Nano-embedded Medical Devices and Delivery Systems in Interventional Radiology

Abstract

Nanomaterials research has significantly accelerated the development of the field of vascular and interventional radiology. The incorporation of nanoparticles with unique and functional properties in medical devices and delivery systems has paved the way for the creation of novel diagnostic and therapeutic procedures for various clinical disorders. In this review, we discuss the advancements in the field of interventional radiology and the role of nanotechnology in maximizing the benefits and mitigating the disadvantages of interventional radiology theranostic procedures. Several nanomaterials have been studied to improve the efficacy of interventional radiology interventions, reduce the complications associated with medical devices, improve the accuracy and efficiency of drug delivery systems, and develop innovative imaging modalities. Here, we summarize the recent progress in the development of medical devices and delivery systems that link nanotechnology in vascular and interventional radiology.

Graphical/Visual Abstract

Interventional and vascular radiology make use of medical devices to deliver minimally invasive means of diagnosis and treatment. Different nanoparticles have been incorporated to improve the existing medical devices that are used in both imaging and treatment procedures.

1. INTRODUCTION

Interventional radiology (IR) is a contemporary subspecialty of radiology that employs minimally-invasive image-guided procedures to diagnose and treat a variety of diseases including malignancies, cardiovascular diseases, and general trauma or bleeding. IR is characterized by a rich history of technological development and innovation that have allowed the improvement of medical procedures and devices. Nanotechnology is one of the areas that has influenced IR due to its tunability, which is greatly useful in designing and performing minimally invasive procedures for the diagnosis and treatment of diseases. In particular, conditions that traditionally required invasive vascular surgery are being increasingly treated with a minimally invasive IR approach enhanced by nanotechnology.

Nanotechnology-enabled medical devices used in IR applications are can be indicated for diagnostics, therapy, or both (currently referred to as theranostics). Interestingly, different methods of fabricating nanoparticle-embedded medical devices have been explored depending on patient-specific needs. Moreover, different means of incorporating nanoparticles into medical devices have also been explored, depending on the characteristics of the nanoparticles used. Different types of nanomaterials including nanowires, nanofibers, nanoparticles, quantum dots, and hollow spheres. These variations have different physicochemical and mechanical properties that can be harnessed to improve the efficacy of the medical devices and delivery systems used in IR procedures (Kargozar & Mozafari, 2018). For example, quantum dots are known for their high photostability and strong tissue-penetrating capacity making them more favourable for use in near infrared (NIR) fluorescence compared to traditionally used organic dyes (Brunetti et al., 2018; Gil et al., 2021). Similarly, the nano-scale size of nanoparticles is very useful in drug delivery due to their increased solubility and enhanced bioavailability to target cells, tissues, or organs at this particle size.

However, the application of nanotechnology in the field of IR still faces many challenges. For example, potential short- and long-term toxicities in living subjects are still major concerns that researchers need to address (Zhang, 2017). Despite the significant advancements in nanodevices, the clinical translation of these innovations has only increased incrementally throughout the years (Arms et al., 2018; Sercombe et al., 2015). Kaushik (2019) suggested re-evaluating and improving the development strategies used in nanomedicine by forming collaborations among academe, industry, consortia, and research hospitals, as well as the regulatory landscape that is associated with advanced nanotechnology research. Rapidly evolving technology, as well as the continuous pursuit of scientific innovation, will contribute to the fast-paced evolution of nanotechnology towards enhancing theranostic methods and approaches in IR. In this review, we cover several nanomaterials and nanodevices that have been employed in IR practice, particularly in vascular applications

2. INTERVENTIONAL RADIOLOGY

Since the performance of the first percutaneous angioplasty by Charles Dotter in 1964, the constantly evolving field of IR has expanded to encompass a broad array of procedures that cover nearly every system of the human body. Figure 1 illustrates some of the common pathologic conditions that are treated with IR techniques.

Figure 1.

Common conditions treated by interventional radiology. As methods and procedures used in IR is continually evolving, the scope of applications covered by IR is also continually expanding. Recent applications include embolization therapy for obesity (Gunn & Oklu, 2014) and inflammatory joint diseases (Iwamoto et al., 2017).

Most procedures in IR involve the use of small, specialized devices, such as needles, guidewires, sheaths, and catheters that are inserted through the skin and blood vessels to reach the target organ under the guidance of modern imaging modalities, such as fluoroscopy, ultrasound, computerized tomography (CT), and magnetic resonance imaging (MRI). Because IR procedures are minimally invasive in nature, IR has the potential to reduce complications, shorten recovery time, and minimize health care costs while maintaining higher success rates compared to traditional surgical approaches. For example, open surgeries for peripheral artery diseases (PAD) can be replaced by needle-access and image guidance for stenting and angioplasty in certain patients. In addition, the unique ability of IR techniques to deliver therapy directly into or in proximity to the target organ provides therapeutic benefits that are not obtained with standard medical strategies. This is classically seen in hepatocellular carcinoma where surgical resection of tumors can be alternatively treated by IR procedures such as microwave ablation or chemoembolization. Multiple studies have demonstrated the advantages of endovascular strategies over surgery in vascular conditions. Evidence from randomized clinical trials shows that endovascular repair of abdominal aortic aneurysms yields significantly lower perioperative and early mortality rates and similar overall survival after 8 years of follow-up versus open repair (Lederle et al., 2019). Endovascular procedures for the treatment of varicose veins have also demonstrated excellent success rates (Kheirelseid et al., 2018) with new, although limited, evidence to support a lower incidence of postoperative complications, such as hematomas, infections, and paresthesia when compared to open surgery (Pan et al., 2014). However, performing minimally invasive procedures requires a specialized set of skills from a trained surgeon, which might in turn be limited only to specialized centers (Pahwa et al., 2014).

Despite limited data on other IR procedures such as bronchial artery embolization for hemoptysis (Panda et al., 2017), CT-guided drainage of mediastinal abscesses (Arellano et al., 2011), and emergency treatment of arterial injury following orthopedic surgery (Carrafiello et al., 2012), high success rates have been reported. Moreover, reduced complications have been demonstrated for catheter-directed thrombolysis for pulmonary embolism (PE) versus anti-coagulation alone (Bloomer et al., 2017). Reduced blood loss, operating time, and hospital stay have been reported for uterine artery embolization versus hysterectomy for postpartum hemorrhage (Liu et al., 2020). Most importantly, reduced health care costs have been reported for dialysis access maintenance via IR procedures (Trivedi et al., 2020), image-guided percutaneous drainage of gastrointestinal anastomotic leaks versus surgical repair (Burke et al., 2015), and chest port insertion when performed in the IR suite (LaRoy et al., 2015).

IR procedures also have disadvantages. In some conditions, the therapeutic effect of the procedures appears to be either temporary or shorter than that of the surgical counterpart. In one study, patients who underwent uterine artery embolization had a higher likelihood of needing another surgical intervention at two-year and at five-year follow-up versus those who had surgery (Gupta et al., 2012). In the case of left main coronary artery disease, a meta-analysis revealed that while percutaneous coronary intervention is associated with a reduced risk of major cardiovascular events at short-term follow-up, it is associated with increased risk for long-term major adverse cardiac and cerebrovascular events (Laukkanen et al., 2017). Furthermore, adverse events (AE) related to IR procedures are rare, but may still occur. Examples of AEs associated with IR procedures found in literature include improper device placement and related infections (Higgins & Herpy, 2021), incorrect procedures, and unnecessary radiation doses (Tarkiainen et al., 2020). These medical errors leading to AEs are preventable, and current research in IR is focused on the mitigation of known clinical risks and the development of new treatment strategies with minimal adverse effects.

Nonetheless, the field of IR continues to expand the therapeutic horizon, especially for diseases with limited treatment options. Techniques such as embolization, targeted delivery of chemotherapy and radiation therapy, ablation strategies, and electroporation are currently available and are being tested for the treatment of solid tumors. Moreover, these techniques, along with drainage, stenting, shunt placement, vertebroplasty, and kyphoplasty, are also used as palliative strategies to improve the quality of life of patients with advanced stages of cancer.

3. NANOTECHNOLOGY APPLICATIONS IN INTERVENTIONAL RADIOLOGY

Nanotechnology encompasses the development of materials in the nanometer scale, with a wide range of applications in medicine, such as biosensors, microfluidics, drug delivery, microarray tests, and tissue engineering (Patra et al., 2018). In IR, nanotechnology is used to enhance the success and efficiency via novel instruments, imaging techniques, and drug delivery systems employed through minimally invasive procedures.

There are several advantages of using nanotechnology in IR. Because of their small size, nanoparticles have 1) a high surface-to-volume ratio and large surface area, which results in a high signal-to-noise ratio for both imaging and medical device visualization; 2) multifunctionality in a single carrier, which results in longer circulation times and multimodal imaging; and 3) specific targeting that could deliver high concentrations of contrast or therapeutic agents within the area of interest (Monsky et al., 2011). Combining nanotechnology and IR has powerful potential in personalized medicine—treating the right condition at the right time in the right patient.

The literature search for this review was limited to original articles from 2017. We found that nanomaterials have been generally used for the imaging or treatment of various diseases in forms of drug delivery systems or enhanced medical devices. Nanoparticles differ in composition, physical, and chemical characteristics, as well as targeting properties and possible metabolic effects; however, their general versatility allows for beneficial and targeted application in clinical practice. Different nanoparticles have already been used as contrast agents, with high sensitivity for various imaging modalities, such as X-ray, CT, MRI, and optical or fluorescence imaging. For example, synthetic metal nanoparticles such as bismuth, gadolinium, and tantalum have been popularly used in X-ray and CT imaging. These elements have high atomic numbers and high X-ray efficiency, making them suitable contrast agents. These nanoparticles have been embedded into different medical devices, such as polymeric inferior vena filters cava (IVCFs), to make them radiopaque. Alternatively, iron oxide nanoparticles are commonly used as contrast agents in MRI because of their unique superparamagnetic properties. Iron oxides consist of maghemite or magnetite (Ali et al., 2016). A popular example would be SPIOs, which are usually nanoparticle-sized cores of magnetite coated with substances such as polysaccharide (Monsky et al., 2011). SPIO tracers have been successfully used for gut bleed detection in murine models, showing their potential application as clinical diagnostic tools for gastrointestinal bleeding.

Owing to their size, surface-to-mass ratio, and ability to bind, adsorb, and carry other compounds, nanoparticles have already been widely used as delivery systems for therapy. Biodistribution, elimination, and target site accumulation are some of the important properties that are considered when designing nanoparticles for use in therapy. The majority of therapeutic nanoparticles are chemotherapeutic drugs that are combined with polymeric nanoparticles. An example is the combination of polymeric micellar paclitaxel with cisplatin for the treatment of non-small cell lung cancer, where the nanoparticles allowed for faster and deeper penetration of the tumor than albumin-bound nab-paclitaxel only (Shi et al., 2021). Other types of polymers used as nanoparticles include polyglycolic acid, mesoporous silica (Lu et al., 2018; Zhang et al., 2019), and hydrogels (He et al., 2020; Mannarino et al., 2020). Hydrogel coating has also been used in vascular catheter access to reduce thrombus accumulation (Mannarino et al., 2020). Metallic nanoparticles such as gold, silver, and iron have also been used as drug carriers, mediator for ablation, or as an aid in radiofrequency radiation therapy (Nikzad et al., 2017).

4. NANOMATERIALS IN MEDICAL DEVICES FOR VASCULAR APPLICATIONS

Cardiovascular diseases (CVDs) such as ischemic heart disease and stroke are responsible for nearly 25% of all deaths worldwide (Cicha et al., 2016). Cardiovascular devices such as angioplasty devices and ablation catheters have been approved for safe use in different CVDs. Different methods and devices are being designed to further address the increasing burden of CVDs by advancing the understanding of pathophysiology and improving detection and treatment through targeted and image-guided theranostics. These methods include the application of nanoparticles to assess the desirable distribution and localization of delivered therapeutics at targets in both existing and innovative devices when monitoring the primary interventional procedure, enhance the effectiveness of the delivered therapeutics to achieve a sufficient level of therapeutic effect, and monitor the function and functional period of the delivered therapeutics (Yang, 2007).

In this section, we enumerate several nanodevices that have been developed and used for vascular interventions as depicted in Figure 2. We also show nanoparticle applications in medical devices as applied to other diseases in Table 2.

Figure 2.

Current vascular medical devices with nanotechnology applications. Different nanoparticles with varying size, morphology, physical, and chemical properties have been explored in use with existing medical devices and has been particularly useful in diagnostic and vascular radiology applications such as vascular access (Dror et al., 2009; Mannarino et al., 2020; Perez et al., 2021a), vascular stents (Hou et al., 2020; Song et al., 2021; Zhao et al., 2018), and inferior vena cava filters (Damasco et al., 2022; Huang et al., 2020; Tian et al., 2017).

Table 2.

Nanoparticles in medical devices (2017–2022).

Indication	Medical Device	Nano-application	Stage	Reference
Intracranial Aneurysm	2nd Gen platinum coil (HES™, MicroVention, Inc)	Second generation contains hydrogel polymer coating that enhances packing density and healing, and reduces recurrence	Clinical Trial/Completed (NCT01407952)	Bendok et al. (2020)
	Polymer-modified coils (Matrix™)	PGA/PLA coating to improve clot organization inside the cavity	Phase 4/Completed (NCT00396981)	McDougall et al. (2021)
	Woven EndoBridge (WEB) Aneurysm Embolization System	Self-expanding embolization implants made of braided nitinol/platinum wires which are highly conformable and visible on fluoroscopy	Clinical Trial/Active (NCT02191618)	Arthur et al. (2019)
	Magnetic Bacterial Nano-cellulose (BNC)	PEG-coated BNC magnetization via SPIO to create local and focal attraction force of cells for reconstruction of tunica media	In vitro	Echeverry-Rendon et al. (2017)
	Magnetic Particle Imaging (MPI)	SPIOs to visualize lumen of nitinol flow diverter stents without relevant stent-induced artifacts	Material development	Herzberg et al. (2021)
Subarachnoid Hemorrhage	Drug-eluting stent	MSNs with paclitaxel within electrospun PLA fibers for better endothelialization and prevention of lumen stenosis	In vivo (canine)	Zhang et al. (2019)
Vascular access	Peripherally inserted central catheters (PICC)	PVA-based hydrogel coating to reduce thrombus accumulation than uncoated polyurethane catheter	In vitro	Mannarino et al. (2020)
Urinary Tract Obstruction	Ureteral Stents	kanamycin-chitosan nanoparticles (KMCSNPs) immobilized on polyurethane ureteral stent (PUS) to increase antibacterial activity of chitosan NP stent and prevent urinary tract-associated infection	In vitro	Venkat Kumar et al. (2016)
	Ureteral Stents	hyperbranched poly(amide-amine)-capped Ag@Au NP-embedded fiber membrane-structured PGA/PLGA ureteral stent as a dual biodegradable and contact-killing antimicrobial ureteral stent	In vivo (pig)	Gao et al. (2020)
Prosthetic Joint Infection	Bone cement	PC-SeNP to improve antibacterial and antioxidant properties of commercially-available bone cements	In vitro	Karahaliloglu and Kilicay (2020)
Bone cancer	Cemex (Tecres Company)	gentamicin+AgNP+CuNP for increased bactericidal properties and improve cytocompatibility of commercially available bone cement	In vitro	Wekwejt et al. (2019)

Abbreviations: PGA: poly(glycolic acid); PLA: poly(lactic acid); PEG: poly(ethylene glycol); SPIO: superparamagnetic iron oxide; MSN: mesoporous silica nanoparticles; PVA: poly(vinyl alcohol); Ag@AuNP: silver shell and gold core nanoparticle PC: phosphatidylcholine; SeNP: selenium nanoparticle; AgNP: silver nanoparticle; CuNP: copper nanoparticle; PLGA: poly(lactic-co-glycolic acid)

There are different means of fabricating polymeric medical devices including 3D printing, electrospinning, or a combination of both. While extrusion-based 3D printing offers patient-specific structures for scaffolds and provides support for cell attachment and proliferation and the generation of new tissues, this method lacks resolution of features in the nanoscale. On the other hand, electrospinning provides an opportunity to introduce nanoscale fibers, which in turn provide a larger surface area or cell attachment. Wang et al. (2021) suggested the use of combination extrusion-based 3D printing and electrospinning to maximize the benefits of both microscale and nanoscale features. Nanoparticles have been incorporated by means of the homogeneous matrix or coating onto the pre-made commercial device by wet-dipping.

4.1. Vascular stents

Vascular stents are percutaneous coronary interventions that were primarily developed to open clogged or damaged coronary arteries. Vascular stents (or scaffolds) are tubular implants used to give mechanical strength to the stenotic arteries or other non-vascular conduits until the risk of full closure can be eliminated (Borhani et al., 2018). Vascular stents were designed to replace percutaneous transluminal coronary angioplasty, which initially made use of a catheter with a folded balloon that is inflated after delivery into the narrowed part of the artery. The inflated balloon should be able to compress the obstruction (i.e. plaques), which causes the inner wall to be enlarged; however, this kind of device puts patients at risk of thrombosis because of the injury caused by the catheter implantation and balloon expansion. Thus, stents have successfully replaced surgeries with the first human implantation of a self-expanding stent in 1986 (Sigwart et al., 1987) and balloon-expandable stent in 1987 (Palmaz, 1988).

Stents have been traditionally categorized into bare metal stents (BMS) or drug-eluting stents (DES). Early stents were mostly bare metal stents that were fabricated from metals such as stainless steel, cobalt-chromium alloys, and nickel-titanium alloys (nitinol) (Borhani et al., 2018). However, BMS have been found to increase the risk of restenosis (the re-narrowing of a previously treated vessels due to intimal hyperplasia), stent underexpansion, stent deformation, and neoatherosclerosis (Goto et al., 2015). DES were developed to address the restenosis experienced from BMS by providing a scaffold surrounded by a degradable drug polymer coating, which significantly reduces restenosis rates (Mohan & Dhall, 2010). However, DES were later found to limit normal blood vessel movement and cause inflammatory reactions of the vascular wall, leading to arterial wall hyperplasia and in-stent restenosis (Gundogan et al., 2014; Zhao et al., 2018). Moreover, drug polymer remnants in vivo, circulating for longer periods of time, also contribute to trigger late-stent thrombosis (Gundogan et al., 2014).

Nanoparticles have been popularly used to address the clinical limitations of vascular stents because of their great potential in sustained drug release, thus effectively regulating the behavior of vascular cells (Zhao et al., 2018). For example, Zhao et al. (2018) addressed restenosis by fabricating poly(L-lactide) (PLLA)-based biodegradable stents (Figure 3) with poly(D,L-lactide) (PDLLA) nanoparticles carrying sirolimus to inhibit vascular smooth muscle cell proliferation. Polyvinylpyrrolidone (PVP) and poly(ethylene-co-vinyl acetate) (PEVA) were coated PLLA stents for better adhesion; the nanoparticle-coated DES had stronger inhibitory effects on smooth muscle cell proliferation than on endothelial cell proliferation, which suggests that it prevented restenosis but permitted faster re-endothelialization of the implanted stents.

Figure 3.

Surface morphology of the novel biodegradable drug-loaded eluting stent by Zhao et al. (2018). Stents were fabricated from poly(L-lactide) (PLLA) with poly(D,L-lactide) (PDLLA) nanoparticles with sirolimus and further coated with polyvinylpyrrolidone (PVP) and poly(ethylene-co-vinyl acetate) (PEVA) for better adhesion and prevention of restenosis. Images were adapted from Zhao et al. (2018).

Song et al. (2021) introduced a new type of nerve growth factor–loaded heparin/chitosan nanoparticle for the surface modification of cardiovascular stents. Heparin and chitosan were found to form 3D nanoparticles by spontaneous electrostatic interaction, and the specific binding properties of heparin and nerve growth factor allowed for improved cellular compatibility and endothelialization. The nerve growth factor–loaded nanoparticles demonstrated effectiveness in enhancing the adhesion and proliferation activity of endothelial cells and showed a strong chemotactic effect on vascular endothelial progenitor cells, suggesting that nerve growth factor–loaded nanoparticles can selectively inhibit blood coagulation and intimal hyperplasia. Another example makes use of exosomes, which are nanovesicular carriers for intracellular communication (Fernandes et al., 2020), immobilized onto a poly-dopamine-coated cardiovascular metal stent surface (Hou et al., 2020). This novel poly-dopamine/exosome material also showed reduced hyperplasia and enhanced endothelial cell growth, as well as regulated attachment of macrophages from M1 to M2 phenotypes. These results suggest the presence of anti-inflammatory properties while promoting the healthy regeneration of endothelial tissue.

4.2. Inferior vena cava filters

Inferior vena cava filters (IVCFs), first introduced in 1973, were designed to trap venous emboli from the lower extremity and prevent clinically significant PE (Duffett & Carrier, 2017). IVCF placement is indicated in patients with venous thromboembolism (VTE) who cannot be given anticoagulants, patients who have VTE and are already on anticoagulant therapy, and patients without VTE but who are considered high risk because of underlying clinical disease (Pillai et al., 2021). Throughout the years, different models of IVCFs have been made available, most of which are placed percutaneously and removed after a few months (retrievable). Permanent or non-retrievable filters have also been made available and are typically placed to mechanically prevent PE in patients with long-term contraindications to anticoagulation (Marron et al., 2020).

In 2003, the U.S. Food and Drug Administration (FDA) cleared retrievable inferior vena cava filters for clinical use as permanent implants, although these devices were originally designed for endovascular retrieval (Grewal et al., 2020). This resulted in an exponential increase in the use of retrievable inferior vena cava filters but subsequently caused low retrieval rates of only 8.5%, with patients being lost to follow-up (Grewal et al., 2020; Pillai et al., 2021). Non-retrieval of IVCF may cause further complications, which include vessel perforation, thrombophlebitis, and thrombosis (Perez et al., 2021b; PREPIC, 2005). Several advanced surgical techniques and procedures have been developed for the retrieval of IVC filters with prolonged dwell time (Al-Hakim et al., 2014; Desai et al., 2015; Kuo et al., 2013). This led to the development of resorbable filters, which protect patients from PE from contraindication to anticoagulation and then be resorbed, eliminating an additional removal procedure. Eggers et al. (2015) initially assessed the feasibility of using polydioxanone (PPDO) polymer as an absorbable filter in a swine model. Later, their studies demonstrated safe implantation, with no PE, in the same animal model, with complete to near-complete resorption of PPDO filters by 32 weeks (Eggers et al., 2019). Recently, these filters have resulted in 100% clinical success, with no adverse events, in the first-in-human deployment (Elizondo et al., 2020).

PPDO has favorable tensile strength retention and adequate absorption time compared with other polymers (Tian et al., 2017); however, resorbable PPDO filters are radiolucent under conventional imaging modalities (Tian et al., 2017). To continuously monitor the positioning and integrity of IVCF by imaging, nanoparticles have been used to coat filters, making them radiosorbable and radiopaque (Huang et al., 2017). Gold nanoparticle (AuNP)–infused PPDO IVCF has been developed to improve the radiolucent nature of PPDO and therefore allow monitoring of these materials under CT or X-ray imaging. AuNP-infused PPDO has been effectively tested in a swine model and successfully demonstrated radiopacity, robust mechanical strength, and biocompatibility (Huang et al., 2020; Tian et al., 2017). Bismuth NP (BiNP)–coated PPDO filters showed higher radiopacity than AuNP and even higher radiopacity when reinforced with polyhydroxybutyrate (PHB), which allows these Bi-coated IVCFs to be imaged on fluoroscopy, which is not possible with AuNP-PPDO (Damasco et al., 2022). Similar to AuNP, BiNP with or without PHB had no effect on the biocompatibility, mechanical strength, and toxicity of the IVCF. Results from these studies are summarized in Figure 4.

Figure 4.

Comparison radiopacity of bare, AuNP-, and BiNP-coated polydioxanone (PPDO) filters in photo, micro-CT(mCT), and in vivo CT imaging in pigs (adapted from the studies of Huang et al. (2017) for bare PPDO, Huang et al. (2020) for PPDO-Au, Damasco et al. (2022) for PPDO-Bi. PPDO filters have significantly improved radiopacity with the addition of Au and Bi nanoparticles. In addition, PHB another biodegradable polymer enhances the infusion of Bi within the PPDO. Decrease in radiopacity at 12 weeks post-implantation shows degradation of the IVCF.

4.3. Vascular access

Vascular access, which is established via a catheter or an arteriovenous (AV) connection, plays an important role in the administration of fluid and medications, monitoring of hemodynamic parameters, provision of extracorporeal therapy, insertion of vascular devices, and delivery of targeted therapy.

4.3.1. Vascular catheters

Vascular catheters are commonly used in the in-patient setting to deliver fluids, medications, and nutritional support. Most catheters are made of elastomers, such as polyurethane (PUR) and silicone, which have excellent conformability and mechanical strength. However, the relatively high lateral friction coefficient of these materials makes them susceptible to adhesion of blood components and microbial contaminants. Specific materials also have certain disadvantages. A study of implantable venous-access ports showed that polyurethane catheters are significantly more susceptible to infections and thrombosis, while silicone catheters are associated with higher rates of mechanical failure (Wildgruber et al., 2016). Catheters impregnated with antimicrobial agents, such as chlorhexidine, silver sulfadiazine, and silver ions, are available, but evidence of their benefits remains limited. A Cochrane study in 2016 concluded that these devices do not appear to reduce overall bloodstream infections and overall mortality (Lai et al., 2016). Thus, novel catheter materials that can reduce the adhesion of procoagulants and microbial contaminants in the blood are being explored to significantly reduce the complications of catheterization. Strategies under investigation include the use of innovative polymer blends (Kleidon et al., 2018), novel coatings (Mannarino et al., 2020), topographic modifications (Hsu et al., 2018), and external-energy activation (Dror et al., 2009).

Several strategies have already gained FDA approval and are currently being used in the clinical setting. Endexo (Interface Biologics, Inc.) is an anti-thrombogenic additive technology that relies on low–molecular weight fluoro-oligomers that can reduce hemostasis and bacterial adhesion. This is an integral polymer and has the advantage of being present throughout the catheter and throughout the life of the catheter, unlike standard coating technology. In addition, this polymer blend is radiopaque under fluoroscopy, which allows temporal visualization as necessary. A small trial showed that peripherally inserted central catheters made of Endexo demonstrated significantly fewer complications, such as thrombosis, occlusion, infection, breakage, or dislodgement, versus a standard PUR catheter (Kleidon et al., 2018). Since the FDA approved BioFlo (AngioDynamics, Inc.) peripherally inserted central catheters (PICC) with Endexo technology in 2012, the application of this technology has expanded to other medical devices, such as cerebroventricular drainage systems and hemodialyzer membranes.

HydroPICC (Access Vascular, Inc.) is a proprietary technology that uses a high-strength thromboresistant hydrogel. Hydrogel coatings form a hydration layer on the surface of catheters, and this layer can provide a hydrophilic barrier against the adhesion of many proteins. In 2020, the HydroPICC gained FDA clearance after demonstrating an average 97% reduction in thrombus accumulation compared to a conventional PUR catheter in a pre-clinical study (Mannarino et al., 2020). Heparin-coated catheters are also available on the market, but there is limited evidence to support their utility in reducing the complications of vascular catheterization. Topographic modification involves the introduction of an unfavorable surface contour through the use of nanostructures that can prevent bacterial adhesion or even promote cell wall rupture (Hsu et al., 2018). However, the production of these nanostructures is resource-intensive, limiting the scalability of this strategy. Finally, external-energy–activated catheters are also in the pre-clinical stage of development. Light is used to promote the photocatalysis of organic contaminants on surfaces impregnated with titanium dioxide, while acoustic energy is used to reduce biofilm formation and promote improved antibiotic penetration (Dror et al., 2009).

4.3.2. Arteriovenous access

AV access is created by introducing a synthetic or biologic graft material between an arterial and a venous vessel. An AV access, either a graft or a fistula, is usually created for patients who require chronic hemodialysis. It is preferred in chronic hemodialysis over catheters because of the lower risk of infection (Lok et al., 2020). In addition to their role in hemodialysis access, vascular grafts are important in surgical bypass. For hemodialysis access, there is no evidence to support the superiority of one graft type over another, but the most commonly used type is a prosthetic graft made of either expanded polytetrafluoroethylene (ePTFE) or PUR. Examples of biological grafts include bovine carotid artery, cryopreserved human femoral veins, and biologically engineered vessels (Matsuzaki et al., 2019). Compared with fistulas, hemodialysis grafts are more susceptible to long-term complications, such as thrombosis, stenosis, and the need for reintervention (Lok et al., 2020). In the case of surgical bypass, autogenous vessels are preferred. For coronary artery bypass, either an internal mammary artery or a radial artery is preferred, depending on the target vessel (Lawton et al., 2022), while for lower extremity bypass, a great saphenous vein is preferentially used, but heparin-bonded ePTFE grafts are used in the absence of a vein with the appropriate diameter, length, and quality. The incorporation of heparin on the luminal surface of grafts is just one of the various modifications that have been implemented to improve their cumulative patency (Matsuzaki et al., 2021). Other examples of modified grafts include reinforced grafts (Benedetto et al., 2017) and self-sealing grafts (Al Shakarchi & Inston, 2019).

Heparin-bonded grafts are produced by covalently attaching heparin to the luminal surface of polymeric grafts, such as ePTFE. Matsuzaki et al. (2021) showed heparin-eluting grafts with PCL/PLCL copolymers (Figure 5). The covalent bond is created in a fashion that preserves the active site of heparin, which allows the anticoagulant to retain its activity. An example of this technology is the Carmeda Bioactive Surface (CBAS) heparin surface modification that is used in the production of GORE PROPATEN vascular grafts for hemodialysis access and lower extremity bypass procedures. Presently, there is conflicting evidence of the benefits of heparin-bonded grafts over standard ePTFE. In terms of hemodialysis access, a prospective study showed a non-significant trend towards improved patency for heparin-bonded grafts (Olsha et al., 2016). Likewise, a similar trend was observed for heparin-bonded grafts in lower extremity bypass (McAnelly et al., 2017). Grafts may also be reinforced through the use of plastic rings and self-expanding stents. Reinforcements are thought to improve cumulative patency by preventing stenosis and reducing graft compressibility. A retrospective study revealed a significant improvement in the 3-year patency of vascular grafts with the use of external reinforcement, such as prosthetic beadings, rings, and spirals (Hung et al., 2010). Stents made of nitinol may also be used to reinforce vascular grafts. Nitinol stents were initially used to reinforce the distal ends of prosthetic grafts; however, small studies have shown that the cumulative patency of these nitinol-reinforced grafts is not superior to that of standard ePTFEs, even for patients with disadvantaged vascular anatomy (Anaya-Ayala et al., 2015; Benedetto et al., 2017). Prosthetic grafts that are reinforced with an external nitinol stent are available on the market, but evidence of their clinical benefits over standard ePTFEs remains lacking. Self-sealing grafts, such as Acuseal (W.L. Gore & Associates, Inc.), Flixene (Getinge AB), Vectra (Thoratec Corp.), and AVflo (Nicast Ltd.), are made of multiple layers of elastomeric polymers that allow these devices to seal immediately after puncture. This property allows for early cannulation. Acuseal and Flixene are made of three layers of PTFE. Vectra is constructed to contain three layers of poly(etherurethaneurea), while AVflo is composed of multiple layers of electrospun polycarbonate urethane nanofibers. These grafts have demonstrated adequate long-term patency, but there is limited evidence to support the use of a specific type of self-sealing graft over the others (Al Shakarchi & Inston, 2019).

Figure 5.

Matsuzaki et al. (2021) showed the fabrication of heparin-eluting grafts consisting of an inner heparin-eluting inner layer made with 50:50 poly(caprolactone) (PCL): poly(lactide-co-ε-caprolactone) (PLCL) copolymer and an electrospun nanofiber PCL layer (15µm) average pore size. Image was adapted from Matsuzaki et al. (2021).

Aside from modified prosthetic grafts, tissue-engineered grafts are also being developed to overcome the limitations associated with the currently available autologous and prosthetic grafts. Most prosthetic grafts face the issue of reactivity, while autologous biological grafts may not always be adequate to cover the vascular area of interest. If harnessed well, a tissue-engineered vascular graft (TEVG) may address these limitations. A TEVG is typically composed of a scaffold, cells, and growth signals. The scaffold may be constructed from either synthetic or natural polymers. Examples of synthetic biodegradable materials for TEVGs are poly(glycolic acid) (PGA), poly(lactic acid) (PLA), PCL, and polyglycerol sebacate (PGS), while natural polymers include collagen, elastin, fibrin, gelatin, and chitosan (Matsuzaki et al., 2019). Several TEVGs have been tested in humans, but successfully bringing one to the market has been a challenge. Clinical success relies on creating a TEVG technology with success in various cohorts and centers, reproducible quality that equals or exceeds the gold standard, and justified economic cost (Pashneh-Tala et al., 2016).

4.3.3. AV fistula

An AV fistula (AVF) is constructed by creating an anastomosis between an arterial and a venous vessel. It is preferred over grafts in chronic hemodialysis because of a lower risk of long-term complications, such as thrombosis, stenosis, and need for reintervention, that are associated with unassisted AVF use (Lok et al., 2020). However, high primary failure rates limit its utility. AVF failure occurs due to neointimal hyperplasia (NIH), a process that results from the synergistic effects of inflammation, hypoxia, and hemodynamic shear stress on vascular tissue. NIH eventually leads to vascular stenosis and thrombosis; thus, several strategies are being explored to regulate the pathways that lead to NIH.

There are currently no recommended therapeutic strategies to improve the outcomes of AVF maturation. A recent Cochrane study reported that there is insufficient evidence to support the use of investigational pharmacologic agents, such as aspirin, clopidogrel, dipyridamole, warfarin, sulphinpyrazone, and glyceryl trinitrate patch; however, ticlopidine was more effective than placebo in a meta-analysis of short-term graft patency (Mohamed et al., 2021). Larger prospective studies are needed to confirm these findings, but alternative strategies should also be explored. These include the administration of elastase, the use of support devices to improve fistula geometry, and the use of multifunctional polymer scaffolds.

A small randomized trial showed that vonapanitase, a recombinant elastase, applied locally during fistula creation, was associated with increased fistula use for hemodialysis and fistula survival (Bleyer et al., 2019). VasQ (Laminate Medical Technologies Ltd.), a nitinol implant placed to externally support the anastomotic site, is an example of a support device that aims to improve flow and mitigate NIH (Figure 6). Another small study demonstrated improved short-term patency rates with this device over unassisted maturation, but larger studies are needed to confirm this clinical benefit (Chemla et al., 2016). The development of a multifunctional radiopaque scaffold that allows the radiographic monitoring of fistula maturation and the delivery of therapeutic immunomodulators is also being explored. A recent study Perez et al. (2021a) showed that the addition of a bioresorbable polymer scaffold loaded with mesenchymal stem cells around the outflow vein of an AVF inhibited NIH and promoted luminal expansion and subsequently AVF maturation. In this study, the immunomodulatory properties of mesenchymal stem cells (MSCs) were maximized by promoting their retention within the vascular adventitia. AuNPs were used to introduce radiopacity to th scaffold, which could be used to radiographically monitor its patency.

Figure 6.

The VasQ device consists of a brace and a braid (A) and its in vivo application over the anastomosis and juxta-anastomotic region of a brachiocephalic AVF (B). Images were adapted from Karydis et al. (2020).

Conclusions

The application of nanotechnology in medicine has the potential to have a major impact on human health and how we diagnose, treat, and prevent diseases. Different nanoparticles and nanomaterials have been developed and are currently being developed to address the limitations of traditional procedures and devices being used in IR. In this review, we described the medical devices used in vascular radiology in which nanoparticles have been employed for improved diagnostics, treatment, or even theranostic options. Specifically, we focused on the application of nanotechnology in existing vascular medical devices such as IVC filters, vascular access, and arteriovenous grafts. Several of these nanodevices have been approved by FDA for use in clinical applications such as vascular catheters with drug-eluting properties and aneurysm coils. On the other hand, majority of the nanodevices and nano-drug delivery systems reviewed in the past five years are still in preclinical studies.

Despite the advances in the use of nanoparticles in IR, majority of these innovations developed in the laboratory still need to be improved in order to be translated and used in clinical practice. In oncology alone, huge efforts to design nanodevices to reach tumor mass have been made in the past 15 years (Hernandez-Camarero et al., 2020); however, only a few nanoformulations have been approved by the USFDA for clinical use including ONPATTRO Patisiran ALN-TTR02 (Alnulam Pharmaceuticals) and VYXEOS CPX-351 (Jazz Pharmaceuticals) (Anselmo & Mitragotri, 2019). In order to increase translation efficiency of nanodevices, it is vital to address challenges in formulation, standardization of methods, toxicity, biocompatibility, as well as production-associated costs.

Nevertheless, the synergy between IR and nanotechnology allows for a diversity of applications in an expanding scope of IR. While several nanoparticle imaging contrasts such as SPIONs have already been successfully used, its application along with image fusion has been foreseen as a promising technique in medical imaging as the combination of both could reveal pathologies less than 1 nm in size (Manson et al., 2020). Another exciting opportunity for IR is the combined application of nanotechnology and artificial intelligence (AI), especially in drug delivery systems. While nanotechnology has the potential to create versatile carriers for improved targeting of pathologies in different sites and localization, AI has a great potential to optimize drug and dose parameters specific to a given patient or situation (Ho et al., 2019).

Table 1.

Novel drug delivery systems that incorporate nanoparticle in recent years (2017–2022).

Indication	Application	Material	Stage	Reference
Coronary Artery Disease	Therapy	stem cell-laden collagen hydrogel	Phase 1/Completed (NCT02635464)	He et al. (2020)
Pulmonary Hypertension	Therapy	PLGA with pitavastatin (NK-104-NP)	Phase 1/Completed (UMIN000014940 and UMIN000019189); 40 patients, Japan	Nakano et al. (2018)
Lung Cancer	Therapy	polymeric micellar paclitaxel	Phase III/Active (NCT02667743); 448 patients, China	Shi et al. (2021)
	Therapy	albumin-bound paclitaxel	Phase III (UMIN000017487); 503 patients, Japan	Yoneshima et al. (2021)
	Therapy	PCL with arachidonoylcyclopropylamide	In vitro	Boyacioglu et al. (2021)
Bone Cancer	Imaging (CT)	mesoporous silica–coated bismuth sulfide loaded with doxorubicin and conjugated with peptide (RGD)	In vivo (mice)	Lu et al. (2018)
Gastrointestinal Bleeding	Imaging (MPI)	PEG-stabilized SPIO	In vivo (mice)	Yu et al. (2017)
Haemorrhage	Therapy	human thrombin (THR) into a sol-gel derived magnetite matrix	In vitro	Shabanova et al. (2018)
	Imaging (NIR, X-ray, CT)	AuNP-loaded with dye (DiD) and peptide (GRGDS)	Material development	Gkikas et al. (2019)
Anastomotic Leak	Therapy	PCL and PLCL	In vivo (pigs)	Rosendorf et al. (2020)
Varicocele	Therapy	curcumin-loaded nanomicelles	In vivo (rat)	Sadraei et al. (2022)
Prostate Enlargement	Therapy (photothermal)	PVP-AgNP	In vivo (rat)	Marghani et al. (2022)
	Therapy	AuNP	In vivo (rat)	Al-Trad et al. (2019)
Uterine Leiomyoma	Therapy	polymeric NP-coated 2-methoxyestradiol (anti-tumor drug)	In vitro	Borahay et al. (2021)
	Imaging (OCT/DRI)	Zinc oxide and titanium dioxide nanoparticles delivered by microneedles for greater signal enhancement	Ex vivo	Gu et al. (2016)
Advanced Kidney Disease	Imaging (MRI)	Ferumoxytol off label use for magnetic resonance angiography	Off-label	Stoumpos et al. (2018)
Renal Cell Carcinoma	Therapy (radiofrequency)	Radiofrequency radiation in the presence of AuNP as an alternative to nephrectomy	In vitro	Nikzad et al. (2017)
Bladder Cancer	Imaging and therapy (photothermal ablation)	DOX&IR780@PEG-PCL-SS NPs with dual sensitivity to glutathione and NIR laser irradiation	In vivo (mice)	Zhu et al. (2020)
Hepatocellular Carcinoma	Therapy	PLGA with iron oxide microspheres	In vitro	Nosrati et al. (2018)
	Therapy	hyaluronic acid/ polyethylenimine/ doxorubicin in gellan gum microspheres	In vivo (rabbit)	Hsu et al. (2018)
Vertebral compression fracture	Therapy	magnetic NP to target spinal regions in pig models	In vivo (pigs)	Denyer et al., 2018
Stroke	Imaging (Optical)	Quantum dot (V&C/PbS@Ag2Se) with NIR dye (Cy7.5)	In vivo (mice)	Yang et al. (2021)
	Therapy	MnO2 with fingolimod	In vivo (rat)	Li et al. (2021)

Abbreviations: PLGA: poly(lactic-co-glycolic acid); PCL: poly(caprolactone); CT: computed tomography; RGD: arginine-glycine-aspartic acid peptide; MPI: magnetic particle imaging; PEG: poly(ethylene glycol); SPIO: superparamagnetic iron oxide; NIR: near infrared; DiD: 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine perchlorate; GRGDS: glycine-arginine-glycine-aspartic acid-serine peptide; PLCL: poly(lactide-co- ε-caprolactone); PVP: poly(N-vinyl pyrrolidone); AgNP: silver nanoparticle; AuNP: gold nanoparticle; OCT: optical coherence tomography; DRI: deep range imaging; DOX&IR780@PEG-PCL-SS NPs: doxorubicin with IR780 NIR dye cross-linked with PEG-PCL-SS polymeric nanoparticles; V&C/PbS@Ag₂Se: targeted and PEGylated lead sulphide-silver selenide; MnO₂: manganese oxide

Table 3.

Clinically used nanoparticles in drug delivery and medical devices as approved by US FDA.

	Nanoparticles	Application	Trade Name/Manufacturer
Drug Delivery	Liposomal NP loaded with Doxorubicin	Chemotherapy	PEGylated: Doxil (Alza Corporation); Lipodox (Sun Pharmaceutical Industries Ltd.)
			UnPEGylated: Myocet (Sopherion Therapeutics)
	Liposomal NP loaded with Irinotecan	Metastatic adenocarcinoma of the pancreas	ONIVYDE (Merrimack Pharmaceuticals Inc)
	Liposomal formulation of cytarabine:daunorubicin	Acute myeloid leukemia	VYXEOS CPX-351 (Jazz Pharmaceuticals)
	Albumin NP loaded with Paclitaxel	Advanced non-small cell lung cancer, metastatic pancreatic cancer, metastatic breast cancer	Abraxane (Bristol-Myers Squibb)
	Lipid NP loaded with siRNA	Polyneuropathy of hereditary TTR-mediated amyloidosis (hATTR)	ONPATTRO (Alnylam Pharmaceuticals)
	Iron oxide NP with carbohydrate shell	Treatment of iron deficiency anemia in patients with chronic kidney disease	Ferumoxytol, Feraheme (AMAG Pharmaceuticals Inc); Feridex (Bayer)
Medical Devices	Polyglycolic/polylactic acid coated coil	Aneurysm coiling	Matrix2 (Boston Scientific Target)
	Nitinol/Platinum wires	Aneurysm coiling	Woven EndoBridge Aneurysm Embolization System (MicroVention, Inc)
	Platinum coil	Aneurysm coiling	HydraCoil Embolic System (MicroVention, Inc)
	BioFlo® (non-eluting polymer that is “blended” into polyurethane)	Vascular Access (PICC)	BioFlo (AngioDynamics, Inc)
	Sirolimus-eluting stent with a biodegradable polymer coating and ultra-thin struts	Vascular Access (PICC)	Supraflex (Sahajanand Medical Technologies)
	Electrospun polycarbonate urethane nanofibers	Arteriovenous access (graft)	AVflo (Nicast Ltd)
	Heparin-bonded expanded polytetrafluoroethylene endografts	Vascular Graft (PAD)	Viabahn (W.L. Gore & Associates,Inc)

Abbreviations: NP: nanoparticle; PEG: polyethylene glycol; HIV: human immunodeficiency virus; PICC: peripherally inserted central catheter; PAD: peripheral arterial diseases