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| Mechanisms and Research Progress of Low-Intensity Ultrasound in Drug Delivery |
| Zhu Wenwu*, Yang Hui, Hu Kai, Yan Guofei, Wang Fan |
| (Evaluation Center of Medical Device of Zhejiang Province, Hangzhou 310000, China) |
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Abstract Noninvasive low-intensity ultrasound (LIUS) has been applied in multiple fields of clinical therapy and widely investigated and discussed due to its excellent therapeutic outcome. Recently, researches on LIUS in promoting drug delivery in many applications have been booming, covering multiple drug delivery scenarios and application directions, including transdermal drug delivery (sonophoresis), sonodynamic therapy, and brain blood barrier (BBB) opening. This article delves into mechanisms of LIUS from above three perspectives, covering many biophysical effects including thermal effect, cavitation effect, mechanical effect, and physiological regulatory effect, with particular emphasis on the importance of local cavitation and mechanical effects. In addition, this article highlights the effectiveness of LIUS in drug delivery, while also points out issues that need to be further addressed, such as controllability of drug release and safety of clinical treatment. Domestic and foreign studies have shown that the combined application of ultrasound and nanomaterials has enormous potential. In the future, combining ultrasound with nanomaterials and other technologies is expected to lead to innovative development in the field of drug delivery and provide more effective treatment plans for clinical treatment.
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Received: 05 May 2022
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Corresponding Authors:
*E-mail: cool.wenwu@QQ.com
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[1] Wood AK, Sehgal CM. A review of low-intensity ultrasound for cancer therapy[J]. Ultrasound in Medicine & Biology, 2015, 41(4): 905-928.
[2] Mitragotri S, Blankschtein D, Langer R. Ultrasound-mediated transdermal protein delivery[J]. Science, 1995, 269(5225): 850-853.
[3] Sirsi SR, Borden MA. State-of-the-art materials for ultrasound-triggered drug delivery[J]. Advanced Drug Delivery Reviews, 2014, 72: 3-14.
[4] Ahmed MH, Hernández-Verdin I, Quissac E, et al. Low-intensity pulsed ultrasound-mediated blood-brain barrier opening increases anti-programmed death-ligand 1 delivery and efficacy in gl261 mouse model[J]. Pharmaceutics, 2023, 15(2): 455.
[5] Azagury A, Khoury L, Enden G, et al. Ultrasound mediated transdermal drug delivery[J]. Advanced Drug Delivery Reviews, 2014, 72: 127-143.
[6] Tawfik MA, Tadros MI, Mohamed MI, et al. Low-frequency versus high-frequency ultrasound-mediated transdermal delivery of agomelatine-loaded invasomes: development, optimization and in-vivo pharmacokinetic assessment[J]. International Journal of Nanomedicine, 2020: 8893-8910.
[7] Park D, Song G, Jo Y, et al. Sonophoresis using ultrasound contrast agents: dependence on concentration[J]. PLoS One, 2016, 11(6): e0157707.
[8] Uddin SM, Komatsu DE, Motyka T, et al. Low-intensity continuous ultrasound therapies-a systematic review of current state-of-the-art and future perspectives[J]. Journal of Clinical Medicine, 2021, 10(12): 2698.
[9] Park D, Won J, Shin U, et al. Transdermal drug delivery using a specialized cavitation seed for ultrasound[J]. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, 2019, 66(6): 1057-1064.
[10] Robertson J, Squire M, Becker S. Circulation cooling in continuous skin sonoporation at constant coupling fluid temperatures[J]. Ultrasound in Medicine & Biology, 2020, 46(1): 137-148.
[11] Polat BE, Figueroa PL, Blankschtein D, et al. Transport pathways and enhancement mechanisms within localized and non-localized transport regions in skin treated with low-frequency sonophoresis and sodium lauryl sulfate[J]. Journal of Pharmaceutical Sciences, 2011, 100(2): 512-529.
[12] Krasovitski B, Frenkel V, Shoham S, et al. Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects[J]. Proceedings of the National Academy of Sciences, 2011, 108(8): 3258-3263.
[13] Madzia A, Agrawal C, Jarit P, et al. Sustained acoustic medicine combined with a diclofenac ultrasound coupling patch for the rapid symptomatic relief of knee osteoarthritis: Multi-site clinical efficacy study[J]. The Open Orthopaedics Journal, 2020, 14: 176.
[14] Krishnan G, Grice JE, Roberts MS, et al. Enhanced sonophoretic delivery of 5-aminolevulinic acid: Preliminary human ex vivo permeation data[J]. Skin Research and Technology, 2013, 19(1): e283-e289.
[15] Ita K, Ashong S. Percutaneous delivery of antihypertensive agents: Advances and challenges[J]. AAPS PharmSciTech, 2020, 21(2): 56.
[16] Zhai Haojie, Zhang Chi, Ou Huilong, et al. Transdermal delivery of heparin using low-frequency sonophoresis in combination with sponge spicules for venous thrombosis treatment[J]. Biomaterials Science, 2021, 9(16): 5612-5625.
[17] Bhatnagar S, Kwan JJ, Shah AR, et al. Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines[J]. Journal of Controlled Release, 2016, 238: 22-30.
[18] Lecomte MM, Atkinson KR, Kay DP, et al. A modified method using the sonoprep® ultrasonic skin permeation system for sampling human interstitial fluid is compatible with proteomic techniques[J]. Skin Research and Technology, 2013, 19(1): 27-34.
[19] Skarbek-Borowska S, Becker BM, Lovgren K, et al. Brief focal ultrasound with topical anesthetic decreases the pain of intravenous placement in children[J]. Pediatric Emergency Care, 2006, 22(5): 339-345.
[20] Huang Da, Sun Mi, Bu Yazhong, et al. Microcapsule-embedded hydrogel patches for ultrasound responsive and enhanced transdermal delivery of diclofenac sodium[J]. Journal of Materials Chemistry B, 2019, 7(14): 2330-2337.
[21] Brotchie A, Mettin R, Grieser F, et al. Cavitation activation by dual-frequency ultrasound and shock waves[J]. Physical Chemistry Chemical Physics, 2009, 11(43): 10029-10034.
[22] Liao Aiho, Lin Kenghsien, Chuang Hochiao, et al. Low-frequency dual-frequency ultrasound-mediated microbubble cavitation for transdermal minoxidil delivery and hair growth enhancement[J]. Scientific Reports, 2020, 10(1): 4338.
[23] Park D, Ryu H, Kim HS, et al. Sonophoresis using ultrasound contrast agents for transdermal drug delivery: an in vivo experimental study[J]. Ultrasound in Medicine & Biology, 2012, 38(4): 642-650.
[24] Zhang Ding, Chen Boqi, Mu Qingke, et al. Topical delivery of gambogic acid assisted by the combination of low-frequency ultrasound and chemical enhancers for chemotherapy of cutaneous melanoma[J]. European Journal of Pharmaceutical Sciences, 2021, 166: 105975.
[25] Tokumoto S, Higo N, Todo H, et al. Effect of combination of low-frequency sonophoresis or electroporation with iontophoresis on the mannitol flux or electroosmosis through excised skin[J]. Biological and Pharmaceutical Bulletin, 2016, 39(7): 1206-1210.
[26] Park J, Lee H, Lim GS, et al. Enhanced transdermal drug delivery by sonophoresis and simultaneous application of sonophoresis and iontophoresis[J]. AAPS PharmSciTech, 2019, 20: 1-7.
[27] Dumitriu Buzia O, P?duraru AM, Stefan CS, et al. Strategies for improving transdermal administration: new approaches to controlled drug release[J]. Pharmaceutics, 2023, 15(4): 1183.
[28] Son Subin, Kim Ji Hyeon, Wang Xianwen, et al. Multifunctional sonosensitizers in sonodynamic cancer therapy[J]. Chemical Society Reviews, 2020, 49(11): 3244-3261.
[29] Canavese G, Ancona A, Racca L, et al. Nanoparticle-assisted ultrasound: a special focus on sonodynamic therapy against cancer[J]. Chemical Engineering Journal, 2018, 340: 155-172.
[30] Choi V, Rajora MA, Gang Zheng. Activating drugs with sound: Mechanisms behind sonodynamic therapy and the role of nanomedicine[J]. Bioconjugate Chemistry, 2020, 31(4): 967-989.
[31] Umemura Si, Yumita N, Nishigaki R, et al. Mechanism of cell damage by ultrasound in combination with hematoporphyrin[J]. Japanese Journal of Cancer Research, 1990, 81(9): 962-966.
[32] Kwan JJ, Myers R, Coviello CM, et al. Ultrasound-propelled nanocups for drug delivery[J]. Small, 2015, 11(39): 5305-5314.
[33] Liang Shuang, Deng Xiaoran, Ma Pingan, et al. Recent advances in nanomaterial-assisted combinational sonodynamic cancer therapy[J]. Advanced Materials, 2020, 32(47): 2003214.
[34] Hao Dongning, Song Yanbin, Che Zhen, et al. Calcium overload and in vitro apoptosis of the c6 glioma cells mediated by sonodynamic therapy (hematoporphyrin monomethyl ether and ultrasound)[J]. Cell Biochemistry and Biophysics, 2014, 70(2): 1445-1452.
[35] Dai Shaochun, Xu Changqing, Tian Ye, et al. In vitro stimulation of calcium overload and apoptosis by sonodynamic therapy combined with hematoporphyrin monomethyl ether in c6 glioma cells[J]. Oncology Letters, 2014, 8(4): 1675-1681.
[36] Li Enze, Sun Yi, Lv Guixiang, et al. Sinoporphyrin sodium based sonodynamic therapy induces anti-tumor effects in hepatocellular carcinoma and activates p53/caspase 3 axis[J]. The International Journal of Biochemistry & Cell Biology, 2019, 113: 104-114.
[37] Sun Duo, Pang Xin, Cheng Yi, et al. Ultrasound-switchable nanozyme augments sonodynamic therapy against multidrug-resistant bacterial infection[J]. ACS Nano, 2020, 14(2): 2063-2076.
[38] Liu Bin, Wang Dongjing, Liu Bingmi, et al. The influence of ultrasound on the fluoroquinolones antibacterial activity[J]. Ultrasonics Sonochemistry, 2011, 18(5): 1052-1056.
[39] Zhu Shuang, Wang Deqiang, Sun Xuehua, et al. Mitochondria-targeted degradable nanocomposite combined with laser and ultrasound for synergistic tumor therapies[J]. Journal of Biomedical Nanotechnology, 2022, 18(3): 763-777.
[40] Wang Lei, Niu Mengya, Zheng Cuixia, et al. A core–shell nanoplatform for synergistic enhanced sonodynamic therapy of hypoxic tumor via cascaded strategy[J]. Advanced Healthcare Materials, 2018, 7(22): 1800819.
[41] Bosca F, Foglietta F, Gimenez A, et al. Exploiting lipid and polymer nanocarriers to improve the anticancer sonodynamic activity of chlorophyll[J]. Pharmaceutics, 2020, 12(7): 605.
[42] Canaparo R, Varchi G, Ballestri M, et al. Polymeric nanoparticles enhance the sonodynamic activity of meso-tetrakis (4-sulfonatophenyl) porphyrin in an in vitro neuroblastoma model[J]. International Journal of Nanomedicine, 2013: 4247-4263.
[43] Zhang Peixia, Zhang Lu, Wang Jun, et al. An intelligent hypoxia-relieving chitosan-based nanoplatform for enhanced targeted chemo-sonodynamic combination therapy on lung cancer[J]. Carbohydrate Polymers, 2021, 274: 118655.
[44] Li Cheng, Yang Xiaoquan, An Jie, et al. Red blood cell membrane-enveloped o2 self-supplementing biomimetic nanoparticles for tumor imaging-guided enhanced sonodynamic therapy[J]. Theranostics, 2020, 10(2): 867-879.
[45] Zhang Cong, Xin Lei, Li Jia, et al. Metal–organic framework (mof)-based ultrasound-responsive dual-sonosensitizer nanoplatform for hypoxic cancer therapy[J]. Advanced Healthcare Materials, 2022, 11(2): 2101946.
[46] Kayani Z, Vais RD, Soratijahromi E, et al. Curcumin-gold-polyethylene glycol nanoparticles as a nanosensitizer for photothermal and sonodynamic therapies: In vitro and animal model studies[J]. Photodiagnosis and Photodynamic Therapy, 2021, 33: 102139.
[47] Nguyen TL, Katayama R, Kojima C, et al. Singlet oxygen generation by sonication using a water-soluble fullerene (c60) complex: a potential application for sonodynamic therapy[J]. Polymer Journal, 2020, 52(12): 1387-1394.
[48] Pan Xueting, Bai Lixin, Wang Hui, et al. Metal–organic-framework-derived carbon nanostructure augmented sonodynamic cancer therapy[J]. Advanced Materials, 2018, 30(23): 1800180.
[49] Huang Ju, Liu Fengqiu, Han Xiaoxia, et al. Nanosonosensitizers for highly efficient sonodynamic cancer theranostics[J]. Theranostics, 2018, 8(22): 6178-6194.
[50] Canaparo R, Foglietta F, Limongi T, et al. Biomedical applications of reactive oxygen species generation by metal nanoparticles[J]. Materials, 2020, 14(1): 53.
[51] Gong Fei, Cheng Liang, Yang Nailin, et al. Ultrasmall oxygen-deficient bimetallic oxide mnwox nanoparticles for depletion of endogenous gsh and enhanced sonodynamic cancer therapy[J]. Advanced Materials, 2019, 31(23): 1900730.
[52] He Xiaojun, Hou Jiting, Sun Xiaoshuai, et al. Nir-ii photo-amplified sonodynamic therapy using sodium molybdenum bronze nanoplatform against subcutaneous staphylococcus aureus infection[J]. Advanced Functional Materials, 2022, 32(38): 2203964.
[53] Ren Qian, Yu Nuo, Wang Leyi, et al. Nanoarchitectonics with metal-organic frameworks and platinum nanozymes with improved oxygen evolution for enhanced sonodynamic/chemo-therapy[J]. Journal of Colloid and Interface Science, 2022, 614: 147-159.
[54] Liu Yang, Wan Guoyun, Guo Hua, et al. A multifunctional nanoparticle system combines sonodynamic therapy and chemotherapy to treat hepatocellular carcinoma[J]. Nano Research, 2017, 10: 834-855.
[55] Jia Lu, Wang Yuzhu, Hu Tingting, et al. Boosting the tumor photothermal therapy with hollow cosnsx-based injectable hydrogel via the sonodynamic and dual-gas therapy[J]. Chemical Engineering Journal, 2023: 143969.
[56] Wang Xianwen, Wang Xiyu, Yue Qingfen, et al. Liquid exfoliation of tin nanodots as novel sonosensitizers for photothermal-enhanced sonodynamic therapy against cancer[J]. Nano Today, 2021, 39: 101170.
[57] Wang Ting, Peng Wangrui, Du Meng, et al. Immunogenic sonodynamic therapy for inducing immunogenic cell death and activating antitumor immunity[J]. Frontiers in Oncology, 2023, 13: 1167105.
[58] Wang Meifang, Hou Zhiyao, Liu Sainan, et al. A multifunctional nanovaccine based on l-arginine-loaded black mesoporous titania: ultrasound-triggered synergistic cancer sonodynamic therapy/gas therapy/immunotherapy with remarkably enhanced efficacy[J]. Small, 2021, 17(6): 2005728.
[59] Hong Liang, Pliss AM, Zhan Ye, et al. Perfluoropolyether nanoemulsion encapsulating chlorin e6 for sonodynamic and photodynamic therapy of hypoxic tumor[J]. Nanomaterials, 2020, 10(10): 2058.
[60] Lin Xiahui, Liu Shuya, Zhang Xuan, et al. An ultrasound activated vesicle of janus au-mno nanoparticles for promoted tumor penetration and sono-chemodynamic therapy of orthotopic liver cancer[J]. Angewandte Chemie, 2020, 132(4): 1699-1705.
[61] An Jie, Hu Yongguo, Li Cheng, et al. A ph/ultrasound dual-response biomimetic nanoplatform for nitric oxide gas-sonodynamic combined therapy and repeated ultrasound for relieving hypoxia[J]. Biomaterials, 2020, 230: 119636.
[62] Zhang Yang, Xu Yanjun, Sun Di, et al. Hollow magnetic nanosystem-boosting synergistic effect between magnetic hyperthermia and sonodynamic therapy via modulating reactive oxygen species and heat shock proteins[J]. Chemical Engineering Journal, 2020, 390: 124521.
[63] Zhang Yi, Zhang Xiangqian, Yang Huocheng, et al. Advanced biotechnology-assisted precise sonodynamic therapy[J]. Chemical Society Reviews, 2021, 50(20): 11227-11248.
[64] Aryal M, Arvanitis CD, Alexander PM, et al. Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system[J]. Advanced Drug Delivery Reviews, 2014, 72: 94-109.
[65] Arvanitis CD, Ferraro GB, Jain RK. The blood–brain barrier and blood–tumour barrier in brain tumours and metastases[J]. Nature Reviews Cancer, 2020, 20(1): 26-41.
[66] Bunevicius A, McDannold NJ, Golby AJ. Focused ultrasound strategies for brain tumor therapy[J]. Operative Neurosurgery, 2020, 19(1): 9.
[67] Beccaria K, Canney M, Bouchoux G, et al. Ultrasound-induced blood-brain barrier disruption for the treatment of gliomas and other primary cns tumors[J]. Cancer Letters, 2020, 479: 13-22.
[68] Aryal M, Fischer K, Gentile C, et al. Effects on p-glycoprotein expression after blood-brain barrier disruption using focused ultrasound and microbubbles[J]. PLoS ONE, 2017, 12(1): e0166061.
[69] Beccaria K, Sabbagh A, de Groot J, et al. Blood–brain barrier opening with low intensity pulsed ultrasound for immune modulation and immune therapeutic delivery to cns tumors[J]. Journal of Neuro-Oncology, 2021, 151: 65-73.
[70] Yang Yanye, Li Qunying, Guo Xiasheng, et al. Mechanisms underlying sonoporation: Interaction between microbubbles and cells[J]. Ultrasonics Sonochemistry, 2020, 67: 105096.
[71] Lionetti V, Fittipaldi A, Agostini S, et al. Enhanced caveolae-mediated endocytosis by diagnostic ultrasound in vitro[J]. Ultrasound in Medicine & Biology, 2009, 35(1): 136-143.
[72] Jameel A, Bain P, Nandi D, et al. Device profile of exablate neuro 4000, the leading system for brain magnetic resonance guided focused ultrasound technology: an overview of its safety and efficacy in the treatment of medically refractory essential tremor[J]. Expert Review of Medical Devices, 2021, 18(5): 429-437.
[73] Mainprize T, Lipsman N, Yuexi Huang, et al. Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study[J]. Scientific Reports, 2019, 9(1): 321.
[74] Carpentier A, Canney M, Vignot A, et al. Clinical trial of blood-brain barrier disruption by pulsed ultrasound[J].Science Translational Medicine, 2016, 8(343): 343re342-343re342.
[75] Idbaih A, Ducray F, Stupp R, et al. Ctni-31. Interim results of a phase i/iia study to evaluate the safety and efficacy of BBB opening with the sonocloud-9 implantable ultrasound device in recurrent glioblastoma patients prior to iv carboplatin[J]. Neuro-Oncology, 2020, 22(Supplement_2): ii49-ii49.
[76] Chen Koting, Chai Wenyen, Lin Yajui, et al. Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors[J]. Science Advances, 2021, 7(6): eabd0772.
[77] Chen Koting, Lin Yajui, Chai Wenyen, et al. Neuronavigation-guided focused ultrasound (navifus) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: clinical trial protocol[J]. Annals of Translational Medicine, 2020, 8(11): 673.
[78] Sun Tao, Samiotaki G, Wang Shutao, et al. Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening[J]. Physics in Medicine & Biology, 2015, 60(23): 9079-9094.
[79] Dauba A, Delalande A, Kamimura HA, et al. Recent advances on ultrasound contrast agents for blood-brain barrier opening with focused ultrasound[J]. Pharmaceutics, 2020, 12(11): 1125.
[80] Chen CC, Sheeran PS, Wu SY, et al. Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets[J]. Journal of Controlled Release, 2013, 172(3): 795-804.
[81] Zhang Xiang, Hu Jiangang, Zhao Guanjian, et al. Pegylated plga-based phase shift nanodroplets combined with focused ultrasound for blood brain barrier opening in rats[J]. Oncotarget, 2017, 8(24): 38927.
[82] Fan Chinghsiang, Cheng Yuhang, Ting Chienyu, et al. Ultrasound/magnetic targeting with spio-dox-microbubble complex for image-guided drug delivery in brain tumors[J]. Theranostics, 2016, 6(10): 1542-1556.
[83] Chen Yungchu, Chiang Chifeng, Wu Shengkai, et al. Targeting microbubbles-carrying tgfβ1 inhibitor combined with ultrasound sonication induce bbb/btb disruption to enhance nanomedicine treatment for brain tumors[J]. Journal of Controlled Release, 2015, 211: 53-62.
[84] Curley CT, Mead BP, Negron K, et al. Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection[J]. Science Advances, 2020, 6(18): eaay1344.
[85] Wang Jieqiong, Xie Liting, Shi Yu, et al. Early detection and reversal of cell apoptosis induced by focused ultrasound-mediated blood–brain barrier opening[J]. Acs Nano, 2021, 15(9): 14509-14521.
[86] Fang Yi, Zhang Gaosen, Bai Zhiqun, et al. Low-intensity ultrasound: A novel technique for adjuvant treatment of gliomas[J]. Biomedicine & Pharmacotherapy, 2022, 153: 113394.
[87] Wang Feng, Dong Lei, Liang Simin, et al. Ultrasound-triggered drug delivery for glioma therapy through gambogic acid-loaded nanobubble-microbubble complexes[J]. Biomedicine & Pharmacotherapy, 2022, 150: 113042.
[88] Yin Liang, Qin FH, Zhou Y, et al. Enhancing percutaneous permeability of sinomenine hydrochloride using dual-frequency sonophoresis[J]. Journal of Drug Delivery Science and Technology, 2016, 36: 62-67.
[89] Aldwaikat M, Alarjah M. Investigating the sonophoresis effect on the permeation of diclofenac sodium using 3d skin equivalent[J]. Ultrasonics Sonochemistry, 2015, 22: 580-587.
[90] Seah BCQ, Teo BM. Recent advances in ultrasound-based transdermal drug delivery[J]. International Journal of Nanomedicine, 2018: 7749-7763.
[91] Zhang Yuqi, Yu Jicheng, Kahkoska AR, et al. Advances in transdermal insulin delivery[J]. Advanced Drug Delivery Reviews, 2019, 139: 51-70.
[92] Snook KA, Robert Van Ess I, Werner JR, et al. Transdermal delivery of enfuvirtide in a porcine model using a low-frequency, low-power ultrasound transducer patch[J]. Ultrasound in Medicine & Biology, 2019, 45(2): 513-525.
[93] Soto F, Jeerapan I, Silva-López C, et al. Noninvasive transdermal delivery system of lidocaine using an acoustic droplet-vaporization based wearable patch[J]. Small, 2018, 14(49): 1803266.
[94] Daffertshofer M, Gass A, Ringleb P, et al. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: Increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: Results of a phase ii clinical trial[J]. Stroke, 2005, 36(7): 1441-1446.
[95] Kovacs ZI, Kim S, Jikaria N, et al. Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation[J]. Proceedings of the National Academy of Sciences, 2017, 114(1): E75-E84.
[96] Meng Ying, Pople CB, Lea-Banks H, et al. Safety and efficacy of focused ultrasound induced blood-brain barrier opening, an integrative review of animal and human studies[J]. Journal of Controlled Release, 2019, 309: 25-36. |
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