Abstract
Cell therapies are emerging as a new therapeutic frontier for the treatment of ischemic disease. However, femoral occlusions can be challenging environments for effective therapeutic cell delivery. In this study, cell-engineered hybrid scaffolds are implanted around the occluded femoral artery and the therapeutic benefit through the formation of new collateral arteries is investigated. First, it is reported the fabrication of different hybrid “hard-soft” 3D channel-shaped scaffolds comprising either poly(ε-caprolactone) (PCL) or polylactic-co-glycolic acid (PLGA) and electro-spun of gelatin (GL) nanofibers. Both PCL-GL and PLGA-GL scaffolds show anisotropic characteristics in mechanical tests and PLGA displays a greater rigidity and faster degradability in wet conditions. The resulting constructs are engineered using human adventitial pericytes (APCs) and both exhibit excellent biocompatibility. The 3D environment also induces expressional changes in APCs, conferring a more pronounced proangiogenic secretory profile. Bioprinting of alginate-pluronic gel (AG/PL), containing APCs and endothelial cells, completes the hybrid scaffold providing accurate spatial organization of the delivered cells. The scaffolds implantation around the mice occluded femoral artery shows that bioengineered PLGA hybrid scaffold outperforms the PCL counterpart accelerating limb blood flow recovery through the formation arterioles with diameters >50 μm, demonstrating the therapeutic potential in stimulating reparative angiogenesis.
Highlights
Acute limb ischemia is the sudden loss of limb perfusion and is typically caused by an occluding embolus, in situ formation of a thrombus, trauma, or dissection of a peripheral artery
The synthetic matrices were manufactured with a customized piston-driven 3D printing system (MandleMax3, Maker’s Tool Works, US) (Figure 1A), which allowed the extrusion of PCL and polylactic-co-glycolic acid (PLGA) through a layerby-layer deposition
The synthetic matrices were manufactured using a customized piston-driven 3D printing system (MandleMax3, Maker’s Tool Works, US), which allowed the extrusion of PCL or PLGA via a layer-by-layer deposition
Summary
Acute limb ischemia is the sudden loss of limb perfusion and is typically caused by an occluding embolus, in situ formation of a thrombus, trauma, or dissection of a peripheral artery. Chronic total occlusions of the femoral artery and implanted bypass grafts are common in patients with symptomatic peripheral artery disease (PAD). It is estimated more than 200 million people worldwide are affected by PAD [1]. 12–20% of people over the age of 60 develop PAD with many developing critical limb ischemia (CLI), which is associated with a poor quality of life and a high risk of amputation and death [2]. The early stage of the pathology is usually treated with pharmacological administration, whilst more acute forms of PAD are treated with surgical intervention, via insertion of hydrophilic wires to dissect through the intima or the media layers of the artery [4, 5]. In the most severe cases of CLI, patients are not suitable for surgical revascularization due to multiple occlusions and lack of autologous vessel replacement [8]
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