Digital Light Processing-3D Printing of Thermoset Materials with High Biodegradability from Amino Acid-Derived Acrylamide Monomers.

Six acrylamide resins, derived from l-phenylalanine and l-leucine, are designed for application in digital light processing (DLP) printers to obtain biodegradable thermoset polymers. The acrylamide copolymers are prepared under light irradiation at 405 nm and thermal post-curing processes. Low molecular weight poly(ethylene glycol)diacrylate (PEGDA) and N,N-dimethylacrylamide (DMAM), both liquid resins, are used as co-monomers and diluents for the amino acid-derived acrylamide solubilization. The presence of two phenylalanine units and two ester groups in the acrylamide monomer accuses a fast degradation rate in hydrolytic medium in 90 days. The residual products leached in the aqueous media prove to be non-cytotoxic, when 3D-printed samples are cultured with osteoblast cells (MG63), which represents an advantage for the safe disposal of printer waste materials. The scaled-up pieces derived from l-phenylalanine and diethylene glycol, as amino acid-derived acrylamide (named compound C), PEGDA and DMAM, present high dimensional stability after DLP printing of complex structures used as testing samples. Layers of 50 µm of thickness are well cohesive having isotropic behavior, as demonstrated with tensile-strain measurements performed in X-Y-Z (plane) directions. The compound C, which contains phenylalanine amino acid, reveals a promising potential to replace non-biodegradable acrylate polymers used in prototyping systems.

Hydroxyapatite-filled osteoinductive and piezoelectric nanofibers for bone tissue engineering.

Osteoporotic-related fractures are among the leading causes of chronic disease morbidity in Europe and in the US. While a significant percentage of fractures can be repaired naturally, in delayed-union and non-union fractures surgical intervention is necessary for proper bone regeneration. Given the current lack of optimized clinical techniques to adequately address this issue, bone tissue engineering (BTE) strategies focusing on the development of scaffolds for temporarily replacing damaged bone and supporting its regeneration process have been gaining interest. The piezoelectric properties of bone, which have an important role in tissue homeostasis and regeneration, have been frequently neglected in the design of BTE scaffolds. Therefore, in this study, we developed novel hydroxyapatite (HAp)-filled osteoinductive and piezoelectric poly(vinylidene fluoride-co-tetrafluoroethylene) (PVDF-TrFE) nanofibers via electrospinning capable of replicating the tissue's fibrous extracellular matrix (ECM) composition and native piezoelectric properties. The developed PVDF-TrFE/HAp nanofibers had biomimetic collagen fibril-like diameters, as well as enhanced piezoelectric and surface properties, which translated into a better capacity to assist the mineralization process and cell proliferation. The biological cues provided by the HAp nanoparticles enhanced the osteogenic differentiation of seeded human mesenchymal stem/stromal cells (MSCs) as observed by the increased ALP activity, cell-secreted calcium deposition and osteogenic gene expression levels observed for the HAp-containing fibers. Overall, our findings describe the potential of combining PVDF-TrFE and HAp for developing electroactive and osteoinductive nanofibers capable of supporting bone tissue regeneration.

Poly(aspartic acid) Biohydrogel as the Base of a New Hybrid Conducting Material.

In the present study, a composite made of conducting polymer, poly(3,4-ethylenedioxythiophene) (PEDOT), and a biodegradable hydrogel of poly(aspartic acid) (PASP) were electrochemically interpenetrated with poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PHMeDOT) to prepare a new interpenetrated polymer network (IPN). Different cross-linker and PEDOT MPs contents, as well as different electropolymerization times, were studied to optimize the structural and electrochemical properties. The properties of the new material, being electrically conductive, biocompatible, bioactive, and biodegradable, make it suitable for possible uses in biomedical applications.

Antimicrobial activity of poly(3,4-ethylenedioxythiophene) n-doped with a pyridinium-containing polyelectrolyte.

In spite of p-doped conducting polymers having been widely studied in the last decades and many applications having been developed, studies based on n-doped conducting polymers are extremely scarce. This fact is even more evident when it comes to conducting polymers n-doped with polycations, even though polyanions, such as poly(styrenesulfonate), are often used to obtain p-doped conducting polymers. In this work poly(pyridinium-1,4-diyliminocarbonyl-1,4-phenylene-methylene chloride), abbreviated as P(Py-1,4-P), has been used to prepare n-doped poly(3,4-ethylenedioxythiophene) (PEDOT) electrodes by applying a reduction potential to a de-doped PEDOT film in a P(Py-1,4-P) water solution. The utilization of this cationic polyelectrolyte as an n-dopant agent results in drastic superficial changes, as is observed by comparing the morphology, topography and wettability of p-doped, de-doped and n-doped PEDOT. Cytotoxicity, cell adhesion and cell proliferation assays, which have been conducted using epithelial and fibroblast cell lines, show that the amount of P(Py-1,4-P) in the re-doped PEDOT films is below that required to observe a cytotoxic harmful response and that n-doped PEDOT:P(Py-1,4-P) films are biocompatible. The non-specific bacteriostatic properties of n-doped PEDOT:P(Py-1,4-P) films have been demonstrated against E. coli and S. aureus bacteria (Gram-negative and Gram-positive, respectively) using bacterial growth curves and adhesion assays. Although the bacteriostatic effect is in part due to the conducting polymer, as is proved by results for p-doped and de-doped PEDOT, the incorporation of P(Py-1,4-P) through the re-doping process greatly enhances this antimicrobial behaviour. Thus, only a small concentration of this cationic polyelectrolyte (∼0.1 mM) is needed to inhibit bacterial growth.

Isomeric cationic ionenes as n-dopant agents of poly(3,4-ethylenedioxythiophene) for in situ gelation.

Three isomeric ionene polymers containing 1,4-diazabicyclo[2.2.2]octane (DABCO) and N,N'-(x-phenylene)dibenzamide (x = ortho-/meta-/para-) linkages have been used as dopant agents to produce n-doped poly(3,4-ethylenedioxythiophene) (PEDOT) electrodes by reducing already dedoped conducting polymer (CP) films. This work focuses on the influence of the ionene topology on both the properties of n-doped PEDOT:ionene electrodes and the success of the in situ thermal gelation of the ionene inside the CP matrix. The highest doping level is reached for the para-isomeric ionene-containing electrode, even though the content of ortho- and meta-topomers in the corresponding n-doped PEDOT:ionene electrodes is greater. Thus, many of the incorporated ionene units are not directly interacting with CP chains and, therefore, they do not play an active role as n-dopant agents but they are crucial for the in situ formation of the ionene hydrogels. The effect of the ionene topology is practically non-existent on properties such as the specific capacitance and wettability of PEDOT:ionene films, and it is small but non-negligible on the electrochemical and thermal stability. In contrast, the surface morphology, topography, and distribution of dopant molecules significantly depend on the ionene topology. In situ thermal gelation was successful in PEDOT films n-doped with the ortho- and para-topomers, even though this assembly process was much faster for the former than for the latter. The gelation considerably improved the mechanical response of the electropolymerized PEDOT film, which was practically non-existent before it. Molecular dynamics simulations prove that the strength and abundance of PEDOTionene specific interactions (i.e. π-π stacking, N-HS hydrogen bonds and both N+O and N+S interactions) are higher for the meta-isomeric ionene, for which the in situ gelation was not achieved, than for the ortho- and para-ones.

Cationic ionene as an n-dopant agent of poly(3,4-ethylenedioxythiophene).

We report the reduction of poly(3,4-ethylenedioxythiophene) (PEDOT) films with a cationic 1,4-diazabicyclo[2.2.2]octane-based ionene bearing N,N'-(meta-phenylene)dibenzamide linkages (mPI). Our main goal is to obtain n-doped PEDOT using a polymeric dopant agent rather than small conventional tetramethylammonium (TMA), as is usual. This has been achieved using a three-step process, which has been individually optimized: (1) preparation of p-doped (oxidized) PEDOT at a constant potential of +1.40 V in acetonitrile with LiClO4 as the electrolyte; (2) dedoping of oxidized PEDOT using a fixed potential of -1.30 V in water; and (3) redoping of dedoped PEDOT applying a reduction potential of -1.10 V in water with mPI. The resulting films display the globular appearance typically observed for PEDOT, with mPI being structured in separated phases forming nanospheres or ultrathin sheets. This organization, which has been supported by atomistic molecular dynamics simulations, resembles the nanosegregated phase distribution observed for PEDOT p-doped with poly(styrenesulfonate). Furthermore, the doping level achieved using mPI as the doping agent is comparable to that achieved using TMA, even though ionene provides distinctive properties to the conducting polymer. For example, films redoped with mPI exhibit much more hydrophilicity than the oxidized ones, whereas films redoped with TMA are hydrophobic. Similarly, films redoped with mPI exhibit the highest thermal stability, while those redoped with TMA show thermal stability that is intermediate between those of the latter and the dedoped PEDOT. Overall, the incorporation of an mPI polycation as the n-dopant into PEDOT has important advantages for modulating the properties of this emblematic conducting polymer.

Hierarchical self-assembly of di-, tri- and tetraphenylalanine peptides capped with two fluorenyl functionalities: from polymorphs to dendrites.

Homopeptides with 2, 3 and 4 phenylalanine (Phe) residues and capped with fluorenylmethoxycarbonyl and fluorenylmethyl esters at the N-terminus and C-terminus, respectively, have been synthesized to examine their self-assembly capabilities. Depending on the conditions, the di- and triphenylalanine derivatives self-organize into a wide variety of stable polymorphic structures, which have been characterized: stacked braids, doughnut-like shapes, bundled arrays of nanotubes, corkscrew-like shapes and spherulitic microstructures. These highly aromatic Phe-based peptides also form incipient branched dendritic microstructures, even though they are highly unstable, making their manipulation very difficult. Conversely, the tetraphenylalanine derivative spontaneously self-assembles into stable dendritic microarchitectures made of branches growing from nucleated primary frameworks. The fractal dimension of these microstructures is ∼1.70, which provides evidence for self-similarity and two-dimensional diffusion controlled growth. DFT calculations at the M06L/6-31G(d) level have been carried out on model ß-sheets since this is the most elementary building block of Phe-based peptide polymorphs. The results indicate that the antiparallel ß-sheet is more stable than the parallel one, with the difference between them growing with the number of Phe residues. Thus, the cooperative effects associated with the antiparallel disposition become more favorable when the number of Phe residues increases from 2 to 4, while those of the parallel disposition remained practically constant.

Self-Assembly of Tetraphenylalanine Peptides.

Three different tetraphenylalanine (FFFF) based peptides that differ at the N- and C-termini have been synthesized by using standard procedures to study their ability to form different nanoassemblies under a variety of conditions. The FFFF peptide assembles into nanotubes that show more structural imperfections at the surface than those formed by the diphenylalanine (FF) peptide under the same conditions. Periodic DFT calculations (M06L functional) were used to propose a model that consists of three FFFF molecules defining a ring through head-to-tail NH3(+)⋅⋅⋅(-)OOC interactions, which in turn stack to produce deformed channels with internal diameters between 12 and 16 Å. Depending on the experimental conditions used for the peptide incubation, N-fluorenylmethoxycarbonyl (Fmoc) protected FFFF self-assembles into a variety of polymorphs: ultra-thin nanoplates, fibrils, and star-like submicrometric aggregates. DFT calculations indicate that Fmoc-FFFF prefers a parallel rather than an antiparallel ß-sheet assembly. Finally, coexisting multiple assemblies (up to three) were observed for Fmoc-FFFF-OBzl (OBzl = benzyl ester), which incorporates aromatic protecting groups at the two peptide terminals. This unusual and noticeable feature is attributed to the fact that the assemblies obtained by combining the Fmoc and OBzl groups contained in the peptide are isoenergetic.

Glyoxal crosslinking of electro-responsive alginate-based hydrogels: Effects on the properties.

To improve the features of alginate-based hydrogels in physiological conditions, Ca2+-crosslinked semi-interpenetrated hydrogels formed by poly(3,4-ethylenedioxythiophene):polystyrene sulfonic acid and alginate (PEDOT/Alg) were subjected to a treatment with glyoxal to form a dual ionic/covalent network. The covalent network density was systematically varied by considering different glyoxalization times (tG). The content of Ca2+ was significantly higher for the untreated hydrogel than for the glyoxalized ones, while the properties of the hydrogels were found to largely depend on tG. The porosity and swelling capacity decreased with increasing tG, while the stiffness and electrical conductance retention capacity increased with tG. The potentiodynamic response of the hydrogels notably depended on the amount of conformational restraints introduced by the glyoxal, which is a very short crosslinker. Thus, the re-accommodation of the polymer chains during the cyclic potential scans became more difficult with increasing number of covalent crosslinks. This information was used to improve the performance of untreated PEDOT/Alg as electrochemical sensor of hydrogen peroxide by simply applying a tG of 5 min. Overall, the control of the properties of glyoxalized hydrogels through tG is very advantageous and can be used as an on-demand strategy to improve the performance of such materials depending on the application.

Recent Progress in Biomedical Sensors Based on Conducting Polymer Hydrogels.

Biosensors are increasingly taking a more active role in health science. The current needs for the constant monitoring of biomedical signals, as well as the growing spending on public health, make it necessary to search for materials with a combination of properties such as biocompatibility, electroactivity, resorption, and high selectivity to certain bioanalytes. Conducting polymer hydrogels seem to be a very promising materials, since they present many of the necessary properties to be used as biosensors. Furthermore, their properties can be shaped and enhanced by designing conductive polymer hydrogel-based composites with more specific functionalities depending on the end application. This work will review the recent state of the art of different biological hydrogels for biosensor applications, discuss the properties of the different components alone and in combination, and reveal their high potential as candidate materials in the fabrication of all-organic diagnostic, wearable, and implantable sensor devices.

Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress.

Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice. Remarkably, sEH degradation caused by ALT-PG2 was accompanied by an increase in the phosphorylated levels of AMP-activated protein kinase (AMPK), while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced. Consistent with the key role of these kinases on endoplasmic reticulum (ER) stress, ALT-PG2 attenuated the levels of ER stress and inflammatory markers. Overall, the findings of this study indicate that targeting sEH with degraders is a promising pharmacological strategy to promote AMPK activation and to reduce ER stress and inflammation.

Properties of poly(3-halidethiophene)s.

The influence of the halogen atom on the intrinsic properties of poly(3-halidethiophene)s has been investigated using experimental and theoretical methodologies. Specifically, the electrochemical, electrical, electronic and morphological properties of poly(3-bromothiophene) have been determined and compared with those recently reported for poly(3-chlorothiophene) [Aradilla et al., Polym. Chem., 2012, 3, 436.]. The electrochemical stability and porosity are smaller for poly(3-bromothiophene) than for poly(3-chlorothiophene) while the π-π* lowest transition energy is higher for the former than for the latter. Moreover, quantum mechanical calculations on model oligomers have evidenced that the conformational properties of poly(3-halidethiophene)s, where the halogen is fluorine, chloride or bromine, are dominated by steric interactions and, therefore, are significantly influenced by the size of the halogen atoms. Both the ionization potential and the π-π* lowest transition energy have been predicted to increase slightly when the π-donor character of the halogen atom decreases, in agreement with experimental observations.

Semi-Interpenetrated Hydrogels-Microfibers Electroactive Assemblies for Release and Real-Time Monitoring of Drugs.

Simultaneous drug release and monitoring using a single polymeric platform represents a significant advance in the utilization of biomaterials for therapeutic use. Tracking drug release by real-time electrochemical detection using the same platform is a simple way to guide the dosage of the drug, improve the desired therapeutic effect, and reduce the adverse side effects. The platform developed in this work takes advantage of the flexibility and loading capacity of hydrogels, the mechanical strength of microfibers, and the capacity of conducting polymers to detect the redox properties of drugs. The engineered platform is prepared by assembling two spin-coated layers of poly-γ-glutamic acid hydrogel, loaded with poly(3,4-ethylenedioxythiophene) (PEDOT) microparticles, and separated by a electrospun layer of poly-ε-caprolactone microfibers. Loaded PEDOT microparticles are used as reaction nuclei for the polymerization of poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PHMeDOT), that semi-interpenetrate the whole three layered system while forming a dense network of electrical conduction paths. After demonstrating its properties, the platform is loaded with levofloxacin and its release monitored externally by UV-vis spectroscopy and in situ by using the PHMeDOT network. In situ real-time electrochemical monitoring of the drug release from the engineered platform holds great promise for the development of multi-functional devices for advanced biomedical applications.

Polypropylene mesh for hernia repair with controllable cell adhesion/de-adhesion properties.

Herein, a versatile bilayer system, composed by a polypropylene (PP) mesh and a covalently bonded poly(N-isopropylacrylamide) (PNIPAAm) hydrogel, is reported. The cell adhesion mechanism was successfully modulated by controlling the architecture of the hydrogel in terms of duration of PNIPAAm grafting time, crosslinker content, and temperature of material exposure in PBS solutions (below and above the LCST of PNIPAAm). The best in vitro results with fibroblast (COS-1) and epithelial (MCF-7) cells was obtained with a mesh modified with a porous iPP-g-PNIPAAm bilayer system, prepared via PNIPAAm grafting for 2 h at the lowest N,N'-methylene bis(acrylamide) (MBA) concentration (1 mM). Under these conditions, the detachment of the fibroblast-like cells was 50% lower than that of the control, after 7 days of cell incubation, which represents a high de-adhesion of cells in a short period. Moreover, the whole system showed excellent stability in dry or wet media, proving that the thermosensitive hydrogel was well adhered to the polymer surface, after PP fibre activation by cold plasma. This study provides new insights on the development of anti-adherent meshes for abdominal hernia repair.

Scaffolds for Sustained Release of Ambroxol Hydrochloride, a Pharmacological Chaperone That Increases the Activity of Misfolded ß-Glucocerebrosidase.

Ambroxol is a pharmacological chaperone (PC) for Gaucher disease that increases lysosomal activity of misfolded ß-glucocerebrosidase (GCase) while displaying a safe toxicological profile. In this work, different poly(ε-caprolactone) (PCL)-based systems are developed to regulate the sustained release of small polar drugs in physiological environments. For this purpose, ambroxol is selected as test case since the encapsulation and release of PCs using polymeric scaffolds have not been explored yet. More specifically, ambroxol is successfully loaded in electrospun PCL microfibers, which are subsequently coated with additional PCL layers using dip-coating or spin-coating. The time needed to achieve 80% release of loaded ambroxol increases from ≈15 min for uncoated fibrous scaffolds to 3 days and 1 week for dip-coated and spin-coated systems, respectively. Furthermore, it is proven that the released drug maintains its bioactivity, protecting GCase against induced thermal denaturation.

Electrochromic Self-Electrostabilized Polypyrrole Films Doped with Surfactant and Azo Dye.

Two azo dyes, acid red 1 (AR1) and acid red 18 (AR18), were used alone or in combination with sodium dodecyl sulfate (SDS) for the electropolymerization of a pyrrole monomer. Polypyrrole (PPy) showed higher redox capacity when SDS and AR18 were used simultaneously as dopant agents (PPy/AR18-SDS) than when the conducting polymer was produced in the presence of SDS, AR18, AR1, or an AR1/SDS mixture. Moreover, PPy/AR18-SDS is a self-stabilizing material that exhibits increasing electrochemical activity with the number of oxidation-reduction cycles. A mechanism supported by scanning electron microscopy and X-ray diffraction structural observations was proposed to explain the synergy between the SDS surfactant and the AR18 dye. On the other hand, the Bordeaux red color of PPy/AR18-SDS, which exhibits an optical band gap of 1.9 eV, rapidly changed to orange-yellow and blue colors when films were reduced and oxidized, respectively, by applying linear or step potential ramps. Overall, the results indicate that the synergistic utilization of AR18 and SDS as dopant agents in the same polymerization reaction is a very successful and advantageous strategy for the preparation of PPy films with cutting-edge electrochemical and electrochromic properties.

Hydrogen-bonding interactions in 2-thiophen-3-ylmalonic acid.

Formation of intra- and intermolecular hydrogen bonds in 2-thiophen-3-ylmalonic acid, the precursor of a polythiophene derivative bearing two carboxylic acid groups in the side chain, have been examined by Fourier transform infrared (FTIR) spectroscopy and ab initio quantum mechanical calculations. Interactions found in the FTIR spectra recorded for the melted and solid states are in good agreement with results provided by MP2/6-31+G(d,p) calculations on monomers and dimers, respectively. Specifically, inter- and intramolecular hydrogen bonds were detected in the solid and melted states, respectively. Calculations on dimers stabilized by intermolecular hydrogen bonds exclusively and by both intra- and intermolecular interactions indicated that the former structures are significantly more stable than the latter ones, which is fully consistent with experimental observations. On the other hand, intramolecular interactions in isolated monomers are favored in the melted state, which is dominated by a thermally driven entropic process.

Pastes and hydrogels from carboxymethyl cellulose sodium salt as supporting electrolyte of solid electrochemical supercapacitors.

Different carboxymethyl cellulose sodium salt (NaCMC)-based pastes and hydrogels, both containing a salt as supporting electrolyte, have been prepared and characterized as potential solid state electrolyte (SSE) for solid electrochemical supercapacitors (ESCs).The characteristics of the NaCMC-based SSEs have been optimized by examining the influence of five different factors in the capacitive response of poly(3,4-ethylenedioxythiophene) (PEDOT) electrodes: i) the chemical nature of the salt used as supporting electrolyte; ii) the concentration of such salt; iii) the concentration of cellulose used to prepare the paste; iv) the concentration of citric acid employed during NaCMC cross-linking; and v) the treatment applied to recover the supporting electrolyte after washing the hydrogel. The specific capacitance of the device prepared using the optimized hydrogel as SSE is 81.5 and 76.8 F/g by means of cyclic voltammetry and galvanostatic charge/discharge, respectively, these values decreasing to 60.7 and 75.5 F/g when the SSE is the paste.

Electrostimulated Release of Neutral Drugs from Polythiophene Nanoparticles: Smart Regulation of Drug-Polymer Interactions.

Poly(3,4-ethylenedioxythiophene) (PEDOT) nanoparticles are loaded with curcumin and piperine by in situ emulsion polymerization using dodecyl benzene sulfonic acid both as a stabilizer and a doping agent. The loaded drugs affect the morphology, size, and colloidal stability of the nanoparticles. Furthermore, kinetics studies of nonstimulated drug release have evidenced that polymer···drug interactions are stronger for curcumin than for piperine. This observation suggests that drug delivery systems based on combination of the former drug with PEDOT are much appropriated to show an externally tailored release profile. This is demonstrated by comparing the release profiles obtained in presence and absence of electrical stimulus. Results indicate that controlled and time-programmed release of curcumin is achieved in a physiological medium by applying a negative voltage of -1.25 V to loaded PEDOT nanoparticles.

Confinement of a ß-barrel protein in nanoperforated free-standing nanomembranes for ion transport.

Bioinspired free-standing nanomembranes (FSNMs) for selective ion transport have been tailored by immobilizing the Omp2a ß-barrel membrane protein inside nanoperforations created in flexible poly(lactic acid) (PLA) nanomembranes. Perforated PLA FSNMs have been prepared by spin-coating a 99 : 1 PLA : poly(vinyl alcohol) mixture, and through a phase segregation process nanofeatures with dimensions similar to the entire nanomembrane thickness (∼110 nm) were induced. These nanofeatures have subsequently been transformed into nanoperforations (diameter: ∼51 nm) by selective solvent etching. The protein confined inside the nanopores of PLA FSNMs preserves the ß-barrel structure and organizes in ovoid aggregates. The transport properties of Na+, K+, and Ca2+ across non-perforated PLA, nanoperforated PLA, and Omp2a-filled nanoperforated PLA have been monitored by measuring the nanomembrane resistance with electrochemical impedance spectroscopy (EIS). The incorporation of nanoperforations enhances the transport of ions across PLA nanomembranes, whereas the functionality of immobilized Omp2a is essential to exhibit effects similar to those observed in biological nanomembranes. Indeed, Omp2a-filled nanoperforated PLA nanomembranes exhibit stronger affinity towards Na+ and Ca2+ ions than towards K+. In summary, this work provides a novel bioinspired strategy to develop mechanically stable and flexible FSNMs with channels for ion transport, which are precisely located inside artificial nanoperforations, thus holding great potential for applications in biofiltration and biosensing.