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

Biocompatible Packagings for Fully Implantable Multi-Panel Devices for Remote Monitoring of Metabolism

This paper compares three different biocompatible packagings suitable to support full implantation of multi-panel sensors for remote monitoring of metabolism. The three packagings have been designed, realized and implanted in mice for 30 days. ATP and neutrophil concentrations have been measured at the implant site after the device was explanted, to assess the level of biocompatibility of the device

Implantable Multi-panel Platform for Continuous Monitoring of Exogenous and Endogenous Metabolites for Applications in Personalized Medicine

Nowadays, scientific advances are leading to the discovery of newer, better, more targeted treatments that will improve the human health. However, despite the promising results and the major advantages in treatments offered to patients, these personalized medical treatments are limited to few cases. Translational medicine research with animals is needed to find innovative, safe and life-saving solutions for patients, especially in drug development. Although technological improvements may lead one day to the end of animal testing, today those strategies are not sufficient, due to the complexity of living organisms. The living conditions of these animals are of primary importance because high stress levels can affect the experimental results. In this respect, the monitoring of the animals in a small living space by means of a fully implantable device, can contribute to minimize the human intervention, increasing the comfort for the animals. The objective of this thesis is the design and characterization of a fully implantable biosensor array for the real-time detection of endogenous and exogenous metabolites, for the monitoring of small caged animals in drug development, and for future applications in personalized medicine. The fully implantable device consists of: a passive sensing platform consisting of an array of four independent electrochemical biosensors, together with a pH sensor and a temperature sensor for the optimization of the sensing performances in different physiological conditions; integrated circuits capable of performing multiple electrochemical measurements; a coil for remote powering of the integrated circuit and the short-range data transmission to an external device; a membrane packaging ensuring measurements with high signal-to-noise ratio, biocompatibility and selectivity against possible interfering molecules in biological fluids. ⢠In vitro monitoring of four anti-cancer drugs and an anti-inflammatory drug within the pharmacological ranges in undiluted human serum; ⢠Demonstration of the in vitro functionality of the complete system, showing that the external powering system correctly operate the device, and receive the data from the sensors; ⢠In vivo biocompatibility tests of the packaging, showing after 30 days a significant reduction of the inflammatory response in time, suggesting normal host recovery; ⢠In vivo continuous monitoring of an anti-inflammatory drug, demonstrating the proof of-concept of the system for future personalized medicine applications

Full System for Translational Studies of Personalized Medicine with Free-Moving Mice (invited)

A full remotely powered system for metabolism monitoring of free-moving mice is presented here. The fully implantable sensing platform hosts two ASICs, one off-the-shelf micro-controller, four biosensors, two other sensors, a coil to receive power, and an antenna to transmit data. Proper enzymes ensure specificity for animal metabolites while Multi-Walled Carbon Nanotubes ensure the due sensitivity. The remote powering is indeed provided by inductive coils located under the floor of the mouse' cage. Two different approaches were investigated to ensure freedom of movement to the animal. The application to studies for personalized medicine is demonstrated by showing continuous monitoring of both glucose and paracetamol

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

Developing Next-generation Brain Sensing Technologies - A Review.

Advances in sensing technology raise the possibility of creating neural interfaces that can more effectively restore or repair neural function and reveal fundamental properties of neural information processing. To realize the potential of these bioelectronic devices, it is necessary to understand the capabilities of emerging technologies and identify the best strategies to translate these technologies into products and therapies that will improve the lives of patients with neurological and other disorders. Here we discuss emerging technologies for sensing brain activity, anticipated challenges for translation, and perspectives for how to best transition these technologies from academic research labs to useful products for neuroscience researchers and human patients

Design of a Customized multipurpose nano-enabled implantable system for in-vivo theranostics

The first part of this paper reviews the current development and key issues on implantable multi-sensor devices for in vivo theranostics. Afterwards, the authors propose an innovative biomedical multisensory system for in vivo biomarker monitoring that could be suitable for customized theranostics applications. At this point, findings suggest that cross-cutting Key Enabling Technologies (KETs) could improve the overall performance of the system given that the convergence of technologies in nanotechnology, biotechnology, micro&nanoelectronics and advanced materials permit the development of new medical devices of small dimensions, using biocompatible materials, and embedding reliable and targeted biosensors, high speed data communication, and even energy autonomy. Therefore, this article deals with new research and market challenges of implantable sensor devices, from the point of view of the pervasive system, and time-to-market. The remote clinical monitoring approach introduced in this paper could be based on an array of biosensors to extract information from the patient. A key contribution of the authors is that the general architecture introduced in this paper would require minor modifications for the final customized bio-implantable medical device

An implantable biosensor array for personalized therapy applications

At present, most of the tests involved in personalized medicine are complex and must be conducted in specialized centers. The development of appropriate, fast and inexpensive diagnostic technologies can encourage medical personnel in performing preventive tests, providing the driving force to push users, industry and administrations to the adoption of personalized therapy policies. In this respect, the development of new biosensors for various healthcare applications needs may represent a concrete incentive. The objective of this PhD project is the development of a fully implantable biosensor plat- form for personalized therapy applications. The thesis present innovative research on the electrochemical detection of common marketed drugs, drug cocktails, glucose and ATP with biosensors based on cytochromes P450 and different oxidases. The inclusion of carbon nan- otubes provided increased sensitivity and detection limit, enabling the detection of several drugs in their therapeutic range in undiluted human serum. A miniaturized, passive substrate capable to host 5 independent biosensor electrodes, a pH sensor, a temperature sensor as well as an interface for the signal processing electron- ics has been designed, microfabricated and tested. Different and reproducible nano-bio- functionalization for the single electrodes was obtained with high spatial resolution via selec- tive electrodeposition of chitosan/carbon nanotubes/enzyme solutions at the various elec- trodes. The array, completely fabricated with biocompatible materials, was then integrated with a CMOS circuit and a remote powering coil for the realization of a fully implantable device. The assembled system has been packaged with an inner moisture barrier in parylene C, to prevent circuit corrosion and toxic metals leaking, and an external biocompatible silicone shell to improve the host tolerance and reduce the local inflammation. The efficacy of the parylene barrier, as well as the toxicity of carbon nanotubes, has been assessed with in-vitro cytotoxicity tests conform to the ISO-109931 standards. The final packaged device was then implanted in mice to assess its short-term biocompatibility. Comparison between 7 and 30 days in in vivo implantations showed significant reduction of the inflammatory response in time, suggesting normal host recovery