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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.

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

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

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.

We have developed surface-crosslinked polymer nanodroplets having capabilities of therapeutic enhancement for high intensity focused ultrasound (HIFU) treatment and image guidance by photoacoustic (PA) and ultrasound (US) imaging. Six-arm-branched poly(ethylene glycol) (PEG) is crosslinked with Pluronic F127 mixed with naphthalocyanine (Nc), and sonicated with liquid perfluorohexane (PFH) to form nanoparticles encapsulating Nc and PFH (Nc/PFH@PCPN). The Nc dye provides high optical absorption at 850 nm wavelength for PA imaging, and improves the stability of the nanodroplets due to its hydrophobicity. PFH evaporates upon reception of HIFU waves to form microbubbles that enhances both visual contrast for US imaging and cavitation effect for HIFU treatment. We have shown from experiments that the nanodroplets significantly increase the signal contrast of the PA/US images, and at the same time they enhance the HIFU cavitation effect and induce necrosis and apoptosis of tumor cells. Thus, we believe Nc/PFH@PCPN can be a biocompatible and stable multi-functional agent for HIFU therapy guided by PA/US images.

With increasing ozone depletion, ultraviolet (UV) exposure from sunlight has become a significant health risk. Although commercially available sun protectants provide reasonable protection, they have limitations in terms of safety and aesthetics. Here, we have developed biocompatible and biodegradable sunscreens by facile synthesis of organosilica nanoparticles (o-SNPs) with self-encapsulated phenyl motifs using phenylsilane precursors. The physical structure of o-SNPs is elaborately controlled such that they are large enough to reflect UVA but small enough to be imperceptible when applied on the skin. The chemically attached phenyl motifs to o-SNPs facilitate filtering UVB via their delocalized π-orbitals. The o-SNPs generate a negligible amount of reactive oxygen species under UV exposure. Ex vivo two-photon microscopy reveals that the o-SNPs tend to adhere to the outer layers of skin without further intradermal penetration, resulting in less skin irritation. In vivo UV protection tests confirmed the excellent sunscreen effect of o-SNPs compared with conventional organic and inorganic UV filters.

The controlled drug delivery devices helps timely drug administrations and maintenance of effective dose to maximize curing effects with minimal side effects. Application of this technology to various body parts has been limited, especially in organs with curved surface, such as the brain and the eye. Herein, we report a flexible drug delivery microdevice (f-DDM) for controlled administration on the curved organ surface. The unique structure of the f-DDM consists of freestanding gold membranes over the multireservoir array was implemented by reversing the typical fabrication order of the reservoir and sealing membrane. We optimized the design of the f-DDM by a finite element analysis to prevent thermal damage during the laser transfer and the applying current density for reliable drug release through an electrochemical analysis. The wireless power transfer system was applied to f-DDM, which shows stable wirelessly powered operation. The f-DDM was flexible enough to be implantable on the curved cerebral cortex and successfully adopted for delivery of two different chemicals or prevention of seizure activity using an anti-epileptic drug. Our study opens a new avenue for the controlled, region-specific, and combinatorial application of drugs, the key factors for precision medicine.

Obesity is associated with the risk of developing several severe diseases, such as metabolic disorder, diabetes, and heart diseases. Despite wide investigation and trials, a noninvasive obesity therapy is still an important medical unmet need, targeting the abnormal adipose tissue. Here, we developed hyaluronate-hollow gold nanosphere-adipocyte-targeting peptide (HA-HAuNS-ATP) conjugates for the photothermal ablation of adipose tissues. The HA-HAuNS-ATP conjugate could be noninvasively delivered into the skin and effectively target to adipocytes in the subcutaneous. With near-infrared laser illumination, HA-HAuNS-ATP conjugate enabled highly effective photothermal ablation of adipose tissues in C57BL/6 obesity mice. The photoacoustic imaging confirmed the successful transdermal delivery and the photothermal lipolysis of HA-HAuNS-ATP conjugate. Taken together, the transdermal HA-HAuNS-ATP conjugate might have a great potential for noninvasive photothermal lipolysis.

The recent progress in photonic nanomaterials has contributed greatly to the development of photomedicines. However, the finite depth of light penetration is still a serious limitation, constraining their clinical applications. Here, we developed a poly(allylamine) (PAAm)-modified upconversion nanoparticle/hyaluronate–rose bengal (UCNP/PAAm/HA-RB) conjugate complex for photochemical bonding of deep tissue with near-infrared (NIR) light illumination. Compared to the conventional invasive treatment via suturing and stapling, the UCNP/PAAm/HA-RB conjugate complex could be noninvasively delivered into the deep tissue and accelerate the tissue bonding upon NIR light illumination. HA in the outer layer of the complex facilitated the penetration of RB into the collagen layer of the dermis. The NIR light triggered UCNP of NaYF4: Yb/Er (Y:Yb:Er = 78:20:2) in the complex to illuminate visible green light under the skin tissue. The activated RB in the HA-RB conjugate by the green light induced radical formation for ...

Since hyaluronate (HA) was firstly isolated from the vitreous of bovine eyes in 1934, HA has been widely investigated for various biomedical applications. As a naturally-occurring polysaccharide, HA has been used for joint lubrication and ocular treatment in its intact form due to the excellent biocompatibility, viscoelasticity, biodegradability, and hygroscopic properties. HA can be easily functionalized via the chemical modification of its carboxyl and hydroxyl groups. Recently, a variety of biological functions of HA have been explored and a number of customized applications have been investigated taking advantages of the interaction between HA and biological tissues. HA has been used for drug delivery to enhance the blood circulation time of drugs with target-specificity to HA receptors in the body. HA has been also used to prepare tissue engineering hydrogel scaffolds for the spatiotemporal control of encapsulated cells. In this review, we describe the key biological functions of HA in the body in terms of its structure, physical properties, biodistribution and interaction with HA receptors. After that, we describe unique advantages that allow HA to be applied in various biomedical fields. Finally, we report the conventional and newly emerging applications of HA and its derivatives under commercial development stages.

Noninvasive real-time biosensors to measure glucose levels in the body fluids have been widely investigated for continuous glucose monitoring of diabetic patients. However, they suffered from low sensitivity and reproducibility due to the instability of nanomaterials used for glucose biosensors. Here, we developed a hyaluronate-gold nanoparticle/glucose oxidase (HA-AuNP/GOx) complex and an ultralow-power application-specific integrated circuit chip for noninvasive and robust wireless patch-type glucose sensors. The HA-AuNP/GOx complex was prepared by the facile conjugation of thiolated HA to AuNPs and the following physical binding of GOx. The wireless glucose sensor exhibited slow water evaporation (0.11 μL/min), fast response (5 s), high sensitivity (12.37 μA·dL/mg·cm2) and selectivity, a low detection limit (0.5 mg/dL), and highly stable enzymatic activity (∼14 days). We successfully demonstrated the strong correlation between glucose concentrations measured by a commercially available blood glucometer and the wireless patch-type glucose sensor. Taken together, we could confirm the feasibility of the wireless patch-type robust glucose sensor for noninvasive and continuous diabetic diagnosis.

Although nanocarriers containing perfluorocarbon (PFC) have been widely investigated as an ultrasound (US) imaging agent and a high intensity focused ultrasound (HIFU) agent, these carriers have suffered from low stability and biocompatibility limiting their further biomedical applications. Here, we developed surface cross-linked polymer nanodroplets as a HIFU therapeutic agent guided by bimodal photoacoustic (PA) and US imaging. Pluronic F127 was reacted with 4-nitrophenyl chloroformate (NPC) and mixed with naphthalocyanine (Nc) in dichloromethane, which was added into the aqueous solution of amine-functionalized six-arm-branched poly(ethylene glycol) (PEG) to form an oil-in-water emulsion for the cross-linking reaction between the terminal NPC of Pluronic F127 and the primary amine of six-arm PEG. The resulting solution was sonicated with liquid perfluorohexane (PFH) to prepare PEG cross-linked Pluronic F127 nanoparticles encapsulating Nc and PFH (Nc/PFH@PCPN). Nc/PFH@PCPN appeared to be stable without any coalescence or vaporization in the physiological condition. Upon the application of HIFU, Nc/PFH@PCPN was vaporized and showed increased US intensity for 180 min. The Nc dye in the nanodroplets enabled the stable encapsulation of PFH and the bimodal US/PA imaging. In vivo PA/US image-guided HIFU ablation therapy confirmed that the nanodroplets increased the cavitation effect, induced necrosis and apoptosis of tumor cells, and reduced tumor growth significantly for 12 days. Taken together, the multifunctional Nc/PFH@PCPN was successfully developed as a new platform for PA/US image-guided HIFU therapy.

On-demand drug delivery systems (DDSs) have been widely investigated for spatiotemporally controlled therapy with greatly improved patient compliance. However, power systems to operate the DDSs are one of the serious unmet needs constraining their further applications. Here, we report implantable organic photovoltaic cells using upconversion nanoparticles (UCNPs) for on-demand controlled drug delivery. Although skin-penetrating near infrared (NIR) light cannot be used for flexible organic photovoltaic cells, UCNPs can convert NIR light to visible light for their operation after implantation to the body. The core-shell structured UCNPs coated on flexible organic photovoltaic cells generate current flow upon NIR irradiation for triggering on-demand drug delivery from microelectromechanical system (MEMS) drug reservoirs. Gold (Au) membrane sealing the reservoirs is dissolved to AuCl4− by the applied electrical current triggering the pulsatile drug release. The successful fabrication of NIR light triggered DDS by UCNPs coated organic photovoltaic cells is confirmed by transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM), UV–vis spectroscopy, photoluminescence, current density–voltage characterization, and gold thin film dissolution tests. Furthermore, on-demand model drug release tests confirm the feasibility of the new paradigm light-triggered DDS and the relevant phototherapy.

An in vivo on–off tattoo system was developed using upconversion nanoparticles conjugated with hyaluronate (HA-UCNPs). Two-photon microscopy clearly visualized the transdermal delivery of HA-UCNPs into the deep skin tissue. Upon near-infrared light irradiation, invisible HA-UCNPs in the skin were visualized showing the feasibility as a new on–off tattoo system.

A variety of receptors for hyaluronate (HA), a natural linear polysaccharide, were found in the body, which have been exploited as target sites for HA-based drug delivery systems. In this work, mesenchymal stem cells (MSCs) were surface-modified with HA - wheat germ agglutinin (WGA) conjugate for targeted systemic delivery of MSCs to the liver. WGA was conjugated to HA by coupling reaction between aldehyde-modified HA and amine group of WGA. The conjugation of WGA to HA was corroborated by gel permeation chromatography (GPC) and the successful surface modification of MSCs with HA-WGA conjugate was confirmed by confocal microscopy. The synthesized HA-WGA conjugate could be incorporated onto the cellular membrane by agglutinating the cell-associated carbohydrates. Fluorescent imaging for in vivo biodistribution visualized the targeted delivery of the HA-WGA/MSC complex to the liver after intravenous injection. This new strategy for targeted delivery of MSCs using HA-WGA conjugate might be successfully exploited for various regenerative medicines including cell therapy.

Vaccines are commonly administered by injection using needles. Although transdermal microneedles are less-invasive promising alternatives, needle-free topical vaccination without involving physical damage to the natural skin barrier is still sought after as it can further reduce needle-induced anxiety and simply administration. However, this long-standing goal has been elusive since the intact skin is impermeable to most macromolecules. Here, we show an efficient, non-invasive transdermal vaccination in mice by employing two key innovations: first, the use of hyaluronan (HA) as vaccine carriers and, second, non-ablative laser adjuvants. Conjugates of a model vaccine ovalbumin (OVA) and HA—HA-OVA conjugates—induced more effective maturation of dendritic cells in vitro, compared to OVA or HA alone, through synergistic HA receptor-mediated effects. Following topical administration in the back skin, HA-OVA conjugates penetrated into the epidermis and dermis in murine and porcine skins up to 30% of the total applied quantity, as revealed by intravital microscopy and quantitative fluorescence assay. Topical administration of HA-OVA conjugates significantly elevated both anti-OVA IgG antibody levels in serum and IgA antibody levels in bronchioalveolar lavage, with peak levels at 4 weeks, while OVA alone had a negligible effect. An OVA challenge at week 8 elicited strong immune-recall humoral responses. With pre-treatment of the skin using non-ablative fractional laser beams (1410 nm wavelength, 10 ms pulse duration, 0.2 mJ/pulse) as laser adjuvant, strong immunization was achieved with much reduced doses of HA-OVA (1 mg/kg OVA). Our results demonstrate the potential of the non-invasive patch-type transdermal vaccination platform.

With biocompatibility, biodegradability, and high functionality, silica nanoparticles (SNPs) have been widely investigated for various biomedical applications. However, lack of optical fluorescence has limited the application of SNPs as a degradable imaging agent. Here, we hydrothermally synthesized fluorescent SNPs by artificially generating optically active defect centers using tetraethyl orthosilicate and (3-aminopropyl)trimethoxysilane. The synthesized SNPs demonstrated strong blue photoluminescence originating from the dioxasilyrane (=Si(O2)) and silylene (=Si:) defect centers with the aid of aminopropyl groups. Furthermore, phosphorescence was observed at 459 nm, indicating the presence of silylene in SNPs. Finally, these SNPs have been successfully utilized as a fluorescent probe for bioimaging of normal, cancer, and macrophage cells.

The commercially pure Ti (CP Ti) and equal-channel angular pressing (ECAP) processed Ti can contribute to the downsizing of medical devices with their superior mechanical properties and negligible toxicity. However, the ECAP-processed pure Ti has the risk of bacterial infection. Here, the coarse- and ultrafine-grained Ti substrates were surface-modified with molybdenum disulfide (MoS2) to improve the cell proliferation and growth with antibacterial effect for further dental applications. According to in vitro tests using the pre-osteoblast of MC3T3-E1 cell and a bacterial model of Escherichia coli (E. coli), MoS2 nanoflakes coated and ECAP-processed Ti substrates showed a significant increase in surface energy and singlet oxygen generation resulting in improved cell attachment and antibacterial effect. In addition, we confirmed the stability of the surface modified Ti substrates in a physiological solution and an artificial bone. Taken together, MoS2 modified and ECAP-processed Ti substrates might be successfully harnessed for various dental applications.

Titanium (Ti) is one of the representative biocompatible metallic materials which has been widely exploited for various implants and bone replacements. Here, commercially pure Ti (CP Ti) was surface-modified with reduced graphene oxide (RGO) for accelerated bone regeneration and osseointegration. Nanoscale RGO coating on CP Ti was clearly confirmed by SEM, AFM, EDS, XPS, HR-TEM and EELS. In addition, pre-osteoblast cells cultured on RGO-CP Ti showed higher cell viability and cell attachment than those on CP Ti. After confirmation of the drug loading capability of RGO-CP Ti, osteogenic dexamethasone loaded RGO-CP Ti (Dex/RGO-CP Ti) was implanted on calvarial bone defects in rats. Synchrotron X-ray imaging successfully visualized more effective bone regeneration on Dex/RGO-CP Ti than CP Ti and RGO-CP Ti after 8 weeks.

Light-absorbing nanoparticles for localized heat generation in tissues have various biomedical applications in diagnostic imaging, surgery, and therapies. Although numerous plasmonic and carbon-based nanoparticles with strong optical absorption have been developed, their clearance, potential cytotoxicity, and long-term safety issues remain unresolved. Here, we show that "generally regarded as safe (GRAS)" melanoidins prepared from glucose and amino acid offer a high light-to-heat conversion efficiency, biocompatibility, biodegradability, nonmutagenicity, and efficient renal clearance, as well as a low cost for synthesis. We exhibit a wide range of biomedical photonic applications of melanoidins, including in vivo photoacoustic mapping of sentinel lymph nodes, photoacoustic tracking of gastrointestinal tracts, photothermal cancer therapy, and photothermal lipolysis. The biodegradation rate and renal clearance of melanoidins are controllable by design. Our results confirm the feasibility of biodegradable melanoidins for various photonic applications to theranostic nanomedicines.

A dual-diagnostic system of endom-icroscope and microneedle sensor is developed to demonstrate high-resolution imaging combined with electrical real-time detection of NO released from cancer tissues. The dual-diagnostic system can be a new platform for facile, precise, rapid, and accurate detection of cancers in various biomedical applications.

On-the-spot visualization of biochemical responses of intact live cells is vital for a clear understanding of cell biology. The main obstacles for instant visualization of biochemical responses of living cells arise from the lack of a sophisticated detecting technique which can simultaneously provide chemical analysis tools and the biocompatible wet conditions. Here we introduce scanning transmission X-ray microscopy (STXM) combined with a liquid-enclosing graphene system (LGS), offering biocompatible conditions and improved X-ray absorption spectra to probe the chemical responses of live cells under wet conditions. This set-up enables us to probe a subtle change in absorption spectra depending on the oxidation state of a miniscule amount of oxygen in the functional groups present in each cell and its surroundings containing a minimal amount of liquid water. As an example of in situ biochemical responses of wet cells, chemical responses of a single Colo 205 cell are visualized and analyzed using X-ray absorption near the oxygen K-edge. This spectromicroscopic method using LGS can be applied to diverse biological samples under wet conditions for the analysis of their biochemical responses.

Carbon nanodots (CNDs) have been widely investigated for theranostic applications including fluorescence imaging, photoacoustic imaging, photothermal therapy, and photodynamic therapy. In article number 1700325, Sei Kwang Hahn, Woosung Kwon, and co‐workers develop dual‐color‐emitting CNDs uniquely designed by the electronic structure engineering for both futuristic multi‐color bioimaging and optogenetic control of ion channels.

Background The injection of botulinum toxin (BTX) to reduce facial wrinkles is one of the most frequently performed plastic surgery procedures. The biocompatible hydrogels are injected with BTX for effective tissue augmentation. However, it is difficult to determine the interval of injection for effective tissue augmentation. Method BTX and hyaluronate (HA) hydrogels were labeled with zwitterionic (ZW) near-infrared (NIR) fluorophores and visualized for 3 weeks after injection to BALB/c nude mice. Results BTX-ZW conjugates and diaminohexane (DAH)-HA-ZW hydrogels were successfully prepared by the conventional EDC/NHS chemistry. Using the NIR fluorescence imaging, we confirmed that approximately 10% of BTX-ZW conjugates and 50% of DAH-HA-ZW hydrogels remained 3 weeks post-injection. Conclusion This bioimaging technique using invisible NIR fluorescence light can be exploited for various biomedical applications.

We developed melanoidin nanoparticles for in vivo noninvasive photoacoustic mapping of sentinel lymph nodes, photoacoustic tomography of gastro-intestinal tracts, and photothermal ablation cancer therapy. In addition, we developed cell-integrated poly(ethylene glycol) hydrogels for in vivo optogenetic sensing and therapy. Real-time optical readout of encapsulated heat-shock-protein-coupled fluorescent reporter cells made it possible to measure the nanotoxicity of cadmium-based quantum dots in vivo. Using optogenetic cells producing glucagon-like peptide-1, we performed lightcontrolled diabetic therapy for glucose homeostasis. Finally, we developed a smart contact lens composed of biosensors, drug delivery systems, and power sources for the treatment of diabetes as a model disease.

Regenerative medicine involves interdisciplinary biomimetic approaches for cell therapy and tissue regeneration, employing the triad of cells, signals, and/or scaffolds. Remarkably, the field of therapeutic cells has evolved from the use of embryonic and adult stem cells to the use of induced pluripotent stem cells. For application of these cells in regenerative medicine, cell fate needs to be carefully controlled via external signals, such as the physical properties of an artificial extracellular matrix (ECM) and biologically active molecules in the form of small molecules, peptides, and proteins. It is therefore crucial to develop biomimetic scaffolds, reflecting the nanoenvironment of three-dimensional (3D) ECM in the body. Here, we describe in situ -forming injectable hydrogel systems, prepared using a variety of chemical crosslinkers and/or physical interactions, for application in regenerative medicine. Selective and fast chemical reactions under physiological conditions are prerequisites for in situ formation of injectable hydrogels. These hydrogels are attractive for regenerative medicine because of their ease of administration, facile encapsulation of cells and biomolecules without severe toxic effects, minimally invasive treatment, and possibly enhanced patient compliance. Recently, the Michael addition reaction between thiol and vinyl groups, the click reaction between bis(yne) molecules and multiarm azides, and the Schiff base reaction have been investigated for generation of injectable hydrogels, due to the high selectivity and biocompatibility of these reactions. Noncovalent physical interactions have also been proposed as crosslinking mechanisms for in situ forming injectable hydrogels. Hydrophobic interactions, ionic interactions, stereocomplex formation, complementary pair formation, and host–guest interactions drive the formation of 3D polymeric networks. In particular, supramolecular hydrogels have been developed using the host–guest chemistry of cyclodextrin (CD) and cucurbituril (CB), which allows highly selective, simple, and biocompatible crosslinking. Molecular recognition and complex formation of supramolecules, without the need for additional additives, have been successfully applied to the 3D network formation of polymer chains. Finally, we review the current state of the art of injectable hydrogel systems for application in regenerative medicine, including cell therapy and tissue regeneration.

Synthetic hydrogels have been extensively investigated as artificial extracellular matrices (ECMs) for tissue engineering in vitro and in vivo. Crucial challenges for such hydrogels are sustaining long-term cytocompatible encapsulation and providing appropriate cues at the right place and time for spatio-temporal control of the cells. Here, in situ supramolecularly assembled and modularly modified hydrogels for long-term engineered mesenchymal stem cell (eMSC) therapy are reported using cucurbit[6]uril-conjugated hyaluronic acid (CB[6]-HA), diaminohexane conjugated HA (DAH-HA), and drug-conjugated CB[6] (drug-CB[6]). The eMSCs producing enhanced green fluorescence protein (EGFP) remain alive and emit the fluorescence within CB[6]/DAH-HA hydrogels in mice for more than 60 d. Furthermore, the long-term expression of mutant interleukin-12 (IL-12M) by eMSCs within the supramolecular hydrogels results in effective inhibition of tumor growth with a significantly enhanced survival rate. Taken together, these findings confirm the feasibility of supramolecular HA hydrogels as 3D artificial ECMs for cell therapies and tissue engineering applications.

Nanoparticles with excellent physical and chemical properties are very promising for biomedical applications. However, their application in clinical trials may be hindered by their toxicity. Among various biomedical materials, silica nanoparticles (SNPs) are most attractive and widely studied materials owing to their high biocompatibility and functionality. In this study, we have synthesized fluorescent SNPs with controlled shapes and sizes by using SiCl4. To control the reaction rate of SiCl4 with water, two solvents immiscible with each other were employed. Our SNPs exhibit fluorescence near 2.95 eV (420 nm), originated from optically active silanone and dioxasilyrane defects, and are applied to in-vitro bioimaging of lung epithelial carcinoma cells (A549) without cytotoxicity. We believe that our novel synthesis method using orthogonal solvents will broaden the application range of highly reactive but potentially suitable precursors, which successfully realizes SNPs with defect-induced optical properties for various biomedical applications.

The phase behaviors of binary blends of poly(styrene-b-butadiene) block copolymers were investigated by a small-angle X-ray scattering technique. The blends were composed of weakly segregated one in a random micellar phase and the other in a cylindrical phase with similar molecular weights and complementary volume fractions. Morphologies, domain spacings, and order–disorder transition temperatures of the blends indicated that the junctions of the constituent block copolymers share the interface at low temperatures. The domain spacing decreased as temperature increased in a blend with a small amount of the weakly segregated block copolymer. In the cases of the blends with a large amount of the weakly segregated constituent, domain spacing increased with increasing temperature. These results implied that some of the weakly segregated block copolymer moved from the interface to one microdomain at higher temperatures. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2014, 52, 470–476

Despite wide exploitation of corticosteroid drugs for the treatment of asthma, the poor therapeutic effect on a neutrophilic subtype of asthma prohibits the full recovery of asthma patients. In this work, dexamethasone (Dexa) was loaded in Flt1 peptide-hyaluronic acid (HA) conjugate nanoparticles to overcome the limitation of corticosteroid resistance for the treatment of neutrophilic pulmonary inflammation. Flt1 peptide-HA conjugates are self-assembled to nanoparticles because of hydrophobic Flt1 peptide conjugated to HA by benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) chemistry. In vitro bioimaging showed efficient internalization of Flt1 peptide-HA conjugate nanoparticles into lung epithelial cells by HA-receptor mediated endocytosis. Also, ex vivo imaging for the biodistribution in ICR mice revealed long-term retention of Flt1 peptide-HA conjugate nanoparticles in deep lung tissues possibly due to mucoadhesive property of HA. On the basis of bioimaging results for pulmonary drug delivery applications, we prepared Dexa-loaded Flt1 peptide-HA conjugate nanoparticles. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) confirmed the formation of nanoparticles, which reduced cytokine levels of lipopolysaccharide (LPS)-stimulated cells more efficiently than free Dexa. Furthermore, according to the bronchoalveolar lavage (BAL) cellularity and histological analysis, Dexa loaded Flt1 peptide-HA conjugate nanoparticles showed remarkable therapeutic effects in both eosinophilic and neutrophilic asthma model mice.

We demonstrated biopolymer waveguides that are gradually resorbed by the tissue and used them for wound closure. The waveguides enabled a 10-fold extension of the photoactivated tissue area in comparision with conventional photochemical bonding.

Ultrafine-grained (UFG) Ti for improved mechanical performance as well as its surface modification enhancing biofunctions has attracted much attention in medical industries. Most of the studies on the surface etching of metallic biomaterials have focused on surface topography and wettability but not crystallographic orientation, i.e., texture, which influences the chemical as well as the physical properties. In this paper, the influences of texture and grain size on roughness, wettability, and pre-osteoblast cell response were investigated in vitro after HF etching treatment. The surface characteristics and cell behaviors of ultrafine, fine, and coarse-grained Ti were examined after the HF etching. The surface roughness during the etching treatment was significantly increased as the orientation angle from the basal pole was increased. The cell adhesion tendency of the rough surface was promoted. The UFG Ti substrate exhibited a higher texture energy state, rougher surface, enhanced hydrophilic wettability, and better cell adhesion and proliferation behaviors after etching than those of the coarse- and fine-grained Ti substrates. These results provide a new route for enhancing both mechanical and biological performances using etching after grain refinement of Ti.

Low density lipoprotein (LDL) plays an important role in transporting fat molecules including cholesterols in the body. In this work, cationic solid lipid nanoparticles (CSLNs), bioinspired and reconstituted from natural LDLs, were designed and applied to target specific systemic delivery of connective tissue growth factor siRNA (siCTGF) for the treatment of liver fibrosis. They could form a nuclease-resistant stable nano-complex with siRNA, which was efficiently internalized into cells achieving targeted gene silencing in the presence of serum with a remarkably low cytotoxicity. After intravenous injection, CSLN/siCTGF complex was target specifically delivered to the liver and resulted in a significant reduction in collagen content and pro-fibrogenic factors like tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), interleukin-6 (IL-6), and CTGF with the dramatic improvement of patho-physiological symptoms in liver fibrosis model rats. The bio-distribution study by fluorescence bioimaging and single-photon emission computed tomography (SPECT) confirmed the target specific delivery and accumulation of CSLN/siCTGF complexes to the liver tissues.

Noninvasive transdermal delivery is a promising method with distinct advantages including patient compliance over other delivery routes. Here, hyaluronate–gold nanorod/death receptor 5 antibody (HA-AuNR/DR5 Ab) complex was developed for transdermal theranosis of skin cancer. The successful formation of the complex was corroborated by 1H nuclear magnetic resonance, UV–vis spectroscopy, dynamic light scattering, zeta potential, and transmission electron microscopy. In vitro biological activity of the complex was verified by ELISA and MTT assay using HCT116 cancer cells. In addition, in vivo photoacoustic imaging and two-photon microscopy clearly visualized the transdermal delivery of HA-AuNR/DR5 Ab complex through the inevitable barrier of stratum corneum in the skin. Furthermore, in vivo antitumor effect on skin cancer model mice was confirmed from statistically significant decrease of tumor-reflecting luciferase expression levels and apoptotic signals in terminal deoxynucleotidyl transferase dUTP nick end...

Multifunctional nanoparticles have been widely investigated for biomedical applications, such as imaging, therapy, and drug delivery. Especially, photoactive nanoparticles have received great attention as theranostic agents because of their heat-generating abilities after exposure to laser irradiation. However, photostability and safety issues have been the technical hurdles for further clinical applications. Here, we designed nitrogen (N)-doped carbon nanodots (N-CNDs) that have strong absorption in the near-infrared region, high photostability, and excellent biodegradability. Optimized N-CNDs can be utilized not only as a new photoacoustic (PA) imaging agent but also as a superior photothermal therapy (PTT) agent in vivo because of their strong optical absorption at a specific wavelength. We used N-CNDs to perform in vivo/ex vivo noninvasive PA imaging of sentinel lymph nodes via local delivery and performed PTT for cancer ablation therapy. Finally, biodegradation and renal clearance were confirmed by performing whole-body PA monitoring and a degradation test.

The use of cell-rich hydrogels for three-dimensional (3D) cell culture has shown great potential for a variety of biomedical applications. However, the fabrication of appropriate constructs has been challenging. In this study, we describe a 3D printing process for the preparation of a multilayered 3D construct containing human mesenchymal stromal cells with a hydrogel comprised of atelocollagen and supramolecular hyaluronic acid (HA). This construct showed outstanding regenerative ability for the reconstruction of an osteochondral tissue in the knee joints of rabbits. We found that the use of a mechanically stable, host-guest chemistry-based hydrogel was essential and allowed two different types of extracellular matrix (ECM) hydrogels to be easily printed and stacked into one multilayered construct without requiring the use of potentially harmful chemical reagents or physical stimuli for post-crosslinking. To the best of our knowledge, this is the first study to validate the potential of a 3D printed multilayered construct consisting of two different ECM materials (atelocollagen and HA) for heterogeneous tissue regeneration using an in vivo animal model. We believe that this 3D printing-based platform technology can be effectively exploited for regeneration of various heterogeneous tissues as well as osteochondral tissue.

Flt1 peptide of GNQWFI is an antagonistic peptide for vascular endothelial growth factor receptor 1 (VEGFR1 or Flt1). In this work, Flt1 peptide-hyaluronate (HA) conjugates were successfully synthesized and the resulting micelle-like nanoparticles were exploited to encapsulate genistein, an inhibitor of tyrosine-specific protein kinases, for the treatment of ocular neovascularization. The mean diameter of genistein-loaded Flt1 peptide-HA conjugate micelles was measured to be 172.0±18.7 nm, with a drug-loading efficiency of 40-50%. In vitro release tests of genistein from the genistein-loaded Flt1 peptide-HA conjugate micelles exhibited the controlled release for longer than 24h. In vitro biological activity of genistein/Flt1 peptide-HA micelles was corroborated from the synergistic anti-proliferation of human umbilical vein endothelial cells (HUVECs). Furthermore, we could confirm the anti-angiogenic effect of genistein/Flt1 peptide-HA micelles from the statistically significant suppression of corneal neovascularization in silver nitrate cauterized corneas of SD rats. The retinal vascular hyperpermeability was also drastically reduced by the treatment in diabetic retinopathy model rats.

Caspase-3 plays an important role in the initiation and propagation of apoptosis which is involved in various kinds of diseases including neurodegenerative diseases and inflammatory diseases. The capase-3 cleavable site of Asp-Glu-Val-Asp (DEVD) connected to a partial sequence of Escherichia coli RNAI was labeled with tetramethyl-6-carboxyrhodamine (TAMRA) as an optical probe. Graphene oxide (GO) was synthesized by a modified Hummer's method and exploited for the preparation of nano-sized GO (NGO) conjugated with polyethylene glycol (PEG). After binding the NGO-PEG by π-π stacking, the quenched fluorescence of TAMRA-DEVD-single stranded DNA (ssDNA) conjugate was recovered via the enzymatic cleavage by caspase-3 in live A549 cells. The comparative study with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay clearly confirmed the specific detection of apoptosis by the non-covalent TAMRA-DEVD-ssDNA/NGO-PEG complex. Furthermore, the self-assembled NGO complex was successfully exploited for in vivo diagnosis of apoptosis-related diseases like hypoxic-ischemic encephalopathy (HIE) and liver cirrhosis.

The temperature-responsive poly(N-isopropylacrylamide) [PNIPAAm] has been exploited for various biomedical applications. In this work, poly(N-isopropylacrylamide-co-dopamine methacrylamide) [P(NIPAAm-co-DMAAm)] was synthesized for facile surface modification and application to cell sheets. 1H NMR, FT-IR, and GPC confirmed the successful synthesis of P(NIPAAm-co-DMAAm). The lower critical solution temperature was measured to be ca. 29.2 °C by UV–Vis spectroscopy. AFM imaging clearly visualized the transient phase transition of the temperature-responsive polymer bound on silicon substrate by coordination bond formation. Furthermore, the adhesive and temperature responsive P(NIPAAm-co-DMAAm) could be successfully applied to the facile preparation of NIH-3T3 fibroblast cell sheets.

Theranostic systems have been widely investigated for application in the diagnostic therapy of cancers. In this work, hyaluronic acid (HA)-doxorubicin (DOX) conjugate was successfully synthesized by the amide bond formation between amine groups of DOX and carboxylic groups of HA activated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysulfosuccinimide. The 1H nuclear magnetic resonance (NMR) and gel permeation chromatographic (GPC) analyses confirmed the successful synthesis of HA-DOX conjugates. HA-DOX conjugates self-assembled to micelle-like nanoparticles in aqueous solution. In vitro anti-proliferation tests of cancer cells confirmed the anti-tumor effect of HA-DOX conjugate micelles. For further application, the micelles were coated with a gold (Au) half-shell by the thermal vapor deposition method, which might contribute to prolonging the residence time in the body with a versatile surface modification on the Au surface. TEM analysis confirmed the successful Au coating on HA-DOX conjugate micelles with a thickness of 15 nm. The Au half-shell-coated HADOX conjugate micelles might be successfully exploited for cancer theranostic applications such as chemotherapy, hyperthermia, and bioimaging.

Interferon alpha (IFNα) conjugated with polyethylene glycol (PEG) has been widely used for the treatment of hepatitis C virus (HCV) infection as a once-a-week injection formulation. However, the PEGylated IFNα has a low efficacy of ca. 39% and a side effect after repeated injections possibly due to the non-specific delivery with PEGylation. In this work, target specific long-acting hyaluronic acid-interferon alpha (HA-IFNα) conjugate was successfully developed for the treatment of HCV infection. HA-IFNα conjugate was synthesized by coupling reaction between aldehyde modified HA and the N-terminal group of IFNα. The IFNα content could be controlled in the range of 2-9 molecules per single HA chain with a bioconjugation efficiency higher than 95%. According to in vitro anti-proliferation assay using Daudi cells, HA-IFNα conjugate showed a comparable biological activity to PEG-Intron. In vivo real-time bioimaging confirmed the target specific delivery of near-infrared fluorescence (NIRF) dye labeled HA-IFNα conjugate to the liver in mice. In addition, pharmacokinetic analysis revealed the enhanced residence time longer than 4 days. After tail-vein injection, HA-IFNα conjugate induced ca. 60% higher expression of 2',5'-oligoadenylate synthetase 1 (OAS 1) for innate immune responses to viral infection in the murine liver tissues than IFNα and PEG-Intron.

Target-specific intracellular delivery of small interfering RNA (siRNA) is regarded as one of the most important technologies for the development of siRNA therapeutics. In this work, a cysteamine modified gold nanoparticles (AuCM)/siRNA/polyethyleneimine (PEI)/hyaluronic acid (HA) complex was successfully developed using a layer-by-layer method for target-specific intracellular delivery of siRNA by HA receptor mediated endocytosis. Atomic force microscopic and zeta potential analyses confirmed the formation of a AuCM/siRNA/PEI/HA complex having a particle size of ca. 37.3 nm and a negative surface charge of ca. -12 mV. With a negligible cytotoxicity, AuCM/siRNA/PEI/HA complex showed an excellent target-specific gene silencing efficiency of ca. 70% in the presence of 50 vol % serum, which was statistically much higher than that of siRNA/Lipofectamine 2000 complex. In the competitive binding tests with free HA, dark-field bioimaging and inductively coupled plasma-atomic emission spectroscopy confirmed the target-specific intracellular delivery of AuCM/siRNA/PEI/HA complex to B16F1 cells with HA receptors. Moreover, the systemic delivery of AuCM/siRNA/PEI/HA complex using apolipoprotein B (ApoB) siRNA as a model drug resulted in a significantly reduced ApoB mRNA level in the liver tissue. Taken together, AuCM/siRNA/PEI/HA complex was thought to be developed as target-specific siRNA therapeutics for the systemic treatment of various liver diseases.

Despite wide applications of bone morphogenetic protein–2 (BMP-2), there are few methods to incorporate BPM-2 within polymeric scaffolds while maintaining biological activity. Solid free-form fabrication (SFF) of tissue-engineering scaffold is successfully carried out with poly(lactic-co-glycolic acid) grafted hyaluronic acid (HA-PLGA) encapsulating intact BMP-2/poly(ethylene glycol) (PEG) complex. HA-PLGA conjugate is synthesized in dimethyl sulfoxide (DMSO) by the conjugation reaction of adipic acid dihydrazide modified HA (HA-ADH) and PLGA activated with N,N′-dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS). BMP-2 is complexed with PEG, which is encapsulated within the PLGA domain of the HA-PLGA conjugate by SFF to prepare tissue-engineering scaffolds. In vitro release tests confirm the sustained release of intact BMP-2 from the scaffolds for up to a month. After confirmation of the enhanced osteoblast cell growth, and high gene-expression levels of alkaline phosphatase (ALP), osteocalcin (OC), and osterix (OSX) in the cells, the HA-PLGA/PEG/BMP-2 scaffolds are implanted into calvarial bone defects of Sprague Dawley (SD) rats. Microcomputed tomography (μCT) and histological analyses with Masson's trichrome, and hematoxylin and eosin (H&E) staining reveal effective bone regeneration on the scaffolds of HA-PLGA/PEG/BMP-2 blends.

HA–HMDA hydrogels were developed by direct amide bond formation between the carboxyl groups of hyaluronic acid (HA) and hexamethylenediamine (HMDA) with an optimized carboxyl group modification in the preliminary experiment. However, these HA–HMDA hydrogels transformed into an unstable liquid form after steam sterilization, and were problematic for application to actual dermal filler. A new method to overcome the problem of the previously developed HA–HMDA hydrogels is to prepare them by adjusting the pH in this study. Not only are these improved HA–HMDA hydrogels prepared with lower amounts of cross-linking and activation agents compared to the previously developed hydrogels, but they also maintain a stable form after steam sterilization. These improved HA–HMDA hydrogels showed higher viscoelasticity and longer lasting effects than the previous ones, despite the fact that the amount of the HMDA used as a cross-linking agent as well as 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) and 1-hydroxybenzotriazole monohydrated (HOBt) used as activation agents were substantially reduced. According to an in vivo test using a wrinkled mouse model, the improved HA–HMDA hydrogels exhibited significantly improved tissue augmentation effects compared to a positive control of Restylane, which is widely used for the tissue augmentation throughout the world. Furthermore, histological analysis revealed excellent biocompatibility and safety of the improved synthesized HA–HMDA hydrogels.

Rheumatoid arthritis (RA) is a chronic inflammatory disease caused by inflammation of the synovial membrane, leading in turn to articular cartilage destruction. In this work, injectable tyramine modified hyaluronic acid (HA-Tyr) hydrogels were developed for the treatment of RA. HA-Tyr conjugate was synthesized by amide bond formation between carboxyl groups of HA and amine groups of tyramine. Then, HA-Tyr hydrogels were prepared by radical crosslinking reaction using H(2)O(2) and horse-radish peroxidase. Intra-articular injection of HA-Tyr hydrogels encapsulating dexamethasone (DMT) as a model drug resulted in successful treatment of RA with reduced interlukine-6, prostaglandin E2 and four types of cytokine levels in collagen-induced arthritis animal models. Histological analysis with hematoxylin and eosin (H&E) staining also confirmed the therapeutic effect of injectable HA-Tyr hydrogels with DMT. Taken together, the injectable HA-Tyr hydrogels were thought suitable to be developed as a therapeutically effective drug carrier for the treatment of RA.

A novel artificial bone substitute composed of bioactive MegaGen synthetic bone (MGSB) and hyaluronate (HA) hydrogels was successfully developed for bone tissue engineering applications. HA is known to play important roles in bone regeneration due to its angiogenic and osteoconductive characteristics. Accordingly, HA hydrogel was designed to supply HA continuously for effective bone regeneration by its controlled degrada- tion in vivo. Synchrotron X-ray bio-imaging clearly visualized 3-dimensional micron scale morphologies of effectively regenerated bones by the bone substitute of MGSB/Hyaluronate-Cystamine hydrogels implanted to the calvarial critical size bone defects in New Zealand white rabbits.

Pharmacological and barrier-based approaches have been exploited for the treatment of post-surgical adhesion. In this study, anti-coagulating hydroxyethyl starch (HES) blended with hyaluronic acid (HA) was assessed as a novel post-surgical adhesion barrier in Sprague-Dawley (SD) rats to take advantage of both approaches. The HES/HA blend solution effectively reduced the adhesion area to 6.5% of the control, which might be due to the inhibited blood coagulation by HES as well as highly effective barrier properties of hygroscopic high molecular weight HA. Histological analysis showed that the HES/HA blend solutions effectively protected the smooth muscle cells and skeletal muscle cells from muscle degeneration by adhesion in the abdominal walls of SD rats.