In vivo continuous monitoring of peptides and proteins: Challenges and opportunities

Fluctuations in the systemic concentration levels of metabolites, nutritionally relevant peptide hormones, protein biomarkers, and therapeutic materials provide a wealth of information that can be used to inform real-time clinical intervention. Thus, therapeutic outcomes for many disease states could be improved through the implementation of continuous monitoring systems. The most well-represented example of in vivo continuous monitoring of a small-molecule metabolite is the continuous glucose monitors used extensively in diabetes management. Unfortunately, to date, there is yet to be a marketed product that meets the engineering challenges or regulatory requirements for continuous sensing of peptides or proteins. A critical limitation of realizing this type of sensing is the limited availability of affinity-type biosensing elements, such as aptamers or antibodies. These molecules, while highly specific, have dissociation constants in the nano-picomolar range, which prevents reversibility between the biosensing element and analyte. In this review, several key challenges regarding the use of affinity-type biosensing elements to measure the concentration of peptides/proteins continuously in vivo are discussed. We discuss several examples of research groups working to overcome these limitations through specific engineering of biosensing elements, or by modulating the binding interaction itself using external energy. We then turn the discussion to insulin, a crucial therapeutic peptide for diabetes with the potential to enhance patient outcomes via continuous monitoring in vivo. This serves as a case study to explain why protein/peptide sensors currently suffer from translation. Finally, we summarize the current literature for insulin detection and discuss general translation toward in vivo continuous sensing of peptide/protein analytes.