Tuning Tissue Ingrowth into Proangiogenic Hydrogels via Dual Modality Degradation

Abstract

The potential to control the rate of replacement of a biodegradable implant by a tissue would be advantageous. Here, we demonstrate that tissue invasion can be tuned through the novel approach of overlaying an enzymatically degradable hydrogel with an increasingly hydrolytically degradable environment. Poly­(ethylene glycol) (PEG) hydrogels were formed from varying proportions of PEG-vinyl sulfone and PEG-acrylate (PEG-AC) monomers via a Michael-type addition reaction with a dithiol-containing matrix-metalloproteinase-susceptible peptide cross-linker. Swelling studies showed that PEG hydrogels with similar initial stiffnesses degraded more rapidly as the PEG-AC content increased. The replacement of subcutaneously implanted PEG hydrogels was also found to be proportional to their PEG-AC content. In addition, it would in many instances be desirable that these materials have the ability to stimulate their neovascularization. These hydrogels contained covalently bound heparin, and it was shown that a formulation of the hydrogel that allowed tissue replacement to occur over 1 month could trap and release growth factors and increase neovascularization by 50% over that time.

Pristine gelatin incorporation as a strategy to enhance the biofunctionality of poly(vinyl alcohol)-based hydrogels for tissue engineering applications

“…This is interesting, as the incorporation of ECM macromolecules or bioactive motifs commonly results in altered degradation profiles of synthetic hydrogels, due to the introduction of motifs susceptible to enzymatic degradation. 2,4,70,77 For instance, Lan et al showed that the presence of 2 mg mL −1 chondroitin sulfate and 5 wt% of collagen type II in 5 wt% PVA hydrogels prepared with the freeze-thaw method promoted faster degradation compared to the non-functionalized construct in a rabbit osteochondral defect. 78 The absence of differences in our work suggests the ability of PVA-Tyr hydrogels to protect incorporated proteins from proteases and confirms that the hydrogel properties are mainly dependant on the PVA-Tyr polymer network.…”

“…As a consequence, cellular infiltration and integration of synthetic hydrogels with the surrounding tissue is reduced, potentially hindering their therapeutic effect. 2,4,5 This is particularly challenging when aiming at TERM applications, where timely blood vessel ingrowth within engineered hydrogels is essential for the survival of the colonizing cells and for the regeneration of the target tissue. [4][5][6][7][8] Several strategies have been used to promote cellular and vascular ingrowth within synthetic hydrogels.…”

“…2,4,5 This is particularly challenging when aiming at TERM applications, where timely blood vessel ingrowth within engineered hydrogels is essential for the survival of the colonizing cells and for the regeneration of the target tissue. [4][5][6][7][8] Several strategies have been used to promote cellular and vascular ingrowth within synthetic hydrogels. For instance, the introduction of microporous structures within synthetic dextran vinyl sulfone hydrogels enhanced the formation of lumenized sprouts and cell infiltration in vivo.…”

“…14 To ensure the survival of infiltrating cells and promote tissue maturation, recruitment of host vasculature within engineered constructs of clinically relevant-size is crucial. [4][5][6][7][8] To guide blood vessel infiltration, a popular method has been to functionalize synthetic hydrogels with pro-angiogenic growth factors (GFs). 8,19,20 Vascular endothelial growth factor (VEGF) is a widely exploited pro-angiogenic GF for tissue engineering (TE) applications due to its role in driving the early stages of angiogenesis, regulating the loosening of endothelial cell junctions and promoting endothelial cell survival.…”

“…2,4,5 This is particularly challenging when aiming at TERM applications, where timely blood vessel ingrowth within engineered hydrogels is essential for the survival of the colonizing cells and for the regeneration of the target tissue. 4–8…”