Dartmouth unDergraDuate Journal of Science14

Bioabsorbable Coronary Stents

Julie ShAbto ‘14

engineering

Heart disease is the leading cause of death in the United States. One of the most com-

mon medical interventions performed today is the percutaneous coronary in-tervention (PCI), which opens clogged or damaged coronary arteries (1). Since its development in 1977, PCI has been a widely used alternative to coronary artery bypass grafting (CABG), and it relieves patients of coronary arte-rial blockage 90-95% of the time (2, 3).

One form of PCI, balloon angio-plasty, improves necessary blood-flow by inserting a balloon into the affected artery and inflating it in order to com-press any plaque present and prop open the artery. A more permanent form of PCI is coronary stenting. Stent-ing involves placing a tiny tube-like metal structure. Stenting can be em-ployed following angioplasty in order to prevent restenosis, the re-narrowing of an artery, or stenting can be per-formed in one step, in which the artery is opened and the stent is implanted (4, 5). Coronary stents have nearly elimi-nated the problem of abrupt occlusion (where the vessel closes), which oc-currs in 5% of patients when just bal-loon angioplasty is performed. Coro-nary stents have reduced the incidence of restenosis by more than 50% (3).

The development of drug-eluting stents (DES) has further enhanced post-operative experiences. DESs are coated in polymeric material that re-leases drugs locally. These polymers completely degrade by the time the drug has been released, but the metal-lic stent remains (6). DES’s are used to prevent restenosis that may oc-cur after PCI (7). In fact, with DES, the restenosis rate is under 10% (3).

The permanence of metallic stents is not necessarily ideal, however. Cur-rent metallic stents can induce late thrombosis and thickening of the inner lining of the artery as a response to ar-terial wall injury. The long-term effects of metallic stents in human coronary arteries are still unknown (1). Perma-

nent stents may interfere with normal vessel functions and stents implanted in children must be designed to last literally a lifetime (9). Furthermore, metallic stents that remain in coronary arteries can present difficulties in later treatment. For example, metallic stents can hinder assessments of coronary arteries through computer tomogra-phy (CT) and magnetic resonance im-aging (MRI), as well as block impor-tant side branches of the artery (1,8).

The Ideal Stentthe significant complications in-

volved with metallic and polymer-coat-ed stents call for further development in the treatment of clogged or damaged coronary arteries. An ideal stent would do its job and then disappear. Further-more, the ideal stent would be made of biocompatible material to prevent ves-sel irritation and would have adequate radial force to prevent collapsing as a

result of any injury responses that oc-cur following implantation (8). With the stent gone after it does its job, late thrombosis is unlikely to occur and the stent would not interfere with CT or MRI evaluations (6, 11). A bioabsorb-able or biodegradeable stent satisfies all the requirements for an ideal stent.

in addition to the clinical benefits of bioabsorbable stents, these stents may prove to be the patient-preferred option. Patients have expressed that they would rather have an effective temporary implant as opposed to a permanent prosthesis that may require surgical removal (7). Moreover, a dis-appearing stent would promote the restoration of the previously clogged or damaged artery to a “healthy artery,” one that can endure the pressures of a normal artery (11). A more specu-lative hypothesis about bioabsorb-able stents is that they can be used to prevent further build up of plaque in arteries; instead of waiting for neces-sary PCI, a bioabsorbable stent could be implanted in the patient so that, by the time the stent fully degrades, the plaque would have regressed (11).

Thus, bioabsorbable stents seem to be a viable alternative to perma-nent coronary stents, but a thor-ough analysis of different stent mod-els and clinical studies is necessary.

Different Bioabsorbable Stent Models: The Key Players

The development of bioabsorbable stents has become a hot topic in the medical device industry (10). Models of bioabsorbable stents that are current-ly being developed are made of either

polymers or corrodible metal alloys.

Polymeric StentsThere are several polymeric bio-

absorbable stents that have been test-

Image courtesy of the Centers for Disease Control and Prevention.

Chest X-ray of individual with congestive heart failure.

15Winter 2011

ed. The Igaki-Tamai coronary stent and the bioabsorbable everolimus-eluting coronary stent (BVS) both use Poly-l-lactic acid (PLLA). Other bioabsorb-able polymeric stents include ones developed by Bioabsorbable Thera-peutics and the REVA Medical stent.

Igaki-TamaiThe Igaki-Tamai stent was the

first bioabsorbable stent to be im-planted in humans. According to the initial 6-month results of the Igaki and Tamai, 15 patients electively un-derwent the stent implantation; 25 stents were successfully implanted in 19 sites in the 15 patients. Their stent is made of PLLA, has a thickness of 0.17 mm, has a zigzag helical coil pat-tern, and is balloon-expandable (1).

The study proved PLLA to be safe in human coronary arteries. In the study, no stent thrombosis and no ma-jor cardiac event occurred within the first 6 months, meaning that there were no deaths, heart attacks, or coronary ar-tery bypass surgeries. Full degradation took 18-24 months. Furthermore, at about 36 months, lumen size increased (12). While they had limited patients, the team viewed their initial 6-month results as promising. However, the Ig-aki-Tamai stent lacked a drug coating, and since focus turned to bioabsorbable stents coated with drugs, the develop-ment of the Igaki-Tamai stent halted.

BVS stentthe BVS everolimus-eluting bio-

absorbable PllA stent is the first bio-absorbable stent to have clinical and imaging outcomes similar to those following metallic DES implantation. the BVS stent has a polymer coat-ing that contains and controls the re-lease of the drug everolimus, which stops cells from reproducing by de-creasing blood supply to the cells. (7)

the BVS stent was tested by Ab-bott in the ABSORB trial, an open-label study in which 30 patients received stent implants. In the study, 80% of the drug was released by the 30-day follow-up and the drug constrained any exces-sive healing response (7). The stent had a thickness of 150 μm (13). Blood vessel lumen diameter decreased and there were higher-than-expected restenosis rates. These initial results led to specu-

lation that the absorption of the stent may have occurred too quickly (11).

After one year follow up, however, there was no stent thrombosis and only one patient experienced a heart attack (13). Full absorption of the stent took a relatively slow 18 months (8). One remarkable finding of the ABSORB trial was that, between 6 months and 2 years, there was an enlargement in lu-men size (7). The increase in lumen size was due to a decrease in plaque size without a change in vessel size (14). This enlargement suggested that after stent absorption, a vessel could poten-tially become a healthy vessel again. the Abbott BVS stent is currently the bioabsorbable stent furthest along in clinical development and may in fact be cleared for sale in Europe (10).

Bioabsorbable therapeuticsThe polymeric stent developed

by Bioabsorbable Therapeutics (BTI) is coated with sirolimus, a drug that suppresses the body’s immune system. Both the base polymer and coating poly-mer of the stent are made up of bonds between salicylic acid molecules. These bonds are hydrolyzed during absorp-tion, resulting in the release of salicylic acid, an anti-inflammatory drug that could potentially prevent restenosis.

The BTI stent has a thickness of 200 μm and is balloon-expandable. In the first human clinical trial, WHiSPER, the stent was implanted in 40 patients. While full absorption was expected within 6 to 12 months, significant thickening of the inner lining of the ar-tery occurred. Thus, subsequent devel-opment of the BTI stent is necessary.

REVA medical the REVA Endovascular Study of

a Bioresorbable Coronary Stent (RE-SORB) is coated with paclitaxel, a drug that inhibits cell division (11). The stent is balloon-expandable and is set into place by sliding and locking parts rath-er than deforming the material, which gives the stent more radial strength (8). The stent has a thickness of 150 μm (15).

The RESORB trial, which began in 2007, enrolled 27 patients. At the 30-day follow-up, two patients expe-rienced a heart attack and one needed another PCI (7). In 2008, between 4 and 6 months after implantation, there was higher-than-anticipated occur-rence of repeated PCI, driven mainly by reduced stent diameter (7). Thus, the REVA Medical model is not flawless.

Image retrieved from http://archiv.ethlife.ethz.ch/images/magnesiumstent-l.jpg (Accessed 29 Jan 2011).

Magnesium stents have potential advantages over polymeric stents in terms of higher radial strength.

Dartmouth unDergraDuate Journal of Science16

Metal alloy stentsMetal alloy bioabsorbable

stents perform similarly to perma-nent metallic stents. So far, two bio-absorbable metal alloys have been proposed for this application: iron and magnesium. However, neither of these stents is coated with drugs.

Bioabsorbable magnesium stent

Magnesium stents have potential advantages over polymeric stents in terms of higher radial strength due to their metallic nature and biocompat-ibility as a naturally occurring element in the body (8). the first metallic bio-absorbable stent implanted in humans was studied in the PROGRESS-AMS trial with 63 patients (8). This stent has a thickness of 165 μm and is balloon-expandable (7). In trial, absorption of a magnesium stent in humans was rapid and mechanical support lasted days or weeks, which is too short to prevent restenosis (6-7, 11). during the first four months, major adverse cardiac events were recorded in 15 of the patients (24%) and additional PCIs were needed after initial implantations (8). After one year, 45% of the patients had additional PCI. The magnesium stent can be safe-ly degraded within 4 months, but the high restenosis rate raises concerns (7).

Bioabsorbable iron stentIron is an essential component

of a variety of enzymes, making iron-based alloys favorable material for bioabsorbable stents. M. Peuster, et al. performed experimental studies with bioabsorbable iron stents. The experi-mental iron stent has a thickness of 100–120 μm and is balloon-inflatable. The researchers implanted stents made of 41 mg of pure iron, an amount equivalent to the monthly oral intake of iron for a human, into the descending aortas of New Zealand white rabbits. During the 6 to 18 months of follow-up, there was no reported thrombosis or any other significant inflammatory injury response. However, the animals experienced destruction of the inter-nal elastic membrane of arteries and products from the degradation of the stent accumulated, resulting in signifi-

cant alteration of the artery wall (9).

ConclusionWhile studies of bioabsorbable

stents have proven effective, small trial sizes and too many controlled variables leave many unconvinced. Currently, there are no bioabsorbable stents commercially available. The developed bioabsorbable stents are unlikely to make their way into ran-domized patients (11). The stents are much larger and bulkier than current permanent stents (10). This difference in size could pose a problem with jag-ged, calcified plaque protruding into the lumen, which many patients have. The calcium might catch on the device, preventing its proper functioning (11).

Polymeric biodegradable stents have demonstrated several limitations and long-term effects of polymer full-absorption products are unclear (6, 16). The polymer that both the Igaki-tamai and BVS stents use, PllA, holds 1,000 mmHg of crush pressure and maintains radial strength for approxi-mately one month. Compared with metallic stents, this radial strength is lower and may result in early recoil post-implantation (8). Meanwhile, metal alloys stents do not seem bio-compatible enough to use in practice.

While bioabsorbable stents may potentially be the ideal stent, further clinical studies and developments are necessary. The right balance between absorption and radial strength must be obtained, and inflammation must be prevented at the same time. Once this balance is found, though, biodegradable stents may have far-reaching implica-tions for the treatment and/or preven-tion of blocked and damaged arteries.

References

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do-coronary-stents-work-2010-02-12 (14 November 2010).6. R. Waksman, Biodegradable Stents: They Do Their Job and Disappear: Why Bioabsorbable Stents?, Journal of American Cardiology 18, 70-74 (2006).7. J. A. Ormiston, P. W. Serruys, Bioabsorbable Coronary Stents, Circulation Cardiovascular Intervention 2, 255-260 (2009).8. R. Bonan, A. Asgar, Biodegradable Stents—Where Are We in 2009?, US Cardiology 6, 81-84 (2009).9. M. Peuster, et al., A novel approach to temporary stenting: degradable cardiovascular stents produced from corrodible metal—results 6-18 months after implantation into New Zealand white rabbits, Heart 86, 563-569 (2001).10. B. Glenn, Cleveland Clinic spinoff raises $8.5M for biodegradable stents, (22 September 2010). Available at http://www.medcitynews.com/2010/09/cleveland-clinic-spinoff-raises-8-5m-for-biodegradable-stents/ (14 November 2010).11. M. O’Riordan, Now you see me, now you don’t: The bioabsorbable stent in clinical practice, (8 November 2010) Available at http://www.theheart.org/article/1144463.do (14 Nov. 2010).12. Editorial Staff, Biodegradable stents could be the ideal stent, (10 March 2009). Available at http://www.cardiovascularbusiness.com/index.php?option=com_articles&view=article&id=16567:biodegradable-stents-could-be-the-ideal-stent (15 November 2010).13. J.A. Ormiston, et al., A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial, The Lancet 371, 899-907 (2008).14. P. W. Serruys, et al., A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods, The Lancet 373, 897-910 (2009).15. X. Ma et al., Drug-eluting stents, International Journal of Clinical and Experimental Medicine 3, 192-201 (2010). 16. J. Kahn, Bioabsorbable Stents, Journal of Interventional Cardiology 20, 564–565 (2007).