Roles of Textural and Surface Properties of Nanoparticles in Ultrasound

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Roles of Textural and Surface Properties of Nanoparticles in Ultrasound-responsive Systems Qiaofeng Jin, Chih-Yu Lin, Yuan-Chih Chang, Chia-Min Yang, and Chih-Kuang Yeh Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b02993 • Publication Date (Web): 29 Dec 2017 Downloaded from http://pubs.acs.org on December 31, 2017

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Roles of Textural and Surface Properties of Nanoparticles in Ultrasoundresponsive Systems Qiaofeng Jin a, Chih-Yu Lin b, c, Yuan-Chih Chang d, Chia-Min Yang b, c* and Chih-Kuang Yeh a* a

Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan

b

Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan

c

Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan

d

Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan

* Corresponding Authors: Chih-Kuang Yeh, PhD Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, Taiwan 30013, Tel: +886-3-571-5131 ext. 34240; Fax: +886-3-571-8649. E-mail address: [email protected] (C.-K. Yeh) Chia-Min Yang, PhD Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, Taiwan 30013, Tel: +886-3-5731282; Fax: +886-3-516-5521. E-mail address: [email protected] (C.-M. Yang) Author contributions Qiaofeng Jin and Chih-Yu Lin contributed equally to this work.

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ABSTRACT: Acoustic inertial cavitation (IC) is a crucial phenomenon for many ultrasound (US)related applications. This study aimed to investigate the roles of textural and surface properties of NPs in IC generation by combining typical IC detection methods with various types of silica model NPs. Acoustic passive cavitation detection, optical high-speed photography and US imaging have been used to quantify IC activities (referred to IC dose, ICD) and describe physical characters of IC activities from NPs, respectively. The results showed that the ICDs from NPs were positively correlated to their surface hydrophobicity, and that their external surface hydrophobicity play a much more crucial role than the textural properties do. The high-speed photography revealed that the sizes of IC-generated bubbles from superhydrophobic NPs ranged 20–40 μm at 4–6 MPa and collapsed in several microseconds. Bubble clouds monitored with US imaging showed that IC from NPs were consistent with their surface hydrophobicity. The simulation results based on crevice model of cavitation nuclei correlated well with experimental results. This study has demonstrated that the surface property, instead of textural property, of NPs dominated the IC generation, and surface nanobubbles adsorbed on NPs surface have been proposed to be cavitation nuclei. KEYWORDS: surface property, inertial cavitation, silica nanoparticle, ultrasound, passive cavitation detection, high-speed photography

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1. INTRODUCTION Inertial cavitation (IC) involves rapid expansion and subsequent violent collapse of bubbles under ultrasound (US) stimulation, during which several physical phenomena such as shock waves1, broadband acoustic signals2, microjetting3, and microstreaming4 can be induced. In addition, chemical products such as reactive oxygen species (ROS) are produced as a result of water pyrolysis caused by the extremely high temperature generated during the violent collapsing process5. IC has been identified as a key mechanism of US-related biomedical applications for preferential accumulation of drug carriers and drug release6, sonodynamic therapy7-8, and acoustic ablation9-10. In general, cavitation nuclei are required to augment IC under sonication, among them microbubbles and liquid perfluorocarbon droplets are the most commonly used ones in bioapplications such as targeted drug/gene delivery11-13, thermal tissue ablation14-16, and sonothrombolysis17-19. However, these applications were hindered by their micron size and rapid depletion in vivo. One of the solutions to overcome the limitations is to develop nanoparticles (NPs) that can stabilize nanobubbles and initiate IC more efficiently. Yildirim et al. recently discovered that mesoporous silica NPs (MSNs) with carbon impurities or methyl-modified MSNs stabilized surface nanobubbles and generated bubble clouds effectively20. Kwan et al. proposed that nanobubbles trapped within nanocups made from polystyrene NPs could nucleate IC for promoting drug delivery21-22. In our previous study, we also found that IC initiation and the generation of ROS from superhydrophobic polytetrafluoroethylene (PTFE) NPs were attributed to the bubble nuclei adsorbed on NPs surface23. Recently, functional NPs to augment IC have received increasing attention in USbased thermal ablation and sonodynamic therapies24-25. However, their IC generation mechanism is still unclear, and few studies discussed the effects of textural and surface properties of NPs. Although some theoretical simulations26-28 and experimental results29-31 have revealed that the cavitation efficiency is greatly influenced by the geometry and hydrophobicity of defects in planar models or materials32-34, the situations might be completely different in the case of NPs. Therefore, it is worthwhile to extend the above studies by investigating the mechanism of IC from NPs and to optimize US-responsive NPs. In this study, we combined acoustic IC detection methods with a set of well-designed model NPs to investigate the IC generation of US-responsive NPs, and to find the key to initiate IC production in NPs. Optical high-speed photography35-37 and acoustic methods such as active cavitation detection and passive cavitation detection (PCD) are commonly used to detect and assess IC activity38-40. PCD was used to assess IC owing to its high sensitivity. High-speed photography and US B-mode imaging 3


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were applied to further observe physical characters of IC activities from NPs. Silica NPs are ideal models due to their diverse texture, versatile surface chemistry, and biocompatibility41-43. MSNs with different mesostructures (MCM-41 with p6mm mesophase and 1D channel-type mesopores and MCM-48 with Ia3d mesophase and 3-D interconnected mesopores), nonporous Stöber silica (SS) NPs, and their derivatives were prepared to elucidate the effects of textural (e.g., porosity and mesostructure) and surface properties (e.g., hydrophobicity) of NPs to IC generation (Figure 1a). In addition, since the mesopores of MSNs facilitate air adsorption and entrapment of surface nanobubbles, the internal mesopore or external surface of MSNs was functionalized selectively, followed by detailed analysis to study the influence of selective functionalization on IC (Figure 1b). Furthermore, theoretical simulations based on the crevice model of cavitation nuclei were conducted to investigate the IC threshold of silica NPs, and the results were compared with the experimental ones. Finally, a possible mechanism of IC generation from NPs was proposed.

Figure 1. (a) A schematic diagram of textural and surface properties of silica NPs. (b) The potential air nuclei in mesopores and external surface nanobubbles for IC initiation by US.

2. EXPERIMENTAL SECTION 2.1 Materials Cetyltrimethylammonium bromide (CTAB), Bovine serum albumin (BSA), and 60% 200-nm PTFE NP dispersion were purchased from Sigma Aldrich. Tetraethoxysilane (TEOS) was obtained from Acros. Hydrogen chloride (37%, w/w) and ammonia (28%) were purchased from Showa. Trimethylchlorosilane (TMCS) was provided by Lancaster, and perfluorodecyltriethoxysilane 4


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(PFDTS) and (3,3,3-trifluoropropyl)trimethoxysilane (CF3-TMS) were purchased from Alfa Aesar. All aqueous solutions were prepared using deionized Millipore Milli-Q water. All the solvents and reagents were analytical purity. 2.2 Preparations of parent MSNs and SS NPs The synthesis of MCM-41 NPs was started from preparing homogeneous solution containing CTAB (1.2 g), NaOH (0.4 M, 20.3 mL) and DI water (576 mL), and TEOS (6.0 mL) was then injected at a rate of 7.5 mL h−1 at 35°C. The mixture was further stirred for 2 h followed by aging at 90°C for 24 h, and the resultant MCM-41 NPs were collected by filtration. The preparations of SS and MCM-48 NPs are described in our previous report44. To remove the surfactants, as-synthesized MCM-41 and MCM-48 MSNs were dispersed in 50 mL of hydrogen chloride-ethanol solution and stirred at 60°C, and the process was repeated. Finally, samples were collected by centrifugation after 30 min, washed with ethanol repeatedly, and then dried at 60°C. 2.3 Preparation of fluorocarbon functionalized silica NPs Perfluorodecylsilyl modified SS (F-SS) and perfluorodecylsilyl MCM-48 (F-48) NPs were prepared by following the procedures as reported previously44, and the protocol was applied to functionalize various types of silica NPs in this study. Noted that in the case of F-48-ext and F-41ext, surfactants were removed after fluorocarbon (FC) silane functionalization to produce hydrophobic external surface and hydrophilic mesochannel surface, Briefly, MCM-48 or MCM-41 MSNs (0.1 g) were dried under vacuum at 150°C for 12 h and then dispersed in a solution containing 10 mL of toluene and 1.0 mL of silane (TMCS for the trimethylsilyl-functionalized sample referred to as CH3-48, CF3-TMS for the (3,3,3-trifluoropropyl)silyl-functionalized sample referred to as CF3-48, and PFDTS for the perfluorodecylsilyl-functionalized samples referred to as F-48-ext and F-41-ext). The mixture was stirred at 25°C for 1 h (for CH3-48 and CF3-48) or 100°C for 48 h (for F-48-ext and F-41-ext), followed by filtration and washing repeatedly with toluene and ethanol, and then dried at 60°C for 12 h. 2.4 BSA coating of F-48 and F-48-ext NPs The sample F-48 or F-48-ext (2 mg) was dispersed in DI water (2 mL) and mixed with aqueous solution of BSA (2 mL, 100 mg mL−1). The solution was sonicated for 5 min and stirred at 500 rpm for 24 h. Then BSA coated NPs were collected by centrifugation at 15000 g relative centrifuge force for 5 min and repeatedly washed with DI water to remove excess BSA. 5


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2.5 Characterization of silica NPs X-ray diffraction (XRD) patterns were recorded using a diffractometer (18MPX, Mac Science) with Cu Kα radiation. FTIR spectra were analyzed using Tensor 27, Bruker. Nitrogen physisorption isotherms were measured at 77 K using a Quantachrome Autosorb-1MP instrument. TEM images were obtained using a microscope (JEM-2010, JEOL) operating at 200 kV. The size distributions and ζ-potentials of the NPs were measured using a dynamic light scattering (DLS) instrument. (Zetasizer Nano ZS, Malvern Instruments, Worcestershire, UK). For contact angle measurements, the NPs films were prepared by dropping the acetone suspension of NPs (5 mg mL−1) on the glass slides, followed by evaporation of the solvent at room temperature for 0.5 h then at 60 °C for 24 h. The static contact angles of the as-prepared NPs films and the rolloff angles of the superhydrophobic films were measured using a contact-angle analyzer (FTA-1000B, First Ten Angstroms). 2.6 IC dose measurement by PCD Figure 2a shows the IC dose (ICD) measurement setup basing on our previous study23. When US was applied to the solutions containing silica NPs, the broadband emissions from collapse of IC bubbles can be acquired by PCD method. Briefly, a 2-MHz high-intensity focused ultrasound (HIFU) transducer (Su-101, Sonic Concepts, Bothell, WA, USA), which was calibrated using a needle hydrophone (model HGL-0085, ONDA Corporation, Sunnyvale, CA, USA), was driven by a power amplifier (150A100B, Amplifier Research, Souderton, PA, USA) and a waveform generator to sonicate the NPs with a 50-cycle pulse at a PRF of 10 Hz. A 15-MHz focused transducer (V319, Olympus, Waltham, MA, USA) was used to receive broadband emission signals. The foci of both transducers were adjusted to overlap at the same position of a 0.58-mm-diameter polyethylene tube (wall thickness: 0.255 mm). The silica NPs suspension at a concentration of 100 μg mL−1 (~108 NPs mL−1 measured using a NanoSight NS300, Malvern; Figure S1) was then injected into the polyethylene tube at a velocity of 0.1 mL min−1 using a syringe pump (KDS120, KD Scientific, New Hope, PA, USA). The IC signals were received and amplified by 20 dB using a pulser/receiver (PR5073, Olympus) and then filtered by a 5-MHz build-in high-pass filter to remove reflections of the incident US beam. Finally, the signals were sampled and acquired at a sampling frequency of 50 MHz using a oscilloscope (LT322, LeCory, Chestnut Ridge, NY, USA) controlled by LabVIEW software (National Instruments).

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Figure 2. (a) Schematic of the experimental setup for ICD measurements using PCD. (b) Received PCD signals with (blue line) and without (black line) F-48 NPs. (c) Frequency spectra of received acoustic PCD signals.

The recorded time-domain signal was first transformed into frequency domain spectrum (A(f)) using fast Fourier transform, as shown in Figure 2b and 2c. The integral values of area under the frequency spectrum from 10 to 20 MHz were termed ICD, which can be used to assess the IC capability and intensity. Each data set comprised 100 signals, and 3 independent tests were applied for statistical analysis. All of the signals were analyzed in MATLAB (MathWorks, Natick, MA, USA). The ICD can be expressed as follows:

|

ICD

| d 1

2.7 Cavitation mapping by high-speed photography Cavitation bubbles generated during IC were directly recorded by using an integrated acousticoptical system with a high-speed camera (FASTCAM SA4, Photron, Tokyo, Japan). A 200-μmdiameter (wall thickness: 8-μm) cellulose tube (Spectrum Labs, Rancho Dominguez, CA, USA), 7


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which is nearly transparent to light and has less acoustic attenuation to US, was immersed in degassed DI water and placed perpendicularly to the 2-MHz HIFU acoustic beam. Then, the tube and HIFU focus was adjusted to overlap at the focus of the water-immersed objective. NPs were then injected into the tube though the syringe pump while acoustic pulses were transmitted at various acoustic pressures, and at least 50 sequential images were recorded synchronously at 5105 frames per second (FPS) or 105 FPS using the high-speed camera for further statistical analysis. 2.8 US imaging of cavitation bubbles

Figure 3. Experimental setup of US B-mode imaging for monitoring cavitation bubble clouds. In addition to PCD and high-speed photography, US imaging was used to monitor bubble clouds generated during IC, and its experimental setup is shown in Figure 3. The MCM-48 type silica NPs suspensions (100 μg mL−1) were injected into a 6-mm-diameter cylinder chamber in an acoustically transparent phantom constructed from agarose gel (1.5%, w/v). A 7.5-MHz linear-array transducer (model L3-12) coupled to an US system (CX50, Philips, Bothell, WA, USA) was aligned with the longitudinal section of the hollow chamber and with the focus of the 2-MHz HIFU transducer, which was placed perpendicularly to the array transducer and driven as in the above-described ICD experiments with 50-cycle pulses at a pulse repetition frequency (PRF) of 100 Hz and at various acoustic pressures. Real-time brightness (B)-mode images were recorded for each sample during HIFU sonication at 2–6 MPa. 2.9 Simulating IC for mesostructured MSNs The crevice theoretical model of cavitation nuclei, which has been widely applied to simulate the cavitation from a cavity under various flow and acoustic-field conditions26, 29 was used to calculate IC threshold from MSNs using the following equations: 8


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2

2

sin

cos 2

3

2 sin

,

3

/sin

3

π

4

π 3

5

4π 3

/

6

The geometric parameters are illustrated in Figure 4, where θ is the contact angle and rc and dc are the radius and depth of the cylindrical cavity, respectively. To simplify the calculation, dc = 2rc is used for all the case in this simulation. g(θ) in Eq. (2) is a geometric function for calculating the surface area and volume of the expanding bubble. σ is air/water surface tension (72 mN m−1 for water at room temperature). The cavitation bubbles would expand explosively at a fixed θ under the acoustic pressure that is larger than the liquid pressure (Pl). The acoustic threshold (corresponds to Pl) for IC at various rc and θ is determined at point R = Rmin = rc/sin θ by Eq. (3), where Pg,0 is the initial gas pressure in the pore, and Pv, the water vapor pressure is negligible in present condition. The energy barrier (Ebarrier) for bubble generation is the sum of surface energy (Es) in Eq. (4) and bulk energy (Ev) in Eq. (4), which is described as the work performed by Pl in Eq. (6). In this section, Ebarrier and Pl as function of θ, as functions of rc or θ are demonstrated, respectively.

Figure 4. Illustration of a cylindrical pore and its dimensions in a silica NP, and an expanding bubble with a radius of R and contact angle θ.

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2.10 Statistical analysis Quantitative data (e.g., the particle size, ζ-potential, ICD, and cavitation bubble size observed by a high-speed camera) were given as mean ± standard-deviation (SD) values obtained by at least three independent experiments. Probability values in Student’s t-test below 0.05 (i.e., p < 0.05) were considered to be statistically significant, and were indicated by asterisks.

3. RESULTS AND DISCUSSION 3.1 Characterization of various silica NPs MCM-48 and MCM-41 MSNs displayed characteristic powder XRD patterns corresponding to Ia3d and p6mm symmetries, respectively (Figure 5a). Their ordered mesostructures could be observed by TEM (Figure 5b). The nitrogen physisorption isotherms (Figure S2) of MCM-48 and MCM-41 MSNs featured an H4-type hysteresis loop with a sharp step at relative pressures (P/P0) of ~0.36 and ~0.34, corresponding to the capillary condensation in 3.0- and 2.8-nm-wide channel-type mesopores, respectively. On the other hand, no peaks were observed in the XRD patterns of the SS (Figure 5a). SS exhibited a typical type III isotherm of nonporous materials (Figure S2). Compared to the parent silica MSNs, the capillary condensation steps of the functionalized MSNs shifted toward lower P/P0 values, suggesting smaller mesopore size due to the presence of organic functional groups (Table 1). The success of functionalization was also confirmed by the FTIR spectra (Figure 5c). Figure 5d shows representative contact-angle images of NPs films produced from parent NPs and the PFDTS-functionalized NPs, and the surface of silica became superhydrophobic (contact angle > 120°) after FC functionalization (Table 2). In addition, we measured the roll-off angles of water droplets on the superhydrophobic films. Very small roll-off angles (less than 3°) were observed on all superhydrophobic surfaces, while the roll-off angles for hydrophilic films were not available due to quick adsorption of the water droplets by the films. After BSA coating, the contact angles of F-48 and F-48-ext films decreased to about 80°, suggesting that their surface became hydrophilic due to the BSA coating. The mean sizes and ζ-potentials of the silica and PTFE NPs were summarized in Table 2. The sizes as measured using DLS were slightly larger than those measured using TEM due to the interference of solvent to the hydrodynamic diameter. The negative charges of superhydrophobic silica NPs could be attributed to adsorbed surface nanobubbles, which possess negative ζ-potentials and could stabilize the NPs in water45-46.

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Figure 5. (a) Powder XRD patterns, (b) TEM images, (c) FTIR spectra, and (d) photographs of the contact angles of parent silica NPs and their derivatives. Table 1. The textural and surface properties of silica NPs Silica NP

Mesopore (nm)

Pore volume (cm3/g)

Internal Pores

External Surface

MCM-41

2.8

0.99

hydrophilic

hydrophilic

F-41-ext

2.8

0.20

hydrophilic

superhydrophobic

SS

NA

NA

NA

hydrophilic

F-SS

NA

NA

NA

superhydrophobic

MCM-48

3.0

1.02

hydrophilic

hydrophilic

CH3-48

2.7

0.81

hydrophobic

hydrophobic

CF3-48

2.7

0.73

hydrophobic

hydrophobic

F-48

1.0

0.41

superhydrophobic

superhydrophobic

F-48-ext

3.0

0.38

hydrophilic

superhydrophobic

F-48 + BSA

1.0

0.37

superhydrophobic

hydrophilic

F-48-ext + BSA

3.0

0.33

hydrophilic

hydrophilic

PTFE

NA

0.10

NA

superhydrophobic

Noted: NA denotes not available

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Table 2. Size distributions, ζ-potentials, and contact angles of silica NPs Roll-off

Silica NP

Size (nm)

ζ-Potential (mV)

Contact Angle (°)

Angle (°)

MCM-41

372.0 ± 159.6

−14.2 ± 1.1

7.4 ± 2.0

NA

F-41-ext

272.1 ± 140.7

−28.2 ± 6.0

145.6 ± 11.0

≤ 3°

SS

520.4 ± 389.6

−33.8 ± 8.4

20.1 ± 2.7

NA

F-SS

500.3 ± 161.3

−33.2 ± 7.7

119.7 ± 2.2

≤ 3°

MCM-48

376.6 ± 285.9

−28.3 ± 6.5

12.6 ± 1.8

NA

CH3-48

389.9 ± 110.4

−21.7 ± 5.5

18.5 ± 2.3

NA

CF3-48

304.3 ± 124.6

−15.2 ± 4.0

133.3 ± 12.1

≤ 3°

F-48

304.2 ± 83.8

−31.6 ± 6.2

145.4 ± 13.1

≤ 3°

F-48-ext

370.3 ± 124.2

−33.5 ± 7.4

151.6 ± 6.8

≤ 3°

F-48 + BSA

330.2 ± 120.1

−26.9 ± 4.3

76.4 ± 12.7

NA

F-48-ext + BSA

341.4 ± 104.5

−26.9 ± 3.3

81.5 ± 17.7

NA

PTFE

219.3 ± 60.3

−34.3 ± 7.9

137.7 ± 5.8

≤ 3°

Noted: NA denotes not available 3.2 Influences of surface properties and mesostructure of silica NPs on IC Figure 6a shows the ICDs of the hydrophilic parent silica NPs as a function of acoustic pressure. Parent pure-silica SS, MCM-41 and MCM-48 behaved similarly and did not enhance ICD even at a peak negative acoustic pressure of 6 MPa. Considering the large pore volumes of the two MSNs (1.02 cm3 g−1 for MCM-48 and 0.96 cm3 g−1 for MCM-41), the results showed that hydrophilic mesoporous MSNs could not augment IC under the circumstance, suggesting that pore-filling upon contacting with water by capillary force is not beneficial to IC. MCM-48 and its derivatives were then used to investigate the effect of hydrophobicity. CH3-48, CF3-48, and F-48 NPs exhibited increasing contact angles due to declining surface free energies of their corresponding silane modifier47. As shown in Figure 6b, the ICD of MCM-48 was as low as DI 12


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water, and the ICDs of other functionalized MCM-48 increased as the hydrophobicity (contact angle) increased or wetting tension reduced (Figure S3). The superhydrophobic F-48 showed much higher ICD than other NPs under each acoustic pressure. The ICD of F-48 at 2 MPa (180.5 ± 8.6) was even higher than that of the MCM-48 at 6 MPa (123.6 ± 11.4), and was as high as 725.3 ± 26.3 at 6 MPa. The cavitation threshold of MCM-48 could be decreased to as low as 2 MPa when they became superhydrophobic (F-48), with the corresponding change of contact angle from 12.6 ± 1.8° (MCM48) to 145.4 ± 13.1° (F-48). The results indicated that the surface property is dominant for the IC of MSNs An additional set of experiments were designed to investigate the effects of mesopore properties on IC using F-48 (with superhydrophobic external and mesopore surfaces) and F48-ext (with superhydrophobic external surface and hydrophilic mesopore surface). Figure 6c shows that the ICD of F-48-ext was nearly identical to that of F-48, indicating that the superhydrophobic external surface alone is sufficient to initiate the cavitation. Moreover, the ICDs of both F-48 and F-48-ext were greatly suppressed to as low as the ICD of DI water when their external surfaces became hydrophilic by BSA coating, which also suggested that the hydrophobicity of the external surface was dominant for IC, while the contributions of mesopore surfaces was low. At last, the ICDs were also greatly increased by superhydrophobic F-41-ext (with 1-D channel-type), F-SS (nonporous), and organic PTFE NPs (nonporous) with various inner texture or chemical properties (Figure 6d). It seems that ICDs were independent of their mesostructures. The results revealed that the hydrophobicity of NPs is much more crucial than textural properties (mesostructure and porosity) to US-induced IC.

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Figure 6. ICDs of (a) hydrophilic parent silica NPs, (b) MCM-48 and its derivatives with various surface property, (c) superhydrophobic MCM-48 derivatives with various internal and external modifications, and (d) other NPs with superhydrophobic external surface. Data are mean and standard deviation values.

3.3 IC detection by high-speed photography PCD relies on a single-element transducer and cannot be used to visualize IC. Therefore, highspeed photography was applied to mark out the positions and to monitor the sizes of cavitation bubbles. Figure 7a shows the setup with an optical microscope coupled to a high-speed camera, and Figure 7b displays representative sequential images of cavitation bubbles photographed at 5105 FPS using F-48 suspension sonicated with a 50-cycle single pulse at 5 MPa. For the initial several cycles, the generated cavitation bubble had a diameter of about 30 μm, and then increased to above 50 μm during successive cycles before finally collapsing in water. Because there is a trade-off between the size of field of view (FOV) and frame rate, the sequential photos at 5105 FPS only recorded part of the cavitation bubble due to a relatively small FOV. In order to capture the complete cavitation bubbles and determine their sizes, a larger FOV was obtained by reducing the frame rate to 105 FPS with a temporal resolution of 10 μs. To clearly define the boundary of a bubble, the 50-cycle pulse (25 μs at 2 MHz) was replaced with a 3-cycle pulse (1.5 μs 14


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at 2 MHz) to further improve the actual temporal resolution to 1.5 μs. Figure 7c shows the optical images obtained at 105 FPS during stimulation at increasing acoustic pressures (4, 5, and 6 MPa). The size of bubbles increased from 26.1 ± 4.6 μm to 36.8 ± 5.0 μm when the acoustic pressure increased from 4 MPa to 6 MPa (Figure 7d), which agreed well with the initial bubble size captured at 5105 FPS for a 50-cycle pulse, which were also consistent with the cavitation bubble size from gas-stabilizing nanocups using an ultra-high-speed camera at 107 FPS37. Bubbles were generated and then collapsed within several microseconds were demonstrated in the representative videos recorded at both 5105 (Videos S1) and 105 FPS (Videos S2). Their asymmetric structures in (Figure S4) indicated that the bubbles are indeed generated by IC induced under 3-cycle pulses. In addition, above sequential photos also revealed that the bubbles generated by IC from NPs were much larger than the NPs themselves.

Figure 7. (a) Experimental setup for monitoring cavitation bubbles using an optical microscope. (b) Representative sequential images obtained at 5105 FPS under a 50-cycle pulse at 5 MPa (c) and at 105 FPS under a 3-cycle pulse at 4–6 MPa. (d) Size of cavitation bubble at 4–6 MPa. * denotes p < 0.05.

3.4 IC monitored by US B-mode imaging 15


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As demonstrated by the PCD and high-speed photography results, IC could be easily generated in aqueous suspension containing F-48. US B-mode imaging was further used to monitor and assess IC activities, Figure 8 displays the B-mode images of the bubble clouds induced by MCM-48 type NPs during stimulation with 50-cycle pulses at 100 Hz PRF, and the IC processes of MCM-48 and F-48 at various acoustic pressures were recorded in Videos S3 and S4, respectively. F-48 showed significant bright bubble clouds under HIFU stimulation above 3 MPa, and the diameter of the cavitation bubble clouds increased from 2.0 ± 0.6 mm at 3 MPa to 3.2 ± 0.9 mm at 6 MPa due to the increased acoustic beam width above the IC threshold. On the contrary, no bubble clouds were observed in other groups except for the case of CF3-48 at 6 MPa. The US imaging did not detect cavitation bubbles in the cases of MCM-48, CH3-48 and CF3-48 NPs below 5 MPa (Figure 8) owing to the fact that B-mode imaging is less sensitive than PCD method in detecting IC activities. As shown in Figure 8, neither F-48 at 2 MPa (ICD: 180.5 ± 8.6) nor CF3-48 at 5 MPa (ICD: 265 ± 27) showed detectable cavitation bubbles, while the cavitation bubbles images of F-48 at 3 MPa (ICD: 330 ± 10.3) could be captured. In addition, the US imaging system was not synchronized with HIFU excitation, so we cannot exclude missing the cavitation bubbles since they could be produced occasionally and vanish in several microseconds. The results further confirmed that the intensity of IC activity was positively related to the surface hydrophobicity of NP, and suggested that US B-mode imaging could be used to monitor where and when IC occurred during US therapeutics.

Figure 8. Representative B-mode images of the cavitation bubble cloud of the MCM-48 type NPs.

3.5 Theoretical simulations The simulations based on the crevice theoretical model of cavitation nuclei described in Section 2.8 were performed to ascertain the rationality of the experimental results. Figure 9a shows that, on the one hand, Ebarrier decreased as θ increased under specific acoustic pressure, and the phenomenon 16


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was more pronounced at relatively low acoustic pressure. On the other hand, at fixed θ, Ebarrier increased with the decreasing of acoustic pressure. Figure 9b shows the IC threshold of NPs with different pore size and θ. For NPs with a radius of 3-nm pore, a negative acoustic pressure of 30 MPa is required to induce cavitation even at a θ of 140° (the red dotted line in Figure 9b). Figure 9c demonstrates that although the threshold decreased as the pore size increased, the cylinder-shaped pores with radius smaller than 10 nm hardly initiated cavitation under the acoustic pressures applied in the present study. Figure 9d further indicates that at a θ of 140°, a cavity with a radius of at least 45 nm was required to induce IC under 2 MPa. Therefore, the 1- to 3-nm mesopores of MSNs should have contributed little to IC, which is in line with the experimental results. Based on these results, we can conclude that the contact angle θ, which is depended on the external surface property of silica NP, plays a dominant role in initiating IC, while the effect of mesopore properties can be neglected.

Figure 9. (a) Ebarrier of NPs under various acoustic pressures and θ. (b) Cavitation threshold of cavities with various θ at specific rc. Cavitation threshold of cavities at specific θ with various rc of (c) 1–20 nm and (d) 20–100 nm.

3.6 Proposed possible mechanisms of IC from NPs Based on the results, we speculated that two factors are involved in the enhancement of IC for superhydrophobic NPs: (1) the Ebarrier of IC which is a cosine function of θ and decreases as the θ increases30,33, and (2) surface nanobubbles which emerge spontaneously on NPs with 17


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superhydrophobic external surface. It is widely accepted that nanobubbles can adhere onto a hydrophobic flat surface and remain stable for quite a long time48-52. The current observations using a high-speed camera showed that the sizes of cavitation bubbles are much larger than the NPs but the number of them are far fewer than NPs, suggesting that the bubbles are generated from a group of NPs rather than a single NP. As depicted in Figure 10a, numerous surface nanobubbles on superhydrophobic NPs located within the HIFU focus together expand to lower IC threshold. Therefore, the cavitation threshold would be decreased by increasing NP concentration, as verified in Figure 10b, the IC threshold for F-48 gradually decreased from 5 to 2 MPa as the concentration increased from 1 to 100 μg mL−1, which again suggested that IC was attributed to group behavior of NPs.

Figure 10. (a) Schematic of surface nanobubbles adsorbed on superhydrophobic NPs and proposed mechanisms of IC initiation from NPs. (b) ICD of F-48 at various concentrations under 2–6 MPa. Arrows indicated the IC threshold at different concentrations of F-48.

The present study has advanced the understanding of the IC mechanism of silica NPs during HIFU sonication, facilitating the development of novel nanoscale US-responsive NPs to overcome the hurdles confronted by microbubble or microdroplet based platforms53-54. Numerous studies have 18


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attempted to develop US-responsive NPs to reduce the IC threshold in tumor thermal ablation and serve as high-efficiency cavitation nuclei55-56, or to enhance targeted drug delivery with HIFU21-22. The results in this study indicate that NPs with superhydrophobic external surface are necessary and sufficient to induce IC, while the textural properties of NPs have limited effect on IC generation. Therefore, NPs can become US-responsive if surface functionalization is applicable despite of their component, and the mesopores of MSNs could be loaded with various agents without weakening the IC capability. Further combination of US and other systems including endogenous (e.g., changes in pH, enzyme concentration, or redox gradients), and exogenous (e.g., light, radiofrequency waves, and magnetic fields) stimuli to develop multifunctional NPs for theranostic applications is possible, and will benefit both thermal and nonthermal treatment involving US and other types of stimulus. However, the biocompatibility and stability of superhydrophobic NPs under physiological conditions is still unclear and should be carefully evaluated prior to further biomedical applications. In addition to biomedical applications, the superhydrophobic NPs can be used to fabricate superhydrophobic films for ultrasonic flow processing, and be used for surface treatments directly to enhance IC, and for that, the underwater stability of superhydrophobic NPs is of importance because it is related not only to their dispersibility in aqueous solutions, but also to their air nuclei longevity in a submerged environment57. Recently, the stability of underwater superhydrophobic surface has been systematically reviewed, and it has been reported that superhydrophobic surface may become wettable when they were submerged underwater due to a series of effects including air diffusion, fluid flow, and the trapped-air condensation under certain hydrostatic pressures58-59. However, unlike superhydrophobic films, the underwater stability of superhydrophobic NPs may be more related to their nanoscale molecular architectures, and NP surface roughness etc. Although we have demonstrated that our superhydrophobic NPs remained US-responsive for three months without extra protection44, transition from Cassie and Baxter state (with air) to Wenzel state (without air) due to water penetration in texture of NPs could take place during US exposure. In certain situation, US could even increase the contact angle of hydrophilic TiO2 surfaces60. Therefore, the possible surface transitions of superhydrophobic NPs induced by US should be taken into consideration and carefully evaluated prior to further industrial applications.

4. CONCLUSIONS 19


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The importance of surface properties of NPs in designing US-responsive system was demonstrated in this study. MSNs with superhydrophobic external surface (F-48, F48-ext and F-41ext) showed significant ICD enhancement in comparison to the hydrophilic parent MSNs (MCM-48 and MCM-41). The external surface properties of silica NPs was found to be the key to inducing IC because the F-48 and F48-ext NPs with opposite internal hydrophobicity but the same external superhydrophobicity surface showed similar ICDs, while both were suppressed when BSA coated on their surface. In addition, nonporous F-SS and PTFE NPs were also US-responsive under same conditions. The simulations results were in good accordance with the experimental ones and revealed that that the surface property instead of mesostructured textural property of NPs was the dominant factor in IC generation in the applied acoustic conditions. In addition, IC characterized by high-speed photography revealed that cavitation bubbles in dozens of micron range were generated from a group of superhydrophobic silica NPs, and the cavitation bubble could be also monitored using US B-mode imaging. Based on the discoveries, we proposed a new approach to develop US-responsive systems by superhydrophobic modification of the external surface of NPs.

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ASSOCIATED CONTENTS Supporting Information The F-48 NP concentration distribution at a 0.1 mg mL−1 measured by Nanosight. N2 physisorption isotherms of F-48, F-41, F-SS and F-48-ext NPs; and of MCM-48, CH3-48 and F-48. The correlations of contact angles of different kinds of NPs and their corresponding wetting tensions. Three representative asymmetric structure of three cavitation bubbles captured by high-speed photography. Videos of cavitation bubble under high-speed photography and cavitation cloud observed by ultrasound imaging.

ACKNOWLEDGEMENTS The authors gratefully acknowledge the support of the Ministry of Science and Technology, Taiwan under Grant No. MOST 106-2627-M-007-007, 106-2221-E-007-008 and 103-2628-M-007-006MY3, National Tsing Hua University (Hsinchu, Taiwan) under Grant No. 106N522CE1, and Chang Gung Memorial Hospital (Linkou, Taiwan) under Grant No. CIRPD2E0051.

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Graphical Abstract

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Figure 1. (a) A schematic diagram of textural and surface properties of silica NPs. (b) The potential air nuclei in mesopores and external surface nanobubbles for IC initiation by US. 70x30mm (300 x 300 DPI)


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Figure 2. (a) Schematic of the experimental setup for ICD measurements using PCD. (b) Received PCD signals with (blue line) and without (black line) F-48 NPs. (c) Frequency spectra of received acoustic PCD signals. 105x88mm (300 x 300 DPI)


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Figure 3. Experimental setup of US B-mode imaging for monitoring cavitation bubble clouds. 53x33mm (300 x 300 DPI)


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Figure 4. Illustration of a cylindrical pore and its dimensions in a silica NP, and an expanding bubble with a radius of R and contact angle θ. 66x73mm (300 x 300 DPI)


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Figure 5. (a) Powder XRD patterns, (b) TEM images, (c) FTIR spectra, and (d) photographs of the contact angles of parent silica NPs and their derivatives. 90x65mm (300 x 300 DPI)


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Figure 6. ICDs of (a) hydrophilic parent silica NPs, (b) MCM-48 and its derivatives with various surface property, (c) superhydrophobic MCM-48 derivatives with various internal and external modifications, and (d) other NPs with superhydrophobic external surface. Data are mean and standard deviation values. 89x66mm (300 x 300 DPI)


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Figure 7. (a) Experimental setup for monitoring cavitation bubbles using an optical microscope. (b) Representative sequential images obtained at 5×105 FPS under a 50-cycle pulse at 5 MPa (c) and at 105 FPS under a 3-cycle pulse at 4–6 MPa. (d) Size of cavitation bubble at 4–6 MPa. * denotes p < 0.05. 128x96mm (300 x 300 DPI)


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Figure 8. Representative B-mode images of the cavitation bubble cloud of the MCM-48 type NPs. 50x27mm (300 x 300 DPI)


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Figure 9. (a) Ebarrier of NPs under various acoustic pressures and θ. (b) Cavitation threshold of cavities with various θ at specific rc. Cavitation threshold of cavities at specific θ with various rc of (c) 1–20 nm and (d) 20–100 nm. 92x66mm (300 x 300 DPI)


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Figure 10. (a) Schematic of surface nanobubbles adsorbed on superhydrophobic NPs and proposed mechanisms of IC initiation from NPs. (b) ICD of F-48 at various concentrations under 2–6 MPa. Arrows indicated the IC threshold at different concentrations of F-48. 104x107mm (300 x 300 DPI)


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33x20mm (300 x 300 DPI)


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Roles of Textural and Surface Properties of Nanoparticles in Ultrasound

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