# Modeling of Integrated Nanoneedle-Microfluidic System for Single Cell Temperature Measurement
## 1 Introduction  
Single cell analysis has become an important field of research in which cell properties are studied for an improved understanding of cellular processes. Cell intracellular temperature has been proven a vital element in most cellular activates. Recently, many attempts by researchers focused on developing sensors that have high accuracy and do not cause any damages to the cells, such as nanogap biosensors [1], nanoneedle biosensors [2; 3], and sensors using extended-gate field-effect transistors [4; 5]. Micro total analysis system (\(\upmu\)TAS) and lab on chip (LOC) attracted many researchers towards improving traditional detection techniques in many chemical, biological and medical areas. The added advantages that these systems provide, such as the ability to combine and automate all the analysis steps from sampling to obtaining data in a single chip, reduce total analysis time and are very cost effective encouraged the development of techniques that support many clinical applications including single cell analysis [6; 7; 8]. Single cell analysis is the type of study that considers the identity of individual cells and cell heterogeneity that made it an expanding field of research worldwide. Different cell properties include chemical, electrical, mechanical and thermal properties. The intracellular temperature of cells has shown to have important roles in cell functions, metabolisms, divisions and many other vital cellular activities [9; 10; 11]. In addition, cells that are characterized with an abnormality such as cancer tend to have higher heat production rates compared to normal cells [12]. Over the years, there have been many attempts to measure internal cellular temperature using different approaches [13]. Some relied on the luminescent change of materials to obtain the temperature gradient, e.g., quantum dots [14], nanoparticles [15], and thermosensitive materials [16; 17]. These methods showed a high level of sensitivity. Yet, photo-bleaching, material movement inside the cell and toxicity are some critical disadvantages [18]. Other methods relied on material properties that were affected by temperature change. A nanoneedle based on thermocouple was one of the pioneer example that had an ability to detect 0.1 \({}^{\circ}\)C change in temperature [19]. A multi-walled carbon nanotube was suggested as a temperature detector for biological cells [20], as was photo acoustic microscopy (PAM), which measured the ultrasound signals induced by light absorption [21]. Another interesting idea was the incorporation of a microfluidic system with a resonant thermal sensor that measured heat generation in living cells, however, the application diversity was limited to a certain type of cells, i.e., brown fat cell (BFC) [22]. These non-luminescent sensors open the door for new fields of single cell thermal property studies which have the potential to produce highly sensitive measurements accurately. In this study, a tungsten-based nanoneedle-microfluidic system is proposed for single cell temperature measurement. The nanoneedle design, characterizations, intracellular temperature detection and nanoneedle-microfluidic channel integration are studied. Considering the importance of finite element analysis as the initial step in designing a system, a thorough study was performed to optimize the necessary parameters that were believed to influence the final performance of the proposed system. The nanoneedle design included a study on two parameters: the shape and size of the sensor, which had the best current density distribution and caused minimal damage on the _saccharomyces cerevisiae_ cell under study. Then, the characterization analysis were on thermal-electric and mechanical characterizations to assess the ability of the nanoneedle to respond to temperature change as well as the nanoneedle's sustainability against external forces. Furthermore, the ability of nanoneedle to measure the temperature of a single cell was performed.