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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.

The design of advanced nanobiomaterials to improve analytical accuracy and therapeutic efficacy has become an important prerequisite for the development of innovative nanomedicines. Recently, phospholipid nanobiomaterials including 2-methacryloyloxyethyl phosphorylcholine (MPC) have attracted great attention with remarkable characteristics such as resistance to nonspecific protein adsorption and cell adhesion for various biomedical applications. Despite many recent reports, there is a lack of comprehensive review on the phospholipid nanobiomaterials from synthesis to diagnostic and therapeutic applications. Here, we review the synthesis and characterization of phospholipid nanobiomaterials focusing on MPC polymers and highlight their attractive potentials for applications in micro/nanofabricated fluidic devices, biosensors, lab-on-a-chip, drug delivery systems (DDSs), COVID-19 potential usages for early diagnosis and even treatment, and artificial extracellular matrix scaffolds for cellular engineering.

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.

Self-propelling micro- and nano-motors (MNMs) have been extensively investigated as an emerging oral drug delivery carrier for gastrointestinal (GI) tract diseases. However, the propulsion of current MNMs reported so far is mostly based on the redox reaction of metals (such as Zn and Mg) with severe propulsion gas generation, remaining non-degradable residue in the GI tract. Here, we develop a bioinspired enzyme-powered biopolymer micromotor mimicking the mucin penetrating behavior of Helicobacter pylori in the stomach. It converts urea to ammonia and the subsequent increase of pH induces local gel-sol transition of the mucin layer facilitating the penetration into the stomach tissue layer. The successful fabrication of micromotors is confirmed by high-resolution transmission electron microscopy, electron energy loss spectroscopy, dynamic light scattering analysis, zeta-potential analysis. In acidic condition, the immobilized urease can efficiently converted urea to ammonia, comparable with that of neutral condition because of the increase of surrounding pH during propulsion. After administration into the stomach, the micromotors show enhanced penetration and prolonged retention in the stomach for 24 h. Furthermore, histological analysis shows that the micromotors are cleared within 3 days without causing any toxicity in the GI tract. The enhanced penetration and retention of the micromotors as an active oral delivery carrier in the stomach would be successfully harnessed for the treatment of various GI tract diseases., Graphical abstract Image 1, Highlights • Polydopamine (PDA) hollow microcapsules are biocompatible, biodegradable, and muco-adhesive. • Urease-powered PDA micromotors are propelled by the decomposition of urea to ammonia and carbon dioxide. • Micromotors increase the local pH to induce the gel-sol transition of the mucus layer. • Micromotors result in enhanced penetration and prolonged retention in the stomach. • Micromotors can be effectively used for oral drug delivery with complete clearance from the GI tract.

Individual recognition technology such as iris recognition and bar coding has been extensively investigated for non-face-to-face authorization. However, there are still strong unmet needs for facile, rapid, and robust individual recognition. Here, we developed multispectral transparent films of upconversion nanoparticles (UCNPs) for near-infrared (NIR) encoding of wearable devices including contact lenses and patch devices. A multispectral UCNP film in a contact lens showed various luminescence colors of patterns under 980 nm NIR light irradiation and each color could be assigned to a specific code by RGB value analysis. The encoded film of UCNPs in the contact lens was successfully decoded by the RGB value analysis with a charge coupled digital (CCD) camera. Furthermore, the UCNP barcode film could be applied in the form of attachable barcode patches onto various substrates like porcine skin and paper currency. Taken together, we could confirm the feasibility of multispectral UCNP transparent films as a facile individual recognition platform for non-face-to-face authorization.

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., Fluorescent nanodiamond conjugated with hyaluronate is developed as a carbon based photostable and biocompatible material for liver-targeted molecular imaging applications.

Magnesium (Mg) and its alloys have presented a paradigm for biodegradability in the field of biomedical devices. However, biodegradation of Mg and its alloys cause the formation of hydrogen gas and...

Two-dimensional (2D) transition metal dichalcogenides (TMDCs) are promising materials for detection of biomolecules due to their large surface-to-volume ratio. However, their poor response to the cellular environment hinders the realization of high-performance 2D TMDC sensors. Here, we present a hierarchical Raman scattering sensor consisting of the WS

Intravesical therapeutic delivery has been extensively investigated for various bladder diseases such as bladder cancer, overactive bladder, urinary incontinence, and interstitial cystitis. However, conventional drug carriers have a low therapeutic delivery efficiency because of the passive diffusion of drug molecules in a bladder and the rapid clearance by periodic urination. Here, we report biocompatible and bioavailable enzyme-powered polymer nanomotors which can deeply penetrate into a mucosa layer of the bladder wall and remain for a long-term period in the bladder. The successful fabrication of nanomotors was confirmed by high-resolution transmission electron microscopy, energy-dispersive X-ray mapping, zeta-potential analysis, Fourier transform infrared spectroscopy, and urease activity and nanomotor trajectory analyses. After injection into the bladder, urease-immobilized nanomotors became active, moving around in the bladder by converting urea into carbon dioxide and ammonia. The nanomotors resulted in the facilitated penetration to the mucosa layer of the bladder wall and the prolonged retention in the bladder even after repeated urination. The enhanced penetration and retention of the nanomotors as a drug delivery carrier in the bladder would be successfully harnessed for treating a variety of bladder diseases.

This article presents a controller IC for smart contact lens (SCL). For wireless telemetry, we propose a transmitter supporting dual-mode operations with a single external loop antenna. In the wireless-powered backscattering load-shift keying (LSK) mode, the transmitter is configured to use the antenna as an ${L}$ for magnetic resonance coupling. The transmitter switches its configuration to be an active LC oscillator circuit in the RF-radiated transmission mode. To suppress the average power consumption, a 0.2% duty cycling is applied with a controlled timing schedule while minimizing static power consumption in the sleep mode. To reduce the effect of instantaneous discharging, the period of data transmission is shortened by transmitting data with a higher rate. The designed IC is fabricated using 0.18- $\mu \text{m}$ CMOS. For in vitro verifications in both modes, an SCL is implemented by integrating the IC, a glucose sensor, a thin-film battery, a loop antenna, and a supply-regulating capacitor. The IC achieves a power consumption of 143 nW with an input dynamic range of 89 dB.

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.

Magnesium (Mg) and its alloys have presented a paradigm for biodegradability in the field of biomedical devices. However, biodegradation of Mg and its alloys cause the formation of hydrogen gas and basic molecules in the body. Here we developed a surface modification method for Mg implants by double-coating with osteogenic dexamethasone (Dex)-loaded black phosphorus (BP) and poly(lactide

Continuous intraocular pressure (IOP) monitoring can provide a paradigm shift in the management of patients with glaucoma as a facile alternative to conventional diagnostic methods. However, the low sensitivity and functional instability of current IOP sensors have limited their clinical utility in the management of glaucoma. Here, we have developed a smart contact lens integrated with a transparent silver nanowire IOP strain sensor and wireless circuits for noninvasive, continuous IOP monitoring. After confirming the robust stability of the IOP sensor within the smart contact lens in the presence of tears and repeated eyelid blink model cycles, we were able to monitor IOP changes on polydimethylsiloxane model eyes

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.

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

The intranasal drug administration has attracted great interest as a non-invasive route allowing targeted delivery of drugs directly to the brain. However, one of the main issues in nasal drug administration is mucociliary clearance. Hyaluronate (HA) has been widely used as a mucoadhesive excipient for ocular, rectal, and vaginal delivery. Here, FG loop peptide (FGL) was conjugated to HA for improving enzymatic stability and delivery efficiency from the nose to the brain. The successful conjugation of FGL to aldehyde modified HA was confirmed by gel permeation chromatography (GPC) and 1H nuclear magnetic resonance (NMR). The outstanding enzymatic stability of HA-FGL conjugate was also corroborated by the GPC. The HA-FGL conjugate showed enhanced binding affinity onto nasal epithelial cells. In addition, in vivo nose-to-brain delivery of HA-FGL conjugate could be visualized by using an IVIS imaging system and fluorescence microscopy. Finally, in vivo therapeutic effect of HA-FGL conjugate was successfully confirmed by histological analysis, transferase-mediated uridine 5-triphosphate-biotin nick end-labeling (TUNEL) assay, immunofluorescent staining, transmission electron microscopy (TEM), and rotarod tests in hypoxic-ischemic encephalopathy model animals.

The recent progress in various biomaterials with unique physiological and pharmacological properties has expedited the development of translational medicines for the diagnosis, prognosis, and therapy of intractable diseases. Hyaluronic acid (HA) is one of such biomaterials that has attracted great attention due to its unique characteristics for biomedical applications. In this Perspective, we provide an overview of HA-based medicines in a variety of forms such as chemical and biological conjugates, nanoparticles, nanoparticle hybrid systems, hydrogels, and nanogels. We highlight the current-state-of-the-art strategies to design and optimize innovative HA-based medicines for their clinical translations. Finally, we discuss the challenges for technical hurdles and the future directions to expand the feasibility of HA-based translational medicines.

Diagnostic and therapeutic nanoparticles have been actively investigated for the last few decades as new platforms for biomedical applications. Despite their great versatility and potency, nanoparticles have generally required further modification with biocompatible materials such as biopolymers and synthetic polymers for in vivo administration to improve their biological functions, stability, and biocompatibility. Among a variety of natural and synthetic biomaterials, hyaluronate (HA) has been considered a promising biomolecule with which to construct nanohybrid systems, as it can enable long-term and efficient delivery of nanoparticles to target sites as well as physiological stabilization of nanoparticles by forming hydrophilic shells. In this review, we first describe various kinds of HA derivatives and their interactions with nanoparticles, and discuss how to design and develop optimal HA-nanoparticle hybrid systems for biomedical applications. Furthermore, we show several exemplary applications of HA-nanoparticle hybrid systems and provide our perspectives to their futuristic translational applications.

The simultaneous neural signal monitoring and stimulation can allow accurate neurotransmitter regulation for patients in various degrees of neural degeneration disorders. Here, we developed a residue-free graphene device as an effective electrical neural interface for dopamine sensing and secretion. We demonstrated the ultrasensitive dopamine sensing of residue-free graphene devices cultured with PC12 cells and the on-demand functional electrical stimulation for electroceutical applications. The doping effect of graphene by the released dopamine from living cells was confirmed from the electrical current change. The dopamine release could be also quantitatively analyzed by ELISA. Then, Ca2+ ion-dependent dopamine release was optically observed by fluorescence microscopy during the stimulation. Taken together, this study confirms the feasibility of graphene surface as a neural interface for electroceutical applications to various central nerve system disorders.

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.

Skin tissue is regenerated by the combinational function of skin cells, extracellular matrix (ECM), and bioactive molecules. As an artificial ECM, supramolecular hydrogels exhibited outstanding capability to mimic the physical properties of ECM. However, the lack of biochemical function in supramolecular hydrogels has limited further tissue engineering applications. Here, we developed self-assembling supramolecular drug delivery hydrogels to mimic the skin tissue regeneration process. The supramolecular hydrogels were prepared to encapsulate fibroblasts by the host-guest interaction of cyclodextrin-modified gelatin (GE-CD) and adamantane-modified hyaluronate (Ad-HA) in conjugation with human growth hormone (hGH) for accelerated skin tissue regeneration. In vitro, GE-CD/Ad-HA-hGH hydrogels showed highly facilitated cell growth by the controlled hGH delivery. After a subcutaneous injection into the back of mice, IVIS imaging of bioengineered fibroblasts to express red fluorescence protein (RFP) revealed prolonged cell survival and proliferation in the supramolecular hydrogels for more than 21 days. We could also observe the improved skin tissue regeneration by the facilitated fibroblast proliferation with angiogenesis. Taken together, we could confirm the feasibility of biomimetic supramolecular drug delivery GE-CD/Ad-HA-hGH hydrogels for various tissue engineering applications.

Large abrasions and deeper ulcers of the cornea can lead to corneal scarring, ulceration and thinning 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, intact linear HA has low retention time on the cornea and chemical crosslinkers to synthesize HA hydrogels can cause toxicity limiting their clinical ocular applications. Here, we used supramolecular HA hydrogels formed by non-covalent host-guest interactions between HA-cyclodextrin and HA-adamantane to evaluate the impact of the hydrogels 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.

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 - black phosphorus (HA-BP) conjugates for capturing copper ions accumulated in the liver for the treatment of WD.Results: HA-BP conjugates 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-BP conjugates to liver cells via HA receptor mediated endocytosis. The cell viability test confirmed the high biocompatibility of HA-BP conjugates.Conclusion: HA-BP conjugates would be an efficient copper chelating agent to remove accumulated copper in the liver for the WD treatment.

Self-propelling micro- and nano-motors (MNMs) are emerging as a multifunctional platform for smart healthcare applications such as biosensing, bioimaging, and targeted drug delivery with high tissue penetration, stirring effect, and rapid drug transport. MNMs can be propelled and/or guided by chemical substances or external stimuli including ultrasound, magnetic field, and light. In addition, enzymatically powered MNMs and biohybrid micromotors have been developed using the biological components in the body. In this review, we describe emerging MNMs focusing on their smart propulsion systems, and diagnostic and therapeutic applications. Finally, we highlight several MNMs for in vivo applications and discuss the future perspectives of MNMs on their current limitations and possibilities toward further clinical applications.

Hyaluronate (HA) has been widely investigated for noninvasive topical drug delivery of chemical drugs and biopharmaceuticals. However, previous noninvasive delivery systems have been facilitated mostly by chemical conjugation of drugs with HA, which can cause reduced therapeutic efficacy and safety issues in chemically modified drugs. Here, HA nanogels were synthesized by crosslinking via “click” chemistry for noninvasive topical delivery of a model drug without chemical modification. The model-drug-encapsulating HA nanogels could be uptaken to the skin melanoma cells in vitro by HA-mediated endocytosis. In addition, histological analysis showed that HA nanogels could be topically delivered to the deep skin and tongue tissues through the noninvasive delivery routes. Taken together, HA nanogels could be effectively used for the noninvasive topical delivery of various therapeutic drugs.

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.

Antigenic peptide-delivery systems have been extensively investigated to harness the immune system for cancer therapy. Cytotoxic T-cell epitope peptide can induce an antigen-specific CD8+ T-cell response, which subsequently inhibits the growth of antigen-bearing tumors. However, there are only a few facile tailored delivery systems of antigenic peptide for effective cancer immunotherapy. Here, we developed a biodegradable microneedle patch delivering a hyaluronate (HA)-antigenic peptide conjugate for prophylactic cancer immunotherapy. Cytotoxic T-cell epitope peptide (SIINFEKL) was conjugated to HA, which was loaded into a biodegradable HA microneedle (MN) patch to efficiently deliver an antigen to the immune system in the skin. HA could act as a transdermal vaccine carrier eliciting strong immune responses by the efficient stimulation of immunocompetent cells. The HA-SIINFEKL conjugates loaded into biodegradable MNs were localized near the MN administration site, exhibiting long-term residence for more than 24 h post-administration. Remarkably, a single transdermal vaccination with the MN patch containing HA-SIINFEKL conjugates resulted in a statistically significant inhibition of tumor growth in B16 melanoma model mice by enhancing antigen-specific cytotoxic T-cell responses.

Numerous light-based diagnostic and therapeutic devices are routinely used in the clinic. These devices have a familiar look as items plugged in the wall or placed at patients' bedsides, but recently, many new ideas have been proposed for the realization of implantable or wearable functional devices. Many advances are being fuelled by the development of multifunctional materials for photonic healthcare devices. However, the finite depth of light penetration in the body is still a serious constraint for their clinical applications. In this Review, we discuss the basic concepts and some examples of state-of-the-art implantable and wearable photonic healthcare devices for diagnostic and therapeutic applications. First, we describe emerging multifunctional materials critical to the advent of next-generation implantable and wearable photonic healthcare devices and discuss the path for their clinical translation. Then, we examine implantable photonic healthcare devices in terms of their properties and diagnostic and therapeutic functions. We next describe exemplary cases of noninvasive, wearable photonic healthcare devices across different anatomical applications. Finally, we discuss the future research directions for the field, in particular regarding mobile healthcare and personalized medicine.