title: Fibrinogen scaffolds with immunomodulatory properties promote in vivo bone regeneration.
abstract: The hypothesis behind this work is that fibrinogen (Fg), classically considered a pro-inflammatory protein, can promote bone repair/regeneration. Injury and biomaterial implantation naturally lead to an inflammatory response, which should be under control, but not necessarily minimized. Herein, porous scaffolds entirely constituted of Fg (Fg-3D) were implanted in a femoral rat bone defect and investigated at two important time points, addressing the bone regenerative process and the local and systemic immune responses, both crucial to elucidate the mechanisms of tissue remodelling. Fg-3D led to early infiltration of granulation tissue (6 days post-implantation), followed by bone defect closure, including periosteum repair (8 weeks post-injury). In the acute inflammatory phase (6 days) local gene expression analysis revealed significant increases of pro-inflammatory cytokines IL-6 and IL-8, when compared with non-operated animals. This correlated with modified proportions of systemic immune cell populations, namely increased T cells and decreased B, NK and NKT lymphocytes and myeloid cell, including the Mac-1+ (CD18+/CD11b+) subpopulation. At 8 weeks, Fg-3D led to decreased plasma levels of IL-1β and increased TGF-β1. Thus, our data supports the hypothesis, establishing a link between bone repair induced by Fg-3D and the immune response. In this sense, Fg-3D scaffolds may be considered immunomodulatory biomaterials.
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Vasconcelos
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Gonçalves
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; Department of Medical Sciences and Institute for Biomedicine - iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal.
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Almeida
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
authors.forename: Inês O
authors.initials: IO
authors.lastname: Pereira
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INL- International Iberian Nanotechnology Laboratory, Braga 4715-330, Portugal.
authors.forename: Marta I
authors.initials: MI
authors.lastname: Oliveira
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; FMUP-Faculdade de Medicina da Universidade do Porto, Departamento de Cirurgia, Serviço de Ortopedia, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Neves
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
authors.forename: Andreia M
authors.initials: AM
authors.lastname: Silva
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
authors.forename: António C
authors.initials: AC
authors.lastname: Ribeiro
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Cunha
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Almeida
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; Instituto Superior de Engenharia do Porto, Instituto Politécnico do Porto, Rua Dr. António Bernardino de Almeida 431, 4249-015 Porto, Portugal.
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Ribeiro
authors.affiliation: CICECO-Aveiro Institute of Materials, Department of Chemistry, Universidade de Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gil
authors.affiliation: Research Center for Experimental Orthopaedics, Department of Orthopaedics, Trauma Surgery and Paraplegiology, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Seebach
authors.affiliation: Research Center for Experimental Orthopaedics, Department of Orthopaedics, Trauma Surgery and Paraplegiology, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Kynast
authors.affiliation: Research Center for Experimental Orthopaedics, Department of Orthopaedics, Trauma Surgery and Paraplegiology, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Richter
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
authors.forename: Meriem
authors.initials: M
authors.lastname: Lamghari
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal. Electronic address: susana.santos@ineb.up.pt.
authors.forename: Susana G
authors.initials: SG
authors.lastname: Santos
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
authors.forename: Mário A
authors.initials: MA
authors.lastname: Barbosa
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004343:Drug Implants / Q000008:administration & dosage*; D005264:Femoral Fractures / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D005340:Fibrinogen / Q000008:administration & dosage* / Q000737:chemistry; D017102:Fracture Healing / Q000187:drug effects / Q000276:immunology; D048091:Guided Tissue Regeneration / Q000295:instrumentation; D007155:Immunologic Factors / Q000008:administration & dosage; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D054457:Tissue Scaffolds; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D004343:Drug Implants; D007155:Immunologic Factors; D005340:Fibrinogen
keywords: Biomaterial; Bone repair/regeneration; Fibrinogen; Inflammation; In vivo