Regenerative medicine strategies for chronic complete spinal cord injury

Spinal cord injury is a condition in which the parenchyma of the spinal cord is damaged by trauma or various diseases.While rapid progress has been made in regenerative medicine for spinal cord injury that was previously untreatable,most research in this field has focused on the early phase of incomplete injury.However,the majority of patients have chronic severe injuries;therefore,treatments for these situations are of fundamental importance.The reason why the treatment of complete spinal cord injury has not been studied is that,unlike in the early stage of incomplete spinal cord injury,there are various inhibitors of neural regeneration.Thus,we assumed that it is difficult to address all conditions with a single treatment in chronic complete spinal cord injury and that a combination of several treatments is essential to target severe pathologies.First,we established a combination therapy of cell transplantation and drug-releasing scaffolds,which contributes to functional recovery after chronic complete transection spinal cord injury,but we found that functional recovery was limited and still needs further investigation.Here,for the further development of the treatment of chronic complete spinal cord injury,we review the necessary approaches to the different pathologies based on our findings and the many studies that have been accumulated to date and discuss,with reference to the literature,which combination of treatments is most effective in achieving functional recovery.

Advances in clinical applications of bioceramics in the new regenerative medicine era

In this editorial,we comment on the hard and soft tissue applications of different ceramic-based scaffolds prepared by different mechanisms such as 3D printing,sol-gel,and electrospinning.The new concept of regenerative medicine relies on biomaterials that can trigger in situ tissue regeneration and stem cell recruitment at the defect site.A large percentage of these biomaterials is ceramic-based as they provide the essential requirements of biomaterial principles such as tailored multisize porosity,antibacterial properties,and angiogenic properties.All these previously mentioned properties put bioceramics on top of the hierarchy of biomaterials utilized to stimulate tissue regeneration in soft and hard tissue wounds.Multiple clinical applications registered the use of these materials in triggering soft tissue regeneration in healthy and diabetic patients such as bioactive glass nanofibers.The results were promising and opened new frontiers for utilizing these materials on a larger scale.The same results were mentioned when using different forms and formulas of bioceramics in hard defect regeneration.Some bioceramics were used in combination with other polymers and biological scaffolds to improve their regenerative and mechanical properties.All this progress will enable a larger scale of patients to receive such services with ease and decrease the financial burden on the government.

Therapeutic potential of urine-derived stem cells in renal regeneration following acute kidney injury:A comparative analysis with mesenchymal stem cells

BACKGROUND Acute kidney injury(AKI)is a common clinical syndrome with high morbidity and mortality rates.The use of pluripotent stem cells holds great promise for the treatment of AKI.Urine-derived stem cells(USCs)are a novel and versatile cell source in cell-based therapy and regenerative medicine that provide advantages of a noninvasive,simple,and low-cost approach and are induced with high multidifferentiation potential.Whether these cells could serve as a potential stem cell source for the treatment of AKI has not been determined.METHODS Stem cell markers with multidifferentiation potential were isolated from human amniotic fluid.AKI severe combined immune deficiency(SCID)mice models were induced by means of an intramuscular injection with glycerol.USCs isolated from human-voided urine were administered via tail veins.The functional changes in the kidney were assessed by the levels of blood urea nitrogen and serum creatinine.The histologic changes were evaluated by hematoxylin and eosin staining and transferase dUTP nick-end labeling staining.Meanwhile,we compared the regenerative potential of USCs with bone marrow-derived mesenchymal stem cells(MSCs).RESULTS Treatment with USCs significantly alleviated histological destruction and functional decline.The renal function was rapidly restored after intravenous injection of 5×105 human USCs into SCID mice with glycerol-induced AKI compared with injection of saline.Results from secretion assays conducted in vitro demonstrated that both stem cell varieties released a wide array of cytokines and growth factors.This suggests that a mixture of various mediators closely interacts with their biochemical functions.Two types of stem cells showed enhanced tubular cell prolif-eration and decreased tubular cell apoptosis,although USC treatment was not more effective than MSC treatment.We found that USC therapy significantly improved renal function and histological damage,inhibited inflammation and apoptosis processes in the kidney,and promoted tubular epithelial proliferation.CONCLUSION Our study demonstrated the potential of USCs for the treatment of AKI,representing a new clinical therapeutic strategy.

Regenerative Braking Energy Recovery System of Metro Train Based on Dual-Mode Power Management

In order to fully utilize the regenerative braking energy of metro trains and stabilize the metro DC traction busbar voltage,a hybrid regenerative braking energy recovery system with a dual-mode power management strategy is proposed.Firstly,the construction of the hybrid regenerative braking energy recovery system is explained.Then,based on the power demand of low-voltage load in metro stations,a dual-mode power management strategy is proposed to allocate the reference power of each system according to the different working conditions,and the control methods of each system are set.Finally,the correctness and effectiveness of the dual-mode strategy are verified through simulation,and the proposed braking energy utilization scheme is compared with other singleform utilization schemes.The results illustrate that the hybrid system with the dual-mode strategy can effectively recycle the regenerative braking energy of metro train and inhibit the busbar voltage fluctuation;the proposed braking energy utilization scheme has certain advantages on energy recovery and DC bus voltage stabilization compared with other single-form schemes;the proposed power management strategy can correctly allocate the reference power of each system with a lower construction cost.

Modified approach of regenerative treatment for distal intrabony defect beneath non-keratinized mucosa at terminal molar:A case report

BACKGROUND Intrabony defects beneath non-keratinized mucosa are frequently observed at the distal site of terminal molars.Consequently,the application of regenerative treatment using the modified wedge-flap technique is considered impractical for these specific dental conditions.CASE SUMMARY This article proposes a modified surgical procedure aimed at exposing the distal intrabony defect by making a vertical incision in the keratinized buccal gingiva.The primary objective is to maintain gingival flap stability,thereby facilitating periodontal regeneration.The described technique was successfully employed in a case involving the left mandibular second molar,which presented with an intrabony defect without keratinized gingiva at the distal site.In this case,an incision was made on the disto-buccal gingival tissue,creating a tunnel-like separation of the distal non-keratinized soft tissue to expose the intrabony defect.Subsequently,bone grafting and guided tissue regeneration surgeries were performed,resulting in satisfactory bone fill at 9 mo postoperatively.CONCLUSION This technique offers a regenerative opportunity for the intrabony defects beneath non-keratinized mucosa and is recommended for further research.

Emergence of the stromal vascular fraction and secretome in regenerative medicine

Recently,we read a mini-review published by Jeyaraman et al.The article explored the optimal methods for isolating mesenchymal stromal cells from adipose tissue-derived stromal vascular fraction(SVF).Key factors include tissue source,processing techniques,cell viability assessment,and the advantages/disadvantages of autologous vs allogeneic use.The authors emphasized the need for standardized protocols for SVF isolation,ethical and regulatory standards for cell-based therapy,and safety to advance mesenchymal stromal cell-based therapies in human patients.This manuscript shares our perspective on SVF isolation in canines.We discussed future directions to potentiate effective regenerative medicine therapeutics in human and veterinary medicine.

Role of immune relevant factors in regenerative processes of bone tissue: a bibliometric and visualized analysis

Background:There is a deficiency of bibliometric and visually represented analysis in research on the immunological related variables involved in bone tissue regeneration.Using bibliometric and visual analysis,this study sought to thoroughly examine the hotspots and future directions in the investigation of immunological important variables in bone tissue regeneration.Methods:The Web of Science Core Collection(WoSCC)database was searched and a collection of published works on the subject of immunological related factors in bone tissue regeneration between 2000 and 2021 was generated.The data chosen from the WoSCC were then subjected to a systematic bibliometric and visualized analysis using the online bibliometric analytics system,Apache ECharts,VOSviewer,Bibliographic Items Co-occurrence Matrix Builder 2.0,and Gcluto 1.0.Results:For this investigation,1,088 publications on the involvement of immune related components in bone tissue regeneration were chosen.Between 2000 and 2021,China maintained its supremacy in global research on the function of immune related components in bone tissue regeneration.Shanghai Jiao Tong University is the most productive institution.Biomaterials has published the most publications on the involvement of immune-related components in bone tissue regeneration.Xiao Y,Schmidt-Bleek K,and Ignatius A all played important roles in the study of immune-related variables in bone tissue regeneration.Research on the role of immune relevant factors in bone tissue regeneration has identified five hotspots:(1)macrophage-based immunomodulation on osteogenesis of mesenchymal stem cells(MSCs);(2)biomaterials for bone repair in bone tissue engineering;(3)osteoimmunomodulation mediated by inflammation and macrophages during bone healing;(4)osteoimmunomodulation in angiogenesis during bone regeneration;and(5)the effect of macrophage polarization regulated by bone tissue engineering on osteogenic differentiation of MSCs as bone tissue.Conclusion:This study represents the first-ever bibliometric and visualized examination of how immune factors contribute to bone tissue regeneration.The focus and forthcoming direction in bone regeneration research will be on macrophage-driven immunomodulation in the process of bone regeneration.

Pitfalls and promises of bile duct alternatives:There is plenty of room in the regenerative surgery

Current abdominal surgery has several approaches for biliary reconstruction.However,the creation of functional and clinically applicable bile duct substitutes still represents an unmet need.In the paper by Miyazawa and colleagues,approaches to the creation of bile duct alternatives were summarized,and the reasons for the lack of development in this area were explained.The history of bile duct surgery since the nineteenth century was also traced,leading to the conclusion that the use of bioabsorbable materials holds promise for the creation of bile duct substitutes in the future.We suggest three ideas that may stimulate progress in the field of bile duct substitute creation.First,a systematic analysis of the causative factors leading to failure or success in the creation of bile duct substitutes may help to develop more effective approaches.Second,the regeneration of a bile duct is delicately balanced between epithelialization and subsequent submucosal maturation within limited time frames,which may be more apparent when using quantitative models to estimate outcomes.Third,the utilization of the organism’s endogenous regeneration abilities may enhance the creation of bile duct substitutes.We are convinced that an interdisciplinary approach,including quantitative methods,machine learning,and deep retrospective analysis of the causes that led to success and failure in studies on the creation of bile duct substitutes,holds great value.Additionally,more attention should be directed towards the balance of epithelialization and submucosal maturation rates,as well as induced angiogenesis.These ideas deserve further investigation to pave the way for bile duct restoration with physiologically relevant outcomes.

Regenerative peripheral nerve interface prevents neuroma formation after peripheral nerve transection

Neuroma formation after peripheral nerve transection often leads to severe neuropathic pain.Regenerative peripheral nerve interface has been shown to reduce painful neuroma in the clinic.However,no reports have investigated the underlying mechanisms,and no comparative animal studies on regenerative peripheral nerve interface and other means of neuroma prevention have been conducted to date.In this study,we established a rat model of left sciatic nerve transfection,and subsequently interfered with the model using the regenerative peripheral nerve interface or proximal nerve stump implantation inside a fully innervated muscle.Results showed that,compared with rats subjected to nerve stump implantation inside the muscle,rats subjected to regenerative peripheral nerve interface intervention showed greater inhibition of the proliferation of collagenous fibers and irregular regenerated axons,lower expressions of the fibrosis markerα-smooth muscle actin and the inflammatory marker sigma-1 receptor in the proximal nerve stump,lower autophagy behaviors,lower expressions of c-fos and substance P,higher expression of glial cell line-derived neurotrophic factor in the ipsilateral dorsal root ganglia.These findings suggested that regenerative peripheral nerve interface inhibits peripheral nerve injury-induced neuroma formation and neuropathic pain possibly via the upregulation of the expression of glial cell line-derived neurotrophic factor in the dorsal root ganglia and reducing neuroinflammation in the nerve stump.

Hypoxic pre-conditioned adipose-derived stem/progenitor cells embedded in fibrin conduits promote peripheral nerve regeneration in a sciatic nerve graft model

Recent results emphasize the supportive effects of adipose-derived multipotent stem/progenitor cells(ADSPCs)in peripheral nerve recovery.Cultivation under hypoxia is considered to enhance the release of the regenerative potential of ADSPCs.This study aimed to examine whether peripheral nerve regeneration in a rat model of autologous sciatic nerve graft benefits from an additional custom-made fibrin conduit seeded with hypoxic pre-conditioned(2%oxygen for 72 hours)autologous ADSPCs(n=9).This treatment mode was compared with three others:fibrin conduit seeded with ADSPCs cultivated under normoxic conditions(n=9);non-cell-carrying conduit(n=9);and nerve autograft only(n=9).A 16-week follow-up included functional testing(sciatic functional index and static sciatic index)as well as postmortem muscle mass analyses and morphometric nerve evaluations(histology,g-ratio,axon density,and diameter).At 8 weeks,the hypoxic pre-conditioned group achieved significantly higher sciatic functional index/static sciatic index scores than the other three groups,indicating faster functional regeneration.Furthermore,histologic evaluation showed significantly increased axon outgrowth/branching,axon density,remyelination,and a reduced relative connective tissue area.Hypoxic pre-conditioned ADSPCs seeded in fibrin conduits are a promising adjunct to current nerve autografts.Further studies are needed to understand the underlying cellular mechanism and to investigate a potential application in clinical practice.

Potential of dental pulp stem cells and their products in promoting peripheral nerve regeneration and their future applications

Peripheral nerve injury(PNI)seriously affects people’s quality of life.Stem cell therapy is considered a promising new option for the clinical treatment of PNI.Dental stem cells,particularly dental pulp stem cells(DPSCs),are adult pluripotent stem cells derived from the neuroectoderm.DPSCs have significant potential in the field of neural tissue engineering due to their numerous advantages,such as easy isolation,multidifferentiation potential,low immunogenicity,and low transplant rejection rate.DPSCs are extensively used in tissue engineering and regenerative medicine,including for the treatment of sciatic nerve injury,facial nerve injury,spinal cord injury,and other neurodegenerative diseases.This article reviews research related to DPSCs and their advantages in treating PNI,aiming to summarize the therapeutic potential of DPSCs for PNI and the underlying mechanisms and providing valuable guidance and a foundation for future research.

Melatonin,tunneling nanotubes,mesenchymal cells,and tissue regeneration

Mesenchymal stem cells are multipotent stem cells that reside in many human tissues and organs.Mesenchymal stem cells are widely used in experimental and clinical regenerative medicine due to their capability to transdifferentiate into various lineages.However,when transplanted,they lose part of their multipotency and immunomodulatory properties,and most of them die after injection into the damaged tissue.In this review,we discuss the potential utility of melatonin in preserving mesenchymal stem cells’survival and function after transplantation.Melatonin is a pleiotropic molecule regulating critical cell functions including apoptosis,endoplasmic reticulum stress,and autophagy.Melatonin is also synthesized in the mitochondria where it reduces oxidative stress,the opening of the mitochondrial permeability transition pore and the downstream caspase activation,activates uncoupling proteins,and curtails the proinflammatory response.In addition,recent findings showed that melatonin also promotes the formation of tunneling nanotubes and the transfer of mitochondria between cells through the connecting tubules.As mitochondrial dysfunction is a primary cause of mesenchymal stem cells death and senescence and a critical issue for survival after transplantation,we propose that melatonin by favoring mitochondria functionality and their transfer through tunneling nanotubes from healthy to suffering cells could improve mesenchymal stem cellbased therapy in a large number of diseases for which basic and clinical trials are underway.

Extracellular vesicles:Emerged as a promising strategy for regenerative medicine

Cell transplantation therapy has certain limitations including immune rejection and limited cell viability,which seriously hinder the transformation of stem cellbased tissue regeneration into clinical practice.Extracellular vesicles(EVs)not only possess the advantages of its derived cells,but also can avoid the risks of cell transplantation.EVs are intelligent and controllable biomaterials that can participate in a variety of physiological and pathological activities,tissue repair and regeneration by transmitting a variety of biological signals,showing great potential in cell-free tissue regeneration.In this review,we summarized the origins and characteristics of EVs,introduced the pivotal role of EVs in diverse tissues regeneration,discussed the underlying mechanisms,prospects,and challenges of EVs.We also pointed out the problems that need to be solved,application directions,and prospects of EVs in the future and shed new light on the novel cell-free strategy for using EVs in the field of regenerative medicine.

Injectable hydrogel made from antler mesenchyme matrix for regenerative wound healing via creating a fetal-like niche

BACKGROUND Scar formation and loss of cutaneous appendages are the greatest challenges in cutaneous wound healing.Previous studies have indicated that antler reserve mesenchyme(RM)cells and their conditioned medium improved regenerative wound healing with partial recovery of cutaneous appendages.AIM To develop hydrogels from the antler RM matrix(HARM)and evaluate the effect on wound healing.METHODS We prepared the hydrogels from the HARM via enzymatic solubilization with pepsin.Then we investigated the therapeutic effects of HARM on a full-thickness cutaneous wound healing rat model using both local injections surrounding the wound and topical wound application.RESULTS The results showed that HARM accelerated wound healing rate and reduced scar formation.Also,HARM stimulated the regeneration of cutaneous appendages and blood vessels,and reduced collagen fiber aggregation.Further study showed that these functions might be achieved via creating a fetal-like niche at the wound site.The levels of fetal wound healing-related genes,including Collagen III and TGFβ3 treated with HARM were all increased,while the expression levels of Collagen I,TGFβ1,and Engrailed 1 were decreased in the healing.Moreover,the number of stem cells was increased in the fetal-like niche created by HARM,which may contribute to the regeneration of cutaneous appendages.CONCLUSION Overall,we successfully developed an injectable hydrogel made from antler RM matrix for the regenerative repair of full-thickness cutaneous wounds.We uncovered the molecular mechanism of the hydrogels in promoting regenerative wound healing,and thus pave the way for HARM to be developed for the clinic use.

Mesenchymal stem cells in ischemic tissue regeneration

Diseases caused by ischemia are one of the leading causes of death in the world.Current therapies for treating acute myocardial infarction,ischemic stroke,and critical limb ischemia do not complete recovery.Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders.Mesenchymal stem cells(MSCs)are the most promising option in the field of cell-based therapies,due to their secretory and immunomodulatory abilities,that contribute to ease inflammation and promote the regeneration of damaged tissues.This review presents the current knowledge of the mechanisms of action of MSCs and their therapeutic effects in the treatment of ischemic diseases,described on the basis of data from in vitro experiments and preclinical animal studies,and also summarize the effects of using these cells in clinical trial settings.Since the obtained therapeutic benefits are not always satisfactory,approaches aimed at enhancing the effect of MSCs in regenerative therapies are presented at the end.

Are bone marrow regenerative cells ideal seed cells for the treatment of cerebral ischemia?

Bone marrow cells for the treatment of ischemic brain injury may depend on the secretion of a large number of neurotrophic factors. Bone marrow regenerative cells are capable of increasing the secretion of neurotrophic factors. In this study, after tail vein injection of 5-fluorouracil for 7 days, bone marrow cells and bone marrow regenerative cells were isolated from the tibias and femurs of rats, and then administered intravenously via the tail vein after focal cerebral ischemia. Immunohistological staining and reverse transcription-PCR detection showed that transplanted bone marrow cells and bone marrow regenerative cells could migrate and survive in the ischemic regions, such as the cortical and striatal infarction zone. These cells promote vascular endothelial cell growth factor mRNA expression in the ischemic marginal zone surrounding the ischemic penumbra of the cortical and striatal infarction zone, and have great advantages in promoting the recovery of neurological function, reducing infarct size and promoting angiogenesis. Bone marrow regenerative cells exhibited stronger neuroprotective effects than bone marrow cells. Our experimental findings indicate that bone marrow regenerative cells are preferable over bone marrow cells for cell therapy for neural regeneration after cerebral ischemia. Their neuroprotective effect is largely due to their ability to induce the secretion of factors that promote vascular regeneration, such as vascular endothelial growth factor.

Unleashing the healing potential:Exploring next-generation regenerative protein nanoscaffolds for burn wound recovery

Burn injury is a serious public health problem and scientists are continuously aiming to develop promising biomimetic dressings for effective burn wound management.In this study,a greater efficacy in burn wound healing and the associated mechanisms ofα-lactalbumin(ALA)based electrospun nanofibrous scaffolds(ENs)as compared to other regenerative protein scaffolds were established.Bovine serum albumin(BSA),collagen type I(COL),lysozyme(LZM)and ALA were separately blended with poly(ε-caprolactone)(PCL)to fabricate four different composite ENs(LZM/PCL,BSA/PCL,COL/PCL and ALA/PCL ENs).The hydrophilic composite scaffolds exhibited an enhancedwettability and variablemechanical properties.The ALA/PCL ENs demonstrated higher levels of fibroblast proliferation and adhesion than the other composite ENs.As compared to PCL ENs and other composite scaffolds,the ALA/PCL ENs also promoted a better maturity of the regenerative skin tissues and showed a comparable wound healing effect to Collagen sponge^(■)on third-degree burn model.The enhanced wound healing activity of ALA/PCL ENs compared to other ENs could be attributed to their ability to promote serotonin production at wound sites.Collectively,this investigation demonstrated that ALA is a unique protein with a greater potential for burn wound healing as compared to other regenerative proteins when loaded in the nanofibrous scaffolds.

A Review of Electromagnetic Energy Regenerative Suspension System&Key Technologies

The active suspension has undoubtedly improved the performance of the vehicle,however,the trend of“lowcarbonization,intelligence,and informationization”in the automotive industry has put forward higher and more urgent requirements for the suspension system.The automotive industry and researchers favor active energy regeneration suspension technology with safety,comfort,and high energy regenerative efficiency.In this paper,we review the research progress of the structure form,optimization method,and control strategy of electromagnetic energy regenerative suspension.Specifically,comparing the pros and cons of the existing technology in solving the contradiction between dynamic performance and energy regeneration.In addition,the development trend of electromagnetic energy regenerative suspension in the field of structure form,optimization method,and control technology prospects.

Energy Management of Networked Smart Railway Stations Considering Regenerative Braking, Energy Storage System, and Photovoltaic Units

The networking of microgrids has received significant attention in the form of a smart grid.In this paper,a set of smart railway stations,which is assumed as microgrids,is connected together.It has been tried to manage the energy exchanged between the networked microgrids to reduce received energy from the utility grid.Also,the operational costs of stations under various conditions decrease by applying the proposed method.The smart railway stations are studied in the presence of photovoltaic(PV)units,energy storage systems(ESSs),and regenerative braking strategies.Studying regenerative braking is one of the essential contributions.Moreover,the stochastic behaviors of the ESS’s initial state of energy and the uncertainty of PV power generation are taken into account through a scenario-based method.The networked microgrid scheme of railway stations(based on coordinated operation and scheduling)and independent operation of railway stations are studied.The proposed method is applied to realistic case studies,including three stations of Line 3 of Tehran Urban and Suburban Railway Operation Company(TUSROC).The rolling stock is simulated in the MATLAB environment.Thus,the coordinated operation of networked microgrids and independent operation of railway stations are optimized in the GAMS environment utilizing mixed-integer linear programming(MILP).

Regenerative Medicine: A Review of Solutions in the Treatment of Skin Defects

The issue of skin defects is a major concern of almost every trauma surgeon after surgery. Despite numerous conventional methods and introduction of the reconstruction ladder, managing skin defects is still a challenge for the trauma surgeons. In recent years, parallel to the advances in the more conventional methods of skin repair, regenerative medicine has offered new and novel treatments. This article aims to explore these contemporary regenerative solutions as well as to review the conventional methods of treating skin defects.