Application fields of micromachined devices are growing very rapidly due to the continuous improvement of three dimensional technologies of micro-fabrication. In particular, applications of micromachined sensors to monitor gas and liquid flows hold immense potential because of their valuable characteristics (e.g., low energy consumption, relatively good accuracy, the ability to measure very small flow, and small size). Moreover, the feedback provided by integrating microflow sensors to micro mass flow controllers is essential to deliver accurately set target small flows. This paper is a review of some application areas in the biomedical field of micromachined flow sensors, such as blood flow, respiratory monitoring, and drug delivery among others. Particular attention is dedicated to the description of the measurement principles utilized in early and current research. Finally, some observations about characteristics and issues of these devices are also reported.

Micromachined Flow Sensors in Biomedical Applications

Worldwide, the microfluidics industry has grown steadily over the last 5 years, with the market for microfluidic medical devices experiencing a compound growth rate of 22%. The number of submissions of microfluidic-based devices to regulatory agencies such as the U.S. Food & Drug Administration (FDA) has also steadily increased, creating a strong demand for the development of consistent and accessible tools for evaluating microfluidics-based devices. The microfluidics community has been slow, or even reluctant, to adopt standards and guidelines, which are needed for harmonization and for assisting academia, researchers, designers, and industry across all stages of product development. Appropriate assessments of device performance also remain a bottleneck for microfluidic devices. Standards reside at the core of mature supply chains generating economies of scale and forging a consistent pathway to match stakeholder expectations, thus creating a foundation for successful commercialization. This article provides a unique perspective on the need for the development of standards specific to the emerging biomedical field of microfluidics. Our aim is to facilitate innovation by encouraging the microfluidics community to work together to help bridge knowledge gaps and improve efficiency in getting high-quality microfluidic medical devices to market faster. We start by acknowledging the progress that has been made in various areas over the past decade. We then describe the existing gaps in the standardization of flow control, interconnections, component integration, manufacturing, assembly, packaging, reliability, performance of microfluidic elements and safety testing of microfluidic devices throughout the entire product life cycle.

Accelerating innovation and commercialization through standardization of microfluidic-based medical devices

Microflow and nanoflow rate calibrations are important in several applications such as liquid chromatography, (scaled-down) process technology, and special health-care applications. However, traceability in the microflow and nanoflow range does not go below 16 μl/min in Europe. Furthermore, the European metrology organization EURAMET did not yet validate this traceability by means of an intercomparison between different National Metrology Institutes (NMIs). The NMIs METAS, Centre Technique des Industries Aerauliques et Thermiques, IPQ, Danish Technological Institute, and VSL have therefore developed and validated primary standards to cover the flow rate range from 0.1 μl/min to at least 1 ml/min. In this article, we describe the different designs and methods of the primary standards of the gravimetric principle and the results obtained at the intercomparison for the upper flow rate range for the various NMIs and Bronkhorst High-Tech, the manufacturer of the transfer standards used.

Primary standards for measuring flow rates from 100 nl/min to 1 ml/min - gravimetric principle

For critical drug delivery, it is important to have a constant and well-known infusion rate delivered by the complete infusion set-up (pump, tubing, and accessories) Therefore, various drug delivery devices and accessories were tested in this article in terms of their infusion accuracy, start-up delay, response time, and dependency on the viscosity These measurements were performed as part of the European funded research project MeDD The obtained results show that the infusion accuracy of the devices is flow rate and accessory depended, especially for low flow rates Viscosity does not have a significant impact on the flow rate accuracy

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Assessment of drug delivery devices.

An increasing number of microfluidic systems operate at flow rates below 1 μl/min. Applications include (implanted) micropumps for drug delivery, liquid chromatography, and microreactors. For the applications where the absolute accuracy is important, a proper calibration is required. However, with standard calibration facilities, flow rate calibrations below ~1 μl/min are not feasible because of a too large calibration uncertainty. In the current research, a traceable flow rate using a certain temperature increase rate is proposed. When the fluid properties, starting mass, and temperature increase rate are known, this principle yields a direct link to SI units, which makes it a primary standard. In this article, it will be shown that this principle enables flow rate uncertainties in the order of 2-3% for flow rates from 30 to 1500 nl/min.

Primary standard for liquid flow rates between 30 and 1500 nl/min based on volume expansion

This work presents the improvements of an experimental setup for measuring ultra-low flow rates down to 5 nl/min. The system uses a telecentric CCD imaging system mounted on a high-precision, computer-controlled linear stage to track a moving liquid meniscus inside a glass capillary. Compared to the original setup, the lowest attainable expanded uncertainty at any flow rate has been reduced from 5.4% to 2%. In addition, the conformity with specification of three commercial micro-fluidic devices was evaluated using the new setup: one syringe pump, one implantable infusion pump and one thermal flow sensor. The flow sensor and the implantable infusion pump met the compliance criteria (coverage probability 95%). The syringe pump however, failed to meet the specifications at 5 nl/min and 10 nl/min. No assessment could be made at higher flow rates.

An experimental setup for traceable measurement and calibration of liquid flow rates down to 5 nl/min

In various recently published studies, it is argued that there are underestimated risks with infusion technology, i.e., adverse incidents believed to be caused by inadequate administration of the drugs. This is particularly the case for applications involving very low-flow rates, i.e., <1 ml/h and applications involving drug delivery by means of multiple pumps. The risks in infusing are caused by a lack of awareness, incompletely understood properties of the complete drug delivery system and a lack of a proper metrological infrastructure for low-flow rates. Technical challenges such as these were the reason a European research project "Metrology for Drug Delivery" was started in 2011. In this special issue of Biomedical Engineering, the results of that project are discussed.

Metrology for drug delivery.

The flow of liquids inside or outside the human body plays a key role in medical technology. Safety and reliability of many medical devices or their components, e.g. dialysis machines, infusion devices, or liquid-handling systems for in-vitro diagnostics, require safe and reliable dosing of liquids. For that reason all aspects of dosing, handling, and measuring of low liquid flows are current topics of many research activities. The results of this efforts are presented and discussed at conferences like, e.g. the International Conference on MicroFluidic Handling Systems (the 2nd conference took place in 2014) [11], the European Conference on Microfluidics (the 4th took place in 2014) [5], or the International Flow Measurement Conference (the 16th took place in 2013) [4]. Many other examples can be found in this issue. This special issue focuses on low liquid flows in medical technology, mainly with regard to drug delivery and infusion systems. Most of the contributions are based on results from the joint EMRP – Metrology for Drug Delivery (MeDD) research project [10]. The project was carried out by the national metrology institutes VSL (NL, coordinator), CETIAT (F), CMI (CZ), DTI (DK), METAS (CH), IPQ (PT), and UME (TK) as well as UMC (University Medical Centre, Utrecht) (NL) and Luebeck University of Applied Sciences (GE). Although the project funding ended in the summer of 2015 the work will partly be continued by some of the partners. This special issue has therefore the character of a status report of ongoing research and discusses the major findings. The contributions of this special issue are categorized as follows. The first two contributions introduce the subject. They explain the background of metrology for drug delivery [8] and offer an overview of studies related to flow variability [16]. The third to fifth articles deal with measurement technologies and assessment. Because the gravimetric method is a common method for a great deal of the relevant flow range, this method has been given specific attention in the project. Several calibration facilities have been developed, validated and accredited during the project [3]. So this paper gives quite a good overview of the European activities. Another research project aiming at realizing gravimetric calibration services for low liquid flow rates is, for example, being carried out by NIST (USA) [12]. In this special issue it is discussed how this method has been used to assess several drug delivery systems [2]. In addition to the common gravimetric method, new methods are discussed that could be applied for extremely low flows in case the gravimetric method is not suitable. This includes an optical front tracking method [1] and flow sources. One source based on volume expansion is introduced in [9]. This is followed by a transition to papers focusing more on application. The first describes the development of a new restrictor to adjust drug flows in gas-driven implantable infusion pumps [7]. Finally there are three papers dealing with the application of low flows in infusion technology in a clinical environment. The influence of components and their properties (e.g. compliance) on multi-infusion systems and their behavior (e.g. interference) is studied in [13]. The influence of two different methods to change syringes is investigated in [6]. Finally, how safety guidelines can be deduced from current best practices and the research conducted in the MeDD project is discussed in [15]. Two workshops were organized by the “Metrology for Drug Delivery” group, one in Luebeck, Germany at Luebeck University of Applied Sciences in September 2014 and one in Utrecht, The Netherlands at University Medical Center in the summer of 2015. While the first one focused mainly on the results of the MeDD project, the second one was more directed to safety aspects in infusion technology and tried to work out possible future work. All presentations can be downloaded at the corresponding websites [14]. The Guest Editors would like to thank all those involved in this special issue, especially the authors for their contributions and the patience needed during the several stages of the review process. We also thank the reviewers for their valuable hints to improve the quality of this issue. Special thanks go to the Editor in Chief and the publisher for their

Low liquid flows - an important aspect in medical technology.

Characterisation of medical microfluidic systems regarding fast changing flow rates using optical front tracking methods

This paper describes an adjustable flow restrictor for use in gas-driven implantable infusion pumps, which is based on the resistance of a flow through a porous ceramic material. The flow inside the walls of a ceramic tube can be adjusted between 270 nl/min and 1260 nl/min by changing the flow path length in the ceramic over a distance of 14 mm. The long-term stability of the flow restrictor has been analyzed. A drift of -8% from the nominal value was observed, which lies within the required tolerance of ±10% after 30 days. The average time needed to change the flow rate is 40 s. In addition, the maximum adjustment time was 110 s, which also lies within the specification.

Stephan Klein

Papers

An experimental setup for traceable measurement and calibration of liquid flow rates down to 5 nl/min

Metrology for drug delivery.

Low liquid flows - an important aspect in medical technology.

Characterisation of medical microfluidic systems regarding fast changing flow rates using optical front tracking methods

An adjustable flow restrictor for implantable infusion pumps based on porous ceramics.