This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B Cite this: DOI: 10.1039/d1tb00802a Modulation of inflammation by anti-TNF a mAb-dendrimer nanoparticles loaded in tyramine-modified gellan gum hydrogels in a cartilage-on-a-chip model I. M. Oliveira, ab M. R. Carvalho, ab D. C. Fernandes, ab C. M. Abreu, ab F. R. Maia, ab H. Pereira, abcd D. Caballero, ab S. C. Kundu, ab R. L. Reis ab and J. M. Oliveira * ab Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease characterized by joint inflammation. Since the inflammatory condition plays an important role in the disease process, it is important to develop and test new therapeutic approaches that specifically target and treat joint inflammation. In this study, a human 3D inflammatory cartilage-on-a-chip model was established to test the therapeutic efficacy of anti-TNFa mAb-CS/PAMAM dendrimer NPs loaded-Tyramine-Gellan Gum in the treatment of inflammation. The results showed that the proposed therapeutic approach applied to the human monocyte cell line (THP-1) and human chondrogenic primary cells (hCH) cell-based inflammation system revealed an anti-inflammatory capacity that increased over 14 days. It was also possible to observe that Coll type II was highly expressed by inflamed hCH upon the culture with anti- TNF a mAb-CS/PAMAM dendrimer NPs, indicating that the hCH cells were able maintain their biological function. The developed preclinical model allowed us to provide more robust data on the potential therapeutic effect of anti-TNF a mAb-CS/PAMAM dendrimer NPs loaded-Ty-GG hydrogel in a physiologically relevant model. Introduction Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease characterized by joint inflammation. In the inflammatory scenario, inflammatory cytokines such as Tumor necrosis factor (TNFa) lead to macrophages activation, which can cause stiffness and swelling of joints, damage to cartilage and erosion of bone. 1–3 Several therapies are currently available for RA treatment, including glucocorticoids, disease- modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, and biological agents to relieve pain and control inflammation. 4,5 Despite the great advances, due to heterogeneity of RA, many patients do not reach continued clinical remission or become resistant to drug therapy. 6,7 In vivo animal models are considered the gold standard in preclinical studies of pathophysiological mechanisms of RA. 8,9 Although animal models present many aspects of human arthritic diseases and are highly useful for testing new therapeutic approaches, they show some limitations, such as the development of arthritis only in predisposed strains of rodents. 10,11 They present limited development of arthritis, and pathophysiology in animals does not fully mimic the human pathogenic disease. 12,13 Furthermore, an increased amount of evidence suggest that current animal models are inadequate for wide drug screening due to their low reproducibility in clinical trials due to interspecies variations. 14,15 Thus, better models are crucial to help improve our knowledge on the pathological mechanisms of RA at pre-clinical level, as well as to develop and test new therapeutic approaches in order to meet patient and medical needs. 16,17 Having these considerations in mind, research has evolved into the next-generation in vitro screening platform based on the development of microphysiologically relevant systems, such as tissue- and organs-on-chips. 18 That models are generally based on primary or patient-derived cells, and can better mimic the disease and its treatment, a 3B’s Research Group, I3Bs - Research 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 Cie ˆncia e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimara ˜es, Portugal. E-mail: miguel.oliveira@i3bs.uminho.pt b ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimara ˜es, Portugal c Orthopedic Department, Povoa de Varzim – Vila do Conde Hospital Centre, Portugal d Ripoll & De Prado Sport Clinic, Spain Received 10th April 2021, Accepted 7th May 2021 DOI: 10.1039/d1tb00802a rsc.li/materials-b Journal of Materials Chemistry B PAPER Published on 10 May 2021. Downloaded by Universidade do Minho (UMinho) on 5/17/2021 11:10:16 AM. View Article Online View Journal