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

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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 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction 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. Results 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. Discussion 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 Fe 4 N 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 Fe 4 N 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. Methods 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 (CH 3 COOC 2 H 5 ) under ultrasound for 20 min to separate the PLA coating from the matrix. The PLA-CH 3 COOC 2 H 5 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. Declarations 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. References Uccioli L, Meloni M, Izzo V, Giurato L, Merolla S, Gandini R (2018) Critical limb ischemia: current challenges and future prospects. Vasc Health Risk Manag 14:63–74 Conte MS, Bradbury A, Kolh W, White P, Dick JV, Fitridge F, Mills R, Ricco JL, Suresh JB, Murad KR, Aboyans MH, Aksoy V, Alexandrescu M, Armstrong V-A, Azuma D, Belch N, Bergoeing J, Bjorck M, Chakfé M, Cheng N, Dawson S, Debus J, Dueck ES, Duval A, Eckstein S, Ferraresi HH, Gambhir R, Gargiulo R, Geraghty M, Goode P, Gray S, Guo B, Gupta W, Hinchliffe PC, Jetty R, Komori P, Lavery K, Liang L, Lookstein W, Menard R, Misra M, Miyata S, Moneta T, Prado G, Munoz JAM, Paolini A, Patel JE, Pomposelli M, Powell F, Robless R, Rogers P, Schanzer L, Schneider A, Taylor P, de Ceniga S, Veller MV, Vermassen M, Wang F, Wang J (2019) The GVG Writing Group, Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg 58:S1–S109 Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Fowkes FGR, Hamburg NM, Kinlay S, Lookstein R, Misra S, Mureebe L, Olin JW, Patel RAG, Regensteiner JG, Schanzer A, Shishehbor MH, Stewart KJ, Treat-Jacobson D, Walsh ME (2017) AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: A report of the American college of cardiology/American heart association task force on clinical practice guidelines. J Am Coll Cardiol 69:1465–1508 Matsuoka EK, Hasebe T, Ishii R, Miyazaki N, Soejima K, Iwasaki K (2022) Comparative performance analysis of interventional devices for the treatment of ischemic disease in below-the-knee lesions: a systematic review and meta-analysis. Circ Cardiovasc Interv 37:145–157 Serruys PW, Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy J, Heuvel J, Delcan P (1994) Morel, M. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. New Eng J Med 331:489–495 Kereiakes DJ, Onuma Y, Serruys PW, Stone GW (2016) Bioresorbable vascular scaffolds for coronary revascularization. Circulation 134:168–182 Sharma U, Concagh D, Core L, Kuang Y, You C, Pham Q, Zugates G, Busold R, Webber S, Merlo J, Langer R, Whitesides GM, Palasis M (2018) The development of bioresorbable composite polymeric implants with high mechanical strength. Nat Mater 17:96–103 Hu S, Li Z, Shen D, Zhu D, Huang K, Su T, Dinh PU, Cores J, Cheng K (2021) Exosome-eluting stents for vascular healing after ischaemic injury. Nat Biomed Eng 5:1174–1188 Borhani S, Hassanajili S, Hossein S, Tafti A, Rabbani S (2018) Cardiovascular stents: overview, evolution, and next generation. Prog Biomater 7:175–205 Hiramoto JS, Teraa M, de Borst GJ (2018) Conte. M. S. Interventions for lower extremity peripheral artery disease. Nat Rev Cardiol 15:332–350 Spreen MI, Martens JM, Knippenberg B, van Dijk LC, de Vries J-PPM, Vos JA, de Borst GJ, Vonken E-JPA, Bijlstra OD, Wever JJ, van Eps RGS, Mali WPTM, van Overhagen H (2017) Long-term follow-up of the PADI trial: Percutaneous transluminal angiopl asty versus drug-eluting stents for infrapopliteal lesions in critical limb ischemia. J Am Heart Assoc 6:e004877 Varcoe RL, DeRubertis BG, Kolluri R, Krishnan P, Metzger DC, Bonaca MP, Shishehbor MH, Holden AH, Bajakian DR, Garcia LA, Kum SWC, Rundback J, Armstrong E, Lee J-K, Khatib Y, Weinberg I, Garcia-Garcia HM, Ruster K, Teraphongphom NT, Zheng Y, Wang J, Jones-McMeans JM, Parikh SA (2023) Drug-Eluting Resorbable Scaffold versus Angioplasty for Infrapopliteal Artery Disease. New Engl J Med Iglesias JF, Roffi M, Losdat S, Muller O, Degrauwe S, Kurz DJ, Haegeli L, Weilenmann D, Kaiser C, Tapponnier M, Cook S, Cuculi F, Heg D, Windecker S, Pilgrim T (2023) Long-term outcomes with biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in ST-segment elevation myocardial infarction: 5-year follow-up of the BIOSTEMI randomised superiority trial. Lancet 402(10416):1979–1990 Gray BH, Diaz-Sandoval LJ, Dieter RS, Jaff MR, White CJ (2014) SCAI expert consensus statement for infrapopliteal arterial intervention appropriate use. Catheter Cardiovasc Interv 84:539–545 Konstantinos K, Dimitris K, Athanasios D, Stavros S, Dimitris S (2012) Cost-effectiveness analysis of infrapopliteal drug-eluting stents. Cardiovasc Intervent Radiol 36:90–97 Varcoe RL, Paravastu SC, Thomas SD, Bennett MH (2019) The use of drug-eluting stents in infrapopliteal arteries: an updated systematic review and meta-analysis of randomized trials. Int Angiol 38:121–135 Jinnouchi H, Torii S, Sakamoto A, Kolodgie FD, Virmani R, Finn AV (2019) Fully bioresorbable vascular scaffolds: lessons learned and future directions. Nat Rev Cardiol 16:286–304 Dia AR, Venturini JM, Kalathiya RJ, Besser S, Estrada JR, Friant J, Paul J, Blair JE, Nathan S (2020) Shah, A. P. Two-year follow-up of bioresorbable vascular scaffolds in severe infra-popliteal arterial disease. Vascular 29:355–362 Bowen PK, Shearier ER, Zhao S, Guillory II, Zhao RJ, Goldman F, Drelich J (2016) Biodegradable metals for cardiovascular stents: from clinical concerns to recent Zn-alloys. Adv Healthc Mater 5:1121–1140 Ryu H, Seo M-H, Rogers JA (2021) Bioresorbable metals for biomedical applications: from mechanical components to electronic devices. Adv Healthc Mater 10:e2002236 Bosiers M, Peeters P, D'Archambeau O, Hendriks J, Pilger E, Düber C, Zeller T, Gussmann A, Lohle PNM, Minar E, Scheinert D, Hausegger K, Schulte K-L, Verbist J, Deloose K, Lammer J (2009) AMS INSIGHT-absorbable metal stent implantation for treatment of below-the-knee critical limb ischemia: 6-month analysis. Cardiovasc Intervent Radiol 32:424–435 Ozaki Y, Garcia-Garcia HM, Shlofmitz E, Hideo-Kajita A, Waksman R (2020) Second-Generation Drug-eluting resorbable magnesium scaffold: Review of the clinical evidence. Cardiovasc Revasc Med 21:127–136 Yang H, Wang C, Liu C, Chen H, Wu Y, Han J, Ji Z, Lin W, Zhang D, Li W, Yuan W, Guo H, Li H, Yang G, Kong D, Zhu D, Takashima K, Ruan L, Nie J, Li X, Zheng Y (2017) Evolution of the degradation mechanism of pure zinc stent in the one-year study of rabbit abdominal aorta model. Biomaterials 145:92–105 Zheng J, Qiu H, Tian Y, Hu X-Y, Luo T, Wu C, Tian Y, Tang Y, Song L, Li L, Xu L, Xu B, Gao R (2019) Preclinical evaluation of a novel sirolimus-eluting iron bioresorbable coronary scaffold in porcine coronary artery at 6 months. JACC Cardiovasc Interv 12:245–255 Shen D, Qi H, Lin W, Zhang W, Bian D, Shi X, Qin L, Zhang G, Fu W, Dou K, Xu B, Yin Z, Rao J, Alwi M, Wang S, Zheng Y, Zhang D, Gao R (2021) PLA-Zn-nitrided Fe bioresorbable scaffold with 53-µm-thick metallic struts and tunable multistage biodegradation function. Sci Adv 7:eabf0614 Lin W, Zhang H, Zhang W, Qi H, Zhang G, Qian J, Li X, Qin L, Li H, Wang X, Qiu H, Shi X, Zheng W, Zhang D, Gao R, Ding J (2021) In vivo degradation and endothelialization of an iron bioresorbable scaffold. Bioact Mater 6:1028–1039 Zhang H, Zhang W, Qiu H, Zhang G, Li X, Qi H, Guo J, Qian J, Shi X, Gao X, Shi D, Zhang D, Gao R, Ding J (2022) A biodegradable metal-polymer composite stent safe and effective on physiological and serum-containing biomimetic conditions. Adv Healthc Mater 11(22):2201740 Sun G, Guo W, Zhang H, Ma X, Jia X, Xiong J (2022) A novel iron-bioresorbable sirolimus-eluting scaffold device for infrapopliteal artery disease. Circ Cardiovasc Interv 15:e57–e59 Qi Y, Qi H, He Y, Lin W, Li P, Qin L, Hu Y, Chen L, Liu Q, Sun H, Liu Q, Zhang G, Cui S, Hu J, Yu L, Zhang D, Ding J (2018) Strategy of metal-polymer composite stent to accelerate biodegradation of iron-based biomaterials. ACS Appl Mater Interfaces 10:182–192 Qi Y, Li X, He Y, Zhang D, Ding J (2019) Mechanism of acceleration of iron corrosion by a polylactide coating. ACS Appl Mater Interfaces 11:202–218 Li X, Zhang W, Lin W, Qiu H, Qi Y, Ma X, Qi H, He Y, Zhang H, Qian J, Zhang G, Gao R, Zhang D, Ding J (2020) Long-term efficacy of biodegradable metal-polymer composite stents after the first and the second implantations into porcine coronary arteries. ACS Appl Mater Interfaces 12:15703–15715 Lee H-W, Kim K-C, Lee J (2006) Review of maglev train technologies. IEEE Trans Magn 42:1917–1925 Ali ZA, Serruys PW, Kimura T, Gao R, Ellis SG, Kereiakes DJ, Onuma Y, Simonton C, Zhang Z, Stone G (2017) W. 2-year outcomes with the absorb bioresorbable scaffold for treatment of coronary artery disease: a systematic review and metaanalysis of seven randomised trials with an individual patient data substudy. Lancet 390:760–772 Shen Y, Zhang W, Xie Y, Li A, Wang X, Chen X, Liu Q, Wang Q, Zhang G, Liu Q, Liu J, Zhang D, Zhang Z, Ding J (2021) Surface modification to enhance cell migration on biomaterials and its combination with 3D structural design of occluders to improve interventional treatment of heart diseases. Biomaterials 279:1–16 Wang L, Wang X, Wu Y, Guo M, Gu C, Dai C, Kong D, Wang Y, Zhang C, Qu D, Fan C, Xie Y, Zhu Z, Liu Y, Wei D (2022) Rapid and ultrasensitive electromechanical detection of ions, biomolecules and SARS-CoV-2 RNA in unamplified samples. Nat Biomed Eng 6:276–285 Wang G, Gao C, Xiao B, Zhang J, Jiang X, Wang Q, Guo J, Zhang D, Liu J, Xie Y, Shu C, Ding J (2022) Research and clinical translation of trilayer stent-graft of expanded polytetrafluoroethylene for interventional treatment of aortic dissection. Regen Biomater 9:rbac049 Maselli D, Matos RS, Johnson RD, Martella D, Caprettini V, Chiappini C, Chiappini C, Camelliti P, Campagnolo P (2022) Porcine organotypic epicardial slice protocol: A tool for the study of epicardium in cardiovascular research. Front Cardiovasc Med 9:920013 Huang J, Xu Y, Xue Y, Huang Y, Li X, Chen X, Xu Y, Zhang D, Zhang P, Zhao J, Ji J (2023) Identification of top-performance antimicrobial peptides from whole combinatorial libraries via a sequential model ensemble machine learning pipeline. Nat Biomed Eng 7:797–810 Kwon K, Kim JU, Won SM, Zhao J, Avila R, Wang H, Chun KS, Jang H, Lee KH, Kim J-H, Yoo S, Kang YJ, Kim J, Lim J, Park Y, Lu W, Kim T-i, Banks A, Huang Y, Rogers JA (2023) A battery-less wireless implant for the continuous monitoring of vascular pressure, flow rate and temperature. Nat Biomed Eng 7:1215–1228 Cao D, Ding J (2022) Recent Advances in regenerative biomaterials. Regen Biomater 9:rbac098 Choi YS, Hsueh Y, Koo J, Yang Q, Avil R, Hu B, Xie Z, Lee G, Ning Z, Liu C, Xu Y, Lee YJ, Zhao W, Fang J, Deng Y, Lee SM, Guardado AV, Stepien I, Yan Y, Song JW, Haney C, Oh YS, Liu W, Yun H, Banks A, MacEwan MR, Ameer GA, Ray WZ, Huang Y, Xie T, Franz CK, Li S, Rogers JA (2020) Stretchable, dynamic covalent polymers for soft, long-lived bioresorbable electronic stimulators designed to facilitate neuromuscular regeneration. Nat Commun 11(1):5990 Liu AP, Appel EA, Ashby PD, Baker BM, Franco E, Gu L, Haynes K, Joshi NS, Kloxin AM, Kouwer PHJ, Mittal J, Morsut L, Noireaux V, Parekh S, Schulman R, Tang SKY, Valentine MT, Vega SL, Weber W, Stephanopoulos N, Chaudhuri O (2022) The living interface between synthetic biology and biomaterial design. Nat Mater 21:390–397 Kolandaivelu K, Swaminathan R, Gibson WJ, Kolachalama VB, Nguyen-Ehrenreich KL, Giddings VL, Coleman L, Wong GK, Edelman ER (2011) Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 123:1400–1409 Lin W, Qin L, Qi H, Zhang D, Zhang G, Gao R, Qiu H, Xia Y, Cao P, Wang X, Zheng W (2017) Long-term in vivo corrosion behavior, biocompatibility and bioresorption mechanism of a bioresorbable nitrided iron scaffold. Acta Biomate 54:454–468 Peuster M, Wohlsein P, Brügmann M, Ehlerding M, Seidler K, Fink C, Brauer H, Fischer A, Hausdorf G (2001) A. novel approach to temporary stenting: degradable cardiovascular stents produced from corrodible metal results 6–18 months after implantation into new zealand white rabbits. Heart 86:563–569 Whitman GW, Russell RP, Altieri VJ (1924) Effect of hydrogen-ion concentration on the submerged corrosion of steel. Ind Eng Chem 16:665–670 Wu L, Ding J (2004) In vitro degradation of three-dimensional porous poly (D, L-lactide-co-glycolide) scaffolds for tissue engineering. Biomaterials 25(27):5821–5830 van Overhagen H, Nakamura M, Geraghty PJ, Rao S, Arroyo M, Soga Y, Iida O, Armstrong E, Nakama T, Fujihara M, Ansari M, Mathews MJ, Gouëffic S, Jaff Y, Weinberg MR, Pinto I, Ohura DS, Couch N, Mustapha K (2023) Primary results of the SAVAL randomized trial of a paclitaxel-eluting nitinol stent versus percutaneous transluminal angioplasty in infrapopliteal arteries. Vasc Med 28(6):571–580 Additional Declarations 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. Supplementary Files Reportingsummaryresubmitted.pdf Reporting summary LBSSlresubmitted.pdf supplementary information policychecklistresubmitted.pdf policy checklist VideoS1.mp4 Video S1 VideoS2LBS1.mp4 Video S2 LBS Cite Share Download PDF Status: Published Journal Publication published 10 Sep, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Ltd., Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Wanqian","middleName":"","lastName":"Zhang","suffix":""},{"id":268553055,"identity":"a6e0c230-cc4e-4e81-a523-fbf1c66bb179","order_by":2,"name":"Xian Gao","email":"","orcid":"","institution":"National and Local Joint Engineering Laboratory of Interventional Medical Biotechnology and System, Biotyx Medical (Shenzhen) Co., Ltd, Lifetech Scientific (Shenzhen) Co. 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Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Haiping","middleName":"","lastName":"Qi","suffix":""},{"id":268553061,"identity":"0d78b138-58b7-4397-9616-d9a25c746a00","order_by":8,"name":"Jingzhen Guo","email":"","orcid":"","institution":"State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Jingzhen","middleName":"","lastName":"Guo","suffix":""},{"id":268553062,"identity":"cbf9fccc-b5ca-4adf-943c-15af1db507a8","order_by":9,"name":"Li Qin","email":"","orcid":"","institution":"Lifetech Scientific (Shenzhen) Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Qin","suffix":""},{"id":268553063,"identity":"a17106fe-0e95-4727-9986-391e9c36a506","order_by":10,"name":"Daokun Shi","email":"","orcid":"","institution":"State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Daokun","middleName":"","lastName":"Shi","suffix":""},{"id":268553064,"identity":"159c0829-d8e3-4dc2-91af-ea1055d94cda","order_by":11,"name":"Xiaoli Shi","email":"","orcid":"","institution":"National and Local Joint Engineering Laboratory of Interventional Medical Biotechnology and System, Biotyx Medical (Shenzhen) Co., Ltd, Lifetech Scientific (Shenzhen) Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Xiaoli","middleName":"","lastName":"Shi","suffix":""},{"id":268553065,"identity":"d0739440-e6f6-4369-8c99-ad8b2302a98c","order_by":12,"name":"Haifeng Li","email":"","orcid":"","institution":"Lifetech Scientific (Shenzhen) Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Haifeng","middleName":"","lastName":"Li","suffix":""},{"id":268553066,"identity":"7f2155f6-864a-4193-8de4-abd23b14aa23","order_by":13,"name":"D.Y. Zhang","email":"","orcid":"https://orcid.org/0000-0001-9401-5032","institution":"Lifetech Scientific (Shenzhen) Co Ltd","correspondingAuthor":false,"prefix":"","firstName":"D.Y.","middleName":"","lastName":"Zhang","suffix":""},{"id":268553067,"identity":"e850e5d1-4d5a-421f-8610-ab071d13c03e","order_by":14,"name":"Wei Guo","email":"","orcid":"https://orcid.org/0000-0001-6212-8390","institution":"Chinese PLA General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Guo","suffix":""}],"badges":[],"createdAt":"2023-11-07 13:35:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3574571/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3574571/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-024-52288-4","type":"published","date":"2024-09-10T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50016782,"identity":"70103d78-0914-4e2b-9a0e-7fa7910e2f5a","added_by":"auto","created_at":"2024-01-23 06:54:03","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":484924,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic presentation of the current situation of percutaneous transluminal intervention in arteriosclerosis obliterans of lower limb artery, the motivation and difficulties to develop a biodegradable long stent, and the rational to design of a long \u0026amp; biodegradable stent (LBS) based on metal-polymer composite, and the main tests of the LBS \u003cem\u003ein vitro\u003c/em\u003eand \u003cem\u003ein vivo\u003c/em\u003e. Here, the term “TLF” denotes target lesion failure.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/6cb9b2577d82f441513ff6fe.jpeg"},{"id":50017296,"identity":"fec3da1b-e7ba-4981-a76d-dcc9aef7d739","added_by":"auto","created_at":"2024-01-23 07:02:04","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":178803,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic diagram of the spray coating process between a conventional coating with unrestricted mode and a Maglev coating mode. The left part shows the inhomogeneity of coating thickness in a long stent without fixing the free end, and the right part presents the homogeneity of coating thickness in a Maglev-fabricated long stent. (Sample size \u003cem\u003en\u003c/em\u003e = 30 for each group. The data are shown in mean ±standard deviation.)\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/50d15ec22b786b43748adad2.jpeg"},{"id":50017297,"identity":"74151e90-b438-4b69-92b0-a2ccfcbdafd9","added_by":"auto","created_at":"2024-01-23 07:02:04","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":129065,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eIn vivo\u003c/em\u003e 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, \u003cem\u003en\u003c/em\u003e = 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.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/12f4333a207b68f4454831f5.jpeg"},{"id":50016783,"identity":"0318514c-0180-4099-a531-67a214e8d70a","added_by":"auto","created_at":"2024-01-23 06:54:04","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":125957,"visible":true,"origin":"","legend":"\u003cp\u003eOCT images in the lumen of the posterior tibial artery in canine model. The upper are follow-up OCT images after 0, 1, 3, and 6 months of LBS and Xience stent implantation. The lower right image demonstrates the areas used to calculate stenosis. The dot and line in the lower left indicates the allowance criterion of area stenosis. For each group \u003cem\u003en\u003c/em\u003e = 5. The data are shown in mean ± standard deviation.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/99d33fce38373ed56b65b595.jpeg"},{"id":50016793,"identity":"1a6d3a9b-f252-41ca-a114-9994f745806b","added_by":"auto","created_at":"2024-01-23 06:54:04","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":216852,"visible":true,"origin":"","legend":"\u003cp\u003eFIM implantation of the LBS in a BTK artery of an 80-year-old male patient as case A. Firstly, an angioplasty was made to find the target lesion with occlusion of TPT; secondly, a pre-dilatation balloon was used to reopen the occluded lesion and then an angioplasty was performed to check the pre-dilatation result; thirdly, as the lesion was partially patent with dissection and recoil that need further treatment, an LBS (Φ3.0 × 38 mm) was deployed by balloon dilatation; finally, the stent was implanted, and a patent with no residual restenosis vessel was seen in the last angioplasty image.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/a132108f70c5422ac2331086.jpeg"},{"id":50016788,"identity":"4885ed49-b204-4735-80a1-50353a9c999e","added_by":"auto","created_at":"2024-01-23 06:54:04","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":164603,"visible":true,"origin":"","legend":"\u003cp\u003eClinical CT and ultrasonography images of FIM implantation of an LBS. The left upper image comes from the preoperative CT of patient’s left leg. The right shows the ultrasonography images of preoperative, postoperative and 13 months’ results in case A. Based on preoperative ultrasonography, the diameter of the occluded lesion was 0.23 cm, and the lesion was measured 2.7 cm in length. P3 segment was patent with 29.3 cm/s flow rate, but the TPT was occluded with 0 cm/s flow rate. After the implantation of LBS, postoperative ultrasonography illustrated increased flow rates in both P3 and TPT, which were 49.4 cm/s and 98.4 cm/s, respectively. After 13 months, the flow rates of PA and TPT read 29.7 cm/s and 56.6 cm/s respectively, which remain satisfied as the blood supply to the foot.\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/e9c9b94cd7c768387f6b65ca.jpeg"},{"id":50017413,"identity":"25152205-5c3e-4a43-ba30-6cbc9c079a0b","added_by":"auto","created_at":"2024-01-23 07:10:04","extension":"jpeg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":335910,"visible":true,"origin":"","legend":"\u003cp\u003ePreoperative, postoperative, and six-month follow up angiograms of the LBS implantation in case B. The preoperative angiography showed that the target lesion was the PTA, and the length of the lesion was approximately 60 mm. As indicated by the postoperative angiography, an LBS (Φ2.75 × 78 mm) was successfully implanted and the target lesion was well stented, and without residual stenosis. By contrast, there was a long-segment occlusive lesion in the PA, which was treated with balloon dilation. After treatment, the residual stenosis was approximately 10%. The six-month follow up angiography showed that the PTA target lesion remained patent without obvious restenosis and the LBS profile maintained well without collapse. The raw image and the schematic image of the LBS profile under X-ray without the contrast agent are presented in the bottom right. At this time, the target lesion stenosis rate of PTA is 30%, while the lesion stenosis rate of PA has increased to 80%. The Rutherford class of the patient was improved from RC5 to RC2 after 6 months.\u003c/p\u003e","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/f55955d18d9329440a8ff39c.jpeg"},{"id":64278975,"identity":"7b6641bb-5c94-4f14-892f-3ca9aabb7b98","added_by":"auto","created_at":"2024-09-11 07:13:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2353268,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/ddacd018-ed5c-4db0-bcc4-a3c60350864c.pdf"},{"id":50016786,"identity":"98c33b87-f982-4ac4-bd39-86708a1d39e1","added_by":"auto","created_at":"2024-01-23 06:54:04","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1649108,"visible":true,"origin":"","legend":"Reporting summary","description":"","filename":"Reportingsummaryresubmitted.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/f9d1428b943fa7eccce9103f.pdf"},{"id":50016784,"identity":"9448e28b-09e6-4330-8eb4-0019b7bfdb14","added_by":"auto","created_at":"2024-01-23 06:54:04","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1799957,"visible":true,"origin":"","legend":"\u003cp\u003esupplementary information\u003c/p\u003e","description":"","filename":"LBSSlresubmitted.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/aaf81308daf27a71c3053cfa.pdf"},{"id":50017298,"identity":"f4da3a7c-e49e-40a6-8d9e-c2f03ee29a5c","added_by":"auto","created_at":"2024-01-23 07:02:04","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1667265,"visible":true,"origin":"","legend":"policy checklist","description":"","filename":"policychecklistresubmitted.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/d22e6a86d5b350a4c53034dd.pdf"},{"id":50016792,"identity":"ba2e4e96-246e-4e16-abb8-3c4cf967ad03","added_by":"auto","created_at":"2024-01-23 06:54:04","extension":"mp4","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":1464274,"visible":true,"origin":"","legend":"Video S1","description":"","filename":"VideoS1.mp4","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/5f9aee14a84c3d403b82b581.mp4"},{"id":50017300,"identity":"f15949e5-9750-423c-934c-5b44e8d19de2","added_by":"auto","created_at":"2024-01-23 07:02:04","extension":"mp4","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":3379323,"visible":true,"origin":"","legend":"Video S2 LBS","description":"","filename":"VideoS2LBS1.mp4","url":"https://assets-eu.researchsquare.com/files/rs-3574571/v1/e2f2199a357d16e16dbb4d2f.mp4"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nIt 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.","formattedTitle":"Maglev-fabricated long and biodegradable stent for interventional treatment of peripheral vessels","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePeripheral 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 (\u003cem\u003e1\u003c/em\u003e). 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 \u003cstrong\u003eFig. S1\u003c/strong\u003e. Most of these clinical symptoms can be remitted by re-opening the occluded lower limb artery (\u003cem\u003e2\u003c/em\u003e). 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 (\u003cem\u003e2, 3\u003c/em\u003e). The below-the-knee (BTK) lesion with chronic limb-threatening ischemia (CLTI) is\u0026nbsp;the\u0026nbsp;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 (\u003cem\u003e4\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003eStents play a crucial role in interventional treatment of cardiovascular diseases (\u003cem\u003e5, 6\u003c/em\u003e). During the latest score years, various stents have been developed\u0026nbsp;(\u003cem\u003e7\u003c/em\u003e\u003cem\u003e,8\u003c/em\u003e); either long or biodegradable cardiovascular stents are dependent upon cutting-edge techniques (\u003cem\u003e9\u003c/em\u003e).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 (\u003cem\u003e10\u003c/em\u003e). 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.\u003c/p\u003e\n\u003cp\u003eConventional 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 (\u003cem\u003e11-13\u003c/em\u003e). But in the real world, the majority of PAD treated lesions are long CTO (\u0026gt;40 mm) and seriously calcified (\u003cem\u003e14\u003c/em\u003e). 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 (\u003cem\u003e15\u003c/em\u003e). 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 (\u003cem\u003e16\u003c/em\u003e). 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 (\u003cem\u003e2\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003eA 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 (\u003cem\u003e17\u003c/em\u003e). Polymer-based BRS has a satisfied patency in short lesions of infrapopliteal artery. Nevertheless, its short stent length (\u0026le; 38 mm) and thick strut thickness (\u0026gt;100 \u0026mu;m)\u0026nbsp;have confined its clinical application for long lesion (\u003cem\u003e18\u003c/em\u003e). Metal-based BRS is another option for the treatment of BTK lesions (\u003cem\u003e19, 20\u003c/em\u003e). Metallic BRSs include magnesium-based (\u003cem\u003e21,22\u003c/em\u003e), zinc-based (\u003cem\u003e23\u003c/em\u003e) and iron-based ones (\u003cem\u003e24-28\u003c/em\u003e). 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\u003csup\u003eTM\u003c/sup\u003e 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.\u003c/p\u003e\n\u003cp\u003eThe present study reports a long \u0026amp; 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 \u0026frac34; 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 \u003cstrong\u003eFig. 1\u003c/strong\u003e. To resolve these difficulties towards and gain the first long and biodegradable cardiovascular stent is the theme of the work in this article.\u003c/p\u003e\n\u003cp\u003eIn 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 \u0026ldquo;composite\u0026rdquo; to describe the polymer-coated metal comes from the unexpected \u0026ldquo;accelerating\u0026rdquo; of iron corrosion by the PLA layer instead of \u0026ldquo;protection\u0026rdquo;, which has been elaborated by us in previous study of coronary stents (\u003cem\u003e29-31\u003c/em\u003e). 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.\u003c/p\u003e\n\u003cp\u003eEventually, 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 (\u003cem\u003e32\u003c/em\u003e). 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 \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e performances.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eStrengthening iron raw material via nitriding\u003c/h2\u003e \u003cp\u003ePure 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\u0026thinsp;~\u0026thinsp;345 MPa, is still lower than that of cobalt-chromium alloy for permanent stents, ~\u0026thinsp;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 \u003cb\u003eFig. S2\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eWhile 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 \u003cb\u003eFig. S2\u003c/b\u003e, which is far larger than the tensile strength of the pure iron tube of 315 MPa.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAchieving a homogeneous PLA coating on a long stent via Maglev\u003c/h2\u003e \u003cp\u003eThe 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 \u003cb\u003eSupplementary Video S1\u003c/b\u003e. This is harmful for a homogeneous coating.\u003c/p\u003e \u003cp\u003eIn 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.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The floated stent was then stable, as shown in the right of \u003cb\u003eSupplementary Video S1\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe lower right curve in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e confirmed the homogeneity of the resultant PLA coating on a long stent surface. We further carried out \u003cem\u003ein vitro\u003c/em\u003e bench tests of our Maglev-fabricated LBS and the results are shown in \u003cb\u003eFig. S3\u003c/b\u003e. The LBS of thinner struts exhibited comparable mechanical performances to Xience.\u003c/p\u003e \u003cp\u003e \u003cb\u003eConfirming the tuned\u003c/b\u003e \u003cb\u003ein vitro\u003c/b\u003e \u003cb\u003edegradation of LBS in Hank\u0026rsquo;s solution and\u003c/b\u003e \u003cb\u003ein vivo\u003c/b\u003e \u003cb\u003edegradation profile in small animals\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe most important bottleneck of iron as a biodegradable material for a stent is its slow \u003cem\u003ein vivo\u003c/em\u003e 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. \u003cem\u003eIn vitro\u003c/em\u003e 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.\u003c/p\u003e \u003cp\u003eWe carried out \u003cem\u003ein vitro\u003c/em\u003e degradation in Hank\u0026rsquo;s solution at 37 ℃ (\u003cb\u003eFig. S4\u003c/b\u003e) and \u003cem\u003ein vivo\u003c/em\u003e degradation in the rabbit model (\u003cb\u003eFig.\u0026nbsp;3\u003c/b\u003e). 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.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;3 \u003cem\u003eIn vivo\u003c/em\u003e 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, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5. The data are shown in mean\u0026thinsp;\u0026plusmn;\u0026thinsp;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.\u003c/p\u003e \u003cp\u003eAn LBS in a balloon delivery system is demonstrated in \u003cb\u003eFig.\u0026nbsp;3(B)\u003c/b\u003e. 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 \u0026micro;m with abluminal coating.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;3(C)\u003c/b\u003e 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.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eConfirming safety and efficacy of LBS in large animals\u003c/h3\u003e\n\u003cp\u003eFDA 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.\u003c/p\u003e \u003cp\u003eWe generated an over-expansion (1.1\u0026ndash;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.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, 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.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eFirst-in-human evaluation of LBS and its follow ups\u003c/h3\u003e\n\u003cp\u003eAfter 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 \u003cb\u003eSupplementary Video S2\u003c/b\u003e, and the typical procedures are demonstrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAdditional diagnostic data, including preoperative computed tomography (CT) and ultrasonography, are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e. 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).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCase 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.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e). Utilizing a guidewire to cross the stenosis PTA lesion and PA lesion, then a balloon of Φ2 \u0026times; 80 mm was used for the PTA. Subsequently, an LBS (Φ2.75 \u0026times; 78 mm) was strategically positioned at the site of the PTA lesion and successfully expanded using nominal inflation pressure.\u003c/p\u003e \u003cp\u003eFor comparison, long-segment occlusive lesions in PA are treated with a Φ2.5 \u0026times; 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%.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCase 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 \u0026times; 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 \u003cb\u003eFig. S5\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eIt 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.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe latest decade has witnessed much progress in biomaterials for medical devices and pharmaceutics etc (\u003cspan additionalcitationids=\"CR34 CR35 CR36 CR37 CR38\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Among various biomaterials (\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e), 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 (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). 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 \u003cb\u003eFig. S6\u003c/b\u003e. 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 \u003cb\u003eFig. S7\u003c/b\u003e. In contrast, a biodegradable stent theoretically would improve the \u0026ldquo;caged vessel\u0026rdquo; result and eliminate the scruple of ISR, as presented in \u003cb\u003eFig. S8\u003c/b\u003e. Then, a biodegradable long stent would be further eliminated stent overlapping limitation and more customized for infrapopliteal artery.\u003c/p\u003e \u003cp\u003eA 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.\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) \u003cem\u003eThe bulk-alloy nitride iron to strengthen the backbone material of the stent\u003c/em\u003e. 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 Fe\u003csub\u003e4\u003c/sub\u003eN 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 Fe\u003csub\u003e4\u003c/sub\u003eN precipitations (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). The first pure iron stent, NOR-I, reported for the preclinical study by Matthias Peuster is of thickness 100\u0026ndash;120 \u0026micro;m, Φ3 \u0026times; 16 mm weighed 41 mg (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). In contrast, our LBS is of strut thickness 53 \u0026micro;m, and a Φ3 \u0026times; 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.\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) \u003cem\u003eMagnetic levitation to enable a homogeneous polymer coating on a long metal stent\u003c/em\u003e. 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.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cb\u003eSupplementary Video S1\u003c/b\u003e). 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.\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) \u003cem\u003eCombination of a microscale PLA coating and a nanoscale Zn layer to adjust the profile of iron corrosion\u003c/em\u003e. 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 (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). It is also known that polyester hydrolysis can lead to an acidic environment (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). 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 \u003cem\u003ein vivo\u003c/em\u003e biodegradation in rabbit aorta/lilac (\u003cb\u003eFig.\u0026nbsp;3\u003c/b\u003e). Eventually, the Fe-Zn-PLA design matches with both stenting at the early stage and remodeling at the late stage.\u003c/p\u003e \u003cp\u003eIn 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.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e) demonstrated the safety and efficacy of LBS in large animals.\u003c/p\u003e \u003cp\u003eWe also demonstrate the clinical cases of the LBS (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e, \u003cb\u003eFig. S5\u003c/b\u003e). 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.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e) further illustrated a preliminary feasibility of LBS applied in BTK application. And the forthcoming two additional clinical cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e \u003cb\u003eand Fig. S5\u003c/b\u003e) further strengthened the operability, safety and effectiveness of the LBS.\u003c/p\u003e \u003cp\u003eAccording 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 (\u003cb\u003eFig. S5\u003c/b\u003e) further strengthened the operability, safety, and effectiveness of the LBS.\u003c/p\u003e \u003cp\u003eVery recently, a longe self-expandable DES (Φ3.5 \u0026times; 80 mm) was compared with balloon angioplasty, and according to the clinical trial results published in December, 2023 (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e), 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.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e), 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.\u003c/p\u003e \u003cp\u003eBasically, 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.\" (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e) 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 (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). 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.\u003c/p\u003e \u003cp\u003eIn conclusion, this paper reports the core technique of the long biodegradable stent for the first time. The LBS of 53-\u0026micro;m 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 \u003cem\u003ein vitro\u003c/em\u003e tests, rabbit and canine \u003cem\u003ein vivo\u003c/em\u003e 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 \u0026amp; 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 \u0026amp; biodegradable medical devices.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eFabrication of nitrided-iron tubes and LBS stents\u003c/h2\u003e \u003cp\u003eA pure iron tube (Φ6.0 mm, wall thickness 0.5 mm) was cut into segments with 25\u0026ndash;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).\u003c/p\u003e \u003cp\u003eThe 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.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCharacterization of nitrogen content and PLA coating\u003c/h3\u003e\n\u003cp\u003eNitrogen 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. %).\u003c/p\u003e \u003cp\u003eThe PLA coating thickness was measured by spectroscopic reflectometry with a 3D optical profilometer (Q six, Sensofar Medical, Spain).\u003c/p\u003e\n\u003ch3\u003eMechanical measurements\u003c/h3\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e \u003cp\u003eA 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.\u003c/p\u003e \u003cp\u003eCrush 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.\u003c/p\u003e \u003cp\u003eWe 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\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2 mm, radial compliance 5\u0026ndash;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\u003c/p\u003e \u003cp\u003eCR\u0026thinsp;=\u0026thinsp;\u003cem\u003ed\u003c/em\u003e/\u003cem\u003eD\u003c/em\u003e \u0026times; 100% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eHere, \u003cem\u003ed\u003c/em\u003e presents the diameter of the LBS under a simulated plaque, and \u003cem\u003eD\u003c/em\u003e represents the diameter of the normally expanded stent.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAnimal models and stent implantation\u003c/h2\u003e \u003cp\u003eThe preclinical study was approved by the Ethics Committee of Shenzhen Advanced Medical Services Corporation in China. Small animals were used to evaluate the \u003cem\u003ein vivo\u003c/em\u003e 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 \u0026times; 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\u0026ndash;10 inflation pressure at a target balloon to artery ratio of 1.1\u0026thinsp;~\u0026thinsp;1.2 to 1.0 over 30 s. Then we deflated the balloon, withdrew the guidewire, and sutured the puncture site.\u003c/p\u003e \u003cp\u003eLarge animals were used to evaluate the operability, safety and effectiveness compared with Xience. All dogs weighed between 20\u0026ndash;35 kg. The preclinical study of LBS was made in canine BTK arteries. The control device was Xience Prime\u0026trade; 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\u0026times;18 mm/Φ2.5\u0026times;8 mm) and 15 Xience Prime (Φ2.5\u0026times;18 mm/Φ2.25\u0026times;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.\u003c/p\u003e \u003cp\u003e \u003cb\u003eQualitative characterization of\u003c/b\u003e \u003cb\u003ein vivo\u003c/b\u003e \u003cb\u003edegradation of LBS through micro-CT analysis\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe 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.\u003c/p\u003e \u003cp\u003e \u003cb\u003eQuantitative characterization of\u003c/b\u003e \u003cb\u003ein vivo\u003c/b\u003e \u003cb\u003ematerial degradation and drug release of nitrided iron, Zn, PLA and sirolimus in LBS\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAt given follow up periods, rabbits were sacrificed and the stented artery segments were dissected. After carefully separating the layers, we quantified the \u003cem\u003ein vivo\u003c/em\u003e 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).\u003c/p\u003e \u003cp\u003eAfter removing the tissues, we immersed the stents in ethyl acetate (CH\u003csub\u003e3\u003c/sub\u003eCOOC\u003csub\u003e2\u003c/sub\u003eH\u003csub\u003e5\u003c/sub\u003e) under ultrasound for 20 min to separate the PLA coating from the matrix. The PLA-CH\u003csub\u003e3\u003c/sub\u003eCOOC\u003csub\u003e2\u003c/sub\u003eH\u003csub\u003e5\u003c/sub\u003e solution was used to test the polymer via gel permeation chromatography coupled with multiangle laser light scattering (GPC-MALLS).\u003c/p\u003e \u003cp\u003eThe 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.\u003c/p\u003e \u003cp\u003eAfter 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eHistological analysis\u003c/h2\u003e \u003cp\u003eWe 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\u0026amp;E). The local tissue response and the biodegradation products were observed with an optical microscope (DM2500, Leica, Germany).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eFIM implantation\u003c/h2\u003e \u003cp\u003eThe 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 \u0026times; 40 mm), and then LBS (Φ3 \u0026times; 38 mm) was implanted to cover the lesion.\u003c/p\u003e \u003cp\u003eIn the second case under consideration, the targeted lesion was situated in the PTA of the left lower extremity. A balloon catheter with dimensions Φ2 \u0026times; 80 mm was deployed for pre-dilatory measures, followed by the implantation of LBS (Φ2.75 \u0026times; 78 mm). In the third case, the lesion was localized in the left PA. A pre-dilation procedure employed a Φ2.5 \u0026times; 60 mm balloon catheter, subsequent to which an LBS (Φ2.75 \u0026times; 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.\u003c/p\u003e \u003cp\u003ePrior 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eMinitab 17 software was used for data analysis. We carried out \u003cem\u003et\u003c/em\u003e tests to evaluate the extent of stent restenosis, and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;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 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5) and XIENCE (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e \u003cp\u003eWe denote the number of animals as \u003cem\u003eN\u003c/em\u003e and the number of stents for each group as \u003cem\u003en\u003c/em\u003e. In tests of the mass loss of the PLA coating, we examined 3 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9), 6 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9), 12 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3), and 18 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3) postimplantation; in tests of mass loss of the Zn sacrificial layer, we examined 1 month (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11), 2 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11), and 3 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11) postimplantation; in test of mass los of the nitride Fe, we examined 2 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11), 3 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11), 6 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11), 9 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11), 12 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11), and 24 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11) postimplantation; in tests of release of the sirolimus, we examined 7 days (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6), 14 days (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6), 1 month (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6), 2 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6), 3 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6), 6 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10), and 12 months (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2) postimplantation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNational Natural Science Foundation of China (grant No. 52130302).\u003c/p\u003e\n\u003cp\u003eNational Key R\u0026amp;D Program of China (grants number 2016YFC1100300 and 2023YFC2410300).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData and materials availability:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data are available in the main text or the supplementary materials.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUccioli L, Meloni M, Izzo V, Giurato L, Merolla S, Gandini R (2018) Critical limb ischemia: current challenges and future prospects. Vasc Health Risk Manag 14:63\u0026ndash;74\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConte MS, Bradbury A, Kolh W, White P, Dick JV, Fitridge F, Mills R, Ricco JL, Suresh JB, Murad KR, Aboyans MH, Aksoy V, Alexandrescu M, Armstrong V-A, Azuma D, Belch N, Bergoeing J, Bjorck M, Chakf\u0026eacute; M, Cheng N, Dawson S, Debus J, Dueck ES, Duval A, Eckstein S, Ferraresi HH, Gambhir R, Gargiulo R, Geraghty M, Goode P, Gray S, Guo B, Gupta W, Hinchliffe PC, Jetty R, Komori P, Lavery K, Liang L, Lookstein W, Menard R, Misra M, Miyata S, Moneta T, Prado G, Munoz JAM, Paolini A, Patel JE, Pomposelli M, Powell F, Robless R, Rogers P, Schanzer L, Schneider A, Taylor P, de Ceniga S, Veller MV, Vermassen M, Wang F, Wang J (2019) The GVG Writing Group, Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg 58:S1\u0026ndash;S109\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Fowkes FGR, Hamburg NM, Kinlay S, Lookstein R, Misra S, Mureebe L, Olin JW, Patel RAG, Regensteiner JG, Schanzer A, Shishehbor MH, Stewart KJ, Treat-Jacobson D, Walsh ME (2017) AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: A report of the American college of cardiology/American heart association task force on clinical practice guidelines. J Am Coll Cardiol 69:1465\u0026ndash;1508\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsuoka EK, Hasebe T, Ishii R, Miyazaki N, Soejima K, Iwasaki K (2022) Comparative performance analysis of interventional devices for the treatment of ischemic disease in below-the-knee lesions: a systematic review and meta-analysis. Circ Cardiovasc Interv 37:145\u0026ndash;157\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerruys PW, Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy J, Heuvel J, Delcan P (1994) Morel, M. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. New Eng J Med 331:489\u0026ndash;495\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKereiakes DJ, Onuma Y, Serruys PW, Stone GW (2016) Bioresorbable vascular scaffolds for coronary revascularization. Circulation 134:168\u0026ndash;182\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharma U, Concagh D, Core L, Kuang Y, You C, Pham Q, Zugates G, Busold R, Webber S, Merlo J, Langer R, Whitesides GM, Palasis M (2018) The development of bioresorbable composite polymeric implants with high mechanical strength. Nat Mater 17:96\u0026ndash;103\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu S, Li Z, Shen D, Zhu D, Huang K, Su T, Dinh PU, Cores J, Cheng K (2021) Exosome-eluting stents for vascular healing after ischaemic injury. Nat Biomed Eng 5:1174\u0026ndash;1188\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorhani S, Hassanajili S, Hossein S, Tafti A, Rabbani S (2018) Cardiovascular stents: overview, evolution, and next generation. Prog Biomater 7:175\u0026ndash;205\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiramoto JS, Teraa M, de Borst GJ (2018) Conte. M. S. Interventions for lower extremity peripheral artery disease. Nat Rev Cardiol 15:332\u0026ndash;350\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpreen MI, Martens JM, Knippenberg B, van Dijk LC, de Vries J-PPM, Vos JA, de Borst GJ, Vonken E-JPA, Bijlstra OD, Wever JJ, van Eps RGS, Mali WPTM, van Overhagen H (2017) Long-term follow-up of the PADI trial: Percutaneous transluminal angiopl asty versus drug-eluting stents for infrapopliteal lesions in critical limb ischemia. J Am Heart Assoc 6:e004877\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVarcoe RL, DeRubertis BG, Kolluri R, Krishnan P, Metzger DC, Bonaca MP, Shishehbor MH, Holden AH, Bajakian DR, Garcia LA, Kum SWC, Rundback J, Armstrong E, Lee J-K, Khatib Y, Weinberg I, Garcia-Garcia HM, Ruster K, Teraphongphom NT, Zheng Y, Wang J, Jones-McMeans JM, Parikh SA (2023) Drug-Eluting Resorbable Scaffold versus Angioplasty for Infrapopliteal Artery Disease. New Engl J Med\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIglesias JF, Roffi M, Losdat S, Muller O, Degrauwe S, Kurz DJ, Haegeli L, Weilenmann D, Kaiser C, Tapponnier M, Cook S, Cuculi F, Heg D, Windecker S, Pilgrim T (2023) Long-term outcomes with biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in ST-segment elevation myocardial infarction: 5-year follow-up of the BIOSTEMI randomised superiority trial. Lancet 402(10416):1979\u0026ndash;1990\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGray BH, Diaz-Sandoval LJ, Dieter RS, Jaff MR, White CJ (2014) SCAI expert consensus statement for infrapopliteal arterial intervention appropriate use. Catheter Cardiovasc Interv 84:539\u0026ndash;545\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKonstantinos K, Dimitris K, Athanasios D, Stavros S, Dimitris S (2012) Cost-effectiveness analysis of infrapopliteal drug-eluting stents. Cardiovasc Intervent Radiol 36:90\u0026ndash;97\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVarcoe RL, Paravastu SC, Thomas SD, Bennett MH (2019) The use of drug-eluting stents in infrapopliteal arteries: an updated systematic review and meta-analysis of randomized trials. Int Angiol 38:121\u0026ndash;135\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJinnouchi H, Torii S, Sakamoto A, Kolodgie FD, Virmani R, Finn AV (2019) Fully bioresorbable vascular scaffolds: lessons learned and future directions. Nat Rev Cardiol 16:286\u0026ndash;304\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDia AR, Venturini JM, Kalathiya RJ, Besser S, Estrada JR, Friant J, Paul J, Blair JE, Nathan S (2020) Shah, A. P. Two-year follow-up of bioresorbable vascular scaffolds in severe infra-popliteal arterial disease. Vascular 29:355\u0026ndash;362\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBowen PK, Shearier ER, Zhao S, Guillory II, Zhao RJ, Goldman F, Drelich J (2016) Biodegradable metals for cardiovascular stents: from clinical concerns to recent Zn-alloys. Adv Healthc Mater 5:1121\u0026ndash;1140\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRyu H, Seo M-H, Rogers JA (2021) Bioresorbable metals for biomedical applications: from mechanical components to electronic devices. Adv Healthc Mater 10:e2002236\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBosiers M, Peeters P, D'Archambeau O, Hendriks J, Pilger E, D\u0026uuml;ber C, Zeller T, Gussmann A, Lohle PNM, Minar E, Scheinert D, Hausegger K, Schulte K-L, Verbist J, Deloose K, Lammer J (2009) AMS INSIGHT-absorbable metal stent implantation for treatment of below-the-knee critical limb ischemia: 6-month analysis. Cardiovasc Intervent Radiol 32:424\u0026ndash;435\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOzaki Y, Garcia-Garcia HM, Shlofmitz E, Hideo-Kajita A, Waksman R (2020) Second-Generation Drug-eluting resorbable magnesium scaffold: Review of the clinical evidence. Cardiovasc Revasc Med 21:127\u0026ndash;136\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang H, Wang C, Liu C, Chen H, Wu Y, Han J, Ji Z, Lin W, Zhang D, Li W, Yuan W, Guo H, Li H, Yang G, Kong D, Zhu D, Takashima K, Ruan L, Nie J, Li X, Zheng Y (2017) Evolution of the degradation mechanism of pure zinc stent in the one-year study of rabbit abdominal aorta model. Biomaterials 145:92\u0026ndash;105\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng J, Qiu H, Tian Y, Hu X-Y, Luo T, Wu C, Tian Y, Tang Y, Song L, Li L, Xu L, Xu B, Gao R (2019) Preclinical evaluation of a novel sirolimus-eluting iron bioresorbable coronary scaffold in porcine coronary artery at 6 months. JACC Cardiovasc Interv 12:245\u0026ndash;255\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShen D, Qi H, Lin W, Zhang W, Bian D, Shi X, Qin L, Zhang G, Fu W, Dou K, Xu B, Yin Z, Rao J, Alwi M, Wang S, Zheng Y, Zhang D, Gao R (2021) PLA-Zn-nitrided Fe bioresorbable scaffold with 53-\u0026micro;m-thick metallic struts and tunable multistage biodegradation function. Sci Adv 7:eabf0614\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin W, Zhang H, Zhang W, Qi H, Zhang G, Qian J, Li X, Qin L, Li H, Wang X, Qiu H, Shi X, Zheng W, Zhang D, Gao R, Ding J (2021) In vivo degradation and endothelialization of an iron bioresorbable scaffold. Bioact Mater 6:1028\u0026ndash;1039\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang H, Zhang W, Qiu H, Zhang G, Li X, Qi H, Guo J, Qian J, Shi X, Gao X, Shi D, Zhang D, Gao R, Ding J (2022) A biodegradable metal-polymer composite stent safe and effective on physiological and serum-containing biomimetic conditions. Adv Healthc Mater 11(22):2201740\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun G, Guo W, Zhang H, Ma X, Jia X, Xiong J (2022) A novel iron-bioresorbable sirolimus-eluting scaffold device for infrapopliteal artery disease. Circ Cardiovasc Interv 15:e57\u0026ndash;e59\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQi Y, Qi H, He Y, Lin W, Li P, Qin L, Hu Y, Chen L, Liu Q, Sun H, Liu Q, Zhang G, Cui S, Hu J, Yu L, Zhang D, Ding J (2018) Strategy of metal-polymer composite stent to accelerate biodegradation of iron-based biomaterials. ACS Appl Mater Interfaces 10:182\u0026ndash;192\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQi Y, Li X, He Y, Zhang D, Ding J (2019) Mechanism of acceleration of iron corrosion by a polylactide coating. ACS Appl Mater Interfaces 11:202\u0026ndash;218\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi X, Zhang W, Lin W, Qiu H, Qi Y, Ma X, Qi H, He Y, Zhang H, Qian J, Zhang G, Gao R, Zhang D, Ding J (2020) Long-term efficacy of biodegradable metal-polymer composite stents after the first and the second implantations into porcine coronary arteries. ACS Appl Mater Interfaces 12:15703\u0026ndash;15715\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee H-W, Kim K-C, Lee J (2006) Review of maglev train technologies. IEEE Trans Magn 42:1917\u0026ndash;1925\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAli ZA, Serruys PW, Kimura T, Gao R, Ellis SG, Kereiakes DJ, Onuma Y, Simonton C, Zhang Z, Stone G (2017) W. 2-year outcomes with the absorb bioresorbable scaffold for treatment of coronary artery disease: a systematic review and metaanalysis of seven randomised trials with an individual patient data substudy. Lancet 390:760\u0026ndash;772\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShen Y, Zhang W, Xie Y, Li A, Wang X, Chen X, Liu Q, Wang Q, Zhang G, Liu Q, Liu J, Zhang D, Zhang Z, Ding J (2021) Surface modification to enhance cell migration on biomaterials and its combination with 3D structural design of occluders to improve interventional treatment of heart diseases. Biomaterials 279:1\u0026ndash;16\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang L, Wang X, Wu Y, Guo M, Gu C, Dai C, Kong D, Wang Y, Zhang C, Qu D, Fan C, Xie Y, Zhu Z, Liu Y, Wei D (2022) Rapid and ultrasensitive electromechanical detection of ions, biomolecules and SARS-CoV-2 RNA in unamplified samples. Nat Biomed Eng 6:276\u0026ndash;285\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang G, Gao C, Xiao B, Zhang J, Jiang X, Wang Q, Guo J, Zhang D, Liu J, Xie Y, Shu C, Ding J (2022) Research and clinical translation of trilayer stent-graft of expanded polytetrafluoroethylene for interventional treatment of aortic dissection. Regen Biomater 9:rbac049\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaselli D, Matos RS, Johnson RD, Martella D, Caprettini V, Chiappini C, Chiappini C, Camelliti P, Campagnolo P (2022) Porcine organotypic epicardial slice protocol: A tool for the study of epicardium in cardiovascular research. Front Cardiovasc Med 9:920013\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang J, Xu Y, Xue Y, Huang Y, Li X, Chen X, Xu Y, Zhang D, Zhang P, Zhao J, Ji J (2023) Identification of top-performance antimicrobial peptides from whole combinatorial libraries via a sequential model ensemble machine learning pipeline. Nat Biomed Eng 7:797\u0026ndash;810\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwon K, Kim JU, Won SM, Zhao J, Avila R, Wang H, Chun KS, Jang H, Lee KH, Kim J-H, Yoo S, Kang YJ, Kim J, Lim J, Park Y, Lu W, Kim T-i, Banks A, Huang Y, Rogers JA (2023) A battery-less wireless implant for the continuous monitoring of vascular pressure, flow rate and temperature. Nat Biomed Eng 7:1215\u0026ndash;1228\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCao D, Ding J (2022) Recent Advances in regenerative biomaterials. Regen Biomater 9:rbac098\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChoi YS, Hsueh Y, Koo J, Yang Q, Avil R, Hu B, Xie Z, Lee G, Ning Z, Liu C, Xu Y, Lee YJ, Zhao W, Fang J, Deng Y, Lee SM, Guardado AV, Stepien I, Yan Y, Song JW, Haney C, Oh YS, Liu W, Yun H, Banks A, MacEwan MR, Ameer GA, Ray WZ, Huang Y, Xie T, Franz CK, Li S, Rogers JA (2020) Stretchable, dynamic covalent polymers for soft, long-lived bioresorbable electronic stimulators designed to facilitate neuromuscular regeneration. Nat Commun 11(1):5990\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu AP, Appel EA, Ashby PD, Baker BM, Franco E, Gu L, Haynes K, Joshi NS, Kloxin AM, Kouwer PHJ, Mittal J, Morsut L, Noireaux V, Parekh S, Schulman R, Tang SKY, Valentine MT, Vega SL, Weber W, Stephanopoulos N, Chaudhuri O (2022) The living interface between synthetic biology and biomaterial design. Nat Mater 21:390\u0026ndash;397\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKolandaivelu K, Swaminathan R, Gibson WJ, Kolachalama VB, Nguyen-Ehrenreich KL, Giddings VL, Coleman L, Wong GK, Edelman ER (2011) Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 123:1400\u0026ndash;1409\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin W, Qin L, Qi H, Zhang D, Zhang G, Gao R, Qiu H, Xia Y, Cao P, Wang X, Zheng W (2017) Long-term in vivo corrosion behavior, biocompatibility and bioresorption mechanism of a bioresorbable nitrided iron scaffold. Acta Biomate 54:454\u0026ndash;468\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeuster M, Wohlsein P, Br\u0026uuml;gmann M, Ehlerding M, Seidler K, Fink C, Brauer H, Fischer A, Hausdorf G (2001) A. novel approach to temporary stenting: degradable cardiovascular stents produced from corrodible metal results 6\u0026ndash;18 months after implantation into new zealand white rabbits. Heart 86:563\u0026ndash;569\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhitman GW, Russell RP, Altieri VJ (1924) Effect of hydrogen-ion concentration on the submerged corrosion of steel. Ind Eng Chem 16:665\u0026ndash;670\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu L, Ding J (2004) In vitro degradation of three-dimensional porous poly (D, L-lactide-co-glycolide) scaffolds for tissue engineering. Biomaterials 25(27):5821\u0026ndash;5830\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Overhagen H, Nakamura M, Geraghty PJ, Rao S, Arroyo M, Soga Y, Iida O, Armstrong E, Nakama T, Fujihara M, Ansari M, Mathews MJ, Gou\u0026euml;ffic S, Jaff Y, Weinberg MR, Pinto I, Ohura DS, Couch N, Mustapha K (2023) Primary results of the SAVAL randomized trial of a paclitaxel-eluting nitinol stent versus percutaneous transluminal angioplasty in infrapopliteal arteries. Vasc Med 28(6):571\u0026ndash;580\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"biodegradable material, peripheral stent, interventional treatment, magnetic levitation, below-the-knee stent, metal, polymer","lastPublishedDoi":"10.21203/rs.3.rs-3574571/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3574571/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile 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 \u0026amp; 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. \u003cem\u003eIn vivo\u003c/em\u003e 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.\u003c/p\u003e","manuscriptTitle":"Maglev-fabricated long and biodegradable stent for interventional treatment of peripheral vessels","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-23 06:53:59","doi":"10.21203/rs.3.rs-3574571/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0d7620ae-e646-49dd-aafc-1495608b42ab","owner":[],"postedDate":"January 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28286976,"name":"Physical sciences/Materials science/Biomaterials/Biomedical materials"},{"id":28286977,"name":"Physical sciences/Engineering/Biomedical engineering"},{"id":28286978,"name":"Physical sciences/Chemistry/Polymer chemistry"},{"id":28286979,"name":"Health sciences/Cardiology/Interventional cardiology"},{"id":28286980,"name":"Biological sciences/Biotechnology/Biomaterials/Implants"}],"tags":[],"updatedAt":"2024-09-11T07:13:33+00:00","versionOfRecord":{"articleIdentity":"rs-3574571","link":"https://doi.org/10.1038/s41467-024-52288-4","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2024-09-10 04:00:00","publishedOnDateReadable":"September 10th, 2024"},"versionCreatedAt":"2024-01-23 06:53:59","video":"","vorDoi":"10.1038/s41467-024-52288-4","vorDoiUrl":"https://doi.org/10.1038/s41467-024-52288-4","workflowStages":[]},"version":"v1","identity":"rs-3574571","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3574571","identity":"rs-3574571","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}