Skin-Integrated wearable systems and implantable biosensors: a comprehensive review

Biosensors devices have attracted the attention of many researchers across the world. They have the capability to solve a large number of analytical problems and challenges. They are future ubiquitous devices for disease diagnosis, monitoring, treatment and health management. This review presents an overview of the biosensors field, highlighting the current research and development of bio-integrated and implanted biosensors. These devices are micro- and nano-fabricated, according to numerous techniques that are adapted in order to offer a suitable mechanical match of the biosensor to the surrounding tissue, and therefore decrease the body’s biological response. For this, most of the skin-integrated and implanted biosensors use a polymer layer as a versatile and flexible structural support, combined with a functional/active material, to generate, transmit and process the obtained signal. A few challenging issues of implantable biosensor devices, as well as strategies to overcome them, are also discussed in this review, including biological response, power supply, and data communication.This research was funded by FCT- FUNDAÇÃO PARA A CIÊNCIA E TECNOLOGIA, grant numbers: PTDC/EMD-EMD/31590/2017 and PTDC/BTM-ORG/28168/2017

Fully Integrated Biochip Platforms for Advanced Healthcare

Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications

Experimentation and Multiphysical Modeling of Bioanalytical Microdevices

Bioanalytics involves quantitative measurements of complex biological samples that contain metabolites, DNA, RNA, and proteins. Efficient sample preparation for downstream analysis and sensitive detection of analytes can be achieved via bioanalytical microdevices. Fully realizing the potential of these devices requires tool characterization and bioprocess optimization, in addition to understanding device physics. Therefore, this thesis introduces multiphysical modeling and experimentation of microdevices, with applications to diabetes care and single-cell analysis. To understand the physics of viscometric glucose microsensors, this thesis presents a model of the sensor, which couples the fluid flow with vibrating diaphragms. The model is used to predict the sensor response to glucose via theory of squeeze-film damping and vibrations of pre-stressed plate. A first-principle-based model resulting from the theory can be evaluated from the device's geometric and material properties, and quantitatively determines the device response to vibrational excitations at varying glucose concentrations. Next, this thesis introduces a theoretical model for viscometric glucose microsensors that employ harmonic microcantilever oscillation in the sensing liquid. The presented model associates the unsteady Stokes equation with the motion of a bounded viscous liquid to understand the hydrodynamic impact on the cantilever. With a proper consideration of the viscosity and bounded geometry of liquid media, the model relaxes the thin-film assumption required for the diaphragm-based model, enabling an accurate representation of fluid-structure interactions based on fundamental structural vibration and fluid flow equations. Next, this thesis presents an experimental exploration of a hydrogel-based affinity microsensor for glucose monitoring via dielectric measurements. The microsensor incorporates a synthetic hydrogel that is attached to the device surface via in situ polymerization, which eliminates mechanical moving parts required in the viscometric glucose sensors. Changes in the dielectric properties of the hydrogel when binding reversibly with glucose molecules have been measured using a MEMS capacitive transducer to determine the glucose concentration. Experimental results demonstrate that in a glucose concentration range of 0–500 mg/dL and with a resolution of 0.35 mg/dL or better, the microsensor exhibits a repeatable and reversible response, and can potentially be useful for continuous glucose monitoring in diabetes care. Additionally, this thesis presents a microfluidic preprocessing method that integrates single-cell picking, lysing, reverse transcription and digital polymerase chain reaction to enable the isolation, tracking and gene expression analysis at single-cell level for individual cells. The approach utilizes a photocleavable bead-based microfluidic device to synthesize and deliver stable complementary DNA for downstream gene expression analysis, thereby allowing chip-based integration of multiple reactions and facilitating the minimization of sample loss or contamination. Finally, this thesis ends with concluding remarks and directions of future work towards continuous glucose monitoring and high-throughput single-cell genetic analysis

Beyond Tissue replacement: The Emerging role of smart implants in healthcare

Smart implants are increasingly used to treat various diseases, track patient status, and restore tissue and organ function. These devices support internal organs, actively stimulate nerves, and monitor essential functions. With continuous monitoring or stimulation, patient observation quality and subsequent treatment can be improved. Additionally, using biodegradable and entirely excreted implant materials eliminates the need for surgical removal, providing a patient-friendly solution. In this review, we classify smart implants and discuss the latest prototypes, materials, and technologies employed in their creation. Our focus lies in exploring medical devices beyond replacing an organ or tissue and incorporating new functionality through sensors and electronic circuits. We also examine the advantages, opportunities, and challenges of creating implantable devices that preserve all critical functions. By presenting an in-depth overview of the current state-of-the-art smart implants, we shed light on persistent issues and limitations while discussing potential avenues for future advancements in materials used for these devices

Modeling and Simulation of Triple Coupled Cantilever Sensor for Mass Sensing Applications

Cantilever sensors have been the growing attention in last decades and their use as a mass detector. This work presents design, modeling and analysis of Triple coupled cantilever(TCC) sensor using MEMS simulation software Comsol Multiphysics with critical  dimensions of 100μm length,20μm width and 2μm thickness. Simulations were performed based on finite element modeling techniques, where different resonant frequencies were observed for different modes of operation. It is also observed that the resonant frequency of the sensor decreases as some mass is applied on one particular cantilever. The various parameters greatly affecting the performance of TCC such as resonant frequency, dimensions, material and pressure or force applied on it.we also observed that while adding some mass on any one lateral cantilever, the resonant frequency of that respective mode reduced

A Viscosity-Dependent Affinity Sensor for Continous Monitoring of Glucose in Biological Fluids

For fifty years, tremendous efforts have been directed towards the development of glucose sensors for tight glycemic control of diabetic patients. Today, millions of diabetics test their blood glucose level daily, making glucose the most commonly tested analyte. Recently, subcutaneous implantable needle-type sensors became commercially available for continuous glucose monitoring. However, these devices require frequent calibrations and are lacking accuracy and reliability. They are based on electrochemical detection, which is strongly affected by the biological environment in which the sensor is placed. In addition, an accurate and reliable continuous glucose sensor would also be of great interest for tight glycemic control in intensive care units of hospitals. However, despite the many impressive breakthroughs, the development of clinically accurate continuous glucose sensors remains a challenge. In this context, alternative approaches to overcome the limitation of electrochemical methods have been actively investigated. Among these, affinity sensing should offer several intrinsic advantages for in vivo monitoring. In this thesis, we investigate a novel viscosity-dependent affinity sensor for continuous monitoring of glucose in biological fluids such as blood and plasma. The sensing principle relies upon the viscosity variation of a sensitive fluid with glucose concentration. The sensitive fluid is based on the competitive binding of glucose and dextran with a glucose-specific binding protein, Concanavalin A. Basically, the sensor is filled with the sensitive fluid, and includes both an actuating and a sensing piezoelectric diaphragm as well as a flow-resistive microchannel. In addition, a nanoporous alumina membrane completely retains the sensitive fluid within the sensor whilst allowing glucose permeation through the membrane. The sensor was extensively tested in isotonic saline solution for physiological blood glucose concentrations between 2 and 20 mM, demonstrating an excellent accuracy, reversibility and stability for up to 3 days. In addition, the response time was close to the 10 minutes required for medical applications. However, despite the excellent short term stability, a progressive loss of sensitivity was observed for long term measurements. Concanavalin A retention by the alumina nanoporous membrane was assessed by ultraviolet absorbance spectrometry. Small leakage through the membrane was detected, which at least partly explains the sensitivity reduction over several days. Finally, the adequacy of the sensor for measurement in human blood serum and plasma was checked. Physiological glucose levels were successfully monitored, meaning that the chemical stability of the sensitive fluid and biofouling of the nanoporous alumina membrane were not an issue for short term applications. Moreover, interferences from biomolecules were limited and the sensitivity was still high enough for glucose monitoring. These results suggest that the combination of the ConA-based sensitive fluid and the microviscometer is a promising sensing principle for continuous glucose monitoring in blood

Nanotechnology‐Based Rapid Diagnostic Tests

Recently, various nanomaterials are used in order to develop nanotechnology‐based rapid diagnostic tests, such as metallic nanoparticles, quantum dots (QDs), silica nanospheres, magnetic nanoparticles, carbon nanotubes (CNTs), silicon nanowires (SiNWs), nanopores, graphene, nanostructured surfaces, and metal films. This novel nanodiagnostic approach will further develop point‐of‐care (POC) diagnostics and monitoring technologies. Nanobiosensors and microarrays of biosensors can create biochip systems and microfluidic platforms that are the most used nanofabrications for rapid diagnostic tests. These nanoplatforms are constructed for the rapid detection of various diseases or pathogen‐specific biomolecules/markers, such as DNA, proteins, whole cells (e.g., circulating tumor cells), and others. The fabrication of small‐scale portable devices with the incorporation of nanostructures will offer many advantages in the early detection of various diseases and health‐threatening infections by pathogens and in the treatment selection and treatment monitoring. The use of nanostructures in in vitro diagnostics gives the opportunity to augment the sensitivity and specificity required in clinical practice, lowers the cost and test time of the assays, and enables portable microfluidic platforms suitable for resource‐constrained settings. In this chapter, all the state‐of‐the‐art advantages in this field are discussed, starting with the nanostructures used for the fabrication of nanobiosensors, nanobiosensors arrays, and nanofluidic platforms and the nanodiagnostic use of rapid tests in the detection of pathogens, in cancer management, and glucose monitoring for the management of diabetes disease

Portable Bio-Devices: Design of Electrochemical Instruments from Miniaturized to Implantable Devices

The integration of biosensors and electronic technologies allows the development of biomedical systems able to diagnose and monitoring pathologies by detecting specific biomarkers. The chapter presents the main modules involved in the development of such devices, generically represented in Fig. 1, and focuses its attention on the essential components of these systems to address questions such as: how is the device powered? How does it communicate the measured data? What kind of sensors could be used?, and What kinds of electronics are used

3D biosensors in advanced medical diagnostics of high mortality diseases

Cardiovascular diseases, cancer, and diabetes are high mortality diseases, which account for almost two thirds of all deaths worldwide. Their early detection and continuous evaluation is fundamental for an improved patient prognosis and reduced socioeconomic impact. Current biosensor technologies are typically based on the analysis of whole blood samples from patients for the detection of disease-specific biomarkers. However, these technologies display serious shortcomings, such as reduced sensitivity and dynamic range, limited in vivo applicability, and lack of continuous monitoring. There is the urgent need for new diagnostic and treatment follow-up tools, which allow for the early detection of the pathology as well as for the continuous monitoring of the physiological response to specific therapies. During the last years, a new generation of biosensor technologies with improved performance has emerged in the biomedical sector. The combination of advanced biomaterial methods, biochemical tools, and micro/nanotechnology approaches has resulted in the development of innovative three-dimensional (3D) biosensor platforms for advanced medical diagnosis. In this review, we report the most recent advances in the field of 3D biosensors for clinical applications, focusing on the diagnosis and monitoring of cardiovascular diseases, cancer, and diabetes. We discuss about their clinical performance compared to standard biosensor technologies, their implantable capability, and their integration into microfluidic devices to develop clinically-relevant models. Overall, we anticipate that 3D biosensors will drive us toward a new paradigm in medical diagnosis, resulting in real-time in vivo biosensors capable to significantly improve patient prognosis.V.M.C., S.C.K, and D.C. acknowledge thefinancial support from theEuropean Union Framework Programme for Research and InnovationHorizon 2020 on Forefront Research in 3D Disease Cancer Models asinvitroScreening Technologies (FoReCaST) under Grant agreement no.668983. V.M.C also thanks the Portuguese Foundation for Science andTechnology (FCT) for his distinction attributed under the FCTInvestigator program (IF/01214/2014). D.C. and S.C.K also acknowl-edge the support from the FCT under the scope of the project ModellingCancer Metastasis into the Human Microcirculation System using aMulti-organ-on-a-Chip Approach (2MATCH) (PTDC/BTM-ORG/28070/2017) funded by the Programa Operacional Regional do Norte sup-ported by Fundo Europeu de Desenvolvimento Regional (FEDER). A.I.B.acknowledges thefinancial support of project FROnTHERA (NORTE-01-0145-FEDER-000023