Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
Division of Vascular and Endovascular Surgery, Center for Vascular Biology Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
J Control Release. 2020 Aug 10;324:450-459. doi: 10.1016/j.jconrel.2020.05.040. Epub 2020 May 26.
Focused ultrasound (FUS) combined with microbubbles is a non-invasive method for targeted, reversible disruption of the blood-brain barrier (FUS-BBB opening). This approach holds great promise for improving delivery of therapeutics to the brain. In order to achieve this clinically important goal, the approach necessarily breaks a protective barrier, temporarily, which plays a fundamental role in maintaining a homeostatic environment in the brain. Preclinical and clinical research has identified a set of treatment parameters under which this can be performed safely, whereby the BBB is disrupted to the point of being permeable to normally non-penetrant agents without causing significant acute damage to endothelial or neuronal cells. Much of the early work in this field focused on engineering questions around how to achieve optimal delivery of therapeutics via BBB disruption. However, there is increasing interest in addressing biological questions related to whether and how various aspects of neurophysiology might be affected when this fundamental protective barrier is compromised by the specific mechanisms of FUS-BBB opening. Improving our understanding of these secondary effects is becoming vital now that FUS-BBB opening treatments have entered clinical trials. Such information would help to safely expand FUS-BBB opening protocols into a wider range of drug delivery applications and may even lead to new types of treatments. In this paper, we will critically review our current knowledge of the secondary effects caused by FUS-BBB opening on brain physiology, identify areas that remain understudied, and discuss how a better understanding of these processes can be used to safely advance FUS-BBB opening into a wider range of clinical applications.
聚焦超声（FUS）联合微泡是一种非侵入性的靶向、可逆的血脑屏障破坏方法（FUS-BBB 开放）。这种方法为提高治疗药物向大脑的递送提供了巨大的潜力。为了实现这一具有临床重要意义的目标，这种方法必然会暂时打破一个保护性屏障，而这个屏障在维持大脑的内环境稳定方面起着至关重要的作用。临床前和临床研究已经确定了一组治疗参数，在这些参数下可以安全地进行这种操作，即 BBB 被破坏到对通常不可穿透的药物具有渗透性的程度，而不会对内皮或神经元细胞造成明显的急性损伤。该领域的早期工作主要集中在如何通过 BBB 破坏实现最佳治疗药物递送的工程问题上。然而，人们越来越感兴趣的是解决与神经生理学的各个方面在基本保护屏障被 FUS-BBB 开放的特定机制破坏时可能受到影响相关的生物学问题。现在，FUS-BBB 开放治疗已经进入临床试验，提高我们对这些次要影响的理解变得至关重要。这些信息将有助于安全地将 FUS-BBB 开放方案扩展到更广泛的药物递送应用中，甚至可能导致新的治疗类型。在本文中，我们将批判性地回顾我们目前对 FUS-BBB 开放对大脑生理学造成的次级效应的认识，确定仍未得到充分研究的领域，并讨论如何更好地理解这些过程，以安全地将 FUS-BBB 开放推进到更广泛的临床应用。
