Liquid metals enabled advanced cryobiology: development and perspectives

Abstract

Cryosurgery and cryopreservation, as two important categories in cryobiology, have been impeded by the poor thermal conductivity of biological tissues or specimens. To improve this, diverse adjuvants, e.g., carbon-based materials, metallic nanoparticles, metallic oxide nanoparticles, etc., have been exploited to improve the heat transfer in heat-targeted regions to increase the tumor elimination efficiency as well as the post-thaw viability of cryopreserved specimens. Nevertheless, these materials suffer poor thermal conductivities, controversial biosafety problems, and high expense. Gallium and its alloys, as a class of room-temperature liquid metals (LMs), have been widely studied in the past decade for their low melting point, minor toxicity, outstanding transformability, and conductivity. Integrated with these superior properties, they have been widely applied in multiple fields, such as thermal management, flexible electronics, and soft robotics. Recently, our laboratory has been devoted to fusing LMs with cryobiology and has made a series of progress. In this article, we will first briefly introduce preparation pathways to LM-based functional nanomaterials and composites. Then, how these materials realize improvement in biological heat transfer will be presented, followed by a discussion about the biosafety of these materials, which is an essential concern for the cryobiological field. Recent studies employing LMs in advanced cryosurgery and cryopreservation will also be highlighted. The present challenges and prospects of LMs towards further development in cryobiology will be put forward to point out the possible research direction.

Keywords

Liquid metal / cryobiology / cryosurgery / cryopreservation / nanomaterials / biomaterials

References

[1] Yan JF.Nanocryosurgery and its mechanisms for enhancing freezing efficiency of tumor tissues.Nanomedicine2008;4:79-87

[2] Hou Y,Rao W.Nanoparticle-mediated cryosurgery for tumor therapy.Nanomedicine2018;14:493-506

[3] Yuan F,Panhwar F.Enhanced killing of HepG2 during cryosurgery with Fe₃O₄-nanoparticle improved intracellular ice formation and cell dehydration.Oncotarget2017;8:92561-77

[4] Khademi R,Razminia A.Thermal analysis of a tumorous vascular tissue during pulsed-cryosurgery and nano-hyperthermia therapy: finite element approach.Int J Heat Mass Tran2019;137:1001-13

[5] Liu Y,Dai Z.Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer.Chem Soc Rev2019;48:2053-108

[6] Pham L,Rubinsky B.An in vivo study of antifreeze protein adjuvant cryosurgery.Cryobiology1999;38:169-75

[7] Muldrew K,Donnelly BJ.Flounder antifreeze peptides increase the efficacy of cryosurgery.Cryobiology2001;42:182-9

[8] Jiang J,Schmechel S,Forster C.Pre-conditioning cryosurgery: cellular and molecular mechanisms and dynamics of TNF-α enhanced cryotherapy in an in vivo prostate cancer model system.Cryobiology2010;61:280-8

[9] Wang CL,Han B.An amino acidic adjuvant to augment cryoinjury of MCF-7 breast cancer cells.Cryobiology2008;57:52-9

[10] Di DR,Sun ZQ.A new nano-cryosurgical modality for tumor treatment using biodegradable MgO nanoparticles.Nanomedicine2012;8:1233-41

[11] Krishnamoorthy K,Hyun HB,Kim SJ.Mechanistic investigation on the toxicity of MgO nanoparticles toward cancer cells.J Mater Chem2012;22:24610-7

[12] Ye P,Chen X.Fe₃O₄ nanoparticles and cryoablation enhance ice crystal formation to improve the efficiency of killing breast cancer cells.Oncotarget2017;8:11389-99

[13] Yu TH,Zhou YX.Selective freezing of target biological tissues after injection of solutions with specific thermal properties.Cryobiology2005;50:174-82

[14] Choi B,Yu B.Synergistic local combination of radiation and anti-programmed death ligand 1 immunotherapy using radiation-responsive splintery metallic nanocarriers.ACS Nano2020;14:13115-26

[15] Nel AE,Velegol D.Understanding biophysicochemical interactions at the nano-bio interface.Nat Mater2009;8:543-57

[16] Giwa S,Alvarez L.The promise of organ and tissue preservation to transform medicine.Nat Biotechnol2017;35:530-42

[17] Pal R,Das AK.Diverse effects of dimethyl sulfoxide (DMSO) on the differentiation potential of human embryonic stem cells.Arch Toxicol2012;86:651-61

[18] Fahy GM,Wu J.Cryopreservation of organs by vitrification: perspectives and recent advances.Cryobiology2004;48:157-78

[19] Finger EB.Cryopreservation by vitrification: a promising approach for transplant organ banking.Curr Opin Organ Tran2018;23:353-60

[20] Morris GJ,Acton E.The high viscosity encountered during freezing in glycerol solutions: effects on cryopreservation.Cryobiology2006;52:323-34

[21] Luyet B. On the possible biological significance of some physical changes encountered in the cooling and the rewarming of aqueous solutions. In: Cellular Injury and Resistance in Freezing Organisms: proceedings. 1967;2:1-20. Available from: http://hdl.handle.net/2115/20405. [Last accessed on 30 Nov 2023]

[22] Debenedetti PG.Supercooled liquids and the glass transition.Nature2001;410:259-67

[23] Han Z,Gao Z.Diffusion limited cryopreservation of tissue with radiofrequency heated metal forms.Adv Healthc Mater2020;9:2000796

[24] Manuchehrabadi N,Zhang JJ.Improved tissue cryopreservation using inductive heating of magnetic nanoparticles.Sci Transl Med2017;9:eaah4586

[25] Khosla K,Hagedorn M,Bischof J.Gold nanorod induced warming of embryos from the cryogenic state enhances viability.ACS Nano2017;11:7869-78

[26] Manuchehrabadi N,Roy P.Ultrarapid inductive rewarming of vitrified biomaterials with thin metal forms.Ann Biomed Eng2018;46:1857-69

[27] Clarkson TW.The toxicology of mercury and its chemical compounds.Crit Rev Toxicol2006;36:609-62

[28] Rao W.Tumor thermal ablation therapy using alkali metals as powerful self-heating seeds.Minim Invasive Ther Allied Technol2008;17:43-9

[29] Rao W.Injectable liquid alkali alloy based-tumor thermal ablation therapy.Minim Invasive Ther Allied Technol2009;18:30-5

[30] Daeneke T,Mahmood N.Liquid metals: fundamentals and applications in chemistry.Chem Soc Rev2018;47:4073-111

[31] Jia X,Li S.High-performance non-silicone thermal interface materials based on tunable size and polymorphic liquid metal inclusions.J Mater Sci2022;57:11026-45

[32] Li J,Gao S.Liquid bridge: liquid metal bridging spherical BN largely enhances the thermal conductivity and mechanical properties of thermal interface materials.J Mater Chem C2022;10:6736-43

[33] Zhang XD,Wang HZ.Thermal interface materials with high thermal conductivity and low young’s modulus using a solid-liquid metal codoping strategy.ACS Appl Mater Interfaces2023;15:3534-42

[34] Wang D,Bai Y.Liquid metal combinatorics toward materials discovery.Adv Mater2023;35:2303533

[35] Tang J,Meftahi N.Unique surface patterns emerging during solidification of liquid metal alloys.Nat Nanotechnol2021;16:431-9

[36] Idrus-Saidi SA,Lambie S.Liquid metal synthesis solvents for metallic crystals.Science2022;378:1118-24

[37] Kang M,Warren MV.Surface plasmon resonances of Ga nanoparticle arrays.Appl Phys Lett2012;101:081905

[38] Qi Y,Yuan K,Shen C.Chemically stable polypyrrole-modified liquid metal nanoparticles with the promising photothermal conversion capability.J Mater Sci Technol2022;127:144-52

[39] Hu JJ,Gao F.Photo-controlled liquid metal nanoparticle-enzyme for starvation/photothermal therapy of tumor by win-win cooperation.Biomaterials2019;217:119303

[40] Sun X,Liu M.Shape tunable gallium nanorods mediated tumor enhanced ablation through near-infrared photothermal therapy.Nanoscale2019;11:2655-67

[41] Liu T,Huang Z.Photothermal photodynamic therapy and enhanced radiotherapy of targeting copolymer-coated liquid metal nanoparticles on liver cancer.Colloid Surface B2021;207:112023

[42] Ding XL,Cheng Q.Multifunctional liquid metal-based nanoparticles with glycolysis and mitochondrial metabolism inhibition for tumor photothermal therapy.Biomaterials2022;281:121369

[43] Wang D.Alginate sponge assisted instantize liquid metal nanocomposite for photothermo-chemotherapy.Appl Mater Today2022;29:101583

[44] Chen S,Zhao RQ,Liu J.Liquid metal composites.Matter2020;2:1446-80

[45] Delmas T,Couffin AC.How to prepare and stabilize very small nanoemulsions.Langmuir2011;27:1683-92

[46] Yamaguchi A,Iyoda T.Reversible size control of liquid-metal nanoparticles under ultrasonication.Angew Chem Int Ed Engl2015;54:12809-13

[47] Chechetka SA,Zhen X,Pu K.Light-driven liquid metal nanotransformers for biomedical theranostics.Nat Commun2017;8:15432

[48] Gan T,Handschuh-Wang S.Light-induced shape morphing of liquid metal nanodroplets enabled by polydopamine coating.Small2019;15:1804838

[49] Chang H,Sun Z.Direct writing and repairable paper flexible electronics using nickel-liquid metal ink.Adv Mater Interfaces2018;5:1800571

[50] Tang J,Li J,Liu J.Liquid metal phagocytosis: intermetallic wetting induced particle internalization.Adv Sci2017;4:1700024

[51] Tang J,Li J,Zhou Y.Gallium-based liquid metal amalgams: transitional-state metallic mixtures (TransM²ixes) with enhanced and tunable electrical, thermal, and mechanical properties.ACS Appl Mater Interfaces2017;9:35977-87

[52] Zhao R,Xu X.A fast and cost-effective transfer printing of liquid metal inks for three-dimensional wiring in flexible electronics.ACS Appl Mater Interfaces2020;12:36723-30

[53] Hou Y,Wang D,Rao W.Liquid metal hybrid platform-mediated ice-fire dual noninvasive conformable melanoma therapy.ACS Appl Mater Interfaces2020;12:27984-93

[54] Park YG,Kim H,Lee CY.Three-dimensional, high-resolution printing of carbon nanotube/liquid metal composites with mechanical and electrical reinforcement.Nano Lett2019;19:4866-72

[55] Chang H,Guo R.Recoverable liquid metal paste with reversible rheological characteristic for electronics printing.ACS Appl Mater Interfaces2020;12:14125-35

[56] Wang X,Guo R.Soft and moldable mg-doped liquid metal for conformable skin tumor photothermal therapy.Adv Healthc Mater2018;7:1800318

[57] Wang D,Guo R,Niu M.Magnetic liquid metal loaded nano-in-micro spheres as fully flexible theranostic agents for SMART embolization.Nanoscale2021;13:8817-36

[58] Li X,Xiao B.Superelongation of liquid metal.Adv Sci2022;9:2105289

[59] Kong W,Wang M.Oxide-mediated formation of chemically stable tungsten-liquid metal mixtures for enhanced thermal interfaces.Adv Mater2019;31:1904309

[60] Kim H,Oh JW.Shape-deformable and locomotive MXene (Ti₃C₂T_x)-encapsulated magnetic liquid metal for 3D-motion-adaptive synapses.Adv Funct Mater2023;33:2210385

[61] Murphy CJ,Gole AM.Anisotropic metal nanoparticles: synthesis, assembly, and optical applications.J Phys Chem B2005;109:13857-70

[62] Lin Y,Genzer J.Shape-transformable liquid metal nanoparticles in aqueous solution.Chem Sci2017;8:3832-7

[63] Li Z,Wang D.Reconfigurable assembly of active liquid metal colloidal cluster.Angew Chem Int Ed Engl2020;59:19884-8

[64] Wang D,Wang W.Shape-transformable, fusible rodlike swimming liquid metal nanomachine.ACS Nano2018;12:10212-20

[65] Sun X,Yuan B.Low-temperature triggered shape transformation of liquid metal microdroplets.ACS Appl Mater Interfaces2020;12:38386-96

[66] Hou Y,Zhang D.Numerical simulation for treatment of hypothermia based on vascular interventional direct heating system.J Therm Biol2018;76:29-37

[67] Deng Y.Hybrid liquid metal-water cooling system for heat dissipation of high power density microdevices.Heat Mass Transfer2010;46:1327-34

[68] Luo M.Experimental investigation of liquid metal alloy based mini-channel heat exchanger for high power electronic devices.Front Energy2013;7:479-86

[69] Wang L,Liu J.Heat dissipation system based on electromagnetic-driven rotational flow of liquid metal coolant.J Thermal Sci Eng Appl2021;13:061023

[70] Deng Y,Jiang Y.Two-stage multichannel liquid-metal cooling system for thermal management of high-heat-flux-density chip array.Energy Convers Manag2022;259:115591

[71] Gao Y.Gallium-based thermal interface material with high compliance and wettability.Appl Phys A2012;107:701-8

[72] Wang X,Zhang J.Printed conformable liquid metal e-skin-enabled spatiotemporally controlled bioelectromagnetics for wireless multisite tumor therapy.Adv Funct Mater2019;29:1907063

[73] Fan P,Wang Y.Nano liquid metal for the preparation of a thermally conductive and electrically insulating material with high stability.RSC Adv2018;8:16232-42

[74] Panhwar F,Hossain SMC.Near-infrared laser mediated modulation of ice crystallization by two-dimensional nanosheets enables high-survival recovery of biological cells from cryogenic temperatures.Nanoscale2018;10:11760-74

[75] Cao Y,Fang C,Liu H.Inhibition effect of Ti₃C₂T_x MXene on ice crystals combined with laser-mediated heating facilitates high-performance cryopreservation.ACS Nano2022;16:8837-50

[76] Zhan T,Yang J,Chen L.Fe₃O₄ nanoparticles with carboxylic acid functionality for improving the structural integrity of whole vitrified rat kidneys.ACS Appl Nano Mater2021;4:13552-61

[77] Tian C,Gong C,Shi Q.Microencapsulation and nanowarming enables vitrification cryopreservation of mouse preantral follicles.Nat Commun2022;13:7515

[78] Jain PK,El-Sayed IH.Noble metals on the nanoscale: optical and photothermal properties and some applications in imaging, sensing, biology, and medicine.Acc Chem Res2008;41:1578-86

[79] Hu JJ,Chen Y.Immobilized liquid metal nanoparticles with improved stability and photothermal performance for combinational therapy of tumor.Biomaterials2019;207:76-88

[80] Lu Y,Lin Y.Transformable liquid-metal nanomedicine.Nat Commun2015;6:10066

[81] Han Z,Gangwar L.Vitrification and nanowarming enable long-term organ cryopreservation and life-sustaining kidney transplantation in a rat model.Nat Commun2023;14:3407

[82] Wang D,Gao Q.Non-magnetic injectable implant for magnetic field-driven thermochemotherapy and dual stimuli-responsive drug delivery: transformable liquid metal hybrid platform for cancer theranostics.Small2019;15:1900511

[83] Kim JH,So JH,Koo HJ.Cytotoxicity of gallium-indium liquid metal in an aqueous environment.ACS Appl Mater Interfaces2018;10:17448-54

[84] Guo R.Implantable liquid metal-based flexible neural microelectrode array and its application in recovering animal locomotion functions.J Micromech Microeng2017;27:104002

[85] Sun X,Yuan B.Liquid metal microparticles phase change medicated mechanical destruction for enhanced tumor cryoablation and dual-mode imaging.Adv Funct Materials2020;30:2003359

[86] Yan J,Liu Y.Shape-controlled synthesis of liquid metal nanodroplets for photothermal therapy.Nano Res2019;12:1313-20

[87] Hou Y,Dou M.Soft liquid metal nanoparticles achieve reduced crystal nucleation and ultrarapid rewarming for human bone marrow stromal cell and blood vessel cryopreservation.Acta Biomater2020;102:403-15

[88] Zhang C,Xie W.Mechanistic observation of interactions between macrophages and inorganic particles with different densities.Small2023;19:2204781

[89] Yang N,Gong F.Injectable nonmagnetic liquid metal for eddy-thermal ablation of tumors under alternating magnetic field.Small Methods2020;4:2000147

[90] Galvao J,Tilley M,Duchen MR.Unexpected low-dose toxicity of the universal solvent DMSO.FASEB J2014;28:1317-30

[91] Wang X,Duan M.Endosomal escapable cryo-treatment-driven membrane-encapsulated Ga liquid-metal transformer to facilitate intracellular therapy.Matter2022;5:219-36

[92] Zhang X,Zhao L.CT-guided conformal cryoablation for peripheral NSCLC: initial experience.Eur J Radiol2012;81:3354-62

[93] Wang Q,Pan K.Liquid metal angiography for mega contrast X-ray visualization of vascular network in reconstructing in-vitro organ anatomy.IEEE Trans Biomed Eng2014;61:2161-6

[94] Fan L,Xie Z.Injectable and radiopaque liquid metal/calcium alginate hydrogels for endovascular embolization and tumor embolotherapy.Small2020;16:1903421

[95] Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer2012;12:252-64

[96] Mellman I.Dendritic cells: specialized and regulated antigen processing machines.Cell2001;106:255-8

[97] Zhang Y,Li CX,Zhang XZ.Tumor cell membrane-coated liquid metal nanovaccine for tumor prevention.Chin J Chem2020;38:595-600

[98] Yakkala C,Kandalaft L,Duran R.Cryoablation and immunotherapy: an enthralling synergy to confront the tumors.Front Immunol2019;10:2283

[99] Bernstein LR.Mechanisms of therapeutic activity for gallium.Pharmacol Rev1998;50:665-82Available from: https://pharmrev.aspetjournals.org/content/50/4/665. [Last accessed on 30 Nov 2023].

[100] Clausen J,Fogh J.⁶⁷Ga binding to human-serum proteins and tumor components.Cancer Res1974;34:1931-7Available from: https://aacrjournals.org/cancerres/article/34/8/1931/480195. [Last accessed on 30 Nov 2023].

[101] Harris WR.Thermodynamics of gallium complexation by human lactoferrin.Biochemistry1986;25:803-8

[102] Weiner RE.Role of phosphate-containing compounds in the transfer of indium-111 and gallium-67 from transferrin to ferritin.J Nucl Med1989;30:70-9Available from: https://jnm.snmjournals.org/content/30/1/70. [Last accessed on 30 Nov 2023].

[103] Chitambar CR.Gallium and its competing roles with iron in biological systems.Biochim Biophys Acta2016;1863:2044-53

[104] Chitambar CR.Effects of different transferrin forms on transferrin receptor expression, iron uptake, and cellular proliferation of human leukemic HL60 cells. Mechanisms responsible for the specific cytotoxicity of transferrin-gallium.J Clin Invest1986;78:1538-46

[105] Hedley DW,Slowiaczek P.Effect of gallium on DNA-synthesis by human T-cell lymphoblasts.Cancer Res1988;48:3014-8Available from: https://aacrjournals.org/cancerres/article/48/11/3014/492615. [Last accessed on 30 Nov 2023].

[106] Chitambar CR,Alhajala HS.Gallium maltolate disrupts tumor iron metabolism and retards the growth of glioblastoma by inhibiting mitochondrial function and ribonucleotide reductase.Mol Cancer Ther2018;17:1240-50

[107] Chitambar CR,Woodliff J,Wereley JP.Development of gallium compounds for treatment of lymphoma: gallium maltolate, a novel hydroxypyrone gallium compound, induces apoptosis and circumvents lymphoma cell resistance to gallium nitrate.J Pharmacol Exp Ther2007;322:1228-36

[108] Feng H,Luo S,Liu K.Evaluation and preservation of vascular architectures in decellularized whole rat kidneys.Cryobiology2020;95:72-9

[109] Maathuis MHJ,Ploeg RJ.Perspectives in organ preservation.Transplantation2007;83:1289-98

[110] Ma Y,Tian Y,Yang J.Advanced biomaterials in cell preservation: hypothermic preservation and cryopreservation.Acta Biomater2021;131:97-116

[111] Niu X,Jeffrey GP.Iron and oxidative stress in cold-initiated necrotic death of rat hepatocyte.Transplant Proc2010;42:1563-8

[112] Zhang TJ,Wen DX,Sieber FE.Hippocampus bcl-2 and bax expression and neuronal apoptosis after moderate hypothermic cardiopulmonary bypass in rats.Anesth Analg2006;102:1018-25

[113] Zhai Y,Hong JC,Kupiec-Weglinski JW.Ischaemia-reperfusion injury in liver transplantation - from bench to bedside.Nat Rev Gastroenterol Hepatol2013;10:79-89

[114] Makkonen N,Savolainen K,Mönkkönen J.The effect of free gallium and gallium in liposomes on cytokine and nitric oxide secretion from macrophage-like cells in vitro.Inflamm Res1995;44:523-8

[115] de Albuquerque Wanderley Sales V,da Silva NM.A systematic review of the anti-inflammatory effects of gallium compounds.Curr Med Chem2021;28:2062-76

[116] Chitambar CR,Matthaeus WG.Modulation of lymphocyte proliferation and immunoglobulin production by transferrin-gallium.Cancer Res1989;49:1125-29Available from: https://aacrjournals.org/cancerres/article/49/5/1125/494569. [Last accessed on 30 Nov 2023].

[117] Chang KL,Yu CL,Chang LW.Effects of gallium on immune stimulation and apoptosis induction in human peripheral blood mononuclear cells.Toxicol Appl Pharmacol2003;193:209-17

[118] Crichton RR,Legssyer R.Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells.J Inorg Biochem2002;91:9-18

[119] Zhang C,Biazik JM.Gallium nanodroplets are anti-inflammatory without interfering with iron homeostasis.ACS Nano2022;16:8891-903

[120] Bamoulid J,Halleck F.The need for minimization strategies: current problems of immunosuppression.Transpl Int2015;28:891-900

[121] Orosz CG,Bergese SD.Prevention of murine cardiac allograft rejection with gallium nitrate. Comparison with anti-CD4 monoclonal antibody.Transplantation1996;61:783-91

[122] Drobyski WR,Majewski D.Modulation of in vitro and in vivo T-cell responses by transferrin- gallium and gallium nitrate.Blood1996;88:3056-64

[123] Li L,Yong N,Hou Y.Superior antibacterial activity of gallium based liquid metals due to Ga³⁺ induced intracellular ROS generation.J Mater Chem B2021;9:85-93

[124] Divakarla SK,Chatterjee C.Antimicrobial and anti-inflammatory gallium-defensin surface coatings for implantable devices.ACS Appl Mater Interfaces2022;14:9685-96

[125] Truong VK,Bright R.Gallium liquid metal: nanotoolbox for antimicrobial applications.ACS Nano2023;17:14406-23