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Ethylene-vinyl alcohol copolymer (EVOH)/clay nanocomposites were prepared via a dynamic melt-intercalation process using a Brabender Plastograph or extruder. The phase morphology and the crystallization behavior of the nanocomposites were investigated, using differential scanning calorimetry (DSC). X-ray diffraction (XRD), and transmission electron microscopy (TEM). Mechanical properties were determined using an Instron machine. It was found that the viscosity of EVOH/clay mixtures increases with processing time. Thermal analysis of the EVOH/clay nanocomposites showed that the melting temperature, crystallization temperature, and heat of fusion of the EVOH matrix sharply decrease when clay is added. XRD verified an increased gallery height for the clay in the composites. Maleic anhydride-grafted ethylene vinyl acetate (EVA-g-MA) or maleic anhydride-grafted linear low-density polyethylene (LLDPE-g-MA) were added as compatibilizers of EVOH with clay, in various concentrations (1, 5 and 10 wt%). Significantly higher viscosity levels were obtained for the compatibilized systems as the torque dramatically increased when processed in the Brabender machine. Enhanced intercalation within the galleries was obtained. EVOH crystallinity decreased with increasing compatibilizer content, until at a certain content no crystallization took place. EVOH/clay composites were also processed in an extruder, showing improved mechanical properties for as low as 1 wt% clay. The strong EVOH/clay interactions are responsible for the unique behavior of their nanocomposites. Polym. Eng. Sci. 44:1019-1026, 2004., INTRODUCTION Polymer melt intercalation is a promising new approach for fabricating polymer-layered silicate nanocomposites, apparently by using a conventional melt-mixing technology. The absence of solvents makes direct intercalation an environmentally [...]

Introduction: Over 6.8 million fractures occur annually in the US, with 10% experiencing delayed- or non-union. Anabolic therapeutics like PTH analogs stimulate fracture repair, and small molecule salt inducible kinase (SIK) inhibitors mimic PTH action. This study tests whether the SIK inhibitor YKL-05-099 accelerates fracture callus osteogenesis., Methods: 126 female mice underwent femoral shaft pinning and midshaft fracture, receiving daily injections of PBS, YKL-05-099, or PTH. Callus tissues were analyzed via RT-qPCR, histology, single-cell RNA-seq, and μCT imaging. Biomechanical testing evaluated tissue rigidity. A hydrogel-based delivery system for PTH and siRNAs targeting SIK2/SIK3 was developed and tested., Results: YKL-05-099 and PTH-treated mice showed higher mineralized callus volume fraction and improved structural rigidity. RNA-seq indicated YKL-05-099 increased osteoblast subsets and reduced chondrocyte precursors. Hydrogel-released siRNAs maintained target knockdown, accelerating callus mineralization., Discussion: YKL-05-099 enhances fracture repair, supporting selective SIK inhibitors' development for clinical use. Hydrogel-based siRNA delivery offers targeted localized treatment at fracture sites., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Momenzadeh, Yeritsyan, Abbasian, Kheir, Hanna, Wang, Dosta, Papaioannou, Goldfarb, Tang, Amar-Lewis, Nicole Prado Larrea, Martinez Lozano, Yousef, Wixted, Wein, Artzi and Nazarian.)

Integrating multimodal neuro- and nanotechnology-enabled precision immunotherapies with extant systemic immunotherapies may finally provide a significant breakthrough for combatting glioblastoma (GBM). The potency of this approach lies in its ability to train the immune system to efficiently identify and eradicate cancer cells, thereby creating anti-tumor immune memory while minimizing multi-mechanistic immune suppression. A critical aspect of these therapies is the controlled, spatiotemporal delivery of structurally defined nanotherapeutics into the GBM tumor microenvironment (TME). Architectures such as spherical nucleic acids or poly(beta-amino ester)/dendrimer-based nanoparticles have shown promising results in preclinical models due to their multivalency and abilities to activate antigen-presenting cells and prime antigen-specific T cells. These nanostructures also permit systematic variation to optimize their distribution, TME accumulation, cellular uptake, and overall immunostimulatory effects. Delving deeper into the relationships between nanotherapeutic structures and their performance will accelerate nano-drug development and pave the way for the rapid clinical translation of advanced nanomedicines. In addition, the efficacy of nanotechnology-based immunotherapies may be enhanced when integrated with emerging precision surgical techniques, such as laser interstitial thermal therapy, and when combined with systemic immunotherapies, particularly inhibitors of immune-mediated checkpoints and immunosuppressive adenosine signaling. In this perspective, we highlight the potential of emerging treatment modalities, combining advances in biomedical engineering and neurotechnology development with existing immunotherapies to overcome treatment resistance and transform the management of GBM. We conclude with a call to action for researchers to leverage these technologies and accelerate their translation into the clinic., Competing Interests: Competing interests statement:A.B.H. serves on the advisory board of Caris Life Sciences and the WCG Oncology Advisory Board. She has received consulting fees from BlueRock Therapeutics and Novocure and been provided in-kind support for research from Moleculin, Takeda, ImmunoGenesis, and Carthera. A.H.K. is a consultant for Monteris Medical and has a received research grant from Stryker for a clinical outcomes study about a dural substitute, which has no direct relation to this study. A.H.S. is a shareholder of Exicure Inc., which develops SNA therapeutic platforms. A.H.S. and C.A.M. are inventors on patent US20150031745A1, which describes SNA nanoconjugates to cross the blood-brain barrier. A.B.H. receives royalty and milestone payments from DNAtrix for the licensing of the patent titled “Biomarkers and combination therapies using oncolytic virus and immunomodulation” (11,065,285). She additionally has active patents titled “miRNA for treating cancer and for use with adoptive immunotherapies” (9,675,633) and “Concurrent chemotherapy and immunotherapy” (9,399,662) “Low intensity ultrasound combination cancer therapies” (International applications PCT/US2022/019435 and US 63/158,642).

Nucleic acid vaccines have become a transformative technology to fight emerging infectious diseases and cancer. Delivery of such via the transdermal route could boost their efficacy given the complex immune cell reservoir present in the skin that is capable of engendering robust immune responses. We have generated a novel library of vectors derived from poly(β-amino ester)s (PBAEs) including oligopeptide-termini and a natural ligand, mannose, for targeted transfection of antigen presenting cells (APCs) such as Langerhans cells and macrophages in the dermal milieu. Our results reaffirmed terminal decoration of PBAEs with oligopeptide chains as a powerful tool to induce cell-specific transfection, identifying an outstanding candidate with a ten-fold increased transfection efficiency over commercial controls in vitro. The inclusion of mannose in the PBAE backbone rendered an additive effect and increased transfection levels, achieving superior gene expression in human monocyte-derived dendritic cells and other accessory antigen presenting cells. Moreover, top performing candidates were capable of mediating surface gene transfer when deposited as polyelectrolyte films onto transdermal devices such as microneedles, offering alternatives to conventional hypodermic administration. We predict that the use of highly efficient delivery vectors derived from PBAEs could advance clinical translation of nucleic acid vaccination over protein- and peptide-based strategies.

Background: Immune-modulating therapies impart positive outcomes in a subpopulation of cancer patients. Improved delivery strategies and non-invasive monitoring of anti-tumor effects can help enhance those outcomes and understand the mechanisms associated with the generation of anti-tumor immune responses following immunotherapy. Methods: We report on the design of a microneedle (MN) platform capable of simultaneous delivery of immune activators and collection of interstitial skin fluid (ISF) to monitor therapeutic responses. While either approach has shown promise, the integration of the therapy and diagnostic arms into one MN platform has hardly been explored before. MNs were synthesized out of crosslinked hyaluronic acid (HA) and loaded with a model immunomodulatory nanoparticle-containing drug, CpG oligodinucleotides (TLR9 agonist), for cancer therapy in melanoma and colon cancer models. The therapeutic response was monitored by longitudinal analysis of entrapped immune cells in the MNs following patch retrieval and digestion. Results: Transdermal delivery of CpG-containing NPs with MNs induced anti-tumor immune responses in multiple syngeneic mouse cancer models. CpG-loaded MNs stimulated innate immune cells and reduced tumor growth. Intravital microscopy showed deposition and spatiotemporal co-localization of CpG-NPs within the tumor microenvironment when delivered with MNs. Analysis of MN-sampled ISF revealed similar immune signatures to those seen in the bulk tumor homogenate, such as increased populations of macrophages and effector T cells following treatment. Conclusions: Our hydrogel-based MNs enable effective transdermal drug delivery into immune cells in the tumor microenvironment, and upon retrieval, enable studying the immune response to the therapy over time. This platform has the theranostic potential to deliver a range of combination therapies while detecting biomarkers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Mining a large cohort of single-cell transcriptomics data, here we employ combinatorial optimization techniques to chart the landscape of optimal combination therapies in cancer. We assume that each individual therapy can target any one of 1269 genes encoding cell surface receptors, which may be targets of CAR-T, conjugated antibodies or coated nanoparticle therapies. We find that in most cancer types, personalized combinations composed of at most four targets are then sufficient for killing at least 80% of tumor cells while sparing at least 90% of nontumor cells in the tumor microenvironment. However, as more stringent and selective killing is required, the number of targets needed rises rapidly. Emerging individual targets include PTPRZ1 for brain and head and neck cancers and EGFR in multiple tumor types. In sum, this study provides a computational estimate of the identity and number of targets needed in combination to target cancers selectively and precisely., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Thermal monitoring during focused ultrasound (FUS) transcranial procedures is mandatory and commonly performed by MRI. Transcranial ultrasonic thermal monitoring is an attractive alternative. Furthermore, using the therapeutic FUS transducer itself for this task is highly desirable. Nonetheless, such application is challenged by massive skull-induced signal attenuation and aberrations. This study examined the feasibility of implementing the Golay-coded excitations (CoE) for temperature monitoring in bovine brain samples in the range of 35 °C-43 °C (hyperthermia). Feasibility was assessed using computer simulations, water-based phantoms, and ex vivo bovine brain white-matter samples. The samples were gradually heated to about 45 °C and sonicated during cool down with a 1-MHz therapeutic FUS implementing Golay CoE. Initially, a calibration curve correlating the normalized time-of-flight (TOF) changes and the temperature was generated. Next, a bovine bone was positioned between the FUS and the brain samples, and the scanning process was repeated for different fresh samples. The calibration curve was then used as a mean for estimating the temperature, which was compared to thermocouple measurements. The simulations demonstrated a substantial improvement in signal-to-noise ratio (SNR) and suggested that the implementation of 4-bit sequences is advantageous. The experimental measurements with bone demonstrated good temperature estimation with an average absolute error for the water phantoms and brains of 1.46 °C ± 1.22 °C and 1.23 °C ± 0.99 °C, respectively. In conclusion, a novel noninvasive method utilizing the Golay CoE for ultrasonic thermal monitoring using a therapeutic FUS transducer is introduced. This method can lead to the development of an acoustic tool for brain thermal monitoring.

Tertiary lymphoid structures (TLSs) have been identified in the parenchyma and/or in the peripheral margins of human solid tumors. Uncovering the functional nature of these structures is the subject of much intensive investigation. Studies have shown a direct correlation of the presence of human tumor-localized TLS and better patient outcome (e.g., increase in overall survival) in certain solid tumor histologies, but not all. We had identified a tumor-derived immune gene-expression signature, encoding 12 distinct chemokines, which could reliably identify the presence of TLSs, of different degrees, in various human solid tumors. We are focused on understanding the influence of TLSs on the tumor microenvironment and leveraging this understanding to both manipulate the antitumor immune response and potentially enhance immunotherapy applications. Moreover, as not all human solid tumors show the presence of these lymphoid structures, we are embarking on bioengineering approaches to design and build "designer" TLSs to address, and potentially overcome, an unmet medical need in cancer patients whose tumors lack such lymphoid structures.

Hydrogels consisting of three-dimensional (3D) polymeric networks have found a wide range of applications in biotechnology due to their large water capacity, high biocompatibility, and facile functional versatility. The hydrogels with stimulus-responsive swelling properties have been particularly instrumental to realizing signal transduction in biosensors and bioelectronics. Graphenes are two-dimensional (2D) nanomaterials with unprecedented physical, optical, and electronic properties and have also found many applications in biosensors and bioelectronics. These two classes of materials present complementary strengths and limitations which, when effectively coupled, can result in significant synergism in their electrical, mechanical, and biocompatible properties. This report reviews recent advances made with hydrogel and graphene materials for the development of high-performance bioelectronics devices. The report focuses on the interesting intersection of these materials wherein 2D graphenes are hybridized with 3D hydrogels to develop the next generation biosensors and bioelectronics., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3'-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug.

Gold nanobeacons can be used as a powerful tool for cancer theranostics. Here, we proposed a nanomaterial platform based on gold nanobeacons to detect, target and inhibit the expression of a mutant Kras gene in an in vivo murine gastric cancer model. The conjugation of fluorescently-labeled antisense DNA hairpin oligonucleotides to the surface of gold nanoparticles enables using their localized surface plasmon resonance properties to directly track the delivery to the primary gastric tumor and to lung metastatic sites. The fluorescently labeled nanobeacons reports on the interaction with the target as the fluorescent Cy3 signal is quenched by the gold nanoparticle and only emit light following conjugation to the Kras target owing to reorganization and opening of the nanobeacons, thus increasing the distance between the dye and the quencher. The systemic administration of the anti-Kras nanobeacons resulted in approximately 60% tumor size reduction and a 90% reduction in tumor vascularization. More important, the inhibition of the Kras gene expression in gastric tumors prevents the occurrence of metastasis to lung (80% reduction), increasing mice survival in more than 85%. Our developed platform can be easily adjusted to hybridize with any specific target and provide facile diagnosis and treatment for neoplastic diseases.

Multidrug resistance (MDR) in cancer cells is a substantial limitation to the success of chemotherapy. Here, we describe facile means to overcome resistance by silencing the multidrug resistance protein 1 (MRP1), before chemotherapeutic drug delivery in vivo with a single local application. Our platform contains hydrogel embedded with dark-gold nanoparticles modified with 5-fluorouracil (5-FU)-intercalated nanobeacons that serve as an ON/OFF molecular nanoswitch triggered by the increased MRP1 expression within the tumor tissue microenvironment. This nanoswitch can sense and overcome MDR prior to local drug release. The nanobeacons comprise a 5-FU intercalated DNA hairpin, which is labeled with a near-infrared (NIR) dye and a dark-quencher. The nanobeacons are designed to open and release the intercalated drug only upon hybridization of the DNA hairpin to a complementary target, an event that restores fluorescence emission due to nanobeacons conformational reorganization. Despite the cross-resistance to 5-FU, more than 90% tumor reduction is achieved in vivo in a triple-negative breast cancer model following 80% MRP1 silencing compared with the continuous tumor growth following only drug or nanobeacon administration. Our approach can be applied to reverse cross-resistance to other chemotherapeutic drugs and restore treatment efficacy. As a universal nanotheranostic probe, this platform can pave the way to early cancer detection and treatment.

There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify "signatures" for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes., (©AlphaMed Press.)

Nanostructured porous silicon (PSi) is emerging as a promising platform for drug delivery owing to its biocompatibility, degradability and high surface area available for drug loading. The ability to control PSi structure, size and porosity enables programming its in vivo retention, providing tight control over embedded drug release kinetics. In this work, the relationship between the in vitro and in vivo degradation of PSi under (pre)clinically relevant conditions, using breast cancer mouse model, is defined. We show that PSi undergoes enhanced degradation in diseased environment compared with healthy state, owing to the upregulation of reactive oxygen species (ROS) in the tumour vicinity that oxidize the silicon scaffold and catalyse its degradation. We further show that PSi degradation in vitro and in vivo correlates in healthy and diseased states when ROS-free or ROS-containing media are used, respectively. Our work demonstrates that understanding the governing mechanisms associated with specific tissue microenvironment permits predictive material performance.

Soft tissue adhesives are employed to repair and seal many different organs, which range in both tissue surface chemistry and mechanical challenges during organ function. This complexity motivates the development of tunable adhesive materials with high resistance to uniaxial or multiaxial loads dictated by a specific organ environment. Co-polymeric hydrogels comprising aminated star polyethylene glycol and dextran aldehyde (PEG:dextran) are materials exhibiting physico-chemical properties that can be modified to achieve this organ- and tissue-specific adhesion performance. Here we report that resistance to failure under specific loading conditions, as well as tissue response at the adhesive material-tissue interface, can be modulated through regulation of the number and density of adhesive aldehyde groups. We find that atomic force microscopy (AFM) can characterize the material aldehyde density available for tissue interaction, and in this way enable rapid, informed material choice. Further, the correlation between AFM quantification of nanoscale unbinding forces with macroscale measurements of adhesion strength by uniaxial tension or multiaxial burst pressure allows the design of materials with specific cohesion and adhesion strengths. However, failure strength alone does not predict optimal in vivo reactivity. Thus, we demonstrate that the development of adhesive materials is significantly enabled when experiments are integrated along length scales to consider organ chemistry and mechanical loading states concurrently with adhesive material properties and tissue response., (Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Soft tissue sealants generally sacrifice adhesive strength for biocompatibility, motivating the development of materials which interact with tissue to a predictable and controllable extent. Crosslinked hydrogels comprising aminated star polyethylene glycol and high molecular weight dextran aldehyde polymers (PEG:dextran) display aldehyde-mediated adhesion and readily tunable reactivity with soft tissue ex-vivo. Evaluation of PEG:dextran compositional variants revealed that the burst pressure of repaired intestinal wounds and the extent of material-induced tissue deformation both increase nonlinearly with formulation aldehyde content and are consistently within the desired range established by traditional sealants. Adhesive test elements featuring PEG:dextran and intestinal tissue exhibited considerable viscoelasticity, prompting use of a standard linear solid (SLS) model to describe adhesive mechanics. Model elements were accurately represented as continuous functions of PEG:dextran chemistry, facilitating prediction of adhesive mechanics across the examined range of compositional formulations. SLS models of traditional sealants were also constructed to allow general correlative analyses between viscoelastic adhesive mechanics and metrics of sealant performance. Linear correlation of equilibrium SLS stiffness to sealant-induced tissue deformation indicates that dense adhesive crosslinking restricts tissue expansion, while correlation of instantaneous SLS stiffness to burst pressure suggests that the adhesive stress relaxation capacity of PEG:dextran enhances their overall performance relative to traditional sealants.