Prohealing coatings: a revolution in medical device surface modification: the local delivery of anti-proliferative compounds from drug eluting stents [DES] has successfully reduced rates of restenosis following stent implantation. However, somewhat higher rates of late stent thrombosis are perceived for DES compared to their bare metal counterparts. This article looks at a promising approach to address this issue.
While implanted medical devices have improved the lives of countless patients, they are nonetheless foreign materials to the human body. As such, they are prone to adverse biological reactions including infection, thrombosis, inflammation, cellular hypertrophy, and fibrosis. The body's response to implanted medical devices comprises a series of events, beginning with acute inflammatory response, followed by chronic inflammatory response, granulation tissue development, and foreign body reaction to implanted biomaterials. (1) The intensity and time course of each depends upon factors such as the extent of injury, and the size, shape, topography, and chemical and physical properties of the implanted biomaterials. The outcome is often the encapsulation of the device in collagenous, avascular, fibrous tissue. Integration of the device with healthy, vascularized, natural tissue has been an elusive goal for both academics and medical device manufacturers.
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An extracellular matrix (ECM) surrounds and supports mammalian epithelial and connective tissue cells. ECM proteins, such as Collagen I and Laminin 1, greatly influence cell physiology. When properly immobilized, these proteins can promote migration of endothelial cells across and into a device surface resulting in a healthy, functioning mature endothelial cell monolayer. Endothelial cells that line blood vessels are important regulators of both thrombosis and inflammation and ensure blood and vessel homeostasis. They greatly influence other cellular activity as well. Materials that heal with vascularized tissues and a healthy endothelial layer may not only provide the means to decrease adverse events associated with current devices such as coronary and peripheral stents, structural heart devices, peripheral vascular grafts, and cardiac patches, but also enable other devices that have thus far proven unsuccessful clinically, such as small diameter coronary grafts.
Drug-eluting stents and vascular grafts represent typical medical device applications complicated by delayed or incomplete endothelialization. While drug-eluting stents (DES) reduce the incidence of coronary artery restenosis compared with bare metal stents (BMS), recent controversy has lessened the use of DES. Finn et al. report that DES impair arterial healing characterized by incomplete reendothelialization and persistence of fibrin leading to late stent thrombosis. (2) Could an ECM protein coating promote the formation of a healthy endothelium on a DES rendering it resistant to late stent thrombosis?
To answer this question, a commercial coronary cobalt chromium BMS platform was first coated with a paclitaxel-eluting matrix. Several Finale ECM protein coating variants were then immobilized to both the BMS and the DES. Coatings applied in this manner effectively mediated human microvascular endothelial cell (HMVEC) adhesion in vitro and proved durable in a simulated stent delivery model (data not shown).
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To determine the effect of the ECM coatings upon stent healing, a double-injury rabbit iliac artery model predictive of human coronary artery healing was selected. (3) Briefly, the vessels of healthy New Zealand White rabbits were first denuded of endothelium prior to stenting by balloon inflation injury without damaging the internal elastic lamina. Stents were randomly implanted in the right and left iliac arteries (one stent per iliac), then retrieved 7 and 14 days later. Retrieved stents were filleted open and examined en face using bisbenzimide (BBI) nuclear stain and scanning electron microscopy (SEM) to evaluate endothelial coverage.
As shown in Figure 1, seven days after implant, cell coverage was significantly greater on laminin-1 modified DES (DES LM 1) than DES. Note the absence of cells on the DES (left), compared with the layer of endothelial cells on the stent with the ECM coating (right). Also note the high concentration of cells that did not populate the DES but instead stopped at the edge of the stent strut. The increased cell coverage on DES LM 1 compared with DES persisted at 14-days (data not shown). Cell-free areas on the DES are also evident in the SEM micrographs in Figure 2. Rapid healing of DES may help prevent late stent thrombosis, thus lessening or eliminating the need for continued systemic anticoagulation. In addition, a healthy, functioning endothelium might itself lessen the amount of antiproliferative drug required to achieve a given rate of restenosis.
ECM protein modification may also enhance current BMS technology by modulating neointimal formation. Cell coverage on uncoated BMS increased from 7 to 14 days (data not shown), trending towards cell densities slightly greater than that of native vessels. This could be indicative of cellular hypertrophy leading to vessel restenosis. Conversely, cell coverage on Finale-coated BMS approached that of a monolayer after 14-days, suggesting healing without cellular hyperplasia. This implies that an ECM-coated BMS might heal without cellular hypertrophy and restenosis due to the homeostatic effect of the endothelial layer.
Vascular grafts perform adequately in large diameters where cellular hypertrophy and resulting lumenal loss do not significantly impede blood flow. However, grafts in humans typically endothelialize only at the ends, leaving the mid-graft susceptible to both thrombosis and infection. When implanted subcutaneously in rats, a prohealing coating improved both angiogenic response (blood vessels in the tissue adjacent to the implant) and neovascularization (blood vessels penetrating the fabric porosity) of e-PTFE fabric relative to controls (Figure 3), as well as greatly enhanced tissue integration into the fabric. This result suggests that ECM prohealing coatings may not only improve the healing of large diameter grafts, but also enable small diameter grafts.
Tissue healing of multiple non-vascular applications may be improved with ECM prohealing coatings. While particular ECM coatings may perform differently in vascular and non-vascular systems, ECM proteins in general affect cells throughout the body and might therefore improve the function of most implanted devices.
For additional information on the products and technologies discussed in this article, see Medical Design Technology online at www.mdtmag.com or SurModics at www.surmodics.com.
(1) Anderson JM "Inflammation, Wound Healing, and the Foreign-Body Response" Biomaterials Science: An Introduction to Materials in Medicine 2nd Ed. Buddy D. Ramer, Allan S. Hoffman, Frederick J. Schoen, Jack E. Lemons, Eds. Elsevier Academic Press, 2004, 296-303.
(2) Finn, Aloke V; et al. "Vascular Responses to Drug Eluting Stents. Importance of Delayed Healing," Arteriosclerosis, Thrombosis, and Vascular Biology. 2007; 27:1500.
(3) Farb, Andrew; et al. "Pathological Analysis of Local Delivery of Paclitaxel Via a Polymer-Coated Stent," Circulation, 2001; 104:473.
Dr. Joseph A. Chinn is a technical advisor for the SurModics Regenerative Technologies business. He is responsible for providing cardiovascular technical expertise to SurModics' customers. Dr. Chinn can be reached at (952) 947-8640 or firstname.lastname@example.org.
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|Title Annotation:||Emphasis On Surface Treatment|
|Author:||Chinn, Joseph A.|
|Publication:||Medical Design Technology|
|Date:||Nov 1, 2007|
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