Physics:Microbubble

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Microbubbles are bubbles smaller than one hundredth of a millimetre in diameter, but larger than one micrometre. They have widespread application in industry, medicine,[1] life science,[2] and food technology.[3] The composition of the bubble shell and filling material determine important design features such as buoyancy, crush strength, thermal conductivity, and acoustic properties. They are used in medical diagnostics as a contrast agent for ultrasound imaging.[4] The gas-filled microbubbles, typically air or perfluorocarbon, oscillate, and vibrate if a sonic energy field is applied and may reflect ultrasound waves. This distinguishes the microbubbles from surrounding tissues. Because gas bubbles in liquid lack stability and would therefore quickly dissolve, microbubbles are typically encapsulated by shells. The shell is made from elastic, viscoelastic, or viscous material. Common shell materials are lipid, albumin, and protein. Materials having a hydrophilic outer layer to interact with the bloodstream and a hydrophobic inner layer to house the gas molecules are thermodynamically stable. Air, sulfur hexafluoride, and perfluorocarbon gases all can serve as the composition of the microbubble interior. Microbubbles with one or more incompressible liquid or solid cores surrounded by gas are referred to as microscopic or endoskeletal antibubbles. For increased stability and persistence in the bloodstream, gases with high molecular weight as well as low solubility in the blood are attractive candidates for microbubble gas cores.[5]

Microbubbles may be used for drug delivery,[6] biofilm removal,[7] membrane cleaning[8][9] /biofilm control and water/waste water treatment purposes.[10] They are also produced by the movement of a ship’s hull through water, creating a bubble layer; this may interfere with the use of sonar because of the tendency of the layer to absorb or reflect sound waves.[11]

Acoustic response

Contrast in ultrasound imaging relies on the difference in acoustic impedance, a function of both the speed of the ultrasound wave and the density of the tissues,[12] between tissues or regions of interest.[5] As the sound waves induced by ultrasound interact with a tissue interface, some of the waves are reflected back to the transducer. The larger the difference, the more waves are reflected, and the higher the signal to noise ratio. Hence, microbubbles that have a core with a density orders of magnitude lower than and compress more readily than the surrounding tissues and blood, afford high contrast in imaging.[5]

Therapeutic application

Physical Response

When exposed to ultrasound, microbubbles oscillate in response to the incoming pressure waves in one of two ways. With lower pressures, higher frequencies, and larger microbubble diameter, microbubbles oscillate, or cavitate, stably.[5]  This causes microstreaming near the surrounding vasculature and tissues, inducing shear stresses that can create pores on the endothelial layer.[13] This pore formation enhances endocytosis and permeability.[13] At lower frequencies, higher pressures, and lower microbubble diameter, microbubbles oscillate inertially; they expand and contract violently, ultimately leading to microbubble collapse.[14] This phenomenon can create mechanical stresses and microjets along the vascular wall, which has been shown to disrupt tight cellular junctions as well as induce cellular permeability.[13] Extremely high pressures cause small vessel destruction, but the pressure can be tuned to only create transient pores in vivo.[5][14] microbubble destruction serves as a desirable method for drug delivery vehicles. The resulting force from destruction can dislodge the therapeutic payload present on the microbubble and simultaneously sensitize the surrounding cells for drug uptake.[14]

Drug Delivery

Microbubbles can serve as drug delivery vehicles in a variety of methods. The most notable of these include: (1) incorporating a lipophilic drug to the lipid monolayer, (2) attaching nanoparticles and liposomes to the microbubble surface, (3) enveloping the microbubble within a larger liposome, and (4) electrostatically bonding nucleic acids to the microbubble surface.[5][15][16][17]

I. Lipophilic Drugs

Microbubbles can facilitate the local targeting of hydrophobic drugs through the incorporation of these agents into the microbubble lipid shell.[18][19][20][21][22][23][24][25] This encapsulation technique reduces systemic toxicity,  increases drug localization, and improves the solubility of hydrophobic drugs.[19] For increased localization, a targeting ligand can be appended to the exterior of the microbubble.[20][21][23][24][25] This improves treatment efficacy.[21] One drawback of the lipid-encapsulated microbubble as a drug delivery vehicle is its low payload efficacy. To combat this, an oil shell can be incorporated to the interior of the lipid monolayer to enhance payload efficacy.[26]

II. Nanoparticle and Liposome Attachment

Attachment of liposomes[27][28][29][30] or nanoparticles [13][31][32][33][34] to the exterior of the lipid microbubble has also been explored to increase microbubble payload. Upon microbubble destruction with ultrasound, these smaller particles can extravasate into the tumor tissue. Furthermore, through attachment of these particles to microbubbles as opposed to co-injection, the drug is confined to the blood stream instead of accumulating in healthy tissues, and the treatment is relegated to the location of ultrasound therapy.[29] This microbubble modification is particularly attractive for Doxil, a lipid formulation of Doxorubicin already in clinical use.[29] An analysis of nanoparticle infiltration due to microbubble destruction indicates that higher pressures are necessary for vascular permeability and likely improves treatment by promoting local fluid movement and enhancing endocytosis.[13]

III. Microbubble Loading Inside Liposome

Another novel acoustically responsive microbubble system is the direct encapsulation of microbubbles inside of a liposome. Theses systems circulate longer in the body than microbubbles alone do, as this packaging method prevents the microbubble from dissolving in the blood stream.[35] Hydrophilic drugs persist in the aqueous media inside the liposome, while hydrophobic drugs congregate in the lipid bilayer.[35][36] It has been shown in vitro that macrophages do not engulf these particles.[36]

IV. Gene Delivery through Electrostatic Interactions   

Microbubbles also serve a non-viral vector for gene transfection through electrostatic bonds between a positively charged microbubble outer shell and negatively charged nucleic acids. The transient pores formed by microbubble collapse allow the genetic material to pass into the target cells in a safer and more specific manner than current treatment methods.[37] Microbubbles have been used to deliver microRNAs,[38][39] plasmids,[40] small interfering RNA,[41] and messenger RNA.[42][43]

Disadvantages of Microbubbles for Drug Delivery

  • Microbubbles do not extravasate easily due to their large size, and hence their effects are relegated to the vasculature. Nanodroplets, perfluorocarbon liquid droplets surrounded by a lipid shell that vaporize due to an ultrasound pulse, offer a small diameter to promote extravasation and afford an alternative to microbubbles.
  • Microbubbles have short half-lives on the order of minutes in circulation, which limits the treatment time.
  • Microbubbles are filtered by the liver and spleen, and any drug conjugation would then also potentially pose a toxicity threat to these organs, should the microbubbles not have already released their cargo.
  • Drug conjugations to microbubbles are complicated for translation, and these formulations would be difficult to scale up for widespread use.
  • There can be a small amount hemorrhage into brain tissue when microbubbles are used to disrupt the blood brain barrier, though this is thought to be reversible.[citation needed]

Unique Applications of Microbubbles for Therapeutic Application

Microbubbles used for drug delivery not only serve as drug vehicles but also as a means to permeate otherwise impenetrable barriers, specifically the blood brain barrier, and to alter the tumor microenvironment.

I. Blood Brain Barrier Disruption

The brain is protected by tight junctions in the endothelial cell wall in the capillaries, known as the blood-brain barrier (BBB).[44] The BBB strictly regulates what passes into the brain from the blood, and while this function is highly desirable in healthy individuals, it also poses a barrier for therapeutics to enter the brain for cancer patients. Ultrasound was shown to disrupt the blood brain barrier in the mid 20th century,[45] and in the early 2000’s, microbubbles were shown to assist in a temporary permeabilization.[46] Since then, ultrasound and microbubble therapy has been used to deliver therapeutics to the brain. As BBB disruption with ultrasound and microbubble treatment has shown to be a safe and promising treatment pre-clinically, two clinical trials are testing delivery of doxorubicin[47] and carboplatin[48] with microbubbles to increase drug concentration locally.

II. Immunotherapy

In addition to permeating the blood brain barrier, ultrasound and microbubble therapy can alter the tumor environment and serve as an immunotherapeutic treatment.[49] High-intensity focused ultrasound (HIFU) alone triggers an immune response, speculated to be through facilitating the release of tumor antigens for immune cell recognition, activating antigen-presenting cells and promoting their infiltration, combatting tumor immunosuppression, and promoting a Th1 cell response.[50][51] Typically, HIFU is used for thermal ablation of tumors. Low-intensity focused ultrasound (LIFU) in combination with microbubbles has also shown to stimulate immunostimulatory effects, inhibiting tumor growth and increasing endogenous leukocyte infiltration.[50][52] Furthermore, lowering the acoustic power required for HIFU yields a safer treatment for the patient, as well as diminished treatment time.[53] Though the treatment itself shows potential, a combinatorial treatment is speculated to be required for a complete treatment. Ultrasound and microbubble treatment without additional drugs impeded the growth of small tumors but required a combinatorial drug treatment to affect medium-sized tumor growth.[54] With their immune stimulating mechanism, ultrasound and microbubbles offer a unique ability to prime or enhance immunotherapies for more effective cancer treatment.

References

  1. ↑ Rodríguez-Rodríguez, Javier; Sevilla, Alejandro; Martínez-Bazán, Carlos; Gordillo, José Manuel (3 January 2015). "Generation of Microbubbles with Applications to Industry and Medicine" (in en). Annual Review of Fluid Mechanics 47 (1): 405–429. doi:10.1146/annurev-fluid-010814-014658. ISSN 0066-4189. Bibcode: 2015AnRFM..47..405R. https://doi.org/10.1146/annurev-fluid-010814-014658. Retrieved 28 March 2023. 
  2. ↑ Zeng, Wenlong; Yue, Xiuli; Dai, Zhifei (19 October 2022). "Ultrasound contrast agents from microbubbles to biogenic gas vesicles" (in en). Medical Review 3: 31–48. doi:10.1515/mr-2022-0020. ISSN 2749-9642. 
  3. ↑ Lu, Jiakai; Jones, Owen G.; Yan, Weixin; Corvalan, Carlos M. (27 March 2023). "Microbubbles in Food Technology" (in en). Annual Review of Food Science and Technology 14 (1): 495–515. doi:10.1146/annurev-food-052720-113207. ISSN 1941-1413. PMID 36972154. 
  4. ↑ Blomley, Martin J K; Cooke, Jennifer C; Unger, Evan C; Monaghan, Mark J; Cosgrove, David O (2001). "Science, medicine, and the future: Microbubble contrast agents: A new era in ultrasound". BMJ 322 (7296): 1222–5. doi:10.1136/bmj.322.7296.1222. PMID 11358777. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Martin, K. Heath; Dayton, Paul A. (July 2013). "Current status and prospects for microbubbles in ultrasound theranostics: Current status and prospects for microbubbles" (in en). Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 5 (4): 329–345. doi:10.1002/wnan.1219. PMID 23504911. 
  6. ↑ Sirsi, Shashank; Borden, Mark (2009). "Microbubble compositions, properties and biomedical applications". Bubble Science, Engineering & Technology 1 (1–2): 3–17. doi:10.1179/175889709X446507. PMID 20574549. 
  7. ↑ Mukumoto, Mio; Ohshima, Tomoko; Ozaki, Miwa; Konishi, Hirokazu; Maeda, Nobuko; Nakamura, Yoshiki (2012). "Effect of microbubbled water on the removal of a biofilm attached to orthodontic appliances — an in vitro study". Dental Materials Journal 31 (5): 821–7. doi:10.4012/dmj.2012-091. PMID 23037846. 
  8. ↑ Agarwal, Ashutosh; Ng, Wun Jern; Liu, Yu (January 1, 2013). "Cleaning of biologically fouled membranes with self-collapsing microbubbles". Biofouling 29 (1): 69–76. doi:10.1080/08927014.2012.746319. PMID 23194437. https://doi.org/10.1080/08927014.2012.746319. 
  9. ↑ Agarwal, Ashutosh; Ng, Wun Jern; Liu, Yu, (2012). "Cleaning of biologically fouled membranes with self-collapsing microbubbles". Biofouling 29 (1): 69-76. doi:10.1080/08927014.2012.746319[yes|permanent dead link|dead link}}]
  10. ↑ Agarwal, Ashutosh; Ng, Wun Jern; Liu, Yu (2011). "Principle and applications of microbubble and nanobubble technology for water treatment". Chemosphere 84 (9): 1175–80. doi:10.1016/j.chemosphere.2011.05.054. PMID 21689840. Bibcode: 2011Chmsp..84.1175A. 
  11. ↑ Griffiths, Brian; Sabto, Michele (25 June 2012). "Quiet on board please: science underway". ECOS. http://www.ecosmagazine.com/paper/EC12330.htm. 
  12. ↑ Cikes, Maja; D’hooge, Jan; Solomon, Scott D. (2019), "Physical Principles of Ultrasound and Generation of Images" (in en), Essential Echocardiography (Elsevier): pp. 1–15.e1, doi:10.1016/b978-0-323-39226-6.00001-1, ISBN 978-0-323-39226-6 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Snipstad, Sofie; Berg, Sigrid; Mørch, Ýrr; Bjørkøy, Astrid; Sulheim, Einar; Hansen, Rune; Grimstad, Ingeborg; van Wamel, Annemieke et al. (November 2017). "Ultrasound Improves the Delivery and Therapeutic Effect of Nanoparticle-Stabilized Microbubbles in Breast Cancer Xenografts" (in en). Ultrasound in Medicine & Biology 43 (11): 2651–2669. doi:10.1016/j.ultrasmedbio.2017.06.029. PMID 28781149. 
  14. ↑ 14.0 14.1 14.2 Hernot, Sophie; Klibanov, Alexander L. (June 2008). "Microbubbles in ultrasound-triggered drug and gene delivery" (in en). Advanced Drug Delivery Reviews 60 (10): 1153–1166. doi:10.1016/j.addr.2008.03.005. PMID 18486268. 
  15. ↑ Klibanov, Alexander L. (March 2006). "Microbubble Contrast Agents: Targeted Ultrasound Imaging and Ultrasound-Assisted Drug-Delivery Applications" (in en). Investigative Radiology 41 (3): 354–362. doi:10.1097/01.rli.0000199292.88189.0f. ISSN 0020-9996. PMID 16481920. 
  16. ↑ Ibsen, Stuart; Schutt; Esener (May 2013). "Microbubble-mediated ultrasound therapy: a review of its potential in cancer treatment" (in en). Drug Design, Development and Therapy 7: 375–88. doi:10.2147/DDDT.S31564. ISSN 1177-8881. PMID 23667309. 
  17. ↑ Mullick Chowdhury, Sayan; Lee, Taehwa; Willmann, Jürgen K. (2017-07-01). "Ultrasound-guided drug delivery in cancer" (in en). Ultrasonography 36 (3): 171–184. doi:10.14366/usg.17021. ISSN 2288-5919. PMID 28607323. 
  18. ↑ Tinkov, Steliyan; Coester, Conrad; Serba, Susanne; Geis, Nicolas A.; Katus, Hugo A.; Winter, Gerhard; Bekeredjian, Raffi (December 2010). "New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: In-vivo characterization" (in en). Journal of Controlled Release 148 (3): 368–372. doi:10.1016/j.jconrel.2010.09.004. PMID 20868711. 
  19. ↑ 19.0 19.1 Ren, Shu-Ting; Liao, Yi-Ran; Kang, Xiao-Ning; Li, Yi-Ping; Zhang, Hui; Ai, Hong; Sun, Qiang; Jing, Jing et al. (June 2013). "The Antitumor Effect of a New Docetaxel-Loaded Microbubble Combined with Low-Frequency Ultrasound In Vitro: Preparation and Parameter Analysis" (in en). Pharmaceutical Research 30 (6): 1574–1585. doi:10.1007/s11095-013-0996-5. ISSN 0724-8741. PMID 23417512. 
  20. ↑ 20.0 20.1 Liu, Hongxia; Chang, Shufang; Sun, Jiangchuan; Zhu, Shenyin; Pu, Caixiu; Zhu, Yi; Wang, Zhigang; Xu, Ronald X. (2014-01-06). "Ultrasound-Mediated Destruction of LHRHa-Targeted and Paclitaxel-Loaded Lipid Microbubbles Induces Proliferation Inhibition and Apoptosis in Ovarian Cancer Cells" (in en). Molecular Pharmaceutics 11 (1): 40–48. doi:10.1021/mp4005244. ISSN 1543-8384. PMID 24266423. 
  21. ↑ 21.0 21.1 21.2 Pu, Caixiu; Chang, Shufang; Sun, Jiangchuan; Zhu, Shenyin; Liu, Hongxia; Zhu, Yi; Wang, Zhigang; Xu, Ronald X. (2014-01-06). "Ultrasound-Mediated Destruction of LHRHa-Targeted and Paclitaxel-Loaded Lipid Microbubbles for the Treatment of Intraperitoneal Ovarian Cancer Xenografts" (in en). Molecular Pharmaceutics 11 (1): 49–58. doi:10.1021/mp400523h. ISSN 1543-8384. PMID 24237050. 
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  29. ↑ 29.0 29.1 29.2 Lentacker, Ine; Geers, Bart; Demeester, Joseph; De Smedt, Stefaan C; Sanders, Niek N (January 2010). "Design and Evaluation of Doxorubicin-containing Microbubbles for Ultrasound-triggered Doxorubicin Delivery: Cytotoxicity and Mechanisms Involved" (in en). Molecular Therapy 18 (1): 101–108. doi:10.1038/mt.2009.160. PMID 19623162. 
  30. ↑ Lentacker, Ine; Geers, Bart; Demeester, Jo; De Smedt, Stefaan C.; Sanders, Niek N. (November 2010). "Tumor cell killing efficiency of doxorubicin loaded microbubbles after ultrasound exposure" (in en). Journal of Controlled Release 148 (1): e113–e114. doi:10.1016/j.jconrel.2010.07.085. PMID 21529584. 
  31. ↑ Gong, Yuping; Wang, Zhigang; Dong, Guifang; Sun, Yang; Wang, Xi; Rong, Yue; Li, Maoping; Wang, Dong et al. (2014-11-04). "Low-intensity focused ultrasound mediated localized drug delivery for liver tumors in rabbits" (in en). Drug Delivery 23 (7): 2280–2289. doi:10.3109/10717544.2014.972528. ISSN 1071-7544. PMID 25367869. 
  32. ↑ Lee; Moon; Han; Lee; Kim; Lee; Ha; Kim et al. (2019-04-24). "Antitumor Effects of Intra-Arterial Delivery of Albumin-Doxorubicin Nanoparticle Conjugated Microbubbles Combined with Ultrasound-Targeted Microbubble Activation on VX2 Rabbit Liver Tumors" (in en). Cancers 11 (4): 581. doi:10.3390/cancers11040581. ISSN 2072-6694. PMID 31022951. 
  33. ↑ Ha, Shin-Woo; Hwang, Kihwan; Jin, Jun; Cho, Ae-Sin; Kim, Tae Yoon; Hwang, Sung Il; Lee, Hak Jong; Kim, Chae-Yong (2019-05-24). "Ultrasound-sensitizing nanoparticle complex for overcoming the blood-brain barrier: an effective drug delivery system" (in English). International Journal of Nanomedicine 14: 3743–3752. doi:10.2147/ijn.s193258. PMID 31213800. 
  34. ↑ Liufu, Chun; Li, Yue; Tu, Jiawei; Zhang, Hui; Yu, Jinsui; Wang, Yi; Huang, Pintong; Chen, Zhiyi (2019-11-15). "Echogenic PEGylated PEI-Loaded Microbubble As Efficient Gene Delivery System" (in English). International Journal of Nanomedicine 14: 8923–8941. doi:10.2147/ijn.s217338. PMID 31814720. 
  35. ↑ 35.0 35.1 Wrenn, Steven; Dicker, Stephen; Small, Eleanor; Mleczko, Michal (September 2009). "Controlling cavitation for controlled release". 2009 IEEE International Ultrasonics Symposium. Rome: IEEE. pp. 104–107. doi:10.1109/ULTSYM.2009.5442045. ISBN 978-1-4244-4389-5. 
  36. ↑ 36.0 36.1 Ibsen, Stuart; Benchimol, Michael; Simberg, Dmitri; Schutt, Carolyn; Steiner, Jason; Esener, Sadik (November 2011). "A novel nested liposome drug delivery vehicle capable of ultrasound triggered release of its payload" (in en). Journal of Controlled Release 155 (3): 358–366. doi:10.1016/j.jconrel.2011.06.032. PMID 21745505. 
  37. ↑ Rychak, Joshua J.; Klibanov, Alexander L. (June 2014). "Nucleic acid delivery with microbubbles and ultrasound" (in en). Advanced Drug Delivery Reviews 72: 82–93. doi:10.1016/j.addr.2014.01.009. PMID 24486388. 
  38. ↑ Meng, Lingwu; Yuan, Shaofei; Zhu, Linjia; ShangGuan, Zongxiao; Zhao, Renguo (2019-09-13). "Ultrasound-microbubbles-mediated microRNA-449a inhibits lung cancer cell growth via the regulation of Notch1" (in English). OncoTargets and Therapy 12: 7437–7450. doi:10.2147/ott.s217021. PMID 31686849. 
  39. ↑ Wang, Xiaowei; Searle, Amy; Hohmann, Jan David; Liu, Leo; Abraham, Meike; Palasubramaniam, Jathushan; Lim, Bock; Yao, Yu et al. (July 2017). "Dual-Targeted Theranostic Delivery of miRs Arrests Abdominal Aortic Aneurysm Development" (in en). Molecular Therapy 26 (4): 1056–1065. doi:10.1016/j.ymthe.2018.02.010. PMID 29525742. 
  40. ↑ Cai, Junhong; Huang, Sizhe; Yi, Yuping; Bao, Shan (May 2019). "Ultrasound microbubble-mediated CRISPR/Cas9 knockout of C-erbB-2 in HEC-1A cells" (in en). Journal of International Medical Research 47 (5): 2199–2206. doi:10.1177/0300060519840890. ISSN 0300-0605. PMID 30983484. 
  41. ↑ Zhao, Ranran; Liang, Xiaolong; Zhao, Bo; Chen, Min; Liu, Renfa; Sun, Sujuan; Yue, Xiuli; Wang, Shumin (August 2018). "Ultrasound assisted gene and photodynamic synergistic therapy with multifunctional FOXA1-siRNA loaded porphyrin microbubbles for enhancing therapeutic efficacy for breast cancer" (in en). Biomaterials 173: 58–70. doi:10.1016/j.biomaterials.2018.04.054. PMID 29758547. 
  42. ↑ Abraham, Meike; Peter, Karlheinz; Michel, Tatjana; Wendel, Hans; Krajewski, Stefanie; Wang, Xiaowei (April 2017). "Nanoliposomes for safe and efficient therapeutic mRNA delivery: A step toward nanotheranostics in inflammatory and cardiovascular diseases as well as cancer" (in en). Nanotheranostics 1 (2): 154–165. doi:10.7150/ntno.19449. PMID 29071184. 
  43. ↑ Michel, Tatjana; Luft, Daniel; Abraham, Meike; Reinhardt, Sabina; Medinal, Martha; Kurz, Julia; Schaller, Martin; Avci-Adali, Meltem et al. (July 2017). "Cationic Nanoliposomes Meet mRNA: Efficient Delivery of Modified mRNA Using Hemocompatible and Stable Vectors for Therapeutic Applications" (in en). Molecular Therapy Nucleic Acids 8: 459–468. doi:10.1016/j.omtn.2017.07.013. PMID 28918045. 
  44. ↑ Abbott, N. Joan; Patabendige, Adjanie A.K.; Dolman, Diana E.M.; Yusof, Siti R.; Begley, David J. (January 2010). "Structure and function of the blood–brain barrier" (in en). Neurobiology of Disease 37 (1): 13–25. doi:10.1016/j.nbd.2009.07.030. PMID 19664713. 
  45. ↑ Bakay, L. (1956-11-01). "Ultrasonically Produced Changes in the Blood-Brain Barrier" (in en). Archives of Neurology and Psychiatry 76 (5): 457–67. doi:10.1001/archneurpsyc.1956.02330290001001. ISSN 0096-6754. PMID 13371961. 
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  48. ↑ "A Study to Evaluate the Safety of Transient Opening of the Blood-Brain Barrier by Low Intensity Pulsed Ultrasound With the SonoCloud Implantable Device in Patients With Recurrent Glioblastoma Before Chemotherapy Administration". October 10, 2018. https://clinicaltrials.gov/ct2/show/NCT02253212. 
  49. ↑ Escoffre, Jean-Michel; Deckers, Roel; Bos, Clemens; Moonen, Chrit (2016), Escoffre, Jean-Michel; Bouakaz, Ayache, eds., "Bubble-Assisted Ultrasound: Application in Immunotherapy and Vaccination", Therapeutic Ultrasound (Springer International Publishing) 880: pp. 243–261, doi:10.1007/978-3-319-22536-4_14, ISBN 978-3-319-22535-7, PMID 26486342 
  50. ↑ 50.0 50.1 Liu, Hao-Li; Hsieh, Han-Yi; Lu, Li-An; Kang, Chiao-Wen; Wu, Ming-Fang; Lin, Chun-Yen (2012). "Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response" (in en). Journal of Translational Medicine 10 (1): 221. doi:10.1186/1479-5876-10-221. ISSN 1479-5876. PMID 23140567. 
  51. ↑ Shi, Guilian; Zhong, Mingchuan; Ye, Fuli; Zhang, Xiaoming (November 2019). "Low-frequency HIFU induced cancer immunotherapy: tempting challenges and potential opportunities". Cancer Biology & Medicine 16 (4): 714–728. doi:10.20892/j.issn.2095-3941.2019.0232. ISSN 2095-3941. PMID 31908890. 
  52. ↑ Sta Maria, Naomi S.; Barnes, Samuel R.; Weist, Michael R.; Colcher, David; Raubitschek, Andrew A.; Jacobs, Russell E. (2015-11-10). Mondelli, Mario U.. ed. "Low Dose Focused Ultrasound Induces Enhanced Tumor Accumulation of Natural Killer Cells" (in en). PLOS ONE 10 (11): e0142767. doi:10.1371/journal.pone.0142767. ISSN 1932-6203. PMID 26556731. Bibcode: 2015PLoSO..1042767S. 
  53. ↑ Suzuki, Ryo; Oda, Yusuke; Omata, Daiki; Nishiie, Norihito; Koshima, Risa; Shiono, Yasuyuki; Sawaguchi, Yoshikazu; Unga, Johan et al. (March 2016). "Tumor growth suppression by the combination of nanobubbles and ultrasound" (in en). Cancer Science 107 (3): 217–223. doi:10.1111/cas.12867. PMID 26707839. 
  54. ↑ Lin, Win-Li; Lin, Chung-Yin; Tseng, Hsiao-Ching; Shiu, Heng-Ruei; Wu, Ming-Fang (April 2012). "Ultrasound sonication with microbubbles disrupts blood vessels and enhances tumor treatments of anticancer nanodrug" (in en). International Journal of Nanomedicine 7: 2143–52. doi:10.2147/IJN.S29514. ISSN 1178-2013. PMID 22619550. 

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