BME 2.0: Engineering the Future of Medicine

If the 20th century was the age of mapping and controlling the external world,the 21st century is the biomedical age of mapping and controlling the biological internal world.The biomedical age is bringing new technological breakthroughs for sensing and controlling human biomolecules,cells,tissues,and organs,which underpin new frontiers in the biomedical discovery,data,biomanufacturing,and translational sciences.This article reviews what we believe will be the next wave of biomedical engineering(BME)education in support of the biomedical age,what we have termed BME 2.0.BME 2.0 was announced on October 122017 at BMES 49(https://www.bme.jhu.edu/news-events/news/miller-opens-2017-bmes-annual-meeting-with-vision-for-new-bme-era/).We present several principles upon which we believe the BME 2.0 curriculum should be constructed,and from these principles,we describe what view as the foundations that form the next generations of curricula in support of the BME enterprise.The core principles of BME 2.0 education are(a)educate students bilingually,from day 1,in the languages of modern molecular biology and the analytical modeling of complex biological systems;(b)prepare every student to be a biomedical data scientist;(c)build a unique BME community for discovery and innovation via a vertically integrated and convergent learning environment spanning the university and hospital systems;(d)champion an educational culture of inclusive excellence;and(e)codify in the curriculum ongoing discoveries at the frontiers of the discipline,thus ensuring BME 2.0 as a launchpad for training the future leaders of the biotechnology marketplaces.We envision that the BME 2.0 education is the path for providing every student with the training to lead in this new era of engineering the future of medicine in the 21st century.

Genetic variation of circHIBADH enhances prostate cancer risk through regulating HNRNPA1-related RNA splicing

The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer(PCa)as well as to elucidate biological mechanisms underlying the associations.We first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify riskassociated circRNAs by using the MiOncoCirc database.We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls,and identified circHIBADH rs11973492 T>C as a significant risk-associated variant(odds ratio=1.20,95%confidence interval:1.08-1.34,P=7.06×10^(-4))in a dominant genetic model,which altered the secondary structure of the corresponding RNA chain.In the in silico analysis,we found that circHIBADH sponged and silenced 21 RNA-binding proteins(RBPs)enriched in the RNA splicing pathway,among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house(four tissue samples)and publicly available single-cell transcriptomes.Additionally,we demonstrated that HNRNPA1 influenced hallmarks including MYC target,DNA repair,and E2F target signaling pathways,thereby promoting carcinogenesis.In conclusion,genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1,playing an oncogenic role in PCa.

Identification of cell surface markers for acute myeloid leukemia prognosis based on multi-model analysis

Given the extremely high inter-patient heterogeneity of acute myeloid leukemia(AML),the identification of biomarkers for prognostic assessment and therapeutic guidance is critical.Cell surface markers(CSMs)have been shown to play an important role in AML leukemogenesis and progression.In the current study,we evaluated the prognostic potential of all human CSMs in 130 AML patients from The Cancer Genome Atlas(TCGA)based on differential gene expression analysis and univariable Cox proportional hazards regression analysis.By using multi-model analysis,including Adaptive LASSO regression,LASSO regression,and Elastic Net,we constructed a 9-CSMs prognostic model for risk stratification of the AML patients.The predictive value of the 9-CSMs risk score was further validated at the transcriptome and proteome levels.Multivariable Cox regression analysis showed that the risk score was an independent prognostic factor for the AML patients.The AML patients with high 9-CSMs risk scores had a shorter overall and event-free survival time than those with low scores.Notably,single-cell RNA-sequencing analysis indicated that patients with high 9-CSMs risk scores exhibited chemotherapy resistance.Furthermore,PI3K inhibitors were identified as potential treatments for these high-risk patients.In conclusion,we constructed a 9-CSMs prognostic model that served as an independent prognostic factor for the survival of AML patients and held the potential for guiding drug therapy.

Erratum to “BME 2.0: Engineering the Future of Medicine”

In the article“BME 2.0:Engineering the Future of Medicine”[1],the competing interests statement was inadvertently omitted by the publisher from the published version of the article.This has now been corrected in the PDF and HTML(full text).

Characterization of cerebrovascular changes in Alzheimer's disease mice by photoacoustic imaging

The cerebral vasculature plays a significant role in the development of Alzheimer's disease(AD),however,the specific association between them remains unclear.In this paper,based on the benefits of photoacoustic imaging(PAI),including label-free,high-resolution,in vivo imaging of vessels,we investigated the structural changes of cerebral vascular in wild-type(WT)mice and AD mice at different ages,analyzed the characteristics of the vascular in different brain regions,and correlated vascular characteristics with cognitive behaviors.The results showed that vascular density and vascular branching index in the cortical and frontal regions of both WT and AD mice decreased with age.Meanwhile,vascular lacunarity increased with age,and the changes in vascular structure were more pronounced in AD mice.The trend of vascular dysfunction aligns with the worsening cognitive dysfunction as the disease progresses.Here,we utilized in vivo PAI to analyze the changes in vascular structure during the progression of AD,elucidating the spatial and temporal correlation with cognitive impairment,which will provide more intuitive data for the study of the correlation between cerebrovascular and the development of AD.

Microarrow sensor array with enhanced skin adhesion for transdermal continuous monitoring of glucose and reactive oxygen species

Conventional blood sampling for glucose detection is prone to cause pain and fails to continuously record glucose fluctuations in vivo.Continuous glucose monitoring based on implantable electrodes could induce pain and potential tissue inflammation,and the presence of reactive oxygen species(ROS)due to inflammationmay affect glucose detection.Microneedle technology is less invasive,yet microneedle adhesion with skin tissue is limited.In this work,we developed a microarrow sensor array(MASA),which provided enhanced skin surface adhesion and enabled simultaneous detection of glucose and H_(2)O_(2)(representative of ROS)in interstitial fluid in vivo.The microarrows fabricated via laser micromachining were modified with functional coating and integrated into a patch of a three-dimensional(3D)microneedle array.Due to the arrow tip mechanically interlocking with the tissue,the microarrow array could better adhere to the skin surface after penetration into skin.The MASA was demonstrated to provide continuous in vivo monitoring of glucose and H_(2)O_(2) concentrations,with the detection of H_(2)O_(2) providing a valuable reference for assessing the inflammation state.Finally,the MASA was integrated into a monitoring system using custom circuitry.This work provides a promising tool for the stable and reliable monitoring of blood glucose in diabetic patients.

Self-supervised learning artificial intelligence noise reduction technology based on the nearest adjacent layer in ultra-low dose CT of urinary calculi

Objective To observe the value of self-supervised deep learning artificial intelligence(AI)noise reduction technology based on the nearest adjacent layer applicated in ultra-low dose CT(ULDCT)for urinary calculi.Methods Eighty-eight urinary calculi patients were prospectively enrolled.Low dose CT(LDCT)and ULDCT scanning were performed,and the effective dose(ED)of each scanning protocol were calculated.The patients were then randomly divided into training set(n=75)and test set(n=13),and a self-supervised deep learning AI noise reduction system based on the nearest adjacent layer constructed with ULDCT images in training set was used for reducing noise of ULDCT images in test set.In test set,the quality of ULDCT images before and after AI noise reduction were compared with LDCT images,i.e.Blind/Referenceless Image Spatial Quality Evaluator(BRISQUE)scores,image noise(SD ROI)and signal-to-noise ratio(SNR).Results The tube current,the volume CT dose index and the dose length product of abdominal ULDCT scanning protocol were all lower compared with those of LDCT scanning protocol(all P<0.05),with a decrease of ED for approximately 82.66%.For 13 patients with urinary calculi in test set,BRISQUE score showed that the quality level of ULDCT images before AI noise reduction reached 54.42%level but raised to 95.76%level of LDCT images after AI noise reduction.Both ULDCT images after AI noise reduction and LDCT images had lower SD ROI and higher SNR than ULDCT images before AI noise reduction(all adjusted P<0.05),whereas no significant difference was found between the former two(both adjusted P>0.05).Conclusion Self-supervised learning AI noise reduction technology based on the nearest adjacent layer could effectively reduce noise and improve image quality of urinary calculi ULDCT images,being conducive for clinical application of ULDCT.

The Application of Permanent Magnet Synchronous Motor with Small Electrical Time Constant in Fiber Positioner

With the development of cutting-edge multi-object spectrographs,fiber positioners located in the focal plane are being scaled down in size,and miniature hollow-cup Permanent Magnet motors are now being considered as a suitable replacement for Faulhaber Precistep stepper motors.However,the small electrical time constant of such coreless motors poses a challenge,as the problem of severe commutation torque ripple in a fiber positioner running a position loop has been tricky.To overcome this challenge,it is advised to increase the Pulse Width Modulation(PWM)frequency as much as possible to mitigate the effects of the current fluctuation.This must be done while ensuring adequate resolution of the PWM generator.By employing a voltage open-loop field-oriented control based on a modulation frequency of 1 MHz,the drive current only costs 25 m A under a 3.3 V power supply.The sine degree of phase current is immaculate,and the repeat positioning accuracy can reach 2μm.Moreover,it is possible to further shrink the bill of devices and the layout area of the Printed Circuit Board,especially in sizesensitive applications.This device has been developed under the new generation of The Large Sky Area MultiObject Fiber Spectroscopic Telescope.

Two Monte Carlo-based simulators for imaging-system modeling and projection simulation of flat-panel X-ray source

The advantages of a flat-panel X-ray source(FPXS)make it a promising candidate for imaging applications.Accurate imaging-system modeling and projection simulation are critical for analyzing imaging performance and resolving overlapping projection issues in FPXS.The conventional analytical ray-tracing approach is limited by the number of patterns and is not applicable to FPXS-projection calculations.However,the computation time of Monte Carlo(MC)simulation is independent of the size of the patterned arrays in FPXS.This study proposes two high-efficiency MC projection simulators for FPXS:a graphics processing unit(GPU)-based phase-space sampling MC(gPSMC)simulator and GPU-based fluence sampling MC(gFSMC)simulator.The two simulators comprise three components:imaging-system modeling,photon initialization,and physical-interaction simulations in the phantom.Imaging-system modeling was performed by modeling the FPXS,imaging geometry,and detector.The gPSMC simulator samples the initial photons from the phase space,whereas the gFSMC simulator performs photon initialization from the calculated energy spectrum and fluence map.The entire process of photon interaction with the geometry and arrival at the detector was simulated in parallel using multiple GPU kernels,and projections based on the two simulators were calculated.The accuracies of the two simulators were evaluated by comparing them with the conventional analytical ray-tracing approach and acquired projections,and the efficiencies were evaluated by comparing the computation time.The results of simulated and realistic experiments illustrate the accuracy and efficiency of the proposed gPSMC and gFSMC simulators in the projection calculation of various phantoms.

Core–Shell Microfiber Encapsulation Enables Glycerol‑Free Cryopreservation of RBCs with High Hematocrit

Cryopreservation of red blood cells(RBCs)provides great potential benefits for providing transfusion timely in emergencies.High concentrations of glycerol(20%or 40%)are used for RBC cryopreservation in current clinical practice,which results in cytotoxicity and osmotic injuries that must be carefully controlled.However,existing studies on the low-glycerol cryopreservation of RBCs still suffer from the bottleneck of low hematocrit levels,which require relatively large storage space and an extra concentration process before transfusion,making it inconvenient(time-consuming,and also may cause injury and sample lose)for clinical applications.To this end,we develop a novel method for the glycerol-free cryopreservation of human RBCs with a high final hematocrit by using trehalose as the sole cryoprotectant to dehydrate RBCs and using core–shell alginate hydrogel microfibers to enhance heat transfer during cryopreservation.Different from previous studies,we achieve the cryopreservation of human RBCs at high hematocrit(>40%)with high recovery(up to 95%).Additionally,the washed RBCs post-cryopreserved are proved to maintain their morphology,mechanics,and functional properties.This may provide a nontoxic,high-efficiency,and glycerol-free approach for RBC cryopreservation,along with potential clinical transfusion benefits.

Three-dimensional morphological and fluorescent imaging of zebrafish with a continuous-rotational light-sheet microscope

Light-sheet fluorescence microscopy(LSFM)has been widely used to image the three-dimensional(3D)structures and functions of various millimeter-size bio-specimen such as zebrafish.However,the sample adsorption and scattering cause shading of the light-sheet illumination,preventing the even 3D image of thick samples.Herein,we report a continuous-rotational light-sheet microscope(CR-LSM)that enables simultaneous 3D bright-field and fluorescence imaging.With a high-accuracy rotational stage,CR-LSM records the outline projections and the fluorescent images of the sample at multiple rotation angles.Then,3D morphology and fluorescent structure were reconstructed with a developed algorithm.Using CR-LSM,zebrafish’s whole-fish contour and blood vessel structures were obtained simultaneously.

Semi-implantable device based on multiplexed microfilament electrode cluster for continuous monitoring of physiological ions

Modern medicine is increasingly interested in advanced sensors to detect and analyze biochemical indicators.Ion sensors based on potentiometric methods are a promising platform for monitoring physiological ions in biological subjects.Current semi-implantable devices are mainly based on single-parameter detection.Miniaturized semi-implantable electrodes for multiparameter sensing have more restrictions on the electrode size due to biocompatibility considerations,but reducing the electrode surface area could potentially limit electrode sensitivity.This study developed a semi-implantable device system comprising a multiplexed microfilament electrode cluster(MMEC)and a printed circuit board for real-time monitoring of intra-tissue K^(+),Ca^(2+),and Na^(+)concentrations.The electrode surface area was less important for the potentiometric sensing mechanism,suggesting the feasibility of using a tiny fiber-like electrode for potentiometric sensing.The MMEC device exhibited a broad linear response(K^(+):2–32 mmol/L;Ca^(2+):0.5–4 mmol/L;Na^(+):10–160 mmol/L),high sensitivity(about 20–45 mV/decade),temporal stability(>2weeks),and good selectivity(>80%)for the above ions.In vitro detection and in vivo subcutaneous and brain experiment results showed that the MMEC system exhibits good multi-ion monitoring performance in several complex environments.This work provides a platform for the continuous real-time monitoring of ion fluctuations in different situations and has implications for developing smart sensors to monitor human health.

Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Human lineage mutations regulate RNA-protein binding of conserved genes NTRK2 and ITPR1 involved in human evolution

Background The role of human lineage mutations(HLMs)in human evolution through post-transcriptional modification is unclear.Aims To investigate the contribution of HLMs to human evolution through post-transcriptional modification.Methods We applied a deep learning model Seqweaver to predict how HLMs impact RNA-binding protein affinity.Results We found that only 0.27%of HLMs had significant impacts on RNA-binding proteins at the threshold of the top 1%of human common variations.These HLMs enriched in a set of conserved genes highly expressed in adult excitatory neurons and prenatal Purkinje neurons,and were involved in synapse organisation and the GTPase pathway.These genes also carried excess damaging coding mutations that caused neurodevelopmental disorders,ataxia and schizophrenia.Among these genes,NTRK2 and ITPR1 had the most aggregated evidence of functional importance,suggesting their essential roles in cognition and bipedalism.Conclusions Our findings suggest that a small subset of human-specific mutations have contributed to human speciation through impacts on post-transcriptional modification of critical brain-related genes.

Controlling the dynamic behavior of decentralized cluster through centralized approaches

How to control the dynamic behavior of large-scale artificial active matter is a critical concern in experimental research on soft matter, particularly regarding the emergence of collective behaviors and the formation of group patterns. Centralized systems excel in precise control over individual behavior within a group, ensuring high accuracy and controllability in task execution. Nevertheless, their sensitivity to group size may limit their adaptability to diverse tasks. In contrast, decentralized systems empower individuals with autonomous decision-making, enhancing adaptability and system robustness. Yet, this flexibility comes at the cost of reduced accuracy and efficiency in task execution. In this work, we present a unique method for regulating the centralized dynamic behavior of self-organizing clusters based on environmental interactions. Within this environment-coupled robot system, each robot possesses similar dynamic characteristics, and their internal programs are entirely identical. However, their behaviors can be guided by the centralized control of the environment, facilitating the accomplishment of diverse cluster tasks. This approach aims to balance the accuracy and flexibility of centralized control with the robustness and task adaptability of decentralized control. The proactive regulation of dynamic behavioral characteristics in active matter groups, demonstrated in this work through environmental interactions, holds the potential to introduce a novel technological approach and provide experimental references for studying the dynamic behavior control of large-scale artificial active matter systems.

Diagnostic performance of intravascular ultrasound-based fractional flow reserve in evaluating of intermediate left main stenosis

BACKGROUND The recently introduced ultrasonic flow ratio(UFR),is a novel fast computational method to derive fractional flow reserve(FFR)from intravascular ultrasound(IVUS)images.In the present study,we evaluate the diagnostic performance of UFR in patients with intermediate left main(LM)stenosis.METHODS This is a prospective,single center study enrolling consecutive patients with presence of intermediated LM lesions(diameter stenosis of 30%-80%by visual estimation)underwent IVUS and FFR measurement.An independent core laboratory assessed offline UFR and IVUS-derived minimal lumen area(MLA)in a blinded fashion.RESULTS Both UFR and FFR were successfully achieved in 41 LM patients(mean age,62.0±9.9 years,46.3%diabetes).An acceptable correlation between UFR and FFR was identified(r=0.688,P<0.0001),with an absolute numerical difference of 0.03(standard difference:0.01).The area under the curve(AUC)in diagnosis of physiologically significant coronary stenosis for UFR was 0.94(95%CI:0.87-1.01),which was significantly higher than angiographic identified stenosis>50%(AUC=0.66,P<0.001)and numerically higher than IVUS-derived MLA(AUC=0.82;P=0.09).Patient level diagnostic accuracy,sensitivity and specificity for UFR to identify FFR≤0.80 was 82.9%(95%CI:70.2-95.7),93.1%(95%CI:82.2-100.0),58.3%(95%CI:26.3-90.4),respectively.CONCLUSION In patients with intermediate LM diseases,UFR was proved to be associated with acceptable correlation and high accuracy with pressure wire-based FFR as standard reference.The present study supports the use of UFR for functional evaluation of intermediate LM stenosis.

Regulation of specific abnormal calcium signals in the hippocampal CA1 and primary cortex M1 alleviates the progression of temporal lobe epilepsy

Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and is not fully understood.Intracellular calcium dynamics have been implicated in temporal lobe epilepsy.However,the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown,and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice.In this study,we used a multichannel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process.We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes.In particular,cortical spreading depression,which has recently been frequently used to represent the continuously and substantially increased calcium signals,was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from gradeⅡto gradeⅤ.However,vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures.Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to gradeⅠepisodes.In addition,the latency of cortical spreading depression was prolonged,and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced.Intriguingly,it was possible to rescue the altered intracellular calcium dynamics.Via simultaneous analysis of calcium signals and epileptic behaviors,we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced,and that the end-point behaviors of temporal lobe epilepsy were improved.Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades.Furthermore,the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy,thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.

Storage time affects the level and diagnostic efficacy of plasma biomarkers for neurodegenerative diseases

Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is known about the long-term stability of these biomarker proteins in plasma samples stored at-80°C.We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort.Plasma samples from 229 cognitively unimpaired individuals,encompassing healthy controls and those experiencing subjective cognitive decline,as well as 99 patients with cognitive impairment,comprising those with mild cognitive impairment and dementia,were acquired from the Sino Longitudinal Study on Cognitive Decline project.These samples were stored at-80°C for up to 6 years before being used in this study.Our results showed that plasma levels of Aβ42,Aβ40,neurofilament light chain,and glial fibrillary acidic protein were not significantly correlated with sample storage time.However,the level of total tau showed a negative correlation with sample storage time.Notably,in individuals without cognitive impairment,plasma levels of total protein and tau phosphorylated protein threonine 181(p-tau181)also showed a negative correlation with sample storage time.This was not observed in individuals with cognitive impairment.Consequently,we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time.Therefore,caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases,such as Alzheimer's disease.Furthermore,in cohort studies,it is important to consider the impact of storage time on the overall results.

Nanomaterial-assisted wearable glucose biosensors for noninvasive real-time monitoring:Pioneering point-of-care and beyond

This review explores glucose monitoring and management strategies,emphasizing the need for reliable and userfriendly wearable sensors that are the next generation of sensors for continuous glucose detection.In addition,examines key strategies for designing glucose sensors that are multi-functional,reliable,and cost-effective in a variety of contexts.The unique features of effective diabetes management technology are highlighted,with a focus on using nano/biosensor devices that can quickly and accurately detect glucose levels in the blood,improving patient treatment and control of potential diabetes-related infections.The potential of next-generation wearable and touch-sensitive nano biomedical sensor engineering designs for providing full control in assessing implantable,continuous glucose monitoring is also explored.The challenges of standardizing drug or insulin delivery doses,low-cost,real-time detection of increased blood sugar levels in diabetics,and early digital health awareness controls for the adverse effects of injectable medication are identified as unmet needs.Also,the market for biosensors is expected to expand significantly due to the rising need for portable diagnostic equipment and an ever-increasing diabetic population.The paper concludes by emphasizing the need for further research and development of glucose biosensors to meet the stringent requirements for sensitivity and specificity imposed by clinical diagnostics while being cost-effective,stable,and durable.

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.