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Applied Materials Today 20 (2020) 100722

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Applied Materials Today


journal homepage: www.elsevier.com/locate/apmt

Liquid metal enabled injectable biomedical technologies and


applications
Xuyang Sun a, Bo Yuan b, Lei Sheng a, Wei Rao a,∗, Jing Liu a,b,∗
a
Beijing Key Lab of Cryo-Biomedical Engineering and Key Lab of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
b
Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China

a r t i c l e i n f o a b s t r a c t

Article history: Liquid metals are arousing increasing interests among many challenging biomedical and healthcare areas,
Received 23 December 2019 owing to their exceptional merits such as outstanding fluidic behavior, excellent electrical and thermal
Revised 10 April 2020
conductivity, tunable mechanical property, high plasticity, low vapor pressure, and favorable biocompat-
Accepted 2 June 2020
ibility. Recent endeavors indicate that liquid metals have quickly become a new generation of functional
biomaterials in both fundamental research and practical applications. Especially, their uniquely low vis-
Keywords: cosity and water-like flowability as metals in liquid state enable many unconventional biomedical opera-
Injectable technology tional modes through the easy-going injection way. This would mold a highly beneficial technology with
Liquid metal numerous advantages distinguishing from those traditional open surgeries. This review is dedicated to
Biomedical technology
systematically draft a new area of liquid metal enabled injectable biomedical technology based on their
Biomaterials
unique characteristics, summarize the recent representative developments and the associated biomedical
progress. The state-of-art materials, technologies, and devices will be interpreted. Scientific opportunities
and challenges will also be discussed. As emerging injectable biomaterials, the fundamentals, technol-
ogy, and potential applications of the liquid metals would endow injectable operations to fulfill urgently
biomedical demand as well as stimulate further endeavors along this critical direction.
© 2020 Elsevier Ltd. All rights reserved.

1. Introduction icity, and proper mobility to fulfill injection [6, 7]. In addition to
the above characteristics, much attention of implantable biomateri-
Injectable medicine is developing into an interdisciplinary field, als is focused on the comparable property, either soft or hard, with
including engineering, materials, biology, and medicine. The appli- suitable mechanical support to maintain the tissue microenviron-
cations of injectable medicine include restoring damaged tissue or ment [8]. The function of injectable materials is not only to substi-
cavities through tissue engineering scaffolds and precise delivery tute the irregular defects but also to offer sustained 3D structural
drugs or energy to specific defect site [1]. Unlike traditional open support and repair capability [9]. In structure, ideal restoring ma-
surgery, the injectable method benefits greatly from injectable ma- terials should enable remodeling capacity, the so-called transfor-
terials with minimal invasiveness, reduced possibility of infection, mation adapted to external circumstance, and appropriate degrad-
easy operation, low cost and short recovery time [2]. At present, able ability while transporting supporting nutrition, such as drugs,
injectable tissue engineering strategy has been considered as an bioactive factors and even various stem cells [10, 11]. Clinically,
attractive alternative to reduce bacterial contamination of surgery injectable biomedical materials are used in tissue engineering for
and come into a myriad of applications in complex tissue regen- trauma and a variety of complex tissue repairs, such as heart, bone,
eration, such as maxillofacial reconstruction, cardiovascular tissue cartilage, and vessels, and in disease treatment like analgesic ther-
regeneration and joint arthroplasty [3-5]. apy and tumor therapy [12, 13]. Till now, different kinds of nature-
Generally, injectable materials should meet several basic re- derived and artificial materials, including autologous tissues, allo-
quirements, like biocompatibility, biodegradability, less or nontox- geneic biological tissues, decellularized matrices, polymers, ceram-
ics, stimuli-response hydrogels and nanomaterials are used as in-
jectable biomaterials for tissue restoration [12, 14, 15]. Especially,

Corresponding authors. Beijing Key Lab of Cryo-Biomedical Engineering and Key hydrogel-based biomaterials are a wide range of injectable materi-
Lab of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of als that could respond to external environments, such as pH, tem-
Sciences, Beijing 100190, China perature, light, electric and magnetic fields [16, 17].
E-mail addresses: weirao@mail.ipc.ac.cn (W. Rao), jliu@mail.ipc.ac.cn (J. Liu).

https://doi.org/10.1016/j.apmt.2020.100722
2352-9407/© 2020 Elsevier Ltd. All rights reserved.
2 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Besides providing mechanical support or chemical drugs to ac- would unveil plenty of game-changing applications, providing con-
complish tissue regeneration, part of the injectable materials are trollable mechanical support with a lower Young’s modulus to the
enabled with electroconductivity, which is also called injectable rigid metal counterparts that is comparable to the human tissue
electronics [18]. Injectable electronics focus more on the electri- and several orders higher electric conductivity than those conduc-
cal energy delivery and in vivo electric signal collection. In partic- tive hydrogels.
ular, injectable electronics was selected as one of the ten world- After injection, long-term monitoring and observation on the
changing ideas in 2015. As is well known, electrical activity is the shapes of biomaterials in vivo, which facilitate our understand-
principal signal that governs human behavior, such as hormone se- ing of the interaction between the implants and their surround-
cretion, muscle contraction, learning and memory capacity of the ing tissues, remains a huge challenge in tissue engineering. Liq-
brain. In order to achieve a better understanding of the basic ner- uid metals with high image contrast under X-ray endow them
vous activity of organism through electric signal, as well as to reg- the ability to directly observe their behavior after implanted into
ulate and promote the function of neurons, artificial electrodes are the deep tissue, especially the inner three-dimensional structure,
usually attached to the surface or implanted in vivo to monitor or which is almost impossible for fluorescent imaging due to the pen-
transport electrical activity, in which several commercialized wear- etrate depth limitation [39]. Thus low-melting liquid metal would
able electronic and small-sized implantable devices are commonly furnish an unconventional injectable technology to address many
utilized in clinics, like wearable ECG signal detection, cardiac pace- complex medical challenges, allowing sophisticated tissue regen-
maker and implanted electrically stimulated probes for treating eration, comprehensive in vivo surveillance of implanted biomate-
Parkinson’s disease [19, 20]. rials, collecting bioelectrical signal and regulating neural activity,
Nevertheless, to reduce the intrinsic difference between biolog- and thus build up an injectable medicine for the biomedical sys-
ical tissue and artificial electronic devices is the most challenging tem, ranging from mechanical support in tissue reconstruction to
part and holds a great space to improve. In order to reduce the monitoring and therapeutic interventions of diseases.
mismatch between the tissue and implantable electronics and in- The combination of a number of extraordinary merits of liq-
crease the stability on the contact interface, a continuous endeavor uid metals (Fig. 1a), including flowability, plasticity, imaging con-
has been made on the discovery of suitable implanted materi- trast enhancer, biosafety and biodegradability, electric and mag-
als, novel technology and advanced integrated equipment [21]. Re- netic properties, enables them to offer pathbreaking ways to tackle
cently, conductive hydrogels have attracted great attention for their many challenging medical puzzles. Moreover, the chemical activ-
conductive ability and flexibility to smooth the interface between ity and stability, the natural flexibility and variable mechanical
humans and machines, which includes ionically conductive hydro- strength empowered by the oxide layer of liquid metal is a double-
gels, conductive nanocomposite hydrogels, and conductive polymer edged sword, carrying pros and cons on many issues.
hydrogels [22, 23]. Unlike traditional rigid electronics, these hy- This review is dedicated to systematically daft a liquid metal-
drogels are not only electrically conductive and flexible but also enabled injectable medical system based on understanding the
enable delivery through a syringe. Besides hydrogels, Lieber et al. physical, chemical, biological characteristics of liquid metal, and fo-
also reported large-scale porous mesh conductive material made of cuses on the typical applications (Fig. 1b) and applied technologies
polymer and encapsulated metal as interconnects with submicron of injectable biotechnology. Liquid metals of NaK alloy, gallium-
thickness. This conductive composition can be injected into defects based alloy, bismuth-based alloy, and gallium-based nanomaterials
or biological tissues, inducing little immune activity and has been are all included as injectable biomaterials in this review, which are
applied to obtain the stable electrophysiological signal from the summarized in Table 1. We will start with a brief overview of the
retina in awake mice [24, 25]. fundamental characteristics of these liquid metals to provide evi-
To improve electric conductivity, hydrogels usually mix with dence as injectable biomaterials. Subsequently, the recent advances
other conductive materials such as ionic liquids or carbon nanoma- of the injection-enabled applications will be introduced. Addition-
terials. However, the electroconductivity of these mixtures is rela- ally, the devices supporting the injection technology and the in-
tively low compared to that of metal materials. Thus, a class of jectable targets will be described. Last but not least, discussions on
metals with low melting points and favorable flowability attracts the opportunities and challenges are outlined.
increasing interest. Recently, liquid metals played critical roles in
a number of fields, such as soft machine [26], printing electron-
2. Characteristics of liquid metals
ics [27-29], hydrogen-producing energy [30-32], human-machine
interface [33], and biomedicine [34], which are inseparable from
This section focuses on several essential features of liquid met-
a series of special uniqueness, including physical, chemical and
als that enable injection technology as well as facilitate their
biological characteristics. Actually, because of the toxicity or ra-
subsequent applications in biomedical areas, including fabrication
dioactivity of several types of liquid metals, such as mercury, ru-
methods of liquid metal droplets for microfluidic devices, imag-
bidium, cesium, francium, only sodium-potassium (NaK) alloy, liq-
ing enhancer agency, electric signal connection and delivery, tu-
uid gallium (Ga), gallium and bismuth (Bi) alloy have been at-
mor therapies, smart robots, and other nanoparticles enabled ap-
tempted to be utilized in the biomedical applications, including
plications in diagnosis and treatments. The characteristics of liq-
liquid metal bath electrode-mediated radiofrequency ablation [35],
uid metal as unique biomaterials are summarized and classified
skin-attachable wireless sensors for physiological signal detection
into eight aspects, such as injectability, self-driven mobility, elec-
[36] and enhanced tumor thermochemical ablation [37, 38].
trical conductivity, plasticity, transformability, biocompatibility and
Room temperature gallium-based liquid metals with flowabil-
degradability, magnetic property and thermal conductivity for fur-
ity and tunable melting points through forming an alloy with one
ther development in a combination of their diverse functionality
or more metals of bismuth, indium (In), tin (Sn), lead (Pb), cad-
into specific applications. The basic physic properties of typical liq-
mium (Cd) etc., display promising potential and hold great value
uid metals are summarized in Table 2.
in biomedical fields. At the same time, the combination of low vis-
cosity, fluidity, and biocompatibility endows these metals’ ability
as injectable biomaterials that can be operated through syringes, 2.1. Injectability
which enables completely filling into the known or most unknown
irregular defects and precise delivery of materials, drugs and elec- Usually, injectable materials are supposed to meet two charac-
tric energy. Through injection, liquid metal-enabled biomaterials teristics, fluidity and moderate viscosity. For low-melting metals,
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 3

Fig. 1. (a) The diverse properties of low melting point liquid metal: injectable feature (liquid metal is conformably filled into irregular intestinal tract [40]), self-driven
mobility (an EGaIn droplet moves in a circular channel [41]), electric property (liquid metal electrodes facilitate the transmission of nerve signals [42]), high plasticity
(the alloy cement is formed in a shape of“BONE” [43]), transformability (shape transformation of a liquid metal droplet under 20 V voltage [44]), biocompatibility and
biodegradable (Liquid metal hybrid materials injected into tumor sites [45]), magnetic property (Liquid metal is placed on a permanent magnet [46]) and thermal property
(liquid metal nanorods produce a large amount of heat under laser irradiation [37]). Reproduced with permission. (b) Injectable liquid metal enabled a series of biomedical
applications.

Table 1
Basic properties of typical injectable liquid metals.

Types Composition Size Ref.

Gallium-based liquid metals Gallium/EGaIn24.5 / Ga67 In20.5 Sn12.5 alloy/ Mg-GaIn mixture/Ga-In-Al mixture/ Liquid Bulk [41, 43, 45, 47-49]
metal hybrid
Alginate modified Ga-In-Al/Nickel cap modified Ga-In-Al/ Liquid metal conjugates Millimeter [50]
droplet
Liquid metal droplets Micro/nanoscale [51, 52]
EGaIn24.5 nanocapsules/ Gallium nanospheres/ Gallium nanorods ~100–300 nm [37, 53, 54]
Bismuth-based liquid metals Bi35 In48.6 Sn16 Zn0.4 alloy Bulk [43]
Sodium-potassium alloys NaK alloy Bulk [55]

Table 2
Physical properties of typical liquid metals [56, 91].

Gallium GaIn24.5 Ga67 In20.5 Sn12.5 Ga61 In25 Sn13 Zn1 Bi35 In48.6 Sn16 Zn0.4

Melting point (°C) 29.8 15.5 10.5 7.6 58.3


Viscosity (mPa•s) 1.75 2.7 2.98 0.71 4
Surface tension (mN m−1 ) 0.72 0.624 0.533 0.5 —
Electrical conductivity (106 S m-1 ) 3.7 3.4 3.1 2.8 7.3
Thermal conductivity (W m−1 K−1 ) 29.4 42.2 16.5 48.2 10.9

including NaK alloy, gallium-based, and bismuth-based liquid met- gen, an oxide skin will form on the surface of liquid metal with a
als present liquid state when the temperature is above their melt- thickness of about 3 nm, which is composed of the surface Ga2 O3
ing points. The dynamic viscosity of gallium is about 1.75 mPa s, and Ga2 O [60]. Compared to gallium, indium and tin are not easy
which is slightly higher than that of water (1.002 mPa s) [56]. Re- to react with oxygen in the open air. The generated oxide film pre-
searchers recorded the splashing process of liquid metal from a vents the internal metal from further oxidation. However, continu-
certain height using a high-speed digital camera, displaying sim- ous stirring in the air would facilitate the whole oxidation process.
ilar fluid properties with water (Fig. 2a) [57]. In practice, syringe Studies have shown that the viscosity of Galinstan would increase
injection provides an easy way to perform and form small-sized with the thickness of the oxide film [60]. Thus through manipula-
droplets or a puddle of liquid metal. In addition, flexibility enables tions of the oxides on the outside could probably be a way to tune
the liquid metal to be shapes or filled into unknown cavities in any the viscosity of liquid metals.
shape. Because the viscosity of the liquid metal is similar to that Considering the high surface tension of liquid metal, it is hard
of the water, when filling into the biological tissue, the material to mix it with other particles. However, the existence of oxide skin
would conformably be attached to the tissues. on the surface would act as a bridge and facilitate the mixture with
The surface tension of Galinstan is about 534.6 mN m−1 , which copper particles, nickel particles, and iron particles [61-65]. The
is more than 7 times higher than that of water (70 mN m−1 ), with accumulation of the oxide contents during the stirring and mix-
a tendency to shrink into a droplet in the aqueous solution to re- ing process increases the viscosity and the adhesive behavior to
duce the surface energy [58, 59]. When in contact with air or oxy- a different surface, such as polyvinyl chloride (PVC), paper, poly-
4 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Fig. 2. Characteristics of smart injectable liquid metals. (a) The fluidic features of liquid metal compared with water. Reproduced with permission [57]. (b) The liquid metal-
based material as an electronic tattoo for human-machine interaction [92]. Reproduced with permission. (c) Tunable rigidity, conductivities, adhesion, and formability of
liquid metal mixture with additive copper particles and the element mapping of the mixture. Reproduced with permission [70]. (d) The light transmittance change of liquid
metal nanoparticles over time (left) and the corresponding TEM images of the liquid metal nanoparticles in acidic PBS solution (pH=5.0). Scale bars, 100 nm (for 5 min);
100 nm (for 1 h); 100 nm (for 4 h); 400 nm (for 72 h). Reproduced with permission [52]. (e) The thermographic images of a representative liquid metal droplet with or
without a 785 nm laser irradiation (left) and 100 μg ml−1 modified liquid metal nanoparticles solution under laser irradiation. Reproduced with permission [53].

dimethylsiloxane (PDMS) and polymethacrylate (PMA) glue, which was used as a sensor to obtain the changes in temperature, humid-
is widely used in flexible electronics, electric skin and transfer ity, and oxygen in stretchable channels, which was demonstrated
printing technology [66-69]. Especially, when liquid metal with a with a higher sensibility [85]. Instead of direct injection of liquid
high packing rate of about 20% copper particles by weight, the metal to form electrodes in situ, several liquid metal microdroplets
rigidity increases, exhibiting a clear solid-like behavior. This me- with stable sphericity could be prepared in advance, taking advan-
chanically regulated property would be advantageous as stiffness tage of the mechanical strength supported by the oxide surface,
variable materials in the soft robotic areas and accomplish a series and injected to form microelectrodes under dielectrophoretic as-
of actions like grasp-and-release, cargo delivery, active protection sembly [86]. Therefore, the fabrication methods of uniform shapes
and support. Moreover, a small amount of copper particles dop- of liquid metal droplets are needed to work as electrodes in mi-
ing would not only influence the fluidity of liquid metal but also crofluidic devices.
enhance the electric and thermal conductivity of the mixture [70, Gallium is easy to alloy with several other metals, including
71]. Bi, In, Sn, Pb, Cd, etc., with tunable melting points through in-
Liquid metal combined with other elastomers, such as silicones, corporating different compositions and proportions [87]. Gener-
also attracts great attention, especially in flexible and wearable ally, gallium-based liquid metals present with melting points lower
electronics with superior compressing, twisting and stretchable ca- than the room temperature. For example, the melting points of
pability in arbitrary shapes [72-80]. Considering the superior soft- GaIn24.5 and Ga67 In20.5 Sn12.5 are 15.5 °C and 10.5 °C, respectively.
ness and fluidity, researchers injected liquid metal directly or un- In several cases, the implanted biomaterials need to satisfy a cer-
der pressure into microchannel made by triblock copolymer gels, tain extent of mechanical strength to fill in the cavity and facilitate
PDMS and the other elastomeric surfaces to fabricate microchan- the tissue with stiffness to remodeling. Of course, incorporating
nel electrodes, flexible antennas and retractable electronics [81- other particles could enhance their mechanical strength. However,
83]. These materials are shown with soft properties from the inner the injectable features of the metal mixture would be damaged to
core consisted of liquid metals as well as the outside elastomers. a certain extent. Actually, bismuth, which is similar with gallium, is
These outside elastomers can also work as potential packaging ma- easy to alloy with In, Sn, Zn to form low-melting alloys possessed
terials to assure the biosafety regarding the further use of metals with higher melting points than gallium-based liquid metals, and
in the body. displays important application in the reversible stiffness and self-
In a microfluidic system, liquid metal enables the one-step in- healing composite materials [88]. For example, Bi35 In48.6 Sn16 Zn0.4
jection instead of the sophisticated patterning technology in the alloy with a higher melting point of 57.5 °C, presents the solid-
fabrication of electrodes, which also provides a novel method of state in ambient temperature as well as body temperature and
pumping and valves control [84]. This liquid metal-based electrode exhibits flowability after short-time heating [43]. Researchers in-
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 5

dicated that the mechanical properties of Bi35 In48.6 Sn16 Zn0.4 alloy the flow of solution in the channel would form a certain resistance
with a compressive strength of 37.6 ± 1.56 MPa, bending stress of as the feedback effect to the moving motor. While for such a pur-
35.31 ± 1.09 MPa and a bending modulus of 6.41 ± 0.81 GPa, was suit problem, the fast-moving machine was still likely to catch up
able to resist the external pressure. After melting on a small heater, with the low moving machine, causing collision and fusion. Finally,
the Bi35 In48.6 Sn16 Zn0.4 alloy could inhale with a needle and pro- the merged large machine could seamlessly connect and continue
ceed through a syringe to the bone. Then the injected low-melting to move forward. However, the large machine after collision and
alloy filled in the irregular defect, solidified and provided more fusion would have higher kinetic energy and velocity due to the
suitable sustainability. Finally, the removal of the alloy could be reduction of the surface free energy.
done by reheating and extracting with a syringe via a non-invasive However, this self-powered machine has to work in an aqueous
way. Besides the direct contact of metals to human tissues, the use solution due to the fact that the driving mechanism is originated
of several packaging materials could further enhance the biosafety from chemical interaction between the mixtures and ions in the
of these liquid metal alloys. water, which might restrict its applications. Our digestive and cir-
Generally, the viscosity and mechanical strength of liquid met- culatory systems are essentially enriched with water and can offer
als can be regulated through oxide skin, extra metal particles ad- circulation pathways for these machines, leaving a large space to
dition or the choice of bismuth-based alloy metals, which was explore the promise aspects of these soft robots in biomedical ar-
mainly owing to the unique physical and chemical properties of eas, such as drug delivery, disease monitor and sample collections
liquid metals. Therefore, guided with the chemical peculiarity of [90]. Through incorporation with other metals, liquid metals are
liquid metals, more fundamental phenomena would thus be dis- discovered with enhanced characteristics and even unusual abili-
covered and turned into practical use. ties without sacrificing their soft nature. Studies are encouraged to
explore more exciting phenomena and fundamental behaviors of
2.2. Self-driven mobility liquid metals in this way.

Micro/nanorobots with self-motion property open up novel 2.3. Electric property


paths in many fields such as cargo transportation, drug delivery,
intelligent sensor and information transmission, etc. Because of the Hydrogels attract great attention as injectable biomaterials due
small size, those micro/nanomachines mainly rely on external en- to their outstanding biocompatibility to the tissue interface [22].
ergy when executing tasks under specific situations in aqueous or Through incorporating other nanocomposites or highly conductive
non-aqueous environments where the energy powered system is metal nanomaterials, hydrogels are endowed with electrical con-
relatively easy to operate outside. While in the macroscopic di- ductivity capability. However, the highest electrical conductivity of
mensions, mainly ranging from millimeter to centimeter scale, re- the conductive hydrogels is about 103 S m−1 , which is still much
searches concerning the self-propelled machines have encountered lower than that of metals [22]. Generally, metals are widely used
enormous challenges. The driving force of those robots usually in- in electronic circuits for their excellent electrical conductivity. The
volves complex and extensive system of energy sources, especially electrical conductivity of the liquid metal, which resembles but
in case of a long-distance and a wide range. Although the electric is slightly lower than steel (6.21 × 106 S m−1 ), is several orders
field and the magnetic field are absolutely the preferred choice due of magnitude higher than those non-metal counterparts, such as
to the precise control technology, this poses significant challenges carbon-based materials, conductive grease, conductive ionic liq-
of materials as well as equipment. If the energy source could be uid or hydrogels [91]. For example, the electrical conductivity of
combined with the machine, the problem would then be simpli- GaIn24.5 , Ga67 In20.5 Sn12.5 , Ga61 In25 Sn13 Zn1 , Bi35 In48.6 Sn16 Zn0.4 are
fied to the battery energy efficiency and the integration issues. The 3.4 × 106 S m−1 , 3.1 × 106 S m−1 , 2.8 × 106 S m−1 , 7.3 × 106
smaller size, lighter weight and higher energy supply capacity is S m−1 , respectively. The differences including but not limited to
highly pursued on the requirements of the battery. While when electric property between the hydrogel and liquid metal are com-
combining the battery and the moving body, the direct interactions pared in Table 3.
might damage the regular operation of the two isolated systems. Moreover, liquid metals are presenting a characteristic with the
So it is very important to improve the interaction effect between tunable electric property through regulation. Firstly, the electrical
the power system and the flexible machines at the same time to resistivity of liquid metal is demonstrated to be correlated with
ensure the overall safety and performance. It is of great meanings the degree of oxidation [91]. Alloying with other metals, such as
to learn from the natural organisms. They eat, digest, absorb food In, Sn, would improve the electrical properties a bit [91]. Beyond
and then convert it into ATP and the diving forces. that, by adding other highly conductive particles into liquid metal
Under an unanticipated discovery, Zhang et al. had observed the would provide a way to enhance its electrical characteristics. In
self-driven motion phenomenon of liquid metal droplets after en- particular, the softness of the materials is shown without sacri-
gulfing a small amount of aluminum. The penetrating of aluminum ficing. Researchers have shown that liquid metal-based skin tattoo
to the liquid metal alloy enables the autonomous locomotion and was able to display diverse flexibility, such as bending, twisting,
maintains the original soft nature to pass through the U-shaped bending and relaxing for 30 0 0 cycles and at the same time main-
and zigzag channel [41], which was considered as the first-ever tain excellent electric properties (Fig. 2b) [92]. After injection into
whole soft metallic robot, not only exhibiting its transformable a hollow elastomeric fiber, the researchers have shown that the
uniqueness but also demonstrating a next-generation robot model conductive wire maintained good conductivity under stretching up
with potential capability to accomplish complex missions through to 700% [93].
slits. Composites combining liquid metals with other elastomers pro-
What’s more, after injection, the large robot of running liquid vide a method to prepare materials with the reversible electri-
metal could be divided into tremendous discrete droplet machines, cal transition. Despite the excellent electric conductivity of bulk
then bouncing and combining together into a large one without liquid metals, the conductive of dispersed liquid metal droplets
sacrificing the mobility [89]. Especially after dividing, the rear of in solutions or elastomers would be significantly decreased. Re-
each machine with individual motor capability could continuously cently, Wang et al. proposed a liquid metal-polymer composites
release bubbles and power the locomotion behavior in its origi- with both outstanding stretchable characteristic and free reversibil-
nal track [26]. When dispersing three motors in the torus groove, ity between conductor and insulator as novel transitional insulator
their speeds could be in synchrony at first. The reason was that and conductor (TIC) materials [94]. After freezing for only a few
6 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Table 3
Comparison between LM and hydrogel.

Hydrogel LM Ref.

Typical source Agarose, alginate, hyaluronic acid, collagen, chitosan, Ga, Bi, In, Sn, Zn [13, 87]
PEG, PVA, PLA, PLGA
Mechanical property Young’s modulus (~10−1 -~103 kPa) Tunable elastic modulus depending on liquid [22, 88]
or solid state (0-~10 GPa)
Electrical property Through incorporating other conductive materials High electrical conductivity [22, 102]
such as metal, carbon nanotubes, graphene, ionic (~ 1 × 106 -8 × 106 S m − 1 )
salts etc. (~ 10−3 –103 S m − 1 )
Stimulus response pH, temperature, light, electric, chemical materials Light, heat, acid [6, 34]
(such as glucose, enzyme)
Imaging Through incorporating other imaging contrast agent High radiopaque [48, 103]
Biocompatibility Excellent Good [13, 34]
Degradability Degrade into harmless organics Under mild acidic environment, gallium turns [34, 52]
into Ga3+
Shape transformation Mainly volume change or some with shape memory Ranging from macroscale to nanoscale [103-105]
function
Fabrication process Relatively hard to handle Relatively easy either preparing alloys or [13, 34]
synthesis nanoparticles
Fabrication into different scales From bulk to nanoscale particles with relatively From bulk to nanoscale particles with [34]
uniform distribution non-uniform distribution

seconds, the resistance could change by 4 × 109 times. The liquid In this process, temperature control is critical, while high heating
metal droplets would go through phase changes, thus increasing temperature would increase the complexity of the operation. How-
the volume. While the surrounding polymers would undergo vit- ever, if the heating temperature is too low, the materials would
rification with stiffness change during the temperature drop. The solidify during the shaping process. Therefore, a precise temper-
two factors induced those isolated liquid metal droplets to connect ature controller has to be utilized to maintain the constant tem-
with each other at low temperature and made the complex ap- perature of the materials. With the device, researchers demon-
pear as a conductor. The more interesting phenomenon was that strated that liquid phase 3D printing technology with liquid metal
the process was reversible. That is to say, the elastomer compos- Bi35 In48.6 Sn15.9 Zn0.4 alloy ink successfully fabricated a diversity of
ites could return to normal isolator state after heating. After 100 3D structures, including balls, rods, frustum of a cone and cylinder
times cycles, the composites could maintain stable structures as [99]. Further, through mixing with copper nanoparticles, the plas-
well as reversibly electrical conductivity. Several influential factors ticity of liquid metals could be enhanced primarily (Fig. 2c) [70].
such as the dispersed state of the droplets inside the elastomer, In particular, liquid metals exhibit distinct elastic modes at
particle sizes, the state of the polymers, the viscosity, curing time, various temperature ranges. For example, due to the high melt-
that could made an impact on the conductivity change were also ing point of Bi–In–Sn alloy, the elastic modulus is extremely high
analyzed. This kind of TIC materials would have significance as (9.25 GPa) above 62 °C, while the elastic modulus can drop to
novel temperature switches, temperature-sensitive circuits and sta- almost zero after melting [88]. Taking advantage of this feature,
ble maintenance of circuit state in an extreme environment. Fur- combining liquid metals with other low elastomers such as silica
ther, Chen et al. discovered a class of temperature-regulated liquid gel with an elastic modulus of 0.54 MPa provided a method of fab-
conductor-insulator transition (LCIT) composites and summarized ricating stiffness tunable multifunctional elastomer foams [88]. At
a generalized role [95]. Dispersing liquid metal droplets in silicone room temperature, the as-made foam could bear a load of 0.5 kg.
oil (dimethicone) acted as a simple method to realize conductive With the temperature increasing, the liquid metals inside the elas-
switching for hundreds of times. The important meaning of this tomer composites would melt but still adhere to the inner silicon
work is to summarize a class of metal materials with the abnor- due to the role of oxide. Besides, the elastomer exhibited excellent
mal volume change, which are mainly gallium-based or bismuth- mechanical properties including all kinds of stretching and defor-
based materials. The low temperature could induce volume expan- mation. At room temperature, the elastomer modulus was 1.8 MPa
sion of the metals to facilitate the contact of these droplets into and 3.1 MPa in the tensile and compression tests. While the elas-
bulk-like conductor in the electronic circuit. When the temperature tomer modulus would decrease to 0.1 MPa after heating. When
rises, the droplets of liquid metal would undergo volume shrinking the foam composite was further encapsulated and molded, it could
into the original isolated state with low conductivity. In addition, form an endoskeleton structure. Covered on the surface of a pneu-
the researchers also revealed the color change phenomenon of the matic arm, it acted as an exoskeleton structure with flexible tun-
liquid composite during the serve temperature change, which can ing capability. Thanks to the favorable fluidity, after cutting, liquid
be used as an indicator of the conductivity. metal could flow and fill into the gaps under high temperature to
reconnect the broken part into a complete elastomer. Although the
cutting damage of silicone elastomer is irreversible, the fluidity of
2.4. High plasticity
liquid metals plays an important role as self-healing and repairing
materials. In another study, the authors prepared composite ma-
Liquid metal could act as 3D printing ink to directly fabricate
terials with several layers to actively regulate the rigidity of the
several fixed models [96, 97]. Besides, uniform micro-sized liq-
materials, including a serpentine structured liquid metal layer, an
uid metal droplets could thus be fabricated via filling into uni-
electric Joule heater layer and the encapsulation layer [100]. It is
formly shaped fixed molds with hydrochloric acid to overcome the
reported that the effective elastic modulus of the composite could
high surface tension and remove the outside oxide skin [98]. For
be electrically modulated with a change of four orders of magni-
bismuth-based alloys, due to the higher melting points, they ap-
tude. At room temperature, the complex was rigid and the mod-
pear as solid at room temperature. Taking advantage of liquid-solid
ulus of elasticity was dominated by the metal materials. While
transition, they can be filled into the unknown 3D structures after
with the power on, the inner metals melted and the elastic mod-
heating and solidification in the cold air to make desired shapes.
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 7

ulus was affected by the acrylic elastomers, so the composite was method is also used to remove the surface oxide skin. The alu-
free to be bent or distorted. After repeated electronic control, the minum sheet was adopted to form a primary cell with liquid metal
composite still remained stable reversibility. In addition, a theoret- materials. The liquid metals as the positive electrode would un-
ical model was established to predict the time consumed to acti- dergo a reduction reaction and the metal oxide could be removed
vate the whole elastomer and the relationships between the rigid- continuously with the inner alloy being exposed continuously and
ity change of the whole composite and the input energy, which the surface tension of the mixture is increased. Then the aluminum
was demonstrated to be in good agreement with the experimental as the negative electrode would be dissolved in the solution and
results. After electric activation, the composite was demonstrated form aluminum ions. Besides, the chemical reaction is another sim-
with multifunction, which holds great application promising in the ple way to eliminate those oxide materials based on the fact that
future. the gallium oxide is amphoteric and can be dissolved in both acidic
Besides, Yuan et al. came up with a method to regulate the and alkaline solutions.
stiffness of copper wire mesh by utilizing the wetting behavior be- On the other hand, applying an electric field to a liquid metal
tween liquid metals and copper wire mesh [101]. They found that sphere in NaOH solution induces reversible deformation of liquid
the rigidness of the composite could be largely enhanced from to- metal from gallium droplet to extended structures with large-scale
tally soft to pretty rigid. What’s more, the enhancer could also re- transformation. The mechanism was disclosed via the synthetically
alize increased load-bearing capability with a multilayer structure chemical-electrical mechanism (SCHEME) [44]. The mechanism un-
to finally support a heavy load of 2 kg at the same time with a thin derlying these phenomena on the surface tension manipulation
thickness of less than 1 mm. The enhancer also exhibited prospects and the control of surface oxide skin was disclosed. The double
in the behaviors like grabbing, releasing and supporting, etc. electric layer on the surface attracts ions in solution around the
surface and affects the surface energy of liquid metals [110]. This
2.5. Transformability transformable phenomenon of liquid metals enabled by electric
fields would open an accurate way of regulations in shapes and
For gallium-based liquid metals, a film of gallium oxides can provide general applications in biomedicine. However, electric ma-
be formed on the skin, which prevents the inner metal from be- nipulation is not a non-contact approach, extra electrodes are also
ing further oxidized. The oxide skin owns a certain rigidity and required.
can tune and shape the liquid metals, the performance of which is Based on the two phenomena of large-scale transformation of
widely applied in the mold, reconstruction and 3D printing [106]. liquid metals, the reversible amorphous deformation can be eas-
Because of the existence of the soft core and rigid skin surface, liq- ily achieved with the external signal changed to a square wave
uid metals can adjust their shapes through tuning the surface ten- signal to automatically switching the positive and negative poles
sion and further mediate various types of transformation, including [44]. While if the external positive pole is contacted continuously
changing from a puddle of liquid metal film to a single droplet, with the liquid metal film, employment of the chemical solution
from a single droplet to a puddle of liquid metal film, reversible through dissolution and controlling the duration of the power can
large-scale deformation of liquid metals, division and fusion of liq- also achieve the performance of reversible shape transformation.
uid metal motors. After the liquid metal droplet is inhaled into the syringe, the
For liquid metals with oxide skin, the morphology changes usu- dispersion of liquid metal droplets can be achieved by controlling
ally involve a certain temperature change or external mechanical the injection speed of the syringe. This method of injection can
forces. Besides, the shapes of liquid metals can also be controlled also be used to disperse multiple self-powered liquid metal mo-
by the electrical field [107-109]. Sheng et al. discovered the un- tors [89]. The discrete liquid metal droplets in the solution with
usual transformable phenomenon of a pool of liquid metal under independent moving capability would collide with each other and
external electric field [104]. Their work reported that the surface further fuse into a single large liquid metal droplet.
area was changed for more than a thousand times from a large film Behaviors, such as planar locomotion and self-rotation, are also
to a tiny sphere. It was found that the phenomenon of liquid metal discovered under DC voltage [111, 112]. In the experiments, liquid
surface change could only happen when the negative electrode was metal droplets in the linear channel were observed to move from
imposed on the liquid metal film. That is to say, the direction of the negative pole to the positive pole of the power [113]. Due to
the electric field determines whether the liquid metal could shrink the uneven intensity of the electric field, the surface charge of the
smoothly. When the negative electrode was connected to the sur- liquid droplets would be influenced and further lead to the imbal-
face of liquid metals, a complete electrical circuit was formed to- ance of the surface tension, which is responsible for the elongated
gether with the positive electrode, solution and external power shape transformation and the locomotion of liquid metal droplet.
supply. After electrification, a redox reaction would occur. For the The surface tension of droplets near the negative electrode was rel-
negative electrode, the liquid metal part would be reduced, and the atively large and the pressure difference between the machine at
gallium oxide was constantly being removed. It was also discov- the negative electrode and the surrounding solution environment
ered that the oxide skin was preferentially removed near the pos- was also large, which could push the droplet to move in the di-
itive electrode, where the electric intensity was high. That is the rection to the positive electrode. The experiments showed that the
reason that the shrink of liquid metal film was initiated from the electric field intensity, solution composition and the machine vol-
negative to the positive electrode. Further several influential factors ume would affect the locomotion of the machine. An appeal of this
such as the intensity of electric voltage, charged ions in the solu- method is that it enables the transformation and shaping of liquid
tion, electrode shapes and electrode spacing, which might have an metal through simple operation and offers opportunities for liquid
effect on the dynamic electric controlled removing process in such metal collection and soft robot manufacture in the future.
as electrical circuit consisting of electrons and ions, were also ana- In addition, the soft nature of liquid metal provides an advan-
lyzed by researchers. In the experiment, since the current intensity tage to manipulate them into small sizes and different shapes.
near the negative electrode is larger than that far away from it, Compared to the complex manufacture of organic and most metal
the oxide formation rate near the negative electrode is thus faster nanomaterials, liquid metal enabled a simple sonication method to
and the surface tension drop is more obvious. So the asymmetric prepare liquid metal nanoparticles in the aqueous solution or in
deformation of the liquid metal machine was observed. ethanol [114-116]. Through functionalization, it is easy to form a
Many experiments were performed with large-scale deforma- stable colloidal suspension or load chemical drugs. One can even
tion taking advantage of this oxide cleanup. The electrochemical control the shapes of liquid metal nanoparticles through tempera-
8 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

ture, light, and surfactants in the solution. Lin et al. discovered that and products in the physiological environment under various treat-
moderate heating at 70 °C for about 20 min could shape eutec- ments should be considered and reevaluated in detail.
tic gallium indium (EGaIn) nanoparticles into nanorods, which are Due to the facile fabrication and easy functionalization of liq-
composed of gallium oxide monohydroxide (GaOOH) [105]. Miyako uid metal nanomaterials, their medical application, as well as the
et al. have further demonstrated the morphological changes of LM biosafety of these tiny materials, received great attention. Through
nanocapsules triggered by laser irradiation [53]. Gu et al. took ad- intravenous injection, liver function markers and urea were de-
vantage of the shape transformable behavior of liquid metal under tected to evaluate the influence of 45 mg kg−1 nanomaterials treat-
heat and combined with graphene quantum dots (GQD) for intra- ment on livers and kidneys. No significant changes in the markers
cellular drug delivery [54]. These shape transformation phenom- were found through a 90 days’ investigation [52]. In addition, be-
ena of liquid metal droplets offer opportunities in the drug deliv- sides a vibration of platelets in the first week, blood routine ex-
ery system, endosomal escape, and enhanced tumor destructions. amination showed no difference from the control group. Results
From bulk liquid metals to nanoscaled droplets, liquid metals of necropsy and H&E staining of the crucial organs indicated that
exhibit high plasticity with tunable behavior in morphology, which no injury was detected. Finally, the excretion investigation implied
could be used either as transformable soft devices in biomedical that these metals might excrete through urine and feces. What is
fields or as smart nanomaterials to accomplish innovative disease more, recent research demonstrates the degradable capability of
therapies. liquid metal nanoparticles resulted from the phenomenon of gal-
lium dissolution in a mild acid environment, which not only con-
2.6. Biocompatibility and degradability tributes chemical drug release in tumor sites but also serves as an
advantage to these inert metals (Fig. 2d) [52]. Although the long-
Different from mercury, gallium-based and bismuth-based met- term toxicity data is still lacking, the current data of liquid metal
als with low vapor pressure render them a better substitute and nanoparticles has shown that these low-melting alloys are rather
much safer materials to humans. Generally, these metals are rather safe until now.
stable in neutral solutions. The oxide skin, mainly Ga2 O3 , would NaK alloy, commonly 22% sodium and 78% potassium by
dissolve in a mild acidic or alkaline solution, which makes a way weight, are mixed through shaking in a reactor with a melting
to remove the oxides. In the alkaline solution such as NaOH solu- point as low as −12.8 °C. NaK alloy is very active in contact with
tion, Ga(OH)4 − would produce on the surface of liquid metal, at- water, producing NaOH, KOH and releasing a large amount of heat
tract positive ions like Na+ to its surface and form an electric dou- and hydrogen gas, which is regarded as harmful material due to
ble layer (EDL), which works as a charged capacitor [117]. their high chemical activity. They are often sealed in an organic
Considering the potential release and cytotoxicity of the im- solution like kerosene or inert dry nitrogen before use. However,
planted materials, researchers tested the element release of owing to the fast reaction speed and heat release, alkali metal was
Bi35 In48.6 Sn16 Zn0.4 alloy through immersion experiments. With 14 demonstrated as a highly economical and efficient heating seed in
days of immersion in Hank’s solution, the ICP-MS results showed tumor hyperthermia.
that except for zinc, other metals were not detected in the solu-
tion [43]. While zinc is the essential element, the low concentra- 2.7. Magnetic property
tion would not harm the human body. The immersion solution was
further used to culture 3T3 cells, and the results showed that the Low-melting liquid metals per se are not magnetic. However,
viability was not influenced. Further, researchers tested the in vivo the electromagnetic field and electrolyte together would induce
biocompatibility of the alloy through subcutaneous implantation. the liquid metal to rotate. Wang et al. discovered that between
After 14 days, the implant was taken out, and no visible damage a pair of concentric ring electrodes with a voltage of 0.03 V, the
was detected. The H&E staining results showed increased infiltra- liquid metal in NaOH solution on a permanent magnet was pro-
tion of inflammatory cells and the formation of neovascularization. pelled to rotate centrifugally on [46]. The magnetic field serves as
Actually, gallium compounds are used in medical applications a better manipulation approach compared to the electric field due
since thirty years ago. For example, the radioactive gallium (67 Ga to the non-contact working modes [123]. Thus researchers pro-
citrate) has been utilized to detect lymphomas as tumor imaging posed many methods to operate them under the magnetic con-
agents [118]. Studies demonstrated that gallium nitrate could be troller. They found that incorporating magnetic particles into liq-
utilized as an active agency to suppress the growth of tumors. Gal- uid metal droplets or coating on their surface would endow them
lium nitrate has already been approved by the Food and Drug Ad- to manipulate by an external magnetic field [124]. For example,
ministration (FDA) for the treatment of hypercalcemia, metabolic Wang et al. fabricated liquid-metal enabled ubiquitous soft mate-
bone disease and other cancers [119]. Besides, the immunosup- rial (PLUS-M) materials with iron particles, exhibiting strong mag-
pressive and anti-inflammatory effect of gallium compounds is also netism and low density [63]. Zhang et al. prepared magnetic EGaIn
discovered [119]. What’ more, the gallium-based alloy has been with Ni cap, which showed the apparent magnetic property to con-
used as a restorative material by the dentist for a long time. As one trol the movement of the droplets. What’ more, the Ni capped self-
of the alloy metals, bismuth was regarded as green metal to substi- driving liquid metal motor could be manipulated to start and stop
tute toxic metal lead, since bismuth and its compound are harm- the movement [50]. Magnetic control provides the manipulation in
less to humans. Mainly, Peptobismol, a bismuth-based compound, a 3D space, high penetration to deep tissues and remote control
is utilized to treat stomach disease [120]. A 28-day study revealed outside the body, which was considered as a promising modality as
that no significant changes in vital clinical signs were detected in transcranial magnetic stimulation in many disease treatment such
SD rats through oral administration of as high as 10 0 0 mg kg−1 as depression, autism, and other nerve diseases.
daily bismuth [121]. For indium, it is only considered of potential Guo et al. developed a magnetic liquid metal-based multifunc-
developmental toxicity to humans under a high level of exposure tional soft electronics [125]. In their study, the designed multi-
[122]. The pure gallium, bismuth and fewer amounts of indium functional flexible electronics showed combined performances of
present less cytotoxicity to humans and some of the metal com- remote self-healing, water-degradable, and thermal transfer print-
pounds even show therapeutic effects in clinics. While the toxicity ing, which attribute to three parts of the materials including Fe-
of pure metals and their compounds varied a lot. Due to the rel- GaIn ink, degradable PVA substrate, and adhesive fructose. Under
atively high chemical activity of gallium, the possible compounds the magnetic field, the Fe particles could be gathered to follow
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 9

the movement of the magnet. Based on this phenomenon, a sin- with superior radiation-shielding capability [130]. Recent studies
gle magnet could facilitate the self-healing behavior of Fe-EGaIn have demonstrated that liquid metal can be used as an imaging
based conductive electric circuit after single or multipoint mechan- contrast agent to display the position of the materials after enter-
ical damage. Under water circumstance, the electric circuits could ing into the body. Because of their excellent radiopaque, it is pos-
be degraded and magnetic liquid metal ink could be further recy- sible to obtain clear photos with better contrast and more detailed
cled to reduce environmental pollution. What’s more, the present- information in deep tissues. In clinics, X-rays are mainly used for
ing electronics could further achieve enhanced transfer printing to bones check for their strong absorption of X-ray than soft tissues.
other highly stretchable polymers through heating to broaden the Yi et al. demonstrated that for porcine femurs, the gray value of
applications in stretchable electronics and flexible sensors. the low-melting alloy is even higher than that of the cortical bone,
displaying better imaging contrast under X-ray and CT radiation
2.8. Thermal property [43].
In clinics, it is often necessary to obtain the position of big
Liquid metals own superior thermal property as metals. The blood vessels adjacent to target organs to reduce the risk of
thermal conductivity of GaIn24.5 is 26.6 W m−1 K−1 , which is al- surgery, because that the systemic circulation involves the supply
most 44 times higher than water (0.6 W m−1 K−1 ) [91]. So low- of oxygen and nutrients to various organs is of great importance.
melting liquid metals are applied in chip cooling for comput- Besides, among the blood vascular system, a better understanding
ers [126-128]. To further improve their thermal property, highly of the terminal blood vessels, especially the capillaries, is signif-
thermally conductive metal particles, such as copper, silver, are icant for the supervision of most disease process [131]. Angiogra-
adopted to regulate the thermal performance in many applications. phy is used in visualizing blood vessels with a contrast agent, com-
For example, the thermal conductivity would have 100% increase monly iodine or iodinated materials [132]. However, their imaging
after doping copper particles [70]. Besides the thermal conductiv- capabilities are very limited for capillaries. Wang et al. for the first
ity, liquid metals were able to transform light energy into heat. time took advantage of the low viscosity and injectable character-
Miyako et al. achieved the thermographic images of a droplet of istic of liquid metals to perform multi-scale vascular imaging [48].
1 mg liquid metal and recorded temperature elevation of about 20 Through comparison, the contrast of blood vessels with the sur-
°C under 785 nm NIR laser (Fig. 2e) [53]. Further, the nanostructure rounding tissues in the liquid gallium perfused group is several or-
of liquid metal via photopolymerization displayed superior temper- ders higher than that with conventional iohexol agent (Fig. 3a). In
ature change in solution with a photothermal conversion efficiency the photos of the porcine kidney, the tiny vessels of 0.1 mm could
of 52% and has been applied in photothermal treatments of tumors be observed clearly (Fig. 3b). Further, the researchers discovered
in vivo. that the injectable nanoscale liquid metal also displayed the capa-
bility to absorb radiation in solutions [52]. They demonstrated that
3. Injectable LM-enabled biomedical applications the photopolymerization modified liquid metal nanoparticles in a
low density would exhibit an enhanced X-ray intensity after light
With diverse merits of flowability, low viscosity, favorable bio- activation. Subsequent injection of liquid metal into various types
compatibility, easy fabrication process and multifunction, many of organs from rabbit or living mice revealed strong X-ray signals
biomedical applications enabled by liquid metal through injection (Fig. 3c) [53].
are introduced in this part and summarized in Table 4. The fabrica- In addition to X-ray and CT imaging, injectable liquid metal was
tion methods of liquid metal materials concerning these biomedi- found to be capable of photoacoustic imaging (Fig. 3d) [53]. Liquid
cal applications are summarized in Table 5. metal nanocapsules present the strongest photoacoustic signal at
680 nm, which are stronger than that of gold nanorods in the same
concentration. Further, researchers injected the nanomaterials into
3.1. Imaging
the lower back of the mice and found that the photoacoustic sig-
nal intensity and the concentration of these nanoparticles showed
As implanted foreign biomaterials, regardless of the therapeutic
a linear relationship. Enhancement of the PA signal was observed
effects or functions, the in vivo monitoring of all kinds of behaviors
in the tumor-bearing mice with anti-EGFR modified liquid metal
of such a dynamic organism is extremely important. These include
nanocapsules injection. Thus, a theranostic platform based on liq-
distribution, metabolism, and interaction with immune systems or
uid metal nanoparticles could be built both for fundamental re-
other organs such as liver, kidney, and target organs, etc., as well as
searches and clinic applications.
acquiring the knowledge of the implants not only for the implants
After being implanted in human bodies, these liquid metal-
at fixed locations but also for transformable materials, where the
based materials with varied sizes ranging from bulk to nanosize
surrounding environment could be more complicated. Understand-
presenting an instant capability of imaging under X-ray or CT, and
ing the knowledge of the in vivo behavior is vital for constructing
providing an easy method of observation in bodies regardless of
integrated materials of diagnostic and therapeutic, and is signifi-
the depth and spatial positions, would definitely benefit the use of
cant in fundamental research and clinic usage. Currently, the most
liquid metals. Furthermore, liquid metal nanoparticles with lower
common imaging technique for injectable hydrogels is to intro-
metal content and radiopaque ability would be hugely beneficial.
duce near-infrared (NIR) probes to perform fluorescence imaging.
As foreign materials, it is exceedingly vital to minimize injected
However, the penetration depth of near-infrared light is limited in
dose without sacrificing their contrast ability. So, further work
the biological body and the stability of long-time imaging is not
could concentrate on the problem to clarify the optimal doses.
enough for long-term investigation [39]. Therefore, in order to im-
On the other hand, it is the fact that X-ray radiation might harm
prove the detective depth, researchers develop radiopaque hydro-
healthy tissues under long exposure time. Thus reducing the dose
gels via adding iodine imaging contrast agent directly or crosslink-
or observation time of radiation would be significantly vital. Other
ing to the hydrogels, enabling X-ray and CT imaging with high spa-
imaging technologies like PA imaging can be combined with CT to
tiotemporal resolution and three-dimension imaging [129]. How-
achieve the aims of long-term monitoring.
ever, this requires a complex process of chemical modification to
obtain a stable imaging modality.
Liquid metals, considered as radiation-proof materials instead of
lead due to their high density, are fabricated into a stretchable film
10
Table 4
Summarized biomedical applications of injectable liquid metal.

Types of liquid metal Injectable Applied mode Device Injectable location Biomedical application Ref.

X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722
X-ray/CT Gallium/ Bi35 In48.6 Sn16 Zn0.4 alloy In situ injection Syringe Heart, kidney, Porcine femurs Monitor [43, 48]
EGaIn24.5 nanocapsules Caudal vein injection Syringe Caudal vein Monitor [53]
Photoacoustic imaging EGaIn24.5 nanocapsules In situ injection Syringe Lower back/Tumor Monitor [53]
Bone cement in tissue Bi35 In48.6 Sn16 Zn0.4 alloy In situ injection Syringe with a covered Porcine femurs Bone recovery [43]
engineering heater
Embolization agent Gallium Vessel injection Syringe Vessel Tumor therapy through [47]
nutrient deprivation
Biomedical electrodes Ga67 In20.5 Sn12.5 alloy Packaging in gelatin Syringe In the left side of the thorax ECG signal recording [9]
Biomedical electrodes EGaIn24.5 In situ injection Syringe Around tumor cells/Various Electrochemical tumor therapy [40]
cavities
Delivery of electric signal GaInSn alloy Around nerves Syringe The capillary pipette linking to Nerve connection [42, 206]
the distal sciatic nerve of frogs
or mice
Photothermal conversion EGaIn24.5 nanocapsules/Gallium Caudal vein injection Syringe Caudal vein Tumor photothermal therapy [37, 53, 202]
nanospheres/nanorods
Heating seed NaK alloy In situ injection Syringe with a In vitro tissue/tumors Hyperthermia of Tumors [55]
protective device
Smart robots Ga-In-Al In situ injection Syringe In vitro solution Cargo delivery [41]
Microfluidic pumps Galinstan droplet Direct injection Syringe Microfluidic channels Pumping of chemical solutions [181]
Smart robots Ga-In-Al In situ injection Syringe In vitro solution Cargo delivery [187]
Alginate modified Ga-In-Al/Nickel cap In situ injection Syringe In vitro solution Cargo delivery [50]
modified Ga-In-Al
Liquid metal conjugates droplet In situ injection Syringe In vitro solution Targeted recognition [51]
Nano-scale liquid metal Liquid metal In situ Syringe Vessel Drug delivery/Molecular [37, 52, 53]
biomaterials nanospheres/nanocapsules/nanorods injection/Intravenous imaging/Tumor
injection therapy/Transformable
nanomachine
Liquid metal hybrid through In situ injection Syringe Tumor Combined magnetic [45]
PEGylation hyperthermia and
chemotherapy
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 11

Table 5
Typical fabrication methods of liquid metal materials.

Types of injectable liquid metals Liquid metal size Fabrication methods Ref.

Gallium/EGaIn24.5 / Ga67 In20.5 Sn12.5 Bulk state Heating and stirring till thoroughly mixed [40, 43, 47, 48]
alloy
Mg-GaIn mixture Bulk state mainly stirring at 300 °C for 60 min [49]
Ga-In-Al Bulk state Through adding a film of Al flake to the Ga–In alloy [41]
EGaIn24.5 nanocapsules ~150 nm Through pulse-type sonication and photopolymerization [53]
Gallium nanospheres ~107 nm Through sonication [52]
Gallium nanorods ~250 nm Through sonication [37]
Alginate modified Ga-In-Al/Nickel Millimeter droplet Through adding a film of Al flake and coating a hydrogel cap with Ni [50]
cap modified Ga-In-Al
Liquid metal conjugates droplet Millimeter droplet Through conjugating the biomolecule to a self-assembled monolayer [51]
(SAM)
Liquid metal hybrid through Bulk state Mixing of liquid metal and PEG with a vortex mixer for 10 s [45]
PEGylation
Liquid metal droplets 172–590 μm Fluidic injection [207]
Liquid metal droplets Microdroplets-nanodroplets Flow-focusing injection [208-210]
Bi35 In48.6 Sn16 Zn0.4 alloy Bulk state Heated at 400 °C for 24 h to make the target alloy [43]
NaK alloy (1:1) Bulk state The same quantity of sodium and potassium are stirred in a glass with [55]
olive oil under nitrogen condition

3.2. Injection-enabled reversible transformable materials for tissue time of liquid metals would avoid possible shape change in vivo
engineering and minimize the damage to surrounding healthy tissues, which
could be favorable as bone cement. Compared to PMMA implan-
Bismuth-based and gallium-based liquid metals exhibit solid tation, they share the advantage of injection operation with min-
and liquid states respectively at room temperature due to the dif- imal invasion. While the removal of liquid metal can be operated
ference in melting points. After injection into the body, different through heating and suction, it is more convenient for the repair
mechanical support can be provided for varied application modal- process.
ities, including bone cement as supporting materials or embolic Since the melting point of this alloy cement is close to 60 °C,
agents in tumor therapy. which is significantly higher than the human body, the researchers
Extensive bone defects usually involve joint replacements. Al- injected this material into fresh porcine femurs and recorded the
though autograft is a gold standard in bone tissue healing, the lim- interface temperature with a thermocouple. They found that the
ited source of donation, donor site defect and long surgical time of time that temperature exceeded 44 °C was less than 1 min, which
surgery still remains the huge challenges [3]. Till now, bone ce- was acceptable for in vivo implantation. From the H&E staining re-
ment is widely applied in the total knee arthroplasty. Acrylic bone sults, no significant thermal damage to the surrounding bone tis-
cement, based on polymethylmethacrylate (PMMA) and formed in sues was observed (Fig. 4c, 4d). Therefore, the implanting process
situ through mixing prepolymerized powder with liquid monomer, would not harm to the surroundings. Furthermore, the alloy was
is mainly applied in cemented total arthroplasty [133]. However, transplanted in mouse for a two-week observation. From the im-
the temperature rise of the cement would cause burns of sur- mersion test, material corrosion of metals, which mainly refers to
rounding tissue and induce chemical necrosis via the unreacted zinc was detected within two weeks. As an essential element for
monomer release [134]. The complete polymerization would take the human body, the appropriate content release of zinc would be
a long time, and the mechanical property of the cement, such as beneficial to humans. While the long term corrosion detection of
tensile, bending and compressive strength, would be thus influ- the implants is still needed for other foreign materials like Ga, In,
enced [135]. In particular, the repairmen surgery, which is often and Sn. Moreover, long-term safety detection requires further eval-
required due to corrosion and wearing issues, would involve spe- uation.
cial instrument operation and injection techniques, including cut-
ting femurs and removing the femoral shaft. Yi et al. proposed 3.3. Injection of liquid metal for tumor vascular embolization therapy
a novel bone cement based on bismuth-based alloy with a melt-
ing point of 57.5 °C presented with a series of merits including The liquid metals’ characteristics of flow and phase change
injectable capability, high plasticity, short consuming time, sim- could also be applied to tumor treatment. As we know, tumor
ple operation procedure and facile repair process [43]. The viscosi- growth requires a large supply of oxygen and nutrients, which is
ties of this liquid metal at 74 °C and 95 °C are 4.0424 ± 0.0459 mainly delivered through blood vessels. So physical embolization
mPa•s, 3.5485 ± 0.0092 mPa•s respectively, which are significantly of tumor vessels offers an effective way to inhibit the rapid growth
lower than the viscosity of PMMA materials of about 20 mPa•s of tumors. For example, transcatheter arterial embolization (TAE)
in a specific range of operational temperature, making the oper- is utilized to prevent aneurysm rupturing via block blood supply
ation of suction and injection easier. After heating, the alloy in in the treatment of aneurysms [103]. Till now, embolism materi-
the liquid state would be formed into desired shapes in a short als contain metal micro coils, microsphere, and hydrogels [136]. To
time (Fig. 4a). For example, the process from injection to shap- improve their visibility, the study has been shown to incorporate
ing a stable scaffold entirely fitting with the inner cavity of bone several metal materials or organic materials into the embolization
takes less than 10 min (Fig. 4b). The solidification time of this agents [137], which increases the complexity of the preparation
bone cement from liquid to fully solid is only 2.93 min. The re- process. Wang et al. proposed that the room temperature liquid
searchers also defined the working time of the liquid metal alloy metal could be adopted as a novel embolization agent with excel-
material by curing time minus injection time, which was less than lent X-ray imaging capability and easy operation method via di-
2 min, much shorter than the working time of PMMA between rect injection (Fig. 5a) [47]. They injected liquid gallium into the
dough time and setting time. The short solidification and working rabbit ear vein at the rim and the tip. The temperature change
around the injection site was observed and captured by a thermal
12 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Fig. 3. The imaging capability of liquid metals. (a) X-ray angiograms of hearts with liquid gallium and iohexol (left) and plots of the grayscale along the horizontal lines
at five different heights labeled in the left (right). (b) Vasculature structure of a pig kidney filled with liquid gallium under X-ray irradiation. Reproduced with permission
[48]. (c) 3D-X-ray photos and sectional views of heart, brain and eyeball of a rabbit after injected with liquid metal nanocapsules. Red arrows indicate the laser-irradiated
sites. Dashed lines represent the location for cross-section views. Scale bars, 1 cm. Reproduced with permission [53]. (d) Antibody-functionalized liquid metal nanocapsules
(100 μg ml−1 ) in tumor site of living mice. Ultrasound (gray) and PA (red) images were taken through the tumor via 750 nm laser excitation. Reproduced with permission
[53].

infrared camera. The decrease in local temperature was observed studies also indicated that the formation of new blood vessels was
due to the retardation of blood flow and necrosis was found after typical in the tumors areas to maintain their aggressive develop-
several days. The cells near the blood vessels blocked by liquid gal- ment [138, 139]. So the embolism of single tumor vessel is not ef-
lium showed an abnormal morphology in the H&E staining results ficient in the complex system of tumor proliferation and invasion
(Fig. 5b). Further, the blood test of more than a week demonstrated [140]. Combination of the tumor embolotherapy with other tumor
the biosafety of the materials. Under X-ray, liquid gallium showed therapies such as chemotherapy, hyperthermia, or immunotherapy
a clear image, which was suitable for the integrated agent of di- might be the solution for a new generation of tumor therapies.
agnosis and treatment. The morphological change of cells and the
occurrence of necrosis indicates the initial therapeutic effect of liq-
3.4. Biomedical electrodes
uid metal embolism agent. While long-time retardation of tumor
growth in this method via embolism still needs more evidence.
With the development of materials and technologies, flexible
Embolism agent of varied types and sizes through liquid metal
electronics have arisen increasing interest in recent years with
integrating with other biomaterials should be introduced. Some
wide spread applications from e-skin, wearable devices to soft
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 13

Fig. 4. Liquid-solid phase transition enabled liquid metal bone cement. (a) A designed molding of alloy cement in the shape of “BONE”. (b) A photo showed a fresh porcine
femur filled with liquid metal cement and placed in a 37 °C water bath (left). The temperature-time plot during the injection process (middle). The H&E staining of bone
tissue surrounding the alloy cement (right). (c) The liquid metal alloy implanted into the subcutaneous site of mice after 3, 7 and 14 days, respectively. (d) The corresponding
H&E staining of tissue underneath the alloy cement, respectively. Reproduced with permission [43].

robots and logic circuits [141]. Inspired by organisms in nature, methods of fabricating soft electronics are to print traditional rigid
flexible electronic materials and devices are designed to mimic metal materials onto a thin film or manipulate them into nanopar-
human bodies, mollusks or physiological structures of various or- ticles on flexible substrates to achieve deformation such as bend-
ganisms, including highly elastic skin or muscle tissues [142-144]. ing, folding, twisting etc. [106]. In particular, special wavy and ser-
These kinds of elastic materials as physiological sensors have an pentine structures, as well as other origami structures, enable var-
advantage of eliminating the mismatch between the external de- ious conductive patterns on elastomer materials, textiles or even
vice and the skin. Till now, liquid metals have already been applied skins for flexible electronics [143, 145]. While due to the specific
as flexible electrical lines, conformable electrodes, interconnects structures and the fabrication techniques, the electrical conductiv-
or reconfigurable antennas, etc. Some novel conductive polymers ity would be decreased compared to the original bulk metals. On
are used in soft electronics, while the limited conductive prop- the other hand, the sophisticated devices, as well as etching tech-
erties hindered several practical applications. Till now, traditional nologies further increase the difficulty for large-scale production.
14 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Fig. 5. The illustration of liquid metal-based tumor vascular embolization. (a) The influence of no occlusion (left), incomplete occlusion (middle) and complete occlusion
(right) on oxygen and nutrition by liquid metal (the first row). The liquid metal could be injected into or sucked out of the vessel as desired (the second row). (b) The
occlusive effect of liquid metal embolization at the rabbit ears. The appearance of necrosis in the ear (left, top) and the temperature distributions after operation for 0 h,
24 h, 48 h and 72 h (left, bottom). The H&E staining of the control and necrosis tissues (right). Reproduced with permission [47].

What’s more, because of the limited stretchability and repeatability or stretching. So recent several years have witnessed increasing at-
of the electronics enabled by special structures, they are suscepti- tention and development of liquid metal materials in various print-
ble to mechanical fatigue, which could influence their functionali- ing and fabrication technologies. Liquid metals have exhibited out-
ties. standing effects and remarkable advantages in flexible electronics
In this regard, liquid metals have tremendous advantages, as multifunctional materials [125]. At the beginning, the high sur-
which attribute to the intrinsically soft core. Thanks to the water- face tension and low adhesion of liquid metals bring difficulties
like flowability, they are less susceptible to sacrifice much to the to pattern them on soft substrates or micro-channels. Then re-
overall structure and function after long-term curling, crumpling, searchers developed a series of preparation methods to decrease
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 15

the surface tension and to enhance the adhesive behavior of liquid configurations according to needs and preferences. Similar to the
metal materials, mainly through regulation of the oxidation degree method, Xin et al. dispersed liquid metal nanoparticles into sul-
to fabricate stably flexible and stretchable electronics. For example, fur polymers with self-healing ability, the as-made composites not
researchers directly injected liquid metals into hydrogel channel to only showed improved mechanical and electrical properties, but
fabricate ultra-soft electrodes with an enhanced ratio of signal-to- also enabled the characteristics of repairing [72]. While the self-
noise of ECG signals [146]. Filling liquid metals into roll-ball pen- healing property was mainly dominated by the polymer and it took
enabled homemade circuits available to the public and got popular a relatively long time to repair. In addition, researches involving
[147]. This direct writing electronics with liquid metal ink made composite of liquid metal and silicone elastomer accomplish auto-
it possible to fabricate flexible electronics directly on a polymer matic self-healing of electrical properties, which is of considerable
substrate with a line width of about 200 μm. There are other re- significance [153].
searchers who developed microcontact printing technology based Besides, liquid metals integrating magnetic particles such as
on liquid metals to realize the printing circuit on silicone elas- iron or nickel particles to enable magnetic liquid metals can also
tomer [148]. Through CO2 laser technology, conductive PDMS and be utilized in the controllable preparation of electronics in a non-
liquid metal ink could achieve direct printing on silicone elastomer contact way. For example, Ma et al. proposed an electronic fabri-
eliminating the time-consuming and laborious operations such as cation technique with magnetic liquid metals [65]. The prepared
photolithography [149]. Atomized spraying deposition technology magnetic liquid metals would produce more oxide in the mixture,
mainly utilized an airbrush and an air pump to spray a stream of which facilitated the adhesive to the substrate. Then through sim-
liquid metal microdroplets on different substrates. To design func- ple magnetic manipulation, it was easy to fabricate various circuits,
tional electronics, a steel mask through chemical etching should including paper, hydrogel, PDMS, Ecoflex, or even on the surface or
be prepared and tightly attached to the substrate to prevent mass in the inner space of 2D or 3D structures. In addition, magnetic
printing [80]. Wang et al. developed a dual-trans printing liquid field could also be adopted to easily control the movement of liq-
metal lines on elastomer substrates [150]. The mechanism involved uid metal droplets in solution or non-solution environments to ful-
transfer printing and low-temperature induced transition technol- fill complex missions such as fusion, deformation, drug delivery or
ogy of liquid metals. First, conductive circuits were fabricated on vessel clean [123, 124].
rigid PVC substrate with liquid metal printer followed with the Besides soft nature enabled high flowability, excellent electrical
procedure that a stretchable film was attached to the conductive conductivity makes liquid metal stand out among those flexible or-
surface and a freeze phase transition. Then the conductive circuits ganic biomaterials and play essential roles in stretchable electron-
can be successfully transferred to the stretchable film as a sen- ics, soft robotics, self-healing electronics and especially biomedi-
sor to collect physiological signals of humans. In addition, Guo cal electronics [26, 36, 72, 114, 154, 155]. The multifunctional mer-
et al. proposed the ideal of modifying liquid metal inks or choos- its of liquid metals render them with diverse applications includ-
ing highly adhesive substrates to prepare conductive electric cir- ing providing mechanical support through phase change, filling the
cuits [66, 67]. Various kinds of metal particles were mixed into liq- damaged cavity as well as recording and delivering electric sig-
uid metal inks to enhance both the electrical conductivity and the nals as biomedical sensors and stimulators [43, 156, 157]. Bene-
wettability on the substrates. Through rolling and transferring, re- fiting from their electrical characteristics, liquid metal electrodes
searches showed that semi-liquid metal inks could enable fast and are utilized to measure, acquire and transmit physiological signals
large-scaled fabrication of electronics on various substrates such as for aims of disease diagnosis, monitoring, and therapeutics. Gen-
PVC (polyvinylchlorid), PET (polyethylene terephthalate) and paper erally, traditional implanted electrodes or stimulators usually in-
etc. [67, 69]. Aided by highly selective adhesion materials, includ- volve massive operative wounds, amounts of medical expenses and
ing PU glue, PMA glue, liquid metal electronics could achieve fast uncomfortable feelings for patients. Other novel micro-injectable
preparation of smart fabrics, e-skins and e-tattoo etc. [66, 92]. electrodes usually require sophisticated technology and high oper-
In addition, Wissman et al. found that the adoption of two liq- ating skills. Liquid alloy, with advantages of transmitting electric
uid metal droplets could help to constitute a programmable elec- energy in high efficiency and an amorphous form, which would
tric switch [141]. The mechanism was to control the generation or greatly reduce the mismatch with biological tissues, offers promis-
the removal of the oxide on the surface to regulate the coales- ing potential as implants in practical applications. The researchers
cence and separation of liquid metal devices. Its applications on used liquid metal as a surface electrode to obtain the physiologi-
the traditional electronic industry show great significance and role cal EEG signal of the rat. The recorded ECG signals were basically
in future development of liquid transistor, data storage and logic the same as the conventional button electrodes (Fig. 6a) [158]. As
circuits. recording electrodes, liquid metals exhibit excellent performance
For soft and stretchable materials, it is inevitable to avoid cir- as the traditional ones. The operation of liquid metal is more com-
cuit breakage and instability induced by mechanical damage after fortable, and the shapes can be manipulated arbitrarily.
long-term deformation such as compressing, stretching, bending Most rigid metals implanted into tissues or organs often call for
and twisting. Therefore, materials with self-repairing function have open surgery, increasing the difficulty of operation and risk of in-
special significance, which can not only maintain the stability of fection. Small wounds would benefit both patients and doctors. Jin
the electronics, but also extend the lifetime of the circuits. Liquid et al. proposed a method of in situ fabricating three-dimensional
metals have been employed as unique self-healing materials based medical electronics via direct injection of liquid metal and packag-
on the excellent fluidity, electrical conductivity and multifunctional ing gel [159]. The in-situ fabrication of the biomedical electrode
properties in combination with other metallic or non-metallic ma- was accomplished through first injecting and forming a packag-
terials. ing gel with a reserved channel followed by injecting liquid metal
Li et al. fabricated a serpentine structure through injecting liq- into the cavity. The injectable liquid electrode was performed on
uid metals into PDMS (polydimethylsiloxane) and the conductive pork tissue. From the cross-sectional photograph, the domain pre-
materials showed with self-healing property after being cut [151]. sented a uniform distribution of liquid metal and the gel, where
Palleau et al. injected liquid metals into self-healing polymers to they were connected closely (Fig. 6b). The formed electrodes on
form self-healing and shape reconfigurable soft electronics [152]. the breast of mice were utilized to record electrocardio signal. The
When the circuit is broken by external damage, the broken part liquid metal electrode with 5 mm in length was formed with a
can be reconnected and then back to work normally. What’s more, tiny wound near the left upper arm of the mice. The recorded
it was also possible to assemble 2D or 3D connectors of different EEG presents with typical characteristics including a P wave, a QRS
16 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Fig. 6. Injectable biomedical electrodes for physiological signal recording. (a) ECG test and signals from a rabbit with a button electrode (top) or liquid metal electrode
(bottom). Reproduced with permission [158]. (b) The cross-sectional photograph of an injectable electrode within porcine tissue. (c) Experimental illustration of in vivo ECG
signal recording with an injectable liquid metal electrode. (d) Schematic illustration of the ECG recording and the recorded ECG signal of a mouse at 5 min and 10 min after
anesthesia. Reproduced with permission [159].

complex and a ST-segment (Fig. 6c, 6d). Besides, researchers also from the fact that the active region of a single electrode is limited
showed that the electrodes could serve as an electric stimulator to and irregularly large tumors would need plenty of electrodes. So
drive muscle contraction with a low voltage of 2 V to frog’s sciatic the treatment effect would be impaired and recurrent could ap-
nerve. As injectable implants, although large bulks of liquid metal pear. Considering those irregular cavities, liquid metal electrodes
in vivo can be sucked out with syringes, clearance of small residue through injection can be conformably filled into and shaped into
of materials would be considered. Regarding the possible leakage various morphologies eliminating the complicated fabrication pro-
issues, the packaging of liquid metals should be emphasized. Be- cess of rigid electrodes. In vitro results with injectable liquid elec-
sides biocompatible gelatin, other hydrogels or polymers with bi- trodes showed that through changing the shape of electrodes, tu-
ological compliance and elastic properties should be considered as mor destruction effect was significantly enhanced (Fig. 7b, 7c). The
packaging materials to reducing the direct exposure of implants to researchers also constructed in vitro experiments to systematically
tissues. compare the treatment effect of injectable liquid metal electrodes
Liquid metal enabled electrodes could also deliver a series of with the traditional Pt electrodes and discovered that liquid metal
electric energy to the tumor site for tumor therapy. Depending on electrodes would deliver more coulomb dose, induce more dra-
the different forms of electrical energy, there are two kinds of ther- matic pH change and produce more electrochemical toxic to fa-
apeutic modalities. One is tumor growth inhibition therapy with cilitate tumor destruction (Fig. 7a). Further, the in vivo animal ex-
alternating current, which was also termed as tumor treating fields periments showed that the amorphous electrodes presented a bet-
(TTFields) and the other is electrochemical tumor therapy with di- ter performance in tumor growth inhibition and lifetime extension.
rect current. The amorphous characteristics of liquid metal electrodes or these
The alternating electric field with a low density and interme- enabled flexible electronics should be extended to more extensive
diate frequency (10 kHz to 1 MHz) has shown to play a pos- applications from other methods of tumor therapies to devices of
itive role in influencing tumor growth via an anti-microtubule detection of physiological, chemical and mechanical signals of bio-
mechanism both in vitro and in vivo [160]. Studies on cancerous logical bodies.
cells, tumor-bearing mice and patients with recurrent glioblastoma
demonstrated the effectiveness of the TTFields [160-162]. The tu- 3.5. Facilitating the delivery of an electric signal
mor growth inhibition was observed and the survival time was
obviously prolonged. In order to solve the uncomfortable prob- Due to the limited regenerative capacity of neurons, central and
lem caused by these rigid electrodes, Li et al. proposed a liquid peripheral nerve diseases arose wide interests in fundamental and
metal-based spray-printing method to cover the tumor skin parts clinic fields [167, 168]. Nerve degeneration induced by peripheral
and conformably deliver the alternative frequency electric of 5 V nerve injury is usually considered as an irreversible process and
300 kHz to suppress tumor growth. Significant tumor volume re- might lead to further dyskinesia [169]. Although the advance of
duction was observed through this approach [163]. material and technology development in autografts, allografts and
Electrochemical tumor therapy employing direct voltage or cur- nerve conduits, the repair of nerve injury still faces enormous chal-
rent has been proven to be a very effective way for local tumor lenges such as limited donor implants, immunological rejection of
treatments [164, 165]. The mechanism of tumor damage lies in allografts and systemic immunosuppression [170]. Electric stimula-
three aspects, including electrolysis, electrophoresis, and electroos- tion has shown positive influence to facilitate nerve repair such as
mosis, which would produce serious pH change and toxic elec- using electric pulse stimulation in the treatment of drug-resistant
trochemical products around electrodes, further inducing dehydra- epilepsy [171], increasing numbers of both motor and sensory neu-
tion around anode and edema around cathode [166]. Liu’s group rons axon after tibial nerve injury [172], and improvements on
proposed to use amorphous liquid metal electrodes to substitute muscle strength and activity after stroke with cyclical electrical
traditional rigid electrodes with many merits, including arbitrary stimulation [173].
shaping ability, alleviating patient’s pain, avoiding the uncomfort- Liu’s group proposed for the first time to use eutectic GaInSn
able feeling, exhibiting great potential regarding those irregular serving as electric channels for the peripheral nerve function re-
tumors and complex cavities in digestive and circulatory systems covery with a number of apparent advantages, such as easy prepa-
[40]. Frequently, the ablation area in electrochemical tumor ther- ration and operation, favorable conductivity, high compliance and
apy is closely related to the arrangement of electrodes and the stretchability, which makes subjects feel comfortable under elon-
experience of the operator without any standardization stemmed gated or contracted force when the body moves [42]. First, the
nerve damage model was realized by using ophthalmic to cut the
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 17

Fig. 7. Injectable biomedical electrodes for tumor therapy. (a) Schematic design of EChT with rigid platinum (left) or liquid metal electrodes (right) in vitro. (b) Five therapeu-
tic method configurations with liquid metal electrodes in different shapes. (c) The cell viability of EChT under different configurations of liquid metal electrodes. Reproduced
with permission [40].

Fig. 8. Facilitation of the connection of electric signal from the transected sciatic nerve with injectable liquid metal. (a) The photograph of bullfrog’s body after GalnSn
alloy injection. (b) The electric stimuli signal and the recorded excitement signal from the intact nerve, the transected nerve connected with Galinstan or Riger’s solution,
respectively. (c) The proposed three kinds of nerve conduits for repairers of the injured peripheral nerve. They are nerve conduit with microchannels (left, top), with a shape
of thin slice (right, top), with concentric tubes (bottom). Reproduced with permission [42].

sciatic nerve on a bullfrog. The transected nerve composed of the would show promising advantages in the transmission of weak
proximal sciatic nerve and the distal sciatic nerve linked with gas- electroneurographic signals. In another study, Liu et al. utilized liq-
trocnemius was reconnected with a capillary pipette infused by uid gallium to repair the sciatic nerve of mammal [174]. The gal-
liquid metal with 3 cm in length and 0.5 mm in diameter to fa- lium was infused in the silicone rubber to facilitate nerve function
cilitate the electrical signal transmission (Fig. 8a). The liquid alloy through the connection the two stumps of the sciatic nerve of the
could be filled through syringe injection and recycled via aspiration mouse. Typically, after neurotmesis, the fiber activity of the den-
after treatment. Square wave electric signal was utilized to stim- ervated muscles would become abnormal. Fib was used to accu-
ulate the proximal part of the transected nerve, and electroneuro- rately detect denervation, the existence of which presents muscle
graphic signal on the distal nerve was recorded and compared with atrophy. The fib signal of the denervated muscles would usually
the sound signal. The electric signal from proximal nerve passing occur at about a week, indicating atrophy. While due to the en-
through liquid metal to the distal nerve was similar to those stan- hanced transmission of the nerve signal, liquid metal connected
dard signals than connection via Riger’s solution, which could in- muscles postponed the occurrence of atrophy until about eight
duce the contraction of the gastrocnemius where the transected weeks. This was also observed from the pathological photo of the
nerve linked (Fig. 8b). Since liquid metal is almost insoluble, it en- denervated gastrocnemius. Besides, they also proposed several ap-
ables high stability of transmission of neural signals without sig- proaches through combining conductive liquid metal with growth
nificant electric leakage phenomenon caused by the Riger’s solu- factors, Schwann cells, extracellular matrices or other scaffolds to
tion group. What’s more, due to the low impedance of liquid metal, promote the regeneration of the nerve tissues (Fig. 8c).
which is several orders lower than electrolyte solution, liquid metal
18 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Fig. 9. Thermal conversion enabled tissue ablation. (a) Schematic illustration of in vivo photothermal therapy with Mg-GaIn (liquid metal-doped magnesium particles).
Reproduced with permission [49]. (b) Photographs of liquid NaK alloy stored in kerosene and two types of the injector. (c) Photographs of the injection area and the burned
areas on a pork tissue. (d) Schematic illustration of administration on tumor site via injectable alkali alloy with protective devices. The transparent glass hood was placed on
the tissue to avoid splashing of alkali alloy and nitrogen gas keeps flowing into the hood as a protective gas under pressure on nitrogen bottle. Reproduced with permission
[55].

Irreversible nerve degeneration diseases, represented by this composite transformation into desired shapes and attached to
Alzheimer disease and Parkinson’s disease that is torturing more irregular surfaces even with a positive curvature without decreas-
and more aged people, remain one of the biggest challenges to ing its photothermal characteristic. As we know, Mg is considered
researchers in the whole world. Till now, no cure is found to as a biodegradable green material to humans. Further, the mix-
reverse the degeneration process of these diseases. Compared to ture was demonstrated with high biosafety. The soaking solution
chemical drugs, electric stimulation could serve as a more direct showed no influence on the cell viability under 48 h co-culture
and accurate method of manipulation. In the recovery process and cells were almost intact under the fluorescence microscope. In
of several axonal injuries, neurons might be more sensitive to vivo tumor ablation on mice showed a promising treatment effect
surrounding environments. The rigid metal implants might neg- on suppressing tumor growth and held great potential in future
atively influence axon growth. Thus highly flexible liquid metals tumor therapy. The plasticity and flowability constraint with each
with soft nature might play a decisive role during the recovery other. Therefore the injectable properties would be impaired with
process. In the complex nerve system where neurons respond to the improvement of the plasticity. So optimal proportion on liquid
both electric and chemical signals, the therapeutic methods should metal and the addition particles could be further confirmed in the
also be diverse and combined therapies with electric stimulation, dynamically balanced relationships. In addition, taking advantage
chemical agents, cytokines, or even involvement of neural stem of the high photothermal property of liquid metals, Fan et al. en-
cells should be considered for future studies. capsulated them into thermal responsive bulk polymeric hydrogels
to achieve rapid temperature rise and volume shrink of hydrogels
3.6. Thermal conversion in energy medicine [176]. Under laser irradiation, these liquid metal nanoparticles with
an average diameter of 530 nm could convert light energy into a
Hyperthermia, using local heat to induce ablation of tumor tis- large amount of heat. When the temperature exceeded the lower
sues, is a minimally invasive tumor therapy, including radiofre- critical solution temperature (LCST), the hydrogel would shrink to
quency, microwave and laser ablation, and so on. [175]. To enhance extrude inner water and molecular, which was expected to be ap-
heat distribution and transfer in the local region, materials with plied in combined hyperthermia and chemotherapy.
high thermal conductivity was employed in the therapy. Liquid Alkali metals are regarded as dangerous materials due to their
metals with multifunctional properties, especially favorable ther- high chemical activity. However, owing to their fast reaction speed
mal property compared to an aqueous solution, could further inte- and a large amount of heat release concerning the chemical reac-
grate with other materials to enhance their combined characteris- tion with water, alkali metals are demonstrated as a highly eco-
tic in conductivity in electric and thermal power as well as pho- nomical and efficient heating seed in tumor hyperthermia [38,
tothermal capability. For example, Wang et al. proposed a Mg-GaIn 177]. The chemical ablation, mainly acidic or alkaline solution, ap-
mixture possessed with favorable thermal conductivity, high plas- peared with minimal invasion and large ablation area was iden-
ticity, flexibility and biocompatibility serving as high photothermal tified as a useful tumor destruction method and the treatments
conversion materials, which can generate a large amount of heat have been tested on experimental animals [178]. Cressman et al.
under laser irradiation (Fig. 9a) [49]. Mg particles were doped into have also done a series of studies on the chemical ablation ef-
GaIn24.5 alloy to achieve conformable photothermal treatments of fect with weak acid and base, such as acetic acid, sodium per-
irregular surface tumors. Upon laser irradiation, this composite manganate, sodium hydroxide, ammonium hydroxide [179, 180].
exhibits noticeable temperature elevation. Flexible nature enables
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 19

The alkali metal therapy takes advantage of the heat release in cations of liquid metal self-driven pump and the liquid switching
the central region, while the resulting alkaline environment is also were proposed in an electrolyte system.
considered as additional chemical ablation to tumors. Besides, the These liquid metals enabled pumping or switching systems in-
metal cation products in this exothermic reaction are mainly Na+ volve the force analysis with regard to surrounding ionic environ-
and K+ , which serve as critical components in our biological flu- ments. The chemical activity and the formation of EDL on the sur-
ids. Rao et al. utilized NaK alloy as an injectable heating seed in face would determine the behaviors of liquid metal droplets such
both in vitro and in vivo thermal ablation of tumors (Fig. 9b, 9c) as rotating, locomotion and shape transformation. Taking advan-
[55]. The resulted ablation region was three times larger in vol- tage of the native chemical environment of the human body, it
ume than that of the injected metal due to the substantial thermal could be used as the source for more biomedical applications.
release. The relationships between injection speed and the tem-
perature rise, hydrogen production were also calculated theoreti- 3.8. Smart robots for cargo delivery
cally. It is noteworthy that the probable occurrence of the metal
splashes and sparks could be very dangerous and personal protec- Traditional drug targeted delivery methods usually involves
tion is necessary. A transparent glass mask should be placed on functionalized materials loading a certain amount of drugs or us-
the ablated tissue and connected with a nitrogen bottle, providing ing microcapsule to encapsulate drugs along with the blood flow
protective nitrogen gas and leaving room for gas outlet (Fig. 9d). or absorbed through the digestive system to specific regions. New
The hyperthermia therapy with injectable alkali metals as heating therapeutic approach employing the use of vascular robots inte-
seed should be reconsidered as effective tumor ablation method as grated with actuation, manipulation and biosafety features under
long as the protective devices are safe enough. the vascular surgery navigation is hopeful of accomplishing a se-
ries of operations including drug delivery, tissue cutting and sam-
ple collection [183, 184]. The power supply is critical in such a
3.7. Microfluidic pumps system, which is provided by a battery or wireless charging tech-
nology [185]. However, the limited capacity of the battery and the
Generally, liquid pumps involving the conversion of various ex- radiofrequency energy with the aid of an external electromagnetic
ternal energies, including electric, magnetic, chemical and heat en- field still need to overcome many challenges.
ergy into the actuated driving force of the liquid, display essen- Therefore, advanced biomaterials-based self-powered micro-
tial applications in energy, environment, biomedical signal detec- robots attracted considerable interest in the field. Especially many
tion, microfluidic system [84]. However, there remain many chal- studies discovered novel actuating phenomenon and allied mi-
lenges in the liquid pump system, such as the miniaturization of croactuators based on liquid metals [186]. For example, Gao et al.
the energy supply systems (especially simplifying the fabrication reported a water-driven micromotor prepared with Al–Ga binary
process), the transmission and conversion efficiency of the energy alloy and powered by the continuous hydrogen generation when
supply system and the flow rate. Especially the actuated device contacting with water [187]. The resulting Al–Ga/Ti micromotor
plays a critical role in the accurate detection of physiological or coated by Ti layer on one side is only about 20 um in diame-
chemical signals in microfluidic pumps. Liquid metal has already ter but could run at a speed of 3 mm s − 1 resulted from the
presented promising prospects as microfluidic channels, electrodes, driving mechanism of the hydrogen bubbles accumulation and
valves, sensors, and chip cooling in biomedical devices [84]. Fur- the directional propulsion thrust. In the different biological en-
ther, the combination of the surface electric double layer in elec- vironments, including PBS buffer, human serum, and cell culture
trolyte solutions and its soft feature enables the liquid metal to medium, the motor displayed excellent locomotion performance. In
exert potential value in the delivery of solution of drugs in mi- another work, Tang et al. observed the jumping behavior of liquid
crofluidic systems. metal droplet in three-dimensional space upon contacting liquid
For example, Tang et al. proposed a liquid pump based on a metal with solid metal [188]. This phenomenon was mainly trig-
droplet of Galinstan utilizing a dynamic electric field to actuate gered by the generation and accumulation of bubbles on the sub-
the flow of the solution (Fig. 10a) [181]. The electrowetting and strate, which was demonstrated with a trail of footprints. Zhang
de-electrowetting of the liquid metal surface lead to the contin- et al. discovered a liquid metal self-driving system that requires
uous conversion of electrical energy into mechanical energy. Liq- no extra energy supply after swallowing a piece of aluminum in
uid metal droplet forms an electric double layer on its surface in advance [41]. Further, the researchers analyzed the mechanism of
NaOH solution (Fig. 10b). The shift of electric charge on the sur- the self-actuated motion of liquid metals. When the aluminum
face happens under the influence of an external non-uniform elec- sheet contacted the liquid alloy, corrosion reaction would occur
tric field, which would further cause the imbalance of surface ten- and the aluminum sheet could be closely attached to the alloy.
sion according to Lippman’s equation and Young-Laplace equation To be specific, the oxide layer on the surface of aluminum sheets
(Fig. 10c). The surface tension difference on the two sides would would be corroded firstly to expose the inner aluminum. Then
generate a force to push liquid metal to the positive electrode di- the active aluminum further reacted with the NaOH solution and
rection, inducing the solution flow in the channel from the an- produced hydrogen, the formation speed of which is related to
ode to cathode direction, which was shown via a droplet of dye the concentration of the alkali solution. The heat generation in
(Fig. 10d). The imbalance pressure on the surface of liquid metal the chemical reaction would also contribute a bit to the forma-
provides a continuous force and liquid flow, which could also be tion and release of the gas. However, the gas alone is not ef-
explained by the continuous electrowetting of liquid metal. Zav- ficient to push the liquid metal to move. A galvanic cell would
abeti et al. utilized the chemical solution in the surroundings to automatically be formed between aluminum and liquid metal al-
induce the transformation and self-propulsion behavior of liquid loy where aluminum as the negative electrode and the alloy as
metal droplet (Fig. 10e) [182]. The designed device was composed the positive electrode and the inner electric field provided driv-
of two U-shaped channels filled with different ionic solutions and ing force to the whole body. Around the aluminum electrode, the
connected with a liquid metal droplet (Fig. 10f, 10g). The influence electroosmotic flow effect would also exert a force on the flex-
of the ionic imbalance on the capacitance of the electric double ible body. On the other hand, electrons continued to flow from
layer would lead to the pressure difference on the surface of liquid the aluminum sheet to the surroundings and the preferential sit-
metal, which was similar to the effect of the electric field. Further- uation of the reduction reaction was on the surface of the alloy,
more, based on the principle of the solution gradients, the appli- which would alter the charge distribution and unbalanced the sur-
20 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Fig. 10. Microfluidic pumps for delivery of solutions and drugs. (a) Schematic illustration of liquid metal enabled pump. (b) Schematic illustration of the surface charge
distribution of a liquid metal droplet in NaOH solution. (c) Schematic illustration of the surface charge distribution of a liquid metal droplet when an electric field is applied
between the electrodes. (d) Sequential snapshots of the pumping effect of a Galinstan droplet under a square wave signal (200 Hz, 5 Vp-p , 2.5-V DC offset, and 50% duty
cycle). At the same time, a droplet of dye is used to visualize the pumping effect. Reproduced with permission [181]. (e) Illustration on the top view of a liquid metal
droplet under dynamic ionic imbalance. (f) The schematic setup with two U-shaped open-top polymethyl methacrylate (PMMA) channels in parallel. The two channels carry
different types of electrolytes, which showed in different colors, acidic in yellow and basic in blue. (g) The actual experimental set-up and the close-up view. The scale bar
is 5 mm. Reproduced with permission [182].

face tension on the liquid metal surface. According to Lippmann’s to the moving and charged object. Further motion direction change
equation, the surface tension around the negative aluminum elec- was observed experimentally and most tiny motors were confined
trode is larger than the positive alloy electrode, where a high push- in the boundary zone under magnetic influence.
ing force would form to driving liquid metal motor forward. Be- Based on the self-powered motor, several biomaterials and
sides the researchers also analyzed several influential factors to drugs can be loaded and delivered to the designated loca-
the self-driving behaviors including solution concentration, viscos- tion. Zhang et al. loaded the alginate-based biomaterials to
ity, temperature and the content of aluminum etc. The average the self-driven liquid metal motor packaging nanoparticles as
speed of a tiny liquid metal machine in a circular petri dish could drugs through electroplating method, which could be manipulated
reach to 4.8 cm/s [189]. The duration of the continuous locomotion through the electric fields (Fig. 11a, 11b, 11c) [50]. The electric field
was more than one hour and the length was more than a hun- can also accelerate the speed. To precisely control the motion of
dred meter. This macroscopical self-motored movement at such a such a machine in the three-dimensional space, a nickel cap is fur-
large scale was very rare where liquid metals had great advantages ther modified on the surface to control the start, stop the locomo-
to tackle difficult tasks when considering complex shape trans- tion of the motor through the external magnetic field. Increasing
formation capability and long endurance. For the application of the velocity of the movement under the electric was also explored,
these motors in the biological system, the clearance of hydrogen which would play an important role in the biomedical device and
could be an issue to be considered. In the digestive system, they drug targeted delivery (Fig. 11d). The loading ability of liquid metal
can be expelled during flatulence or burping during the digestive alone was also studied. Liang et al. prepared a kind of fluorescent
process. liquid metal droplets like a transformable chameleon with locomo-
However, the movement direction of these motors is random- tion movement under external electric field stimulation (Fig. 11e,
ized or hard to change from their original orbits. Efforts on the 11f) [192]. The shape tunable liquid metal marble can release its
manipulation of the direction and speed of these systems include loaded nanoparticles on its surface in the electrolyte with a stim-
electric driving and magnetic controlling. For example, Tan et al. ulus.
attempted to utilize external electric to increase the driving capa- To improve delivery accuracy, with the aid of chemical modi-
bility of Al–Ga–In motor [190]. The speed was accelerated to about fication, Miyako and co-workers proposed a new strategy of liq-
43 cm s−1 under 20 V electrical stimuli and the movement tra- uid metal functionalization in the macroscopic scale, which en-
jectories were similar to the electric field lines. In another study, abled operation in a physiological environment [51]. The approach
researchers utilized an external magnetic field to restrict the lo- was executed through a self-assembled monolayer (SAM) coating
comotion of the self-moving motors [191]. In Al–Ga–In motor, the method, involving the formation of liquid metal conjugates via
galvanic cell would form between Ga–In and Al, and charge transi- 16-MHDA, which offers promising applications for molecular re-
tion and distribution would happen inside the motor. According to actions and might further mediate cell interaction. Based on this
the Lorentz force formula F=QVB, where the Q represents the elec- approach, fluorescence tags and other biomolecules like antibody
tric charge, V represents the speed and B represents the magnetic and enzyme can be assembled on the surface, enabling visualiza-
field flux density, the external magnetic field would impose a force tion, chemical reaction, and antibody-receptor interactions.
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 21

Fig. 11. Smart robots for cargo delivery. (a) The prepared hybrid droplets, the Hyd/EGaIn-Al droplet (left), the Hyd/Al/EGaIn-Al motor (middle) and the Hyd/Ni/Al/ EGaIn-
Al motor (right). Scale bar, 2 mm. (b) The Hyd/EGaIn-Al droplet movement under an external electric field. (c) The spatiotemporal evolutional photographs of a 50 μL
Hyd/Ni/Al/EGaIn-Al motor in 0.2 mol L − 1 NaOH solution. (d) The snapshots of the “stop and go” behavior of the Hyd/Ni/Al/EGaIn-Al motor under the magnetic field. Scale
bar, 15 mm (top) and the acceleration of the Hyd/Ni/Al/EGaIn-Al motor by an electric field. Scale bar, 15 mm (bottom). Reproduced with permission [50]. (e) The movement
of a fluorescent liquid metal marble under an external electric field of 15 V. The corresponding mechanism is illustrated schematically in the right. (f) Photographs of the
actuation of a fluorescent liquid metal marble. Reproduced with permission [192].

In addition, there are other methods to control the movement 3.9. Injectable nano-scale liquid metal biomaterials
of liquid metals. Hu et al. discovered that graphene could regulate
the electrons on the surface of liquid metals [112]. They demon- Ultrasonication offers a straightforward approach to disperse
strated that liquid metal amoeba could climb the hills against grav- liquid metal into nanoscale form, through which the liquid metal
ity under electrical fields. The mechanism lies in the modified elec- surface would be automatically covered by a slim oxide [116].
tron distribution and the unbalanced surfaced tension of the soft Many chemical molecules and biomolecules would readily bind
body of liquid metals. Then the larger surface force on one side of to its surface due to the thiolated ligands functionalization of
the electrical field would push liquid metal robots to move forward nanoparticles to enhance its biocompatibility, biostability and tar-
and constantly, which was large enough to overcome the gravity geting capability. The method would thus enable a series of appli-
of the earth. On the other hand, the extraordinary flexibility of liq- cations via in site injection or through intravenous injection, which
uid metals can be easily adopted as the biomimetic object of soft includes molecular imaging, targeted drug delivery, photothermal
robots. Chen et al. discovered that liquid metals exhibited special therapy and combined tumor therapy, based on which an inte-
serpentine locomotion in CuSO4 solution [193]. The mechanism grated theranostic platform can thus be built [194-196].
mainly lied in the chemical reaction between gallium and copper During the sonication process, Yamaguchi et al. systematically
ions, which could produce gallium ions and copper. The movement analyzed several influential factors such as power, duration, and
of electrons on the surface would then induce the surface tension temperature of sonication and the acid environment that have an
unbalance. In the redox process, the liquid metal was also discov- impact on the size of liquid metal nanoparticles [197]. The factors
ered with a phagocytosis effect to the newly formed copper, the of break-up and the coalescence provide two opposite forces and
presence of which was detected in the inner part of the mixture. contribute to the final size of these particles. Meanwhile, Hohman
This surface electron movement induced unique phenomenon dis- et al. emphasized the choice of the interacting ligand that might
plays promising aspects in self-growing circuits, ion detectors and facilitate the size reduction of these nanoparticles [198]. Based on
ion-motivated soft robots. the sonication approach, Lu et al. further designed a transformable
The realization of smart robots is of great value in biomedi- nanomedicine with a diameter of 107 nm that could actively tar-
cal fields, especially precision medicine. As mentioned above, liq- get to tumor site for drug delivery [52]. Liquid metal nanocapsules
uid metals have the potential to work as both transformable mo- prepared by Chechetka et al. with high biocompatibility and favor-
tors and cargo carriers, which are expected to achieve precise cell able biosafety were used for tumor photothermal therapy due to a
recognition and drug delivery via accurate functionalization. Till mass of heat release under NIR laser irradiation (Fig. 12a) [53].
now, the mechanisms of actuating these motors are being unveiled Generally, liquid metal nanoparticles usually present in a sphere
and the modification of liquid metals based on the understanding form due to the high surface energy, while the interaction with
of the formation of the oxide film is being refined via various ap- their surrounding environment would enable several chemical re-
proaches. These fabricated motors all show excellent performances actions and change the shapes of nanoparticles [199]. For example,
in a physiological solution environment, exhibiting the potential to Lu et al. proposed transformable liquid metal nanoparticles modi-
use in the blood circulation system or digestive system. Besides fied with GQDs, which can respond to the light stimulus, convert
small molecule drugs, protein drugs, genes or even cells might also the energy to dramatic morphological change from nanosphere to
be delivered in this way. nanorod and enable drug release to across the endosomal mem-
22 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Fig. 12. Injection-enabled nano-scale liquid metal biomaterials. (a) Liquid metal nanocapsule prepared via crosslinking of butadiyne moieties from DC(8,9)PC with 254 nm
ultraviolet irradiation. Reproduced with permission [53]. (b) The preparation route of the transformable liquid metal nanoparticles and their application scenery under light
irradiation, where the GQDs generate local heat and ROS, inducing the transition of gallium to GaOOH along with the shape transformation from nanospheres to nanorods.
Reproduced with permission [54]. (c) Schematic illustration of the construction process of the LM@MSN/DOX@HA liquid metal nanoparticles for integrated photothermal
and chemotherapy of tumors. Reproduced with permission [200]. (d) The preparation process of liquid gallium nanomachines via the pressure-filter-template method. (e)
Schematic illustration of the propelled motion of the asymmetric liquid metal nanomachines in the levitation plane through acoustic energy. (f) Schematic illustration of the
actively seeking and targeting of the liquid metal nanomachines to tumor cells and the subsequent photothermal therapy. Reproduced with permission [201].

brane barriers (Fig. 12b) [54]. The shape transformation was then From bulk to nanosize liquid metals, sonication provides an
demonstrated to be associated with the production of reactive oxy- easy preparation approach. With size decreasing, these particles
gen species (ROS) and GaOOH, which might facilitate further the are prone to be injected through syringes like biomedicine. On the
cargo delivery of other biomolecules or genes not just for drugs other hand, with the dose decrease, the biosafety of their biomed-
with enhanced endosomal escape. To further enhance the tumor ical applications might be enhanced. Further, several untraditional
therapeutic effect, Hu et al. improved the stability and photother- phenomena concerning shape transformation endow liquid metal
mal performance of liquid metal nanoparticles via mesoporous sil- nanoparticles with stimuli-response ability to light, temperature
ica coating strategy and combined the photothermal method with and chemical surfactants, which are beneficial for targeted cargo
chemotherapy for synergistic therapy (Fig. 12c) [200]. delivery and development of smart nanorobots.
Most of the studies reported the transformable phenomenon
of liquid metal particles from nanospheres to nanorods via chem-
ical reactions. While a fusible nanomedicine from rodlike to 3.10. Liquid metal composite enabled biomedical applications
nanosphere via the remove of gallium oxide layers was proposed
by He’s group [201], they demonstrated a liquid metal nanoma- Magnetic-mediated tumor hyperthermia, usually involving the
chine prepared through a pressure filter method and presented use of magnetic nanoparticles, attracted increasing interest as a
with a liquid metal core and an oxide shell, which enables ac- useful tumor destruction method [203, 204]. Without the penetra-
tive movement under ultrasound driving. This pressure-filter tem- tion limits of the NIR laser beam, the electromagnetic field could
plate approach provides an easy way of shaping the size and shape cover the three-dimensional space and reach those located deep
of these nanorods that can be tuned through regulating the fil- in the body with no restriction, which is hard by other means.
ter templates (Fig. 12d). Stemmed from the asymmetric shape of Based on this, Zhao et al. tested the inductive heating property of
the nanorod machine in two ends, the acoustic wave would offer liquid metals and discovered that the non-magnetic liquid metal
a driving force to facilitate the movement of these nanomotors to could produce a large amount of heat under the alternative mag-
designated sites like tumor cells in a much precise way (Fig. 12e). netic field (AMF) [45]. Based on this phenomenon, they designed
Interestingly, the entrance of these motors into HeLa cells and the an injection-enabled liquid metal hybrid material via a PEGylation
active transformation into a droplet were observed in experiments. method, showing superior advantages for combined magnetic hy-
Through laser irradiation, these motors enable photothermal ther- perthermia and chemotherapy (Fig. 13). The prepared materials en-
apy of tumor cells, which hold great potential in biomedical ap- dow with CT imaging capability in vivo and at the same time, en-
plications (Fig. 12f). Liu’s group and other researchers systemat- ables stimuli-responsive drug release upon both pH and AFM dual
ically compared the nanoparticles with different constitutes and stimulation. This multifunctional tumor therapy enabled by this
shapes, further demonstrating that the nanorod exhibited better amorphous liquid metal would open up the huge potential for fur-
photothermal performance and tumor destructive effect [37, 202]. ther theranostic applications. Actually, other polymers or hydrogels
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 23

Fig. 13. Schematic illustration of the synergetic treatment of hyperthermia therapy and chemotherapy in breast cancer with liquid metal and drug-loaded mesoporous silica
hybrid (DOX-MS/LM). Reproduced with permission [45].

can also be considered as injectable materials for tumor therapy or 4.1.2. Injection for 3D printing
combined therapy [205]. 3D printing technology attracts broad interest in recent years,
which usually involves materials like polymers [212]. Generally,
4. Injection-enabled technologies and allied devices due to the limitation of high melting points, traditional metals re-
quire complicated procedures and sophisticated equipment in 3D
Due to the use of liquid metal involving various types and printing. Metals or alloys with melting points lower than 300 °C
sizes, the fabrication of liquid metal materials would thus be clas- and higher than room temperature, allowing constructing free-
sified according to specific applications. In this part, we concen- standing stable structures, would innovate the field and be used
trate on a discussion about the injection-enabled liquid metal fab- in the fabrication of conductive 3D objects or biomaterials. Wang
rication technologies and allied devices, including direct injection et al. proposed a 3D printing technology in liquid phase with
for preparing bulk liquid metal materials and 3D printing meth- bismuth-based liquid metal as alloy ink and provided the model
ods, fluidic injection, and microfluidic flow-focusing injection for of the corresponding device (Fig. 14a) [99]. Liquid cooling with
preparing microscale and nanoscale liquid metal droplets. water or ethanol is adopted to fasten the cooling rate and pre-
vent over oxidation in the air for liquid droplets. To avoid solidi-
fication of the Bi35 In48.6 Sn15.9 Zn0.4 alloy, an aluminum alloy jacket
4.1. Injection of bulk liquid metals
was covered outside of the injection tube, heated by a constan-
tan resistance wire and monitored with a temperature controller.
4.1.1. Direct injection
A nitrogen cylinder provided the pressure for pushing out the liq-
It is straightforward to use a syringe to directly inject into in
uid metal ink into the liquid cooling pool. Several two or three-
vivo defects to form amorphous shapes conformably filling into the
dimensional structures were successfully fabricated via this liquid
irregular sites or into microfluidic channels to form electrodes. Sev-
injection technology, including rods, cone and cylinder objects. Im-
eral studies are utilizing liquid metal electrodes to stimulate the
portant factors including the types and temperature of the cooling
activity of neural cells [211].
fluids, air pressure in the syringe, the inner diameter of the nee-
While if the operation involves liquid metal with high melting
dle, injection speed and the natural properties of the alloy ink that
points, the specific device is needed to guarantee the process that
have an impact on the size of resulting droplets and the structure
the bulk liquid metal is heated up and kept warm at constant op-
were also discussed. To improve the properties of the fabricated
eration temperature in a liquid state and on the other hand, the
objects, the ink could adopt gallium-based, bismuth-based, or liq-
injection syringe can withstand the high temperature. For example,
uid metal composite either with other metal particles or combined
Yi et al. proposed a scheme of a tailor-made syringe composed of a
with other nonmetal materials [213]. Further, a schematic descrip-
syringe and a heating cover to regulate the temperature of the in-
tion of the future liquid metal 3D printer was illustrated with a
ner liquid metals [43]. This method ensures injecting liquid metal
syringe needle array and a computer to adjust and regulate the
in a liquid state and filling the in vivo cavities. While the injected
whole fabricated process (Fig. 14b). This novel approach provides
liquid metal will experience a solidify process during which they
an easy fabrication way for constructing 3D liquid metal biomate-
can be shaped into different morphologies. Making full use of this
rials, which could be very useful in the future biomedical applica-
solidification process, 3D printing of liquid metal objects is easy to
tions.
achieve.
24 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Fig. 14. 3D printing devices. (a) Schematic illustration of the experimental apparatus used in 3D liquid metal printing. (b) Schematic illustration of the injection needle array
of future 3D printer. Reproduced with permission [99].

4.2. Preparation of liquid metal droplets tion to prepare microspheres [207]. Compared to water or oil sys-
tem, when ejected from a small aperture, liquid metal with high
Preparation of liquid metal droplets in varied scales from mil- surface tension would quickly break up into microdroplets under
limeter to nanometer, displays versatile roles in diverse biomedi- the effect of Plateau-Rayleigh instability [217]. The injection de-
cal applications, including flexible electronics, bioelectrodes, elec- vice composed of three parts, including a syringe filled with liquid
trochemical sensors, microfluidic pumps, valves, switches, soft mo- gallium, an aqueous solution, and a petri dish to collect droplets
tors, 3D microelectrodes or 3D materials, micro-electro-mechanical (Fig. 15a). In order to prevent the collision and coalescence of these
systems (MEMS), catalysts, drug delivery and tumor therapy [84, microdroplets into large ones, different surfactants are added to
156, 214, 215]. Due to the unique soft nature, which is different the solution to stabilize the droplets. Through injection, a large
from the synthesis of most rigid nanomaterials from the molecular number of droplets could be prepared readily. Through observa-
level, the preparation of liquid metal droplets or nanoparticles pri- tion with a high-speed camera, the formation process of the liq-
marily adopts top-down methods, which includes direct injection, uid metal droplets would go through five procedures, including
flow-focusing, mold patterning, shearing liquids into complex par- a stream, neck appearing, shuttle shape, irregular and spherical
ticles and sonication with the aid of syringes, microfluidic devices shapes.
or ultrasonic equipment to provide disruptive force [216]. In this Further, several key factors, such as the size of the pinhead,
section, we focus our interest on the injection-enabled technology viscosity, and density of the fluid solution, injecting velocity and
for droplets fabrication in varied sizes and emphasis syringe nee- types of the surfactants are also analyzed and discussed. The di-
dle or capillary injection, on-chip flow-focusing ejection in the mi- ameters of droplets would decrease with the increase of the flow
crofluidic system and their allied devices. velocity and reduction on the inner size of the needle. By using
a needle with different diameters, the average droplet size var-
4.2.1. Fluidic injection ied between 172 μm and 590 μm (Fig. 15b, 15c). The resulting
To accomplish large-scale liquid metal droplets fabrication, Yu droplets can be stored for a long time when solidified under low
et al. utilized a syringe, taking advantage of the autonomous break- temperature. The droplets fabricated in this way can be used to
ing behavior, to directly inject liquid metal into an aqueous solu- form a porous metallic foam, which may have potential applica-
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 25

Fig. 15. Methods and devices of fluidic injection. (a) Device for the fabrication of liquid metal droplets with a syringe. (b) Photograph of liquid metal droplets fabricated
via a syringe with a pinhead of 0.41 mm (left) and the diameter distribution of the sample (right). (c) Photograph of liquid metal droplets fabricated via a syringe with
a pinhead of 0.41 mm (left) and the diameter distribution of the sample (right). Reproduced with permission [218]. (d) A large number of small liquid metal autonomous
running motors. Reproduced with permission [89]. (e) Schematic illustration of the electro-hydrodynamic shooting device, the droplet motion (left, bottom) and the force
analysis (right, bottom). Reproduced with permission [219].

tions in battery fabrication and thermal management. Using this 4.2.2. Microfluidic flow-focusing
method, Sheng et al. fabricated thousands of tiny running motors The flow focusing method has been widely used in applica-
in NaOH solution through direct injection of the freedom running tions, including the analysis of the fluidic property and the produc-
large droplets (Fig. 15d) [89]. This direct injection method has a tion of the microparticles. To produce liquid metal droplets with
variety of advantages, such as low cost, high efficiency, and sim- smaller size and monodispersity, a flow focusing method was pro-
ple operation. While the large size distribution span a wide range posed based on liquid metal and another one or two immiscible
caused by the uneven injection velocity and the limited needle size continuous-phase solution going through a microscale orifice in
might restrict its applications. PDMS-based microfluidic devices [208]. Thelen et al. designed a
To further reduce the physical labor, an electro-hydrodynamic microfluidic device with two inlets for liquid metal and a mixture
method was proposed by Fang et al. to substitute the mechani- of glycerol and water, and one outlet for droplets production [209].
cal efforts by hands with electric energy (Fig. 15e) [219]. The cath- Three stream fluids focused on the flow focusing orifice and the
ode of the DC charge was connected with a liquid metal container central liquid metal stream would be broken into small droplets
and the anode was linked with the NaOH solution. Then a cap- and pushed to flow forward by the other two streams (Fig. 16a).
illary tube filled with liquid metal served as a bridge of the two Results have shown that the formation of oxide film on the sur-
fluids. Under the non-uniform electric stimulation, the charge dis- face and the additive PVA-doped surfactants in the continuous-
tribution on the surface of the liquid metal would change, push- phase stream play an important role in stabilizing these micro-
ing liquid metal to transform and move forward to the anode. Due spheres (Fig. 16b). Through removal of the oxide skin, these liq-
to the high surface tension, liquid metal would quickly form into uid metal droplets can be recycled and reused. Taking advantage
a sphere state in NaOH solution. The automatic ejection of liquid of the oxide skin, Hutter et al. successfully prepared non-spherical
metal was observed from cathode to anode. droplets with a micro-rice morphology covered by a rigid skin
Further, the influence of the capillary size, the magnitude of [220]. Through regulating the recipe of silicone oil, shape tun-
voltage on the ejection velocity and the resulting sizes of the able microdroplets can be easily fabricated with a microfluidic ap-
droplets was also discussed. This electro-hydrodynamic method proach, which holds potential prospects in MEMS devices.
presents a new approach of continuous fabrication of discrete liq- However, due to the influence of high interfacial tension, liq-
uid metal droplets in a large quantity under a low voltage. The uid metal droplets were usually formed with another high viscos-
droplets’ size was highly dependent on the capillary nozzle, which ity continuous-phase fluid and extra efforts are paid on in separat-
potentially provides a way to decrease the size of droplets. ing and transferring droplets to an aqueous solution for further us-
26 X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722

Fig. 16. Methods and devices of microfluidic flow-focusing. (a) A typical micrograph of a flow-focusing device. Three streams composed of the liquid metal stream and
two continuous-phase solution are forced to an orifice to produce liquid metal droplets. (b) The prepared liquid metal droplets (b1) and the time-lapse photographs of
these microspheres stabilized by an oxide skin and PVA after addition of HCl, t = 2 min (b2), t = 22.5 h (b3), and sample after centrifuging for 1 min at 20 0 0 rpm
(b4). Reproduced with permission [209]. (c) Schematic illustration of the microfluidic chip for continuous generation and transfer of liquid metal droplet to NaOH solution.
(d) Photographs captured via high-speed camera recorded the transition process of Galinstan droplet from glycerol into NaOH solution, including approach (d1), reaching
the interface (d2), deforming when crossing the interface (d3, d4), transferring into NaOH flow (d5, d6). Reproduced with permission [221]. (e) Schematic illustration of a
monolithic chip combined the process of continuous production of Galinstan microdroplets in glycerol and transferring into secondary liquid. Scale bar is 200 μm. Reproduced
with permission [223]. Schematic illustration of the on-chip nanoparticle production platform (f) and its working mechanism under acoustic waves that the microdroplets
are formed at the T-junction and later gradually broken into nanoparticles when travelling along the microchannel (g). (h) Snapshots of the formation and the subsequent
breaking down of a microdroplet into nanoparticles with time within the microchannel. The scale bar is 1 cm. (i) The proposed scheme of the conjugation between bPEG
molecules and EGaIn particle. (j) TEM photographs of the EGaIn nanoparticles coated with bPEG. Reproduced with permission [210].

age. To solve this issue, Gol et al. designed a monolithic chip com- hydrodynamic force and the surface tension play a crucial role in
bined with the process of continuous production of Galinstan mi- transferring across the fluid-fluid interface [222].
crodroplets in glycerol and transferring into secondary liquid like To achieve variable sizes of droplets with fixed microfluidic de-
NaOH solution (Fig. 16c) [221]. High-speed photos have shown that vices without changing the viscosity of the continuous fluid and
liquid metal droplets could approach and transit from high viscous the flow rates, Tang et al. proposed a novel idea to quickly regulate
fluid to a low viscous solution due to the existence of the hydro- the interfacial tension of the liquid metal through electric stimula-
dynamic force (Fig. 16d). Theoretical simulation, as well as experi- tion (Fig. 16e) [223]. The mechanism was revealed via the electro-
mental results also demonstrated that the critical factors including chemical and electrocapillarity effect to modulate the resulting size
X. Sun, B. Yuan and L. Sheng et al. / Applied Materials Today 20 (2020) 100722 27

and the microdroplets with a diameter smaller than the width of development, single treatment model is not enough to destroy the
the orifice were first fabricated in this technique. whole tumor. Synergistic treatment model of occlusion therapy,
Generally, the formation of liquid metal particles requires the chemotherapy, photothermal therapy and radiotherapy should be
use of a high viscous fluid, offering a shearing force to pinch off considered in future tumor treatment. In particular, compared to
the liquid metal stream. In order to improve the fabrication pro- bulk liquid metal, micro/nano-scale liquid metal particles with de-
cess directly in aqueous solution, Tang et al. employed an ultra- sirable characteristics, rendering them accessible to hybrid or form
sonic bath providing extra oscillating shear force to facilitate the conjugation with other non-metal materials, are suitable to ac-
formation process of microdroplets without the need of the high complish the theranostic function and the combined therapy es-
flow rate and the high viscous liquid (Fig. 16f, 16g) [210]. With the pecially tackling complicated issues. In this way, we believe that
flow of the continuous phase fluid, the microdroplets would fur- micro/nano-scale liquid metal particles would be doomed to dis-
ther be broken into nanodroplets in a serpentine-shaped channel play a crucial part for various biomedical applications. Till now, the
under the effect of acoustic waves (Fig. 16h). Through conjugating fabrication method via sonication would lead to a wide distribu-
with trithiocarbonate groups on the bPEG polymers, liquid metal tion range and particle size is hard to achieve below 100 nm. From
nanoparticles are enabled biostability and biocompatibility, mak- this point of view, the improvement of the uniform distribution in
ing it easy for further functionalization with other molecules like smaller sizes and separation method calls for new technology and
fluorescence group or antibody, thus providing a nanoplatform for more endeavors.
further biomedical applications (Fig. 16i, 16j). Last but not least, the toxicity issue is always an essential fac-
Compared to fluidic injection, the microfluidic flow-focusing tor for implants. Several studies till now have demonstrated the
method enables the production of liquid metal droplets with more biosafety of bulk liquid metal and nanoparticles. However, research
uniform distribution and smaller size from micrometer to nanome- on the long term influence of foreign materials on the human body
ter. The prepared microfluidic device and several influence fac- is still lacking. Mainly, materials and the accompanying affected
tors, which might affect the resulting size of liquid metal droplets characters regarding electrical and mechanical aspects under var-
should be noted. Especially, electric field exerts as a positive tuning ious perturbations of physiological change still need a series of re-
force to the size of liquid metal. searches to test and give clear evidence.
Overall, along with the outstanding advantages, recent advances
5. Discussion and perspectives and injection-enabled biomedical applications, technologies, and
devices based on liquid metal alloys are systematically reviewed
With various combined advantages of leading electrical, ther- and interpreted. It is expected that such novel materials and their
mal, mechanical, biosafe and in particular injectable merits, liq- allied technologies would play an ever increasingly important role
uid metal enabled injection technology shows promising prospects in future biomedical and biomedicine fields.
in broad diagnosis and therapeutic areas and would innovate the
biomedical fields. As surveyed above, liquid metals have displayed Declaration of competing interest
diverse applications in tissue engineering, bioimaging, nerve con-
nection, thermal conversion, microfluidic pumps and smart robots The authors declare that they have no known competing finan-
and so on. However, opportunity accompanies with a challenge. cial interests or personal relationships that could have appeared to
This novel technology still faces many challenges ahead. For ex- influence the work reported in this paper.
ample, in the fluidic injection, the operation is mainly achieved by
hands and the fact that the injectable speed and the uniform of the Acknowledgments
liquid metal stream are hard to be guaranteed in this way needs
further investigation. So the development of more sophisticated This work was financially supported by the National Natural
and reliable devices is of great urgency. It is the truth that the Science Foundation of China Key Project under Grant No. 51890893
injection provides a straightforward approach. However, accuracy and 91748206, the National Natural Science Foundation of China
should not be sacrificed in this way. The oxide skin offers liquid (No. 81701850), the China Postdoctoral Science Foundation (grant
metal with the possibility to shape its morphology and regulate number 2018M641486), the Key Laboratory of Cryogenics Foun-
the mechanical property. While the slim film would increase the dation of TIPC, CAS (No.CRYOQN201709), the Frontier Project of
viscosity and make it adhere more easily to the inner wall of the the Chinese Academy of Sciences, the Presidential Foundation of
needle, thus decreasing the precise dose due to the residue. One the Chinese Academy of Sciences, the Beijing Municipal Science &
possible solution is to remove the oxide skin before injection via Technology Commission research fund (No. Z17110 0 0 0 04170 04).
acidic or alkaline solution. Of course, fabrication of injectable sy-
ringe integrated with chemical pretreatment or oxygen resistance References
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