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

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

Development of an optical measurement method for “sampled” micro-volumes and nano-flow rates

https://run.unl.pt/bitstream/10362/105971/1/1_s2.0_S0955598620301345_main.pdf

Development of an experimental setup for microflow measurement using interferometry

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

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

Steuerungssystem fur ein Mikroskop, mit einer Sensoreinheit, einer Auswerteeinheit und mindestens einer Antriebseinheit, wobei die Sensoreinheit mindestens einen Bewegungssensor aufweist, am Mikroskop befestigt und zur Erkennung von Kopfbewegungen des Mikroskopbenutzers auf den Kopf des Mikroskopbenutzers ausgerichtet ist, die Auswerteeinheit zum Berechnen der von der Sensoreinheit empfangenen Daten und zum Ubermitteln eines Steuerungssignals an die mindestens eine Antriebseinheit ausgebildet ist und die mindestens eine Antriebseinheit zum Antrieb von Mitteln, die zur Einstellung wenigstens einer physikalischen Eigenschaft des Mikroskops eingerichtet sind, ausgebildet ist.

Steuerungssystem für Mikroskope

Implantable, gas-driven drug pumps are safe, cost-effective and do not require internal batteries like their motor-driven counterparts. However, their flow rate cannot be changed after implantation. This work focuses on the development of an adjustable micro-flow regulator to be used in a programmable gas-driven pump. Several concepts of flow-restrictors made of microstructured silicone-elastomers have been evaluated and the manufacturing techniques have been optimized. Currently, fixed flowrates down to 250 nl/min can be achieved for a pressure drop of 3,4 × 105 Pa. Development of prototypes with adjustable flowrate is in progress. A test bench based on optical front-tracking for dynamic flowrate-analysis down to 10 nl/min has also been implemented. This enables an independent calibration of thermal micro-flow sensors as well as wide-range, low impedance flowrate measurements.

Measurement and Control of Ultra-Low Liquid Flowrates for Drug Delivery Application

This work presents a fabrication method for an elastic urinary bladder model with near-physiological mechanical and thermal properties using Rapid Prototyping. The model is part of an experimental setup for in-vitro simulation of the Transurethral Resection of the Prostate (TURP). Tensile tests of commercial silicone elastomers, together with FEM simulations were used to find a suitable material for the Bladder-model. A mold was then fabricated by selective laser sintering and the model was manually casted. The mechanical compliance of the finished model shows a reasonable agreement with the predicted behavior, with a max. discrepancy of 15% at 40 mbar.

/pdf/rapid-prototyping-of-an-elastic-bladder-model-for-in-vitro-3dgqrqlljp.pdf

Christian Damiani

Papers

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

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

Steuerungssystem für Mikroskope

Measurement and Control of Ultra-Low Liquid Flowrates for Drug Delivery Application

Rapid prototyping of an elastic bladder model for in-vitro simulation of the transurethral resection of the prostate