Development of a Portable Hypoxia Chamber for Ultra-high Dose Rate Laser-Driven Proton Radiobiology Applications

BackgroundThere is currently significant interest in assessing the role of oxygen in the radiobiological effects at ultra-high dose rates. Oxygen modulation is postulated to play a role in the enhanced sparing effect observed in FLASH radiotherapy, where particles are delivered at 40-1000 Gy/s. Furthermore, the development of laser-driven accelerators now enables radiobiology experiments in extreme regimes where dose rates can exceed 10^9 Gy/s, and predicted oxygen depletion effects on cellular response can be tested. Access to appropriate experimental enviroments, allowing measurements under controlled oxygenation conditions, is a key requirement for these studies. We report on the development and application of a bespoke portable hypoxia chamber specifically designed for experiments employing laser-driven sources, but also suitable for comparator studies under FLASH and conventional irradiation conditions.Materials and MethodsWe used oxygen concentration measurements to test the induction of hypoxia and the maintenance capacity of the chambers. Cellular hypoxia induction was verified using hypoxia inducible factor-1α immunostaining. Calibrated radiochromic films and GEANT-4 simulations verified the dosimetry variations inside and outside the chambers. We irradiated hypoxic human skin fibroblasts (AG01522B) and patient-derived glioblastoma (E2) cancer stem cells with laser-driven protons, conventional protons and reference 225 kVp X-rays to quantify DNA DSB damage and repair under hypoxia. We further measured the oxygen enhancement ratio for cell survival exposed to cyclotron-accelerated protons and X-rays in the normal fibroblast and radioresistant GBM stem cells. ResultsOxygen measurements showed that our chambers maintained a radiobiological hypoxic environment for at least 45 minutes and pathological hypoxia for up to 24 hrs after disconnecting the chambers from the gas supply. We observed a significant reduction in the 53BP1 foci induced by laser-driven protons, conventional protons and X-rays in the hypoxic cells compared to normoxic cells at 30 minutes post-irradiation. Under hypoxic irradiations, the Laser-driven protons induced significant residual DNA DSB damage in hypoxic AG01522 cells compared to the conventional dose rate protons suggesting an important impact of these extreme high dose-rate exposures. We obtained an oxygen enhancement ratio (OER) of 2.1 ± 0.108 and 2.501 ±0.125 respectively for the AG01522 and patient derived GBM stem cells for the X-rays using our hypoxia chambers for irradiation. ConclusionWe demonstrated the design and application of portable hypoxia chambers for studying cellular radiobiological endpoints after laser-driven protons at ultra-high dose, conventional protons and X-ray exposures. Good levels of reduced oxygen concentration could be maintained in the absence of external gassing to quantify hypoxic effects and the data obtained provided an indication of an enhanced residual DNA DSB damage under hypoxic conditions at ultra-high dose rate compared to the conventional protons or X-rays.

Impact of Hypoxia on Relative Biological Effectiveness and Oxygen Enhancement Ratio for a 62-MeV Therapeutic Proton Beam

This study uses the yields of double-strand breaks (DSBs) to determine the relative biological effectiveness (RBE) of proton beams, using cell survival as a biological endpoint. DSB induction is determined when cells locate at different depths (6 positions) along the track of 62 MeV proton beams. The DNA damage yields are estimated using Monte Carlo Damage Simulation (MCDS) software. The repair outcomes are estimated using Monte Carlo excision repair (MCER) simulations. The RBE for cell survival at different oxygen concentrations is calculated using the repair-misrepair-fixation (RMF) model. Using 60Co γ-rays (linear energy transfer (LET) = 2.4 keV/μm) as the reference radiation, the RBE for DSB induction and enzymatic DSB under aerobic condition (21% O2) are in the range 1.0–1.5 and 1.0–1.6 along the track depth, respectively. In accord with RBE obtained from experimental data, RMF model-derived RBE values for cell survival are in the range of 1.0–3.0. The oxygen enhancement ratio (OER) for cell survival (10%) decreases from 3.0 to 2.5 as LET increases from 1.1 to 22.6 keV/μm. The RBE values for severe hypoxia (0.1% O2) are in the range of 1.1–4.4 as LET increases, indicating greater contributions of direct effects for protons. Compared with photon therapy, the overall effect of 62 MeV proton beams results in greater cell death and is further intensified under hypoxic conditions.

Strategy for Improving the Level of Community Health Through Rural Innovation Program (Case Studies in Center Bangka and Banyuwangi)

The health sector is an important part and must be considered by the Government of Indonesia. The people who really need health are the people, both rural and urban. Public health is an indicator of the quality of human life which is strongly influenced by environmental conditions in an area. One sign of low environmental health is air pollution. Air pollution is defined as the presence of foreign materials or substances in the air which causes changes in the composition (composition) of the air from its normal state, which can cause several diseases such as respiratory diseases. Tuberculosis (TB) infection is a disease whose spread is influenced by environmental and behavioral factors. In addition, reduced levels of oxygen in the environment are also caused by air pollution. For that we need innovations that can improve environmental health so that people's welfare can increase. For this reason, a rural innovation program related to the health of rural communities, especially in the health of respiratory diseases, in this case is TB, was created, which can improve the quality of environmental health and also the welfare of the community. In addition, it also identifies the influence of innovative oxygen enhancement programs by planting trees in rural communities. This research was conducted to identify rural innovation programs related to rural public health, especially on respiratory disease health, and also to identify the effects of innovative oxygen enhancement programs by planting trees in rural environments. The method used in this research is descriptive qualitative method. As a result, there was an increase in the percentage of TB sufferers because of the Ketok Pintu Sekaput program. In addition, the Shodaqoh Oxygen program, which was carried out in villages in Banyuwangi Regency, succeeded in planting 7,444,764 trees in 2018. Suggestions for the future, it is better for the community to always practice clean and healthy living, and better prevent preventive and make tree planting programs. at the RW level so that they can provide seeds according to the needs of each area.