Ultrasound-guided percutaneous delivery of tissue-engineered endothelial cells to the adventitia of stented arteries controls the response to vascular injury in a porcine model

ObjectiveHigh restenosis rates are a limitation of peripheral vascular interventions. Previous studies have shown that surgical implantation of a tissue-engineered endothelium onto the adventitia surface of injured vessels regulates vascular repair. In the present study, we developed a particulate formulation of tissue-engineered endothelium and a method to deliver the formulation perivascular to injured blood vessels using a percutaneous, minimally invasive technique.MethodsStainless steel stents were implanted in 18 balloon-injured femoral arteries of nine domestic swine, followed by ultrasound-guided percutaneous perivascular injection of gelatin particles containing cultured allogeneic porcine aortic endothelial cells (PAE). Controls received injections of empty particles (matrix) or no perivascular injection (sham) after stent deployment. Animals were sacrificed after 90 days.ResultsAngiographic analysis revealed a significantly greater lumen diameter in the stented segments of arteries treated with PAE/matrix (4.72 ± 0.12 mm) compared with matrix (4.01 ± 0.20 mm) or sham (4.03 ± 0.16 mm) controls (P < .05). Similarly, histologic analysis revealed that PAE/matrix-treated arteries had the greatest lumen area (20.4 ± 0.7 mm2; P < .05) compared with controls (16.1 ± 0.9 mm2 and 17.1 ± 1.0 mm2 for sham and matrix controls, respectively) and the smallest intimal area (3.3 ± 0.4 mm2; P < .05) compared with controls (6.2 ± 0.5 mm2 and 4.4 ± 0.5 mm2 for sham and matrix controls, respectively). Overall, PAE-treated arteries had a 33% to 50% decrease in percent occlusion (P < .05) compared with controls. Histopathological analysis revealed fewer leukocytes present in the intima in the PAE/matrix group compared with control groups, suggesting that the biological effects were in part due to inhibition of the inflammatory phase of the vascular response to injury.ConclusionsMinimally invasive, perivascular delivery of PAE/matrix to stented arteries was performed safely using ultrasound-guided percutaneous injections and significantly decreased stenosis. Application at the time of or subsequent to peripheral interventions may decrease clinical restenosis rates.

Clinical RelevanceEndovascular interventions performed in the peripheral circulation are limited by restenosis. Thrombosis, inflammation, smooth muscle cell proliferation, and negative remodeling result in significant obstruction to the blood vessel lumen. While some trials have shown the beneficial effects of drug-eluting stents, data from large, randomized controlled clinical trials of peripheral arterial disease are lacking. In a large animal model of peripheral arterial stenting, we demonstrated that perivascular, ultrasound-guided injections of matrix-embedded endothelial cells significantly increased lumen diameter and decreased stenosis at 90 days. Development of techniques to deliver viable, functional cells is essential to realize the potential therapeutic impact of cell transplantation and expands the opportunity for the clinical application of cell-based therapy subsequent to endovascular interventions for peripheral arterial disease.