Preparation and application of nano-enzyme implant material

Abstract

The invention discloses preparation and application of a nano-enzyme implant material, and belongs to the technical field of medicines.The preparation method of the nano-enzyme implant material comprises the following steps that S1, a biocompatible stent is provided, and the stent is cleaned and dried; s2, placing the stent treated in the step S1 in an ion implanter, and performing ion implantation under the implantation energy of 20-140 keV and the implantation dose of 1 * 10 < 12 >-5 * 10 < 17 > ions / cm < 2 > by taking one or more elements selected from carbon, magnesium, aluminum, titanium, chromium, iron, cobalt, nickel, copper, silver, platinum, vanadium and manganese as implantation element sources, so as to form a nano-enzyme modification layer on the surface of the stent, the nano-enzyme implant material is obtained. The nano-enzyme implant material which can be produced on a large scale and freely regulated and controlled is developed, shows excellent biological catalytic activity close to that of natural enzyme, has long-term sustainable biological catalytic activity and good catalytic stability, can inhibit inflammation and avoid collagen adhesion when being applied to diseases, and is beneficial to body recovery.

Description

Technical Field

[0001] This invention belongs to the field of medical technology, specifically relating to the preparation and application of a nanozyme implantation material. Background Technology

[0002] In modern medicine, implantable materials are widely used in various scenarios such as tissue repair, drug delivery, and medical device support, including artificial joints, cardiovascular stents, and bone repair materials. However, once these implantable materials enter the body, they are recognized as foreign bodies by the host system, triggering a series of local or systemic adverse reactions, mainly including acute inflammation, fibrosis, coagulation, and infection. Fibrinogen adsorbed on the surface of the implant is a crucial determinant of acute inflammatory responses, often leading to collagen deposition around the material, forming fibrous encapsulations that isolate the implant from the host tissue, and even causing device failure or rejection. Therefore, implantable materials are typically inert and non-toxic. Surface engineering is an important means of regulating the interaction between implants and the host, aiming to reduce oxidative stress and inhibit chronic inflammation, thereby improving the long-term safety of materials. However, existing technologies often face problems such as large chemical usage, high energy consumption, and high cost, limiting their widespread application. Polyethylene glycol (PEG), as a commonly used bio-inert coating material, improves material compatibility to some extent, but it is prone to oxidative degradation under physiological conditions, resulting in limited inhibitory effects on chronic inflammation, thus failing to meet the biostability requirements for long-term implantation.

[0003] Nanozymes, as novel artificial enzymes with advantages such as tunable catalytic activity, multifunctionality, and high stability, have shown great potential in the fields of disease diagnosis and treatment. However, their catalytic activity is generally lower than that of natural enzymes, and current methods of modifying them into implant materials through chemical synthesis face problems such as high cost and long processing time, making it difficult to achieve large-scale application.

[0004] Therefore, developing implantable materials that combine long-term sustainable bioactivity with the feasibility of large-scale fabrication to effectively suppress acute and chronic inflammation has become an urgent need in this field. Next-generation nanozyme implantable materials, through precise catalytic design, are expected to achieve long-lasting anti-inflammatory, antioxidant, and antibacterial functions in vivo. This not only paves the way for performance improvements in long-term implants such as cardiovascular stents and bone repair materials, but also has the potential to drive the intelligent evolution of implantable medical devices. Summary of the Invention

[0005] The primary objective of this invention is to overcome the shortcomings of existing technologies and provide a method for preparing nanozyme implant materials. This method is simple, highly controllable, and suitable for large-scale production. Another objective of this invention is to provide nanozyme implant materials prepared by this method, whose surface exhibits stable and efficient nanozyme catalytic activity. A third objective of this invention is to provide the application of the above-mentioned nanozyme implant materials in the preparation of medical devices for anti-inflammatory, antioxidant, and tissue repair promotion purposes.

[0006] To achieve the above objectives, a specific embodiment of the present invention provides the following technical solution: A method for preparing a nanozyme implant material includes the following steps: S1. Provide a biocompatible scaffold, and clean and dry the scaffold; S2. Place the scaffold treated in step S1 into an ion implanter, using one or more elements selected from carbon, magnesium, aluminum, titanium, chromium, iron, cobalt, nickel, copper, silver, platinum, vanadium, and manganese as the implantation element source, with an implantation energy of 20-140 keV and an implantation frequency of 1×10⁻⁶. 12 -5×10 17 ions / cm 2 Ion implantation is performed at a specific injection dose to form a nanozyme-modified layer on the surface of the scaffold, thereby obtaining the nanozyme implantation material.

[0007] In one or more embodiments of the present invention, in S1, the cleaning includes ultrasonic cleaning of the stent in sequence with acetone and anhydrous ethanol.

[0008] In one or more embodiments of the present invention, in step S2, the implanted element source further includes one of niobium, molybdenum, hafnium, tungsten, bismuth, uranium, lithium, calcium, scandium, silicon, zinc, germanium, palladium, strontium, yttrium, zirconium, cadmium, indium, tin, antimony, barium, lanthanum, cerium, praseodymium, samarium, neodymium, gadolinium, dysprosium, holmium, erbium, thulium, ytterbium, tantalum, iridium, gold, palladium, and thorium, for single metal ion implantation; or, two of the metals are implanted sequentially or simultaneously to form a bimetallic nanozyme modification layer.

[0009] In one or more embodiments of the present invention, in S1, the biocompatible scaffold is selected from one of titanium alloy, cobalt alloy, niobium alloy, zirconium alloy, stainless steel, alumina, medical carbon, hydroxyapatite, bone cement, bioactive glass, polyetheretherketone, polylactic acid, polyorthoester, polyanhydride, polyphosphate, polyhydroxyacetic acid, and polycaprolactone.

[0010] A nanozyme implantation material, which is prepared by the method described above for preparing nanozyme implantation materials.

[0011] In one or more embodiments of the present invention, the injected elements are dispersed in atomic form at a depth of 10-20 nm below the surface of the scaffold.

[0012] In one or more embodiments of the present invention, the nanozyme implant material has one or more enzyme-like activities selected from the following: antioxidant activity, peroxidase-like activity, catalase-like activity, and NADH oxidase-like activity.

[0013] The use of the nanozyme implant material described above in the preparation of medical devices for the treatment or prevention of implant-related inflammation, fibrosis or restenosis.

[0014] In one or more embodiments of the present invention, the medical device is used to treat or prevent restenosis following vascular injury, or to promote the repair of bone defects.

[0015] In one or more embodiments of the present invention, the nanozyme implant material is fabricated in the form of bone plates, bone nails, bone needles, bone rods, spinal fixation devices, heart or tissue repair materials, intraocular filling materials, intrauterine devices, nerve patches, artificial esophagus, artificial blood vessels, artificial vertebrae, artificial joints, artificial urethra, artificial valves, artificial kidneys, breast prostheses, artificial skulls, artificial jaws, artificial hearts, artificial tendons, cochlear implants, artificial anal closure devices, vascular stents, prostate stents, biliary stents, and esophageal stents.

[0016] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a method for preparing nanozyme implantation materials. Through high-energy ion implantation technology, active metal elements are directly embedded into the crystal lattice of the implant substrate material, forming atomic-level bonds. This avoids the problem of easy detachment of traditional coatings, allowing the catalytic activity of the nanozyme implantation material to be maintained for a long time. Furthermore, ion implantation technology is a mature semiconductor industry technology with precise and controllable process parameters. It is environmentally friendly, requires no large amounts of chemical solvents, and is easy to implement for large-scale, standardized surface functionalization production of medical devices. In addition, by precisely selecting the type of implanted element (single metal or bimetal), energy, and dosage, the catalytic activity type and intensity of the nanozyme implantation material can be customized to meet the needs of different disease microenvironments.

[0017] This invention develops a nanoenzyme implant material that can be mass-produced and freely controlled, exhibiting excellent biocatalytic activity close to that of natural enzymes. It has long-term sustainable biocatalytic activity, good catalytic stability, and when applied to diseases, it can inhibit inflammation, prevent collagen adhesion, reduce oxidative stress, inhibit the development of inflammation, and help the body recover. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 This is a schematic diagram of the design of the nanozyme implantation material in one embodiment of the present invention; Figure 2 Comparative structural characterization diagrams of nanoenzyme implantation materials in one embodiment of the present invention: CoV single-atom scaffold (Fig. a, b), PtCu single-atom scaffold (Fig. c, d). Figure 3 This is a comparative diagram of the biocatalytic activity of nanoenzyme implantation materials in one embodiment of the present invention; Figure 4 This is a schematic diagram of the expression of inflammatory factors in serum after a carotid artery injury model treated with nanozyme implantation material stent in one embodiment of the present invention; Figure 5 This is a schematic diagram of endothelial regeneration and inhibition of smooth muscle expression in cells and animals after intervention with nanozyme implantation material in one embodiment of the present invention: 28 days after material implantation in SD rats, α-SMA and CD31 expression in vascular tissue (Figure a), migration of endothelial cells and smooth muscle cells after intervention (Figure b), and α-SMA and CD31 expression in endothelial cells and smooth muscle cells after intervention (Figure c). Figure 6 This is a schematic diagram showing the oxidative stress and inflammation levels in brain tissue after a skull defect model of traumatic brain injury was treated with nanozyme implantation material in one embodiment of the present invention. Detailed Implementation

[0020] To enable those skilled in the art to better understand the technical solutions in this disclosure, the technical solutions in the embodiments of this disclosure will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this disclosure, and not all embodiments. Based on the embodiments in this disclosure, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this disclosure.

[0021] Example 1: Preparation of single-metal nanozyme implantation materials A method for preparing a nanozyme implant material includes the following steps: (1) Rinse the purchased implant material with deionized water, then ultrasonically clean it in acetone and anhydrous ethanol in sequence, and dry it. (2) Fix the implantation material from step (1) into the ion implanter, and implant the metal target M (one of the following: iron (Fe), cobalt (Co), vanadium (V), chromium (Cr), manganese (Mn), platinum (Pt), copper (Cu), silver (Ag), etc.), set the implantation energy to 20keV-140keV, and the implantation dose to 1×10⁻⁶. 12 -5×10 17 ions / cm 2 A single-metal nanozyme implant material was obtained.

[0022] Example 2: Preparation of bimetallic nanozyme implantation materials A method for preparing a nanozyme implant material includes the following steps: (1) Rinse the purchased implant material with deionized water, then ultrasonically clean it in acetone and anhydrous ethanol in sequence, and dry it. (2) Fix the implantation material from step (1) into the ion implanter. First, implant a metal target M1 (one of the following: iron (Fe), cobalt (Co), vanadium (V), chromium (Cr), manganese (Mn), platinum (Pt), copper (Cu), silver (Ag), etc.). Set the implantation energy to 20keV-140keV and the implantation dose to 1×10⁻⁶. 12 -5×10 17 ions / cm 2 Then, another metal M2 (one of the following: iron (Fe), cobalt (Co), vanadium (V), chromium (Cr), manganese (Mn), platinum (Pt), copper (Cu), silver (Ag), etc.) is injected, with the injection energy set to 20keV-140keV and the injection dose to be 1×10⁻⁶. 12 -5×10 17 ions / cm 2 A bimetallic nanozyme implant material was obtained.

[0023] Example 3: Characterization and catalytic activity testing of nanozyme implantation materials (prepared in Examples 1 and 2): (1) The ions implanted on the substrate surface of the nanozyme implantation material are distributed in the range of 10-20 nm on the surface, such as Figure 2 As shown in b and d, the injected ions are dispersed in the substrate lattice in the form of single atoms.

[0024] (2) Total antioxidant capacity test: The total antioxidant capacity of different metals in the nanozyme implanted material was determined using the ABTS rapid method with a total antioxidant capacity assay kit. The antioxidant capacity was assessed by measuring the absorbance at 414 nm wavelength using a UV-Vis spectrophotometer. Figure 3 As shown, PtCu and CoV were approximately 6.0 times and 3.7 times higher than the natural antioxidant (Trolox), respectively.

[0025] (3) Enzyme activity assay: Quantification was performed using the TMB substrate chromogenic kit (ELISA, SenBeiJia) colorimetric method. During the experiment, firstly, the sample (1cm × 0.5cm) and working solution (500 mL) were... L) Add to a centrifuge tube. Then, monitor the change in absorbance at 652 nm over time using a microplate spectrophotometer. Figure 3 As shown, among the 21 nanozyme implantation materials, Pt and PtCu had the highest POD-like specific activity, at 140.3 U / mg and 106.9 U / mg, respectively.

[0026] The CAT-like activity of nanozyme implantation materials was evaluated by measuring the decomposition rate of hydrogen peroxide. Simply put, the sample was added to an aqueous hydrogen peroxide solution (500... In L), the absorbance at 240 nm was measured over time using spectrophotometry, and the extinction coefficient of H2O2 (43.6 mM) was used as the extinction coefficient. -1 -cm -1 The activity was quantified using [method name]. The results are as follows: Figure 3 As shown, CoV exhibited excellent specific activity of 589.5 U / mg.

[0027] To evaluate the NOx-like activity of the nanozyme implanted material, a multifunctional microplate reader was used. During the experiment, 500 μL of NADH solution (dissolved in PBS) and the nanozyme implanted material were added to 96-well plates, and the absorbance was monitored over time at 340 nm. PtCu exhibited the best specific activity at 2.799 U / mg, slightly lower than the highly active natural NOx from Bacillus licheniformis (35 U / mg).

[0028] Example 4: Application of nanozyme implantation materials in a vascular injury model This embodiment evaluates the efficacy of the nanozyme implant materials prepared in Examples 1 and 2 in treating carotid artery injury.

[0029] Animal-level experiments: Methods for constructing a carotid artery injury model: Sprague Dawley rats (male, weighing 350-450 g) were grouped as follows: (1) normal group; (2) injury control group; (3) NiTi stent group; (4) drug-eluting stent group (DES); (5) PtCu stent group; (6) CoV stent group. Animals were anesthetized with isoflurane and disinfected, and then the left side of the neck was opened to separate the left carotid artery. Both ends of the carotid artery were clamped with hemostatic forceps, and a small incision was made at one end. After opening the left carotid artery, the vessel was damaged with a balloon, a stent was placed, and then sutured. Heparin sodium (100 U / kg) was injected intravenously.

[0030] Animals with balloon-induced injury were designated as the injury control group (Sham), while those implanted with various types of scaffolds were designated as the treatment group. After establishing the model, the animals' weight and recovery progress were tracked and recorded daily. Tissue samples were collected from the animals on day 28 after scaffold implantation to measure relevant parameters.

[0031] Cellular level assays: Human umbilical vein endothelial cells (HUVECs) and human umbilical artery smooth muscle cells (HUASMCs) were purchased from Beijing Nabai Biotechnology Co., Ltd. Cells were cultured in DMEM (Gibico, USA) medium containing 10% fetal bovine serum (FBS, Capricorn Scientific, Germany), 100 U / mL penicillin, and 100 mg / mL streptomycin (Sigma-Aldrich, USA) at 37°C with 5% CO2. Cells were passaged when the confluence reached 90%. RAOECs and MPASMCs were subjected to proliferation, co-incubation, and migration experiments.

[0032] Following treatment with nanozyme implantation materials, rat serum was collected to measure the expression levels of inflammatory factors. Figure 4 As shown in the figure, the serum inflammatory factor map shows that, compared with the NiTi group, the PtCu and CoV scaffolds have a positive regulatory effect on anti-inflammatory factor (IL-10) and a negative regulatory effect on pro-inflammatory factors (IL-12, IL-1β, IL-6, IL-17A, TNF-α and IFN-γ).

[0033] Simultaneously, immunofluorescence staining was performed on rat carotid arteries to further evaluate the effects of the nanozyme implant material on angiogenesis and restenosis on day 28. Figure 5 As shown in Figure a, α-SMA expression in the vascular media and intima of the nanozyme implantation material group was uniform and lower than that in the nickel-titanium group, indicating reduced proliferation and migration. In particular, the CoV group showed reduced vascular wall thickness compared to the nickel-titanium group.

[0034] Secondly, through fluorescence staining, CCK8 assay, and migration assay, we observed that single-atom scaffolds promoted the proliferation and migration of HUVECs and inhibited the proliferation and migration of HUASMCs. Figure 5 As shown in b in the figure.

[0035] Previous studies have shown that in neointimal restenosis, the phenotype of stromal cysts (SMCs) changes from contractile to synthetic. Compared with nickel-titanium scaffolds, upregulation of α-SMA (a contractile marker) was observed in SMCs co-cultured with nanozyme implants, indicating that nanozyme implants have a phenotypic regulatory role. CD31 expression was also upregulated in ECs co-cultured with nanozyme implants, leading to neointimal formation, such as... Figure 5 As shown in c in the figure.

[0036] CD31 staining of functional endothelial cells showed that the endothelial cells in the CoV group were completely identical to those in the nickel-titanium group.

[0037] Example 5: Application of nanozyme implantation materials in skull defect models This embodiment evaluates the efficacy of the nanozyme implant materials prepared in Examples 1 and 2 in treating skull defects.

[0038] Animal-level experiments: Establishment of a mouse model of traumatic brain injury (TBI): 7-9 week old male C57BL / 6 mice weighing 21-23g were used in the experiment and divided into the following groups: (1) normal group; (2) TBI control group; (3) PEEK treatment group (substrate material); (4) Pt nanozyme implantation material treatment group (prepared in Example 1 / 2); (5) PtCu nanozyme implantation material treatment group (prepared in Example 1 / 2); 20 mice per group. The first step involved injecting chloral hydrate (10%, 0.2... L) Anesthetize the mice, remove hair from their heads while they are in a completely comatose state, then fix the mice's brains, make a 1.5-2 cm long incision on the scalp, and drill a 4 mm diameter window in the skull. Next, use a hydraulic impact injury device to strike the mouse's brain at the window site, place a 4 mm diameter nanozyme implant material into the skull defect, and suture the scalp.

[0039] Mice with injuries were randomly assigned to two groups: the TBI group (no implantation material) and the treatment group (skull implantation with various nanozyme implantation materials). The weight and wound status of mice in each group were tracked and recorded daily after injury. On the seventh day post-injury, relevant indicators of the skull and brain were measured.

[0040] Brain oxidative stress levels were measured. Experimental results showed that mice in the TBI group still exhibited significant excessive oxidative stress seven days after injury. In contrast, mice treated with nanozyme implantation showed significant recovery in oxidative stress indicators, including MDA, SOD, GSH, and H2O2, more closely resembling those of the normal group. These results indicate that nanozyme implantation treatment can significantly alleviate oxidative stress levels in the brains of mice with skull defects, thereby promoting skull healing.

[0041] Results of inflammatory factor level detection experiments, such as Figure 6 As shown in the figure, seven days after injury, the inflammatory expression levels in the TBI group mice were significantly upregulated, indicating severe brain inflammation. The PtCu treatment group showed a sharp downregulation of inflammatory cytokines, including IL-6, IL-1β, and TNF-α, indicating that the nanozyme implant material has anti-inflammatory effects.

[0042] The above embodiments fully demonstrate that the nanozyme implantation material prepared by the present invention through ion implantation technology has the advantages of reliable preparation process, stable catalytic function, good biocompatibility, and clear anti-inflammatory and antioxidant effects, and has broad application prospects in cardiovascular intervention, orthopedic implantation and other fields.

[0043] The present invention provides a method for preparing nanozyme implantation materials. Through high-energy ion implantation technology, active metal elements are directly embedded into the crystal lattice of the implant substrate material, forming atomic-level bonds. This avoids the problem of easy detachment of traditional coatings, allowing the catalytic activity of the nanozyme implantation material to be maintained for a long time. Furthermore, ion implantation technology is a mature semiconductor industry technology with precise and controllable process parameters. It is environmentally friendly, requires no large amounts of chemical solvents, and is easy to implement for large-scale, standardized surface functionalization production of medical devices. In addition, by precisely selecting the type of implanted element (single metal or bimetal), energy, and dosage, the catalytic activity type and intensity of the nanozyme implantation material can be customized to meet the needs of different disease microenvironments.

[0044] The nanozyme implant material provided by this invention can effectively remove excess reactive oxygen species, reduce local oxidative stress levels, regulate the expression of inflammatory factors, thereby inhibiting acute and chronic inflammation, reducing fibrosis and restenosis, and promoting endothelialization and tissue repair. It has shown clear therapeutic effects in animal models.

[0045] It will be apparent to those skilled in the art that this disclosure is not limited to the details of the exemplary embodiments described above, and that this disclosure can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of this disclosure is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within this disclosure. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0046] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for preparing a nanozyme implant material, characterized in that, Includes the following steps: S1. Provide a biocompatible scaffold, and clean and dry the scaffold; S2. Place the scaffold treated in step S1 into an ion implanter, using one or more elements selected from carbon, magnesium, aluminum, titanium, chromium, iron, cobalt, nickel, copper, silver, platinum, vanadium, and manganese as the implantation element source, with an implantation energy of 20-140 keV and an implantation frequency of 1×10⁻⁶. 12 -5×10 17 ions / cm 2 Ion implantation is performed at a specific injection dose to form a nanozyme-modified layer on the surface of the scaffold, thereby obtaining the nanozyme implantation material.

2. The method for preparing the nanozyme implant material according to claim 1, characterized in that, In step S1, the cleaning process includes ultrasonic cleaning of the stent using acetone and anhydrous ethanol in sequence.

3. The method for preparing the nanozyme implant material according to claim 1, characterized in that, In step S2, the implanted element source further includes one of the following: niobium, molybdenum, hafnium, tungsten, bismuth, uranium, lithium, calcium, scandium, silicon, zinc, germanium, palladium, strontium, yttrium, zirconium, cadmium, indium, tin, antimony, barium, lanthanum, cerium, praseodymium, samarium, neodymium, gadolinium, dysprosium, holmium, erbium, thulium, ytterbium, tantalum, iridium, gold, palladium, and thorium, for single metal ion implantation; or, two of the metals are implanted sequentially or simultaneously to form a bimetallic nanozyme modification layer.

4. The method for preparing the nanozyme implant material according to claim 1, characterized in that, In S1, the biocompatible scaffold is selected from one of the following: titanium alloy, cobalt alloy, niobium alloy, zirconium alloy, stainless steel, alumina, medical carbon, hydroxyapatite, bone cement, bioactive glass, polyetheretherketone, polylactic acid, polyorthoester, polyanhydride, polyphosphate, polyhydroxyacetic acid, and polycaprolactone.

5. A nanoenzyme implantation material, characterized in that, It is prepared by the method of any one of claims 1 to 4 for the preparation of nanozyme implantation material.

6. The nanozyme implantation material according to claim 5, characterized in that, The injected elements are dispersed in atomic form at a depth of 10-20 nm below the surface of the scaffold.

7. The nanozyme implantation material according to claim 5, characterized in that, The nanozyme implant material has one or more enzyme catalytic activities selected from the following: antioxidant activity, peroxidase-like activity, catalase-like activity, and NADH oxidase-like activity.

8. The use of a nanozyme implant material as described in any one of claims 5 to 7 in the preparation of a medical device for treating or preventing implant-related inflammation, fibrosis, or restenosis.

9. The application according to claim 8, characterized in that, The medical device is used to treat or prevent restenosis following vascular injury, or to promote the repair of bone defects.

10. The application according to claim 8 or 9, characterized in that, The nanozyme implant material is fabricated in the form of bone plates, bone nails, bone needles, bone rods, spinal fixation devices, heart or tissue repair materials, intraocular filling materials, intrauterine devices, nerve patches, artificial esophagus, artificial blood vessels, artificial vertebrae, artificial joints, artificial urethra, artificial valves, artificial kidneys, breast prostheses, artificial skulls, artificial jaws, artificial hearts, artificial tendons, cochlear implants, artificial anal closure devices, vascular stents, prostate stents, biliary stents, and esophageal stents.

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