Cold-Responsive Hyaluronated Upconversion Nanoplatform for Transdermal Cryo-Photodynamic Cancer Therapy.

Cryotherapy leverages controlled freezing temperature interventions to engender a cascade of tumor-suppressing effects. However, its bottleneck lies in the standalone ineffectiveness. A promising strategy is using nanoparticle therapeutics to augment the efficacy of cryotherapy. Here, a cold-responsive nanoplatform composed of upconversion nanoparticles coated with silica - chlorin e6 - hyaluronic acid (UCNPs@SiO2-Ce6-HA) is designed. This nanoplatform is employed to integrate cryotherapy with photodynamic therapy (PDT) in order to improve skin cancer treatment efficacy in a synergistic manner. The cryotherapy appeared to enhance the upconversion brightness by suppressing the thermal quenching. The low-temperature treatment afforded a 2.45-fold enhancement in the luminescence of UCNPs and a 3.15-fold increase in the photodynamic efficacy of UCNPs@SiO2-Ce6-HA nanoplatforms. Ex vivo tests with porcine skins and the subsequent validation in mouse tumor tissues revealed the effective HA-mediated transdermal delivery of designed nanoplatforms to deep tumor tissues. After transdermal delivery, in vivo photodynamic therapy using the UCNPs@SiO2-Ce6-HA nanoplatforms resulted in the optimized efficacy of 79% in combination with cryotherapy. These findings underscore the Cryo-PDT as a truly promising integrated treatment paradigm and warrant further exploring the synergistic interplay between cryotherapy and PDT with bright upconversion to unlock their full potential in cancer therapy.

Long-term stable wireless smart contact lens for robust digital diabetes diagnosis.

Wearable devices for digital continuous glucose monitoring (CGM) have attracted great attention as a new paradigm medical device for diabetes management. However, the relatively inaccurate performance and instability of CGM devices have limited their wide applications in the clinic. Here, we developed hyaluronate (HA) modified Au@Pt bimetallic electrodes for long-term accurate and robust CGM of smart contact lens. After glucose oxidation reaction, the bimetallic electrodes facilitated the rapid decomposition of hydrogen peroxide and charge transfer for robust CGM. The passivation of Au@Pt bimetallic electrode with branch-type thiolated HA prevented the dissolution of Au electrode by chloride ions in tears. In diabetic and normal rabbits, the smart contact lens with HA-Au@Pt bimetallic electrodes enabled the high correlation (ρ = 0.88) CGM with 98.6% clinically acceptable data for 3 weeks. Taken together, we could confirm the feasibility of our smart contact lens for long-term CGM for further clinical development.

Multifunctional Intelligent Wearable Devices Using Logical Circuits of Monolithic Gold Nanowires.

Although multifunctional wearable devices have been widely investigated for healthcare systems, augmented/virtual realities, and telemedicines, there are few reports on multiple signal monitoring and logical signal processing by using one single nanomaterial without additional algorithms or rigid application-specific integrated circuit chips. Here, multifunctional intelligent wearable devices are developed using monolithically patterned gold nanowires for both signal monitoring and processing. Gold bulk and hollow nanowires show distinctive electrical properties with high chemical stability and high stretchability. In accordance, the monolithically patterned gold nanowires can be used to fabricate the robust interfaces, programmable sensors, on-demand heating systems, and strain-gated logical circuits. The stretchable sensors show high sensitivity for strain and temperature changes on the skin. Furthermore, the micro-wrinkle structures of gold nanowires exhibit the negative gauge factor, which can be used for strain-gated logical circuits. Taken together, this multifunctional intelligent wearable device would be harnessed as a promising platform for futuristic electronic and biomedical applications.

Smart contact lens systems for ocular drug delivery and therapy.

Ocular drug delivery and therapy systems have been extensively investigated with various methods including direct injections, eye drops and contact lenses. Nowadays, smart contact lens systems are attracting a lot of attention for ocular drug delivery and therapy due to their minimally invasive or non-invasive characteristics, highly enhanced drug permeation, high bioavailability, and on-demand drug delivery. Furthermore, smart contact lens systems can be used for direct light delivery into the eyes for biophotonic therapy replacing the use of drugs. Here, we review smart contact lens systems which can be classified into two groups of drug-eluting contact lens and ocular device contact lens. More specifically, this review covers smart contact lens systems with nanocomposite-laden systems, polymeric film-incorporated systems, micro and nanostructure systems, iontophoretic systems, electrochemical systems, and phototherapy systems for ocular drug delivery and therapy. After that, we discuss the future opportunities, challenges and perspectives of smart contact lens systems for ocular drug delivery and therapy.

Supramolecular Hydrogels for Precisely Controlled Antimicrobial Peptide Delivery for Diabetic Wound Healing.

Diabetic wound patients are often exposed to bacterial infections with delayed healing process due to hyperglycemia in the damaged skin tissue. Antimicrobial peptides (AMPs) have been investigated for the treatment of infection-induced diabetic wounds, but their low stability and toxicity have limited their further applications to diabetic chronic wound healing. Here, we developed a precisely controlled AMP-releasing injectable hydrogel platform, which could respond to infection-related materials of matrix metalloproteinases (MMPs) and reactive oxygen species (ROS). The injectable supramolecular hydrogel was prepared by the simple mixing of hyaluronic acid modified with cyclodextrin (HA-CD) and adamantane (Ad-HA). Ad-HA was conjugated with AMP via the cyclic peptide linker composed of MMP and ROS cleavable sequence (Ad-HA-AMP). Remarkably, only when the AMP-tethered hydrogel was exposed to both MMP and ROS simultaneously, AMP was released from the hydrogel, enabling the controlled release of AMP without causing cytotoxicity. In addition, we confirmed the enhanced serum stability of the Ad-HA-AMP conjugate. The antimicrobial activity of Ad-HA-AMP was maintained much longer than that of the native AMP. Finally, we could demonstrate the greatly improved wound-healing effect of AMP-tethered hydrogels with enhanced safety for the treatment of infection-induced diabetic chronic wounds. Taken together, we successfully demonstrated the feasibility of sHG-AMP for diabetic chronic wound healing.

Hydrogel Microneedles Extracting Exosomes for Early Detection of Colorectal Cancer.

There are several methods for early diagnosis of tumors, such as detecting circulating tumor DNAs, detecting circulating tumor cells, or imaging with tumor-targeting contrast agents. However, these assays are time-consuming and may cause patient discomfort during the biopsy collecting process. Here, we develop a facile method for early diagnosis of tumors by extracting exosomes from interstitial fluid (ISF) using hydrogel microneedles (MNs). The hydrogel MNs expand in the skin to absorb the ISF, and the tumor exosomes contained in the ISF bind with the glypican-1 antibodies inside the hydrogel of MNs. After removing the hydrogel on the MNs, exosomes are separately purified from the ISF to analyze tumor-related biomarkers. Finally, colorectal cancer can be diagnosed by ELISA for the colorectal cancer-induced model mice. This noninvasive hydrogel MN system to obtain the exosome samples would play an important role in early cancer diagnosis.

Bimetallic Hyaluronate-Modified Au@Pt Nanoparticles for Noninvasive Photoacoustic Imaging and Photothermal Therapy of Skin Cancer.

Although spherical gold (Au) nanoparticles have remarkable photothermal conversion efficiency and photostability, their weak absorption in the near-infrared (NIR) region and poor penetration into deep tissues have limited further applications to NIR light-mediated photoacoustic (PA) imaging and noninvasive photothermal cancer therapy. Here, we developed bimetallic hyaluronate-modified Au-platinum (HA-Au@Pt) nanoparticles for noninvasive cancer theranostics by NIR light-mediated PA imaging and photothermal therapy (PTT). The growth of Pt nanodots on the surface of spherical Au nanoparticles enhanced the absorbance in the NIR region and broadened the absorption bandwidth of HA-Au@Pt nanoparticles by the surface plasmon resonance (SPR) coupling effect. In addition, HA facilitated the transdermal delivery of HA-Au@Pt nanoparticles through the skin barrier and enabled clear tumor-targeted PA imaging. Compared to conventional PTT via injection, HA-Au@Pt nanoparticles were noninvasively delivered into deep tumor tissues and completely ablated the targeted tumor tissues by NIR light irradiation. Taken together, we could confirm the feasibility of HA-Au@Pt nanoparticles as a NIR light-mediated biophotonic agent for noninvasive skin cancer theranostics.

Effect of chitooligosaccharide on the inhibition of SARS-CoV-2 main protease.

BACKGROUND: The main protease (Mpro) is a crucial target for severe acute respiratory syndrome coronavirus (SARS-CoV-2). Chitooligosaccharide (CS) has broad-spectrum antiviral activity and can effectively inhibit the activity of SARS-CoV. Here, based on the high homology between SARS-CoV-2 and SARS-CoV, this study explores the effect and mechanism of CS with various molecular weights on the activity of SARS-CoV-2 Mpro. METHODS: We used fluorescence resonance energy transfer (FRET), UV-Vis, synchronous fluorescence spectroscopy, circular dichroism (CD) spectroscopy and computational simulation to investigate the molecular interaction and the interaction mechanism between CS and SARS-CoV-2 Mpro. RESULTS: Four kinds of CS with different molecular weights significantly inhibited the activity of Mpro by combining the hydrogen bonding and the salt bridge interaction to form a stable complex. Glu166 appeared to be the key amino acid. Among them, chitosan showed the highest inhibition effect on Mpro enzyme activity and the greatest impact on the spatial structure of protein. Chitosan would be one of the most potential anti-viral compounds. CONCLUSION: This study provides the theoretical basis to develop targeted Mpro inhibitors for the screening and application of anti-novel coronavirus drugs.

Principles and applications of sono-optogenetics.

Optogenetics has revolutionized neuroscience research through its spatiotemporally precise activation of specific neurons by illuminating light on opsin-expressing neurons. A long-standing challenge of in vivo optogenetics arises from the limited penetration depth of visible light in the neural tissue due to scattering and absorption of photons. To address this challenge, sono-optogenetics has been developed to enable spatiotemporally precise light production in a three-dimensional volume of neural tissue by leveraging the deep tissue penetration and focusing ability of ultrasound as well as circulation-delivered mechanoluminescent nanotransducers. Here, we present a comprehensive review of the sono-optogenetics method from the physical principles of ultrasound and mechanoluminescence to its emerging applications for unique neuroscience studies. We also discuss a few promising directions in which sono-optogenetics can make a lasting transformative impact on neuroscience research from the perspectives of mechanoluminescent materials, ultrasound-tissue interaction, to the unique neuroscience opportunities of "scanning optogenetics".

Microalgae-Based Biohybrid Microrobot for Accelerated Diabetic Wound Healing.

A variety of wound healing platforms have been proposed to alleviate the hypoxic condition and/or to modulate the immune responses for the treatment of chronic wounds in diabetes. However, these platforms with the passive diffusion of therapeutic agents through the blood clot result in the relatively low delivery efficiency into the deep wound site. Here, a microalgae-based biohybrid microrobot for accelerated diabetic wound healing is developed. The biohybrid microrobot autonomously moves at velocity of 33.3 µm s-1 and generates oxygen for the alleviation of hypoxic condition. In addition, the microrobot efficiently bound with inflammatory chemokines of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) for modulating the immune responses. The enhanced penetration of microrobot is corroborated by measuring fibrin clots in biomimetic wound using microfluidic devices and the enhanced retention of microrobot is confirmed in the real wounded mouse skin tissue. After deposition on the chronic wound in diabetic mice without wound dressing, the wounds treated with microrobots are completely healed after 9 days with the significant decrease of inflammatory cytokines below 31% of the control level and the upregulated angiogenesis above 20 times of CD31+ cells. These results confirm the feasibility of microrobots as a next-generation platform for diabetic wound healing.

Wireless theranostic smart contact lens for monitoring and control of intraocular pressure in glaucoma.

Glaucoma is one of the irreversible ocular diseases that can cause vision loss in some serious cases. Although Triggerfish has been commercialized for monitoring intraocular pressure in glaucoma, there is no smart contact lens to monitor intraocular pressure and take appropriate drug treatment in response to the intraocular pressure levels. Here, we report a precisely integrated theranostic smart contact lens with a sensitive gold hollow nanowire based intraocular pressure sensor, a flexible drug delivery system, wireless power and communication systems and an application specific integrated circuit chip for both monitoring and control of intraocular pressure in glaucoma. The gold hollow nanowire based intraocular pressure sensor shows high ocular strain sensitivity, chemical stability and biocompatibility. Furthermore, the flexible drug delivery system can be used for on-demand delivery of timolol for intraocular pressure control. Taken together, the intraocular pressure levels can be successfully monitored and controlled by the theranostic smart contact lens in glaucoma induced rabbits. This theranostic smart contact lens would be harnessed as a futuristic personal healthcare platform for glaucoma and other ocular diseases.

Engineered Biomimetic Membranes for Organ-on-a-Chip.

Organ-on-a-chip (OOC) systems are engineered nanobiosystems to mimic the physiochemical environment of a specific organ in the body. Among various components of OOC systems, biomimetic membranes have been regarded as one of the most important key components to develop controllable biomimetic bioanalysis systems. Here, we review the preparation and characterization of biomimetic membranes in comparison with the features of the extracellular matrix. After that, we review and discuss the latest applications of engineered biomimetic membranes to fabricate various organs on a chip, such as liver, kidney, intestine, lung, skin, heart, vasculature and blood vessels, brain, and multiorgans with perspectives for further biomedical applications.

Controlled afterglow luminescent particles for photochemical tissue bonding.

Upconversion materials (UCMs) have been developed to convert tissue-penetrating near-infrared (NIR) light into visible light. However, the low energy conversion efficiency of UCMs has limited their further biophotonic applications. Here, we developed controlled afterglow luminescent particles (ALPs) of ZnS:Ag,Co with strong and persistent green luminescence for photochemical tissue bonding (PTB). The co-doping of Ag+ and Co2+ ions into ZnS:Ag,Co particles with the proper vacancy formation of host ions resulted in high luminescence intensity and long-term afterglow. In addition, the ALPs of ZnS:Ag,Co could be recharged rapidly under short ultraviolet (UV) irradiation, which effectively activated rose bengal (RB) in hyaluronate-RB (HA-RB) conjugates for the crosslinking of dissected collagen layers without additional light irradiation. The remarkable PTB of ZnS:Ag,Co particles with HA-RB conjugates was confirmed by in vitro collagen fibrillogenesis assay, in vivo animal wound closure rate analysis, and in vivo tensile strength evaluation of incised skin tissues. Taken together, we could confirm the feasibility of controlled ALPs for various biophotonic applications.

Hyaluronate-Black Phosphorus-Upconversion Nanoparticle Complex for Non-invasive Theranosis of Skin Cancer.

Despite the wide investigation on black phosphorus (BP) for biophotonic applications, the finite depth of light penetration has limited further development of BP-based photomedicines. Here, we developed a hyaluronate-BP-upconversion nanoparticle (HA-BP-UCNP) complex for near-infrared (NIR) light-mediated multimodal theranosis of skin cancer with photoacoustic (PA) bioimaging, photodynamic therapy (PDT), and photothermal therapy (PTT). In contrast to the conventional BP-based skin cancer theranosis, the HA-BP-UCNP complex could be non-invasively delivered into the tumor tissue to induce the cancer cell apoptosis upon NIR light irradiation. The PA imaging of BP successfully visualized the non-invasive transdermal delivery of the HA-BP-UCNP complex into the mice skin. HA in the complex facilitated the transdermal delivery of BP into the tumor tissue under the skin. Upon 980 nm NIR light irradiation, the UCNP converted the light to UV-blue light to generate reactive oxygen species by sensitizing BP in the HA-BP-UCNP complex for PDT. Remarkably, 808 nm NIR irradiation with PTT triggered the apoptosis of tumor cells. Taken together, we could confirm the feasibility of the HA-BP-UCNP complex for NIR light-mediated multimodal theranosis of skin cancers.

Smart contact lens containing hyaluronate-rose bengal conjugate for biophotonic myopia vision correction.

As the collagen layer weakens with increasing age or certain diseases such as keratoconus and myopia, the mechanical property of the collagen layer decreases with corneal deformation. To circumvent these problems, the corneal collagen has been crosslinked with the photosensitizer riboflavin under UV light after de-epithelialization. However, this treatment with riboflavin and UV light can cause notable damage to the eye. Here, the biocompatible rose bengal (RB) dye was conjugated to hyaluronic acid (HA) to enhance the corneal permeability, which can be activated by safe green light with a wavelength of 530 nm. Two-photon microscopy revealed the deep tissue penetration of the HA-RB conjugate in comparison with RB. Collagen fibrillogenesis, ex vivo tensile test, and ex vivo histological analysis confirmed the effective collagen crosslinking by HA-RB conjugate and the light irradiation. Furthermore, we developed a smart contact lens for on-demand HA-RB conjugate delivery from the reservoir embedded in the contact lens. Taken together, we could envision the feasibility of a smart contact lens for biophotonic myopia vision correction.

Upconversion nanomaterials and delivery systems for smart photonic medicines and healthcare devices.

In the past decade, upconversion (UC) nanomaterials have been extensively investigated for the applications to photomedicines with their unique features including biocompatibility, near-infrared (NIR) to visible conversion, photostability, controllable emission bands, and facile multi-functionality. These characteristics of UC nanomaterials enable versatile light delivery for deep tissue biophotonic applications. Among various stimuli-responsive delivery systems, the light-responsive delivery process has been greatly advantageous to develop spatiotemporally controllable on-demand "smart" photonic medicines. UC nanomaterials are classified largely to two groups depending on the photon UC pathway and compositions: inorganic lanthanide-doped UC nanoparticles and organic triplet-triplet annihilation UC (TTA-UC) nanomaterials. Here, we review the current-state-of-art inorganic and organic UC nanomaterials for photo-medicinal applications including photothermal therapy (PTT), photodynamic therapy (PDT), photo-triggered chemo and gene therapy, multimodal immunotherapy, NIR mediated neuromodulations, and photochemical tissue bonding (PTB). We also discuss the future research direction of this field and the challenges for further clinical development.

Bimetallic Nanocatalysts Immobilized in Nanoporous Hydrogels for Long-Term Robust Continuous Glucose Monitoring of Smart Contact Lens.

Smart contact lenses for continuous glucose monitoring (CGM) have great potential for huge clinical impact. To date, their development has been limited by challenges in accurate detection of glucose without hysteresis for tear glucose monitoring to track the blood glucose levels. Here, long-term robust CGM in diabetic rabbits is demonstrated by using bimetallic nanocatalysts immobilized in nanoporous hydrogels in smart contact lenses. After redox reaction of glucose oxidase, the nanocatalysts facilitate rapid decomposition of hydrogen peroxide and nanoparticle-mediated charge transfer with drastically improved diffusion via rapid swelling of nanoporous hydrogels. The ocular glucose sensors result in high sensitivity, fast response time, low detection limit, low hysteresis, and rapid sensor warming-up time. In diabetic rabbits, smart contact lens can detect tear glucose levels consistent with blood glucose levels measured by a glucometer and a CGM device, reflecting rapid concentration changes without hysteresis. The CGM in a human demonstrates the feasibility of smart contact lenses for further clinical applications.

Smart Wireless Near-Infrared Light Emitting Contact Lens for the Treatment of Diabetic Retinopathy.

Diabetic retinopathy is currently treated by highly invasive repeated therapeutic injections and surgical interventions without complete vision recovery. Here, a noninvasive smart wireless far red/near-infrared (NIR) light emitting contact lens developed successfully for the repeated treatment of diabetic retinopathy with significantly improved compliance. A far red/NIR light emitting diode (LED) is connected with an application-specific integrated circuit chip, wireless power, and communication systems on a PET film, which is embedded in a silicone elastomer contact lens by thermal crosslinking. After in vitro characterization, it is confirmed that the retinal vascular hyper-permeability induced by diabetic retinopathy in rabbits is reduced to a statistically significant level by simply repeated wearing of smart far red/NIR LED contact lens for 8 weeks with 120 µW light irradiation for 15 min thrice a week. Histological analysis exhibits the safety and feasibility of LED contact lenses for treating diabetic retinopathy. This platform technology for smart LED contact lens would be harnessed for various biomedical photonic applications.

Supramolecular host-guest hyaluronic acid hydrogels enhance corneal wound healing through dynamic spatiotemporal effects.

Severe corneal wounds can lead to ulceration and scarring if not promptly and adequately treated. Hyaluronic acid (HA) has been investigated for the treatment of corneal wounds due to its remarkable biocompatibility, transparency and mucoadhesive properties. However, linear HA has low retention time on the cornea while many chemical moieties used to crosslink HA can cause toxicity, which limits their clinical ocular applications. Here, we used supramolecular non-covalent host-guest interactions between HA-cyclodextrin and HA-adamantane to form shear-thinning HA hydrogels and evaluated their impact on corneal wound healing. Supramolecular HA hydrogels facilitated adhesion and spreading of encapsulated human corneal epithelial cells ex vivo and improved corneal wound healing in vivo as an in situ-formed, acellular therapeutic membrane. The HA hydrogels were absorbed within the corneal stroma over time, modulated mesenchymal cornea stromal cell secretome production, reduced cellularity and inflammation of the anterior stroma, and significantly mitigated corneal edema compared to treatment with linear HA and untreated control eyes. Taken together, our results demonstrate supramolecular HA hydrogels as a promising and versatile biomaterial platform for corneal wound healing.