Biological Window Research Articles

Single walled carbon nanotube optical reporter for amyloid beta detection

AbstractBackgroundAmyloid beta (Aß) extracellular deposits are one of the pathohistological hallmarks of Alzheimer’s Disease (AD). In recent years intracellular accumulation of Aß has been linked with early pathogenic mechanisms. Recent reports now associate intracellular Aβ accumulation, and lysosomal disfunction as an early event in the disease, preceding extracellular amyloid‐deposits. Today methods to visualize intracellular Aβ accumulation rely on antibody staining or pre‐labeled Aβ. There is an outstanding need for live‐imaging tools capable of monitoring Aβ dynamics at the cellular level.MethodWe have developed an optical sensor that can monitor Aß in live cells transiently. Single wall carbon nanotubes (SWCNT) present advantages as optical sensors owing to their near‐infrared emission, as well as photostability and high‐sensitivity. SWCNT emission spectra (wavelength ranges of 1100‐1150nm) is within the biological transparency window (1000‐1700nm) allowing for optimal imaging in live samples. SWCNT were non‐covalently biofunctionalized; by which we confer selectivity to Aβ.To obtain intracellular detection we used two cell lines: monocytes (THP‐1) and differentiated SH‐SY5Y. Cells were incubated with functionalized nanotubes. We utilized near‐infrared spectroscopy and hyper‐spectral microscopy to obtain spectral response from live‐cells.ResultWe developed and characterized a new class of bio‐functionalized intrinsically photoluminescent SWCNT sensor that can detect Aß via shifting of their intrinsic near‐infrared emission wavelength. Our biofunctionalized sensors specifically recognize Aβ in the solution phase, showing a monochromatic center wavelength decrease in a dose‐dependent fashion. The reporters show high specificity compared to competing analytes and in serum samples. In cell models, nanosensors accumulate intracellularly and probe Aβ introduced to the cells specifically. Finally, initial through‐skull near‐IR imaging in‐vivo in an AD model (5XFAD), following intracranial injection, show significant decrease in central wavelength in AD mice compared to wild type.ConclusionThe SWCNT sensor provide a framework for dynamically investigating Aβ in live samples. We believe utilizing the nanosensors can enhance the study of Aβ ‐pathogenic mechanism, structure and molecular function and consequently improve and accelerate effective amyloid‐targeted therapies.

Optical Bioimaging and Therapy

Optical Bioimaging and Therapy

Colloidal suspensions of totally inorganic perovskites nanoparticles: A new photoluminescent emission in the near-IR

Luminescent materials have attracted great attention due to the amazing applications. In this sense, perovskite halide materials have shown promising luminescent properties which allows them to be useful in various applications such as LEDs, sensors. In this work, colloidal suspensions of CsPbI3 and Pd-doped CsPbI3 perovskite nanoparticles were prepared at different temperatures, and their structure and luminescence properties were characterized to analyse the effect of the synthesis temperature and the Pd-doping. With the increase of temperature, the main photoluminescence band of perovskite nanoparticles are slightly red-shifted. But the most amazing result is that the Pd-doped CsPbI3 shows a new emission band at 877 nm under excitation at 785 nm. Therefore, this compound may be used as a highly sensitive luminescent sensor in several applications, such as in biosystems due to their emission in the first biological window under NIR excitation.

Dual‐Wavelength Comparative Imaging Based on a Novel NIR‐II/IIb Emissive Rare Earth‐Doped Nanoparticle

AbstractThe second near‐infrared biological window two (NIR‐II, 1000–1700 nm) imaging has made remarkable achievements in fluorescence imaging of diseases. Here, this work takes advantage of the rich spectral properties of rare‐earth doped nanoparticles (RENPs) and their capability to present multiple emission peaks in different luminescence regions simultaneously; novel RENPs are synthesized that have emission peaks in the NIR‐II1000nm (1000–1300 nm) region and enhanced emission in the NIR‐IIb (1500–1700 nm) window and are named as NEU‐RENPs. These RENPs with new compositions enable a fair comparison to evaluate their imaging performance in NIR‐II1000nm and NIR‐IIb regions under the same conditions. The imaging abilities of the resulted nanoparticles in NIR‐II1000 nm and NIR‐IIb regions are investigated systematically for local blood vessels, tumor vessels, acute inflammatory vessels, arterial thrombosis, cerebrovascular inflammation, and brain injury models. The results indicate that imaging of NIR‐IIb shows higher resolution and sensitivity than that of NIR‐II1000nm, and it has a stronger ability to accurately distinguish normal and pathological tissues. Interestingly, the fuzzy image of NIR‐II1000nm reveals more information about the background structure of the target, which is difficult to be achieved in NIR‐IIb imaging. The results prove NEU‐RENPs based NIR‐IIb imaging is preferable for biomedical applications.

Study of fluorescent nanodiamonds concentrations in aqueous solutions for biological applications

Commercial fluorescent nanodiamonds constitute a new class of nanoprobes with excellent perspectives for biomedical applications. They produce a broad emission spectrum partially matching the biological window for high tissue penetration, which can be excited in the visible region (380–780 nm) and in the biological window (1000–2500 nm) using two-photon excitation processes, giving a chance for high-resolution multi-photon fluorescence imaging at a sub-cellular resolution scale. Because of their carbon-based structure, nanodiamonds are highly biocompatible and display low toxicity if adequately coated. The nanodiamonds fluorescence spectrum arises due to the so-called Nitrogen-Vacancy (NV) color centers, which are highly photostable and are formed by local charge density compensating defects because of the typical nitrogen presence impurity ions in the host nanocrystals. In this work, a study of different nanodiamonds’ concentrations in terms of their fluorescent activity was investigated in the range of 0.1–10 mg/mL by means of fluorescence spectroscopy with the purpose of determining which concentration of nanodiamonds suspended in milliQ water achieves the maximum intensity, in which it was found that the 5 mg/mL was the most intense in our experimental observations. Additionally, a non-linear fit of the experimental observations of intensity was performed to predict the fluorescence intensity following an expression of a fourth order polynomial with respect to concentration, with a figure of merit, FOM = 0.03–0.04 (3–4%). Based on this effect, the optimal nanodiamonds/aqueous media solution has been determined by means of cell viability assays, finding that concentrations ≤0.1 mg/mL are as biocompatible as milliQ water.

Monitoring the Formation of Fibrin Clots as Part of the Coagulation Cascade Using Fluorescent Single-Walled Carbon Nanotubes.

Blood coagulation is a critical defense mechanism against bleeding that results in the conversion of liquid blood into a solid clot through a complicated cascade, which involves multiple clotting factors. One of the final steps in the coagulation pathway is the conversion of fibrinogen to insoluble fibrin mediated by thrombin. Because coagulation disorders can be life-threatening, the development of novel methods for monitoring the coagulation cascade dynamics is of high importance. Here, we use near-infrared (NIR)-fluorescent single-walled carbon nanotubes (SWCNTs) to image and monitor fibrin clotting in real time. Following the binding of fibrinogen to a tailored SWCNT platform, thrombin transforms the fibrinogen into fibrin monomers, which start to polymerize. The SWCNTs are incorporated within the clot and can be clearly visualized in the NIR-fluorescent channel, where the signal-to-noise ratio is improved compared to bright-field imaging in the visible range. Moreover, the diffusion of individual SWCNTs within the fibrin clot gradually slows down after the addition of thrombin, manifesting a coagulation rate that depends on both fibrinogen and thrombin concentrations. Our platform can open new opportunities for coagulation disorder diagnostics and allow for real-time monitoring of the coagulation cascade with a NIR optical signal output in the biological transparency window.

Composition-Dependent Optical Properties of Cu–Zn–In–Se Colloidal Nanocrystals Synthesized via Cation Exchange

Copper chalcogenide-based nanocrystals (NCs) are a suitable replacement for toxic Cd/Pb chalcogenide-based NCs in a wide range of applications including photovoltaics, optoelectronics, and biological imaging. However, despite rigorous research, direct synthesis approaches of this class of compounds suffer from inhomogeneous size, shape, and composition of the NC ensembles, which is reflected in their broad photoluminescence (PL) bandwidths. A partial cation exchange (CE) strategy, wherein host cations in the initial binary copper chalcogenide are replaced by incoming cations to form ternary/quaternary multicomponent NCs, has been proven to be instrumental in achieving better size, shape, and composition control to this class of nanomaterials. Additionally, adopting synthetic strategies which help to eliminate inhomogeneities in the NC ensembles can lead to narrower PL bandwidths, as was shown by single-particle studies on I–III–VI2-based semiconductor NCs. In this work, we formulate a two-step colloidal synthesis of Cu–Zn–In–Se (CZISe) NCs via a partial CE pathway. The first step is the synthesis of Cu2–xSe NCs, which serve as a template for the subsequent CE reaction. The second step is the incorporation of the In3+ and Zn2+ guest cations into the synthesized Cu2–xSe NCs via simultaneous injection of both metal precursors, which results in gradient-alloyed CZISe NCs with a Zn-rich surface. The as-synthesized NCs exhibit near-infrared (NIR) PL without an additional shell growth, which is typically required in most of the developed protocols. The photoluminescence quantum yield (PLQY) of these Cu chalcogenide-based NCs reaches 20%. These NCs also exhibit intriguingly narrow PL bands, which challenges the notion of broad PL bands being an inherent property of this class of NCs. Additionally, a variation in the feed ratios of the incoming cations, i.e., In/Zn, results in the variation of the composition of the synthesized NCs. Henceforth, the optical properties of these NCs could be tuned by a simple variation of the composition of the NCs achieved by varying the feed ratios of the incoming cations. Within a narrow size distribution, the PL maxima range from 980 to 1060 nm, depending on the composition of the NCs. Post-synthetic surface modification of the synthesized NCs enabled the replacement of the parent long-chain organic ligands with smaller species, which is essential for their prospective applications requiring efficient charge transport. With PL emission extended into the NIR, the synthesized NCs are suitable for an array of potential applications, most importantly in the area of solar energy harvesting and bioimaging. The large Stokes shift inherent to these materials, their absorption in the solar range, and their NIR PL within the biological window make them suitable candidates.

Ratiometric nanothermometer CaSc2O4: Nd3+ operating in biological window for deep-tissue photothermal therapy

Accurate and real-time temperature detection is an urgent requirement in photothermal therapy (PTT). In this work, the CaSc2O4: Nd3+ nanorod with an average length of 150 nm has been determined to be an outstanding optical thermometer based on the fluorescence intensity ratio (FIR) of thermally coupled Stark sublevels of Nd3+: 4F3/2 → 4I11/2 transition, of which the excitation and emission wavelength are located in the first and second biological window respectively, resulting in an 8 mm penetration depth in the biological tissues. The maximal absolute sensitivity and relative sensitivity as well as the minimal temperature resolution of the present sample is 0.0008 K-1, 0.0018 K-1 and 0.19 K respectively, which is superior to the vast majority of the same type thermometers. Besides that, the nanorods show a 7 K temperature increment after 180 s’ 808 nm-laser radiation, revealing its photothermal conversion capacity thanks to the considerable nonradiative relaxation processes among the metastable energy levels of Nd3+. These results indicate that Nd3+ single-doped CaSc2O4 nanorods can be utilized as the optical thermometer in the deep-tissue PTT process for real-time thermometry along with the function of light-to-heat conversion.

Investigating the Thermometric Performance of Inorganic Materials Doped with Nd3+ under Infrared LED Excitation: An Alternative for Deep Tissue Luminescent Thermometry

Luminescent thermometers based on the luminescence intensity ratio between two thermally coupled levels have a strong appeal in the biomedical area due to the possibility of monitoring the temperature of deep tissues. In such procedures, it is necessary that the excitation and emission wavelengths are within the biological windows. Probes based on neodymium luminescence, with excitation and emission around 800 and 880 nm, are frequently proposed but have low relative sensitivity (0.2%.K−1) due to the small energy separation between the explored Stark sublevels. By changing the excitation wavelength to around 750 nm, it is possible to explore the thermal coupling between the 4F5/2 and 4F3/2 levels. However, lasers in this wavelength range are not common. An alternative is to use LEDs as an excitation source. As a proof of concept, we investigated the thermometric performance of three distinct Nd-doped luminescent probes under 730 nm LED excitation and 532 nm laser excitation: nanocrystalline Y2O3, LiBaPO4 microcrystals, and lithium-boron-aluminum (LBA) glass. The results indicated that the use of LEDs as an excitation source can be applied in nano-, micro- and macro-structured probes, as it does not compromise the thermometric performance of the systems, which exhibited relative sensitivities of approximately 2%.K−1.

Tunable Nanoparticles with Aggregation-Induced Emission Heater for Precise Synergistic Photothermal and Thermodynamic Oral Cancer Therapy of Patient-Derived Tumor Xenograft.

The fluorophores in the second near-infrared (NIR-II) biological window (1000 - 1700nm) show great application prospects in the fields of biology and optical communications. However, both excellent radiative transition and nonradiative transition cannot be achieved simultaneously for the majority of traditional fluorophores. Herein, tunable nanoparticles formulated with aggregation-induced emission (AIE) heater are developed rationally. The system can be implemented via the development of an ideal synergistic system that can not only produce photothermal from nonspecific triggers but also trigger carbon radical release. Once accumulating in tumors and subsequently being irradiated with 808nm laser, the nanoparticles (NMB@NPs) encapsulated with NMDPA-MT-BBTD (NMB) are splitted due to the photothermal effect of NMB, leading to the decomposition of azo bonds in the nanoparticle matrix to generate carbon radical. Accompanied by second near-infrared (NIR-II) window emission from the NMB, fluorescence image-guided thermodynamic therapy (TDT) and photothermal therapy (PTT) which significantly inhibited the growth of oral cancer and negligible systemic toxicity is achieved synergistically. Taken together, this AIE luminogens-based synergistic photothermal-thermodynamic strategy brings a new insight into the design of superior versatile fluorescent NPs for precise biomedical applications and holds great promise to enhance the therapeutic efficacy of cancer therapy.

Achieving High Quantum Efficiency Broadband NIR Mg4 Ta2 O9 :Cr3+ Phosphor Through Lithium-Ion Compensation.

Ultra-efficient broadband near-infrared (NIR) phosphor-converted light-emitting diodes (pc-LEDs) are urgently needed to improve the detection sensitivity and spatial resolution of current smart NIR spectroscopy-based techniques. Nonetheless, the performance of NIR pc-LED has severely limited owing to the external quantum efficiency (EQE) bottleneck of NIR light-emitting materials. Herein, a blue LED excitable Cr3+ -doped tetramagnesium ditantalate (Mg4 Ta2 O9 , MT) phosphor is advantageously modified through lithium ion as a key efficient broadband NIR emitter to achieve high optical output power of the NIR light source. The emission spectrum encompasses the 700-1300nm electromagnetic spectrum of first biological window (λmax = 842nm) with a full-width at half-maximum (FWHM) of ≈2280 cm-1 (≈167nm), and achieves a record EQE of 61.25% detected at 450nm excitation through Li-ion compensation. A prototype NIR pc-LED is fabricated with MT:Cr3+ , Li+ to evaluate its potential practical application, which reveals an NIR output power of 53.22mW at a driving current of 100mA, and a photoelectric conversion efficiency of 25.09% at 10mA. This work provides an ultra-efficient broadband NIR luminescent material, which shows great promise in practical applications and presents a novel option for the next-generation high-power compact NIR light sources.

Structurally Simple Osmium(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy in the Near Infrared.

Five osmium(II) polypyridyl complexes of the general formula [Os(4,7-diphenyl-1,10-phenanthroline)2 L]2+ were synthesized as photosensitizers for photodynamic therapy by varying the nature of the ligand L. Thanks to the pronounced π-extended structure of the ligands and the heavy atom effect provided by the osmium center, these complexes exhibit a high absorption in the near-infrared (NIR) region (up to 740 nm), unlike related ruthenium complexes. This led to a promising phototoxicity in vitro against cancer cells cultured as 2D cell layers but also in multicellular tumor spheroids upon irradiation at 740 nm. The complex [Os(4,7-diphenyl-1,10-phenanthroline)2 (2,2'-bipyridine)]2+ was found to be the most efficient against various cancer cell lines, with high phototoxicity indexes. Experiments on CT26 tumor-bearing BALB/c mice also indicate that the OsII complexes could significantly reduce tumor growth following 740 nm laser irradiation. The high phototoxicity in the biological window of this structurally simple complex makes it a promising photosensitizer for cancer treatment.

Structurally Simple Osmium(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy in the Near Infrared**

AbstractFive osmium(II) polypyridyl complexes of the general formula [Os(4,7‐diphenyl‐1,10‐phenanthroline)2L]2+ were synthesized as photosensitizers for photodynamic therapy by varying the nature of the ligand L. Thanks to the pronounced π‐extended structure of the ligands and the heavy atom effect provided by the osmium center, these complexes exhibit a high absorption in the near‐infrared (NIR) region (up to 740 nm), unlike related ruthenium complexes. This led to a promising phototoxicity in vitro against cancer cells cultured as 2D cell layers but also in multicellular tumor spheroids upon irradiation at 740 nm. The complex [Os(4,7‐diphenyl‐1,10‐phenanthroline)2(2,2′‐bipyridine)]2+ was found to be the most efficient against various cancer cell lines, with high phototoxicity indexes. Experiments on CT26 tumor‐bearing BALB/c mice also indicate that the OsII complexes could significantly reduce tumor growth following 740 nm laser irradiation. The high phototoxicity in the biological window of this structurally simple complex makes it a promising photosensitizer for cancer treatment.

Design of novel photothermal conversion nanoparticles integrated with temperature self-response ability based on thermal-enhanced NIR to NIR luminescence

The development of photothermal therapy (PTT) agents possessing temperature self-response ability and working in the deep tissues is an urgent need for noninvasive cancer treatment. Herein, a nanocomposite material hexagonal phase NaLuF4: Yb3+/Nd3+@SiO2@Cu2S is successfully constructed for the purpose of meeting the above demands. Under the irradiation of 980 nm near-infrared (NIR) light, the prepared nanocrystals (NCs) exhibit good photothermal conversion capacity and ultrasensitive temperature sensing properties along with remarkable resolution. The optical thermometry is realized by the fluorescence intensity ratio of Nd3+: 4Fj (j = 7/2, 5/2, and 3/2) levels, of which the NIR emission intensities are strongly enhanced with the increasing temperature due to the phonon-assisted energy transfer mechanisms between Yb3+ and Nd3+. As the excitation and emission wavelength of the sample are all located in the biological window, its penetration depth in the biological tissues can be reached to 8 mm. The adsorptive Cu2S NCs on the surface of NaLuF4: Yb3+/Nd3+@SiO2 provide the required light-to-heat conversion capacity, which has been investigated in detail through the laser-irradiated and bactericidal experiment respectively. These findings provide a feasible strategy to design high-performance PTT agents integrated with precise temperature self-measurement function for deep-tissue therapy.

Dibenzodipyridophenazines with Dendritic Electron Donors Exhibiting Deep-Red Emission and Thermally Activated Delayed Fluorescence

The development of deep-red thermally activated delayed fluorescence (TADF) emitters is important for applications such as organic light-emitting diodes (OLEDs) and biological imaging. Design strategies for red-shifting emission include synthesizing rigid acceptor cores to limit nonradiative decay and employing strong electron-donating groups. In this work, three novel luminescent donor-acceptor compounds based on the dibenzo[a,c]dipyrido[3,2-h:20-30-j]-phenazine-12-yl (BPPZ) acceptor were prepared using dendritic carbazole-based donors 3,3″,6,6″-tetramethoxy-9'H-9,3':6',9″-tercarbazole (TMTC), N3,N3,N6,N6-tetra-p-tolyl-9H-carbazole-3,6-diamine (TTAC), and N3,N3,N6,N6-tetrakis(4-methoxyphenyl)-9H-carbazole-3,6-diamine (TMAC). Here, dimethoxycarbazole, ditolylamine, and bis(4-methoxyphenyl)amine were introduced at the 3,6-positions of carbazole to increase the strength of these donors and induce long-wavelength emission. Substituent effects were investigated with experiments and theoretical calculations. The emission maxima of these materials in toluene were found to be 562, 658, and 680 nm for BPPZ-2TMTC, BPPZ-2TTAC, and BPPZ-2TMAC, respectively, highlighting the exceptional strength of the TMAC donor, which pushes the emission into the deep-red region of the visible spectrum as well as into the biological transparency window (650-1350 nm). Long-lived emission lifetimes were observed in each emitter due to TADF in BPPZ-2TMC and BPPZ-2TTAC, as well as room-temperature phosphorescence in BPPZ-2TMAC. Overall, this work showcases deep-red emissive dendritic donor-acceptor materials which have potential as bioimaging agents with emission in the biological transparency window.

Theoretical Investigation of Ru(II) Complexes with Long Lifetime and a Large Two-Photon Absorption Cross-Section in Photodynamic Therapy.

Two-photon photodynamic therapy (TP-PDT), as a new method for cancer, has shown unique advantages in tumors. A low two-photon absorption cross-section (δ) in the biologic spectral window and a short triplet state lifetime are the important issues faced by the current photosensitizers (PSs) in TP-PDT. In this paper, the photophysical properties of a series of Ru(II) complexes were studied by density functional theory and time-dependent density functional theory methods. The electronic structure, one- and two-photon absorption properties, type I/II mechanisms, triplet state lifetime, and solvation free energy were calculated. The results showed that the substitution of methoxyls by pyrene groups greatly improved the lifetime of the complex. Furthermore, the addition of acetylenyl groups subtly enhanced δ. Overall, complex 3b possess a large δ(1376 GM), a long lifetime (136 μs), and better solvation free energy. It is hoped that it can provide valuable theoretical guidance for the design and synthesis of efficient two-photon PSs in the experiment.

Highly localized, efficient, and rapid photothermal therapy using gold nanobipyramids for liver cancer cells triggered by femtosecond laser

In this study, the photothermal effect and up-conversion florescence imaging effect of gold nanobipyramids in liver cancer cells are investigated theoretically and experimentally to explore the photothermal ablation tumor therapy with higher photothermal conversion efficiency, shorter laser action time, smaller action range and lower laser power. The small-size gold nanobipyramids with good biocompatibility and infrared absorption peak located in the first biological window are synthesized. Femtosecond laser is focused on the nanobipyramids clusters in cells and the cells die after being irradiated for 20 s at a power as low as 3 mW. In contrast, the control cells die after irradiation with 30 mW laser for 3 min. The theoretical simulation results show that: under femtosecond laser irradiation, the local thermal effect of gold nanoclusters is produced in the range of hundreds of square nanometers and the temperature rises by 516 °C in 106 picoseconds. This therapy reduces the treatment time to seconds level, and the treatment range to square micrometer level, the power to milliwatt level. In this treatment, cells die by apoptosis rather than necrosis, which reduces inflammation. This result opens up a new way to develop photothermal ablation therapy with less side effects and more minimally invasive.

Analysis of Excitation Energy Transfer in LaPO4 Nanophosphors Co-Doped with Eu3+/Nd3+ and Eu3+/Nd3+/Yb3+ Ions.

Nanophosphors are widely used, especially in biological applications in the first and second biological windows. Currently, nanophosphors doped with lanthanide ions (Ln3+) are attracting much attention. However, doping the matrix with lanthanide ions is associated with a narrow luminescence bandwidth. This paper describes the structural and luminescence properties of co-doped LaPO4 nanophosphors, fabricated by the co-precipitation method. X-ray structural analysis, scanning electron microscope measurements with EDS analysis, and luminescence measurements (excitation 395 nm) of LaPO4:Eu3+/Nd3+ and LaPO4:Eu3+/Nd3+/Yb3+ nanophosphors were made and energy transfer between rare-earth ions was investigated. Tests performed confirmed the crystal structure of the produced phosphors and deposition of rare-earth ions in the structure of LaPO4 nanocrystals. In the range of the first biological window (650-950 nm), strong luminescence bands at the wavelengths of 687 nm and 698 nm (5D0 → 7F4:Eu3+) and 867 nm, 873 nm, 889 nm, 896 nm, and 907 nm (4F3/2 → 4I9/2:Nd3+) were observed. At 980 nm, 991 nm, 1033 nm (2F5/2 → 2F7/2:Yb3+) and 1048 nm, 1060 nm, 1073 nm, and 1080 nm (4F3/2 → 4I9/2:Nd3+), strong bands of luminescence were visible in the 950 nm-1100 nm range, demonstrating that energy transfer took place.

3D printed hydrogel/bioceramics core/shell scaffold with NIR-II triggered drug release for chemo-photothermal therapy of bone tumors and enhanced bone repair

The treatment of bone defect caused by osteosarcoma remains an intractable problem. Scaffolds with multi-functions are the potential candidates to kill recurrent tumor and to repair the bone defects after tumorectomy. However, most of these scaffolds employed photothermal therapy using near‐infrared laser inthe first biological window (NIR‐I)with intrinsic poor tissue penetration depth. Some scaffolds loading drugs for chemotherapy generally lack the accurate control of on-demand drugs release to reduce the side effects and enhance the therapeutic efficacy. Herein, 3D printed gelatin/bioceramics core/shell scaffolds were developed with doxorubicin (DOX) loaded gelatin as the core part and SrCuSi4O10 (SC) nanosheets/beta-tricalcium phosphate (β-TCP) as the shell part of the printed filaments. SC nanosheets endowed the scaffolds with photothermal therapy under NIR-IIlaser irradiation. Simultaneously, the generated extensive hyperthermia could induce the gel-sol transition of the gelatin in the core part of the filaments, which subsequently triggered the on-demand DOX release from the loosened gelatin achieving chemo-photothermal therapy. The in vitro and in vivo data demonstrated that chemo-photothermal therapy showed a synergetic effect on anti-tumor. Additionally, the degradation/release of gelatin from the filaments resulted in the hollow channels in the scaffold, which provided clear architectural cues for promoting the ingrowth of bone tissues. Meanwhile, the degradation of the SC nanosheets contributed to the sustained release of bioactive ions (Sr, Cu and Si), which further enhanced vascularized bone regeneration. All these results indicated that the 3D printed DOX loaded gelatin-TCP/SC scaffolds had a great potential application for the treatment of bone defects caused by osteosarcoma in effective killing cancer cells and repairing tumor-induced bone defects.

Stimuli‐Responsive Organic Near‐Infrared Photoacoustic Probes

AbstractPhotoacoustic (PA) imaging is an emerging biomedical imaging technique with the features of non‐invasiveness and non‐ionization. It takes advantage of the photothermal effect of PA probes to convert absorbed photon energy into heat and subsequent transient thermoelastic tissue expansion for ultrasonic waves for PA images. Thus, PA imaging exhibits the combined superiority of high‐contrast optical imaging and deep tissue penetration of acoustic imaging, which furnishes high‐resolution and high‐contrast tissue images. Stimuli‐responsive organic PA agents in the near‐infrared (NIR) biological window have attracted increasing attention because of their low biological toxicity and response characteristics. This review focuses on the recent research progress of stimuli‐responsive organic NIR probes for PA imaging, including the temperature response, pH response, redox response, metal ion response, and enzyme response. And the stimuli‐responsive mechanisms are highlighted in detail. Moreover, their perspectives and challenges are discussed. It will be of great help for the further development of organic NIR PA probes with stimuli‐response.