ABSTRACT
Past studies have demonstrated higher clearance for monoclonal antibodies possessing increased rates of non-specific endocytosis. However, this metric is oftentimes evaluated indirectly using biophysical techniques or cell surface binding studies that may not provide insight into the specific rates of cellular turnover. Furthermore, few examples evaluating non-specific endocytosis have been reported for a therapeutic antibody that reached clinical assessment. In the current report, we evaluated a therapeutic human immunoglobulin G2 monoclonal antibody targeted against the interleukin-4 receptor alpha chain (IL-4Rα) that exhibited elevated target independent clearance in previous Phase 1 and 2 studies. We confirmed high non-specific clearance of the anti-IL-4Rα antibody as compared to a reference antibody during pharmacokinetic assessments in wild type mice where target-mediated disposition was absent. We then developed a cell-based method capable of measuring cellular protein endocytosis and demonstrated the anti-IL-4Rα antibody exhibited marked non-specific uptake relative to the reference compound. Antibody homology modeling identified the anti-IL-4Rα antibody possessed positive charge patches whose removal via targeted mutations substantially reduced its non-specific endocytosis. We then expanded the scope of the study by evaluating panels of both preclinical and clinically relevant monoclonal antibodies and demonstrate those with the highest rates of non-specific uptake in vitro exhibited elevated target independent clearance, low subcutaneous bioavailability, or both. Our results support the observation that high non-specific endocytosis is a negative attribute in monoclonal antibody development and demonstrate the utility of a generic cell-based screen as a quantitative tool to measure non-specific endocytosis of protein therapeutics at the single-cell level.
ABSTRACT
Using scanning electron microscopy (SEM), six Salsola species from Iran were examined for their epidermis, seed, and fruit micromorphology. Among them were S. brachiata from section Heterotricha, S dendroides, S. incanescens, and S. orientalis from section Caroxylon, S. kali from section Kali, and S. turcomanica from section Physurus. Epidermal cells are divided into three types. There were diamond, irregular, and polygonal cells, as well as straight and undulated walls. Studied species of Salsola have smooth or sculptured fruit surfaces, and there are three main types of fruit surface ornamentation. There is a significant difference between these species based on the type of hair and density of the fruit. Seed shape and color have little systematic significance. The seed epidermis is composed of polygonal, elongated polygonal, irregular, and diamond cells. Although polygonal and irregular testa cells are most common, their size and shape can provide additional information and useful diagnostic characteristics at both specific and infraspecific levels. For taxonomic separation, the current study provides novel insights at micromorphological levels. RESEARCH HIGHLIGHTS: This article reports halophyte are shown as models for adaptation to extreme habitats. These plants are placed among the ecological communities of xerophytes. Here, for the first time, the microstructural analysis of Salsola has been investigated. Additionally, it provides new insights into plant species' response to extreme conditions, as well as possible adaptation strategies at the micromorphological level.
ABSTRACT
Aerogel-based biomaterials are increasingly being considered for biomedical applications due to their unique properties such as high porosity, hierarchical porous network, and large specific pore surface area. Depending on the pore size of the aerogel, biological effects such as cell adhesion, fluid absorption, oxygen permeability, and metabolite exchange can be altered. Based on the diverse potential of aerogels in biomedical applications, this paper provides a comprehensive review of fabrication processes including sol-gel, aging, drying, and self-assembly along with the materials that can be used to form aerogels. In addition to the technology utilizing aerogel itself, it also provides insight into the applicability of aerogel based on additive manufacturing technology. To this end, how microfluidic-based technologies and 3D printing can be combined with aerogel-based materials for biomedical applications is discussed. Furthermore, previously reported examples of aerogels for regenerative medicine and biomedical applications are thoroughly reviewed. A wide range of applications with aerogels including wound healing, drug delivery, tissue engineering, and diagnostics are demonstrated. Finally, the prospects for aerogel-based biomedical applications are presented. The understanding of the fabrication, modification, and applicability of aerogels through this study is expected to shed light on the biomedical utilization of aerogels.
Subject(s)
Biocompatible Materials , Tissue Engineering , Desiccation/methods , Wound HealingABSTRACT
The gypsum habitats of Iran are significant reserves of biodiversity containing endemic and rare species. Despite the limited understanding of its characteristics and habitat, it has become essential to study the endemic species of the Semnan gypsic soil. Fresh samples of studied species including Acantholimon cymosum, Astragalus fridae, Astragalus semnanensis, Euphorbia gypsicola, Gypsophila mucronofolia, Moltkia gypsaceae and Nepeta eremokosmus were collected in the wild during the growth season. Leaf surface and leaf cross-sections were considered. The longest hair length was related to A. fridae, A. semnanensis and M. gypsaceae species. The shorter hairs belong to the species A. cymosum, G. mucronofolia and E. gypsicola. Crystals called cystolites were seen in the epidermal cell wall of A. semnanensis leaves. The anatomical characteristics of these species' leaves indicate the presence of dry structures. Using micromorphological studies, we analyzed the hairs of the studied species in terms of their shapes, sizes, and densities. We found some species have hairs with special appendages, which is due to the special conditions in which they have grown. Xeromorphic stomata were found on both leaf surfaces of all endemic gypsophyte plants of Semnan. Several studies have shown that gypsophytes have a specialized mechanism for regulating the absorption of sulfur and calcium from soils containing calcium sulfate or gypsum by their roots. The current study provides novel insights into the response of plant species to extreme conditions and potential adaptation strategies at micromorphological levels.
Subject(s)
Calcium Sulfate , Soil , Soil/chemistry , Calcium Sulfate/analysis , Iran , Plant Leaves/anatomy & histology , Plant Leaves/chemistry , PlantsABSTRACT
The extinction of a species in a plant-pollinator mutualistic community can cause cascading effects and lead to major biodiversity loss. The ecologically important task of predicting the severity of the cascading effects is made challenging by the complex network of interactions among the species. In this work, we analyze an ensemble of models of communities of plant and pollinator species. These models describe the mutualistic inter-species interactions by Boolean threshold functions. We show that identifying generalized positive feedback loops can help pinpoint the species whose extinction leads to catastrophic and substantial damage to the whole community. We compare these results with the damage percentage caused by the loss of species identified as important by previously studied structural measures and show that positive feedback loops and the information gained from them can identify certain crucial species that the other measures fail to find. We also suggest mitigation measures for two specific purposes: (1) prevent the damage to the community by protecting a subset of the species, and (2) restore the community after the damage by restoring a subset of species. Our analyses indicate that the generalized positive feedback loops predict the most efficient strategies to achieve these purposes. The correct identification of species in each category has important implications for conservation efforts and developing community management strategies.
Subject(s)
Biodiversity , Pollination , Feedback , Plants , EcosystemABSTRACT
Microneedles (MNs) have been developed as minimally invasive tools for diagnostic and therapeutic applications. However, in recent years, there has been an increasing interest in developing smart multifunctional MN devices to provide automated and closed-loop systems for body fluid extraction, biosensing, and drug delivery in a stimuli-responsive manner. Although this technology is still in its infancy and far from being translated into the clinic, preclinical trials have shown some promise for the broad applications of multifunctional MN devices. The main challenge facing the fabrication of smart MN patches is the integration of multiple modules, such as drug carriers, highly sensitive biosensors, and data analyzers in one miniaturized MN device. Researchers have shown the feasibility of creating smart MNs by integrating stimuli-responsive biomaterials and advanced microscale technologies, such as microsensors and microfluidic systems, to precisely control the transportation of biofluids and drugs throughout the system. These multifunctional MN devices can be envisioned in two distinct strategies. The first type includes individual drug delivery and biosensing MN units with a microfluidic system and a digital analyzer responsible for fluid transportation and communication between these two modules. The second type relies on smart biomaterials that can function as drug deliverers and biosensors by releasing drugs in a stimuli-responsive manner. These smart biomaterials can undergo structural changes when exposed to external stimuli, such as pH and ionic changes, mimicking the biological systems. Studies have demonstrated a high potential of hydrogel-based MN devices for a wide variety of biomedical applications, such as drug and cell delivery, as well as interstitial fluid extraction. Biodegradable hydrogels have also been advantageous for fabricating multifunctional MNs due to their high loading capacity and biocompatibility with the drug of choice. Here, we first review a set of MN devices that can be employed either for biosensing or delivery of multiple target molecules and compare them to the conventional and more simple systems, which are mainly designed for single-molecule sensing or delivery. Subsequently, we expand our insight into advanced MN systems with multiple competencies, such as body fluid extraction, biosensing, and drug delivery at the point of care. The improvement of biomaterials knowledge and biofabrication techniques will allow us to efficiently tune the next generation of smart MNs and provide a realistic platform for more effective personalized therapeutics.
Subject(s)
Biosensing Techniques , Drug Delivery Systems , Biocompatible Materials/chemistry , Biosensing Techniques/methods , Drug Delivery Systems/methods , Hydrogels/chemistry , NanotechnologyABSTRACT
Droplet-based microfluidic systems have been employed to manipulate discrete fluid volumes with immiscible phases. Creating the fluid droplets at microscale has led to a paradigm shift in mixing, sorting, encapsulation, sensing, and designing high throughput devices for biomedical applications. Droplet microfluidics has opened many opportunities in microparticle synthesis, molecular detection, diagnostics, drug delivery, and cell biology. In the present review, we first introduce standard methods for droplet generation (i.e. passive and active methods) and discuss the latest examples of emulsification and particle synthesis approaches enabled by microfluidic platforms. Then, the applications of droplet-based microfluidics in different biomedical applications are detailed. Finally, a general overview of the latest trends along with the perspectives and future potentials in the field are provided.
Subject(s)
Microfluidic Analytical Techniques , MicrofluidicsABSTRACT
Attractors in Boolean network models representing complex systems such as ecological communities correspond to long-term outcomes (e.g., stable communities) in such systems. As a result, identifying efficient methods to find and characterize these attractors allows for a better understanding of the diversity of possible outcomes. Here we analyze networks that model mutualistic communities of plant and pollinator species governed by Boolean threshold functions. We propose a novel attractor identification method based on generalized positive feedback loops and their functional relationships in such networks. We show that these relationships determine the mechanisms by which groups of stable positive feedback loops collectively trap the system in specific regions of the state space and lead to attractors. Put into the ecological context, we show how survival units-small groups of species in which species can maintain a specific survival state-and their relationships determine the final community outcomes in plant-pollinator networks. We find a remarkable diversity of community outcomes: up to an average of 43 attractors possible for networks with 100 species. This diversity is due to the multiplicity of survival units (up to 34) and stable subcommunities (up to 14). The timing of species influx or outflux does not affect the number of attractors, but it may influence their basins of attraction.
Subject(s)
Plants , FeedbackABSTRACT
METHODS: This study included patients from two prospective studies conducted in our institute from April 2007 to March 2009. Ninety-one women with axillary lymph node-positive breast cancer who had received four cycles of dose-dense epirubicin and cyclophosphamide were treated with either weekly paclitaxel (80 mg/m2) for 12 doses or biweekly docetaxel (75 mg/m2) for four cycles. RESULTS: After a median follow-up of 88 and 109 months, 11 (23.4%) and 10 (22.7%) patients had experienced disease recurrence (p = 0.16), while 10 (21.3%) and 5 (11.4%) patients had died in the paclitaxel and docetaxel arm, respectively (p = 0.56). No significant difference could be seen in 5-year DFS or OS among groups (HR: 0.58; 95% CI: 0.19-1.81, p = 0.35; HR: 0.58; 95% CI: 0.19-1.81, p = 0.35, respectively). CONCLUSION: In conclusion, both evaluated adjuvant chemotherapy regimens have comparable effectiveness regarding DFS and OS.
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Viral infection is one of the leading causes of mortality worldwide. The growth of globalization significantly increases the risk of virus spreading, making it a global threat to future public health. In particular, the ongoing coronavirus disease 2019 (COVID-19) pandemic outbreak emphasizes the importance of devices and methods for rapid, sensitive, and cost-effective diagnosis of viral infections in the early stages by which their quick and global spread can be controlled. Micro and nanoscale technologies have attracted tremendous attention in recent years for a variety of medical and biological applications, especially in developing diagnostic platforms for rapid and accurate detection of viral diseases. This review addresses advances of microneedles, microchip-based integrated platforms, and nano- and microparticles for sampling, sample processing, enrichment, amplification, and detection of viral particles and antigens related to the diagnosis of viral diseases. Additionally, methods for the fabrication of microchip-based devices and commercially used devices are described. Finally, challenges and prospects on the development of micro and nanotechnologies for the early diagnosis of viral diseases are highlighted.
Subject(s)
COVID-19 , Virus Diseases , Humans , Nanotechnology , Pandemics , SARS-CoV-2 , Virus Diseases/diagnosisABSTRACT
Tissue reconstruction requires the utilization of multiple biomaterials and cell types to replicate the delicate and complex structure of native tissues. Various three-dimensional (3D) bioprinting techniques have been developed to fabricate customized tissue structures; however, there are still significant challenges, such as vascularization, mechanical stability of printed constructs, and fabrication of gradient structures to be addressed for the creation of biomimetic and complex tissue constructs. One approach to address these challenges is to develop multimaterial 3D bioprinting techniques that can integrate various types of biomaterials and bioprinting capabilities towards the fabrication of more complex structures. Notable examples include multi-nozzle, coaxial, and microfluidics-assisted multimaterial 3D bioprinting techniques. More advanced multimaterial 3D printing techniques are emerging, and new areas in this niche technology are rapidly evolving. In this review, we briefly introduce the basics of individual 3D bioprinting techniques and then discuss the multimaterial 3D printing techniques that can be developed based on combination of these techniques for the engineering of complex and biomimetic tissue constructs. We also discuss the perspectives and future directions to develop state-of-the-art multimaterial 3D bioprinting techniques for engineering tissues and organs.
Subject(s)
Biomimetics , Bioprinting , Biocompatible Materials , Printing, Three-Dimensional , Tissue EngineeringABSTRACT
Irregular hemodynamics affects the progression of various vascular diseases, such atherosclerosis or aneurysms. Despite the extensive hemodynamics studies on animal models, the inter-species differences between humans and animals hamper the translation of such findings. Recent advances in vascular tissue engineering and the suitability of in vitro models for interim analysis have increased the use of in vitro human vascular tissue models. Although the effect of flow on endothelial cell (EC) pathophysiology and EC-flow interactions have been vastly studied in two-dimensional systems, they cannot be used to understand the effect of other micro- and macro-environmental parameters associated with vessel wall diseases. To generate an ideal in vitro model of the vascular system, essential criteria should be included: 1) the presence of smooth muscle cells or perivascular cells underneath an EC monolayer, 2) an elastic mechanical response of tissue to pulsatile flow pressure, 3) flow conditions that accurately mimic the hemodynamics of diseases, and 4) geometrical features required for pathophysiological flow. In this paper, we review currently available in vitro models that include flow dynamics and discuss studies that have tried to address the criteria mentioned above. Finally, we critically review in vitro fluidic models of atherosclerosis, aneurysm, and thrombosis.
Subject(s)
Atherosclerosis , Hemodynamics , Animals , Endothelial Cells , Humans , Models, Cardiovascular , Myocytes, Smooth Muscle , Pulsatile FlowABSTRACT
Brain tumors' severity ranges from benign to highly aggressive and invasive. Bioengineering tools can assist in understanding the pathophysiology of these tumors from outside the body and facilitate development of suitable antitumoral treatments. Here, we first describe the physiology and cellular composition of brain tumors. Then, we discuss the development of three-dimensional tissue models utilizing brain tumor cells. In particular, we highlight the role of hydrogels in providing a biomimetic support for the cells to grow into defined structures. Microscale technologies, such as electrospinning and bioprinting, and advanced cellular models aim to mimic the extracellular matrix and natural cellular localization in engineered tumor tissues. Lastly, we review current applications and prospects of hydrogels for therapeutic purposes, such as drug delivery and co-administration with other therapies. Through further development, hydrogels can serve as a reliable option for in vitro modeling and treatment of brain tumors for translational medicine.
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Oral administration is a pillar of the pharmaceutical industry and yet it remains challenging to administer hydrophilic therapeutics by the oral route. Smart and controlled oral drug delivery could bypass the physiological barriers that limit the oral delivery of these therapeutics. Micro- and nanoscale technologies, with an unprecedented ability to create, control, and measure micro- or nanoenvironments, have found tremendous applications in biology and medicine. In particular, significant advances have been made in using these technologies for oral drug delivery. In this review, we briefly describe biological barriers to oral drug delivery and micro and nanoscale fabrication technologies. Micro and nanoscale drug carriers fabricated using these technologies, including bioadhesives, microparticles, micropatches, and nanoparticles, are described. Other applications of micro and nanoscale technologies are discussed, including fabrication of devices and tissue engineering models to precisely control or assess oral drug delivery in vivo and in vitro, respectively. Strategies to advance translation of micro and nanotechnologies into clinical trials for oral drug delivery are mentioned. Finally, challenges and future prospects on further integration of micro and nanoscale technologies with oral drug delivery systems are highlighted.
Subject(s)
Drug Delivery Systems , Microspheres , Nanoparticles , Administration, Oral , Animals , Drug Carriers/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Microtechnology/methods , Nanotechnology/methods , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/chemistryABSTRACT
The unique properties of graphene quantum dots (GQDs) which include high loading capacity, excellent physiological stability, strong photoluminescence, biocompatibility, and facile production make them attractive nanomaterials for biomedical applications. In this work, GQDs have been explored as dual-functional targeted drug carriers and cellular bioimaging agents. The GQDs were conjugated to single chain variable fragment of antibody (scFv), which had been engineered with high affinity (B10) to epidermal growth factor receptor (EGFR), via amide covalent linkages (GQDs-scFvB10). The morphology and surface modification of GQDs were characterized by HRTEM, SDS-PAGE, FT-IR, UV-vis and fluorescence spectroscopies. Western blot analysis along with the confocal imaging of EGFR-overexpressing breast cancer cells (MDA-MB-231) demonstrated the targeting functionality of scFvB10 after conjugation to the GQDs, as well as the potential application of GQDs-scFvB10 in targeted bioimaging. The surface of targeted GQDs had a high cisplatin (CDDP) loading capacity of 50% and a pH-dependent release with slower release rate at neutral conditions, which can reduce the commonly observed systemic toxicity of CDDP. The targeted CDDP-loaded nanocarriers ((CDDP)GQDs-scFvB10) exhibited significantly higher toxicity on MDA-MB-231 cells compared to non-targeted ones suggesting their efficient uptake through EGFR. In contrast, cells with saturated EGFR showed lower uptake and cytotoxic effect of (CDDP)GQDs-scFvB10, demonstrating selectivity of the nanocarriers towards EGFR-overexpressing cells. The scFvB10-functionalized GQD is a promising platform for targeted cellular imaging and delivery of CDDP through interactions with EGFRs.
Subject(s)
Cisplatin/administration & dosage , Drug Delivery Systems , ErbB Receptors/metabolism , Graphite/chemistry , Molecular Imaging , Quantum Dots/chemistry , Cell Death/drug effects , Cell Line, Tumor , Cisplatin/pharmacology , Drug Carriers/chemistry , Drug Liberation , Humans , Quantum Dots/ultrastructure , Single-Chain Antibodies/chemistryABSTRACT
The exceptional chemical and physical properties of graphene oxide (GO) make it an attractive nanomaterial for biomedical applications, particularly in drug delivery. In this work we synthesized a novel, GO-based nanocarrier for the delivery of docetaxel (DTX), a potent hydrophobic chemotherapy drug. The GO was functionalized with transferrin (Tf)-poly(allylamine hydrochloride) (PAH), which provided targeted and specific accumulation to extracellular Tf receptors and stabilized GO in physiological solutions. Tf was conjugated to PAH via amide covalent linkages, and Tf-PAH coated the surface of DTX-loaded GO through electrostatic interactions. The morphology and structure of the resulting nanostructure, along with its surface modifications, were verified by use of Fourier transform infrared (FT-IR) and UV-vis spectroscopy, atomic force microscopy (AFM), and scanning electron microscopy (SEM). DTX was loaded at a relatively high loading capacity of 37% and released in a pH-dependent and sustained manner under physiological conditions. The targeting efficiency and cytotoxicity of this drug delivery system were evaluated on MCF-7 breast cancer cells. Improved efficacy of targeted DTX-loaded nanocarrier was observed compared to nontargeted carrier and free DTX, especially at high drug concentrations. The Tf-PAH-functionalized GO nanocarrier is a promising candidate for targeted delivery and controlled release of DTX.
Subject(s)
Drug Carriers/chemistry , Drug Delivery Systems , Oxides/chemistry , Polyamines/chemistry , Taxoids/administration & dosage , Transferrin/chemistry , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Cell Survival/drug effects , Docetaxel , Drug Carriers/toxicity , Graphite/chemistry , Humans , MCF-7 Cells , Spectroscopy, Fourier Transform Infrared , Taxoids/pharmacologyABSTRACT
Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement in node-positive breast cancer patients but the optimal dose schedule has still remained undetermined. Objectives. The feasibility of dose-dense epirubicin in combination with cyclophosphamide (EC) followed by weekly paclitaxel as adjuvant chemotherapy in node-positive breast cancer patients was investigated. Methods. All patients were treated with epirubicin (100 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every two weeks for four cycles with daily Pegfilgrastim (G-CSF) that was administered 3-10 days after each cycle of epirubicin and cyclophosphamide infusion which followed by (80 mg/m(2)) paclitaxel for twelve consecutive weeks. Results. Sixty consecutive patients were analyzed, of whom 57 patients (95%) completed the regimen and no case of toxicity-related death was observed. Grade 3/4 hematologic toxicity was uncommon and the most common grade 3/4 nonhematological adverse event was neuropathy disorders. Conclusions. Dose-dense epirubicin and cyclophosphamide followed by weekly paclitaxel with G-CSF support is a well-tolerated and feasible regimen in node-positive breast cancer patients without serious complications.
ABSTRACT
Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement particularly in node-positive patients, but optimal dose and schedule remain undetermined. Objectives. This study aimed to assess the feasibility of dose-dense epirubicin and cyclophosphamide followed by docetaxel in node-positive breast cancer. Methods. All Patients first received 4 cycles of epirubicin (100 mg/m(2)) and cyclophosphamide (600 mg/m(2)) at 2-week interval then followed by docetaxel (100 mg/m(2)) at 2-week interval for 4 cycles, with daily Pegfilgrastim (G-CSF) that was administered in all patients on days 3-10 after each cycle of epirubicin and cyclophosphamide infusion. Results. Fifty-eight patients with axillary lymph node-positive breast cancer were enrolled in the study, of whom 42 (72.4%) completed the regimen. There were two toxicity-related deaths, one patient due to grade 4 febrile neutropenia and the other due to congestive heart failure. Grade 3/4 neutropenia and febrile neutropenia were 13.8% and 5.1%. The most common grade 3/4 nonhematological complications were as follows: skin-nail disorders (48.3%), hand-foot syndrome (34.4%), paresthesia (38%), arthralgia (27.5%), and paresis (24.1%). Conclusions. Dose-dense epirubicin and cyclophosphamide followed by docetaxel with G-CSF support are not feasible, and it is not recommended for further investigation.