Since I started research on how to merge electrochemistry and in vivo analysis, I have never stopped thinking about improving the long-term performance of electrochemical sensors implanted in rat brains. One inescapable obstacle is that the sensor would not work if not wired to a potentiostat. We can, of course, choose wireless measurement circuits and a small head-mounted potentiostat, but what if we took the initiative in designing the sensing process instead of system engineering? The essence of sensing is energy conversion, and most processes of interest must be driven under external forces through purposely designed energetic routes to obtain readable signals in return. For our case, the electric field applied (by the potentiostat) on a working electrode acts like an electrical energetic “trigger”; otherwise, most electrode reactions would not occur by themselves. It looks as if the trigger is indispensable for electrochemical sensing. However, exceptions do exist. The classical potentiometric sensors for ion measurement, e.g., pH meter, utilize the diffusion of ions along the concentration gradient through permselective membranes. It is obviously the spontaneous process that drives sensing. So, one may be wondering if we could design such “self-triggered” implantable sensors for analyzing brain molecules. This was later realized by the marriage of potentiometry and galvanic cells. From the thermodynamic perspective, any cell process with a negative Gibbs free energy will allow spontaneous occurrence of its half reactions at compartmentalized electrodes and irreversible delivery of electricity. Typically, the sensor utilizes a galvanic cell configuration that an oxygen-reducing biocathode (commonly modified with laccase or bilirubin oxidase) with high electrode potential and a bioanode with lower electrode potential are connected to initiate current flows through circuits, as seen in self-powered biosensors. However, we decided to maintain the reversibility of electrode processes at the open-circuit condition by wiring the cathode and anode to a high-resistance voltmeter. Circuit currents are minimized and a Nernstian relationship can be easily established between cell voltages (open-circuit potentials) and reactant concentrations. The so-termed galvanic redox potentiometry (GRP) has been enabled by configuring new miniature implantable electrochemical sensors from the traditional two-electrode setup to a single bipolar carbon fiber that has half reactions spontaneously occurring at its two poles. In the area of optical sensing, naturally evolved light-producing luciferase–luciferin systems have lighted a unique path. Spontaneous conversion of chemical energy under enzyme activation to photons defines “self-luminescent” biosensors. These laser-free optical sensors are quite appealing because of the opportunities for in vivo imaging without worrying about laser-induced issues, but the practical limitation lies in that the involvement of multiple reagents (d-luciferin, ATP, Mg²⁺, and O₂) may complicate in vivo analysis. So, new bioluminescent schemes calling for fewer participants like the luciferase–coelenterazine were reported. Luciferase-independent chemiluminescent biosensors using synthetic reporters further simplified the sensing process and resulted in more alternatives for bioimaging. For example, Schaap’s dioxetane can be tethered to various protecting groups that are removable in response to specific analytes, leaving highly emissive products. Although the list of light-excited optical sensors is far more elongated than that of self-luminescent sensors, I believe that the latter is worthy of attention for frontier in vivo exploration, such as neurotransmission imaging with bioluminescent membrane proteins or extracellular space tracking with self-luminescent nanomaterials. Not limited to chemical reactions, spontaneous physical processes also confer benefits on sensing, the realization of which is frequently aided by an interface as I found. There are two good examples. One is the coffee-ring effect—essentially the self-driven partition of dispersed particles between bulk solvents and the liquid–air interface. Changing the hydrophilicity/hydrophobicity of particles or solvents changes the partition process, thus providing useful means of analyte enrichment and measurement. The other is the self-driven fluidics as seen in the capillary effect—essentially the outcome of liquid surface tension and solid surface wetting. This phenomenon has inspired tremendous inventions of microfluidic or nanofluidic sensors. Now, you may ask, why do we want sensing to be spontaneous? My answer is because of self-sustainability, which prolongs the in vivo lifetime of implantable sensors, cancels the possible adverse effects imposed by external triggers, breaks size limits on sensor miniaturization, and promotes development of cheap, user-friendly portable sensors. These advantages illustrate a bright future picture in many applications, such as personalized healthcare and on-site environmental monitoring. Particularly, the final point becomes increasingly important under the current antiepidemic situation that instant on-site separation and detection techniques are urgently demanded. This article has not yet been cited by other publications.

中文翻译：

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由自发过程驱动的传感

自从我开始研究如何将电化学和体内分析结合起来，我就一直在思考如何提高植入大鼠大脑的电化学传感器的长期性能。一个不可避免的障碍是，如果没有连接到恒电位仪，传感器将无法工作。我们当然可以选择无线测量电路和小型头戴式恒电位仪，但如果我们主动设计传感过程而不是系统工程呢？传感的本质是能量转换，大多数感兴趣的过程必须在外力的作用下通过有目的地设计的能量路线来获得可读信号作为回报。在我们的例子中，（由恒电位仪）施加在工作电极上的电场就像一个电能量“触发器”；除此以外，大多数电极反应不会自行发生。看起来触发器对于电化学传感是必不可少的。然而，例外确实存在。用于离子测量的经典电位传感器，例如 pH 计，利用离子沿浓度梯度扩散穿过选择性渗透膜。显然，驱动感知的是自发过程。因此，人们可能想知道我们是否可以设计这种“自触发”可植入传感器来分析大脑分子。后来通过电位计和原电池的结合实现了这一点。从热力学的角度来看，任何具有负吉布斯自由能的电池过程都将允许其在分隔电极上的半反应自发发生和不可逆的电力传输。通常，该传感器采用原电池配置，其中连接具有高电极电位的氧还原生物阴极（通常用漆酶或胆红素氧化酶修饰）和具有较低电极电位的生物阳极以启动电流流过电路，如自供电生物传感器中所见。然而，我们决定通过将阴极和阳极连接到高电阻电压表来保持开路条件下电极过程的可逆性。电路电流被最小化，并且可以很容易地在电池电压（开路电位）和反应物浓度之间建立 Nernstian 关系。通过将新型微型可植入电化学传感器从传统的双电极设置配置为单个双极碳纤维，在其两个极上自发发生半反应，从而实现了所谓的电偶氧化还原电位 (GRP)。在光学传感领域，自然进化的发光荧光素酶-荧光素系统开辟了一条独特的道路。在酶激活下化学能自发转化为光子定义了“自发光”生物传感器。这些无激光光学传感器非常有吸引力，因为它有机会 在酶激活下化学能自发转化为光子定义了“自发光”生物传感器。这些无激光光学传感器非常有吸引力，因为它有机会 在酶激活下化学能自发转化为光子定义了“自发光”生物传感器。这些无激光光学传感器非常有吸引力，因为它有机会体内成像而不必担心激光诱导的问题，但实际限制在于多种试剂（d-荧光素、ATP、Mg ²⁺和 O ₂）的参与可能会使体内复杂化分析。因此，报道了需要较少参与者的新生物发光方案，例如荧光素酶-腔肠素。使用合成报告基因的不依赖荧光素酶的化学发光生物传感器进一步简化了传感过程，并为生物成像提供了更多替代方案。例如，Schaap 的二氧杂环丁烷可以连接到各种保护基团上，这些保护基团可以响应特定分析物而去除，从而留下高发射性产品。虽然光激发光传感器的名单远比自发光传感器拉长，但我相信后者在体内前沿值得关注探索，例如使用生物发光膜蛋白进行神经传递成像或使用自发光纳米材料进行细胞外空间追踪。不仅限于化学反应，自发的物理过程也有利于传感，正如我发现的那样，它的实现经常得到接口的帮助。有两个很好的例子。一种是咖啡环效应——本质上是散装溶剂和液-气界面之间分散颗粒的自驱动分配。改变颗粒或溶剂的亲水性/疏水性会改变分配过程，从而提供有用的分析物富集和测量手段。另一种是自驱动流体，如毛细管效应中所见——本质上是液体表面张力和固体表面润湿的结果。这种现象激发了微流体或纳米流体传感器的巨大发明。现在，您可能会问，为什么我们希望感知是自发的？我的回答是因为自我可持续性，这延长了植入式传感器的体内寿命，消除了外部触发可能带来的不利影响，打破了传感器小型化的尺寸限制，并促进了廉价、用户友好的便携式传感器的发展。这些优势说明了许多应用的光明前景，例如个性化医疗保健和现场环境监测。尤其是在当前急需现场即时隔离检测技术的抗疫形势下，最后一点变得越来越重要。这篇文章还没有被其他出版物引用。