Junnosuke Okajima

Dimensionless solutions and general characteristics of bioheat transfer during thermal therapy

Abstract The derivation and application of the general characteristics of bioheat transfer for medical applications are shown in this paper. Two general bioheat transfer characteristics are derived from solutions of one-dimensional Pennes’ bioheat transfer equation: steady-state thermal penetration depth, which is the deepest depth where the heat effect reaches; and time to reach steady-state, which represents the amount of time necessary for temperature distribution to converge to a steady-state. All results are described by dimensionless form; therefore, these results provide information on temperature distribution in biological tissue for various thermal therapies by transforming to dimension form.

Photothermal therapy of tumors in lymph nodes using gold nanorods and near-infrared laser light

Lymph node dissection for regional nodal metastasis is a primary option, but is invasive and associated with adverse effects. The development of non-invasive therapeutic methods in preclinical experiments using mice has been restricted by the small lymph node size and the limited techniques available for non-invasive monitoring of lymph node metastasis. Here, we show that photothermal therapy (PTT) using gold nanorods (GNRs) and near-infrared (NIR) laser light shows potential as a non-invasive treatment for tumors in the proper axillary lymph nodes (proper-ALNs) of MXH10/Mo-lpr/lpr mice, which develop systemic swelling of lymph nodes (up to 13mm in diameter, similar in size to human lymph nodes). Tumor cells were inoculated into the proper-ALNs to develop a model of metastatic lesions, and any anti-tumor effects of therapy were assessed. We found that GNRs accumulated in the tumor in the proper-ALNs 24h after tail vein injection, and that irradiation with NIR laser light elevated tumor temperature. Furthermore, combining local or systemic delivery of GNRs with NIR irradiation suppressed tumor growth more than irradiation alone. We propose that PTT with GNRs and NIR laser light can serve as a new therapeutic method for lymph node metastasis, as an alternative to lymph node dissection.

Photothermal therapy of tumors in lymph nodes using gold nanorods and near-infrared laser light with controlled surface cooling

Photothermal therapy (PTT) using near-infrared (NIR) laser light and gold nanorods (GNRs) shows promise as a novel cancer treatment modality. However, the laser intensity required to destroy tumor cells located beneath the skin is greater than the threshold intensity that causes skin damage; thus, irradiation with laser light damages the skin as well as the tumor. Here, we show that a temperature control system allows metastatic lymph nodes (LNs) to be treated by PTT using NIR laser light and GNRs, without skin damage. A mouse model of LN metastasis was developed by injection of tumor cells, and the tumor-bearing proper axillary LN was treated with NIR laser light after injection of GNRs. The skin temperature was maintained at 45 °C during irradiation by using a temperature control system. Bioluminescence imaging revealed that tumor progression was less in LNs exposed to NIR laser light and GNRs than in LNs exposed to NIR laser light alone or controls (no irradiation or GNRs). Furthermore, the skin and LN capsule were macroscopically intact on day 9 after irradiation with NIR laser light, whereas tumor cells within the LN showed apoptosis. A numerical analysis demonstrated that the high-temperature zone and the LN region showing damage were localized to an area up to 3 mm in depth. The proposed novel PTT technique, using NIR laser light and GNRs with controlled surface cooling, could be applied clinically to treat metastatic LNs located within or outside the area accessible for surgical dissection.

Development and estimation of a novel cryoprobe utilizing the Peltier effect for precise and safe cryosurgery

We have developed a novel cryoprobe for skin cryosurgery utilizing the Peltier effect. The four most important parameters for necrotizing tissue efficiently are the cooling rate, end temperature, hold time and thawing rate. In cryosurgery for small skin diseases such as flecks or early carcinoma, it is also important to control the thickness of the frozen region precisely to prevent necrotizing healthy tissue. To satisfy these exacting conditions, we have developed a novel cryoprobe to which a Peltier module was attached. The cryoprobe makes it possible to control heat transfer to skin surface precisely using a proportional-integral-derivative (PID) controller, and because it uses the Peltier effect, the cryoprobe does not need to move during the operation. We also developed a numerical simulation method that allows us to predict the frozen region and the temperature profile during cryosurgery. We tested the performance of our Peltier cryoprobe by cooling agar, and the results show that the cryoprobe has sufficient cooling performance for cryosurgery, because it can apply a cooling rate of more than 250 degrees C/min until the temperature reaches -40 degrees C. We also used a numerical simulation to reconstruct the supercooling phenomenon and examine the immediate progress of the frozen region with ice nucleation. The calculated frozen region was compared with the experimentally measured frozen region observed by an interferometer, and the calculation results showed good agreement. The results of numerical simulation confirmed that the frozen region could be predicted accurately with a margin of error as small as 150 microm during use of the cryoprobe in cryosurgery. The numerical simulation also showed that the cryoprobe can control freezing to a depth as shallow as 300 microm.

24-gauge ultrafine cryoprobe with diameter of 550 μm and its cooling performance.

This paper describes the development of a novel cryoprobe with the same size as a 24-gauge injection needle and the evaluation of its cooling performance. This ultrafine cryoprobe was designed to reduce the invasiveness and extend application areas of cryosurgery. The ultrafine cryoprobe has a double-tube structure and consists of two stainless steel microtubes. The outer diameter of the cryoprobe is 550 μm, and the inner tube has a 70-μm inner diameter to depressurize the high-pressure refrigerant. By solving the bioheat transfer equation and considering freezing phenomena, the relationship between the size of the frozen region and the heat transfer coefficient of the refrigerant flow in an ultrafine cryoprobe was derived analytically. The results showed that the size of the frozen region is strongly affected by the heat transfer coefficient. A high heat transfer coefficient such as that of phase change heat transfer is required to generate a frozen region of sufficient size. In the experiment, trifluoromethane (HFC-23) was used as the refrigerant, and the cooling effects of the gas and liquid phase states at the inlet were evaluated. When the ultrafine cryoprobe was cooled using a liquid refrigerant, the surface temperature was approximately -50°C, and the temperature distribution on the surface was uniform for a thermally insulated condition. However, for the case with vaporized refrigerant, the temperature distribution was not uniform. Therefore, it was concluded that the cooling mechanism using liquid refrigerant was suitable for ultrafine cryoprobes. Furthermore, to simulate cryosurgery, a cooling experiment using hydrogel was conducted. The results showed that the surface temperature of the ultrafine cryoprobe reached -35°C and formed a frozen region with a radius of 4 mm in 4 min. These results indicate that the ultrafine cryoprobe can be applied in actual cryosurgeries for small affected areas.

Cooling Characteristics of Ultrafine Cryoprobe Utilizing Convective Boiling Heat Transfer in Microchannel

This paper describes a novel cooling system to be applied in cryosurgery. An ultrafine cryoprobe has been developed to treat small lesions which cannot be treated by conventional cryoprobes. The main problem of the ultrafine cryoprobe is the reduction of the heat transfer rate by the small flow rate due to the large pressure drop in a microchannel and the large ratio of the surface area to the volume. In order to overcome these problems, we utilized boiling heat transfer in a microchannel as the heat transfer mechanism in the ultrafine cryoprobe. The objectives of this paper are to develop an ultrafine cryoprobe and evaluate its cooling characteristics. The ultrafine cryoprobe has a co-axial double tube structure which consists of inner and outer stainless steel tubes. The outer and inner diameters of the outer tube are 0.55mm and 0.3mm, respectively. The outer and inner diameters of the inner tube are 0.15mm and 0.07mm, respectively. The inner tube serves as a capillary tube to change the refrigerant from liquid state to two-phase flow. Furthermore, two-phase flow passes through the annular passage between the inner and out tube. The hydraulic diameter of the annular passage is 0.15mm. Furthermore, HFC-23 (Boiling point is −82.1°C at 1atm) is used as the refrigerants. The temperature of the ultrafine cryoprobe was measured. The lowest temperatures were −45°C in the insulated condition and −35°C in the agar at 37°C (which simulates in vivo condition). Furthermore, the frozen region which is generated around the ultrafine cryoprobe was measured 5mm from the tip of cryoprobe at 120s, and resulted to be 3mm in diameter. Moreover, the change of the refrigerant state is calculated by using the energy conservation equation and the empirical correlations of two-phase pressure drop and boiling heat transfer. As a result, the refrigerant state in the ultrafine cryoprobe depends on the external heat flux. Finally, the required geometry of the ultrafine cryoprobe to make high cooling performance is evaluated.Copyright

A novel treatment for metastatic lymph nodes using lymphatic delivery and photothermal therapy

Systemic delivery of an anti-cancer agent often leads to only a small fraction of the administered dose accumulating in target sites. Delivering anti-cancer agents through the lymphatic network can achieve more efficient drug delivery for the treatment of lymph node metastasis. We show for the first time that polymeric gold nanorods (PAuNRs) can be delivered efficiently from an accessory axillary lymph node to a tumor-containing proper axillary lymph node, enabling effective treatment of lymph node metastasis. In a mouse model of metastasis, lymphatic spread of tumor was inhibited by lymphatic-delivered PAuNRs and near-infrared laser irradiation, with the skin temperature controlled by cooling. Unlike intravenous injection, lymphatic injection delivered PAuNRs at a high concentration within a short period. The results show that lymphatic administration has the potential to deliver anti-cancer agents to metastatic lymph nodes for inhibition of tumor growth and could be developed into a new therapeutic method.

Development and Clinical Application of a Precise Temperature-Control Device as an Alternate for Conventional Moxibustion Therapy

Moxibustion therapy has been used in East Asian medicine for more than a thousand years. However, there are some problems associated with this therapy in clinical practice. These problems include lack of control over the treatment temperature, emission of smoke, and uneven temperature distribution over the treatment region. In order to resolve these problems, we developed a precise temperature-control device for use as an alternate for conventional moxibustion therapy. In this paper, we describe the treatment of a single patient with paralytic ileus that was treated with moxibustion. We also describe an evaluation of temperature distribution on the skin surface after moxibustion therapy, the development of a heat-transfer control device (HTCD), an evaluation of the HTCD, and the clinical effects of treatment using the HTCD. The HTCD we developed can heat the skin of the treatment region uniformly, and its effect may be equivalent to conventional moxibustion, without the emission of smoke and smell. This device can be used to treat ileus, abdominal pain, and coldness of abdomen in place of conventional moxibustion in modern hospitals.

Measurement of the Molecular Mass Dependence of the Mass Diffusion Coefficient in Protein Aqueous Solutions

This paper reports the measurement of the binary mass diffusion coefficient for proteins with a wide range of molecular size. The diffusion coefficient is obtained by conducting diffusion experiments in the dilute region. Transient concentration profiles were measured by a phase shifting interferometer and subsequently compared with a numerical calculation based on Ficks law to determine the diffusion coefficient. Distilled water was used as solvent in free diffusion experiments conducted at T = (25 ± 1.0)°C. The method was validated by measuring the diffusion coefficient of aqueous NaCl, Sucrose, and BSA, which values have been extensively reported in the literature. The values of the diffusion coefficient for seven proteins: aprotinin (6.5 kDa), α-lactalbumin (14.2 kDa), lysozyme (14.3 kDa), trypsin inhibitor (20.1 kDa), ovalbumin (44.2 kDa), bovine serum albumin (66.7 kDa), and phosphorylase b (97.2 kDa), were determined in the dilute region of 0-3 mg/ml. The results are compared with the Stokes-Einstein equation. The influence of the molecular structure and pH on the diffusion coefficient is discussed.

Treatment of tumor in lymph nodes using near-infrared laser light-activated thermosensitive liposome-encapsulated doxorubicin and gold nanorods

Tumor metastasis to lymph nodes is an important contributory factor for cancer-related deaths despite recent developments in cancer therapy. In this study, we demonstrate that tumor in the proper axillary lymph node (PALN) of the mouse can be treated by the application of external laser light to trigger the unloading of doxorubicin (DOX) encapsulated in thermosensitive liposomes (TSLs) administered together with gold nanorods (GNRs). GNRs + DOX-TSLs were injected into a mouse lymph node containing cancer cells (malignant fibrous histiocytoma-like cells) and intranodal DOX release was activated using near-infrared (NIR) laser irradiation. The temperature changes arising from the laser-irradiated GNRs triggered the release of DOX from the TSLs. A greater degree of inhibition of tumor growth was found in the co-therapy group compared to the other groups. The treatment effect was achieved by a combination of chemotherapy and NIR-activated hyperthermia. In vivo bioluminescence imaging and histological analysis confirmed tumor necrosis in response to combined treatment. This work presents a theranostic approach with excellent treatment results that has the potential to be developed into an alternative to surgery for the treatment of breast cancer metastasis.