Oral delivery of peptide therapeutics as a convenient alternate to injections has been an area of research for the pharmaceutical scientific community for the last several decades. However, systemic ...delivery of therapeutic peptides via the oral route has been a daunting task due to the low pH denaturation of the peptides in the stomach, enzymatic instability, and poor transport across the tight junctions resulting in very low bioavailability. The low bioavailability is accompanied by large intra- and inter-subject variability leading to translational issues, preventing the development of successful peptide therapeutics. The inter-subject variability leads to large differences in pharmacologic responses in individuals and thus the dose required to produce therapeutic effect could vary between individuals making the development of drug product a very difficult task. A substantial amount of research has been (and continues to be) performed with a focus on getting acceptable absorption and reproducible results. Nonetheless, the high variability and low bioavailability during oral administration of peptides is still a work in progress and under-explored in a systematic way. While there are several review articles and scattered publications that discuss potential technologies for oral peptide delivery, a detailed look into the physiological challenges and absorption barriers which are a hindrance to successful clinical translation, is lacking. Herein, we have analyzed the physiological barriers within the gastrointestinal (GI) tract that are the root causes for the low bioavailability and high variability of oral delivery of peptides in humans. In particular, we have taken a detailed look at the key influencing factors such as the nature of various GI tract parameters, components of the GI tract that influences the uptake, site of absorption, pH of the gastric and intestinal compartments, food effect, and role of peptidases in affecting oral peptide absorption. Lack of in vitro - in vivo correlations and variability in animal models have also been highlighted as key impediments in understanding the challenges. The unique perspective presented herein for overcoming the physiological absorption barriers, will offer better developability approaches and will positively impact clinical translation of future oral peptide therapeutics. A deep understanding of these effects are vital, given the emergence of microbiome and oral biologic drug delivery that are fast emerging as the next wave of personalized patient centric therapies.
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Chemotherapy is the traditional treatment for intermediate and late stage cancers. The search for treatment options with minimal side effects has been ongoing for several years. Drug delivery ...technologies that result in minimal or no side effects with improved ease of use for the patients are receiving increased attention. Polymer drug conjugates and nanoparticles can potentially offset the volume of drug distribution while enhancing the accumulation of the active drug in tumors thereby reducing side effects. Additionally, development of localized drug delivery platforms is being investigated as another key approach to target tumors with minimal or no toxicity. Development of in-situ depot-forming gel systems for intratumoral delivery of immuno-oncology actives can enhance drug bioavailability to the tumor site and reduce systemic toxicity. This field of drug delivery is critical to develop given the advent of immunotherapy and the availability of novel biological molecules for treating solid tumors. This article reviews the advances in the field of engineered in-situ gelling platforms as a practical tool for local delivery of active oncolytic agents to tumor sites.
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The recent advancement and prevalence of wearable technologies and their ability to make digital measurements of vital signs and wellness parameters have triggered a new paradigm in ...the management of diseases. Drug delivery as a function of stimuli or response from wearable, closed-loop systems can offer real-time on-demand or preprogrammed drug delivery capability and offer total management of disease states. Here we review the key opportunities in this space for development of closed-loop systems, given the advent of digital wearable technologies. Particular considerations and focus are given to closed-loop systems combined with transdermal drug delivery technologies.
Controlling the biodistribution of nanoparticles upon intravenous injection is the key to achieving target specificity. One of the impediments in nanoparticle-based tumor targeting is the inability ...to limit the trafficking of nanoparticles to liver and other organs leading to smaller accumulated amounts in tumor tissues, particularly via passive targeting. Here we overcome both these challenges by designing nanoparticles that combine the specificity of antibodies with favorable particle biodistribution profiles, while not exceeding the threshold for renal filtration as a combined vehicle. To that end, ultrasmall silica nanoparticles are functionalized with anti-human epidermal growth factor receptor 2 (HER2) single-chain variable fragments to exhibit high tumor-targeting efficiency and efficient renal clearance. This ultrasmall targeted nanotheranostics/nanotherapeutic platform has broad utility, both for imaging a variety of tumor tissues by suitably adopting the targeting fragment and as a potentially useful drug delivery vehicle.
Organic soils are mostly composed of decayed plant matter and weathered rock material. Often, these soils are known for their inferior engineering behavior including very high compressibility and low ...shear strength. In order to improve these properties, organic soils are, by and large, modified with calcium based stabilizers such as lime, cement and fly ash. However, transportation agencies in the United States have mentioned that the anticipated improvements were never achieved or the improvement obtained disappeared quickly with time. Therefore, a research study was initiated to understand the behavioral mechanisms of lime and cement stabilized organic soils. Eight natural expansive soils bearing different organic contents (varying between 2 and 6%) were selected for the present investigation. First, optimum dosages of lime and cement were determined for the selected soils. Then treated and untreated (control) specimens were prepared to study their physical and engineering behaviors of the soil specimens at varied curing periods. There is a drastic increase in unconfined compressive strength (UCS) of lime and cement treated specimens until 28days of curing. Beyond which, a negligible improvement in UCS property was recorded for lime treated specimens and a slight decrease in UCS for cement treated soils was noticed. This reduction in strength for cement treated specimens could be attributed to the reduction in pH concentration with curing as well as the formation of inorganic calcium humic acid at this stage.
•In organic clays, lime is effective in reducing plasticity than cement.•Organics have moderate influence on unconfined compressive strength (UCS) of clays.•The strength reduction is evident in high PI clays holding high organic content.•High reduction in shrinkage strains for high PI organic clays treated with cement.•The combination of PI and organic content governs the behavior of stabilized clay.
Nanotechnology ushered the field of medicine in to a new era. Miniaturization, increased surface area, and the unique physicochemical properties in the nano dimension were explored for new ...applications. Pharmaceutical industry picked up the technology and early success came fast for oral drug delivery through improvement in dissolution properties of the active molecules. Many products were launched using the nanocrystal technology on the oral side. Further development of polymeric nanoparticles led to wide spread research of nanocarriers for parenteral delivery. While considerable efforts have gone in the last two decades for testing nanoparticles for tumor targeting, delivery into tumors has remained challenging and suboptimal. Inadequate in vivo models that didn't accurately reflect the age and vascularity of human tumors, and inability to reproducibly target therapeutic drugs to the tissue of interest due to intrinsic biodistribution of the particles and hence side effects, limited the number of studies that advanced to the clinic. Our article addresses the questions commonly asked by scientific researchers in nanomedicine: “Has nanoparticle technology yielded on its initial promise that scientists predicted towards improving therapeutic index and avoid toxicity by delivering molecules to target tissues or was it more of wishful thinking that had several roadblocks?” We answer this question by linking the relevance of nanoparticles to cancer immunotherapy. The advent of immunotherapy has begun to show the potential applicability of nanoparticles in a different light, to target the immune system. In this approach, nanoparticles may positively influence the immune system rather than create the targeted “magic bullet”. Utilizing the intrinsic properties of nanoparticles for immune targeting as opposed to targeting the tumor can bring about a positive difference due to the underlying complex cancer mechanisms that can potentially overlap with the heterogeneous biodistribution of nanoparticles towards improving the acquired and innate immune responses. In this review, we have followed the progress of nanotechnology in pharmaceutical applications with key insights from oral and parenteral drug delivery, and how to modify our thinking to better utilize nanoparticles for immuno-oncology. In contrast to conventional “local” tumor targeting by nanoparticles, we propose a new mechanism whereby nanoparticles trigger priming of the T cells towards tumor destruction. The heterogenous biodistribution of nanoparticles lends itself to stimulating immune cells systemically in a “global” manner and with the right therapeutic combinations will be able to trigger tumor antigens to continually activate, retain memory effects and destroy tumor cells.
Schematic representation of nanotherapeutics in the nanorobot avatar. Cancer utilizes complex regulatory networks and nanorobots will seek out and interact with tumor cells using its unique surface functionalization and sensing capabilities for improving immune response. Circulating nanoparticles can interact with dentritic cells and macrophages to activate T cells for improving the immune response. Display omitted
The built environment serves as a dynamic interface through which human society and the ecosystem interact and influence each other. Understanding this interdependence is a key to understanding ...sustainability as it applies to civil engineering. There is a growing consensus that delivering a sustainable built environment starts with incorporating sustainability thoughts at the planning and design stages of an infrastructure construction project. Geotechnical engineering can significantly influence the sustainability of infrastructure development because of its early position in the construction process. In this paper, the scope of geotechnical engineering towards sustainable development of civil infrastructure is reviewed. The philosophies and definitions of sustainability as applicable to geotechnical engineering are discussed. A comprehensive review of the research and case studies performed in geotechnical engineering, in relation to sustainable development, is presented in an effort to outline the scope and goals of sustainable geotechnical engineering.
•Using red mud waste can improve the compaction, strength and dynamic properties of loess dramatically.•The optimum content of red mud waste used in loess subgrade is proposed to be ...15%–20%.•Mechanism of red mud reinforcement in RMCL mixture is revealed through a series of microstructure analysis.•A new Gauss 2D model is obtained to predict the strength of the RMCL mixture considering red mud content and curing age.•Red mud waste can be a potential candidate for performance improvement in loess subgrade filling.
The disposal of red mud waste has induced critical environmental issue worldwide. While adding red mud waste as a partial alternative in loess subgrade projects can effectively reduce the red mud waste accumulation and engineering cost. Therefore, the feasibility study of red mud waste as loess subgrade filling is in urgent demand. In this study, the mechanical characteristics and micro-mechanism of red mud-treated loess with a small amount of cement additive (RMCL) were analyzed systematically. In order to study the effect of red mud addition on RMCL, tests on the compaction characteristics, strength properties, dynamic behaviors of RMCL were carried. The action mechanism of red mud was also revealed through a series of X-ray diffraction (XRD), light microscope (LM) and scanning electron microscope (SEM) with energy dispersive spectrometer (EDS) test. The results show that the red mud content CR has a significant effect on the unconfined compressive strength (UCS) of RMCL. An appropriate amount of red mud waste can effectively improve the mechanical properties of loess subgrade filling. The optimal CR is approximately 15%–20% for loess roadbed filling in this study. In addition, the UCS of RMCL increases with the increasing curing time, but first increases and then decreases with the increase of CR. Considering the effect of CR and curing time, an empirical Gauss 2D model is strongly proposed to predict the UCS value. A good linear relationship is also observed between the UCS value and the resistivity for RMCL. Moreover, the dynamic elastic modulus of RMCL is four times higher than that of untreated loess. Both dynamic stress and confining pressure have significant effect on the dynamic characteristics of RMCL. Based on the microanalysis of XRD, LM, SEM, and EDS, red mud can promote the generation of more cementitious hydrate such as C-S-H/C-A-S-H and Aft due to its strong alkalinity and hydrolysis. These hydrates, red mud fine particles, and aggregates can adhere to the surface of loess particles or fill inter-granular pores to obtain a more compact and stable soil structure, leading to a significant improvement of mechanical properties. The study provides an effective way to recycle red mud waste as a substitutable filler in loess roadbed, exhibiting environmental and economic benefits.
Wearable biosensors for sweat-based analysis are gaining wide attention due to their potential use in personal health monitoring. Flexible wearable devices enable sweat analysis at the molecular ...level, facilitating noninvasive monitoring of physiological states via real-time monitoring of chemical biomarkers. Advances in sweat extraction technology, real-time biosensors, stretchable materials, device integration, and wireless digital technologies have led to the development of wearable sweat-biosensing devices that are light, flexible, comfortable, aesthetic, affordable, and informative. Herein, we summarize recent advances of sweat wearables from the aspects of sweat extraction, fabrication of stretchable biomaterials, and design of biosensing modules to enable continuous biochemical monitoring, which are essential for a biosensing device. Key chemical components of sweat, sweat capture methodologies, and considerations of flexible substrates for integrating real-time biosensors with electronics to bring innovations in the art of wearables are elaborated. The strategies and challenges involved in improving the wearable biosensing performance and the perspectives for designing sweat-based wearable biosensing devices are discussed.
•An optimal percentage of bentonite fraction was determined for quartz sand–bentonite–carbon fiber mixtures.•Main heat transfer chains of quartz sand–bentonite–carbon fiber mixtures were ...proposed.•Interfacial mechanisms of heat conduction between carbon fibers and sand–bentonite were analyzed in detail.•Practicality of borehole backfilling material was verified by TICA GSHP Design Program.
Ground source heat pumps (GSHPs) use sustainable technology and renewable geothermal energy to exchange heat between the ground and the interior of residential, industrial, and commercial buildings. The borehole grouting material is a key contributor to the stability and thermal transmission properties of GSHPs. To investigate the thermomechanical properties of quartz sand–bentonite–carbon fiber mixtures to assess their potential as a borehole backfilling material, the thermal needle and unconfined compressive strength (UCS) tests were conducted. The thermal conductivity of quartz sand–bentonite–carbon fiber mixtures increased with the sand particle size, and the thermal conductivity showed a parabolic relationship with bentonite fraction for all sand particle sizes. The thermal conductivity of the mixtures increased with increasing moisture content and degree of saturation, and increased linearly with increasing dry density. The optimal percentage of bentonite, by dry mass, was approximately 10–12%. A relatively high thermal conductivity (1.90–1.98 W/m·K) and an unconfined compressive strength of 124–200 kPa were considered acceptable for borehole backfilling material used for GSHP. The practicality of quartz sand–bentonite–carbon fiber mixtures as borehole backfilling material for GSHPs was verified using the TICA GSHP Design Program. This research confirms that quartz sand–bentonite–carbon fiber mixtures are viable new borehole backfilling material that enhance the thermal efficiency and reduce the costs of GSHPs.
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