Mixtures of crushed ice with salts were, however, not capable of reducing tissue temperature enough to destroy tumor cells. Lower temperatures were needed, and they were finally attained in the last part of the nineteenth century thanks to the discovery of the necessary technology to liquefy gases. First it was oxygen and then nitrogen. Raoul-Pierre Pictet (Switzerland, 1846–1929) (Fig. 1.2) [7] was the first person to liquefy oxygen. On December 22, 1877, the Academy of Sciences in Paris received a telegram from Pictet in Geneva reading as follows: “Oxygen liquefied today under 320 atmospheres and 140 degrees of cold by combined use of sulfurous and carbonic acid.” Two days later – and following the paradigm of multiple independent discoveries – the French scientist Cailletet announced having liquefied oxygen by a completely different process [8]. Louis-Paul Cailletet Laperouse (1832–1913) (Fig. 1.3) [9] demonstrated at the French Academy of Science that oxygen and carbon monoxide could be liquefied [10]; he built an apparatus that allowed him to produce droplets of liquid oxygen (Fig. 1.4) [11]; he was also the first to liquefy carbon monoxide [12]. Pictet and Cailletet share credit of being the first men to liquefy an atmospheric gas.

Carl von Linde (Germany, 1842–1934) (Fig. 1.5) [13] had achieved the first liquefaction of gases at the end of the nineteenth century [5]. By 1871, he built his first ammonia compression machine, and by 1905 he obtained pure oxygen and nitrogen. He was the first to create a continuous process for liquid gas production. Linde became an expert in refrigeration and gas separation technologies and was the founder (1879) of what is today a leading multinational gases corporation.

In 1891 the physical chemist James Dewar (Scotland, 1842–1923) (Fig. 1.6) [14] built a machine capable of making liquid oxygen in large quantities. Dewar worked throughout his life on the behavior of gases at very low temperatures. He made liquid forms of many gases and designed many devices to produce them or to store them. In 1898, Dewar condensed liquid hydrogen with the help of one of the devices he had invented, the Dewar flask. He needed a place to store the liquefied gases he produced. In 1892, he developed the idea of a flask with two silvered walls separated by an evacuated air chamber, thus insulating the inside from the outside of the flask. He knew heat transfer occurred by three physical phenomena: convection, conduction, and radiation. Vacuum eliminated convection, since there are no moving molecules in the gas to transfer heat, and also greatly reduced conduction, as there would be far fewer adjacent gas molecules. Dewar’s invention allowed for the first time the use of liquid gases outside the laboratory, thus making liquefied gases accessible to physicians. In his honor or perhaps unknowingly, the insulating storage vessel commonly used to keep liquid nitrogen is still called Dewar flask.

Zygmunt Florenty Wróblewski (Russian Empire, today Belarus, 1845–1888) (Fig. 1.7) [15] and Karol Stanisław Olszewski (Poland, 1846–1915) (Fig. 1.8) [16] were the first scientists reporting liquefaction of oxygen, nitrogen, and carbon dioxide in a stable condition (1883). At the Jagiellonian University in Krakow, where the two scientists met as professors, Olszewski had started his experiments compressing and condensing carbon dioxide. In 1884, Olszewski was the first to liquefy hydrogen in a dynamic state at −225 °C. Wróblewski died of severe burns (1888) during an experiment to study the properties of hydrogen. Olszewski liquefied argon in 1895, but he failed at liquefying helium. In 1886, just a few days after learning about Wilhelm Röntgen’s work on X-rays, Olszewski replicated the experiment.

Although part of the physical chemical laboratories, liquefied gases were not yet available for medical use. Archibald Campbell White (New York, USA) at Vanderbilt clinic, Columbia University, was the first one to use liquefied gas in medicine. Although he died at the age of 39 [17], he left a significant legacy in the form of the medical use of liquefied gases. White had worked together with Thurston G. Lusk and his associates at Roosevelt Hospital at Columbia University and with George M. Fox, a renowned dermatologist.

In 1899, he reported successful use of liquid air for the treatment of dermatologic pathologies such as lupus erythematosus, herpes zoster, chancroid, nevi, warts, varicose leg ulcers, carbuncles, and epitheliomas [18–20]. He reported positive results by using liquid air for the treatment of skin cancer [21, 22]. To get the liquid air sprayed, he used a glass flask with two glass tubes going through a double pierced cork. One tube went down to the bottom of the flask, finishing on the outside end on a spout with a small hole the size of a pencil point; the other tube was shorter, being used with a thumb to control the entrance of free air from the outside. The flask acted as a liquid air sprayer, becoming the first handheld cryosurgery device (Fig. 1.9) [23]. Sometimes he rolled a glass flask partially filled with the refrigerant over the lesion (Fig. 1.10) [24, 25] as in the doorknob probe used today for vascular hypertrophic lesions. At other times, he used a cotton swab dipped in the liquid air.

White used cold application to “allay or abort an acute inflammation” while “not neglecting to treat the cause.” He sprayed liquid air with the same technique used today in acne: “I would completely freeze it, possibly pricking it while frozen here and there with a needle, in order to relieve any subsequent congestion…. only one application is necessary.” His description of the postoperative effects of cryosurgery is identical to that of liquid nitrogen treatment, in a manner that is impressively similar to the postoperative events with today’s liquid nitrogen cryosurgery: “after freezing, the carbuncle should be dressed with a dry absorbent dressing, so that discharge, which will be abundant and accompanied with considerable bleeding, can be readily absorbed.” White treated inflammatory conditions such as lupus or chronic ulcers with superficial spraying technique, as well as “nevi and other hypertrophies.” In cancer, as a curative treatment he mentions “the great good liquid air has done in these cases.” “I believe that epithelioma, treated early in its existence by liquid air, will always be cured by its application.” White also praised the palliative effect “even in cases in which the treatment has failed to cure.” “The great good done in the relief of pain and the destruction of bad odor, both so characteristic of this disease, places liquid air in efficiency far above any other treatment we have today” [26, 27]. White was the first one to use liquefied gas and deep freeze (−195 °C) as a medical treatment, thus giving birth to deep-freeze cryosurgery.

Liquid air used by White was supplied by Charles E. Triplet, the inventor of the process to produce low-cost liquid air. Triplet was a New York entrepreneur who helped White to promote the medical use of liquid air. Before the White and Triplet collaboration, liquid air and other liquid gases were not available for medical use; Triplet also promoted liquid air as an energy source for transportation, building the first automobile powered by liquid air (Fig. 1.11) [23]. Thanks to the commercial interest of Triplet to promote different uses for liquid air, White could have enough liquid air for experimenting and treating patients. Although liquid air was announced by Triplet as a cheap product – “the cost being hardly more than that of mineral water” [28] that could be delivered to the clinic in an insulated one-gallon tank – it was never widely used due to its poor availability.

The first known combination treatment in cryosurgery was performed in 1907. H. Whitehouse (New York, USA) used sprayed liquid air combined with radiotherapy to treat a wide variety of skin conditions that ranged from epitheliomas to lupus erythematosus to vascular nevi. He froze recurrent tumors previously treated with radiotherapy. He found that this combination gave better results than repeating radiotherapy [29]. He later stopped using the spray technique in favor of a cotton swab.

In 1907, Bowen and Towle reported the successful use of liquid air for vascular tumors [30]. They also used liquid air for the treatment of pigmented hairy nevi and lymphangiomas.

Because of a similar boiling temperature (−182.9 °C), liquid oxygen was used as a cryogenic agent in a similar way to liquid air, particularly during the 1920s and 1930s. It was mainly used to treat acne. In 1929, Irvine and Turnacliff reported good results with some skin conditions such as warts and lichen planus. Liquid oxygen soon became obsolete as a cryogenic agent because of its high combustibility [31]. One of the last reports on liquid oxygen as cryogenic agent is the one by Kile and Welsh (1948); they published the results of a study on approximately 1,000 patients of a diversity of nonmalignant tumors that included warts, hemangiomas, mucosal diseases, and leukoplakia [32].

Arnott was the first to suggest that solid carbon dioxide might be used to achieve a more effective cold treatment in patients [5], but there is no evidence that he might have tried it. Solid carbon dioxide did not become commercially available until the end of the nineteenth century, thanks to the then new advances in gas physical chemistry.

Solid carbon dioxide was first described in 1830 by French inventor Adrien-Jean-Pierre Thilorier (1790–1844) (Fig. 1.12) [33], who published the first account of the substance [34]. According to the official Bulletin of the Laws of the Kingdom of France, Thilorier, still an employee of the postal office of Paris, obtained in 1832 legal protection for his invention of a gas compression machine [35]. He had filed for a patent back in May 1831, but not until 5 years later was he identified as the inventor of a gas compression machine (Fig. 1.13) [36]. He was the winner of the French Academy of Sciences’ Montyon Prize for Mechanics (1829) [37].