New antibody-based method for rapid detection of SARS-CoV-2 uses interstitial fluid (ISF)


Despite significant and stunning advances in vaccine technology, the COVID-19 global pandemic is not over. A key challenge in limiting the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is identifying infected individuals.

Now, investigators from Japan have developed a new antibody-based method for the rapid and reliable detection of SARS-CoV-2 that does not require a blood sample.

The ineffective identification of SARS-CoV-2-infected individuals has severely limited the global response to the COVID-19 pandemic, and the high rate of asymptomatic infections (16%–38%) has exacerbated this situation. The predominant detection method to date collects samples by swabbing the nose and throat.

However, the application of this method is limited by its long detection time (4–6 hours), high cost, and requirement for specialized equipment and medical personnel, particularly in resource-limited countries.

An alternative and complementary method for the confirmation of COVID-19 infection involves the detection of SARS-CoV-2-specific antibodies.

Testing strips based on gold nanoparticles are currently in widespread use for point-of-care testing in many countries. They produce sensitive and reliable results within 10–20 minutes, but they require blood samples collected via a finger prick using a lancing device. This is painful and increases the risk of infection or cross-contamination, and the used kit components present a potential biohazard risk.

Lead author Leilei Bao from the Institute of Industrial Science, The University of Tokyo, explains, “To develop a minimally invasive detection assay that would avoid these drawbacks, we explored the idea of sampling and testing the interstitial fluid (ISF), which is located in the epidermis and dermis layers of human skin.

Although the antibody levels in the ISF are approximately 15%–25% of those in blood, it was still feasible that anti-SARS-CoV-2 IgM/IgG antibodies could be detected and that ISF could act as a direct substitute for blood sampling.”

After demonstrating that ISF could be suitable for antibody detection, the researchers developed an innovative approach to both sample and test the ISF. “First, we developed biodegradable porous microneedles made of polylactic acid that draws up the ISF from human skin,” explains Beomjoon Kim, senior author.

“Then, we constructed a paper-based immunoassay biosensor for the detection of SARS-CoV-2-specific antibodies.” By integrating these two elements, the researchers created a compact patch capable of on-site detection of the antibodies within 3 minutes (result from in vitro tests).

This novel detection device has great potential that is safe and acceptable to patients for the rapid screening of COVID-19 and many other infectious diseases.

It holds promise for use in many countries regardless of their wealth, which is a key aim for the global management of infectious disease.

Syringes and hypodermic needles have been used to deliver drugs to patients for more than 160 years and are still the most routine and effective means [1]. However, there are some obvious limitations of this traditional syringe injection or needle delivery method in clinical application.

First of all, there is obvious pain resulting from needle insertion, and a large proportion of patients, especially children, show needle phobia and poor compliance, causing patients to psychologically reject the treatment, seriously affecting the effectiveness of the drugs. Secondly, needle reuse errors may lead to risk of infection with blood-borne pathogens, posing an incalculable risk to patients.

In addition, drug administration requires practitioners with a foundation of professional training to perform drug administration, which is very inconvenient, especially for patients requiring frequent drug administration. Therefore, the cost and risk should be taken into consideration. Moreover, the needles and syringes used by patients are mostly disposable medical supplies, resulting in the production of a lot of sharp waste [2].

In addition to percutaneous administration, there are also obvious problems with other conventional administration methods. For example, oral administration cannot be used for many drugs due to the limitation of enzyme metabolism in the gastrointestinal tract and liver, leading to low bioavailability of drugs [3].

Medicated baths are a traditional percutaneous administration method, but due to skin obstruction, the medicinal effect is greatly degraded, while the medication is also inconvenient. Topical ointment administration involves the penetration of the drug through the skin into the body, which is limited to lipophilic small molecule drugs [2,4].

Hypodermic injection is still an irreplaceable method of drug delivery, as it can enable the drug to reach the lesion site more quickly and effectively. Therefore, developing hypodermic delivery methods that can alleviate pain and infection is particularly important for effective drug delivery.

The skin is the largest organ, and is a strong biological barrier, preventing infectious diseases and harmful substances from entering the body. However, the skin is also a major barrier to the effective delivery of drugs to lesions via percutaneous administration, while meanwhile also being susceptible to pain [5]. The skin consists of three morphologically distinct layers: the cuticle, the living epidermis, and the dermis [6].

The skin acts as a barrier to drug absorption largely by means of the outermost stratum corneum (10–20 μm) [2,7,8,9]. The protective function of the skin is mainly provided by the stratum corneum. The stratum corneum consists of dead keratinocytes and intercellular matrix (commonly referred to as brick and mortar, respectively).

The latter is composed primarily of cholesterol, triglycerides, and ceramides, forming a dense structure with lipophilic properties (1.4 g/cm3). Due to the dense structure, it is almost impossible for drugs with molecular weight >500 Da and Log P in the 1–3 range to penetrate the cuticle [10].

Drugs with low molecular weight (<500 Da), high lipophilicity, and requiring doses as low as a milligram are allowed to pass through the cuticle [9,11]. Below the cuticle is a living epidermis (50–100 μm), which is responsible for the formation of the cuticle. The living epidermis is composed of different layers—basal layer, spinous layer, and granular layer from inside to outside, respectively—and without neural networks [6,12,13]. The dermis (1–2 mm) includes a wide range of nerve endings and blood vessels, so it can feel pain [13].

Microneedles (MNs), as the name implies, are a drug delivery tool with a pointer size in the micron scale, and consists of an MN patch in the form of many MN arrays with a needle length of 25–1000 μm that can only penetrate the active cuticle and live epidermis without reaching the nerve endings and blood vessels. Because of the microscopic size of MNs, the use of MNs does not stimulate nerves in the dermis or damage blood vessels, and thus patients do not feel intense pain during the process [14,15].

MNs could also overcome patients’ fear of needles, and avoid the liver and adverse metabolic and gastrointestinal side effects of oral administration, while penetrating the barrier of the cuticle without producing obvious pain. In addition, through the unique material selection and design, it can achieve the sustained long release of drugs under specific conditions [16,17,18,19].

In this review, we firstly introduce the background and the typical variety of MN drug delivery methods, including solid MNs, coated MNs, hollow MNs, degradable or soluble MNs, swelling MNs and porous MNs. Then we summarize the typical MN fabrication techniques and recent progress.

However, in real application, the complete process route for making target MNs usually requires a combination of multiple techniques. Next, we review the latest research status of MNs and summarize the application of MNs in the treatment of various diseases, including chronic illnesses such as arthritis, diabetes, cancer, dermatology, cosmetics, family planning, and epidemic disease prevention.

Finally, this paper gives an overview of the functional design of MN drug delivery systems using nano-engineering technology, which could be used to realize intelligent control of drug release amount, release kinetics, or stimuli-responsive delivery. In addition, we also present a research prospect for combining nanotechnology with MNs technology to achieve intelligent drug delivery.

Figure 1
The typical variety of drug delivery methods using MNs. (A) Solid MNs. Adapted with permission from Ref. [22]. (B) Coated MNs. Adapted from Ref. [23]. (C) Hollow MNs. Adapted with permission from Ref. [24]. (D) Degradable or soluble MNs (a) before insertion, and (b) 10 s, (c) 1 min, (d) 15 min, and (e) 1 h after insertion into pig cadaver skin. Adapted with permission from Ref. [25]. (E) Swelling MNs. Adapted with permission from Ref. [26]. (F) Porous MNs. Adapted with permission from Ref. [27].

reference link :

More information: Anti SARS CoV 2 IgM/IgG antibodies detection using a patch sensor containing porous microneedles and a paper based immunoassay, Scientific Reports (2022). DOI: 10.1038/s41598-022-14725-6


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