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.

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.

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.

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.

Star Movement Is Not Predicted Two-Compartment Model of the Universe

A two-compartment model of the universe is proposed to further refine Albert Einstein’s insight into curvature of space and the energy tensor. The two compartments are energy contained by a shell prism. The model allows for a non-unification of fundamental forces with gravity resulting from the curvature of a space-time prism. Carrier forces travel within the prism and particles emerge from the prism. Giving a thickness to the manifold negates infinity and will allow solutions at both microscopic and cosmic levels. Geometry is the link between quantum mechanics and general relativity. Negative entropy, as proposed by Erwin Schrödinger, gives order to particles and the cosmic. The source of this energy is in the shell of the containment vessel. The acceleration of the expansion of the universe occurred when energy within the container transformed into mass, warping the space-time container and causing an explosion of the container. Star movement is explained by the surface tension of the prism of space-time.

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.

Human induced pluripotent stem cell-derived therapies for regeneration after central nervous system injury

In recent years,the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine.Considering the non-regenerative nature of the mature central nervous system,the concept that“blank”cells could be reprogrammed and functionally integrated into host neural networks remained intriguing.Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells,such as neurons.While embryonic stem cells demonstrated great potential in treating central nervous system pathologies,ethical and technical concerns remained.These barriers,along with the clear necessity for this type of treatment,ultimately prompted the advent of induced pluripotent stem cells.The advantage of pluripotent cells in central nervous system regeneration is multifaceted,permitting differentiation into neural stem cells,neural progenitor cells,glia,and various neuronal subpopulations.The precise spatiotemporal application of extrinsic growth factors in vitro,in addition to microenvironmental signaling in vivo,influences the efficiency of this directed differentiation.While the pluri-or multipotency of these cells is appealing,it also poses the risk of unregulated differentiation and teratoma formation.Cells of the neuroectodermal lineage,such as neuronal subpopulations and glia,have been explored with varying degrees of success.Although the risk of cancer or teratoma formation is greatly reduced,each subpopulation varies in effectiveness and is influenced by a myriad of factors,such as the timing of the transplant,pathology type,and the ratio of accompanying progenitor cells.Furthermore,successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration.Lastly,host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression.Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes.This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.

Burner effects on melting process of regenerative aluminum melting furnace

According to the features of melting process of regenerative aluminum melting furnaces, a three-dimensional mathematical model with user-developed melting model, burner reversing and burning capacity model was established. The numerical simulation of melting process of a regenerative aluminum melting furnace was presented using hybrid programming method of FLUENT UDF and FLUENT scheme based on the heat balance test. Burner effects on melting process of aluminum melting furnaces were investigated by taking optimization regulations into account. The change rules of melting time on influence factors are achieved. Melting time decreases with swirl number, vertical angle of burner, air preheated temperature or natural gas flow; melting time firstly decreases with horizontal angle between burners or air-fuel ratio, then increases; melting time increases with the height of burner.

AUTOMATIC CONTROL OF REGENERATIVE CUTTING CHATTER BASED ON OPTIMAL REGULATION OF SPINDLE SPEED

An applicable method to control regenerative cutting chatter automatically based on the optimal regulation of spindle speed is introduced. The optimal value of the phase shift angle of the regenerative chatter signal between the two successive cuts is 270°. The cutting process can be adjusted from the unstable region to stable one whenever regenerative chatter occurs if the phase shift angle is kept 270° by the optimal regulation of spindle speed. The theoretical analysis and the experimental results prove that the optimal regulation of spindle speed can effectively control regenerative cutting chatter. In addition, a reliablelly optimal control system of reliable spindle speed is presented. There is no need for system identification of the machine tool, and it is easy to put this regenerative chatter control method into practice, so the method has excellent application prospect.

Design and Analysis of Electro-mechanical Hybrid Anti-lock Braking System for Hybrid Electric Vehicle Utilizing Motor Regenerative Braking

Braking on low adhesion-coefficient roads, hybrid electric vehicle＇s motor regenerative torque is switched off to safeguard the normal anti-lock braking system （ABS） fimction. When the ABS control is terminated, the motor regenerative braking is readmitted. Aiming at avoiding permanent cycles from hydraulic anti-lock braking to motor regenerative braking, a novel electro-mechanical hybrid anti-lock braking system using fuzzy logic is designed. Different from the traditional single control structure, this system has a two-layered hierarchical structure, The first layer is responsible for harmonious adjustment or interaction between regenerative system and anti-lock braking system. The second layer is responsible for braking torque distribution and adjustment. The closed-loop simulation model is built. Control strategy and method for coordination between regenerative and anti-lock braking are developed. Simulation braking on low adhesion-coefficient roads with fuzzy logic control and real vehicle braking field test are presented. The results from simulating analysis and experiment show braking performance of the vehicle is perfect, harmonious coordination between regenerative and anti-lock braking function, significant amount of braking energy can be recovered and the proposed control strategy and method are effective.

Role and prospects of regenerative biomaterials in the repair of spinal cord injury

Axonal junction defects and an inhibitory environment after spinal cord injury seriously hinder the regeneration of damaged tissues and neuronal functions. At the site of spinal cord injury, regenerative biomaterials can fill cavities, deliver curative drugs, and provide adsorption sites for transplanted or host cells. Some regenerative biomaterials can also inhibit apoptosis, inflammation and glial scar formation, or further promote neurogenesis, axonal growth and angiogenesis. This review summarized a variety of biomaterial scaffolds made of natural, synthetic, and combined materials applied to spinal cord injury repair. Although these biomaterial scaffolds have shown a certain therapeutic effect in spinal cord injury repair, there are still many problems to be resolved, such as product standards and material safety and effectiveness.

Advances in regenerative therapies for spinal cord injury:a biomaterials approach

Spinal cord injury results in the permanent loss of function, causing enormous personal, social and economic problems. Even though neural regeneration has been proven to be a natural mech- anism, central nervous system repair mechanisms are ineffective due to the imbalance of the inhibitory and excitatory factors implicated in neuroregeneration. Therefore, there is growing re- search interest on discovering a novel therapeutic strategy for effective spinal cord injury repair. To this direction, cell-based delivery strategies, biomolecule delivery strategies as well as scaf- fold-based therapeutic strategies have been developed with a tendency to seek for the answer to a combinatorial approach of all the above. Here we review the recent advances on regenerativel neural engineering therapies for spinal cord injury, aiming at providing an insight to the most promising repair strategies, in order to facilitate future research conduction.

Stem cells as delivery vehicles for regenerative medicinechallenges and perspectives

The use of stem cells as carriers for therapeutic agents is an appealing modality for targeting tissues or organs of interest. Combined delivery of cells together with various information molecules as therapeutic agents has the potential to enhance, modulate or even initiate local or systemic repair processes, increasing stem cell efficiency for regenerative medicine applications. Stem-cell-mediated delivery of genes, proteins or small molecules takes advantage of the innate capability of stem cells to migrate and home to injury sites. As the native migratory properties are affected by in vitro expansion, the existent methods for enhancing stem cell targeting capabilities(modified culture methods, genetic modification, cell surface engineering) are described. The role of various nanoparticles in eq-uipping stem cells with therapeutic small molecules is revised together with their class-specific advantages and shortcomings. Modalities to circumvent common challenges when designing a stem-cell-mediated targeted delivery system are described as well as future prospects in using this approach for regenerative medicine applications.

Regenerative therapy for neuronal diseases with transplantation of somatic stem cells

Pluripotent stem cells, which are capable of differentiating in various species of cells, are hoped to be donor cells in transplantation in regenerative medicine. Embryonic stem(ES) cells and induced pluripotent stem cells have the potential to differentiate in approximately all species of cells. However, the proliferating ability of these cells is high and the cancer formation ability is also recognized. In addition, ethical problems exist in using ES cells. Somatic stem cells with the ability to differentiate in various species of cells have been used as donor cells for neuronal diseases, such as amyotrophic lateral sclerosis, spinal cord injury, Alzheimer disease,cerebral infarction and congenital neuronal diseases.Human mesenchymal stem cells derived from bone marrow, adipose tissue, dermal tissue, umbilical cord blood and placenta are usually used for intractable neuronal diseases as somatic stem cells, while neural progenitor/stem cells and retinal progenitor/stem cells are used for a few congenital neuronal diseases and retinal degenerative disease, respectively. However,non-treated somatic stem cells seldom differentiate to neural cells in recipient neural tissue. Therefore, the contribution to neuronal regeneration using non-treated somatic stem cells has been poor and various differential trials, such as the addition of neurotrophic factors,gene transfer, peptide transfer for neuronal differentiation of somatic stem cells, have been performed. Here,the recent progress of regenerative therapies using various somatic stem cells is described.

Gingival-derived mesenchymal stem cells:An endless resource for regenerative dentistry

The gingiva, the masticatory portion of the oral mucosa, is excised and discarded frequently during routine dental treatments and following tooth extraction, dental crown lengthening, gingivectomy and periodontal surgeries. Subsequent to excision, healing eventually happens in a short time period after gingival surgery. Clinically, the gingival tissue can be collected very easily and, in the laboratory, it is also very easy to isolate gingival-derived mesenchymal stem cells (GMSCs) from this discarded gingival tissue. GMSCs, a stem cell population within the lamina propria of the gingival tissue, can be isolated from attached and free gingiva, inflamed gingival tissu-es, and from hyperplastic gingiva. Comparatively, they constitute more attractive alternatives to other dental-derived mesenchymal stem cells due to the availability and accessibility of gingival tissues. They have unique immunomodulatory functions and well-documented self-renewal and multipotent differentiation properties. They display positive signals for Stro-1, Oct-4 and SSEA-4 pluripotency-associated markers, with some co-expre-ssing Oct4/Stro-1 or Oct-4/SSEA-4. They should be considered as the best stem cell source for cell-based therapies and regenerative dentistry. The clinical use of GMSCs for regenerative dentistry represents an attrac-tive therapeutic modality. However, numerous biological and technical challenges need to be addressed prior to considering transplantation approaches of GMSCs as clinically realistic therapies for humans.

Regenerative medicine in China:main progress in different fields

Regenerative medicine(RM) is an emerging interdisciplinary field of research and China has developed the research quickly and impressed the world with numerous research findings in stem cells,tissue engineering,active molecules and gene therapy.Important directions are induced differentiation of induced pluripotent stem and embryo stem cells as well as somatic stem cell differentiation potential and their application in trauma,burns,diseases of aging and nerve regeneration.The products Activ Skin and bone repair scaffolds have been approved and are applied in the clinic,and similar products are being studied.About 10 engineered growth-factor drugs for repair and regeneration have been approved and are used in the clinic.Gene therapy,therapeutic cloning and xenotransplantation are some of the strategies being studied.However,China needs to develop standards,regulations and management practices suitable for the healthy development of RM.Aspects that should be strengthened include sound administrative systems,laws,and technical specifications and guidelines;conservation of stem cell resources;emphasis on training and retention of talented stem cell researchers;and reasonable allocation of resources,diversification of investment and breakthroughs in key areas.Finally,broad and deep international cooperation is necessary.

Optimizing stem cells for cardiac repair:Current status and new frontiers in regenerative cardiology

Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the postischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit andstrategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel "pharmacooptimizer" as well as genetic modifications.

Nodular regenerative hyperplasia:Evolving concepts on underdiagnosed cause of portal hypertension

Nodular regenerative hyperplasia(NRH)is a rare liver condition characterized by a widespread benign transformation of the hepatic parenchyma into small regenerative nodules.NRH may lead to the development of non-cirrhotic portal hypertension.There are no published systematic population studies on NRH and our current knowledge is limited to case reports and case series.NRH may develop via autoimmune,hematological,infectious,neoplastic,or drug-related causes.The disease is usually asymptomatic,slowly or nonprogressive unless complications of portal hypertension develop.Accurate diagnosis is made by histopathology,which demonstrates diffuse micronodular transformation without fibrous septa.Lack of perinuclear collagen tissue distinguishes NRH from typical regenerative nodules in the cirrhotic liver.While the initial treatment is to address the underlying disease,ultimately the therapy is directed to the management of portal hypertension.The prognosis of NRH depends on both the severity of the underlying illness and the prevention of secondary complications of portal hypertension.In this review we detail the epidemiology,pathogenesis,diagnosis,management,and prognosis of NRH.

A new braking force distribution strategy for electric vehicle based on regenerative braking strength continuity

Regenerative braking was the process of converting the kinetic energy and potential energy, which were stored in the vehicle body when vehicle braked or went downhill, into electrical energy and storing it into battery. The problem on how to distribute braking forces of front wheel and rear wheel for electric vehicles with four-wheel drive was more complex than that for electric vehicles with front-wheel drive or rear-wheel drive. In this work, the frictional braking forces distribution curve of front wheel and rear wheel is determined by optimizing the braking force distribution curve of hydraulic proportional-adjustable valve, and then the safety brake range is obtained correspondingly. A new braking force distribution strategy based on regenerative braking strength continuity is proposed to solve the braking force distribution problem for electric vehicles with four-wheel drive. Highway fuel economy test(HWFET) driving condition is used to provide the speed signals, the braking force equations of front wheel and rear wheel are expressed with linear equations. The feasibility, effectiveness, and practicality of the new braking force distribution strategy based on regenerative braking strength continuity are verified by regenerative braking strength simulation curve and braking force distribution simulation curves of front wheel and rear wheel. The proposed strategy is simple in structure, easy to be implemented and worthy being spread.