Table 3.

Smart paper-based biosensor devices classified according to the principle and the type of detection.

Applications	Biosensor Type	Evaluated in Real Samples?	Pat. Nº, Year, State	Improvements of Smart Sensor vs. Benchtop Techniques	Ref.
µCTX-II in urine	Immunological	No. Tested with artificial urine solution (AUS) with the same composition as real urine	US20180371529A1, 2015 Pending [72]	Effective smart optical biosensor, highly correlated with benchtop techniques and higher LOD for the use in patients with complications of renal insufficiency and also for the diagnosis and/or prognosis of osteoarthritis.	[73]
Hemoglobin	Colorimetric	Yes. Finger-pricked blood	WO2021019553A1, 2019 Pending [74] WO2021019552A1, 2020 Pending [75]	Fast, sensitive, and specific device for the detection of anemia with good correlation with the results of an automated hematology analyzer and on par with other POC test platforms. The results differ from the pathological estimates within the range of 0.5 g/dL for all severely anemic samples and <1.5 g/dL for the rest of the samples.	[76]
Urinary microbial ATP	Bioluminescent	No. A urine sample inoculated with E.Coli was used to simulate a urinary tract infection.	US8642272B2, 2014 [77]	First device bioluminescent on paper for the detection of low-cost ATP, based on the reaction of Luciferase/D-Luciferina that exploits the smartphone camera as a detector. The ATP sensing paper includes an Innovator Lyophilized “Nano-Lantern” With Reaction Components. The mentioned patent does not correspond to the device but is related to its manufacturing materials.	[78]
Human IgM and IgG	Immunological	Yes. Human serum	US20210382048A1, 2021 Pending [79]	This paper device has a detection limit of 100 fg/mL demonstrated for the biomarkers of the IgG and IgM protein, which is higher than the one achieved with a traditional Benchtop ELISA test. It is also a much faster method (<5 min), portable, resistant, stable, and low cost, which uses serum without sample preparation and can be easily discarded.	[80]
SARS-CoV-2	Genetic: AuNPs capped with highly specific antisense oligonucleotides (ssDNA)	Yes. Samples collected from Vero cells infected with SARS-CoV-2 virus and clinical samples	US20210388454A1, 2020 Pending [81]	This device can successfully and precisely distinguish the positive samples from Covid-19 from negatives, with sensitivity and specificity of almost 100%. It also presents sensing feasibility even for virus genomic mutation events due to the use of AuNPs, covered with highly specific antisense oligonucleotides (SSDNA) that are simultaneously directed to two separate regions of the same SAR-CoV-2 N gene	[82]
Cotinine in Urine	Immunological-Electrochemical	Yes. Urine samples of smoker and non-smokers patients	WO2019139537A1, 2019 Pending [83]	A simple lateral flow competitive immunochromatography was successfully integrated with the AgNP/HRP/AuNP-modified electrode. Immunoreaction can be monitored by either electrochemical measurement or wireless detection. Wireless sensing was realized for cotinine in the range of 100–1000 ng/mL (R2 = 0.96) in PBS medium. For 1:8 diluted urine samples, the device differentiated positive and negative samples and exhibited cotinine discrimination at levels higher than 12 ng/mL.	[84]
IL-6 levels in blood and respiratory samples	Immunological	Yes. Human blood and bronchial aspirate samples	WO2021048087A1, 2019 Pending [85]	Paper immunosensor interfaced with a smartphone that generates intense colorimetric signals when the sample contains ultralow concentrations of IL-6. The device combines a paper-based signal amplification mechanism with polymer-filled reservoirs for dispensing antibody-decorated nanoparticles and a bespoken app for color quantification. Semi-quantitative measurements of IL-6 can be facilitated in 10 min with a LOD of 1.3 pg mL−1 and a dynamic range of up to 102 pg mL−1 in diluted blood samples.	[86]