Making it to market

The many benefits of microfluidics suffer from transition problems when moving from research to a commercial product - Neil Campbell and Paul Wilkins discuss how to change this.

Although microfluidics has been a buzz word within industrial applications over the past 20 years, few developments in this point of care diagnostic sector have managed to make the transition from the research setting to a commercial product that can be manufactured in high volume. The potential benefits of microfluidics are still, however, numerous: ease of use, reduced sample volumes and reaction times, higher data quality, reliable parameter control and use of low-cost production.

The intricacy of the microfluidic chip means that little is required of the detection instrument and the integral automation means the user does not need to engage in multi-step reactions requiring a high level of skill. Despite this, we are still faced with the well known challenges that involve ensuring the efficiency of the complex processes required to deliver reagents at the right time, in the correct order and sufficiently mixed for reactions to proceed. In addition to the technical issues associated with microfluidic platforms, the diagnostics industry has also faced difficultly in identifying a low cost manufacturing technique that can produce the micro patterning needed.

Whilst the paramount requirement is result accuracy, any device designed for use at the point of care also needs to be small, cheap, mobile, robust and fast to be successful. Microfluidic techniques allow manufacturers to produce devices which are lower cost, smaller and potentially hand-held. At the same time, all of the profit of a microfluidic diagnostic kit sits with the consumable device, so manufacturers need to focus on keeping development costs low while maintaining efficacy of the device.

“Microfluidics as a basic processing technology clearly works at the proof of principle level but that is where most of the work ends, usually in a publication. Engineering the device into a manufacturable product requires some consideration of substrate material, device functionalisation, packaging and performance testing. Currently the biggest opportunity and largest potential barrier to moving micro and nano technology into the commercial environment lies in innovative manufacturing,” comments key opinion leader on Lab-on-a-Chip and Microfluidic Technology Professor Steve Haswell, University of Hull.

In terms of polymer based devices, there are two leading technologies that can be applied to enable cost-effective mass production of microfluidic devices: Injection Moulding (IM) and Polymer Laminate Technology (PLT).

Injection Moulding carries many advantages in addition to its rapid manufacture: it is low cost with secure supply chains from multiple manufacturers and a large palette of polymers is available. Mass production of microfluidic chips using IM is however perceived to be problematic because it lacks the precision required to reproduce the micron sized features reliably. The common effects of polymer creep or shrinkage in the final products through IM imposes great challenges on those trying to obtain the tight tolerances of forming fine features in a device. This means that both the design of the device architecture and good control of moulding conditions are required to avoid unacceptable variations that would impact on the reproducible production of devices.

At Sagentia, our understanding of both injection moulding and microfluidic device design have allowed us to include some well-known microfluidic channel geometries in conventional moulded parts. The chip previously developed with micro injection moulding can now be manufactured reliably in high volume using cost effective conventional injection moulding. Extreme tolerance tests on the microfluidic chip showed minimal drop-off in accuracy of results, meaning that the device could be converted into a design suitable for a conventional low cost manufacturing process.

PLT offers another suitable alternative, offering rapid manufacturing which can be conducted on a continuous production line of devices. It carries the benefit that manufacturers can incorporate secondary components or equipment such as microelectro-mechanical systems (MEMS) and fibre optics. This technique is not without restrictions, and a limited palette of chemical resistant laminate materials, used to form fluidic channels and vias, is available compared to polymers available for IM.

Microfluidic device design has been assisted by the advances of micro rapid prototyping, such as the development of multi-polymer micro stereolithography (µSLA). This allows a number of complex microfluidic architectures from PDMS or PMMA to be used, which in conjunction with Design of Experiments (DoE) tools can be used to optimise the device design. This is of particular importance when integrating connections to other equipment such as sample delivery systems, analytical readers, electrical contacts and the integration of MEMS. µSLA can reduce the design time associated with traditional techniques and provides designers with the opportunity to develop more complex and multifunctional devices that can even work with live cells or tissue, leading to an almost infinite palette of possible functionality.

While these methods are suitable for manufacturing the whole device, there may be occasions a combination of techniques are required. In such circumstances, a successful device will have to accommodate the challenges that can arise at the interface between such ‘hybrid’ systems.

Looking to the horizon of next generation microfluidic diagnostics, a great deal of research is being focused on microfluidic devices being produced on paper. Analogous to lateral flow diagnostics technologies, microfluidic channels on the paper allow the liquid flow direction and speed to be controlled. The channel walls and features are produced through the treatment of the paper with a hydrophobic polymer. These paper based devices have a number of advantages, such as being made from extremely low cost materials and ease of disposal. Up until now these devices have been limited to relatively simple device architectures, but this new approach, being developed by various groups worldwide, is certainly one to watch for the future. One such company, Diagnostics for All (Boston, MA), are using technology pioneered by Professor George Whitesides and his team to develop diagnostic tests specifically aimed at the developing world.

Another emerging trend in device application is the advancement of diagnostic technologies into producing “prognostics”. Not only does the device perform a diagnosis test for a disorder but conducts further onboard complex assays on the individual’s sample to provide information on the best course of treatment. This personalised medicine approach has recently seen a great deal of success in the area of chemotherapy and a number of devices are already undergoing clinical trials.

Applications even extend to biopsies of head and neck tumours being placed into the microfluidic chip. These viable tissue samples are then exposed to a combinatorial array of chemotherapy agents in order to quantify the effects of these chemotherapy agents on the samples, with the aim of developing a personalised chemotherapy model. This allows the best treatment for the patient to be rapidly prescribed to maximise the chance of success.

Prognostics identifying the problem and highlighting a solution through a smart use of combinatorial chemistry and microfluidics looks to be the next evolutionary step in the consumable medical diagnostic device industry.

Advances in microfluidic architecture, coupled with the application of established techniques such as IM and PLT, offer a viable solution to the challenge of transferring microfluidic technology from niche research settings to mass production. This will enable exploitation in a much wider range of settings, for example, neonatal care where sample size is naturally very limited and the developing world where lab infrastructure is not available but rapid diagnosis is invaluable. We still have some road ahead of us to get there, but with continued investment, technology advancements and potentially successful new approaches, we have a chance of truly creating a small, cheap and fast point of care diagnostic. Only then will the true potential of microfluidic technologies in the diagnostics sector be unlocked.