Norepinephrine-loaded thermoresponsive hydrogel-like system for enhanced angiogenesis in tissue engineering

Author(s)

Martins, Tassia Joi ; Calori, Italo Rodrigo ; Guimaraes, Ana Paula Pereira ; Ribeiro, Gabriel Henrique ; Venancio, Tiago ; Martins, Fiama ; Ribeiro, Lucas da Silva ; Camargo, Emerson ; Tedesco, Antonio Claudio

• Document type: Journal article
• Source: JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY; v. 110, p. 9-pg., 2025-08-01.

Abstract

Inadequate vascularization in thick biofabricated tissues and organs leads to hypoxia and graft failure, highlighting the critical role of angiogenesis in the clinical translation of tissue engineering. Norepinephrine (NE), a neurotransmitter and hormone, regulates vascular tone and modulates angiogenesis through proangiogenic factors, offering an option for improving vascularization and tissue integration. This study aimed to characterize an injectable and in situ forming hydrogel-like system made of poly(N-vinylcaprolactam) (PNVCL) loaded with NE, and evaluate its effects on endothelial cell models. PNVCL was successfully synthesized via free-radical polymerization, as indicated by 1H NMR and FTIR spectroscopy. The polymer exhibited a glass transition temperature (Tg) of 194 degrees C and thermoresponsive behavior with a lower critical solution temperature of 34 degrees C. NMR spectroscopy indicated through-space dipolar couplings between NE and PNVCL hydrogens, which suggest interaction groups within the NE-PNVCL system. This system protects NE from degradation, as indicated by absorption spectroscopy. The PNVCL system exhibited a burst release of NE followed by a controlled release profile, with approximately 80 % and 87 % of the NE released within 24 h and 72 h, respectively. In human umbilical vein endothelial cells (HUVEC) culture, NE reduced migration and enhanced tubulogenesis, indicating a dual role in angiogenesis. In addition, NE promoted sprout formation in endothelial cell spheroids. These findings highlight the potential of NE-loaded PNVCL systems to enhance angiogenesis and vascularization in tissue engineering. (AU)

• FAPESP's process: 23/14112-7 - Development of hydrolysable polymers for protection, transport and controlled release of plant growth-promoting microorganisms
• Grantee: Lucas da Silva Ribeiro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/04507-6 - HYDROGENLS CONFINED IN 3D PRINTED MATRIX TO CONTROLLED AND SITE-SPECIFIC DELIVERY OF INGENOL-3-DODECANOATE AND FLUOROCHROME FOR PHOTODIAGNOSTIC AND THERAPY OF CEREBRAL TUMORS
• Grantee: Italo Rodrigo Calori
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/12871-0 - Modification of the temperature transition profile of thermosensitive nanocomposites
• Grantee: Lucas da Silva Ribeiro
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 21/08111-2 - Development of rare earth based light converters: luminescent markers, optical sensors, and amplifiers
• Grantee: Hermi Felinto de Brito
• Support Opportunities: Research Projects - Thematic Grants