Engineering organoid microfluidic system for biomedical and health engineering:A review

In recent years,organoid technology,i.e.,in vitro three-dimensional(3D)tissue culture,has attracted increasing attention in biomedical engineering.Organoids are cell complexes induced by differentiation of stem cells or organ-progenitor cells in vitro using 3D culture technology.They can replicate the key structural and functional characteristics of the target organs in vivo.With the opening up of this new field of health engineering,there is a need for engineering-system approaches to the production,control,and quantitative analysis of organoids and their microenvironment.Traditional organoid technology has limitations,including lack of physical and chemical microenvironment control,high heterogeneity,complex manual operation,imperfect nutritional supply system,and lack of feasible online analytical technology for the organoids.The introduction of microfluidic chip technology into organoids has overcome many of these limitations and greatly expanded the scope of applications.Engineering organoid microfluidic system has become an interdisciplinary field in biomedical and health engineering.In this review,we summarize the development and culture system of organoids,discuss how microfluidic technology has been used to solve the main technical challenges in organoid research and development,and point out new opportunities and prospects for applications of organoid microfluidic system in drug development and screening,food safety,precision medicine,and other biomedical and health engineering fields.

A Review of Nano/Micro/Milli Needles Fabrications for Biomedical Engineering

Needles,as some of the most widely used medical devices,have been effectively applied in human disease prevention,diagnosis,treatment,and rehabilitation.Thin 1D needle can easily penetrate cells/organs by generating highly localized stress with their sharp tips to achieve bioliquid sampling,biosensing,drug delivery,surgery,and other such applications.In this review,we provide an overview of multiscale needle fabrication techniques and their biomedical applications.Needles are classified as nanoneedles,microneedles and millineedles based on the needle diameter,and their fabrication techniques are highlighted.Nanoneedles bridge the inside and outside of cells,achieving intracellular electrical recording,biochemical sensing,and drug delivery.Microneedles penetrate the stratum corneum layer to detect biomarkers/bioelectricity in interstitial fluid and deliver drugs through the skin into the human circulatory system.Millineedles,including puncture,syringe,acupuncture and suture needles,are presented.Finally,conclusions and future perspectives for next-generation nano/micro/milli needles are discussed.

Ophthalmological instruments of Al-Halabi fill in a gap in the biomedical engineering history

Al-Halabi is an intriguing ophthalmologist who invented numerous surgicalinstruments for treating various eye diseases. The illustrations of such instrumentsin his invaluable book “Kitab Al-Kafi fi Al-Kuhl” reflect his willingness toteach. Moreover, he included in his book a magnificent illustration of theanatomical structure of the eye. The book reflects Al-Halabi’s medical practice andteaching and shows several advanced medical techniques and tools. Hisinvaluable comments reflect his deep experimental observations in the field ofophthalmology. The current article provides proof that Al-Halabi is one of ourearly biomedical engineers from more than 800 years ago. Al-Halabi represents aring in the chain of biomedical engineering history. His surgical instrumentsrepresent the biomechanics field. Al-Halabi should be acknowledged among thebiomedical engineering students for his various contributions in the field ofsurgical instruments.

Auxetics in Biomedical Applications: A Review

Materials exhibiting auxetic properties have a negative Poisson’s ratio, which intrigued researchers to understand the behavior of auxetic structure. Several researchers focused on the different auxetic cell designs, while others focused on the auxetic applications. With the advance of additive manufacturing methods, computer-aided design and finite element analysis in recent decades, auxetics have been explored. One of the interesting applications is in the field of biomedical devices or implants, especially for certain natural biomedical organs such as tissues, certain ligaments that have auxetic properties. This paper is an overview of auxetic design approaches and biomedical applications.

Porous nanofibrous dressing enables mesenchymal stem cell spheroid formation and delivery to promote diabetic wound healing

Delayed and nonhealing of diabetic wounds imposes substantial economic burdens and physical pain on patients.Mesenchymal stem cells(MSCs)promote diabetic wound healing.Particularly when MSCs aggregate into multicellular spheroids,their therapeutic effect is enhanced.However,traditional culture platforms are inadequate for the efficient preparation and delivery of MSC spheroids,resulting in inefficiencies and inconveniences in MSC spheroid therapy.In this study,a three-dimensional porous nanofibrous dressing(NFD)is prepared using a combination of electrospinning and homogeneous freeze-drying.Using thermal crosslinking,the NFD not only achieves satisfactory elasticity but also maintains notable cytocompatibility.Through the design of its structure and chemical composition,the NFD allows MSCs to spontaneously form MSC spheroids with controllable sizes,serving as MSC spheroid delivery systems for diabetic wound sites.Most importantly,MSC spheroids cultured on the NFD exhibit improved secretion of vascular endothelial growth factor,basic fibroblast growth factor,and hepatocyte growth factor,thereby accelerating diabetic wound healing.The NFD provides a competitive strategy for MSC spheroid formation and delivery to promote diabetic wound healing.

Millimetric devices for nerve stimulation:a promising path towards miniaturization

Nerve stimulation is a rapidly developing field,demonstrating positive outcomes across several conditions.Despite potential benefits,current nerve stimulation devices are large,complicated,and are powered via implanted pulse generators.These facto rs necessitate invasive surgical implantation and limit potential applications.Reducing nerve stimulation devices to millimetric sizes would make these interventions less invasive and facilitate broader therapeutic applications.However,device miniaturization presents a serious engineering challenge.This review presents significant advancements from several groups that have overcome this challenge and developed millimetricsized nerve stimulation devices.These are based on antennas,mini-coils,magneto-electric and optoelectronic materials,or receive ultrasound power.We highlight key design elements,findings from pilot studies,and present several considerations for future applications of these devices.

MXene‑Graphene Composites:A Perspective on Biomedical Potentials

MXenes,transition metal carbides and nitrides with graphene-like structures,have received considerable attention since their first discovery.On the other hand,Graphene has been extensively used in biomedical and medicinal applications.MXene and graphene,both as promising candidates of two-dimensional materials,have shown to possess high potential in future biomedical applications due to their unique physicochemical properties such as superior electrical conductivity,high biocompatibility,large surface area,optical and magnetic features,and extraordinary thermal and mechanical properties.These special structural,functional,and biological characteristics suggest that the hybrid/composite structure of MXene and graphene would be able to meet many unmet needs in different fields;particularly in medicine and biomedical engineering,where high-performance mechanical,electrical,thermal,magnetic,and optical requirements are necessary.However,the hybridization and surface functionalization should be further explored to obtain biocompatible composites/platforms with unique physicochemical properties,high stability,and multifunctionality.In addition,toxicological and long-term biosafety assessments and clinical translation evaluations should be given high priority in research.Although very limited studies have revealed the excellent potentials of MXene/graphene in biomedicine,the next steps should be toward the extensive research and detailed analysis in optimizing the properties and improving their functionality with a clinical and industrial outlook.Herein,different synthesis/fabrication methods and performances of MXene/graphene composites are discussed for potential biomedical applications.The potential toxicological effects of these composites on human cells and tissues are also covered,and future perspectives toward more successful translational applications are presented.The current state-of-the-art biotechnological advances in the use of MXene-Graphene composites,as well as their developmental challenges and future prospects are also deliberated.Due to the superior properties and multifunctionality of MXene-graphene composites,these hybrid structures can open up considerable new horizons in future of healthcare and medicine.

Computer Oriented Numerical Scheme for Solving Engineering Problems

In this study,we construct a family of single root finding method of optimal order four and then generalize this family for estimating of all roots of non-linear equation simultaneously.Convergence analysis proves that the local order of convergence is four in case of single root finding iterative method and six for simultaneous determination of all roots of non-linear equation.Some non-linear equations are taken from physics,chemistry and engineering to present the performance and efficiency of the newly constructed method.Some real world applications are taken from fluid mechanics,i.e.,fluid permeability in biogels and biomedical engineering which includes blood Rheology-Model which as an intermediate result give some nonlinear equations.These non-linear equations are then solved using newly developed simultaneous iterative schemes.Newly developed simultaneous iterative schemes reach to exact values on initial guessed values within given tolerance,using very less number of function evaluations in each step.Local convergence order of single root finding method is computed using CAS-Maple.Local computational order of convergence,CPU-time,absolute residuals errors are calculated to elaborate the efficiency,robustness and authentication of the iterative simultaneous method in its domain.

An Optimal Framework for Alzheimer’s Disease Diagnosis

Alzheimer’s disease(AD)is a kind of progressive dementia that is frequently accompanied by brain shrinkage.With the use of the morpho-logical characteristics of MRI brain scans,this paper proposed a method for diagnosing moderate cognitive impairment(MCI)and AD.The anatom-ical features of 818 subjects were calculated using the FreeSurfer software,and the data were taken from the ADNI dataset.These features were first removed from the dataset after being preprocessed with an age correction algorithm using linear regression to estimate the effects of normal aging.With these preprocessed characteristics,the extreme learning machine served as a classifier for the diagnosis of AD and MCI.For determining accuracy,sensitivity,specificity,and area under the curve,ten-fold cross validation was used.The accuracy of AD diagnosis was 87.62 percent on average after 100 runs,while the area under curve was 94.25 percent.The sensitivity of the MCI diagnosis was 83.88 percent,while the accuracy was 73.38 percent.The age correction can help diagnose MCI more accurately.The outcomes showed that the proposed strategy for diagnosing AD and MCI was more effective than existing methods.

An Optimized Technique for RNA Prediction Based on Neural Network

Pathway reconstruction, which remains a primary goal for many investigations, requires accurate inference of gene interactions and causality. Non-coding RNA (ncRNA) is studied because it has a significant regulatory role in manyplant and animal life activities, but interacting micro-RNA (miRNA) and longnon-coding RNA (lncRNA) are more important. Their interactions not only aidin the in-depth research of genes’ biological roles, but also bring new ideas forillness detection and therapy, as well as plant genetic breeding. Biological investigations and classical machine learning methods are now used to predict miRNAlncRNA interactions. Because biological identification is expensive and time-consuming, machine learning requires too much manual intervention, and the featureextraction process is difficult. This research presents a deep learning model thatcombines the advantages of convolutional neural networks (CNN) and bidirectional long short-term memory networks (Bi-LSTM). It not only takes intoaccount the connection of information between sequences and incorporates contextual data, but it also thoroughly extracts the sequence data’s features. On thecorn data set, cross-checking is used to evaluate the model’s performance, andit is compared to classical machine learning. To acquire a superior classificationeffect, the proposed strategy was compared to a single model. Additionally, thepotato and wheat data sets were utilized to evaluate the model, with accuracy ratesof 95% and 93%, respectively, indicating that the model had strong generalization capacity.

Fabrication of micro-nano patterned materials mimicking the topological structure of extracellular matrix for biomedical applications

With the advent of tissue engineering and biomedicine,the creation of extracellular matrix(ECM)biomaterials for in vitro applications has become a prominent and promising strategy.These ECM materials provide physical,biochemical,and mechanical properties that guide cellular behaviors,such as proliferation,differentiation,migration,and apoptosis.Because micro-and nano-patterned materials have a unique surface topology and low energy replication process that directly affect cellular biological behaviors at the interface,the fabrication of micro-nano pattern biomaterials and the regulation of surface physical and chemical properties are of great significance in the fields of cell regulation,tissue engineering,and regenerative medicine.Herein,we provide a comprehensive review of the progress in the fabrication and application of patterned materials based on the coupling of mechanical action at the micro-and nano-meter scale,including photolithography,micro-contact printing,electron beam lithography,electrospinning,and 3D printing technology.Furthermore,a summary of the fabrication process,underlying principles,as well as the advantages and disadvantages of various technologies are reviewed.We also discuss the influence of material properties on the fabrication of micro-and nano-patterns.

Control and Treatment of Bone Cancer: A Novel Theoretical Study

The human body has symmetric bones.This paper uses control engineering concepts to design a suitable controller to synchronize two symmetric bones of the human body to control and treat bone cancer.A Nonsingular Terminal Sliding Mode Control(NTSMC)method will be employed to design the proposed control inputs.The control inputs can be the chemical drugs that can be used to treat bone cancer.The dynamical equations of bone cancer will be used to apply the designed control method and test it.For testing the designed controller,Simulink/MATLAB software will be used.The proposed controller is chattering-free,robust against uncertainties and external disturbances,and finite-time stable in the control engineering view.Bone cancer will be treated for almost one year using the proposed control method.

Recent progress in the green synthesis of rare-earth doped upconversion nanophosphors for optical bioimaging from cells to animals

Rare-earth doped upconversion nanophosphors(UCNPs), which convert low energy near-infrared(NIR) photons into high energy photons such as ultraviolet, visible light and NIR light, have found various applications in optical bioimaging. In this review article, we summarize recent advances in the synthesis and applications of UCNPs achieved by us and other groups in the past few years. The approaches for the synthesis of UCNPs are presented,with an emphasis on the role of green chemistry in the advancement of this field, followed by a focused overview on their latest applications in optical bioimaging from subcellular structures through cells to living animals. Challenges and opportunities for the use of UCNPs in biomedical diagnosis and therapy are discussed.

Applications of nanogenerators for biomedical engineering and healthcare systems

The dream of human beings for long living has stimulated the rapid development of biomedical and healthcare equipment.However,conventional biomedical and healthcare devices have shortcomings such as short service life,large equipment size,and high potential safety hazards.Indeed,the power supply for conventional implantable device remains predominantly batteries.The emerging nanogenerators,which harvest micro/nanomechanical energy and thermal energy from human beings and convert into electrical energy,provide an ideal solution for self-powering of biomedical devices.The combination of nanogenerators and biomedicine has been accelerating the development of self-powered biomedical equipment.This article first introduces the operating principle of nanogenerators and then reviews the progress of nanogenerators in biomedical applications,including power supply,smart sensing,and effective treatment.Besides,the microbial disinfection and biodegradation performances of nanogenerators have been updated.Next,the protection devices have been discussed such as face mask with air filtering function together with real-time monitoring of human health from the respiration and heat emission.Besides,the nanogenerator devices have been categorized by the types of mechanical energy from human beings,such as the body movement,tissue and organ activities,energy from chemical reactions,and gravitational potential energy.Eventually,the challenges and future opportunities in the applications of nanogenerators are delivered in the conclusive remarks.

Exploring novel cell cryoprotectants based on neutral amino acids

Cryoprotectants play a key role in cell cryopreservation because they can reduce cryoinjuries to cells associated with ice formation.To meet the clinical requirements of cryopreserved cells,cryoprotectants should be biocompatible,highly efficient and easily removable from cryopreserved cells.However,integration of these properties into one cryoprotectant still remains challenging.Herein,three biocompatible neutral amino acids,includingβ-alanine,γ-aminobutyric acid andε-aminocaproic acid,are first reported to have the potential as such ideal cryoprotectants.The results demonstrate that they can inhibit ice formation and reduce osmotic stress to provide extracellular and intracellular protection,thereby ensuring high cryopreservation efficiency for both anuclear and nucleated cells.More importantly,due to the remarkable osmotic regulation ability,the neutral amino acids can be rapidly removed from cryopreserved cells via a one-step method without causing observable damage to cells,superior to the current state-of-the-art cryoprotectants—dimethyl sulfoxide and glycerol.This work provides a new perspective to develop novel cryoprotectants,which may have dramatic impacts on solvent-free cryopreservation technology to support the cell-based applications,such as cell therapy and tissue engineering,etc.

Plasma-activated interfaces for biomedical engineering

As an important phenomenon to monitor disease development,cell signaling usually takes place at the interface between organisms/cells or between organisms/cells and abiotic materials.Therefore,finding a strategy to build the specific biomedical interfaces will help regulate information transmission and produce better therapeutic results to benefit patients.In the past decades,plasmas containing energetic and active species have been employed to construct various interfaces to meet biomedical demands such as bacteria inactivation,tissue regeneration,cancer therapy,and so on.Based on the potent functions of plasma modified surfaces,this mini-review is aimed to summarize the state-of-art plasma-activated interfaces and provide guidance to researchers to select the proper plasma and processing conditions to design and prepare interfaces with the optimal biological and related functions.After a brief introduction,plasma-activated interfaces are described and categorized according to different criteria including direct plasma-cells interfaces and indirect plasma-material-cells interfaces and recent research activities on the application of plasma-activated interfaces are described.The authors hope that this mini-review will spur interdisciplinary research efforts in this important area and expedite associated clinical applications.

Preparation of CePO_4-coated zirconia ceramics and their mechanical behavior

Tetragonal ZrO2-3 mol% Y2O3 （3Y-TZP） coated with CePO4 was synthesized by a co-precipitation method and the effects of CePO4 content and sintering temperature on its mechanical properties were investigated. The microstructure and phase composition of the products were characterized using scanning and transmission electron microscopy as well as X-ray diffraction, respectively. The machinability index of CePO4-coated zirconia was calculated to be 1.05 when the CePO4 content is 25 wt.%. The sample hardness, bending strength and fracture toughness are 7.08 GPa, 457.85 MPa and 9.75 MPa m1/2, respectively, when the sintering temperature is 1400°C. The results show that as-prepared CePO4-coated 3Y-TZP ceramics are highly suitable biomaterials for dental applications and are expected to be used in a com-puter-aided design and computer-aided manufacturing （CAD/CAM） system to make dental crowns or bridge prostheses in a one-step sinter-ing process.

The facile method developed for preparing polyvinylidene fluoride plasma separation membrane via macromolecular interaction

The design of membrane pore is critical for membrane preparation. Polyvinylidene fluoride(PVDF) membrane exhibits outstanding properties in the water-treatment field. However, it is a huge challenge to prepare PVDF macro-pore plasma separation membrane by non-solvent induced phase separation(NIPS). Herein, a facile strategy is proposed to prepare PVDF macro-pore plasma separation membrane via macromolecular interaction. ATR-FTIR and ^(1)H NMR showed that the intermolecular interaction existed between polyethylene oxide(PEO) and polyvinylpyrrolidone(PVP). It could significantly affect the PVDF macro-pore membrane structure. The maximum pore of the PVDF membrane could be effectively adjusted from small-pore/medium-pore to macro-pore by changing the molecular weight of PEO. The PVDF macro-pore membrane was obtained successfully when PEO-200 k existed with PVP. It exhibited higher plasma separation properties than the currently used plasma separation membrane.Moreover, it had excellent hemocompatibility due to the similar plasma effect, hemolysis, prothrombin time, blood effect and complement C_(3a) effect with the current utilized plasma separation membrane,implying its great potential application. The proposed facile strategy in this work provides a new method to prepare PVDF macro-pore plasma separation membrane by NIPS.

Medical Image Registration Based on Phase Congruency and Regional Mutual Information

In this paper, a new approach of muhi-modality image registration is represented with not only image intensity, but also features describing image structure. There are two novelties in the proposed method. Firstly, instead of standard mutual information （ MI ） based on joint intensity histogram, regional mutual information （ RMI ） is employed, which allows neighborhood information to be taken into account. Secondly, a new feature images obtained by means of phase congruency are invariants to brightness or contrast changes. By incorporating these features and intensity into RMI, we can combine the aspects of both structural and neighborhood information together, which offers a more robust and a high level of registration accuracy.

Enhancing gene editing efficiency for cells by CRISPR/Cas9 system-loaded multilayered nanoparticles assembled via microfluidics

Most non-viral carriers for in vitro delivery of nucleic acids suffer from low efficiency of introducing m RNA and other nucleic acids,especially large m RNA.Cas9 protein is the nuclease part of the powerful gene-editing tool,CRISPR/Cas9 system,Cas9 m RNA is particularly large,thus presents a big challenge for delivery.We assembled a multilayered biodegradable nanocarrier to load Cas9 m RNA inside to protect Cas9 m RNA from degradation.We used a microfluidic chip to synthesize a small,positively charged,and degradable core to attract negatively charged Cas9 m RNA.The microfluidic assembly allows the core to be small enough to incorporate into a cationic liposome.The multilayered nanocarriers elevated the delivery efficiency of Cas9 m RNA by over 2 folds and increased the expression by over 5 folds compared to commercially used non-viral carriers.In addition,the multilayered nanocarriers do not require reduced serum medium for transfection.When using the standard complete medium for transfection,the multilayered nanocarriers could increase the expression of Cas9 m RNA by over 15 folds compared to commercially used non-viral carriers.The co-delivery of Cas9 m RNA and sg RNA via LRC elevated the gene-editing efficiency by 3 folds compared to that via commercially used non-viral carriers.Based on the higher transfection efficiency of Cas9 m RNA/sg RNA than commercially used non-viral carriers,these multilayered nanocarriers may have a good prospect as efficient commercial delivery carriers for Cas9 m RNA/sg RNA and other nucleic acids.