缺血性中風藉由溶栓使血液再度流通來治療。當血液再灌注於缺血組織時，會產生大量活性氧對細胞與神經造成損傷，此損傷稱為缺血性中風再灌注(IR)損傷。現今治療IR損傷以各式神經保護劑、血管擴張劑與高壓氧治療，來抑制細胞凋亡並提升組織氧含量。但此種全身性治療，可能造成系統性的副作用，減少治療部位之藥物累積量。聚焦式超音波搭配微氣泡(MB)已被廣泛運用於腦部局部治療。微氣泡可在腦部複雜細小的血管中穿梭，受到超音波刺激後產生穴蝕效應，並釋放出搭載在微氣泡上的藥物或氣體，達到局部治療的效果。因此，本研究使用微氣泡搭載氧氣(OMB)，在IR受損區域進行局部給氧的治療，以調控炎症與凋亡因子，降低梗塞區域並保護神經。小鼠以光血栓產生腦中風，接著搭配溶血栓劑，形成小鼠IR損傷模型。OMB經靜脈注射後，將聚焦式超音波(1-MHz，300 kPa，1000 cycle，PRF 1 Hz)置於腦部IR受損區域，刺激OMB產生穴蝕效應並釋放氧氣。相較於未治療的對照組，OMB治療能提升小鼠腦部血管氧分壓10±2% (19±4 mmHg)，梗塞面積再治療1、7、14天後，分別減少了2.5±0.2、2.4±0.2、9.4±4.7倍。藉由組織切片染色分析，OMB治療後可提升M2抗炎型態的小膠質細胞、神經元與星狀膠質的分布，並減少M1促炎型態的小膠質細胞數量。藉由蛋白質與mRNA表現量的檢測，發現OMB治療後，可減少促炎因子（HIF-1α、NF-κB、MMP-9）的表現，並提升抗炎、抗凋亡因子（Bcl-2、BDNF）的表現。此外，因OMB穴蝕作用增加的血管內皮剪切力，可促進血管舒張因子（eNOS）的活化，避免二次血栓的發生。本研究證明使用OMB搭配超音波可局部釋放氧氣，抑制炎症與凋亡反應，藉此保護神經與減少腦梗塞面積，治療IR損傷。

Ischemic stroke is treated by thrombolysis to let blood reperfusion, however, which would generate a lot of reactive oxygen species at reperfused site to damage cells and neurons, known as ischemic stroke-reperfusion (IR) injury. To prevent IR injury, neuron protect agents, vasodilators, and hyperbaric oxygen therapy are applied to reduce cell apoptosis and enhance tissue oxygenation. Nevertheless, this systemic therapy might reduce drug accumulation at target site and cause systemic side effects. Focused ultrasound with microbubbles has been widely applied in the local brain therapy. During ultrasound stimulation, the intravascular microbubbles start to cavitate and release the drugs or gas which be carried by microbubbles for accomplishing the local triggered therapy. Hence, our study used oxygen-loaded microbubbles (OMB) with focused ultrasound to process local oxygen therapy for preventing IR injury. The mice IR model was produced via photothrombosis and thrombolysis. After intravenous injection of OMBs, the local cavitation effect and oxygen release at IR sites were triggered by focused ultrasound (1-MHz, 300 kPa, 1000 cycle, PRF 1 Hz). Relative to the untreated control group, OMB treatment enhanced 10±2% partial oxygen pressure (19±4 mmHg) at IR site. The size of brain infarct reduced 2.5±0.2, 2.4±0.2, 9.4±4.7 folds after OMB treatment 1, 7, 14 days, respectively. Histological assessment revealed the increase in M2 microglia (anti-inflammatory type), neuron, and astrocyte distribution, and decrease in M1 microglia (inflammatory type)after OMB treatment. The protein and mRNA expressions were evaluated to show the high level in anti-inflammatory and anti-apoptotic factors (Bcl-2, BDNF), and low level in inflammatory factors (HIF-1α、NF-κB、MMP-9). Moreover, the vascular endothelial shear stress enhanced by OMB cavitation also promoted the activation of eNOS to induce vasodilation for avoiding secondary thrombosis. Our study demonstrated that the use of OMB combined with focused ultraosund can locally release oxygen to inhibit inflammatory and apoptotic responses, thereby protecting neuron and reducing infarct size for preveting IR injury.

摘要 i
Abstract ii
誌謝 iv
目錄 v
圖目錄 viii
表目錄 x
第 1 章 緒論 1
1.1 缺血性中風再灌注損傷 1
1.1.1 缺血性中風與治療 1
1.1.2缺血性中風再灌注損傷 3
1.2缺血再灌注損傷之治療途徑 6
1.2.1神經藥物治療 6
1.2.2高壓氧治療 8
1.2.3目前缺血性中風再灌注損傷之治療困境 9
1.3超音波 10
1.3.1超音波顯影劑微氣泡 10
1.3.2微氣泡於缺血再灌注損傷之應用 11
1.3.3帶氧氣微氣泡之應用 13
1.4研究目的與內容 14
第2章 材料與方法 15
2.1緒論 15
2.2微氣泡之製備 15
2.2.1帶氧微氣泡製備 15
2.2.2粒徑量測 18
2.2.3體外穩定性量測 18
2.2.4微氣泡擊破閥值量測 20
2.2.5穴蝕效應劑量量測 22
2.2.6氧分壓量測 25
2.3小鼠腦部缺血性中風再灌注損傷模型 27
2.3.1缺血性中風模型 27
2.3.2缺血性中風再灌注模型 29
2.3.3帶微氣泡治療之安全性測試 29
2.3.4帶氧微氣泡治療流程 31
2.4動物行為測試 32
2.4.1 獨木橋試驗 32
2.4.2 線掛測試 32
2.4.3梗塞面積染色 33
2.5帶氧微氣泡治療之生理機制調控 34
2.5.1免疫組織化學染色 34
2.5.2酵素結合免疫吸附分析法 36
2.5.3定量即時聚合酶鏈鎖反應 38
2.6治療時間點之調控 41
2.7統計分析 42
第3章 結果與討論 43
3.1帶氧微氣泡物理特性分析 43
3.1.1粒徑分析 43
3.1.2體外穩定性 44
3.1.3微氣泡擊破閥值 45
3.1.4 ICD、SCD分析 46
3.1.5氧分壓測試 48
3.2小鼠腦部缺血再灌注損傷模型與治療 50
3.2.1缺血性中風模型血流血氧與梗塞面積變化 50
3.2.2缺血再灌注損傷模型血流血氧與梗塞面積變化 53
3.2.3帶氧微氣泡治療參數安全性測試 55
3.2.4帶氧微氣泡治療結果 56
3.3梗塞區域與動物行為追蹤 59
3.3.1獨木橋試驗之分析 59
3.3.2線掛測試之分析 60
3.3.3長時間梗塞面積變化 62
3.4治療缺血再灌注損傷組織相關因子分析 64
3.4.1細胞分布 64
3.4.2蛋白質表現量 67
3.4.3 mRNA表現量 69
3.5調控治療時間點之梗塞面積變化 71
第4章 結論與未來工作 72
4.1結論 72
4.2未來應用與發展 73
參考文獻 75

[1] E. H. Lo, T. Dalkara, and M. A. Moskowitz, "Mechanisms, challenges and opportunities in stroke," Nat Rev Neurosci, vol. 4, no. 5, pp. 399-415, May 2003, doi: 10.1038/nrn1106.
[2] S. S. Virani et al., "Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association," Circulation, vol. 141, no. 9, pp. e139-e596, Mar 3 2020, doi: 10.1161/CIR.0000000000000757.
[3] C. Lewandowski and W. Barsan, "Treatment of acute ischemic stroke," Annals of emergency medicine, vol. 37, no. 2, pp. 202-216, 2001.
[4] S. M. Allan and N. J. Rothwell, "Cytokines and acute neurodegeneration," Nature Reviews Neuroscience, vol. 2, no. 10, pp. 734-744, 2001.
[5] S. S. Rathore, A. R. Hinn, L. S. Cooper, H. A. Tyroler, and W. D. Rosamond, "Characterization of incident stroke signs and symptoms: findings from the atherosclerosis risk in communities study," Stroke, vol. 33, no. 11, pp. 2718-2721, 2002.
[6] J. R. Shiber, E. Fontane, and A. Adewale, "Stroke registry: hemorrhagic vs ischemic strokes," The American journal of emergency medicine, vol. 28, no. 3, pp. 331-333, 2010.
[7] D. Barthels and H. Das, "Current advances in ischemic stroke research and therapies," Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, vol. 1866, no. 4, p. 165260, 2020.
[8] Y. Liu et al., "Cerebral hemodynamics in human acute ischemic stroke: a study with diffusion-and perfusion-weighted magnetic resonance imaging and SPECT," Journal of Cerebral Blood Flow & Metabolism, vol. 20, no. 6, pp. 910-920, 2000.
[9] W. Jiang, W. Gu, K.-A. Hossmann, G. Mies, and P. Wester, "Establishing a photothrombotic ‘ring’stroke model in adult mice with late spontaneous reperfusion: quantitative measurements of cerebral blood flow and cerebral protein synthesis," Journal of Cerebral Blood Flow & Metabolism, vol. 26, no. 7, pp. 927-936, 2006.
[10] C. Hui, P. Tadi, and L. Patti, "Ischemic stroke," in StatPearls [Internet]: StatPearls Publishing, 2022.
[11] P. Tadi and F. Lui, "Acute stroke," 2018.
[12] B. Eckert, "Acute stroke therapy 1981–2009," Clinical Neuroradiology, vol. 19, no. 1, pp. 8-19, 2009.
[13] S. N. Chapman, P. Mehndiratta, M. C. Johansen, T. L. McMurry, K. C. Johnston, and A. M. Southerland, "Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke," Vascular health and risk management, vol. 10, p. 75, 2014.
[14] J. L. Frey, "Recombinant tissue plasminogen activator (rtpa) for stroke: The perspective at 8 years," The Neurologist, vol. 11, no. 2, pp. 123-133, 2005.
[15] J. L. Saver, "Time is brain—quantified," Stroke, vol. 37, no. 1, pp. 263-266, 2006.
[16] T. Fukuta et al., "Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke," The FASEB Journal, vol. 31, no. 5, pp. 1879-1890, 2017.
[17] S. E. Tsirka, "Clinical implications of the involvement of tPA in neuronal cell death," Journal of molecular medicine, vol. 75, no. 5, pp. 341-347, 1997.
[18] H. C. Emsley and P. J. Tyrrell, "Inflammation and infection in clinical stroke," Journal of Cerebral Blood Flow & Metabolism, vol. 22, no. 12, pp. 1399-1419, 2002.
[19] P. Deb, S. Sharma, and K. Hassan, "Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis," Pathophysiology, vol. 17, no. 3, pp. 197-218, 2010.
[20] A. Ludhiadch, R. Sharma, A. Muriki, and A. Munshi, "Role of Calcium Homeostasis in Ischemic Stroke: A Review," CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), vol. 21, no. 1, pp. 52-61, 2022.
[21] U. Dirnagl, C. Iadecola, and M. A. Moskowitz, "Pathobiology of ischaemic stroke: an integrated view," Trends in neurosciences, vol. 22, no. 9, pp. 391-397, 1999.
[22] A. F. Samdani, T. M. Dawson, and V. L. Dawson, "Nitric oxide synthase in models of focal ischemia," Stroke, vol. 28, no. 6, pp. 1283-1288, 1997.
[23] M.-S. Sun et al., "Free radical damage in ischemia-reperfusion injury: an obstacle in acute ischemic stroke after revascularization therapy," Oxidative medicine and cellular longevity, vol. 2018, 2018.
[24] U. Förstermann, "Nitric oxide and oxidative stress in vascular disease," Pflügers Archiv-European Journal of Physiology, vol. 459, no. 6, pp. 923-939, 2010.
[25] M. Hemann and S. Lowe, "The p53-BCL-2 connection," Cell death and differentiation, vol. 13, no. 8, p. 1256, 2006.
[26] H. Endo, H. Kamada, C. Nito, T. Nishi, and P. H. Chan, "Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats," Journal of Neuroscience, vol. 26, no. 30, pp. 7974-7983, 2006.
[27] S. Matsumoto, M. Murozono, M. Kanazawa, T. Nara, T. Ozawa, and Y. Watanabe, "Edaravone and cyclosporine A as neuroprotective agents for acute ischemic stroke," Acute medicine & surgery, vol. 5, no. 3, pp. 213-221, 2018.
[28] D. B. Zorov, M. Juhaszova, and S. J. Sollott, "Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release," Physiological reviews, vol. 94, no. 3, pp. 909-950, 2014.
[29] J.-L. Yang, S. Mukda, and S.-D. Chen, "Diverse roles of mitochondria in ischemic stroke," Redox biology, vol. 16, pp. 263-275, 2018.
[30] H. Pradeep, J. B. Diya, S. Shashikumar, and G. K. Rajanikant, "Oxidative stress–assassin behind the ischemic stroke," Folia neuropathologica, vol. 50, no. 3, pp. 219-230, 2012.
[31] D. Tekin, A. D. Dursun, and L. Xi, "Hypoxia inducible factor 1 (HIF-1) and cardioprotection," Acta Pharmacologica Sinica, vol. 31, no. 9, pp. 1085-1094, 2010.
[32] Z.-Z. Chen, X. Gong, Q. Guo, H. Zhao, and L. Wang, "Bu Yang Huan Wu decoction prevents reperfusion injury following ischemic stroke in rats via inhibition of HIF-1 α, VEGF and promotion β-ENaC expression," Journal of ethnopharmacology, vol. 228, pp. 70-81, 2019.
[33] M.-H. Yi et al., "Expression of CD200 in alternative activation of microglia following an excitotoxic lesion in the mouse hippocampus," Brain research, vol. 1481, pp. 90-96, 2012.
[34] S. Denieffe, R. J. Kelly, C. McDonald, A. Lyons, and M. A. Lynch, "Classical activation of microglia in CD200-deficient mice is a consequence of blood brain barrier permeability and infiltration of peripheral cells," Brain, behavior, and immunity, vol. 34, pp. 86-97, 2013.
[35] S.-c. Zhao, L.-s. Ma, Z.-h. Chu, H. Xu, W.-q. Wu, and F. Liu, "Regulation of microglial activation in stroke," Acta Pharmacologica Sinica, vol. 38, no. 4, pp. 445-458, 2017.
[36] K. Nakajima, Y. Tohyama, S. Kohsaka, and T. Kurihara, "Ceramide activates microglia to enhance the production/secretion of brain‐derived neurotrophic factor (BDNF) without induction of deleterious factors in vitro," Journal of neurochemistry, vol. 80, no. 4, pp. 697-705, 2002.
[37] P. Lyden et al., "Clomethiazole acute stroke study in ischemic stroke (CLASS-I) final results," Stroke, vol. 33, no. 1, pp. 122-129, 2002.
[38] R. A. Patel and P. W. McMullen, "Neuroprotection in the treatment of acute ischemic stroke," Progress in cardiovascular diseases, vol. 59, no. 6, pp. 542-548, 2017.
[39] Y. Yamamoto, "Plasma marker of tissue oxidative damage and edaravone as a scavenger drug against peroxyl radicals and peroxynitrite," Journal of clinical biochemistry and nutrition, pp. 16-63, 2017.
[40] K. Yagi et al., "Edaravone, a free radical scavenger, inhibits MMP-9–related brain hemorrhage in rats treated with tissue plasminogen activator," Stroke, vol. 40, no. 2, pp. 626-631, 2009.
[41] J. J. Secades, "Citicoline: pharmacological and clinical review, 2010 update," Rev Neurol, vol. 52, no. Suppl 2, pp. S1-S62, 2011.
[42] C. Mir et al., "CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons," Journal of Molecular Neuroscience, vol. 20, no. 1, pp. 53-59, 2003.
[43] W. M. Clark, N. Lessov, J. D. Lauten, and K. Hazel, "Doxycycline treatment reduces ischemic brain damage in transient middle cerebral artery occlusion in the rat," Journal of Molecular Neuroscience, vol. 9, no. 2, pp. 103-108, 1997.
[44] J. A. Switzer et al., "Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke," Stroke, vol. 42, no. 9, pp. 2633-2635, 2011.
[45] H. Lutsep, "Neuroprotective Agents in Stroke Overview of Neuroprotective Agents," ed, 2020.
[46] A. Dávalos et al., "Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials," Stroke, vol. 33, no. 12, pp. 2850-2857, 2002.
[47] S. C. Fagan et al., "Minocycline to improve neurologic outcome in stroke (MINOS) a dose-finding study," Stroke, vol. 41, no. 10, pp. 2283-2287, 2010.
[48] L. K. Weaver et al., "Hyperbaric oxygen for acute carbon monoxide poisoning," New England Journal of Medicine, vol. 347, no. 14, pp. 1057-1067, 2002.
[49] S. R. Thom, "Hyperbaric oxygen–its mechanisms and efficacy," Plastic and reconstructive surgery, vol. 127, no. Suppl 1, p. 131S, 2011.
[50] E. C. Sanchez, "Mechanisms of action of hyperbaric oxygenation in stroke: a review," Critical care nursing quarterly, vol. 36, no. 3, pp. 290-298, 2013.
[51] C. Hentia et al., "An overview of protective strategies against ischemia/reperfusion injury: The role of hyperbaric oxygen preconditioning," Brain and Behavior, vol. 8, no. 5, p. e00959, 2018.
[52] C. Gao-Yu, D. Cong-Yina, Z. Li-Jun, L. Fei, and F. Hua, "Effects of hyperbaric oxygen preconditioning on energy metabolism and glutamate level in the peri-infarct area following permanent MCAO," Undersea & Hyperbaric Medicine, vol. 38, no. 2, p. 91, 2011.
[53] W.-w. Zhai, L. Sun, Z.-q. Yu, and G. Chen, "Hyperbaric oxygen therapy in experimental and clinical stroke," Medical Gas Research, vol. 6, no. 2, p. 111, 2016.
[54] G. A. Matchett, R. D. Martin, and J. H. Zhang, "Hyperbaric oxygen therapy and cerebral ischemia: neuroprotective mechanisms," Neurological Research, vol. 31, no. 2, pp. 114-121, 2009.
[55] E. M. Nemoto and K. Betterman, "Basic physiology of hyperbaric oxygen in brain," Neurological research, vol. 29, no. 2, pp. 116-126, 2007.
[56] J. Li et al., "Hyperbaric oxygen preconditioning induces tolerance against brain ischemia–reperfusion injury by upregulation of antioxidant enzymes in rats," Brain research, vol. 1210, pp. 223-229, 2008.
[57] Z.-j. Yang, Y. Xie, G. M. Bosco, C. Chen, and E. M. Camporesi, "Hyperbaric oxygenation alleviates MCAO-induced brain injury and reduces hydroxyl radical formation and glutamate release," European journal of applied physiology, vol. 108, no. 3, pp. 513-522, 2010.
[58] C.-H. Kim, H. Choi, Y.-S. Chun, G.-T. Kim, J.-W. Park, and M.-S. Kim, "Hyperbaric oxygenation pretreatment induces catalase and reduces infarct size in ischemic rat myocardium," Pflügers Archiv, vol. 442, no. 4, pp. 519-525, 2001.
[59] L. Sun, H. H. Marti, and R. Veltkamp, "Hyperbaric oxygen reduces tissue hypoxia and hypoxia-inducible factor-1α expression in focal cerebral ischemia," Stroke, vol. 39, no. 3, pp. 1000-1006, 2008.
[60] R. P. Ostrowski, V. Jadhav, W. Chen, and J. H. Zhang, "Reduced matrix metalloproteinase-9 activity and cell death after global ischemia in the brain preconditioned with hyperbaric oxygen," in Brain Edema XIV: Springer, 2010, pp. 47-49.
[61] Z. Ding, W. C. Tong, X.-X. Lu, and H.-P. Peng, "Hyperbaric oxygen therapy in acute ischemic stroke: a review," Interventional Neurology, vol. 2, no. 4, pp. 201-211, 2013.
[62] P.-A. Tai, C.-K. Chang, K.-C. Niu, M.-T. Lin, W.-T. Chiu, and C.-M. Lin, "Attenuating experimental spinal cord injury by hyperbaric oxygen: stimulating production of vasculoendothelial and glial cell line-derived neurotrophic growth factors and interleukin-10," Journal of Neurotrauma, vol. 27, no. 6, pp. 1121-1127, 2010.
[63] A. Günther et al., "Reduced infarct volume and differential effects on glial cell activation after hyperbaric oxygen treatment in rat permanent focal cerebral ischaemia," European Journal of Neuroscience, vol. 21, no. 11, pp. 3189-3194, 2005.
[64] J. Z. Yogaratnam, G. Laden, L. Guvendik, M. Cowen, A. Cale, and S. Griffin, "Pharmacological preconditioning with hyperbaric oxygen: can this therapy attenuate myocardial ischemic reperfusion injury and induce myocardial protection via nitric oxide?," Journal of Surgical Research, vol. 149, no. 1, pp. 155-164, 2008.
[65] P. Bath, L. Gray, A. Bath, A. Buchan, T. Miyata, and A. Green, "Effects of NXY‐059 in experimental stroke: an individual animal meta‐analysis," British journal of pharmacology, vol. 157, no. 7, pp. 1157-1171, 2009.
[66] Á. Chamorro, "Neuroprotectants in the era of reperfusion therapy," Journal of stroke, vol. 20, no. 2, p. 197, 2018.
[67] L. Shi et al., "A new era for stroke therapy: Integrating neurovascular protection with optimal reperfusion," Journal of Cerebral Blood Flow & Metabolism, vol. 38, no. 12, pp. 2073-2091, 2018.
[68] K. Garber, "Stroke treatment--light at the end of the tunnel?," Nature biotechnology, vol. 25, no. 8, pp. 838-841, 2007.
[69] X.-Y. Xiong, L. Liu, and Q.-W. Yang, "Refocusing neuroprotection in cerebral reperfusion era: new challenges and strategies," Frontiers in Neurology, vol. 9, p. 249, 2018.
[70] S. Ambiru, N. Furuyama, M. Aono, H. Otsuka, T. Suzuki, and M. Miyazaki, "Analysis of risk factors associated with complications of hyperbaric oxygen therapy," Journal of critical care, vol. 23, no. 3, pp. 295-300, 2008.
[71] K. K. Jain, "Indications, contraindications, and complications of HBO therapy," in Textbook of hyperbaric medicine: Springer, 2017, pp. 79-84.
[72] J. Jo, M. L. Forrest, and X. Yang, "Ultrasound‐assisted laser thrombolysis with endovascular laser and high‐intensity focused ultrasound," Medical Physics, vol. 48, no. 2, pp. 579-586, 2021.
[73] M. V. Novoselova et al., "Multifunctional nanostructured drug delivery carriers for cancer therapy: Multimodal imaging and ultrasound-induced drug release," Colloids and Surfaces B: Biointerfaces, vol. 200, p. 111576, 2021.
[74] H. Lea-Banks, Y. Meng, S.-K. Wu, R. Belhadjhamida, C. Hamani, and K. Hynynen, "Ultrasound-sensitive nanodroplets achieve targeted neuromodulation," Journal of Controlled Release, vol. 332, pp. 30-39, 2021.
[75] M. G. Cohen et al., "Transcutaneous ultrasound-facilitated coronary thrombolysis during acute myocardial infarction," The American journal of cardiology, vol. 92, no. 4, pp. 454-457, 2003.
[76] D. Plummer, "Principles of emergency ultrasound and echocardiography," Annals of emergency medicine, vol. 18, no. 12, pp. 1291-1297, 1989.
[77] F. Forsberg et al., "Effect of filling gases on the backscatter from contrast microbubbles: theory and in vivo measurements," Ultrasound in medicine & biology, vol. 25, no. 8, pp. 1203-1211, 1999.
[78] W.-S. Chen, T. J. Matula, A. A. Brayman, and L. A. Crum, "A comparison of the fragmentation thresholds and inertial cavitation doses of different ultrasound contrast agents," The Journal of the Acoustical Society of America, vol. 113, no. 1, pp. 643-651, 2003.
[79] I. Lentacker, S. C. De Smedt, and N. N. Sanders, "Drug loaded microbubble design for ultrasound triggered delivery," Soft Matter, vol. 5, no. 11, pp. 2161-2170, 2009.
[80] A. W. Appis, M. J. Tracy, and S. B. Feinstein, "Update on the safety and efficacy of commercial ultrasound contrast agents in cardiac applications," Echo research and practice, vol. 2, no. 2, pp. R55-R62, 2015.
[81] Z. Izadifar, P. Babyn, and D. Chapman, "Mechanical and biological effects of ultrasound: A review of present knowledge," Ultrasound in medicine & biology, vol. 43, no. 6, pp. 1085-1104, 2017.
[82] J. Wu, "Shear stress in cells generated by ultrasound," Progress in biophysics and molecular biology, vol. 93, no. 1-3, pp. 363-373, 2007.
[83] E. VanBavel, "Effects of shear stress on endothelial cells: possible relevance for ultrasound applications," Progress in biophysics and molecular biology, vol. 93, no. 1-3, pp. 374-383, 2007.
[84] S. E. Ahmed, A. M. Martins, and G. A. Husseini, "The use of ultrasound to release chemotherapeutic drugs from micelles and liposomes," Journal of drug targeting, vol. 23, no. 1, pp. 16-42, 2015.
[85] H. Flynn, "Generation of transient cavities in liquids by microsecond pulses of ultrasound," The Journal of the Acoustical Society of America, vol. 72, no. 6, pp. 1926-1932, 1982.
[86] Y. Li et al., "Ultrasound Controlled Anti‐Inflammatory Polarization of Platelet Decorated Microglia for Targeted Ischemic Stroke Therapy," Angewandte Chemie International Edition, vol. 60, no. 10, pp. 5083-5090, 2021.
[87] P. Dijkmans et al., "Microbubbles and ultrasound: from diagnosis to therapy," European Journal of Echocardiography, vol. 5, no. 4, pp. 245-246, 2004.
[88] F. Teng, M. Shen, L. Wang, F. Gao, and C. Zhang, "Ultrasound/microbubble-mediated tetramethylpyrazine for neuroprotection against cerebral ischemia/reperfusion-injured rat brain," Applied Acoustics, vol. 183, p. 108330, 2021.
[89] S.-K. Wu et al., "Targeted delivery of erythropoietin by transcranial focused ultrasound for neuroprotection against ischemia/reperfusion-induced neuronal injury: a long-term and short-term study," PLoS One, vol. 9, no. 2, p. e90107, 2014.
[90] Z. Liang et al., "Ultrasound-Induced Destruction of Nitric Oxide–Loaded Microbubbles in the Treatment of Thrombus and Ischemia–Reperfusion Injury," Frontiers in pharmacology, vol. 12, 2021.
[91] M. E. Downs et al., "Long-term safety of repeated blood-brain barrier opening via focused ultrasound with microbubbles in non-human primates performing a cognitive task," PloS one, vol. 10, no. 5, p. e0125911, 2015.
[92] K. Hynynen, N. McDannold, N. Vykhodtseva, and F. A. Jolesz, "Noninvasive MR imaging–guided focal opening of the blood-brain barrier in rabbits," Radiology, vol. 220, no. 3, pp. 640-646, 2001.
[93] C. Yang et al., "Lipid microbubbles as ultrasound-stimulated oxygen carriers for controllable oxygen release for tumor reoxygenation," Ultrasound in medicine & biology, vol. 44, no. 2, pp. 416-425, 2018.
[94] J. R. Eisenbrey et al., "Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue," International journal of pharmaceutics, vol. 478, no. 1, pp. 361-367, 2015.
[95] A. Bisazza et al., "Microbubble-mediated oxygen delivery to hypoxic tissues as a new therapeutic device," in 2008 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 2008: IEEE, pp. 2067-2070.
[96] Y.-J. Ho et al., "Normalization of tumor vasculature by oxygen microbubbles with ultrasound," Theranostics, vol. 9, no. 24, p. 7370, 2019.
[97] N. D. Legband, J. A. Feshitan, M. A. Borden, and B. S. Terry, "Evaluation of peritoneal microbubble oxygenation therapy in a rabbit model of hypoxemia," IEEE Transactions on Biomedical Engineering, vol. 62, no. 5, pp. 1376-1382, 2015.
[98] F. Fluri, M. K. Schuhmann, and C. Kleinschnitz, "Animal models of ischemic stroke and their application in clinical research," Drug design, development and therapy, vol. 9, p. 3445, 2015.
[99] C. J. Sommer, "Ischemic stroke: experimental models and reality," Acta neuropathologica, vol. 133, no. 2, pp. 245-261, 2017.
[100] L.-D. Liao et al., "Transcranial imaging of functional cerebral hemodynamic changes in single blood vessels using in vivo photoacoustic microscopy," Journal of Cerebral Blood Flow & Metabolism, vol. 32, no. 6, pp. 938-951, 2012.
[101] C. T. Sullender et al., "Imaging of cortical oxygen tension and blood flow following targeted photothrombotic stroke," Neurophotonics, vol. 5, no. 3, p. 035003, 2018.
[102] B. P. Chugh et al., "Measurement of cerebral blood volume in mouse brain regions using micro-computed tomography," Neuroimage, vol. 47, no. 4, pp. 1312-1318, 2009.
[103] E. W. Stein, K. I. Maslov, and L. V. Wang, "Noninvasive, in vivo imaging of blood-oxygenation dynamics within the mouse brain using photoacoustic microscopy," Journal of biomedical optics, vol. 14, no. 2, p. 020502, 2009.
[104] D. Vivien, "Can the benefits of rtPA treatment for stroke be improved?," Revue Neurologique, vol. 173, no. 9, pp. 566-571, 2017.
[105] E. J. Su et al., "Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke," Nature medicine, vol. 14, no. 7, pp. 731-737, 2008.
[106] I. García-Yébenes et al., "A mouse model of hemorrhagic transformation by delayed tissue plasminogen activator administration after in situ thromboembolic stroke," Stroke, vol. 42, no. 1, pp. 196-203, 2011.
[107] C. Orset et al., "Mouse model of in situ thromboembolic stroke and reperfusion," Stroke, vol. 38, no. 10, pp. 2771-2778, 2007.
[108] Y. F. Wang, S. E. Tsirka, S. Strickland, P. E. Stieg, S. G. Soriano, and S. A. Lipton, "Tissue plasminogen activator (tPA) increase neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice," Nature medicine, vol. 4, no. 2, pp. 228-231, 1998.
[109] J. J. Lochhead et al., "Oxidative stress increases blood–brain barrier permeability and induces alterations in occludin during hypoxia–reoxygenation," Journal of Cerebral Blood Flow & Metabolism, vol. 30, no. 9, pp. 1625-1636, 2010.
[110] G.-Y. Yang and A. L. Betz, "Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats," Stroke, vol. 25, no. 8, pp. 1658-1664, 1994.
[111] E. E Konofagou, Y.-S. Tunga, J. Choia, T. Deffieuxa, B. Baseria, and F. Vlachosa, "Ultrasound-induced blood-brain barrier opening," Current pharmaceutical biotechnology, vol. 13, no. 7, pp. 1332-1345, 2012.
[112] K.-H. Song, B. K. Harvey, and M. A. Borden, "State-of-the-art of microbubble-assisted blood-brain barrier disruption," Theranostics, vol. 8, no. 16, p. 4393, 2018.
[113] K. Arai, G. Jin, D. Navaratna, and E. H. Lo, "Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke," The FEBS journal, vol. 276, no. 17, pp. 4644-4652, 2009.
[114] S. Kaur, A. K. Rehni, N. Singh, and A. S. Jaggi, "Studies on cerebral protection of digoxin against ischemia/reperfusion injury in mice," Yakugaku Zasshi, vol. 129, no. 4, pp. 435-443, 2009.
[115] K. S. Bora, S. Arora, and R. Shri, "Role of Ocimum basilicum L. in prevention of ischemia and reperfusion-induced cerebral damage, and motor dysfunctions in mice brain," Journal of ethnopharmacology, vol. 137, no. 3, pp. 1360-1365, 2011.
[116] P. Curzon, M. Zhang, R. J. Radek, and G. B. Fox, "The behavioral assessment of sensorimotor processes in the mouse: acoustic startle, sensory gating, locomotor activity, rotarod, and beam walking," 2011.
[117] A. Aartsma-Rus and M. van Putten, "Assessing functional performance in the mdx mouse model," JoVE (Journal of Visualized Experiments), no. 85, p. e51303, 2014.
[118] T. Brott and J. Bogousslavsky, "Treatment of acute ischemic stroke," New England Journal of Medicine, vol. 343, no. 10, pp. 710-722, 2000.
[119] M. Fatar, M. Griebe, M. Stroick, R. Kern, M. Hennerici, and S. Meairs, "Neuroprotective effect of combined ultrasound and microbubbles in a rat model of middle cerebral artery infarction," in AIP Conference Proceedings, 2005, vol. 754, no. 1: American Institute of Physics, pp. 62-64.
[120] A. Al Mamun, A. Chauhan, H. Yu, Y. Xu, R. Sharmeen, and F. Liu, "Interferon regulatory factor 4/5 signaling impacts on microglial activation after ischemic stroke in mice," European Journal of Neuroscience, vol. 47, no. 2, pp. 140-149, 2018.
[121] E. I. Yakupova, G. V. Maleev, A. V. Krivtsov, and E. Y. Plotnikov, "Macrophage polarization in hypoxia and ischemia/reperfusion: Insights into the role of energetic metabolism," Experimental Biology and Medicine, p. 15353702221080130, 2022.
[122] M.-Y. Wu et al., "Current mechanistic concepts in ischemia and reperfusion injury," Cellular Physiology and Biochemistry, vol. 46, no. 4, pp. 1650-1667, 2018.
[123] A. R. Young, C. Ali, A. Duretête, and D. Vivien, "Neuroprotection and stroke: time for a compromise," Journal of neurochemistry, vol. 103, no. 4, pp. 1302-1309, 2007.
[124] A. Alonso, E. Reinz, M. Fatar, M. G. Hennerici, and S. Meairs, "Clearance of albumin following ultrasound-induced blood–brain barrier opening is mediated by glial but not neuronal cells," Brain research, vol. 1411, pp. 9-16, 2011.
[125] S. Chen et al., "A review of bioeffects induced by focused ultrasound combined with microbubbles on the neurovascular unit," Journal of Cerebral Blood Flow & Metabolism, vol. 42, no. 1, pp. 3-26, 2022.
[126] R. J. Turner and F. R. Sharp, "Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke," Frontiers in cellular neuroscience, vol. 10, p. 56, 2016.
[127] S. Meairs and A. Alonso, "Ultrasound, microbubbles and the blood–brain barrier," Progress in biophysics and molecular biology, vol. 93, no. 1-3, pp. 354-362, 2007.
[128] T. R. Porter and F. Xie, "Ultrasound, microbubbles, and thrombolysis," Progress in cardiovascular diseases, vol. 44, no. 2, pp. 101-110, 2001.
[129] H. M. Honda, P. Korge, and J. N. Weiss, "Mitochondria and ischemia/reperfusion injury," Annals of the New York Academy of Sciences, vol. 1047, no. 1, pp. 248-258, 2005.
[130] W. Jassem, S. V. Fuggle, M. Rela, D. D. Koo, and N. D. Heaton, "The role of mitochondria in ischemia/reperfusion injury," Transplantation, vol. 73, no. 4, pp. 493-499, 2002.
[131] A. Williams and D. Miller, "Photometric detection of ATP release from human erythrocytes exposed to ultrasonically activated gas-filled pores," Ultrasound in medicine & biology, vol. 6, no. 3, pp. 251-256, 1980.
[132] C. R. Hill, J. C. Bamber, and G. R. ter Haar, "Physical principles of medical ultrasonics," ed: Acoustical Society of America, 2004.
[133] M. Aryal, C. D. Arvanitis, P. M. Alexander, and N. McDannold, "Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system," Advanced drug delivery reviews, vol. 72, pp. 94-109, 2014.
[134] K.-T. Chen, K.-C. Wei, and H.-L. Liu, "Focused ultrasound combined with microbubbles in central nervous system applications," Pharmaceutics, vol. 13, no. 7, p. 1084, 2021.
[135] M. L. Edwards, "Hyperbaric oxygen therapy. Part 2: application in disease," Journal of Veterinary Emergency and Critical Care, vol. 20, no. 3, pp. 289-297, 2010.