Portable sensing devices for smart healthcare and prevention of lead poisoning

Abstract

Lead (Pb) poisoning can damage human bodies silently, without specific symptoms or conspicuous warning signs. To provide safe and user-friendly tools for detecting heavy metals at low concentrations, scientists have developed and optimized versatile biosensors. To practically employ the developed biosensors specific for Pb (eg, the optimized Met-lead 1.44 M1), smartphone applications designed for user convenience and are easily operable for the on-site detection of Pb in environmental water, drinking water, food, and blood/urine are urgently needed. To establish a monitoring system for home health maintenance, a portable device and useful apps installed on a smartphone can be integrated, and the data acquired can be sent to and stored in the cloud for further analysis and evidence preservation. With the high transmissions speeds for 4G and 4G wireless Internet, such a system can be applied for health protection; water-quality data can be provided by anyone and publicly shared for display on smartphone interfaces, alerting individuals of heavy metal contamination. In this review, we describe recent developments in heavy metal–sensing devices, including home health maintenance systems, which have been successfully and practically applied to prevent heavy metal Pb poisoning.

1. LEAD AS AN UNSEEN HAZARD

The heavy metal lead (Pb) has adversely affected human health for thousands of years.¹ Although people have gradually discovered its toxic impacts, Pb remains dangerous because of the lack of conspicuous signs of Pb poisoning, especially with low exposure.² Substantial Pb exposure can cause severe health problems such as cardiovascular and renal dysfunctions, and irreversible neuronal damage is observed, but no symptoms specific to Pb poisoning can be used to confirm a diagnosis; sampled body fluid must be discovered directly to contain Pb.³ Thus, Pb-painted toys continue to be sold, and many cities still use old leaded pipes, meaning that billions of children may live in Pb-contaminated environments.^4,5 However, the extent of Pb exposure is poorly understood by most people.

Defining “safe” levels of Pb in the environment and drinking water is challenging. Pb concentrations of 10 (1 μg/dL; 50 nM) and 15 ppb are the upper limits for tap water set by the World Health Organization (WHO) and the United States Environmental Protection Agency, respectively. Moreover, experts cannot agree on the levels of Pb content required to cause cell, tissue, or organ damage. The blood lead level (BLL) is the only standard of Pb exposure, which can typically only be evaluated at a hospital. The physician makes final diagnostic decisions based on the BLL and observable symptoms. Generally, the BLL of adults should not exceed 10 μg/dL (100 ppb; 500 nM), which is 10 times the WHO’s permissible level for tap water, and that of children should not surpass 3.5 μg/dL (35 ppb; 175 nM).⁶ Patients with BLLs below these values are treated as healthy. Even if a patient’s BLL exceeds 20 μg/dL (two times the accepted BLL), a patient may present only mild symptoms (eg, fatigue, insomnia, and emotional instability in adults and abnormal cognition, behavior, or balance in children), which can easily be associated with other diseases; typical symptoms of Pb poisoning in adults and children are listed in Tables 1 and 2, respectively. This is the major reason for Pb poisoning still often ignored. Chronic Pb exposure, even very low amounts, can irreversibly damage organs in children.⁷ Thus, the “safe” BLL remains dubious.⁸ In fact, a chronically low (but nonzero) BLL has been found to be a major cause of anemia, infertility, and related disorders such as hypertension.⁹ The limits considered safe for tap water, and BLLs remain uncertain but tend to decrease as new data become available. However, the goal of reducing these limits is hampered by insufficiently sensitive detection methods.

Table 1.

Selected symptoms of Pb poisoning found in adults

Severity of Pb poisoning	BLL (μg/dL)
Server
Central nervous system (CNS): brain lesions, coma, epilepsy, obtuse, delirium, local movement disorder, headache, papilledema, optic neuritis, increase of intracranial pressure	>100
Peripheral nervous system (PNS): foot of perpendicular, wrist drop
Digestion system: abdominal colic
Blood: anemia
Kidney: nephropathy
Middle
CNS: headache, memory loss, insomnia, loss of libido	70-100
PNS: peripheral neuropathy
Digestion system: metallic taste, abdominal colic, anorexia, constipate
Kidney: arthritis, malfunction in uric acid excretion
Others: mild anemia, muscle ache, muscle weakness, joint pain
Mild
CNS: fatigue, insomnia, emotional unstable, decrease of interests in leisure activities	20-69
Others: adverse effects in cognition, reproduction, kidney functions, and bone density, high blood pressure and cardiovascular diseases (CVDs), high risk in cancer

As standard regulation, BLL should be less than 10 μg/dL.

BLL = blood lead level.

Table 2.

Selected symptoms of Pb poisoning found in children

Severity of Pb poisoning	BLL (μg/dL)
Server
CNS: brain lesions, coma, epilepsy, cranial nerve palsy, dysesthesia, indifferent, papilledema etc.	> 70
Digestion system: vomit
Blood: anemia
Middle
CNS: irritability, hypersomnia, no interests in any things	50 - 70
Digestion system: intermittent vomit, abdominal pain, anorexia
Mild
CNS: abnormal in cognition, behavior, balance, and coordination	<49
Others: loss of hearing ability, developmental retardation

As standard regulation, BLL should be less than 5 μg/dL.

BLL = blood lead level; CNS = central nervous system.

BLL and environmental Pb monitoring is generally achieved through the use of a precision instrument, such as in inductively coupled plasma mass spectrometry (ICP-MS), which is the gold standard. Such analytical instruments are generally restricted to hospitals or certified laboratories, require professional training (eg, specialists), and entail complicated and time-consuming procedures.^10,11 In addition, patients must visit the hospital for blood drawing (for BLL testing) or the environmental examination department (for drinking water testing). To alleviate such inconvenience and remove these barriers, new Internet-enabled, smartphone-integrated methods that can provide prompt and precise real-time monitoring of Pb content in drinking water or blood/urine have been explored.⁶

2. SMARTPHONE-BASED PB SENSING WITH INTERNET OF MEDICAL THINGS

With the rapid development of electronics, especially powerful smartphones, various software and hardware aspects have been considerably improved, including smartphone cameras, computation ability, wireless Internet connectivity (4G/5G), and portability.¹² Many target of interest (TOI) can be captured by sensing technologies, including blood glucose¹³ and related metabolites, such as maltose,¹⁴ biomolecular signal transduction molecules such as cyclic adenosine monophosphate,¹⁵ neurotransmitters^16–18 such as glutamate, and enzymes for detecting tumor cells.^19,20 TOI detection methods are crucial for the biomedical and pharmaceutical industries as well as for disease diagnosis and treatment.^21,22 Many portable sensing devices have been developed for examinations and other biomedical applications (Table 3).^23–35 Some such devices integrate smartphones and associated applications with TOI detection means, such as immune assays,^28,29 electrochemistry, fluorescence detection techniques (eg, fluorescence resonance energy transfer [FRET] assays),³⁵ versatile optics (eg, single-ball lenses^24,25 with magnificent amplification and microprism arrays),^28,29 microfluidic sampling,³² and magnetic separation,³⁰ for easy operation and prompt readout.

Table 3.

Smartphone-based portable catchers to sense the target of interests

Targets of detection (TOI)	Smartphone and built-in camera	Image qualities	Ref
	Outlet and specs
	Cost
Blood cells (malaria, sickle-cell anemia), tuberculosis	Nokia N73 (CMOS 2048 × 1536)	Amplification: 28 X	23
	LED (455 nm)	Resolution: 1.2 μm
		Field-of-view (FOV): 180 μm2
		Computed image analyzed
Blood cell tests	iPhone 2G, 4G; Ball lens	Amplification: 350 X	24
		Resolution: 1.5 μm
		FOV: 150 μm2
		Computed algorithm analyzed
Malaria parasite detection	iPhone 4S; Ball lens	Amplification: 4.5 X	25
	Cost: USD $ 70.13	Resolution: 1 μm
	Mechatronics design	FOV: 150 μm2
Virus detection	Nokia PureView 808 (CMOS 7728 × 5386)	Amplification: external 2 X	26
	Laser Diode (450 nm); Weight: 186 g	Resolution: 2 μm
		FOV: 0.36 mm2
		Computed algorithm analyzed
Various types of cells	iPhone 4S	Amplification: 14.4 X	27
	Cost: USD $ 6	Resolution: 5 μm
		FOV: 15.7 mm2
IL-6, FBS and plant virus immune analysis	iPhone 5 (CMOS 3264 × 2448)	Resolution: 252 nm/pixel	28
	Size: 142 × 160 × 41 mm	FOV: 33 mm2/ 85.5 x 127.8 mm2	29
	Cost: USD $ 50; 150	Cell phone app. image analyzed
	Limit of detection (LOD): 10.6 pg/mL
	8 × 8 Microprism array (96 well plate)
Cell counting (A549, HeyA8, etc.)	Samsung Galaxy S6 (Sony IMX240)	Resolution: 10 μm	30
	Size: 165 × 75 × 50 mm; Weight: 214 g	FOV: 700 μm2
	3 LEDs; Cost: USD $ 105.87
	Magnetic separation design
Cell counting (white blood cells and others)	Sony-Ericsson U10i Aino (CMOS)	Resolution: 20 μm	31
	LED (470, 580 nm)	FOV: 81 mm2
	Size: 35 × 55 × 24 mm; Weight: 28 g	Computed image analyzed
	Cost: USD $ 14.5
Cell counting (white blood cells)	Sony-Ericsson U10i Aino (CMOS)	Amplification: 7.8 X	32
	Size: 35 × 55 × 27.9 mm; Weight: 18 g	Resolution: 2 μm
	Cost: USD $ 3.9; Microfluidic design	Computed algorithm analyzed
Hg	Samsung Galaxy S II (CMOS)	Amplification: 7 X	33
	LED (523 nm, 625 nm); Weight: 37 g	Cell phone app. image analyzed
	LOD: 17.3 nM (3.5 ppb) (Cuvette)
Hg	Z17 mini (CMOS)	Resolution: 2.2 μm	34
	Laser Diode (405 nm)	FOV: 1.5 mm2
	Size: 170 × 113 × 168 mm	Cell phone app. image analyzed
	LOD: 1 nM
Pb	Asus ZenFone 3 (CMOS 4608 × 3456)	Amplification: 50 X	35
	Laser diode (405 nm); Weight: 1800 g	Resolution: 10 μm
	Size: 190 × 140 × 105 mm (Chamber)	FOV: 700 μm2
	Cost: USD $ 544; LOD: 24 nM (4.7 ppb)	Computed image analyzed

CMOS = complementary metal-oxide-semiconductor; FBS = fetal bovine serum; IL-6 = interleukin 6.

Table 3 lists some representative smartphone-based portable devices.^23–35 The detection, counting, and monitoring of TOIs can involve pathogens (malarial parasites),^23,25 viruses,^26,28,29 normal cells,^{23,24,27,31,32} cancer cells,³⁰ and heavy metals (eg, mercury³³ and Pb).³⁵ The sensing ability of such smartphone-based catchers as those listed in Table 3 indicates the bright future of such portable tools for use with the Internet of medical things (IoMT), especially during the pandemic of COVID-19.^36,37

3. USER-FRIENDLY SMARTPHONE-BASED PB DETECTORS

Over the years, scientists have devoted themselves to constructing reliable chemical and biological tools for detecting Pb in samples more easily than can be achieved through ICP-MS.^35,38–45 Such devices can consist of fluorescence sensors,^{35,39,43–45} either chemosensors,⁴¹ or genetically encoded protein biosensors,³⁵ with extremely high sensitivity; however, such devices require special readout systems.^35,46 Such devices may also utilize colorimetric sensors,^38–40,42 which generally have low sensitivity. Sensors using test papers are among the most convenient,^39,42,44 but their sensitivity is often low (with some exceptions).³⁹ Alternatively, portable smartphone-compatible devices are now capable of high sensitivity because of advancements in built-in camera technology, and the cost of such a device may decrease over time. However, the reliability of such smart sensing devices remains unproven. To validate the values acquired from such devices, test samples need to be examined again using the gold standard ICP-MS method.^{10,11,35,40,42–44}

As developers of Pb detection technology, we have spent years constructing and optimizing fluorescent protein biosensors for detecting Pb (Met-leads)³⁵ and various other applications.^46–50 The sensitivity (limit of detection [LOD]) of our optimal sensor, Met-lead 1.44 M1, is 10 nM (0.2 μg/dL; 2 ppb), which is 17 times lower than the determined BLL in children (3.5 μg/dL) and five times lower than the limit for tap water (10 ppb) set by the WHO.⁴⁸ Our data show that Met-lead 1.44 M1 is suitable for practical Pb detection through sampling of general sources, and people globally can benefit from the widespread use of this invention. The sensor can be used on a sensing chip within a detection device for portable monitoring. Recently, we integrated Met-lead 1.44 M1 with a smartphone to construct a new portable Pb sensor, the pMet-lead.³⁵ The animated diagram of pMet-lead can be found at https://reurl.cc/KQlZmg.³⁵ With this novel pMet-lead containing a biosensor chip coated with Met-lead 1.44 M1–expressing cells, we for the first time practically revealed that the drinking water from two regions of Taiwan contains excess Pb contents, 10.6 and 15.24 ppb (Fig. 1).³⁵ This new easy-to-handle device will soon enable for prompt and precise Pb detection in irrigation water, tap water, and human blood/serum or urine.

Fig. 1.

Practical on-site Pb detection in selected areas using the portable FRET-based Pb-sensing device pMet-lead. (A) Geographical regions where water samples were randomly collected in selected cities of Taiwan: I. Taipei city; II. New Taipei; III. Taoyuan; IV. Miaoli; V. Nantou; VI. Yunlin. (B) Representative ratio color images of samples I–VI analyzed using pMet-lead. (C) Average ratio for each geographical region compared to control water samples. The mean differences are described as significant at the 0.0005 (***) level. (D) pMet-lead FRET ratio values of Pb measurements from various geographic sources of water were validated by the general standard method (ICP-MS). Scale bar, 30 μm. The ratio color bar is from 2 to 4.5. The data are originally from Lai et al³⁵ and reproduced with permission from Lai et al³⁵ to use the same here. FRET = fluorescence resonance energy transfer; ICP-MS = inductively coupled plasma mass spectrometry; Pb = lead.

Several smart portable Pb-sensing platforms have been developed.^35,38–45 Among the nine selected smartphone-based devices listed in Table 4, only four have an LOD sufficient for detecting Pb at 10 ppb (the WHO’s limit).^35,38–40 Three are colorimetric methods (including paper strip–based methods) that have not yet been validated through ICP-MS.^38–40 Additionally, colorimetric methods may be problematic in that smartphones with various white-balance methods may present color and images differently. Our pMet-lead (with an LOD of 4.7 ppb confirmed through ICP-MS)³⁵ is the only validated device for on-site Pb detection, and despite its high cost, it remains cheaper than a high-end FRET microscope. The fact that Met-lead 1.44 M1 employs living cells limits its applicability. In the future, purified Met-lead 1.44 M1 proteins can be employed to overcome this obstacle. However, further refinement to reduce the cost of manufacturing components for the pMet-lead will be essential in the development of the cheaper second-generation pMet-lead II. Sensors with poor LODs (eg, the paper strip–based Alizarin Red S complex with a LOD of 30 ppb costs only US$0.01)⁴² can still be applied to confirm the sufficient clearance of heavy pollutants from factory wastewater, another crucial application of Pb detection.

Table 4.

Examples of smartphone-based portable Pb-sensing devices

General components	Mechanism	LOD	Time	Ref.
	Preprocessing	Selectivity
	Cost	Practical applications
Smartphone, inkjet-printed objective lens, image processing	Smartphone nano-colorimetry (SNC): single-step sedimentation (yellow sediment)	1.37 ppb (DI water); 5 ppb (city water)	10 min	38
	K2CrO4, PDMS; HNO3	Ba (>100 ppb), CO3 (precipitate)
		Tap water simulating with Pb
Smartphone, Paper Strip; UV lamp (365nm); App. (Color recognizer, Xiyi Technology).	Colorimetric paper-based dual-emission carbon dots (CDs) B/R fluorescence ratio (8/1); BCDs (452 nm); RCDs (620 nm), Paper Strip; L-cysteine (Cu Chelation)	0.58 ppb (solution instrument)	5 min	39
		7.03 ppb (solution smartphone)
		9.13 ppb (paper strip smartphone)
		Cu (interfere)
		Tap and lake water simulating with Pb
Smartphone, TFT LCD, App. (Image process & predict)	Colorimetric machine learning algorithm (localized surface plasmon resonance, LSPR)	0.5 ppb	30 min.	40
	Gold nanoparticles (GNPs, red to purple)	Tap water (Tehran, Iran)
		River water (Mazandaran, Iran)
		Zamzam water (Mecca, Saudi Arabia)
Smartphone, Optics, LED, Laser diode (405 nM), App.	FRET protein biosensor	4.7 ppb	10-60 min	35
	PBS (pH 7.4), ionomycin (5 μM), Tricine (10 mM) to chelate Zn	Zn (interfere)
	USD $544	Tap water (Taiwan)
Smartphone, microcontroller, App. Bluetooth, cloud	Whole-copper electrochemical sensor (WCES) chip, Acetate buffer	14.9045 ppb	10 min	41
		Lake water (Binya Lake, Haikou city, China)
Smartphone, Paper Strip, Laptop, LED, App.	Pb-Alizarin red S (ALS) complex purple color	30 ppb (LOD)	1 min	42
	ALS; (color picker application)	Ni (tolerance ratio > 10)
	USD$0.01	Waste water (electronics factory) simulating with Pb
Smartphone, LED (365 nm); diffuser; lens; microarray chip; SBR-App.	Smartphone-based reader (SBR) for paper-based microarray	60 ppb (experiment);	5 min	43
	Emission carbon dot (CD)	15.6 ppb (practical application)
	CDs (450 nm)	Pearl River water (five samples)
	USD $180; 130 g
Smartphone, Paper Strip, Laptop, LED, App.	RD6G-1 probe with ring opening of the corresponding spirolactam ring	120 ppb (LOD)	31 min	44
	RD6G-1 probe, APTES, AuNPs (Color Picker application)	Cu (color change)
		Chicken meat, liver, heart
		Duck meat and eggs
Smartphone, App.	SPR, interparticle plasmon coupling through agglomeration	1.5 ppm	N.A.	45
	AgNP, DHCA, L-DOPA
		Water pollution

Generally, most of the targets are water from various sources. The WHO/EPA standard is no less than 10/15 ppb.

AgNP = silver nanoparticle; DHCA = deep hypothermic circulatory arrest; DI water = De Ion water or deionized water; FRET = fluorescence resonance energy transfer; L-DOPA = levodopa or l-3,4-dihydroxyphenylalanine; LOD = limit of detection; PBS = phosphate buffered saline; PDMS = polydimethylsiloxane; UV = ultraviolet.

4. FUTURE PERSPECTIVES

In this review article, we provide nine examples of portable Pb-sensing devices that have the potential to be combined with the powerful IoMT for fast Pb detection in environmental water (eg, a river near a factory) or drinking water and the establishment of stricter BLLs (requiring further integration of the device for blood sampling, another issue to be resolved). With these new IoMT devices, people can prevent Pb poisoning. We hope that the IoMT and easy-to-use Pb biosensors become available worldwide, achieving at least two of the 17 Sustainable Development Goals: clean water and sanitation and good health and well-being.

ACKNOWLEDGMENTS

This work was supported by Ministry of Science and Technology of Taiwan (MOST 110-2320-B-075-005, MOST 108-2745-8-075-001-, MOST 105-2320-B-075-002) and Taipei Veterans General Hospitals (V110C-018).