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

Abstract

Objective High 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. Methods Stainless 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. Results Angiographic 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 mm[superscript 2]; P < .05) compared with controls (16.1 ± 0.9 mm[superscript 2] and 17.1 ± 1.0 mm[superscript 2] for sham and matrix controls, respectively) and the smallest intimal area (3.3 ± 0.4 mm[superscript 2]; P < .05) compared with controls (6.2 ± 0.5 mm[superscript 2] and 4.4 ± 0.5 mm[superscript 2] 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. Conclusions Minimally 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.