# Breath Analysis: A Promising Tool for Disease Diagnosis--The Role of Sensors
## 5 Conclusions and Future Perspectives  
Exhaled breath analysis, especially using selective or cross-reactive sensors, comprises a non-invasive method that holds a great promise for application in early-stage and differential diagnosis of not only respiratory but also systemic diseases. The aim of this review was to present the main categories of nanomaterials and sensors that have been used up to now in exhaled breath analysis for disease diagnosis as well as to demonstrate the applicability of breath analysis in differential diagnosis, phenotyping, and staging of several types of diseases, especially via the use of cross-reactive sensing devices.  
The progressive development of novel nanomaterials offers a great opportunity to develop more effective sensing elements, both for selective and cross-reactive sensors and especially for point-of-care diagnosis, treatment monitoring and population screening. However, fundamental challenges in this novel research field inhibit the application of breath analysis in clinical practice and should therefore be addressed. Concerning analytical techniques used for exhaled VOCs identification, the use of bulky, expensive, and complex analytical devices is limited in hospitals while their incorporation in portable point-of-care systems is still unattainable [251]. In addition, the validity of breath analysis results is of major concern since the trace levels of exhaled VOCs affect the analysis accuracy [252]. At the same time the lack of clear breath sampling protocols [252], e.g., breath collection [251] and breath storage, could potentially change sample composition [251] and therefore emerge as important challenges. Sample composition can be also affected by confounding factors, i.e., age, gender, place of living, habits, and nutrition. In the case of sensors exhalation rate, a hardly controlled parameter, may also play a confusing role hence complicating the procedure [251].  
For those limitations to be overcome, breath analysis research should focus on sampling and procedure protocols standardization [118; 251] and system improvement towards technical/physiological/pathophysiological confounders [118], in order to determine the endogenous VOCs and to define valid exhaled patterns of biomarkers. Towards this direction, standard correlations between blood and breath VOC concentrations could be established [251]. Furthermore, the development of portable/wearable and low-cost nanomaterial-based sensors that are resistant to humidity [251] and serve the clinical needs (i.e., selectivity for disease-specific VOCs and inorganic gases, small recovery time for population screening), along with the optimization of sensor training and validation by using different subject-groups comprise critical steps for the development of sensors applicable in clinical diagnosis [118]. Notably, the ability of new sensing systems to discriminate different diseases, to achieve precise early diagnosis of diseases with similar symptoms and underlying mechanisms, is a major concern [200] that has only recently been considered.  
In order to meet all of the aforementioned goals, interdisciplinary research and cooperation is an essential prerequisite [251]. Breath analysis poses as a powerful and promising diagnostic tool that could eventually be used in clinical practice or in portable and compact health monitoring systems, provided it meets most of the existing challenges.  
Conceptualization, M.K., E.S. and D.T.; methodology, M.K., E.S. and D.T.; investigation, M.K.; writing--original draft preparation, M.K.; writing--review and editing, E.S.; supervision, E.S. and D.T.; project administration D.T., E.E. and N.L. All authors have read and agreed to the published version of the manuscript.  
This research received no external funding.  
Not applicable.  
The authors declare no conflict of interest.