DEVELOPING COLLABORATIVE STRATEGIES TO GUIDE FUTURE DIRECTIONS IN MICROBUBBLE ENHANCED THERAPEUTIC ULTRASOUND

现代医学超声学可以被看作是经过三代应用发展而来的。第一代强调诊断成像，采用相对被动的超声场。第二代有意识地开发了更积极的超声方案用于直接介入方法，包括碎石术（导管结石）、超声乳化术（白内障）和HIFU用于肿瘤消融、血栓溶解和止血。第三个新兴领域涉及超声的间接治疗应用，以主动致敏组织，或以其他方式提高生物治疗药物平行给药的疗效。在此，超声辅助透皮给药已经取得了特别的进展。然而，这已经被部分地促进，因为靶组织（即，角质层）是无活力的。也许治疗性超声最具挑战性的途径是促进分子递送，同时保持组织活力，这是基于药物和基因的治疗所必需的标准。令人兴奋的是，最初的体外证明，增强转染和化疗药物的敏感性增加，现在也已经实现了令人信服的体内验证。显然，后一类超声介导治疗有望实现多种潜在用途。然而，将这些抽象的可能性的多样性减少到最适合超声增强的更精细的具体实现基础需要战略行动。有针对性的研究与最大的影响，需要了解的优势和弱点，超声的生物效应，这仍然是知之甚少，在机械水平。这种情况阻碍了对这一领域未来的洞察力和远见。后一段包含了本建议的精神。建议与几个新的英国和国际合作伙伴进行互动，以满足下一代声孔试验的需求，这将有助于将该技术转化为临床。需要回答的关键问题包括：超声本身的主要效应是否对生物效应负责，或者是否涉及冲击波、流体剪切和声化学的次要效应？如果是这样，在决定整体生物效应方面，每种药物的相对重要性是什么？哪种形式的超声波效应是基因转染、癌症治疗、细胞内药物输送的敏感性增加的原因？体外有效的超声效应能否在体内重现，其中空化成核位点的灌注（例如，造影剂微泡）和刺激实体组织的致密环境中的气泡活动可能是困难的吗？离体细胞和单个气泡实验能否预测多细胞组织暴露于体内发现的气泡云的行为？最后，微泡应该表现出哪些物理特性，以针对特定的治疗，以及如何设计超声换能器来控制和优化体内的空化和其他活动？

Modern medical ultrasonics may be viewed as having evolved through three generations of applications. The first generation emphasizes diagnostic imaging, employing relatively passive ultrasound fields. The second generation has deliberately exploited more aggressive ultrasound regimes for direct interventional approaches, including lithotripsy (of ductal calculi), phacoemulsification (of cataracts), and HIFU for tumour ablation, thrombolysis, and haemostatis.A third and emerging area involves an indirect therapeutic application of ultrasound to actively sensitize tissue, or otherwise enhance the efficacy for parallel administration of biotherapeutics. Here, particular progress has been achieved with ultrasound assisted transdermal delivery. However, this has been facilitated, in part, because the target tissue (i.e., stratum corneum) is non-viable. Perhaps the most challenging avenue for therapeutic ultrasound is to facilitate molecular delivery whilst retaining tissue viability, the criteria necessary for drug- and gene-based therapies. Excitingly, initial in vitro demonstrations of enhanced transfection and also increased sensitivity to chemotherapeutic agents, have now also been realized with compelling in-vivo validations. Evidently, this latter category of ultrasound-mediated therapy holds promise for a diversity of potential uses. However, reducing the multiplicity of these abstract possibilities to the more refined base of concrete realizations that are best suited to ultrasonic enhancement requires strategic action. Targeting research with the greatest impact requires an understanding of the strengths and weaknesses of ultrasound's bioeffects, which remain poorly understood at a mechanistic level. This situation hinders insight and indeed foresight into the future of this field. THis latter paragraph embraces the spirit of the present proposal. It is proposed to interact with several new UK and international partners in order to meet the needs of the next generation of sonoporation trials that will assist translation of this technique towards the clinic. The critical questions to be answered include:Are the primary effects of ultrasound itself responsible for bioeffects, or are secondary effects involving shock waves, fluid shearing, and sonochemistry involved? If so, what is the relative importance of each in dictating overall bioeffect? Which forms of ultrasonic effects are responsible for increased sensitivity to gene transfection, to cancer therapy, to intracellular drug delivery? Can ultrasonic effects that are effective in vitro be reproduced in vivo, where perfusion of cavitation nucleation sites (e.g., contrast agent microbubbles) and stimulation of bubble activity in the dense environment of a solid tissue may be difficult? Can isolated cell and single-bubble experiments in vitro predict behaviour of multicellular tissue exposure to bubble clouds found in vivo? Finally, which physical properties should micro-bubbles exhibit in order to target specific therapies, and how should ultrasound transducers be designed to control and optimize cavitational and other activity within the body?