Maglev-fabricated long and biodegradable stent for interventional treatment of peripheral vessels

doi:10.21203/rs.3.rs-3574571/v1

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Maglev-fabricated long and biodegradable stent for interventional treatment of peripheral vessels

https://doi.org/10.21203/rs.3.rs-3574571/v1

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published 10 Sep, 2024

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While chronic limb-threatening ischemia is a serious peripheral artery disease, the lack of an appropriate stent significantly limits the potential of interventional treatment. In spite of much progress in coronary stents, little is towards peripheral stents, which are expected to be long and biodegradable and thus require more breakthroughs in core techniques. Herein, we develop a long & biodegradable stent (LBS) with a length of up to 118 mm based on a metal-polymer composite material. Nitriding treated iron with elevated mechanical performance was applied as the skeleton of the stent, and a polylactide coating was used to accelerate iron degradation. To achieve a well-prepared homogeneous coating on a long stent during ultrasonic spraying, a magnetic levitation (Maglev) was employed. In vivo degradation of the LBS was investigated in rabbit abdominal aorta/iliac arteries, and preclinical safety and efficacy were evaluated in canine infrapopliteal arteries. First-in-man implantation of LBS was carried out in the below-the-knee artery, and the 6–13 months follow-ups demonstrated the feasibility of the first LBS.

Physical sciences/Materials science/Biomaterials/Biomedical materials

Physical sciences/Engineering/Biomedical engineering

Physical sciences/Chemistry/Polymer chemistry

Health sciences/Cardiology/Interventional cardiology

Biological sciences/Biotechnology/Biomaterials/Implants

biodegradable material

peripheral stent

interventional treatment

magnetic levitation

below-the-knee stent

metal

polymer

Peripheral arterial disease (PAD) is one of the most prevalent diseases in the world, resulting in around a quarter million of amputations in United States and Europe annually and millions worldwide (1). Claudication, ischemic rest pain, non-healing ulcer, focal gangrene and tissue loss in lower limb are the early symptoms before amputation, and the classification of Rutherford class about symptoms relevant to low limb artery is schematically presented in Fig. S1. Most of these clinical symptoms can be remitted by re-opening the occluded lower limb artery (2). The main endovascular-first therapy for PAD is percutaneous transluminal angioplasty (PTA) with bare balloon, which results, however, in high incidence of restenosis due to limited acute lumen gain, elastic recoil and dissections (2, 3). The below-the-knee (BTK) lesion with chronic limb-threatening ischemia (CLTI) is the most difficult to treat due to complex anatomy such as long diffuse stenosis, chronic total occlusion (CTO) and serious calcification; the patency of PTA was 50%-80% after one year (4).

Stents play a crucial role in interventional treatment of cardiovascular diseases (5, 6). During the latest score years, various stents have been developed (7,8); either long or biodegradable cardiovascular stents are dependent upon cutting-edge techniques (9).There is so far no stent of both biodegradability and long length, which is, however, much demanded for millions of patients of PAD and much challenging in science and technology (10). Although many coronary stents have been applied in intentional treatment, the development of peripheral stents is very limited due to the bottleneck to fabricate a long biodegradable stent.

Conventional stenting was ever tried to improve the patency issue in BTK. Bare metal stents (BMS) have failed to prove its superior over PTA, and drug eluting stents (DES) have only been successful in shorter infrapopliteal lesions in some randomized controlled trials (11-13). But in the real world, the majority of PAD treated lesions are long CTO (>40 mm) and seriously calcified (14). The DES is normally non-biodegradable and short (8-38 mm), and thus it is inevitable to use two or more stents to cover the entire BTK lesion, which raises uncertain prognosis results for the interventional lesions (15). Another main issue of a permanent stent applied in BTK lesions is of high target lesion failure (TLF), which lead to higher rates of in-stent restenosis (ISR) or occlusion, and it is difficult to re-canalize or re-dilated an ISR lesion due to the cage of the original stent (16). Thus, no DES has been approved by US food and drug administration (FDA) in the treatment of BTK lesion. Other technologies, such as debulking/atherectomy equipment, score/ultrasonic balloon, and drug coated balloon were tried for infrapopliteal lesion, but failed to be a mainstream therapy over PTA with limited comparative data (2).

A bioresorbable stent (BRS) is expected to not only keep the lumen away from recoil and dissection in the early stage, but also avoid long term side effects of permanent implants, and thus promising as an ideal solution for PAD intervention in the future (17). Polymer-based BRS has a satisfied patency in short lesions of infrapopliteal artery. Nevertheless, its short stent length (≤ 38 mm) and thick strut thickness (>100 μm) have confined its clinical application for long lesion (18). Metal-based BRS is another option for the treatment of BTK lesions (19, 20). Metallic BRSs include magnesium-based (21,22), zinc-based (23) and iron-based ones (24-28). Among these three metal-based BRSs, iron-based stents can provide the strongest mechanical performance, which is comparable to the gold-standard permanent CoCr alloy stent, Xience prime^TM stent. The other two BRSs have to compromise their strut thickness to reach equal mechanical performance. However, iron degrades slowly in human body (more than five years). If one technique can speed up iron degradation (less than two years) in human body, an improved iron-based stent with thin strut and appropriate degradation period might revolutionize the interventional treatment of BTK diseases, which frequently accompany with the long and seriously calcified infrapopliteal lesion.

The present study reports a long & biodegradable stent (LBS) with metal-polymer composite technique to treat infrapopliteal artery disease. While a biodegradable long stent is much required for treatment of PAD, three key problems need to be solved ¾ how to maintain early stenting while degradation until remodeling, how to achieve homogeneous coating, and how to access its safety and effectiveness after implantation, as schematically presented in Fig. 1. To resolve these difficulties towards and gain the first long and biodegradable cardiovascular stent is the theme of the work in this article.

In this work, we introduced appropriate nitriding of iron to enhance its mechanical performance of the metal, a zinc layer to prevent early corrosion of iron, and a poly(D, L-lactide) (PDLLA or simply denoted as PLA) coating to speed up the corrosion of iron with the metal-polymer composite technique. The term “composite” to describe the polymer-coated metal comes from the unexpected “accelerating” of iron corrosion by the PLA layer instead of “protection”, which has been elaborated by us in previous study of coronary stents (29-31). However, we found that it is hard to prepare the homogeneous PLA coating on a long stent simply by ultrasonic spraying, the main technique to coat short stents.

Eventually, we introduced a magnetic levitation (Maglev) technique into the field of biomedical engineering to improve the homogeneity of the coating in a long stent. Here, the Maglev technique is not identical to, and in fact more convenient than that used in high-speed train in the field of transportation vehicles (32). The state-of-the-art technique to fabricate a long composite stent achieved by the Maglev principle will be revealed in this article for the first time. The resultant LBS with the length of 118 mm and struts thickness of 70 mm is suitable for infrapopliteal anatomy lesions, which is of small diameter (2-4 mm), serious calcification, CTO lesion or long and diffuse stenosis lesion. The present paper reports the core technique and the underlying principle of the novel LBS, its fabrication, and the corresponding in vitro and in vivo performances.

Strengthening iron raw material via nitriding

Pure iron has higher strength, ductility, and formability than zinc and magnesium, which allows iron stents with thinner struts and more delicate patterns. Nevertheless, its tensile strength, ranging 230 ~ 345 MPa, is still lower than that of cobalt-chromium alloy for permanent stents, ~ 1000 MPa. In order to further increase the tensile strength of iron without sacrificing its biological performance, we tried to add trace nitrogen into iron matrix. A schematic diagram of the nitriding process is given in the left part of Fig. S2.

While the nitriding technique has been widely applied to improve surface performances of metal such as hardness, fatigue strength and corrosion resistance, the present technique is unique because the nitriding technique as bulk alloying instead of the surface modification and can enhance the ability of the whole metal. The tensile strength of the iron tube increased with nitrogen content till 1000 MPa when nitrogen concentration reached 0.08% as shown in the right part of Fig. S2, which is far larger than the tensile strength of the pure iron tube of 315 MPa.

Achieving a homogeneous PLA coating on a long stent via Maglev

The evenness of the polymer coating is critical for a metal-polymer composite based stent, which is particularly important and yet difficult for an LBS. A long stent must be flexible to match the curved vessels and avoid additional mechanical stimulation to vessel walls. However, one end of the stent must be fixed to enable another end exposed to the spayed solution in order to avoid the blank of coating on the fixing points, and thus a long stent was bent and woggled during the spraying blow and stent gravity, as demonstrated in the left of Supplementary Video S1. This is harmful for a homogeneous coating.

In order to improve the uniformity and integrity of the coating on a long stent, the technique must be compatible with fixing the free end of the stent and contactless. It has eventually achieved by us after introducing a Maglev technique. A non-contact magnet is exerted to the free end, as schematically presented in Fig. 2. The floated stent was then stable, as shown in the right of Supplementary Video S1.

The lower right curve in Fig. 2 confirmed the homogeneity of the resultant PLA coating on a long stent surface. We further carried out in vitro bench tests of our Maglev-fabricated LBS and the results are shown in Fig. S3. The LBS of thinner struts exhibited comparable mechanical performances to Xience.

Confirming the tuned in vitro degradation of LBS in Hank’s solution and in vivo degradation profile in small animals

The most important bottleneck of iron as a biodegradable material for a stent is its slow in vivo degradation. The content of iron in the LBS can be significant reduced due to great mechanical performance by nitriding, and the less iron usage may contribute partially to less degradation time of the stent. To further accelerate the degradation of the nitrided iron, we applied a PLA coating on the iron. In vitro testing demonstrated the faster mass loss of iron in the Fe-PLA composite. Nevertheless, an ideal design of a biodegradable stent provides sufficient radial strength until remodeling of the damaged vessel. Overly rapid degradation of a stent will lead to its early collapse. So we further introduced a zinc layer, making use of more activity zinc to delay the early degradation.

We carried out in vitro degradation in Hank’s solution at 37 ℃ (Fig. S4) and in vivo degradation in the rabbit model (Fig. 3). The results illustrated that our LBS of Fe-Zn-PLA is capable of both early supporting and in-time degradation. In the rabbit model, the LBS degraded mostly within 24 months after implantation, maintained intact in the first 2 months, the Zn buffer layer completely degraded in about 3 months. The 70% sirolimus was released in the first three months, and the remaining part was slowly released via degradation of PLA till about 18 months.

Figure 3 In vivo degradation of LBS in rabbit abdominal aorta/iliac model. (A) The left part is a schematic presentation of the degradation profiles of nitrided Fe, Fe-PLA and Fe-Zn-PLA. Here, Fe means the bare nitrided iron stent, Fe-PLA means the bare nitrided iron stent coating with a PLA layer loaded with sirolimus, and Fe-Zn-PLA means the bare nitrided iron stent coating with a zinc layer and a PLA layer loaded with sirolimus. The right part shows the degradation profiles of Fe, Zn and PLA in the LBS in rabbits, and the release curve of the drug. For each group, n = 5. The data are shown in mean ± standard deviation. (B) The sirolimus-eluting biodegradable LBS. The top shows an LBS stent system before balloon inflation and after balloon inflation; the bottom shows a scanning electron microscopy (SEM) image of the cross section of the stent and the cross section of the strut. (C) The typical micro-computed tomography (micro-CT) images and histopathology images of LBS.

An LBS in a balloon delivery system is demonstrated in Fig. 3(B). When the balloon was inflated, the pattern of the stent can be evenly expanded. The SEM image of the cross-section also confirmed the uniform expansion and coating evenness of the LBS, and the strut thickness of the LBS was 70 µm with abluminal coating.

Figure 3(C) presents the typical micro-CT images and the histological observations of our LBS in rabbit aorta/lilac. The stent struts kept clear and intact at 1 month, then the struts turned to obscure and degraded at 12 months. No stent collapse was found during the degradation, demonstrating that the duration of stent stenting was sufficient for vessel remodeling. Only a slight inflammatory response was observed in the optical micrograph, while brownish particles indicated the degradation products which were covered by a neointimal layer.

Confirming safety and efficacy of LBS in large animals

FDA recommends minipig coronary and rabbit iliac models for preclinical animal study of bioresorbable coronary stents, and a large amount of historical data has been accumulated. However, those animal models have not a blood vessel suitable for mimicking the human infrapopliteal artery. Herein, we select the model of canine BTK vessels to access peripheral-vessel stents, considering their similar vessel dimension, location, movement, and physiological indicators such as body temperature, blood pH, blood pressure and blood flow velocity.

We generated an over-expansion (1.1–1.2 folds of vessel reference diameter) injury to stimulate the proliferation in canine infrapopliteal artery and create the injury model. Our LBS as well as the gold standard Xience stents were implanted into the posterior tibial artery in the left and right hind legs. Optical coherence tomography (OCT) measurements were performed immediately after stent implantation and at the expected angiographic follow-up time windows. According to Fig. 4, no stent discontinuity or collapse was observed at the examined time points. In the group of LBS, the shadow behind the struts became obscure after 6 months, indicating the corrosion of the stent struts; in contrast, there was no change of struts in Xience stents with time. The area stenosis in LBS was as small as in Xience.

First-in-human evaluation of LBS and its follow ups

After approval, we carried out the first-in-human or first-in-man (FIM) examination of LBS. The first patient (case A) was an octogenarian male with a six-decade history of managed hypertension, absent of any diabetic complications. The patient had experienced bilateral lower extremity claudication for a duration of two years, constrained to a limping distance of approximately 20 meters. Notably, symptoms were more pronounced in the left lower extremity compared to the right. Clinical evaluation yielded a diagnosis of lower extremity arteriosclerosis with Rutherford class 3, denoting severe intermittent claudication. To ameliorate functional impairment and enhance life quality of the patient, percutaneous transluminal angioplasty was initially conducted. Angiographic assessment revealed occlusions in the tibio-peroneal trunk (TPT) and peroneal artery (PA) of the left leg; only the posterior tibial artery (PTA) remained patent. Subsequently, BTK interventional theprapy was executed, following informed consent from the patient and ethical committee approval. The interventional process is shown in Supplementary Video S2, and the typical procedures are demonstrated in Fig. 5.

Additional diagnostic data, including preoperative computed tomography (CT) and ultrasonography, are presented in Fig. 6. In this patient, the CT demonstrated that there was an infrapopliteal disease with a patent P3 (popliteal artery, from the center of knee joint space to the origin of anterior tibial artery) and PTA. No patent PA and TPT were found. According to the ultrasonography evaluation, the P3 segment was patent and the preoperative flow rate was 29.3 cm/s, the TPT was occluded with zero flow rate. In order to achieve at least one direct flow to the foot, the TPT need to be re-canalized. After stent implantation, the occluded TPT was stented and with significant increased blood flow from 0.0 cm/s to approximately 98.4 cm/s, owing to effective lumen maintenance by the LBS. The long-term follow-up at 13 months confirmed the enduring functionality of the stent and sustained arterial patency (Rutherford class 0).

Case B is a 69-year-old male of Rutherford class 5 with a non-healing ulcer, focal gangrene, and small tissue loss. According to preoperative angioplasty, there were a patent TPT, a diffuse stenosis PTA, and an occluded PA (Fig. 7). Utilizing a guidewire to cross the stenosis PTA lesion and PA lesion, then a balloon of Φ2 × 80 mm was used for the PTA. Subsequently, an LBS (Φ2.75 × 78 mm) was strategically positioned at the site of the PTA lesion and successfully expanded using nominal inflation pressure.

For comparison, long-segment occlusive lesions in PA are treated with a Φ2.5 × 170 mm balloon dilatation in case B. Post-angioplasty imaging revealed a fully patent PTA and PA, correlating with immediate symptom alleviation (Rutherford class 2) subsequent to the intervention. The 6-month follow-up angiography of this case showed that the stenosis rate of the PTA lesion with implantation of LBS was 30% while the stenosis rate of the PA lesion treated only by balloon was 80%.

Case C is also a 69-year-old male but with a Rutherford classification 3 with severe claudication and the patient involved an LBS (Φ2.75 × 58 mm) implanted in his PA. The six-month follow up demonstrated that the PA lesion was patent and the LBS stented well (depicted in Fig. S5).

It is satisfactory that Rutherford classifications improved from class 5 to class 2 (with only mild claudication) in the patient Band from class 3 to class 0 (asymptomatic) in the patient C after six months after LBS implantation. Cumulatively, the cases presented herein validate the operability, safety, and efficacy of the LBS technology. We are currently in the clinical trial phase. Comprehensive statistics from multi-center trials will be reported by clinical teams in the future.

The latest decade has witnessed much progress in biomaterials for medical devices and pharmaceutics etc (33–39). Among various biomaterials (40–42), a cardiovascular stent is of much importance in clinics and has much difficulty in technique. An ideal stent appropriate for interventional treatment is expected to be highly deliverable with a thin-strut, low profile, flexible design and high radial strength (43). The current commercialized permanent stents for infrapopliteal artery are only for bail-out failing balloon angioplasty, namely, PTA. There is much demand to develop an ideal treatment to re-open CTO, as schematically presented in Fig. S6. The long lesion prevalence in peripheral artery and the scruple for ISR have hindered the stent application as a primary treatment. Repair of a long lesion needs to implant more than one stent, and the overlapping area or the gap area of two stents leads to an intrinsic risk of focal in-stent restenosis, as schematically presented by us in Fig. S7. In contrast, a biodegradable stent theoretically would improve the “caged vessel” result and eliminate the scruple of ISR, as presented in Fig. S8. Then, a biodegradable long stent would be further eliminated stent overlapping limitation and more customized for infrapopliteal artery.

A biodegradable long stent is first reported in this article. The innovations of biomaterials supporting the advantages of our metal-polymer composite based LBS over other BRSs and permanent stents are summarized from the following three aspects.

(1) The bulk-alloy nitride iron to strengthen the backbone material of the stent. We applied nitriding followed by heat treatment and drawing of the iron tubes to strengthen iron. During the whole nitriding process, no other metallic or toxic element but nitrogen was incorporated into the LBS matrix. Bulky alloying of the iron stent through nitriding elevates the tensile strength by dispersive precipitates of Fe₄N and over-saturated solution of nitrogen in iron lattices without formulation of any white nitriding layer on the surface. Moreover, nitrided iron degrades faster than pure iron owing to the additional galvanic corrosion between iron matrix and dispersive scattered Fe₄N precipitations (44). The first pure iron stent, NOR-I, reported for the preclinical study by Matthias Peuster is of thickness 100–120 µm, Φ3 × 16 mm weighed 41 mg (45). In contrast, our LBS is of strut thickness 53 µm, and a Φ3 × 15 mm LBS contains only 9 mg of iron. Owing to the enhanced mechanical properties after alloying, the amount of iron has been reduced about 80%, which also shortens the degradation period of the stent. The resultant thin stent affords a sufficient mechanical stenting in BTK artery as a balloon expandable stent like the Xience prime stent approved by conformity with European in BTK.

(2) Magnetic levitation to enable a homogeneous polymer coating on a long metal stent. Fabrication of a long peripheral biodegradable stent is faced with difficulties such as mitigating the deviation of the dimension and homogeneity of a long stent in axial direction. Herein we introduced a magnetic levitation to fix the free end of the long stent in a contactless way. This technique avoids stent bending and fluctuating during the coating process, and thus significantly improves the coating homogeneity (Fig. 2, Supplementary Video S1). Based on characteristics of the iron materials, and the infrapopliteal lesion (long and seriously calcified), the designed longest Maglev-fabricated LBS was 118 mm, almost triple times of the longest balloon-expandable peripheral stents (38 mm) in the world market.

(3) Combination of a microscale PLA coating and a nanoscale Zn layer to adjust the profile of iron corrosion. There are many advantages of iron stents as peripheral stents, such as high mechanical performance, good biocompatibility and established absorption mechanism. A challenge of iron as a biodegradable material for a BTK stent is how to mediate its degradation in arterial blood under a weak alkaline environment (pH 7.4). Early in 1924, Whitman et al. from the Massachusetts Institute of Technology found that the local pH and thus hydrogen-ion concentration could influence metal corrosion significantly (46). It is also known that polyester hydrolysis can lead to an acidic environment (47). Herein, we introduced a PLA coating to creating a local acid environment, taking advantage of hydrolysis of aliphatic polyester. In order to avoid early stent collapse while speeding up iron degradation, we applied a polyester of 200 kDa molecule weight for the PLA coating, where the relatively high molecular PLA would hydrolyze and create acid local environment in a sustained manner. Another critical design of our LBS as the BTK stent is the addition of a Zn buffer layer on iron surface to prevent overly early iron degradation. To this end, we prepared a zinc layer of 600 nm thickness by electroplating on iron as a sacrifice anode to delay the onset of iron corrosion owing to a galvanic effect. This Zn layer was found to prevent iron from degradation for first three months after implantation, as reflected from the in vivo biodegradation in rabbit aorta/lilac (Fig. 3). Eventually, the Fe-Zn-PLA design matches with both stenting at the early stage and remodeling at the late stage.

In order to evaluate safety and efficacy of the new stent, we implanted an LBS and a gold standard non-biodegradable stent (Xience) into canine infrapopliteal arteries of each hind legs for control. No stent thrombosis was found in both groups according to OCT observations on 28, 90, and 180 days after implantation. It is interesting that both groups had a trend of less restenosis along with time, which might be influenced by the early fibrosis deposition in the canine model. The 6-month follow ups (Fig. 4) demonstrated the safety and efficacy of LBS in large animals.

We also demonstrate the clinical cases of the LBS (Figs. 5–7, Fig. S5). According to the BTK quantitative vessel angioplasty of the first patient, there is a chronic total occlusion of 25 mm length in TPT. Other main artery such as anterior and peroneal arteries are with even longer CTO to the footage. In order to relieve the ischemic, this operation was to acquire at least one patent artery directly to the foot. Thus, a pre-dilatation balloon was applied to reanalyze the tibio-peroneal CTO lesion. Angioplasty demonstrated a limited dissection that need further treatment. An LBS was thus used to settle the dissection and a desired lumen gain was achieved without any residual stenosis. Both the flow rates of PA and TPT vessels were significantly improved and kept patent till the longest follow-up to (13 months). The long-term follow-up of TPT lesion (Fig. 6) further illustrated a preliminary feasibility of LBS applied in BTK application. And the forthcoming two additional clinical cases (Fig. 7 and Fig. S5) further strengthened the operability, safety and effectiveness of the LBS.

According to the BTK quantitative vessel angioplasty of the second patient, there is a severe stenosis of 60 mm length in the PTA. Other main artery such as the middle segment of the peroneal artery and the anterior tibial artery are with even longer CTO to the footage. In order to relieve the ischemic, this operation was to acquire at least one patent artery directly to the foot. Thus, a pre-dilatation balloon was applied to reanalyze the PTA lesion. Angioplasty demonstrated a limited dissection that needs further treatment. An LBS was thus used to settle the dissection and a desired lumen gain was achieved without any residual stenosis. The flow rate of PTA vessels was significantly improved and kept patent till the longest follow-up (6 months). The third case (Fig. S5) further strengthened the operability, safety, and effectiveness of the LBS.

Very recently, a longe self-expandable DES (Φ3.5 × 80 mm) was compared with balloon angioplasty, and according to the clinical trial results published in December, 2023 (48), the self-expandable DES showed no benefit related to effectiveness and safety with the classical PTA based on the one-year patency etc. Thus, an appropriate stent applied in infrapopliteal artery, which should first focus on the decrease ISR and then be longer. Our LBS with similar ISR compared with golden standard DES, might inherit the merits of typical DES to further eliminate the scruple of ISR. In our FIM study (Fig. 7), case B is so special that the doctor implanted our stent to one of the main BTK vessels and dealt with another parallel BTK vessel using only balloon. The follow-ups indicate that the ISR after 6 months was 30% for the vessel with LBS and 80% for the vessel only expanded by a balloon. In spite of only one clinical case, the data preliminarily indicate the benefit of our LBS compared with PTA in a long infrapopliteal artery lesion.

Basically, there are two fashions of stents for interventional treatments, namely, self-expandable and balloon-expandable. All of the commercializable self-expandable stents are, just like examined in this reference, made of nitinol, taking advantage of the superelasticity of this marvelous alloy. Unfortunately, this metal is of low modulus and thus as indicated the Discussion of this important clinical paper "nitinol stents, as used in this trial, have greater wall thickness and other geometric differences compared with balloon-expandable metallic coronary stents used below the knee, which may affect endothelialization and thus clinical outcomes." (48) The valuable 2023 clinical article releases objectively a failure result, and calls for "Continued innovation to provide optimal treatments for CLTI is needed" in the end of its abstract (48). Our study of balloon-expandable stents is just a demonstration of "innovation for CLTI". While long lesions frequently occur in the case of BTK artery, the longest balloon-expandable stent is of 38 mm length owing to engineering difficulty. It is even more challenging to prepare a stent which is both long and biodegradable. Hence, our development of the first long (up to 118 mm) and biodegradable balloon-expandable stent is of significant technological advance.

In conclusion, this paper reports the core technique of the long biodegradable stent for the first time. The LBS of 53-µm strut thickness is based on a metal-polymer composite, which is mainly composed of nitrided iron and PLA. The PLA coating was found not to protect iron from degradation but to speed up its degradation. Inspired by the Maglev train, we employed this remote-control technique to achieve a stable and homogeneous ultrasonic spray of a PLA solution to a long stent. Furthermore, this study demonstrates the feasibility of LBS applied in BTK lesion based on in vitro tests, rabbit and canine in vivo experiments, and the FIM clinical study. The three clinical cases have covered all of the main BTK arteries, namely, TPT, PTA, and PA. While stent based interventional treatment is currently not the first-line therapy due to lack of an appropriate stent, the present report might trigger the forthcoming research & development of more biodegradable stents and revolutionize the first-line surgical method to deal with diseases of peripheral vessels. The clinical implantation of our LBS is the first case for a long and biodegradable stent to be applied in interventional therapy of not only infrapopliteal artery disease but also in other indication with stent-like medical treatment. Therefore, the present bench-to-bedside study from the fundamental research of biomaterials to the FIM implantation in BTK arteries sheds new insight to develop various long & biodegradable medical devices.

Fabrication of nitrided-iron tubes and LBS stents

A pure iron tube (Φ6.0 mm, wall thickness 0.5 mm) was cut into segments with 25–35 cm length. The tube segments were put into an in-house-design nitriding furnace to be nitrided with a gas method. We carried out the initial nitriding at 500 ℃ with nitrogen for 30 min, then started vacuuming. The samples were heated at 950 ℃ for 30 min, and finally annealed at 500 ℃ for 30 min. The semi-finished nitride tube was drawn into nitride iron tubes of desired sizes (Φ1.6 mm, wall thickness 0.11 mm).

The finished nitride-iron tube was laser-cut into multiple stents. All the stents were polished to accurate dimensions. A nitride-iron stent was eletroplated with a pure zinc layer with 600 nm thickness. We then used a Sono-Tek system (2012 Route 9W, Milton, N.Y. 12547 USA) to spray a solution of PLA (Evonik Industries, Germany) on the surface of stent.

Characterization of nitrogen content and PLA coating

Nitrogen content was measured with an ONH analyzer (ONH-2000, ELTRA Inc., Germany). Nitrogen-permeable semi-finished iron pipe (500 mg) was used to determine the nitrogen content of the stent (wt. %).

The PLA coating thickness was measured by spectroscopic reflectometry with a 3D optical profilometer (Q six, Sensofar Medical, Spain).

Mechanical measurements

The tensile strength of the finished iron tube of 100 mm was measured with a universal test machine (C43.504, MTS Inc., USA) at room temperature. The measurement standard follows ASTM E8.

A radial strength tester (RX550-100, Machine Solution Inc., USA) was applied to detect the radial force of LBS with a 0.1 mm/s of compression rate. The strength at 10% compression of the outer diameter of the initial stent was defined as the radial strength in units of kilopascal.

Crush resistance was evaluated by compression between parallel plates perpendicular to the longitudinal axis of the stent. The measurement was done in an electromechanical universal testing machine (C43.504, MTS, USA) with a 0.1 mm/s of compression rate. The force per unit length at 50% compression of outer diameter of the original stent was defined as crush resistance in units of N/mm.

We also determined local compression resistance (CR), which is important to deal with the case of calcified plaque. As such, we implanted the stent with nominal pressure into a mock vessel (inner diameter 2.7 ± 0.2 mm, radial compliance 5–7% per 100 mmHg@72 bpm, Dynatec Labs, Inc., Galena, MO, USA) with a simulated plaque and record the resist distance. The height, width and length of the simulated plaque in the experiment read 6.8 mm, 2.8 mm and 1.7 mm, respectively. The CR is defined as

CR = d/D × 100% (1)

Here, d presents the diameter of the LBS under a simulated plaque, and D represents the diameter of the normally expanded stent.

Animal models and stent implantation

The preclinical study was approved by the Ethics Committee of Shenzhen Advanced Medical Services Corporation in China. Small animals were used to evaluate the in vivo drug release and individual content degradation profile of the LBS. New Zealand rabbits of an average weight of 2.5 kg ranging from 1.9 to 3.2 kg experienced a standard diet without cholesterol or lipid supplements. The implantation sites were, the abdominal aorta and iliac arteries. We first punctured the right femoral artery of the rabbit and introduced a 5 F guide catheter over a 0.014-inch guidewire. Then, a Φ3 × 8 mm LBS was introduced and positioned in the vessel segments avoiding the main branch of aorta under the fluoroscopic control. The stent was deployed under 8–10 inflation pressure at a target balloon to artery ratio of 1.1 ~ 1.2 to 1.0 over 30 s. Then we deflated the balloon, withdrew the guidewire, and sutured the puncture site.

Large animals were used to evaluate the operability, safety and effectiveness compared with Xience. All dogs weighed between 20–35 kg. The preclinical study of LBS was made in canine BTK arteries. The control device was Xience Prime™ stents (Abbott Vascular, Santa Clara, CA, USA), which has obtained CE mark for additional infrapopliteal indication. A total of 15 dogs were implanted with 15 LBS (Φ2.5×18 mm/Φ2.5×8 mm) and 15 Xience Prime (Φ2.5×18 mm/Φ2.25×8 mm). Each dog received one LBS and one Xience in each of the two hind legs. Infrapopliteal artery OCT (C7 XR Fourier-Domain System, LightLab Imaging, Westford, Massachusetts) imaging were performed before and after implantation, at 1, 3, and 6 months follow ups.

Qualitative characterization of in vivo degradation of LBS through micro-CT analysis

We implanted LBSs into rabbit iliac arteries. At given follow-up periods, animals were sacrificed, and the stented artery segments were dissected. We then scanned the stents with vessel tissues through high-resolution micro-CT (Skyscan1172, Bruker, Germany) to acquire images and conducted 3D reconstruction to analyze the degradation extent of the LBS.

Quantitative characterization of in vivo material degradation and drug release of nitrided iron, Zn, PLA and sirolimus in LBS

At given follow up periods, rabbits were sacrificed and the stented artery segments were dissected. After carefully separating the layers, we quantified the in vivo degradation of LBS via atomic absorption spectroscopy and the mass loss method. We carefully separated the vessel tissues from the stents and dissolved them through microwave nitrification. The solution was then filtered. The Zn concentration in the tissues was determined with an atomic absorption spectroscope (AA240FS, Agilent, USA).

After removing the tissues, we immersed the stents in ethyl acetate (CH₃COOC₂H₅) under ultrasound for 20 min to separate the PLA coating from the matrix. The PLA-CH₃COOC₂H₅ solution was used to test the polymer via gel permeation chromatography coupled with multiangle laser light scattering (GPC-MALLS).

The stents were immersed in tartaric acid (3 wt. %) under ultrasound for 20 mins to remove the biodegradation products. The remaining stent struts were cleaned with NaOH, deionized water, and absolute ethyl alcohol, in sequence. Then we weighed the dried metal platform and calculated the biodegradation rate via the mass loss method.

After removing the tissues, we also immersed a part of the LBS into a bottom of acetonitrile to quantify the drug content. The drug eluted LBS was ultrasonically treated for 20 mins to extract the residual sirolimus, which was further measured by high performance liquid chromatography using a machine Agilent 1260 (Agilent Technologies, USA) with C18 column and a flow rate of 1 mL/min at room temperature. Sirolimus was analyzed at 278 nm with the mixture of acetonitrile and purified water (65:35 v/v) as the mobile phase. The drug release of each LBS was calculated from the initial total drug amount and the residual drug amount on the LBS.

Histological analysis

We fixed the segments of the stented artery dissected from the sacrificed rabbits with 4% (w/v) paraformaldehyde. The samples were dehydrated and embedded in paraffin. The slices were stained with hematoxylin and eosin (H&E). The local tissue response and the biodegradation products were observed with an optical microscope (DM2500, Leica, Germany).

FIM implantation

The FIM study of the LBS implantation for infrapopliteal lesions was approved by the Institutional Review Board of Chinese PLA General Hospital with approval number S2020-184-01. An 80-year-old man presented with left foot rest pain was first enrolled in this study. Written informed consent was obtained from the patient. All procedures in this article were performed at the First Medical Center of Chinese PLA General Hospital (Beijing, China). Patients received dual antiplatelet therapy (100 mg aspirin and 75 mg clopidogrel once daily) for at least 3 days in advance. During the procedures, 5000 IU (50 IU/kg) of unfractionated heparin was administrated after 6 French sheath was placed. The target lesion in the first case was TPT of the left leg. The lesion was pre-dilated by plain old balloon angioplasty (Φ2 × 40 mm), and then LBS (Φ3 × 38 mm) was implanted to cover the lesion.

In the second case under consideration, the targeted lesion was situated in the PTA of the left lower extremity. A balloon catheter with dimensions Φ2 × 80 mm was deployed for pre-dilatory measures, followed by the implantation of LBS (Φ2.75 × 78 mm). In the third case, the lesion was localized in the left PA. A pre-dilation procedure employed a Φ2.5 × 60 mm balloon catheter, subsequent to which an LBS (Φ2.75 × 58 mm) was implanted. Both interventions serve to augment the cumulative evidence regarding the operability and efficacy of the LBS technology in the management of lower extremity arterial occlusions.

Prior to stent implantation, peripheral arterial assessments were conducted via CT imaging systems (GE Company, USA). Digital subtraction angiography (Angiostar, Siemens, Germany) was performed both pre- and post-implantation to evaluate vascular patency. Follow-up ultrasonography evaluations were carried out using an EPIQ 7 system (Philips, Netherlands) at immediate post-procedure intervals, as well as at 6- or 13-month time points. Subsequent to the interventional procedures, patients were prescribed a daily regimen of 100 mg aspirin and 75 mg clopidogrel, to be maintained for a duration of 6- or 13-month. These comprehensive diagnostic and therapeutic protocols serve to reinforce the evidentiary basis for the efficacy and safety of the LBS technology in the treatment of PAD.

Statistical analysis

Minitab 17 software was used for data analysis. We carried out t tests to evaluate the extent of stent restenosis, and p < 0.05 was considered statistically significant. The fraction of stent restenosis in canine infrapopliteal artery was defined as the ratio of the lumen area to the stent area at the same follow up date. Group of LBS (n = 5) and XIENCE (n = 5) at 1 month, 3 months and 6 months after implantation were analyzed. We conducted pooled analysis after collecting follow-up date from rabbits to evaluate the mass loss of every content. Since the drug content of a single LBS was too small to detect and measure, we combined the stents collected from each rabbit as one sample. The mass loss of The PLA coating, nitrided-iron, zinc and sirolimus were analyzed by pooled date collecting from follow-up date.

We denote the number of animals as N and the number of stents for each group as n. In tests of the mass loss of the PLA coating, we examined 3 months (N = 3, n = 9), 6 months (N = 3, n = 9), 12 months (N = 1, n = 3), and 18 months (N = 1, n = 3) postimplantation; in tests of mass loss of the Zn sacrificial layer, we examined 1 month (N = 10, n = 11), 2 months (N = 10, n = 11), and 3 months (N = 7, n = 11) postimplantation; in test of mass los of the nitride Fe, we examined 2 months (N = 9, n = 11), 3 months (N = 7, n = 11), 6 months (N = 9, n = 11), 9 months (N = 6, n = 11), 12 months (N = 9, n = 11), and 24 months (N = 7, n = 11) postimplantation; in tests of release of the sirolimus, we examined 7 days (N = 3, n = 6), 14 days (N = 3, n = 6), 1 month (N = 3, n = 6), 2 months (N = 3, n = 6), 3 months (N = 3, n = 6), 6 months (N = 5, n = 10), and 12 months (N = 1, n = 2) postimplantation.

Funding:

National Natural Science Foundation of China (grant No. 52130302).

National Key R&D Program of China (grants number 2016YFC1100300 and 2023YFC2410300).

Author contributions:

J.D., W.G. and D.Z. conceived the concept. J.D., W.G., D.Z. and W.Z. designed the experiments. W.Z., X.G., H.Z, G.S, G.Z., X.L. and H.Q. did most of experiments and collected most of data. J.D., W.G., D.Z., and W.Z. carried out most of data analysis. All of the authors partially joined in pertinent experiments and manuscript writing. J.D., W.Z. and X.G. prepared the manuscript with devotion from all co-authors.

Competing interests:

It is declared that W.Z., X.G., G.Z., H.Q., X.S., H.L. and D.Z., are employees of Biotyx Medical (Shenzhen) Co., Ltd. The other authors declare no conflict of interest.

Data and materials availability:

All data are available in the main text or the supplementary materials.

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Yes there is potential Competing Interest. It is declared that W.Z., X.G., G.Z., H.Q., X.S., H.L. and D.Z., are employees of Biotyx Medical (Shenzhen) Co., Ltd. The other authors declare no conflict of interest.

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Maglev-fabricated long and biodegradable stent for interventional treatment of peripheral vessels

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Abstract

Figures

Introduction

Results

Strengthening iron raw material via nitriding

Achieving a homogeneous PLA coating on a long stent via Maglev

Confirming safety and efficacy of LBS in large animals

First-in-human evaluation of LBS and its follow ups

Discussion

Methods

Fabrication of nitrided-iron tubes and LBS stents

Characterization of nitrogen content and PLA coating

Mechanical measurements

Animal models and stent implantation

Histological analysis

FIM implantation

Statistical analysis

Declarations

References

Additional Declarations

Supplementary Files

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