(Invited) Modularized Inexpensive Detection of Biomarkers for Medical Applications
Authors: Carey Patrick H , Yang Jiancheng , Chang Chin-Wei , Ren Fan , Pearton Stephen J. , Lu Shao-Yung , Lin Jenshan , Liao Yu-Te , Lobo Brian , Gebhard Michael , Leon Marino E 
Published: February 2020

Miniaturized portable electronic sensors are a burgeoning new field of explosive growth with many new companies competing to bring their design to market first. The idea behind these devices are relatively straightforward, using an electrical signal to test for a biological marker. The exact method and biomarker vary, but the general backbone of all the sensors is a field effect transistor (FET). Previously AlGaN/GaN High Electron Mobility Transistors (HEMTs) were the primary workhorse as the electron flow is generally within 50 nm of the surface and is easily modulated by changes in surface chemistry. Thus, by functionalizing the gate with an antibody, a change in drain current can easily be observed as a function of target concentration. Previously, this method has been used by our group to detect c-erB-2 and botulinum toxin using a constant applied bias to measure the change in current as the target solution is applied. A major issue with applying a constant bias and measuring the change is the inability to operate in highly ionic solutions due to the Debye screening length [1]. To function in highly ionic solutions is of upmost importance if whole blood, urine, saliva, etc. are to be tested in the field at point-of-care. To work around this issue, a short pulse of voltage is sent to the sensor and a spring-like response of the antibody-protein complex can be detected regardless of solution ionicity.

With this new pulse method, the first step to modularization is to externalize the sensing area from the HEMT; this allows for reuse of the device and simple swapping of a sensing strip. In this case, an electrode, which has been functionalized with the target antibody, is connected to the gate of the HEMT [2,3]. To compare the externalized sensor with the traditional gate-functionalized HEMT, cardiac Troponin I and Zika Virus were selected as targets. Both the traditional HEMT along with the externalized sensing HEMT were successful in detection down to 0.1 ng/mL with the pulse method. Both Langmuir and double-spring elastic relaxation models were used to simulate the steady state and dynamic sensor responses.

Since the sensing portion has been externalized, the need for expensive AlGaN HEMT has been mitigated and a Si MOSFET can be substituted. A PCB board with a Si MOSFET was designed to remove the need for expensive semiconductor analysis equipment. A digital readout has been incorporated to make the final product simple to use and understand for any user and removes the need for a parameter analyzer or oscilliscope. To test the prototypes of the PCB board, we have investigated the sensing of Cerebral Spinal Fluid (CSF). CSF is a liquid found through the brain’s ventricles and around the brain and spinal cord [4]. A leak of CSF will primarily occur due to accidental damage to the skull or spine whether that is from an impact or during otolaryngology (ENT) surgery. In all cases the major concern of a CSF leak is the possibility for a direct avenue of invading bacteria to access and infect the brain – left untreated such an infection can be lethal. Our sensing of CSF electrically is the first of any such report, and all previous works have performed sensing through immunofixation assay or ELISA assay, which require multiple hour waiting periods, a trained technician to perform, and have poor lower limits of detection. The CSF sensor using the external PCB successfully detected from 0.1 ng/mL to 100 µg/mL of CSF in 1X PBS. A new sensing electrode was used for every test run and demonstrated strong uniformity amongst fabricated sensing electrodes.

References

[1] Chu, I. Sarangadharan, A. Regmi, Y. Chen, C. Hsu, W. Chang, G. Lee, J. Chyi, C. Chen, S. Shiesh, G. Lee and Y. Wang, "Beyond the Debye length in high ionic strength solution: direct protein detection with field-effect transistors (FETs) in human serum", Scientific Reports, vol. 7, no. 1, 2017.

[2] Yang, P. Carey, F. Ren, Y. Wang, M. Good, S. Jang, M. Mastro and S. Pearton, "Rapid detection of cardiac troponin I using antibody-immobilized gate-pulsed AlGaN/GaN high electron mobility transistor structures", Applied Physics Letters, vol. 111, no. 20, p. 202104, 2017.

[3] Yang, P. Carey, F. Ren, M. Mastro, K. Beers, S. Pearton and I. Kravchenko, "Zika virus detection using antibody-immobilized disposable cover glass and AlGaN/GaN high electron mobility transistors", Applied Physics Letters, vol. 113, no. 3, p. 032101, 2018.

[4] C. Lobo, M. Baumanis, R.F. Nelson, “Surgical Repair of Spontaneous CSF Leaks: A Systematic Review. Laryngoscope Investigative Otolaryngology. 2017.

Figure 1