Glucose biosensors in clinical practice: principles, limits and perspectives of currently used devices

Abstract

The demand of glucose monitoring devices and even of updated guidelines for the management of diabetic patients is dramatically increasing due to the progressive rise in the prevalence of diabetes mellitus and the need to prevent its complications. Even though the introduction of the first glucose sensor occurred decades ago, important advances both from the technological and clinical point of view have contributed to a substantial improvement in quality healthcare. This review aims to bring together purely technological and clinical aspects of interest in the field of glucose devices by proposing a roadmap in glucose monitoring and management of patients with diabetes. Also, it prospects other biological fluids to be examined as further options in diabetes care, and suggests, throughout the technology innovation process, future directions to improve the follow-up, treatment, and clinical outcomes of patients.

Keywords: assessment of glycemic control; biological fluids; diabetes technology; glucose sensors; point-of-care testing..

Figure 1

Milestones in the development of actual glucose sensor systems technology. In the inset, available literature and estimated patents filed involving glucose sensors (1955-2020). Sourced from Scopus (blue) and Google (red).

Figure 2

Error grid analysis proposed by Clarke et al., for clinical accuracy (A), and further modified by Parkes et al., for type 1 (B) and type 2 (C) diabetes. System bias plot (D), dashed black lines indicate the predetermined accuracy limits. FS represents the full-scale level for glucose concentration of the tested and reference sensor. Classically, it is set at 400 mg/dL (blood-based sensors).

Figure 3

(A) Schematic classification of the glucose biosensors evolution distinguished into generations according to the sensing mechanism. (B) Representative enzyme immobilization techniques: i, adsorption; ii, covalent bonding; iii, cross-linking; iv, entrapment. (C) Schematic representation of a characteristic direct electro-oxidation of glucose in non-enzymatic glucose sensors and the most investigated materials used as catalyst.

Figure 4

Main biofluids and technologies investigated for glucose monitoring, which include: (A) the gold standard venous blood and the widespread used peripheral blood for auto-monitoring; (B) ISF; (C) sweat; (D), saliva; (E) tears; (F) urine.

Figure 5

Roadmap for the management of diabetes mellitus. Summarized steps for the treatment and follow-up of type 1, type 2 and gestational diabetes are indicated. SGLT2, sodium glucose cotransporter 2; GLP-1RAs, glucagone-like peptide-1 receptor agonists; DPP-4i, dipeptydil peptidase-4 inhibitors; HbA1c, hemoglobin A1c; SGM, self glucose monitoring; CGM, continuous glucose monitoring; ASCVD, atherosclerotic cardiovascular disease; DKD, diabetic kidney disease.

Figure 6

Schematic representation of current and future monitoring of glycemic control in type 1, type 2 and gestational diabetes. In green, blood is used for the detection of glucose and other markers of glycemic control. In orange, non-invasive biological fluids for glucose detection. Currently, the only approved FDA non-invasive methods for glucose detection employ ISF. Multiplex invasive or non-invasive assays may be foreseen in the future to integrate glucose measurement in the follow-up of patients with diabetes, elderly type 2 diabetes, and prediabetes, as well as to support diabetes related research.