{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T12:06:27Z","timestamp":1772539587723,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T00:00:00Z","timestamp":1626825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Norte2020 project","award":["NORTE-08-5369-FSE000044"],"award-info":[{"award-number":["NORTE-08-5369-FSE000044"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Rheumatoid Arthritis (RA) is an incurable autoimmune disease that promotes the chronic impairment of patients\u2019 mobility. For this reason, it is vital to develop therapies that target early inflammatory symptoms and act before permanent articular damage. The present study offers two novel therapies based in advanced drug delivery systems for RA treatment: encapsulated chondroitin sulfate modified poly(amidoamine) dendrimer nanoparticles (NPs) covalently bonded to monoclonal anti-TNF \u03b1 antibody in both Tyramine-Gellan Gum and Tyramine-Gellan Gum\/Silk Fibroin hydrogels. Using pro-inflammatory THP-1 (i.e., human monocytic cell line), the therapy was tested in an inflammation in vitro model under both static and dynamic conditions. Firstly, we demonstrated effective NP-antibody functionalization and TNF-\u03b1 capture. Upon encapsulation, the NPs were released steadily over 21 days. Moreover, in static conditions, the approaches presented good anti-inflammatory activity over time, enabling the retainment of a high percentage of TNF \u03b1. To mimic the physiological conditions of the human body, the hydrogels were evaluated in a dual-chamber bioreactor. Dynamic in vitro studies showed absent cytotoxicity in THP-1 cells and a significant reduction of TNF-\u03b1 in suspension over 14 days for both hydrogels. Thus, the developed approach showed potential for use as personalized medicine to obtain better therapeutic outcomes and decreased adverse effects.<\/jats:p>","DOI":"10.3390\/pharmaceutics13081111","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T22:35:31Z","timestamp":1626993331000},"page":"1111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Bioengineered Nanoparticles Loaded-Hydrogels to Target TNF Alpha in Inflammatory Diseases"],"prefix":"10.3390","volume":"13","author":[{"given":"Isabel Matos","family":"Oliveira","sequence":"first","affiliation":[{"name":"13B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Braga, Portugal"}]},{"given":"Diogo Castro","family":"Fernandes","sequence":"additional","affiliation":[{"name":"13B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2271-515X","authenticated-orcid":false,"given":"F\u00e1tima Raquel","family":"Maia","sequence":"additional","affiliation":[{"name":"13B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9504-4206","authenticated-orcid":false,"given":"Raphael Faustino","family":"Canadas","sequence":"additional","affiliation":[{"name":"13B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Braga, Portugal"}]},{"given":"Rui Lu\u00eds","family":"Reis","sequence":"additional","affiliation":[{"name":"13B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7052-8837","authenticated-orcid":false,"given":"Joaquim Miguel","family":"Oliveira","sequence":"additional","affiliation":[{"name":"13B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Braga, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41413-018-0016-9","article-title":"Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies","volume":"6","author":"Guo","year":"2018","journal-title":"Bone Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1097\/BOR.0000000000000017","article-title":"When and where does inflammation begin in rheumatoid arthritis?","volume":"26","author":"Demoruelle","year":"2014","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"84","DOI":"10.18053\/jctres.02.201603.005","article-title":"The role of TNF-\u03b1 in rheumatoid arthritis: A focus on regulatory T cells","volume":"2","author":"Farrugia","year":"2016","journal-title":"J. Clin. Transl. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"K\u00f6hler, B.M., G\u00fcnther, J., Kaudewitz, D., and Lorenz, H.-M. (2019). Current Therapeutic Options in the Treatment of Rheumatoid Arthritis. J. Clin. Med., 8.","DOI":"10.3390\/jcm8070938"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10856-021-06547-1","article-title":"Hydrogels in the treatment of rheumatoid arthritis: Drug delivery systems and artificial matrices for dynamic in vitro models","volume":"32","author":"Oliveira","year":"2021","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1208\/s12248-015-9814-9","article-title":"Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges","volume":"17","author":"Wen","year":"2015","journal-title":"AAPS J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.berh.2012.03.001","article-title":"Advances in the treatment of inflammatory arthritis","volume":"26","author":"Pisetsky","year":"2012","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1007\/s11926-012-0275-1","article-title":"Treatment strategies in early rheumatoid arthritis and prevention of rheumatoid arthritis","volume":"14","author":"Demoruelle","year":"2012","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.3390\/ma3021420","article-title":"Self-assembled hydrogel nanoparticles for drug delivery applications","volume":"3","author":"Pereira","year":"2010","journal-title":"Materials"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1039\/C3NR05961H","article-title":"Effect of drug release kinetics on nanoparticle therapeutic efficacy and toxicity","volume":"6","author":"Sethi","year":"2014","journal-title":"Nanoscale"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1021\/nn900002m","article-title":"Impact of nanotechnology on drug delivery","volume":"3","author":"Farokhzad","year":"2009","journal-title":"ACS Nano"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-matsci-062910-100359","article-title":"Advances in drug delivery","volume":"41","author":"Timko","year":"2011","journal-title":"Annu. Rev. Mater. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nmat2441","article-title":"Complexity in biomaterials for tissue engineering","volume":"8","author":"Place","year":"2009","journal-title":"Nat. Mater."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/nature08601","article-title":"Inspiration and application in the evolution of biomaterials","volume":"462","author":"Huebsch","year":"2009","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16071","DOI":"10.1038\/natrevmats.2016.71","article-title":"Designing hydrogels for controlled drug delivery","volume":"1","author":"Li","year":"2016","journal-title":"Nat. Rev. Mater."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Narayanaswamy, R., and Torchilin, V.P. (2019). Hydrogels and Their Applications in Targeted Drug Delivery. Molecules, 24.","DOI":"10.3390\/molecules24030603"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.4252\/wjsc.v11.i12.1065","article-title":"Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling","volume":"11","author":"Chaicharoenaudomrung","year":"2019","journal-title":"World J. Stem Cells"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1089\/adt.2014.573","article-title":"Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors","volume":"12","author":"Edmondson","year":"2014","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.drudis.2013.05.016","article-title":"The use of bioreactors as in vitro models in pharmaceutical research","volume":"18","author":"Ginai","year":"2013","journal-title":"Drug Discov. Today"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10529-018-2611-7","article-title":"New generation of bioreactors that advance extracellular matrix modelling and tissue engineering","volume":"41","author":"Ahmed","year":"2019","journal-title":"Biotechnol. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.tibtech.2003.12.001","article-title":"The role of bioreactors in tissue engineering","volume":"22","author":"Martin","year":"2004","journal-title":"Trends Biotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"167","DOI":"10.4161\/biom.22170","article-title":"The role of perfusion bioreactors in bone tissue engineering","volume":"2","author":"Gaspar","year":"2012","journal-title":"Biomatter"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1007\/s13346-020-00855-9","article-title":"Enzymatically crosslinked tyramine-gellan gum hydrogels as drug delivery system for rheumatoid arthritis treatment","volume":"11","author":"Oliveira","year":"2020","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Oliveira, I.M., Gon\u00e7alves, C., Shin, M.E., Lee, S., Reis, R.L., Khang, G., and Oliveira, J.M. (2020). Anti-Inflammatory Properties of Injectable Betamethasone-Loaded Tyramine-Modified Gellan Gum\/Silk Fibroin Hydrogels. Biomolecules, 10.","DOI":"10.3390\/biom10101456"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"111845","DOI":"10.1016\/j.msec.2020.111845","article-title":"PAMAM Dendrimers Functionalised with an Anti-TNF \u03b1 Antibody and Chondroitin Sulphate for Treatment of Rheumatoid Arthritis","volume":"121","author":"Oliveira","year":"2021","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1804148","DOI":"10.1002\/adfm.201804148","article-title":"Biochemical Gradients to Generate 3D Heterotypic-Like Tissues with Isotropic and Anisotropic Architectures","volume":"28","author":"Canadas","year":"2018","journal-title":"Adv. Funct. Mater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.clim.2007.08.013","article-title":"TNFalpha blockade in human diseases: Mechanisms and future directions","volume":"126","author":"Wong","year":"2008","journal-title":"Clin. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1400010","DOI":"10.1002\/advs.201400010","article-title":"Nanoparticle-Hydrogel Composites: Concept, Design, and Applications of These Promising, Multi-Functional Materials","volume":"2","author":"Thoniyot","year":"2015","journal-title":"Adv. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Dannert, C., Stokke, B.T., and Dias, R.S. (2019). Nanoparticle-Hydrogel Composites: From Molecular Interactions to Macroscopic Behavior. Polymers, 11.","DOI":"10.3390\/polym11020275"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cca.2016.02.010","article-title":"Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis","volume":"455","author":"Mateen","year":"2016","journal-title":"Clin. Chim. Acta"},{"key":"ref_31","first-page":"581","article-title":"Macrophages in rheumatoid arthritis","volume":"22","author":"Maruotti","year":"2007","journal-title":"Histol. Histopathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e12854","DOI":"10.1111\/cpr.12854","article-title":"Emerging role of targeting macrophages in rheumatoid arthritis: Focus on polarization, metabolism and apoptosis","volume":"53","author":"Yang","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_33","first-page":"1","article-title":"The macrophages in rheumatic diseases","volume":"9","author":"Laria","year":"2016","journal-title":"J. Inflamm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s40744-017-0073-3","article-title":"Treatment with Biologicals in Rheumatoid Arthritis: An Overview","volume":"4","author":"Rein","year":"2017","journal-title":"Rheumatol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.progpolymsci.2010.04.006","article-title":"Dendrimers and derivatives as a potential therapeutic tool in regenerative medicine strategies\u2014A review","volume":"35","author":"Oliveira","year":"2010","journal-title":"Prog. Polym. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Costa, L., Silva-Correia, J., Oliveira, J.M., and Reis, R.L. (2018). Gellan gum-based hydrogels for osteochondral repair. Osteochondral Tissue Eng., 281\u2013304.","DOI":"10.1007\/978-3-319-76711-6_13"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.ejpb.2013.11.001","article-title":"Gellan gum nanohydrogel containing anti-inflammatory and anti-cancer drugs: A multi-drug delivery system for a combination therapy in cancer treatment","volume":"87","author":"Navarro","year":"2014","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"490514","DOI":"10.1155\/2012\/490514","article-title":"Design and Characterization of a Silk-Fibroin-Based Drug Delivery Platform Using Naproxen as a Model Drug","volume":"2012","author":"Dyakonov","year":"2012","journal-title":"J. Drug Deliv."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/8\/1111\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:32:57Z","timestamp":1760164377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/8\/1111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,21]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["pharmaceutics13081111"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13081111","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,21]]}}}