Progression in Quantum Sensing/Bio-Sensing Technologies for Healthcare

The 5th/6th generation bio-sensing technology is an emerging field which connects smart technologies like Artificial Intelligence, Internet of Things and Machine Learning with efficient micro/nano-enabled sensing platform for making point-of-care (POC) devices to investigate health management strategies. Recently, the integration and interfacing between quantum measurement, signaling, and optimized bio-actives has led to investigate the minute biological events with anomalous sensitivity. Such technologies are expected to provide the possibility to measure and record changes at quantum scales with varying pressure, temperature, and electromagnetic fields. Considering current scenarios, this perspective critically highlights state-of-art quantum sensing technology along with their challenges and prospects.

Quantum sensing (Q-S) is a cutting-edge emerging sensing technology which enables the measurement of a response data with accuracy via detecting variations in the motion of magnetic and electrical fields, as the output data/signaling is extracted to generate from a single atom rather than their massive groups as the case in classical sciences. 1 These salient features are of high significance because such sensing increases the precision, thoroughness, efficiency, and productivity of modern technical systems to locate, analyze, discover, perceive, and engage with the surroundings. The informatics collected using Q-S provides greater accuracy that can improve the functionality and applicability of existing sensing technology by gathering and exploiting finer statistics to produce enhanced data outcomes. Better than any conventional measuring method, quantum sensors have the ability to sense atomlevel alterations by utilizing so-called "quantum resources." 2 For instance, quantum sensors could be created via atoms and molecules in open space and specific solid phase gadgets, despite the fact that quantum optics normally depends on assessments utilizing different characteristics of light or photons. 3 Research groups are working on developing different modern-day devices based on the 5th/6th generation sensor technology where focus is on the utilization and combination of advanced technologies like Internet of Things (IoT), Artificial Intelligence (AI), and tailored nano-systems functionalized (NSs). 4,5 With the help of Q-S, a quick, more precise, and much more consistent geo-location which are now feasible using GPS systems that rely on satellites with a lot less restrictions. Q-S present caregivers with less expensive, more precise, and less likely to cause adverse clinical consequences clinical diagnostic scans. Improved, healthier automated land, aerial, and marine global positioning systems, even in densely populated regions as well as over unforeseen impediments is possible due to the quantum technology, 6 as illustrated in Fig. 1. Different applications of quantum-based sensors have been illustrated in Fig. 2, and one of such sensing approach is quantum biosensing (Q-BS). These includes bioimaging (neuronal sensing and heart imaging), spectroscopy (imaging of molecular structures like proteins), communication (signal receiving and amplification of radar communication, calibrating electrical standards to support 5 G/6 G technology), navigation (providing high-accuracy GPS; assisting with navigation inside building and underground), environmental monitoring (predicting volcanic disruption and measuring CO 2 emissions), infrastructure monitoring (monitoring mechanical stability and detecting leaks), geographical surveying (assisting with the location of oil and gas), and fundamental science (assessing high-energy physics beyond the standard model). The Q-S is used in highly precise and resilient guiding technologies for use in space, undersea, and the growing variety of areas where radiofrequency (RF) transmissions is overwhelming. Accurate identification, scanning, and modelling of subsurface settings, including plumbing fixtures, sewage, and transportation corridors as well as subsurface mines, wrecks, and ecosystems are all possible with the advancement of Quantum technology. [7][8][9] State-of-Art Q-BS To diagnose diseases, identify multi drug resistance organisms, identify emerging epidemics, and recognize very less concentration of poisons and microorganisms in potable water or food, biosensors are amongst the greatest propitious instruments now available in the bio-medical and global fields of healthcare. But the difficulties facing engineers and scientists who are tackling such problems are significant. For example, biosensors should be sensitive enough to identify even minute levels of microorganisms in bloodstream or other bodily samples if they are to improve the accuracy and efficacy of medical diagnosis. 10 The sensors must be sensitive enough to pick up disease-causing microorganisms in bloodstream or other body fluids in even the tiniest quantities. The Q-BS has a variety of potential applications, including precisely demarcating tumor boundaries throughout the treatment and monitoring a medicine all over a cell's membrane and cytoplasm. 11 Particularly crucial biological operations like folding of protein, the passage of particles via signaling pathways in cell membranes, and the propagation of electrical impulses via synapses may be captured by Q-S platform. The Q-S/BS potentially can monitor a solitary ion travelling across a cell membrane, quantify the electrical forces at a neural synapse, or capture the movement of peptides amongst microscopic organelles present inside a cell-all difficult to visually witness activities. Quantum engineering and biology-related technology have the possibility to completely transform how we comprehend medicine at the most fundamental levels. 12 Q-BS must be placed precisely where intriguing biological processes are occurring to obtain the data that scientists are looking for. Experts are developing novel methods to operate quantum sensors in hotter, and in lesser regulated conditions so they may view "movies" of occurrences instead of just "snapshots" to using the capabilities of quantum biosensors fully. Discussed below are some advancements of biomedical application using quantum Technology.

Emerging Nanotechnology for Q-S/BS
Due to large part to the hectic lifestyle and growing departures from nature, effective wellness and healthcare has recently become a top research priority. In order to reduce the impairment that come along with illnesses and chronic diseases, a cautious and correct diagnosis has been required, for which different materials are being explored. Different materials are discussed in the subsequent sections that have their application in quantum technology.
Higher stimulus-discrete materials, such as Quantum dots (QDs), 2D materials, and now perhaps metallic nanomaterials, could substitute classic electronics systems in biosensors. The tightly packed energy bands in these kinds of nanomaterials, which are easily adjusted by external disruption, are credited with this characteristic. In this manner, even a small deviation from the expected reaction might be effectively detected. 13 Some of the stateof-art NSs are emerging suitable for developing Q-S/BS technology, as discussed below.
• High-performance NSsNSs can be incorporated via altering the design of analytes as well as transduction circuitry, with the latter having more natural occurrences and relying on size and shapemodified energy bandgap tailoring for quick detection. The NSs are most suitable as substructure for detecting moiety and for quickly masking transduction reactions. 14 The determinants of NSs applicability in enhanced transduction circuits are the allocation of energy levels that rely on shape and size. Together, these characteristics drive NSs as quantum mechanically propelled systems that are controlled by a limited number of outcomes that are conventionally not possible. 15 The NSs could be substantially designed and synthesized for promoting several engagements simultaneously with improved surface area and numerous binding areas.Nanomoieties can be synthesized using various synthesis routes depending upon the intended application and uses. The use of green route for synthesis of nanomaterials has made them less-toxic, costeffective, biocompatible and has also improved their other substantial properties. [16][17][18] Due to these material's tighter energy levels, just a little variation in expropriated external energy is quickly sensed, that is the key to their microscopic biological responsiveness. 19,20 The operational responsiveness of NSs that is shape and size dependency, and a large surface energy is yet another characteristic of their capability for bio-sensing. Electrical uses and individual charge particle transport are particularly well adapted to the geometries of graphene, CNTs, and semiconducting nanowires. 21 Adding to it, the feature of NSs employment in biosensing is unavoidably related to their enhanced functionalization capacities brought on by their high surface area levels. The ease of modification of these materials, makes them highly selective to their target which enable the tracking of whatever stimulus or material reaction in both biotic and abiotic settings. 22 Figure 1. Q-S/BS technology towards personalized healthcare management. Exploring high-performance and tunable properties of nanostructures at atomic level to achieve, low level detection of a biomarkers for early-stage diagnostics, improve imaging for diseases monitoring, improving testing at point-of-care (POC)-assisted by IoMT, and establishing AI-based inventions including risk-assessments & timely decision. Based on outcomes, QB can be projected for efficient diseases management as a result the expected market of quantum sensing is estimated as $11400 million by 2022-2031 (Source: Inside Quantum Technology News).
• QDs for Q-S/BS applicationSynthetically synthesised nanoscale crystals called QDs can carry electrons. These semi -conductive nanoparticles can release a range of coloured hues when exposed to UV radiation. These synthetic particles have discovered use in fluorescent biological markers, solar cells, and composite materials. Quantum effects restrict the frequencies during which electron and hole pair can exist in semiconductor particles if the particles are made tiny enough. That implies that the visual characteristics of the nanoparticle can be precisely modified based on the size because energy and wavelength (or colour) are connected. Thus, by simply adjusting their size, these particles could be designed to absorb or emit particular light wavelengths (colours). 23 The detection and therapy of ailments like cancer may be greatly enhanced by quantum dots, which allow researchers to analyse biological activities at the scale of one molecule. The QDs are either employed as proactive sensor components in cellular imaging, in which the fluorescence characteristics of the QDs are altered upon response to the analyte, or in silent tag probes, where specific surface molecules, such as proteins, antibodies, have been coupled to the exterior of the dots. 24 Biocompatibility is one of the gravest concerns which has to be taken care of while using these materials into/for human body. Some research groups have already explored the biocompatibility issue of the quantum technology. 25,26 The QDs based on carbon materials like graphene, popularly known as the graphene-QDSs can breach through the blood-brain barrier owing to their extremely small size. 27 The field of medicine could be revolutionised by quantum dots. Sadly, the majority of these are poisonous. Strangely, the inclusion of major metals in QDs, such as cadmium, a known human toxicant and carcinogen raises significant risks, particularly for applications in medicine when QDs are administered into the system on purpose. Ecological pollution and toxicology issues must be tackled in order to make a non-toxic and compatible nanomaterial. 28 • MXenes as newly emerged 2D platform for Q-S/BS applicationsEarly transition metal carbonitrides and carbides in two dimensions, known as MXenes, are becoming a distinctive class of faceted metals with appealing properties, including high conductivity on level terms with metallic materials, augmented ionic conduction, water-repelling properties resulting from their own oxygen or hydroxyl-terminated surface irregularities, and stretchability. 29 The formation of nanomaterials, single-layer, or multi-layer nano-sheets, which have high particular contact area and thus are advantageous for improving the device effectiveness of MXenes-based sensors, may be successfully regulated using customizable etching techniques. 30 MXenes-based biosensors provide good repeatability of data over an extended duration of time due to their wide porous structure, strong bio -compatibility, and abiding resilience. The typical formula for MXene, a 2D transition metallic material, is Mn + 1AXn (n = 1, 2, 3). 31 These ceramic materials were dubbed MAX phases by scientists. MXenes can very easily be used to create hybrids with various elements. MXenes and their composites exhibit improved elastic properties and adaptability with structural design, enabling a wide range of applications in the areas of wearable sensing devices, storing energy, and electro-magnetic quantum shields. 32 MXenes have the potential to form composite with different classes of materials such as metallic nanomaterials and polymers. 33 These composites can be further clubbed with advanced technologies like AI, ML and IOT to develop quantum-based healthcare devices. 34 • Graphene for Q-S/BS applicationA monolayer of carbon atoms which are sp 2 -hybridized, ordered into honeycomb-like frameworks makes graphene, the celebrity of 2D inorganic layered materials, and it has drawn enormous scientific interest over the years. 35 Due to its enormous relative surface area, high stability, atomic homogeneity, great mechanical qualities, superior bio-compatibility, and distinctive and customizable optical and electrical properties, graphene has been used in a variety of fields ever since discovery. 36,37 Numerous research has clarified how graphene and its analogues' diverse biosensing properties are governed by their remarkable conductivity, high surface area, and large adsorbing capacities. The extraordinary surface modification capabilities of graphene, which enable demandbased applications and assay design to be tuned, are clearly the driving force behind the growing usage of graphene and its analogues in biosensing. 38,39 Figure 2. Q-S supported by electrical, mechanical, and magnetic engineering to achieve high-performance biomedical application involve biosensing, imaging, and drug delivery.
• Borophene for Q-S/BS applicationThe smallest basic Dirac material and a 2D allotrope of boron, borophene is the most recent and most promising 2D material due to its distinct structural and electrical properties in the β12 and X3 phases. An outstanding edensity at the conductivity level and, consequently, a substantially high metallic behaviour is produced by the large atomic volume on ridgelines of the borophene β12 phase. Considerable scientific curiosity is generated by the borophene's distinct structure and electrical features. 40,41 Presumably, the anisotropic crystal phases of borophene, which possesses a remarkable unique chemical interaction, have high Young's moduli and thermal conductivities. 42 Borophene is readily usable in bendable hetero-layered systems, sensors, quick electrical devices, and excitonic gadgets. Interfacial coupling is essential for regulated functionality because it enables individual atomic layers to collaborate effectively. 40 • Transition Metal Dichalcogenides for Q-S/BS application A continuous layer of transition metal dichalcogenides (TMDs) is composed of metal atoms wedged among chalcogen atoms. By covalent bonding, the metal atom is joined to the nearby chalcogen atoms. TMDs have been found to have graphene-like mechanical, chemical, physical, and electrical characteristics and are better suited for numerous optoelectronic purposes. 13 TMDs include substances like tungsten disulphide, molybdenum ditelluride, and molybdenum disulphide.
TMDs feature a significant number of activated sites for the contact adsorption of foreign materials due to their high surface area to volume ratio. This offers the adsorbents a great foundation for fastening on the surfaces. 34 TMDs are also surface-keen materials, which makes them extremely susceptible to alterations in the surroundings. With adsorption of surface, doping of the surface, stress/strain, or any other such modifications, the characteristics of TMDs can alter. 43 Through a variety of methods, the bandgap of TMDs can be modified to provide an acceptable energy band gap and band integration with its composition. Additionally, it is simple to manufacture TMD defects to render it better suited for sensing purposes. 44 QS-assisted neuroimaging; towards colorful brain.-During the past 100 years, medical imaging has advanced significantly. However, the visuals produced by our existing neuro-imaging technologies are comparable to the way a black-and-white camera sees the world. It should be a network of links that is engaging, dynamic, and very intricate. Researchers have had a difficult time creating practical techniques to precisely visualize brain functioning due to the incredibly appropriate shell living beings have developed to reflect the brains, skulls, and cerebrospinal fluids. Researchers studying neurodegenerative ailments, which frequently include underlying neural circuits, have thus confronted formidable obstacles, which have limited our knowledge of these conditions. 45 Methods for neuroimaging have benefited from the advancement of quantum sensor equipment. Specifically, the use of quantum sensors to improve the magnetic fields sourced by the electrical pursuit of neurons. Studies utilizing quantum sensors have shown that they can be integrated into magnetoencephalography systems to enable the observation of activity in brain networks on a millisecond timeframe whilst subject is in motion. Although these methods are still in their early stages, we will surely learn more about neurological disorders as they advance, facilitating the development of improved clinical and clinical screening applications. 46 The magnetic fields that are present in our brain is a trillion time less than that present in a refrigerator magnet. In order to detect these extremely weak fields, a sensor need to be exceedingly sensitive which cannot be achieved through classical sensors. A research group at the University of Sussex have successfully developed a modular Q-S for detecting these extremely fragile magnetic fields in the brain. They have used a Lego brick structure to connect two sensors to map the neural activity of the brain by using the ultra-sensitive quantum sensing technology. This sensor was placed outside the participant's scalp near to the visual cortex of the brain and signals were recorded. 47

Detection of Neurodegenerative Diseases Using Q-BS
A glimpse of inside the brain which is not possible with conventional imaging methods is delivered by quantum sensors. This is crucial for enhancing the effectiveness of neurodegenerative disease treatments. Additionally, it gives researchers the ability to deepen their knowledge of the underlying basis of neurodegenerative illness. This will result in more potent therapeutic alternatives and disease prevention measures for conditions like Alzheimer's and Parkinson's. 48 Several of the finest cutting-edge biosensors have recently been developed by researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago. These diamondbased sensors can measure the electric and magnetic field, temp, and interior tension of a cell. The use of this technique to examine the minute folding of protein associated with Parkinson's, Alzheimer's, and Huntington's disease is anticipated in the future. 49 While the natural mechanism of folding of protein is a normal one, neurodegenerative diseases are characterized by the sorting out of protein aggregates. In order to avoid and cure these disorders, we must certainly better comprehend its process. 50 However, the true capability of quantum computing is yet being fully realized.

Nitrogen-Vacancy Center (N-V center) -Based Q-BS
A physical phenomenon known as quantum entanglement could be witnessed when two particles engage or are in close vicinity to one another; in this case, the quantum states of the two particles cannot be represented separately, even at a great distance. While spin-based systems will primarily react to magnetic fields, charged ions will be sensitive to electric forces. However, it demonstrates what is known as "intrinsic sensitivity," meaning that they respond strongly to received signal and are little impacted by undesirable noise. The spin method involves removing two neighboring carbon adjuncts from a diamond lattice and replacing either of those by a nitrogen atom. 51 This defect center is filled with an extra nitrogen electron, creating a structure known as a nitrogen-vacancy center (N-V center). The spin impact in the diamond may be visually started and retrieved off, and this electron has a spin. Regarding state stability and/or the potential for quantum entanglement, the spins adhere to the concept outlined above. 52 It is possible to create a solitary photon source or an isolated NV center for quantum magnetometry. These NV centers can be created in a capacity or simply on surfaces. The development of sensing devices that are smaller, quieter, and more sensitive than current sensors is made possible by N-V centers.
Biomedical implementations for N-V centers-based sensors, such as nanodiamonds, include better MRI, the identification of especially fragile magnetic fields generated by the physiology of living cells, and the diagnostic test of heart ailments by evaluating the faintest magnetic fields all through metabolism of cardiac tissue. Thus, it is possible to detect NMR signal from various nuclear entities in a specimen of about 20 nm, enabling the application of NMR methods to studies within the cells. 53 IoT & AI-supported Q-BS Platform Because of its capability for processing massive quantities of information, producing precise results, and controlling processes to create the best possible outcome, AI has attracted the attention of scientists and the healthcare sectors. Using trustworthy machinealgorithm synchronized outputs, a number of aspects are taken into consideration, including interpretability, fairness, responsibility, dependability, and acceptability. 54 A contemporary technique centered on computing science called AI creates algorithms and programmed to render machines smart and effective at carrying out activities that often call for expert human intellect. 34 These clever solutions make it easier for humans to intervene in medical imaging, clinical diagnostics, and resolution settlement. The Internet of Medical Things (IoMT), a next bioanalytical tool that integrates software applications and networkconnected biomedical devices for improving human healthcare, appears in the same time period. 55 The IoMT comprises of medical equipment that is networked together for the purpose of evaluating patient care. This approach is based on optimized integrated automation, nano/micro-scale sensors, point-of-care testing, bioinformatics generation, AI-based analytics using modern techniques to provide continuous healthcare tracking and management without human involvement. 56 IoMT-assisted technologies enable wirelessly monitoring health parameters, which reduces unneeded hospital visits and, consequently, the related health expenses. 57 To facilitate physiological, functional, and behavioral scanning, tackle social engagement of daily life, and either focus on specific health-related conditions or support the more general goal of comfort, well-being, and quality of life, these modern technologies make use of a wide range of commercially available smart sensors and medical devices based on quantum techniques. 58,59 Future Needs and Prospects Q-S/BS exhibited a great sensitivity, but they are nevertheless susceptible to specific kinds of disturbances, which limits their applicability in many scenarios. One impediment to developing quantum systems is the paucity of equipment accessible for sensing the quantities beyond the laboratory environment. Due to these limitations, there is a topic gap among quantum physics studies and real-world settings. Since quantum sensors are primarily intended for laboratory use, scaling one up to a commercial scale is similarly difficult. The S/N ratio of quantum sensors, like as that employed in spectroscopy purposes, is additionally hampered by elements like quantum coherence, which is followed by environmental losses and disturbances. The efficient modifications and functionalization of quantum-based materials needs to be further taken care of as it plays a key role in eliminating/reducing the toxicity of these materials.
Q-S/BS are anticipated to transit beyond quantum concept investigations into a common, practical quantum system as the need for improved quantum innovations and Q-S/BS worldwide. Q-S/BS will undoubtedly advance with more financing for quantum science and commercial interest, despite the fact that there are numerous obstacles to overcome until quantum sensors are widely used.

Conclusions
Due to their feasibility and technological capabilities, sensors focused on the NV centers in synthetic bulk materials and nanodiamonds are among the developing quantum technologies with enormous potential for use in biological systems. Such Q-S are useful and effective particularly for biomedical activities because they can initialize and check out the spin state visually at ambient temperature. Additionally, the obtained degrees of spatial resolution and sensitivity are exceedingly high, which in theory permits prospective use towards this identification of incredibly weak electromagnetic fields such as those produced by mammalian, and possibly human, cells. The latest advancement of such methods, along with the rising popularity in neurological field identification as therapeutic and diagnostic techniques for neurodegenerative diseases and the impacts of ageing, are anticipated to accelerate technological advancements and ultimately the commercial success of quantum aided biosensing.