Abstract
Angiogenesis induction into damaged sites has long been an unresolved issue. Local treatment with pro-angiogenic molecules has been the most common approach. However, this approach has critical side effects including inflammatory coupling, tumorous vascular activation, and off-target circulation. Here, the concept that a structure can guide desirable biological function is applied to physically engineer three-dimensional channel networks in implant sites, without any therapeutic treatment. Microchannel networks are generated in a gelatin hydrogel to overcome the diffusion limit of nutrients and oxygen three-dimensionally. Hydrogel implantation in mouse and porcine models of hindlimb ischemia rescues severely damaged tissues by the ingrowth of neighboring host vessels with microchannel perfusion. This effect is guided by microchannel size-specific regenerative macrophage polarization with the consequent functional recovery of endothelial cells. Multiple-site implantation reveals hypoxia and neighboring vessels as major causative factors of the beneficial function. This technique may contribute to the development of therapeutics for hypoxia/inflammatory-related diseases.
Highlights
Angiogenesis induction into damaged sites has long been an unresolved issue
The neighboring blood vessels can grow into damaged sites whereas stem cells or monocytes can differentiate to endothelial progenitor cells (EPCs) even in the absence of blood vessels[21,22]
In the rescue process developed in this study, the proximal and distal host vessels grew into the hydrogel, and were followed by perfusion connection with the microchannel network (Supplementary Fig. 5b)
Summary
Angiogenesis induction into damaged sites has long been an unresolved issue. Local treatment with pro-angiogenic molecules has been the most common approach. Hydrogel implantation in mouse and porcine models of hindlimb ischemia rescues severely damaged tissues by the ingrowth of neighboring host vessels with microchannel perfusion This effect is guided by microchannel size-specific regenerative macrophage polarization with the consequent functional recovery of endothelial cells. The neighboring blood vessels can grow into damaged sites (angiogenesis) whereas stem cells or monocytes can differentiate to endothelial progenitor cells (EPCs) even in the absence of blood vessels (vasculogenesis)[21,22] These processes can be induced by local pathogenic events such as hypoxia and inflammation[23,24,25]. This study examines the induction of blood perfusion to damaged sites by implanting a hydrogel containing microchannel networks to obtain functional vascular structures. Its functional vascular structure with microchannel size results in promoted proangiogenic M2 polarization of macrophages and consequent functional endothelial cell (EC) recovery
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