"Tree to Bone": Lignin/Polycaprolactone Nanofibers for Hydroxyapatite Biomineralization.

Bone contains an organic matrix composed of aligned collagen fibers embedded with nanosized inorganic hydroxyapatite (HAp). Many efforts are being made to mimic the natural mineralization process and create artificial bone scaffolds that show elaborate morphologies, excellent mechanical properties, and vital biological functions. This study reports a newly discovered function of lignin mediating the formation of human bone-like HAp. Lignin is the second most abundant organic material in nature, and it exhibits many attractive properties for medical applications, such as high durability, stability, antioxidant and antibacterial activities, and biocompatibility. Numerous phenolic and aliphatic hydroxyl moieties exist in the side chains of lignin, which donate adequate reactive sites for chelation with Ca2+ and the subsequent nucleation of HAp through coprecipitation of Ca2+ and PO43-. The growth of HAp crystals was facilitated by simple incubation of the electrospun lignin/polycaprolactone (PCL) matrix in a simulated body fluid. Multiple analyses revealed that HAp crystals were structurally and mechanically similar to the native bone. Furthermore, the mineralized lignin/PCL nanofibrous films facilitated efficient adhesion and proliferation of osteoblasts by directing filopodial extension. Our results underpin the expectations for this lignin-based biomaterial in future biointerfaces and hard-tissue engineering.

Multivalent Polyaspartamide Cross-Linker for Engineering Cell-Responsive Hydrogels with Degradation Behavior and Tunable Physical Properties.

Hydrogels possess favorable physical properties ideally suited for various biotechnology applications. To tailor to specific needs, a number of modification strategies have been employed to tune their properties. Herein, a multifunctional polymeric cross-linker based on polyaspartamide is developed, which allows for the facile adjustment of the type and number of reactive functional groups to fit different reaction schemes and control the physical properties of the hydrogels. The amine-based nucleophiles containing desired functional groups are reacted with polysuccinimide to synthesize polyaspartamide cross-linkers. The cross-linking density and the concurrent change in mechanical properties of the resulting hydrogels are controlled in a wide range only with the degree of substitution. This multivalency of the polyaspartamide linkers also induced the degradation of hydrogels by the unreacted functional groups on polyaspartamide involved in the hydrolysis. Furthermore, the polyaspartamide cross-linker conjugated with cell-recognition molecules via the same conjugation mechanism (i.e., nucleophilic substitution) render the hydrogels cell-responsive without the need of additional processing steps. This versatility of polyaspartamide-based cross-linker is expected to provide an efficient and versatile route to engineer hydrogels with controllable properties for biomedical applications.

Stacking Geometries of Early Protoporphyrin IX Aggregates Revealed by Gas-Phase Infrared Spectroscopy.

Amphiphilic porphyrins are of great interest in the field of supramolecular chemistry because they can be fabricated into highly ordered architectures that are stabilized by π-π stacking of porphine rings as well as by non-covalent interactions between their hydrophilic substituents. Protoporphyrin IX (PPIX) has two flexible propionic acid tails and is one of the most common amphiphilic porphyrins. However, unlike other PPIX analogues, PPIX does not form stable extended nanostructures, and the reason for this is still not understood. Here, we employ ion mobility mass spectrometry in combination with infrared multiple photon dissociation spectroscopy to investigate early aggregates of PPIX. The ion mobility results show that growth occurs via single-stranded face-to-face stacking of PPIX. From the infrared spectroscopy on well-defined aggregates, it can be concluded that pairing of the carboxylic acid groups of the tails is a stabilizing element and that such a pairing occurs across a third residue from residue n to residue n+2. The tetramer appears to be especially stable, because all of its propionic acid tails are optimally paired and no free tails to promote further growth are present, which possibly prevents PPIX from forming larger, well-ordered assemblies.

Lateral Piezoelectricity of Alzheimer's Aß Aggregates.

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder in the elderly aged over 65. The extracellular accumulation of beta-amyloid (Aß) aggregates in the brain is considered as the major event worsening the AD symptoms, but its underlying reason has remained unclear. Here the piezoelectric characteristics of Aß aggregates are revealed. The vector piezoresponse force microscopy (PFM) analysis results exhibit that Aß fibrils have spiraling piezoelectric domains along the length and a lateral piezoelectric constant of 44.1 pC N-1. Also, the continuous sideband Kelvin probe force microscopy (KPFM) images display that the increment of charge-induced surface potential on a single Aß fibril is allowed to reach above +1700 mV in response to applied forces. These findings shed light on the peculiar mechano-electrical surface properties of pathological Aß fibrils that exceed those of normal body components.

Linnaeite Mineral for NIR Light-Triggered Disruption of Alzheimer's Pore-Forming Aß Oligomers.

Minerals in the Earth's crust have contributed to the natural functioning of ecosystems via biogeochemical interactions. Linnaeite is a cobalt sulfide mineral with a cubic spinel structure that promotes charge transfer reactions with its surroundings. Here we report the hidden feature of linnaeite mineral to dissociate Alzheimer's ß-amyloid (Aß) oligomers under near-infrared (NIR) light irradiation. Alzheimer's disease (AD) is a neurodegenerative disorder caused by the abnormal accumulation of self-assembled Aß peptides in the elderly brain. The ß-sheet structured pore-forming Aß oligomer (ßPFO) is the most neurotoxic species exacerbating the symptoms of AD. However, a therapeutic agent that is capable of inactivating ßPFO has not yet been developed. Our microscopic and spectroscopic analysis results have revealed that NIR-excited linnaeite mineral can modulate the structure of ßPFO by inducing oxidative modifications. We have verified that linnaeite mineral is biocompatible with and has a mitigating effect on the neurotoxicity of ßPFO. This study suggests that minerals in nature have potential as drugs to reduce AD pathology.

Magnetoelectric dissociation of Alzheimer's ß-amyloid aggregates.

The abnormal self-assembly of ß-amyloid (Aß) peptides and their deposition in the brain is a major pathological feature of Alzheimer's disease (AD), the most prevalent chronic neurodegenerative disease affecting nearly 50 million people worldwide. Here, we report a newly discovered function of magnetoelectric nanomaterials for the dissociation of highly stable Aß aggregates under low-frequency magnetic field. We synthesized magnetoelectric BiFeO3-coated CoFe2O4 (BCFO) nanoparticles, which emit excited charge carriers in response to low-frequency magnetic field without generating heat. We demonstrated that the magnetoelectric coupling effect of BCFO nanoparticles successfully dissociates Aß aggregates via water and dissolved oxygen molecules. Our cytotoxicity evaluation confirmed the alleviating effect of magnetoelectrically excited BCFO nanoparticles on Aß-associated toxicity. We found high efficacy of BCFO nanoparticles for the clearance of microsized Aß plaques in ex vivo brain tissues of an AD mouse model. This study shows the potential of magnetoelectric materials for future AD treatment using magnetic field.

Metal-Organic Framework-Derived Carbon as a Photoacoustic Modulator of Alzheimer's ß-Amyloid Aggregate Structure.

Photoacoustic materials emit acoustic waves into the surrounding by absorbing photon energy. In an aqueous environment, light-induced acoustic waves form cavitation bubbles by altering the localized pressure to trigger the phase transition of liquid water into vapor. In this study, we report photoacoustic dissociation of beta-amyloid (Aß) aggregates, a hallmark of Alzheimer's disease, by metal-organic framework-derived carbon (MOFC). MOFC exhibits a near-infrared (NIR) light-responsive photoacoustic characteristic that possesses defect-rich and entangled graphitic layers that generate intense cavitation bubbles by absorbing tissue-penetrable NIR light. According to our video analysis, the photoacoustic cavitation by MOFC occurs within milliseconds in the water, which was controllable by NIR light dose. The photoacoustic cavitation successfully transforms robust, ß-sheet-dominant neurotoxic Aß aggregates into nontoxic debris by changing the asymmetric distribution of water molecules around the Aß's amino acid residues. This work unveils the therapeutic potential of NIR-triggered photoacoustic cavitation as a modulator of the Aß aggregate structure.

Light-Stimulated Carbon Dot Hydrogel: Targeting and Clearing Infectious Bacteria In Vivo.

Infectious bacteria evolve fast into resistance to conventional antimicrobial agents, whereas treatments for drug resistance bacteria progress more slowly. Here, we report a universally applicable photoactivated antimicrobial modality through light-responsive carbon dot-embedding soft hyaluronic acid hydrogel (CDgel). Because of the innate nature of the infectious bacteria that produce hyaluronidase, applied hyaluronic acid-based CDgel breaks down via bacteria and releases carbon dots (CDs) into the infectious sites. The released CDs possess photodynamic capabilities under light irradiation, inducing 1O2 generation and growth inhibition of the infectious bacteria, S. aureus and E. coli (∼99% and ∼97%, respectively), in vitro. In particular, these photodynamic effects of CDs from CDgel have been shown to accelerate the healing of infected wounds in vivo, showing a higher wound regeneration rate as compared to that of untreated wounds. Our work demonstrates that the biocompatible and shape-controllable CDgel possesses therapeutic potential as a treatment modality for the light-driven control of drug-resistant bacterial infections.

Siloxane Hybrid Material-Encapsulated Highly Robust Flexible µLEDs for Biocompatible Lighting Applications.

Flexible micro-light-emitting diodes (f-µLEDs) have been regarded as an attractive light source for the next-generation human-machine interfaces, thanks to their noticeable optoelectronic performances. However, when it comes to their practical utilizations fulfilling industrial standards, there have been unsolved reliability and durability issues of the f-µLEDs, despite previous developments in the high-performance f-µLEDs for various applications. Herein, highly robust flexible µLEDs (f-HµLEDs) with 20 × 20 arrays, which are realized by a siloxane-based organic-inorganic hybrid material (SHM), are reported. The f-HµLEDs are created by combining the f-µLED fabrication process with SHM synthesis procedures (i.e., sol-gel reaction and successive photocuring). The outstanding mechanical, thermal, and environmental stabilities of our f-HµLEDs are confirmed by a host of experimental and theoretical examinations, including a bending fatigue test (105 bending/unbending cycles), a lifetime accelerated stress test (85 °C and 85% relative humidity), and finite element method simulations. Eventually, to demonstrate the potential of our f-HµLEDs for practical applications of flexible displays and/or biomedical devices, their white light emission due to quantum dot-based color conversion of blue light emitted by GaN-based f-HµLEDs is demonstrated, and the biocompatibility of our f-HµLEDs is confirmed via cytotoxicity and cell proliferation tests with muscle, bone, and neuron cell lines. As far as we can tell, this work is the first demonstration of the flexible µLED encapsulation platform based on the SHM, which proved its mechanical, thermal, and environmental stabilities and biocompatibility, enabling us to envisage biomedical and/or flexible display applications using our f-HµLEDs.

Near-Infrared-Active Copper Molybdenum Sulfide Nanocubes for Phonon-Mediated Clearance of Alzheimer's ß-Amyloid Aggregates.

Ternary chalcogenide materials have attracted significant interest in recent years because of their unique physicochemical and optoelectronic properties without relying on precious metals, rare earth metals, or toxic elements. Copper molybdenum sulfide (Cu2MoS4, CMS) nanocube is a biocompatible ternary chalcogenide nanomaterial that exhibits near-infrared (NIR) photocatalytic activity based on its low band gap and electron-phonon coupling property. Here, we study the efficacy of CMS nanocubes for dissociating neurotoxic Alzheimer's ß-amyloid (Aß) aggregates under NIR light. The accumulation of Aß aggregates in the central nervous system is known to cause and exacerbate Alzheimer's disease (AD). However, clearance of the Aß aggregates from the central nervous system is a considerable challenge due to their robust structure formed through self-assembly via hydrogen bonding and side-chain interactions. Our spectroscopic and microscopic analysis results have demonstrated that NIR-excited CMS nanocubes effectively disassemble Aß fibrils by changing Aß fibril's nanoscopic morphology, secondary structure, and primary structure. We have revealed that the toxicity of Aß fibrils is alleviated by NIR-stimulated CMS nanocubes through in vitro analysis. Moreover, our ex vivo evaluations have suggested that the amount of Aß plaques in AD mouse's brain decreased significantly by NIR-excited CMS nanocubes without causing any macroscopic damage to the brain tissue. Collectively, this study suggests the potential use of CMS nanocubes as a therapeutic ternary chalcogenide material to alleviate AD in the future.

Extremely Stable Luminescent Crosslinked Perovskite Nanoparticles under Harsh Environments over 1.5 Years.

Organic-inorganic hybrid perovskite nanoparticles (NPs) are a very strong candidate emitter that can meet the high luminescence efficiency and high color standard of Rec.2020. However, the instability of perovskite NPs is the most critical unsolved problem that limits their practical application. Here, an extremely stable crosslinked perovskite NP (CPN) is reported that maintains high photoluminescence quantum yield for 1.5 years (>600 d) in air and in harsher liquid environments (e.g., in water, acid, or base solutions, and in various polar solvents), and for more than 100 d under 85 °C and 85% relative humidity without additional encapsulation. Unsaturated hydrocarbons in both the acid and base ligands of NPs are chemically crosslinked with a methacrylate-functionalized matrix, which prevents decomposition of the perovskite crystals. Counterintuitively, water vapor permeating through the crosslinked matrix chemically passivates surface defects in the NPs and reduces nonradiative recombination. Green-emitting and white-emitting flexible large-area displays are demonstrated, which are stable for >400 d in air and in water. The high stability of the CPN in water enables biocompatible cell proliferation which is usually impossible when toxic Pb elements are present. The stable materials design strategies provide a breakthrough toward commercialization of perovskite NPs in displays and bio-related applications.

Piezoelectric materials for ultrasound-driven dissociation of Alzheimer's ß-amyloid aggregate structure.

Piezoelectric materials can evoke electrochemical reactions by transferring charge carriers to reactants upon receiving mechanical stimuli. We report a newly discovered function of piezoelectric bismuth oxychloride (BiOCl) nanosheets for dissociating Alzheimer's ß-amyloid (Aß) aggregates through ultrasound-induced redox reactions. The accumulation of Aß aggregates (e.g., Aß fibrils, plaques) in the central nervous system is a major pathological hallmark of Alzheimer's disease (AD). Thus, clearing Aß aggregates is considered a key for treating AD, but the dissociation of Aß aggregates is challenging due to their extremely robust structure consisting of ß-sheets. BiOCl nanosheets are a biocompatible piezoelectric material with piezocatalytic activity in response to ultrasound. Our analyses using multiple spectroscopic and microscopic tools have revealed that BiOCl nanosheets effectively disassemble Aß fibrils under ultrasound stimulation. Sono-activated BiOCl nanosheets produce piezo-induced oxidative stress, which effectively destabilizes the ß-sheets in Aß fibrils. In vitro evolution has also shown that sono-activated BiOCl nanosheets can effectively alleviate the neuro-toxicity of Aß fibrils. Furthermore, ex vivo evolution demonstrated that amount of Aß plaques in AD mouse's brain slices was drastically reduced by treatment with sono-activated BiOCl nanosheets.

Near-Infrared-Active Copper Bismuth Oxide Electrodes for Targeted Dissociation of Alzheimer's ß-Amyloid Aggregates.

The abnormal accumulation of ß-amyloid (Aß) aggregates in the brain is a major pathological hallmark of Alzheimer's disease. We report a near-infrared (NIR)-active CuBi2O4-based photocathodic platform that can target intact Aß aggregates and dissociate them into nontoxic species. Because of its relatively narrow band gap, CuBi2O4 exhibits strong absorption of NIR light, which allows for deeper tissue penetration and causes less photodamage to tissues compared to visible light. Furthermore, its high stability in aqueous media, biocompatibility, and robustness against photocorrosion make CuBi2O4 an ideal material for medical applications. For the targeted clearance of Aß aggregates, we have conjugated the KLVFF peptide which specifically recognizes and captures Aß aggregates on the surface of silver-doped CuBi2O4 (Ag:CuBi2O4). Upon illumination of NIR light under a cathodic bias, the KLVFF-immobilized Ag:CuBi2O4 (KLVFF-Ag:CuBi2O4) effectively dissociated ß-sheet-rich, long, and entangled Aß fibrillary aggregates into small fragmented, soluble species through photo-oxygenation. We also verified that the KLVFF-Ag:CuBi2O4 photocathode is biocompatible and effective in reducing Aß aggregate-induced neurotoxicity. Our work demonstrates the potential of the KLVFF-Ag:CuBi2O4 platform for the targeted disassembly of cytotoxic, robust Aß aggregates with the aid of NIR energy and cathodic bias.

Photomodulating Carbon Dots for Spatiotemporal Suppression of Alzheimer's ß-Amyloid Aggregation.

Extracellular deposition of ß-amyloid (Aß) peptide aggregates is a major characteristic of Alzheimer's disease (AD) brain. Because Aß peptide aggregates aggravate neuropathy and cognitive impairment for AD patients, numerous efforts have been devoted to suppressing Aß self-assembly as a prospective AD treatment option. Here, we report Aß-targeting, red-light-responsive carbon dots (CDs), and their therapeutic functions as a light-powered nanomodulator to spatiotemporally suppress toxic Aß aggregation both in vitro and in vivo. Our aptamer-functionalized carbon dots (Apta@CDs) showed strong targeting ability toward Aß42 species. Moreover, red LED irradiation induced Apta@CDs to irreversibly denature Aß peptides, impeding the formation of ß-sheet-rich Aß aggregates and attenuating Aß-associated cytotoxicity. Consequently, Apta@CDs-mediated photomodualtion modality achieved effective suppression of Aß aggregation in vivo, which significantly reduced the Aß burden at the targeted sites in the brain of 5xFAD mice by ∼40% and ∼25% according to imaging and ELISA analyses, respectively. Our work demonstrates the therapeutic potential of photomodulating CDs for light-driven suppression against Aß self-assembly and related neurotoxicity.

Siloxane-Encapsulated Upconversion Nanoparticle Hybrid Composite with Highly Stable Photoluminescence against Heat and Moisture.

Herein, we report a siloxane-encapsulated upconversion nanoparticle hybrid composite (SE-UCNP), which exhibits excellent photoluminescence (PL) stability for over 40 days even at an elevated temperature, in high humidity, and in harsh chemicals. The SE-UCNP is synthesized through UV-induced free-radical polymerization of a sol-gel-derived UCNP-containing oligosiloxane resin (UCNP-oligosiloxane). The siloxane matrix with a random network structure by Si-O-Si bonds successfully encapsulates the UCNPs with chemical linkages between the siloxane matrix and organic ligands on UCNPs. This encapsulation results in surface passivation retaining the intrinsic fluorescent properties of UCNPs under severe conditions (e.g., 85 °C/85% relative humidity) and a wide range of pH (from 1 to 14). As an application example, we fabricate a two-color binary microbarcode based on SE-UCNP via a low-cost transfer printing process. Under near-infrared irradiation, the binary sequences in our barcode are readable enough to identify objects using a mobile phone camera. The hybridization of UCNPs with a siloxane matrix provides the capacity for highly stable UCNP-based applications in real environments.

Carbon nanomaterials as versatile platforms for theranostic applications.

Theranostic nanomedicine, utilizing state-of-the-art, multifaceted nanomaterials and devices with therapeutic and diagnostic dual functions, has emerged as a highly attractive and promising new field of medicine. The theory behind the use of nanomaterials for theranostic applications is to impart multifunctionality by applying various engineering strategies to combine different modalities on a nanoscale. Carbon nanomaterials, which have been a subject of intense scientific research and industrial applications in recent years, have also found their way into theranostic nanomedicine owing to their innate multifunctionality. In this review, we outline recent research progress and trends in utilizing various types of carbon nanomaterial for theranostic applications.

Effects of precursor composition and mode of crosslinking on mechanical properties of graphene oxide reinforced composite hydrogels.

Graphene oxide (GO) is increasingly investigated as a reinforcing nanofiller for various hydrogels for biomedical applications for its superior mechanical strength. However, the reinforcing mechanism of GO in different hydrogel conditions has not been extensively explored and elucidated to date. Herein, we systematically examine the effects of various types of precursor molecules (monomers vs. macromers) as well as mode of GO incorporation (physical vs. covalent) on the mechanical properties of resulting composite hydrogels. Two hydrogel types, (1) polyacrylamide hydrogels with varying concentrations of acrylamide monomers and (2) poly(ethylene glycol) (PEG) hydrogels with varying molecular weights of PEG macromers, are used as model systems. In addition, incorporation of GO is also controlled by using either unmodified GO or methacrylic GO (MGO) which allows for covalent incorporation. The results in this study demonstrate that the interaction between GO and the surrounding network and its effect on the mechanical properties (i.e. rigidity and toughness) of composite hydrogels are highly dependent on both the type and concentration of precursors and the mode of crosslinking. We expect this study will provide an important guideline for future research efforts on controlling the mechanical properties of GO-based composite hydrogels.