Abstract
Spatiotemporally controlled growth factor (GF) delivery is crucial for achieving functional vasculature within engineered tissues. However, conventional GF delivery systems show inability to recapitulate the dynamic and heterogeneous nature of developing tissue's biochemical microenvironment. Herein, an aptamer-based programmable GF delivery platform is described that harnesses dynamic affinity interactions for facilitating spatiotemporal control over vascular endothelial GF (VEGF165) bioavailability within gelatin methacryloyl matrices. The platform showcases localized VEGF165 sequestration from the culture medium (offering spatial-control) and leverages aptamer-complementary sequence (CS) hybridization for triggering VEGF165 release (offering temporal-control), without non-specific leakage. Furthermore, extensive 3D co-culture studies (human umbilical vein-derived endothelial cells & mesenchymal stromal cells), in bi-phasic hydrogel systems revealed its fundamentally novel capability to selectively guide cell responses and manipulate lumen-like microvascular networks via spatiotemporally controlling VEGF165 bioavailability within 3D microenvironment. This platform utilizes CS as an external biochemical trigger for guiding vascular morphogenesis which is suitable for creating dynamically controlled engineered tissues.
Highlights
A long-sought goal of tissue engineering is to successfully bioengi neer artificial tissues that could repair or regenerate damaged tissues after implantation in patients
To develop the desired versatile platform, we synthesized photo crosslinked aptamer-functionalized gelatin methacryloyl (GelMA) hydrogels via free-radical polymerization initiated with UV light exposure (Fig. 1A)
We demonstrated the bioactivity of the platform throughout the process of VEGF165 loading and triggered complementary sequence (CS) mediated release; co-cultures of human umbilical vein endothelial cells (HUVECs) and human mesenchymal stromal cells (MSCs) were used as model cell systems and were subjected to 3D cell encapsulation for fabricating cellladen aptamer-functionalized hydrogels
Summary
A long-sought goal of tissue engineering is to successfully bioengi neer artificial tissues that could repair or regenerate damaged tissues after implantation in patients. Establishing hierarchically organized, perfusable and mature vascular networks within engineered tissues is fundamental for their survival post-implantation. Various processes are synergistically responsible for achieving vascularization, including vasculogenesis (de novo vessel formation), angiogenic sprouting, intussusception, vascular remodeling and matu ration. Similar to other tissue formation processes, vascularization is spatiotemporally controlled via various interactions of the cells with the extracellular matrix (ECM) which undergoes constant biochemical modifications. The complex, dynamic and interde pendent nature of these interactions in native tissues provides great challenges in tissue engineering, and highlights the need to design dynamic biomaterials that could spatiotemporally control various biochemical cues for better mimicking the in vivo microenvironment.
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