In vivo imaging of the neuronal response to spinal cord injury:a narrative review

Deciphering the neuronal response to injury in the spinal cord is essential for exploring treatment strategies for spinal cord injury(SCI).However,this subject has been neglected in part because appropriate tools are lacking.Emerging in vivo imaging and labeling methods offer great potential for observing dynamic neural processes in the central nervous system in conditions of health and disease.This review first discusses in vivo imaging of the mouse spinal cord with a focus on the latest imaging techniques,and then analyzes the dynamic biological response of spinal cord sensory and motor neurons to SCI.We then summarize and compare the techniques behind these studies and clarify the advantages of in vivo imaging compared with traditional neuroscience examinations.Finally,we identify the challenges and possible solutions for spinal cord neuron imaging.

Epidemiological and clinical features,treatment status,and economic burden of traumatic spinal cord injury in China:a hospital-based retrospective study

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death.China has the largest population of patients with traumatic spinal cord injury.Previous studies of traumatic spinal cord injury in China have mostly been regional in scope;national-level studies have been rare.To the best of our knowledge,no national-level study of treatment status and economic burden has been performed.This retrospective study aimed to examine the epidemiological and clinical features,treatment status,and economic burden of traumatic spinal cord injury in China at the national level.We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China.Patient epidemiological and clinical features,treatment status,and total and daily costs were recorded.Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program.The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall(annual percentage change,-0.5%and 2.1%,respectively).A total of 10,053(74.7%)patients underwent surgery.Only 2.8%of patients who underwent surgery did so within 24 hours of injury.A total of 2005(14.9%)patients were treated with high-dose(≥500 mg)methylprednisolone sodium succinate/methylprednisolone(MPSS/MP);615(4.6%)received it within 8 hours.The total cost for acute traumatic spinal cord injury decreased over the study period(-4.7%),while daily cost did not significantly change(1.0%increase).Our findings indicate that public health initiatives should aim at improving hospitals’ability to complete early surgery within 24 hours,which is associated with improved sensorimotor recovery,increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

Application value of biofluid-based biomarkers for the diagnosis and treatment of spinal cord injury

Recent studies in patients with spinal cord injuries(SCIs)have confirmed the diagnostic potential of biofluid-based biomarkers,as a topic of increasing interest in relation to SCI diagnosis and treatment.This paper reviews the research progress and application prospects of recently identified SCI-related biomarkers.Many structural proteins,such as glial fibrillary acidic protein,S100-β,ubiquitin carboxy-terminal hydrolase-L1,neurofilament light,and tau protein were correlated with the diagnosis,American Spinal Injury Association Impairment Scale,and prognosis of SCI to different degrees.Inflammatory factors,including interleukin-6,interleukin-8,and tumor necrosis factorα,are also good biomarkers for the diagnosis of acute and chronic SCI,while non-coding RNAs(micro RNAs and long non-coding RNAs)also show diagnostic potential for SCI.Trace elements(Mg,Se,Cu,Zn)have been shown to be related to motor recovery and can predict motor function after SCI,while humoral markers can reflect the pathophysiological changes after SCI.These factors have the advantages of low cost,convenient sampling,and ease of dynamic tracking,but are also associated with disadvantages,including diverse influencing factors and complex level changes.Although various proteins have been verified as potential biomarkers for SCI,more convincing evidence from large clinical and prospective studies is thus required to identify the most valuable diagnostic and prognostic biomarkers for SCI.

Ferroptosis inhibition protects vascular endothelial cells and maintains integrity of the blood-spinal cord barrier after spinal cord injury

Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord injury.Ferro ptosis contributes to the pathogenesis of spinal cord injury.We hypothesized that ferroptosis is involved in disruption of the blood-s pinal cord barrier.In this study,we administe red the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal co rd injury in rats.Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord inju ry.Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein.Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury,as shown by the immunofluorescence of an endothelial cell marker(rat endothelium cell antigen-1,RECA-1) and fe rroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase.Liproxstatin-1reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member4 and 15-lipoxygenase.Furthermore,inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment.In summary,liproxstatin-1im proved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-s pinal co rd barrier integrity.

Adhesive hydrogels in osteoarthritis:from design to application

Osteoarthritis(OA)is the most common type of degenerative joint disease which affects 7%of the global population and more than 500 million people worldwide.One research frontier is the development of hydrogels for OA treatment,which operate either as functional scaffolds of tissue engineering or as delivery vehicles of functional additives.Both approaches address the big challenge:establishing stable integration of such delivery systems or implants.Adhesive hydrogels provide possible solutions to this challenge.However,few studies have described the current advances in using adhesive hydrogel for OA treatment.This review summarizes the commonly used hydrogels with their adhesion mechanisms and components.Additionally,recognizing that OA is a complex disease involving different biological mechanisms,the bioactive therapeutic strategies are also presented.By presenting the adhesive hydrogels in an interdisciplinary way,including both the fields of chemistry and biology,this review will attempt to provide a comprehensive insight for designing novel bioadhesive systems for OA therapy.

Clinical guidelines for indications,techniques,and complications of autogenous bone grafting

Autogenous bone grafts have long been considered the“gold standard”and most effective material in bone regeneration procedures.[1]Autogenous bone grafts are used to repair bone defects caused by nonunion,infection,tumor resection,and spinal and joint fusion.[2]It has been reported that more than 200,000 autologous bone grafts are performed in the United States each year.[3]Although there are no specific statistics on the annual number of bone grafts performed in China,autologous bone grafting is the most common surgical technique in orthopedics.The iliac crest remains the most common donor site,along with the fibula,ribs,tibial metaphysis,proximal humerus,distal radius,and greater trochanter.[4,5]Various bone-graft options provide different amounts and qualities of cortical,cancellous,and corticocancellous bone.[6,7]Autogenous bone graft is osteogenic,histocompatible,provides structural support.

Self-rectifying magnetoelectric device for remote neural regeneration and function restoration

Recently,Joshua C.Chen,Gauri Bhave,and Jacob T.Robinson from Rice University reported a magnetoelectric nonlinear metamaterial(MNM)for neural signal transmission and nerve function restoration.1 Nonlinear charge transport between the semiconductor layers enabled this magnetoelectric(ME)metamaterial to have a nonlinear ME coupling coefficient,which allowed for self-rectification(Figure 1).

Skeleton-vasculature chain reaction: a novel insight into the mystery of homeostasis

Angiogenesis and osteogenesis are coupled.However,the cellular and molecular regulation of these processes remains to be further investigated.Both tissues have recently been recognized as endocrine organs,which has stimulated research interest in the screening and functional identification of novel paracrine factors from both tissues.This review aims to elaborate on the novelty and significance of endocrine regulatory loops between bone and the vasculature.In addition,research progress related to the bone vasculature,vessel-related skeletal diseases,pathological conditions,and angiogenesis-targeted therapeutic strategies are also summarized.With respect to future perspectives,new techniques such as single-cell sequencing,which can be used to show the cellular diversity and plasticity of both tissues,are facilitating progress in this field.Moreover,extracellular vesicle-mediated nuclear acid communication deserves further investigation.In conclusion,a deeper understanding of the cellular and molecular regulation of angiogenesis and osteogenesis coupling may offer an opportunity to identify new therapeutic targets.

Chitin scaffold combined with autologous small nerve repairs sciatic nerve defects

Although autologous nerve transplantation is the gold standard for treating peripheral nerve defects,it has many clinical limitations.As an alternative,various tissue-engineered nerve grafts have been developed to substitute for autologous nerves.In this study,a novel nerve graft composed of chitin scaffolds and a small autologous nerve was used to repair sciatic nerve defects in rats.The novel nerve graft greatly facilitated regeneration of the sciatic nerve and myelin sheath,reduced atrophy of the target muscle,and effectively restored neurological function.When the epineurium of the small autogenous nerve was removed,the degree of nerve regeneration was similar to that which occurs after autogenous nerve transplantation.These findings suggest that our novel nerve graft might eventually be a new option for the construction of tissue-engineered nerve scaffolds.The study was approved by the Research Ethics Committee of Peking University People's Hospital(approval No.2019 PHE27)on October 18,2019.

Early patellar tendon rupture after total knee arthroplasty: A direct repair method

BACKGROUND Patellar tendon rupture after total knee arthroplasty(TKA)is a catastrophic complication.Although the occurrence of this injury is rare,it can lead to significant dysfunction for the patient and is very tricky to deal with.There has been no standard treatment for early patella tendon rupture after TKA,and long-term follow-up data are lacking.AIM To introduce a direct repair method for early patella tendon rupture following TKA and determine the clinical outcomes and complications of this method.METHODS During the period of 2008 to 2021,3265 consecutive TKAs were retrospectively reviewed.Twelve patients developed early patellar tendon rupture postoperatively and were treated by a direct repair method.Mean follow-up was 5.7 years.Demographic,operative,and clinical data were collected.The clinical outcomes were assessed using the Western Ontario and McMaster Universities(WOMAC)score,the Hospital for Special Surgery(HSS)score,knee range of motion,extensor lag,and surgical complications.Descriptive statistics and paired t test were employed to analyze the data.RESULTS For all 12 patients who underwent direct repair for early patellar tendon rupture,3 patients failed:One(8.3%)for infection and two(17.6%)for re-fracture.The two patients with re-fracture both underwent reoperation to reconstruct the extensor mechanism and the patient with infection underwent revision surgery.The range of motion was 109.2°±10.6°preoperatively to 87.9°±11°postoperatively,mean extensor lag was 21°at follow-up,and mean WOMAC and HSS scores were 65.8±30.9 and 60.3±21.7 points,respectively.CONCLUSION This direct repair method of early patellar tendon rupture is not an ideal therapy.It is actually ineffective for the recovery of knee joint function in patients,and is still associated with severe knee extension lag and high complication rates.Compared with the outcomes of other repair methods mentioned in the literature,this direct repair method shows poor clinical outcomes.

Bone microenvironment regulative hydrogels with ROS scavenging and prolonged oxygen-generating for enhancing bone repair

Large bone defects resulting from fractures and disease are a major clinical challenge,being often unable to heal spontaneously by the body’s repair mechanisms.Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration.However,replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells.Therefore,reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair.Herein,we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels(CPP-L/GelMA)as a“bone microenvironment regulative hydrogel”to reverse the hypoxic microenvironment in bone defects region.CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase(CAT)and ROS-responsive oxygen-releasing nanoparticles(PFC@PLGA/PPS)co-loaded liposome(CCP-L)and GelMA hydrogels.Under hypoxic condition,CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks.The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis.Finally,CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway.Hence,CPP-L/GelMA,as a bone microenvironment regulative hydrogel for bone tissue respiration,can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region,possessing of great clinical therapeutic potential.

3D-printed fish gelatin scaffolds for cartilage tissue engineering

Knee osteoarthritis is a chronic disease caused by the deterioration of the knee joint due to various factors such as aging,trauma,and obesity,and the nonrenewable nature of the injured cartilage makes the treatment of osteoarthritis challenging.Here,we present a three-dimensional(3D)printed porous multilayer scaffold based on cold-water fish skin gelatin for osteoarticular cartilage regeneration.To make the scaffold,cold-water fish skin gelatin was combined with sodium alginate to increase viscosity,printability,and mechanical strength,and the hybrid hydrogel was printed according to a pre-designed specific structure using 3D printing technology.Then,the printed scaffolds underwent a double-crosslinking process to enhance their mechanical strength even further.These scaffolds mimic the structure of the original cartilage network in a way that allows chondrocytes to adhere,proliferate,and communicate with each other,transport nutrients,and prevent further damage to the joint.More importantly,we found that cold-water fish gelatin scaffolds were nonimmunogenic,nontoxic,and biodegradable.We also implanted the scaffold into defective rat cartilage for 12 weeks and achieved satisfactory repair results in this animal model.Thus,cold-water fish skin gelatin scaffolds may have broad application potential in regenerative medicine.

Fish scale-derived scaffolds with MSCs loading for photothermal therapy of bone defect

Tissue engineering scaffolds have presented effective value in bone repair.However,the integration of the diverse components,complex structures,multifunction to impart the scaffolds with improved applicability is still a challenge.Here,we propose a novel fish-derived scaffold combined with photothermal therapy and mesenchymal stem cells(MSCs)to promote bone regeneration.The fish-derived scaffold is composed of the decellularized fish scale and gelatin methacrylate synthesized from fish gelatin(fGelMA),which can promote the proliferation and osteogenesis of MSCs with no obvious immunological rejection.Furthermore,the black phosphorus(BP)nanosheets are incorporated into the fGelMA hydrogel network,which can endow the hydrogel with the capacity of photothermal conversion stimulated by near-infrared(NIR)light.The fish-derived scaffold can promote the osteogenesis process of MSCs with higher expression of osteogenic markers and higher mineralization assisted by the NIR light in vitro.The regeneration of mice calvarial defect has also been accelerated by the scaffold with photothermal therapy and MSCs.These results suggest that the fish-derived scaffold,photothermal therapy,MSCs-based regenerative therapy is a promising clinical strategy in bone regeneration.

Chinese expert consensus on organ protection of transplantation(2022 edition)

Introduction Organ transplantation increases survival and improves qual-ity of life to many patients with end-stage organ failure.Or-gan shortage is a worldwide problem that restricts organ trans-plantation[1].Organ procurement and preservation as well as ischemia-reperfusion injury(IRI)after transplantation are the im-portant factors affecting prognosis of recipients.Since the de-velopment of organ transplantation technology in the 20th cen-tury,organ protection technology has been a most promising con-cept in this field.Organ preservation solutions such as the Collins solution,University of Wisconsin(UW)solution,and histidine-tryptophan-ketoglutarate(HTK)solution were developed sequen-tially[2],which developed rapidly in static cold storage(SCS)tech-niques.SCS remains the standard preservation technique for organ transplantation[2].

Liposomalα-cyperone targeting bone resorption surfaces suppresses osteoclast differentiation and osteoporosis progression via the PI3K/Akt axis

Osteoporosis is a metabolic dysregulation of bone that occurs mainly in postmenopausal women,and the hyperfunction of osteoclasts is the primary contributor to postmenopausal osteoporosis.However,the development of effective therapeutic drugs and precise delivery systems remains a challenge in the field of anti-absorption therapy.Here,we reported theα-cyperone(α-CYP)for anti-osteoporosis and developed a liposome-based nano-drug delivery system ofα-CYP,that specifically targets the bone resorption interface.Firstly,we found that theα-CYP,one of the major sesquiterpenes of Cyperus rotundus L.,attenuated the progression of osteoporosis in ovariectomized(OVX)mice and down-regulated the expression of phosphorylated proteins of phosphoinositide 3-kinase(PI3K)and protein kinase B(Akt),causing down-regulation of osteoclast-related genes/proteins and curbing osteoclast differentiation.Furthermore,α-CYP reversed the activation of osteoclastic differentiation and enhanced osteoporosis-related proteins expression caused by PI3K/Akt agonist(YS-49).More importantly,we adopted the osteoclastic resorption surface targeting peptide Asp8 and constructed the liposome(lipαC@Asp8)to deliverα-CYP to osteoclasts and confirmed its anti-osteoporosis effect and enhanced osteoclast inhibition by blocking PI3K/Akt axis.In conclusion,this study demonstrated thatα-CYP inhibits osteoclast differentiation and osteoporosis development by silencing PI3K/Akt pathway,and the liposome targeting delivery systems loaded withα-CYP might provide a novel and effective strategy to treat osteoporosis.

Bone targeting antioxidative nano-iron oxide for treating postmenopausal osteoporosis

Osteoporosis is the most common degenerative orthopedic disease in the elderly.Recently,the therapeutic methods for osteoporosis have shifted towards the regulation of local immunity in bone tissues,which could provide a suitable environment for the positive regulation of bone metabolism,promoting osteogenic differentiation and inhibiting osteoclast differentiation.Our previous work demonstrated that iron oxide nanoparticles(IONPs)could positively regulate bone metabolism in vitro.In this study,we further demonstrated that daily administration of IONPs relieved estrogen deficiency-induced osteoporosis via scavenging reactive oxygen species in vivo.Meanwhile,IONPs promoted the osteogenic differentiation of bone marrow mesenchymal stem cells and inhibited the osteoclast differentiation of monocytes from IONPs treated mice.Besides,alendronate,a clinically used anti-osteoporosis bisphosphate,was employed to precisely deliver the IONPs to the bone tissues and played a synergically therapeutic role.Eventually,we verified the bone targeting ability,therapeutic efficiency,and biocompatibility of the novel bone target iron oxides in ovariectomy-induced osteoporotic mice.By applying BTNPs,the OVX-induced osteoporosis was significantly revised in mice models via the positive regulation of bone metabolism.

Phosphorylation inhibition of protein-tyrosine phosphatase 1B tyrosine-152 induces bone regeneration coupled with angiogenesis for bone tissue engineering

A close relationship has been reported to exist between cadherin-mediated cell-cell adhesion and integrin-mediated cell mobility,and protein tyrosine phosphatase 1B(PTP1B)may be involved in maintaining this homeostasis.The stable residence of mesenchymal stem cells(MSCs)and endothelial cells(ECs)in their niches is closely related to the regulation of PTP1B.However,the exact role of the departure of MSCs and ECs from their niches during bone regeneration is largely unknown.Here,we show that the phosphorylation state of PTP1B tyrosine-152(Y152)plays a central role in initiating the departure of these cells from their niches and their subsequent recruitment to bone defects.Based on our previous design of a PTP1B Y152 region-mimicking peptide(152RM)that significantly inhibits the phosphorylation of PTP1B Y152,further investigations revealed that 152RM enhanced cell migration partly via integrinαvβ3 and promoted MSCs osteogenic differentiation partly by inhibiting ATF3.Moreover,152RM induced type H vessels formation by activating Notch signaling.Demineralized bone matrix(DBM)scaffolds were fabricated with mesoporous silica nanoparticles(MSNs),and 152RM was then loaded onto them by electrostatic adsorption.The DBM-MSN/152RM scaffolds were demonstrated to induce bone formation and type H vessels expansion in vivo.In conclusion,our data reveal that 152RM contributes to bone formation by coupling osteogenesis with angiogenesis,which may offer a potential therapeutic strategy for bone defects.

Nanoenzyme engineered neutrophil-derived exosomes attenuate joint injury in advanced rheumatoid arthritis via regulating inflammatory environment

Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by synovitis and destruction of cartilage,promoted by sustained inflammation.However,current treatments remain unsatisfactory due to lacking of selective and effective strategies for alleviating inflammatory environments in RA joint.Inspired by neutrophil chemotaxis for inflammatory region,we therefore developed neutrophil-derived exosomes functionalized with sub-5 nm ultrasmall Prussian blue nanoparticles(uPB-Exo)via click chemistry,inheriting neutrophil-targeted biological molecules and owning excellent anti-inflammatory properties.uPB-Exo can selectively accumulate in activated fibroblast-like synoviocytes,subsequently neutralizing pro-inflammatory factors,scavenging reactive oxygen species,and alleviating inflammatory stress.In addition,uPB-Exo effectively targeted to inflammatory synovitis,penetrated deeply into the cartilage and real-time visualized inflamed joint through MRI system,leading to precise diagnosis of RA in vivo with high sensitivity and specificity.Particularly,uPB-Exo induced a cascade of anti-inflammatory events via Th17/Treg cell balance regulation,thereby significantly ameliorating joint damage.Therefore,nanoenzyme functionalized exosomes hold the great potential for enhanced treatment of RA in clinic.

Antibiotic-loaded amphora-shaped pores on a titanium implant surface enhance osteointegration and prevent infections

Artificial prostheses for joint replacement are indispensable in orthopedic surgery.Unfortunately,the implanted surface is attractive to not only host cells but also bacteria.To enable better osteointegration,a mechanically stable porous structure was created on a titanium surface using laser treatment and metallic silver particles were embedded in a hydrophilic titanium oxide layer on top.The laser structuring resulted in unique amphora-shaped pores.Due to their hydrophilic surface conditions and capillary forces,the pores can be loaded preoperative with the antibiotic of choice/need,such as gentamicin.Cytotoxicity and differentiation assays with primary human osteoblast-like cells revealed no negative effect of the surface modification with or without gentamicin loading.An in vivo biocompatibility study showed significantly enhanced osteointegration as measured by push-out testing and histomorphometry 56 days after the implantation of the K-wires into rat femora.Using a S.aureus infection model,the porous,silver-coated K-wires slightly reduced the signs of bone destruction,while the wires were still colonized after 28 days.Loading the amphora-shaped pores with gentamicin significantly reduced the histopathological signs of bone destruction and no bacteria were detected on the wires.Taken together,this novel surface modification can be applied to new or established orthopedic implants.It enables preoperative loading with the antibiotic of choice/need without further equipment or post-coating,and supports osteointegration without a negative effect of the released dug,such as gentamicin.