Liquid metal biomaterials: translational medicines, challenges and perspectives

Abstract

Until now, significant healthcare challenges and growing urgent clinical requirements remain incompletely addressed by presently available biomedical materials. This is due to their inadequate mechanical compatibility, suboptimal physical and chemical properties, susceptibility to immune rejection, and concerns about long-term biological safety. As an alternative, liquid metal (LM) opens up a promising class of biomaterials with unique advantages like biocompatibility, flexibility, excellent electrical conductivity, and ease of functionalization. However, despite the unique advantages and successful explorations of LM in biomedical fields, widespread clinical translations and applications of LM-based medical products remain limited. This article summarizes the current status and future prospects of LM biomaterials, interprets their applications in healthcare, medical imaging, bone repair, nerve interface, and tumor therapy, etc. Opportunities to translate LM materials into medicine and obstacles encountered in practices are discussed. Following that, we outline a blueprint for LM clinics, emphasizing their potential in making new-generation artificial organs. Last, the core challenges of LM biomaterials in clinical translation, including bio-safety, material stability, and ethical concerns are also discussed. Overall, the current progress, translational medicine bottlenecks, and perspectives of LM biomaterials signify their immense potential to drive future medical breakthroughs and thus open up novel avenues for upcoming clinical practices.

Keywords: clinical device; healthcare; liquid metal biomaterials; therapeutics; translational medicine.

Figure 1.

The clinical applications and translational medicine continuum of LM biomaterials. (a) Clinical applications of LM biomaterials in three fields: monitoring and imaging, tissue repairing, and tumor therapy. Monitoring and imaging applications include (i) LM healthcare monitoring devices (ii) LM biomimetic eyes (iii) LM intravascular contrast agents; Tissue repairing applications include (iv) LM external fixators (v) LM bone cement (vi) LM exoskeleton (vii) LM nerve interface (viii) LM deep brain stimulation; Tumor therapy applications include: (ix) LM vascular embolic agent (x) LM-based targeted drug delivery (xi) LM skin patch (xii) LM-enabled hybrid hyperthermia and cryoablation therapy. (b) Translational medicine continuum of LM biomaterials including innovation, implementation, pre-clinical test and early/late phase clinical trials.

Figure 2.

LM wearable electronics for healthcare. (a) Clinical monitoring devices: ECG monitors and ultrasound, pictures from Tsinghua Changgung Hospital. (b) Schematic view of the 3D-printed LM-based pressure sensor and its flexible tests [11]. Copyright 2020 John Wiley & Sons. (c) Schematic design of the LM-based wearable and self-healing electronic device (iMethy) for monitoring of methylated circulating tumor DNAs (ctDNAs) [17]. Copyright 2022 John Wiley & Sons. (d) LM particles with robust wear resistance for skin electronics [19]. Copyright 2022 American Chemical Society. (e) LM electrode for wearable ultrasonic device [12]. Copyright 2023 Springer Nature. (f) The intelligent electronic skin network based on the LM [20]. Copyright 2018 Springer. (g) Biomimetic eye based on LM, modified from [25]. (h) Schematic diagram of commercial eye tracker. (i) LM coil embedded in PDMS on the artificial eyeball, and adhered to a water-filled balloon to show flexibility [27]. Copyright 2018 IEEE.

Figure 3.

Applications of LM in the field of medical imaging. (a) Comparison of contrast effects between angiograms with LM gallium and conventional agent iohexol under X-ray irradiation [29]. Copyright 2014 IEEE. (b) Illustrated scheme of the injection process of Ga particles solution into the animal body, X-ray images and reconstructed micro-CT 3D models of rat kidney with GaPs perfused into blood vessels [30]. Copyright 2021 Elsevier. (c) The structure of CT assistant localization marker and the usage on rabbit [31]. Copyright 2020 Royal Society of Chemistry. (d) Pseudo color MRI images of T1 WI and T2 WI of the rabbit ears in embolization (right) and control (left) groups [32]. Copyright 2022 John Wiley & Sons. (e) LM particles for CT and MR dual-mode imaging [33]. Copyright 2020 John Wiley & Sons. (f) Ultrasound image of ear auricular artery with embolization (red circle: SA/LM/DOX microspheres in the artery) [35]. Copyright 2023 John Wiley & Sons. (g) US, PA and 3D imaging of tumor treated by antibody-functionalized LM nanocapsules in living mice [36]. Copyright 2017 Springer Nature.

Figure 4.

Applications of LM in orthopedics. (a) Clinical materials for bone repair: gypsum mortar (above) [39], and high-viscosity PMMA cement ready for implantation in the cavity left by debridement (below) [40]. Copyright 2022 Elsevier. (b) LM-based orthopedic external fixators, pictures from Yunnan Maiteli Medical Company. (c) The transverse and coronal sections of CT slice with LM-based bone cement inside and general observation of subcutaneous implantation of LM-based bone cement in mice after 7 days [41]. Copyright 2014 Elsevier. (d) Illustration of Bi alloy-based bone defect filling and analgesia [42]. Copyright 2021 John Wiley & Sons. (e) Exoskeleton in clinics for training people with disabilities, pictures from Beijing Tsinghua Changgung Hospital. (f) Schematics of exoskeleton system [49]. Copyright 2021 Springer Nature. (g) Prototype of the flexible mechanical joint based on a low-melting-point alloy [50]. Copyright 2014 American Society of Mechanical Engineers.

Figure 5.

Applications of LM in nerve interface. (a) Three kinds of nerve conduits to repair the injured peripheral nerve, and the photograph and plain radiograph of bullfrog's lower body after injecting GaInSn alloy [56]. Copyright 2014 arXiv. (b) Schematic diagram of LM nerve electrode and pictures of electrodes implanted into the bullfrog sural nerve and tibial nerve [58]. Copyright 2017 Institute of Physics Publishing. (c) The positions of LM cuff electrode and EEG electrode array inside the rat body, and graphical representation of sciatic nerve signals and EEG after stimulation with bipolar pulses in freely moving rats on a treadmill [59]. Copyright 2022 Elsevier. (d) LM-based probe with variable stiffness [61]. Copyright 2019 Science. (e) Schematic diagram of deep brain stimulation device [62]. Copyright 2022 Elsevier.

Figure 6.

LM for tumor therapy through vascular embolization and drug delivery. (a) Schematic diagram of clinical liquid/solid vascular embolization. (b) Injectable LM [32]. Copyright 2022 John Wiley & Sons. (c) The principle illustration of LM-based tumor vascular embolization therapy [69]. Copyright 2014 arXiv. (d) The injectable liquid embolic agent enabled tumor embolization and hyperthermia [32]. Copyright 2022 John Wiley & Sons. (e) Illustration of the component of a transformable LM nanocapsule, optical control of LM nanocapsules transformation, and TEM images of laser-induced morphological changes in LM nanocapsules [36]. Copyright 2017 Springer Nature. (f) Schematic design of the pH-driven transformable LM-based delivery system [75]. Copyright 2015 Springer Nature. (g) Illustration of SA/LM/DOX microspheres for chemical therapy and artery embolization [35]. Copyright 2023 John Wiley & Sons.

Figure 7.

LM for tumor therapy through hyperthermia, cryoablation, and electrical stimulation, vascular embolization and drug delivery. (a) Clinical hyperthermia equipment, picture from Tsinghua Changgung Hospital. (b) Mg-doped LM for skin tumor photothermal therapy [78]. Copyright 2018 John Wiley & Sons. (c) Illustration of core-shell GaIn@Pt heterogeneous NPs for enhanced photothermal therapy [79]. Copyright 2021 Elsevier. (d) Schematic illustration of LM e-skin and AMF-based tumor therapy and pattern with O-GaIn directly printed on skin surface [81]. Copyright 2019 John Wiley & Sons. (e) Schematic of combined therapy in breast cancer with DOX-MS/LM [82]. Copyright 2019 John Wiley & Sons. (f) Clinical AI Epic Co-Ablation System, pictures from Hygea company. (g) Schematic of gallium microparticles (GMs) induced mechanical disruption of tumors for cryoablation [33]. Copyright 2020 John Wiley & Sons. (h) Illustration of cryo-facilitated LM particle transformation for endosomal escape [30]. Copyright 2021 Elsevier. (i) Flexible skin patch enabled tumor hybrid thermophysical therapy [86]. Copyright 2022 John Wiley & Sons. (j) Clinical medium frequency electrical stimulation therapy instrument, picture from Tsinghua Changgung Hospital. (k) LM-based injectable electrodes [90]. Copyright 2013 Springer Nature. (l) A schematic illustration of the conceptual application and the mechanism induced by injectable LM soft electronics in EChT and design of EChT with LM electrodes in vitro [91]. Copyright 2017 Elsevier.

Figure 8.

LM for anti-microbial and inflammatory. (a) Schematic of competition between Ga³⁺ and Fe³⁺ in metalloproteins [93]. Copyright 2016 American Chemical Society. (b) Ga for cancer chemotherapy [94]. Copyright 2023 John Wiley & Sons. (c) Schematic and principle of LM-based antimicrobial fabrics [95]. Copyright 2021 John Wiley & Sons. (d) Mechanism of Ga-based anti-inflammatory [96]. Copyright 2022 American Chemical Society.

Figure 9.

Imagination map of LM-enabled artificial organs, including the LM brain, cochlea, eyes, bones, nerves, lungs, heart, stomach, liver, intestines, pancreas, etc.