This Scientific Short is an update to Is it time to give Paper based Sweat Chloride Testing Another Chance provided by the original author.

Cystic Fibrosis (CF), one of the most common and probably best-known inherited disorders, has been diagnosed using sweat or perspiration from the skin for centuries. CF is caused by mutations of a single gene, CF transmembrane conductance regulator (CFTR), which leads to defective transepithelial ion transportation in multiple organs, such as the skin, lung, pancreas, and intestines. Due to the defective ion transportation, the sweat of people with CF usually exhibits a significantly elevated level of chloride (Cl-)(> 60 mM), one of the most notable clinical manifestations of CF. This symptom led to European folklore back to the 15th century pronounced, “Woe to the child who tastes salty from a kiss on the brow…” In addition, the excessive salt loss through sweat in CF leads to an increased risk of heat prostration. Dr. Dorothy H. Anderson established a connection between the abnormal ion composition of sweat and cystic fibrosis (1), which underpins the development of modern sweat tests for diagnosing CF.

Sweat tests rely on the phenotype of CFTR, thus remaining a diagnostic gold standard in the era of genomic medicine. However, collecting a sufficient amount of sweat is one of the major hurdles in centralized laboratory-based sweat tests, especially for newborns within three months. Samples with low volume are termed “quantity not sufficient” (QNS), a common preanalytical issue. For example, around 10% to 40% of sweat tests have been reported to collect less than 15 μl sweat in a 30-minute collection, which is the volume required by Clinical and Laboratory Standards Institutes (CLSI) for accurate testing (2). The high QNS rates are attributed to the unoptimized design of devices and the discrete and cumbersome protocols for sweat collection. For instance, the sweat on the skin tends to evaporate, leading to volume reduction and condensation errors. Eventually, the high QNS rates lead to an indefinite test outcome and prevent an early clinical intervention for people with CF.

Flexible and wearable biosensors (3), resembling a Band-Aid and skin stickers, perform tests on the skin and exhibit substantial potential in addressing the high QNS rates. The advent of wearable biosensors is largely due to the advances in microfabrication, bioelectronics, and microfluidics, which enable conformal attachment to soft and curved skin and the seamless integration of multiple units, thus facilitating sweat collection for CF diagnosis. In addition, configurational optimizations of the iontophoresis in wearable biosensors have been reported to enhance the volume of collected sweat. Furthermore, one colorimetric detection mechanism of Cl-, based ion exchange in a paper-based skin patch (4,5), requires only 1-2 µl sweat, which also contributes to the reduction of QNS rates. The signal readout of wearables can be assisted by a smartphone via an electrical interface or the capture and process of photos, which enables the decentralized and point-of-care diagnosis of CF.

The wearable configuration of biosensors is promising to shift the paradigm of diagnosing and managing people with CF. CFTR modulators become increasingly available as a highly effective treatment for more than 90% of people with CF. Thus, a timely and accessible sweat chloride test is even more demanding and necessary for early CF diagnosis that would reduce pulmonary exacerbation and improve the quality of life of people with CF. In addition, the promise of wearable biosensors in CF is expected to inspire efforts in transforming other bench-top clinical tests into wearable ones.

References

  1. W. R. Kessler, D. H. Anderson. Pediatrics 8, 648-656 (1951).
  2. P. M. Farrell et al., The Journal of Pediatrics 181, S4-S15. e11 (2017).
  3. J. Kim, A. S. Campbell, B. E.-F. de Ávila, J. Wang. Nat. Biotechnol. 37, 389-406 (2019).
  4. X. Mu et al., Clinical Chemistry 59, A181 (2013).
  5. X. Mu et al., Chemical Communications 51, 6365-6368 (2015).