Machine learning-guided accelerated discovery of structure-property correlations in lean magnesium alloys for biomedical applications

Magnesium alloys are emerging as promising alternatives to traditional orthopedic implant materials thanks to their biodegradability,biocompatibility,and impressive mechanical characteristics.However,their rapid in-vivo degradation presents challenges,notably in upholding mechanical integrity over time.This study investigates the impact of high-temperature thermal processing on the mechanical and degradation attributes of a lean Mg-Zn-Ca-Mn alloy,ZX10.Utilizing rapid,cost-efficient characterization methods like X-ray diffraction and optical microscopy,we swiftly examine microstructural changes post-thermal treatment.Employing Pearson correlation coefficient analysis,we unveil the relationship between microstructural properties and critical targets(properties):hardness and corrosion resistance.Additionally,leveraging the least absolute shrinkage and selection operator(LASSO),we pinpoint the dominant microstructural factors among closely correlated variables.Our findings underscore the significant role of grain size refinement in strengthening and the predominance of the ternary Ca_(2)Mg_(6)Zn_(3)phase in corrosion behavior.This suggests that achieving an optimal blend of strength and corrosion resistance is attainable through fine grains and reduced concentration of ternary phases.This thorough investigation furnishes valuable insights into the intricate interplay of processing,structure,and properties in magnesium alloys,thereby advancing the development of superior biodegradable implant materials.

Development and Characterization of Calcium Based Biocomposites Using Waste Material (Calcite Stones) for Biomedical Applications

Calcium-based biocomposite materials have a pivotal role in the biomedical field with their diverse properties and applications in combating challenging medical problems. The study states the development and characterization of Calcium-based biocomposites: Hydroxyapatite (HAP), and PVA-Gelatin-HAP films. For the preparation of Calcium-based biocomposites, an unconventional source, the waste material calcite stone, was used as calcium raw material, and by the process of calcination, calcium oxide was synthesized. From calcium oxide, HAP was prepared by chemical precipitation method, which was later added in different proportions to PVA-Gelatin solution and finally dried to form biocomposite films. Then the different properties of PVA/Gelatin/HAP composite, for instance, chemical, mechanical, thermal, and swelling properties due to the incorporation of various proportions of HAP in PVA-Gelatin solution, were investigated. The characterization of the HAP was conducted by X-ray Diffraction Analysis, and the characterization of HAP-PVA-Gelatin composites was done by Fourier Transform Infrared Spectroscopy, Thermomechanical Analysis, Tensile test, Thermogravimetric Differential Thermal Analysis, and Swelling Test. The produced biocomposite films might have applications in orthopedic implants, drug delivery, bone tissue engineering, and wound healing.

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.

Local dose-dense chemotherapy for triple-negative breast cancer via minimally invasive implantation of 3D printed devices

Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer(TNBC),a highly aggressive disease with a poor prognosis.This treatment uses the same drug doses as conventional chemotherapy but with shorter dosing intervals,allowing for promising clinical outcomes with intensive treatment.However,the frequent systemic administration used for this treatment results in systemic toxicity and low patient compliance,limiting therapeutic efficacy and clinical benefit.Here,we report local dose-dense chemotherapy to treat TNBC by implanting 3D printed devices with timeprogrammed pulsatile release profiles.The implantable device can control the time between drug releases based on its internal microstructure design,which can be used to control dose density.The device is made of biodegradable materials for clinical convenience and designed for minimally invasive implantation via a trocar.Dose density variation of local chemotherapy using programmable release enhances anti-cancer effects in vitro and in vivo.Under the same dose density conditions,device-based chemotherapy shows a higher anticancer effect and less toxic response than intratumoral injection.We demonstrate local chemotherapy utilizing the implantable device that simulates the drug dose,number of releases,and treatment duration of the dose-dense AC(doxorubicin and cyclophosphamide)regimen preferred for TNBC treatment.Dose density modulation inhibits tumor growth,metastasis,and the expression of drug resistance-related proteins,including p-glycoprotein and breast cancer resistance protein.To the best of our knowledge,local dose-dense chemotherapy has not been reported,and our strategy can be expected to be utilized as a novel alternative to conventional therapies and improve anti-cancer efficiency.

Activation of endogenous neurogenesis and angiogenesis by basic fibroblast growth factor-chitosan gel in an adult rat model of ischemic stroke

Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.

The secondary injury cascade after spinal cord injury:an analysis of local cytokine/chemokine regulation

After spinal cord injury,there is an extensive infiltration of immune cells,which exacerbates the injury and leads to further neural degeneration.Therefore,a major aim of current research involves targeting the immune response as a treatment for spinal cord injury.Although much research has been performed analyzing the complex inflammatory process following spinal cord injury,there remain major discrepancies within previous literature regarding the timeline of local cytokine regulation.The objectives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord injury,identify sexual dimorphisms in terms of cytokine levels,and determine local cytokines that significantly change based on the severity of spinal cord injury.Rats were inflicted with either a mild contusion,moderate contusion,severe contusion,or complete transection,7 mm of spinal cord centered on the injury was harvested at varying times post-injury,and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex assay.Results demonstrated pro-inflammatory cytokines including tumor necrosis factorα,interleukin-1β,and interleukin-6 were all upregulated after spinal cord injury,but returned to uninjured levels within approximately 24 hours post-injury,while chemokines including monocyte chemoattractant protein-1 remained upregulated for days post-injury.In contrast,several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days post-injury.After spinal cord injury,tissue inhibitor of metalloproteinase-1,which specifically affects astrocytes involved in glial scar development,increased more than all other cytokines tested,reaching 26.9-fold higher than uninjured rats.After a mild injury,11 cytokines demonstrated sexual dimorphisms;however,after a severe contusion only leptin levels were different between female and male rats.In conclusion,pro-inflammatory cytokines initiate the inflammatory process and return to baseline within hours post-injury,chemokines continue to recruit immune cells for days post-injury,while anti-inflammatory cytokines are downregulated by a week post-injury,and sexual dimorphisms observed after mild injury subsided with more severe injuries.Results from this work define critical chemokines that influence immune cell infiltration and important cytokines involved in glial scar development after spinal cord injury,which are essential for researchers developing treatments targeting secondary damage after spinal cord injury.

Soft,body conformable electronics for thermoregulation enabled by kirigami

The application of thermoelectric devices(TEDs)for personalized thermoregulation is attractive for saving energy while balancing the quality of life.TEDs that directly attach to human skin remarkably minimized the energy wasted for cooling the entire environment.However,facing the extreme dynamic geometry change and strain of human skin,conventional TEDs cannot align with the contour of our bodies for the best thermoregulation effect.Hence,we designed a kirigami-based wearable TED with excellent water vapor permeability,flexibility,and conformability.Numerical analysis and experimental results reveal that our product can withstand various types of large mechanical deformation without circuit rupture.The stated outcome and proposed facile approach not only reinforce the development of wearable TEDs but also offer an innovative opportunity for different electronics that require high conformability.

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).

Prognostic value of ultrasound in early arterial complications post liver transplant

Liver transplantation is the primary therapeutic intervention for end-stage liver disease.However,vascular complications,particularly those involving the hepatic artery,pose significant risks to patients.The clinical manifestations associated with early arterial complications following liver transplantation are often non-specific.Without timely intervention,these complications can result in graft fai-lure or patient mortality.Therefore,early diagnosis and the formulation of an op-timal treatment plan are imperative.Ultrasound examination remains the pre-dominant imaging modality for detecting complications post liver transplan-tation.This article comprehensively reviews common causes and clinical present-ations of early hepatic artery complications in the post-transplantation period and delineates abnormal sonographic findings for accurate diagnosis of these con-ditions.Overall,ultrasound offers the advantages of convenience,safety,effect-iveness,and non-invasiveness.It enables real-time,dynamic,and precise evalua-tion,making it the preferred diagnostic method for post-liver transplantation assessments.INTRODUCTION Liver transplantation stands as the primary therapeutic approach for end-stage liver disease.Continuous advancements in surgical techniques and the application of novel immunosuppressive agents contribute to ongoing improvements in the success rate and overall survival in patients undergoing liver transplantation procedures.Despite these advan-cements,vascular complications,particularly those involving the hepatic artery,pose significant risks to patients.During the early stages following liver transplantation(within the first 30 d),proper hepatic artery function is crucial for hepatic arterial blood flow.During later stages,collateral circulation,including arteries such as the phrenic artery,right gastric artery,and gastroduodenal artery,becomes important for maintaining hepatic blood supply.It is now understood that the establishment of effective collateral circulation is pivotal for determining the prognosis of hepatic artery complic-ations.The clinical manifestations of these complications are closely linked to factors such as timing,severity,and the specific type of onset.Insufficient hepatic arterial blood flow can lead to abnormal liver function,hepatic infarction,and the formation of hepatic abscesses.Additionally,since the hepatic artery is the sole blood supply to the biliary tract,hepatic artery-related ischemia may result in biliary stricture,obstruction,and the formation of bile ducts.Ultrasound examination remains the primary imaging modality for diagnosing complications post liver transplantation.This article comprehensively reviews common causes and clinical presentations of early hepatic artery complications in the post-transplantation period and outlines abnormal sonographic findings for accurately diagnosing these conditions.NORMAL HEPATIC ARTERY During the intraoperative phase,an ultrasound examination is typically conducted to evaluate the hepatic artery anas-tomosis.The normal internal diameter of the hepatic artery typically ranges from 2 to 5 mm.Two strong echo points are typically identified near the anastomosis.To assess blood flow dynamics,peak systolic velocity,end-diastolic velocity,and resistance index are measured at the donor and recipient sides of the anastomosis following angle correction.Anastomotic stenosis presence and severity can be evaluated by comparing the velocity at the anastomotic site with that at the recipient side.Postoperatively,direct visualization of the anastomosis site through gray ultrasound scans is often challenging.The surgical approach has a significant impact on the proper hepatic artery’s position,resulting in a lower overall success rate of continuous visualization.Color Doppler ultrasound is primarily employed to trace the artery’s path,and spectral measurements are taken at the brightest position of the Color Doppler blood flow signal,primarily used to identify the presence of high-speed turbulence.Hepatic artery spectrum examination plays a crucial role,as a favorable arterial spectral waveform and appropriate hepatic artery flow velocity typically indicate a successful anastomosis,even in cases where the hepatic artery anastomosis cannot be directly visualized by ultrasound.The hepatic artery runs alongside the portal vein,often selected as a reference due to its larger inner diameter.A normal hepatic artery spectrum displays a regular pulsation pattern with a rapid rise in systole and a slow decline in diastole.Parameters for assessing hepatic artery resistance include a resistance index between 0.5 to 0.8 and an artery systolic acceleration of less than 80 ms.Instantaneous increases in the resistance index(RI>0.8)often occur within 2 d after surgery,followed by a subsequent return to normal hepatic arterial parameters.It has been established that the maximum blood flow velocity during systole in the hepatic artery should not exceed 200 cm/s[1].

Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion?Findings from the NCAA and Department of Defense CARE Consortium

Background:Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion.Therefore,more accurate diagnostic markers are needed for sport-related concussion.Methods:This was a multicenter,prospective,case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association-Department of Defense Concussion Assessment,Research,and Education Consortium conducted between 2015 and 2019.The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints.Athletes with concussion were divided into 6 h post-injury(0-6 h post-injury)and after 6 h postinjury(7-48 h post-injury)groups.We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305proteins in plasma samples from athletes with and without sport-related concussion.Results:A total of 140 athletes with concussion(79.3%males;aged 18.71±1.10 years,mean±SD)and 21 non-concussed athletes(76.2%males;19.14±1.10 years)were included in this study.We identified 338 plasma proteins that significantly differed in abundance(319 upregulated and 19 downregulated)in concussed athletes compared to non-concussed athletes.The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve(AUC)of 0.954(95%confidence interval:0.922-0.986).Specifically,after 6 h of injury,the individual AUC of plasma erythrocyte membrane protein band 4.1(EPB41)and alpha-synuclein(SNCA)were 0.956 and 0.875,respectively.The combination of EPB41 and SNCA provided the best AUC(1.000),which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury.Conclusion:Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.

The fabrication of hydroxyapatite mineralized hydrogels for bone tissue engineering

Bone is a complex but orderly mineralized tissue with hydroxyapatite(HA)as the inorganic phase and collagen as the organic phase.Inspired by natural bone tissues,HA-mineralized hydrogels have been widely designed and used in bone tissue engineering.HA is majorly utilized for the treatment of bone defects because of its excellent osteoconduction and bone inductivity.Hydrogel is a three-dimensional hydrophilic network structure with similar properties to the extracellular matrix(ECM).The combination of HA and hydrogels produces a new hybrid material that could effectively promote osteointegration and accelerate the healing of bone defects.In this review,the structure and growth of bone and the common strategies used to prepare HA were briefly introduced.Importantly,we discussed the fabrication of HA mineralized hydrogels from simple blending to in situ mineralization.We hope this review can provide a reference for the development of bone repair hydrogels.

In vivo measurement of NADH fluorescence lifetime in skeletal muscle via -ber-coupled time-correlated single photon counting

Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXPHOS).NADH is autofluorescent,and itsfluorescence lifetime can be used to infer metabolic dynamics in living cells.Fiber-coupled time-correlated single photon counting(TCSPC)equipped with an implantable needle probe can be used to measure NADH lifetime in vivo,enabling investigation of changing metabolic demand during muscle contraction or tissue regeneration.This study illustrates a proof of concept for point-based,minimally-invasive NADHfluorescence lifetime measurement in vivo.Volumetric muscle loss(VML)injuries were created in the left tibialis anterior(TA)muscle of male Sprague Dawley rats.NADH lifetime measurements were collected before,during,and after a 30 s tetanic contraction in the injured and uninjured TA muscles,which was subsequently-t to a biexponential decay model to yield a metric of NADH utilization(cytoplasmic vs protein-bound NADH,the A11/A22 ratio).On average,this ratio was higher during and after contraction in uninjured muscle compared to muscle at rest,suggesting higher levels of free NADH in contracting and recovering muscle,indicating increased rates of glycolysis.In injured muscle,this ratio was higher than uninjured muscle overall but decreased over time,which is consistent with current knowledge of inflammatory response to injury,suggesting tissue regeneration has occurred.These data suggest that-ber-coupled TCSPC has the potential to measure changes in NADH binding in vivo in a minimally invasive manner that requires further investigation.

Automated body composition analysis system based on chest CT for evaluating content of muscle and adipose

Objective To establish a body composition analysis system based on chest CT,and to observe its value for evaluating content of chest muscle and adipose.Methods T7—T8 layer CT images of 108 pneumonia patients were collected(segmented dataset),and chest CT data of 984 patients were screened from the COVID 19-CT dataset(10 cases were randomly selected as whole test dataset,the remaining 974 cases were selected as layer selection dataset).T7—T8 layer was classified based on convolutional neural network(CNN)derived networks,including ResNet,ResNeXt,MobileNet,ShuffleNet,DenseNet,EfficientNet and ConvNeXt,then the accuracy,precision,recall and specificity were used to evaluate the performance of layer selection dataset.The skeletal muscle(SM),subcutaneous adipose tissue(SAT),intermuscular adipose tissue(IMAT)and visceral adipose tissue(VAT)were segmented using classical fully CNN(FCN)derived network,including FCN,SegNet,UNet,Attention UNet,UNET++,nnUNet,UNeXt and CMUNeXt,then Dice similarity coefficient(DSC),intersection over union(IoU)and 95 Hausdorff distance(HD)were used to evaluate the performance of segmented dataset.The automatic body composition analysis system was constructed based on optimal layer selection network and segmentation network,the mean absolute error(MAE),root mean squared error(RMSE)and standard deviation(SD)of MAE were used to evaluate the performance of automatic system for testing the whole test dataset.Results The accuracy,precision,recall and specificity of DenseNet network for automatically classifying T7—T8 layer from chest CT images was 95.06%,84.83%,92.27%and 95.78%,respectively,which were all higher than those of the other layer selection networks.In segmentation of SM,SAT,IMAT and overall,DSC and IoU of UNet++network were all higher,while 95HD of UNet++network were all lower than those of the other segmentation networks.Using DenseNet as the layer selection network and UNet++as the segmentation network,MAE of the automatic body composition analysis system for predicting SM,SAT,IMAT,VAT and MAE was 27.09,6.95,6.65 and 3.35 cm 2,respectively.Conclusion The body composition analysis system based on chest CT could be used to assess content of chest muscle and adipose.Among them,the UNet++network had better segmentation performance in adipose tissue than SM.

Enhanced axonal regeneration and functional recovery of the injured sciatic nerve in a rat model by lithium-loaded electrospun nanofibrous scaffolds

Increasing evidence indicates that engineered nerve grafts have great potential for the regeneration of peripheral nerve injuries(PNIs).While most studies have focused only on the topographical features of the grafts,we have considered both the biophysical and biochemical manipulations in our applied nanoscaffold.To achieve this,we fabricated an electrospun nanofibrous scaffold(ENS)containing polylactide nanofibers loaded with lithium(Li)ions,a Wnt/β-catenin signaling activator.In addition,we seeded human adipose-derived mesenchymal stem cells(hADMSCs)onto this engineered scaffold to examine if their differentiation toward Schwann-like cells was induced.We further examined the efficacy of the scaffolds for nerve regeneration in vivo via grafting in a PNI rat model.Our results showed that Li-loaded ENSs gradually released Li within 11 d,at concentrations ranging from 0.02 to(3.64±0.10)mmol/L,and upregulated the expression of Wnt/β-catenin target genes(cyclinD1 and c-Myc)as well as those of Schwann cell markers(growth-associated protein 43(GAP43),S100 calcium binding protein B(S100B),glial fibrillary acidic protein(GFAP),and SRY-box transcription factor 10(SOX10))in differentiated hADMSCs.In the PNI rat model,implantation of Li-loaded ENSs with/without cells improved behavioral features such as sensory and motor functions as well as the electrophysiological characteristics of the injured nerve.This improved function was further validated by histological analysis of sciatic nerves grafted with Li-loaded ENSs,which showed no fibrous connective tissue but enhanced organized myelinated axons.The potential of Li-loaded ENSs in promoting Schwann cell differentiation of hADMSCs and axonal regeneration of injured sciatic nerves suggests their potential for application in peripheral nerve tissue engineering.

Multilevel analysis of the central-peripheral-target organ pathway:contributing to recovery after peripheral nerve injury

Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.

Experimental realization of fractal fretwork metasurface for sound anomalous modulation

Natural creatures and ancient cultures are full of potential sources to provide inspiration for applied sciences.Inspired by the fractal geometry in nature and the fretwork frame in ancient culture,here we design the acoustic metasurface to realize sound anomalous modulation,which manifests itself as an incident-dependent propagation behavior:sound wave propagating in the forward direction is allowed to transmit with high efficiency while in the backward direction is obviously suppressed.We quantitatively investigate the dependences of asymmetric transmission on the propagation direction,incident angle and operating frequency by calculating sound transmittance and energy contrast.This compact fractal fretwork metasurface for acoustic anomalous modulation would promote the development of integrated acoustic devices and expand versatile applications in acoustic communication and information encryption.

Perspectives for delivery of therapeutics by extravasation of biodegradable microspheres in the brain

Development of therapeutics for brain diseases has remained challenging,in particular due to the difficulty of passing the blood-brain barrier.As a result,the current arsenal of therapeutics targeting the brain is limited to small,lipid-soluble drugs and there is a lack of options for treating neuroblastomas,Alzheimer’s disease,and many other devastating pathologies.Despite the advances in strategies for crossing the blood-brain barrier such as the use of nanoparticles(Hersh et al.,2022;Duan et al.,2023),such delivery systems have not yet reached clinical practice.Therefore,novel platforms for the transport of therapeutics across the blood-brain barrier remain highly desired.This specifically holds for large molecules such as monoclonal antibodies and recombinant proteins,as well as nucleotide-based therapeutics and cell therapies.Research efforts in this field are increasing exponentially,with thousands of publications in the last few years.

Brain regulates weight bearing bone through PGE2 skeletal interoception: implication of ankle osteoarthritis and pain

Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment.However,it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain.In this study,we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2(PGE2)concentration in response to mechanical loading.Bone PGE2 levels are in proportion to their weight bearing.When weight bearing changes in the tail-suspension mice,the PGE2 concentrations in bones change in line with their weight bearing changes.Deletion of cyclooxygenase-2(COX2)in the osteoblast lineage cells or knockout of receptor 4(EP4)in sensory nerve blunts bone formation in response to mechanical loading.Moreover,knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation.Moreover,mechanical loading induces cAMP-response element binding protein(CREB)phosphorylation in the hypothalamic arcuate nucleus(ARC)to inhibit sympathetic tyrosine hydroxylase(TH)expression in the paraventricular nucleus(PVN)for osteogenesis.Finally,we show that elevated PGE2 is associated with ankle osteoarthritis(AOA)and pain.Together,our data demonstrate that in response to mechanical loading,skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis,while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.

Spatiotemporal variations of sand hydraulic conductivity by microbial application methods

The spatiotemporal distributions of microbes in soil by different methods could affect the efficacy of the microbes to reduce the soil hydraulic conductivity.In this study,the specimens of bio-mediated sands were prepared using three different methods,i.e.injecting,mixing,and pouring a given microbial so-lution onto compacted sand specimens.The hydraulic conductivity was measured by constant-head tests,while any soil microstructural changes due to addition of the microbes were observed by scan-ning electron microscope(SEM)and mercury intrusion porosimetry(MIP)tests.The amount of dextran concentration produced by microbes in each type of specimen was quantified by a refractometer.Results show that dextran production increased exponentially after 5-7 d of microbial settling with the supply of culture medium.The injection and mixing methods resulted in a similar amount and uniform dis-tribution of dextran in the specimens.The pouring method,however,produced a nonuniform distri-bution,with a higher concentration near the specimen surface.As the supply of culture medium discontinued,the dextran content near the surface produced by the pouring method decreased dramatically due to high competition for nutrients with foreign colonies.Average dextran concentration was negatively and correlated with hydraulic conductivity of bio-mediated soils exponentially,due to the clogging of large soil pores by dextran.The hydraulic conductivity of the injection and mixing cases did not change significantly when the supply of culture medium was absent.

Microfluidic thermotaxic selection of highlymotile sperm and in vitro fertilization

The selection of the most motile and functionally competent sperm is an essential basis for in vitro fertilization(IVF)and normal embryonic development.Widely adopted clinical approaches for sperm sample processing intensely rely on centrifugation and wash steps that may induce mechanical damage and oxidative stress to sperm.Although a few microfluidic sperm sorting devices may avoid these adverse effects by exploiting intrinsic guidance mechanisms of sperm swimming,none of these approaches have been fully validated by clinical-grade assessment criteria.In this study,a microfluidic sperm sorting device that enables the selection of highly motile and functional sperm via their intrinsic thermotaxis is presented.Bioinspired by the temperature microenvironment in the fallopian tube during natural sperm selection,a microfluidic device with controllable temperature gradients along the sperm separation channel was designed and fabricated.This study investigated the optimal temperature conditions for human sperm selection and fully characterized thermotaxis-selected sperm with 45 human sperm samples.Results indicated that a temperature range of 35–36.5℃along the separation channel significantly improves human sperm motility rate((85.25±6.28)%vs.(60.72±1.37)%;P=0.0484),increases normal sperm morphology rate((16.42±1.43)%vs.(12.55±0.88)%;P<0.0001),and reduces DNA fragmentation((7.44±0.79)%vs.(10.36±0.72)%;P=0.0485)compared to the nonthermotaxis group.Sperm thermotaxis is species-specific,and selected mouse sperm displayed the highest motility in response to a temperature range of 36–37.5℃ along the separation channel.Furthermore,IVF experiments indicated that the selected sperm permitted an increased fertilization rate and improved embryonic development from zygote to blastocyst.This microfluidic thermotaxic selection approach will be translated into clinical practice to improve the IVF success rate for patients with oligozoospermia and asthenozoospermia.