The “Bloodless” Blood Test: Intradermal Prick Nanoelectronics for the Blood Extraction-Free Multiplex Detection of Protein Biomarkers

Abstract

Protein biomarkers’ detection is of utmost importance for preventive medicine and early detection of illnesses. Today, their detection relies entirely on clinical tests consisting of painful, invasive extraction of large volumes of venous blood; time-consuming postextraction sample manipulation procedures; and mostly label-based complex detection approaches. Here, we report on a point-of-care (POC) diagnosis paradigm based on the application of intradermal finger prick-based electronic nanosensors arrays for protein biomarkers’ direct detection and quantification down to the sub-pM range, without the need for blood extraction and sample manipulation steps. The nanobioelectronic array performs biomarker sensing by a rapid intradermal prick-based sampling of proteins biomarkers directly from the capillary blood pool accumulating at the site of the microneedle puncture, requiring only 2 min and less than one microliter of a blood sample for a complete analysis. A 1 mm long microneedle element was optimal in allowing for pain-free dermal sampling with a 100% success rate of reaching and rupturing dermis capillaries. Current common micromachining processes and top-down fabrication techniques allow the nanobioelectronic sensor arrays to provide accurate and reliable clinical diagnostic results using multiple sensing elements in each microneedle and all-in-one direct and label-free multiplex biomarkers detection. Preliminary successful clinical studies performed on human volunteers demonstrated the ability of our intradermal, in-skin, blood extraction-free detection platform to accurately detect protein biomarkers as a plausible POC detection for future replacement of today’s invasive clinical blood tests. This approach can be readily extended in the future to detect other clinically relevant circulating biomarkers, such as miRNAs, free-DNAs, exosomes, and small metabolites.

Modern microelectronics and microfluidics on microneedles

“…21 For example, Harpak et al then used micromachining mechanical thinning and deep reactive ion etching (DRIE) technology to attain the final needle structure, which has a sharp tip that can simply pierce the skin layer and is approximately 150 μm wide and 250 μm thick. 82…”

“…Moreover, there are not single but array MNs in the system, so needles with different chemical modifications (mostly connecting specific proteins) can quantitatively detect the contents of different markers through the current change caused by antigen–antibody reactions. 82…”

“…(F) Making MNs by micromanufacturing technology and deep silicon etching. 82 Copyright 2022 American Chemical Society. (G) Illustration of the fabrication of MNs by the magnetic-field-induced spray self-assembly method.…”

“…21 For example, Harpak et al then used micromachining mechanical thinning and deep reactive ion etching (DRIE) technology to attain the final needle structure, which has a sharp tip that can simply pierce the skin layer and is approximately 150 μm wide and 250 μm thick. 82 Superparamagnetism is a specific magnetic behavior observed in small nanoparticles (NPs) of ferromagnetic materials (e.g., iron oxide) and composites containing these NPs (in the absence of an external magnetic field, superparamagnetic materials have zero magnetization strength; they have no residual magnetization and thus can be easily manipulated by the applied magnetic field). In magnetic-fieldinduced spray self-assembly, these superparamagnetic colloidal particles can self-assemble into a variety of anisotropic structures in the presence of an applied field.…”

“…Moreover, there are not single but array MNs in the system, so needles with different chemical modifications (mostly connecting specific proteins) can quantitatively detect the contents of different markers through the current change caused by antigen-antibody reactions. 82 It is also an idea to detect biomarkers with the current generated by enzyme-catalyzed biochemical reactions. For example, Park et al developed a patch-type MN glucose sensor and self-powered solid-state supercapacitors (SPSC) for continuous monitoring in diabetic patients (Fig.…”