A key yet often overlooked factor in the unpredictable failure of degradable systems is “acquired”; heterogeneity—a spatially and temporally evolving unevenness of degradation that emerges and aggravates during service, rather than originating from manufacturing defects. Controlling this inherent randomness is particularly critical for biodegradable implants, where corrodible metals offer the necessary strength but are susceptible to such unpredictable localized weakness throughout the therapeutic window. Herein, we propose that the reliability of a biodegradable device is highly dependent upon the extent of such “acquired”; heterogeneity. We derive an equation set of random degradation inspired by the Poisson raindrop question, and employ them to quantify the acquired heterogeneity of biometals with and without polymer coatings. We find that coating iron with polylactide increases the corrosion rate by 3-fold but reduces the inhomogeneity by 4,000-fold in a blood-mimetic medium, surprisingly leading to later device fracture despite faster degradation. The resulting biodegradation-controlled metal-polymer composite stents for interventional treatment prevent high-risk early and random fractures. Preclinical studies in pigs, clinical trials involving 1108 patients across multiple cohorts, and 5-year outcomes of 45 first-in-human implantations illustrate that the biodegradation-controlled metal-polymer composite stents are safe, durable, and reliable. Our theoretical framework is relevant to any discipline in which random tempospatial variability undermines system performance.

A big diameter bioresorbable scaffold is expected to be used for treatment of vessel stenosis of children with congenital heart disease to adapt the growth characteristics of vessel of children and avoid the late adverse events of permanent stent implanted in children. However, it is challenging to fabricate a big diameter bioresorbable scaffold that is appropriate for percutaneous implantation with enough mechanical performance and can be smoothly delivered in children's small vessel. In this study, a novel iron big and bioresorbable Scaffold (BBS) for pulmonary artery stenosis of children with congenital cardiovascular diseases was fabricated and evaluated. The BBS was made of nitrided iron tube and processed by laser cutting and polishing. The testing results of radial strength, recoil, shortening, maximal expansion diameter and side-branch accessability illustrated the BBS has good mechanical performance. The animal study showed that the percentage of area stenosis of BBSs was 18.1 ± 8.6%, 20.2 ± 5.9% and 20.4 ± 6.1% at 28, 90 and 180 days after implantation in 17 rabbits, and no malposition, thrombus, dissection or tissue necrosis in the rabbit model was detected by micro-CT, STEM and histological examinations. An φ8 × 23 mm BBS was implanted into a 55-month-old child with left pulmonary stenosis, and multiple spiral CT was conducted. No lumen area loss appeared at 1- and 2-year follow-ups in this first-in-man study. It suggested that the BBS might be a new strategy for the therapy of pulmonary artery stenosis in children.

BACKGROUND AND AIMS:Infrapopliteal artery intervention has yielded suboptimal results in below-the-knee (BTK) arterial disease. However, bioresorbable scaffolds are a potential treatment for this condition. This study compared the support performance, anti-hyperplastic effects, and histological manifestations between a sirolimus-eluting iron bioresorbable scaffold (IBS) and an everolimus-eluting stent (EES) within 6 months and the corrosion profile during 12 months in canine BTK arteries. METHODS:Eighteen IBS and twelve EES systems were implanted into nonatherosclerotic BTK arteries in dogs. Support performance and inhibit intimal hyperplasia, histological manifestations, and the corrosion profile were compared between the two systems using angiography, optical coherence tomography (OCT), micro-computed tomography, and histopathologic evaluation at 1, 3, 6, and 12 months. RESULTS:All systems were successfully implanted. There was no significant difference in the area of stenosis between the IBS and EES groups within 6 months. Semi-quantitative OCT revealed degradation of the IBS at 3 months, with strut corrosion rates of 24.6 %, 45.0 %, and 69.2 % at 3, 6, and 12 months. Micro-computed tomography showed that the IBS maintained its integrity at 1 month without corrosion, with more struts fractured because of degradation at 6 and 12 months. Endothelialization was complete at 1 month in both groups. There was no significant between-group difference in cell responses during 6 months of follow-up, with the exception of macrophages. CONCLUSION:This preclinical study suggests that the IBS has performance support, anti-hyperplastic effects, and histological manifestations comparable to those of the EES within 6 months, with a reasonable corrosion profile over 12 months.

Iron is considered as an attractive alternative material for bioresorbable scaffolds (BRS). The sirolimus eluting iron bioresorbable scaffold (IBS), developed by Biotyx Medical (Shenzhen, China), is the only iron-based BRS with an ultrathin-wall design. The study aims to investigate the long-term efficacy, safety, biocompatibility, and lumen changes during the biodegradation process of the IBS in a porcine model. A total of 90 IBSs and 70 cobalt-chromium everolimus eluting stents (EES) were randomly implanted into nonatherosclerotic coronary artery of healthy mini swine. The multimodality assessments including coronary angiography, optical coherence tomography, micro-computed tomography, magnetic resonance imaging, real-time polymerase chain reaction (PCR), and histopathological evaluations, were performed at different time points. There was no statistical difference in area stenosis between IBS group and EES group at 6 months, 1year, 2 years and 5 years. Although the scaffolded vessels narrowed at 9 months, expansive remodeling with increased mean lumen area was found at 3 and 5 years. The IBS struts remained intact at 6 months, and the corrosion was detectable at 9 months. At 5 years, the iron struts were completely degraded and absorbed in situ, without in-scaffold restenosis or thrombosis, lumen collapse, aneurysm formation, and chronic inflammation. No local or systemic toxicity and abnormal histopathologic manifestation were found in all experiments. Results from real-time PCR indicated that no sign of iron overload was reported in scaffolded segments. Therefore, the IBS shows comparable efficacy, safety, and biocompatibility with EES, and late lumen enlargement is considered as a unique feature in the IBS-implanted vessels.

While chronic limb-threatening ischemia is a serious peripheral artery disease, the lack of an appropriate stent significantly limits the potential of interventional treatment. In spite of much progress in coronary stents, little is towards peripheral stents, which are expected to be both long and biodegradable and thus require a breakthrough in core techniques. Herein, we develop a long and biodegradable stent with a length of up to 118mm based on a metal-polymer composite material. To achieve a well-prepared homogeneous coating on a long stent during ultrasonic spraying, a magnetic levitation is employed. In vivo degradation of the stent is investigated in rabbit abdominal aorta/iliac arteries, and its preclinical safety is evaluated in canine infrapopliteal arteries. First-in-man implantation of the stent is carried out in the below-the-knee artery. The 13 months' follow-ups demonstrate the feasibility of the long and biodegradable stent in clinical applications.

Fe-based stents have been made a figure in biodegradable stents by their good mechanical capacity and biocompatibility, appropriate strength–ductility combination. Although the iron corrosion rate was not ideal, which had been optimized by iron alloy and polymer coating introduction. As a long-term implanted biodegradable material, the real concern about iron-based stents mainly laid in long-term biosafety. In this work, rats were used as an animal model to study the chronic toxicity and carcinogenicity of iron-based stents. Two years later, the changes in body weight and the physiological status during the experiment were monitored, and the blood routine and blood analysis combined with the health of major organs and histopathological tests were performed. The results demonstrated that there was no significant difference compared with the control group (316L SS) in body weight, blood routine index, blood biochemical index, and carcinogenic rate that further confirmed the biosafety of iron-based material.

This study aimed to investigate the long-term biocompatibility, safety, and degradation of the ultrathin nitrided iron bioresorbable scaffold (BRS) in vivo, encompassing the whole process of bioresorption in porcine coronary arteries. Fifty-two nitrided iron scaffolds (strut thickness of 70 mu m) and 28 Vision Co-Cr stents were randomly implanted into coronary arteries of healthy mini-swine. The efficacy and safety of the nitrided iron scaffold were comparable with those of the Vision stentwithin 52 weeks after implantation. In addition, the long-term biocompatibility, safety, and bioresorption of the nitrided iron scaffold were evaluated by coronary angiography, optical coherence tomography, micro-computed tomography, scanning electron microscopy, energy dispersive spectrometry and histopathological evaluations at 4, 12, 26, 52 weeks and even at 7 years after implantation. In particular, a large number of struts were almost completely absorbed in situ at 7 years follow-up, which were first illustrated in this study. The lymphatic drainage pathway might serve as the potential clearance way of iron and its corrosion products.

The new-generation coronary stents are expected to be biodegradable, and then the biocompatibility along with biodegradation becomes more challenging. It is a critical issue to choose appropriate biomimetic conditions to evaluate biocompatibility. Compared with other candidates for biodegradable stents, iron-based materials are of high mechanical strength, yet have raised more concerns about biodegradability and biocompatibility. Herein, a metal-polymer composite strategy is applied to accelerate the degradation of iron-based stents in vitro and in a porcine model. Furthermore, it is found that serum, the main environment of vascular stents, ensured the safety of iron corrosion through its antioxidants. This work highlights the importance of serum, particularly albumin, for an in vitro condition mimicking blood-related physiological condition, when reactive oxygen species, inflammatory response, and neointimal hyperplasia are concerned. The resultant metal-polymer composite stent is implanted into a patient in clinical research via interventional treatment, and the follow-up confirms its safety, efficacy, and appropriate biodegradability.

In-stent restenosis after interventional therapy remains a severe clinical complication. Current evidence indicates that neointimal hyperplasia induced by vascular smooth muscle cell (VSMC) proliferation is a major cause of restenosis. Thus, inhibiting VSMC proliferation is critical for preventing in-stent restenosis. The incidence of restenosis was reduced in nitrided iron-based stents (hereafter referred to as iron stents). We hypothesized that the corroded granules produced by the iron stent would prevent in-stent restenosis by inhibiting VSMC proliferation. To verify this hypothesis, we introduced a dynamic circulation device to analyze the components of corroded granules. To investigate the effects of corroded granules on VSMC proliferation, we implanted the corroded iron stent into the artery of the atherosclerotic artery stenosis model. Moreover, we explored the mechanism underlying the inhibition of VSMC proliferation by iron corroded granules. The results indicated that iron stent produced the corroded granules after implantation, and the main component of the corrosion granules was iron oxide. Remarkably, the corroded granules reduced the neointimal hyperplasia in an atherosclerotic artery stenosis model, and iron corroded granules decreased the neointimal hyperplasia by inhibiting VSMC proliferation. In addition, we revealed that corroded granules reduced VSMC proliferation by activating autophagy through the AMPK/mTOR signaling pathway. Importantly, safety of iron corroded granules was evaluated and proved to be satisfactory hemocompatibility in rabbit model. Overall, the role of corroded granules in restenosis prevention was described for the first time. This finding highlighted the implication of corroded granules produced by iron stent in inhibiting VSMC proliferation, pointing to a new direction to prevent in-stent restenosis.

Abstract Poststent restenosis is caused by insufficient endothelialization and is one of the most serious clinical complications of stenting. We observed a rapid endothelialization rate and increased fibrin deposition on the surfaces of the corroded iron stents. Thus, we hypothesized that corroded iron stents would promote endothelialization by increasing fibrin deposition on rough surfaces. To verify this hypothesis, we conducted an arteriovenous shunt experiment to analyze fibrin deposition in the corroded iron stents. We implanted a corroded iron stent in both the carotid and iliac artery bifurcations to elucidate the effects of fibrin deposition on endothelialization. Co‐culture experiments were conducted under dynamic flow conditions to explore the relationship between fibrin deposition and rapid endothelialization. Our findings indicate that, from the generation of corrosion pits, the surface of the corroded iron stent was rough, and numerous fibrils were deposited in the corroded iron stent. Fibrin deposition in corroded iron stents facilitates endothelial cell adhesion and proliferation, which, in turn, promotes endothelialization after stenting. Our study is the first to elucidate the role of iron stent corrosion in endothelialization, pointing to a new direction for preventing clinical complications caused by insufficient endothelialization.

To evaluate the safety of stent malapposition of corrodible nitride iron stent as biodegradable cardiovascular implants, a total of 108 stents were implanted into the abdominal aortas, iliac arteries, and iliac artery bifurcations of 36 New Zealand white rabbits separately. Each rabbit was implanted with three stents. After a follow-up period of 3 months, no thrombus and embolism were found in local and downstream vessels. And no other adverse events occurred either. Stent strut covered by endothelial layer started to show signs of degradation, while struts exposed to bifurcated blood flow covered by a layer of tissue and no rust particle was found on the surface. Also, there were no traces of thrombosis and traces of excess inflammation. The authors conclude that the risk brought by stent malapposition in less than 9 months is acceptable.

Balancing the biodegradability and mechanical integrity of a bioresorbable scaffold (BRS) with time after implantation to match the remodeling of the scaffolded blood vessel is important, but a key challenge in doing so remains. This study presents a novel intercalated structure of a metallic BRS by introducing a nanoscale Zn sacrificial layer between the nitrided Fe platform and the sirolimus-carrying poly(d,l-lactide) drug coating. The PDLLA-Zn-FeN BRS shows a multistage biodegradation behavior, maintaining mechanical integrity at the initial stage and exhibiting accelerated biodegradation at the subsequent stage in both rabbit abdominal aortas and human coronary arteries, where complete biodegradation was observed about 2 years after implantation. The presence of the nanoscale Zn sacrificial layer with an adjustable thickness also contributes to the tunable biodegradation of BRS and allows the reduction of the metallic strut thickness to 53 μm, with radial strength as strong as that of the current permanent drug-eluting stents.

The next-generation closure device for interventional treatment of congenital heart disease is regarded to be biodegradable, yet the corresponding biomaterial technique is still challenging. Herein, we report the first fully biodegradable atrial septal defect (ASD) occluder finally coming into clinical use, which is made of biodegradable poly(l-lactic acid) (PLLA). We characterized the physico-chemical properties of PLLA fibers as well as the raw polymer and the operability of the as-fabricated occluders. Cell behaviors on material were observed, and in vivo fiber degradation and inflammatory responses were examined. ASD models in piglets were created, and 44 PLLA ASD occluders were implanted via catheter successfully. After 36 months, the PLLA ASD occluders almost degraded without any complications. The mechanical properties and thickness between newborn and normal atrial septum showed no significant difference. We further accomplished the first clinical implantation of the PLLA ASD occluder in a four-year boy, and the two-year follow-up up to date preliminarily indicated safety and feasibility of such new-generation fully biodegradable occluder made of synthetic polymers.

Detection of in vivo biodegradation is critical for development of next-generation medical devices such as bioresorbable stents or scaffolds (BRSs). In particular, it is urgent to establish a nondestructive approach to examine in vivo degradation of a new-generation coronary stent for interventional treatment based on mammal experiments; otherwise it is not available to semi-quantitatively monitor biodegradation in any clinical trial. Herein, we put forward a semi-quantitative approach to measure degradation of a sirolimus-eluting iron bioresorbable scaffold (IBS) based on optical coherence tomography (OCT) images; this approach was confirmed to be consistent with the present weight-loss measurements, which is, however, a destructive approach. The IBS was fabricated by a metal-polymer composite technique with a polylactide coating on an iron stent. The efficacy as a coronary stent of this new bioresorbable scaffold was compared with that of a permanent metal stent with the name of trade mark Xience, which has been widely used in clinic. The endothelial coverage on IBS was found to be greater than on Xience after implantation in a rabbit model; and our well-designed ultrathin stent exhibited less individual variation. We further examined degradation of the IBSs in both minipig coronary artery and rabbit abdominal aorta models. The present result indicated much faster iron degradation of IBS in the rabbit model than in the porcine model. The semi-quantitative approach to detect biodegradation of IBS and the finding of the species difference might be stimulating for fundamental investigation of biodegradable implants and clinical translation of the next-generation coronary stents.

A biodegradable coronary stent is expected to eliminate the adverse events of an otherwise eternally implanting material after vessel remodeling. Both biocorrodible metals and biodegradable polymers have been tried as the matrix of the new-generation stent. Herein, we utilized a metal-polymer composite material to combine the advantages of the high mechanical strength of metals and the adjustable degradation rate of polymers to prepare the biodegradable stent. After coating polylactide (PLA) on the surface of iron, the degradation of iron was accelerated significantly owing to the decrease of local pH resulting from the hydrolysis of PLA, etc. We implanted the metal-polymer composite stent (MPS) into the porcine artery and examined its degradation in vivo, with the corresponding metal-based stent (MBS) as a control. Microcomputed tomography (micro-CT), coronary angiography (CA), and optical coherence tomography (OCT) were performed to observe the stents and vessels during the animal experiments. The MPS exhibited faster degradation than MBS, and the inflammatory response of MPS was acceptable 12 months after implantation. Additionally, we implanted another MPS after 1-year implantation of the first MPS to investigate the result of the MPS in the second implantation. The feasibility of the biodegradable MPS in second implantation in mammals was also confirmed.

Fully bioresorbable scaffolds have been designed to overcome the limitations of traditional drug-eluting stents (DESs), which permanently cage the native vessel wall and pose possible complications. The ultrathin-strut designed sirolimus-eluting iron bioresorbable coronary scaffold system (IBS) shows comparable mechanical properties to traditional DESs and exhibits an adaptive degradation profile during target vessel healing, which makes it a promising candidate in all-comers patient population. For implanted medical devices, magnetic resonance (MR) imaging properties, including MR safety and compatibility, should be evaluated before its clinical use, especially for devices with intrinsic ferromagnetism. In this study, MR safety and compatibility of the IBS scaffold were evaluated based on a series of well-designed in-vitro, ex-vivo and in-vivo experiments, considering possible risks, including scaffold movement, over-heating, image artifact, and possible vessel injury, under typical MR condition. Traditional ASTM standards for MR safety and compatibility evaluation of intravascular devices were referred, but not only limited to that. The unique time-relevant MR properties of bioresorbable scaffolds were also discussed. Possible forces imposed on the scaffold during MR scanning and MR image artifacts gradually decreased along with scaffold degradation/absorption. Rigorous experiments designed based on a scientifically based rationale revealed that the IBS scaffold is MR conditional, though not MR compatible before complete absorption. The methodology used in the present study can give insight into the MR evaluation of magnetic scaffolds (bioresorbable) or stents (permanent).

Objective To evaluate the safety and feasibility of a modified poly(l-lactic acid) (PLLA) atrial septal defect (ASD) occluder. Methods Forty-five piglets were divided into two groups: an experimental group (n = 27) and a control group (n = 18). The experimental group underwent percutaneous implantation of a modified PLLA ASD device while the control group underwent percutaneous implantation of a widely used metal ASD device. X-ray imaging, transthoracic echocardiography (TTE), electrocardiogram (ECG), histopathology and electron microscopic examination were performed at 7 days, 1, 3, 6, and 12 months after implantation. Results Twenty-seven experimental piglets and 18 control piglets were all successfully implanted with modified biodegradable and metal ASD devices, respectively. While both devices exhibited very good occluding effects, the modified PLLA ASD devices were completely endothelialized at 3 months after implantation, and the endothelialization appeared to be more complete compared to the control group. Degradation of the PLLA devices was noted at 12 months follow-up with no loss of integrity at the atrial septum. Conclusion This animal model with implanting of the occluders was effective and not associated with complications. The modified PLLA ASD devices are more controllable and practical than our previous devices. The implanted devices demonstrated good endothelialization and degradability in short and moderate term follow-up. Long-term studies are now underway to further evaluate the biodegradability of this novel device.

Pure iron as a potential bioresorbable material for bioresorbable coronary scaffold has major disadvantages of slow corrosion and bioresorption. However, so far, there are neither quantitative data of long-term in vivo corrosion nor direct experimental evidence for bioresorption of pure iron and its alloys, which are fundamental and vital for developing novel Fe-based alloys overcoming the intrinsic drawbacks of pure iron. This work systemically investigated scaffold performance, long-term in vivo corrosion behavior and biocompatibility of a nitrided iron coronary scaffold and explored its bioresorption mechanism. It was found that the 70 mu m Fe-based scaffold was superior to a state of the art Co-Cr alloy stent (Xience Prime (TM)) in terms of crossing profile, recoil and radial strength. Mass loss was 76.0 +/- 8.5 wt% for the nitrided iron scaffold and 44.2 +/- 11.4 wt% for the pure iron scaffold after 36 months implantation in rabbit abdominal aorta (p < 0.05). The Fe-based scaffold showed good long-term biocompatibility in both rabbit and porcine model. Its insoluble corrosion products were demonstrated biosafe and could be cleared away by macrophages from in situ to adventitia to be indiscernible by Micro Computed Tomography and probably finally enter the lymphatics and travel to lymph nodes after 53 months implantion in porcine coronary artery. The results indicate that the nitrided iron scaffold with further improvements shall be promising for coronary application.Statement of SignificancePure iron as a potential bioresorbable material has major disadvantages of slow corrosion and bioresorption. However, so far, there are neither quantitative data of long-term in vivo corrosion nor direct experimental evidence for bioresorption of pure iron and its alloys. Only this work systemically investigated long-term in vivo corrosion behavior and biocompatibility of a nitrided iron coronary scaffold up to 53 months after implantation and explored its bioresorption mechanism. These are fundamental and vital for developing novel Fe-based alloys overcoming the intrinsic drawbacks of pure iron. Novel testing and section-preparing methods were also provided in this work to facilitate future research and development of novel Fe-based alloy scaffolds. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The new principle and technique to tune biodegradation rates of biomaterials is one of the keys to the development of regenerative medicine and next-generation biomaterials. Biodegradable stents are new-generation medical devices applied in percutaneous coronary intervention, etc. Recently, both corrodible metals and degradable polymers have drawn much attention in biodegradable stents or scaffolds. It is, however, a dilemma to achieve good mechanical properties and appropriate degradation profiles. Herein, we put forward a metal-polymer composite strategy to achieve both. Iron stents exhibit excellent mechanical properties but low corrosion rate in vivo. We hypothesized that coating of biodegradable aliphatic polyester could accelerate iron corrosion due to the acidic degradation products, etc. To demonstrate the feasibility of this composite material technique, we first conducted in vitro experiments to affirm that iron sheet corroded faster when covered by polylactide (PLA) coating. Then, we fabricated three-dimensional metal-polymer stents (MPS) and implanted the novel stents in the abdominal aorta of New Zealand white rabbits, setting metal-based stents (MBS) as a control. A series of in vivo experiments were performed, including measurements of residual mass and radial strength of the stents, histological analysis, micro-computed tomography, and optical coherence tomography imaging at the implantation site. The results showed that MPS could totally corrode in some cases, whereas iron struts of MBS in all cases remained several months after implantation. Corrosion rates of MPS could be easily regulated by adjusting the composition of PLA coatings.

OBJECTIVES:The aim of this study is to evaluate the long-term effectiveness and safety of a self-expandable, double-disk biodegradable device made of poly-L-lactic acid (PLLA) for closure of atrial septal defects (ASDs) in swine.METHODS:ASDs were created by transseptal needle puncture followed by balloon dilatation in 20 piglets. The experimental group comprised 18 animals, while the remaining 2 animals were used as controls. Effectiveness and safety were evaluated by rectal temperature, leukocyte count, chest radiography, electrocardiogram, transthoracic echocardiography (TTE), intracardiac echocardiography (ICE), and histologic studies. Animals were followed up at 1, 3, 6, and 12 months.RESULTS:An ASD model was successfully created in 19 animals; 1 piglet died during the procedure. The ASD diameters that were created ranged from 5 to 6.4 mm. Devices were successfully implanted in 17 animals. No animal died during the follow-up studies. Rectal temperatures and electrocardiograms were normal at follow-up, while leukocyte counts transiently increased from 1 to 6 months. Radiography, TTE, ICE, and macroscopic studies demonstrated that PLLA occluders were positioned well, with no shifting, mural thrombus formation, or atrioventricular valve insufficiency. Histologic evaluations showed that PLLA devices were partially degraded in the follow-up study.CONCLUSIONS:ASD closure with the novel PLLA biodegradable device is safe and effective. Longer-term studies are needed to evaluate long-term biodegradability.