Preparation and polymeric encapsulation of powder mineral pellets for self-healing cement based materials

Using mineral additives and admixtures as self-healing agents in cement-based composites has been extensively researched. However, if the minerals are added directly to the cementitious matrix without any protection, they could immediately react, leading to a decrease in self-healing efficiency with further associated side-effects on the mechanical properties of cementitious composites. Thus, this paper describes the development of coated pellets as a self-healing system in cement based materials. Pan pelletisation was utilised for producing pellets from three different powder minerals as potential healing agents: reactive magnesium oxide (MgO), silica fume and bentonite. Of these materials, two types of developed prototype pellets in addition to another two commercial types of MgO pellets with different pellet sizes were then encapsulated in a polyvinyl alcohol (PVA) based film coating. The PVA coating was evaluated for the apparent solubility in water and in alkaline solution, swelling property, water permeability, dynamic mechanical properties, and shell thickness on pellets. Although PVA coating exhibited a decrease in its mechanical properties in water or in the simulated concrete environment, it retained integrity and stability in both environments. The PVA shell thickness varied from 10 to 50 µm. As the coated pellets partially replaced the natural sand in mortar mixtures, they were characterised in comparison with sand for the particle size distribution, density, porosity, crushing strength and particle shape. Experimental results indicated that the different types of pellets showed higher porosity and lower crushing strength compared to sand. In mortar mixtures, the pellets showed excellent compatibility with minimal influence on the fresh mixture properties and the compressive strength of the hardened specimens. This was accompanied by good distribution inside the concrete matrix. Further investigations on the self-healing performance of these pellets are under way

Impregnation and encapsulation of lightweight aggregates for self-healing concrete

This study investigated a technique of impregnating potential self-healing agents into lightweight aggregates (LWA) and the self-healing performance of concrete mixed with the impregnated LWA. Lightweight aggregates with a diameter range of 4–8 mm were impregnated with a sodium silicate solution as a potential self-healing agent. Concrete specimens containing the impregnated LWA and control specimens were pre-cracked up to 300 μm crack width at 7 days. Flexural strength recovery and reduction in water sorptivity were examined. After 28 days healing in water, the specimens containing the impregnated LWA showed ∼80% recovery of the pre-cracking strength, which accounts more than five times of the control specimens’ recovery. The capillary water absorption was also significantly improved; the specimens healed with the impregnated LWA showed a 50% reduction in the sorptivity index compared with the control cracked specimens and a very similar response to the control uncracked specimens. The contribution of sodium silicate in producing more calcium silicate hydrate gel was confirmed by characterisation the healing products using X-ray diffraction, Fourier transform spectroscopy, and scanning electron microscopy.Yousef Jameel Foundation through Cambridge Commonwealth, European & International Trust, Engineering and Physical Sciences Research Council (Project Ref. EP/K026631/1 – ‘‘Materials for Life”

Current Approaches for Glioma Gene Therapy and Virotherapy

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.Fil: Banerjee, Kaushik. University of Michigan; Estados UnidosFil: Núñez Aguilera, Felipe Javier. Fundación Instituto Leloir; ArgentinaFil: Haase, Santiago. University of Michigan; Estados UnidosFil: McClellan, Brandon L.. University of Michigan; Estados UnidosFil: Faisal, Syed M.. University of Michigan; Estados UnidosFil: Carney, Stephen V.. University of Michigan; Estados UnidosFil: Yu, Jin. University of Michigan; Estados UnidosFil: Alghamri, Mahmoud S.. University of Michigan; Estados UnidosFil: Asad, Antonela Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Varela, Maria Luisa. University of Michigan; Estados UnidosFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Lowenstein, Pedro R.. University of Michigan; Estados UnidosFil: Castro, Maria G.. University of Michigan; Estados Unido

Immunotherapy for gliomas: shedding light on progress in preclinical and clinical development

Gliomas are infiltrating brain tumors associated with high morbidity and mortality. Current standard of care includes radiation, chemotherapy and surgical resection. Today, survival rates for malignant glioma patients remain dismal and unchanged for decades. The glioma microenvironment is highly immunosuppressive and consequently this has motivated the development of immunotherapies for counteracting this condition, enabling the immune cells within the tumor microenvironment to react against this tumor.Areas covered: The authors discuss immunotherapeutic strategies for glioma in phase-I/II clinical trials and illuminate their mechanisms of action, limitations and key challenges. They also examine promising approaches under preclinical development.Expert opinion: In the last decade there has been an expansion in immune-mediated anti-cancer therapies. In the glioma field, sophisticated strategies have been successfully implemented in preclinical models. Unfortunately, clinical trials have not yet yielded consistent results for glioma patients. This could be attributed to our limited understanding of the complex immune cell infiltration and its interaction with the tumor cells, the selected time for treatment, the combination with other therapies and the route of administration of the agent. Applying these modalities to treat malignant glioma is challenging, but many new alternatives are emerging to by-pass these hurdles.Fil: Garcia Fabiani, Maria Belen. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ventosa, Maria. University of Michigan; Estados UnidosFil: Comba, Andrea. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Alghamri, Mahmoud S.. University of Michigan; Estados UnidosFil: Kadiyala, Padma. University of Michigan; Estados UnidosFil: Carney, Stephen. University of Michigan; Estados UnidosFil: Faisal, Syed M.. University of Michigan; Estados UnidosFil: Schwendeman, Anna. University of Michigan; Estados UnidosFil: Moon, James J.. University of Michigan; Estados UnidosFil: Scheetz, Lindsay. University of Michigan; Estados UnidosFil: Lahann, Joerg. University of Michigan; Estados UnidosFil: Mauser, Ava. University of Michigan; Estados UnidosFil: Lowenstein, Pedro R.. University of Michigan; Estados UnidosFil: Castro, Maria Gabriela. University of Michigan; Estados Unido

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.Fil: Garcia Fabiani, Maria Belen. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Haase, Santiago. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Comba, Andrea. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Carney, Stephen. University of Michigan; Estados UnidosFil: McClellan, Brandon. University of Michigan; Estados UnidosFil: Banerjee, Kaushik. University of Michigan; Estados UnidosFil: Alghamri, Mahmoud S.. University of Michigan; Estados UnidosFil: Syed, Faisal. University of Michigan; Estados UnidosFil: Kadiyala, Padma. University of Michigan; Estados UnidosFil: Nuñez, Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Asad, Antonela Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: González, Nazareno. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Aikins, Marisa E.. University of Michigan; Estados UnidosFil: Schwendeman, Anna. University of Michigan; Estados UnidosFil: Moon, James J.. University of Michigan; Estados UnidosFil: Lowenstein, Pedro R.. University of Michigan; Estados UnidosFil: Castro, Maria G.. University of Michigan; Estados Unido

Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy

Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4+ monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.Fil: Alghamri, Mahmoud S.. University Of Michigan Medical School; Estados UnidosFil: Banerjee, Kaushik. University Of Michigan Medical School; Estados UnidosFil: Mujeeb, Anzar A.. University Of Michigan Medical School; Estados UnidosFil: Mauser, Ava. University of Michigan; Estados UnidosFil: Taher, Ayman. University Of Michigan Medical School; Estados UnidosFil: Thalla, Rohit. University Of Michigan Medical School; Estados UnidosFil: McClellan, Brandon L.. University Of Michigan Medical School; Estados UnidosFil: Varela, Maria L.. University Of Michigan Medical School; Estados UnidosFil: Stamatovic, Svetlana M.. University Of Michigan Medical School; Estados UnidosFil: Martinez Revollar, Gabriela. University Of Michigan Medical School; Estados UnidosFil: Andjelkovic, Anuska V.. University Of Michigan Medical School; Estados UnidosFil: Gregory, Jason V.. University of Michigan; Estados UnidosFil: Kadiyala, Padma. University Of Michigan Medical School; Estados UnidosFil: Calinescu, Alexandra. University Of Michigan Medical School; Estados UnidosFil: Jiménez, Jennifer A.. University of Michigan; Estados UnidosFil: Apfelbaum, April A.. University of Michigan; Estados UnidosFil: Lawlor, Elizabeth R.. University of Washington; Estados UnidosFil: Carney, Stephen. University of Michigan; Estados UnidosFil: Comba, Andrea. University Of Michigan Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Faisal, Syed Mohd. University Of Michigan Medical School; Estados UnidosFil: Barissi, Marcus. University Of Michigan Medical School; Estados UnidosFil: Edwards, Marta B.. University Of Michigan Medical School; Estados UnidosFil: Appelman, Henry. University Of Michigan Medical School; Estados UnidosFil: Sun, Yilun. Case Western Reserve University; Estados UnidosFil: Gan, Jingyao. University of Michigan; Estados UnidosFil: Ackermann, Rose. University of Michigan; Estados UnidosFil: Schwendeman, Anna. University of Michigan; Estados UnidosFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Olin, Michael R.. University of Minnesota; Estados UnidosFil: Lahann, Joerg. University of Michigan; Estados UnidosFil: Lowenstein, Pedro R.. University of Michigan; Estados UnidosFil: Castro, Maria G.. University of Michigan; Estados Unido

A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality

The coronavirus disease 19 (COVID-19) pandemic is currently the most acute healthcare challenge in the world. Despite growing knowledge of the nature of Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), treatment options are still poorly defined. The safety of non-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen, has been openly questioned without any supporting evidence or clarity over dose, duration, or temporality of administration. This has been further conflicted by the initiation of studies to assess the efficacy of ibuprofen in improving outcomes in severe COVID-19 patients. To clarify the scientific reality, a literature search was conducted alongside considerations of the pharmacological properties of ibuprofen in order to construct this narrative review. The literature suggests that double-blind, placebo-controlled study results must be reported and carefully analysed for safety and efficacy in patients with COVID-19 before any recommendations can be made regarding the use of ibuprofen in such patients. Limited studies have suggested: (i) no direct interactions between ibuprofen and SARS-CoV-2 and (ii) there is no evidence to suggest ibuprofen affects the regulation of angiotensin-converting-enzyme 2 (ACE2), the receptor for COVID-19, in human studies. Furthermore, in vitro studies suggest ibuprofen may facilitate cleavage of ACE2 from the membrane, preventing membrane-dependent viral entry into the cell, the clinical significance of which is uncertain. Additionally, in vitro evidence suggests that inhibition of the transcription factor nuclear factor-κB (NF-kB) by ibuprofen may have a role in reducing excess inflammation or cytokine release in COVID-19 patients. Finally, there is no evidence that ibuprofen will aggravate or increase the chance of infection of COVID-19

Preparation and polymeric encapsulation of powder mineral pellets for self-healing cement based materials

Using mineral additives and admixtures as self-healing agents in cement-based composites has been extensively researched. However, if the minerals are added directly to the cementitious matrix without any protection, they could immediately react, leading to a decrease in self-healing efficiency with further associated side-effects on the mechanical properties of cementitious composites. Thus, this paper describes the development of coated pellets as a self-healing system in cement based materials. Pan pelletisation was utilised for producing pellets from three different powder minerals as potential healing agents: reactive magnesium oxide (MgO), silica fume and bentonite. Of these materials, two types of developed prototype pellets in addition to another two commercial types of MgO pellets with different pellet sizes were then encapsulated in a polyvinyl alcohol (PVA) based film coating. The PVA coating was evaluated for the apparent solubility in water and in alkaline solution, swelling property, water permeability, dynamic mechanical properties, and shell thickness on pellets. Although PVA coating exhibited a decrease in its mechanical properties in water or in the simulated concrete environment, it retained integrity and stability in both environments. The PVA shell thickness varied from 10 to 50 µm. As the coated pellets partially replaced the natural sand in mortar mixtures, they were characterised in comparison with sand for the particle size distribution, density, porosity, crushing strength and particle shape. Experimental results indicated that the different types of pellets showed higher porosity and lower crushing strength compared to sand. In mortar mixtures, the pellets showed excellent compatibility with minimal influence on the fresh mixture properties and the compressive strength of the hardened specimens. This was accompanied by good distribution inside the concrete matrix. Further investigations on the self-healing performance of these pellets are under way

Self-healing of cracks in mortars using novel PVA-coated pellets of different expansive agents

The potential for fine aggregates, a basic constituent of any mortar or concrete mix, has not been sufficiently exploited in developing self-healing systems. This paper investigates the self-healing capability of mortar mixes that contain polymeric coated pellets containing several potential self-healing agents. The pellets replaced 10% of the sand by weight in mortar mixtures and mortar prisms were pre-cracked up to 0.3 mm crack width at seven days. It was demonstrated through microscopy and ultrasonic observations that the addition of the coated pellets resulted in an improvement of the crack mouth and depth sealing by ~ 20–60% over and above the healing observed in the control samples. Water sorptivity and gas permeability tests confirmed the capability of the formed healing products through the use of the pellets in preventing the ingress of water, gas and/or deleterious liquids. In addition, the samples containing the pellets showed a considerable regain of flexural strength and stiffness after two rounds of water curing of the cracked samples. The significant contribution of pellets in forming the healing products in the crack volume was clear from the microstructural analyses conducted

Research Data Supporting "Impregnation and encapsulation of lightweight aggregates for self-healing concrete"

The data supports the findings and discussion on the field of impregnation and encapsulation of lightweight aggregates for self-healing concrete.Yousef Jameel Foundation through Cambridge Commonwealth, European & International Trus