturation requirements for dendritic cells in T cell stimulation leading to tolerance versus immunity","volume":"78","author":"Tan","year":"2005","journal-title":"J. Leukoc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"156","DOI":"10.3109\/08830180903281193","article-title":"Development of Dendritic Cell-Based Immunotherapy for Autoimmunity","volume":"29","author":"Hilkens","year":"2010","journal-title":"Int. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/cei.12038","article-title":"Tolerogenic dendritic cell therapy for rheumatoid arthritis: Where are we now?","volume":"172","author":"Hilkens","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1159\/000334245","article-title":"Dendritic Cells and Damage-Associated Molecular Patterns: Endogenous Danger Signals Linking Innate and Adaptive Immunity","volume":"4","author":"Nace","year":"2011","journal-title":"J. Innate Immun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1172\/JCI31720","article-title":"APC-derived cytokines and T cell polarization in autoimmune inflammation","volume":"117","author":"Gutcher","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Mariani, E., Lisignoli, G., Borz\u00ec, R.M., and Pulsatelli, L. (2019). Biomaterials: Foreign Bodies or Tuners for the Immune Response?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030636"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6692","DOI":"10.1016\/j.biomaterials.2011.05.078","article-title":"Immune responses to implants\u2014A review of the implications for the design of immunomodulatory biomaterials","volume":"32","author":"Franz","year":"2011","journal-title":"Biomaterials"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.smim.2007.11.004","article-title":"Foreign body reaction to biomaterials","volume":"20","author":"Anderson","year":"2008","journal-title":"Semin. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Christo, S.N., Diener, K.R., Bachhuka, A., Vasilev, K., and Hayball, J.D. (2015). Innate Immunity and Biomaterials at the Nexus: Friends or Foes. BioMed Res. Int., 2015.","DOI":"10.1155\/2015\/342304"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41578-023-00552-2","article-title":"The protein corona from nanomedicine to environmental science","volume":"8","author":"Mahmoudi","year":"2023","journal-title":"Nat. Reviews. Mater."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1002\/jbm.a.32487","article-title":"Dendritic cell responses to self-assembled monolayers of defined chemistries","volume":"92A","author":"Shankar","year":"2010","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1016\/j.biomaterials.2011.10.066","article-title":"Predicting biomaterial property-dendritic cell phenotype relationships from the multivariate analysis of responses to polymethacrylates","volume":"33","author":"Kou","year":"2012","journal-title":"Biomaterials"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1016\/j.actbio.2010.10.020","article-title":"Dendritic cell responses to surface properties of clinical titanium surfaces","volume":"7","author":"Kou","year":"2011","journal-title":"Acta Biomater."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1039\/c3tb20383b","article-title":"Surface hydrophobicity of microparticles modulates adjuvanticity","volume":"1","author":"Liu","year":"2013","journal-title":"J. Mater. Chem. B"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/jbm.a.30429","article-title":"Differential levels of dendritic cell maturation on different biomaterials used in combination products","volume":"74A","author":"Babensee","year":"2005","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3606","DOI":"10.1016\/j.actbio.2012.06.006","article-title":"Differential functional effects of biomaterials on dendritic cell maturation","volume":"8","author":"Park","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1021\/acsbiomaterials.9b01987","article-title":"Dendritic Cells as Targets for Biomaterial-Based Immunomodulation","volume":"6","author":"Sarafbidabad","year":"2020","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ijpharm.2005.03.035","article-title":"Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model","volume":"298","author":"Foged","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5210","DOI":"10.1128\/IAI.71.9.5210-5218.2003","article-title":"Liposomal Meningococcal B Vaccination: Role of Dendritic Cell Targeting in the Development of a Protective Immune Response","volume":"71","author":"Arigita","year":"2003","journal-title":"Infect. Immun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1039\/c1nr10166h","article-title":"The role of surface charge density in cationic liposome-promoted dendritic cell maturation and vaccine-induced immune responses","volume":"3","author":"Ma","year":"2011","journal-title":"Nanoscale"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1007\/s00018-011-0908-y","article-title":"Geometry sensing by dendritic cells dictates spatial organization and PGE2-induced dissolution of podosomes","volume":"69","author":"Dries","year":"2012","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3109\/1547691X.2015.1045636","article-title":"Effects of 3-dimensional culture conditions (collagen-chitosan nano-scaffolds) on maturation of dendritic cells and their capacity to interact with T-lymphocytes","volume":"13","author":"Daneshmandi","year":"2016","journal-title":"J. Immunotoxicol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5106","DOI":"10.1039\/D0BM01141J","article-title":"Dendritic cell immune potency on 2D and in 3D collagen matrices","volume":"8","author":"Sapudom","year":"2020","journal-title":"Biomater. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zheng, X., Zhou, F., Gu, Y., Duan, X., and Mo, A. (2017). Effect of Different Titanium Surfaces on Maturation of Murine Bone Marrow-Derived Dendritic Cells. Sci. Rep., 7.","DOI":"10.1038\/srep41945"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6811","DOI":"10.1016\/j.biomaterials.2005.04.063","article-title":"Endotoxin: The uninvited guest","volume":"26","author":"Gorbet","year":"2005","journal-title":"Biomaterials"},{"key":"ref_64","first-page":"388","article-title":"Methods of endotoxin removal from biological preparations: A review","volume":"10","author":"Lopes","year":"2007","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.tibtech.2021.12.001","article-title":"Impact of endotoxins on bioengineered tissues and models","volume":"40","author":"Heinrich","year":"2022","journal-title":"Trends Biotechnol."},{"key":"ref_66","first-page":"115","article-title":"Bacterial endotoxin-lipopolysaccharide; structure, function and its role in immunity in vertebrates and invertebrates","volume":"52","author":"Sampath","year":"2018","journal-title":"Agric. Nat. Resour."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1084\/jem.170.4.1231","article-title":"Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages","volume":"170","author":"Wright","year":"1989","journal-title":"J. Exp. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1126\/science.1698311","article-title":"CD14, a Receptor for Complexes of Lipopolysaccharide (LPS) and LPS Binding Protein","volume":"249","author":"Wright","year":"1990","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4100","DOI":"10.1074\/jbc.271.8.4100","article-title":"Catalytic Properties of Lipopolysaccharide (LPS) Binding Protein. Transfer of LPS to soluble CD14 (*)","volume":"271","author":"Yu","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.immuni.2016.11.007","article-title":"Reconstruction of LPS Transfer Cascade Reveals Structural Determinants within LBP, CD14, and TLR4-MD2 for Efficient LPS Recognition and Transfer","volume":"46","author":"Ryu","year":"2017","journal-title":"Immunity"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.cyto.2008.01.006","article-title":"LPS\/TLR4 signal transduction pathway","volume":"42","author":"Lu","year":"2008","journal-title":"Cytokine"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s12979-023-00383-3","article-title":"Toll-like receptor 4 (TLR4): New insight immune and aging","volume":"20","author":"Kim","year":"2023","journal-title":"Immun. Ageing"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.actbio.2022.11.003","article-title":"Interplay between biomaterials and the immune system: Challenges and opportunities in regenerative medicine","volume":"155","author":"Salthouse","year":"2023","journal-title":"Acta Biomater."},{"key":"ref_74","unstructured":"FDA (2023, January 10). Guidance for Industry: Pyrogen and Endotoxins Testing: Questions and Answers, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/guidance-industry-pyrogen-and-endotoxins-testing-questions-and-answers."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Schwarz, H., Schmittner, M., Duschl, A., and Horejs-Hoeck, J. (2014). Residual Endotoxin Contaminations in Recombinant Proteins Are Sufficient to Activate Human CD1c+ Dendritic Cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0113840"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Reay, S.L., Jackson, E.L., Salthouse, D., Ferreira, A.M., Hilkens, C.M.U., and Novakovic, K. (2023). Effective Endotoxin Removal from Chitosan That Preserves Chemical Structure and Improves Compatibility with Immune Cells. Polymers, 15.","DOI":"10.3390\/polym15071592"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Salthouse, D., Goulding, P.D., Reay, S.L., Jackson, E.L., Xu, C., Ahmed, R., Mearns-Spragg, A., Novakovic, K., Hilkens, C.M.U., and Ferreira, A.M. (2024). Amine-reactive crosslinking enhances type 0 collagen hydrogel properties for regenerative medicine. Front. Bioeng. Biotechnol., 12.","DOI":"10.3389\/fbioe.2024.1391728"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Harm, S., Schildb\u00f6ck, C., Strobl, K., and Hartmann, J. (2021). An in vitro study on factors affecting endotoxin neutralization in human plasma using the Limulus amebocyte lysate test. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-83487-4"},{"key":"ref_79","unstructured":"Merck (2023, January 10). Cell Culture FAQs: Bacterial Endotoxin Contamination. Available online: https:\/\/www.sigmaaldrich.com\/GB\/en\/technical-documents\/technical-article\/microbiological-testing\/pyrogen-testing\/what-is-endotoxin."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5402\/2012\/649746","article-title":"Chromatographic Removal of Endotoxins: A Bioprocess Engineer\u2019s Perspective","volume":"2012","author":"Ongkudon","year":"2012","journal-title":"ISRN Chromatogr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1111\/jphp.13082","article-title":"Easy and effective method to generate endotoxin-free chitosan particles for immunotoxicology and immunopharmacology studies","volume":"71","author":"Lebre","year":"2019","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Novikov, V.Y., Derkach, S.R., Konovalova, I.N., Dolgopyatova, N.V., and Kuchina, Y.A. (2023). Mechanism of Heterogeneous Alkaline Deacetylation of Chitin: A Review. Polymers, 15.","DOI":"10.3390\/polym15071729"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4552","DOI":"10.4049\/jimmunol.171.9.4552","article-title":"Cross-Linking of the Mannose Receptor on Monocyte-Derived Dendritic Cells Activates an Anti-Inflammatory Immunosuppressive Program","volume":"171","author":"Chieppa","year":"2003","journal-title":"J. Immunol."},{"key":"ref_84","unstructured":"Salter, R.D., and Dong, X. (2001). Part II: Dendritic cell biology. Dendritic Cells, Elsevier. [2nd ed.]."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1084\/jem.182.2.389","article-title":"Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: Downregulation by cytokines and bacterial products","volume":"182","author":"Sallusto","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Feng, H., Yang, X., Zhang, L., Liu, Q., Feng, Y., Wu, D., Liu, Y., and Yang, J. (2021). Mannose-Modified Chitosan Poly(lactic-co-glycolic acid) Microspheres Act as a Mannose Receptor-Mediated Delivery System Enhancing the Immune Response. Polymers, 13.","DOI":"10.3390\/polym13132208"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1016\/j.jsps.2020.10.008","article-title":"Mannose receptor targeted bioadhesive chitosan nanoparticles of clofazimine for effective therapy of tuberculosis","volume":"28","author":"Pawde","year":"2020","journal-title":"Saudi Pharm. J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.imbio.2008.11.004","article-title":"Influence of the mannose receptor in host immune responses","volume":"214","author":"Gazi","year":"2009","journal-title":"Immunobiology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e201846065","DOI":"10.15252\/embr.201846065","article-title":"The fungal ligand chitin directly binds TLR2 and triggers inflammation dependent on oligomer size","volume":"19","author":"Fuchs","year":"2018","journal-title":"EMBO Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.4049\/jimmunol.0802113","article-title":"Chitin Is a Size-Dependent Regulator of Macrophage TNF and IL-10 Production","volume":"182","author":"Silva","year":"2009","journal-title":"J. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Hatase, R., Li, Q., Hatakeyama, M., and Kitaoka, T. (2025). Direct activation of Toll-like receptor 2 signaling stimulated by contact with the interfacial structures of chitin nanofibers. Int. J. Biol. Macromol., 284.","DOI":"10.1016\/j.ijbiomac.2024.138092"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Oliveira-Nascimento, L., Massari, P., and Wetzler, L.M. (2012). The Role of TLR2 in Infection and Immunity. Front. Immunol., 3.","DOI":"10.3389\/fimmu.2012.00079"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Koller, B., M\u00fcller-Wiefel, A.S., Rupec, R., Korting, H.C., and Ruzicka, T. (2011). Chitin Modulates Innate Immune Responses of Keratinocytes. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016594"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.intimp.2014.09.007","article-title":"Toll like receptor 4 (TLR4) mediates the stimulating activities of chitosan oligosaccharide on macrophages","volume":"23","author":"Zhang","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1074\/mcp.M800589-MCP200","article-title":"From secretome analysis to immunology: Chitosan induces major alterations in the activation of dendritic cells via a TLR4-dependent mechanism","volume":"8","author":"Villiers","year":"2009","journal-title":"Mol. Cell. Proteom."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"63","DOI":"10.2147\/JIR.S287453","article-title":"Inhibition of Dectin-1 on Dendritic Cells Prevents Maturation and Prolongs Murine Islet Allograft Survival","volume":"14","author":"Ren","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2018.08.054","article-title":"Immunomodulatory properties of chitosan polymers","volume":"184","author":"Moran","year":"2018","journal-title":"Biomaterials"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"136","DOI":"10.22203\/eCM.v024a10","article-title":"Chitosan drives anti-inflammatory macrophage polarisation and pro-inflammatory dendritic cell stimulation","volume":"24","author":"Oliveira","year":"2012","journal-title":"Eur. Cells Mater."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.jconrel.2006.06.020","article-title":"Stable cationic microparticles for enhanced model antigen delivery to dendritic cells","volume":"114","author":"Wischke","year":"2006","journal-title":"J. Control. Release"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.immuni.2016.02.004","article-title":"The Vaccine Adjuvant Chitosan Promotes Cellular Immunity via DNA Sensor cGAS-STING-Dependent Induction of Type I Interferons","volume":"44","author":"Carroll","year":"2015","journal-title":"Immunity"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Ravindranathan, S., Koppolu, B.P., Smith, S.G., and Zaharoff, D.A. (2016). Effect of Chitosan Properties on Immunoreactivity. Mar. Drugs, 14.","DOI":"10.3390\/md14050091"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.immuni.2016.03.002","article-title":"Chitosan: An Adjuvant with an Unanticipated STING","volume":"44","author":"Riteau","year":"2016","journal-title":"Immunity"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"5707","DOI":"10.2147\/JIR.S374318","article-title":"LPS-Induced Activation of the cGAS-STING Pathway is Regulated by Mitochondrial Dysfunction and Mitochondrial DNA Leakage in Endometritis","volume":"15","author":"Li","year":"2022","journal-title":"J. Inflamm. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41419-024-06600-1","article-title":"STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury","volume":"15","author":"Cao","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Kelley, N., Jeltema, D., Duan, Y., and He, Y. (2019). The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133328"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1016\/j.imbio.2012.07.020","article-title":"Acute lipopolysaccharide priming boosts inflammasome activation independently of inflammasome sensor induction","volume":"217","author":"Schroder","year":"2012","journal-title":"Immunobiology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"35447","DOI":"10.1074\/jbc.M111.274936","article-title":"Chitosan but Not Chitin Activates the Inflammasome by a Mechanism Dependent upon Phagocytosis","volume":"286","author":"Bueter","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.biomaterials.2017.03.022","article-title":"Lysosomal rupture induced by structurally distinct chitosans either promotes a type 1 IFN response or activates the inflammasome in macrophages","volume":"129","author":"Fong","year":"2017","journal-title":"Biomaterials"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Turley, J.L., Moran, H.B.T., McEntee, C.P., O\u2019Grady, K., Mu\u00f1oz-Wolf, N., Jin, L., Follmann, F., Andersen, P., Andersson, M., and Lavelle, E.C. (2021). Chitin-derived polymer deacetylation regulates mitochondrial reactive oxygen species dependent cGAS-STING and NLRP3 inflammasome activation. Biomaterials, 275.","DOI":"10.1016\/j.biomaterials.2021.120961"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Muthu, M., Gopal, J., Chun, S., Devadoss, A.J.P., Hasan, N., and Sivanesan, I. (2021). Crustacean Waste-Derived Chitosan: Antioxidant Properties and Future Perspective. Antioxidants, 10.","DOI":"10.3390\/antiox10020228"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.intimp.2010.10.016","article-title":"Chitosan oligosaccharides protect mice from LPS challenge by attenuation of inflammation and oxidative stress","volume":"11","author":"Qiao","year":"2011","journal-title":"Int. Immunopharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.fct.2007.09.111","article-title":"Effects of chitosan oligosaccharide (COS) on the glycerol-induced acute renal failure in vitro and in vivo","volume":"46","author":"Yoon","year":"2008","journal-title":"Food Chem. Toxicol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"91","DOI":"10.5937\/FFR1702091H","article-title":"Antioxidative activity of chitosan and chitosan based biopolymer film","volume":"44","author":"Bulut","year":"2017","journal-title":"Food Feed Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"109","DOI":"10.5530\/ijper.50.1.14","article-title":"Chitooligosaccharides Attenuate Lipopolysaccharideinduced Inflammation and Apoptosis of Intestinal Epithelial Cells: Possible Involvement of TLR4\/NF-\u03baB Pathway","volume":"50","author":"Yang","year":"2016","journal-title":"Indian J. Pharm. Educ. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.ijbiomac.2016.02.015","article-title":"Chitosan nanoparticles reduce LPS-induced inflammatory reaction via inhibition of NF-\u03baB pathway in Caco-2 cells","volume":"86","author":"Tu","year":"2016","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.carbpol.2013.08.082","article-title":"Chitosan oligosaccharides block LPS-induced O-GlcNAcylation of NF-\u03baB and endothelial inflammatory response","volume":"99","author":"Li","year":"2013","journal-title":"Carbohydr. Polym."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Jhundoo, H.D., Siefen, T., Liang, A., Schmidt, C., Lokhnauth, J., B\u00e9duneau, A., Pellequer, Y., Larsen, C.C., and Lamprecht, A. (2020). Anti-Inflammatory Activity of Chitosan and 5-Amino Salicylic Acid Combinations in Experimental Colitis. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12111038"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.bbrc.2007.05.042","article-title":"Chitosan oligosaccharide (COS) inhibits LPS-induced inflammatory effects in RAW 264.7 macrophage cells","volume":"358","author":"Yoon","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.carbpol.2012.05.023","article-title":"\u03b1-Chitin nanofibrils improve inflammatory and fibrosis responses in inflammatory bowel disease mice model","volume":"90","author":"Azuma","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Hsu, S.-M., Yang, C.-H., Tsai, H.-Y., Lin, C.-J., Fang, Y.-H., Shieh, C.-C., and Chen, S.-H. (2020). Chitosan Oligosaccharides Suppress Nuclear Factor-Kappa B Activation and Ameliorate Experimental Autoimmune Uveoretinitis in Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218326"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.carbpol.2010.04.079","article-title":"Chitosan oligosaccharides suppressant LPS binding to TLR4\/MD-2 receptor complex","volume":"82","author":"Qiao","year":"2010","journal-title":"Carbohydr. Polym."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Donaldson, A.R., Tanase, C.E., Awuah, D., Bathrinarayanan, P.V., Hall, L., Nikkhah, M., Khademhosseini, A., Rose, F., Alexander, C., and Ghaemmaghami, A.M. (2018). Photocrosslinkable Gelatin Hydrogels Modulate the Production of the Major Pro-inflammatory Cytokine, TNF-\u03b1, by Human Mononuclear Cells. Front. Bioeng. Biotechnol., 6.","DOI":"10.3389\/fbioe.2018.00116"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"20608","DOI":"10.1038\/s41598-021-98931-8","article-title":"Effect of chitosan on blood profile, inflammatory cytokines by activating TLR4\/NF-\u03baB signaling pathway in intestine of heat stressed mice","volume":"11","author":"Mohyuddin","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"6210","DOI":"10.3390\/md13106210","article-title":"Immunostimulative Activity of Low Molecular Weight Chitosans in RAW264.7 Macrophages","volume":"13","author":"Wu","year":"2015","journal-title":"Mar. Drugs"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Zheng, B., Wen, Z.-S., Huang, Y.-J., Xia, M.-S., Xiang, X.-W., and Qu, Y.-L. (2016). Molecular Weight-Dependent Immunostimulative Activity of Low Molecular Weight Chitosan via Regulating NF-\u03baB and AP-1 Signaling Pathways in RAW264.7 Macrophages. Mar. Drugs, 14.","DOI":"10.3390\/md14090169"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ijbiomac.2019.02.066","article-title":"Effect of chitosan molecular weight on anti-inflammatory activity in the RAW 264.7 macrophage model","volume":"131","author":"Chang","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1016\/j.ijbiomac.2021.11.024","article-title":"Effects of molecular weight of chitosan on anti-inflammatory activity and modulation of intestinal microflora in an ulcerative colitis model","volume":"193 Pt B","author":"Niu","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_128","first-page":"1082","article-title":"Interaction of bacterial endotoxins with chitosan. Effect of endotoxin structure, chitosan molecular mass, and ionic strength of the solution on the formation of the complex","volume":"65","author":"Davydova","year":"2000","journal-title":"Biochemistry. Biokhimiia"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1134\/S0003683824020029","article-title":"The Influence of Chitosan on the Ability of LPS to Interact with Cells of the Immune System","volume":"60","author":"Davydova","year":"2024","journal-title":"Appl. Biochem. Microbiol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.carbpol.2015.01.028","article-title":"The supramolecular structure of LPS\u2013chitosan complexes of varied composition in relation to their biological activity","volume":"123","author":"Davydova","year":"2015","journal-title":"Carbohydr. Polym."}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/17\/1\/19\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:00:01Z","timestamp":1760115601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/17\/1\/19"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,25]]},"references-count":130,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["polym17010019"],"URL":"https:\/\/doi.org\/10.3390\/polym17010019","relation":{},"ISSN":["2073-4360"],"issn-type":[{"value":"2073-4360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,25]]}}}