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.

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