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CRISPR-Enabled Graphene-Based Bio-Cyber Interface Model for In Vivo Monitoring of Non-Invasive Therapeutic Processes
Abstract
In this paper, we present a model of the bio-cyber interface for the Internet of Bio-Nano Things application. The proposed model is inspired by the gains of integrating the Clustered Regularly Interspace Short Palindromic Repeats (CRISPR) technology with the Graphene-Field effect transistor (GFET). The capabilities of the integrated system are harnessed to detect nucleic acids transcribed by another component of the bio-cyber interface, a bioreporter, on being exposed to the signalling molecule of interest. The proposed model offers a label-free real-time signal transduction with multi-symbol signalling capability. We model the entire operation of the interface as a set of simultaneous differential equations representing the process’s kinetics. The solution to the model is obtained using a numerical method. Numerical results show that the performance of the interface is influenced by parameters such as the concentrations of the input signalling molecules, the surface receptor on the bioreporter, and the CRISPR complex. The interface’s performance also depends considerably on the elimination rate of the signalling molecules from the body. For multi-symbol molecular signalling, the rate of degradation of the transcribed RNAs influences the system’s susceptibility to inter-symbol interference.
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The Internet of Bio-Nano Things (IoBNT) is a transformative communication framework characterized by heterogeneous networks comprising both biological entities and artificial micro/nano-scale devices, so-called Bio-Nano Things (BNTs), interfaced with conventional communication networks for enabling innovative biomedical and environmental applications. Realizing the potential of IoBNT requires the development of new and unconventional communication technologies, such as molecular communications, as well as the corresponding transceivers, bio-cyber interfacing technologies connecting the biochemical domain of IoBNT to the electromagnetic domain of conventional networks, and miniaturized energy harvesting and storage components for the continuous power supply to BNTs. Graphene and related materials (GRMs) exhibit exceptional electrical, optical, biochemical, and mechanical properties, rendering them ideal candidates for addressing the challenges posed by IoBNT. This perspective article highlights recent advancements in GRM-based device technologies that are promising for implementing the core components of IoBNT. By identifying the unique opportunities afforded by GRMs and aligning them with the practical challenges associated with IoBNT, particularly in the materials domain, our aim is to accelerate the transition of envisaged IoBNT applications from theoretical concepts to practical implementations while also uncovering new application areas for GRMs.
The purpose of this work is to demonstrate the fabrication process of cleanroom-free solid metal microneedles and quantify their insertion profiles. Metal microneedles were created using a modified wire-bonding process and inserted into porcine tissue to determine the design efficacy. The microneedle arrays were analyzed using optical imaging and SEM. The insertion forces were measured using a combined uniaxial load cell and resistance measurement data. Microneedle arrays were successfully inserted into porcine tissues with high repeatability and reliability. These arrays demonstrate lower or equivalent insertion forces (less than 3 N) to other forms of microneedles in the literature, without the need for complex cleanroom fabrication processes. The microneedle fabrication method presented here rapidly produces mass-manufacturable, high-quality microneedle arrays with minimal insertion forces that can reliably penetrate tissue samples. The manufacturing method presented here achieved array densities as high as 3200 needles per square centimeter. These microneedle arrays demonstrate the simple fabrication of a reliable, high-density, pain-free drug delivery system with potential applications in biosensing and electric-field-modulated drug delivery.
CRISPR/Cas technology originated from the immune mechanism of archaea and bacteria and was awarded the Nobel Prize in Chemistry in 2020 for its success in gene editing. Molecular diagnostics is highly valued globally for its development as a new generation of diagnostic technology. An increasing number of studies have shown that CRISPR/Cas technology can be integrated with biosensors and bioassays for molecular diagnostics. CRISPR-based detection has attracted much attention as highly specific and sensitive sensors with easily programmable and device-independent capabilities. The nucleic acid-based detection approach is one of the most sensitive and specific diagnostic methods. With further research, it holds promise for detecting other biomarkers such as small molecules and proteins. Therefore, it is worthwhile to explore the prospects of CRISPR technology in biosensing and summarize its application strategies in molecular diagnostics. This review provides a synopsis of CRISPR biosensing strategies and recent advances from nucleic acids to other non-nucleic small molecules or analytes such as proteins and presents the challenges and perspectives of CRISPR biosensors and bioassays.
The novel concept of Internet of Nano Things (IoNT) brings even larger groups of nanomachines collaborating to achieve more complex tasks in the military, medical, and security fields. Moreover, Internet of Bio-Nano Things (IoBNT) is an emerging technology defining the seamless connection of nanomachines and biological entities with each other where they can access the traditional wireless communication networks to provide novel Internet of Things (IoT) applications, such as health monitoring, healthcare, and targeted therapy. The exchange of information between biological cells is based on the synthesis, transformation, emission, propagation, and reception of molecules. This information exchange is recently classified in telecommunications as molecular communication which is a biologically inspired technique to communicate in very small dimension networks. In nanonetworks, a high number of nanothings will operate in the same medium and they interfere with each other. Multiuser interference will create significant limits. Hence, we introduce to use the direction of releasing molecules as a new property to convey information. Releasing the molecules to the specific directions enhances the performance of molecular communication systems due to multiusers interference mitigation. Hence, adjacent transmitters can convey information in different directions, simultaneously. Then, we propose the binary direction shift keying (BDSK) modulation scheme where the transmitter pumps molecules in two different directions. Next, we obtain the error probability and achievable bit rate of BDSK modulation. Finally, we evaluate the performance of BDSK modulation by numerical results. The result of this article can be useful for molecular communication relay systems where relay nodes convey information to the different destinations.
Cancer is a major public health problem and one of the leading causes of death. However, traditional cancer therapy may damage normal cells and cause side effects. Many targeted drug delivery platforms have been developed to overcome the limitations of the free form of therapeutics and biological barriers. The commonly used cancer cell surface targets are CD44, matrix metalloproteinase-2, folate receptors, etc. Once the drug enters the cell, active delivery of the drug molecule to its final destination is still preferred. The subcellular targeting strategies include using glucocorticoid receptors for nuclear targeting, negative mitochondrial membrane potential and N-acetylgalactosaminyltransferase for Golgi apparatus targeting, etc. Therefore, the most effective way to deliver therapeutic agents is through a sequential drug delivery system that simultaneously achieves cellular- and subcellular-level targeting. The dual-targeting delivery holds great promise for improving therapeutic effects and overcoming drug resistance. This review classifies sequential drug delivery systems based on final targeted organelles. We summarize different targeting strategies and mechanisms and gave examples of each case.
Purpose
We investigated the intensive care unit (ICU) outcomes of patients who used targeted therapy compared to those who received cytotoxic chemotherapy.
Materials and Methods
This study was based on Korean administrative health insurance claims from 2015 to 2019. We extracted data on lung cancer patients (>18 years old) who were admitted to the ICU after receiving chemotherapy.
Results
6,930 lung cancer patients who received chemotherapy within 30 days before ICU admission were identified; the patients received cytotoxic chemotherapy (85.4%, n = 5,919) and molecular targeted therapy (14.5%, n = 1,011). Grade 4 neutropenia was identified only in the cytotoxic chemotherapy group (0.6%). Respiratory failure requiring ventilator treatment was more common in the cytotoxic chemotherapy group than in the targeted therapy group (HR, 3.30; 95% CI, 2.99–3.63), and renal failure requiring renal replacement therapy was not significantly different between the two groups (HR, 1.57; 95% CI, 1.36–1.80). Patients who received targeted chemotherapy stayed longer in the ICU than the cytotoxic chemotherapy. The 28-day mortality was 23.4% (HR, 0.79; 95% CI, 0.67–0.90, p < 0.05) among patients who received targeted agents compared with 29.6% among patients who received cytotoxic chemotherapy.
Conclusion
Targeted chemotherapy for lung cancer may contribute to increasing access to critical care for lung cancer patients, which may play a role in improving critical care outcomes of lung cancer patients.
Bio-inspired molecular communications (MC), where molecules are used to transfer information, is the most promising technique to realise the Internet of Nano Things (IoNT), thanks to its inherent biocompatibility, energy-efficiency, and reliability in physiologically-relevant environments. Despite a substantial body of theoretical work concerning MC, the lack of practical micro/nanoscale MC devices and MC testbeds has led researchers to make overly simplifying assumptions about the implications of the channel conditions and the physical architectures of the practical transceivers in developing theoretical models and devising communication methods for MC. On the other hand, MC imposes unique challenges resulting from the highly complex, nonlinear, time-varying channel properties that cannot be always tackled by conventional information and communication tools and technologies (ICT). As a result, the reliability of the existing MC methods, which are mostly adopted from electromagnetic communications and not validated with practical testbeds, is highly questionable. As the first step to remove this discrepancy, in this study, we report on the fabrication of a nanoscale MC receiver based on graphene field-effect transistor biosensors. We perform its ICT characterisation in a custom-designed microfluidic MC system with the information encoded into the concentration of single-stranded DNA molecules. This experimental platform is the first practical implementation of a micro/nanoscale MC system with nanoscale MC receivers, and can serve as a testbed for developing realistic MC methods and IoNT applications.
MicroRNAs (miRNAs) have a prominent role in virtually every aspect of cell biology. Due to the small size of mature miRNAs, the high degree of similarity between miRNA family members, and the low abundance of miRNAs in body fluids, miRNA expression profiling is technically challenging. Biosensors based on electrochemical detection for nucleic acids are a novel category of inexpensive and very sensitive diagnostic tools. On the other hand, after recognizing the target sequence, specific CRISPR-associated proteins, including orthologues of Cas12, Cas13, and Cas14, exhibit collateral nonspecific catalytic activities that can be employed for specific and ultrasensitive nucleic acid detection from clinically relevant samples. Recently, several platforms have been developed, connecting the benefits of enzyme-assisted signal amplification and enzyme-free amplification biosensing technologies with CRISPR-based approaches for miRNA detection. Together, they provide high sensitivity, precision, and fewer limitations in diagnosis through efficient sensors at a low cost and a simple miniaturized readout. This review provides an overview of several CRISPR-based biosensing platforms that have been developed and successfully applied for ultrasensitive and specific miRNA detection.
The detection and quantification of protein biomarkers in interstitial fluid is hampered by challenges in its sampling and analysis. Here we report the use of a microneedle patch for fast in vivo sampling and on-needle quantification of target protein biomarkers in interstitial fluid. We used plasmonic fluor—an ultrabright fluorescent label—to improve the limit of detection of various interstitial fluid protein biomarkers by nearly 800-fold compared with conventional fluorophores, and a magnetic backing layer to implement conventional immunoassay procedures on the patch and thus improve measurement consistency. We used the microneedle patch in mice for minimally invasive evaluation of the efficiency of a cocaine vaccine, for longitudinal monitoring of the levels of inflammatory biomarkers, and for efficient sampling of the calvarial periosteum—a challenging site for biomarker detection—and the quantification of its levels of the matricellular protein periostin, which cannot be accurately inferred from blood or other systemic biofluids. Microneedle patches for the minimally invasive collection and analysis of biomarkers in interstitial fluid might facilitate point-of-care diagnostics and longitudinal monitoring. A microneedle patch that samples and quantifies target protein biomarkers in interstitial fluid allows for longitudinal monitoring of the levels of a range of disease-relevant biomarkers, as shown in live mice.
Communication between nano-machines is still an important topic in the construction of the Internet of Bio-Nano Things (IoBNT). Currently, molecular communication (MC) is expected to be a promising technology to realize IoBNT. To effectively serve the IoBNT composed of multiple nano-machine clusters, it is imperative to study multiple-access MC. In this paper, based on the molecular division multiple access technology, we propose a novel multi-user MC system, where information molecules with different diffusion coefficients are first employed. Aiming at the user fairness in the considered system, we investigate the optimization of molecular resource allocation, including the assignment of the types of molecules and the number of molecules of a type. Specifically, three performance metrics are considered, namely, min-max fairness for error probability, max-min fairness for achievable rate, and weighted sum rate maximization. Moreover, we propose two assignment strategies for types of molecules, i.e., best-to-best (BTB) and best-to-worst (BTW). Subsequently, for a two-user scenario, we analytically derive the optimal allocation for the number of molecules when types of molecules are fixed for all users. By contrast, for a three-user scenario, we prove that the BTB and BTW schemes with the optimal allocation for the number of molecules can provide the lower and upper bounds on system performance, respectively. Finally, numerical results show that the combination of BTW and the optimal allocation for the number of molecules yields better performance than the benchmarks.
Novel nano-scale communication techniques are inspired by biological systems. Neuro-spike communication is an example of this communication paradigm which transfers vital information about external and internal conditions of the body through the nervous system. The analysis of this communication paradigm is beneficial to exploit in the artificial neural systems where nano-machines are linked to neurons to treat the neurodegenerative diseases. In these networks, nano-machines are used to replace the damaged segments of the nervous system and they exactly behave like biological entities. In neuro-spike communication, neurons / nano-machines exploit the electro-chemical spikes and molecular communication to transfer information. This communication paradigm can be divided into three main parts, namely the axonal pathway, the synaptic transmission and the spike generation. In this paper, we focus on the axonal transmission part as a separate channel since the capacity of the axonal pathway has a significant effect on the capacity of neuro-spike communication channel. In thinner axons, the capacity of this part is the bottleneck of the neuro-spike communication channel capacity. Hence, we investigate the restricting factors of the axonal transmission which limit its capacity. We derive the capacity of Single-Input Single-Output (SISO) and Multiple-Input Single-Output (MISO) axonal channels. In the MISO case, we investigate the effect of the correlation among inputs on the channel capacity. Moreover, we derive a closed form description for the optimum value of the input spike rate to maximize the capacity of the axonal channel when the information is encoded by firing rate of neurons / nano-machines.
Sensitive and specific CRISPR diagnostics
Methods are needed that can easily detect nucleic acids that signal the presence of pathogens, even at very low levels. Gootenberg et al. combined the allele-specific sensing ability of CRISPR-Cas13a with recombinase polymerase amplification methods to detect specific RNA and DNA sequences. The method successfully detected attomolar levels of Zika virus, as well as the presence of pathogenic bacteria. It could also be used to perform human genotyping from cell-free DNA.
Science , this issue p. 438
Graphene is an ideal candidate for next generation applications as a transparent electrode for electronics on plastic due to its flexibility and the conservation of electrical properties upon deformation. More importantly, its field-effect tunable carrier density, high mobility and saturation velocity make it an appealing choice as a channel material for field-effect transistors (FETs) for several potential applications. As an example, properly designed and scaled graphene FETs (Gr-FETs) can be used for flexible high frequency (RF) electronics or for high sensitivity chemical sensors. Miniaturized and flexible Gr-FET sensors would be highly advantageous for current sensors technology for in vivo and in situ applications. In this paper, we report a wafer-scale processing strategy to fabricate arrays of back-gated Gr-FETs on poly(ethylene naphthalate) (PEN) substrates. These devices present a large-area graphene channel fully exposed to the external environment, in order to be suitable for sensing applications, and the channel conductivity is efficiently modulated by a buried gate contact under a thin Al2O3 insulating film. In order to be compatible with the use of the PEN substrate, optimized deposition conditions of the Al2O3 film by plasma-enhanced atomic layer deposition (PE-ALD) at a low temperature (100 °C) have been developed without any relevant degradation of the final dielectric performance.
The concept of Internet of Things has opened up many possibilities such as the prospective application domain where very tiny, biocompatible, and non-intrusive devices can communicate through the internet. This concept is termed the Internet of Bio-Nano Things (IoBNT). The interconnection and co-operability of bio-nanodevice networks have the potential to offer new technological innovations and solutions especially in ambient assisted living (AAL) and remote therapy. A crucial functionality of a typical IoBNT is to be able to eliminate a set of nanodevices from the network or subnetwork when the need arises. In this paper, we present a model example of an IoBNT that has the capability to initiate the elimination of bio-nanodevices from the network when desired. This model mimics the apoptotic signalling pathways in living organisms, where death molecules are sent to cells to initiate their self-annihilation from the system. To quantify the success of the elimination process, we introduced a performance parameter termed the residence factor, which related the number of eliminated devices to the non-eliminated ones. Numerical results show that for low concentration of the transmitted death molecules, the performance of the system significantly depends on the distances between a death initiating nanotransmitter and the nanodevices marked for elimination. The system performance also depends on the dimensional size of the nanodevices targeted for elimination.
This paper considers the scenario of a targeted drug delivery system, which consists of deploying a number of biological nanomachines close to a biological target (e.g. a tumor), able to deliver drug molecules in the diseased area. Suitably located transmitters are designed to release a continuous flow of drug molecules in the surrounding environment, where they diffuse and reach the target. These molecules are received when they chemically react with compliant receptors deployed on the receiver surface. In these conditions, if the release rate is relatively high and the drug absorption time is significant, congestion may happen, essentially at the receiver site. This phenomenon limits the drug absorption rate and makes the signal transmission ineffective, with an undesired diffusion of drug molecules elsewhere in the body. The original contribution of this paper consists of a theoretical analysis of the causes of congestion in diffusion-based molecular communications. For this purpose, it is proposed a reception model consisting of a set of pure loss queuing systems. The proposed model exhibits an excellent agreement with the results of a simulation campaign made by using the Biological and Nano-Scale communication simulator version 2 (BiNS2), a well-known simulator for molecular communications, whose reliability has been assessed through in-vitro experiments. The obtained results can be used in rate control algorithms to optimally determine the optimal release rate of molecules in drug delivery applications.
In recent years, progresses in nanotechnology have established the foundations for implementing nanomachines capable of carrying out simple but significant tasks. Under this stimulus, researchers have been proposing various solutions for realizing nanoscale communications, considering both electromagnetic and biological communications. Their aim is to extend the capabilities of nanodevices, so as to enable the execution of more complex tasks by means of mutual coordination, achievable through communications. However, although most of these proposals show how devices can communicate at the nanoscales, they leave in the background specific applications of these new technologies. Thus, this paper shows an overview of the actual and potential applications that can rely on a specific class of such communications techniques, commonly referred to as molecular communications. In particular, we focus on health-related applications. This decision is due to the rapidly increasing interests of research communities and companies to minimally invasive, biocompatible, and targeted health-care solutions. Molecular communication techniques have actually the potentials of becoming the main technology for implementing advanced medical solution. Hence, in this paper we provide a taxonomy of potential applications, illustrate them in some details, along with the existing open challenges for them to be actually deployed, and draw future perspectives.
The Internet of Things (IoT) has become an important research topic in the last decade, where things refer to interconnected machines and objects with embedded computing capabilities employed to extend the Internet to many application domains. While research and development continue for general IoT devices, there are many application domains where very tiny, concealable, and non-intrusive Things are needed. The properties of recently studied nanomaterials, such as graphene, have inspired the concept of Internet of NanoThings (IoNT), based on the interconnection of nanoscale devices. Despite being an enabler for many applications, the artificial nature of IoNT devices can be detrimental where the deployment of NanoThings could result in unwanted effects on health or pollution. The novel paradigm of the Internet of Bio-Nano Things (IoBNT) is introduced in this paper by stemming from synthetic biology and nanotechnology tools that allow the engineering of biological embedded computing devices. Based on biological cells, and their functionalities in the biochemical domain, Bio-NanoThings promise to enable applications such as intra-body sensing and actuation networks, and environmental control of toxic agents and pollution. The IoBNT stands as a paradigm-shifting concept for communication and network engineering, where novel challenges are faced to develop efficient and safe techniques for the exchange of information, interaction, and networking within the biochemical domain, while enabling an interface to the electrical domain of the Internet.
BioNumbers (http://www.bionumbers.hms.harvard.edu) is a database of key numbers in molecular and cell biology—the quantitative properties of biological systems of interest
to computational, systems and molecular cell biologists. Contents of the database range from cell sizes to metabolite concentrations,
from reaction rates to generation times, from genome sizes to the number of mitochondria in a cell. While always of importance
to biologists, having numbers in hand is becoming increasingly critical for experimenting, modeling, and analyzing biological
systems. BioNumbers was motivated by an appreciation of how long it can take to find even the simplest number in the vast
biological literature. All numbers are taken directly from a literature source and that reference is provided with the number.
BioNumbers is designed to be highly searchable and queries can be performed by keywords or browsed by menus. BioNumbers is
a collaborative community platform where registered users can add content and make comments on existing data. All new entries
and commentary are curated to maintain high quality. Here we describe the database characteristics and implementation, demonstrate
its use, and discuss future directions for its development.
With the advances in nanotechnology, novel nanosensing technologies can play a pivotal role in today’s society. Plasmonic sensing has demonstrated unprecedented detection reliability and resolution in a very compact form factor. Traditional plasmonic sensors leverage biofunctionalized metallic grating structures whose frequency response in transmission or reflection changes according to the presence of targeted biomarkers. However, these sensing setups require bulky measurement equipment to couple light to and from sensors for excitation and detection. In parallel, for over a decade, the nanoscale electromagnetic communication community has been leveraging plasmonic structures to transmit information at the nanoscale efficiently. By combining the two realms, this paper proposes the concept of joint nanoscale communication and bio-sensing systems enabled by plasmonic sensing nanoantennas. Sensing nanonodes can communicate from nanonode to nanonode for intra-body networks and from nanonode to a wearable device which, by leveraging the edge, can process and transmit the sensing information to the cloud, resulting in accurate diagnosis and reduced load on the medical testing infrastructure. First, we model the changes in the frequency response of a biofunctionalized plasmonic nanoantenna when exposed to different biomarkers. Then, we propose a chirp-spread spectrum excitation and detection system to enable simultaneous communication and sensing at the nanoscale. We present a data-driven human tissue model for communication through human tissue. We also present numerical results to demonstrate the performance of the proposed system.
Microneedle arrays provide an efficient tool for transdermal drug delivery in a minimally invasive and painless manner, showing great potential applications in medicine. However, it remains challenges in fabricating the desired microneedle arrays, because of their micron-scale size and fine structure. Novel manufacturing technologies are very wanted for the development of microneedle arrays, which would solidly advance the clinical translation of microneedle arrays. 3D printing technology provides a powerful manufacturing technology with superiority in fabricating the personalized and complex structures. Currently, 3D printing technology has been employed to fabricate the microneedle arrays, which could push more microneedle arrays into clinic and inspire the development of future microneedle arrays. This work will review the art of 3D printing microneedle arrays, the benefits of fabricating microneedle arrays with 3D printing, and the considerations for clinical translation of 3D-printed microneedle arrays. This work would provide an overview of the current 3D-printed microneedle arrays in drug delivery.
CRISPR systems are prokaryotic adaptive immune systems that use RNA-guided Cas nucleases to recognize and destroy foreign genetic elements. To overcome CRISPR immunity, bacteriophages have evolved diverse families of anti-CRISPR proteins (Acrs). Recently, Lin et al. (2020) described the discovery and characterization of 7 Acr families (AcrVIA1-7) that inhibit type VI-A CRISPR systems. We detail several inconsistencies that question the results reported in the Lin et al. (2020) study. These include inaccurate bioinformatics analyses and bacterial strains that are impossible to construct. Published strains were provided by the authors, but MS2 bacteriophage plaque assays did not support the published results. We also independently tested the Acr sequences described in the original report, in E. coli and mammalian cells, but did not observe anti-Cas13a activity. Taken together, our data and analyses prompt us to question the claim that AcrVIA1-7 reported in Lin et al. are type VI anti-CRISPR proteins.
Bodies have continuous reticular networks, comprising collagens, elastin, glycosaminoglycans, and other extracellular matrix components, within and around all organs. Fibrous tissue coverings of nerves and blood vessels create structural continuity beyond organ boundaries. We recently validated fluid flow through human fibrous tissues, though whether these interstitial spaces are continuous through the body or discontinuous, confined within individual organs, remains unlcear. We investigated continuity of interstitial spaces using two approaches. Non-biological particles (tattoo pigment, colloidal silver, anthracotic pigment) were tracked within colon, skin, and lung interstitial spaces and into adjacent fascia. Hyaluronic acid, a macromolecular component of interstitial spaces, was also visualized, analyzing skin and subcutaneous fascia, colon and mesenteric fascia, lung and pleura, gynecologic organs and their fascial sheathes, breast, and heart and great vessels. Both techniques demonstrate interstitial space continuity within and between organs including within perineurium and vascular adventitia traversing organs and the spaces between them. We suggest that there is a body-wide network of fluid-filled interstitial spaces that has significant implications for molecular signaling, cell trafficking, and the spread of malignant and infectious disease.
The current outbreaking of the coronavirus SARS-CoV-2 pandemic threatens global health and has caused serious concern. Currently there is no specific drug against SARS-CoV-2, therefore, a fast and accurate diagnosis method is an urgent need for the diagnosis, timely treatment and infection control of COVID-19 pandemic. In this work, we developed a field effect transistor (FET) biosensor based on graphene oxide-graphene (GO/Gr) van der Waals heterostructure for selective and ultrasensitive SARS-CoV-2 proteins detection. The GO/Gr van der Waals heterostructure was in-situ formed in the microfluidic channel through π-π stacking. The developed biosensor is capable of SARS-CoV-2 proteins detection within 20 min in the large dynamic range from 10 fg/mL to 100 pg/mL with the limit of detection of as low as ∼8 fg/mL, which shows ∼3 × sensitivity enhancement compared with Gr-FET biosensor. The performance enhancement mechanism was studied based on the transistor-based biosensing theory and experimental results, which is mainly attributed to the enhanced SARS-CoV-2 capture antibody immobilization density due to the introduction of the GO layer on the graphene surface. The spiked SARS-CoV-2 protein samples in throat swab buffer solution were tested to confirm the practical application of the biosensor for SARS-CoV-2 proteins detection. The results indicated that the developed GO/Gr van der Waals heterostructure FET biosensor has strong selectivity and high sensitivity, providing a potential method for SARS-CoV-2 fast and accurate detection.
As biological research has synthesized genomics, proteomics, metabolomics, and transcriptomics into systems biology, a new multiomics approach to biological research has emerged. Today, multiomics studies are challenging and expensive. An experimental platform that could unify the multiple omics approaches to measurement could increase access to multiomics data by enabling more individual labs to successfully attempt multiomics studies. Field effect biosensing based on graphene transistors have gained significant attention as a potential unifying technology for such multiomics studies. This review article highlights the outstanding performance characteristics that makes graphene field effect transistor an attractive sensing platform for a wide variety of analytes important to system biology. In addition to many studies demonstrating the biosensing capabilities of graphene field effect transistors, they are uniquely suited to address the challenges of multiomics studies by providing an integrative multiplex platform for large scale manufacturing using the well-established processes of semiconductor industry. Furthermore, the resulting digital data is readily analyzable by machine learning to derive actionable biological insight to address the challenge of data compatibility for multiomics studies. A critical stage of systems biology will be democratizing multiomics study, and the graphene field effect transistor is uniquely positioned to serve as an accessible multiomics platform.
Internet of bio-nano things (IoBNT) is a novel communication paradigm where tiny, biocompatible and non-intrusive devices collect and sense biological signals from the environment and send them to data centers for processing through the internet. The concept of the IoBNT has stemmed from the combination of synthetic biology and nanotechnology tools which enable the fabrication of biological computing devices called Bio-nano things. Bio-nano things are nanoscale (1-100 nm) devices that are ideal for in vivo applications, where non-intrusive devices can reach hard-to-access areas of the human body (such as deep inside the tissue) to collect biological information. Bio-nano things work collaboratively in the form of a network called nanonetwork. The interconnection of the biological world and the cyber world of the Internet is made possible by a powerful hybrid device called Bio Cyber Interface. Bio Cyber Interface translates biochemical signals from in-body nanonetworks into electromagnetic signals and vice versa. Bio Cyber Interface can be designed using several technologies. In this paper, we have selected bio field-effect transistor (BioFET) technology, due to its characteristics of being fast, low-cost, and simple The main concern in this work is the security of IoBNT, which must be the preliminary requirement, especially for healthcare applications of IoBNT. Once the human body is accessible through the Internet, there is always a chance that it will be done with malicious intent. To address the issue of security in IoBNT, we propose a framework that utilizes Particle Swarm Optimization (PSO) algorithm to optimize Artificial Neural Networks (ANN) and to detect anomalous activities in the IoBNT transmission. Our proposed PSO-based ANN model was tested for the simulated dataset of BioFET based Bio Cyber Interface communication features. The results show an improved accuracy of 98.9% when compared with Adam based optimization function.
A minimally invasive microneedle patch detects specific protein biomarkers in dermal interstitial fluid at high sensitivity via a needle-integrated immunoassay coupled with an ultrabright fluorescent label.
Cas13 has demonstrated unique and broad utility in RNA editing, nucleic acid detection, and disease diagnosis; however, a constantly active Cas enzyme may induce unwanted effects. Bacteriophage- or prophage-region-encoded anti-CRISPR (acr) gene molecules provide the potential to control targeting specificity and potency to allow for optimal RNA editing and nucleic acid detection by spatiotemporally modulating endonuclease activities. Using integrated approaches to screen acrVI candidates and evaluate their effects on Cas13 function, we discovered a series of acrVIA1-7 genes that block the activities of Cas13a. These VI-A CRISPR inhibitors substantially attenuate RNA targeting and editing by Cas13a in human cells. Strikingly, type VI-A anti-CRISPRs (AcrVIAs) also significantly muffle the single-nucleic-acid editing ability of the dCas13a RNA-editing system. Mechanistically, AcrVIA1, -4, -5, and -6 bind LwaCas13a, while AcrVIA2 and -3 can only bind the LwaCas13-crRNA (CRISPR RNA) complex. These identified acr molecules may enable precise RNA editing in Cas13-based application and study of phage-bacterium interaction.
The liver performs critical physiological functions such as metabolism/detoxification and blood homeostasis/biliary excretion. A high degree of blood access means that a drug's resident time in any cell is relatively short. This short drug exposure to cells requires local sequential delivery of multiple drugs for optimal efficacy, potency, and safety. The high metabolism and excretion of drugs also impose both technical challenges and opportunities to sequential drug delivery. This review provides an overview of the sequential events in liver regeneration and the related liver diseases. Using selected examples of liver cancer, hepatitis B viral infection, fatty liver diseases, and drug-induced liver injury, we highlight efforts made for the sequential delivery of small and macromolecular drugs through different biomaterials, cells, and microdevice-based delivery platforms that allow fast delivery kinetics and rapid drug switching. As this is a nascent area of development, we extrapolate and compare the results with other sequential drug delivery studies to suggest possible application in liver diseases, wherever appropriate.
Significance
Diagnosis and monitoring of disease is often done by measuring biomarkers found in blood, urine, saliva, and other bodily fluids. Another rich source of biomarkers is the interstitial fluid that surrounds cells and tissues in the body, but difficulty in accessing this fluid has limited its use in research and medicine. Here, we conducted experimental studies coupled with theoretical modeling to design a patch containing microscopic needles that puncture into superficial layers of skin and thereby enable withdrawal of interstitial fluid through micropores in a simple, minimally invasive manner. This patch can help researchers access interstitial fluid to advance discovery of novel biomarkers and enable doctors to use interstitial fluid for possible future diagnosis and monitoring of disease.
Molecular communication (MC) and molecular network (MN) are communication paradigms that use biochemical signalling to achieve information exchange among naturally and artificially synthesized nanosystems. Among the envisaged application areas of MC and MN is the field of nanomedicine where the subject of targeted drug delivery (TDD) is at the forefront. Typically, when someone gets sick, therapeutic drugs are administered to the person for healing purpose. Since no therapeutic drug can be effective until it is delivered to the target site in the body, different modalities to improve the delivery of drugs to the targeted sites are being explored in contemporary research. The most promising of these modalities is TDD. TDD modality promises a smart localization of appropriate dose of therapeutic drugs to the targeted part of the body at reduced system toxicity. Research in TDD has been going on for many years in the field of medical science; however, the translation of expectations and promises to clinical reality has not been satisfactorily achieved because of several challenges. The exploration of TDD ideas under the MC and MN paradigms is considered as an option to addressing these challenges and to facilitate the translation of TDD from the bench to the patients’ bedsides. Over the past decade, there have been some research efforts made in exploring the ideas of TDD on the MC and MN platforms. While the number of research output in terms of scientific articles is few at the moment, the desire in the scientific community to participate in realizing the goal of TDD is quite high as is evidence from the rise in research output over the last few years. To increase awareness and provide the multidisciplinary research community with the necessary background information on TDD, this paper presents a visionary survey of this subject within the domain of MC and MN. We start by introducing in an elaborate manner, the motivation behind the application of MC and MN paradigms to the study and implementation of TDD. Specifically, an explanation on how MC-based TDD concepts differ from traditional TDD being explored under the field of medical science is provided. We also summarize the taxonomy of the different perspectives through which MC-based TDD research can be viewed. System models and design challenges/requirements for developing MC-based TDD are discussed. Various metrics that can be used to evaluate the performance of MC-based TDD systems are highlighted. We also provide a discussion on the envisaged path from contemporary research activities to clinical implementation of the MC-based TDD. Finally, we discuss issues such as informatics and software tools, as well as issues that border on the requirement for standards and regulatory policies in MC-based TDD research and practice.
Molecular communication (MC) is the most promising communication paradigm for nanonetwork realization since it is a natural phenomenon observed among living entities with nanoscale components. Since MC significantly differs from classical communication systems, it mandates reinvestigation of information and communication theoretical fundamentals. The closest examples of MC architectures are present inside our own body. Therefore, in this paper, we investigate the existing literature on intrabody nanonetworks and different MC paradigms to establish and introduce the fundamentals of molecular information and communication science. We highlight future research directions and open issues that need to be addressed for revealing the fundamental limits of this science. Although the scope of this development encompasses wide range of applications, we particularly emphasize its significance for life sciences by introducing potential diagnosis and treatment techniques for diseases caused by dysfunction of intrabody nanonetworks.
With the advent of nanotechnology, concepts related to the Internet of Things, such as the Internet of NanoThings and Internet of Bio-NanoThings (IoBNT) have also emerged in the classical literature. The main concern of this paper is the IoBNT, which projects the prospective application domain where the activities of very tiny, biocompatible, and non-intrusive devices operating in an in-body nanonetwork can be monitored and controlled through the Internet. In this paper, we present an illustrative scenario and system model of an IoBNT for application in an advanced healthcare delivery system. To address one of the major challenges of the IoBNT, we present an exemplary architecture and model of a bio-cyber interface for connecting the conventional electromagnetic-based Internet to the biochemical signaling-based bionanonetwork. The bio-cyber interface is designed and modeled by employing biological concepts, such as the responsiveness of certain biomolecules to thermal and light stimuli, and the bioluminescence phenomenon of some biochemical reactions. The analysis in this paper focuses on the system that comprises the bio-cyber interface and the information propagation network of the blood vessel that leads to the in-body nanonetwork location. The effects of the system and design parameters associated with the IoBNT models presented are numerically evaluated.
Repositioning of approved drugs has recently gained new momentum for rapid identification and development of new therapeutics for diseases that lack effective drug treatment. Reported repurposing screens have increased dramatically in number in the past five years. However, many newly identified compounds have low potency; this limits their immediate clinical applications because the known, tolerated plasma drug concentrations are lower than the required therapeutic drug concentrations. Drug combinations of two or more compounds with different mechanisms of action are an alternative approach to increase the success rate of drug repositioning.
Molecular communications, where molecules are used to encode, transmit, and receive information, are a promising means of enabling the coordination of nanoscale devices. The paradigm has been extensively studied from various aspects, including channel modeling and noise analysis. Comparatively little attention has been given to the physical design of molecular receiver and transmitter, envisioning biological synthetic cells with intrinsic molecular reception and transmission capabilities as the future nanomachines. However, this assumption leads to a discrepancy between the envisaged applications requiring complex communication interfaces and protocols, and the very limited computational capacities of the envisioned biological nanomachines. In this paper, we examine the feasibility of designing a molecular receiver, in a physical domain other than synthetic biology, meeting the basic requirements of nanonet-work applications. We first review the state-of-the-art biosensing approaches to determine whether they can inspire a receiver design. We reveal that the nanoscale field effect transistor-based electrical biosensor technology (bioFET) is particularly a useful starting point for designing a molecular receiver. Focusing on bioFET-based molecular receivers with a conceptual approach, we provide a guideline elaborating on their operation principles, performance metrics, and design parameters. We then provide a simple model for signal flow in silicon nanowire FET-based molecular receiver. Finally, we discuss the practical challenges of implementing the receiver and present the future research avenues from a communication theoretical perspective.
Seamless connection of molecular nanonetworks to macroscale cyber networks is
envisioned to enable the Internet of Bio-NanoThings, which promises for
cutting-edge applications, especially in the medical domain. The connection
requires the development of an interface between the biochemical domain of
molecular nanonetworks and the electrical domain of conventional
electromagnetic networks. To this aim, in this paper, we propose to exploit
field effect transistor based biosensors (bioFETs) to devise a molecular
antenna capable of transducing molecular messages into electrical signals. In
particular, focusing on the use of SiNW FET-based biosensors as molecular
antennas, we develop deterministic and noise models for the antenna operation
to provide a theoretical framework for the optimization of the device from
communication perspective. We numerically evaluate the performance of the
antenna in terms of the Signal-to-Noise Ratio (SNR) at the electrical output.
The purpose of this textbook is to serve as an introductory overview of computational tools to solve numerical problems in the rapidly emerging discipline of biomedical engineering. Despite the popularity of bioengineering as a major in engineering, only a handful of textbooks have been written primarily for the instruction of under-graduates in bioengineering, none in the area of numerical methods in biomedical engineering. Addressing this void was one of the driving forces for the current effort.
The ability of engineered biological nanomachines to communicate with biological systems at the molecular level is anticipated to enable future applications such as monitoring the condition of a human body, regenerating biological tissues and organs, and interfacing artificial devices with neural systems. From the viewpoint of communication theory and engineering, molecular communication is proposed as a new paradigm for engineered biological nanomachines to communicate with the natural biological nanomachines which form a biological system. Distinct from the current telecommunication paradigm, molecular communication uses molecules as the carriers of information; sender biological nanomachines encode information on molecules and release the molecules in the environment, the molecules then propagate in the environment to receiver biological nanomachines, and the receiver biological nanomachines biochemically react with the molecules to decode information. Current molecular communication research is limited to small-scale networks of several biological nanomachines. Key challenges to bridge the gap between current research and practical applications include developing robust and scalable techniques to create a functional network from a large number of biological nanomachines. Developing networking mechanisms and communication protocols is anticipated to introduce new avenues into integrating engineered and natural biological nanomachines into a single networked system. In this paper, we present the state-of-the-art in the area of molecular communication by discussing its architecture, features, applications, design, engineering, and physical modeling. We then discuss challenges and opportunities in developing networking mechanisms and communication protocols to create a network from a large number of bio-nanomachines for future applications.
The concept of combining chemotherapeutic agents to increase the cytotoxic efficacy has evolved greatly over the past several years. In the past, the rationale for combination chemotherapy centered on attacking different biochemical targets, overcoming drug resistance in heterogenous tumors, and increasing the dose-density of combination chemotherapy to take advantage of tumor growth kinetics. The overall goal was to improve clinical efficacy with acceptable clinical toxicity. It is now apparent that the sequence of drug administration can significantly enhance the therapeutic effect of chemotherapy. These sequence-dependent effects can be explained by chemotherapy-induced cell cycle perturbations, or by pharmacodynamic interactions between the agents in combination. In this review, we focus on drug combinations with taxanes and camptothecins, which we believe best illustrate the importance of the cell cycle and pharmacologic interactions in the sequential administration of chemotherapy. As our understanding of the cell cycle grows, our ability to appropriately sequence chemotherapy can have a great impact on the treatment of human cancers. Copyright 2000 Harcourt Publishers Ltd.