Abstract
Blood-derived growth factor preparations have long been employed to improve perfusion and aid tissue repair. Among these, platelet-rich plasma (PRP)-based therapies have seen the widest application, albeit with mixed clinical results to date. Hypoxia-preconditioned blood products present an alternative to PRP, by comprising the complete wound healing factor-cascade, i.e., hypoxia-induced peripheral blood cell signaling, in addition to platelet-derived factors. This study set out to characterize the preparation of hypoxia preconditioned serum (HPS), and assess the utility of HPS–fibrin hydrogels as vehicles for controlled factor delivery. Our findings demonstrate the positive influence of hypoxic incubation on HPS angiogenic potential, and the individual variability of HPS angiogenic factor concentration. HPS–fibrin hydrogels can rapidly retain HPS factor proteins and gradually release them over time, while both functions appear to depend on the fibrin matrix mass. This offers a means of controlling factor retention/release, through adjustment of HPS fibrinogen concentration, thus allowing modulation of cellular angiogenic responses in a growth factor dose-dependent manner. This study provides the first evidence that HPS–fibrin hydrogels could constitute a new generation of autologous/bioactive injectable compositions that provide biochemical and biomaterial signals analogous to those mediating physiological wound healing. This therefore establishes a rational foundation for their application towards biomimetic tissue regeneration.
Highlights
A wound is characterized as a disorder of tissue structure and function [1,2] that, under physiological conditions, is regenerated through a series of defined wound healing stages: haemostasis, inflammation, proliferation, and angiogenesis, and eventually tissue remodeling [2,3]
This matrix remodeling may be mediated through the pro-angiogenic effect of hypoxia preconditioned serum (HPS) on endothelial cells (Figure 4A,B), and as shown here, via the ability to support fibroblast proliferation and migration toward the target area (Figure 4D,E), processes that are known to be stimulated by FGF, which is present in peripheral blood cells (PBCs)-derived secretomes [17,18]
From the plethora of pro- and anti-angiogenic factors that we have previously identified in hypoxia pre-conditioned blood-derived secretomes [4,15], as well as those detected here, we have deliberately chosen to examine in more detail two key antagonists, namely VEGF and TSP-1, since these are factors that are known to actively interact with the fibrin matrix [4,23,24]
Summary
A wound is characterized as a disorder of tissue structure and function [1,2] that, under physiological conditions, is regenerated through a series of defined wound healing stages: haemostasis, inflammation, proliferation, and angiogenesis, and eventually tissue remodeling [2,3]. We previously developed the first concepts for therapeutic angiogenesis based on this idea, using dermal fibroblasts, which were employed as growth factor producing cells, integrated into implantable/injectable systems [12,13,14] This provided a platform for the controlled release of hypoxia-induced protein factors, which has been shown in vivo to be effective in promoting vascularization, oxygenation, and integration of subcutaneously implanted collagen matrices [12,13]. The provision of a standardized ex vivo hypoxic microenvironment for PBCs, which simulates that of an in vivo wound, could aid the obtainment of physiological pro-angiogenic growth factor mixtures, at naturally occurring concentrations and ratios [15] This admittedly offers an improved alternative to concentrating platelet-derived factors to supra-physiological levels, e.g., platelet-rich plasma (PRP), an approach that currently represents the gold-standard of blood-based regenerative therapies
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