A rapamycin-releasing perivascular polymeric sheath produces highly effective inhibition of intimal hyperplasia.
Intimal hyperplasia produces restenosis (re-narrowing) of the vessel lumen following vascular intervention. Drugs that inhibit intimal hyperplasia have been developed, however there is currently no clinical method of perivascular drug-delivery to prevent restenosis following open surgical procedures. Here we report a poly(ε-caprolactone) (PCL) sheath that is highly effective in preventing intimal hyperplasia through perivascular delivery of rapamycin. We first screened a series of bioresorbable polymers, i.e., poly(lactide-co-glycolide) (PLGA), poly(lactic acid) (PLLA), PCL, and their blends, to identify desired release kinetics and sheath physical properties. Both PLGA and PLLA sheaths produced minimal (<30%) rapamycin release within 50days in PBS buffer. In contrast, PCL sheaths exhibited more rapid and near-linear release kinetics, as well as durable integrity (>90days) as evidenced in both scanning electron microscopy and subcutaneous embedding experiments. Moreover, a PCL sheath deployed around balloon-injured rat carotid arteries was associated with a minimum rate of thrombosis compared to PLGA and PLLA. Morphometric analysis and immunohistochemistry revealed that rapamycin-loaded perivascular PCL sheaths produced pronounced (85%) inhibition of intimal hyperplasia (0.15±0.05 vs 1.01±0.16), without impairment of the luminal endothelium, the vessel's anti-thrombotic layer. Our data collectively show that a rapamycin-loaded PCL delivery system produces substantial mitigation of neointima, likely due to its favorable physical properties leading to a stable yet flexible perivascular sheath and steady and prolonged release kinetics. Thus, a PCL sheath may provide useful scaffolding for devising effective perivascular drug delivery particularly suited for preventing restenosis following open vascular surgery.
Department of Biomedical Engineering, University of Wisconsin, 5009 Wisconsin Institute of Medical Research, 1111 Highland Ave, Madison, WI, 53705, USA.
Xiaohua
X
Yu
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute of Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Toshio
T
Takayama
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute of Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Shakti A
SA
Goel
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute of Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Xudong
X
Shi
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute of Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Yifan
Y
Zhou
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute of Medical Research, 1111 Highland Ave, Madison, WI 53705, USA; Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, USA.
K Craig
KC
Kent
Department of Biomedical Engineering, University of Wisconsin, 5009 Wisconsin Institute of Medical Research, 1111 Highland Ave, Madison, WI, 53705, USA. Electronic address: wlmurphy@wisc.edu.
William L
WL
Murphy
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute of Medical Research, 1111 Highland Ave, Madison, WI 53705, USA. Electronic address: guo@surgery.wisc.edu.
Lian-Wang
LW
Guo
D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000737:chemistry; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000473:pathology; D016893:Carotid Stenosis / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004337:Drug Carriers; D006965:Hyperplasia; D007700:Kinetics; D016014:Linear Models; D008297:Male; D058426:Neointima; D011091:Polyesters / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage* / Q000737:chemistry; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods
D002317:Cardiovascular Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011091:Polyesters; C016240:polycaprolactone; D020123:Sirolimus
Intimal hyperplasia; Open vascular surgery; Perivascular drug delivery; Ploy(ε-caprolactone) (PCL) sheath; Rapamycin