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# Bacterial capture efficiency in fluid bloodstream improved by bendable nanowires

• Nature Communicationsvolume 9, Article number: 444 (2018)
• doi:10.1038/s41467-018-02879-9
Accepted:
Published online:

## Abstract

Bacterial infectious diseases, such as sepsis, can lead to impaired function in the lungs, kidneys, and other vital organs. Although established technologies have been designed for the extracorporeal removal of bacteria, a high flow velocity of the true bloodstream might result in low capture efficiency and prevent the realization of their full clinical potential. Here, we develop a dialyzer made by three-dimensional carbon foam pre-grafted with nanowires to isolate bacteria from unprocessed blood. The tip region of polycrystalline nanowires is bent readily to form three-dimensional nanoclaws when dragged by the molecular force of ligand-receptor, because of a decreasing Young’s moduli from the bottom to the tip. The bacterial capture efficiency was improved from ~10% on carbon foam and ~40% on unbendable single-crystalline nanowires/carbon foam to 97% on bendable polycrystalline nanowires/carbon foam in a fluid bloodstream of 10 cm s−1 velocity.

## Introduction

In general, pathogens in the blood of healthy people can trigger serious infectious diseases, such as sepsis, a potentially fatal systemic illness characterized by whole-body inflammation in response to microbial invasion1, 2. The general therapeutic strategy for sepsis is to use empiric, broad-spectrum antibiotic therapy3. However, these broad-spectrum antibiotics are less effective than therapeutics designed to target specific microbes or antibiotic-resistant pathogens. It has been reported that the blood pathogen load is the main reason for disease severity and mortality in patients with sepsis, therefore extracorporeal blood-cleansing therapy is considered a potential option for addressing the root of the problem, by which the blood pathogen can be quickly cleared without the prerequisite of identifying the infection source or changing the blood contents.

To achieve this goal of cleansing the blood, many methods for isolating pathogens have been examined, such as filtration4, microfluidic devices5,6,7,8, and magnetic nanoparticle separation9. Additionally, combining synergistic effects of surface chemistry (specific ligand/receptor recognition) and nanotopography (suitable micro- or nano-topographical interactions), three-dimensional (3D) nanostructures, including stiff inorganic materials such as Si nanowires (NWs)10, 11, TiO2 nanosisal-like12 and quartz NW arrays13 and softer materials such as polystyrene nanotubes14, polypyrrole NWs15, and poly(dimethylsiloxane) (PDMS) microposts16, have been investigated to capture circulating tumor cells17 or bacteria18. However, these may fail to display an impressive performance in patient’s bloodstream conditions because of the bacteria falling off, driven by the shearing force of fluid bloodstream. The common characteristic of these existing isolation technologies is that they introduce relatively weak interaction forces of synthetic small molecules19, natural lectin20, and antibodies21.

Inspired by the natural trapping process of the Venus flytrap, whereby its two lobes open widely and snap shut when stimulated by prey to prevent them from escaping, we describe here an approach to design 3D nanoclaws, improving bacterial capture efficiency in a patient’s bloodstream. The 3D nanoclaws are made by bendable polycrystalline NWs pre-grafted on 3D carbon foam (CF). Specifically, in the unclosed state, the bendable polycrystalline NWs are straight (pointing outward); however, in the closed state, as long as the targeted bacteria are trapped in the NW arrays, these NWs are instantly triggered, bending to close the trap. Therefore, these bendable polycrystalline NWs simultaneously satisfy two requirements of an ideal dialyzer substrate: firstly, negligible deformation at high flow velocities to provide a high sensitivity to targeted microorganisms and secondly, significant bending at the tip region under weak carbohydrate–protein-binding forces to avoid desorption of immobilized bacteria by the shear stress of fluid bloodstream. Compared to unbendable single-crystalline NWs, such bendable polycrystalline NWs efficiently improve the number of captured bacteria in patient’s bloodstream at various velocities, showing minimal interactions with other blood components.

## Results

### Fabrication and characterization of dialyzer

Ordinarily, blood is considered a pathogenic bacteria-free zone. Once pathogenic bacteria enter the bloodstream, they begin producing antigens that are recognized by the immune system, triggering systemic inflammation, which can lead to multiorgan system failure, septic shock, and death (Fig. 1a)22. A hemodialysis device filled with NWs pre-grafted on CF is designed to remove microbial pathogens from patient’s bloodstream (Fig. 1b and Supplementary Fig. 1). The backbone of the filter was prepared by directly carbonizing a melamine foam. Considering the size of an erythrocyte (5–7 μm in diameter), a leukocyte (7–15 μm in diameter), and bacteria (Salmonella, rod of 0.5 × 1.5 μm), the ~200 μm pore size of CF was selected, which is approximately two orders of magnitude larger than the bacterial cells and one order than the blood cells (Fig. 1c and Supplementary Fig. 2). The original bloodstream rate was mainly maintained because of big pore aspect ratio of CF23. Subsequently, metal precursors (Ni, Co) were hydrothermally deposited on the CF to grow a high density of needle-like NiCo(OH)2CO3 NWs with a length of 5 ± 0.5 μm, a root diameter of 160 ± 10 nm, and a head diameter of 20 ± 15 nm (Fig. 1d, e and Supplementary Fig. 3). Their single-crystalline nature was confirmed by high-resolution transmission electron microscopy (HRTEM; Fig. 1f). The corresponding selected-area electron diffraction (SAED) pattern (Fig. 1g) shows sharp and clear Bragg spots. These pristine single-crystalline NiCo(OH)2CO3 NWs are converted into polycrystalline NiCo2O4 NWs by annealing at 300 °C for 2 h without noticeable alterations in morphology (Fig. 1h). About 28 wt% of CO2 and H2O are released according to thermogravimetric analysis (TGA; Supplementary Fig. 4a). The 15‒30 nm small crystal domains in the polycrystalline NWs (Fig. 1i, j) are consistent with the X-ray diffraction (XRD) analysis that reveals an average crystallite size of 20 ± 4.5 nm (Supplementary Fig. 4b). The corresponding SEAD pattern indicates typical polycrystalline diffraction rings, corresponding to the (220), (222), (400), and (440) planes (Fig. 1k).

### Nanomechanical properties of NWs

Deformation in materials occurs most commonly due to the slip process of grain boundaries, which involves dislocation motions24, 25. Single-crystalline NWs have only one grain or crystal without grain boundaries. Consequently, the single-crystalline NWs clearly show higher moduli compared to the polycrystalline NWs. Representative atomic force microscopy (AFM) height images and their corresponding quantitative nanomechanical maps are shown in Fig. 2a–f, along with schematic representations of the nanoscale structures. The Young’s modulus (E) values of single-crystalline and polycrystalline NWs were estimated according to the Derjaguin‒Mueller‒Toporov (DMT) model, in which their corresponding modulus distributions were collected along the contours of a single NW. Both showed decreases in E with decreasing NW diameter, ranging from ~3 to ~15 GPa along the 30 nm head to the 160 nm root for an individual single-crystalline NW (Fig. 2g), and ~0.8 to ~1.3 GPa for a single polycrystalline NW (Fig. 2h). This phenomenon can be explained by the fact that the atomic coordination and cohesion near the surface in small-diameter NWs are relatively weaker vs. larger diameter ones26. Based on the hyperelastic model of the St. Venant‒Kirchhoff theory (see Supplementary Methods), the relationship between the transverse force (F) and x-displacement (δ) was derived (Fig. 2i), in which the NW shape was modeled as a truncated cone according to the TEM and scanning electron microscopy (SEM) results. When we simulated the bending performance of a single NW by a finite element method (FEM) analysis using the COMSOL Multiphysics software (ver. 5.2; COMSOL AB, Stockholm, Sweden), the relatively soft polycrystalline NWs preferred to be bent when a transverse force was applied. The deformation of polycrystalline NWs was significant under a pN transverse force.

Furthermore, the relationship between F and δ was demonstrated by in situ bending experiments in an environmental SEM (ESEM) system equipped with a micromanipulator. An individual NW was pushed horizontally using a tungsten probe driven by a holder with a movable piezoelectric head. As shown in Fig. 2j, k, the polycrystalline NW had a larger bending curvature than that of the single-crystalline NW, in good agreement with the simulation (Fig. 2i). After releasing from pushing, the single-crystalline NW displayed an elastic behavior by recovering its initial straight shape, while the polycrystalline NW showed plastic deformation, still maintaining its bent status due to its lower E value.

### Formation conditions of 3D nanoclaws at high flow velocity

Two aspects must be considered in the design of an ideal dialyzer with efficient capture: sorption and desorption of the bacteria. For clinical hemodialysis, soft NWs (E < 1 GPa), such as polystyrene nanotubes14, polypyrrole NWs (0.53 MPa)15, and PDMS microposts (2.5 MPa)16, are seriously deformed by the high shear stresses of the fluid at 10 cm s−1 velocity (Fig. 3a and Supplementary Fig. 5a). The bacteria are only adsorbed on the surfaces of bending nanostructures16, and thus the bacteria will fall off readily because of losing landing site, resulting in a low bacteria capturing efficiency. Contrastively, although stiff NWs (E > 2 GPa), such as ZnO (~8 GPa)27, gold (~70 GPa)28, Si (~150 GPa)29, and gallium phosphide (~150 GPa)30, maintain their straight shape at high velocities, these adsorbed bacteria can dynamically be drove away from the surface/material by the shear force of the fluid, resulting in desorption of the bacteria (Fig. 3b). When the Young’s modulus ranges from 1 to 2 GPa, such moderately stiff NWs cannot be bent by the shear force of the 10 cm s−1 velocity fluid, but are deformed by the ~100 pN molecular force of ligand-receptor (Fig. 3c). The strain-producing NW deformation as a function of stiffness or flow velocity was simulated by a computational fluid dynamics method, using a fluid structure interaction method and the incompressible Navier–Stokes equation (Supplementary Fig. 5b). Bloodstream moving along a CF pore will incur a shear stress, in which the fluid speed at the bottom of the NW is nearly zero and eventually increases to the speed at the tip region. The shear stress is proportional to the relative velocity. Therefore, significant deformation occurs at the tip region of NWs (Fig. 3d). For example, in the case of a flow rate of 10 cm s−1 and an E value of 0.06 GPa, von Mises stresses generated 1.65 μm displacement for a NW with a size consistent with the as-prepared NWs (Fig. 3e). The displacements of the prepared single-crystalline NWs and polycrystalline NWs correlated positively with the flow velocity (Fig. 3f). Because the shear stress arises from the force vector component perpendicular to the NW cross-section on which it acts, the NW deformation has an angle-dependent behavior with the fluid direction (Supplementary Fig. 5c–f).

### Characterization of 3D nanoclaws formation

The present driving force for bacterial capture is mainly focused on molecular recognition such as carbohydrate–protein interaction and antigen–antibody binding. Concanavalin A (Con A) and Salmonella, pathogenic Gram-negative bacteria, which cause various illnesses including gastroenteritis and systemic febrile disease31, were selected for a molecular recognition model. The driving force was generated by specific lectin‒carbohydrate recognition between Con A and mannose of the bacterial surface lipopolysaccharide (Fig. 4a, b and Supplementary Fig. 6), which is ~100 pN32,33,34. This strong adhesion force enables the deformation of polycrystalline NWs when the bacteria are trapped in NW arrays. To demonstrate this, parallel experiments were performed to replace the strong molecular recognition by a relatively weak electrostatic interaction force, in which polyethylenimine (PEI) was modified on the NW surface to capture negatively charged bacteria35 (Supplementary Fig. 7 and Fig. 4c, d). The successful modification of NWs with Con A was evidenced by fluorescence detection using rhodamine B-labeled Con A (Supplementary Fig. 8). The bacterial capture performance was evaluated by a homemade dialyzer filled with CF, and single-crystalline NWs/CF and polycrystalline NWs/CF (Supplementary Fig. 9). Compared to PEI, conjugating Con A significantly improved the bacteria capturing ability, from 15.1 ± 1.9 × 108 CFU cm−3 on bare single-crystalline NWs/CF, and 19.1 ± 2.2 × 108 CFU cm−3 on PEI-single-crystalline NWs/CF, to 42.2 ± 2.2 × 108 CFU cm−3 on Con A-single-crystalline NWs/CF. Similarly, this enhancement effect was also observed in polycrystalline NWs/CF, from 17.9 ± 3.1 × 108 CFU cm−3 on bare, and 27.4 ± 2.6 × 108 CFU cm−3 on PEI coated, to 84.2 ± 1.8 × 108 CFU cm−3 on Con A conjugated (Fig. 4e). The bacterial capture amount is the largest on Con A-polycrystalline NWs/CF, which is attributed to the formation of nanoclaws by average four bending polycrystalline NWs (Supplementary Fig. 10).

The polycrystalline NW deformation induced by the strong adhesion force of Con A was confirmed by SEM, in which FEM analysis was performed to gain an insight into the NW deformation. The single-crystalline NWs nearly maintained their pristine status (Fig. 4f, g), whereas the polycrystalline NWs showed a ~1 μm bend (Fig. 4h, i). The lateral deflection distance of NWs changed with diameter size (Supplementary Fig. 11), and the NW with a sharp tip showed a more metamorphous nature than that of a blunt NW under a constant and weak driving force of 100 pN. The von Mises stresses were concentrated at the NW tip, resulting in 100 nm displacement for single-crystalline NWs and 1 μm deformation at the tips of polycrystalline NWs (Supplementary Fig. 12). The driving force increased almost linearly as E, ranging from 0.5 to 50 GPa (Supplementary Fig. 13), which suggests that the polycrystalline NWs could create more significant deformation when increasing the driving force.

A 1-μm deflection distance of the polycrystalline NWs was sufficient to prevent the trapped bacteria from desorbing, which was examined by the washing processes at high flow rates using 4′-6-diamidino-2 phenylindole (DAPI) stain. Before washing, the polycrystalline NWs/CF dialyzer had the highest bacterial capture capacity (Fig. 5a). After washing with sterile normal saline at 20 cm s−1 for 2 min, 85% of the bacteria in the polycrystalline NWs/CF dialyzer were still held, while only 35% and 5% of residual bacteria were retained on a single-crystalline NWs/CF dialyzer and a smooth CF dialyzer (Fig. 5b, c and Supplementary Fig. 14). The shear force effect on bacterial capturing capabilities was assessed by a peristaltic pump that controlled the flow velocities (Fig. 5d). The numbers of captured bacteria in the dialyzers filled with single-crystalline or polycrystalline NWs/CF reached a maximum at 10 cm s−1. At low flow velocities (2.5, 5, 7.5 cm s−1), the behavior of the two dialyzers was comparable, but bendable NWs represented significant advantage at higher flow velocities (10, 12.5, 15 cm s−1). Increasing the bacterial capture ability of two dialyzers from 2.5 to 10 cm s−1 of flow velocity could be attributed to two aspects: the first is to bring more bacteria to the surface because of increasing total volume to flow through, and the second is to increase the collision frequency between bacteria and NWs.

### Bacterial capture performance in bloodstream

To assess the capture capabilities in a practical system, adult human blood containing 1.0 × 108 CFU mL−1 bacteria was passed through the dialyzers filled by CF, single-crystalline NWs/CF, and polycrystalline NWs/CF at 10 cm s−1. The bacterial capture efficiency on CF, single-crystalline NWs/CF, and polycrystalline NWs/CF were ~10, ~40, and ~97%, respectively (Fig. 5e), which was similar to the sterile normal saline (Supplementary Fig. 15a), indicating a favorable performance in the complex bloodstream environment. Moreover, there is no marked difference in bacterial capture ability whether the anticoagulants were added or not (Supplementary Fig. 15b). The residual bacteria were further confirmed by growing on agar plates (Fig. 5f–h). Non-specific adsorption of human blood components (red blood cells, white blood cells, and platelets) were rarely observed on the NWs/CF dialyzers (Supplementary Fig. 16). As shown in Supplementary Fig. 17, the damage of sharp NWs for blood cells is negligible, which could be attributed to two reasons. First, the pore size of CF (~200 μm) is large enough to allow the blood cells smoothly through the dialyzer. Second, the NWs are coated with Con A that binds specifically to the surfaces of clinical pathogens, rather than blood cells. Additionally, an important consideration for clinical implementation of a dialyzer is minimization of the time that the blood spends outside the body, to avoid coagulation or infection. The flow rate in our system can reach as high as 50 mL min−1 (Eq. 2 in the Methods), which is much higher than that in previously reported methods, such as the biospleen device (0.167 mL min−1)36, a track-etched polycarbonate filter (0.667 mL min−1)37, and magnetic nanoparticles (1.0 mL min−1)9.

## Discussion

Our data show that bendable polycrystalline NWs can improve the bacterial capturing efficiency of the dialyzer to patient’s bloodstream. One would expect nanomaterials to offer an excellent opportunity to improve the capture sensitivity of biomolecules due to their high surface area-to-volume ratio and similar size, but ignoring the immobilized biomolecule desorption due to the high shear forces of the fluid bloodstream. The observed increase in the bacterial capture efficiency in the bloodstream at a 10 cm s−1 velocity, from ~10% on CF and ~40% on unbendable single-crystalline NW/CF to 97% on bendable polycrystalline NW/CF, is significant because the bent NWs should increase the anti-shearing force of the captured bacteria. Such deformation of polycrystalline NWs was understood in terms of the simulated and measured Young’s modulus distribution along a single NW. The demonstration of efficient bacterial capture in normal saline and the human bloodstream, in a dialyzer filled by bendable polycrystalline NWs/CF, is clearly a major step toward the development of a nanotechnology platform that can meet evolving clinical and lifestyle needs. In principle, other microorganisms, such as viruses, circulating cancer cells, and stem cells, could be used according to this proof-of-concept to create a nanobiotechnology platform for the fabrication of multifunctional artificial kidneys.

## Methods

### Preparation of CF

The CF was prepared by carbonizing melamine foam (MF) under an argon atmosphere. MF was first cut into 1.2 × 1.2 × 0.8 cm3 pieces before carbonization. Carbonization used a previously reported method38, 39. First, the temperature was raised from room temperature to 300 °C, at a rate of 5 °C min−1, and then held constant for 5 min. Second, the temperature was further raised to 400 °C at a rate of 1 °C min−1 and held for 5 min. Finally, the temperature was raised to 700 °C at a rate of 2 °C min−1 and held for 120 min. The as-prepared CF was removed once the temperature was below 80 °C.

### Synthesis of NiCo(OH)2CO3 NWs/CF and NiCo2O4 NWs/CF

In a typical process, 2 mmol of CoCl2·6H2O, 1.25 mmol of NiCl2·6H2O, and 3 mmol of urea were dissolved in 15 mL of water to form a transparent pink solution. A piece of carbonized CF (0.8 × 0.8 × 0.3 cm3) was placed in the solution, and the solution was then transferred to a 25 mL Teflon-lined stainless steel autoclave and held at 120 °C for 6 h. After hydrothermal growth, the NiCo(OH)2CO3 NWs/CF was washed carefully with deionized water and ethanol several times to remove the excess surfactant and dissociative ions, and then finally dried in air. To obtain the NiCo2O4 NWs/CF, the NiCo(OH)2CO3 NWs/CF sample was placed in a quartz tube and annealed at 300 °C for 2 h to obtain well-defined crystallized NiCo2O4 NWs on CF.

### Bacterial filtrating and staining

For bacterial filtering, Con A-functionalized pieces having dimensions 0.4 × 0.4 × 0.3 cm3 of CF, NiCo(OH)2CO3/CF, and NiCo2O4/CF were fixed on a homemade filtration device. Then, the bacterial stock solutions were passed through the substrates at a flow rate of 50 mL min−1. After filtering, the substrates were removed from the device and dried in an argon atmosphere prior to fluorescent staining. The bacterial capture number (Nc) of the substrates was defined as the number of bacteria captured before and after filtering and calculated as follows:

$N c = V × C a - C b V s ,$
(1)

where Ca and Cb represent the concentration of bacteria in the test solution before and after filtering, respectively, and V and Vs are the volumes of the test solution and substrate, respectively. The bacterial concentrations were determined using the standard colony counting method in our experiments.

For bacterial staining, the substrate with captured bacteria was first incubated with DAPI (5 μg mL−1) for 15 min in the dark, and then rinsed three times with sterile normal saline before microscopy imaging.

The flow rate, Q, was calculated using the following equation:

$Q=v×π r 2 ,$
(2)

where v and r are the flow velocity and radius of the tube (0.16 cm), respectively.

### Bacterial capture from bloodstream

The bacteria (1.0 × 108 CFU mL−1) were first spiked into healthy adult human blood (5.0 × 107 mL−1), which was pretreated with anticoagulants (heparin) to prepare artificial septic blood samples. After dialyzer separation, the number of bacteria were quantified using the standard plate count method in an appropriate culturing agar medium. Blood cells were counted using a conventional blood counting chamber. Blood cell viability was determined by using calcein acetoxymethyl ester (AM) assay40. Calcein-AM was added to the blood at the final concentration of 1 mM and the cells were incubated at 37 °C in the dark for 40 min. The fluorescence was read at an excitation wavelength of 490 nm and an emission wavelength of 520 nm using a microwell plate reader. The relative cell viability was obtained by comparing the fluorescence signals of pre-and post-filtration.

### Data availability

The authors declare that all data supporting the findings of this study are available within the article and its Supplementary Information files or from the corresponding author on reasonable request.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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## Acknowledgements

T.W. acknowledges the support from the 1000 Young Talents program, the National Natural Science Foundation of China (Grant Nos. 21321003, 21635002, 21621062), and ICCAS. J.L.W. acknowledges the support from the New Century Excellent Talents in University (NCET-13-0483) and National Natural Science Foundation of China (No. 31371813, No. 31201357, and No. 21675127).

## Author information

### Affiliations

1. #### Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, 100190, Beijing, China

• Lizhi Liu
• , Zhenjie Xue
• , Zhen Zhang
• , Xuezhi Qiao
• , Zongxiu Nie
•  & Tie Wang
2. #### University of Chinese Academy of Sciences, 100049, Beijing, China

• Lizhi Liu
• , Zhenjie Xue
• , Zhen Zhang
• , Xuezhi Qiao
• , Zongxiu Nie
•  & Tie Wang
3. #### College of Food Science and Engineering, Northwest A&F University, Yangling, 712100, Shaanxi, China

• Lizhi Liu
•  & Jianlong Wang

• Sheng Chen

• Dong Han

### Contributions

L.Z.L. and T.W. conceived and designed the project. L.Z.L. carried out the synthesis and performed all the experiments. S.C. performed the FEM simulations. Z.J.X. assisted the AFM test. Z.Z. conducted HRTEM characterization. X.Z.Q. assisted the TEM characterization. Z.X.N. offered the bacteria culture platforms. D.H. assisted the in situ ESEM characterization. L.Z.L., J.L.W., and T.W. co-wrote the manuscript. All authors discussed the results and commented on the manuscript.

### Competing interests

The authors declare no competing financial interests.

### Corresponding author

Correspondence to Tie Wang.