Chronic diseases (CDs) are noncommunicable illnesses with long-term symptoms accounting for ~70% of all deaths worldwide. For the diagnosis and prognosis of CDs, accurate biomarker detection is essential. Currently, the detection of CD-associated biomarkers is employed through complex platforms with certain limitations in their applicability and performance. There is hence unmet need to present innovative strategies that are applicable to the point-of-care (PoC) settings, and also, provide the precise detection of biomarkers. On the other hand, especially at PoC settings, microneedle (MN) technology, which comprises micron-size needles arranged on a miniature patch, has risen as a revolutionary approach in biosensing strategies, opening novel horizons to improve the existing PoC devices. Various MN-based platforms have been manufactured for distinctive purposes employing several techniques and materials. The development of MN-based biosensors for real-time monitoring of CD-associated biomarkers has garnered huge attention in recent years. Herein, we summarize basic concepts of MNs, including microfabrication techniques, design parameters, and their mechanism of action as a biosensing platform for CD diagnosis. Moreover, recent advances in the use of MNs for CD diagnosis are introduced and finally relevant clinical trials carried out using MNs as biosensing devices are highlighted. This review aims to address the potential use of MNs in CD diagnosis.

In this manner, sensor technologies have garnered great attention in various fields, including biomedicine, [2][3][4][5] environmental monitoring, [6][7][8][9] smart devices, [10] wearable devices, [11] automobile manufacturing [12] since the semiconductor materials and circuits have been developed. In particular, biosensors are powerful and innovative analytical tools that incorporate biological receptors to recognize biological analytes through either physical or chemical transducers. Primarily, bio-receptors are responsible for identifying and capturing target analytes, and the transducer basically translates biological and chemical information into the detectable signals, which are eventually converted into the concentration of the analyte. [13,14] Considering gold standard methods, such as enzyme-linked immunosorbent assay (ELISA) [15] and polymerase chain reaction (PCR)-based strategies, [16] biosensors mostly hold crucial features, such as i) short assay time, [17] ii) affordable tools and reagents, [18] iii) portability, [19] and iv) facile use and minimum user interpretation. [20] Nowadays, the applications of biosensors have been leveraged by the advancements of portable and miniaturized platforms. In particular, over the past years, wearable health monitoring devices have notable impact on continuous and real-time monitoring of health parameters, thereby accelerating the deployment of biosensing strategies to daily lives. Besides, non-invasive and ease-of-collecting information supports the benefits of the wearable systems for enhancing the awareness of individuals and communities. [21][22][23] The special features of the mechanically flexible and stable wearable sensors include remarkable means, such as portability, comfortability, light-weight, non-invasive, and reliable performance. To put it simply, wearable sensors are readily attached to skin or organ surfaces through an adhesive tape [24] or microneedles, [25] and because of such easy integrations, several researchers have focused on developing wearable sensors for real-time health monitoring. A wearable sensor is basically composed of some vital elements, including a flexible base material attached to the skin or an organ, a signal transfer electrode, and a biorecognition element. Recently, researchers have concentrated on creating integrated sensors that are able to measure various parameters simultaneously, such as pressure, temperature,The healthcare system has a drastic paradigm shift from centralized care to home-based and self-monitoring strategies; aiming to reach more individuals, minimize workload in hospitals, and reduce healthcare-associated expenses. Particularly, wearable technologies are garnering considerable interest by tracking physiological parameters through motion and activities, and monitoring biochemical markers from sweat, saliva, and tears. Through their integrations with sensors, microfluidics, and wireless communication systems, they allow physicians, family members, or individuals to monitor multiple parameters withou...

devices, where engineering, biochemistry, molecular biology, and biomedical technologies are integrated seamlessly with each other. POC devices have great advantages due to their portability, size, accuracy, and low volume of samples. These advantages are fundamentally changing the workflow of health care systems by shortening the turnaround time, accelerating the clinical decisionmaking with early treatment possibilities, and enabling to test individuals at resource-scarce settings, including but not limited to disaster areas, remote settings, or physician office with the limited laboratory access. Ultimately, this crucial direction makes health delivery closer to the patient rather than the provider. [4] In addition, even if the patient is not living in the countryside, the utilization of POC devices at hospitals has exhibited a remarkable reduction in the duration of hospital stay due to the elimination of time-consuming, centralized laboratory testing. [5,6] Since the size and portability are great advantages of POC devices, storage, proper usage, and quality control of tests are still unmet challenges. For instance, external factors, e.g., light, humidity, and temperature, hinder the performance of these tests potentially, and thereby, they need to be controlled comprehensively through regular calibrations, technical service, and maintenance performed by trained and experienced personnel, which potentially increase their cost and complexity, as well as limit their utility at the resourceconstrained settings. [7,8] Microfluidics, on the other hand, denotes a unique opportunity by controlling and manipulating the low volume of liquids (10 -9 to 10 -18 L) precisely; handling samples easily; offering inexpensive and large-scale production with the desired parameters; modulating surface properties and integrating multiple control units; and presenting versatile integrity with different sensing modalities. All these features highlight the potential of microfluidics as a full or integrative unit of POC diagnostic devices. From the production perspective, there are many microfabrication methods, such as replica molding, nanoimprint lithography, SU-8 photoresist, rapid prototyping, microinjection molding, and plasma processing. [9,10] In these platforms, liquids can be controlled in microscale membranes, valves, chambers, reservoirs by mixing or reacting them with each other. Moreover, all these kinds of fashions manipulating the low volume of liquids are creating great opportunities for POC applications, where integration, miniaturization, computerization Over four decades, point-of-care (POC) technologies and their pivotal applications in the biomedical arena have increased irrepressibly and allowed to realize the potential of portable and accurate diagnostic strategies. Today, in the light of these advances, POC systems dominate the medical inventions and bring the diagnostics to the bedside settings, potentially minimizing the workload in the centralized laboratories, as well as remarkably reducing the associated...

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