Uncoupling angiogenesis and inflammation in peripheral artery disease with therapeutic peptide-loaded microgels

Abstract

Peripheral artery disease (PAD) is characterized by vessel occlusion and ischemia in the limbs. Treatment for PAD with surgical interventions has been showing limited success. Moreover, recent clinical trials with treatment of angiogenic growth factors proved ineffective as increased angiogenesis triggered severe inflammation in a proportionally coupled fashion. Hence, the overarching goal of this research was to address this issue by developing a biomaterial system that enables controlled, dual delivery of pro-angiogenic C16 and anti-inflammatory Ac-SDKP peptides in a minimally-invasive way. To achieve the goal, a peptide-loaded injectable microgel system was developed and tested in a mouse model of PAD. When delivered through multiple, low volume injections, the combination of C16 and Ac-SDKP peptides promoted angiogenesis, muscle regeneration, and perfusion recovery, while minimizing detrimental inflammation. Additionally, this peptide combination regulated inflammatory TNF-α pathways independently of MMP-9 mediated pathways of angiogenesis in vitro, suggesting a potential mechanism by which angiogenic and inflammatory responses can be uncoupled in the context of PAD. This study demonstrates a translatable potential of the dual peptide-loaded injectable microgel system for PAD treatment.

Pendant allyl crosslinking as a tunable shape memory actuator for vascular applications

“…Wild type A/J mice were used to develop a model of hindlimb ischemia by ligating the femoral artery and vein at one ligation below the epigastric artery and a second ligation around the artery and vein at a distal location just proximal to the deep femoral branch [65-67]. The femoral artery and vein were then cut between these two sutures.…”

Engineering Integrative Stem Cell and Biomaterial Therapies for Peripheral Artery Disease

“…Vessel density continued to increase over the course of one month with little evidence of residual hydrogel after 2 weeks, thereby implying the robust new tissue formation in the leg. Recently, our research group (Hak-Joon Sung laboratory) took a similar approach using a PEL-PCL hydrogel that contained both pro-angiogenic and antiinflammatory peptide sequences to modulate nearby cells for healing of PAD in mouse models without the need of cell injections [114]. Pro-angiogenic C16 peptide and anti-inflammatory Ac-SDKP peptides in PEG-PCL was injected into the adductor muscle of an ischemic leg of a mouse following ligation surgery, with injection volumes as little as 1uL.…”

Methods for Generating Hydrogel Particles for Protein Delivery

“…77 The microgels were delivered into thigh muscle adjacent to the femoral artery ligations in a murine hind limb ischemia model of peripheral artery disease. Microgels in a series of 1 μL injections, allowing for thermosensitive in situ polymerization, were tested against preformed implantable scaffolds.…”