Camilla Baj-Rossi

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.

Electrochemical detection of anti-breast-cancer agents in human serum by cytochrome P450-coated carbon nanotubes.

We report on the electrochemical detection of anti-cancer drugs in human serum with sensitivity values in the range of 8–925 nA/μM. Multi-walled carbon nanotubes were functionalized with three different cytochrome P450 isoforms (CYP1A2, CYP2B6, and CYP3A4). A model used to effectively describe the cytochrome P450 deposition onto carbon nanotubes was confirmed by Monte Carlo simulations. Voltammetric measurements were performed in phosphate buffer saline (PBS) as well as in human serum, giving well-defined current responses upon addition of increasing concentrations of anti-cancer drugs. The results assert the capability to measure concentration of drugs in the pharmacological ranges in human serum. Another important result is the possibility to detect pairs of drugs present in the same sample, which is highly required in case of therapies with high side-effects risk and in anti-cancer pharmacological treatments based on mixtures of different drugs. Our technology holds potentials for inexpensive multi-panel drug-monitoring in personalized therapy.

Continuous monitoring of Naproxen by a cytochrome P450-based electrochemical sensor

This paper reports the characterization of an electrochemical biosensor for the continuous monitoring of Naproxen based on cytochrome P450. The electrochemical biosensor is based on the drop-casting of multi-walled carbon-nanotubes (MWCNTs) and microsomal cytochrome P4501A2 (msCYP1A2) on a graphite screen-printed electrode (SPE). The proposed biosensor was employed to monitor Naproxen (NAP), a well-known anti-inflammatory compound, through cyclic voltammetry. The dynamic linear range for the amperometric detection of NAP had an upper limit of 300 µM with a corresponding limit of detection (LOD) of 16 ± 1 µM (S/N=3), which is included in NAP physiological range (9-300 µM). The MWCNT/msCYP1A2-SPE sensor was also calibrated for NAP detection in mouse serum that was previously extracted from mice, showing a slightly higher LOD (33 ± 18 µM). The stability of the msCYP1A2-based biosensor was assessed by longtime continuous cyclic voltammetric measurements. The ability of the sensor to monitor drug delivery was investigated by using a commercial micro-osmotic pump. Results show that the MWCNT/msCYP1A2-SPE sensor is capable of precisely monitoring the real-time delivery of NAP for 16 h. This work proves that the proposed electrochemical sensor might represent an innovative point-of-care solution for the personalization of drug therapies, as well as for pharmacokinetic studies in both animals and humans.

Full fabrication and packaging of an implantable multi-panel device for monitoring of metabolites in small animals.

In this work, we show the realization of a fully-implantable device for monitoring free-moving small animals. The device integrates a microfabricated sensing platform, a coil for power and data transmission and two custom designed integrated circuits. The device is intended to be implanted in mice, free to move in a cage, to monitor the concentration of metabolites. We show the system level design of each block of the device, and we present the fabrication of the passive sensing platform and its employment for the electrochemical detection of endogenous and exogenous metabolites. Moreover, we describe the assembly of the device to test the biocompatibility of the materials used for the microfabrication. To ensure biocompatibility, an epoxy enhanced polyurethane membrane was used to cover the device. We proved through an in-vitro characterization that the membrane was capable to retain enzyme activity up to 35 days. After 30 days of implant in mice, in-vivo experiments proved that the membrane promotes the integration of the sensor with the surrounding tissue, as demonstrated by the low inflammation level at the implant site.

An Integrated Control and Readout Circuit for Implantable Multi-Target Electrochemical Biosensing

We describe an integrated biosensor capable of sensing multiple molecular targets using both cyclic voltammetry (CV) and chronoamperometry (CA). In particular, we present our custom IC to realize voltage control and current readout of the biosensors. A mixed-signal circuit block generates sub-Hertz triangular waveform for the biosensors by means of a direct-digital-synthesizer to control CV. A current to pulse-width converter is realized to output the data for CA measurement. The IC is fabricated in 0.18 μm technology. It consumes 220 μW from 1.8 V supply voltage, making it suitable for remotely-powered applications. Electrical measurements show excellent linearity in sub- μA current range. Electrochemical measurements including CA measurements of glucose and lactate and CV measurements of the anti-cancer drug Etoposide have been acquired with the fabricated IC and compared with a commercial equipment. The results obtained with the fabricated IC are in good agreement with those of the commercial equipment for both CV and CA measurements.

An implantable bio-micro-system for drug monitoring

Multi-target and continuous monitoring by wireless implantable devices is of increasing interest for personalized therapy. In this work an implantable system is presented which is capable of measuring different drugs with Cyclic Voltammetry (CV) method. The wireless microsystem consists of four modules, namely (i) The inductive coil; (ii) Power management IC; (iii) Readout and control IC; (iv) Biosensor array. The power management IC provides 1.8 V with as high as 2 mW power for the readout IC. The configurable readout IC is able to control the biosensor array and measure the sensor current in CV method. CV experiments performed with this microsystem well agree with a commercial equipment for two well known anti-cancer drugs, Etoposide and Mitoxantrone, detection.

P450-Based Nano-Bio-Sensors for Personalized Medicine

Reference EPFL-CHAPTER-164196doi:10.5772/16328 URL: http://www.intechopen.com/articles/show/title/p450-based-nano-bio-sensors-for-personalized-medicine Record created on 2011-03-10, modified on 2016-08-09

Wireless Monitoring of Endogenous and Exogenous Biomolecules on an Android Interface

Monitoring patients in intensive care units is generally expensive and time consuming. A prompter medical intervention for those critical patients is a key factor for their safety. Therefore, a system that offers immediate visualization of the monitored data represents a great advance in the field. In this paper, the design, the development, and the validation of an android interface for the continuous and wireless monitoring of up to five compounds are described. Continuous monitoring of the biomolecules is addressed by using a fully integrated hardware platform consisting of biosensors connected to a read-out circuit on a printed circuit board. The electrochemical platform uses Rovings Bluetooth module RN-42 to send the measured data to the mobile device. For the validation of the system, some biomolecules are taken as reference: glucose and lactate for endogenous metabolites and paracetamol for exogenous biomolecules. Chronoamperometries are performed at +650 mV for glucose and lactate and at +450 mV for paracetamol. Multi-walled carbon nanotubes are deposited on working electrodes for glucose and lactate for enhanced signal. Instead, for paracetamol, bare working electrodes are used. The measured data are continuously displayed on the screen of the mobile device because of the android interface. Current step for every variation of glucose, lactate, or paracetamol is clearly visible by the trend of the graphs.

A System for Wireless Power Transfer and Data Communication of Long-Term Bio-Monitoring

A system for wireless power transfer and data communication of implantable bio-monitoring systems is presented. The proposed solution uses a servo-controlled power transmitter moved under the animal moving space. An x-y movable magnetic coil transmits the required power with a level able to keep constant the received energy by the bio-sensor system. The power is transferred via the optimized remote powering link at 13.56 MHz. The received ac signal is converted to dc voltage with a passive full-wave integrated rectifier and the voltage regulator supplies 1.8 V for the implantable sensor system. The sensor control and readout circuit measures the current on the bio-sensors and transmit the data to the transmitter. The sensor data are transmitted to an external reader by a low-power OOK transmitter and received by a custom designed receiver at 869 MHz. The results are shown in a tablet computer in real time continuously. The long-term characterization of the implantable system is verified by a fully bio-compatible packaged implant with 30 days measurement. A complete prototype is also presented to prove the overall system performance with the experimental in vitro measurement.

Nano-sensor and circuit design for anti-cancer drug detection

The development of new technologies to monitor drugs concentration directly in patients blood is absolutely required to succeed in personalized drug therapies. In this study, Etoposide - a well-known anti-cancer drug - has been chosen as model for cyclic voltammetry detection of drugs. Carbon nanotubes are chosen as electron-transfer mediators to enhance the system sensitivity. A very low frequency and low slope triangular-wave potential is required to acquire cyclic voltammograms. Cyclic voltammograms are definitely needed for a correct identification and quantification of the drug concentration in the patient serum. The aim of the paper is to investigate the feasibility of VLSI fully-integration of cyclic voltammetry measurements as a tool to develop a low-cost chip for drug monitoring in personalized therapy. A triangular wave generator CMOS circuit is proposed by using Direct Digital Synthesis (DDS) method. The circuit is implemented in 0.18 µm technology and it presents the possibility of changing the slope of the triangular voltage in a wide range of 10 to 100mV/s.