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Electrospun Scaffolds Functionalized with a Hydrogen Sulfide Donor Stimulate Angiogenesis.

ABSTRACT: Tissue-engineered constructs are currently limited by the lack of vascularization necessary for the survival and integration of implanted tissues. Hydrogen sulfide (H₂S), an endogenous signaling gas (gasotransmitter), has been recently reported as a promising alternative to growth factors to mediate and promote angiogenesis in low concentrations. Yet, sustained delivery of H₂S remains a challenge. Herein, we have developed angiogenic scaffolds by covalent attachment of an H₂S donor to a polycaprolactone (PCL) electrospun scaffold. These scaffolds were engineered to include azide functional groups (on 1, 5, or 10% of the PCL end groups) and were modified using a straightforward click reaction with an alkyne-functionalized N-thiocarboxyanhydride (alkynyl-NTA). This created H₂S-releasing scaffolds that rely on NTA ring-opening in water followed by conversion of released carbonyl sulfide into H₂S. These functionalized scaffolds showed dose-dependent release of H₂S based on the amount of NTA functionality within the scaffold. The NTA-functionalized fibrous scaffolds supported human umbilical vein endothelial cell (HUVEC) proliferation, formed more confluent endothelial monolayers, and facilitated the formation of tight cell-cell junctions to a greater extent than unfunctionalized scaffolds. Covalent conjugation of H₂S donors to scaffolds not only promotes HUVEC proliferation in vitro, but also increases neovascularization in ovo, as observed in the chick chorioallantoic membrane assay. NTA-functionalized scaffolds provide localized control over vascularization through the sustained delivery of a powerful endogenous angiogenic agent, which should be further explored to promote angiogenesis in tissue engineering.

SUBMITTER: Yao T

PROVIDER: S-EPMC9247975 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Vascular endothelial growth factor (VEGF) plays a vital role in promoting attachment and proliferation of endothelial cells, and induces angiogenesis. In recent years, much research has been conducted on functionalization of tissue engineering scaffolds with VEGF or VEGF-mimetic peptide to promote angiogenesis. However, most chemical reactions are nonspecific and require organic solvents, which can compromise control over functionalization and alter peptide/protein activity. An attractive alternative is the fabrication of functionalizable electrospun fibers, which can overcome these hurdles. In this study, we used thiol-ene chemistry for the conjugation of a VEGF-mimetic peptide to the surface of poly (ε-caprolactone) (PCL) fibrous scaffolds with varying amounts of a functional PCL-diacrylate (PCL-DA) polymer. 30% PCL-DA was selected due to homogeneous fiber morphology. A VEGF-mimetic peptide was then immobilized on PCL-DA fibrous scaffolds by a light-initiated thiol-ene reaction. 7-Mercapto-4-methylcoumarin, RGD-FITC peptide and VEGF-TAMRA mimetic peptide were used to validate the thiol-ene reaction with fibrous scaffolds. Tensile strength and elastic modulus of 30% PCL-DA fibrous scaffolds were significantly increased after the reaction. Conjugation of 30% PCL-DA fibrous scaffolds with VEGF peptide increased the surface water wettability of the scaffolds. Patterned structures could be obtained after using a photomask on the fibrous film. Moreover, in vitro studies indicated that scaffolds functionalized with the VEGF-mimetic peptide were able to induce phosphorylation of VEGF receptor and enhanced HUVECs survival, proliferation and adhesion. A chick chorioallantoic membrane (CAM) assay further indicated that the VEGF peptide functionalized scaffolds are able to promote angiogenesis in vivo. These results show that scaffold functionalization can be controlled via a simple polymer mixing approach, and that the functionalized VEGF peptide-scaffolds have potential for vascular tissue regeneration.

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Electrospun Scaffolds Functionalized with a Hydrogen Sulfide Donor Stimulate Angiogenesis.

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