Lumbar instability remodels cartilage endplate to induce intervertebral disc degeneration by recruiting osteoclasts via Hippo-CCL3 signaling

Degenerated endplate appears with cheese-like morphology and sensory innervation,contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population.1 However,the origin and development mechanism of the cheese-like morphology remain unclear.Here in this study,we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change.

Monitoring somatosensory evoked potentials in spinal cord ischemia-reperfusion injury

It remains unclear whether spinal cord ischemia-reperfusion injury caused by ischemia and other non-mechanical factors can be monitored by somatosensory evoked potentials. Therefore, we monitored spinal cord ischemia-reperfusion injury in rabbits using somatosensory evoked potential detection technology. The results showed that the somatosensory evoked potential latency was significantly prolonged and the amplitude significantly reduced until it disappeared during the period of spinal cord ischemia. After reperfusion for 30-180 minutes, the amplitude and latency began to gradually recover; at 360 minutes of reperfusion, the latency showed no significant difference compared with the pre-ischemic value, while the somatosensory evoked potential amplitude in- creased, and severe hindlimb motor dysfunctions were detected. Experimental findings suggest that changes in somatosensory evoked potentia~ ~atency can reflect the degree of spinat cord ischemic injury, while the amplitude variations are indicators of the late spinal cord reperfusion injury, which provide evidence for the assessment of limb motor function and avoid iatrogenic spinal cord injury.

The effect of the fibre orientation of electrospun scaffolds on the matrix production of rabbit annulus fibrosus-derived stem cells

Annulus fibrosus （AF） tissue engineering has recently received increasing attention as a treatment for intervertebral disc 0VD） degeneration; however, such engineering remains challenging because of the remarkable complexity of AF tissue. In order to engineer a functional AF replacement, the fabrication of cell-scaffold constructs that mimic the cellular, biochemical and structural features of native AF tissue is critical. In this study, we fabricated aligned fibroua polyurethane scaffolds using an electrospinning technique and used them for culturing AF-derived-stem/progenitor cells （AFSCs）. Random fibrous scaffolds, also prepared via electrospinningy were used as a control. We compared the morphology, proliferation, gene expression and matrix production of AFSCs on aligned scaffolds and random scaffolds. There was no apparent difference in the attachment or proliferation of cells cultured on aligned scaffolds and random scaffolds. However, compared to cells on random scaffolds, the AFSCs on aligned scaffolds were more elongated and better aligned, and they exhibited higher gene expression and matrix production of coUagen-I and aggrecan. The gene expression and protein production of coUagen-II did not appear to differ between the two groups. Together, these findings indicate that aligned fibrous scaffolds may provide a favourable microenvironment for the differentiation of AFSCs into cells similar to outer AF cells, which predominantly produce collagen-I matrix.

Functional recovery and microenvironmental alterations in a rat model of spinal cord injury following human umbilical cord blood-derived mesenchymal stem cells transplantation

BACKGROUND： Transplantation of human umbilical cord blood-derived mesenchymal stem cells （MSCs） has been shown to benefit spinal cord injury （SCI） repair. However, mechanisms of microenvironmental regulation during differentiation of transplanted MSCs remain poorly understood. OBJECTIVE： To observe changes in nerve growth factor （NGF）, brain-derived neurotrophic factor （BDNF）, and interleukin-8 （IL-8） expression following transplantation of human umbilical cord-derived MSCs, and to explore the association between microenvironment and neural functional recovery following MSCs transplantation. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Department of Orthopedics, First Affiliated Hospital of Soochow University from April 2005 to March 2007. MATERIALS： Human cord blood samples were provided by the Department of Gynecology and Obstetrics, First Affiliated Hospital of Soochow University. Written informed consent was obtained. METHODS： A total of 62 Wister rats were randomly assigned to control （n = 18）, model （n = 22, SCI ＋ PBS）, and transplantation （n = 22, SCI ＋ MSCs） groups. The rat SCI model was established using the weight compression method. MSCs were isolated from human umbilical cord blood and cultured in vitro for several passages. 5-bromodeoxyuridine （BrdU）-Iabeled MSCs （24 hours before injection） were intravascularly transplanted. MAIN OUTCOME MEASURES： The rats were evaluated using the Basso, Beattie and Bresnahan （BBB） locomotor score and inclined plane tests. Transplanted cells were analyzed following immunohistochemistry. Enzyme-linked immunosorbant assay was performed to determine NGF, BDNF, and IL-8 levels prior to and after cell transplantation. RESULTS： A large number of BrdU-positive MSCs were observed in the SCI region of the transplantation group, and MSCs were evenly distributed in injured spinal cord tissue 1 week after transplantation. BBB score and inclined plane test results revealed significant functional improvement in the transplantation group compared to the model group （P 〈 0.05）, which was maintained for 2-3 weeks. Compared to the model group, NGF and BDNF levels were significantly increased in the injured region following MSCs transplantation at 3 weeks （P 〈 0.05）, but IL-8 levels remained unchanged （P 〉 0.05）. CONCLUSION： MSCs transplantation increased NGF and BDNF expression in injured spinal cord tissue. MSCs could promote neurological function recovery in SCI rats by upregulating NGF expression and improving regional microenvironments.

A novel rat tail disc degeneration model induced by static bending and compression

Background:A new rat tail intervertebral disc degeneration model was established to observe the morphologic and biologic changes of static bending and compression applied to the discs.Methods:In total,20 Sprague-Dawley rats with similar weight were randomly di-vided into 4 groups.Group 1 served as a control group for a baseline assessment of normal discs.Group 2 underwent a sham surgery,using an external device to bend the vertebrae of coccygeal 8-10.Groups 3 and 4 were the loaded groups,and exter-nal devices were instrumented to bend the spine with a compression level of 1.8 N and 4.5 N,respectively.Magnetic resonance imaging(MRI),histological,and quanti-tative real-time PCR(qRT-PCR)analysis were performed on all animals on day 14 of the experiment.Results:Magnetic resonance imaging and histological results showed that the changes of intervertebral disc degeneration increased with the size of compression load.Some architecture disorganizations in nucleus pulposus and annulus fibro-sus were found on both of the convex and concave side in the groups of 1.8 N and 4.5 N.An upregulation of MM-3,MM-13,and collagen 1-α1 mRNA expression and a downregulation of collagen 2-α1 and aggrecan mRNA expression were observed in the sham and loading groups.Significant changes were found between the loading groups,whereas the sham group showed similar results to the control group.Conclusions:Static bending and compression could induce progressive disc degen-eration,which could be used for biologic study on disc degeneration promoted by static complex loading.

Comprehensive overview of microRNA function in rheumatoid arthritis

MicroRNAs(miRNAs),a class of endogenous single-stranded short noncoding RNAs,have emerged as vital epigenetic regulators of both pathological and physiological processes in animals.They direct fundamental cellular pathways and processes by fine-tuning the expression of multiple genes at the posttranscriptional level.Growing evidence suggests that mi RNAs are implicated in the onset and development of rheumatoid arthritis(RA).RA is a chronic inflammatory disease that mainly affects synovial joints.This common autoimmune disorder is characterized by a complex and multifaceted pathogenesis,and its morbidity,disability and mortality rates remain consistently high.More in-depth insights into the underlying mechanisms of RA are required to address unmet clinical needs and optimize treatment.Herein,we comprehensively review the deregulated mi RNAs and impaired cellular functions in RA to shed light on several aspects of RA pathogenesis,with a focus on excessive inflammation,synovial hyperplasia and progressive joint damage.This review also provides promising targets for innovative therapies of RA.In addition,we discuss the regulatory roles and clinical potential of extracellular mi RNAs in RA,highlighting their prospective applications as diagnostic and predictive biomarkers.

Medical Additive Manufacturing: From a Frontier Technology to the Research and Development of Products

1.Research and development(R&D)and the challenges of raw materials for medical additive manufacturing Raw materials for medical additive manufacturing have a wide range of commonalities that are also seen in many other fields,making them an important basis in the field of three-dimensional(3D)printing.Problems and challenges related to material types,powder properties,formability,viscoelasticity,and so forth also share common features.For example,many metal materials are used in the field of aviation,while metals,polymers,and inorganic materials are used in the field of biomedicine.The most widely used materials in biomedicine are biocompatible.Various homogeneous and non-homogeneous composites are also available for 3D printing,and impose an additional challenge in additive manufacturing;the use of heterogeneous composites in 3D printing is particularly challenging.

Association Analysis of Hyperlipidemia with the 28-Day All-Cause Mortality of COVID-19 in Hospitalized Patients

Objective This study aimed to determine the association of hyperlipidemia with clinical endpoints among hospitalized patients with COVID-19,especially those with pre-existing cardiovascular diseases(CVDs)and diabetes.Methods This multicenter retrospective cohort study included all patients who were hospitalized due to COVID-19 from 21 hospitals in Hubei province,China between December 31,2019 and April 21,2020.Patients who were aged<18 or≥85 years old,in pregnancy,with acute lethal organ injury(e.g.,acute myocardial infarction,severe acute pancreatitis,acute stroke),hypothyroidism,malignant diseases,severe malnutrition,and those with normal lipid profile under lipid-lowering medicines(e.g,statin,niacin,fenofibrate,gemfibrozil,and ezetimibe)were excluded.Propensity score matching(PSM)analysis at 1:1 ratio was performed to minimize baseline differences between patient groups of hyperlipidemia and non-hyperlipidemia.PSM analyses with the same strategies were further conducted for the parameters of hyperlipidemia in patients with increased triglyceride(TG),increased low・density lipoprotein cholesterol(LDL-C),and decreased high-density lipoprotein cholesterol(HDL-C).Mixed-effect Cox model analysis was performed to investigate the associations of the 28-days all-cause deaths of COVID-19 patients with hyperlipidemia and the abnormalities of lipid parameters.The results were verified in male,female patients,and in patients with pre-existing CVDs and type 2 diabetes.Results Of 1094S inpatients confirmed as COVID-19,there were 9822 inpatients included in the study,comprising 3513(35.8%)cases without hyperlipidemia and 6309(64.2%)cases with hyperlipidemia.Based on a mixed-effect Cox model after PSM at 1:1 ratio,hyperlipidemia was not associated with increased or decreased 28-day all-cause death[adjusted hazard ratio(HR),1.17(95%C/,0.95-1.44),P二0.151].Wb found that the parameters of hyperlipidemia were not associated with the risk of 28-day all-cause mortality[adjusted HR,1.23(95%CI,0.98-1.55),P=0.075 in TG increase group;0.78(95%CI,0.57-1.07),P=0.123 in LDL-C increase group;and 1.12(95%CI,0.9-1.39),P=0.299 in HDL-C decrease group,respectively].Hyperlipidemia was also not significantly associated with the increased mortality of COVID-19 in patients accompanied with CVDs or type 2 diabetes,and in both male and female cohorts.Conclusion Our study support that the imbalanced lipid profile is not significantly associated with the 28-day all-cause mortality of COVID-19 patients,even in those accompanied with CVDs or diabetes.Similar results were also obtained in subgroup analyses of abnormal lipid parameters.Therefore,hyperlipidemia might be not a major causative factor for poor outcome of COVID-19,which provides guidance for the intervention of inpatients during the epidemic of COVID-19.

Combining Posterolateral Lumbar Fusion and Posterior Lumber Interbody Fusion Surgery for Treating Three-Level Lumber Spondylolysis and Single-Level Spondylolisthesis: Case Report

Lumbar spondylolysis is a relatively common condition that can cause a variety of clinical manifestations related to the lumbar spine. However, multi-level lumbar spondylolysis is rare and accounts for less than 6% of lumbar spondylolysis. We report a case of three-level lumbar spondylolysis with single-level spondylolisthesis. A 47-year-old woman presented to us with low back pain for 9 years that progressively worsened and the pain was exacerbated with standing and walking. She was diagnosed with three-level lumbar spondylolysis at L3-5 and spondylolisthesis at L4. We performed posterolateral lumber fusion (PLF) and posterior lumbar interbody fusion (PLIF) surgery for her. During the same period, pain recovery and fusion rate of the patient were evaluated after surgery. The results were favorable and proved the efficacy of combining PLF and PLIF technique for treatment for three-level lumbar spondylolysis and single-level spondylolisthesis.

Mechanical force enhanced bony formation in defect implanted with calcium sulphate cement

To improve the osteogenic property of bone repairing materials and to accelerate bone healing are major tasks in bone biomaterials research. The objective of this study was to investigate if the mechanical force could be used to accelerate bone formation in a bony defect in vivo. The calcium sulfate cement was implanted into the left distal femoral epiphyses surgically in 16 rats. The half of rats were subjected to external mechanical force via treadmill exercise, the exercise started at day 7 postoperatively for 30 consecutive days and at a constant speed 8 m·min-1 for 45 min·day-1, while the rest served as a control. The rats were scanned four times longitudinally after surgery using microcomputed tomography and newly formed bone was evaluated. After sacrificing, the femurs had biomechanical test of three-point bending and histological analysis. The results showed that bone healing under mechanical force were better than the control with residual defect areas of 0.64±0.19 mm2 and 1.78±0.39 mm2（P〈0.001）, and the ultimate loads to failure under mechanical force were 69.56±4.74 N, stronger than the control with ultimate loads to failure of 59.17±7.48 N（P=0.039）. This suggests that the mechanical force might be used to improve new bone formation and potentially offer a clinical strategy to accelerate bone healing.

土家族200例单纯肥胖儿童血清HCY水平调查研究

目的调查研究土家族200例单纯肥胖儿童血清同型半胱氨酸(homocysteine,HCY)水平。方法选择2016年2月-2016年10月铜仁市土家族200例单纯肥胖儿童为观察组,同期选择200例健康儿童为对照组。分别采集两组受检者2 mL空腹肘静脉血,检测血清HCY水平及血脂水平[总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、高密度脂蛋白-胆固醇(high density lipoprotein-cholesterol,HDL-C)、低密度脂蛋白-胆固醇(low density lipoprotein-cholesterol,LDL-C)],并比较两组受检者血清HCY及血脂水平。结果观察组中血清HCY水平为(10.91±2.57)μmol/L,对照组中血清HCY水平为(5.13±1.11)μmol/L,组间比较差异具有统计学意义(P<0.05);对照组中LDL-C、TC、TG水平均显著高于观察组,HDL-C水平明显提高,组间比较,差异有统计学意义(P<0.05);单纯性肥胖儿童中,Hcy、TG、TC、LDL-C水平随着肥胖程度增加均渐增加,而HDL-C水平渐降低,差异具有统计学意义(P<0.05);Hcy水平与体质量指数(body mass index,BMI)、TG、TC、LDL-C水平之间均存在明显的正相关性,与HDL-Ch水平呈负相关性。结论与健康儿童相比,单纯肥胖儿童存在明显的脂质代谢异常;血清HCY水平明显高于健康儿童,且随着肥胖程度的增加明显增高,血清HCY水平与血脂及体质量指数有明显的相关性。。

Neural differentiation of allogenic mixed-cultured rat bone mesenchymal stem cells

Many studies showed that bone mesenchymal stem cells (BMSCs) can transdifferentiate to neural cell in vitro. The purpose of this study was to investigate the mixed-culture of allogenic rat BMSCs in vitro, and to perform neural differentiation potential characterization. Rat BMSCs were isolated and cultured by plastic adherence and density gradient centrifugation respectively, and the 3rd passage cells were harvested and mixed-cultured with same concentration. The second passage cells of the mixed-cultured cells were obtained to perform Wright-Gemsa staining for morphological observation, to identify the surface marker of CD29, CD45, CD90 by flow cytometry and induced to differentiate into neural cell, then performed immunocytochemistry of Nestin, NSE and GFAP. Results showed that after Wright-Giemsa staining, the mixed-cultured cells displayed typical spindle-shape, presented layered and whirlpool-like growth;and the mixed-cultured cells were positive for CD29 and CD90, but negative for CD45 by flow cytometry. After induction, the mixed-cultured cells appeared morphological changes of neuron and glial cell, and were positive expression of Nestin, neuron specific enolase (NSE) and glial fibrillary acidic protein (GFAP). The results demonstrated that the mixed-cultured allogenic rat BMSCs can be induced into neural cell such as neuron and glial cell in vitro.

3D-bioprinted anisotropic bicellular living hydrogels boost osteochondral regeneration via reconstruction of cartilage–bone interface

Reconstruction of osteochondral(OC)defects represents an immense challenge due to the need for synchronous regeneration of special stratified tissues.The revolutionary innovation of bioprinting provides a robust method for precise fabrication of tissue-engineered OCs with hierarchical structure;however,their spatial living cues for simultaneous fulfilment of osteogenesis and chondrogenesis to reconstruct the cartilage-bone interface of OC are underappreciated.Here,inspired by natural OC bilayer features,anisotropic bicellular living hydrogels(ABLHs)simultaneously embedding articular cartilage progenitor cells(ACPCs)and bone mesenchymal stem cells(BMSCs)in stratified layers were precisely fabricated via two-channel extrusion bioprinting.The optimum formulation of the 7%GelMA/3%AlgMA hydrogel bioink was demonstrated,with excellent printability at room temperature and maintained high cell viability.Moreover,the chondrogenic ability of ACPCs and the osteogenic ability of BMSCs were demonstrated in vitro,confirming the inherent differential spatial regulation of ABLHs.

Cartilage-inspired self-assembly glycopeptide hydrogels for cartilage regeneration via ROS scavenging

Cartilage injury represents a frequent dilemma in clinical practice owing to its inherently limited self-renewal capacity.Biomimetic strategy-based engineered biomaterial,capable of coordinated regulation for cellular and microenvironmental crosstalk,provides an adequate avenue to boost cartilage regeneration.The level of oxidative stress in microenvironments is verified to be vital for tissue regeneration,yet it is often overlooked in engineered biomaterials for cartilage regeneration.Herein,inspired by natural cartilage architecture,a fibril-network glycopeptide hydrogel(Nap-FFGRGD@FU),composed of marine-derived polysaccharide fucoidan(FU)and naphthalenephenylalanine-phenylalanine-glycine-arginine-glycine-aspartic peptide(Nap-FFGRGD),was presented through a simple supramolecular self-assembly approach.The Nap-FFGRGD@FU hydrogels exhibit a native cartilage-like architecture,characterized by interwoven collagen fibers and attached proteoglycans.Beyond structural simulation,fucoidan-exerted robust biological effects and Arg-Gly-Asp(RGD)sequence-provided cell attachment sites realized functional reinforcement,synergistically promoted extracellular matrix(ECM)production and reactive oxygen species(ROS)elimination,thus contributing to chondrocytes-ECM harmony.In vitro co-culture with glycopeptide hydrogels not only facilitated cartilage ECM anabolic metabolism but also scavenged ROS accumulation in chondrocytes.Mechanistically,the chondro-protective effects induced by glycopeptide hydrogels rely on the activation of endogenous antioxidant pathways associated with nuclear factor erythroid 2-related factor 2(NRF2).In vivo implantation of glycopeptide hydrogels successfully improved the de novo cartilage generation by 1.65-fold,concomitant with coordinately restructured subchondral bone structure.Collectively,our ingeniously crafted bionic glycopeptide hydrogels simultaneously rewired chondrocytes’function by augmenting anabolic metabolism and rebuilt ECM microenvironment via preserving redox equilibrium,holding great potential for cartilage tissue engineering.

Irisin-loaded electrospun core-shell nanofibers as calvarial periosteum accelerate vascularized bone regeneration by activating the mitochondrial SIRT3 pathway

The scarcity of native periosteum poses a significant clinical barrier in the repair of critical-sized bone defects.The challenge of enhancing regenerative potential in bone healing is further compounded by oxidative stress at the fracture site.However,the introduction of artificial periosteum has demonstrated its ability to promote bone regeneration through the provision of appropriate mechanical support and controlled release of proosteogenic factors.In this study,a poly(L-lactic acid)(PLLA)/hyaluronic acid(HA)-based nanofibrous membrane was fabricated using the coaxial electrospinning technique.The incorporation of irisin into the core-shell structure of PLLA/HA nanofibers(PLLA/HA@Irisin)achieved its sustained release.In vitro experiments demonstrated that the PLLA/HA@Irisin membranes exhibited favorable biocompatibility.The osteogenic differentiation of bone marrow mesenchymal stem cells(BMMSCs)was improved by PLLA/HA@Irisin,as evidenced by a significant increase in alkaline phosphatase activity and matrix mineralization.Mechanistically,PLLA/HA@Irisin significantly enhanced the mitochondrial function of BMMSCs via the activation of the sirtuin 3 antioxidant pathway.To assess the therapeutic effectiveness,PLLA/HA@Irisin membranes were implanted in situ into critical-sized calvarial defects in rats.The results at 4 and 8 weeks post-surgery indicated that the implantation of PLLA/HA@Irisin exhibited superior efficacy in promoting vascularized bone formation,as demonstrated by the enhancement of bone matrix synthesis and the development of new blood vessels.The results of our study indicate that the electrospun PLLA/HA@Irisin nanofibers possess characteristics of a biomimetic periosteum,showing potential for effectively treating critical-sized bone defects by improving the mitochondrial function and maintaining redox homeostasis of BMMSCs.

One-year clinical study of NeuroR egen scaffold implantation following scar resection in complete chronic spinal cord injury patients

The objective of this clinical study was to assess the safety and feasibility of the collagen scaffold, Neuro Regen scaffold, one year after scar tissue resection and implantation. Scar tissue is a physical and chemical barrier that prevents neural regeneration. However, identification of scar tissue is still a major challenge. In this study, the nerve electrophysiology method was used to distinguish scar tissue from normal neural tissue, and then different lengths of scars ranging from 0.5–4.5 cm were surgically resected in five complete chronic spinal cord injury(SCI) patients. The NeuroR egen scaffold along with autologous bone marrow mononuclear cells(BMMCs), which have been proven to promote neural regeneration and SCI recovery in animal models, were transplanted into the gap in the spinal cord following scar tissue resection. No obvious adverse effects related to scar resection or Neuro Regen scaffold transplantation were observed immediately after surgery or at the 12-month follow-up. In addition, patients showed partially autonomic nervous function improvement, and the recovery of somatosensory evoked potentials(SSEP) from the lower limbs was also detected. The results indicate that scar resection and Neuro Regen scaffold transplantation could be a promising clinical approach to treating SCI.

Punicalagin ameliorates collagen-induced arthritis by downregulating M1 macrophage and pyroptosis via NF-κB signaling pathway

Rheumatoid arthritis(RA)is a chronic inflammatory disease that eventually leads to disability.Inflammatory cell infiltration,severe joint breaking and systemic bone loss are the main clinical symptoms.In this study,we established a collagen-induced arthritis(CIA)model and found a large number of M1 macrophages and pyroptosis,which are important sources of proinflammatory cytokines.Punicalagin(PUN)is an active substance extracted from pomegranate peel.We found that it inhibited joint inflammation,cartilage damage and systemic bone destruction in CIA mice.PUN effectively alleviated the high expression of inflammatory cytokines in synovial tissue in vivo.PUN treatment shifted macrophages from the M1 phenotype to the M2 phenotype after stimulation with lipopolysaccharide(LPS)and interferon(IFN)-γ.The expression of inducible nitric oxide synthase(i NOS)and other proinflammatory cytokines released by M1 macrophages was decreased in the PUN treatment group.However,simultaneously,the expression of markers of anti-inflammatory M2 macrophages,such as arginase(Arg)-1 and interleukin(IL)-10,was increased.In addition,PUN treatment attenuated pyroptosis by downregulating the expression of NLRP3 and caspase-1,thereby preventing inflammatory cell death resulting from the release of IL-1βand IL-18.Mechanistically,PUN inhibited the activation of receptor activators of the nuclear factor-κB(NF-κB)signaling pathway,which contributes to M1 polarization and pyroptosis of macrophages.We concluded that PUN ameliorated pathological inflammation by inhibiting M1 phenotype polarization and pyroptosis and has great potential as a therapeutic treatment for human RA.

Regulation of the inflammatory cycle by a controllable release hydrogel for eliminating postoperative inflammation after discectomy

Surgery is the final choice for most patients with intervertebral disc degeneration(IDD).Operation-caused trauma will cause inflammation in the intervertebral disc.Serious inflammation will cause tissue defects and induce tissue degeneration,IDD recurrence and the occurrence of other diseases.Therefore,we proposed a scheme to treat recurrence after discectomy by inhibiting inflammation with an aspirin(ASP)-loaded hydrogel to restore the mechanical stability of the spine and relieve local inflammation.ASP-liposomes(ASP-Lips)were incorporated into a photocrosslinkable gelatin-methacryloyl(GelMA)via mixing.This material can effectively alleviate inflammation by inhibiting the release of high mobility group box 1(HMGB1)from the nucleus to the cytoplasm.We further assessed the expression of inflammatory cytokines,such as interleukin 6(IL-6)and tumor necrosis factor-α(TNF-α),and degeneration-related factors,such as type II collagen(COL-2),Aggrecan,matrix metallopeptidases-3(MMP-3),MMP-13,a disintegrin and metalloproteinase with thrombospondin motifs-4(ADAMTS-4)and ADAMTS-5 in rat nucleus pulpous cells.The level of IDD was analyzed through H&E,safranin-O staining and immunohistochemistry in rabbit samples.In vitro,we found that ASP-Lip@GelMA treatment significantly decreased inflammatory cytokines,MMP-3 and-13,and ADAMTS-4 and-5 and up-regulated COL-2 and Aggrecan via the inhibited release of HMGB-1 from the nucleus.In vivo,ASP-Lip@GelMA can effectively inhibit inflammation of local tissue after disc surgery and fill local tissue defects.This composite hydrogel system is a promising way to treat the recurrence of IDD after surgery without persistent complications.

Long-term clinical observation of patients with acute and chronic complete spinal cord injury after transplantation of Neuro Regen scaffold

Spinal cord injury(SCI)often results in an inhibitory environment at the injury site.In our previous studies,transplantation of a scaffold combined with stem cells was proven to induce neural regeneration in animal models of complete SCI.Based on these preclinical studies,collagen scaffolds loaded with the patients’own bone marrow mononuclear cells or human umbilical cord mesenchymal stem cells were transplanted into SCI patients.Fifteen patients with acute complete SCI and 51 patients with chronic complete SCI were enrolled and followed up for 2 to 5 years.No serious adverse events related to functional scaffold transplantation were observed.Among the patients with acute SCI,five patients achieved expansion of their sensory positions and six patients recovered sensation in the bowel or bladder.Additionally,four patients regained voluntary walking ability accompanied by reconnection of neural signal transduction.Among patients with chronic SCI,16 patients achieved expansion of their sensation level and 30 patients experienced enhanced reflexive defecation sensation or increased skin sweating below the injury site.Nearly half of the patients with chronic cervical SCI developed enhanced finger activity.These long-term follow-up results suggest that functional scaffold transplantation may represent a feasible treatment for patients with complete SCI.

Characterization and immunogenicity of bone marrow-derived mesenchymal stem cells under osteoporotic conditions

Mesenchymal stem cells (MSCs) are characterized by their multilineage potential and low immunogenicity.However,the properties of MSCs under pathological conditions are unclear.The current study investigated the differentiation potential and immunological characteristics of bone marrow-derived MSCs from ovariectomized-osteoporotic rats (OP-BMSCs).Although the expression of cell morphology-and sternness-related surface markers was similar between OP-BMSCs and BMSCs from healthy rats (H-BMSCs),the proliferation rate was significantly decreased compared with that of H-BMSCs.Regarding multilineage potential,osteogenesis and chondrogenesis abilities of OP-BMSCs decreased,but the adipogenesis ability was significantly enhanced compared with that of H-BMSCs.As expected,decreased osteogenesis following osteogenic induction resulted in reduced expression of p-catenin,osteocalcin,and runt-related transcription factor 2 in OP-BMSCs.Remarkably,the expression of the co-stimulatory proteins CD40 and CD80 was significantly higher,whereas the expression of the negative costimulatory molecule programmed cell death ligand 1 was significantly lower in the OP-BMSCs than that in H-BMSCs.Consequently,H-BMSCs inhibited the proliferation and secretion of inflammatory cytokines from anti-CD3 antibody-activated T cells,whereas OP-BMSCs did not.These results indicate that decreased osteogenesis and increased immunogenicity of OPBMSCs contribute to bone loss in osteoporosis.