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.

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.

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.

Fluorescent nanodiamond - hyaluronate conjugates for target-specific molecular imaging.

Despite wide investigation on molecular imaging contrast agents, there are still strong unmet medical needs to enhance their signal-to background ratio, brightness, photostability, and biocompatibility with multimodal imaging capability. Here, we assessed the feasibility of fluorescent nanodiamonds (FNDs) as carbon based photostable and biocompatible materials for molecular imaging applications. Because FNDs have negatively charged nitrogen vacancy (NV) centers, they can emit bright red light. FNDs were conjugated to hyaluronate (HA) for target-specific molecular imaging. HA is a biocompatible, biodegradable, and linear polysaccharide with abundant HA receptors in the liver, enabling liver targeted molecular imaging. In vitro cell viability tests revealed the biocompatibility of HA-FND conjugates and the competitive cellular uptake test confirmed their target-specific intracellular delivery to HepG2 cells with HA receptors. In addition, in vivo fluorescence lifetime (FLT) assessment revealed the imaging capability of FNDs and HA-FND conjugates. After that, we could confirm the statistically significant liver-targeted delivery of HA-FND conjugates by in vivo imaging system (IVIS) analysis and ex vivo biodistribution tests in various organs. The renal clearance test and histological analysis corroborated the in vivo biocompatibility and safety of HA-FND conjugates. All these results demonstrated the feasibility of HA-FND conjugates for further molecular imaging applications.

Hyaluronate/black phosphorus complexes as a copper chelating agent for Wilson disease treatment.

BACKGROUND: Wilson disease (WD) is a genetic disorder of copper storage, resulting in pathological accumulation of copper in the body. Because symptoms are generally related to the liver, chelating agents capable of capturing excess copper ions after targeted delivery to the liver are highly required for the treatment of WD. METHODS: We developed hyaluronate-diaminohexane/black phosphorus (HA-DAH/BP) complexes for capturing copper ions accumulated in the liver for the treatment of WD. RESULTS: HA-DAH/BP complexes showed high hepatocyte-specific targeting efficiency, selective copper capturing capacity, excellent biocompatibility, and biodegradability. HA enhanced the stability of BP nanosheets and increased copper binding capacity. In vitro cellular uptake and competitive binding tests verified targeted delivery of HA-DAH/BP complexes to liver cells via HA receptor mediated endocytosis. The cell viability test confirmed the high biocompatibility of HA-DAH/BP complexes. CONCLUSION: HA-DAH/BP complexes would be an efficient copper chelating agent to remove accumulated copper in the liver for the WD treatment.

Dissolving microneedles delivering cancer cell membrane coated nanoparticles for cancer immunotherapy.

Recently, a variety of tumor vaccines and immune system stimulators such as toll-like receptor (TLR) agonists have been widely investigated for cancer immunotherapy via transdermal delivery. Despite these great research efforts, low efficiency and discomfort remain a huge technical hurdle for the development of immunotherapeutics. Here, we design a facile method to deliver drugs to the skin through microneedles (MNs) to stimulate the immune system in two ways. As one of the tumor vaccines, cancer cell membrane proteins can act as tumor-specific antigens that are presented to antigen presenting cells (APCs) to activate the immune system. In addition, a toll-like receptor 7 (TLR7) agonist of imiquimod (R837) can suppress cancer cell growth by inhibiting angiogenesis. Using poloxamer 407 (F127) as a nanocarrier, F127 nanoparticles (F127 NPs) are loaded with R837 and then coated with cancer cell membranes (M). These F127-R837@M NPs are loaded in rapidly dissolving MNs and delivered through the skin. MNs loaded with F127-R837@M NPs show significant inhibition of cancer cell growth in both prophylactic vaccination and antitumor immunotherapy in vivo. The dual immune system stimulating F127-R837@M NPs could be effectively used for cancer immunotherapy.