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Tunable non-linear acoustic reporters using micron and nano-sized air-bubbles with porous polymeric hard-shells Yifeng Peng, Qian Li, Raymond P Seekell, Tyrone M. Porter, John Kheir, and Brian Polizzotti ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b16737 • Publication Date (Web): 16 Nov 2018 Downloaded from http://pubs.acs.org on November 22, 2018
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ACS Applied Materials & Interfaces
Tunable Non-Linear Acoustic Reporters Using Micron- and Nano-Sized Air-Bubbles with Porous Polymeric Hard-Shells Yifeng Peng, † Qian Li, ‡ Raymond R. Seekell, † Tyrone M. Porter, ‡ John N. Kheir, † and Brian D. Polizzotti†, *. † Department
of Cardiology, Boston Children’s Hospital; Department of Pediatrics, Harvard Medical School, Boston, MA, USA ‡ Biomedical Engineering, Boston University, Boston, MA, USA.
Supporting Information Placeholder ABSTRACT: The ability to tailor acoustic cavitation of contrast agents is pivotal for ultrasound applications in enhanced imaging, drug delivery, and cancer therapy, etc. A biopolymer-based system of microbubbles and nanobubbles was developed as acoustic reporters that consist of extremely porous hard-shells. Despite the existence of an incompressible shell, these porous contrast agents exhibited strong non-linear acoustic response under very low acoustic pressure, e.g, harmonics, characteristic of free gas bubbles. The large air/water surface area within the transmural capillaries are believed to facilitate oscillation of the inner gas core. Furthermore, the acoustic cavitation can be tailored by variation of polymer structures. This synthetically-based platform offers insight for the rational design of advanced acoustic biomaterials.
KEYWORDS: Ultrasound Contrast Agents, Polymers, Microbubbles, Nanobubbles, Acoustics, Cavitation, Biomaterials Coated microbubbles have served as the primary contrast agent (CA) for diagnostic ultrasound for decades.1 Due to the compressibility of the gas core, coated microbubbles can oscillate and radiate sound in response to an ultrasound pulse.2 Consequently, coated microbubbles are more echogenic than cells and tissue and provide exceptional contrast in diagnostic ultrasound images.1,2 When the ultrasound pressure is sufficiently high, the oscillations become nonlinear (stable cavitation) and ultimately the coated microbubbles collapse, a process known as inertial cavitation. Nonlinear bubble oscillations are imperative to enable nonlinear contrast-enhanced imaging methods, such as harmonic imaging,3,4 and theranostic applications of ultrasound, such as drug and gene delivery.5,6 The pressure threshold for nonlinear oscillations depends largely on the composition of the outer shell. Microbubbles coated with soft thin shells composed of surfactants or lipids respond nonlinearly at relatively low acoustic pressures (≤ 300 kPa).7 However, the entrapped gas can readily diffuse through thin shells and the usefulness of the coated microbubbles is shortlived;8 thus extensive efforts were made to overcome this limitation by searching for alternative CA materials.9-18 Notably, polymeric shells of “hard-shelled” CAs are less permeable to the entrapped gas and thus are a more durable CA.9-18 Various polymeric CAs were developed, e.g. poly(lactic-co-glycolic acid) PLGA microand nanobubbles, and showed remarkable improvement in stability,
circulation time, drug loading for delivery, etc.14-18 However, the shells of first-generation polymer-coated microbubbles were too rigid and suppressed bubble oscillations.18-21 Reportedly, high pressures (> 1 MPa) were required to fracture the polymer shell and liberate the microbubble before nonlinear oscillations were detected.19-21 Ideally, a CA should behave like elastic lipid bubbles that allow nonlinear oscillations at relatively low acoustic pressures, and also possess high stability similar to polymeric shells that are sufficiently impermeable to minimize gas efflux, thus prolonging the utility of the CA in vivo. Moreover, for advanced biomedical applications, it is increasingly important to achieve the ability to control and tailor the acoustic response of CAs, i.e. stable and inertial cavitation. For example, Sun et al 22 recently showed continuous stable cavitation by lipid MBs offers a safer way to deliver drugs across blood-brain barriers; however, this must be achieved by careful monitoring the acoustic pressure and signals to circumvent the complication of lipid MBs depletion and minimize uncontrollable inertial cavitation. Notably, Shapiro group recently engineered a new type of gas-vesicle based nano-CAs.23,24 By genetically manipulating the shell proteins, they acquired unprecedented control over critical acoustic parameters of CAs, including 2nd harmonic and triggerable collapse pressure; such abilities were shown to expand the utilities of US, such as multiplex, multimodal harmonic US imaging, targeting, acoustically modulated magnetic resonance imaging.23,24 Therefore, it remains highly desirable to develop synthetically based CAs with enhanced and tunable non-linear acoustic response, and to further explore structural-properties understanding in order to facilitate rational design of future CAs. Herein, we describe a polymeric CA system consisting of both micron and nano-size bubbles with highly porous "hard-shells" prepared from modified dextrans. We discovered that air bubbles entrapped in extremely porous hard-shells preserve stable cavitation (i.e. stable bubble oscillations) and display strong nonlinear acoustic response under very low acoustic pressure, characteristic of free gas bubbles. We speculate that the presence of large air-liquid surface area within densely populated transmural capillaries may facilitate stable cavitation of the gas core. Furthermore, we show that modification of polymer structures can be used to tailor non-linear acoustic characteristics including 2nd harmonic imaging and collapse pressure.
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Scheme 1. Fabrication of highly porous polymeric hard-shelled MBs and NBs from chemically modified dextrans using air-templated or PFC o/w emulsion templated (phase separation/solvent evaporation) methods.
A
B
C
D
E
F
G
H
I
Figure-1. SEM characterization of MBs and NBs. P1-MBs (A-C). A: a full view of a MB, scale bar 1 μm; B: a close-up of outer shell densely populated with pores, scale bar 200 nm. C: a cross-sectioned MB showing high porosity of the inner shell, scale bar 200 nm. P2MBs (D,E). D: scale bar 1μm; E: scale bar 300 nm. P2-NBs (F, G), F: panoramic view of P2-NBs with rough shells, scale bar 300 nm; G: cross section of P2-NBs showing inner gas core, scale bar 200 nm. P3-MBs (H, I), H: smooth outer shell of P3-MBs, scale bar 2 μm; I: cross section of P3-MBs showing smooth inner shells, scale bar 3 μm.
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ACS Applied Materials & Interfaces
As in Scheme 1, to fabricate micron and nano-sized bubbles with porous polymeric hard-shells, we designed either air templated or perfluorocarbon (PFC) o/w emulsion templated method by using modified dextrans that were acylated with acetal and/or butylaminooxobutyryl, or octanoyl groups (P1, P2 or P3) (Figure S1-3). For air-templated fabrication, previous work showed that modified dextran with tailored amphiphilicity can self-assemble at air/liquid interface in DMSO/H2O, and subsequently undergo interfacial nanoprecipitation to form stable MBs.25 Using the same method, P1- and P2-MBs were prepared by interfacial nanoprecipitation under various homogenization speeds (Table 1), whereas P3 was not soluble in the co-solvents to produce MBs. Similar size of P1-MB (3.35 ± 1.38 μm) and P2-MB (3.12 ±1.41 μm) was obtained at 16.5k and 10.5k rpm respectively. Previously, CryoSEM of MBs in aqueous solution only showed the shell surfaces consisted of nanoparticle aggregates. 25 Here, on the other hand, we used freeze-dried MB preparations which completely removed surface water and revealed that the shells of P1- and P2-MBs were densely populated with nano-scaled capillary channels imparting the particles with extreme porosity (Figure 1A,B). The transmural nature of the shell porosity was observable in cross-sectioned images, and was further confirmed by surfactant test (Figure S4,5). However, we were unable to generate nanobubble preparations by increasing homogenization speed using the air-templating approach. Alternatively, we prepared porous nanobubbles (NBs) using a surfactant-free PFC-o/w emulsion templating method based on P2 (Scheme 1). Briefly, unlike a typical PFC-templated phaseseparation method that needs extra surfactants to generate emulsion droplets,26-27 P2 served as both emulsifier and shell material to form PFC-cored nanodroplets. After freeze-drying to remove PFC core, the air-filled NBs (P2-NB) were obtained; the SEM analysis revealed the rough surfaces of P2-NB, and its porous nature was evidenced by surfactant-induced capillary wetting tests28,29 (SI-S6). Interestingly, we noticed the droplet size as well as shell porosity depended not only on stirring speed but also polymeric structures which affect surface tension. Using the same PFC emulsion template, P1 and P3 produced only micron-sized droplets (Table 1), likely because they had weaker emulsifying ability than P2. Furthermore, the PFC core cannot be removed through P1-shelled droplets via freeze-drying, indicating low PFOB gas permeability of P1. P3 allowed the removal of PFC to generate stable MB (P3MB), likely because bulkier octanoyl moieties improved the gas permeability; however, the SEM analysis showed P3-MB contains only non-porous shells (Figure 1D). Clearly, the results suggest the shell morphology produced by the process of phase-separation depends on polymer structures, which may be fine-tuned by further modification. Table-1. Sizes of MBs and NBs under different homongenization speeds. (*measured by dynamic light scattering). Template Speed Mean S.D. of Dia. (rpm) Diameter P1-MB P2-MB P2-NB P3-MB P2-NB2 P1-MB2
air air PFC PFC PFC PFC
16.5K 10.5 k 9.5k 3.5 k 3.5k 3.5k
3.35 μm 3.12 μm 394 nm* 5.63 μm 912nm 6.05 μm
1.38 μm 1.41 μm 48.4nm* 1.84 μm 220 nm 3.65 μm
To test the acoustic response of the polymeric CAs prepared above, we applied 1 MHz pulses (20 cycles, PRF 30) to monitor their backscatter at 90o as a function of US intensity by following an established procedure (Figure S7). Unlike hard-shelled CAs,16-21 P1- and P2-MBs showed non-linear backscatter at low acoustic pressure, a feature that is characteristic for highly compressible gas bubbles with elastic surface, such as lipids. For example, P2-MB readily produced strong 2nd harmonic at 279.3 kPa (MI 0.28, Figure 2A), while with increased US intensity, inertial cavitation took place, as evidenced by the increase in broadband noise between 2nd and 3rd harmonics (Figure 2B and C).
Figure 2. Non-linear response of P2-MBs as a function of acoustic pressure (104#/ml). (A: stable cavitation; B, mixed cavitation; C, inertial cavitation. Control: 5μm polystyrene beads). We further summarized the acoustic response of P1-, P2- and P3MBs to different US intensities by normalizing to polystyrene beads of same concentration (104#/ml) in water (Figure 3). Not surprisingly, the non-porous hard-shelled P3-MB behaved exactly like traditional polymeric CAs and produced no non-linear backscatter, since the rigid shells prevented the gas cores from compressing or expanding. In contrast, the porous P1-MB displayed prominent 2nd harmonic (>10dB) at extremely low power (74Kpa, MI ~0.07), comparable to most lipid MBs (Figure 3A). P1-MB also showed a rather low characteristic collapse pressure ~200KPa (Figure 3B). P2-MB emitted 2nd harmonic at greater US intensity with a much higher collapse pressure at ~550 kPa, likely
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the result of decreased porosity or pore size (Figure 3). The 2nd harmonic generated by P1- and P2-MBs under such low acoustic energy input was unlikely caused by mere dampening of the rigid shells (brittle and semi-crystalline polymers with Tm >120 oC) , but characteristic of low-amplitude cavitation of free gas bubbles. We suspect that the existence of a transmural porous shell (which provides an extremely large air/water surface-area ratio) facilitated the oscillation of the inner gas cores, where the Laplace capillary pressure provided resistance to water infiltration from outside. Importantly, P1- and P2- MBs clearly displayed distinct acoustic features, and this difference can be attributed to polymer structures, which further affect shell porosity such as size, density, tortuosity, as well as surface tension and Laplace capillary pressure, which in turn collectively regulate the acoustic response. For example, a visual inspection (Figure 1) showed P1-MBs had larger pore size, and this likely result in decreased hydrostatic pressure that oscillation of gas core needs to overcome, which might account for its greater harmonic response observed at low acoustic pressure, as well as lower collapse pressure. Furthermore, although the acoustic response of elastic lipid MBs is a function of MB size and polydispersity, we did not observe such size dependences in P1 and P2 based MBs manufactured under our current conditions (Figure S8,9). These interesting phenomena are under further investigation.
P2-MBs subject to continuous stable cavitation. Whereas stable cavitation of lipid MBs were known to suffer from signal loss and resonance shift within seconds due to gas dissolution,30 P1- and P2MBs possess good acoustic stability. As in Figure 5, the stable cavitation of P1- and P2-MBs subjected to continuously pulsed cycles of 10 min caused no significant loss of signals. Furthermore, the in-vivo non-linear contrast-enhanced imaging of Inferior Vena Cava (IVC) in rodents using P2-MB was also performed and demonstrated excellent contrast and prolonged echogenicity (Figure S10).
A Figure 4. Phantom imagining of P1- and P2- MBs (1x105 #/ml) (f=1-5 MHz). Good contrast signals were seen at low MI 0.1 (the bright circle in the center of the image), and higher MI (0.3) led to collapse of P1-MBs (disappearance of the bright circle), while P2MB remain intact.
B
Figure 5. Acoustic response of P1- and P2-MBs subject to continuous pulse cycle under stable cavitation for 10 min (106#/ml). Figure 3. Acoustic response of porous P1- and P2-MBs and nonporous P3-MB. (A, 2nd harmonic during stable cavitation. B, broadband noise(bn) caused by inertial cavitation; the collapse pressure defined as bn=20dB) Recently, Shapiro group pioneered genetically engineered CAs with tailorable collapse pressure that demonstrated robust potential for nonlinear and multi-modal imaging. 23,24 We expect that the present synthetic system shares similar advantages. As proof-ofconcept, we explored the pressure-specific destruction of P1- and P2-MBs in phantom imaging by utilizing their distinct collapse pressure with a clinical US system (Philips iE33) (Figure 4). Under Contrast-mode, both P1- and P2- MBs were highly echogenic at MI as low as 0.1; after excitation with a higher MI (0.3), P1-MB lost signals due to inertial cavitation, yet the echogenicity of P2MB remained stable, confirming their well-defined acoustic characters. Next, we demonstrated the acoustic stability of P1- and
Figure 6. Non-linear response by P2-NB under stable cavitation (0.025mg/ml).
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ACS Applied Materials & Interfaces Finally, the acoustic response of porous P2-NB was investigated, which also generated strong 2nd harmonic when subject to very low-energy excitation, e.g., 20db at 148kPa (Figure 6). Interestingly, in comparison with MBs, we noticed that P2-NB had lower stability when subject to stable cavitation, thus it is likely the transmural pores or the presence of shell defects were less effectively at preventing water infiltration and led to gas dissolution (Figure S11). Future efforts to increase the half-life of NBs would be highly beneficial, and we suspect it may be achievable by optimizing the design of polymer structures. To conclude, by chemically modifying dextran to modulate their interfacial phase-separation behaviors, micron and nano-sized CAs with extremely porous shells were prepared via air or PFC templated fabrication method. Traditionally, hard-shelled polymeric CAs often lack non-linear acoustic responses, especially under low-intensity US, which has limited their use as diagnostic imaging agents. This work demonstrated that incorporation of pores into hard-shells facilitated cavitation of gas cores and achieved strong non-linear backscatter. Moreover, the present results further point to the importance of better understanding the mechanisms of bubble cavitation within nano-capillaries. Finally, we also showed that the important acoustic parameters of CAs can be tailored by chemical modification of polymers. We expect that this work will offer insight for rational design of advanced acoustic materials with tunable acoustic properties for various biomedical applications.
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ASSOCIATED CONTENT
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Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Materials and general methods; synthetic methods for dextran derivatives, micro and nanobubbles morphology characterization; acoustic characterizations; in-vivo contrast-enhanced imaging. (PDF)
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AUTHOR INFORMATION
Corresponding Author (19)
E-mail:
[email protected].
Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT We are grateful to Prof. Nikolay V. Vasilyev (M.D.) and Dr. Mossab Yousif Saeed (M.B., B.S.) who assisted the operation of echocardiography system.
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REFERENCES (1) (2) (3)
Kaul, S. Myocardial Contrast Echocardiography: a 25-year Retrospective. Circulation 2008, 118, 291-308. Goldberg, B. B.; Liu, J. B.; Forsberg, F. Ultrasound Contrast Agents: a Review. Ultrasound Med. Biol. 1994, 20, 319-333. de Jong, N.; Bouakaz, A.; Ten Cate, F. J. Contrast harmonic Imaging. Ultrasonics 2002, 40, 567-573.
(23)
(24)
Chung, Y. E.; Kim, K. Whang. Contrast-Enhanced Ultrasonography: Advance and Current Status in Abdominal Imaging. Ultrasonography 2015, 34, 3-18. Ferrara, K.; Pollard, R.; Borden, M.; Ultrasound Microbubble Contrast Agents: Fundamentals and Application to Gene and Drug Delivery. Annu. Rev. Biomed. Eng. 2007, 9, 415-447. Tsutsui, J. M.; Xie, F.; Porter, R. T. The Use of Microbubbles to Target Drug Delivery. Cardiovasc. Ultrasound 2004, 2, 23. Qin, S. P.; Caskey, C. F.; Ferrara, K. W. Ultrasound Contrast Microbubbles in Imaging and Therapy: Physical Principles and Engineering. Phys. Med. Biol. 2009, 54, R27-R57. Narayan, P.; Wheatley, M. A. Preparation and Characterization of Hollow Microcapsules for Use as Ultrasound Contrast Agents. Polym. Eng. Sci. 1999, 39, 2242-2255. Huang, Y.; Vezeridis, A. M.; Wang, J.; Wang, Z.; Thompson, M.; Mattrey, R. F.; Gianneschi, N. C.; Polymer-Stabilized Perfluorobutane Nanodroplets for Ultrasound Imaging Agents. J. Am. Chem. Soc. 2017, 139, 15-18. Wang, Y.; Liu, G.; Hu, H.; Li, T. Y.; Johri, A. M.; Li, X.; Wang, J. Stable Encapsulated Air Nanobubbles in Water. Angew. Chem. Int. Ed. 2015, 54, 14291-14294. Tsao, N. H.; Hall, E. A. H. Enzyme-Degradable Hybrid Polymer/Silica Microbubbles as Ultrasound Contrast Agents. Langmuir 2016, 32, 6534-6543. Capece, S.; Chiessi, E.; Cavalli, R.; Giustetto, P.; Grishenkov, D.; Paradossi, G. A General Strategy for Obtaining Biodegradable Polymer Shelled Microbubbles as Theranostic Devices. Chem. Commun. 2013, 49, 5763-5765. Capece, S.; Domenici, F.; Brasili, F.; Oddo, L.; Cerroni, B.; Bedini, A.; Bordi, F.; Chiessi, E.; Paradossi, G. Complex Interfaces in “Phase-Change” Contrast Agents. Phys. Chem. Chem. Phys. 2016, 18, 8378-8388. Song, R.; Peng, C.; Xu, X.; Wang, J.; Yu, M.; Hou, Y.; Zou, R.; Yao, S. Controllable Formation of Monodisperse Polymer Microbubbles as Ultrasound Contrast Agents. ACS Appl. Mater. Interfaces 2018, 10, 14312-14320. Zhang, X.; Zheng, Y.; Wang, Z.; Huang, S.; Chen, Y.; Jiang, W.; Zhang, H.; Ding, M.; Li, Q., Xiao, X.; Luo, X.; Wang, Z.; Qi, H. Methotrexate-loaded PLGA Nanobubbles for Ultrasound Imaging and Synergistic Targeted Therapy of Residual Tumor during HIFU Ablation. Biomaterials 2014, 35, 5148-5161. Straub, J. A.; Chickering, D. E.; Church, C. C.; Shah, B.; Hanlon, T.; Bernstein, H. Porous PLGA Microparticles: AI-700, an Intravenously Administered Ultrasound Contrast Agent for Use in Echocardiography. J. Control. Release 2005, 108, 21-32. El-Sherif, D. M.; Wheatley. M. A. Development of a Novel Method for Synthesis of a Polymeric Ultrasound Contrast Agent. J. Biomed. Mater. Res. A 2003, 66, 347-355. Forsberg, F.; Lathia, J. D.; Merton, D. A.; Liu, J. B.; Le, N. T.; Goldberg, B. B.; Wheatley, M. A. Effect of Shell Type on the in vivo Backscatter from Polymer-Encapsulated Microbubbles. Ultrasound Med. Biol. 2004, 30, 1281-1287. Bloch, S. H.; Wan, M.; Dayton, P. A.; Ferrara, K. W. Optical Observation of Lipid- and Polymer-Shelled Ultrasound Microbubble Contrast Agents. Appl. Phys. Lett. 2004, 84, 631-633. Lentacker, I.; De Cock, I.; Deckers, R.; De Smedt, S. C.; Moonen, C. T. W. Understanding Ultrasound Induced Sonoporation: Definititions and Underlying Mechanisms. Adv. Drug Deliv. Rev. 2014, 72, 49-64. Paefgen, V.; Doleschel, D.; Kiessling, F. Evolution of Contrast Agents for Ultrasound Imaging and Ultrasound-Mediated Drug Delivery. Front Pharmacol. 2015, 6, 197. Sun, T.; Zhang, Y.; Power, C.; Alexander, P. M.; Sutton, J. T.; Aryal, M.; Vykhodtseva, N.; Miller, E. L.; McDannold, N. J. Closed-Loop Control of Targeted Ultrasound Drug Delivery Across the Blood-Brain/Tumor Barriers in a Rat Glioma Model. PNAS 2017, 114, E10281-E10290. Lakshmanan, A.; Farhadi, A.; Nety, S. P.; Lee-Gosselin, A.; Bourdeau, R. W.; Maresca, D.; Shapiro, M. G. Molecular Engineering of Acoustic Protein Nanostructures. ACS Nano 2016, 10, 7314-7322. Lu, G. J.; Farhadi, A.; Szablowski, J. O.; Lee-Gosselin, A.; Barnes, S. R.; Lakshmanan, A.; Bourdeau, R. W.; Shapiro, M. G. Acoustically Modulated Magnetic Resonance Imaging of GasFilled Protein Nanostructures. Nat. Mater. 2018, 17, 456-463.
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(25) Peng, Y.; Seekell, R. P.; Cole, A. R.; Lamothe, J. R.; Lock, A. T.; van den Bosch, S.; Tang, X.; Kheir, J. N.; Polizzotti, B. D. Interfacial Nanoprecipitation toward Stable and Responsive Microbubbles and their Use as a Resuscitative Fluid. Angew. Chem. Int. Ed. 2018, 57, 1271-1276. (26) Seekell, R. P.; Peng, Y.; Lock, A. T.; Kheir, J. N.; Polizzotti, B. D. Tunable Polymer Microcapsules for Controlled Release of Therapeutic Gases. Langmuir 2018, 34, 9175-9183. (27) Tasker, A. L.; Hitchcock, J. P.; He, L.; Baxter, E. A.; Biggs, S.; Cayre, O. J. The Effect of Surfactant Chain Length on the Morphology of Poly(methyl methacrylate) Microcapsules for Fragrance Oil Encapsulation. J. Colloid Interface Sci. 2016, 484, 10-16.
(28) Chen, Y.; Wang, Z.; Jennings, G. K.; Lin, S. Probing Pore Wetting in Membrane Distillation Using Impedance: Early Detection and Mechanism of Surfactant-Induced Wetting, Environ. Sci. Technol. Lett. 2017, 4, 505-510. (29) Pompano, R. R.; Platt, C. E.; Karymov, M. A.; Ismagilov, R. F. Control of Initiation, Rate, and Routing of Spontaneous CapillaryDriven Flow of Liquid Droplets through Microfluidic Channels on Slipchip, Langmuir 2012, 28, 1931-1941. (30) Marmottant, P.; van der Meer, S.; Emmer, M.; Versluis, M.; de Jong, N. A Model for Large Amplitude Oscillations of Coated Bubbles Accounting for Buckling and Rupture. J. Acoust. Soc. Am. 2005, 118, 3499-3505.
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