© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003

15.5.3.2 Vascular Response to Stenting

Mechanical biocompatibility must also be demonstrated by intravascular nanorobots that are intended to remain in long-term contact with blood vessel walls. A good medical analog is the vascular stent. A stent is a flexible metal coil or open-mesh tube that is surgically inserted into a narrowed artery, then expanded and pressed into the vascular wall at up to 10-20 atm pressure. The stent ensures long-term local vascular patency by providing a scaffold to hold the artery open. Within 4 days, SMC begin to appear in the intima [3868]. After a few months the stent is completely encased in new endothelium, forming a neointima, although the media is usually compressed with smooth muscle cell atrophy in all stented regions. Stenosis is prevented in vessels 10 mm or greater in diameter but is not precluded in vessels smaller than 6 mm [3869]. Histologically, in-stent restenosis appears to derive almost exclusively from neointimal hyperplasia [3870, 3871]. Hyperplasia appears more abundant following stent implantation than balloon angioplasty, and more abundant in stents of greater stent length and smaller vessel caliber, or after inadequate stent expansion [3872]. Restenosis occurs in 22-46% of all stents emplaced within 6-12 months [3873]), in some cases requiring the insertion of a second stent into the first [3874]. Restenosis varies according to the material used. In one experiment [1372], the thickness of the neointimal layer formed over wire-mesh stents placed in canine aortas was 83.9 microns thick for gold, 103.6 microns for stainless steel, 115 microns for Teflon, 209.6 microns for silicone, and 228.6 microns for silver. A copper stent produced severe erosion of the vessel wall, marked thrombus formation, and aortic rupture [1372].

Improved prospects are reported for diamond-coated stents (Section 15.3.1.3), and stent surface coatings and textures can affect platelet-leukocyte aggregation and platelet activation [3875]. But all these devices are far from ideally mechanocompatible with blood vessel walls. For example, stents placed endovascularly in dog aorta for 4-45 weeks and then examined histologically show medial atrophy, intimal hyperplasia (tissue ingrowth), and proliferation of the vasa vasorum (the microvasculature of the aorta) more prominently for covered stents than for bare stents, probably due to hypoxia in the aortic wall [3876]. Cellular proliferation is highest when the artery wall is most hypoxic [3877]. Medical nanorobot aggregates that entirely cover the vascular endothelium can precisely regulate wall oxygenation by controlled oxygenation of the underlying tissue, using oxygen sourced directly from the blood.

Nanorobotic stents also should be able to inhibit stenosis due to vascular smooth muscle proliferation, migration, and neointima formation, without inducing apoptosis – e.g., possibly by releasing the topoisomerase I SMC-proliferation inhibitor topotecan in a localized 20-min exposure [3878], or by using other similar drugs [4913]. In 2002, a new generation of vascular stents employing a similar strategy was introduced in the U.S. after previous testing in Europe. These new stents were impregnated with antibiotics such as Rapamune (sirolimus or rapamycin) [4892-4897] or other stent-eluting agents such as paclitaxel (an antimitotic drug that inhibits vascular smooth muscle proliferation in vitro) [4897-4902], docetaxel (a microtubule polymerizing agent with antiproliferative properties) [4903] or taxane [4904] in some cases virtually eliminating restenosis. The protection against restenosis persists even after the stent eluate is exhausted. Other impregnating agents such as human recombinant hepatocyte growth factor (a potent endothelial cell mitogen) [4906] can attenuate neointimal proliferation via quick endothelialization, and thus might also be useful in stents to prevent restenosis. Beta-particle radiation-emitting stents [4907-4911] can reduce luminal restenosis but induce restenosis at the edges (the “candy wrapper” effect [4897]) and have other undesirable long-term complications [4912].

Arterial stents can also trigger thrombosis by inducing platelet activation due to shear forces, contact to the biomaterial, and release of metal ions. These triggers are all significantly lessened in diamond-coated (DLC) stents, reducing thrombogenicity and neointimal hyperplasia [4723, 4725]. Drug-coated stents (e.g., dexamethasone [4905, 4913]) can reduce or eliminate inflammation as well.

Last updated on 30 April 2004