Incorporating Microfabrication in Diagnostic Instruments

MANUFACTURING

MANUFACTURING

Seeking faster development

Point-of-care (POC) diagnostic instruments typically employ a disposable test cartridge in conjunction with a sensitive reader. Given the requirement for quantitative measurements with reduced sample volumes, microfabrication technologies are emerging as the prime means to deliver the required measurement precision. However, adopting this technology, which is often proprietary in nature, can entail considerable risk.

Microfabrication offers advantages based on fundamental scaling principles, the obvious benefit of porta-bility, and therefore the promise of real-time diagnosis for a patient. Using techniques such as micromachining, laser machining, embossing, high-aspect-ratio micromoulding and precision injection moulding, it is possible to fully integrate miniaturised diagnostic systems onto a single disposable cartridge.

Current market

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Table I: (click to enlarge) [6] Products incorporating microfabricated components.

Competition in the diagnostic market sector is strong with several companies vying to launch products and secure market share. Studying the POC market sector, it is evident that products incorporating microfabricated components have been slow to emerge and to-date only a few exist (Table I [6]). A further issue is that for POC diagnostics to be truly successful, production volumes need to be greater than one million units per year to drive the commercial revenue for these products, which is derived from the sales of the disposable tests. Because microfabrication processes are continually developing, there are few companies that offer a full range of developed processes. Even fewer have been involved in large-volume production, which reduces the choice of fabrication houses still further.

Improving the timescales

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Figure 1: (click to enlarge) [7] Schematic overview of the product development cycle and the different stages of microfabrication required.

Growth in the POC and home-care diagnostic market is providing escalating motivation for efficient product development. Considering Figure 1 [7] in conjunction with the short product development timescales that are required to compete in this market, there is a clear need for robust microfabrication processes that can support this development process. This can mean that in the concept phase, a new microfabricated design is required each day to allow different chemistry formulations or assay configurations to be tested. Looking in detail at a typical process for rapid prototyping (Figure 2 [8]), it can be seen that with focus and dedication a standard process can be created in 24 hours. To achieve this, a complete set of available skills is required and it is unlikely that this will exist within an internal product-development team.

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Figure 2: (click to enlarge) [8] Illustration of soft lithography rapidprototyping to support the development process.1

Determining which fabrication method or combination of methods to use for a particular application depends on a variety of factors such as feature size, lidding technique, complexity and optical properties. Typical expected time scales to manufacture components for different microfabrication processes are shown in Table II [9]. The time spent by internal development teams attempting to perfect and control microfabrication processes to achieve reproducible components is often the most critical part of the process and is usually significantly longer than the times shown in Table II [9].

Coupling to instrumentation

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Table II: (click to enlarge) [9] Summary of available microfabrication techniques.

It is commonly accepted that microfabrication techniques used in the early stage of a development programme are employed to demonstrate a proof of principle. To expedite the development cycle, development teams, which usually possess few instrumentation skills, manufacture rapidly prototyped diagnostics and utilise, as a means of measurement, high-sensitivity laboratory analysers that have often been hastily adapted. Laboratory analysers are usually configured to only read a range of predefined microtiter plates. Customising a laboratory analyser to read a prototyped microfabricated device is often difficult and usually requires high-tolerance fixtures to mount the prototyped device. This requirement for repeatable alignment offered by custom fixtures is often overlooked and leads to variability in measurements.

With internal development teams driven to achieve fast and efficient product development, the necessary resource and rigor to make thorough measurements and characterise microfabricated diagnostics is often lacking, and resulting concepts and ideas remain unproven. This is usually because of the use of immature microfabrication processes and the lack of repeatable measurements from reconfigured laboratory analysers. Recognising that once a microfabricated diagnostic is integrated into instrumentation the programme becomes truly multidisciplinary is a significant step. Interfacing biology, chemistry, fabrication and instrumentation is a complex and difficult area, if not one of the most difficult, in this type of programme. By producing a product requirement specification, which details the main features and requirements of the product, and by identifying interfaces between the biology, chemistry, instrument and disposable cartridge, each of these areas can be developed in parallel and integrated subsequently. From this, a development plan can be written that clearly identifies each stage of the product development from which the requirements for instrumentation and microfabrication at each stage of the programme can be derived. From this newly derived plan it should be apparent that instrumentation resource is required earlier to allow for laboratory analysers to be modified or custom instrumentation produced specifically. In providing instrumentation to support the programme not only will robust characterisation of the microfabricated devices be made, but the instrumentation will actually help to drive the programme.

Finding the right method

Determining the right microfabrication method has traditionally been a process of trial and error. It is crucial to select the correct fabrication technique to support each stage of the development programme. As part of the design cycle, the chosen microfabrication technique should not be the limiting factor. Within the research phase, flexible processes need to be adopted, which can support many changes. During the later stages of the development programme microfabrication techniques should be used that will provide the volume of components required for large-scale laboratory testing, whilst moving toward the target cost of goods and the features required in the product requirement specification.

Many companies recognise that they do not have the internal resources to support the microfabrication work. Microfabrication houses offer contract research and development that appears to be a cost-effective solution for companies in this position. However, all too often, the tools and processes on offer are limited in scope. Processes offered as a complete solution at the start of a programme often require further development, and the adopted solutions are driven by the expertise of the supplier and not the needs of the application. In these cases, the process will not have been fully demonstrated, or equivalence that has been shown during the microfabrication supplier selection phase,will often prove not to be as robust as first presented.

Microfabrication providers will undoubtedly aim to impress with the range of their capabilities. Without performing a thorough due diligence exercise, it is often impossible to gain a reliable assessment of their capabilities. One approach to aid development with an external microfabrication house is to provide a clear product requirement specification and a development plan. This will help ensure a smooth transition through the design process to the final cartridge production. To obtain an understanding of the likely turnaround time for prototyping, Table II [9], in conjunction with the available microfabrication processes, will help drive the design process and make supplier selection much easier.

By adopting an approach that identifies product requirements and discrete phases within a development programme, it is possible to control the development process and select appropriate microfabrication suppliers to support the development plan. Although in the early stages of development this approach may be considered onerous, imposing a degree of formality into the development will serve to facilitate and shorten the development programme. In employing this approach, together with the concept of microfabrication process selection, a flexible and fast route to product development can be achieved.

Portability

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Figure 3: (click to enlarge) [10] Integrating microfabrication into the diagnostic development.

To overcome the limited range of processes offered by a single fabrication house, a number of houses may be required to cover the range of processes, coatings and techniques that are required. It is important that any processes used or developed during the early stage of development should be portable and not supplier limited (Figure 3 [11]). For example, a lidding technique that has been developed to be compatible with a protein coating during the research phase with one supplier should be transferrable to another supplier in a subsequent development phase. This requires processes to be documented and available for release to a third party and allows for a continuation of processes through to production. Provided care is taken when initiating contracts to ensure that processes are portable between suppliers, combining a flexible supplier strategy with structured development approach offers a truly flexible and rapid route to product development. Ultimately, having achieved a robust, portable microfabricated design, a high-volume production facility should be able to fabricate the diagnostic instrument with low cost of goods and thus achieve the goal of the diagnostic company.

Multiple sourcing

By adopting a flexible multisupplier approach to sourcing of microfabrication services, the time to reliably develop products can be reduced. The likelihood of failure because of limited process capability or the limited design scope will be significantly diminished.

Simon Burnell is a Programme Manager with Cambridge Consultants Ltd, Science Park, Milton Road, Cambridge CB4 0DW, UK, tel. +44 1223 420 024, e-mail: simon.burnell@cambridgeconsultants.com [12], www.cambridgeconsultants.com [13].