Ultrasonic particle manipulation technique is a non-contact label-free method for manipulating micro- and nano-scale particles using ultrasound, which has obvious advantages over traditional optical, magnetic, and electrical micro-manipulation techniques; it has gained extensive attention in micro-nano manipulation in recent years. This paper introduces the basic principles and manipulation methods of ultrasonic particle manipulation techniques, provides a detailed overview of the current mainstream acoustic field generation methods, and also highlights, in particular, the applicable scenarios for different numbers and arrangements of ultrasonic transducer devices. Ultrasonic transducer arrays have been used extensively in various particle manipulation applications, and many sound field reconstruction algorithms based on ultrasonic transducer arrays have been proposed one after another. In this paper, unlike most other previous reviews on ultrasonic particle manipulation, we analyze and summarize the current reconstruction algorithms for generating sound fields based on ultrasonic transducer arrays and compare these algorithms. Finally, we explore the applications of ultrasonic particle manipulation technology in engineering and biological fields and summarize and forecast the research progress of ultrasonic particle manipulation technology. We believe that this review will provide superior guidance for ultrasonic particle manipulation methods based on the study of micro and nano operations. How to achieve precise manipulation of particles at the micro- and nano-scale is a popular area of research. Due to the tiny scale of nanoparticles, direct manipulation of particles by mechanical external forces is often difficult to achieve. To date, non-contact particle manipulation is usually dynamic by changing the external gradient force field, and several different forms of energy are available, including electrical , magnetiOptical actuation requires complex optical systems, including high-power lasers and high numerical aperture objectives, which may cause physiological and thermal damage to the cells ; magnetiThe main component of the ultrasonic particle manipulation device is the ultrasonic transducer, which converts electrical energy into mechanical vibrations that produce acoustic waves in the fluid medium. When acoustic waves interact with the medium, two acoustic phenomena occur: acoustic streaming-induced forces and acoustic radiation forces, and one of these phenomena or a combination of them manipulates particles. Two different acoustic modes are commonly used to manipulate particles: surface acoustic wave (SAW)  and bulkIn recent years, with the wide application of micro-nano technology, ultrasonic particle manipulation techniques have experienced vigorous development, and a large number of research results have been achieved in theoretical calculation methods, transducer arrangement and acoustic field design, and manipulation of various morphologies of various particles. In this paper, we present a concise review of recent research advances in operational methods, sound field generation methods, and sound field reconstruction algorithms for ultrasonic particle manipulation techniques. The characteristics of each method are described according to the sound field morphology, and we explore the effects of each method on the particle manipulation morphology and the scenarios in which they are applicable. We present the applications of ultrasonic particle manipulation techniques in the fields of engineering control, biomedicine, micro-robotics, and materials preparation. Finally, we address the limitations of current ultrasonic particle manipulation techniques, describe the current technical difficulties, and point out future research directions.There are two main acoustic forces in ultrasonic particle manipulation, namely, the acoustic radiation force and the acoustic streaming-induced forces. In order to calculate these two forces, the spatial distribution of acoustic waves in the acoustic field  or acousp denotes the variation of sound pressure with time, k is the wave number, −Sound propagation satisfies three fundamental laws of physics, namely, Newton’s second law, the law of conservation of mass, and the temperature, pressure, and volume relationships, from which the equations of continuity, conservation of momentum, and equation of matter for sound waves are derived. In the idealized state where the propagating medium is viscosity-free, homogeneous, stationary, and adiabatic, the three-dimensional fluctuation equation of the acoustic wave is derived as follows:φ are related. Therefore, when multiple acoustic waves arrive at a location point of the same phase of vibration, the location point is of the enhanced vibration; when the phase is opposite, the location point is of the weakened vibration.As can be seen from the formula, sound waves have an interference effect, and the frequency of synthetic sound waves remains constant, while sound pressure amplitude and phase difference P separated by any wavefront surface S. The resulting surface element dS is regarded as the new wave source, and the sound pressure at the field point P is obtained by superimposed interference of each surface element dS. Assuming that the wavefront surface S is planar (z = 0), the sound pressure P(r) at a site in space can be expressed asr is the distance from the surface element dS to the field point P, P with respect to the surface element dS. In addition to the Huygens–Fresnel principle, the far-field characteristics of the piston model [xy plane and the total acoustic radiation pressure P at any point r in space is linearly superimposed by the acoustic radiation pressure of each transducer as follows:N represents the number of array elements in the transducer array, A is the peak amplitude of the excitation signal, r, k represents the wave number, and a is the radius of the transducer, and θ is the angle between the point r and the z-axis.The Huygens–Fresnel principle  can be uon model  can be uU and the acoustic radiation force F are equal in magnitude and opposite in direction:R is the spherical target radius, Ultrasonic propagation encounters particles  that will be reflected, scattered, refracted, and have other physical reactions. Gor’kov’s theoretical model  assumes R is the particle size, (−) represents the velocity of the particle relative to the liquid, and the motion of the particle is governed by Newton’s second law:In most cases, the acoustic radiation force is the main driving force for particle manipulation. However, in some specific cases, the state of motion of the particles is the result of the combined action of two forces, the acoustic radiation force, and the acoustic streaming-induced forces. For a uniformly isotropic fluid, the acoustic streaming-induced forces can be determined from Stokes’ law :(10)FdraCurrently, acoustic radiation force and acoustic streaming-induced forces are the two most widely used physical effects in ultrasonic particle manipulation. Particles  can be manipulated using either combination of their effects . DependiUltrasonic particle manipulation based on the standing wave principle has been widely used in the study of aeroacoustic levitation , cell maStanding waves can generate significant acoustic radiation forces to capture specific particles between acoustic devices, but standing wave sound fields have limited application scenarios because they require at least one set of acoustic devices with strict relative positions , and in Ultrasonic particle manipulation based on the traveling wave principle has been widely used for cell mechanics measurements ,36 and sThe gradient of the acoustic field generated by traveling waves is weak, and the particles are subject to smaller acoustic radiation force, vulnerable to external interference, and less stable, but the equipment used for traveling wave manipulation is simpler compared to standing waves and more suitable for modulating any pair of patterns or individual objects in real time.The fluid medium in an acoustic field gains momentum by absorbing acoustic waves, and when the acoustic streaming effect plays a major role, the particles move with the fluid motion. Ultrasonic particle manipulation based on the acoustic streaming principle has been used for submicron particle trapping , three-dAcoustic streaming-induced forces manipulation effectively overcomes the disadvantages of low flexibility and single mode of manipulation of acoustic radiation force manipulation and expands the scope of use of acoustic manipulation techniques. The characteristic of the acoustic streaming-induced forces manipulation technique is the low temperature of the control zone, which has a greater advantage in handling temperature-sensitive samples . It is eThe shape of the sound field generated by a single array or two transducers is generally fixed, and the particles are subjected to a fixed acoustic radiation force in the sound field, which makes it difficult to manipulate them flexibly and multi-functionally. With the development of transducer processing and circuit-driven systems, designs with combined arrangements of multiple transducers have emerged , where tThe acoustic emission power and detection sensitivity of ultrasonic transducer arrays are far superior to those of single array elements. Its greatest feature is that it can control the acoustic beam morphology flexibly and effectively, which enriches the variety of particle motion and manipulation methods and greatly expands the application scenarios of ultrasonic particle manipulation. Asier Marzo et al.  proposedDifferent arrangements of ultrasonic transducer arrays are used for different purposes. The transducer circuit of one-dimensional linear arrangement is simple to build and is often used for simple levitation and translation of particles. Peter Glynne-Jones et al.  formed aUltrasonic transducer arrays can generate arbitrary patterns of sound fields to accomplish flexible, dynamic manipulation, which provides fundamental support for various scenario applications. However, ultrasonic transducer arrays require the construction of programmable multichannel drive systems and precise mathematical manipulation models for the independent control of each transducer circuit. For example, Antoine Riaud et al.  developeHowever, the complexity and cost of transducer arrays become higher as the flexibility of particle manipulation and the weight of particles increase, and these difficulties make the design and fabrication of ultrasonic transducer arrays difficult. To address these difficulties, some researchers would simplify the system design by techniques such as sparsely arranged transducer arrays ,60 and eParticle manipulation based on structural sound fields can be applied to static sound fields for specific driving purposes. Artificially designed structural parameters and material parameters can enable acoustic materials to achieve a variety of acoustic properties , and theThe interaction between acoustic waves and matter has enriched the means of acoustic wave modulation, and many novel acoustic wave propagation effects have been realized, such as the resonance , transmiSpecific acoustic structures can generate corresponding acoustic fields such as vortex fields, focusing fields, or arbitrary morphological acoustic fields to achieve manipulation of objects. Wang T et al.  obtainedStructural sound field-based methods for manipulating particles enrich the acoustic wave form, and the sound field has the advantages of high information content, strong pre-programming capabilities, and simple reproduction, but the sound field is static and not suitable for dynamic applications, nor can it be dynamically reconfigured like tweezers . The strThe accuracy of the sound field reconstruction is an important factor in determining the performance of the system and a key core in determining the effectiveness of sound field manipulation. A low-quality sound field may lead to inaccurate suspension capture points and affect the accuracy of particle manipulation. For ultrasonic particle manipulation systems based on transducer arrays, solving the phase distribution of the corresponding transducer array backward from the acoustic field distribution is a mathematically difficult nonlinear system to solve. An effective method is still lacking, so the exact reproduction of the phase distribution by the expected acoustic field is a hot topic in acoustic field research. There are several methods in the existing literature to solve this problem. The traditional method approach  is solveIn terms of optimization methods for acoustic metamaterials, Melde et al.  proposedIn terms of optimization methods for PAT controllers, Asier Marzo et al.  proposedThe GS algorithm can be used to recover the extracted phase information from the intensity information of a known signal, but many limitations of the traditional GS algorithm make it inappropriate for PTA devices, such as the non-planar arrangement of PTAs and arbitrary 3D positions. In order to be able to compute multipoint sound fields using PAT at high rates, in 2020, Diego Martinez Plasencia et al.  reformulDiego Martinez Plasencia et al.  comparedThe least squares method (LSM) is a mathematical optimization method to solve fitting problems, which can be described as an algebraic process of fitting data using a system of linear equations. However, LSM is not satisfactory for complex problems, especially nonlinear problems. After optimization improvements by Kenneth Levenberg et al. , an iterThe LMA algorithm can be used for phase optimization of transducers in PTA devices, and Emiri Sakiyama et al. in 2020  proposedIn general, optimization methods that control both amplitude and phase can reconstruct higher-quality holographic acoustic fields than pure phase methods. However, Tatsuki Fushimi et al.  proposedNeural networks have powerful fitting abilities to accomplish complex linear or nonlinear mappings, and Chengxi Zhong et al.  used a dUltrasonic particle manipulation technology has the advantages of no damage, no contact, good biocompatibility, no additional biochemical labeling of particles, etc. These advantages will make ultrasonic particle manipulation more useful in biomedicine, materials science, engineering control, micro-robotics, and other fields, with a wide range of application prospects and promoting new applications of ultrasonic energy transfer.In the field of precision electronics manufacturing and assembly, processing and transporting parts need to be more precise, and surface damage or structural damage can cause failure in product production, resulting in a great waste of resources in human and material resources. Acoustic manipulation techniques can solve the problem of contactless pickup and release of microcomponents. Kun Jia et al.  proposedThe manipulation of biomolecular nanoparticles  using ultrasound techniques has attracted much attention in medical applications. For example, Filip Petersson et al.  proposedAcoustic waves can penetrate complex media in living organisms at low incident power. Kirk Shung’s team at the University of Southern California has successfully trapped particles in vascular mimics using single-focused acoustic beam acoustic tweezers (SBAT)—a study that provides an exploration of the feasibility of in vivo applications of acoustic tweezers in biomedicine . Recent Micro-robots can access tissues or cavities that are difficult to reach by other devices in order to perform minimally invasive medical diagnostic or therapeutic operations. Amirreza Aghakhani et al.  proposedIn material preparation, acoustic manipulation can rely on acoustic radiation force against gravity to achieve the levitation of the target object in the acoustic radiation potential field, thus providing a container-free environment. Shen Changle et al.  used acoCurrently, ultrasonic transducer array-based particle manipulation techniques have been increasingly used for the manipulation of cells, particles, and organisms, but most of the literature has focused on in vitro applications. Due to the non-invasive nature of acoustic waves and deep tissue penetration properties, ultrasonic particle manipulation has every potential to manipulate cells or foreign bodies in vivo, but less three-dimensional particle manipulation based on transducer arrays in living bodies in water has been reported. Because the difficulties in water compared with air are the following: (1) the electrical conductivity of water puts high requirements on array design and manufacturing process, and (2) the manipulation in water is not negligible by acoustic streaming factors. The challenges to realizing ultrasonic particle manipulation in vivo are the following: (1) non-transparent tissue structure hinders the visualization of particle manipulation based on optical images, and (2) acoustic distortion caused by non-uniform tissue poses a challenge to precise particle manipulation. To address these difficulties, the authors suggest that experimental studies on the 3D manipulation of particles such as cells in vivo should be carried out after solving the 3D manipulation of objects with different acoustic properties in water.Ultrasonic particle manipulation, as a technology with practical application prospects, still has a large number of technical limitations to be solved. The authors believe that the future development direction of ultrasonic particle manipulation is in terms of hardware enhancement, such as (1) combining transducer arrays with artificial acoustic structures to achieve high-precision acoustic field dynamic modulation and precise manipulation beyond diffraction limits; (2) integrating with existing biomedical research systems and instruments and combining with image-guided technology to achieve in vivo visualization and precise manipulation in terms of application expansion, such as (1) combining with other non-contact manipulation means, such as acoustic tweezers and optical tweezers, magnetic tweezers, dielectric electrophoresis, etc., to realize manipulation under multi-physical field coupling.In short, with the booming development of precision manufacturing and precision medicine, the precise manipulation of tiny particles is the core technology for the development of these fields. As a non-contact, non-damaging, particle manipulation technology that can achieve a variety of manipulation actions, acoustic manipulation can be miniaturized, integrated, and used intelligently for various devices and equipment. Further research on the theory of ultrasonic particle manipulation and the development of precise and sensitive acoustic manipulation technology for application scenarios is needed to provide core technology support for the realization of precision manufacturing and precision medicine.


Depression is a severe mental disorder among public health issues. Researchers in the field of mental health and clinical psychiatrists have long been faced with difficulties in slow treatment cycles, high recurrence rates, and lagging efficacy. These obstacles have forced us to seek more advanced and effective treatments. Research has shown that novel drug delivery strategies for natural medicinal plants can effectively improve the utilization efficiency of the active molecules in these plants and therefore improve their efficacy. Currently, with the development of treatment technologies and the constant updating of novel drug delivery strategies, the addition of natural medicinal antidepressant therapy has given new significance to the study of depression treatment against the background of novel drug delivery systems. Based on this, this review comprehensively evaluates and analyses the research progress in novel drug delivery systems, including nanodrug delivery technology, in intervention research strategies for neurological diseases from the perspective of natural medicines for depression treatment. This provided a new theoretical foundation for the development and application of novel drug delivery strategies and drug delivery technologies in basic and clinical drug research fields. Depression is a widespread and potentially life-threatening neurological disorder that has garnered attention from researchers around the world. It not only has psychological manifestations involving emotions and cognition but also manifests neurological damage, such as decreased volition and cognitive impairment, and even physical symptoms, such as autonomic nervous system dysfunction. Moreover, depression often co-occurs with other psychiatric disorders, such as posttraumatic stress disorder, anxiety disorders, obsessive–compulsive disorder, and substance use disorders, and comorbidities, such as cardiovascular disease, diabetes, stroke, and cancer, frequently occur . DepressThe attributes of natural medicines, possessing mechanisms of action that can intervene in multiple disease targets and pathways, have stimulated considerable interest among researchers in natural drug antidepressant therapies. Natural medications have the characteristics of fewer adverse reactions, significant therapeutic effects, and the ability to function in synergy with multiple components. Compared to traditional synthesized small-molecule drugs, natural drugs also have the advantages of abundant resources, low cost, and easy availability, making them an important source of new drug development. More than half of the new chemical entity drugs developed internationally are directly or indirectly derived from natural medications. Natural medications have enormous medical value and market potential.The vigorous development of science and technology has brought breakthroughs in medical technology. The updating of the research content and paradigm in the field of drug delivery systems has solved multiple problems in drug bioavailability and stability, providing more possibilities for the treatment of clinical nervous system disorders. The breakthroughs in drug delivery routes and delivery vehicle research in the drug delivery system field have improved the efficacy of drugs used to treat nervous system diseases. The emergence of NDDSs has shown new clinical prospects in the formulation research of drugs. The development and maturity of drug delivery technology have provided impetus for the clinical transformation of many new drugs.With the development of pharmaceuticals and the high pursuit of efficacy, the medical community has conducted further development and research on the enhancement of the absorption efficiency of active ingredients in natural medicines through the application of NDDS technology, which has resulted in notable therapeutic outcomes. Mature scientific research methods, such as nanotechnology, have significantly propelled the development of natural medicinal plant antidepressant treatment practices. Therefore, this review discusses interventions in neurological disease research from the perspective of novel drug delivery systems and involves exploring natural medicinal plant antidepressant strategies. The information in this review provides a novel theoretical foundation for studying new delivery strategies of natural medicinal plant active ingredients in the field of psychiatric research.Based on the evidence from modern medical systems, natural medicines encompass plant-, animal-, and mineral-derived drugs that possess pharmacological effects. Among these, plant-based medicines predominate in natural medicine, whereas animal, mineral, and other forms of natural medicines are used to a relatively lesser extent. Over time, various applied systematic theories have evolved in the field of natural medicine, including Chinese medicine, Indian Buddhist medicine, Islamic medicine, European traditional herbal medicine, South American ethnomedicine, and African ethnomedicine.Huang Di Nei Jin’ also contains numerous discussions on brain disorders . A. A132]. Based on this, the bibliometric statistical method was used in this study; the CBM, Wanfang Data, Pubmed, Web of Science, Cochrane, CNKI, and Vip Information Chinese journal service platform were selected as the search databases; and the research trends of novel routes of administration were analysed with “Novel route of administration” as the search term. The search yielded 26,973 journal articles related to the “Novel route of administration” since the library was built. All retrieved articles were imported into an EndNote database, 7963 duplicate articles were deleted. The remaining 20,010 articles were imported into VosViewer for the analysis of keyword co-occurrence frequency Fig. . The anaTransdermal drug delivery systems can be utilized as an effective means of medication administration to assist with drug application when patients experience intolerable gastrointestinal side effects or swallowing difficulties associated with traditional oral dosage forms . The traFor example, in nicotine withdrawal therapy, a nicotine agonist is formulated into patches that are applied to the skin to aid smoking cessation . StudiesIn regard to transdermal drug delivery, there are a few different methods that can be employed. Along with drug patches, percutaneous penetration therapy can also be utilized. Subcutaneous implantation may prove to be beneficial in the treatment of certain mental disorders. Research has shown that haloperidol biodegradable polylactic-coglycolic acid (PLGA) pellets implanted via surgery can provide steady drug release for up to 5 months in vitro. This approach has proven to be a more effective means of treating long-term psychotic episodes than traditional drugs. Furthermore, in vivo animal models have demonstrated increased expression of striatal dopamine 2 (D2) receptors, validating the effectiveness of this drug delivery system . Rabin eThe BBB poses a significant obstacle to the transport of various therapeutic agents to the brain, and as of yet, we have been unable to administer most drug molecules in effective therapeutic doses. To overcome the hindrances of the BBB, researchers have begun exploring novel pathways for drug delivery, such as the nasal-brain transport approach . The int'Complete Book of Sores and Ulcers' and the 'Miraculous Pivot', which are regarded as traditional Chinese medicine classics, have detailed the intricate relationship between the nose and the brain .Tab.Tab64].TScientists have used drug modification to adjust the release rate of drugs to an ideal constant rate of release. For example, some scholars have combined two types of preservatives, including one that is hydrolyzable, as a template to prepare pH-sensitive mesoporous silica-based nanocontainers with extremely high effective payloads to achieve controllable rates of drug release . AlternaThe development of new drug delivery systems is a key focus of research and development efforts in the market. In particular, nanomedicine has emerged as a critical player in this field, given its proven efficacy in targeting specific organisms. By allowing more targeted delivery, nanomedicines address the issues associated with traditional drug delivery methods, such as the wide distribution of drugs throughout the body. This approach increases the specific affinity of the active molecule to the lesion, thereby avoiding nonspecific toxicity and other adverse side effects associated with high doses of the drug. As such, nanomedicine is viewed as a highly effective means of addressing the challenges involved in drug delivery . The curNanoparticle technology serves as a robust foundation for the development of tissue-specific drug loading systems that are both highly versatile and customizable . The impAs a cutting-edge therapeutic modality in novel drug delivery systems, nanomedicine harbours the capacity to surmount the diverse impediments associated with neurological disorders. Presently, over 20 nanomedicines have received clinical therapeutic or diagnostic approval from the FDA or the European Medicines Agency (EMA), and an additional 75 clinical trials examining nanoparticles have been initiated in recent years . AlthougOral ingestion is the most convenient route for herbal medicine utilization, but first-pass metabolism in the liver and intestine adversely affects the effective conversion of active herbal ingredients. Recent years have witnessed the rapid advancement of advanced molecular technologies such as high-throughput sequencing and metabolomics. These techniques have revealed the close connection between the transformation of active ingredients of Chinese medicines and intestinal flora . The intThe intestinal flora boasts formidable metabolic capacity and is rightfully regarded as a vital “metabolic organ” of the body. It performs crucial functions in various aspects of the host's well-being, such as digestion, nutrient absorption, metabolism, and immunity . The potMicroenvironmental modification is a rapidly developing research area that focuses on the environmental factors that impact drug action. This approach includes a variety of methods, ranging from site-specific alterations in the region of drug action to systemic administration of adjuvants that modify the host environment. As a comprehensive drug delivery strategy, microenvironmental regulation has the potential to improve drug bioavailability and effectiveness in diseased tissues by helping drugs penetrate biological barriers . The bloModulating BBB permeability is a microenvironmental modification strategy aimed at selectively enhancing or restricting the passage of substances. The permeability of the blood‒brain barrier is primarily dictated by the integrity of the tight junctions between cerebral vascular endothelial cells, as well as the activity of efflux transporters such as P-glycoprotein (P-gp). Other factors, such as intercellular gaps, endocytosis, and transcytosis, also play a role in regulating BBB permeability . Due to In recent years, there has been a gradual increase in the incidence of depression. However, due to the unique structural characteristics of the BBB in neurological disorders, active drug molecules are unable to accumulate in brain lesions, severely impacting the effectiveness of treatment. Therefore, the search for novel and efficient drugs to treat brain diseases has become an urgent matter in today’s society. Domestic and international research has demonstrated that certain new drug delivery systems are capable of partially overcoming the BBB limitations and delivering drugs to focal areas in the brain, thus improving therapeutic effectiveness. The research and development of new systems have become a focus of clinical development. The aim of novel drug delivery systems, such as nanomedicines, liposomes, microneedles, and subcutaneous injections, is to improve drug efficacy and reduce side effects while enhancing patient compliance. These systems have advantages in terms of drug delivery, enhanced drug efficacy, controlled drug release, and other aspects and have achieved certain results in clinical development Table .Table 5NNDDSs are the foundation of drug formulation research and play a pivotal role in the development of the global pharmaceutical industry. The focus of NDDS research is to optimize drug efficacy and reduce unwanted side effects by implementing three fundamental strategies: targeting space, release time, and dose. The scope of NDDSs encompasses various objectives, such as controlled drug release, drug targeting, enhanced drug stability, the regulation of drug metabolism time, improved drug absorption, and overcoming biological barriers.The cornerstone of modernizing Chinese medicine lies in the modernization of Chinese medicine formulations. By harnessing the advantages of traditional Chinese medicine in treating brain diseases and integrating modern new drug delivery systems, Chinese medicine can effectively treat brain diseases and the dosage forms of Chinese medicines can be improved. The key factors affecting the ability of a drug to cross the BBB include its lipid solubility, molecular weight, and dissociated or nondissociated form under physiological conditions. NDDSs have demonstrated the ability to enhance the ability of Chinese medicines to penetrate the BBB and increase drug concentrations in the brain. This combination of strengths minimizes the adverse effects of Chinese medicines while maximizing their therapeutic benefits.In conclusion, the vast potential of Chinese medicine remains largely untapped. Outdated drug delivery methods have limited the efficacy of Chinese medicines. The application of new drug delivery technologies to Chinese herbal medicines will undoubtedly help to enhance the therapeutic efficacy of various Chinese medicinal compounds and herbs while reducing the side effects of drugs. The progress made by modern science has provided additional opportunities to explore the benefits of Chinese medicine. While new drug delivery systems have shown promise in treating brain diseases, they are still in their early stages, and numerous challenges are encountered. Further research is necessary to refine drug delivery carriers and optimize TCM formulations.


Food of the Future: Algae and Aquaculture” emphasizes on the advanced technologies for the sustainable development of aquaculture and exploitation of algae as functional food. Articles of this Research Topic cover the aspects of algae-based aquatic food, genomic analysis of algae and fish, and algae-based functional diet.Food and feed shortage are serious problems challenging the sustainable development of human society. Besides, food-related health is becoming an emerging topic attracting researchers' attentions. In recent years, more and more studies are exploiting new food resources from algae and aquaculture and also exploring novel technologies for the improvement of nutritional values of food. The Research Topic entitled “Chen et al. explored the feasibility of using Chlorella pyrenoidosa as an alternative ingredient in aquaculture. The experimental results demonstrated that the microalgae contain some key nutrients, such as essential amino acids and unsaturated fatty acids, as well as bioactive compounds, which are essential for the growth and immune responses of aquatic organisms. The high protein content (>52%) in Chlorella pyrenoidosa is regarded as a great advantage of using algae an ingredient in aquafeeds. It is noteworthy that this study firstly discovered the presence of anti-nutritional factors (ANFs) in algae and compared algae and soybean meal in relation to ANF content. The analysis of molecular characterization of proteins in algae, fish meal, and soybean meal showed that high-molecular-weight proteins in algae may be a factor limiting the application of algal biomass as fish diet, and suggested the adoption of pretreatment to lower the molecular weights of proteins and improve their digestion. Based on the work of Chen et al. both advantage and disadvantage of growing algae for aquafeeds are discovered, providing an objective opinion on the exploitation of algae-based fish diets. Accordingly, appropriate technologies can be employed to eliminate the limiting factors in algae for aquaculture practices.The study of Manoppo et al.Caulerpa lentillifera, a species of green algae, was provided to rat fed with a cholesterol- and fat-enriched diets (CFED) to ameliorate obesity-related metabolic disorders. It was discovered that supplementation of Caulerpa lentillifera effectively reduced blood glucose level and total cholesterol level in CFED rats. In addition, the increments of peroxisome proliferator-activated receptor γ coactivator-1α and liver superoxide dismutase were observed in CFED rats supplemented with Caulerpa lentillifera, confirming the contribution of algae to the improvement of antioxidant capacity in CFED rats. As a consequence, cellular energy metabolism of rat is impacted owing to the changes of antioxidant properties in the internal environment of rat. Manoppo et al. also pointed out that anti-hyperglycemic activity of Caulerpa lentillifera is partly attributed to a variety of bioactive molecules, such as sulfated polysaccharides and monosaccharides. Finally, a dose of 150 mg/kg of body weight was identified as an effective way to ameliorate metabolic problems caused by CFED in rats. Potentially, the dose achieved from these preclinical trials could be a reference for future clinical trials in humans.In the study of Radwan et al. studied the dual effect of dietary supplements of Grateloupia acuminata and Grateloupia doryphore nanoparticles (GNS) at different concentrations with bionanocomposite cellulose acetate membranes (CA/bio-AgNps) on growth performance and health status of Oreochromis niloticus, a species of Nile tilapia native to the Levante area and the northern half of Africa. The results showed that supplementing GNS diets improved the growth rate, weight gain, carcass weight, and crude protein content of tilapia. In addition, survival ratios of tilapia supplemented with GNS diets  in the Aeromonas hydrophila challenge test were much higher than that of tilapia in the control group. Antioxidative, stress-related, and proinflammatory-related genes were up-regulated with the addition of GNS in fish diets. It was also discovered that the aquaculture water after filtering through CA/bio-AgNps contained much lower concentrations of some chemical and bacteriological parameters. Therefore, dietary supplements of GNS with CA/bio-AgNps could positively impact growth performance, immune response, and health status of Nile tilapia.Luo et al. to demonstrate the markers and candidate genes associated with seven growth traits of the rice flower carp, which is an important economic fish species of integrated rice-fish culture in China. In addition, it was discovered that B6_4352672 and A8_4978825 were significantly associated with more than five growth traits of the rice flower carp. Among 411,913 loci obtained from the reduced-representation genome, 90 loci were significantly associated with the growth traits of carp. Particularly, ccdc92, nbeal1, prkn, adipor2, trim25, tlr13, usp49, otud5, elk1, and nfic were associated to the metabolism, immunity, osteogenic differentiation, and visual function. Luo et al. emphasized that the supply of rice flower carp can be increased to match increasing market demand by employing growth-trait associated markers for the improvement of fish growth ratio. In general, Luo et al. not only revealed the genetic mechanisms related to rice flower carp growth, but also provided a potential way to increase rice flower carp production for market.The first genome-wide association study was performed by Huang et al. to predict the breeding values of the haploid gametophytes of Saccharina latissima, which is economically and ecologically important in the North Atlantic Oceans and the eastern North Pacific. It should be mentioned that this empirical research conducted by Huang et al. is the first to report the applicability of genomic prediction of haploid breeding values. The results of this work can be applied to shorten the time per breeding cycle of Saccharina latissima by predicting the breeding values of non-phenotyped individuals. In addition to Saccharina latissima, the developed GS model developed by Huang et al. may be applicable for some other bi- and tri phasic algae, such as Gracilaria sp. and Asparagopsis sp.A genomic selection (GS) model was trained and a mixed-ploidy additive relationship matrix was employed by In summary, articles of this Research Topic provide recent progresses and insights on advanced technologies in the industries of algae and aquaculture. Some of the results obtained from these studies are expected to solve food shortage globally and improve the health status of humans in modern society.QL contributed to manuscript writing. CN-G and SR contributed to manuscript revision. All authors contributed to the article and approved the submitted version.


Sensors on “Multi-Sensors for Human Activity Recognition” brings together works from various domains to share their findings on a variety of aspects regarding the monitoring of human activity. This Special Issue focused on the current state-of-the-art works related to the broader field of HAR, with a special emphasis on multi-sensor environments. The following section offers a summary of the nine featured articles regarding applications of HAR in smart homes, speech and gesture recognition and security issues of IoT systems, among others.Human activity recognition (HAR) has made significant progress in recent years, with growing applications in various domains, and the emergence of wearable and ambient sensors has provided new opportunities in the field. The use of multi-sensor systems, which integrate data from multiple sensors, has the potential to improve the accuracy and reliability of human activity recognition. This Special Issue of Activity recognition can have applications in the security domain, for surveillance purposes, which is usually achieved through visual sensors. The types of activities relevant to this application are violent actions. There are already available databases regarding general violence detection; however, the authors of  contribuAssisted living environments are probably the field with the most applications of HAR. Numerous works can be found in the relevant literature, testing a variety of methods and sensors for monitoring the activities of people living in these environments and for detecting harmful events. This paper  tested tThis review  presentsIn the sports field, the interest of researchers lies in a subfield of HAR, pose estimation. Its applications can be found in everyday apps in smartwatches and smartphones for monitoring exercise, burnt calories, etc. HAR systems can be adapted to be applied in specific sports and detect certain movements. Likewise, in , the autAn important aspect of multi-sensor systems, besides their performance in recognition tasks, is the secure exchange and storage of data. The authors in  exploredA sub-category of HAR is the recognition of hand gestures that can be exploited to control home appliances and robots or to assist in communication with people who are deaf and people who cannot speak. In , a syste2 from people wearing four different types of masks. Using a multi-sensor system of four low-cost carbon dioxide (CO2) sensors, the authors measured CO2 in two indoor spaces and created spatial heatmaps to visualize the CO2 concentration. In the broader context of monitoring human activity, this Special Issue published a paper  monitoriBesides data-driven approaches, knowledge-based approaches are also adopted in multi-sensor IoT environments to allow interoperability and represent data and events. The authors in  presenteAn application of HAR regarding safety while driving is presented in , where t


Recognizing the risk of pandemic and the importance of monitoring and data sharing, we highlight the importance of establishing a global wastewater surveillance consortium, particularly under the umbrella of an international organization such as WHO, to strengthen future pandemic preparedness. Wastewater surveillance is the most cost-effective means of assessing COVID-19 infectionhttps://wastewater-observatory.jrc.ec.europa.eu/). However, establishing an effective global wastewater surveillance consortium calls for the participation of more countries from a wide range of geographical areas and economic levels under G7 initiatives, and possibly under the umbrella of an international organization such as the WHO. Such a consortium could share experiences and protocols and support monitoring in low-income countries, for building a valuable public health tool for future pandemic preparedness.Given the need for a global surveillance network that provides early warnings against potential health threats, the role of wastewater surveillance is increasing rapidly as an approach for assessing the international transmission of SARS-CoV-2, its variants and other pathogens. To date, the monitoring system has evolved with the global outbreak of infectious diseases. The International Health Regulations were revised according to the experience from the SARS outbreak in 2002–03. In the revised regulations, it is mandated to share the status of infectious diseases under the umbrella of the WHO when a pathogen that may pose a public health emergency of international concern is identified. In this context, we propose here that wastewater surveillance should be incorporated into such international and regulatory framework as a global infectious disease surveillance system. Urban wastewater data generated in a geographical region can be used to prepare appropriate infection control measures in another geographical region. Furthermore, aircraft wastewater genomic surveillance can potentially track the transboundary pathways of emerging viruses. The EU, in collaboration with Canada, the USA, the UK, Malaysia, Australia and other countries, is establishing an international wastewater monitoring consortium by open data sharing regarding SARS-CoV-2 in urban and aircraft wastewater (


The links between built environments (BE) and commute durations have been extensively studied. However, relatively few studies have considered the effects of BEs at different spatial levels within a unified framework, or identified the gendered relationships between BEs and commute durations. Using survey data from 3209 household couples in 97 Chinese cities, this study investigates the effects of neighborhood- and city-level BEs on commute durations and the potential differences in these effects between the male and female members of the same household couple. A multi-group generalized multilevel structural equation model is applied to reveal the gendered relationships between neighborhood- and city-level BEs and commute durations. The findings suggest that the BE variables at two levels have significant effects on the commute duration. The mediating roles that the traffic congestion, car ownership, and commuting modes play in linking these BEs and commute durations are confirmed. Both levels of the BE variables are more influential factors for males’ commuting durations. These findings have policy implications for the design of gender-equal transportation systems. Car-oriented suburbanization and urban sprawl have increased traffic congestion and commute durations. Almost all commuters in large cities over the world are suffering from commuting burdens. For example, the number of inter-city commuters in Germany has increased from 2,442,630 in 2004 to 3,123,924 in 2014 [To reduce commute durations, many transport practitioners and researchers have studied their relationship with the built environment (BE). Most of them focus on Western cities , which aThis study identifies the effects of both neighborhood- and city-level BE variables on commute duration, with a focus on gender differences, using survey data from 3209 household couples in 97 Chinese cities. This study contributes to the international literature on BEs and commute durations by answering the following questions: (1) Do the two levels of BE variables correlate with commute durations? (2) Do the effects of the BE variables differ between the male and female members of the same household couple?The reminder of this paper is organized as follows. The next section reviews the existing studies related to BEs, commute durations, and gender differences. The data, conceptual framework, and method used in this study are then introduced. Next, the estimation results are presented. Finally, the key findings are discussed, followed by the conclusions.To reduce the negative effects of long commutes, previous studies have explored the relationship between BEs and commute durations ,7,8,9,10Apart from the neighborhood-level BE and commute durations, some prior studies have examined the BE beyond residential locations ,13,14,15Although interdependencies exist between household members’ activities and travels, household couples tend to have different commute behaviors, owing to gendered resources, family roles, work disparities, and perception differences ,25,26,27However, relatively few studies have provided evidence for the gender differences in the association between BEs and travel behavior. The male and female members of the same household couple not only attach a different importance to different life domains, but also have different perceptions of spatial attributes . For insChina has experienced impressive economic growth since implementing market-oriented reforms. This growth causes widening income gaps and gives rises to social inequality in post-reform China . In thisBased on this brief review, two main gaps are identified in the literature. First, most prior research on commute durations focuses on the neighborhood-level BE. The impacts of neighborhood- and city-level BEs on commute durations have been poorly investigated within a unified framework. Some researchers have investigated the impacts of two-level BEs on travel behavior and found that the city-level BE plays a more important role ,53; howeSecond, most prior studies have used an individual as the analysis unit when examining the link between BEs and travel behavior, and ignore the gender differences between the male and female members of the same household couple. Although some researchers have found spousal similarity in a multidisciplinary behavior analysis ,55,56, tBased on existing empirical evidence, this study aims to investigate the impacts of the BE at different spatial levels on commuting durations and how these impacts differ between the male and female members of the same household couple. To achieve these objectives, we hypothesize that both the neighborhood- and city-level BE variables affect commute durations in this study. It is recognized that the impacts of the BE variables on commute durations are hierarchical. Moreover, we hypothesize that the impacts of the BE variables on commute durations differ between the male and female members of the same household couple. The intermediary nature of traffic congestion, car ownership, and commuting modes is also considered in this study.The data for this analysis are obtained from the 2014 China Labor-force Dynamics Survey (CLDS), which provides a large-scale dataset to examine the influential factors of commute durations. The survey is conducted by Sun Yat-sen University and it covers 29 provinces in China. Owing to the huge differences in the population sizes and economic development levels of Chinese cities, a multi-stage cluster and stratified PPS sampling method is used to guarantee the representativeness of the national labor force . First, The dependent variable is one-way commute duration, which is directly extracted from the dataset. Individual socio-economic variables are also recorded in the dataset. The statistical descriptions of the variables at the individual level are presented in Among the neighborhood-level BE variables, the distance to transit stations and the distance to the CBD are directly extracted from the dataset. The population sizes and areas of the surveyed neighborhoods are recorded in the dataset and used to calculate the population density. The facility diversity is measured using the sum of seven types of facilities . Thus, the value of the facility diversity is between 0 and 7. A higher value indicates higher diversities.https://www.beijingcitylab.com/ for details accessed on 1 February 2023). The land use mix is calculated based on eight categories of POIs (points of interest), including commercial sites, office buildings, transport facilities, governments, educational facilities, residential communities, green spaces, and others. The bus coverage rate is also directly extracted from the dataset. Second, as the CLDS provides the city information, the population density, metro, public transit supply, and road areas per person are directly extracted or indirectly calculated based on the data from the China City Statistical Yearbook 2014. In this study, polycentricity refers to the degree to which employments or inhabitants are concentrated around sub-centers. The polycentricity index is calculated as follows:N is the number of sub-centers, which should meet three criteria: (1) the sub-center’s density is higher than the city density, (2) the adjacent polygons above the threshold are grouped together, and (3) the sub-centers should contain The city-level variables include traffic congestion and the city-level BE variables. Traffic congestion is treated as a binary variable, according to whether the city entered the top ten congested cities at least once in China in 2014. These rankings are released by AMAP every quarter, which is one of the most popular web mapping service applications in China. Chinese cities are ranked according to their congestion delay indexes during peak hours. The congestion delay index is obtained by dividing actual travel time by free-flow travel time. In total, two datasets are used to calculate the city-level BE variables. First, the land use mix and bus coverage rate are extracted from Beijing City Lab , the city-level built environment variables, and the neighborhood-level variables. The independent variables not only affect commute durations directly, but also affect commute durations via the mediating variables. Car ownership, traffic congestion, and commuting modes serve as mediating variables in this study. The mediating variables are affected by the independent variables, and, in turn, they affect the dependent variable.The structural equation model (SEM) is a powerful method to model the complex relationships among exogenous variables and endogenous variables ,55. In aIn this study, a conceptual framework is proposed , in whicTo examine whether the impacts of the BE variables at two levels vary between the male and female members of the same household couple, the multiple-group modeling approach is incorporated into the GMSEM. The multiple-group GMSEM can perform one single analysis, in which the parameters are estimated for both males (group 1) and females (group 2). In this study, a constrained model is first used to examine the relationships based on the total sample, in which all the parameters are assumed to be the same in the two groups. Then, an unconstrained model is applied to examine the difference between the two groups.The Akaike information criterion (AIC) and Bayesian information criterion (BIC) are applied to confirm the effectiveness of the multi-group GMSEM. Smaller values of the AIC and BIC indicate better fitness. The AIC and BIC can be obtained based on Equations (2) and (3).The model fitness of the constrained and unconstrained models is shown in Traffic congestion and car ownership are the endogenous variables at the city and household levels, and should not be affected by gender. Thus, we assume that the impacts of the independent variables on traffic congestion and car ownership remain the same for the male and female members of the same household couple. The estimated results of the GMSEM models are shown in Among the city-level BE variables, the population density, polycentricity, and road areas per person show significant effects on traffic congestion. The population density shows a significantly positive impact on traffic congestion, whereas the polycentricity and road areas per person show significantly negative impacts.Most of the variables show significant impacts on car ownership. Among the city-level BE variables, the population density, land use mix, polycentricity, public transit supply, road areas per person, and bus coverage rate show significantly negative impacts on car ownership. Regarding the neighborhood-level BE variables, the population density, distance to transit stations, and distance to the CBD show significantly negative impacts on car ownership, which are in line with most existing studies ,64,65,66The results demonstrate that the relationships between the two levels of BE variables and commuting mode choices differ between the male and female members of the same household couple. In addition, the BE variables are more influential to males’ commuting mode choices. Among the city-level BE variables, the population density and public transit supply show significantly positive impacts on commuting by active modes for males, whereas their impacts are not significant for females. The variable of road areas per person only shows a significantly negative impact on commuting by active modes for males. All the neighborhood-level BE variables show significant impacts on commuting by active modes for males, whereas the impact of the distance to the local CBD is not significant for females. The facility accessibility shows a significant impact on commuting by public transit for males, whereas its impact is not significant for females. Except for the above variables, the other BE variables show no different impacts for males and females. The polycentricity and land use mix show significantly positive impacts on active modes, suggesting that people living in a region with polycentricity and more balanced land use have a higher probability of commuting by active modes. The polycentricity, metro, road areas per person, and bus coverage rate show significant impacts on commuting by active modes. The population density at the neighborhood level has a significantly positive impact on commuting by active modes for both males and females. The distance to transit stations shows significantly positive impacts on commuting by active modes and public transit for both males and females.The gendered relationships between the factors and commute durations are shown in Among the city-level variables, traffic congestion shows a significant impact on commuting durations, suggesting that people living in more congested cities tend to have longer commuting durations. In terms of the total effects, most of the city-level BE variables show significant impacts on commuting durations, and males’ commute duration is more strongly associated with the BE variables. Specifically, the impacts of the population density and metro are significantly positive for both males and females. The direct effect of the population density is strengthened by the corresponding indirect effects, whereas the total effect of the population density is weakened by the corresponding indirect effects. The land use mix and polycentricity show significantly negative impacts on commuting durations for both males and females. The negative impact of the land use mix indicates that diversified land-use developments can reduce commute durations. This result is consistent with several previous studies ,12. The Regarding the neighborhood-level variables, most of the BE variables show significant impacts on commuting durations. Additionally, the impacts of the population density and facility diversity differ between the male and female members of the same household couple. Specifically, the distance to transit stations and the distance to the CBD show significantly positive impacts on commuting durations for both females and males, and the corresponding indirect effects weaken their direct effects. In contrast, the impacts of the population density and facility diversity on commuting durations are significant for males, whereas their impacts are insignificant for females. In addition, the corresponding indirect effects strengthen the direct effects of the population density and facility diversity.As for factors at the individual level, the impacts of age, education, hukou, and electric bike ownership show the same statistical significance for both females and males. The positive impacts of education and hukou suggest that well-educated people with a local hukou tend to have longer commutes. Some variables produce different impacts for the male and female members of a household couple. Income and household size only show significantly negative impacts on the commute durations for females. This result may be because females tend to have greater family responsibilities , and thuThis study has significant implications for whether and how the BE variables at different spatial levels affect commute durations. It enriches prior studies by including both neighborhood- and city-level BEs. Additionally, the findings highlight the importance of identifying the gendered relationships between BEs and commute durations. This section presents the key findings of this study.First, the findings appear as additional evidence for BEs and commute durations by including city-level BE variables. The findings suggest that the BE variables at the two levels play critical roles in influencing commute durations. This result is similar to previous studies that found that the BE variables at different spatial levels are the key factors of travel-related issues ,6. SpeciSecond, this study further demonstrates the gender differences in the impacts of the BE variables on commute durations. The results suggest that the BE variables have a greater impact on commute durations for males. Specifically, most of the BE variables show significant impacts for males, whereas only the impacts of the city population density, metro, land use mix, polycentricity, distance to transit stations, and distance to the CBD are statistically significant for females. This result suggests that males are more sensitive to BEs than females, and this difference is consistent with some existing studies that have found that males tend to attach more importance to their external environment, including their social and physical environments ,71. ThisThird, the impacts of the population density at the city and neighborhood levels are positive. This result is inconsistent with most previous studies ,12,58, iFinally, we find that the impact of car ownership is significantly positive for males. This result suggests that male commuters who own a car tend to commute for a longer duration. Regarding the link between commuting and car ownership, prior studies have provided mixed evidence ,31,73. PThese findings provide policy implications for reducing commuting durations. First, policy makers should pay more attention to the impacts of the city-level BE variables on commute durations and try to mitigate the negative effects that are induced by overly compact development patterns. Specifically, maintaining a reasonable city population density and promoting polycentric development patterns help to shorten commute durations. Second, the urbanization process has caused large-scale rural-to-urban migrations and urban sprawl in China. Most migrant workers live in urban villages because they cannot afford the high rent in other areas. They have a strong travel demand for work and other activities, but they tend to have no car. In other words, migrant workers living in urban villages should have a higher motorized demand that needs to be satisfied by public transit systems. Moreover, the results suggest that people living farther from transit stations tend to have a longer commuting duration. Thus, it is important to increase the investments into developing public transit systems around urban villages, in order to reduce the imbalance of the public transport between the migrant workers and local residents. Finally, the results suggest that policy makers should pay more attention to reducing females’ commuting durations. Females tend to have greater family responsibilities , and thuUsing survey data from 3209 household couples across 329 communities nested within 97 cities, this study reveals the impacts of neighborhood- and city-level BE variables on commute durations, and identifies the gender gaps in these impacts. The mediating effects of traffic congestion, car ownership, and commuting modes are considered. The findings show that most of the BE variables at the two levels are key factors of commute durations. Moreover, the gender differences in these impacts are observed through the impact of the BE variables. Specifically, the population density, land use mix, polycentricity, metro, public transit supply, and road areas per person at the city level show significant impacts on commute durations for males, whereas only the population density, land use mix, polycentricity and metro show significant impacts for females. Regarding neighborhood-level BEs, the impacts of the population density, facility diversity, distance to transit stations, and distance to the CBD are statistically significant for males, whereas only the distance to transit stations and distance to the CBD show significant impacts for females. The direct effects of the BE variables are strengthened or weakened by the corresponding indirect effects via traffic congestion, car ownership, and commuting modes. These findings highlight the importance of understanding gender differences when designing gender-equal transportation systems.Several limitations of this study should be noted in future studies. First, the causal links between the BE and commute durations are not addressed in this study, because the survey data are cross-sectional. Future studies need more longitudinal data to capture causal links. Second, only household couples are considered, and the commuting behaviors of other household members are ignored in this study. Other members’ travel behaviors may be associated with household couples’ commuting durations, which should be paid attention to in future studies. Third, the self-selection effect is not fully considered in this paper, because the attitudes and preferences for travel and land use are not surveyed in the travel survey.


The objective of this work was to perform an integrative review of the inspection of peri-implant bone defects using cone beam computed tomography (CBCT). An electronic search was performed in the PubMed database using the following scientific terms: CBCT or Cone Beam computed tomography; dental implant; peri-implant; bone loss; defects. The survey identified 267 studies, of which 18 were considered relevant to this study. These studies provided important data taking into account the accuracy of cone beam computed tomography in the detection and measurement of peri-implant bone defects such as fenestrations, dehiscence and intraosseous circumferential defects. The effectiveness of CBCT in aiding in geometric bone calculations and in the diagnosis of peri-implant defects was influenced by factors such as artefacts, defect size, bone wall thickness, implant material, adjustment of acquisition parameters and observer experience. A not insignificant number of studies compared intraoral radiography to CBCT in the detection of peri-implant bone loss. CBCT was clearly superior to intraoral radiography in the detection of all peri-implant bone defects, except for defects located in the interproximal zone. In general, studies have shown that peri-implant bone measurements adjacent to the implant surface can be correctly determined, as well as the diagnosis of peri-implant bone defects with an average discrepancy of less than 1 mm from the actual measurement of the defect. The importance of radiology in assessing the bone around the implants is undeniable. In this sense, postoperative radiographic evaluation of dental implants and the advantages and disadvantages of different radiographic modalities are important .In 1998/1999, Mozzo et al. introduced cone beam computed tomography (CBCT) , which, depending on the specific configurations of the device and the CBCT units, allows three-dimensional images to be obtained with relatively low doses of radiation .The detection of peri-implant bone loss is considered an important criterion for assessing implant performance and diagnosing potential peri-implantitis , 3. CurrIn cases where three-dimensional visualization of the bone is necessary, CBCT may be an alternative , 14, 15.The benefits of CBCT include its distortion-free and overlay-free images; however, the relatively high radiation exposure and artefacts in the vicinity of metallic objects limit the application of this technique as a method for routine evaluation of dental implants , 9, 10. The purpose of this work was to perform an integrative review of the use of CBCT for peri-implant bone loss identification and measurement. It was hypothesized that CBCT would show greater precision in the detection of peri-implant bone defects than traditional X-ray techniques.A bibliographic search was carried out in the PubMed database  using the following combination of search terms: “CBCT” or “Cone beam computed tomography” AND “dental implant” AND “peri-implant” AND “bone loss” AND “Defects”.The studies were considered eligible if they addressed the question of the focus, “What is the diagnostic value of CBCT images in direct peri-implant bone measurements?”Inclusion criteria included articles published in the English language, in vivo and in vitro studies, meta-analyses or bibliographic reviews that diagnosed peri-implant bone loss using CBCT, studies that analysed the accuracy of CBCT in peri-implant bone analysis and studies comparing intraoperative or histological reference measures showing measurable results of diagnostic performance. Additionally, studies that analysed the modifying factors of the performance of CBCT in peri-implant bone analysis were also included.The exclusion criteria included articles that did not answer the focus question.The total number of articles was compiled for each combination of key terms; subsequently, duplications were removed using Mendeley®  citation manager (version 1.19.4).A preliminary assessment of the abstracts was carried out to determine whether the articles corresponded to the objective of the study. The selected articles were read and evaluated individually regarding their purpose and relevance.The PRISMA flowchart describing the study selection process is shown in Fig. For this review, the following factors were considered: author, title, year of publication, type of study , number of implants analysed, type of reference or comparative measure used in the CBCT and other X-ray diagnostic means , and reported results.The literature search identified a total of 267 articles on PubMed using keyword combinations. A total of 56 articles were selected by title, and after eliminating duplicates with the citation manager Mendeley, 35 articles were considered.Abstracts were read, and 8 articles were excluded because they did not meet the inclusion criteria. The remaining potentially relevant studies were evaluated.Of these studies, nine were excluded because they did not provide comprehensive data regarding the objective of the present study. Thus, 18 studies were included in this review.In total, 14 in vitro studies, 3 in vivo and 1 systematic review were included.The main characteristics and conclusions of the study are summarized in Table Of the 18 selected studies, 5 in vitro studies evaluated the effectiveness of cone beam computed tomography in detecting peri-implant dehiscence, 3 in vitro studies validated the accuracy of CBCT in the diagnosis of fenestration defects, and 8 studies, 5 in vitro and 3 in vivo, evaluated the performance of CBCT in the detection of peri-implant circumferential intraosseous defects.A systematic review was also included that evaluated the performance of cone beam computed tomography in the evaluation of peri-implant bone loss.While the aforementioned studies validated the effectiveness of CBCT in detecting peri-implant defects, 1 in vitro study evaluated the factors that affect the possibility of analysing the bone condition around dental implants using cone beam computed tomography.Of these studies, 1 in vitro study evaluated the effectiveness of low radiation dose protocols in detecting peri-implant bone defects, while two in vitro studies also validated the effect of the field of view (FOV) and the number of CBCT acquisition frames in detecting chemically simulated bone loss around the implants.Regarding the method of creating peri-implant defects in vitro, surgical creation was the most common method, while five studies applied a chemical attack with perchloric acid. Two studies placed implants in surgically created chronic alveolar defects , 12, andRegarding the reference standards, all in vitro studies used direct measurements of the defects as a reference, while the three in vivo studies used histomorphometry as the “gold standard”.The in vivo studies revealed a high precision of the peri-implant bone measurements, giving a high diagnostic value to CBCT in the detection of peri-implant bone loss, despite the presence of underestimation and overestimation of measurements with respect to histology , 11.CBCT demonstrated high precision in the diagnosis of peri-implant defects in almost all included studies, with a discrepancy in the real value of the defect averaging less than 1 mm , 15–17.The main limitation of CBCT is the presence of metallic artefacts, that is, image flaws unrelated to the digitized object, caused by metals such as dental implants and amalgam restorations, or to a lesser extent, by root canal filling materials in endodontic treatments .Overall, the comparison between CBCT and two-dimensional radiography reported significantly higher sensitivity and specificity values for CBCT, as it was more effective than two-dimensional radiography in detecting and classifying peri-implant bone defects , 13.Adjustment of technical acquisition parameters in relation to image quality control and exposure to reduced artefacts  may have a direct impact on detecting relatively small deficiencies in the implant region .The main results are presented below:The accuracy of CBCT in the analysis of peri-implant bone was tested in different experimental models. In general, the selected studies varied markedly in their design, acquisition parameters of CBCT, image processing and reported diagnostic results, so all data presented should be interpreted with caution, as several factors limit the translatability of these preclinical findings.. showed statistically significant correlations between radiographic images obtained with CBCT and histological sections; however, the CBCT images produced, unlike the findings of Fienitz et al., a mean underestimation of the depth of bone defects of 1.2 mm, as 50% of the deviations were less than 0.5 mm and, therefore, considered clinically insignificant [The in vivo studies revealed a high precision of peri-implant bone measurements, indicating that CBCT had high diagnostic value in the detection of peri-implant bone loss, despite the presence of underestimation and overestimation of measurements when compared with histology , 11. Thenificant  because This could be the first explanation of the difference, albeit minimal, between CBCT and histological measurements. In addition, the sample orientation for CBCT images appears to affect the accuracy of peri-implant bone measurements .In the study by Ritter et al., the orientation of the sample affected the direction of the artefacts, changing the precision of peri-implant measurements; more specifically, the direction of the artefacts, diagonal to the implant axis, artificially increased the bone level on the buccal side by 0.3 mm on average, while the level of the lingual bone was hidden by the extinction of artefacts, resulting in a real underestimation of the bone by approximately 0.83 mm. Measurements in the mesial and distal directions showed a similar effect: in the mesial direction, the beam hardening artefacts attenuated the measured values more strongly with respect to histomorphometry than at the distal sites. Based on these studies, the orientation of the implants in relation to the X-ray axis must be considered in the interpretation of the images because they can directly influence the peri-implant bone measurements. In addition, the importance of adequate bone thickness for efficient peri-implant radiographic identification seems evident.CBCT demonstrated high precision in the diagnosis of peri-implant defects in almost all included studies, with a discrepancy in the real value of the defect averaging less than 1 mm , 15–17. Kamburoglu et al. surgically created dehiscence defects of different sizes in implants inserted in the mandibles of cadavers, classifying the defects according to depth and width as small, between 1 and 3 mm, medium, between 3 and 5 mm, and or large, greater than 5 mm, establishing a high correlation between the depth and width measurements of the defects with the actual physical measurements, although the small defects resulted in less accurate diagnoses than the medium and large defects . Similar. reported that the deviations of the measurements in relation to the real value of the defects were greater around the zirconium implants than the titanium implants [There are different types and brands of dental implants on the market, each with their own characteristics, and after a careful analysis of the articles, the type of implant material analysed also seemed to influence CBCT measurements in a different way. Titanium has been established as the preferred metal for dental implants due to its unique mechanical properties and its high resistance to corrosion, while zirconium dioxide has become more popular as a biocompatible and aesthetic alternative to titanium due to its biophysical properties and white colour . Schribeimplants .In some studies, it was suggested that there is also a possible impact of different levels of examiner experience on the interpretation of radiographic images , 15. In Analysing the results of the studies, the diagnostic value of CBCT for peri-implant defects appears to be high, with minimal discrepancy from the reference values.Clearly, the transfer to clinical application requires further investigation due to the several disadvantages that an experimental model imparts , 15, as Therefore, the expected accuracy in real-life situations may be different from that found in studies.The importance of radiography in the analysis of the bone condition around the implants is indisputable  due to tIn regard to detecting circumferential intraosseous defects, peri-apical radiography demonstrated greater diagnostic accuracy than in detecting dehiscence and fenestration defects; however, CBCT has demonstrated to be the most accurate technique, capable of providing additional information on the location and precise morphology of the defects, as the lower effectiveness of periapical radiography in detecting dehiscence defects and fenestrations was mainly due to its two-dimensional nature, unable to show the buccal and lingual parts of the implants.Schwindling et al. and Hilgelfeld et al. reported that the precision and reliability were comparable between intraoral radiography and CBCT in relation to the detection of 1–4 wall intraosseous circumferential defects, that is, the separation of samples with and without defects.Regarding the more complex task of defect classification, that is, the recognition of defect geometry, significant differences were detected between the techniques, with CBCT demonstrating significantly higher sensitivity and specificity values than intraoral radiography , 13, as The main limitation of CBCT is the presence of metallic artefacts, that is, image flaws unrelated to the digitized object caused by metals such as dental implants and amalgam restorations, or to a lesser extent, by root canal filling materials in endodontic treatments . Several., who found a higher mean deviation from defect status for depth than for width measurements [In the study of Schwindling et al., beam hardening artefacts made it difficult to define the depth of the circumferential defects, while the width measurements substantially agreed with the reference measurements , in lineurements . The expurements , as staturements .. observed that CBCT images compatible with bone defects were characterized by hypodense and irregular zones, with small hyperdense areas (remnants of trabecular bone), while images produced by metal artefacts were more regular and completely hypodense, suggesting that this small difference can be useful in establishing correct diagnoses [The distinction between image artefacts and peri-implant bone loss has often proven to be a challenge, especially since they can be confused with one another, leading to false positives or false negatives. Albeit L.R. Pinheiro et aliagnoses .. investigated the effect of artefact reduction software on the ability to accurately detect mechanically created peri-implant and periodontal defects from CBCT images and found no difference in the use of artefact reduction software but reported that peri-implant defects were detected with greater difficulty than periodontal defects [Kamburoglu et al defects .However, the results described cannot be generalized, as CBCT scanners from different manufacturers with different spatial resolutions (voxel sizes), fields of view (FOV), patient positioning systems or scanning durations are in use worldwide, which will influence the quality and interpretability of the scans .Several factors in relation to image quality control, exposure to reduced artefacts  and technical acquisition parameters may have a direct impact on detecting relatively small deficiencies in the implant region, and the size of the field of view (FOV), thickness of the voxel, and the number of acquisition frames can directly influence the image quality of the CBCT scan .. and Pinheiro et al. tested the influence of different sizes of FOV in the detection of peri-implant bone lesions, and they did not find significant differences in the detection rates; however, the results in the study by Kamburoglu et al.are confusing, since the size of the voxel varies between protocols [FOV is the term used to refer to the scanning volume of a specific CBCT unit and is determined by the size and shape of the detector, beam projection geometry and beam collimation, which limits radiation exposure to a specific region of interest . A “voxerotocols , 15.According to Pinheiro et al. , the pro. investigated the diagnostic accuracy of a low-dose protocol (LD-CBCT) compared with that of a high-dose protocol (HD-CBCT) in the detection and classification of peri-implant bone lesions [. conducted a study in which the accuracy of CBCT was compared between 75 and 90 kVp protocols in the detection of circumferential peri-implant defects and found that CBCT images at 90 kVp were associated with a significantly higher rate of detection of chemically simulated bone defects than 75 kVp CBCT [There is evidence in the field of endodontics and periodontology that acceptable image quality can be achieved with reduced kV, mA and exposure time . Schwind lesions  and foun lesions . While SIn the study by Eskandarloo et al., in which three CBCT systems for detecting peri-implant fenestration were compared, the CBCT NewTom 3G, which was associated with a higher KVp, showed the highest diagnostic accuracy in detecting peri-implant fenestration, although no significant differences were found between the three CBCT systems .CBCT images can be used with high diagnostic precision in the detection of peri-implant bone defects, with an average discrepancy of less than 1 mm from the actual size of the defect. CBCT provides useful information about bone in all dimensions around the implants with varying accuracy depending on several factors.The presence of artefacts in the peri-implant area was the most frequent limitation of CBCT in the detection and measurement of bone defects, resulting in an underestimation or overestimation of the size, depending mainly on the implant material and the sample orientation.Larger peri-implant defects showed greater detection accuracy, while small defects (less than 1 mm) were more difficult to detect.Adjusting the acquisition parameters such as FOV, acquisition time and voxel size does not seem to significantly affect the image quality in detecting bone loss, while kVp does. However, the results found on the adjustment of the acquisition parameters are difficult to interpret given that the variables are innumerable. More standardized studies should address this issue.Intraoral radiography can be recommended as an initial method of diagnosis due to its low cost and low dose of administered radiation, in addition to its comparability to CBCT with regard to mesial and distal peri-implant bone analysis. However, it was unable to show the buccal and oral aspects of the implants and was, therefore, unable to diagnose bone defects such as fenestrations and dehiscence.In general, CBCT can be considered a useful and reliable tool for the diagnosis of peri-implant bone loss. However, special attention should be given to the radiation dose administered. Further studies comparing different CBCT machines in the diagnosis of peri-implant bone loss should become available, as the market offers a wide variety.


Recently, there has been an upsurge in the extent to which electrochemiluminescence (ECL) working in synergy with bipolar electrochemistry (BPE) is being applied in simple biosensing devices, especially in a clinical setup. The key objective of this particular write-up is to present a consolidated review of ECL-BPE, providing a three-dimensional perspective incorporating its strengths, weaknesses, limitations, and potential applications as a biosensing technique. The review encapsulates critical insights into the latest and novel developments in the field of ECL-BPE, including innovative electrode designs and newly developed, novel luminophores and co-reactants employed in ECL-BPE systems, along with challenges, such as optimization of the interelectrode distance, electrode miniaturization and electrode surface modification for enhancing sensitivity and selectivity. Moreover, this consolidated review will provide an overview of the latest, novel applications and advances made in this field with a bias toward multiplex biosensing based on the past five years of research. The studies reviewed herein, indicate that the technology is rapidly advancing at an outstanding purse and has an immense potential to revolutionize the general field of biosensing. This perspective aims to stimulate innovative ideas and inspire researchers alike to incorporate some elements of ECL-BPE into their studies, thereby steering this field into previously unexplored domains that may lead to unexpected, interesting discoveries. For instance, the application of ECL-BPE in other challenging and complex sample matrices such as hair for bioanalytical purposes is currently an unexplored area. Of great significance, a substantial fraction of the content in this review article is based on content from research articles published between the years 2018 and 2023. Analytical techniques based on electrochemiluminescence (ECL) and bipolar electrochemistry (BPE) [ECL-BPE] have in recent times emerged as indispensable tools in various fields, and of particular interest, in biosensing. Principally, biosensing involves the detection and collection of biological and biochemical information, which would be critical for diagnosing diseases  diseasesA number of studies have shown that many of the widely employed biomarker assays used in medical facilities need constant improvement which may result from both low specificity and sensitivity associated with them . DevelopAs the field of biosensing continues to evolve, research scientists are constantly seeking new methods for improved and efficient single and more advantageous, multiplex assaying of various chemical species of interest within a single run. Multiplex detection has become progressively important in reducing false positives and improving diagnostic accuracy . ECL-BPEThe review also discusses the existing challenges, including optimizing the interelectrode distance, the aspect of BPE miniaturization, and electrode surface modification, to improve sensitivity and selectivity, particularly for multiplex assaying. This write-up will not only present a three-dimensional perspective of ECL-BPE as an analytical tool, but its vast research content also highlights novel perspectives and identifies significant areas for future research and development. This perspective is especially relevant to the scientific community interested in exploring the latest advances in ECL-BPE and its appropriateness for a wide range of scientific fields, particularly in clinical settings. Furthermore, it adds value to the current literature as it not only discusses the strengths and limitations of ECL-BPE but also delves into its potential applications in multiplex biosensing, a topic that has not been adequately covered.A systematic and thorough approach to ensure accuracy of the content of this review paper was used to collect information. Firstly, when collecting the content, relevant keywords and concepts relating to the topic at hand were identified. These keywords and concepts aided in locating pertinent articles and papers from academic journals and databases. The majority of the scientific articles used here were obtained from Scopus, Web of Science, and PubMed. The titles, keywords, and abstract were first evaluated to determine the relevance of the article content. Any articles that lacked in their scope, the linkage between classical electrochemistry and BPE, closed and open bipolar electrodes, ECL-BPE and biosensing, the chemistry of luminophores and the concept of bipolar electrodes in synergy with ECL and their recent, novel applications in biosensing of a single bioanalyte or for multiplex assaying, were in the preliminary stage were not included. Much of the content in this review other than the typical theoretical aspect of both ECL and BPE is based on the past half a decade (between 2018 and 2023) of research work. The pie chart below  represen(a)What are the strengths and limitations of closed bipolar electrochemistry (c-BPE) versus open bipolar electrochemistry (o-BPE) in biosensing applications?(b)Which configuration of BPE is commonly employed in biosensing for improved multiplex assaying? For what reasons is it predominantly used?(c)What are the available synthesis and functionalization strategies for bipolar electrodes, and how might they impact their suitability for biosensing applications in ECL-BPE, particularly in multiplex assays?(d)Over the past half a decade of research, what advancements have been achieved in the development of novel ECL luminophores, and how have these advancements affected the ECL technique?(e)During the past 5 years, what novel applications of ECL-BPE have emerged for multiplex assaying?(f)With the focus on research conducted between 2018–2023, what are some of the challenges associated with using ECL-BPE for multiplex assays, and how have they been addressed, if at all?By and large, the following research questions guided this review:Electrochemistry in general is a vibrant and versatile field that has seen increased attention due to its applications in various areas, including biosensors, chemical sensors, and electroanalytical chemistry. One of the most exciting aspects of electrochemistry is the existence of BPE designs that offers unique advantages in terms of sensitivity and selectivity. BPE exploits a working electrode being a bipolar electrode BE,  which isAs will be noted later, the BE can essentially be regarded as the heart of BPE. Worth noting is that BPE and traditional electrolysis are different but only slightly so. For example, the former is also a well-established “wireless technique”  that useIn the classical three-electrode electrochemistry system, the working electrode is the electrode of interest; depending on its polarization with regard to the electrolyte, either a reduction or an oxidation reaction takes place. On the contrary, this is not the case with BPE because as earlier stated, both reduction and oxidation take place simultaneously on the BE . MoreoveBPE has been a robust and reliable technique for some time now, and it has been used since the early 1970s for designing electrochemical reactors and batteries . This waWhereas BPE can be applied for analytical and biosensing purposes, it still requires appropriate instrumentation and methods of detection to interpret the electrochemical signal that is produced at the BE. So in many cases for the purposes of providing an optical signal readout, BPE is usually used in combination with ECL, fluorescence, and anodic dissolution . HoweverWhen BPE works in synergy with ECL, the sufficiently high voltage applied to the driving electrodes generates ECL at the anodic pole of each BE  which inBPE, as aforesaid is essentially composed of a conductor (a BE) submerged in an electrolyte solution without direct connection to the external power source. A BE is an object made of a conductive material, such as a metal strip or bead, that facilitates electrically coupled Faradaic reactions at its opposing poles . In termBPE) floats to a value intermediate to that of the electrolyte it is in contact with. In a BPE cell, there is the development of interfacial potential differences with opposite signs at the ends of the BE. These interfacial potential differences are the anodic and cathodic overpotentials /TPA) and one involving 3-aminophthalhydrazide/hydrogen peroxide (luminol/H2O2) are among the most effective and broadly employed ECL reactions [Manz et al. in the year 2001 were the first researchers that introduced and incorporated ECL into BPE where it was ably applied for micellar electro-kinetic chromatographic separation of dichloro-trisruthenium(II) hydrate (Ru(bpy)en)32+)) ,54. The eactions . Despiteeactions . Currenteactions  especialAs stated in the foregoing text, to successfully conduct multiplex assaying using ECL-BPE, the system may exploit a collection of multiple electrodes besides fabrication. This particular electrochemical technique has appealing characteristics, such as the option to drive multiple electrochemical reactions simultaneously on several BEs located in the same electrochemical cell setup. Additionally, in the case of c-BPE, the ability to modify the shape and location of the driving electrodes provides considerable flexibility in designing reaction systems . In thisFurthermore, when the paper and cloth-based ECL system is in use, fabrication using a complex and time-consuming screen-printing process has extensively been employed. To counteract these issues, M.L. Bhaiyya and coworkers  for the As can be noted above, ECL-BPE offers several advantages over other electrochemical biosensors. However, there exist several limitations that limit the widespread adoption of this technology in detection purposes. As discussed in the preceding sections, one of the primary limitations of ECL detection using BPE would result from the lack of alternative appropriate electroactive probes. Conventional luminophores such as ruthenium complexes have several limitations, including poor stability and being costly. Regardless, several alternatives to these luminophores have been proposed, including CdSe/ZnS quantum dots, graphene oxide, and other nanomaterials, and research in this area is very currently very active. Another limitation that may be associated with this technique is the intricacy linked to the process of fabricating the electrode. The process of fabrication of BEs is complex as it requires the deposition of two separate metal layers. In an attempt to overcome this challenge, 3D printing of microchannels has been proposed .Taking everything into account, the use of the ECL-BPE technique in biosensing applications has shown great potential for further enhanced selectivity and sensitivity for multiplex assaying. More studies are needed to explore the practical applications of the ECL-BPE sensors in both clinical and environmental settings and to further optimize their sensitivity and selectivity. Future studies could also focus on the development of novel BE materials as well as functionalization strategies that may be able to selectively detect specific analytes in complex samples, as well as the exploration of more diverse applications for the technology. One of the main research gaps observed from this endeavor is the need for further validation and characterization of the biosensors in other complex sample matrices other than blood such as hair, saliva, urine, and environmental samples. For example, the use of ECL-BPE for the detection of drug residues in hair could be an exciting area of research, as it could offer a sensitive and non-invasive tool for drug testing and monitoring. To the best of our knowledge, by the time of writing this review, this application had not been explored, and if it has been, then not as extensively so. The application of the ECL-BPE technique for hair sample analysis can offer significant, distinctive advantages over traditional methods involving sample matrices such as blood. As the hair can store information about drug exposure for months or years , hair anFurther, this review has also looked at different ECL luminophores and how they help address challenges in bioanalytical applications. Since different fields and ECL applications have diverse requirements, new luminophores are highly demanded to address current challenges. Despite ECL advances, some challenges remain and need practical solutions. For example, most ECL luminophores typically emit in a limited spectrum range, making it necessary to develop novel luminophores with tunable colors across the visible spectrum. This will enhance selectivity and enable the detection of multiple analytes . MoreoveResulting from ECL-BPE biosensors possessing several advantages including higher sensitivity, stability, and low limits of detection, its use has emerged as a promising approach for the development of high-performance multiplex biosensors. As such, further research and development of this technique could be crucial for the advancement of clinical diagnosis and forensic science. The use of these methods and related technologies can lead to innovative and cost-effective methods with advantages over traditional, more complex analytical techniques such as HPLC-MS/MS, NMR, etc. Our research group is also yet to extensively explore a number of fundamental aspects and applications of ECL-BPE in the biosensing of a range of biomarkers for diagnostic purposes, for example. It is also recommended to further explore the single electrode electrochemical system in the area of multiplex assaying owing to its inherent superior qualities discussed in the previous sections. While there are still several gaps in the research on the ECL-BPE technique for biosensing, the studies reviewed indicate that this technology has great potential for a wide range of applications in the clinical, environmental, and forensic settings. Further studies in this area could lead to the development of more efficient, sensitive, and selective biosensors with diverse applications.