Mechanisms of controlled drug release from drug-eluting stents

doi:10.1016/j.addr.2006.01.016

Advanced Drug Delivery Reviews

Volume 58, Issue 3, 3 June 2006, Pages 387-401

https://doi.org/10.1016/j.addr.2006.01.016 Get rights and content

Abstract

The clinical importance of drug-eluting stents (DESs) has been demonstrated by their unparalleled success in preventing restenosis after stenting procedures. The magnitude of success is historic despite their short history. The current DESs deliver a single drug aiming to prevent or minimize proliferation of smooth muscle cells. Since the restenosis process involves several different biological responses, the ability to deliver the right drugs at the right times is critical for further development of the second generation of DESs. As the type of drugs that can be delivered from DESs varies, it is imperative to understand the drug delivery mechanisms and the approaches available for drug coating on the stents. The drug delivery mechanisms of current DESs that have been used clinically and under clinical trials are explained.

Introduction

A stent is a small, expandable wire mesh in a tube form that is used to maintain an artery open after balloon angioplasty. Stent implantation, however, tends to cause injury to the blood vessel resulting in neointimal proliferation, known as in-stent restenosis, which continues to hamper initial procedural success in 10% to 50% of patients undergoing coronary intervention [1], [2], [3]. Recently, the concept of using coronary stents for localized delivery of antiproliferative drugs with programmed pharmacokinetics has emerged as an appealing solution to overcome the restenosis problem [4], [5], [6]. The aim of such localized drug delivery is to control, or reduce, smooth muscle cell growth and migration as well as to prevent inflammatory response, which are the predominant causes of neointimal proliferation and in-stent restenosis [7].

Localized drug delivery from drug-eluting stents (DESs) has been shown to be quite effective and accepted as one of the most promising treatment methods for preventing restenosis after stenting procedures. DESs ensure maximum delivery of the pharmacological agent directly to the target site, since they are in immediate contract with the coronary artery wall [8]. The DES approach has several advantages. Biologically active agents can be directly delivered to the target site, resulting in therapeutically effective drug concentrations in the surrounding tissues with the minimal systemic release of the drug and thus, negligible risk of systemic toxicity [9], [10].

Despite its relatively short history, DESs have already made seminal impacts in the interventional cardiology. While a few DESs are clinically available, many more DESs are expected to be developed in the near future. Currently, only two drugs, sirolimus and paclitaxel, are used in DESs approved by the Food and Drug Administration. There are many other drugs that are potentially useful for treating restenosis. Selection of a controlled drug delivery technology suitable for each drug depends on many factors, including physicochemical properties of the drug, duration of release and the release profiles. It is important to understand the currently available drug delivery technologies and how they can be applied to optimize the existing DESs and to develop new DESs. This article reviews the current DES formulations and their drug release kinetics, so that it can serve as a useful source of information for those who are involved in the DES area.

Section snippets

Drug delivery mechanisms

To appreciate the technologies associated with the current DESs and to develop new formulations, it would be beneficial to briefly review the drug delivery technologies. The controlled release technologies have been advanced during the last four decades. As a result, hundreds of commercial products have been developed based on the controlled drug delivery technologies. Despite such a large number of clinical products, there are only several distinct mechanisms for controlled drug release. Many

Drugs used in controlling restenosis

The drugs that are released from DESs are expected to inhibit inflammation and neiointimal formation after stent implantation. Since the inflammatory and proliferative responses are results of the complex cascade of events, various cells and tissue components involved in the vascular reparative process are all potential targets of therapeutic approaches [20]. For this reason, various drugs with widely different properties can be used for the same purpose of reducing neointimal proliferation [21]

Coating strategies for prevention of restenosis

Many different approaches have been used for drug delivery from stents, and the duration of drug delivery has been varied. It has been suggested that vascular smooth muscle cells start proliferation only a day after the injury resulting from balloon angioplasty/stent deployment for about 2 weeks [25]. Thus, it is believed that antirestenotic drugs need to be delivered for at least 3 weeks after stent deployment to prevent smooth muscle cell migration and proliferation [26], [27]. It is

Coating strategies for improving biocompatibility

In addition to prevention of restenosis, another important requirement of DESs is absence of inflammation and thrombogenicity [20], [21]. Selection of noninflammatory, nonthrombogenic coating materials has been a major obstacle in the development of DESs. This problem has been compounded by the possibility that delivery of unnecessarily high drug dose may result in delayed wound healing and endothelialization, which would increase thrombogenicity. The Cypher stent and the Taxus stent, the two

Some issues in the development of drug-eluting stents

Drug delivery from stents has become a very important research area that has shown immediate, huge benefits in clinical applications. The fact that there are a few DESs in clinical applications should not mask the importance and need of continued research on drug delivery from stents. There are still a few issues to be resolved in the development of DESs.

Summary

Despite the phenomenal advances in stent design, incidence of restenosis of bare metal stents remains unacceptably high. The interventional cardiology has been rapidly evolving and DESs have emerged as a breakthrough technology. The localized delivery of a drug directly to the target site resulted in prevention of restenosis without side effects associated with systemic delivery of the same drug at much higher concentrations. A number of different controlled drug delivery technologies can be

References (56)

R. Fattori et al.
Drug-eluting stents in vascular intervention
Lancet
(2003)
Q. Tan et al.
Constructing thromboresistant surface on biomedical stainless steel via layer-by-layer deposition anticoagulant
Biomaterials
(2003)
C. Boura et al.
Endothelial cells grown on thin polyelectrolyte mutlilayered films: an evaluation of a new versatile surface modification
Biomaterials
(2003)
C. Janicki et al.
Dose model for stent-based delivery of a radioactive compound for the treatment of restenosis in coronary arteries
Med. Phys.
(2003)
D.E. Drachman
Clinical experience with drug-eluting stents
Rev. Cardiovasc. Med.
(2002)
D.G. Rizik
T-stenting with drug-eluting stents for the treatment of bifurcation in-stent restenosis
J. Interv. Cardiol.
(2002)
S.H. Hofma et al.
Recent developments in coated stents
Curr. Interv. Cardiol. Rep.
(2001)
R.S. Schwartz
Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group
Circulation
(2002)
F. Liistro
First clinical experience with a paclitaxel derivate-eluting polymer stent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome
Circulation
(2002)
E.J. Smith et al.
Antiproliferative coatings for the treatment of coronary heart disease: what are the targets and which are the tools?
J. Interv. Cardiol.
(2003)

P. Serruys et al.

Handbook of Drug-Eluting Stents, Martin Dunitz pages

(2005)

F. Liistro et al.

Drug-eluting stents

Heart Drug

(2003)

D.R. Mcclean et al.

Stent design: implications for restenosis

Rev. Cardiovasc. Med.

(2002)

J.R. Robinson

Y.W. Chien

H.C. Ansel et al.

K. Park

W.M. Saltzman

Drug Delivery. Engineering Principles for Drug Therapy

(2001)

M.J. Rathbone et al.

G. Decher et al.

Multilayer Thin Films. Sequential Assembly of Nanocomposite Materials

(2003)

C.W. Hwang et al.

Physiological transport forces govern drug distribution for stent-based delivery

Circulation

(2001)

C.-W. Hwang et al.

Impact of transport and drug properties on the local pharmacology of drug-eluting stents

Int. J. Cardiovasc. Interv.

(2003)

E. Regar et al.

Stent development and local drug delivery

Br. Med. Bull.

(2001)

C.D.K. Rogers

Drug-eluting stents: role of stent design, delivery vehicle, and drug selection

Rev. Cardiovasc. Med.

(2002)

J.E. Sousa et al.

New frontier in cardiology. Drug eluting stents: Part II

Circulation

(2003)

X. Liu et al.

Dexamethasone-eluting stent: an anti-inflammatory approach to inhibit coronary restenosis

Exp. Rev. Cardiovasc. Ther.

(2004)

F.C. Tanner et al.

Expression of cyclin-dependent kinase inhibitors in vascular disease

Circ. Res.

(1998)

M.N. Babapulle et al.

Coated stents for the prevention of restenosis: Part II

Circulation

(2002)

Cited by (314)

Stimuli-responsive polysaccharide-based smart hydrogels for diabetic wound healing: Design aspects, preparation methods and regulatory perspectives
2024, Carbohydrate Polymers
Diabetes adversely affects wound-healing responses, leading to the development of chronic infected wounds. Such wound microenvironment is characterized by hyperglycaemia, hyperinflammation, hypoxia, variable pH, upregulation of matrix metalloproteinases, oxidative stress, and bacterial colonization. These pathological conditions pose challenges for the effective wound healing. Therefore, there is a paradigm shift in diabetic wound care management wherein abnormal pathological conditions of the wound microenvironment is used as a trigger for controlling the drug release or to improve properties of wound dressings. Hydrogels composed of natural polysaccharides showed tremendous potential as wound dressings as well as stimuli-responsive materials due to their unique properties such as biocompatibility, biodegradability, hydrophilicity, porosity, stimuli-responsiveness etc. Hence, polysaccharide-based hydrogels have emerged as advanced healthcare materials for diabetic wounds. In this review, we presented important aspects for the design of hydrogel-based wound dressings with an emphasis on biocompatibility, biodegradability, entrapment of therapeutic agents, moisturizing ability, swelling, and mechanical properties. Further, various crosslinking methods that enable desirable properties and stimuli responsiveness to the hydrogels have been mentioned. Subsequently, state-of-the-art developments in mono- and multi- stimuli-responsive hydrogels have been presented along with the case studies. Finally regulatory perspectives, challenges for the clinical translation and future prospects have been discussed.
Surface modification of WE43 magnesium alloy via alkali/stearic acid treatment for biodegradable drug-eluting stent applications
2023, Materials Chemistry and Physics
WE43 is a biodegradable magnesium alloy with a high potential for cardiovascular stent applications. Although it has many adequate properties, there are barriers to using it as a drug-eluting stent vehicle. Corrosion and hydrogen gas formation have an adverse effect on the surface, causing attached drug carriers to separate, which limits its functionality as a stent. An alkali treatment in 1 M NaOH solution at various applied potentials was utilized to fix this issue. Subsequently, a stearic acid layer was formed by two different methods to reduce corrosion by decreasing water uptake of the surface. The anodic film's surface morphology and phase structure were analysed using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). Nanoindentation tests were carried out to evaluate the anodic layer's mechanical properties. Its corrosion behaviour was characterized using potentiodynamic polarization (PDP), electrochemical impedance spectroscopy (EIS) and hydrogen evolution tests. The adhesive, thin yet effective oxide layers achieved in all the potentials showed increased corrosion resistance. It significantly decreased hydrogen formation, which were then sealed with stearic acid, and the surface became hydrophobic. This sealing layer acted as an additional barrier and enhanced the corrosion resistance of the magnesium alloy up to fifteen times bigger.
Enhancement of critical-sized bone defect regeneration by magnesium oxide-reinforced 3D scaffold with improved osteogenic and angiogenic properties
2023, Journal of Materials Science and Technology
The healing of critical-sized bone defects (CSD) remains a challenge in orthopedic medicine. In recent years, scaffolds with sophisticated microstructures fabricated by the emerging three-dimensional (3D) printing technology have lighted up the treatment of the CSD due to the elaborate microenvironments and support they may build. Here, we established a magnesium oxide-reinforced 3D-printed biocomposite scaffold to investigate the effect of magnesium-enriched 3D microenvironment on CSD repairing. The composite was prepared using a biodegradable polymer matrix, polycaprolactone (PCL), and the dispersion phase, magnesium oxide (MgO). With the appropriate surface treatment by saline coupling agent, the MgO dispersed homogeneously in the polymer matrix, leading to enhanced mechanical performance and steady release of magnesium ion (Mg²⁺) for superior cytocompatibility, higher cell viability, advanced osteogenic differentiation, and cell mineralization capabilities in comparison with the pure PCL. The in-vivo femoral implantation and critical-sized cranial bone defect studies demonstrated the importance of the 3D magnesium microenvironment, as a scaffold that released appropriate Mg²⁺ exhibited remarkably increased bone volume, enhanced angiogenesis, and almost recovered CSD after 8-week implantation. Overall, this study suggests that the magnesium-enriched 3D scaffold is a potential candidate for the treatment of CSD in a cell-free therapeutic approach.
Cellulose nanocrystals based delivery vehicles for anticancer agent curcumin
2022, International Journal of Biological Macromolecules
Cancer is a complex disease that starts with genetic alterations and mutations in healthy cells. The past decade has witnessed a huge demand for new biocompatibility and high-performance intelligent drug delivery systems. Curcumin (CUR) is a bioactive stimulant with numerous medical benefits. However, because of its hydrophobic nature, it has low bioavailability. The utilization of many biobased materials has been found to improve the loading of hydrophobic drugs. Cellulose nanocrystals (CNCs) with exceptional qualities and a wide range of applications, feature strong hydrophilicity and lipophilicity, great emulsification stability, high crystallinity and outstanding mechanical attributes. In this review, numerous CNCs-based composites have been evaluated for involvement in the controlled release of CUR. The first part of the review deals with recent advancements in the extraction of CNCs from lignocellulose biomass. The second elaborates some recent developments in the post-processing of CNCs in conjunction with other materials like natural polymers, synthetic polymers, β-CD, and surfactants for CUR loading/encapsulation and controlled release. Furthermore, numerous CUR drug delivery systems, challenges, and techniques for effective loading/encapsulation of CUR on CNCs-based composites have been presented. Finally, conclusions and future outlooks are also explored.
Wearable and implantable devices for drug delivery: Applications and challenges
2022, Biomaterials
Poor adherence to drug dosing schedule is responsible for ∼50% of hospitalization cases. Most patients fail to adhere to a strict dosing schedule due to invasive drug administration, off-target toxicities, or medical conditions like dementia. The emerging concept of wearable devices (WDs), implantable devices (IDs) and combined wearable and implantable devices (WIDs) for drug delivery has created new opportunities for treating patients with chronic diseases needing repeated and long-term medical attention like diabetes, ocular disorders, cancer, wound healing, cardiovascular diseases, and contraception. WDs, worn on the body surface have created appealing non-invasive, self-administrable drug delivery platforms which receive huge patient compliance. Microneedle-skin patches, wound healing patches, drug-eluting contact lenses, mouth guards, intra-vaginal rings, pharmaceutical jewelry, and drug-loaded self-care textiles are popular WDs explored in drug delivery. In contrast, IDs are surgically placed inside body tissue allowing higher payload and enhanced localized effect for an extended duration. Hormone micropumps, hydrogel/nanofibrous depot, coronary stents, intravitreal devices, and intrauterine devices are some representative examples of IDs. In this review, we have described the past 10 years of research progress on drug-delivering WDs and IDs in the context of treating diseases that demand repeated and long-term medication, especially those affecting soft tissues. We highlighted several technical challenges that need to be addressed before considering the translation of such technologies to clinics.
Thermo/glutathione-sensitive release kinetics of heterogeneous magnetic micro-organogel prepared by sono-catalysis
2021, Colloids and Surfaces B: Biointerfaces
To improve the loading and delivery for hydrophobic drugs and optimize the release efficiency in tumor microenvironment, a novel core-shell magnetic micro-organogel carrier was successfully prepared by a sono-catalysis process in the study. As-synthesized magnetic micro-organogel had an appropriate dispersibility in water owing to the hydrophilicity of protein shell and could be kept steadily with a well-defined spherical morphology owing to the three-dimensional gel structure of oil core, and it promised an accessible targeted drug delivery owing to its good magnetism-mediated motion ability. Moreover, the magnetic micro-organogel showed a high loading efficiency up to 94.22% for coumarin 6 which was dissolved into the micro-organogel as a model hydrophobic drug. More importantly, the release kinetics revealed that the magnetic micro-organogel had a thermo-sensitive and glutathione (GSH)-sensitive ability to control the drug release, and proved that its release mechanisms referred to the combination of erosion, diffusion and degradation.

View all citing articles on Scopus

^☆: This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug-Eluting Stents: an Innovative Multidisciplinary Drug Delivery Platform”, Vol. 58/3, 2006.

View full text

Mechanisms of controlled drug release from drug-eluting stents☆

Abstract

Introduction

Section snippets

Drug delivery mechanisms

Drugs used in controlling restenosis

Coating strategies for prevention of restenosis

Coating strategies for improving biocompatibility

Some issues in the development of drug-eluting stents

Summary

Lancet

Biomaterials

Biomaterials

Dose model for stent-based delivery of a radioactive compound for the treatment of restenosis in coronary arteries

Med. Phys.

Clinical experience with drug-eluting stents

Rev. Cardiovasc. Med.

T-stenting with drug-eluting stents for the treatment of bifurcation in-stent restenosis

J. Interv. Cardiol.

Recent developments in coated stents

Curr. Interv. Cardiol. Rep.

Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group

Circulation

First clinical experience with a paclitaxel derivate-eluting polymer stent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome

Circulation

Antiproliferative coatings for the treatment of coronary heart disease: what are the targets and which are the tools?

J. Interv. Cardiol.

Handbook of Drug-Eluting Stents, Martin Dunitz pages

Drug-eluting stents

Heart Drug

Stent design: implications for restenosis

Rev. Cardiovasc. Med.

Drug Delivery. Engineering Principles for Drug Therapy

Multilayer Thin Films. Sequential Assembly of Nanocomposite Materials

Physiological transport forces govern drug distribution for stent-based delivery

Circulation

Impact of transport and drug properties on the local pharmacology of drug-eluting stents

Int. J. Cardiovasc. Interv.

Stent development and local drug delivery

Br. Med. Bull.

Drug-eluting stents: role of stent design, delivery vehicle, and drug selection

Rev. Cardiovasc. Med.

New frontier in cardiology. Drug eluting stents: Part II

Circulation

Dexamethasone-eluting stent: an anti-inflammatory approach to inhibit coronary restenosis

Exp. Rev. Cardiovasc. Ther.

Expression of cyclin-dependent kinase inhibitors in vascular disease

Circ. Res.

Coated stents for the prevention of restenosis: Part II

Circulation