A BRIEF REVIEW ON CRYOGUN MACHINE FOR PRE-CERVICAL CANCER HEALING

Cervical cancer is generally found in women of all ages due to virus infection on epithelial cells of female cervix. It is known that a certain type of Human Papilloma Virus (HPV) is suspected to cause cervix cancer in women from various ethnics. Several therapies have been used to cure cancer diseases like cone biopsy, laser treatment, electrosurgical excision, thermocoagulation, ablation therapy, and cryotherapy. This paper has highlighted on the role of cryogun machine applied in cryotherapy for pre-cervical cancer treatment in relation to freezing technique using liquid nitrogen to kill cancer cells on infectious area.


Cancer Disease
Cancer has recognized as malignant disease related to uncontrollable cell splitting and propagating to adjacent cell tissues. Moreover, the disease may attack to other tissues via cell growth causing serious damages of tissues. The malicious cell growth is due to a damage of DNA triggering genes mutation corresponding with cell splitting. Cell mutation may occur due to certain chemical or physical agent known as carcinogen. Cancer disease may show with different symptoms depends on level of malignancy, characters of cell splitting or metastasis effect.
Cancer may cause fatalistic death particularly in many developing countries. However, earlier detection of the symptom can handle cancer disease. Nevertheless, cancer has still remarked as horrible disease until today. Up to date, the main cause of cancer is still unknown.

Cervix Cancer
Cervix cancer is commonly found as the third cancer disease. Cervix cancer begins with virus infection destroying epithelial cells of vital female organ. According to level of mortality cervical cancer is in the second order after breast cancer.
However, in many developing countries this type of cancer has placed in the first order causing death of women in their reproductive period. Moreover, Marton [1] reported 80% pre-cervix cancer cases found in undeveloped countries.
Furthermore, about 90% cervix cancer found in low-income society and undeveloped countries with less screening program and minimum HPV vaccination [2]. Almost every year more than half million women have undergone cervical cancer and resulted about 300 000 death cases all over the world [3]. However, most of this type of cancer can be prevented if earlier symptom is promptly detected and cured.

Cryotherapy
Several therapies are done to treat cervical cancer. Cone biopsy is known as treatment for cone removal where a layer of cervix tissue suspected an abnormality in cone form is removed. Laser treatment applied narrow laser wavelength to kill cancer cells by laser light exposure on suspected infectious area. Loop electrosurgical excision is a method to remove cancer cells from cervix applying electrical cable acting as sharp knife to cut cancel cells. Hysterectomy is a treatment method to discard large part of tissues from cervix and uterus. Cryotherapy is a medical treatment by freezing and killing cancer cells in suspected area. This study has interested in cryotherapy as the topic of the article because cryotherapy has effectively assumed for curing pre-cervical cancer.
Furthermore, cryotherapy is a medical method in order to destroy abnormal tissues in cervix area applying very low temperature. Cryotherapy applies a device namely cryogun for pre-cervical cancer remedy. During the treatment process, the cryogun is adhered to abnormal cervix area for several minutes. The cryogun will flow low temperature nitrogen liquid through cryogen probe. The low temperature nitrogen liquid will freeze cervix cancer cells and kill the cells [4].
The destroying of cancer cells during the process of cryotherapy implicated with intricate mechanism related to direct and indirect effects. The direct effect implies with intracellular and extracellular states of ice crystals retarding membrane cells, causing dehydration in cells, changing electrolyte concentration, causing enzyme malfunction and protein denaturation, and liquefaction resulting cell emptiness, swelling and cell breaking namely cell thermal shock. The indirect effect implies with vascular change causing ischemic necrosis of tissues and affects body resistant yielding cells damage through mechanism of immune cell toxicity [5].
Nowadays, the cryotherapy method takes benefit from the properties of nitrogen liquid that it can decrease the temperature until -50 o C. This condition causes the death of body cell tissues or called as frost bite. When the cell tissues undergone frost bite the treatment to remove cancer cells is much easier [6]. The cryogun device can do this kind of treatment. investigated the treatment effect of cervical cryotherapy and TCA methods on cervical cancer in Indonesia and the comparison yielded no significant difference. All cryogun devices in Indonesia medical hospitals are coming from abroad. In our knowledge Indonesia has the basic components in order to produce this kind of device. This article attempts to develop the design of cryogun and therefore, this current study is the strength of this paper.

Cryogun Machine
The design of cryogun is built for the purpose of generating low temperature liquid nitrogen. The principal operation in a cryogun based on the Joule -Thomson effect in relation to adiabatic process corresponding with gas expansion through a small opening. The pressurized nitrogen gas flows down through the narrow cryogun tank.
Table-2 listed documents of components used in cryogenic device and reported in patent form( [37] - [41]). Only small number of documents presented here and therefore, this is the limitation of this study.
Several important points related to cryogun machine will be described in the following section.

Basic Operation
The shape of a cryogun is likely a hand gun that has a trigger, which its function is to flow liquid nitrogen until the cryoprobe. Before the liquid nitrogen entered the device, a given size of cryoprobe is pasted to an abnormal cervix area. When the cancer cells get freezing, that part of cervix area is abandoned to liquid. The cryoprobe is abandoned to release spontaneously from the abnormal tissues during liquefaction process. The probe is not allowed to withdraw earlier. According to Cohen [2] and Peter [42], this method needs longer freezing time. When the liquid nitrogen flows to the cryoprobe, it is expected the probe temperature decreased to -50 o C so that the part of cervix area infected by abnormality undergone frost bite and the cancer cells dead. The material used for cryogun machine is varied, it depends on the manufacture brand but usually the basic material is a combination of stainless steel and brass alloy for long life usage. Sometimes polypropylene is utilized to increase stability, while the cover and collar are made of polypropylene for hand insulating.

Pressure Regulator
The function of pressure regulator is to manage the liquid pressure when the cryogun connected to a liquid nitrogen cylinder tank. It should maintain the nitrogen gas under pressure so that the gas can stream down through a small opening to the cylinder tank. The pressure regulator (Fig. 2) simply indicates pressure unit, recorded as kg/cm2 or lbs/in 2 , which is divided into three pressure zones. The high zone indicates excessive cylinder pressure or a sign of safety hazard. The middle zone indicates adequate or optimum pressure. The low zone indicates low gas pressure or a sign of inadequate freezing.

Main Hose
The main hose connected the pressure regulator to the cryogun machine. The function of connecting hose is to transmit nitrogen gas from cylinder tank to cryogun device. It is usually made of polypropylene material to enhance its strength.

Main Body.
In the main body there is a switching mechanism in order to control liquid flow in the cryogun machine. It consists of a hand grip or handle, a trigger for activation, and the cryoprobe tip. Some modified units have the on/off switch for the gas valve that is located in the cryogun.

Trigger Switch
The function of trigger switch is to yield forces in switching mechanism in the main body. Activation triggers varied in function. In some modified units, depression of the trigger initiates the freeze, while in others it defrosts the probe tip. Most triggers are in a locked position setting so that the trigger need not be depressed during freezing process.

Cryoprobe Tip
The cryoprobe tip is a part of cryogun directly contacted with the abnormal cervix area. The probe tip is made of stainless steel material for safety reason. The probe tip has several shapes depend on its application related to infectious area. Moreover, as the pressurized nitrogen gas reaches the hollow probe tip, the gas rapidly expands, lowering it to a temperature below freezing. Although the probe tip visibly cools, the probe tip has to be maintained as a heat sink. As the probe tip removes heat from cell tissue, the cell tissue gradually cools. Then the infectious cell tissue experiences destruction. The capacity of the probe tip as a heat sink is affected by several factors such as size, material, composition and temperature of the probe tip [8]. According to Fanyi [9], factors such as tissue moistness, extent of tissue contact, freeze duration and gas pressure also influence the heat diffusion.

Discussion
Cryotherapy is used to destroy abnormal cells in human body. In many cancer cases, this kind of therapy has not used as the first priority. Nevertheless, cryotherapy will be applied when other kind of treatment is not successful particularly if the recovered cancer case came back after had treated by other therapy.
Nevertheless, cryotherapy is often used to cure either skin cancer or pre-cancer. However, this kind of treatment is used for healing abnormality in some internal organs as liver and cervix in the emergency condition that conventional operation is not possible to be conducted due to other disease problem [6].
In addition, cryotherapy is very efficient from the standpoint of level of recovery and level of operation.
A clinical study reported level of recovery of 83% for curing chronics cervix by cryotherapy compared to the same case by electrical cautery (62%) [1]. The comparison is shown in Table-3. On other occasion, Duan [10] reported investigation on pre-cervix cancer using two methods, i.e. thermocoagulation and cryotherapy and the results show no significant difference with respect to vaginal discharge as shown in Table-4. The process of cryotherapy applying cryogun has some advantages over several factors. The cryotherapy using cryogun is relatively low cost. When large scale production can be managed it can reduce production cost and import tax can be avoided particularly for developing countries. Furthermore, more health institutions may handle the management of pre-cervical cancer treatment. Besides big hospitals can handle cryotherapy, more small clinics in district area may manage this kind of therapy. As a portable device, the cryogun can be carried anywhere even to isolated or remote area. In the forthcoming, an aluminium battery is designed to be applied in this portable device [11]. Nevertheless, this portable cryogun is still under designing process and needs further assessment to investigate the temperature distribution in the cryogun. Another disadvantage, this device can not kill cancer cells in broader spectrum area [4].
In addition, the role of cryoprobe tip as the component part may affect the operation of cryogun. As already mentioned above, the heat diffusion is influenced by the material and size of cryoprobe tip. A good cryoprobe tip has to be made of a good thermal conducting metal, such as silver, gold, or copper [8]. The interchangeable tips are available in various shapes and sizes to ensure maximum contact of the tip with the infectious cell tissues to be destroyed. Furthermore, the cryoprobe tip must be disinfected by certain chemical disinfectant. Some cryosurgical units are provided with pyrometer to show the real temperature of activated cryoprobe tip. Some pyrometers indicate continuous thermal data. Pyrometer types are available in digital or analog mode. Fig. 6 shows the cryosurgical unit provided with a cylinder tank, pressure regulator, cryogun and cryoprobe tip [8]. As we may see in Fig. 6, the cryogun is the component part of the cryosurgical unit that we discussed in this writing. Although cryotherapy has some risk factors, nevertheless, the risk factor is assumed to be lower than other kind of cancer therapy like operation and radiation. The risk factors in relation to cryotherapy included: infection, healthy cell and tissue damage near exposed area, skin abrasion, scarring, sexual malfunction, white spots, loss of sense feeling and painful feeling. Some investigators reported that patients might go home after cryotherapy treatment at the same day, however, there were patients that had to overstay in hospital due to internal organ treatment [6].
Ablation technique in relation to tissues removal has become very popular during last decades such as microdermabration treatment using vacuum pressure for skin treatment [12].

Conclusions
From the brief discussion mentioned above, the cryogun is a simple machine used for ablation technique corresponding with tissue removal either by vaporation, abrasion, or destruction in cryosurgery. The portable cryogun is still under developing process that will be adapted for many developing countries in the forthcoming application. In addition, the cryogen equipment has positive prospect for cryosurgical treatment especially on the case of pre-cervix cancer remedial.
Up to date, publication reports focused on instrumentation used for cryotherapy are limited. With limited publication numbers, this article reported that most cryotherapy has used for oral mucositis treatment due to chemotherapy and for reducing perineal pain due to childbirth, as well as for cervical cancer treatment. Available reports on cryotherapy in Indonesia are concentrated on oral therapy and cervical cancer through See and Treat approach.

Acknowledgements
The authors would like to thanks Universitas Mercu Buana Jakarta to sponsor this article that gives valuable contribution and information for medical therapy.