3D-Printable Photothermal and Temperature-Controlled Polycaprolactone Scaffolds Incorporating Gold Plasmonic Blackbodies for Bone Tissue Engineering.

Near infrared dye-conjugated oxidative stress amplifying polymer micelles for dual imaging and synergistic anticancer phototherapy

Hydrogen-Bonding-Induced H-Aggregation of Charge-Transfer Complexes for Ultra-Efficient Second Near-Infrared Region Photothermal Conversion

Photothermal therapy (PTT) has been developed as a useful therapeutic method for cancer treatment. Localization of PTT agents in cancer sites and targeting capacity are required to further increase therapeutic efficacy. In this study, gold nanoparticles (AuNPs) and gelatin were functionalized with folic acid (FA) and hybridized to prepare FA-functionalized gelatin–AuNPs composite scaffolds. AuNPs with rod and star shapes of three sizes (40, 70, and 110 nm) were used for the hybridization to investigate the influence of AuNPs shape and size. The composite scaffolds showed porous structures with good interconnectivity. Modification with FA increased capture capacity of the composite scaffolds. Hybridization with AuNPs rendered the composite scaffold a good photothermal conversion property under near-infrared (NIR) laser irradiation. Temperature change during laser irradiation increased with the laser power intensity and irradiation time. The shape and size of AuNPs also affected their photothermal conversion property. The composite scaffold of gold nanorods 70 (FA-G/R70) had the highest photothermal conversion capacity. Breast cancer cells cultured in the FA-G/R70 composite scaffold were killed under NIR laser irradiation. Mouse subcutaneous implantation further demonstrated the excellent photothermal ablation capability of FA-G/R70 composite scaffold to breast cancer cells. The FA-functionalized composite scaffolds were demonstrated a high potential for local PPT of breast cancer.

Cancer theranostics, the combination of imaging and therapeutic agents in a smart nanocarriers, has been a promising approach towards cancer [1]. And the chemotherapy combining with photothermal therapy to treat tumors can efficiently improve therapeutic efficacies [2].Herein, we report a theranostic nanoplatform based on PLGA nanoparticles, which are constructed by simultaneous encapsulating indocyanine green (ICG), a widely used near‐infrared (NIR) dye in photothermal therapy, and doxorubicin (Dox), a chemotherapy drug, into biodegradable poly(D, L‐lactic‐co‐glycolic acid) (PLGA) polymeric nanoparticles and decorated with bovine serum albumin (BSA) using the double emulsion solvent evaporation method (W/O/W). The as fabricated IDP NPs with the mean diameter of 220 nm exhibited good dispersity, excellent size stability, especially enhanced photostability (fluorescence stability) compared with free ICG, and is able to efficiently load chemotherapeutic drug doxorubicin (Dox) into the PLGA core. When the weight ratio of added ICG to Dox was 0.075 (μg ICG/μg Dox), the encapsulation efficiency of the Dox and ICG can be reached approximately 42.0% and 55.3%, respectively. It was confirmed that IDP NPs showed preferable photothermal effect, favorable photoacoustic (PA) imaging properties and faster release of Dox when exposed to near‐infrared (NIR) laser irradiation or acidic conditions. Moreover, the NIR light‐induced photothermal heat can enhance the permeability of the lysosomal membrane resulting in efficient Dox translocation from lysosomes to cytoplasm indicating by intracellular distribution assay. In comparison with the chemo‐ or photothermal treatment alone, the combined treatment of IDP NPs with laser irradiation achieving a marked synergistic therapeutic effect. The tumor cell viability was ~5% when treated with IDP NPs ([ICG] =15 μg/mL, [Dox] =3.9 μg/mL) under NIR laser irradiation (808 nm, 1.5 W/cm2). Our work validates that the developed co‐loaded BSA‐decorated IDP NPs could serve as a promising platform for PA imaging‐guided combined chemo‐ and photothermal therapy with reducing side effects in cancer theranostics.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The conjugates of gold nanorods and the model drug, fluorescein isothiocyanate (FITC), embedded inside polyelectrolytes (GNRs/FITC@PLE) were synthesized to study the release kinetics of FITC under femtosecond near-infrared (NIR) laser irradiation. The optical and structural properties of GNRs/FITC@PLE conjugates before and after laser treatments were examined using UV-vis spectroscopy, confocal microscopy, and transmission electron microscopy (TEM). The release of FITC from the conjugates was induced by the heat generated from gold nanorods under laser irradiation. The concentration of released FITC was measured as the time of continuous and periodic laser irradiation was varied. Within 5 min of the laser exposure, the release rates of FITC exhibited zero-order and first-order kinetics under continuous and periodic irradiation, respectively. Furthermore, a drug release system was designed based on the conjugates of gold nanorods and the anticancer drug, paclitaxel (PTX), embedded inside polyelectrolytes (GNRs/PTX@PLE). The conjugates were applied for in vitro studies with breast cancer cells. The release of PTX from the conjugates was triggered by NIR laser irradiation, and the inhibition rates of the cells showed strong dependencies on the irradiation modes and time. The results suggested that the multiple releases of PTX from the conjugates can be controlled by laser irradiation within a long period of time. Our system holds great potential for future therapeutic applications on breast cancers.

Melanoma is an aggressive form of skin cancer, and single-modality treatments often fail to prevent tumor recurrence and metastasis. Combination therapy has emerged as an effective approach to improve treatment outcomes. In this study, we developed a multifunctional nanoplatform, MIL@DOX@ICG, utilizing MIL-101-NH2(Fe) as a carrier to co-deliver the chemotherapeutic agent doxorubicin (DOX) and the photosensitizer indocyanine green (ICG). MIL-101-NH2(Fe) was synthesized via a hydrothermal method. Drug release was evaluated under different pH conditions, and the photothermal effect was tested under near-infrared (NIR) laser irradiation. Hydroxyl radical and reactive oxygen species generation capacities were quantified. Cellular studies using B16F10 cells assessed cytotoxicity, cellular uptake, migration inhibition, and colony formation suppression. In vivo experiments in melanoma-bearing mice evaluated antitumor efficacy and systemic safety through tumor growth inhibition, histological analyses, and toxicity assessments. MIL@DOX@ICG exhibited a uniform octahedral structure with a particle size of approximately 139 nm and high drug loading efficiencies for DOX (33.70%) and ICG (30.59%). The nanoplatform demonstrated pH-responsive drug release and potent photothermal effects. The generation of hydroxyl radicals via the Fenton reaction and reactive oxygen species production under NIR laser irradiation by MIL@DOX@ICG were confirmed. In vitro assessments revealed significant cytotoxicity of MIL@DOX@ICG against B16F10 cells under NIR laser irradiation, with improved efficacy in inhibiting cell proliferation and migration. In vivo studies confirmed the superior antitumor efficacy of MIL@DOX@ICG + NIR treatment, synergistically harnessing chemotherapy, photothermal therapy, photodynamic therapy, and chemodynamic therapy effects while maintaining excellent biocompatibility. Our findings underscore the potential of MIL-101-NH2(Fe) nanoparticles as a versatile and effective platform for synergistic melanoma therapy, offering a promising strategy for overcoming the limitations of conventional treatment modalities.

Icariin loaded-hollow bioglass/chitosan therapeutic scaffolds promote osteogenic differentiation and bone regeneration

Wound infection is a serious clinical challenge, often accompanied by persistent inflammatory response and the threat of increased bacterial resistance, there is an urgent requirement to develop a wound dressing with potent antimicrobial as well as immunomodulatory effects. In this study, we developed a multifunctional wound dressing to promote healing of infected wounds by doping puerarin-loaded mesoporous polydopamine nanoparticles into a carboxymethyl chitosan/sodium alginate oxide-based hydrogel. The hydrogel has good injectability, adhesion, and self-healing capabilities, and can be well matched to irregular wounds and against external injuries. The loaded PUE is rapidly released from the hydrogel in response to near-infrared (NIR) laser irradiation, which has a controlled release property. In addition, under NIR laser irradiation, the hydrogel with good photothermal properties exerted good antimicrobial properties through localized high temperature, and exhibited good antioxidant, immune microenvironment modulation, and pro-angiogenic effects through accelerated released PUE. In the E. coli-infected full-thickness skin wounds healing experiments, the hydrogel can effectively kill bacteria, regulate the immune microenvironment, promote collagen deposition and angiogenesis, and significantly accelerate the wound healing, showing promising applications.

Considering the future clinical applications of localized cancer therapy, it is of great importance to construct injectable biodegradable nanocomposite hydrogels with combinatorial therapeutic efficacy. Here, porous silicon nanoparticles (PSiNPs) as host matrix were chosen to fabricate PSiNPs@Au nanocomposites via in situ reductive synthesis of gold nanoparticles. Then PSiNPs@Au nanocomposites were further incorporated into thermosensitive chitosan (CS) hydrogels to construct CS/PSiNPs@Au nanocomposite hydrogels, which showed in situ gelation at physiological temperature, excellent biodegradability, and biocompatibility. Especially with the encapsulation of CS hydrogels, PSiNPs@Au nanocomposites had a long-term stable photothermal effect with higher local temperature under near-infrared (NIR) laser irradiation, whether in vitro or in vivo. Besides, assisted by NIR laser irradiation, CS/PSiNPs@Au nanocomposite hydrogels exhibited a long-term sustained release of anticancer drugs (doxorubicin hydrochloride, DOX) in acidic tumor environments. Finally, DOX/CS/PSiNPs@Au precursors were administrated into tumor-bearing mice via a single intratumoral injection, which presented a significant synergistic chemo-photothermal therapeutic efficacy under repeated NIR laser irradiation during long-term cancer treatments. Accordingly, we developed a novel strategy to prepare multifunctional CS/PSiNPs@Au nanocomposite hydrogels and also demonstrated their potential applications in localized cancer therapy in future clinics.

BackgroundHeat generation in a drug delivery carrier by exposure to near-infrared (NIR) light with excellent tissue transmittance is an effective strategy for drug release and tumor therapy. Because liposomes have amphiphilic properties, they are useful as drug carriers. Liposomes are also very suitable for drug delivery strategies using heat generation by NIR laser because lipid bilayers are easily broken by heat. Thermally generated bubbles from liposomes not only induce drug release, but also enable ultrasound imaging.MethodsMelanin, perfluorohexane (PFH), and 5-fluorouracil (5-FU)-loaded liposomes (melanin@PFH@5-FU-liposomes) that can generate heat and bubble by NIR laser irradiation were prepared by a thin film method. Conversion of light to heat and bubble generation of melanin@PFH@5-FU-liposomes were evaluated using an infrared (IR) thermal imaging camera and an ultrasound imaging system both in vitro and in vivo. To investigate tumor therapeutic effect, NIR laser of 808 nm was used to irradiate tumor site for 10 min after injecting melanin@PFH@5-FU-liposome into tail veins of CT26-bearing mice.ResultsMelanin@PFH@5-FU-liposomes showed a spherical shape with a size of 209.6 ± 4.3 nm. Upon NIR laser irradiation, melanin@PFH@5-FU-liposomes exhibited effective temperature increase both in vitro and in vivo. In this regard, temperature increase caused a phase transition of PFH to induce bubble generation dramatically, resulting in effective drug release behavior and ultrasound imaging. The temperature of the tumor site was increased to 52 t and contrast was greatly enhanced during ultrasound imaging due to the generation of bubble. More importantly, tumor growth was effectively inhibited by injection of melanin@PFH@5-FU-liposomes with laser irradiation.ConclusionsBased on intrinsic photothermal properties of melanin and phase transition properties of PFH, melanin@PFH@5-FU-liposomes exhibited effective heat and bubble generation upon NIR laser irradiation. The elevated temperature induced bubble generation, resulting in contrast enhancement of ultrasound imaging. Melanin@PFH@5-FU-liposomes under NIR laser irradiation induced the death of cancer cells, thereby effectively inhibiting tumor growth. These results suggest that melanin@PFH@5-FU-liposomes can be utilized as a promising agent for photothermal tumor therapy and ultrasound imaging.

Femtosecond Near-Infrared Laser Pulses Elicit Generation of Reactive Oxygen Species in Mammalian Cells Leading to Apoptosis-like Death

Three-dimensional (3-D) printing technology is affecting how orthopaedic surgeries are planned and executed. Like many innovations, 3-D printers are becoming smaller, more affordable, and more accessible. Free access to open-source 3-D imaging software has also made clinical implementation of this technology widely feasible. Within the last decade, 3-D printing advancements have improved the way orthopaedic surgeons can approach both common and complex cases. Advanced imaging studies can be used to create musculoskeletal models, which can then be used to create custom orthopaedic guides and instruments. Similarly, 3-D printing is being applied to improve the field of biologic therapies in orthopaedics. Application of 3-D printing technology has been associated with important improvements in education, preoperative planning, surgical care, and patient-specific devices and treatments. Improvements in cost-effectiveness, access, and usability of 3-D printing technology have made it possible for orthopaedic surgeons to use this powerful tool using desktop 3-D printers in their clinic or office. The types of printers and materials available to print are constantly expanding, but many of the basic 3-D printing principles persist throughout these advances in the field. A clear understanding of this technology is important to the clinical implementation of 3-D printing for current and future practice of orthopaedic care.

Bone defect therapy frequently encounters bacterial infections and chronic inflammation, which impair bone regeneration and threaten implant stability. Iron oxide nanoparticles have attracted attention due to cost-effectiveness, biocompatibility, and metabolic safety. However, iron oxide nanoparticles still struggle to balance low-temperature efficient antibacterial activity, effective immunomodulation, and bone regeneration. Therefore, inspired by diatoms, a multifunctional bone repair scaffold based on chitosan-hydroxyapatite (CH) is developed by integrating the multifunctional properties of copper-doped iron goethite (Fe(Cu)OOH) nanoparticles and a mesoporous SiO2 protective layer (CH/FeCu@SiO2). The "cytoskeleton" CH scaffold stabilizes the nanoparticles and supports tissue growth. The "chloroplast" Fe(Cu)OOH and the " frustule" SiO2 layer synergistically capture near-infrared (NIR) light to generate localized mild hyperthermia (≈42°C), with the release of Cu2+ to achieve antibacterial effects (>99%). In addition, Fe(Cu)OOH exhibits enzyme-like antioxidant activity, scavenging reactive oxygen species (ROS) (69.20%) and thereby promoting M2 macrophage polarization (1.64-fold), which protects stem cells and creates osteogenic immune microenvironment. Moreover, the mild hyperthermia and ion release upregulate the TGF-β signaling pathway and inhibit osteoclast differentiation, promoting vascularized bone regeneration and defect repair (1.3-fold). Overall, this biomimetic scaffold, enabling synergistic antibacterial, immunomodulatory, and osteogenic activities, offers a promising therapeutic strategy for infectious bone defects treatment.

Tissue-engineered approaches to regenerate bone in the craniomaxillofacial region utilize biomaterial scaffolds to provide structural and biological cues to stem cells to stimulate osteogenic differentiation. Bioactive scaffolds are typically comprised of natural components but often lack the manufacturability of synthetic materials. To circumvent this trade-off, we 3D printed materials comprised of decellularized bone (DCB) matrix particles combined with polycaprolactone (PCL) to create novel hybrid DCB:PCL scaffolds for bone regeneration. Hybrid scaffolds were readily printable at compositions of up to 70% bone by mass and displayed robust mechanical properties. Assessments of surface features revealed both collagenous and mineral components of bone were present. Qualitative and quantitative assessments showed increased surface roughness relative to that of pure PCL scaffolds. These findings correlated with enhanced cell adhesion on hybrid surfaces relative to that on pure surfaces. Human adipose-derived stem cells (hASCs) cultured in DCB:PCL scaffolds without soluble osteogenic cues exhibited significant upregulation of osteogenic genes in hybrid scaffolds relative to pure PCL scaffolds. In the presence of soluble phosphate, hybrid scaffolds resulted in increased calcification. The hASC-seeded scaffolds were implanted into critical-sized murine calvarial defects and yielded greater bone regeneration in DCB:PCL scaffolds compared to that in PCL-only at 1 and 3 months post-transplantation. Taken together, these results demonstrate that 3D printed DCB:PCL scaffolds might be effective for stimulating bone regeneration.

A biomimetic surface for water collection was successfully engineered using three-dimensional (3D) printing technology. The fused deposition modeling-type 3D printing was used to create a reusable mold. This was used to cast waveform microstructures on a hydrophobic polymer surface, which was induced by using stacked filaments. The etching was performed on the printed mold by using a chemical solvent to generate nano/micro pores, which enhanced the rolling-off motion of water droplets. To create a hydrophilic region on the hydrophobic surface, the metal deposition was achieved using a 3D-printed mask and the self-masking effect of the tilted tips of waveform microstructures. The metal array served as seeding points for the growth of water droplets in foggy conditions. As a result, the fabricated biomimetic surface exhibited the highest water-collecting performance (average 0.77 g for 10 min) compared with the other four different surfaces. This study demonstrates the use of 3D printing technology to rapidly and simply fabricate engineered (hybrid) surfaces for various applications involving facile control of wettability.