The Hedenstierna Laboratory

The Hedenstierna Laboratory continues the legacy of two renowned biomedical laboratories at Uppsala University, symbolizing the strong commitment to cutting-edge research and innovation of the University. It represents the merger of two historic and prestigious translational laboratories: the Clinical Physiology Laboratory and the Anesthesia and Intensive Care Laboratory.

The history dates back in the 1950s, when researchers performed physiology studies on rodents and larger species at the Experimental Surgery Laboratory, which was located at the top of the dome in Building 40 of the Akademiska Sjukhuset.

Twenty years later, in 1972, a new laboratory was established on the third floor of the new 70 building as part of a clinical research department after the proposal by Martin Holmdahl and other researchers.

Sven Jakobsson headed this laboratory after returning from his postdoctoral work in the USA, where he focused on respiratory mechanics. The laboratory underwent further expansion in 1982. During these years, thoracic surgeons and anesthesiologists studied the use of heart-lung machines in the facility as well as the effects of new pharmacological drugs for anesthesia and analgesia. At that time, the director of the research department was Prof. Henry Johansson.

By the end of the 1980s, the activities of this now three-laboratory facility diminished and were eventually discontinued in Building 70.

In fact, simultaneously (1990), the young Göran Hedenstierna established a new laboratory in the Building 30 with the thorax surgeons of the previous laboratory. Göran Hedenstierna was returning from his postdoc in San Diego with Prof. John West, where he developed a deep knowledge of the relationship between lung ventilation and perfusion.

The School of San Diego became a source of inspiration for the research activity of Göran’s laboratory, which now got the name of Laboratory of Clinical Physiology and welcomed the researchers of the previous Surgical Laboratory. San Diego laboratories had developed method to assess the compartmental kinetics of lung function based on the Multiple Gas Elimination Technique (MIGET) that Göran successfully transferred and implemented in the Clinical Physiology Laboratory. San Diego and Uppsala were the only places in the world where it was possible to compute the ventilation/perfusion characteristics of the lung

The love for new technologies and his exceptional capacity of creating collaborations with other disciplines was a key of the success of those years.

Göran Hedenstierna in the translational laboratory of clinical physiology of Uppsala was the first to study lung physiology using Computed Tomography (CT) during the late 1980s, opening a new research chapter in anesthesia and intensive care medicine, e.g., lung collapse as a reason for hypoxemia. While this new method flourished, it attracted the most sparkling junior researchers and the most promising young professors of Scandinavia, Europe, and America.

The laboratory has been the home of many studies involving researchers from all over the world. It is worth mentioning the seminal studies on the first implementations of Electrical Computed Tomography, Neural-Adjusted Ventilator Assist, and Artificial Neural Networks in respiratory monitoring.

Between the end of the 1990s and the beginning of the new century came the time of exploring new ideas about protective ventilation in intensive care, the physiology behind recruitment maneuvers, the mechanism of inflammation behind the injurious ventilation, and different aspects of methods of lung imaging and function. Many of these studies, performed closely with researchers from all over Europe and South America, were groundbreaking.

In year 2012, Professor Anders Sune Larsson (former director of the laboratory and Göran’s successor), in order to honor the lifelong achievements of this giant of research, proposed to entitle the laboratory to Göran Hedenstierna.

(We thank prof. em. Torsten Gordh for the help in documenting and writing the history of the laboratory)

The Hedenstierna Laboratory is a part of the Department of Surgical Sciences at Uppsala University. It is renowned for its historical research in the pathophysiology of intensive care patients, particularly in the development of translational models of acute respiratory injury and the research of treatments for patients with severe respiratory distress disorders.

A substantial portion of experimentation focuses on investigating physiological mechanisms using also advanced imaging techniques (as detailed below).

The institution not only engages in extensive research but also plays a crucial role in the teaching activities of the Medical Faculty at Uppsala University for both undergraduate and postgraduate students. Many PhD candidates from the Faculties of Pharmacological/Medical Sciences and the Faculty of Technology conduct their research here.

Moreover, Hedenstierna laboratory is frequently approached by medical device manufacturers to rigorously test their prototypes under strictly controlled conditions, demonstrating H*Lab (as commonly nicknamed around the world, red as “aitch-star-lab), commitment to excellence in both academic research and industry collaboration.

The Hedenstierna Laboratory organizes an annual masterclass on specific topics of interest.

This symposium is an academic meeting dealing with physiological mechanisms relevant to intensive care and anesthesia. It was established in 2011 and during the years it has gained a reputation for its quality. It is traditionally composed of two meeting days. During the first day high profile scientists present state of the art knowledge about the masterclass topics. Then the speakers are asked to engage in discussions with each other and with the audience. Panel discussions are part of the program. The audience comprises both young and senior specialist in anaesthesia and intensive care who are eager to keep abreast with recent findings. During the day before the symposium is organized the traditional annual brainstorming. The different research groups that compose the Hedenstierna Laboratory together with the scientists that form the international network of researchers using the infrastructures of the laboratory, offer presentations of their state-of-the-art research. Around the table sit together young and senior scientists, including the speakers and the moderators of the symposium. The time frame of the presentations is organized to allow elaborate and open discussions, with direct and frank questions in a pure scientific spirit.

(More information at www.hedenstiernasymposium.com)

Our main activity is to perform, support and facilitate research on translational models of human diseases. The laboratory has the know-how, the equipment and the permission to perform such type of research. The platform has the capacity of performing all kinds of biomedical research, but historically the focus has been on projects related to the pathological processes encountered in the intensive care environment.

Code of conduct

In the lab, we treat each other respectfully and do not accept discrimination or incivility against anyone. “Lika villkor” means equal opportunities, rights and obligations for all, regardless of sex, gender identity, age, sexual orientation, ethnicity, aspect, social, cultural or religious background or disability. In Sweden discrimination is prohibited by the law called “ Discrimination act”. (More info at https://www.do.se/).

Modus operandi

All experimental activities must have documented ethical approval before starting any procedures. This is non-negotiable, and no waivers are allowed. Subsequently, the researcher must provide the laboratory staff with a detailed description of the research plan well in advance, which is particularly important for new protocols.

Each month, the laboratory council reviews new project requests and, based on its decade of experience, assesses the feasibility of these projects in terms of sustainability and resource use. This evaluation process is conducted in a friendly and interactive manner, inviting the responsible researchers to present their project to the laboratory staff a few weeks in advance. The aim of these auditions is to assist novice researchers in finding solutions to critical issues they may encounter.

It is essential to emphasize that the laboratory council's role is not to replace ethical evaluation by the institutional review board; rather, it steps in only after the appropriate permissions have been secured.

According to local and international rules, in order to conduct an independent experiment, all the researchers must have overcome a course in the specific field of translational research they want to conduct. Also this is non-negotiable, and no waivers are allowed. Specific information is provided to the single researchers.

The researchers that approach the Hedenstierna laboratory for conducting experiments receive a personal letter where all the details of the process are explained in details as well as (especially for the ones coming from other cities or countries) advices about many practical issues (from the access to the building to how to move in the city).

The laboratory has four main internal research lines and is open to collaborations with external actors in these research fields. However also researchers who study different topics are welcome to use the infrastructure to perform their experiments, following rules and guidelines defined by Swedish laws and good laboratory practice routines. See also the paragraph on manifesto and modus operandi.
These lines are (in parenthesis the line coordinator):

1. Hemodynamics and cardiac arrest (Prof. Sten Rubertsson)
2. Respiratory mechanics and artificial ventilation (Prof. Gaetano Perchiazzi, assoc.)
3. Renal physiology and failure (Prof. Robert Frithiof)
4. Sepsis, inflammation and metabolic derangements (Prof. Miklós Lipcsey)

The Hedenstierna Laboratory is built around a former cardio-thoracic operating theater and consists of three separate areas for translational research, each equipped with two operating tables. This setup allows for six simultaneous experimental procedures, with each setup having its own multiparameter monitor and ventilator. Additionally, there is a dedicated area for procedures on a smaller scale, complete with all necessary equipment for histological and biological experiments.

A significant advantage of the laboratory lies in its direct access to the hospital's advanced imaging facilities. This seamless integration allows researchers to conduct transfers under carefully monitored conditions, specifically during anesthesia and mechanical ventilation. Such operations are executed with precision, ensuring that every step is carried out in a controlled environment, which enhances the quality and reliability of the imaging results obtained from the selected facility.

The accessible imaging techniques are:

• Computed tomography (CT, also as dual energy and photon counting methods)
• Single photon emission tomography (SPECT)
• Magnetic Resonance Imaging
• Positron emission tomography (also combined with CT or with MR)

It is worth mentioning that the laboratory has special equipment that might transferred to other laboratories in the world in order to organize research expeditions, as the ones performed at the Synchrotron Radiation Computed Tomography at the European Synchrotron Radiation Facility in Grenoble, France.

The laboratory owns two Electrical Impedance Tomography machines (Timpel and Dräger systems) and has the technical capability to retrieve and analyze digitally the recorded data.

The laboratory is equipped with:

• Multiparametric monitors (Philips) with modules for capnography, pulse oxymetry, invasive systemic and pulmonary pressure measurements
• Racks of micro-controlled infusion pumps (several per operating table)
• Full scale of surgical instruments for abdominal surgery
• C-arm system for bedside roentgenography (including X-ray protective clothing for several researchers)
• Controlled warming system for the operating table
• Management of core temperature via intravascular catheter for hypothermia studies (Zoll Thermogard platform)
• Two dialysis machines (Fresenius)
• Three dedicated ultrasound machines for transthoracic, transesophageal and abdominal examination
• Microdialysis system for microfluidic analysis from various districts of the body
• Direct data acquisition from Electrical Impedance Tomography machines

The data acquisition systems are based on:

• AD-Instruments PowerLab platform, connected to respiratory data sensors (three independent multichannel machines)
• Medicollector system
• Hemodynamic data sensors:
  • Millar technology (two independent machines), for measuring pressure and volume inside the two cardiac chambers, simultaneously
  • Transonic technology for multiple perivascular measuring of blood flow
• Direct data acquisition from mechanical ventilators (Getinge Servo-I, Servo-U and Flow-I machines)

Data analysis and management

The complex data analysis is performed using the platform MatLab and its toolboxes, for which the lab owns the respective licenses). This allows to analyse images directly in DICOM format and customize the method of analysis, without needing to rely upon third-part´s commercial software.

Access is also available to the most important Statistical software program and statistical consultation from the UCR (Uppsala Clinical Research Center). Cloud data storage services are available through the platforms provided by Uppsala University.

Laboratory analysis

The Hedenstierna Laboratory promote the connections to the network of specialized laboratories of Uppsala University and helps external researchers to create a pathway from the execution of the experiment to the desired specific analysis.

Office space

There is office space for guest researchers and internal PhD students, with toilets and locker rooms. A big coffee room with fifteen seats can be used also for small internal meetings. In the availability of the laboratory there are two other middle-size conference rooms (25 seats) and a lecture hall. A general medical library is nearby, however all scientific literature is available through intranet connection (both journals and books). The laboratory is inside the University Hospital of Uppsala, connected by a network of tunnels to all the other parts of the hospital and can benefit from the internal restaurants, coffee shops and pharmacy.

Human Resources

The laboratory has a permanent staff of four research engineers and two senior medical researchers. According to Swedish and European laws, all of them possess the necessary certifications for performing translational research. All together they constitute a board that meets not less than once a month and discuss all the issues arising from the laboratory management.

How to start a project:

Our recommendation is to contact the Laboratory well in advance before the wished date of the experiments. Use, please the functional e-mail address reported below (“contacts”). We know that the researchers who wish to perform an experiment may have very different background and experience.

Explorative phase and preliminary plan

For the ones that are inexperienced (like young PhD students at the beginning of their research career) we are happy to give advice also in the preliminary, explorative phase. We use to meet the young scientists and explain all the steps that are necessary. This leads to the preparation of a preliminary plan. We are available to give advice also in the phase of writing the ethical application: this specifically useful for the ones that do not have experience with advanced anesthesia procedures and instrumentation. For the many researchers the contact us from other countries we are also keen to help with the preparation of the ethical application in Swedish.

Planning and administration

After the explorative phase it is necessary to get a formal ethical permission from the Swedish Board of Agriculture (https://jordbruksverket.se/), have a financial plan with a documented source of money. At this point it is possible to prepare the experimental flowchart (where is written which procedure/measurements and at which time they should be performed) and a separate list of drugs and instruments are needed for the experiment.

The timing of the experiments and the needed resources are important because allows us to know how many hours of laboratory activity and the necessary working activity of laboratory research engineers.

At this point, if the activity is only internal to the laboratory, it is already possible to organize the experiment's calendar, considering that different groups may work on the same day. The laboratory will take care to plan the dates so that there is no conflict in accessing the same equipment at the same time.

When the research activity involves also other infrastructures (like imaging facilities) the coordination of the availability is more complex: it is needed that the imaging is available at the same time and day of the experiment and moreover the corresponding technician is available. This is usually coordinated by the responsible research engineer of the Hedenstierna laboratory.

There are groups that need special instruments that they wish to bring from their own laboratories, sometimes from other countries. We have standard routines for shipping back and forth the laboratory machines av various dimensions: our advice is to take contact with us as soon as this necessity arises.

The experiment

When everything is ready, the experiments can be conducted. In several cases, when it is necessary to have multiple and repeated sampling of biological fluids, a good norm is to prepare and label the bottles from the day before. The same applies when the technical set-up is specifically complex. As a routine the experimental activities start early in the morning and finish during the afternoon. In some exceptional cases the translational research can be conducted up to 72 hours continuously. However this requires specific permission and the availability on site of a certified researcher responsible for the procedure during all the time (even during the night).

The principal investigator for the project is responsible for ascertaining that the sampled data (tracings, recordings, etc.) are correctly saved. The same applies to the imaging data: it is a good norm to discuss the data retrieving process with the laboratory and the imaging technicians.

After the experiment

The laboratory has the know-how to help with tracings and image analysis by using advanced mathematical and statistical tools. Usually, as consolidated tradition, for reasons bound to privacy and confidentiality this is not part of a customary collaboration with external actors, not being an institutional task to be provided without a specific agreement.

However, if the project involves PhD students and/or personal of Uppsala University we are happy to help with advice and instructions. Systematic and detailed data analysis is only performed if we have preliminary agreed on that.

Costs

It is not possible to provide a generic list of costs for the differences among the various protocols. In general, the sources of costs include not only the raw materials and consumables but also the duration of the experiment and the number of research engineers required.

By the way the applied cost model depends also on whether it is academic or industrial research and which kind of resources are going to be used.

Contact:

Hx-lab@uu.se

The infrastructure is open for scientists within and outside Uppsala University who are able to present a scientific project plan that is feasible and of good scientific quality, holds a valid ethical permit, a billing address, necessary skills and complies with applicable regulation.

The price list for using the Hedenstierna laboratory is developed to cover costs.

Uppsala University is tasked with conducting research and education. External users pay a fee to cover full costs corresponding to market prices.

Assessment and prioritization of projects are done by Hedenstierna laboratory´s director and chief engineer.