Philips Applied Technologies, Eindhoven, The Netherlands
Speed and convenience
The in vitro identification of biologically active molecules in fluid samples has important applications in medicine, agriculture and environmental control. With improvements in the ability to detect ever smaller concentrations of specific proteins in body fluids such as urine, saliva and blood, it may soon be possible to diagnose the presence of disease and treat it before patients start to suffer symptoms. Early diagnosis and treatment will reduce the need for late stage interventions such as surgery and, therefore, improve patient outcomes. The identification of waterborne pathogens, infectious agents and biological contaminants is another important application.
Although many of these tests are already performed, they often involve complex laboratory procedures. As a result, it can often take one hour or more to obtain results. Thus, there is a real need, particularly in the medical world where time is often crucial, to find ways of automating these tests. Using fast easy-to-use and comparatively low cost handheld equipment or table top instruments allows diagnostic testing to move from the laboratory to the bedside, or from the laboratory into the field/home.
Because it is rarely possible to change the underlying biochemistry or biophysics on which these tests are based, producing easy-to-use portable, automated solutions means achieving a high level of system integration. Thanks to the latest silicon chip technology, the computing power needed for this is readily available. However, these systems require a lot more than digital computing power. They need sensors to detect biological activity and actuators to physically move fluid samples or other material towards and across the sensor surfaces. They may also need communication interfaces such as wireless transceivers to communicate data via local area networks. Although some of this functionality can be contained in a handheld reader, anything that comes into contact with the biological sample needs to be integrated into a “use-once” module that can be disposed of after use. This typically means incorporating sensor, fluid handling and actuator functions, together with at least some of the control electronics, into a highly integrated low-cost system-in-package (SiP) solution. SiP focuses on the integration of electronics; fluidics; and optical, mechanical and biological functions into one module, where packaging is a functional element and critical differentiator. This enables applications of microsystem technology in market leading products.
In addition, recent developments in thin-film magnetic technology have resulted in films exhibiting a large change in resistance with magnetic field. This phenomenon is known as giant magnetoresistance (GMR) to distinguish it from conventional anisotropic magnetoresistance (AMR). Whereas AMR resistors exhibit a change of resistance of less than 3%, various GMR materials achieve a change in resistance of 10 to 20%.
Drugs of abuse tester
Figure 1: Prototype of the future analyser and disposable based on biosensor technology for a roadside drugs-of-abuse tester.
Figure 1 shows an example in which this technology is employed. This SiP biosensor, which was developed for drugs-of-abuse testing, consists of four giant GMR sensors fabricated on a silicon chip and integrally mounted in a plastic chamber that is capillary fed with a diluted saliva sample. The chamber is preloaded with colloidal magnetic particles and selectively coated with antibodies that bind to different drugs, for example, opiate, cocaine, ecstasy or cannabis.
When the saliva sample enters the chamber, these magnetic particles go into suspension, where their antibody coatings bind to the corresponding drug molecules if those drugs are present in the sample. The particles are then driven towards the sensor surface by an externally applied magnetic field, where unbound particles bind to receptors that are precoated onto the sensor surface. The particles that are bound to drug molecules in the sample, together with excess unbound particles, are then driven away from the sensor surface by reversing the magnetic field. This allows a quantitative assessment to be made of the number bound to the sensor surface by activating the GMR sensor’s integrated drive electronics.
If there are no drug molecules in the saliva sample, all the corresponding colloidal particles bind to the surface of the sensor up to saturation and the GMR signal is maximum. If there is a high concentration of the drug in the sample, no colloidal particles bind to the sensor surface, because their antibody coatings are already bound to drug molecules and the GMR signal is minimum. The assay is therefore a “competitive assay,” because drug molecules in the sample and the receptors on the surface of the sensors compete for the colloidal particles. This automated process, which can achieve assay times in 30 seconds, is illustrated in Figure 2.
Fast device creation
One of the obstacles to developing diagnostic disposable products is the creation of experimental devices for testing the various functions. In the development of the SiP biosensor, a design methodology was adopted that allowed for rapid interaction around function development by a short cycle of device design, realisation and evaluation, in other words, “fast device creation” (Figure 3). Working in this way at every stage of design and development models or prototype devices for experimental evaluation must be provided. In parallel with this, field trials are held, which ensures real manufacturing and application knowledge can be built into the process.
Design for manufacturability
By their very nature, SiP solutions such as the drugs-of-abuse tester described above involve complex interactions between the different materials and processes that lie in different technology domains (Table I). For example, unless properly treated, a silicon chip designed for encapsulation in a conventional integrated circuit packaging material may quickly degrade when exposed to the materials or processes that it will encounter when being integrated into a SiP biosensor. Compatibility of the materials with respect to the biochemical assay must also be ensured.
The SiP developed for the drugs-of-abuse tester is a typical example of heterogeneous integration. It involved the integration of several different technologies: silicon microelectronics, GMR sensor, electronic interconnects, colloidal particles and microfluidics in a single package that becomes a “use-once and throw away” item with low enough cost price. Throughout the design process, design for manufacturability (DFM) is therefore of paramount importance.
Current design tools, especially those that incorporate significant DFM capability, only cover single technologies, for example, they are dedicated to silicon chip design or the design of injection moulded plastic components. Within a SiP, however, the materials and processes involved in the different technologies interact with one another.
DFM must, therefore, take into account the integration of all different functions, that is, electrical, mechanical, thermal, physics and chemical functions and biocompatibility, and the multiple technologies used in the manufacturing process. The only way to achieve the required manufacturability and reliability is to create multidisciplinary design teams in which experts in each of the required technology domains understand each other’s language and work together to find the required solutions.
Partnering for success
Figure 3: With fast device creation, at every stage of design and development, models or prototypes must be provided for experimental evaluation. At the same time, field trials are held so that real manufacturing and application knowledge can be built into the process.
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One of the essential factors for success when developing these complicated products is the availability of a “powerhouse” that has most technologies inhouse and knows how to integrate and apply design for manufacturing as an art. The magnetic biosensor is an example of a product that has been developed by the availability of this type of organisation. The significant feature of this product is the integration of the magnetic actuation that minimises the assay time.
For many of the highly innovative biosensor industry’s small- and medium-sized enterprises (SMEs) that have recently emerged from academia and research institutes, this type of organisation offers an opportunity to commercialise their ideas. Most of the time, the SMEs have unique knowledge in a particular area, for example, in ligand/antibody development for the detection of specific disease biomarkers. But it is often a challenge for them to have the resources to put together the multidisciplinary teams needed to bring their ideas to commercial reality. To speed up the whole process, they could partner with technology providers that have the multitechnology expertise and resources needed to produce SiPs. Both partners can benefit from operating in a spirit of open innovation, with clear ground rules agreed on intellectual property ownership and reward.
Table I: The SiP developed for the drugs-of-abuse tester is a typical example of heterogeneous integration, involving the integration of many different technologies and capabilities.
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There is another advantage to this partnership approach: it encourages thinking in platforms rather than products. Platform thinking allows design re-use and also allows process re-use and minimises risk. For example, a microfluidics platform that addresses most of the materials and process issues at platform level will be applicable across many in vitro testing domains at every stage in the design process.
The development of a comprehensive microfluidics platform can be an effective way to broaden applications areas, for example, into proteomics with protein assays and genomics with deoxyribonucleic acid (DNA) assays. DNA assays involve a significant number of other processing steps and functions such as cell separation and rupturing, followed by DNA/protein separation, amplification and detection. Each of these involves fluid handling processes, for example, dilutions, separations and chamber transfers. Virtually all of these processes have already been automated in laboratory-based systems.
However, if they are to be transferred to “lab-on-chip” environments so that these assays can be performed in the field, for example, by paramedics to detect patients infected with pathogens such as methicillin-resistant staphylococcus aureus, a fluidics platform capable of being implemented at chip-scale will need to be developed.
Dr Thijs Viegers is Chief Technology Officer, Dr Eduard Pelssers is Project manager Ing Emiel Lenders is Domain Leader of Molecular Healthcare at Philips Applied Technologies, High Tech Campus 7, NL-5656 AE Eindhoven, The Netherlands, tel. +31 402 748 882, e-mail: email@example.com, www.apptech.philips.com.
Source: Dr Thijs Viegers, Dr Eduard Pelssers, and Ing Emiel Lenders, Originally Published MDT March/April 2008, DESIGN, A Microfluidics Platform for In Vitro Testing, Copyright ©2008 Medical Device Technology