Cobalt-induced hypoxia as biomimetic strategy for advanced biomaterials developing

• Grant number: 22/15157-1
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2023
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Willian Fernando Zambuzzi
• Grantee: Willian Fernando Zambuzzi
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• City of the host institution: Botucatu

Abstract

Despite appearing to be static, bone tissue is highly dynamic, with a recognized ability to reshape and regenerate throughout the life of vertebrates; the coupling between osteoblasts and osteoclasts controls this activity. In case of extensive, critically sized lesions, support material is needed to contribute to tissue repair/regeneration events, requiring the clinical use of biomaterials such as metallic and ceramic biomaterials. With population growth and aging, new metal alloys appear to improve clinical issues and reduce patient recovery time, a process that seeks to develop effective osteointegration and vascular supply to result in proper healing of periimplant tissues. Our group has shown that these metal alloys are not inert to the tissue; we also show that they release chemical elements capable of altering cells at a distance, potentiating biological events in the tissue around the implant and not just in the cells adhered to its surface. The release of active elements for cellular activity requires a better understanding of these events, such as those that combine angiogenesis and osteogenesis. In this case, we will use lessons from the literature that show us the power of Cobalt hypoxia, which may intensify the capacity of periimplant vasculogenesis. To test this hypothesis, we will use in vitro assays in Step I, which have already been standardized in LaBIO, Department of Chemistry and Biochemistry, using endothelial cells and osteoblasts. In this case we will work with CoCl2, to better control the cytotoxic concentration of Co, as well as unravel the signaling pathways involved (survival and inflammatory). The hypoxicating power of CoCl2 will be verified by monitoring HIF1alpha, as well as the participation of the proteasome pathway in this response. Eventually, as HIF1alpha is degraded by the proteasome when under normoxic conditions, we will challenge the cells with CoCl2 in the presence of the proteasome inhibitor MG32 to verify the potential effect of this inhibitor on osteogenesis processes. In Step II, we will use the data obtained in Step I to propose a better CoCl2 concentration for synthesis of a new ceramic biomaterial, based on Hydroxyapatite (we have the expertise to synthesize HA), and thus we will have a Co-doped HA It is noteworthy that this new biomaterial will be physically and chemically characterized. Later, in STEP III, we will do in vivo testing of these materials, seeking to understand, histologically, the osteo-reparative capacity of this proposed new material. For these tests, we will use rats (Rattus norvegicus), which will be submitted to biological tests very well described in the literature, such as the subcutaneous implantation of the material, as well as the filling of a critical lesion experimentally made in the skullcap of these animals of experimentation. The in vitro tests will give us important parameters for the rational use of these animals, within the teachings of the 3Rs policy. This work will help us develop previous synthesis protocols and combinations, providing new alternative routes to clinical practice and optimizing biomaterial applications in bone tissue injuries. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FERNANDES, CELIO JUNIOR DA C.; DE ALMEIDA, GERSON SANTOS; WOOD, PATRICIA FRETES; GOMES, ANDERSON M.; BEZERRA, FABIO J.; VIEIRA, JOSE C. S.; PADILHA, PEDRO M.; ZAMBUZZI, WILLIAN F.. Mechanosignaling-related angiocrine factors drive osteoblastic phenotype in response to zirconia. JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY, v. 81, p. 9-pg., 2023-11-23. (22/15157-1)

MAURICIO, DANILO CERVANTES; GONCALVES, VINICIUS RICHIERI MANSO; TORRENTO, JHULIENE ELEN MURO; PINTAO, CARLOS ALBERTO FONZAR; GRANDINI, CARLOS ROBERTO; AFONSO, CONRADO RAMOS MOREIRA; DE ALMEIDA, GERSON SANTOS; ZAMBUZZI, WILLIAN FERNANDO; CORREA, DIEGO RAFAEL NESPEQUE. In-situ production of a biomedical metal-matrix composite based on a high entropy alloy reinforced with TiC and TiB. JOURNAL OF MATERIALS RESEARCH AND TECHNOLOGY-JMR&T, v. 35, p. 11-pg., 2025-03-01. (23/09532-7, 22/15157-1, 24/01132-2, 24/03148-3, 24/03886-4, 21/13921-3)

DE ALMEIDA, GERSON SANTOS; SUTER, LUISA CAMILO; PINTO, THAIS SILVA; CARRA, MARIA GABRIELA JACHETO; FELTRAN, GEORGIA DA SILVA; DE MORAES, JULIA FERREIRA; CORREA, DIEGO RAFAEL NESPEQUE; SAEKI, MARGARIDA JURI; LISBOA-FILHO, PAULO NORONHA; ZAMBUZZI, WILLIAN FERNANDO. The Biological Properties of Co-Doped Monetite Are Influenced by Thermal Treatment. JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS, v. 113, n. 2, p. 21-pg., 2025-02-01. (19/26854-2, 24/03886-4, 22/15157-1)

MACHADO, MARIANA ISSLER PINHEIRO; GOMES, ANDERSON MOREIRA; ZAMBUZZI, WILLIAN FERNANDO. Hypoxia modulates the phenotype of mechanically stressed endothelial cells responding to CoCr-enriched medium. JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY, v. 82, p. 6-pg., 2023-12-12. (19/26854-2, 22/15157-1)

GOMES, ANDERSON M.; DA SILVA, DANIELLE F.; BEZERRA, FABIO J.; ZAMBUZZI, WILLIAN F.. Nanohydroxyapatite-Coated Titanium Surface Increases Vascular Endothelial Cells Distinct Signaling Responding to High Glucose Concentration. JOURNAL OF FUNCTIONAL BIOMATERIALS, v. 14, n. 4, p. 11-pg., 2023-04-01. (22/15157-1)

ZAMBUZZI, WILLIAN FERNANDO; FERREIRA, MARCEL RODRIGUES. Dynamic ion-releasing biomaterials actively shape the microenvironment to enhance healing. JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY, v. 89, p. 12-pg., 2025-04-17. (22/15157-1)

GONCALVES, VINICIUS RICHIERI MANSO; CORREA, DIEGO RAFAEL NESPEQUE; CARDOSO, GIOVANA COLLOMBARO; DE ALMEIDA, GERSON SANTOS; ZAMBUZZI, WILLIAN FERNANDO; AFONSO, CONRADO RAMOS MOREIRA; LISBOA-FILHO, PAULO NORONHA; GRANDINI, CARLOS ROBERTO. Micro-arc oxidation treatment applied on the surface of β Ti-Nb matrix composites as a strategy to modulate cellular behavior. SURFACE & COATINGS TECHNOLOGY, v. 506, p. 15-pg., 2025-06-15. (18/00746-6, 18/18293-8, 15/50280-5, 24/00306-7, 22/15157-1, 24/03886-4)