A reconfigurable integrated smart device for real-time monitoring and synergistic treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a global autoimmune disease that requires long-term management. Ambulatory monitoring and treatment of RA favors remission and rehabilitation. Here, we developed a wearable reconfigurable integrated smart device (ISD) for real-time inflammatory monitoring and synergistic therapy of RA. The device establishes an electrical-coupling and substance delivery interfaces with the skin through template-free conductive polymer microneedles that exhibit high capacitance, low impedance, and appropriate mechanical properties. The reconfigurable electronics drive the microneedle-skin interfaces to monitor tissue impedance and on-demand drug delivery. Studies in vitro demonstrated the anti-inflammatory effect of electrical stimulation on macrophages and revealed the molecular mechanism. In a rodent model, impedance sensing was validated to hint inflammation condition and facilitate diagnosis through machine learning model. The outcome of subsequent synergistic therapy showed notable relief of symptoms, elimination of synovial inflammation, and avoidance of bone destruction.

Smartphone conducted DNA portable quantitative detection platform based on photonic crystals chip and magnetic nanoparticles.

It is of great significance to develop a highly sensitive and intuitive virus detection tool. A portable platform is constructed for quantitative detection of viral DNA based on the principle of fluorescence resonance energy transfer (FRET) between upconversion nanoparticles (UCNPs) and graphene oxide nanosheets (GOs) in this work. To implement a high sensitivity and low detection limit, GOs are modified by magnetic nanoparticles to prepare magnetic graphene oxide nanosheets (MGOs). Among them, the application of MGOs can not only eliminate the background interference, but also amplify the fluorescence intensity to a certain extent. Whereafter, a simple carrier chip based on photonic crystals (PCs) is introduced to realize a visual solid-phase detection, which also amplifies the luminescence intensity of the detection system. Finally, under the application of the 3D printed accessory and smartphone program of red-green-blue (RGB) evaluation, the portable detection can be completed simply and accurately. In a word, this work proposes a portable DNA biosensor with the triple functions of quantification, visualization and real-time detection can be used as a high-quality viral detection strategy and clinical diagnosis method.

Radiopaque and X-ray-Responsive Nanomedicine for Preventive Therapy of Radiation-Induced Heart Disease.

Radiation-induced heart disease (RIHD) is a common radiotherapy complication. Reducing radiation exposure and post-irradiation antioxidant therapy are promising approaches. Here, a liquid metal-based core-shell nanomedicine (LMN) composed of a gallium core and a multifunctional polymeric shell with radiopaque, X-ray shielding, and X-ray-responsive antioxidation properties for preventive therapy of RIHD is developed. The liquid metal provides radiopaque properties to enhance X-ray and computed tomography imaging and attenuate radiation to prevent primary myocardial damage. Under X-ray radiation, cleavage of the diselenide bond on the polymeric shell results in the release of LMN and controlled antioxidation. In vitro and in vivo experiments have demonstrated that LMN significantly reduces myocardial injury and impaired cardiac function, stabilizes mitochondrial function, and inhibits myocardial fibrosis. This nanomedicine with radiographic contrast, radiation shielding, and responsive features provides a new strategy for the prevention of radiation-related diseases.

Photoresponsive Hydrogel-Coated Upconversion Cyanobacteria Nanocapsules for Myocardial Infarction Prevention and Treatment.

Myocardial infarction (MI) is a common disease that seriously threatens human health. It is noteworthy that oxygen is one of the key factors in the regulation of MI pathology procession: the controllable hypoxic microenvironment can enhance the tolerance of cardiac myocytes (CMs) and oxygen therapy regulates the immune microenvironment to repair the myocardial injury. Thus, the development of an oxygen-controllable treatment is critically important to unify MI prevention and timely treatment. Here, a hydrogel encapsulated upconversion cyanobacterium nanocapsule for both MI prevention and treatment is successfully synthesized. The engineered cyanobacteria can consume oxygen via respiration to generate a hypoxic microenvironment, resulting in the upregulation of heat shock protein70 (HSP70), which can enhance the tolerance of CMs for MI. When necessary, under 980 nm near-infrared (NIR) irradiation, the system releases photosynthetic oxygen through upconversion luminescence (UCL) to inhibit macrophage M1 polarization, and downregulates pro-inflammatory cytokines IL-6 and tumor necrosis factor-α (TNF-α), thereby repairing myocardial injury. To sum up, a photoresponsive upconversion cyanobacterium nanocapsule is developed, which can achieve MI prevention and treatment for only one injection via NIR-defined respiration and photosynthesis.

Adropin Carried by Reactive Oxygen Species-Responsive Nanocapsules Ameliorates Renal Lipid Toxicity in Diabetic Mice.

Diabetic kidney disease (DKD) is a common diabetes complication mainly caused by lipid toxicity characterized by oxidative stress. Studies have shown that adropin (Ad) regulates energy metabolism and may be an effective target to improve DKD. This study investigated the effect of exogenous Ad encapsulated in reactive oxygen species (ROS)-responsive nanocapsules (Ad@Gel) on DKD. HK2 cells were induced with high glucose (HG) and intervened with Ad@Gel. A diabetes mouse model was established using HG and high-fat diet combined with streptozotocin and treated with Ad@Gel to observe its effects on renal function, pathological damage, lipid metabolism, and oxidative stress. Results showed that Ad@Gel could protect HK2 from HG stimulation in vitro. It also effectively controls blood glucose and lipid levels, improves renal function, inhibits excessive production of ROS, protects mitochondria from damage, improves lipid deposition in renal tissues, and downregulates the expression of lipogenic proteins SEBP-1 and ADRP in DKD mice. In HG-induced HK2 cells or the kidney of DKD patients, the low expression of neuronatin (Nnat) and high expression of translocator protein (TSPO) were observed. Knockdown Nnat or overexpression of TSPO significantly reversed the effect of Ad@Gel on improving mitochondrial damage. In addition, knockdown Nnat also significantly reversed the effect of Ad@Gel on lipid metabolism. The results suggest that the effect of Ad on DKD may be achieved by activating Nnat to improve lipid metabolism and inhibit TSPO activity, thereby enhancing mitochondrial function.

Photoresponsive Vaccine-Like CAR-M System with High-Efficiency Central Immune Regulation for Inflammation-Related Depression.

Increasing evidence suggests that activation of microglia-induced neuroinflammation plays a crucial role in the pathophysiology of depression. Consequently, targeting the central nervous system to reduce neuroinflammation holds great promise for the treatment of depression. However, few drugs can enter the brain via a circulatory route through the blood-brain barrier (BBB) to reach the central nervous system efficiently, which limits the pharmacological treatment for neuropsychiatric diseases. Herein, a light-responsive system named UZPM, consisting of blue-emitting NaYF4 :Yb, Tm@zeolitic-imidazolate framework (UCNP@ZIF-8), photoacid (PA), and melatonin (MT) is developed to address the above issues. Meanwhile, UZPM is introduced into macrophages by functional liposomes fusion and modified with hydroxylamine groups on the cell surface. Aldehyde-modified cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is used as a chimeric antigen receptor (CAR) targeting group to modify the surface of macrophages by aldehyde/hydroxylamine condensation to precisely target central M1-type microglia (CAR-M-UZPM). Both in vitro and in vivo experiments demonstrate that the CAR-M-UZPM drug delivery system can efficiently penetrate the BBB, targeting centrally activated microglia, and thus, inhibiting the M1-type polarization of microglia, producing continuous vaccine-like anti-inflammatory effects that prevent the occurrence and development of inflammation-related depression.

Coherence scanning and phase imaging optical interference microscopy at the lateral resolution limit.

To get physical insight into the 3D transfer characteristics of interference microscopy at high numerical apertures we study reflecting rectangular grating structures. In general, the height obtained from phase information seems to be reduced, whereas height values resulting from coherence scanning sometimes seem to be systematically overestimated. Increasing the numerical aperture of an interference microscope broadens the spectra of the resulting interference signals, thus offering a broad variety of wavelength contributions to be analyzed. If phase analysis of a measured far-field interference wavefront is performed at very short wavelengths the periodical profiles obtained from coherence scanning and phase shifting analysis differ only by the measured amplitude. However, at longer wavelength there is a 180° phase shift of the measured profiles obtained from phase analysis compared to coherence peak analysis. Increasing the evaluation wavelength improves the lateral resolution since the long wavelength contributions are related to electromagnetic waves of high angles of incidence. This behavior is to the best of our knowledge not documented in literature so far. It was first observed experimentally and could be confirmed by simulation results obtained from either Kirchhoff diffraction theory or an extended Richards-Wolf model developed in our group. Compared to original input profiles used for the simulation the profiles obtained from phase evaluation correspond quite well at longer wavelength, whereas the results obtained from coherence peak analysis are typically inverted with respect to height.

Signal modeling in low coherence interference microscopy on example of rectangular grating.

Besides the illumination wavelength also the numerical aperture (NA) of a microscope objective affects the fringe spacing in interference microscopy. Therefore, at high NA values an effective wavelength should be obtained by calibration. At step height structures both, the effective wavelength and the batwing effect strongly depend on the height-to-wavelength-ratio (HWR). Therefore, changes of the effective wavelength considering temporal and spatial coherence enable us to estimate the batwing effect in measurement results. For high NA systems and broadband illumination two different theoretical approaches for signal modeling are introduced to study the influence of the center wavelength, the temporal, and the spatial coherence of the illuminating light on measurement results of a rectangular grating. In both models diffraction is considered. While the first simulation model (Kirchhoff) is mostly analytical the second one (Richards-Wolf) is primarily numerical. Simulation results of both models show a good agreement with experimental measurement results.

Lateral resolution and transfer characteristics of vertical scanning white-light interferometers.

White-light interferometers are widely used for high-accuracy topography measurement in industrial and scientific applications. A common way to characterize a white-light interferometer is to assume small surface amplitudes resulting in linear transfer characteristics described by the instrument transfer function (ITF). However, the well-known batwing effect gives rise to systematic errors, causing extra nonlinearity to the ITF. In this paper a model to simulate an interference pattern in the image plane as it is obtained by a vertical scanning white-light interferometer is introduced in order to overcome the limitation of small surface amplitudes. Repeating the simulation procedure for different height positions of the object results in an image stack that can be analyzed by the same algorithms as real measurement data. The simulation results agree with experimental observations: the batwing effect occurs in certain situations and the correct amplitude of a rectangular grating structure can be obtained as long as the structure is optically resolved. Both simulation, as well as experimental results, provide transfer characteristics of broader bandwidth than predicted by theoretical approaches based on linear system behavior.

Transfer characteristics of rectangular phase gratings in interference microscopy.

In this Letter, the transfer characteristics of rectangular periodic phase objects are studied. It turns out that there are significant differences compared to amplitude objects. The imaging of an amplitude object can be understood as a linear process, whereas phase objects behave nonlinearly. It is shown that under certain conditions the correct shape of a rectangular phase grating can be obtained by an interference microscope as long as the first order diffraction component passes the optical imaging system. This result is in a good agreement with experimental observations and computer simulation results.

[Multi-center phase II clinical trial of humanized anti-epidermal factor receptor monoclonal antibody h-R3 combined with radiotherapy for locoregionally advanced nasopharyngeal carcinoma].

OBJECTIVE: To evaluate the efficacy and safty of the humanized anti-epidermal factor receptor monoclonal antibody h-R3 in combination with radiotherapy for locoregionally advanced nasopharyngeal carcinoma. METHODS: Totally, 137 patients from 7 medical center around China were randomly divided into combined therapy group or control group. There was no difference in Karnofsky performance score between two groups. All patients in both groups received radical conventionally fractionated radiotherapy to the total dose of D(T) 70-76 Gy. For the combined therapy group, h-R3 was added at a dose of 100 mg i.v. weekly for 8 weeks started at the beginning of radiotherapy. RESULTS: Of the 137 eligilbe patients, 70 were in the combined therapy group treated by h-R3 plus radiotherapy and 67 in the control group by radiotherapy alone. The intent-to-treat (ITT) population consisted of 130 patients, while the per-protocol (PP) population was composed of 126 patients. The efficacy was assessed respectively at three point of time: the end of treatment, the 5th- and 17th-week after treatment. The complete response (CR) of the combined therapy group was significantly higher than that of the control group in both ITT and PP (ITT: 65.63%, 87.50%, 90.63% versus 27.27%, 42.42%, 51.52%; PP: 67.21%, 90.16%, 93.44% versus 27.69%, 43.08%, 52.31%; P < 0.05, respectively). The most common h-R3-related adverse reactions were fever (4.3%), hypotension (2.9%), nausea (1.4%), dizziness (2.9%) and rash (1.4%), which could be reversible if treated properly. Radiotherapy combined with 100 mg h-R3 i. v. weekly was tolerable and did not aggravate the side effects of radiation. The quality of life in the combined therapy group was comparable to that in the control group. CONCLUSION: This phase 1 multicenter clinical trial shows that h-R3 in combination with radiotherapy is effective and well-tolerated for the treatment of locoregionally advanced nasopharyngeal carcinoma.