What Are Bioresorbable Drug-Eluting Stents? Definition, Evolution, and Composition

1. Introduction

   Definition of Bioresorbable Drug-Eluting Stents

   Bioresorbable drug-eluting stents, commonly abbreviated to just BRS, are medical devices that are used to treat coronary artery disease. Coronary artery disease (CAD) is a condition that develops when the blood vessels that are responsible for supplying oxygen-rich blood to the heart muscle become narrowed or blocked due to the buildup of plaque. Plaque is a combination of cholesterol, fat, and other substances that build up or start accumulating inside the artery walls. This accumulation of plaque reduces the blood flow to the heart muscle, which can cause chest pain (angina), shortness of breath, and many other symptoms. ^(1,2,3)

   Bioresorbable drug-eluting stents are similar in function to the more conventional metallic stents, which are inserted into a narrowed or blocked artery to help keep it open and allow the blood to flow freely. However, unlike the traditional metallic stents, BRS is manufactured from a special material that actually gets absorbed gradually by the body over a period of time. Bioresorbable drug-eluting stents are typically covered with a medication, such as an anti-inflammatory or an anti-proliferative drug, which then slowly gets released over time into the body to prevent restenosis, or the re-narrowing of the artery, and also to promote healing. As the stent starts to get absorbed by the body, it is then also eventually replaced by natural tissue, which thus successfully restores the natural function of the artery and also gets rid of any long-term risk associated with the traditional permanent metallic stents.

   It is safe to say that BRS have the potential to provide much better outcomes when compared to traditional stents since they dramatically reduce the risk of long-term complications, which may include stent thrombosis, restenosis, and even chronic inflammation. However, since BRS is still a relatively new technology, its long-term efficacy and safety are still being researched and debated. ^(4,5)

   Historical Background and Evolution Of Coronary Stents

   The first successful coronary angioplasty, which is a minimally invasive procedure done to open any blocked or narrowed arteries in the heart, was performed all the way back in 1977 by Andreas Gruentzig. However, at that time, the benefits of an angioplasty were quite limited because of the high rates of restenosis. Restenosis occurs when the artery gets narrowed again after the procedure. ⁽⁶⁾

   The in the early 1980s, it was Julio Palmaz, a physician and engineer, who invented the first stent. This first ever stent to be used was a small metal mesh tube that could be inserted into the artery in order to hold it open after an angioplasty. The first stent was manufactured from stainless steel and was permanently implanted inside the artery. While using this stent significantly reduced the rates of restenosis, it also increased the risk of thrombosis, or blood clotting. This, in turn, led to the development of antiplatelet medications such as aspirin and clopidogrel, which doctors started to prescribe to prevent the clotting of blood after an angioplasty. ^(7,8)

   Over the next few decades, the technology behind manufacturing of stents continued to evolve. These years witnessed various improvements in materials, design, and even drug coatings – all focused on reducing the risk of restenosis and thrombosis. Then in 1990s, second-generation stents were introduced, which were made out of cobalt-chromium and had much better flexibility, durability, as well as biocompatibility when compared to the first-generation stents. ⁽⁹⁾

   It was in the early 2000s that drug-eluting stents were introduced. These stents were coated with medications that prevented restenosis as they inhibited cell growth. These stents revolutionized the field of interventional cardiology and significantly cut down the rates of restenosis as compared to the bare-metal traditional stents. ⁽¹⁰⁾

   More recently, bioresorbable stents have been developed that are made out of materials that get gradually absorbed into the body over a period of time. These stents now have the potential to reduce the risk of developing any type of long-term complications associated with insertion of the permanent metallic stents. However, their long-term efficacy and safety are still being researched.

2. Design and Composition of Bioresorbable Drug-Eluting Stents

   Materials Used in Stent Fabrication (e.g. Polymers)

   With the advent of new technologies, it is now possible to make stents from a variety of materials, including metals and polymers. Here are some of the materials that are commonly used in the manufacturing of stents:

   • Metals: As mentioned above, the very first stents were made up of stainless steel, and the subsequent stents were made from other metals like cobalt-chromium, nickel-titanium (also known as nitinol), and platinum-chromium. These metals are known to be biocompatible and they have very good mechanical properties like durability, flexibility, and radial strength, which are all important factors needed for optimum stent performance. ^(11,12)
   • Polymers: Polymers are synthetic materials that can be designed to have certain properties such as biodegradability and drug release. Polymers are being used in the manufacturing of drug-eluting stents, which are also coated with medications that prevent the occurrence of restenosis by inhibiting cell growth. Some of the polymers that are being used in the manufacturing of drug-eluting stents include polylactide (PLA), polyglycolide (PGA), and their copolymers (PLGA), as well as polyethylene-co-vinyl acetate (PEVA) and polyurethane (PU). ^(13,14,15)
   • Bioresorbable Polymers: Bioresorbable stents are made up of materials that get gradually absorbed into the body over a period of time. These stents are commonly made up of polymers such as polylactide (PLA), polyglycolide (PGA), and their copolymers (PLGA), as well as poly(ε-caprolactone) (PCL) and polydioxanone (PDO). ⁽¹⁶⁾
   • Composites: Certain stents can also be manufactured out of composite materials that combine the properties of both metals and polymers. For example, certain stents are made up of a metal frame that is then coated with a polymer layer which releases the drugs.

   Drug Delivery Mechanisms

   As mentioned above, bioresorbable drug-eluting stents (BRS) are a more efficient form of stents that are able to deliver drugs to the target site and prevent the occurrence of restenosis, while also promoting tissue healing. When we look at the drug delivery mechanism of BRS, it typically includes the gradual release of the drug from the stent into the surrounding tissue. There are two main mechanisms of drug release from BRS that are used:

   The first one is known as diffusion-controlled release. In this mechanism, the drug is dispersed or dissolved within the polymer coating of the stent. It then diffuses or comes out from the coating into the surrounding tissue. The exact rate of the drug release depends on the concentration gradient of the drug present between the coating and the tissue, as well as the properties of the polymer coating that is used to make the stent, such as its porosity and permeability. ^(17,18)

   The second drug delivery mechanism used in bioresorbable drug-eluting stents is known as degradation-controlled release. In this process, the drug gets released as the polymer coating of the stent degrades over a period of time. This polymer coating is specially designed to degrade at a controlled rate, thus releasing the drug as it breaks down. The exact rate of drug release in this mechanism depends on the rate of degradation of the polymer. This, in turn, is also influenced by many factors, including the polymer composition, molecular weight, and its crystallinity. ^(19,20)

   The choice of drug and polymer coating further depends on a wide variety of factors. These include: ⁽²¹⁾

   • The desired drug release profile
   • The pharmacokinetics of the drug
   • The biocompatibility of the polymer

   Structural and Mechanical Properties

   The bioresorbable drug-eluting stents can be made up of a wide variety of materials that are specially designed to have particular structural and mechanical properties. The structural and mechanical properties of such stents are especially important because these factors determine the effectiveness and safety for these medical devices.

   As mentioned above, the most common materials used to manufacture bioresorbable drug-eluting stents are bioresorbable polymers such as polylactic acid (PLA), polyglycolic acid (PGA), and polycaprolactone (PCL). These materials are selected because they are biocompatible, biodegradable, and they also have the ability to degrade over time, allowing the stent to eventually get absorbed by the body. ^(17,22)

   When we look at the mechanical properties of BRS, these get influenced by the exact design of the stent. This includes factors such as the strut thickness, diameter, and inter-strut distance. These properties determine the stent’s ability to withstand mechanical forces like radial compression, axial compression, and bending. The mechanical properties of BRS also have an impact on their flexibility, conformability, and overall radial strength. ^(23,24)

   Over the years, there have been many studies done that have looked at the structural and mechanical properties of BRS, including the influence of the polymer composition, strut thickness, and stent design on the mechanical behavior of BRS. These studies have used different techniques like mechanical testing, finite element analysis, and optical coherence tomography to analyze the mechanical behavior of BRS and then optimize their design to achieve maximum effectiveness and safety. ⁽²⁵⁾

3. Pharmacokinetics and Pharmacodynamics Of Bioresorbable Drug-Eluting Stents

   Drug Release Kinetics

   The drug and polymer coating can also be customized to achieve specific drug release kinetics. For example, if the doctor is looking at a sustained release or pulsatile release mechanism which will best optimize the therapeutic effect of the BRS.

   Tissue Drug Concentrations and Duration of Drug Effects

   Bioresorbable drug-eluting stents are manufactured in a manner that will allow the stent to successfully deliver a drug to the target tissue, such as the coronary artery. At the same time, the stent should also be capable of maintaining the required therapeutic concentration of the drug for a required duration to prevent restenosis. ^(26,27)

   The duration and intensity of the drug effects in the tissue after the stent is implanted depends on many factors, including the type and dosage of the drug being used, the characteristics of the polymer coating, and the rate of stent degradation. ⁽²⁸⁾

   Studies have shown that the drug release kinetics from bioresorbable drug-eluting stents can differ depending on the type of polymer used. For example, some polymers are able to release the drug quickly over a short period of time, while others release the drug at a slower rate over a longer period. The drug release profile will also impact the concentration of the drug in the tissue and the duration of its effects. ⁽²⁹⁾

   Remember that the rate of stent degradation also has an impact on duration of how long the drug’s effects lasts for. If the stent degrades too quickly, the drug may not be released at the required therapeutic concentration for the required duration. On the other hand, if the stent degrades too slowly, the drug may be released at a higher concentration for too long, which may increase the risk of developing adverse effects. ⁽³⁰⁾

   Comparison with Traditional Drug-Eluting Stents

   Bioresorbable drug-eluting stents are designed to eventually dissolve over a period of time after getting implanted in a blood vessel. Unlike the more traditional drug-eluting stents (DES), which remain in the body permanently, BRS can potentially eliminate the need for a permanent implant, which may offer certain benefits such as improved vessel healing and the restoration of normal vessel function. There are many differences between the traditional DES and the new BRS, including: ^(31,32)

   • Manufacturing Material: BRS are typically made of a biodegradable polymer or a metallic alloy that is designed to gradually dissolve over time. In contrast, traditional DES are made of a permanent metallic alloy such as stainless steel, cobalt-chromium, or platinum-chromium.
   • Drug Delivery System: Both BRS and traditional DES release a drug to prevent restenosis (re-narrowing of the artery) after the stent has been implanted. However, the drug release mechanism is different. BRS typically release the drug from a polymer coating on the stent struts, which gradually degrades over time, while traditional DES release the drug from a permanent coating on the stent struts. ⁽³³⁾
   • Design of the Stent: BRS have a unique design that allows them to degrade over time, which can potentially restore normal vessel function and reduce the risk of long-term complications. Traditional DES are designed to remain in the body permanently and typically have a thicker strut size. ⁽³⁴⁾
   • Clinical Outcomes: Clinical studies comparing BRS with traditional DES have shown mixed results. While some studies have shown that BRS can be as effective as traditional DES in terms of preventing restenosis and major adverse cardiac events, other studies have reported higher rates of stent thrombosis (blood clots) with BRS. ⁽³⁵⁾

4. Clinical Performance and Safety of Bioresorbable Drug-Eluting Stents

   Efficacy in Reducing Restenosis and Major Adverse Cardiovascular Events

   Bioresorbable drug-eluting stents (BRS) have been found to be effective in reducing restenosis and major adverse cardiovascular events (MACE) compared to bare-metal stents (BMS) and traditional drug-eluting stents (DES). The efficacy of BRS in reducing restenosis and MACE has been demonstrated in several clinical trials and meta-analyses. ⁽³⁶⁾

   For example, in the ABSORB III trial, a randomized controlled trial comparing the Absorb BVS (BRS) with the Xience (DES), the BRS was non-inferior to the DES in terms of the primary endpoint of target lesion failure (a composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization) at 1 year. However, there was a higher rate of device thrombosis with the BRS compared to the DES. ⁽³⁷⁾

   In a meta-analysis of 25 randomized controlled trials including 8,326 patients, BRS were associated with a lower risk of MACE, target vessel revascularization, and stent thrombosis compared to BMS. In addition, BRS had similar rates of MACE and target vessel revascularization as DES, but with a higher risk of stent thrombosis. ⁽³⁸⁾

   So while the BRS have shown promise in reducing restenosis and MACE, further research is still required to optimize their efficacy and safety compared to BMS and DES.

   Comparison with Traditional Stents in Randomized Clinical Trials

   There have been several randomized clinical trials comparing the safety and efficacy of bioresorbable drug-eluting stents (BRS) with traditional drug-eluting stents (DES).

   One of the largest and most well-known trials is the ABSORB III trial, which was conducted by Abbott Vascular. This trial compared the safety and efficacy of the Absorb BVS (a type of BRS) with the Xience (a type of DES) in patients with coronary artery disease. The trial included over 2,000 patients and found that while the Absorb BVS was non-inferior to Xience at one year, it was associated with a higher rate of target lesion failure and device thrombosis. ^(39,40)

   Another important trial is the BIOSCIENCE trial, which compared the safety and efficacy of the BioMatrix Flex (a type of DES) with the BioFreedom (a type of BRS) in patients with stable coronary artery disease. This trial included over 2,000 patients and found that the two devices were similar in terms of safety and efficacy at one year, with no significant differences in target lesion revascularization or stent thrombosis. ^(41,42)

   Other trials comparing BRS and DES include the TROFI II trial, the AIDA trial, and the PRAGUE-18 trial, among others. These trials have provided important insights into the safety and efficacy of BRS compared to traditional stents in different patient populations and with different types of devices. ^(43,44)

   Long-Term Safety and Potential Adverse Events

   The long-term safety and potential adverse events of bioresorbable drug-eluting stents (BRS) are still being studied and are a topic of ongoing research. Some potential concerns with BRS include:

   • Increased risk of stent thrombosis: Studies have shown a higher incidence of stent thrombosis with BRS compared to traditional drug-eluting stents (DES), particularly during the first year after implantation. ⁽³⁹⁾
   • Delayed healing: BRS may take longer to fully resorb and may delay vessel healing compared to traditional DES, which could increase the risk of adverse events such as restenosis or thrombosis. ⁽⁴⁰⁾
   • Device-related complications: There have been reports of device-related complications with BRS, such as strut fracture or mal-apposition, which can lead to adverse events.
   • Incomplete resorption: While BRS are designed to fully resorb over time, there have been reports of incomplete resorption and persistent material in the vessel wall. ⁽⁴¹⁾

   The long-term safety and efficacy of BRS are still being evaluated, and further studies are still needed to fully understand their potential benefits and risks compared to traditional DES.

5. Future Directions for Bioresorbable Drug-Eluting Stents

   Ongoing Research and Development Efforts

   There are ongoing research and development efforts to improve the safety and efficacy of bioresorbable drug-eluting stents and to expand their use to new patient populations and clinical settings. One of the main areas of focus is improving the mechanical properties of BRS to make them more durable and resistant to fractures and other complications. Researchers are also investigating new materials and manufacturing techniques to enhance the biocompatibility and drug-delivery properties of BRS. ⁽⁴²⁾

   Another area of research is exploring the use of BRS in high-risk patient populations, such as those with diabetes or chronic kidney disease, where traditional stents may be less effective. Studies are also underway to evaluate the use of BRS in complex lesions and in combination with other interventional procedures, such as rotational atherectomy and intravascular lithotripsy. ⁽⁴³⁾

   Researchers are also investigating new drug therapies and delivery mechanisms to improve the efficacy of BRS and reduce the risk of adverse events, such as late stent thrombosis.

   Potential Clinical Applications and Advantages Over Traditional Stents

   There are many potential clinical applications and advantages of using bioresorbable drug-eluting stents over traditional stents, including:

   • Restoration of vessel flexibility: BRS can restore the natural flexibility of the artery after the stent has dissolved, which may reduce the risk of future blockages.
   • Lower risk of thrombosis: BRS has been shown to reduce the risk of thrombosis compared to traditional stents, as the scaffold material gradually dissolves and does not leave a foreign body in the artery.
   • Better long-term outcomes: BRS has the potential to improve long-term outcomes by allowing the artery to heal and regain normal function, reducing the risk of future complications.
   • Treatment of complex lesions: BRS has shown promise in treating complex lesions, such as bifurcation lesions and chronic total occlusions, where traditional stents may have limited effectiveness.
   • Reduced need for dual antiplatelet therapy (DAPT): BRS may allow for a shorter duration of DAPT, reducing the risk of bleeding complications associated with prolonged antiplatelet therapy. ⁽⁴⁵⁾

6. Conclusion

   Summary of Key Points

   Some of the key take-aways about bioresorbable drug-eluting stents (BRS) are as follows:

   • BRS is a stent made of a biodegradable polymer material that is designed to dissolve over time. This is unlike the traditional metallic stents, which remain in the artery permanently.
   • BRS delivers drugs to prevent restenosis, which is the re-narrowing of the artery due to the formation of scar tissue after the implantation of the stent.
   • BRS has shown promising results in reducing the risk of thrombosis and allowing for a quicker return to normal artery function compared to traditional stents.
   • BRS has the potential to treat complex lesions and reduce the need for prolonged dual antiplatelet therapy.

   However, the long-term safety and effectiveness of BRS are still being studied, and more research is needed to fully understand its clinical potential.

The use of bioresorbable drug-eluting stents (BRS) has a wide variety of clinical implications and considerations for patient care. Some of these include:

• Selection of Suitable Patient Candidates: Patients with certain anatomical and clinical characteristics may be more suitable candidates for BRS. It is important to carefully assess the patient’s medical history, anatomy of the target lesion, and overall health status before choosing to implant a BRS.
• Antiplatelet Therapy: Dual antiplatelet therapy (DAPT) is typically required for a period of time after stent implantation to prevent thrombosis. However, the optimal duration of DAPT for BRS is still being studied. The decision to use BRS should take into account the patient’s ability to comply with DAPT and the risk of bleeding.
• Implantation Technique: Implantation technique is critical for successful deployment of BRS. The use of proper equipment and techniques, such as optimal balloon sizing and post-dilation, can help ensure optimal stent expansion and apposition.
• Follow-up Imaging To Look At Long-Term Safety & Efficiency: Follow-up imaging is important to assess the long-term safety and efficacy of BRS. Imaging modalities such as angiography, optical coherence tomography (OCT), and intravascular ultrasound (IVUS) can provide valuable information on stent healing, resorption, and potential complications.
• High Cost: BRS may be more expensive than traditional metallic stents, and cost-effectiveness analyses are needed to determine their value in clinical practice.

Keeping all these factors in mind, it is important to understand that the use of BRS requires careful patient selection, optimal implantation technique, follow-up imaging, and cost considerations. By keeping these factors into consideration, bioresorbable drug-eluting stents can be used safely and effectively in the management of coronary artery disease.

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