Design details
GRE were contracted to design and manufacture a liquid nitrogen (LN2) control and delivery infrastructure with the ability to automatically and simultaneously supply seven Thermofisher Scientific Cryo-EM microscopes with high-quality liquid at stable pressures. These microscopes, each costing around €8M are used for cutting edge scientific research across many fields. Notably, they were used in the development of a covid vaccine in 2020-1 and are in almost constant use for drug discovery, antibody and vaccine research.
Some of the test campaigns run for many days and require a constant supply of liquid nitrogen throughout. Any interruption in the supply can cause an expensive experiment or automatic sample changeover to fail, requiring it to be repeated from the start – an expensive result, in both time and money.
The contract was to replace an existing pipework delivery infrastructure (from bulk tank to microscope delivery point), which was not functioning. The previous system had been installed for approximately three years and was disconnected because it was not capable of reliably delivering quality LN2 to the point of use without excessive boil-off gas and excessive condensation on the pipe outer jackets. This led to multiple failed experiments, which ultimately lead to the facility switching to a manual, dewar-fed, process of suppling the microscopes with LN2.
Whilst this solved the technical problems, it of course introduced safety implications (asphyxiation, cold surfaces, manual handling etc) in the laboratory, which had to be managed, in addition to scheduling resource to undertake the Dewar fills, transportation and connection.
The Challenge
The problems experienced with the previous system were:
In addition to avoiding the performance issues described above, a further challenge for GREs engineers was that, as a retrofit installation, it was necessary to design a pipework infrastructure which navigated the existing run through the labs and corridors of the facility, taking into account existing equipment placement. As the pipe run incorporated several level changes through several different laboratories, the design had to well-considered, so as to avoid gas lock, whilst achieving a high-quality liquid flow at a stable pressure, direct to the point of use.
The Design Process
GRE worked with the Diamond Light Source Cryogenic experts and considered extensive data on the required performance of the microscopes, to develop a design which would overcome these difficulties and ultimately deliver a good supply of liquid to the valves.
Using a combination of physical measurements, calculations/analysis tools, Computer Aided Design Tools and LIDAR site mapping (which enabled GRE’s engineers to overlay a theoretical CAD model over a real-world scan of the client’s facility for extreme levels of design accuracy) a comprehensive design was produced and presented to the team at Diamond Light Source.
Further to the general requirements, GRE was also able to incorporate some additional features, such as the ability to measure the temperature and pressure of the LN2 supply at the take-off points and to holistically monitor the whole system, including the custom-built phase separator, from Diamond’s Building Management System (this was achieved by GRE programmers incorporating a BACnet communications module/software to the SIVL control system).
At the start of the design phase, an ‘all hands’ brainstorming meeting was held to gather input from the various stakeholders. Diamond’s hugely experienced cryogenic engineering department, the lab technicians and the scientists themselves all provided extremely useful feedback, which aided the concept design.
The solution
After extensive research, investigation and design, the GRE design team delivered a system comprising:
- A stored reservoir (Phase Separator) of liquid nitrogen at a common location within the building.
- This was kept at a constant pressure and level – based on setpoints defined and adjustable by the user – using a pair of modulating cryogenic valves.
- This additional feature (there was no such feature on the original installation, therefore, no additional inventory) provided constant flow of good quality liquid nitrogen when it was required, as well as a ‘1 day store/buffer’ of LN2, which would be available in the unlikely event of an interruption in the upstream supply of LN2.
- This additional ‘interim’ buffer volume also served to smooth out any spikes in pressure from the main supply line, for example as would occur when the tank was being filled.
- This phase separator had its own PLC controller, with a colour, touch-screen user interface and custom-written software with control algorithms for level and pressure.
- Approximately 100 metres of high-quality vacuum insulated pipework (in approximately 70 separate sections/modules, delivering Liquid nitrogen (1) to the internal reservoir of the phase separator and from there (2) to the microscopes themselves.
- The vacuum insulation has been implemented using GRE’s own custom designed and built, £200,000 vacuum conditioning facility, which uses automated cycles of heat, dry nitrogen purges and vacuum to achieve a vacuum that GRE are then able to guarantee for 5 years.
- This process was developed and refined by extensive R&D, and verified using a Residual Gas Analyser (RGA). Furthermore, an RGA is used on each batch to verify the cleanliness and vacuum quality of each and every transfer line and vacuum insulated assembly.
- GRE’s unique bayonet design allowed us to:
- Eliminate making vacuum joints on site, which are often the root of problems arising from poor or degrading vacuum.
- Prefabricate all vacuum insulated assemblies, and therefore control & verify the quality of the vacuum at the GRE headquarters
- Install the system without the need for welding / hot works and therefore on a much-compressed timescale, whilst at the same time vastly improving the lifetime of the vacuum.
- Custom gas vent/isolation modules at the point of delivery to each of the microscopes; these were an essential feature in ensuring that the very best quality liquid was available, on demand, direct to the point of use.
- There was one of these for each and every microscope, all with standalone instrumentation to verify the quality of the supply. This data was also sent to Diamond’s master controller by BACnet.
- Due to the sensitivity of the client’s equipment, the gas vents also had built in filtration to protect it, along with supply and vent isolation for ease of maintenance.
- Even with world-leading vacuum insulation, it is inevitable that some boil off gas is produced, because no insulation is 100% effective. The small amounts of gas produced are all diverted to an exhaust manifold, from where they are vented outdoors.
- GRE included a temperature-controlled exhaust gas outlet flow management device, which ensures frost-free conditions at the gas outlet and therefore eliminates the possibility of the outlet being blocked by condensed water turning to ice.
- The exhaust vent design also incorporates a clever non-return valve, which is closed when there is no flow, to prevent backstream moisture ingress into the exhaust pipework.
- All exhaust pipework was also vacuum insulated to prevent condensation / moisture in the laboratory environment
- Once designed and manufactured, GRE’s highly skilled installation engineers, fitted, tested, commissioned handed over the whole system, over the course of 4-week period.
As with all of GRE’s vacuum insulated pipework/systems the client was then presented with a comprehensive document package including:
- Full system P & ID with mechanical drawings for each component
- Material Test Certificates
- Individual line/component factor test reports (Vacuum Conditioning, Helium leak and positive pressure tests)
- Site Acceptance test report (Helium leak and positive pressure tests)
- Installation and operation manuals
- Declaration of conformance documentation
All actuated and manual isolation valves were from the Stohr range of cryogenic equipment, provided by Gas and Liquid Controls Ltd www.gasandliquidcontrols.com
The End Result
The successful installation now enables the client to run all seven of their microscope’s simultaneously, with a full programme of experiments, no interruptions and no downtime.
Moreover, the system can now be left unattended to run an experimental campaign over a number of days/weeks with minimal operator oversight.
The system has now been in use for many months with no significant fluctuations in pressure or quality of the liquid nitrogen supplied to the microscopes, resulting in extremely stable operation and maximum scientific output.
The system was commissioned and tuned in September/October 2024 and the microscope scientists felt comfortable enough by the Christmas break to run the system in fully automatic, with remote monitoring only. At the time of writing this report (late 2025), the system has required no extra intervention and has saved the client a huge amount of time and money – not least as it is proving to be saving around 30% of the previous LN2 costs, due to the vastly reduced boil-off.
To date, we understand that our system is the only one is the world that supplies multiple Cryo-EM microscopes on a fully automated basis.