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.

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(2); P < .05) compared with controls (16.1 ± 0.9 mm(2) and 17.1 ± 1.0 mm(2) for sham and matrix controls, respectively) and the smallest intimal area (3.3 ± 0.4 mm(2); P < .05) compared with controls (6.2 ± 0.5 mm(2) and 4.4 ± 0.5 mm(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.

Delivery site of perivascular endothelial cell matrices determines control of stenosis in a porcine femoral stent model.

PURPOSE: Endothelial cells, grown within gelatin matrices and implanted onto the adventitia of injured vessels, inhibit stenosis in experimental models. To determine if this technology could be adapted for minimally invasive procedures, the authors compared the effects of cells in an implantable sponge to that of an injectable formulation and investigated the importance of delivery site in a stent model. MATERIALS AND METHODS: Stents were implanted in the femoral arteries of 30 pigs. This was followed by perivascular implantation of sponges or injection of particles containing allogeneic endothelial cells. Controls received acellular matrices or nothing. The effects of delivery site were assessed by injecting cellular matrices into or adjacent to the perivascular tissue or into the neighboring muscle. Animals were sacrificed after 28 days. Pre-sacrifice angiograms and tissue sections were evaluated for stenosis. RESULTS: Arteries treated with cellular matrices had a 55%-63% decrease in angiographic stenosis (P < .05) and a 38%-43% reduction in histologic stenoses (P < .05) compared to controls. Intimal area was greatest when cellular matrices were delivered into the muscle (6.35 mm(2) +/- 0.95) rather than into or adjacent to the perivascular tissue (4.05 mm(2) +/- 0.56 and 4.73 mm(2) +/- 0.53, respectively; P < .05). CONCLUSIONS: Perivascular endothelial cell matrices reduced stenosis after stent-induced injury. The effects were not dependent on the formulation but appeared to be dependent on delivery site. Minimally invasive injections of endothelial cell matrices to the adventitia of arteries following peripheral interventions may decrease restenosis rates.