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![Characterization requirements for medical devices containing nanostructures and nanomaterials as recommended by ISO/TR 10993-22. The extent of characterization is dependent on the type and state of nano-based medical devices. The nanomaterial exposure risk via direct contact or unintended nanoparticle leakage from the device needs to be considered in the device characterization to properly assess safety and efficacy of nanotechnology-based medical devices. The degradation or dissolution and stability of nanostructures in relevant biological media need to be monitored and characterized over the shelf life and active lifetime of medical devices. Finally, the structures need to be fully characterized both in vitro and in in vivo proxies to ensure the design and physicochemical properties do not compromise the safety and efficacy of the medical devices. The scrutiny of the evaluation will increase if the nanostructures are designed to release from the device or pose the risk of undesired release in biological fluids. In addition to the above-mentioned evaluations, further tests (e.g., biodistribution, toxicity, and release kinetics of nanomaterials) are required to ensure the nanomedical device is safe for use in the clinic. The ISO/TR 10993-22 standards provide a framework and guidelines for characterization of nanomaterials. More specific physicochemical characteristic testing of nanomaterials is detailed in ISO/TR 13014. The figure is drawn based on the information provided in ISO/TR 10993-22 [41]](publication/362828027/figure/fig2/AS:11431281080051909@1661043574572/Characterization-requirements-for-medical-devices-containing-nanostructures-and.png)
Characterization requirements for medical devices containing nanostructures and nanomaterials as recommended by ISO/TR 10993-22. The extent of characterization is dependent on the type and state of nano-based medical devices. The nanomaterial exposure risk via direct contact or unintended nanoparticle leakage from the device needs to be considered in the device characterization to properly assess safety and efficacy of nanotechnology-based medical devices. The degradation or dissolution and stability of nanostructures in relevant biological media need to be monitored and characterized over the shelf life and active lifetime of medical devices. Finally, the structures need to be fully characterized both in vitro and in in vivo proxies to ensure the design and physicochemical properties do not compromise the safety and efficacy of the medical devices. The scrutiny of the evaluation will increase if the nanostructures are designed to release from the device or pose the risk of undesired release in biological fluids. In addition to the above-mentioned evaluations, further tests (e.g., biodistribution, toxicity, and release kinetics of nanomaterials) are required to ensure the nanomedical device is safe for use in the clinic. The ISO/TR 10993-22 standards provide a framework and guidelines for characterization of nanomaterials. More specific physicochemical characteristic testing of nanomaterials is detailed in ISO/TR 13014. The figure is drawn based on the information provided in ISO/TR 10993-22 [41]
Source publication
Understanding the interaction between biological structures and nanoscale technologies, dubbed the nano-bio interface, is required for successful development of safe and efficient nanomedicine products. The lack of a universal reporting system and decentralized methodologies for nanomaterial characterization have resulted in a low degree of reliabi...
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Context 1
... for nanomaterials used in medical devices, either as surface-bound nanostructures, which are to be incorporated within a medical device with or without the intention of being released, versus nano-objects that might be released from a medical device as a product of degradation, versus medical devices that are themselves nanoscale objects (Fig. 4). Proper knowledge and identification of nanomaterials' physicochemical characteristics and biocompatibility prior to incorporation into medical devices are essential to understand their compatibility with other composites and determine the final product's biocompatibility and toxicological effects [42]. In addition, nanomaterials used ...
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... requirements and especially characterization criteria and reporting requirements for nanomaterials used in the clinic. In addition to the surface topology example above, these standards cover various aspects of in vitro biological testing, sample preparation, and interaction of the nanomaterials with biofluids relevant to their intended use (Fig. 4). It is worth to note that demonstration of compliance to these standards is a regulatory requirement for product approval and market launch. The extent of characterization is dependent on the type and state of nano-based medical devices. The nanomaterial exposure risk via direct contact or unintended nanoparticle leakage from the ...
Citations
... This review focuses on the current status, challenges, and future prospects of drug/gene delivery NPs, especially the characterization of the efficacies therapeutic efficiency of drug delivery systems and to minimize drug side effects while also reducing the wastefulness of drugs and targeting ligands used and reducing production costs. Therefore, there is a need to improve quality control for targeted nanoparticles and to help push the translation progress of nanotechnology into the clinic [21]. ...
... Adequate quality control can help minimize the dosage of materials and drugs used and maximize the efficiency of drug delivery systems, thereby also reducing possible drug side effects. There is a need to strengthen the characterization methods that can push the translation progress of targeted nanoparticles [21]. ...
Active targeting nanoparticles are a new generation of drug and gene delivery systems with the potential for greatly improved therapeutics delivery compared to conventional nanomedicine approaches. Despite their potential, the translation of active targeting nanoparticles faces challenges in production scale-up and batch consistency. Accurate quality control methods for nanoparticle therapeutic payload and coating characterization are critical for attaining the desired levels of batch repeatability, drug/gene loading efficiency, targeting molecule coating effectiveness, and safety profiles. Current limitations in nanoparticle characterization technologies, such as relying on ensemble-average analysis, pose challenges in assessing the drug/gene content and surface modification heterogeneity, which can greatly affect therapeutic outcomes. Single-molecule analysis technologies have emerged as a promising alternative, offering rich information on heterogeneity and stochastic variations between nanoparticle batches. This review first evaluates and identifies the challenges of traditional nanoparticle characterization tools that rely on indirect, bulk solution quantification methods. Subsequently, newly emerging characterization technologies are introduced for the quantification of therapeutic loading and targeted moiety coating efficiencies with single-nanoparticle resolution, to help guide researchers towards advancing the translation of active targeting nanoparticles into the clinical setting.
... The large-scale consumption of products containing SiO 2 NPs has increased the risk of human exposure; however, their health effects remain poorly understood and may depend on factors such as particle size, shape, exposure route, and duration [1,6,10]. Assessing these health effects remains challenging due to the absence of regulatory frameworks and standardized testing protocols, leading to inconsistent study results and difficulties in drawing definitive conclusions about long-term impacts [16,17]. ...
Silicon dioxide nanoparticles (SiO2 NPs) are widely used to manufacture products for human consumption. However, their large-scale use in many fields poses risks to industrial workers. In this study, we investigated the cytotoxic and inflammatory potential of SiO2 NPs in the human cell line A549, representing the human alveolar epithelium. The NPs were characterized using energy-dispersive x-ray spectroscopy coupled with scanning electron microscopy, x-ray diffraction, transmission electron microscopy, dispersion, and dynamic light scattering. The effects on A549 cells were monitored by cell adhesion and proliferation using electrical impedance, as well as cell viability, apoptosis, necrosis, and secretion of multiple inflammatory mediators. SiO2 NPs did not alter the adhesion and proliferation of A549 cells but led to cell death by apoptosis at the highest concentrations tested. SiO2 NP impacted the secretion of pro-inflammatory (tumor necrosis factor-α, interleukin (IL)-8, monocyte chemoattractant protein-1, eotaxin, regulated upon activation, normal T cell expressed and secreted, vascular growth factor, granulocyte–macrophage colony-stimulating factor, and granulocyte-colony stimulating factor) and anti-inflammatory (IL-1ra and IL-10) mediators. These results indicate that, even with little impact on cell viability, SiO2 NPs can represent a silent danger, owing to their influence on inflammatory mediator secretion and unbalanced local homeostasis.
... AFM enables precise characterization and control of these features, facilitating the development of next-generation implants with enhanced performance . Figure 2 shows the characterization requirements for medical devices containing nanostructures and nanomaterials as recommended by ISO/TR 10993-22 as presented by Sharifi, et al. (2022). Recommended by ISO/TR 10993-22 (Sharifi, et al., 2022). ...
... Figure 2 shows the characterization requirements for medical devices containing nanostructures and nanomaterials as recommended by ISO/TR 10993-22 as presented by Sharifi, et al. (2022). Recommended by ISO/TR 10993-22 (Sharifi, et al., 2022). ...
Ensuring the accuracy and safety of medical devices is paramount to guaranteeing their effectiveness in clinical applications. The integration of nanometrology and non-destructive testing (NDT) techniques has emerged as a critical approach for enhancing the precision, reliability, and regulatory compliance of medical device manufacturing. Nanometrology, the science of measurement at the nanoscale, enables the characterization of microstructural properties, surface topography, and dimensional accuracy with unprecedented precision. Meanwhile, non-destructive testing (NDT) methods, such as ultrasonic testing, X-ray computed tomography (XCT), and optical coherence tomography (OCT), offer real-time evaluation without compromising the structural integrity of medical components. This study explores advanced nanometrology techniques, including atomic force microscopy (AFM), scanning electron microscopy (SEM), and white light interferometry, for assessing surface roughness, dimensional tolerances, and coating uniformity in biomedical implants and devices. These techniques are crucial for verifying nanostructured surfaces, which are increasingly used to improve biocompatibility and antimicrobial properties. Furthermore, the implementation of NDT methods in medical device manufacturing ensures early defect detection, material integrity assessment, and process optimization. The adoption of advanced imaging and spectroscopic techniques, such as terahertz imaging and laser-induced breakdown spectroscopy (LIBS), enhances defect identification, layer thickness analysis, and
... However, size is not the only property that matters for the desirable or harmful effects of nanomaterials. In fact, it is important to know not only the size of the material, but also what it is made of, as well as the shape and how the material interacts in different environments, including the biological one (Sharifi et al. 2022;Fadeel et al. 2015). Most of the studies presented the main characteristics of exposure to nematodes such as larval stage, exposure medium, time and concentrations, etc. ...
Inorganic nanoparticles are nanomaterials with a central core composed of inorganic specimens, especially metals, which give them interesting applications but can impact the environment and human health. Their short- and long-term effects are not completely known and to investigate that, alternative models have been successfully used. Among these, the nematode Caenorhabditis elegans has been increasingly applied in nanotoxicology in recent years because of its many features and advantages for toxicological screening. This non-parasitic nematode may inhabit any environment where organic matter is available; therefore, it is interesting for ecotoxicological assessments. Moreover, this worm has a high genetic homology to humans, making the findings translatable. A notable number of published studies unraveled the level of toxicity of different nanoparticles, including the mechanisms by which their toxicity occurs. This narrative review collects and describes the most relevant toxicological data for inorganic nanoparticles obtained using C. elegans and also supports its application in safety assessments for regulatory purposes.
... The incorporation of hydrophobic motifs offers interesting opportunities for tailoring the assembling and structural properties of HA-based nanocarriers [36−39]. To induce the assembling, phosphatidylcholine (PC) was selected, which is commonly employed in liposome production [40]. ...
... The rationale behind this design rested on leveraging the hydrophobic domains [46] and net positive charge under physiological conditions [47] of mAbs, which would maximize the interactions with the negatively charged and hydrophobic HA. Furthermore, the incorporation of Lipoid S100, commonly employed in liposome production [40], facilitated the assembling process. Our selection not only enabled the efficient encapsulation of the model mAb, BVZ, a straightforward assembly technique, but also imparted an advantageous regulatory profile to the resultant HANAs (Fig. 1). ...
The current spotlight of cancer therapeutics is shifting towards personalized medicine with the widespread use of monoclonal antibodies (mAbs). Despite their increasing potential, mAbs have an intrinsic limitation related to their inability to cross cell membranes and reach intracellular targets. Nanotechnology offers promising solutions to overcome this limitation, however, formulation challenges remain. These challenges are the limited loading capacity (often insufficient to achieve clinical dosing), the complex formulation methods, and the insufficient characterization of mAb-loaded nanocarriers. Here, we present a new nanocarrier consisting of hyaluronic acid-based nanoassemblies (HANAs) specifically designed to entrap mAbs with a high efficiency and an outstanding loading capacity (50%, w/w). HANAs composed by an mAb, modified HA and phosphatidylcholine (PC) resulted in sizes of ~ 100 nm and neutral surface charge. Computational modeling identified the principal factors governing the high affinity of mAbs with the amphiphilic HA and PC. HANAs composition and structural configuration were analyzed using the orthogonal techniques cryogenic transmission electron microscopy (cryo-TEM), asymmetrical flow field-flow fractionation (AF4), and small-angle X-ray scattering (SAXS). These techniques provided evidence of the formation of core-shell nanostructures comprising an aqueous core surrounded by a bilayer consisting of phospholipids and amphiphilic HA. In vitro experiments in cancer cell lines and macrophages confirmed HANAs’ low toxicity and ability to transport mAbs to the intracellular space. The reproducibility of this assembling process at industrial-scale batch sizes and the long-term stability was assessed. In conclusion, these results underscore the suitability of HANAs technology to load and deliver biologicals, which holds promise for future clinical translation.
... There is a rising requirement for the development and adoption of standardized protocols for characterizing nanomaterials, including their physicochemical properties, stability, and potential for aggregation or transformation. Standardized characterization methods will enable accurate assessments of the safety and efficacy of nanomedicine products and facilitate regulatory approval processes [146]. Another regulatory issue in nanomedicines is the absence of appropriate classification and regulatory pathways for nanomedicine products. ...
This analysis explores the principal regulatory concerns linked to nanomedicines and gene vaccines, including the complexities involved and the perspectives on how to navigate them. In the realm of nanomedicines, ensuring the safety of nanomaterials is paramount due to their unique characteristics and potential interactions with biological systems. Regulatory bodies are actively formulating guidelines and standards to assess the safety and risks associated with nanomedicine products, emphasizing the need for standardized characterization techniques to accurately gauge their safety and effectiveness. Regarding gene vaccines, regulatory frameworks must be tailored to address the distinct challenges posed by genetic interventions, necessitating special considerations in safety and efficacy evaluations, particularly concerning vector design, target specificity, and long-term patient monitoring. Ethical concerns such as patient autonomy, informed consent, and privacy also demand careful attention, alongside the intricate matter of intellectual property rights, which must be balanced against the imperative of ensuring widespread access to these life-saving treatments. Collaborative efforts among regulatory bodies, researchers, patent offices, and the private sector are essential to tackle these challenges effectively, with international cooperation being especially crucial given the global scope of nanomedicine and genetic vaccine development. Striking the right balance between safeguarding intellectual properties and promoting public health is vital for fostering innovation and ensuring equitable access to these ground-breaking technologies, underscoring the significance of addressing these regulatory hurdles to fully harness the potential benefits of nanomedicine and gene vaccines for enhancing healthcare outcomes on a global scale.
... A current challenge is the lack of standardization in characterization methods, which results in a low degree of reliability and reproducibility in the nanomedicine literature [9]. Properly characterizing nanoparticles is a fundamental step in their potential application, as their physical and chemical properties can differ vastly at the nanoscale. ...
Super-resolution microscopy and Single-Molecule Localization Microscopy (SMLM) are a powerful tool to characterize synthetic nanomaterials used for many applications such as drug delivery. In the last decade, imaging techniques like STORM, PALM, and PAINT have been used to study nanoparticle size, structure, and composition. While imaging has progressed significantly, often image analysis did not follow accordingly and many studies are limited to qualitative and semi-quantitative analysis. Therefore, it is imperative to have a robust and accurate method to analyze SMLM images of nanoparticles and extract quantitative features from them. Here we introduce nanoFeatures , a cross-platform Matlab-based app for the automatic and quantitative analysis of super-resolution images. NanoFeatures makes use of clustering algorithms to identify nanoparticles from the raw data (localization list) and extract quantitative information about size, shape, and molecular abundance at the single-particle and single-molecule levels. Moreover, it applies a series of quality controls, increasing data quality and avoiding artifacts. NanoFeatures , thanks to its intuitive interface is also accessible to non-experts and will facilitate analysis of super-resolution microscopy for materials scientists and nanotechnologies. This easy accessibility to expansive feature characterization at the single particle level will bring us one step closer to understanding the relationship between nanostructure features and their efficiency. https://github.com/n4nlab/nanoFeatures
... a) The lack of standardized methods and protocols for synthesizing, characterizing, and testing nanomaterials [5,6]. ...
In the realm of science and medicine, nanotechnology emerges as a beacon of hope, promising to revolutionize healthcare with its ability to manipulate matter at the molecular level. As a passionate advocate for this field, we have witnessed firsthand the transformative potential of nanoscale innovations. The promise of nanotechnology lies not only in its current applications but also in its vast, untapped potential to address some of the most pressing medical challenges of our time. Nanotechnology is a branch of science and medicine that explores the possibilities of manipulating matter at the molecular scale. Nanotechnology has already demonstrated its usefulness in various fields and has enormous, untapped potential to address some of the most pressing medical challenges of our era. However, nanotechnology also poses some risks that need to be carefully assessed by toxicology studies on nanomedicines. Nanotechnology offers many benefits for the development of new drugs and delivery systems, but it also has some potential drawbacks that require careful evaluation by toxicological studies on nanomaterials. These studies aim to identify and quantify the possible adverse effects of nanotechnology on human health and the environment, as well as to guide the safe and ethical use of nanomedicines. Nanotechnology has the potential to improve the lives of millions of people around the world, especially in developing countries where access to health care and other resources is limited. However, to achieve this goal, we need to create a culture of collaboration and transparency among all the stakeholders involved in the development and application of nanotechnology. This includes scientists, doctors, policymakers, and the public. By sharing knowledge, data, and best practices, we can ensure that nanotechnology is used ethically, safely, and effectively for the common good. Overcoming Barriers Despite the advancements, the journey of nanotechnology from the lab bench to the bedside is fraught with barriers. Regulatory hurdles, public perception, and a lack of interdisciplinary collaboration often slow the pace of progress. It is imperative that we, as a scientific community, work together to overcome these obstacles. By fostering an environment of open communication and cooperation between researchers, clinicians, and policymakers, we can ensure that the benefits of nanotechnology reach those in need. Nanomaterials are very small particles that have unique properties and applications in medicine, engineering, and other fields. However, before they can be used safely and effectively in humans or animals, they need to undergo rigorous testing to evaluate their biocompatibility. This means that they should not interfere with the normal functions of living tissues, cells, and molecules, or cause any adverse effects or toxicity. Biocompatibility testing is essential for ensuring the safety and efficacy of nanomaterials in clinical settings, where they can be used for diagnosis, treatment, or prevention of diseases. Nanotechnology has made significant progress in various fields of medicine, such as drug delivery, imaging, diagnosis, and therapy. However, there are still many challenges and obstacles that hinder the translation of nanotechnology from the laboratory to the clinic. One of the major hurdles is the evaluation of the safety and efficacy of nanomaterials in biological systems, both in vivo and in vitro. These assessments are crucial for ensuring the biocompatibility, functionality, and performance of nanomaterials in clinical applications. These tests are essential for ensuring that nanomaterials are compatible with living tissues, cells, and molecules and that they can perform their intended functions without causing harm or side effects in clinical settings.
... In this regard, common approaches to study and determine nanoparticle size and size distribution include dynamic light scattering (DLS) and differential centrifugal sedimentation (DCS) ( Figure 2). DLS is a fast and general-purpose method of nanoparticle dispersions, and it is of low resolution, though it is limited in terms of sample concentration, small nm shifts in size, non-spherical particles, or the dynamic range of nanoparticle size [32]. In the case of most precise nanoparticle size studies, more accurate techniques such as DCS are required. ...
... In this regard, common approaches to study and determine nanoparticle s size distribution include dynamic light scattering (DLS) and differential centrifug mentation (DCS) ( Figure 2). DLS is a fast and general-purpose method of nano dispersions, and it is of low resolution, though it is limited in terms of sample con tion, small nm shifts in size, non-spherical particles, or the dynamic range of nano size [32]. In the case of most precise nanoparticle size studies, more accurate tech such as DCS are required. ...
... The lack of standard methods hinders the comparison of different materials and the evaluation of the applicability of new design alternatives. Furthermore, there is a growing concern over the increasing nanomedicine products commercially available given the current lack of such control and standard nanoparticle characterization protocols [32]. ...
The prolific applicability of nanomaterials has made them a common citizen in biological systems, where they interact with proteins forming a biological corona complex. These complexes drive the interaction of nanomaterials with and within the cells, bringing forward numerous potential applications in nanobiomedicine, but also arising toxicological issues and concerns. Proper characterization of the protein corona complex is a great challenge typically handled with the combination of several techniques. Surprisingly, despite inductively coupled plasma mass spectrometry (ICP-MS) being a powerful quantitative technique whose application in nanomaterials characterization and quantification has been consolidated in the last decade, its application to nanoparticle–protein corona studies is scarce. Furthermore, in the last decades, ICP-MS has experienced a turning point in its capabilities for protein quantification through sulfur detection, hence becoming a generic quantitative detector. In this regard, we would like to introduce the potential of ICP-MS in the nanoparticle protein corona complex characterization and quantification complementary to current methods and protocols.
... However, realizing such at an industrial scale may be expensive and challenging (Jacquemart et al. 2016). Furthermore, the complex nature of nanomedicine formulation and manufacturing requires close scrutiny to minimize batch-to-batch variations (Sharifi et al. 2022). Therefore, for successful development and commercialization, it is necessary to ensure the purity, potency, safety, and efficacy of the nanomedicines (Desai 2012). ...
Background
In recent decades, there has been a considerable increase in the number of nanomedicine-based formulations, and their advantages, including controlled/targeted drug delivery with increased efficacy and reduced toxicity, make them ideal candidates for therapeutic delivery in the treatment of complex and difficult-to-treat diseases, such as cancer.
Areas coveredThis review focuses on nanomedicine-based formulation development, approved and marketed nanomedicines, and the challenges faced in nanomedicine development as well as their future prospects.Expert opinionTo date, the Food and Drug Administration and the European Medicines Agency have approved several nanomedicines, which are now commercially available. However, several critical challenges, including reproducibility, proper characterization, and biological evaluation, e.g., via assays, are still associated with their use. Therefore, rigorous studies alongside stringent guidelines for effective and safe nanomedicine development and use are still warranted. In this study, we provide an overview of currently available nanomedicine-based formulations. Thus, the findings here reported may serve as a basis for further studies regarding the use of these formulations for therapeutic purposes in near future.
