EIPC Workshop on PCB Bio MEMs, London Heathrow, 8 December 2016
The Premier Inn conference centre at Heathrow Airport was the venue for the EIPC workshop on PCB Bio MEMs. What, I hear you ask, is a PCB Bio MEM? This is an abbreviation for biomedical (or biological) microelectromechanical systems, otherwise known as Lab-on-Chip. Given the strong market “pull” for more BioMEM devices (USD 2.5 billion in 2014 and anticipated to grow at CAGR of over 25% from 2016 to 2023), the commercialization of Lab-on-Chip devices is currently the “holy grail” of the research community. The Lab-on-PCB approach (aka PCB BioMEMs) is being followed in various research groups all over Europe, owing to its inherent upscaling potential: the PCB industry is well-established all around the world, with standardized fabrication facilities and processes, however is commercially exploited currently only for electronics.
The workshop began with an introduction from Dr. Despina Moschou, 50th Anniversary Prize Fellow/Lecturer at the Centre for Advanced Sensor Technologies at the University of Bath. It was Despina who first introduced the concept of PCB BioMEMs to the EIPC at its Summer
Conference in Edinburgh, June 2016 which ignited interest. She asked why Lab-on-Chip is not already more established using PCB technologies to provide the needed integration between the microfluidics, the biological elements and the electronics required to form an
analytical system highlighting the long-standing industrial infrastructure, microfabrication capabilities and intuitive integration of electronics.
The first speaker was Dr Yuksel Temiz of IBM’s Zurich Research Laboratory. Dr Temiz explained that although there are over 1400+ infectious species and 347 significant diseases less than 5% of their prevalence has been accurately mapped. He postulated that the use of IoT (Internet of Things) based devices linked to Smartphones or a handheld reader could revolutionise infectious disease mapping. He contrasted conventional lateral flow technology, such as that used in pregnancy detectors noting that microfluidics technology would require a much smaller sample size and optimised flow control to give much better quantitative results when used in a portable immunodiagnostic microfluidic platform. Dr Temiz then showed a fascinating video of a microfluidic system incorporating valve, reagent mixing, flow splitters and capillary pumps but on a microscopic scale. Being based in Switzerland Dr Temiz couldn’t resist explaining “Chip-olate” which is a high-throughput fabrication and efficient chip singulation technology having closed microfluidic structures taking advantage of dry-film resists (DFRs) for efficient sealing of capillary systems. The outlook was shown as including microfluidic chips with autonomous capillary driven flow, integrated receptors with controlled release of detection antibodies, assay validation and compact readers including Smartphone integration. Dr Temiz closed with an explanation of microflow monitoring with the use of integrated electrodes.
Dr Moschou then introduced Dr Peter Hewkin, the CEO of the Centre for Business Innovation (CfBI) whose organisation creates international collaborative communities and runs a consortium, MF-8, which brings together stakeholders in Microfluidics from across Europe and the USA.
MF-8 members were invited to the workshop with the purpose of bringing together European academics working on PCB-based LoC devices, providing the PCB industry with information on Lab-on-Chip technology/potential/challenges and to promote synergies between academics, PCB and the microfluidics industry amongst all interested stakeholders. Peter explained that microfluidics is about doing chemistry on a tiny scale and trying to emulate nature, in our bodies microfluidics is manifest in capillaries with their large surface area. It was noted that microfluidics is a term covering feature sizes in the range of 10-9 to 100 and a key feature is to use as little reagent as possible. Applications were identified as medical devices, drug delivery, point of care diagnostics, genomic diagnostics, high throughput screening, environmental sensing and chemical synthesis. Hewkin went on to describe how applications could be lead to personalised medication whereby drugs could be tested on a cell, tissue or even organ on a chip simulating an individuals personalised response before applying the drug to the patient. The potential for such personalised medication would lead to a drastic reduction of unnecessary or ineffective drug use and much quicker diagnostic and treatment regimes. For now the main focus is on medical uses, however the technology could also be beneficial in testing water, air, food and crops in a future connected world.
The traditional model of table top or large chamber reactors in laboratories employing large numbers of skilled analytical staff could be effectively replaced with single use microfluidics devices employed at the point of care. It was noted that the workload of traditional testing laboratories is reducing by around 5% per year as diagnostics functions are becoming more distributed and less centralised.
Hewkin asked “is there a market”? This was answered with a resounding “Yes” supported by a series of charts showing growth in medical markets with the USA leading the way. Current mass market applications were identified as pregnancy and blood glucose testing. There are obstacles to gaining approval from regulatory authorities for new devices, but once approval had been granted this gives a commercial advantage as a barrier to competition.
Hewkin explained that the microfluidics market is highly fragmented and showed many examples of real product examples including a sweat sensor and an electrochemical immunoassay system. In concluding Hewkin highlighted the opportunity to embed microfluidic functionality into electronic devices and vice-versa and left us with the knowledge that 40% of all microfluidic disposable systems already integrate some electronics content.
Next we heard from Prof Lienhard Pagel, Professor for Microsystems at the Faculty of Computer Science and Electrical Engineering at the University of Rostock, Germany. Prof Pagel contrasted the differences between using Silicon and PCB technologies for MEMs. He noted the advantage of rapid prototyping with PCB MEMs, but identified the disadvantages of minimum feature size in the 20 to 100 micron range and the relatively high tolerances. But he asked “Who needs nano structures”? Pagel went on to explain that systems could be categorizes into two basic structures, microstructures in the range of 10 to 300 microns and macrostructures in the range of 0.3 to 10 millimetres. He explained that microstructures are characterised by low flow and features produced by chemical processes whereas macrostructures are characterised by high flow and features produced by mechanical milling processes. Some systems integrate both micro and macro channels in a single package and Pagel considered the key to success was the integration of microfluidics and electronics in a stacked system. He described a project whereby apertures to be used as microfluidic channels were formed in a PCB structure using multilayer lamination techniques. Pagel explained that the project faced some challenges, especially of delamination in the low pressure areas but these were eventually overcome by the use of a two stage production technique and the application of no flow prepregs.
The next example was that of a CO2 insufflator which is a device used to inflate body cavities during laparoscopic surgery and other minimally-invasive surgical procedures. These devices use flow rates of between 1 and 45 litres of gas per minute and achieve an intraabdominal pressure in the range of 9 to 15 mmHg. Pavel showed the PCB design using embedded channels instead of discrete piping and integrated flow and pressure sensors. The PCB version of the insufflator achieved a significant size reduction from its predecessor and a cost reduction of 75%.
Pavel concluded by showing an example of a micro PCR (polymerase chain reaction) device for in vitro amplification of specific DNA or RNA sequences, allowing small quantities of short sequences to be analysed without cloning. PCR is a technique used in the diagnosis and monitoring of genetic diseases and studying the function of a targeted segment of DNA. The microfluidics version uses 4 integrated heating zones and 8 CV (coefficient of variation) sensors in a single unit. The advantages of using PCB technology for this device were explained as short prototyping timeframe, low cost production and miniaturisation.
Dr Angeliki Tserepi of The Institute of Nanoscience & Nanotech at the National Centre for Scientific Research “Demokritos”, Greece took the podium next. Tserepi expanded on the theme of DNA amplification principles using PCR & isothermal amplification explaining that traditional techniques required 2 – 3 days for diagnosis, however using a PCB solution could reduce that time to 3 hours. A microPCR design was shown fabricated on a thin flexible polyimide substrate with copper heaters defining each of the three thermal zones and a plasma etched microfluidic channel. A flow rate of 8 μl per minute was established as the maximum flow rate for good linearity of the DNA amplification. Simulations performed allowed optimisation of parameters to achieve temperature uniformity and linearity of the temperature/resistance curve. The device demonstrated integration in Lab-on-Chip for a DNA-based pathogen detection system with sufficient amplification comparable to conventional thermocyclers. The system was capable of using different thermal and flow templates to enable detection of a wide range of pathogens including salmonella for food safety and mycoplasma for pneumonia.
The benefits of using PCB technology for the system were explained as being quick, cheap, low power, reproducible and amenable to mass production in addressing point of care/point of need diagnostics, food safety and in-the-field environmental analysis. Dr Tserepi ended with showing a video animation of a prototype portable MicroNanoBioSystem and Instrument for ultra-fast analysis of pathogens in food.
After lunch Prof Jose Manuel Quero of the SOLAR MEMS Technologies unit at the University of Seville, Spain explained that now was the right time for deployment of PCB technologies in lab-on-chip applications. He considered mature PCB technologies to be a natural partner to Lab-on-Chip development. Examples of devices including a pressure sensor using capacitance changes in adjacent copper layers, a fluid impulsion device, a flow meter and nebuliser were explained. The flow meter utilised a tiny wheel produced in copper with an opto coupler to detect and measure air or fluid flow. Flow focussing was the key feature of the nebuliser using PCB technology to produce the flow focussing elements which were capable of producing a very consistent bubble size for drug delivery. The fluid impulsion device was novel in that it used a fusible element formed in copper as a single-use microfluidic valve. This device demonstrated that a fully integrated microfluidic circuits can be implemented within a PCB substrate without the need of complex interfaces to external impulsion actuation. Quero explained that this technology also brings outstanding advantages of the possibility of integration with sensing and auxiliary electronics and a significant reduction in fabrication cost. A series of microvalves has been characterized varying their parameters of fabrication, leading to a device that requires 0.35 J of electrical energy and supports a range of differential pressures from 50 to 400 kPa.
Quero summed up by stating that PCB technology is a good candidate as a Lab-on-Chip substrate as its flexibility allows for a large diversity of devices and manufacturing techniques and was competitive as a mature technology for mass production of devices. In closing he emphasised the importance of technology transfer from academia to industry to take advantage of the synergies.
Next we learnt about the requirements for fluidic PCB MEMS devices from Prof. Stefan Gassmann, of Jade University of Applied Sciences, Wilhelmshaven, Germany. Gassmann explained the route from the laboratory to full scale production and chose the examples of bubble detectors, active valves, analytical systems, micropumps, static mixers, pressure sensors and a water sample treatment system with which to whet our appetite. He considered the use of PCB technologies as a low cost route to fabricating MEMs, often utilising non-standard properties. Gassmann explained that to achieve success in novel application of PCB technology it was essential to find the right PCB fabricator who was innovative enough to find solutions. A 5cm x 5 cm monolithic chip system for a miniaturised flow injected analysis system for ferrite ion detection was the next example. The channel structures were formed from 4 PCBs with a polyimide film forming the pumps. An example of the issues facing novel design was next expounded on a disposable device for genetic testing utilising 32 sensors for DNA detection on a 20μl sample. The device uses PCR for DNA amplification and it was very important that wetted parts should not inhibit the PCR process. It is known that many metals used in PCB fabrication can act as biocides and it was therefore decided to use gold plated sensors which were known to be inert to the PCR process. However, after initial prototypes were built it was discovered that the standard gold plating was not pure enough with nickel and copper being detected at the sensor surface. Gassmann explained that the solution eventually required a redesign of the sensor with a secondary solder mask defined gold plated layer. The PCB fabricators in the audience were not at all surprised at this and an interesting discussion on precious metal plating technology ensued.
Grassman closed by emphasising the need for innovative PCB fabricators to partner with technically minded researchers and commented that from “lab to fab” a special effort is needed.
Dr Felismina Moreira, post‐doctoral researcher at BioMark Sensor Research in the School of Engineering of the Instituto Superior de Engenharia do Porto, Portugal was next to address the audience. Moreira described a fabrication process for screen printed electrodes (SPE) on conductive paper using a PVC, ceramic or PCB support. The biorecognition elements of the sensor used biomimetic techniques of molecular imprinting to make “plastic antibodies”, the plastic being later extracted to form artificial antibodies. The technology was demonstrated with the example of a carcinogenic embryonic antigen detector using a silver electrode on a PCB support. Carcinoembryonic antigens are harmful substances (usually proteins) that are produced by some types of cancer, the test is used to check how well treatment is working in certain types of cancer. The electrochemical behaviour of the electrodes and the analytical response and selectivity of the detector were shown, this demonstrated the sensing materials stability and suitability for the task. Moreira closed by stating that PCB technology with silver tracks offers great advantages in terms of cost with real cost of each SPE in the range of a few Euro cents.
The workshop then moved on to the subject of bioanalysis integration which was presented by Prof Frank Bier of the Department of Biosystems Integration and Automation at the Fraunhofer Institute for Cell Therapy and Immunology, Germany. Bier explained that diagnostics are moving to where they are needed – the point of care. He stated that with an ageing society and better known biomarkers that diagnostics will be the pharma market of the future. He used an image of a “Star Trek” tricorder and went on to say that the best solution would be based on less infrastructure and miniaturisation but that diagnostic quality must equal that of a traditional laboratory. An integrated approach with new interfaces, perhaps expert systems and sensor ruled implants would form the necessary diagnostics as part of an early warning health system. Bier stated that it was critical to make the correct decision on technology early in the development cycle as this defines the ultimate cost of production and avoids falling into “Death Valley” on the product life cycle curve.
Bier ended his presentation with an introduction to the “Fraunhofer ivD-platform” which consists of a credit-card sized cartridge and a small read-out unit. By taking a small volume of sample and insertion into the Fraunhofer ivD-platform, assays based on a microarray are performed automatically. Within 10 to 15 minutes, a multitude of different parameters can simultaneously be measured and displayed. Bier explained that the platform minimises interfaces between the test cartridge and the measurement device and is an open platform for different sensor types including optical and electronic. Developments of the ivD platform are continuing and will cover new assay formats including nucleic acid based detection for antibody resistance, epigenetic patterns for transfusions and transplants, non-coding and circular RNA and liquid biopsy.
Prior to the open panel discussion Steve Driver, the CEO of SCL PCB Solutions Group, addressed the delegates and thanked the speakers and participants in an enthusiastic address highlighting his passion for this technology and motivation to make products for an industry with a bright future. He echoed the sentiment around the room from those connected with the PCB industry in wanting to be a part of this exciting future. Steve concluded by telling us that his Grandmother thought of a PCB as “that green thing in the back of a TV set”, he explained that he now knew that actually it was a manifold for liquids!
The day ended with an open panel discussion led by Dr Moschou where the interconnectivity between the technical and commercial aspects were further explored by an enlightened audience.
The event was attended by 25 delegates covering a wide spectrum of expertise from academia to industry. The organisers, EIPC, were very grateful to Dr Despina Moschou of Bath University and Dr Peter Hewkin of CfBI for bringing together such a knowledgeable and interesting group of delegates and speakers. PCB technology and medical advances rarely fail to surprise, this was especially true at this workshop where those from the PCB industry left excited about the role they could play in the advancement of technology that would transform medical diagnosis and much more besides!
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