羟基丁酸-戊酸共聚物/生物活性玻璃复合多孔支架材料对骨缺损的修复作用

目的探讨羟基丁酸-戊酸共聚物/生物活性玻璃(PHBV/SGBG)复合多孔支架材料对骨缺损的修复能力。方法将PHBV/SGBG复合多孔支架材料植入兔的桡骨缺损模型中,PHBV/羟基磷灰石(HA)作为实验对照组,利用放射学、组织学、组织切片的计算机图像分析、生物力学测定等方法,观察其降解性、生物相容性以及成骨能力。结果PHBV/SGBG复合多孔支架材料修复骨缺损,新生骨形成时间早:术后2周,植入材料内部有骨小粱形成,术后8周移植材料四周及内部均有大量新生骨形成,骨缺损区被新生骨填充;骨修复完成时间早:术后12周,新生皮质骨结构清晰,与宿主皮质骨自然连接,新生骨显示出正常骨结构,髓腔再通;抗压力强:12周时所修复骨缺损标本的抗压力,PHBV/SGBG组明显高于PHBV/HA组(P<0.05),而与自体松质骨组间差异无显著性(P>0.05);降解速度快:术后4周材料开始降解,术后12周材料大部分已被吸收,材料与新骨面积的百分比由4周时的60%下降到8%。结论PHBV/SGBG复合多孔支架材料修复骨缺损,成骨时间早并且修复完全,材料本身可以完全降解,是一种理想的骨科替代材料,亦可以用于骨组织工程的支架材料。

Layered Double Hydroxide Modified by PEGylated Hyaluronic Acid as a Hybrid Nanocarrier for Targeted Drug Delivery

In recent years, organic-inorganic hybrid nanocarriers are explored for effective drug delivery and preferable disease treatments. In this study, using 5-fluorouracil(5-FU)as electronegative model drug, a new type of organic-inorganic hybrid drug delivery system(LDH/HA-PEG/5-FU)was conceived and manufactured by the adsorption of PEGylated hyaluronic acid(HA-PEG)on the surface of layered double hydroxide(LDH, prepared via hydrothermal method)and the intercalation of 5-FU in the interlamination of LDH via ion exchange strategy. The drug loading amount of LDH/HA-PEG/5-FU achieved as high as 34.2%. LDH, LDH/5-FU and LDH/HA-PEG/5-FU were characterized by FT-IR, XRD, TGA, laser particle size analyzer and SEM. With the benefit of p Hdegradable feature of LDH and enzyme-degradable feature of HA, LDH/HA-PEG/5-FU showed p H-degradable and enzyme-degradable capacity in in vitro drug release. Moreover, the drug carrier LDH/HA-PEG contained biocompatible PEG and tumor-targeted HA, resulting in lower cytotoxicity and better endocytosis compared with LDH in vitro. It was suggested that the organic-inorganic hybrid drug delivery system, which was endowed with the properties of controlled release, low toxicity and tumor-targeting delivery for ameliorative cancer therapy, was advisable and might be applied further to fulfill other treatments.

Delivery of nitric oxide-releasing silica nanoparticles for in vivo revascularization and functional recovery after acute peripheral nerve crush injury

Nitric oxide(NO)has been shown to promote revascularization and nerve regeneration after peripheral nerve injury.However,in vivo application of NO remains challenging due to the lack of stable carrier materials capable of storing large amounts of NO molecules and releasing them on a clinically meaningful time scale.Recently,a silica nanoparticle system capable of reversible NO storage and release at a controlled and sustained rate was introduced.In this study,NO-releasing silica nanoparticles(NO-SNs)were delivered to the peripheral nerves in rats after acute crush injury,mixed with natural hydrogel,to ensure the effective application of NO to the lesion.Microangiography using a polymer dye and immunohistochemical staining for the detection of CD34(a marker for revascularization)results showed that NO-releasing silica nanoparticles increased revascularization at the crush site of the sciatic nerve.The sciatic functional index revealed that there was a significant improvement in sciatic nerve function in NO-treated animals.Histological and anatomical analyses showed that the number of myelinated axons in the crushed sciatic nerve and wet muscle weight excised from NO-treated rats were increased.Moreover,muscle function recovery was improved in rats treated with NO-SNs.Taken together,our results suggest that NO delivered to the injured sciatic nerve triggers enhanced revascularization at the lesion in the early phase after crushing injury,thereby promoting axonal regeneration and improving functional recovery.

dECM restores macrophage immune homeostasis and alleviates iron overload to promote DTPI healing

Due to its highly insidious and rapid progression,deep tissue pressure injury(DTPI)is a clinical challenge.Our previous study found that DTPI may be a skeletal muscle injury dominated by macrophage immune dysfunction due to excessive iron accu-mulation.Decellularized extracellular matrix(dECM)hydrogel promotes skeletal muscle injury repair.However,its role in po-larizing macrophages and regulating iron metabolism in DTPI remains unclear.Here,porcine dECM hydrogel was prepared,and its therapeutic function and mechanism in repairing DTPI were investigated.The stimulus of dECM hydrogel toward RAW264.7 cells resulted in a significantly higher percentage of CD2o6+macrophages and notably decreased intracellular divalent iron levels.In mice DTPI model,dECM hydrogel treatment promoted M1 to M2 macrophage conversion,improved iron metabolism and reduced oxidative stress in the early stage of DTPI.In the remodeling phase,the dECM hydrogel remarkably enhanced revascularization and accelerated skeletal muscle repair.Furthermore,the immunomodulation of dEcM hydrogels in vivo was mainly involved in the P13k/Akt signaling pathway,as revealed by GO and KEGG pathway analysis,which may ameliorate the iron deposition and promote the healing of DTPI.Our findings indicate that dECM hydrogel is promising in skeletal muscle repair,inflammation resolution and tissue injury healing by effectively restoring macrophage immune homeostasis and normalizing iron metabolism.

Bone-derived MSCs encapsulated in alginate hydrogel prevent collagen-induced arthritis in mice through the activation of adenosine A_(2A/2B)receptors in tolerogenic dendritic cells

Tolerogenic dendritic cells(tol DCs)facilitate the suppression of autoimmune responses by differentiating regulatory T cells(Treg).The dysfunction of immunotolerance results in the development of autoimmune diseases,such as rheumatoid arthritis(RA).As multipotent progenitor cells,mesenchymal stem cells(MSCs),can regulate dendritic cells(DCs)to restore their immunosuppressive function and prevent disease development.However,the underlying mechanisms of MSCs in regulating DCs still need to be better defined.Simultaneously,the delivery system for MSCs also influences their function.Herein,MSCs are encapsulated in alginate hydrogel to improve cell survival and retention in situ,maximizing efficacy in vivo.The three-dimensional co-culture of encapsulated MSCs with DCs demonstrates that MSCs can inhibit the maturation of DCs and the secretion of pro-inflammatory cytokines.In the collagen-induced arthritis(CIA)mice model,alginate hydrogel encapsulated MSCs induce a significantly higher expression of CD39^(+)CD73^(+)on MSCs.These enzymes hydrolyze ATP to adenosine and activate A_(2A/2B)receptors on immature DCs,further promoting the phenotypic transformation of DCs to tol DCs and regulating naive T cells to Tregs.Therefore,encapsulated MSCs obviously alleviate the inflammatory response and prevent CIA progression.This finding clarifies the mechanism of MSCs-DCs crosstalk in eliciting the immunosuppression effect and provides insights into hydrogel-promoted stem cell therapy for autoimmune diseases.

Highly sensitive H_(2)O_(2)-scavenging nano-bionic system for precise treatment of atherosclerosis

In atherosclerosis,chronic inflammatory processes in local diseased areas may lead to the accumulation of reactive oxygen species(ROS).In this study,we devised a highly sensitive H_(2)O_(2)-scavenging nanobionic system loaded with probucol(RPP-PU),to treat atherosclerosis more effectively.The RPP material had high sensitivity to H_(2)O_(2),and the response sensitivity could be reduced from 40 to 10μmol/L which was close to the lowest concentration of H_(2)O_(2)levels of the pathological environment.RPP-PU delayed the release and prolonged the duration of PU in vivo.In Apolipoprotein E deficient(ApoE-/-)mice,RPP-PU effectively eliminated pathological ROS,reduced the level of lipids and related metabolic enzymes,and significantly decreased the area of vascular plaques and fibers.Our study demonstrated that the H_(2)O_(2)-scavenging nanobionic system could scavenge the abundant ROS in the atherosclerosis lesion,thereby reducing the oxidative stress for treating atherosclerosis and thus achieve the therapeutic goals with atherosclerosis more desirably.

A fully biodegradable polydioxanone occluder for ventricle septal defect closure

Ventricular septal defect(VSD)is one of the commonest congenital heart diseases(CHDs).Current occluders for VSD treatment are mainly made of nitinol,which has the risk of nickel allergy,persistent myocardial abrasion and fatal arrythmia.Herein,a fully biodegradable polydioxanone(PDO)occluder equipped with a shape line and poly-L-lactic acid PLLA membranes is developed for VSD closure without the addition of metal marker.PDO occluder showed great mechanical strength,fatigue resistance,geometry fitness,biocompatibility and degradability.In a rat subcutaneous implantation model,PDO filaments significantly alleviated inflammation response,mitigated fibrosis and promoted endothelialization compared with nitinol.The safety and efficacy of PDO occluder were confirmed in a canine VSD model with 3-year follow-up,demonstrating the biodegradable PDO occluder could not only effectively repair VSD,induce cardiac remodeling but also address the complications associated with metal occluders.Furthermore,a pilot clinical trial with five VSD patients indicated that all the occluders were successfully implanted under the guidance of echocardiography and no adverse events occurred during the 3-month follow-up.Collectively,the fully bioresorbable PDO occluder is safe and effective for clinical VSD closure and holds great promise for the treatment of structural CHDs.

Macrophage metabolism reprogramming EGCG-Cu coordination capsules delivered in polyzwitterionic hydrogel for burn wound healing and regeneration

Excessive reactive oxygen species(ROS)at severe burn injury sites may promote metabolic reprogramming of macrophages to induce a deteriorative and uncontrolled inflammation cycle,leading to delayed wound healing and regeneration.Here,a novel bioactive,anti-fouling,flexible polyzwitterionic hydrogel encapsulated with epigallocatechin gallate(EGCG)-copper(Cu)capsules(termed as EGCG-Cu@CBgel)is engineered for burn wound management,which is dedicated to synergistically exerting ROS-scavenging,immune metabolic regulation and pro-angiogenic effects.EGCG-Cu@CBgel can scavenge ROS to normalize intracellular redox homeostasis,effectively relieving oxidative damages and blocking proinflammatory signal transduction.Importantly,EGCG-Cu can inhibit the activity of hexokinase and phosphofructokinase,alleviate accumulation of pyruvate and convert it to acetyl coenzyme A(CoA),whereby inhibits glycolysis and normalizes tricarboxylic acid(TCA)cycle.Additionally,metabolic reprogramming of macrophages by EGCG-Cu downregulates M1-type polarization and the expression of proinflammatory cytokines both in vitro and in vivo.Meanwhile,copper ions(Cu^(2+))released from the hydrogel facilitate angiogenesis.EGCG-Cu@CBgel significantly accelerates the healing of severe burn wound via promoting wound closure,weakening tissue-damaging inflammatory responses and enhancing the remodeling of pathological structure.Overall,this study demonstrates the great potential of bioactive hydrogel dressing in treating burn wounds without unnecessary secondary damage to newly formed skin,and highlights the importance of immunometabolism modulation in tissue repair and regeneration.

新型完全生物可吸收封堵器经导管封堵膜周部室间隔缺损:一项多中心前瞻性随机对照研究

生物可吸收封堵器的应用有望降低传统金属封堵器并发症的风险.之前研制的生物可吸收封堵器存在不完全降解的局限性并导致新的并发症,因此目前尚未有相关产品获批上市.本研究使用了一种新型完全可吸收封堵器,旨在探索完全可吸收封堵器治疗室间隔缺损的疗效和安全性.从2019年4月到2020年1月,本研究在七个医学中心入组125名膜周部室间隔缺损患者,经筛查后108名患者被纳入研究并随机分为植入生物可吸收封堵器实验组和金属封堵器组.所有受试者均成功植入封堵器并完成24个月的随访.生物可吸收封堵器组患者经胸超声心动图显示高亮回声在24个月内逐渐消失,说明可吸收封堵器在体内实现完全降解.对比金属封堵器,实验组器械相关心律失常发生率(5.56%vs.14.81%,P=0.112)和持续传导阻滞发生率(0/54 vs.6/54,P=0.036)显著降低.本研究提示新型完全可吸收封堵器可以在单纯超声引导下实现成功植入,同时降低术后永久性心律失常的发生率.

Dual pH-responsive “charge-reversal like” gold nanoparticles to enhance tumor retention for chemo-radiotherapy

The strategy of pH-responsive aggregation in tumor micro-environment(TME)provides an intriguing platform for enhancing tumor retention and exerting therapeutic effects sufficiently.In this work,we have designed an intelligent dual pH-responsive self-aggregating nano gold system(Au@PAH-Pt/DMMA)for the combined chemo-radiotherapy,in which a“charge-reversal like”strategy was utilized to realize irreversible stable aggregation and pH-specific release of cisplatin prodrug in TME.Responsive aggregation increases the cellular uptake of Au@PAH-Pt/DMMA by 55%–60%,and the cellular uptake of Pt after X-ray irradiation can be further enhanced by 80%.Additionally,responsive aggregation greatly slows down the rate of efflux from tumor in vivo.This system not only promotes B16 cell apoptosis as a chemotherapeutic agent(30.4%),it also enhances the effect of chemo-radiotheray(CRT)by promoting apoptosis as a radiosensitizer(55.3%).The colony formation assay results were fitted to cell survival curve of B16 cells and the sensitization enhancement ratio(SER)was calculated to be 1.29,which shows a good radiosensitizing ability.When exposed to X-ray,this nanoplatform reached the ideal therapeutic effect,and the tumor inhibition rate of Au@PAH-Pt/DMMA reached 91.6%with low drug administration frequency and dose of X-ray.Overall,the dual pH-responsive nanoparticles Au@PAH-Pt/DMMA could effectively enhance tumor therapeutic efficiency by combined chemo-radiotherapy,which provides a potential method for clinical transformation of cancer treatment.

ROS-responsive capsules engineered from EGCG-Zinc networks improve therapeutic angiogenesis in mouse limb ischemia

The successful treatment of limb ischemia requires that promote angiogenesis along with microenvironment improvement.Zinc ions have been reported to stimulate angiogenesis,but application was limited to the toxicity concerns.We hypothesized that zinc based metal-EGCG capsule(EGCG/Zn Ps)can achieve sustained release Zn2+resulting in reduced toxicity and improve angiogenesis as well as the improvement of microenvironment by ROS scavenging of EGCG.The surface morphology,zeta potential,infrared absorbance peaks and zinc ion release profile of the EGCG/Zn Ps were measured.In vitro,EGCG/Zn showed significantly antioxidant,antiinflammatory and induced cell migration effect.In addition,EGCG/Zn Ps enabled the sustained release of zinc ions,which reduced cytotoxicity and enhanced the secretion of vascular endothelial growth factor(VEGF)in vitro and in vivo.In mouse models of limb ischemia,EGCG/Zn Ps promoted angiogenesis and cell proliferation in ischemic tissues.Moreover,EGCG/Zn Ps group exhibited the most significant recovery of limb ischemic score,limb temperature and blood flow than other groups.In conclusion,EGCG/Zn Ps is a safe and promising approach to combine the merit of Zn2+and EGCG,thus enabling the direct application to limb ischemia.

Self-assembled PEG-b-PDPA-b-PGEM copolymer nanoparticles as protein antigen delivery vehicles to dendritic cells:preparation,characterization and cellular uptake

Antigen uptake by dendritic cells(DCs)is a key step for initiating antigen-specific T cell immunity.In the present study,novel synthetic polymeric nanoparticles were prepared as antigen delivery vehicles to improve the antigen uptake by DCs.Well-defined cationic and acid-responsive copolymers,monomethoxy poly(ethylene glycol)-block-poly(2-(diisopropyl amino)ethyl methacrylate)-block-poly(2-(guanidyl)ethyl methacrylate)(mPEG-b-PDPA-b-PGEM,PEDG)were synthesized by reversible addition-fragmentation chain transfer polymerization of 2-(diisopropylamino)ethyl methacrylate and N-(tert-butoxycarbonyl)amino ethyl methacrylate monomers,followed by deprotection of tert-butyl protective groups and guanidinylation of obtained primary amines.1H NMR,13C NMR and GPC results indicated the successful synthesis of well-defined PEDG copolymers.PEDG copolymers could self-assemble into nanoparticles in aqueous solution,which were of cationic surface charges and showed acid-triggered disassembly contributed by PGEM and PDPA moieties,respectively.Significantly,PEDG nanoparticles could effectively condense with negatively charged model antigen ovalbumin(OVA)to form OVA/PEDG nanoparticle formulations with no influence on its secondary and tertiary structures demonstrating by far-UV circular dichroism and UV-vis spectra.In vitro antigen cellular uptake by bone marrow DCs(BMDCs)indicated using PEDG nanoparticles as antigen delivery vehicles could significantly improve the antigen uptake efficiency of OVA compared with free OVA or the commercialized Alum adjuvant.Moreover,as the surface cationic charges of OVA/PEDG nanoparticle formulations reduced,the uptake efficiency decreased correspondingly.Collectively,our work suggests that guanidinylated,cationic and acid-responsive PEDG nanoparticles represent a new kind of promising antigen delivery vehicle to DCs and hold great potential to serve as immunoadjuvants in the development of vaccines.

Radial porous SiO_(2) nanoflowers potentiate the effect of antigen/adjuvant in antitumor immunotherapy

Here,we reported a cancer nanovaccine based on SiO_(2)nanoflowers with a special radial pore structure,which greatly enhanced cross-presentation and induced the production of cytotoxic T lymphocyte cells secreting granzymes B and interferon-γ.The antigen ovalbumin was covalently conjugated onto the as-synthesized hierarchical SiO_(2)nanoflowers,and the adjuvant cytosine-phosphate-guanine was electrostatically adsorbed into their radial pore by simple mixing before use.The nanovaccine exhibited excellent storage stability without antigen release after 27 days of incubation,negligible cytotoxicity to dendritic cells,and a high antigen loading capacity of 430±66 mg·g^(−1)support.Besides,the nanovaccine could be internalized by dendritic cells via multiple pathways.And the enhancement of antigen/adjuvant uptake and lysosome escape of antigen were observed.Noteworthy,in vitro culture of bone marrow-derived dendritic cells in the presence of nanovaccine proved the activation of dendritic cells and antigen cross-presentation as well as secretion of proinflammatory cytokines.Besides,in vivo study verified the targeting of nanovaccine to draining lymph nodes,the complete suppression of tumor in six out of ten mice,and the triggering of notable tumor growth delay.Overall,the present results indicated that the nanovaccine can be served as a potential therapeutic vaccine to treat cancer.

Polarization of tumor-associated macrophages by TLR7/8 conjugated radiosensitive peptide hydrogel for overcoming tumor radioresistance

Radioresistance reduces the antitumor efficiency of radiotherapy and further restricts its clinical application,which is mainly caused by the aggravation of immunosuppressive tumor microenvironment(ITM).Especially tumor-associated macrophages(TAMs)usually display the tumor-promoting M2 phenotype during high-dose fractional radiotherapy mediating radiotherapy resistance.Herein,the toll like receptor agonist TLR7/8a was conjugated with radiosensitive peptide hydrogel(Smac-TLR7/8 hydrogel)to regulate TAMs repolarization from M2 type into M1 type,thus modulating the ITM and overcoming the radioresistance.The Smac-TLR7/8 hydrogel was fabricated through self-assembly with nanofibrous morphology,porous structure and excellent biocompatibility.Uponγ-ray radiation,Smac-TLR7/8 hydrogel effectively polarized the macrophages into M1 type.Notably,combined with radiotherapy,TAMs repolarization regulated by Smac-TLR7/8 hydrogel could increase tumor necrosis factor secretion,activate antitumor immune response and effectively inhibit tumor growth.Moreover,TAMs repolarization rebuilt the ITM and elicited the immunogenic phenotypes in solid tumors,thus enhanced the PD1-blockade efficacy through increasing tumor infiltrating lymphocytes(TILs)and decreasing Treg cells in two different immune activity tumor mice models.Overall,this study substantiated that recruiting and repolarization of TAMs were critical in eliciting antitumor immune response and overcoming radioresistance,thus improving the efficacy of radiotherapy and immunotherapy.

Significant difference between sirolimus and paclitaxel nanoparticles in antiproliferation effect in normoxia and hypoxia: The basis of better selection of atherosclerosis treatment

Compared with paclitaxel,sirolimus has been more used in the treatment of vascular restenosis gradually as an anti-proliferative drug,but few basic studies have elucidated its mechanism.The anti-proliferative effects of sirolimus or paclitaxel have been demonstrated by numerous studies under normoxia,but few studies have been achieved focusing hypoxia.In this study,porcine carotid artery injury model and classical cobalt chloride hypoxia cell model were established.Sirolimus nanoparticles(SRM-NPs),paclitaxel nanoparticles(PTX-NPs)and blank nanoparticles(Blank-NPs)were prepared respectively.The effect of RPM-NPs on the degree of stenosis,proliferative index and the expression of PCNA after 28 days of porcine carotid artery injury model was evaluated.Compared with saline group and SRM groups,SRM-NPs group suppressed vascular stenosis,proliferative index and the expression of PCNA(P<0.01 and P<0.05).Endothelial cell(EC)and smooth muscle cell(SMC)were pre-treated with cobaltous chloride,followed by SRM-NPs,PTX-NPs,Blank-NPs or PBS control treating,the effects on cell proliferation,HIF-1 expression and glycolysis were detected.SRM-NPs could inhibit EC and SMC proliferation under hypoxia,while PTX-NPs couldn't(P<0.001).Significant differences between sirolimus and paclitaxel NPs in anti-proliferation effect under normoxia and hypoxia may due to the different inhibitory effects on HIF-1αexpression and glycolysis.In conclusion,these results suggest that sirolimus can inhibit the proliferation of hypoxic cells more effectively than paclitaxel.These observations may provide a basis for understanding clinical vascular stenosis therapeutic differences between rapamycin and paclitaxel.

Supramolecular co-assembly of self-adjuvanting nanofibrious peptide hydrogel enhances cancer vaccination by activating MyD88-dependent NF-κB signaling pathway without inflammation

Peptide vaccine targeting tumor-specific antigens is a promising cancer treatment regimen.However,peptide vaccines are commonly low-immunogenic,leading to suboptimal antitumor T-cell responses.Current peptide vaccination approaches are challenged by the variability of peptide physicochemical characters and vaccine formulations,flexibility,and the broad feasibility.Here,the supramolecular co-assembly of antigen epitope-conjugated peptides(ECPs)targeting CD8 or CD4 T-cell receptors was used to engineer a nanofibrious hydrogel vaccine platform.This approach provided precise and tunable loading of peptide antigens in nanofibers,which notably increased the antigen uptake,cross-presentation,and activation of dendritic cells(DCs).Immunization in mice indicated that the co-assembled peptide hydrogel did not induce local inflammation responses and elicited significantly promoted T-cell immunity by activating the MyD88-dependent NF-κB signaling pathway in DCs.Vaccination of mice using co-assembled peptide vaccine stimulated both enhanced CD8 and CD4 T cells against EG.7-OVA tumors without additional immunoadjuvants or delivery systems,and resulted in a more remarkable cancer immunotherapy efficacy,compared with free peptide vaccine or aluminum-adjuvanted peptide formulation.Altogether,peptide co-assembly demonstrated by three independent pairs of ECPs is a facile,customizable,and chemically defined approach for co-delivering peptide antigens in self-adjuvanting hydrogel vaccines that could induce stronger anticancer T-cell responses.

Titanium alloy composited with dual-cytokine releasing polysaccharide hydrogel to enhance osseointegration via osteogenic and macrophage polarization signaling pathways

Titanium alloy has been widely used in orthopedic surgeries as bone defect filling.However,the regeneration of high-quality new bones is limited due to the pro-inflammatory microenvironment around implants,resulting in a high occurrence rate of implant loosening or failure in osteological therapy.In this study,extracellular matrix-mimetic polysaccharide hydrogel co-delivering BMP-2 and interleukin(IL)-4 was composited with 3D printed titanium alloy to promote the osseointegration and regulate macrophage response to create a pro-healing microenvironment in bone defect.Notably,it is discovered from the bioinformatics data that IL-4 and BMP-2 could affect each other through multiple signal pathways to achieve a synergistic effect toward osteogenesis.The composite scaffold significantly promoted the osteoblast differentiation and proliferation of human bone marrow mesenchyme stem cells(hBMSCs).The repair of large-scale femur defect in rat indicated that the dual-cytokinedelivered composite scaffold could manipulate a lower inflammatory level in situ by polarizing macrophages to M2 phenotype,resulting in superior efficacy of mature new bone regeneration over the treatment of native titanium alloy or that with an individual cytokine.Collectively,this work highlights the importance of M2-type macrophages-enriched immune-environment in bone healing.The biomimetic hydrogel–metal implant composite is a versatile and advanced scaffold for accelerating in vivo bone regeneration,holding great promise in treating orthopedic diseases.

Programmed nanoparticle-loaded microparticles for effective antigen/adjuvant delivery

A microscale vaccine containing SiO_(2)nanoparticles loaded in CaC〇3 microparticles was constructed using the co-precipitation method.The antigen ovalbumin(OVA)was covalently conjugated with SiO_(2)nanoparticles,and these nanoparticles and CpG were co-encapsulated into CaCO_(3)microparticles,generating a vaccine with a size of approximately 5.2μm.Scanning electron microscopy(SEM),energy-dispersive X-ray(EDX),elemental mapping,and Fourier transform infrared(FTIR)analyses confirmed the successful preparation of the microscale vaccine;the vaccine had good storage stability without sustained antigen release,and negligible cytotoxicity to dendritic cells(DCs)and macrophages.Compared to SiO_(2)nanoparticles,the microscale vaccine can significantly improve antigen/adjuvant uptake.DCs internalized the entire microscale vaccine into lysosomes via macropinocytosis,and an increase in antigen endo/lysosomal escape was observed by confocal User scanning microscopy(CLSM).Specifically,DCs pulsed with the vaccine were fully mature,expressing high levels of costimulatory molecules(CD40,CD80,and CD86),MHCⅡ,and MHCⅠand secreting high levels of proinflammatory cytokines(IL-12,TNF-α,IL-1β,and IL-6).In addition,the vaccine had good in vivo biocompatibility,could protect the antigen from rapid degradation,and increased the retention time in lymph nodes.SiO_(2)nanoparticles-in-CaCO_(3)microparticles were an excellent carrier for antigen and adjuvant delivery.Hopefully,this study can provide some information on the design of microscale carriers for vaccine delivery systems.

Cascaded amplification of intracellular oxidative stress and reversion of multidrug resistance by nitric oxide prodrug based-supramolecular hydrogel for synergistic cancer chemotherapy

1.Introduction Chemotherapy is the traditional treatment for clinical cancer patient[1,2].However,the therapeutic effect is often severely limited by the multidrug resistance(MDR)[3,4],which was commonly mediated by inactivating drugs,increasing efflux,stimulating DNA repair mechanisms,and/or activating detoxification pathways[5-7].Recent studies are committing to develop reasonable strategies for intervention of the molecular pathways mediating MDR,of which P-glycoprotein(P-gp)has been widely investigated[8].So far,several kinds of P-gp inhibitors,including verapamil[9],vitamin E[10],cyclosporin A[11],and small interfering RNA(siRNA)[12].

Prosthetic venous valves for chronic venous insufficiency:Advancements and future design directions

With the serious aging population and lifestyle changes,chronic venous insufficiency accounts for approximately 25.95%of the population,which may lead to lower limb edema and leg heaviness,as well as severe infections of skin ulcers that can result in sepsis and necessitate amputation.Conservative treatment and other supportive measures can only slow the disease's progression but are unable to drastically reverse it;surgical interventions are rarely used due to the high risk of catastrophic postoperative consequences.As one of the most promising minimally invasive therapies,percutaneous prosthetic valve replacement has emerged in light of this situation,providing novel alternatives for patients with deep venous valve insufficiency.We reviewed the historical prosthetic venous valve designs,including their structure and materials,animal evaluation models,and assessment criteria.On the basis of the findings from in vitro tests,animal studies,and clinical trials,we summarized the major challenges and potential solutions for the development of advanced prosthetic venous valves.