Fibrin glue containing fibroblast growth factor type 1 and heparin with autologous endothelial cells reduces intimal hyperplasia in a canine carotid artery balloon injury model.
OBJECTIVE
Intimal hyperplasia plagues all types of vascular intervention. Early confluent re-endothelialization may attenuate the smooth muscle cell (SMC) proliferative response. We previously reported that fibroblast growth factor type 1 (FGF-1) and heparin at relative concentrations of 10 ng/ml:250 U/ml delivered in a fibrin glue (FG) suspension can selectively stimulate endothelial cells (EC) and inhibit SMC proliferation in cell culture. This current study evaluates this surface treatment with and without seeded autologous ECs on intimal hyperplasia in a canine carotid artery balloon injury model.


METHODS
Twenty-nine adult dogs underwent bilateral balloon injury to a 6 cm segment of their carotid arteries. The injury resulted in a reproducible removal of the intima and 4 to 6 medial lamellae. Nine dogs were used in part I to determine the percent retention of FGF-1 and EC when applied in a FG suspension to the balloon-injured carotid arteries. Part 2 used the remaining 20 dogs to determine the effect of this surface treatment on intimal hyperplasia. In 10 group I dogs, FG (fibrinogen 32.1 mg/ml and thrombin 0.32 U/ml) containing FGF-1 (11 ng/ml) and heparin (250 U/ml) was applied to the luminal surface of one carotid artery, whereas the contralateral carotid artery underwent balloon injury alone. In 10 group II dogs, an identical FG preparation with FGF-1 and heparin was applied to the surface of one carotid artery, whereas the contralateral carotid artery received FG/FGF-1/heparin that also contained autologous ECs (P3; 5 x 10(4) to 10 x 10(4) cells/cm2). Five dogs from both group I and group II were killed at 10 days and the remaining 10 dogs at 30 days. Histologic analysis and computerized morphometric analysis were used to determine intimal and medial thickness and area, percent endothelialization, and medial SMC proliferative rate.


RESULTS
There was no measurable neointima in any 10-day dog. There was no difference in neointimal area between the treatments in group I 30-day dogs. There was a significant decrease in maximal neointimal area, intima/media thickness ratio, and intima/media area ratio in group II 30-day dogs that were treated with FG/FGF-1/heparin plus EC. There was an insignificant increase in percent EC coverage and an insignificant decrease in medial SMC proliferative rate in group II 10-day dogs treated with FG/FGF-1/heparin plus EC.


CONCLUSIONS
In this canine carotid model, FG with FGF-1 and heparin did not induce significant intimal or medial thickening after 10 or 30 days when compared with vessels that were only balloon-injured. The seeding of autologous ECs within the FG/FGF-1/heparin suspension caused a reduction in neointima formation with no concomitant medial thickening 30 days after injury. The use of FG to locally deliver FGF-1 and ECs may have clinical relevance in the inhibition of intimal hyperplasia.
Zarge
J I
JI
Department of Surgery, Loyola University Medical Center, Maywood, Ill 60153, USA.
Huang
P
P
Husak
V
V
Kim
D U
DU
Haudenschild
C C
CC
Nord
R M
RM
Greisler
H P
HP
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology; D020212:Carotid Artery Injuries; D002404:Catheterization / Q000009:adverse effects* / Q000295:instrumentation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000166:cytology* / Q000637:transplantation; D015718:Fibrin Tissue Adhesive / Q000627:therapeutic use*; D016220:Fibroblast Growth Factor 1 / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use*; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D004338:Drug Combinations; D015718:Fibrin Tissue Adhesive; D016220:Fibroblast Growth Factor 1; D006493:Heparin