Development of a microfluidic electroosmosis pump on a chip for steady and continuous fluid delivery.

Infusion therapy is the most common form of therapy used in health care. However, the existing infusion devices show higher flow discrepancies as flow rates decrease to a few nL min-1. As a result, dosing errors can contribute to the morbidity and mortality of patients. In the scope of project 18HLT08 MeDD II - Metrology for drug delivery, this investigation aims at the development of a silicon microchip flow pump capable of steadily and continuously dispense very low flow rates of a few nL min-1. The fabrication methodologies explored here use a combination of typical cleanroom micro/nanofabrication techniques and off-the-shelf equipment. Preliminary tests show flow rates as low as 45 nL min-1 can be obtained in this microfluidic electroosmotic pump. The experimental flow rates are in good agreement with results predicted by multiphysics simulation, with less than 8% deviation ratio. This cost effective electroosmotic micropump has the potential to act as a steady and continuous drug delivery system to neonatal patients as well as to organs on chip (OoC), determining the stability of the shear stress imposed on the cells or the right cell culture medium conditions.

Assessment of drug delivery devices working at microflow rates.

Almost every medical department in hospitals around the world uses infusion devices to administer fluids, nutrition, and medications to patients to treat many different diseases and ailments. There have been several reports on adverse incidents caused by medication errors associated with infusion equipment. Such errors can result from malfunction or improper use, or even inaccuracy of the equipment, and can cause harm to patients' health. Depending on the intended use of the equipment, e.g. if it is used for anaesthesia of adults or for medical treatment of premature infants, the accuracy of the equipment may be more or less important. A well-defined metrological infrastructure can help to ensure that infusion devices function properly and are as accurate as needed for their use. However, establishing a metrological infrastructure requires adequate knowledge of the performance of infusion devices in use. This paper presents the results of various tests conducted with two types of devices.

Metrology in health: challenges and solutions in infusion therapy and diagnostics.

The significance of Metrology in infusion therapy and diagnostics, both critical in health care safety and quality, is discussed in this article. Although infusion therapy is the most used form of drug administration, infusion errors are often made with reported dramatic effects in different applications, especially in neonatology. Adverse incidents, morbidity, and mortality have often been traced back to poor or inaccurate dosing. For critical infusion applications to vulnerable patients, well-controlled medication administration might be accomplished by improved dosing accuracy, traceable measurement of volume, flow, and pressure in existing drug delivery devices and in-line sensors operating at very low flow rates. To this end, the contribution of recently upgraded metrological infrastructures in European Metrology Institutes to a safer infusion therapy in health care is described in detail. Diagnostics, on the other hand is a sector characterized by rapid developments further triggered recently by the necessity for the management and prevention of infectious diseases like COVID-19. In this context, the impact of metrology in future large-scale commercialization of next generation diagnostics (e.g., point-of-care) is highlighted. Moreover, the latest contributions of Metrology in the development of traceable testing methods and protocols to ensure the sensitivity and accuracy of these devices are described.

Measurement of internal diameters of capillaries and glass syringes using gravimetric and optical methods for microflow applications.

OBJECTIVES: Microflow measurement devices are used in several science and health applications, mainly drug delivery. In the last decade, several new methods based on optical technology were developed, namely the front tracking and interferometric method, in which the knowledge of the inner diameter of the syringe or the capillary used is critical. Only a few National Metrology Institutes (NMIs) can perform inner diameter measurements below 1 mm, which requires expensive technology. Therefore, IPQ, in cooperation with CETIAT, CMI and UNIDEMI, under the EMPIR project 18HLT08 MeDDII - Metrology for Drug Delivery, developed new measurement methods for small inner diameter tubes based on the gravimetric principle and optical methods in order to simplify the apparatus used for this type of measurements without increasing uncertainty. METHODS: The gravimetric experimental setup consists of measuring the liquid volume on a specific length of the glass tube. The optical method used is based on the front track principle that uses a high-resolution camera and ImageJ software, to determine the diameter at both ends of each capillary. RESULTS: To validate the developed methods, a comparison was performed between CETIAT, CMI and IPQ and the results obtained were all consistent. CONCLUSIONS: This work allowed the determination of inner diameter of syringes or capillaries using two different methods with relative expanded uncertainties from 0.1 to 0.5% (k=2), that can be applied for flow measurements using optical technology.

Calibration methods for flow rates down to 5 nL/min and validation methodology.

Improving the accuracy and enabling traceable measurements of volume, flow, and pressure in existing drug delivery devices and in-line sensors operating at very low flow rates is essential in several fields of activities and specially in medical applications. This can only be achieved through the development of new calibrationmethods and by expanding the existing metrological infrastructure to perform micro-flow and nano-flow measurements. In this paper, we will investigate new traceable techniques for measuring flow rate, from 5 nL/min to 1,500 nL/min and present the results of an inter-comparison between nine laboratories for the calibration of two different flow meters and a syringe pump.

Calibration of insulin pumps based on discrete doses at given cycle times.

One application in the medical treatment at very small flow rates is the usage of an Insulin pump that delivers doses of insulin at constant cycle times for a specific basal rate as quasi-continuous insulin delivery, which is an important cornerstone in diabetes management. The calibration of these basal rates are performed by either gravimetric or optical methods, which have been developed within the European Metrology Program for Innovation and Research (EMPIR) Joint Research Project (JRP) 18HLT08 Metrology for drug delivery II (MeDDII). These measurement techniques are described in this paper, and an improved approach of the analytical procedure given in the standard IEC 60601-2-24:2012 for determining the discrete doses and the corresponding basal rates is discussed in detail. These improvements allow detailed follow up of dose cycle time and delivered doses as a function of time to identify some artefacts of the measurement method or malfunctioning of the insulin pump. Moreover, the calibration results of different basal rates and bolus deliveries for the gravimetric and the optical methods are also presented. Some analysis issues that should be addressed to prevent misinterpreting of the calibration results are discussed. One of the main issues is the average over a period of time which is an integer multiple of the cycle time to determine the basal rate with the analytical methods described in this paper.

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

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 Aérauliques 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.

Assessment of drug delivery devices.

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.