High Resolution SQUID Magnetometer for Imaging Biological Systems

提出的研究目标是开发超高分辨率，超导量子干涉器件（SQUID）磁力计（UHRSM），该磁力计优化用于在100m尺度的孤立活组织和小型实验动物制剂中对作用电流，剩余磁化率和磁化率产生的磁场进行成像。这种测量方法尚未广泛使用，主要是因为现有仪器的局限性和成本。这个项目是专门为解决这些问题而设计的。所提出的仪器将能够进行任何其他技术无法进行的测量，并将导致对细胞生物学和电生理学的新见解。随着这些仪器的开发，它们将立即被纳入范德比尔特大学正在进行的关于心肌、神经和肠平滑肌的电生理学研究，并将提供给其他机构的合作者。提出的研究包括分阶段开发利用液氦冷却的低温超导（LTS） SQUID和利用液氮冷却的高温超导（HTS） SQUID的低灵敏度、高分辨率UHRSM所需的低温恒温器、SQUID和真空窗。第一个系统将使用手动缠绕的采集线圈、商业包装的LTS SQUID和定制的连续流低温恒温器，该系统将提供一个半自动系统，不需要定期氦气和氮气传输。更先进的版本将使用定制的LTS和HTS SQUID梯度仪和磁力计，安装在为红外光谱设计的廉价商业杜瓦瓶中。在开发过程中，美国国家科学基金会将在Hypres工厂免费制造带有片上拾取线圈的专用LTS squid。将使用apodiization和其他线圈设计技术来开发squid阵列，其拾取线圈被优化为高分辨率生物磁成像和生物样品中电流和磁化分布的反计算。Hypres将提供数字乌贼进行评估。这些仪器是基于成熟的冷却和真空窗技术；挑战在于将它们与优化的SQUID磁力计集成在一起，以创建用户友好且廉价的磁显微镜。这些仪器在近细胞水平上定量测量磁场的能力将是独一无二的。虽然神经和心脏组织的电测量在过去的一个世纪里已经被广泛探索，但直到最近几年，才有可能使用squid来成像细胞的动作电流。高分辨率磁化率成像尚未应用于生物系统。许多涉及细胞间电通信和非均匀传播的生物现象，如那些对心肌和肠平滑肌行为至关重要的生物现象，都是由电荷转移控制的。由于这些系统的分布电阻率和电容通常是未知的或特征不明显，因此仅靠电测量不足以量化这种电荷转移。因此，电流的直接测量对于理解细胞间耦合是至关重要的。更重要的是，电流的磁测量与电压的电和光学测量相结合，不仅为提高对细胞间电荷转移的理解，而且为提高对电流与电压相关的组织特性的理解提供了独特的希望。其他的生物学应用包括研究皮层振荡、扩展洼地、藻类和高等植物的作用电流、生命系统中的铁生物矿物和磁示踪剂。拟议的仪器开发计划，加上积极的生物物理测量计划，应该提高研究细胞系统的电行为及其对物理和药物干预的反应的能力。

The objective of the proposed research is to develop ultra-high resolution, Superconducting QUantum Interference Device (SQUID) magnetometers (UHRSM) that are optimized for the imaging of the magnetic fields produced by action currents, remanent magnetization, and magnetic susceptibility in isolated living tissue and small experimental animal preparations at the scale of 100m.. Such measurements are not yet in wide spread use, primarily because of the limitations and costs of existing instrumentation. This project is designed specifically to address these points. The proposed instruments will be capable of making measurements that are impossible with any other technique, and should lead to new insights into cellular biology and electrophysiology. As they are being developed, these instruments will be immediately incorporated into the electrophysiological research on cardiac muscle, nerves, and intestinal smooth muscle that is ongoing at Vanderbilt, and will be made available to collaborators from other institutions. The proposed research involves the staged development of the cryostats, SQUIDs, and vacuum windows required for a high-sensitivity UHRSM utilizing a liquid-helium-cooled, low-temperature superconductivity (LTS) SQUID, and a lower sensitivity, higher resolution UHRSM with a liquid-nitrogen-cooled, high-temperature superconductivity (HTS) SQUID. The first system will use hand-wound pickup coils, a commercially-packaged LTS SQUID, and a custom-built, continuous-flow cryostat that should provide a semi- automatic system not requiring periodic helium and nitrogen transfers. The more advanced versions will utilize custom LTS and HTS SQUID gradiometers and magnetometers mounted in inexpensive commercial dewars designed for infrared spectroscopy. While this is under development, specialized LTS SQUIDs with on-chip pickup coils will be fabricated at Hypres at no cost to NSF. Apodization and other coil design techniques will be used , to develop arrays of SQUIDs whose pickup coils are optimized for high- resolution biomagnetic j imaging and inverse calculations of the current and magnetization distributions in the biological samples. Digital SQUIDs will be provided by Hypres for evaluation. These instruments are based upon proven cooling and vacuum- window technologies; the challenge lies in integrating these with optimized SQUID magnetometers to create user-friendly, inexpensive magnetic microscopes. These instruments will be unique in their ability to measure quantitatively magnetic fields at the near-cellular level. While electrical measurements of neural and cardiac tissue have been explored extensively over the past century, only in the past few years has it been possible to use SQUIDs to image cellular action currents. High resolution magnetic susceptibility imaging has yet to be applied to biological systems. Many biological phenomena involving electrical cell-to-cell communication and non-uniform propagation, such as those that are key to the behavior of cardiac~ihuscle and intestinal smooth muscle, are governed by the transfer of electrical charge. Since the distributed electrical resistivity and capacitance of these systems is often unknown or poorly characterized, electrical measurements alone cannot suffice to quantify this charge transfer. Hence direct measurements of current are crucial to understanding cell-to-cell coupling. More importantly, the combination of magnetic measurements of current and electrical and optical measurements of voltage offers unique promise towards improving the understanding of not only th e transfer of charge between cells but also the tissue properties that relate current to voltage. Other biological applications include the study of cortical oscillations, spreading depression, action currents in algae and higher plants, iron biominerals in living systems, and magnetic tracers. The proposed program of instrumentation development, coupled with an aggressive program of biophysical measurements, should advance the ability to study the electrical behavior of cellular systems and their response to physical and pharmacological interventions.