(Meth)acrylate-Free Three-Dimensional Printing of Bio-Derived Photocurable Resins with Terpene- and Itaconic Acid-Derived Poly(ester-thioether)s.

Vat photopolymerization, a very efficient and precise object manufacturing technique, still strongly relies on the use of acrylate- and methacrylate-based formulations because of their low cost and high reactivity. However, the environmental impact of using fossil fuel-based, volatile, and toxic (meth)acrylic acid derivatives is driving the scientific community toward the development of alternatives that can match the mechanical performance and three-dimensional (3D) printing processability of traditional photocurable mixtures but are made from environmentally friendly building blocks. Herein, itaconic acid is polymerized with polyols derived from naturally occurring terpenes to produce photocurable poly(ester-thioether)s. The formulation of such polymers using itaconic acid-based reactive diluents allows the preparation of a series of (meth)acrylate-free photocurable resins, which can be 3D printed into solid objects. Extensive analysis has been conducted on the properties of photocured polymers including their thermal, thermomechanical, and mechanical characteristics. The findings suggest that these materials exhibit properties comparable to those of traditional alternatives that are created using harmful and toxic blends. Notably, the photocured polymers are composed of biobased constituents ranging from 75 to 90 wt %, which is among the highest values ever recorded for vat photopolymerization applications.

Loco-regional treatment with temozolomide-loaded thermogels prevents glioblastoma recurrences in orthotopic human xenograft models.

Glioblastoma multiforme (GBM) is the most aggressive primary tumor of the central nervous system and the diagnosis is often dismal. GBM pharmacological treatment is strongly limited by its intracranial location beyond the blood-brain barrier (BBB). While Temozolomide (TMZ) exhibits the best clinical performance, still less than 20% crosses the BBB, therefore requiring administration of very high doses with resulting unnecessary systemic side effects. Here, we aimed at designing new negative temperature-responsive gel formulations able to locally release TMZ beyond the BBB. The biocompatibility of a chitosan-ß-glycerophosphate-based thermogel (THG)-containing mesoporous SiO2 nanoparticles (THG@SiO2) or polycaprolactone microparticles (THG@PCL) was ascertained in vitro and in vivo by cell counting and histological examination. Next, we loaded TMZ into such matrices (THG@SiO2-TMZ and THG@PCL-TMZ) and tested their therapeutic potential both in vitro and in vivo, in a glioblastoma resection and recurrence mouse model based on orthotopic growth of human cancer cells. The two newly designed anticancer formulations, consisting in TMZ-silica (SiO2@TMZ) dispersed in the thermogel matrix (THG@SiO2-TMZ) and TMZ, spray-dried on PLC and incorporated into the thermogel (THG@PCL-TMZ), induced cell death in vitro. When applied intracranially to a resected U87-MG-Red-FLuc human GBM model, THG@SiO2-TMZ and THG@PCL-TMZ caused a significant reduction in the growth of tumor recurrences, when compared to untreated controls. THG@SiO2-TMZ and THG@PCL-TMZ are therefore new promising gel-based local therapy candidates for the treatment of GBM.

Gold nanorods assisted photothermal therapy of bladder cancer in mice: A computational study on the effects of gold nanorods distribution at the centre, periphery, and surface of bladder cancer.

BACKGROUND AND OBJECTIVES: Gold nanorod-assisted photothermal therapy (GNR-PTT) is a cancer treatment whereby GNRs incorporated into the tumour act as photo-absorbers to elevate the thermal destruction effect. In the case of bladder, there are few possible routes to target the tumour with GNRs, namely peri/intra-tumoural injection and intravesical instillation of GNRs. These two approaches lead to different GNR distribution inside the tumour and can affect the treatment outcome. METHODOLOGY: The present study investigates the effects of heterogeneous GNR distribution in a typical setup of GNR-PTT. Three cases were considered. Case 1 considered the GNRs at the tumour centre, while Case 2 represents a hypothetical scenario where GNRs are distributed at the tumour periphery; these two cases represent intratumoural accumulation with different degree of GNR spread inside the tumour. Case 3 is achieved when GNRs target the exposed tumoural surface that is invading the bladder wall, when they are delivered by intravesical instillation. RESULTS: Results indicate that for a laser power of 0.6 W and GNR volume fraction of 0.01%, Case 2 and 3 were successful in achieving complete tumour eradication after 330 and 470 s of laser irradiation, respectively. Case 1 failed to form complete tumour damage when the GNRs are concentrated at the tumour centre but managed to produce complete tumour damage if the spread of GNRs is wider. Results from Case 2 also demonstrated a different heating profile from Case 1, suggesting that thermal ablation during GNR-PTT is dependant on the GNRs distribution inside the tumour. Case 3 shows similar results to Case 2 whereby gradual but uniform heating is observed. Cases 2 and 3 show that uniformly heating the tumour can reduce damage to the surrounding tissues. CONCLUSIONS: Different GNR distribution associated with the different methods of introducing GNRs to the bladder during GNR-PTT affect the treatment outcome of bladder cancer in mice. Insufficient spreading during intratumoural injection of GNRs can render the treatment ineffective, while administered via intravesical instillation. GNR distribution achieved through intravesical instillation present some advantages over intratumoural injection and is worthy of further exploration.

Iridium-Functionalized Cellulose Microcrystals as a Novel Luminescent Biomaterial for Biocomposites.

Microcrystalline cellulose (MCC) is an emerging material with outstanding properties in many scientific and industrial fields, in particular as an additive in composite materials. Its surface modification allows for the fine-tuning of its properties and the exploitation of these materials in a plethora of applications. In this paper, we present the covalent linkage of a luminescent Ir-complex onto the surface of MCC, representing the first incorporation of an organometallic luminescent probe in this biomaterial. This goal has been achieved with an easy and sustainable procedure, which employs a Bronsted-acid ionic liquid as a catalyst for the esterification reaction of -OH cellulose surface groups. The obtained luminescent cellulose microcrystals display high and stable emissions with the incorporation of only a small amount of iridium (III). Incorporation of MCC-Ir in dry and wet matrices, such as films and gels, has been also demonstrated, showing the maintenance of the luminescent properties even in possible final manufacturers.

Itaconic-Acid-Based Sustainable Poly(ester amide) Resin for Stereolithography.

Material science is recognized as a frontrunner in achieving a sustainable future, owing to its primary reliance upon petroleum-based chemical raw materials. Several efforts are made to implement common renewable feedstocks as an alternative to common fossil resources. For this purpose, additive manufacturing (AM) represents promising and effective know-how for the replacement of high energy- and resource-demanding processes with more environmentally friendly practices. This work presents a novel biobased ink for stereolithography, which has been formulated by mixing a photocurable poly(ester amide) (PEA) obtained from renewable resources with citrate and itaconate cross-linkers and appropriate photopolymerization initiators, terminators, and dyes. The mechanical features and the relative biocompatibility of 3D-printed objects have been carefully studied to evaluate the possible resin implementation in the field of the textile fashion industry.

Early diagnosis of bladder cancer by photoacoustic imaging of tumor-targeted gold nanorods.

Detection and removal of bladder cancer lesions at an early stage is crucial for preventing tumor relapse and progression. This study aimed to develop a new technological platform for the visualization of small and flat urothelial lesions of high-grade bladder carcinoma in situ (CIS). We found that the integrin α5ß1, overexpressed in bladder cancer cell lines, murine orthotopic bladder cancer and human bladder CIS, can be exploited as a receptor for targeted delivery of GNRs functionalized with the cyclic CphgisoDGRG peptide (Iso4). The GNRs@Chit-Iso4 was stable in urine and selectively recognized α5ß1 positive neoplastic urothelium, while low frequency ultrasound-assisted shaking of intravesically instilled GNRs@Chit-Iso4 allowed the distribution of nanoparticles across the entire volume of the bladder. Photoacoustic imaging of GNRs@Chit-Iso4 bound to tumor cells allowed for the detection of neoplastic lesions smaller than 0.5 mm that were undetectable by ultrasound imaging and bioluminescence.

An Application of Multivariate Data Analysis to Photoacoustic Imaging for the Spectral Unmixing of Gold Nanorods in Biological Tissues.

Gold nanorods (GNRs) showed to be a suitable contrast agent in photoacoustics (PA), and are able to provide a tunable absorption contrast against background tissue, while a detectable PA signal can be generated from highly localized and targeted areas. A crucial issue for these imaging techniques is represented by the discrimination between exogenous and endogenous contrast and the assessment of the real PA signal magnitude. The application of image resolution/unmixing methods was implemented and optimized to recover the relative magnitude spectra and distribution maps of image constituents of the biological sample based on multivariate analysis (multivariate curve resolution-alternating least squares, MCR-ALS) in the presence of GNRs with tunable absorption properties. The proposed data analysis methodology is demonstrated on real PA images from experimental animal models and ex-vivo preparations.

Synthesis of Ultrasmall Single-Crystal Gold-Silver Alloy Nanotriangles and Their Application in Photothermal Therapy.

Photothermal therapy has always been a very attractive anti-cancer strategy, drawing a lot of attention thanks to its excellent performance as a non-invasive and pretty safe technique. Lately, nanostructures have become the main characters of the play of cancer therapy due to their ability to absorb near-infrared radiation and efficient light-to-heat conversion. Here we present the synthesis of polyethylene glycol (PEG)-stabilized hybrid ultrasmall (<20 nm) gold-silver nanotriangles (AuAgNTrs) and their application in photothermal therapy. The obtained AuAgNTrs were deeply investigated using high-resolution transmission electron microscopy (HR-TEM). The cell viability assay was performed on U-87 glioblastoma multiforme cell model. Excellent photothermal performance of AuAgNTrs upon irradiation with NIR laser was demonstrated in suspension and in vitro, with >80% cell viability decrease already after 10 min laser irradiation with a laser power P = 3W/cm2 that was proved to be harmless to the control cells. Moreover, a previous cell viability test had shown that the nanoparticles themselves were reasonably biocompatible: without irradiation cell viability remained high. Herein, we show that our hybrid AuAgNTrs exhibit very exciting potential as nanostructures for hyperthermia cancer therapy, mostly due to their easy synthesis protocol, excellent cell compatibility and promising photothermal features.

Zein as a versatile biopolymer: different shapes for different biomedical applications.

In recent years, the interest regarding the use of proteins as renewable resources has deeply intensified. The strongest impact of these biomaterials is clear in the field of smart medicines and biomedical engineering. Zein, a vegetal protein extracted from corn, is a suitable biomaterial for all the above-mentioned purposes due to its biodegradability and biocompatibility. The controlled drug delivery of small molecules, fabrication of bioactive membranes, and 3D assembly of scaffold for tissue regeneration are just some of the topics now being extensively investigated and reported in the literature. Herein, we review the recent literature on zein as a biopolymer and its applications in the biomedical world, focusing on the different shapes and sizes through which it can be manipulated.

A numerical study to investigate the effects of tumour position on the treatment of bladder cancer in mice using gold nanorods assisted photothermal ablation.

Gold nanorods assisted photothermal therapy (GNR-PTT) is a new cancer treatment technique that has shown promising potential for bladder cancer treatment. The position of the bladder cancer at different locations along the bladder wall lining can potentially affect the treatment efficacy since laser is irradiated externally from the skin surface. The present study investigates the efficacy of GNR-PTT in the treatment of bladder cancer in mice for tumours growing at three different locations on the bladder, i.e., Case 1: closest to skin surface, Case 2: at the bottom half of the bladder, and Case 3: at the side of the bladder. Investigations were carried out numerically using an experimentally validated framework for optical-thermal simulations. An in-silico approach was adopted due to the flexibility in placing the tumour at a desired location along the bladder lining. Results indicate that for the treatment parameters considered (laser power 0.3 W, GNR volume fraction 0.01% v/v), only Case 1 can be used for an effective GNR-PTT. No damage to the tumour was observed in Cases 2 and 3. Analysis of the thermo-physiological responses showed that the effectiveness of GNR-PTT in treating bladder cancer depends not only on the depth of the tumour from the skin surface, but also on the type of tissue that the laser must pass through before reaching the tumour. In addition, the results are reliant on GNRs with a diameter of 10 nm and an aspect ratio of 3.8 - tuned to exhibit peak absorption for the chosen laser wavelength. Results from the present study can be used to highlight the potential for using GNR-PTT for treatment of human bladder cancer. It appears that Cases 2 and 3 suggest that GNR-PTT, where the laser passes through the skin to reach the bladder, may be unfeasible in humans. While this study shows the feasibility of using GNRs for photothermal ablation of bladder cancer, it also identifies the current limitations needed to be overcome for an effective clinical application in the bladder cancer patients.

Surface-Modified Nanocellulose for Application in Biomedical Engineering and Nanomedicine: A Review.

Presently, a plenty of concerns related to the environment are due to the overuse of petroleum-based chemicals and products; the synthesis of functional materials, starting from the natural sources, is the current trend in research. The interest for nanocellulose has recently increased in a huge range of fields, from the material science to the biomedical engineering. Nanocellulose gained this leading role because of several reasons: its natural abundance on this planet, the excellent mechanical and optical features, the good biocompatibility and the attractive capability of undergoing surface chemical modifications. Nanocellulose surface tuning techniques are adopted by the high reactivity of the hydroxyl groups available; the chemical modifications are mainly performed to introduce either charged or hydrophobic moieties that include amination, esterification, oxidation, silylation, carboxymethylation, epoxidation, sulfonation, thiol- and azido-functional capability. Despite the several already published papers regarding nanocellulose, the aim of this review involves discussing the surface chemical functional capability of nanocellulose and the subsequent applications in the main areas of nanocellulose research, such as drug delivery, biosensing/bioimaging, tissue regeneration and bioprinting, according to these modifications. The final goal of this review is to provide a novel and unusual overview on this topic that is continuously under expansion for its intrinsic sophisticated properties.

Current concepts in nanostructured contrast media development for in vivo photoacoustic imaging.

Photoacoustic (PA) imaging is indeed one of the most promising bioimaging techniques for theranostics applications in humans, allowing for the visualization of blood vessels and melanomas with high spatial resolution. However, in order to overcome the endogenous contrast arising from interfering endogenous species such as haemoglobin and melanin, specific contrast agents need to be developed, allowing PAI to successfully identify targeted contrast in the range of wavelengths in which interference from the biomatrix is minimized. This has been first performed by small molecule dyes, which, however, suffer from some important limitations such as low hydrophilicity and short circulation times. For this reason, scientific research has recently directed its efforts towards the development of nanostructured contrast agents capable of providing efficient PA contrast at low concentrations with low toxicity and high biocompatibility. The principal nanostructures are based on (1) metal and semiconducting nanoparticles, amongst which variously shaped nano-gold plays the main role, (2) carbon nanomaterials, such as carbon nanotubes and graphene, and (3) conjugated polymer nanoparticles. In this review, the principal characteristics of this class of materials are reported and greater focus is directed towards in vivo studies. A detailed analysis is performed on various physical-chemical parameters that define the PA response of reported contrast agents, like absorption coefficients and photoacoustic efficiencies. By comparing the experimental data, this review provides a comprehensive tool for the evaluation of new nanostructured contrast agents for PA imaging.

A novel theranostic gold nanorods- and Adriamycin-loaded micelle for EpCAM targeting, laser ablation, and photoacoustic imaging of cancer stem cells in hepatocellular carcinoma.

INTRODUCTION AND PURPOSE: Cancer stem cells (CSCs) present a higher capacity to evade being killed by cancer agents and developing chemoresistance, thus leading to failure of conventional anticancer therapeutics. Nanomaterials specifically designed for targeting and treating not only tumor cells, but also CSCs, may encompass therapeutic and diagnostic tools, thus successfully eradicating the tumor. MATERIALS AND METHODS: Polymeric micelles simultaneously loaded with gold nanorods (GNRs) and Adriamycin were prepared and used as a novel therapeutic and diagnostic weapon. Epithelial cell adhesion molecule (EpCAM) is an important CSC surface marker and has been exploited in this work as an active targeting agent. Photoacoustic imaging was applied for GNR individuation and tissue recognition. RESULTS: The nanosystem was demonstrated to be able to elicit effective targeting of cancer cells and cause their killing, in particular under laser ablation. Moreover, ex vivo photoacoustic imaging is able to clearly identify tumor regions thanks to GNR's contrast. CONCLUSION: The nanosystem can be considered a powerful and promising theranostic weapon for hepatocellular carcinoma treatment.

Soft Piezoionic/Piezoelectric Nanocomposites Based on Ionogel/BaTiO3 Nanoparticles for Low Frequency and Directional Discriminative Pressure Sensing.

We report on the fabrication and electro-mechanical characterization of a nanocomposite system exhibiting anisotropic electrical response under the application of tactile compressive stresses (5 kPa) at low frequencies (0.1-1 Hz). The nanocomposite is based on a chemically cross-linked gel incorporating a highly conductive ionic liquid and surface functionalized barium titanate (BaTiO3) ferroelectric nanoparticles. The system was engineered to respond to mechanical stimulations by combining piezoionic and piezoelectric activity, generating electric charge due to a redistribution of the mobile ions across the polymer matrix and to the presence of the electrically polarized ceramic nanoparticles, respectively. The nanocomposite response was characterized in a quasi-static regime using a custom-designed apparatus. The results obtained showed that the combination of both piezo-effects led to output voltages up to 8 mV and anisotropy in the response. This allows to discriminate the sample orientation with respect to the load direction by monitoring the phase and amplitude modulation of the output signal. The integration of cluster-assembled gold electrodes produced by Supersonic Cluster Beam Deposition (SCBD) was also performed, enabling to enhance the charge transduction efficiency by a factor of 10, compared to the bare nanocomposite. This smart piezoionic/piezoelectric nanocomposite represents an interesting solution for the development of soft devices for discriminative touch sensing and objects localization in physically unstructured environments.

Smart assembly of Mn-ferrites/silica core-shell with fluorescein and gold nanorods: robust and stable nanomicelles for in vivo triple modality imaging.

Herein we report the synthesis of a resilient nanosystem based on silica-coated magnetic MnFe2O3 nanoparticles conjugated to fluorescein and PEGylated gold nanorods embedded in polymeric micelles (MnFe2O4@SiO2@GNRs@PMs), for magnetic-photoacoustic-optical triple-modality imaging. The magnetic relaxivity of the nanosystem has been evaluated, revealing high r2/r1 ratios that suggest the effectiveness of the nanosystem as the T2-contrast agent. In addition, contrast-based fluorescence imaging has been tested both in vitro and ex vivo, showing that the nanosystem exhibits the suitable optical properties of fluorescein, with contrast intensities comparable with previously reported results. Finally, photoacoustic, due to gold nanorods, performances of the nanosystem have been evaluated, revealing good linearity between concentration and photoacoustic response in the 25-250 nM concentration under irradiation at 690 nm. The results showed a contrast-to-noise ratio (CNR) as high as 60 in a mouse leg subcutaneously injected with the nanosystem. Biocompatibility studies revealed no hemolytic effect induced by the nanoconstruct, revealing the applicability of the studied diagnostic tool for medical studies.

The DnaE polymerase from Deinococcus radiodurans features RecA-dependent DNA polymerase activity.

We report in the present study on the catalytic properties of the Deinococcus radiodurans DNA polymerase III α subunit (αDr). The αDr enzyme was overexpressed in Escherichia coli, both in soluble form and as inclusion bodies. When purified from soluble protein extracts, αDr was found to be tightly associated with E. coli RNA polymerase, from which αDr could not be dissociated. On the contrary, when refolded from inclusion bodies, αDr was devoid of E. coli RNA polymerase and was purified to homogeneity. When assayed with different DNA substrates, αDr featured slower DNA extension rates when compared with the corresponding enzyme from E. coli (E. coli DNA Pol III, αEc), unless under high ionic strength conditions or in the presence of manganese. Further assays were performed using a ssDNA and a dsDNA, whose recombination yields a DNA substrate. Surprisingly, αDr was found to be incapable of recombination-dependent DNA polymerase activity, whereas αEc was competent in this action. However, in the presence of the RecA recombinase, αDr was able to efficiently extend the DNA substrate produced by recombination. Upon comparing the rates of RecA-dependent and RecA-independent DNA polymerase activities, we detected a significant activation of αDr by the recombinase. Conversely, the activity of αEc was found maximal under non-recombination conditions. Overall, our observations indicate a sharp contrast between the catalytic actions of αDr and αEc, with αDr more performing under recombination conditions, and αEc preferring DNA substrates whose extension does not require recombination events.