Abstract Plasma biomedicine has arisen more than 20 years ago, and multiple technologies have been certified by the united states food and drug administration (FDA) and promoted for application. However, the most widely adopted application method is using plasma to directly treat living organisms, which have problems such as small treatment areas, shallow action depth, short effective time, and insufficient stability, limiting its application scope and effectiveness. Therefore, based on nearly 10 years of research, this paper develops plasma-activated media technology, which uses plasma to activate media such as gas, liquid, or hydrogel to load reactive species into the media. Plasma-activated media technology transforms plasma biomedicine from direct treatment to indirect treatment, and promote supgrading applications with “larger area, deeper site, superior safety and stability, sustained effectiveness”. However, compared with direct plasma treatment, the addition of media significantly changes the transfer chain of reactive species, causing significant changes in the composition and concentration of reactive species that ultimately act on the lesion. The yield improvement of reactive species from the plasma level, efficient loading of reactive species from the plasma-media interaction level, long-term storage and stable release of reactive species from the media level, and plasma-activated media equipment development from the application level, and optimization of biological and clinical therapeutic effects are problems should be solved. This paper summarizes the background and current status of plasma-activated media technology, as well as the key scientific and technical issues from three aspects: the methods of plasma activation and its optimized designs, the selection of plasma types and working gas, and the selection of media and its performance evaluation. Then, the plasma-activated media prototype equipment and its latest biomedical applications are displayed. During more than ten years of explorations, studies focus on the generation, loading, storage, release, penetration, and biological effects of reactive species, and various discharge forms and working gases are used to activate three types of media (gas, liquid, and hydrogel). The mode conversion mechanism of air discharge is revealed, and generation efficiency and precise concentration control are improved. The safety evaluation and the effectiveness of key reactive species such as N2O5 are achieved, and various plasma-activated media equipment for biomedical applications is developed. Nonetheless, there is still a lot of work to be done in the future, including: (1) improving biomedical efficacy from the technical level to better meet practical application needs; (2) elucidating the mechanism of biological effect to provide a theoretical foundation for the development of plasma-activated media technology; (3) promoting clinical transformation from the application level to truly serve the cause of people's life and health.
[1] Laroussi M.Sterilization of contaminated matter with an atmospheric pressure plasma[J]. IEEE Transactions on Plasma Science, 1996, 24(3): 1188-1191. [2] 戴栋, 宁文军, 邵涛. 大气压低温等离子体的研究现状与发展趋势[J]. 电工技术学报, 2017, 32(20): 1-9. Dai Dong, Ning Wenjun, Shao Tao.A review on the state of art and future trends of atmospheric pressure low temperature plasmas[J]. Transactions of China Electrotechnical Society, 2017, 32(20): 1-9. [3] Bär W, Márquez de Bär G, Naumann A, et al. Contamination of bronchoscopes with mycobacterium tuberculosis and successful sterilization by low- temperature hydrogen peroxide plasma sterilization[J]. American Journal of Infection Control, 2001, 29(5): 306-311. [4] Filis K, Galyfos G, Sigala F, et al.Utilization of low- temperature helium plasma (J-Plasma) for dissection and hemostasis during carotid endarterectomy[J]. Journal of Vascular Surgery Cases and Innovative Techniques, 2020, 6(1): 152-155. [5] Bogle M A, Arndt K A, Dover J S.Evaluation of plasma skin regeneration technology in low-energy full-facial rejuvenation[J]. Archives of Dermatology, 2007, 143(2): 168-174. [6] Sun Tao, Zhang Bowen, Xiong Rui, et al.Clinical observation of low-temperature plasma ablation combined with drug therapy in the treatment of fungal keratitis[J]. Infection and Drug Resistance, 2023, 16: 1895-1904. [7] Brehmer F, Haenssle H A, Daeschlein G, et al.Alleviation of chronic venous leg ulcers with a hand-held dielectric barrier discharge plasma generator (PlasmaDerm(®) VU-2010): results of a monocentric, two-armed, open, prospective, randomized and controlled trial (NCT01415622)[J]. Journal of the European Academy of Dermatology and Venereology: JEADV, 2015, 29(1): 148-155. [8] Zhai Siyue, Xu Meifeng, Li Qiaosong, et al.Suc- cessful treatment of vitiligo with cold atmospheric plasma-activated hydrogel[J]. Journal of Investigative Dermatology, 2021, 141(11): 2710-2719. [9] Sun Peng, Pan Jie, Tian Ye, et al.Tooth whitening with hydrogen peroxide assisted by a direct-current cold atmospheric-pressure air plasma microjet[J]. IEEE Transactions on Plasma Science, 2010, 38(8): 1892-1896. [10] Metelmann H R, Seebauer C, Miller V, et al.Clinical experience with cold plasma in the treatment of locally advanced head and neck cancer[J]. Clinical Plasma Medicine, 2018, 9: 6-13. [11] 刘定新, 何桐桐, 张浩. 等离子体对人体组织的渗透作用: 研究现状与前沿问题[J]. 高电压技术, 2019, 45(7): 2329-2342. Liu Dingxin, He Tongtong, Zhang Hao.Penetration effect of gas plasmas on human tissues: state-of-the- art and current issues[J]. High Voltage Engineering, 2019, 45(7): 2329-2342. [12] Laroussi M.Plasma medicine: a brief introduction[J]. Plasma, 2018, 1(1): 47-60. [13] Shimada K, Takashima K, Kimura Y, et al.Humi- dification effect of air plasma effluent gas on suppressing conidium germination of a plant pathogenic fungus in the liquid phase[J]. Plasma Processes and Polymers, 2020, 17(1): 15. [14] Kimura Y, Takashima K, Sasaki S, et al.Investigation on dinitrogen pentoxide roles on air plasma effluent exposure to liquid water solution[J]. Journal of Physics D Applied Physics, 2019, 52(6): 064003. [15] Lu X, Naidis G V, Laroussi M, et al.Reactive species in non-equilibrium atmospheric-pressure plasmas: generation, transport, and biological effects[J]. Physics Reports, 2016, 630: 1-84. [16] Chen Zeyu, Liu Dingxin, Chen Chen, et al.Analysis of the production mechanism of H2O2 in water treated by helium DC plasma jets[J]. Journal of Physics D: Applied Physics, 2018, 51(32): 325201. [17] Kaushik N K, Ghimire B, Li Ying, et al.Biological and medical applications of plasma-activated media, water and solutions[J]. Biological Chemistry, 2018, 400(1): 39-62. [18] 满晨曦, 黄邦斗, 章程, 等. 不同脉冲参数下等离子体活化水活性氮特性[J]. 高电压技术, 2022, 48(6): 2326-2335. Man Chenxi, Huang Bangdou, Zhang Cheng, et al.Reactive nitrogen species characteristic of plasma- activated water under different pulsed parameters[J]. High Voltage Engineering, 2022, 48(6): 2326-2335. [19] Tanaka H, Mizuno M, Ishikawa K, et al.Plasma- activated medium selectively kills glioblastoma brain tumor cells by down-regulating a survival signaling molecule, AKT kinase[J]. Plasma Medicine, 2011, 1(3/4): 265-277. [20] Duan J, Lu X, He G.The selective effect of plasma activated medium in an in vitro co-culture of liver cancer and normal cells[J]. Journal of Applied Physics, 2017, 121(1): 6. [21] Sears J, Mohades S, Razavi H, et al.Using fluorescence to measure hydrogen peroxide concentrations in plasma activated media[C]//2015 IEEE International Conference on Plasma Sciences (ICOPS), Antalya, Turkey, 2015: 1. [22] Zhang H, Chen M, Huang L L, et al.Using cold atmospheric plasma treated-air for COVID-19 disinfection in cold-chain environment[J]. Journal of Physics D: Applied Physics, 2021, 54(40): 5. [23] Zhang Hao, Xu Shengduo, Zhang Jishen, et al.Plasma-activated thermosensitive biogel as an exogenous ROS carrier for post-surgical treatment of cancer[J]. Biomaterials, 2021, 276: 121057. [24] 张浩, 张基珅, 许德晖, 等. 等离子体活化水溶液用于癌症治疗的研究综述[J]. 电工技术学报, 2023, 38(增刊1): 231-246. Zhang Hao, Zhang Jishen, Xu Dehui, et al.Advances of plasma-activated solutions for cancer therapy[J]. Transactions of China Electrotechnical Society, 2023, 38(S1): 231-246. [24] 张浩, 张基珅, 许德晖, 等. 等离子体活化水溶液用于癌症治疗的研究综述[J]. 电工技术学报, 2023, 38(增刊1):231-246. Zhang Hao, Zhang Jishen, Xu Dehui, et al.Advances of plasma-activated solutions for cancer therapy[J]. Transactions of China Electrotechnical Society, 2023, 38(S1): 231-246. [25] Li Jiacheng, Lan Cuntao, Nie Lanlan, et al.Plasma- activated hydrogel: fabrication, functionalization, and effective biological model[J]. Plasma Science and Technology, 2023, 25(9): 093001. [26] 孙冰. 液相放电等离子体及其应用[M]. 北京: 科学出版社, 2013. [27] Zhou Renwu, Zhang Tianqi, Zhou Rusen, et al.Sustainable plasma-catalytic bubbles for hydrogen peroxide synthesis[J]. Green Chemistry, 2021, 23(8): 2977-2985. [28] Guo Li, Zhao Pengyu, Jia Yikang, et al.Inactivation of airborne pathogenic microorganisms by plasma- activated nebulized mist[J]. Journal of Hazardous Materials, 2023, 459: 132072. [29] Xu Dehui, Liu Dingxing, Wang Biqing, et al.In situ OH generation from and H2O2 plays a critical role in plasma-induced cell death[J]. PLoS One, 2015, 10(6): e0128205. [30] Wang Sui, Liu Dingxin, Wang Zifeng, et al.Interfacial current distribution between helium plasma jet and water solution[J]. Plasma Sources Science and Technology, 2020, 29(6): 065007. [31] Wang Zifeng, Xu Shengduo, Liu Dingxin, et al.An integrated device for preparation of plasma-activated media with bactericidal properties: an in vitro and in vivo study[J]. Contributions to Plasma Physics, 2022, 62(3): e202100125. [32] Liu Z C, Liu D X, Chen C, et al.Physicochemical processes in the indirect interaction between surface air plasma and deionized water[J]. Journal of Physics D: Applied Physics, 2015, 48(49): 495201. [33] Lu Xinpei, Liu Dawei, Xian Y, et al. Cold atmospheric-pressure air plasma jet: physics and opportunities[J/OL]. Physics of Plasmas, 2021, 28(10). https://www.aminer.cn/pub/628d23a15aee126c0f470c8f. [34] 李和平, 李果, 王森, 等. 裸露金属电极大气压射频辉光放电研究进展[J]. 科技导报, 2009, 27(5): 81-86. Li Heping, Li Guo, Wang Sen, et al.Recent progress of atmospheric-pressure glow discharges with bare- metallic electrodes[J]. Science & Technology Review, 2009, 27(5): 81-86. [35] Fried A, Henry B E, Calvert J G, et al.The reaction probability of N2O5 with sulfuric acid aerosols at stratospheric temperatures and compositions[J]. Journal of Geophysical Research: Atmospheres, 1994, 99(D2): 3517-3532. [36] Thomas K, Volz-Thomas A, Mihelcic D, et al.On the exchange of NO3 radicals with aqueous solutions: solubility and sticking coefficient[J]. Journal of Atmospheric Chemistry, 1998, 29(1): 17-43. [37] Park J Y, Lee Yin Nan.Solubility and decomposition kinetics of nitrous acid in aqueous solution[J]. The Journal of Physical Chemistry, 1988, 92(22): 6294-6302. [38] Lelieveld J, Crutzen P J.The role of clouds in tropospheric photochemistry[J]. Journal of Atmospheric Chemistry, 1991, 12(3): 229-267. [39] Zhou Xianliang, Lee Yin Nan.Aqueous solubility and reaction kinetics of hydroxymethyl hydroperoxide[J]. The Journal of Physical Chemistry, 1992, 96(1): 265-272. [40] Bratsch S G.Standard electrode potentials and temperature coefficients in water at 298.15 K[J]. Journal of Physical and Chemical Reference Data, 1989, 18(1): 1-21. [41] Yan Dayun, Nourmohammadi N, Bian Ka, et al.Stabilizing the cold plasma-stimulated medium by regulating medium’s composition[J]. Scientific Reports, 2016, 6: 26016. [42] 谭桂霞, 陈烨璞, 徐晓萍. 臭氧在气态和水溶液中的分解规律[J]. 上海大学学报(自然科学版), 2005, 11(5): 510-512. Tan Guixia, Chen Yepu, Xu Xiaoping.Ozone decomposition rules in gaseity and aqueous solution[J]. Journal of Shanghai University (Natural Science Edition), 2005, 11(5): 510-512. [43] Yan Dayun, Nourmohammadi N, Milberg J, et al.Guidelines for using 3-nitro-l-tyrosine as an antidegradation reagent of H2O2 in the cold atmospheric plasma-stimulated solutions[J]. Plasma Medicine, 2018, 8(2): 121-130. [44] Gjika E, Pal-Ghosh S, Tang Anna, et al.Adaptation of operational parameters of cold atmospheric plasma for in vitro treatment of cancer cells[J]. ACS Applied Materials & Interfaces, 2018, 10(11): 9269-9279. [45] Brisset J L, Hnatiuc E.Peroxynitrite: a re- examination of the chemical properties of non- thermal discharges burning in air over aqueous solutions[J]. Plasma Chemistry and Plasma Processing, 2012, 32(4): 655-674. [46] Yan Dayun, Horkowitz A, Wang Qihui, et al. On the selective killing of cold atmospheric plasma cancer treatment: status and beyond[J]. Plasma Processes and Polymers, 2021, 18(10): e2100020.1-e2100020.17. [47] Liu D X, Bruggeman P, Iza F, et al.Global model of low-temperature atmospheric-pressure He+H2O plasmas[J]. Plasma Sources Science and Technology, 2010, 19(2): 025018. [48] 方志, 靳君, 张荐, 等. 大气压Ar/H2O等离子体射流的放电特性[J]. 高电压技术, 2014, 40(7): 2049-2056. Fang Zhi, Jin Jun, Zhang Jian, et al.Characteristics of atmospheric pressure Ar/H2O plasma jet discharge[J]. High Voltage Engineering, 2014, 40(7): 2049-2056. [49] 丁蕴函, 王晓龙, 谭震宇, 等. 大气压He/O2等离子体活性粒子在水溶液中传质的氧含量效应[J]. 电工技术学报, 2023, 38(11): 2977-2988. Ding Yunhan, Wang Xiaolong, Tan Zhenyu, et al.Oxygen concentration effect on the mass transfer of reactive species of the atmospheric-pressure He/O2 plasma in aqueous solution[J]. Transactions of China Electrotechnical Society, 2023, 38(11): 2977-2988. [50] Bolouki N, Kuan Wenhui, Huang Yuyun, et al.Characterizations of a plasma-water system generated by repetitive microsecond pulsed discharge with air, nitrogen, oxygen, and argon gases species[J]. Applied Sciences, 2021, 11(13): 6158. [51] Wang Wei, Guo Li, Yao Zhiqian, et al.Nitrox surface discharge used for water activation: the reactive species and their correlation to the bactericidal effect[J]. Journal of Physics D: Applied Physics, 2022, 55(26): 265203. [52] Wang Wei, Liu Zhijie, Chen Jinkun, et al.Surface air discharge used for biomedicine: the positive correlation among gaseous NO3, aqueous O2-/ONOO- and biological effects[J]. Journal of Physics D: Applied Physics, 2021, 54(49): 495201. [53] Bansemer R, Schmidt-Bleker A, van Rienen U, et al. Investigation and control of the O3- to NO-transition in a novel sub-atmospheric pressure dielectric barrier discharge[J]. Plasma Sources Science and Technology, 2017, 26(6): 065005. [54] Vervloessem E, Aghaei M, Jardali F, et al.Plasma-based N2 fixation into NOx: insights from modeling toward optimum yields and energy costs in a gliding arc plasmatron[J]. ACS Sustainable Chemistry & Engineering, 2020, 8(26): 9711-9720. [55] Atkinson R, Baulch D L, Cox R A, et al.Evaluated kinetic and photochemical data for atmospheric chemistry: volume I - gas phase reactions of Ox, HOx, NOx and SOx species[J]. Atmospheric Chemistry and Physics, 2004, 4(6): 1461-1738. [56] Liu Zhichao, Guo Li, Liu Dingxin, et al.Chemical kinetics and reactive species in normal saline activated by a surface air discharge[J]. Plasma Processes and Polymers, 2017, 14(4/5): 1600113. [57] Kurake N, Tanaka H, Ishikawa K, et al.Cell survival of glioblastoma grown in medium containing hydrogen peroxide and/or nitrite, or in plasma- activated medium[J]. Archives of Biochemistry and Biophysics, 2016, 605: 102-108. [58] Wang Zifeng, Liu Linbo, Liu Dingxin, et al. Combination of NOx mode and O3 mode air discharges for water activation to produce a potent disinfectant[J]. Plasma Sources Science and Technology, 2022, 31(5): 05LT01. [59] Judée F, Fongia C, Ducommun B, et al.Short and long time effects of low temperature plasma activated media on 3D multicellular tumor spheroids[J]. Scientific Reports, 2016, 6: 21421. [60] Zou Xianyun, Xu Maoyuan, Pan Shuhui, et al.Plasma activated oil: fast production, reactivity, stability, and wound healing application[J]. ACS Biomaterials Science & Engineering, 2019, 5(3): 1611-1622. [61] Chen Jinkun, Wang Zifeng, Sun Jiachen, et al.Plasma- activated hydrogels for microbial disinfection[J]. Advanced Science, 2023, 10(14): e2207407. [62] Labay C, Roldán M, Tampieri F, et al.Enhanced generation of reactive species by cold plasma in gelatin solutions for selective cancer cell death[J]. ACS Applied Materials & Interfaces, 2020, 12(42): 47256-47269. [63] Solé-Martí X, Vilella T, Labay C, et al.Thermosensitive hydrogels to deliver reactive species generated by cold atmospheric plasma: a case study with methylcellulose[J]. Biomaterials Science, 2022, 10(14): 3845-3855. [64] Fang Tianxu, Cao Xiaona, Shen Bingzheng, et al.Injectable cold atmospheric plasma-activated immunotherapeutic hydrogel for enhanced cancer treatment[J]. Biomaterials, 2023, 300: 122189. [65] Pang Xinghuo, Ren Lili, Wu Shuangsheng, et al.Cold-chain food contamination as the possible origin of COVID-19 resurgence in Beijing[J]. National Science Review, 2020, 7(12): 1861-1864. [66] Chen Min, Yan Jinwei, Feng Yue, et al.Sterilization of salmonella typhimurium and staphylococcus aureus in different cold-chain environments by combining NOx mode and O3 mode air discharges[J]. Plasma Sources Science and Technology, 2022, 31(12): 125006.
2024, Vol. 39 
