Intervertebral disc degeneration(IVDD)is a leading cause of chronic lower back pain,affecting a significant portion of the global population.Traditional treatments,including drug administration and surgery,focus prima...Intervertebral disc degeneration(IVDD)is a leading cause of chronic lower back pain,affecting a significant portion of the global population.Traditional treatments,including drug administration and surgery,focus primarily on symptom relief but fail to address the underlying pathological mechanisms of IVDD,Extracellular matrix(ECM)degradation is closely related to the senescence of nucleus pulposus cells(NPCs)caused by highly levels of inflammation,overproduction of reactive oxygen species(ROS),DNA damage,low levels of autophagy,and the acidic microenvironment in the disc.This review explores the pathogenesis of IVDD mediated by NPC senescence,summarizes recent advances in biological therapy,and highlights the latest developments in antisenescent biomaterials.These biomaterials have the potential to delay disc degeneration by clearing senescent cells,inhibiting oxidative stress and inflammation,activating autophagy,and modulating the acidic microenvironment of the disc.A deeper understanding of the molecular mechanisms underlying IVDD,coupled with the design of more effective antisenescent biomaterials,offers promising avenues for optimizing therapeutic outcomes and improving patients'quality of life.展开更多
Blood vessels are essential for nutrient and oxygen delivery and waste removal.Scaffold-repairing materials with functional vascular networks are widely used in bone tissue engineering.Additive manufacturing is a manu...Blood vessels are essential for nutrient and oxygen delivery and waste removal.Scaffold-repairing materials with functional vascular networks are widely used in bone tissue engineering.Additive manufacturing is a manufacturing technology that creates three-dimensional solids by stacking substances layer by layer,mainly including but not limited to 3D printing,but also 4D printing,5D printing and 6D printing.It can be effectively combined with vascularization to meet the needs of vascularized tissue scaffolds by precisely tuning the mechanical structure and biological properties of smart vascular scaffolds.Herein,the development of neovascularization to vascularization to bone tissue engineering is systematically discussed in terms of the importance of vascularization to the tissue.Additionally,the research progress and future prospects of vascularized 3D printed scaffold materials are highlighted and presented in four categories:functional vascularized 3D printed scaffolds,cell-based vascularized 3D printed scaffolds,vascularized 3D printed scaffolds loaded with specific carriers and bionic vascularized 3D printed scaffolds.Finally,a brief review of vascularized additive manufacturing-tissue scaffolds in related tissues such as the vascular tissue engineering,cardiovascular system,skeletal muscle,soft tissue and a discussion of the challenges and development efforts leading to significant advances in intelligent vascularized tissue regeneration is presented.展开更多
Over the past few decades,biomaterials have made rapid advances in tissue engineering.In particular,there have been several studies on vascularization during skin flap regeneration for plastic surgery.From the perspec...Over the past few decades,biomaterials have made rapid advances in tissue engineering.In particular,there have been several studies on vascularization during skin flap regeneration for plastic surgery.From the perspective of function,the biomaterials used to improve the vascularization of skin flaps are primarily classified into two types:(1)electrospun nanofibrous membranes as porous scaffolds,and(2)hydrogels as cell or cytokine carriers.Based on their source,various natural,synthetic,and semi-synthetic biomaterials have been developed with respective characteristics.For the ischemic environment of the flap tissue,the therapeutic effect of the combination of biomaterials was better than that of drugs,cytokines,and cells alone.Biomaterials could improve cell migration,prolong the efficacy of cytokines,and provide an advantageous survival environment to transplanted cells.展开更多
The immune response after implantation is a primary determinant of the tissue-repair effects of threedimensional(3D)-printed scaffolds.Thus,scaffolds that can subtly regulate immune responses may display extraordinary...The immune response after implantation is a primary determinant of the tissue-repair effects of threedimensional(3D)-printed scaffolds.Thus,scaffolds that can subtly regulate immune responses may display extraordinary functions.Inspired by the angiogenesis promotion effect of humoral immune response,we covalently combined mesoporous silica micro rod(MSR)/polyethyleneimine(PEI)/ovalbumin(OVA)self-assembled vaccines with 3D-printed calcium phosphate cement(CPC)scaffolds for local antigen-specific immune response activation.With the response activated,antigen-specific CD4+T helper2(Th2)cells can be recruited to promote early angiogenesis.The silicon(Si)ions from MSRs can accelerate osteogenesis,with an adequate blood supply being provided.At room temperature,scaffolds with uniformly interconnected macropores were printed using a self-setting CPC-based printing paste,which promoted the uniform dispersion and structural preservation of functional polysaccharides oxidized hyaluronic acid(OHA)inside.Sustained release of OVA was achieved with MSR/PEI covalently attached to scaffolds rich in aldehyde groups as the vaccine carrier.The vaccine-loaded scaffolds effectively recruited and activated dendritic cells(DCs)for antigen presentation and promoted the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)in vitro.When embedded subcutaneously in vivo,the vaccine-loaded scaffolds increased the proportion of Th2 cells in the spleen and locally recruited antigenspecific T cells to promote angiogenesis in and around the scaffold.Furthermore,the result in a rat skull defect-repair model indicated that the antigen-specific vaccine-loaded scaffolds promoted the regeneration of vascularized bone.This method may provide a novel concept for patient-specific implant design for angiogenesis promotion.展开更多
The crosstalk between immune cells and the neurovascular unit plays a pivotal role in neural regeneration following central nervous system(CNS)injury.Maintaining brain immune homeostasis is crucial for restoring neuro...The crosstalk between immune cells and the neurovascular unit plays a pivotal role in neural regeneration following central nervous system(CNS)injury.Maintaining brain immune homeostasis is crucial for restoring neurovascular function.In this study,an interactive bridge was developed via an immunomodulatory hydrogel microsphere to link the interaction network between microglia and the neurovascular unit,thereby precisely regulating immune-neurovascular crosstalk and achieving neural function recovery.This immunomodulatory crosstalk microsphere(MP/RIL4)was composed of microglia-targeted RAP12 peptide-modified interleukin-4(IL-4)nanoparticles and boronic ester-functionalized hydrogel using biotin-avidin reaction and air-microfluidic techniques.We confirmed that the immunomodulatory microspheres reduced the expression of pro-inflammatory factors including IL-1β,iNOS,and CD86,while upregulating levels of anti-inflammatory factors such as IL-10,Arg-1,and CD206 in microglia.In addition,injection of the MP/RIL4 significantly mitigated brain atrophy volume in a mouse model of ischemic stroke,promoted neurobehavioral recovery,and enhanced the crosstalk between immune cells and the neurovascular unit,thus increasing angiogenesis and neurogenesis of stroke mice.In summary,the immunomodulatory microspheres,capable of orchestrating the interaction between immune cells and neurovascular unit,hold considerable therapeutic potential for ischemic stroke and other CNS diseases.展开更多
Excessive uptake of purine and glucose can lead to hyperglycemia and hyperuricemia,mediated by specific intestinal transport proteins.Currently,there is a deficiency in targeted regulation of these proteins.In this st...Excessive uptake of purine and glucose can lead to hyperglycemia and hyperuricemia,mediated by specific intestinal transport proteins.Currently,there is a deficiency in targeted regulation of these proteins.In this study,we introduce an oral approach for targeted modulation using electrospun core–shell short-fibers that settle on the intestinal mucosa.These fibers,designed for the controlled in situ release of phlorizin—a multi-transporter inhibitor—are crafted through a refined electrospinning-homogenizing process using polylactic acid and gelatin.Phlorizin is conjugated via a phenyl borate ester bond.Furthermore,a calcium alginate shell ensures intestinal disintegration triggered by pH changes.These fibers adhere to the mucosa due to their unique structure,and phlorizin is released in situ post-ingestion through glucose-sensitive cleavage of the phenyl borate ester bond,enabling dual-target inhibition of intestinal transporter proteins.Both in vitro and in vivo studies confirm that the short-fibers possess intestine-settling and glucose-responsive properties,facilitating precise control over transport proteins.Using models of hyperuricemia and diabetes in mice,treatment with short-fibers results in reduc-tions of 49.6%in blood uric acid and 17.8%in glucose levels,respectively.Additionally,16S rRNA sequencing indicates an improved intestinal flora composition.In conclusion,we have developed an innovative oral strategy for the prevention of hyperglycemia and hyperuricemia.展开更多
Bioelectrical stimulation is a powerful technique used to promote tissue regeneration,but it can be hindered by an“electrical overload”phenomenon in the core region of stimulation.We develop a threaded microneedle e...Bioelectrical stimulation is a powerful technique used to promote tissue regeneration,but it can be hindered by an“electrical overload”phenomenon in the core region of stimulation.We develop a threaded microneedle electrode system that protects against“electrical overload”by delivering medicinal hydrogel microspheres into the core regions.The threaded needle body is coated with polydopamine and chitosan to enhance the adhesion of microspheres,which are loaded into the threaded grooves,allowing for their stereoscopic release in the core regions.After the electrode is inserted,the microspheres can be delivered three-dimensionally through physical swelling and the shear-thinning effect of chitosan,mitigating the electrical damage.Microspheres are designed to release alkylated vitamin B12 and vitamin E,providing antioxidant and cell protection effects upon in-situ activation,reducing reactive oxygen species(ROS)by 72.8%and cell death by 59.5%.In the model of peripheral nerve injury,the electrode system improves the overall antioxidant capacity by 78.5%and protects the surrounding cells.Additionally,it leads to an improved nerve conduction velocity ratio of 41.9%and sciatic nerve function index of 12.1%,indicating enhanced neuroregeneration.The threaded microneedle electrode system offers a promising approach for nerve repair by inhibiting“electrical overload”,potentially improving outcomes for tissue regeneration.展开更多
Correction:Advanced Fiber Materials,https://doi.org/10.1007/s42765-025-00513-0.The authors regret for the following corrections in the manuscript.The correction information is presented as following description.1.In t...Correction:Advanced Fiber Materials,https://doi.org/10.1007/s42765-025-00513-0.The authors regret for the following corrections in the manuscript.The correction information is presented as following description.1.In the published article(Fig.3c-m),the figures were corrected as the following Figure.2.In the Results and Discussion 2.2,the text was replaced with the following.展开更多
In the intricate labyrinth of modern medical advancements,the quest for non-invasive and precise diagnostic tools is a journey of continual discovery and innovation.One of the most compelling frontiers in this realm i...In the intricate labyrinth of modern medical advancements,the quest for non-invasive and precise diagnostic tools is a journey of continual discovery and innovation.One of the most compelling frontiers in this realm is the monitoring of cerebral blood flow,a critical parameter that holds the key to understanding a myriad of neurological conditions[1,2].Traditional Transcranial Doppler(TCD)sonography,despite its widespread application,has been hindered by a number of limitations[3].展开更多
Mussels are animals that survive along the coast and are exposed to external risks such as shockwaves,bird hunting,and mating struggles.Therefore,many shellfish species either stick to each other or to rocks to protec...Mussels are animals that survive along the coast and are exposed to external risks such as shockwaves,bird hunting,and mating struggles.Therefore,many shellfish species either stick to each other or to rocks to protect themselves.Their adhesive ability is maintained in humid and underwater environments,which indicates that the mussel adhesive proteins have potential applications in medical adhesives[1-3].To date,most studies have focused on the super-strong underwater adhesion mechanism of mussels.However,when exposed to unfavorable or harsh environments,they quickly discard their filaments,fall off rocks,regain mobility,and escape to new habitats.Their filaments regrow within a few hours and help them to reattach to new rocks.展开更多
Lubrication is an important prerequisite and foundation for the organism to protect biological tissues from mechanical friction damage and to maintain their normal life functions[1,2].After mechanical friction trauma,...Lubrication is an important prerequisite and foundation for the organism to protect biological tissues from mechanical friction damage and to maintain their normal life functions[1,2].After mechanical friction trauma,the lubrication matrix repairs damaged tissue by protecting the host from external impact and promotes the restoration of lubrication balance in the body.The process of lubrication typically unfolds in a series of events,beginning with a rapid response phase where lubricating fluids flow within the organism,reducing wear between tissues.This is followed by a gradual transition into a lubrication phase involving various lubrication mechanisms,such as fluid lubrication(The load is fully sustained by lubricant due to viscous forces in the space or gap between the components that are moving in relation to another object,while preventing solid-to-solid contact),boundary lubrication(The load is carried by surface high points rather than by lubricant),hydration lubrication(Hydration layers are tightly bound by the surrounding charges,allowing them to withstand significant pressure without being displaced,while also being able to quickly relax,resulting in a fluid-like response to shear forces),and mixed lubrication(This regime exists between full film lubrication and boundary lubrication,where the lubricant film generated is inadequate to fully separate the surfaces in contact,yet the hydrodynamic effect is significant)[3-5].Thus,lubrication plays a vital role in protecting living beings.However,if this well-coordinated wear reduction process is disrupted,lubrication can become uncontrolled or deteriorate,potentially leading to a range of lubrication-related diseases,including osteoarthritis,tendon adhesion,intervertebral disc degeneration,femoral head necrosis,cardiovascular blockages,tooth wear,and implant infections[1].展开更多
Hyperglycemia and bacterial colonization in diabetic wounds aberrantly activate Nod-like receptor protein 3(NLRP3)in macrophages,resulting in extensive inflammatory infiltration and impaired wound healing.Targeted sup...Hyperglycemia and bacterial colonization in diabetic wounds aberrantly activate Nod-like receptor protein 3(NLRP3)in macrophages,resulting in extensive inflammatory infiltration and impaired wound healing.Targeted suppression of the NLRP3 inflammasome shows promise in reducing macrophage inflammatory disruptions.However,challenges such as drug off-target effects and degradation via lysosomal capture remain during treatment.In this study,engineered apoptotic bodies(BHB-dABs)derived from adipose stem cells loaded with β-hydroxybutyric acid(BHB)were synthesized via biosynthesis.These vesicles target M1-type macrophages,which highly express the folic acid receptor in the inflammatory microenvironment,and facilitate lysosomal escape through 1,2-distearoyl-sn-propyltriyl-3-phosphatidylethanolaminepolyethylene glycol functionalization,which may enhance the efficacy of NLRP3 inhibition for managing diabetic wounds.Invitro studies demonstrated the biocompatibility of BHB-dABs,their selective targeting of M1-type macrophages,and their ability to release BHB within the inflammatory microenvironment via folic acid and folic acid receptor signaling.These nanovesicles exhibited lysosomal escape,antiinflammatory,mitochondrial protection,and endothelial cell vascularization properties.Invivo experiments demonstrated that BHB-dABs enhance the recovery of diabetic wound inflammation and angiogenesis,accelerating wound healing.These functionalized apoptotic bodies efficiently deliver NLRP3 inflammasome inhibitors using a dual strategy of targeting macrophages and promoting lysosomal escape.This approach represents a novel therapeutic strategy for effectively treating chronic diabetic wounds.展开更多
Given the high malignancy of liver cancer and the liver's unique role in immune and metabolic regulation,current treatments have limited efficacy,resulting in a poor prognosis.Hydrogels,soft 3-dimensional network ...Given the high malignancy of liver cancer and the liver's unique role in immune and metabolic regulation,current treatments have limited efficacy,resulting in a poor prognosis.Hydrogels,soft 3-dimensional network materials comprising numerous hydrophilic monomers,have considerable potential as intelligent drug delivery systems for liver cancer treatment.The advantages of hydrogels include their versatile delivery modalities,precision targeting,intelligent stimulus response,controlled drug release,high drug loading capacity,excellent slow-release capabilities,and substantial potential as carriers of bioactive molecules.This review presents an in-depth examination of hydrogel-assisted advanced therapies for hepatocellular carcinoma,encompassing small-molecule drug therapy,immunotherapy,gene therapy,and the utilization of other biologics.Furthermore,it examines the integration of hydrogels with conventional liver cancer therapies,including radiation,interventional therapy,and ultrasound.This review provides a comprehensive overview of the numerous advantages of hydrogels and their potential to enhance therapeutic efficacy,targeting,and drug delivery safety.In conclusion,this review addresses the clinical implementation of hydrogels in liver cancer therapy and future challenges and design principles for hydrogel-based systems,and proposes novel research directions and strategies.展开更多
Precise regulation of intraosseous angiogenesis is essential for effectively repairing osteoporotic bone defects.However,the dual imbalance of redox homeostasis and the osteogenesis-angiogenesis coupling within the os...Precise regulation of intraosseous angiogenesis is essential for effectively repairing osteoporotic bone defects.However,the dual imbalance of redox homeostasis and the osteogenesis-angiogenesis coupling within the osteoporotic microenvironment poses significant challenges for bone regeneration.Here,we developed a poly-dopamine(PDA)-modified injectable short-fiber 3D scaffold(PSF@P-SLP)via short fibers homogenization to remodel the osteoporotic microenvironment and enhance bone healing.The scaffold surface was modified with PDA,which induced the in situ aggregation of short fibers into a porous 3D network,promoting directional cell migration and nutrient exchange.Moreover,parathyroid hormone[PTH(1-34)]loaded ROS-responsive thio-ether-phospholipid liposomes(P-SLP)were conjugated to the PDA coating through catechol groups,enabling sustained PTH release and efficient ROS scavenging via thioether oxidation.In vitro,PSF@P-SLP significantly reduced ROS levels,promoted osteogenic differentiation of mesenchymal stem cells,and enhanced the prolif-eration and migration of endothelial cells.In vivo,the scaffold facilitated both type H vessels formation and osteogenesis,accelerating the repair of osteoporotic bone defects.Collectively,this study presents a novel therapeutic strategy utilizing PTH(1-34)-loaded injectable short-fiber 3D scaffolds that modulate oxidative stress and restore osteogenesis-angiogenesis coupling within the osteoporotic niche,demonstrating strong translational potential for bone tissue engineering.展开更多
The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis.The restoration of mitochondrial homeostasis,serving as a pivotal rheostat for ba...The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis.The restoration of mitochondrial homeostasis,serving as a pivotal rheostat for balancing glucose metabolism in immune cells,can effectively mitigate inflammation and initiate osteogenesis.Herein,an ion-activated mitochondrial rheostat fiber-microsphere polymerization system(FM@CeZnHA)was innovatively constructed.Physical-chemical and molecular biological methods confirmed that CeZnHA,char-acterized by a rapid degradation rate,releases Ce/Zn ions that restore mitochondrial metabolic homeostasis and M1/M2 balance of macrophages through swift redox reactions.This process reduces the glycolysis level of macrophages by down-regulating the NF-κB p65 signaling pathway,enhances their mitochondrial metabolic dependence,alleviates excessive early inflammatory responses,and promptly initiates osteogenesis.The FM network provided a stable platform for macrophage glycolytic transformation and simulated extracellular matrix microenvironment,continuously restoring mitochondrial homeostasis and accelerating ossification center for-mation through the release of metal ions from the internal CeZnHA for efficient bone immune cascade reactions.This strategy of bone immunity mediated by the restoration of macrophage mitochondrial metabolic function and glucose metabolic flux homeostasis opens up a new approach to treating bone defects.展开更多
Repair and regeneration of damaged neurons is a promising therapeutic strategy for central nervous system(CNS)diseases such as ischemic stroke(IS).However,achieving efficient neuronal repair and regeneration after CNS...Repair and regeneration of damaged neurons is a promising therapeutic strategy for central nervous system(CNS)diseases such as ischemic stroke(IS).However,achieving efficient neuronal repair and regeneration after CNS injury through noninvasive methods remains a significant challenge.Therefore,this study proposes,for the first time,an ultrasonic nasal drop formulation that induces efficient regeneration of damaged neurons through electropharmacological coupling in an noninvasive manner.Liposomes containing the natural anti-inflammatory drug Timosaponin B-Ⅱ(TB)were coated onto barium titanate nanoparticles(BTO)to form LTO@TB.Using microfluidic technology and a Schiff base reaction,LTO@TB was encapsulated into aldehyde-based and methacrylate-modified microspheres(MS)to create the ultrasonic nasal drop MS@LTO@TB.The aldehyde groups of MS@LTO@TB spontaneously formed amide bonds with the numerous amino groups in the nasal mucosa,facilitating specific adhesion.Due to its enhanced bioadhesion and efficient transmembrane transport,LTO@TB was continuously and noninvasively delivered to the brain when administered nasally.Additionally,under ultrasonic stimulation,LTO@TB in the brain exerted an electropharmacological coupling effect,achieving noninvasive electrical stimulation of damaged neurons.MS@LTO@TB modulated microglial phenotypes,restored electrical signal conduction among damaged neurons,reshaped the inflammatory microenvironment,reduced neuronal apoptosis,activated the PI3K/AKT signaling pathway,and promoted axonal regeneration.MS@LTO@TB also showed the unique ability to alleviate inflammation and promote neuronal remodeling in a mouse model of middle cerebral artery occlusion/reperfusion(MCAO/R).This study presents a promising strategy involving the nasal administration of ultrasonic nasal drops as a noninvasive and efficient treatment for CNS injuries.展开更多
Abnormal mitochondrial division in microglia significantly impacts central nervous system(CNS)diseases.However,treating CNS diseases through microglial mitochondria presents several challenges:intracerebral de-livery ...Abnormal mitochondrial division in microglia significantly impacts central nervous system(CNS)diseases.However,treating CNS diseases through microglial mitochondria presents several challenges:intracerebral de-livery of drugs,microglial targeting,and mitochondrial regulation.Herein,a novel three-stage sequential tar-geted nasal drops delivery system that achieves precise drug delivery to the core of brain lesions through noninvasive nasal delivery,targeting microglia,and regulating mitochondria were developed.Firstly,dehy-droepiandrosterone(DHEA),identified from clinical data and transcriptomic analyses as a key neurosteroid regulating mitochondrial fission,was selected.Secondly,surface-positively charged hydrogel microspheres were prepared to adhere to the nasal mucosa,thereby avoiding rapid clearance and achieving the first stage of nasal mucosa targeting.Subsequently,targeted liposomes carrying cytotoxic T lymphocyte-associated protein-4 were constructed and modified into microspheres,which released liposomes through the nasal cavity to enter the brain and bound to the activated microglial surface receptors CD80/86 accomplishing the second stage of cell targeting.In the third stage,the system released DHEA in response to the microenvironment,precisely regulating dynamin-related protein 1 involved in mitochondrial membrane remodeling,which inhibited abnormal mito-chondrial division,stabilized mitochondrial morphology and function,inhibited microglial activation.This study demonstrated that three-stage sequential nasal drops efficiently traversed the nose-to-brain pathway via nasal mucosa in both murine(n=200)and porcine(n=16)models,while significantly ameliorating anesthesia/surgery-induced cognitive dysfunction in mice.Therefore,the three-stage sequential nasal drip is a promising method for the treatment of central nervous system diseases.展开更多
A traumatic tissue adhesive technology is highly sought after in ophthalmic surgery;however,many polymeric adhesives face significant limitations in clinical ophthalmology, particularly incorneal transplantation. A ma...A traumatic tissue adhesive technology is highly sought after in ophthalmic surgery;however,many polymeric adhesives face significant limitations in clinical ophthalmology, particularly incorneal transplantation. A major challenge is achieving rapid adhesion without introducingpolymer barriers or chemical toxicity from cross-linking. To address this, we developed a novelcornea-specific nanoadhesive constructed through protein-DNA co-assembly and applied it tocorneal transplantation. In this system, a rigid tetrahedral DNA framework was employed toguide the spatial distribution of polycationic recombinant proteins (K72) and serve as the coreof the nanoadhesive, facilitating energy conversion during tissue connection. The adhesivedemonstrated a strength of 2.3 kPa between corneal lenticules. After modification with RGDpeptides, the adhesive system significantly enhanced corneal epithelialization, reducedinflammation and neovascularization, and ultimately promoted corneal repair. This studyrepresents the first application of a nanoadhesive in ophthalmic surgery, providing a novelsolution for developing ophthalmic-specific adhesives for clinical use.展开更多
The growth plate is crucial for skeletal growth in children,but research on repairing growth plate damage and restoring growth is limited.Here,a high-toughness adaptive dualcrosslinked hydrogel is designed to mimic th...The growth plate is crucial for skeletal growth in children,but research on repairing growth plate damage and restoring growth is limited.Here,a high-toughness adaptive dualcrosslinked hydrogel is designed to mimic the growth plate's structure,supporting regeneration and bone growth.Composed of aldehyde-modified bacterial cellulose(DBNC),methacrylated gelatin(GelMA)and sodium alginate(Alg),the hydrogel is engineered through ionic bonding and Schiff base reactions,creating a macroporous structure.This structure can transform into a denser form by binding with calcium ions.In vitro,the loose macroporous structure of the hydrogels can promote chondrogenic differentiation,and when it forms a dense structure by binding with calcium ions,it also can activate relevant chondrogenic signaling pathways under the influence of insulin-like growth factor I(IGF-1),further inhibiting osteogenesis.In vivo experiments in a rat model of growth plate injury demonstrated that the hydrogel promoted growth plate cartilage regeneration and minimized bone bridge formation by creating a hypoxic microenvironment that activates IGF-1-related pathways.This environment encourages chondrogenic differentiation while preventing the undesired formation of bone tissue within the growth plate area.Overall,the dual-crosslinked hydrogel not only mimics the growth plate's structure but also facilitates localized IGF-1 expression,effectively reshaping the growth plate's function.This approach represents a promising therapeutic strategy for treating growth plate injuries,potentially addressing challenges associated with skeletal growth restoration in pediatric patients.展开更多
Neural cell senescence hinders spinal cord nerve function recovery,and existing therapies that target senescent cell clearance haven’t effectively addressed cellular senescence.In this study,injectable short fibers t...Neural cell senescence hinders spinal cord nerve function recovery,and existing therapies that target senescent cell clearance haven’t effectively addressed cellular senescence.In this study,injectable short fibers that accurately maintain genome homeostasis in real time were developed,which for the first time reversed neural cell senescence by blocking the excessive intervention of cell inspection points.First,the oxidization-sensitive hybrid liposomes were prepared by combining Bakuchiol(BAK),a natural plant extract with the ability of DNA protection,with the oxidization-sensitive phospholipid S-PC.Subsequently,the short fibers regulating the cell inspection points(ISN@n-BAK)were constructed by further complexing the oxidation-sensitive hybrid liposomes with short fibers throughπ–πconjugation and catechol groups mussel-stimulated polydopamine(PDA).In vitro experiments demonstrated that ISN@n-BAK promotes neural stem cell differentiation into neurons and has anti-aging effects across various aging stages.In vivo,ISN@n-BAK responded to excessive ROS by triggering oxidation-sensitive liposomes to release BAK,protecting against DNA damage,suppressing aging-related gene expression in Cdkn2a and Cdkn2c and inhibiting inspection point restrictions.Bioinformatics showed that ISN@n-BAK reversed neural cell senescence and aided spinal cord nerve regeneration by activating the endogenous cell cycle,downregulating the PI3K-Akt pathway and upregulating the Rap1 pathway.This study introduces a novel therapeutic approach using short fibers that inhibit inspection points intervention to rejuvenate injured spinal cords.展开更多
基金supported by the National Natural Science Foundation of China(81902306 and 82174406)the Shanghai Municipal Health Commission Traditional Chinese Medicine Research Project(2024QN012)+1 种基金the Shanghai Science and Technology Committee(22Y11923200 and 22ZR1453000)the Shanghai University of Traditional Chinese Medicine Science and Technology Development Project(23KFL023)。
文摘Intervertebral disc degeneration(IVDD)is a leading cause of chronic lower back pain,affecting a significant portion of the global population.Traditional treatments,including drug administration and surgery,focus primarily on symptom relief but fail to address the underlying pathological mechanisms of IVDD,Extracellular matrix(ECM)degradation is closely related to the senescence of nucleus pulposus cells(NPCs)caused by highly levels of inflammation,overproduction of reactive oxygen species(ROS),DNA damage,low levels of autophagy,and the acidic microenvironment in the disc.This review explores the pathogenesis of IVDD mediated by NPC senescence,summarizes recent advances in biological therapy,and highlights the latest developments in antisenescent biomaterials.These biomaterials have the potential to delay disc degeneration by clearing senescent cells,inhibiting oxidative stress and inflammation,activating autophagy,and modulating the acidic microenvironment of the disc.A deeper understanding of the molecular mechanisms underlying IVDD,coupled with the design of more effective antisenescent biomaterials,offers promising avenues for optimizing therapeutic outcomes and improving patients'quality of life.
基金supported by grants from the National Key Research and Development Program of China (2020YFA0908200)Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20171906)+2 种基金Shanghai Municipal Health and Family Planning Commission (2022XD055)Natural Science Foundation of Shandong Province (Shandong) (ZR2020QH121)GuangCi Professorship Program of Ruijin Hospital Shanghai Jiao Tong University School of Medicine
文摘Blood vessels are essential for nutrient and oxygen delivery and waste removal.Scaffold-repairing materials with functional vascular networks are widely used in bone tissue engineering.Additive manufacturing is a manufacturing technology that creates three-dimensional solids by stacking substances layer by layer,mainly including but not limited to 3D printing,but also 4D printing,5D printing and 6D printing.It can be effectively combined with vascularization to meet the needs of vascularized tissue scaffolds by precisely tuning the mechanical structure and biological properties of smart vascular scaffolds.Herein,the development of neovascularization to vascularization to bone tissue engineering is systematically discussed in terms of the importance of vascularization to the tissue.Additionally,the research progress and future prospects of vascularized 3D printed scaffold materials are highlighted and presented in four categories:functional vascularized 3D printed scaffolds,cell-based vascularized 3D printed scaffolds,vascularized 3D printed scaffolds loaded with specific carriers and bionic vascularized 3D printed scaffolds.Finally,a brief review of vascularized additive manufacturing-tissue scaffolds in related tissues such as the vascular tissue engineering,cardiovascular system,skeletal muscle,soft tissue and a discussion of the challenges and development efforts leading to significant advances in intelligent vascularized tissue regeneration is presented.
基金Yunkun Pei and Liucheng Zhang contributed equally to this work.This work was supported,in part,by the National Natural Science Foundation of China(81772099,81701907,81801928,and 81772087)Shanghai Sailing Program(18YF1412400)+3 种基金Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(20171906)Shanghai talent development fund(2018099)Shanghai Municipal Health and Family Planning Commission(201840027)and Shanghai Jiao Tong University“Medical and Research”Program(ZH2018ZDA04)。
文摘Over the past few decades,biomaterials have made rapid advances in tissue engineering.In particular,there have been several studies on vascularization during skin flap regeneration for plastic surgery.From the perspective of function,the biomaterials used to improve the vascularization of skin flaps are primarily classified into two types:(1)electrospun nanofibrous membranes as porous scaffolds,and(2)hydrogels as cell or cytokine carriers.Based on their source,various natural,synthetic,and semi-synthetic biomaterials have been developed with respective characteristics.For the ischemic environment of the flap tissue,the therapeutic effect of the combination of biomaterials was better than that of drugs,cytokines,and cells alone.Biomaterials could improve cell migration,prolong the efficacy of cytokines,and provide an advantageous survival environment to transplanted cells.
基金supported by the National Key Research and Development Program of China(2019YFA0112000 and 2018YFB1105600)the National Natural Science Foundation of China(81930051)+2 种基金Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(20171906)Shanghai Jiao Tong University “Medical and Research”Program(ZH2018ZDA04)Foundation of National Facility for Translational Medicine(Shanghai)(TMSK-2020-117)。
文摘The immune response after implantation is a primary determinant of the tissue-repair effects of threedimensional(3D)-printed scaffolds.Thus,scaffolds that can subtly regulate immune responses may display extraordinary functions.Inspired by the angiogenesis promotion effect of humoral immune response,we covalently combined mesoporous silica micro rod(MSR)/polyethyleneimine(PEI)/ovalbumin(OVA)self-assembled vaccines with 3D-printed calcium phosphate cement(CPC)scaffolds for local antigen-specific immune response activation.With the response activated,antigen-specific CD4+T helper2(Th2)cells can be recruited to promote early angiogenesis.The silicon(Si)ions from MSRs can accelerate osteogenesis,with an adequate blood supply being provided.At room temperature,scaffolds with uniformly interconnected macropores were printed using a self-setting CPC-based printing paste,which promoted the uniform dispersion and structural preservation of functional polysaccharides oxidized hyaluronic acid(OHA)inside.Sustained release of OVA was achieved with MSR/PEI covalently attached to scaffolds rich in aldehyde groups as the vaccine carrier.The vaccine-loaded scaffolds effectively recruited and activated dendritic cells(DCs)for antigen presentation and promoted the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)in vitro.When embedded subcutaneously in vivo,the vaccine-loaded scaffolds increased the proportion of Th2 cells in the spleen and locally recruited antigenspecific T cells to promote angiogenesis in and around the scaffold.Furthermore,the result in a rat skull defect-repair model indicated that the antigen-specific vaccine-loaded scaffolds promoted the regeneration of vascularized bone.This method may provide a novel concept for patient-specific implant design for angiogenesis promotion.
基金supported by National Natural Science Foundation of China 81930051(WC)“Chenguang Program”(22CGA16)supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission,the National Key R&D Program of China#2019YFA0112000(YT)+4 种基金National Natural Science Foundation of China 82071284(YT),82371307(YT),82372120(HR)Shanghai Rising-Star Program(21QA1405200,YT)Young Leading Scientists Cultivation Plan supported by Shanghai Municipal Education Commission(ZXWH1082101,YT)“Two Hundred Talent”Program supported by Shanghai Jiao Tong University School of Medicine(20240701,HR)the Fundamental Research Funds for the Central Universities(YG2023ZD02,YT).
文摘The crosstalk between immune cells and the neurovascular unit plays a pivotal role in neural regeneration following central nervous system(CNS)injury.Maintaining brain immune homeostasis is crucial for restoring neurovascular function.In this study,an interactive bridge was developed via an immunomodulatory hydrogel microsphere to link the interaction network between microglia and the neurovascular unit,thereby precisely regulating immune-neurovascular crosstalk and achieving neural function recovery.This immunomodulatory crosstalk microsphere(MP/RIL4)was composed of microglia-targeted RAP12 peptide-modified interleukin-4(IL-4)nanoparticles and boronic ester-functionalized hydrogel using biotin-avidin reaction and air-microfluidic techniques.We confirmed that the immunomodulatory microspheres reduced the expression of pro-inflammatory factors including IL-1β,iNOS,and CD86,while upregulating levels of anti-inflammatory factors such as IL-10,Arg-1,and CD206 in microglia.In addition,injection of the MP/RIL4 significantly mitigated brain atrophy volume in a mouse model of ischemic stroke,promoted neurobehavioral recovery,and enhanced the crosstalk between immune cells and the neurovascular unit,thus increasing angiogenesis and neurogenesis of stroke mice.In summary,the immunomodulatory microspheres,capable of orchestrating the interaction between immune cells and neurovascular unit,hold considerable therapeutic potential for ischemic stroke and other CNS diseases.
基金supported by the National Key Research and Development Program of China(2020YFA0908200)the National Natural Science Foundation of China(81930051 and 22105127)+1 种基金the Shanghai Municipal Health Commission(2022XD055 and 202140128)the Shanghai Jiao Tong University School of Medicine PhD Cultivation Fund for Science and Innovation(24KCPYYB005).
文摘Excessive uptake of purine and glucose can lead to hyperglycemia and hyperuricemia,mediated by specific intestinal transport proteins.Currently,there is a deficiency in targeted regulation of these proteins.In this study,we introduce an oral approach for targeted modulation using electrospun core–shell short-fibers that settle on the intestinal mucosa.These fibers,designed for the controlled in situ release of phlorizin—a multi-transporter inhibitor—are crafted through a refined electrospinning-homogenizing process using polylactic acid and gelatin.Phlorizin is conjugated via a phenyl borate ester bond.Furthermore,a calcium alginate shell ensures intestinal disintegration triggered by pH changes.These fibers adhere to the mucosa due to their unique structure,and phlorizin is released in situ post-ingestion through glucose-sensitive cleavage of the phenyl borate ester bond,enabling dual-target inhibition of intestinal transporter proteins.Both in vitro and in vivo studies confirm that the short-fibers possess intestine-settling and glucose-responsive properties,facilitating precise control over transport proteins.Using models of hyperuricemia and diabetes in mice,treatment with short-fibers results in reduc-tions of 49.6%in blood uric acid and 17.8%in glucose levels,respectively.Additionally,16S rRNA sequencing indicates an improved intestinal flora composition.In conclusion,we have developed an innovative oral strategy for the prevention of hyperglycemia and hyperuricemia.
基金supported by various grants,including the National Key Research and Development Program of China(2020YFA0908200)National Natural Science Foundation of China General Program(81930051,82205244)China Postdoctoral Science Foundation(2022M712135).
文摘Bioelectrical stimulation is a powerful technique used to promote tissue regeneration,but it can be hindered by an“electrical overload”phenomenon in the core region of stimulation.We develop a threaded microneedle electrode system that protects against“electrical overload”by delivering medicinal hydrogel microspheres into the core regions.The threaded needle body is coated with polydopamine and chitosan to enhance the adhesion of microspheres,which are loaded into the threaded grooves,allowing for their stereoscopic release in the core regions.After the electrode is inserted,the microspheres can be delivered three-dimensionally through physical swelling and the shear-thinning effect of chitosan,mitigating the electrical damage.Microspheres are designed to release alkylated vitamin B12 and vitamin E,providing antioxidant and cell protection effects upon in-situ activation,reducing reactive oxygen species(ROS)by 72.8%and cell death by 59.5%.In the model of peripheral nerve injury,the electrode system improves the overall antioxidant capacity by 78.5%and protects the surrounding cells.Additionally,it leads to an improved nerve conduction velocity ratio of 41.9%and sciatic nerve function index of 12.1%,indicating enhanced neuroregeneration.The threaded microneedle electrode system offers a promising approach for nerve repair by inhibiting“electrical overload”,potentially improving outcomes for tissue regeneration.
文摘Correction:Advanced Fiber Materials,https://doi.org/10.1007/s42765-025-00513-0.The authors regret for the following corrections in the manuscript.The correction information is presented as following description.1.In the published article(Fig.3c-m),the figures were corrected as the following Figure.2.In the Results and Discussion 2.2,the text was replaced with the following.
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0500700)Program of Shanghai Academic/Technology Research Leader(22XD1422600)。
文摘In the intricate labyrinth of modern medical advancements,the quest for non-invasive and precise diagnostic tools is a journey of continual discovery and innovation.One of the most compelling frontiers in this realm is the monitoring of cerebral blood flow,a critical parameter that holds the key to understanding a myriad of neurological conditions[1,2].Traditional Transcranial Doppler(TCD)sonography,despite its widespread application,has been hindered by a number of limitations[3].
基金supported by the National Natural Science Foundation of China(52305206)Shanghai Pujiang Program(23PJD056)+1 种基金Postdoctoral Fellowship Program of CPSF(GZC20231623)Postdoctoral Fellowship Programs(2024M752001 and 2024T170570)。
文摘Mussels are animals that survive along the coast and are exposed to external risks such as shockwaves,bird hunting,and mating struggles.Therefore,many shellfish species either stick to each other or to rocks to protect themselves.Their adhesive ability is maintained in humid and underwater environments,which indicates that the mussel adhesive proteins have potential applications in medical adhesives[1-3].To date,most studies have focused on the super-strong underwater adhesion mechanism of mussels.However,when exposed to unfavorable or harsh environments,they quickly discard their filaments,fall off rocks,regain mobility,and escape to new habitats.Their filaments regrow within a few hours and help them to reattach to new rocks.
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0500700)the National Natural Science Foundation of China(52305206)the Shanghai Pujiang Programme(23PJD056)。
文摘Lubrication is an important prerequisite and foundation for the organism to protect biological tissues from mechanical friction damage and to maintain their normal life functions[1,2].After mechanical friction trauma,the lubrication matrix repairs damaged tissue by protecting the host from external impact and promotes the restoration of lubrication balance in the body.The process of lubrication typically unfolds in a series of events,beginning with a rapid response phase where lubricating fluids flow within the organism,reducing wear between tissues.This is followed by a gradual transition into a lubrication phase involving various lubrication mechanisms,such as fluid lubrication(The load is fully sustained by lubricant due to viscous forces in the space or gap between the components that are moving in relation to another object,while preventing solid-to-solid contact),boundary lubrication(The load is carried by surface high points rather than by lubricant),hydration lubrication(Hydration layers are tightly bound by the surrounding charges,allowing them to withstand significant pressure without being displaced,while also being able to quickly relax,resulting in a fluid-like response to shear forces),and mixed lubrication(This regime exists between full film lubrication and boundary lubrication,where the lubricant film generated is inadequate to fully separate the surfaces in contact,yet the hydrodynamic effect is significant)[3-5].Thus,lubrication plays a vital role in protecting living beings.However,if this well-coordinated wear reduction process is disrupted,lubrication can become uncontrolled or deteriorate,potentially leading to a range of lubrication-related diseases,including osteoarthritis,tendon adhesion,intervertebral disc degeneration,femoral head necrosis,cardiovascular blockages,tooth wear,and implant infections[1].
基金supported by grants from the National Key Research and Development Program of China(2020YFA0908200)the National Natural Science Foundation of China(82072177,82272263,and 82272264)+2 种基金the“Two Hundred Talent”Program and the first Continuous Outstanding Special Technology Supporting Project and Shanghai Municipal Key Clinical Specialty(shslczdzk00901)the Shanghai“Rising Stars of Medical Talents”Youth Development Program,Shanghai Clinical Research Center of Plastic and Reconstructive Surgery supported by Science and Technology Commission of Shanghai Municipality(grant 22MC1940300)the Science and Technology Commission of Shanghai Municipality(23015820800).
文摘Hyperglycemia and bacterial colonization in diabetic wounds aberrantly activate Nod-like receptor protein 3(NLRP3)in macrophages,resulting in extensive inflammatory infiltration and impaired wound healing.Targeted suppression of the NLRP3 inflammasome shows promise in reducing macrophage inflammatory disruptions.However,challenges such as drug off-target effects and degradation via lysosomal capture remain during treatment.In this study,engineered apoptotic bodies(BHB-dABs)derived from adipose stem cells loaded with β-hydroxybutyric acid(BHB)were synthesized via biosynthesis.These vesicles target M1-type macrophages,which highly express the folic acid receptor in the inflammatory microenvironment,and facilitate lysosomal escape through 1,2-distearoyl-sn-propyltriyl-3-phosphatidylethanolaminepolyethylene glycol functionalization,which may enhance the efficacy of NLRP3 inhibition for managing diabetic wounds.Invitro studies demonstrated the biocompatibility of BHB-dABs,their selective targeting of M1-type macrophages,and their ability to release BHB within the inflammatory microenvironment via folic acid and folic acid receptor signaling.These nanovesicles exhibited lysosomal escape,antiinflammatory,mitochondrial protection,and endothelial cell vascularization properties.Invivo experiments demonstrated that BHB-dABs enhance the recovery of diabetic wound inflammation and angiogenesis,accelerating wound healing.These functionalized apoptotic bodies efficiently deliver NLRP3 inflammasome inhibitors using a dual strategy of targeting macrophages and promoting lysosomal escape.This approach represents a novel therapeutic strategy for effectively treating chronic diabetic wounds.
基金supported by National Natural Science Foundation of China(grant numbers 52273133 and 32101104)The Shanghai Municipal Health and Family Planning Commission(grant number 2022XD055)+3 种基金National Science Fund for Distinguished Young Scholars(grant number 82003147)China Postdoctoral Science Foundation(grant number 2023MD734156)Nanchong Science and Technology Bureau Basic Research Platform Project(grant number 23JCYJPT0043)Affiliated Hospital of North SiChuan Medical College unveils marshal program(grant number 2022JB003).
文摘Given the high malignancy of liver cancer and the liver's unique role in immune and metabolic regulation,current treatments have limited efficacy,resulting in a poor prognosis.Hydrogels,soft 3-dimensional network materials comprising numerous hydrophilic monomers,have considerable potential as intelligent drug delivery systems for liver cancer treatment.The advantages of hydrogels include their versatile delivery modalities,precision targeting,intelligent stimulus response,controlled drug release,high drug loading capacity,excellent slow-release capabilities,and substantial potential as carriers of bioactive molecules.This review presents an in-depth examination of hydrogel-assisted advanced therapies for hepatocellular carcinoma,encompassing small-molecule drug therapy,immunotherapy,gene therapy,and the utilization of other biologics.Furthermore,it examines the integration of hydrogels with conventional liver cancer therapies,including radiation,interventional therapy,and ultrasound.This review provides a comprehensive overview of the numerous advantages of hydrogels and their potential to enhance therapeutic efficacy,targeting,and drug delivery safety.In conclusion,this review addresses the clinical implementation of hydrogels in liver cancer therapy and future challenges and design principles for hydrogel-based systems,and proposes novel research directions and strategies.
基金supported by the National Natural Science Foundation of China(W2411085)Zhejiang Provincial Natural Science Foundation of China(LBZ24H060001)+5 种基金Undergraduate Training Program for Innovation and Entrepreneurship(202410285263Y)Health Talents Projects of Suzhou(GSWS2021023)Innovation and Entrepreneurship Training Program(202410285263Y)Suzhou Key R&D Program(Medical and Health Innovation)Project(SYW2025042)Suzhou‘National Mentor’Program for Young Core Healthcare Talents(Gngg2021008)Natural Science Foundation of Shandong Province(ZR2024MH091)。
文摘Precise regulation of intraosseous angiogenesis is essential for effectively repairing osteoporotic bone defects.However,the dual imbalance of redox homeostasis and the osteogenesis-angiogenesis coupling within the osteoporotic microenvironment poses significant challenges for bone regeneration.Here,we developed a poly-dopamine(PDA)-modified injectable short-fiber 3D scaffold(PSF@P-SLP)via short fibers homogenization to remodel the osteoporotic microenvironment and enhance bone healing.The scaffold surface was modified with PDA,which induced the in situ aggregation of short fibers into a porous 3D network,promoting directional cell migration and nutrient exchange.Moreover,parathyroid hormone[PTH(1-34)]loaded ROS-responsive thio-ether-phospholipid liposomes(P-SLP)were conjugated to the PDA coating through catechol groups,enabling sustained PTH release and efficient ROS scavenging via thioether oxidation.In vitro,PSF@P-SLP significantly reduced ROS levels,promoted osteogenic differentiation of mesenchymal stem cells,and enhanced the prolif-eration and migration of endothelial cells.In vivo,the scaffold facilitated both type H vessels formation and osteogenesis,accelerating the repair of osteoporotic bone defects.Collectively,this study presents a novel therapeutic strategy utilizing PTH(1-34)-loaded injectable short-fiber 3D scaffolds that modulate oxidative stress and restore osteogenesis-angiogenesis coupling within the osteoporotic niche,demonstrating strong translational potential for bone tissue engineering.
基金supported by the Program of Shanghai Academic/Technology Research Leader(22XD1422600)the Research Fellow(Grant No.353146)+2 种基金Research Project(347897)Solution for Health Profile(336355)InFLAMES Flagship(337531)grants and Printed Intelligence Infrastructure"(PII-FIRI)from Research Council of Finland.
文摘The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis.The restoration of mitochondrial homeostasis,serving as a pivotal rheostat for balancing glucose metabolism in immune cells,can effectively mitigate inflammation and initiate osteogenesis.Herein,an ion-activated mitochondrial rheostat fiber-microsphere polymerization system(FM@CeZnHA)was innovatively constructed.Physical-chemical and molecular biological methods confirmed that CeZnHA,char-acterized by a rapid degradation rate,releases Ce/Zn ions that restore mitochondrial metabolic homeostasis and M1/M2 balance of macrophages through swift redox reactions.This process reduces the glycolysis level of macrophages by down-regulating the NF-κB p65 signaling pathway,enhances their mitochondrial metabolic dependence,alleviates excessive early inflammatory responses,and promptly initiates osteogenesis.The FM network provided a stable platform for macrophage glycolytic transformation and simulated extracellular matrix microenvironment,continuously restoring mitochondrial homeostasis and accelerating ossification center for-mation through the release of metal ions from the internal CeZnHA for efficient bone immune cascade reactions.This strategy of bone immunity mediated by the restoration of macrophage mitochondrial metabolic function and glucose metabolic flux homeostasis opens up a new approach to treating bone defects.
基金Funded by Outstanding Leaders Training Program of Pudong New Area Health System of Shanghai(Grant No.PWRl 2020–08)Important Weak Subject Construction Project of Pudong Health and Family Planning Commission of Shanghai(Grant No.PWZbr2022-13)+3 种基金National Natural Science Foundation of China(82372120,82272128)“Chenguang Program”(22CGA16)supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission,“Two Hundred Talent”Program supported by Shanghai Jiao Tong University School of Medicine(20240701)China Postdoctoral Science Foundation(2023M742360,2023M742361,and GZB20230443)China National Postdoctoral Program for Innovative Talents(BX20230228).
文摘Repair and regeneration of damaged neurons is a promising therapeutic strategy for central nervous system(CNS)diseases such as ischemic stroke(IS).However,achieving efficient neuronal repair and regeneration after CNS injury through noninvasive methods remains a significant challenge.Therefore,this study proposes,for the first time,an ultrasonic nasal drop formulation that induces efficient regeneration of damaged neurons through electropharmacological coupling in an noninvasive manner.Liposomes containing the natural anti-inflammatory drug Timosaponin B-Ⅱ(TB)were coated onto barium titanate nanoparticles(BTO)to form LTO@TB.Using microfluidic technology and a Schiff base reaction,LTO@TB was encapsulated into aldehyde-based and methacrylate-modified microspheres(MS)to create the ultrasonic nasal drop MS@LTO@TB.The aldehyde groups of MS@LTO@TB spontaneously formed amide bonds with the numerous amino groups in the nasal mucosa,facilitating specific adhesion.Due to its enhanced bioadhesion and efficient transmembrane transport,LTO@TB was continuously and noninvasively delivered to the brain when administered nasally.Additionally,under ultrasonic stimulation,LTO@TB in the brain exerted an electropharmacological coupling effect,achieving noninvasive electrical stimulation of damaged neurons.MS@LTO@TB modulated microglial phenotypes,restored electrical signal conduction among damaged neurons,reshaped the inflammatory microenvironment,reduced neuronal apoptosis,activated the PI3K/AKT signaling pathway,and promoted axonal regeneration.MS@LTO@TB also showed the unique ability to alleviate inflammation and promote neuronal remodeling in a mouse model of middle cerebral artery occlusion/reperfusion(MCAO/R).This study presents a promising strategy involving the nasal administration of ultrasonic nasal drops as a noninvasive and efficient treatment for CNS injuries.
基金supported by the National Natural Science Foundation(52273133,52303190,82271223,82271220,82301369)Shanghai Municipal Health and Family Planning Commission(2022XD055)+3 种基金Shanghai Nat-ural Science Foundation(25ZR1402458)Shanghai Municipal Health Commission(20244Z0007)Shanghai Municipal Committee of Science and Technology(23XD1422900)Hongkou district Health Commission(Hongwei2401-03,HKLCFC202405,HKLCYQ2024-02,HKLCYQ2024-04).
文摘Abnormal mitochondrial division in microglia significantly impacts central nervous system(CNS)diseases.However,treating CNS diseases through microglial mitochondria presents several challenges:intracerebral de-livery of drugs,microglial targeting,and mitochondrial regulation.Herein,a novel three-stage sequential tar-geted nasal drops delivery system that achieves precise drug delivery to the core of brain lesions through noninvasive nasal delivery,targeting microglia,and regulating mitochondria were developed.Firstly,dehy-droepiandrosterone(DHEA),identified from clinical data and transcriptomic analyses as a key neurosteroid regulating mitochondrial fission,was selected.Secondly,surface-positively charged hydrogel microspheres were prepared to adhere to the nasal mucosa,thereby avoiding rapid clearance and achieving the first stage of nasal mucosa targeting.Subsequently,targeted liposomes carrying cytotoxic T lymphocyte-associated protein-4 were constructed and modified into microspheres,which released liposomes through the nasal cavity to enter the brain and bound to the activated microglial surface receptors CD80/86 accomplishing the second stage of cell targeting.In the third stage,the system released DHEA in response to the microenvironment,precisely regulating dynamin-related protein 1 involved in mitochondrial membrane remodeling,which inhibited abnormal mito-chondrial division,stabilized mitochondrial morphology and function,inhibited microglial activation.This study demonstrated that three-stage sequential nasal drops efficiently traversed the nose-to-brain pathway via nasal mucosa in both murine(n=200)and porcine(n=16)models,while significantly ameliorating anesthesia/surgery-induced cognitive dysfunction in mice.Therefore,the three-stage sequential nasal drip is a promising method for the treatment of central nervous system diseases.
基金supported by National Natural Science Foundation of China(Grant Nos.82471116,82271119,82371096,82401300,and 22277018)Shanghai RisingStar Program(23QA1401000)+3 种基金Healthy Young Talents Project of Shanghai Municipal Health Commission(2022YQ015)National Funded Postdoctoral Program of China(GZB20230158)China Postdoctoral Science Foundation(2024M750550)Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar(LR23B030001)。
文摘A traumatic tissue adhesive technology is highly sought after in ophthalmic surgery;however,many polymeric adhesives face significant limitations in clinical ophthalmology, particularly incorneal transplantation. A major challenge is achieving rapid adhesion without introducingpolymer barriers or chemical toxicity from cross-linking. To address this, we developed a novelcornea-specific nanoadhesive constructed through protein-DNA co-assembly and applied it tocorneal transplantation. In this system, a rigid tetrahedral DNA framework was employed toguide the spatial distribution of polycationic recombinant proteins (K72) and serve as the coreof the nanoadhesive, facilitating energy conversion during tissue connection. The adhesivedemonstrated a strength of 2.3 kPa between corneal lenticules. After modification with RGDpeptides, the adhesive system significantly enhanced corneal epithelialization, reducedinflammation and neovascularization, and ultimately promoted corneal repair. This studyrepresents the first application of a nanoadhesive in ophthalmic surgery, providing a novelsolution for developing ophthalmic-specific adhesives for clinical use.
基金sponsored by the National Natural Science Foundation of China(U23A20406/32301095)Shanghai Science and Technology Program(22YF1441700)Shanghai Municipal Health Commission(20244Y0178).
文摘The growth plate is crucial for skeletal growth in children,but research on repairing growth plate damage and restoring growth is limited.Here,a high-toughness adaptive dualcrosslinked hydrogel is designed to mimic the growth plate's structure,supporting regeneration and bone growth.Composed of aldehyde-modified bacterial cellulose(DBNC),methacrylated gelatin(GelMA)and sodium alginate(Alg),the hydrogel is engineered through ionic bonding and Schiff base reactions,creating a macroporous structure.This structure can transform into a denser form by binding with calcium ions.In vitro,the loose macroporous structure of the hydrogels can promote chondrogenic differentiation,and when it forms a dense structure by binding with calcium ions,it also can activate relevant chondrogenic signaling pathways under the influence of insulin-like growth factor I(IGF-1),further inhibiting osteogenesis.In vivo experiments in a rat model of growth plate injury demonstrated that the hydrogel promoted growth plate cartilage regeneration and minimized bone bridge formation by creating a hypoxic microenvironment that activates IGF-1-related pathways.This environment encourages chondrogenic differentiation while preventing the undesired formation of bone tissue within the growth plate area.Overall,the dual-crosslinked hydrogel not only mimics the growth plate's structure but also facilitates localized IGF-1 expression,effectively reshaping the growth plate's function.This approach represents a promising therapeutic strategy for treating growth plate injuries,potentially addressing challenges associated with skeletal growth restoration in pediatric patients.
基金supported by the National Nature Science Foundation of China(32000937,81871549 and 81971312)Science and Technology Commission of Shanghai Municipality(23015820800)Shanghai Municipal Health Commission(20204Y0355).
文摘Neural cell senescence hinders spinal cord nerve function recovery,and existing therapies that target senescent cell clearance haven’t effectively addressed cellular senescence.In this study,injectable short fibers that accurately maintain genome homeostasis in real time were developed,which for the first time reversed neural cell senescence by blocking the excessive intervention of cell inspection points.First,the oxidization-sensitive hybrid liposomes were prepared by combining Bakuchiol(BAK),a natural plant extract with the ability of DNA protection,with the oxidization-sensitive phospholipid S-PC.Subsequently,the short fibers regulating the cell inspection points(ISN@n-BAK)were constructed by further complexing the oxidation-sensitive hybrid liposomes with short fibers throughπ–πconjugation and catechol groups mussel-stimulated polydopamine(PDA).In vitro experiments demonstrated that ISN@n-BAK promotes neural stem cell differentiation into neurons and has anti-aging effects across various aging stages.In vivo,ISN@n-BAK responded to excessive ROS by triggering oxidation-sensitive liposomes to release BAK,protecting against DNA damage,suppressing aging-related gene expression in Cdkn2a and Cdkn2c and inhibiting inspection point restrictions.Bioinformatics showed that ISN@n-BAK reversed neural cell senescence and aided spinal cord nerve regeneration by activating the endogenous cell cycle,downregulating the PI3K-Akt pathway and upregulating the Rap1 pathway.This study introduces a novel therapeutic approach using short fibers that inhibit inspection points intervention to rejuvenate injured spinal cords.
