TIME-COURSE OF SMOOTH-MUSCLE CELL-PROLIFERATION AFTER LOCAL-DRUG DELIVERY OF LOW-MOLECULAR-WEIGHT HEPARIN USING A POROUS BALLOON CATHETER

It has been reported previously that systemic application of low molec ular weight heparin (LMWH) suppresses smooth muscle cell (SMC) prolife ration after balloon angioplasty in experimental studies. However, the high concentration of heparin required for a beneficial effect may ca use severe bleeding complications. The ideal situation to overcome the systemic side effects would be to administer LMWH locally and deep in to the arterial wall, which became possible by the development of poro us balloon catheters. The in vivo feasibility of local delivery of LMW H using the porous balloon has been assessed by delivering tritium-mar ked LMWH into rabbit carotid arteries. The efficacy of the system was investigated by using a second injury animal model, After development of an intimal plaque by electrical stimulation, 61 rabbits were treate d with the porous balloon after balloon angioplasty. In 23 rabbits, lo cal drug delivery was accomplished with a porous balloon catheter (35 holes, hole diameter 75 mu m, 2.5 mm catheter diameter). LMWH was loca lly administered with 4 mi (solution 375 anti-Xa-units/ml) and 2 atm. To study the extent of restenosis and morphological changes, these ani mals were killed 3, 7, 14, 28, or 56 d after intervention. After stain ing (hematoxylin, van Gieson, BrdU, RAM 11, alpha-actin) procedures to quantify SMC proliferation, intimal macrophages and morphological ana lysis were performed. Porous balloon treatment led to an increase in i ntimal SMC proliferation rate in the early stage after intervention. H owever, during the following time period, a significant decrease of th e proliferation rate as compared with the animals treated with balloon angioplasty alone could be observed, which resulted in an only modera te increase of the intimal layer after local drug delivery compared wi th balloon angioplasty alone. (C) 1997 Wiley-Liss, Inc.