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Core/Shell Piezoelectric Nanofibers with Spatial SelfOrientated #-Phase Nanocrystals for Real-Time Micro-Pressure Monitoring of Cardiovascular Walls Tong Li, Zhang-Qi Feng, Minghe Qu, Ke Yan, Tao Yuan, Bingbing Gao, Ting Wang, Wei Dong, and Jie Zheng ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.9b02483 • Publication Date (Web): 30 Aug 2019 Downloaded from pubs.acs.org on August 30, 2019
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Core/Shell Piezoelectric Nanofibers with Spatial Self-Orientated β-Phase Nanocrystals for Real-Time Micro-Pressure Monitoring of Cardiovascular Walls Tong Li†,#, Zhang-Qi Feng*,†,#, Minghe Qu†, Ke Yan†, Tao Yuan‡, Bingbing Gao┴, Ting Wang┴, Wei Dong† and Jie Zheng*,╨ †School
of Chemical Engineering, Nanjing University of Science and Technology, Nanjing,
China, 210094 ‡Department ┴State
of Orthopedic, Nanjing Jinling Hospital, Nanjing, China, 210002
Key Laboratory of Bioelectronics, Southeast University, Nanjing, China, 210096
╨Department
of Chemical and Biomolecular Engineering, The University of Akron, Akron,
USA, Ohio 44325
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ABSTRACT Implantable pressure biosensors show great potential for assessment and diagnostics of pressure-related diseases. Here, we present a structural design strategy to fabricate core/shell polyvinylidene difluoride (PVDF)/hydroxylamine hydrochloride (HHE) organic piezoelectric nanofibers (OPNs) with well-controlled and self-orientated nanocrystals in the spatial uniaxial orientation (SUO) of β-phase-rich fibers, which significantly enhance piezoelectric performance, fatigue resistance, stability, and biocompatibility. Then, PVDF/HHE OPNs soft sensors are developed and used to monitor subtle pressure changes in vivo. Upon implanting into pig, PVDF/HHE OPNs sensors demonstrate their ultra-high detecting sensitivity and accuracy to capture micro-pressure changes at the outside of cardiovascular walls, and output piezoelectric signals can real-time and synchronously reflect and distinguish changes of cardiovascular elasticity and occurrence of atrioventricular heart-block and formation of thrombus. Such biological information can provide a diagnostic basis for the early assessment and diagnosis of thrombosis and atherosclerosis, especially for postoperative recrudescence of thrombus in the deep of human body. KEYWORDS organic piezoelectric nanofibers, self-orientated nanocrystals, implantable micro-pressure sensor, cardiovascular system, internal pressure monitoring
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Accurate detection and measurement of subtle changes of internal micro-pressures in living organisms (e.g. heart, blood vessel, brain, eye, bladder) have been proved to be extremely challenging for the development of diagnostic biosensors for the real-time monitoring of pressure-related chronic diseases, such as vascular occlusion, arterial hypertension, brain injury, hydrocephalus, glaucoma, and tumors regeneration.1-3 While conventional capacitiveand inductor-based sensors have been widely used for pressure detection and diagnostics for different bench-to-bedside applications, these pressure sensors are only workable for detecting either relatively large pressure changes (> 7 kPa) or small pressure changes near local tissues for a very short-time period (mins to hours).4-6 Particularly, when applying these sensors made of inorganic dielectric materials as implanted devices, they often suffer from poor structural flexibility, static discharge defect, and biocompatibility issue, all of which lead to detection baseline drifting, exogenous infection, and inflammatory response.7-12 Thus, a great challenge still remains to develop soft, self-powered and miniature pressure sensors made of flexible, biocompatible, electrical sensing materials and capable for real-time sensing a internal micropressure of < 1 kPa at any peripheral tissues (not necessary to be near pathological tissues and organs) for a long-time period in vitro and in vivo.13-14 Among different intelligent electrical sensing materials, organic piezoelectric nanofibers (OPNs) demonstrate their advantageous features of soft structural flexibility, excellent biocompatibility, and continuous nanofiber structure, in which the former two features empower OPNs to be easily and friendly adhered onto soft tissues and organs for detecting small internal pressures, while the latter one allows to accelerate piezoelectric charge transfer and prevent cross-coupling of charge transfer, thus improving the pressure-to-electric conversion efficiency.15-17 Nowadays, OPNs materials have been widely used as self-powered mechanical energy collectors/generators/sensors by converting mechanical energy from different subtle, automatous, often wasted biomechanical actions (e.g. heart beating, breathing, blood flow, and walking) to electrical energy in vitro.18-20 However, very few efforts and progress have been made successfully to develop OPNs-implanted biosensors for real-time monitoring and detecting the internal micro-pressures in vivo, because the complex biological media and ions in living organs often cause OPNs to lose its piezoelectric signals and detection sensitivity, thus failing to sense the change of subtle internal micro-pressure (< 1 kPa) particularly at very low frequency (< 3 Hz).2, 5, 17 To overcome such limits, it is highly urgent and rewarding to fabricate the next generation of OPNs with optimized molecular structure for achieving ultrahigh sensitivity and piezoelectric conversion efficiency, which will enable OPNs-implanted biosensors to measure internal micro-pressure wherever 3 ACS Paragon Plus Environment
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biosensors are implanted or attached and to offer reliable, timely, global and local pressurerelated information for human health monitoring and disease diagnosis.2, 16, 21 Recent works demonstrate that abundant β-phase with noncentrosymmetric molecular structure in OPNs functions as the working dipole to promote pressure-induced piezoelectricity. Different processing technologies (e.g. electrospinning, nanotemplate, nanoimprinting) and fabrication materials (e.g. doping with organically modified nanoclays,22 metal nanoparticles,23 functionalized multi-walled carbon nanotubes,24 and graphene and its derivatives25-26) have been developed to increase the content of β-phase and to achieve a conjugation effect between doped molecules and organic piezoelectric chains in OPNs. But such improvement is still very limited, mainly because these nanofillers often cause a mixed anisotropic crystalline structure containing α, β, and γ-phase in the spatial uniaxial orientation (SUO) along OPNs, which will cause piezoelectric charge annihilation at different crystal interfaces and thus reducing the intensity and sensitivity of output piezoelectric signals of OPNs.25,
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Additional concern is that the doped inorganic perovskite ferroelectric and
piezoelectric ceramics are very likely to induce biological toxicity.28-29 So, it is equally important yet very challenging to increase β-phase content and precisely control the arrangement of β-phase along the SUO direction, both of which will promote overflow and transmission of piezoelectric charges among the continuous β-phase domains, for ultimately improving the sensitivity and piezoelectric conversion efficiency of OPNs. To address the aforementioned challenges, here we proposed and demonstrated a distinctive molecular structural design strategy for fabricating core/shell polyvinylidene difluoride (PVDF)/hydroxylamine hydrochloride (HHE) OPNs with β-phase-rich and selforientated nanocrystals in SUO using a simple one-step electrospinning method (Figure S1a) with HHE as inducer, which enabled to transform the nonpolar α-phase with random orientation of dipoles to the polar β-phase with well-aligned dipoles along the nanofiber axis, thus producing OPNs with β-phase-rich domains and well-oriented dipoles. The resultant PVDF/HHE OPNs possessed excellent stability and recoverability of piezoelectricity, extremely high sensitivity and piezoelectric conversion efficiency (up to 1154 V/cm3 at a low frequency of 1.5 Hz and pressure of 1 kPa), and high biocompatibility. More importantly, we fabricated OPNs-based soft sensors and implanted them onto the cardiovascular walls of the heart and femoral artery in a pig, which realized the real-time monitoring and recording of subtle pressure changes from these cardiovascular walls at abnormal disease and normal
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physiological states. Our PVDF/HHE OPNs soft sensor provides a platform for monitoring internal micro-pressure for cardiovascular disease diagnosis.
Figure 1. Molecular structure and characterization of the core/shell PVDF/HHE OPNs with spatial self-orientated β-phase nanocrystals. (a) Molecular modeling and structure of the OPNs in the presence of well-orientated dipoles between -NH2 groups of HHE and -CF2 groups of PVDF chains, inset: TEM image of PVDF/HHE OPNs. (b) HRTEM, SAED, and inverse FFT images of OPNs consistently show the orientated β-phase nanocrystals of PVDF chains in SUO. 5 ACS Paragon Plus Environment
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RESULTS/DISCUSSION To fabricate the core/shell OPNs made of PVDF/HHE, we proposed to dope HHE into PVDF electrospinning solution. Our molecular modeling and simulations have shown that that since HHE contains abundant -NH2 groups, it is likely to interact with negatively charged -CF2 groups of PVDF and form a massive, stable NH2-CF2 dipole network (Figure 1a). During the electrospinning process, -NH2 groups were readily polarized to possess positive charges under the strong electric fields of >105 V/m.30 Upon -NH2 groups polarization, electrostatic repulsion will drive HHE to migrate from the inside to the surface of OPNs along the radial direction (Figure 1a and Figure S1b).31-32 The resulting OPNs possessed a coreshell structure with diameters of 338 ± 85 nm, in which ultrathin HHE shells (thickness of 14.6 ± 5.2 nm) continuously and tightly wrapped around the entire external surface of OPNs (Figure 1a inset and Figure S2). Meanwhile, by applying constant force during electrospinning fabrication, PVDF molecular chains were uniaxially stretched, leading to in situ formation of ordered NH2-CF2 dipoles that further induced a phase transition from the nonpolar α-phase with random orientation of dipoles to the polar β-phase with well-aligned dipoles in SUO in OPNs. High resolution TEM (HRTEM) in Figure 1b confirmed the NH2CF2 dipole-induced spatial self-oriented β-phase nanocrystals in SUO of OPNs. It can be seen that most of PVDF chains in β-phase were aligned and oriented in parallel to form a nanocrystal assay with varied length of 5 - 30 nm and the inter chain distance of 0.548 ± 0.05 nm. Diffraction patterns produced by the inverse Fast Fourier transform (FFT) of HRTEM image also displayed β-phase nanocrystals in a parallel organization. Again, the selected area electron diffraction (SAED) patterns of the crystal area in PVDF also showed the diffraction spots corresponding to the crystallographic plane of β (110, 200).25 For comparison, pure PVDF OPNs without HHE, as a control, showed the less content of β-phase with disorder arrangement (Figure S3), confirming the important role of NH2-CF2 dipole in promoting the recrystallization of β-phase in OPNs. The above results clearly indicate that doping of HHE significantly enhances the formation of β-phase nanocrystals in SUO with high spatial consistency and content. To better understand the role of HHE in the formation of β-phase nanocrystals in SUO, we further prepared different PVDF/HHE OPNs with different HHE contents and compared their molecular structures and morphologies by DSC, FTIR, and XRD. As shown in the Figure S4, collective structural information showed that a low HHE content of 0.5 wt% caused discontinuous β-phase containing a large amount of randomly oriented PVDF chains, leading to low crystallinity (75%) and β-phase content (83%). On the other hand, the excess HHE of 6 ACS Paragon Plus Environment
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1.5 wt% also disrupted the original lattice structure of PVDF chains due to redundant and polarized -NH2 groups, thus preventing the directional crystal growth of the β-phase in SUO with the lower crystallinity (69%) and β-phase content (54%). Only at an optimal value of HHE (1.0 wt%) with balanced molecular pairing between -NH2 and -CF2, PVDF/HHE OPNs increased its crystallinity to 80% and β-phase content to 96% (Figure S3 and S4), and both values were higher than those as reported in literatures.15, 33-37 As a result, a very thin HHE shell was formed to wrap around the external surface of PVDF OPNs, forming a core-shell structure that help to reinforce the stability of the β-phase nanocrystals in SUO. Thus, the proper addition of HHE can effectively order the PVDF chain arrangement due to the specific dipole interactions between PVDF chains and HHE, resulting in predominant crystallization of β-phase crystalline in the PVDF/HHE OPNs. XPS and Raman spectroscopies were used to characterize molecular interactions between HHE and PVDF chains upon the formation of the β-phase nanocrystals in SUO. XPS spectra in Figure 2a showed the heterogeneous distribution of elements in the thin HHE shell (the probing depth of XPS was 4-10 nm), as evidenced by the change of stoichiometric ratio of O:N from 1:1 in bulk at an original state to 64:1 in the HHE shell at a final state. Such element distribution change indicates that (i) upon the OPNs fabrication, -NH2 groups in HHE shell are mainly distributed near the PVDF core, while -OH groups in HHE shell are likely located at the far end of the PVDF core; (ii) due to their locations, -NH2 groups preferentially interact with -CF2 to form working dipoles that in turn induce the phase transition from α to βphase in the OPNs and the formation of β-phase nanocrystals in SUO. Meanwhile, both C1s XPS (Figure 2a, and Figure S5) and Raman (Figure 2b) spectra exhibit two of additional carbon binding peaks; the former two peaks located at 286.9 eV (C-CF2) and 287.6 eV (C-CF), while the latter ones at 841 cm-1 and 876 cm-1. All these peaks indicate strong intermolecular interactions between -CF2 and -NH2 to form NH2-CF2 dipoles that further induce preferential molecular orientation in more homogeneous β-phase nanocrystals.31,32 In addition, in order to visualize the distribution of elements in the PVDF/HHE OPNs, the elemental mapping crosssection images were analyzed by TEM (Figure S6).25 It can be seen that both carbon and fluorine elements were distributed along convex curves, while oxygen and nitrogen elements along concave curves (Figure S6a), in which the convex peak of oxygen element appeared ~4 nm ahead of that of nitrogen element (Figure S6b). Further data fitting also confirms heterogeneous distributions of different elements in the OPNs, i.e. most of oxygen and nitrogen elements tend to distribute along nanofiber peripheries, while nitrogen element is much closer to PVDF core (Figure S6c and d). 7 ACS Paragon Plus Environment
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Figure 2. Molecular interaction mechanism between doped HHE molecules and PVDF chains in OPNs. (a) XPS and (b) Raman spectrum spectra of OPNs. Differences in these spectra confirm the existence of NH2-CF2 dipoles in PVDF/HHE OPNs. (c) Molecular modeling and MD simulations of PVDF/HHE OPNs, as evidenced by a core (PVDF)-shell (HHE) structure at the equilibrium state. (d) Interfacial interactions between the PVDF core and the HHE shell via hydrogen bonds and electrostatic dipoles. (e) Pair correlation functions between -NH2 groups in HHE and -CF2 groups in PVDF and between -OH groups in HHE and -CF2 groups in PVDF.
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In parallel to experimental observations, molecular modelling and molecular dynamics (MD) simulations were conducted to study the structure, dynamics, orientation, and interaction of PVDF OPNs in the presence of HHE. A close visual inspection of MD trajectories in Figure 2c showed that different from -OH groups that stayed away from PVDF chains, most of -NH2 groups were oriented towards -CF2 of PVDF chains to form intermolecular dipoles, which are considered as major driving force to promote the formation of self-orientated β-phase nanocrystals in SUO. Figure 2e shows radial distribution functions (RDF) of F atoms of -CF2 groups and N atoms of -NH2 groups (N-H--F) or O atoms of -OH groups (O-H--F). The N-H--F RDF showed an integral area of 0.33 from 0.20 nm to 0.31 nm, and the O-H--F RDF was only 0.06. This difference in their RDF peaks indicates that -NH2 groups form both electrostatic dipoles and hydrogen bonds with -CF2 groups, while -OH groups do not. In line with of XPS and Raman data, HHE and PVDF molecules are likely to interact with each other via the formation of a six-member ring bonding mode (Figure 2d), which offers the stable and dynamic complexes at the lowest free energy state (Figure S7, Table S1).38-39 We first integrated PVDF/HHE and pure PVDF OPNs with electrodes to fabricate micropressure sensors (Figure S8a and b), and then tested and compared their piezoelectric performance. By repeatedly pressing and releasing both sensors with a auto step-motor controller at the micro-pressure of 1 kPa and low frequency of 1.5 Hz, Figure 3a showed that PVDF/HHE OPNs soft sensor can repeatedly generate stable output voltage of 18 V (size of OPNs, 2 cm (width) × 3 cm (length) × 26 μm (thickness)), and this value was almost 3.6 times higher than that of pure PVDF OPNs soft sensor without HHE. This indicates that PVDF/HHE OPNs not only sensitively converts the subtle micro-pressure into electricity via repeated press-release motions, but also demonstrates its highest piezoelectricity performance (1154 V/cm3) as compared to the reported OPNs and organic piezoelectric materials (0.16 – 666.67 V/cm3, Table S2). Furthermore, Figure 3b showed that after 5-days non-stop pressing and releasing (i.e. 288000 cycles), PVDF/HHE OPNs sensor exhibited excellent fatigue resistance, and its output voltages of 18 V still remained almost unchanged, but pure PVDF OPNs sensor gradually reduced its output voltage from 5.1 to 3.5 V. Clearly, the doped HHE significantly improved the pressured-induced piezoelectricity performance of the OPNs. It is worth noting that the thickness of the OPNs can also affect their piezoelectric performance, i.e. the decease of OPNs thickness leads to the increase of output voltage, and sensitivity under micro-pressure
