Dr Tracy Brown is head of life sciences at TÜV SÜD National Engineering Laboratory. She outlines the role of microfluidics in healthcare in particular improving infusion drug delivery techniques.
Microfluidics technology provides tools that enable the precise control and manipulation of fluids in the microlitre to picolitre range (less than one thousandth of a mL). Its growing application across healthcare and pharmaceutical fields, including drug infusion and organ-on-a-chip (OOAC), is creating demand for increased fundamental understanding of microflows.
Infusion is the most common form of therapy in a clinical setting. Each day, millions of patients worldwide receive intravenous infusion treatment, eg nutrient or electrolyte replacement, anaesthesia, chemotherapy. Its widespread use in critical healthcare settings means infusion errors are often made which can lead to adverse incidents, morbidity and, at worst, prove fatal. While monitoring a patient’s vital signs can indicate potential dosing errors, they cannot be relied upon as a means of ensuring safe drug delivery and only indicate the error after it has occurred, ie. when it is too late.
The growing focus on a personalised approach to healthcare brings with it a commensurate impetus for greater metrological understanding. Precision medicine is expected to change fundamentally the delivery of medical treatments and is predicated on the idea that different sizes of dose can be delivered accurately. The journey towards therapeutic and prophylactic interventions tailored to individuals that take into account their genetic blueprint, environment and lifestyle is underway. Intrinsically, this will necessitate the need for enhanced measurement capability to ensure the accurate dosing of infusions containing novel complex therapeutics designed to treat niche illnesses.
TÜV SÜD National Engineering Laboratory based in the UK is part of a consortium of European national measurement and designated institutes, universities and manufacturers that has embarked upon a three-year project aimed at improving dosing accuracy and enabling the traceable measurement of volume, flow and pressure of drug delivery devices used in infusion therapy. It will develop traceable calibration procedures for medical flow devices such as infusion pumps, down to very challenging low flow rates in the nanolitre (nL) per minute range necessary for infusions in certain patient groups, eg. neonates. It will develop techniques for generating and measuring the response or delay time of these devices and examining the influence of fast-changing flow rates and innovative approaches, for example, optical methods, to make these challenging measurements. It will also investigate how mixtures of liquids with differing viscosities mix and flow in multi-infusion systems and how this affects the therapeutic drug concentration over the course of an infusion. Such rigorous metrology will prevent harm to patients arising from inappropriate mixing such as therapeutic failure or toxicity.
The primary infusion devices used for administration have a significant impact on metrology. In the case of intravenous administration, for example, various devices with differing purposes may be used (syringe pumps, peristaltic pumps, insulin pumps). Each method must be capable of delivering traceable, accurate and reproducible metered doses of drug. Understanding the sources of, and minimising, measurement uncertainties attributable to the operation of each device is key to achieving this and is a fundamental aspect of the work being undertaken in this multi-partner project where uncertainties of 1-2% are being targeted.
In addition to existing drug delivery devices, the metrology infrastructure and standards arising from this project are also aimed at future technologies for managing drug delivery for quality validation and reproducibility. Amongst these are microneedles, which are, essentially, miniaturised needles offering more effective drug delivery with less pain. There are different types including dissolvable microneedles which, as their name suggests, dissolve following insertion into the skin and release of the drug enclosed within them.
OOAC microfluidic devices are evolving rapidly and present exciting opportunities across the drug discovery pipeline from candidate identification to efficacy, toxicity and safety. These microscale in vitro human physiological models are efficient and cost-effective with their added potential to reduce the use of animal models offering an ethical alternative to conventional pre-clinical drug discovery approaches. Moreover, OOAC technology can be used as implantable drug delivery devices capable of producing continuous, non-continuous or pulsatile delivery patterns by less painful means. Fluid flow measurement has an integral role to play in the translational journey of these novel microfluidic applications from bench to clinic. For example, the interconnection by microfluidic flow of single organ models enabling the study of biological interactions between organs. The burgeoning adoption of technologies such as OOAC in healthcare will necessitate the development of a metrological infrastructure to validate their accuracy and reproducibility. Accordingly, a further aim of the collaborative European metrology project is the development of a proof-of-concept microfluidic microchip flow pump for use as a moveable traceable transfer standard for the calibration of drug delivery devices used in drug discovery and OOAC for ultra-low flow rates (below 100 nL/min).
Regulatory compliance underpins every innovation or innovative methodology within the medical device sector; an obligation which is set to increase from May 2020 when the new Medical Devices Regulation (Regulation (EU) 2017/745) comes into full force. The increasing innovation and complexity of drug infusion systems will inevitably see metrological information form an essential part of the regulatory approval process for these medical devices. Their characteristically judicious approach will see regulators seeking to require device manufacturers to apply metrological standards at national, European and international level. Not only will this entail the development of existing standards, it will require the creation of new ones to address their diversity and increasing complexity. Whilst at an embryonic stage, microfluidic technology is progressing apace. In parallel, work is needed to define measurement standards for microfluidic devices covering areas such as the control and quantification of fluid flows. Developing microfluidics measurement standards will facilitate their uptake across the pharmaceutical and health sectors by providing the necessary accuracy and reliability in their manufacture and performance.
The advantages of microfluidic devices as drug discovery and delivery platforms cannot be underestimated; they are quick, inexpensive, portable and effective. However, developing a robust flow metrology infrastructure to validate their quality, reduce dosing errors and ensure device efficacy and safety is key to unlocking their potential.