by Boris Rubinsky, Professor of the Graduate School, University of California Berkeley

Part 1 – Cryosurgery

The field of cryogenics has been connected with medical applications since its inception, with advances in cryogenics leading rapidly to those in medical technology. What follows is a historical review of some of the major applications within medicine where the term cryogenic is used in a specific manner.

Among physicists, temperatures are considered cryogenic when lower than about 123 K, the temperature where gases begin to liquefy. But in the context of biological matter that is made mostly of water, the so-called cryogenic range is below the freezing temperature of water. This position is not an accident or mistake, but is related to the fact that in biological matter there is a continuity of biophysical processes from 273 K to close to 0 K.

The ultimate goal of cryogenic processes is often to bring the biological matter to what the physics and engineering community consider the cryogenic range, but it makes no biophysics sense to separate the temperature range from the freezing temperature of water to absolute zero into arbitrary ranges of temperature. Furthermore, the science of subfreezing temperature biology, or cryobiology, has evolved and follows developments in refrigeration and cryogenic technology.

In a series of articles, I will discuss the history and the status of the various fields in which cryogenics intersects with medicine, beginning with the field of cryosurgery. It was the first field where medicine benefited from advances in cryogenics since the early work of Michael Faraday in the middle of the 19th century. This will be followed by an article on the history of the field of cryobiology that began in the 1920s; the history of cryogenics in medical and biological imaging that led to the 2017 Nobel Prize in chemistry; the history of the now-ubiquitous MRI in relation to cryogenics; and the emerging field of cryogenics in tissue engineering. There are other relevant fields at the intersection of life sciences and cryogenics, from the esoteric, such as life under conditions of extreme temperatures[1], life on the ice moons in the solar system, on Mars, or in space, to the very important use of cryogenics in food processing.

Cryosurgery is an established surgical technique, sometimes referred to as cryotherapy or cryoablation, where doctors use freezing to destroy undesirable tissue. The use of freezing to destroy tissue began around the middle of the 19th century and is an outgrowth of research on the physics of temperatures below freezing. Physicists in that period became interested in achieving and studying low temperatures by mixing ice with various solutes [2]. Around 1845, Michael Faraday achieved a temperature of 163 K by mixing solid carbon dioxide and alcohol under vacuum. Shortly thereafter, M.J. Arnott—the 1848 president of the Royal Medical and Chirurgical Society of London and considered the pioneer of cryosurgery—began using a solution of crushed ice and sodium chloride to freeze advanced cancers on the breast and uterus [3]. The procedure was recognized and even incorporated in textbooks on the treatment of cancer, while the second part of the nineteenth century witnessed several major discoveries in the field of cryogenics.

In 1877, Louis Paul Cailletet of France and Amé Pictet of Switzerland began developing adiabatic expansion systems for cooling gases, leading to the liquefaction of oxygen, air and nitrogen. In 1892, James Dewar of Great Britain designed the first vacuum flask, facilitating the storage and handling of liquefied gases. And in 1895, Carl von Linde of Germany and William Hampson of England began using throttle expansion, or the Joule-Thomson effect, to produce continuously operating air liquefiers. Solid carbon dioxide, liquid air and other liquefied gases were also commercially available at the end of the century.

Commercial availability led to a report from A. C. White on tissue ablation [4] that mentions Charles Tripler, a physical sciences professor from New York who made liquid air in large quantities. For the previous two years, Tripler had apparently urged the use of liquid air in therapeutics and supplied the liquid air to various physicians. Interestingly, the field of cryosurgery had since its inception required an interaction between physicists, engineers and physicians—a trend that has continued until now.

At the beginning of the 20th century, liquid air lost popularity to dry ice which was readily available and produced from the expansion of compressed, liquefied CO2 to atmospheric pressure. During the first half of the 20th century, the use of solid CO2 became the most popular method of tissue freezing for applications primarily in dermatology and gynecology for ablations on the surface of and readily accessible parts of the body. Freezing was and remains an important technology in dermatology and gynecology.

Liquid oxygen became commercially available in the 1920s with the development of large new air separation facilities, such as the Linde Company’s air separation plants that use regenerators [2]. However, liquid oxygen is a fire hazard and has never become a popular cryogen for cryosurgery. In the early 1940s, Pyotr Kapitza in the Soviet Union and Samuel Collins in the United States began developing commercial techniques for large-scale liquefaction of hydrogen and helium, with liquid nitrogen as an abundant and low-cost byproduct [2]. Liquid nitrogen began to replace dry ice in dermatology and gynecology soon after it became readily available commercially, and was generally delivered with a cotton swab.

The next major advance in cryosurgery was linked to advances in insulation technology that allowed the convenient use of the now commercially available liquid nitrogen. In 1959, the Linde Company also developed a new reflectory shield that made it possible to achieve much greater insulation around a cryogenic container when incorporated in a vacuum insulation system [2].

Modern cryosurgery began from the collaborative work of neurosurgeon Irving Cooper and neurosurgeon engineer Arnold Lee that combined the availability of liquid nitrogen with novel insulation manufacturing technologies. The two built a finger-like cryosurgical probe, as seen in Figure 1, insulated along the shaft with the ability to freeze only at the tip. The cryosurgery probe is essentially the prototype from which every subsequent cryosurgical probe using liquid nitrogen was built. The probe, made of three long concentric tubes, is supplied with liquid nitrogen from a pressurized source. The inner tube serves as a conduit for liquid nitrogen flow to the tip of the probe, while the space between the inner tube and the middle tube serves as a path for the return of gaseous nitrogen from the tip of the probe.

The space between the outer tube and the middle tube is vacuum insulated and has a radiative shield that essentially allows the liquid nitrogen to be conducted without heat loss to the tip of the probe. The tip of the probe is a chamber where the liquid nitrogen flows in from the inner tube and from where the gaseous nitrogen returns through the space between the inner and the middle tube. Freezing takes place in the tissue around the chamber on the tip of the probe and expands from the tip outward, allowing freezing deep in the body. It was first used by Cooper for treatment of Parkinson’s disease, and after the introduction of this cryosurgical probe the field of cryosurgery began to experience rapid growth that lasted to the end of the 1970s. Andrew Gage summarized the various applications of cryosurgery to that time and also made some of the most important contributions to the field of cryosurgery throughout the end of the 20th and the beginning of the 21st century [5].

The field of cryosurgery reverted towards the end of the 1970s to a primary use in dermatology and other tissues accessible to visual monitoring of the extent of freezing because—while the new cryosurgical probes were able to freeze deep in the body—it was very difficult to monitor in real time the extent of the three-dimensional frozen lesion.

The next major advance in cryosurgery, the intraoperative imaging with ultrasound, is also due to a technological innovation. Physician Gary Onik and engineer Boris Rubinsky pioneered the use of medical imaging to monitor the process of freezing deep in the body in real time [6]. The procedure led to the development of multiprobe cryosurgical systems [7] that allowed for real time control and complex sculpting of the frozen lesion, deep inside the body, to completely ablate tumors.

Several additional technological advances have been made since the 1990s, in particular the use of Joule-Thomson cycles with a variety of gas mixtures instead of boiling liquid nitrogen [8]. Joule Thomson cryosurgical probes are more flexible and have a smaller diameter than liquid nitrogen probes. And since the introduction of intraoperative imaging of cryosurgery in the 1980s, this technology has been used to treat thousands of patients with various cancers, including prostate, liver, kidney and others.

Medical imaging has made important contributions to advances in the field of cryosurgery, but there are two aspects that are yet not resolved. The biophysics of cell death by freezing is complicated and will be discussed in the subsequent article on cryobiology. John Baust and Gage have made important contributions to understanding the mechanisms of cell death from cryosurgery [9], showing that cells survive freezing in the temperature range from freezing to about –30° C. The extent of cell death therefore does not correspond entirely to the extent of freezing as seen by medical imaging, and substantial efforts are now underway to find ways to induce cell death to the margin of the frozen lesion [10]. The second area of current research is an outgrowth of the finding by Richard Ablin concerning the occurrence of an immunological response to cryosurgery [11] [12]. Both these areas and advances in miniaturization of cryogenics systems will probably preoccupy researchers in the field of cryosurgery over the next decade.

References
[1] E. Cravalho, et al., “Blood freezing to -272.29 degrees C,” Cryobiology, Vol. 9, No. 4, 1972.
[2] A. Arkharov, et al., Theory and Design of Cryogenic Systems, Moskow: Mir, 1980.
[3] J. Arnott, On the Treatment of Cancer by the Regulated Application of an Anesthetic Temperature, London: Churchill, 1850.
[4] A.C. White, “Liquid air: its application in medicine and surgery,” Med. Rec., Vol. 56, 1899.
[5] A. Gage, “History” in Cryosurgery: Mechanisms and Applications, L. Lucas, Ed. ParisInt. Inst. Refrig, 1995, p. 140.
[6] B. Rubinsky and G. Onik, “Cryosurgery: advances in the application of low temperatures to medicine,” Int. J. Refrig., Vol. 14, No. 4, 1991.
[7] B. Rubinsky, et al., “Cryosurgical system for destroying tumors by freezing,” US patent 5,334,181, 1994.
[8] K. Fredrickson, et al., “A design method for mixed gas Joule-Thomson refrigeration cryosurgical probes,” Int. J. Refrig., Vol. 29, No. 5, 2006.
[9] J.G. Baust, et al., “Mechanisms of cryoablation: Clinical consequences on malignant tumors,” Cryobiology, Vol. 68, No. 1, 2014.
[10] F. Lugnani, et al., “Cryoelectrolysis; an acute case study in the pig liver,” Cryobiology, Vol. 78, 2017.
[11] W.A. Soanes, et al., “Remission of metastatic lesions following cryosurgery in prostatic cancer: immunologic considerations.,” J. Urol., Vol. 104, No. 1, 1970.
[12] Y. Takahashi, et al., “Optimized magnitude of cryosurgery facilitating anti-tumor immunoreaction in a mouse model of Lewis lung cancer,” Cancer Immunology. Immunotherapy., Vol. 65, No. 8, 2016. ■