First implantable device for hypoxia-mediated angiogenic induction.

Delayed or inadequate vascularisation is one of the major factors leading to tissue infarction and poor graft survival. Current vascularisation strategies that rely on delivering single growth factors have proved ineffective or hard to control in practise. An alternative approach has been identified by this group that relies on stimulation of physiological angiogenic factor cascades by engineering local cell-hypoxia, within a nano-fibrillar collagen material. Here we report on a novel, practical and effective implantable device for delivering engineered angiogenic signalling, on demand. Human dermal fibroblast-seeded dense-collagen depots were pre-conditioned under physiological cell-generated hypoxia to up-regulate production of key angiogenic factors, including HIF1α and VEGF(165). The level of VEGF(165) protein retained within depots (indicating general angiogenic factor production) was directly correlated to the duration of pre-conditioning. Angiogenic factor delivery from pre-conditioned, non-viable depots rapidly induced an angiogenic response within endothelial cell-seeded constructs in vitro, while implanted acellular 3D constructs incorporating such angiogenic depots in their core were infiltrated with perfused vessels by 1 week in vivo, at which stage non-angiogenic implants were minimally perfused. Depot stability, tuneability of cell/matrix composition with long clinical experience of the collagen material, together with cost effectiveness, make this angiogenic therapy a promising addition to a clinician's tool kit for improving local tissue perfusion.