Biomaterials and tissue engineering in traumatic brain injury:novel perspectives on promoting neural regeneration

Traumatic brain injury is a serious medical condition that can be attributed to falls, motor vehicle accidents, sports injuries and acts of violence, causing a series of neural injuries and neuropsychiatric symptoms. However, limited accessibility to the injury sites, complicated histological and anatomical structure, intricate cellular and extracellular milieu, lack of regenerative capacity in the native cells, vast variety of damage routes, and the insufficient time available for treatment have restricted the widespread application of several therapeutic methods in cases of central nervous system injury. Tissue engineering and regenerative medicine have emerged as innovative approaches in the field of nerve regeneration. By combining biomaterials, stem cells, and growth factors, these approaches have provided a platform for developing effective treatments for neural injuries, which can offer the potential to restore neural function, improve patient outcomes, and reduce the need for drugs and invasive surgical procedures. Biomaterials have shown advantages in promoting neural development, inhibiting glial scar formation, and providing a suitable biomimetic neural microenvironment, which makes their application promising in the field of neural regeneration. For instance, bioactive scaffolds loaded with stem cells can provide a biocompatible and biodegradable milieu. Furthermore, stem cells-derived exosomes combine the advantages of stem cells, avoid the risk of immune rejection, cooperate with biomaterials to enhance their biological functions, and exert stable functions, thereby inducing angiogenesis and neural regeneration in patients with traumatic brain injury and promoting the recovery of brain function. Unfortunately, biomaterials have shown positive effects in the laboratory, but when similar materials are used in clinical studies of human central nervous system regeneration, their efficacy is unsatisfactory. Here, we review the characteristics and properties of various bioactive materials, followed by the introduction of applications based on biochemistry and cell molecules, and discuss the emerging role of biomaterials in promoting neural regeneration. Further, we summarize the adaptive biomaterials infused with exosomes produced from stem cells and stem cells themselves for the treatment of traumatic brain injury. Finally, we present the main limitations of biomaterials for the treatment of traumatic brain injury and offer insights into their future potential.

A core scientific problem in the treatment of central nervous system diseases:newborn neurons

It has long been asserted that failure to recover from central nervous system diseases is due to the system's intricate structure and the regenerative incapacity of adult neurons.Yet over recent decades,numerous studies have established that endogenous neurogenesis occurs in the adult central nervous system,including humans'.This has challenged the long-held scientific consensus that the number of adult neurons remains constant,and that new central nervous system neurons cannot be created or renewed.Herein,we present a comprehensive overview of the alterations and regulatory mechanisms of endogenous neurogenesis following central nervous system injury,and describe novel treatment strategies that to rget endogenous neurogenesis and newborn neurons in the treatment of central nervous system injury.Central nervous system injury frequently results in alterations of endogenous neurogenesis,encompassing the activation,proliferation,ectopic migration,diffe rentiation,and functional integration of endogenous neural stem cells.Because of the unfavorable local microenvironment,most activated neural stem cells diffe rentiate into glial cells rather than neurons.Consequently,the injury-induced endogenous neurogenesis response is inadequate for repairing impaired neural function.Scientists have attempted to enhance endogenous neurogenesis using various strategies,including using neurotrophic factors,bioactive materials,and cell reprogramming techniques.Used alone or in combination,these therapeutic strategies can promote targeted migration of neural stem cells to an injured area,ensure their survival and diffe rentiation into mature functional neurons,and facilitate their integration into the neural circuit.Thus can integration re plenish lost neurons after central nervous system injury,by improving the local microenvironment.By regulating each phase of endogenous neurogenesis,endogenous neural stem cells can be harnessed to promote effective regeneration of newborn neurons.This offers a novel approach for treating central nervous system injury.

Preparation of Biologically Active Materials by Biomimetic Process

In order to form the apatite nuclei on a surface of the substrate, the substrate was placed on or in CaO, SiO2-based glass particles which were soaked in a simulated body fluid with ion concentrations nearly e-qual to those of human blood plasma, and to make the apatite nuclei grow on the substrate in situ, the substrate, was soaked in another solution highly supersaturated with respect to the apatite. The induction period for the apatite nucleation varied from 0 to 4 days depending on the kind of the substrate. The thickness of the apatite layer increases linearly with increasing soaking time in the second solution. The rate of growth of the apatite layer increases with increasing degree of the supersaturation and temperature of the second solution, reaching 7um/d in a solution with ion concentrations which is as 1.5 times as those of the simulated body fluid at 60℃. The adhesive strength of the apatite layer to the substrate varies depending on the kind and roughness of the substrate. Polyethyleneterephthalate and polyethersulfone plates abraded with No. 400 diamond paste show adhesive strengths of as high as 4 MPa. This type of composite of the bone-like apatite with metals, ceramics and organic polymers might be useful not only as highly biaactive hard tissue-repairing materials with analogous mechanical properties to those of the hard tissues , but also as highly biocompatible soft tissue-repairing materials with ductility.

Sustained delivery of vascular endothelial growth factor mediated by bioactive methacrylic anhydride hydrogel accelerates peripheral nerve regeneration after crush injury

Neurotrophic factors,currently administered orally or by intravenous drip or intramuscular injection,are the main method for the treatment of peripheral nerve crush injury.However,the low effective drug concentration arriving at the injury site results in unsatisfactory outcomes.Therefore,there is an urgent need for a treatment method that can increase the effective drug concentration in the injured area.In this study,we first fabricated a gelatin modified by methacrylic anhydride hydrogel and loaded it with vascular endothelial growth factor that allowed the controlled release of the neurotrophic factor.This modified gelatin exhibited good physical and chemical properties,biocompatibility and supported the adhesion and proliferation of RSC96 cells and human umbilical vein endothelial cells.When injected into the epineurium of crushed nerves,the composite hydrogel in the rat sciatic nerve crush injury model promoted nerve regeneration,functional recovery and vascularization.The results showed that the modified gelatin gave sustained delivery of vascular endothelial growth factors and accelerated the repair of crushed peripheral nerves.

Advances in orthodontic clear aligner materials

Rapid technological improvements in biomaterials,computer-aided design(CAD)and manufacturing(CAM)have endorsed clear aligner therapy(CAT)as a mainstay of orthodontic treatment,and the materials employed for aligner fabrication play an all-important role in determining the clinical performance of clear aligners.This narrative review has attempted to comprehensively encompass the entire gamut of materials currently used for the fabrication of clear aligners and elucidate their characteristics that are crucial in determining their performance in an oral environment.Historical developments and current protocols in aligner fabrication,features of contemporary bioactive materials,and emerging trends related to CAT are discussed.Advances in aligner material chemistry and engineering possess the potential to bring about radical transformations in the therapeutic applications of CAT;in the absence of which,clear aligners would continue to underperform clinically,due to their inherent biomechanical constraints.Finally,while innovations in aligner materials such as shape memory polymers,direct three-dimensional(3D)printed clear aligners and bioactive materials combined with clear aligner materials are essential to further advance the applications of CAT;increased awareness of environmental responsibilities among aligner manufacturers,aligner prescribing clinicians and aligner users is essential for better alignment of our climate change goals towards a sustainable planet.

Engineering multifunctional bioactive citrate-based biomaterials for tissue engineering

Developing bioactive biomaterials with highly controlled functions is crucial to enhancing their applications in regenerative medicine.Citrate-based polymers are the few bioactive polymer biomaterials used in biomedicine because of their facile synthesis,controllable structure,biocompatibility,biomimetic viscoelastic mechanical behavior,and functional groups available for modification.In recent years,various multifunctional designs and biomedical applications,including cardiovascular,orthopedic,muscle tissue,skin tissue,nerve and spinal cord,bioimaging,and drug or gene delivery based on citrate-based polymers,have been extensively studied,and many of them have good clinical application potential.In this review,we summarize recent progress in the multifunctional design and biomedical applications of citrate-based polymers.We also discuss the further development of multifunctional citrate-based polymers with tailored properties to meet the requirements of various biomedical applications.

Calcium Silicate Cements Application in Lateral Root Perforation Repair: A Case Report with 16-Month Follow-Up

Lateral root perforations are unfortunate procedures during endodontic treatment and often lead to tooth extraction. Conditioning factors such as time, size, location, inappropriate disinfection and sealing, are indispensable to achieve acceptable long-term outcomes. Calcium silicate cements are bioactive materials used for perforation repair. They can be set in moist environments such as blood, saliva and dentinal fluid making them a reliable material for clinical applications. This case report describes the treatment and repair after a 16-month follow-up of a lateral root perforation of the maxillary lateral incisor.

Heterocyclic Molecules Tethered Branched Polymers with Innate Immune Stimulating Activity

We report herein an interesting finding that heterocyclic molecules tethered branched polymers exhibit innate immune stimulating activity.When we conjugated a series of five-,six-,or seven-membered heterocyclic molecules to branched polyethylenimine(bPEI),over 70%of them could induce the secretion of interferon-β(IFN-β)from murine dendritic and human leukemia monocytic(DC2.4 and THP-1)cells through activating the stimulator of interferon genes(STING)pathway.We further proved that this kind of innate stimulating activity was dependent on the macromolecular architecture as heterocyclic molecules tethered linear PEI(lPEI)or dendritic polyamidoamine(PAMAM)induced no or much less IFN-βsecretion.Furthermore,we prepared a series of poly-L-lysine(PLL)-derivatives with different branches to tether with heterocyclic molecules and proved that this kind of bPEI-like structure was important in en hancing the binding affinity with STING proteins and for exhibiting innate stimulating activity.

Chitosan based bioactive materials in tissue engineering applications-A review

In recent years,there have been increasingly rapid advances of using bioactive materials in tissue engineering applications.Bioactive materials constitute many different structures based upon ceramic,metallic or polymeric materials,and can elicit specific tissue responses.However,most of them are relatively brittle,stiff,and difficult to form into complex shapes.Hence,there has been a growing demand for preparing materials with tailored physical,biological,and mechanical properties,as well as predictable degradation behavior.Chitosan-based materials have been shown to be ideal bioactive materials due to their outstanding properties such as formability into different structures,and fabricability with a wide range of bioactive materials,in addition to their biocompatibility and biodegradability.This review highlights scientific findings concerning the use of innovative chitosan-based bioactive materials in the fields of tissue engineering,with an outlook into their future applications.It also covers latest developments in terms of constituents,fabrication technologies,structural,and bioactive properties of these materials that may represent an effective solution for tissue engineering materials,making them a realistic clinical alternative in the near future.

Development of bioactive materials for glioblastoma therapy

Glioblastoma is the most common and deadly human brain cancers.Unique barriers hinder the drug delivering pathway due to the individual position of glioblastoma,including blood-brain barrier and blood-brain tumor barrier.Numerous bioactive materials have been exploited and applied as the transvascular delivery carriers of therapeutic drugs.They promote site-specific accumulation and long term release of the encapsulated drugs at the tumor sites and reduce side effects with systemic delivery.And the delivery systems exhibit a certain extent of anti-glioblastoma effect and extend the median survival time.However,few of them step into the clinical trials.In this review,we will investigate the recent studies of bioactive materials for glioblastoma chemotherapy,including the inorganic materials,lipids and polymers.These bioactive materials construct diverse delivery vehicles to trigger tumor sites in brain intravenously.Herein,we exploit their functionality in drug delivery and discuss the deficiency for the featured tumors,to provide guidance for establishing optimized therapeutic drug formulation for anti-glioblastoma therapy and pave the way for clinical application.

Development of methods for detecting the fate of mesenchymal stem cells regulated by bone bioactive materials

The fate of mesenchymal stem cells(MSCs)is regulated by biological,physical and chemical signals.Developments in biotechnology and materials science promoted the occurrence of bioactive materials which can provide physical and chemical signals for MSCs to regulate their fate.In order to design and synthesize materials that can precisely regulate the fate of MSCs,the relationship between the properties of materials and the fate of mesenchymal stem cells need to be clarified,in which the detection of the fate of mesenchymal stem cells plays an important role.In the past 30 years,a series of detection technologies have been developed to detect the fate of MSCs regulated by bioactive materials,among which high-throughput technology has shown great advantages due to its ability to detect large amounts of data at one time.In this review,the latest research progresses of detecting the fate of MSCs regulated by bone bioactive materials(BBMs)are systematically reviewed from traditional technology to high-throughput technology which is emphasized especially.Moreover,current problems and the future development direction of detection technologies of the MSCs fate regulated by BBMs are prospected.The aim of this review is to provide a detection technical framework for researchers to establish the relationship between the properties of BMMs and the fate of MSCs,so as to help researchers to design and synthesize BBMs better which can precisely regulate the fate of MSCs.

Advanced application of collagen-based biomaterials in tissue repair and restoration

In tissue engineering,bioactive materials play an important role,providing structural support,cell regulation and establishing a suitable microenvironment to promote tissue regeneration.As the main component of extracellular matrix,collagen is an important natural bioactive material and it has been widely used in scientific research and clinical applications.Collagen is available from a wide range of animal origin,it can be produced by synthesis or through recombinant protein production systems.The use of pure collagen has inherent disadvantages in terms of physico-chemical properties.For this reason,a processed collagen in different ways can better match the specific requirements as biomaterial for tissue repair.Here,collagen may be used in bone/cartilage regeneration,skin regeneration,cardiovascular repair and other fields,by following different processing methods,including cross-linked collagen,complex,structured collagen,mineralized collagen,carrier and other forms,promoting the development of tissue engineering.This review summarizes a wide range of applications of collagen-based biomaterials and their recent progress in several tissue regeneration fields.Furthermore,the application prospect of bioactive materials based on collagen was outlooked,aiming at inspiring more new progress and advancements in tissue engineering research.

Gallium containing bioactive materials: A review of anticancer, antibacterial, and osteogenic properties

The incorporation of gallium into bioactive materials has been reported to enhance osteogenesis,to influence blood clotting,and to induce anti-cancer and anti-bacterial activity.Gallium-doped biomaterials prepared by various techniques include melt-derived and sol-gel-derived bioactive glasses,calcium phosphate bioceramics,metals and coatings.In this review,we summarize the recently reported developments in antibacterial,anti-cancer,osteogenesis,and hemostasis properties of Ga-doped biomaterials and briefly outline the mechanisms leading to Ga biological effects.The key finding is that gallium addition to biomaterials has great potential for treating bone-related diseases since it can be efficiently transferred to the desired region at a controllable rate.Besides,it can be used as a potential substitute for antibiotics for the inhibition of infections during the initial and advanced phases of the wound healing process.Ga is also used as an anticancer agent due to the increased concentration of gallium around excessive cell proliferation(tumor)sites.Moreover,we highlight the possibility to design different therapeutic approaches aimed at increasing the efficiency of the use of gallium containing bioactive materials for multifunctional applications.

Multivalent network modifier upregulates bioactivity of multispecies biofilm-resistant polyalkenoate cement

Polyalkenoate cement(PAC)is a promising material for regenerative hard tissue therapy.The ionically rich glass component of PAC encourages bioactive interaction via.the release of essential ions.However,PAC bioactivity is restricted owing to(i)structurally inherent cationic network formers and(ii)surface bacterial biofilm formation.These two factors cause a deficiency in ion release,further complicated by secondary infections and premature therapeutic failure.Here,a multivalent zwitterionic network modifier(mZM)is presented for upregulation of ionic exchange and bioactivity enhancement.By introducing a non-zero charged mZM into PACs,an increase in the proportion of non-bridging oxygen occurs.The network modification promotes ion channel formation,causing a multiple-fold increase in ion release and surface deposition of hydroxy-carbonate apatite(ca.74%).Experiments ex vivo and animal models also demonstrate the efficient remineralization ability of the mZM.Furthermore,divalent cationic interaction results in bacterial biofilm reduction(ca.68%)while also influencing a shift in the biofilm species composition,which favors commensal growth.Therefore,PAC modification with mZM offers a promising solution for upregulation of bioactivity,even aiding in customization by targeting site-specific regenerative therapy in future applications.

An enamel-inspired bioactive material with multiscale structure and antibacterial adhesion property

Conventional dental materials lack of the hierarchical architecture of enamel that exhibits excellent intrinsic-extrinsic mechanical properties.Moreover,restorative failures frequently occur due to physical and chemical mismatch between artificial materials and native dental hard tissue followed by recurrent caries which is caused by sugar-fermenting,acidogenic bacteria invasion of the defective cite.In order to resolve the limitations of the conventional dental materials,the aim of this study was to establish a non-cell-based biomimetic strategy to fabricate a novel bioactive material with enamel-like structure and antibacterial adhesion property.The evaporation-based,bottom-up and self-assembly method with layer-by-layer technique were used to form a large-area fluorapatite crystal layer containing antibacterial components.The multilayered structure was constructed by hydrothermal growth of the fluorapatite crystal layer and highly conformal adsorption to the crystal surface of a polyelectrolyte matrix film.Characterization and mechanical assessment demonstrated that the synthesized bioactive material resembled the native enamel in chemical components,mechanical properties and crystallographic structure.Antibacterial and cytocompatibility evaluation demonstrated that this material had the antibacterial adhesion property and biocompatibility.In combination with the molecular dynamics simulations to reveal the effects of variables on the crystallization mechanism,this study brings new prospects for the synthesis of enamel-inspired materials.

Multi-layer-structured bioactive glass nanopowder for multistage-stimulated hemostasis and wound repair

Current treatments for full-thickness skin injuries are still unsatisfactory due to the lack of hierarchically stimulated dressings that can integrate the rapid hemostasis,inflammation regulation,and skin tissue remodeling into the one system instead of single-stage boosting.In this work,a multilayer-structured bioactive glass nanopowder(BGN@PTE)is developed by coating the poly-tannic acid andε-polylysine onto the BGN via facile layer-by-layer assembly as an integrative and multilevel dressing for the sequential management of wounds.In comparison to BGN and poly-tannic acid coated BGN,BGN@PTE exhibited the better hemostatic performance because of its multiple dependent approaches to induce the platelet adhesion/activation,red blood cells(RBCs)aggregation and fibrin network formation.Simultaneously,the bioactive ions from BGN facilitate the regulation of the inflammatory response while the poly-tannic acid and antibacterialε-polylysine prevent the wound infection,promoting the wound healing during the inflammatory stage.In addition,BGN@PTE can serve as a reactive oxygen species scavenger,alleviate the oxidation stress in wound injury,induce the cell migration and angiogenesis,and promote the proliferation stage of wound repair.Therefore,BGN@PTE demonstrated the significantly higher wound repair capacity than the commercial bioglass dressing Dermlin™.This multifunctional BGN@PTE is a potentially valuable dressing for full-thickness wound management and may be expected to extend to the other wounds therapy.

Polymer-based synthetic oncolytic virus-like nanoparticles for cancer immunotherapy

Oncolytic viruses have emerged as new powerful therapeutic agents for cancer therapy by specifically lysing cancer cells while activating innate immune responses at the same time.However,due to the thorny issues of safety concerns and host immune reaction,the clinical application of oncolytic viruses is still limited.Herein,we report a rationally designed oncolytic virus-like nanoparticles(OV-NPs)composed of stimulator of interferon genes(STING)-stimulating polymer loaded with therapeutic genes for cancer immunotherapy.After injection into tumor,the OV-NPs carrying OX40L plasmid could reprogram tumor cells to express OX40L immune checkpoint molecules and activate the STING pathway for cooperatively enhancing antitumor immunity,with a tumor suppression rate of 92.3%in B16F10 tumor model and 78.7%in MC38 tumor model without causing any toxicity.The OV-NPs could be further applied in carrying other plasmids(IL-12)and utilization in gene combination therapy.This study should inspire designing synthetic OV-NPs as alternative strategies for extending oncolytic virus application in cancer immunotherapy.

Design and fabrication of high-performance injectable self-setting trimagnesium phosphate

Magnesium phosphate bone cement has become a widely used orthopedic implant due to the advantages of fast-setting and high early strength. However, developing magnesium phosphate cement possessing applicable injectability, high strength, and biocompatibility simultaneously remains a significant challenge. Herein, we propose a strategy to develop high-performance bone cement and establish a trimagnesium phosphate cement (TMPC) system. The TMPC exhibits high early strength, low curing temperature, neutral pH, and excellent injectability, overcoming the critical limitations of recently studied magnesium phosphate cement. By monitoring the hydration pH value and electroconductivity, we demonstrate that the magnesium-to-phosphate ratio could manipulate the components of hydration products and their transformation by adjusting the pH of the system, which will influence the hydration speed. Further, the ratio could regulate the hydration network and the properties of TMPC. Moreover, in vitro studies show that TMPC has outstanding biocompatibility and bone-filling capacity. The facile preparation properties and these advantages of TMPC render it a potential clinical alternative to polymethylmethacrylate and calcium phosphate bone cement. This study will contribute to the rational design of high-performance bone cement.

Bioactive nanoglass regulating the myogenic differentiation and skeletal muscle regeneration

Bioactive glass nanoparticles(BGNs)are widely used in the field of biomedicine,including drug delivery,gene therapy,tumor therapy,bioimaging,molecular markers and tissue engineering.Researchers are interested in using BGNs in bone,heart and skin regeneration.However,there is inadequate information on skeletal muscle tissue engineering,limited information on the biological effects of BGNs on myoblasts,and the role of bioactive glass composite materials on myogenic differentiation is unknown.Herein,we report the effects of BGNs with different compositions(60Si-BGN,80Si-BGN,100Si-BGN)on the myogenic differentiation in C2C12 cells and in vivo skeletal tissue regeneration.The results showed that 80Si-BGN could efficiently promote the myogenic differentiation of C1C12 cells,including the myotube formation and myogenic gene expression.The in vivo experiment in a rat skeletal muscle defect model also confirmed that 80Si-BGN could significantly improve the complete regeneration of skeletal muscle tissue during 4 weeks implantation.This work firstly demonstrated evidence that BGN could be the bioactive material in enhancing skeletal muscle regeneration.

3D bioactive cell-free-scaffolds for in-vitro/in-vivo capture and directed osteoinduction of stem cells for bone tissue regeneration

Hydrophilic bone morphogenetic protein 2(BMP2)is easily degraded and difficult to load onto hydrophobic carrier materials,which limits the application of polyester materials in bone tissue engineering.Based on soybean-lecithin as an adjuvant biosurfactant,we designed a novel cell-free-scaffold of polymer of poly(ε-caprolactone)and poly(lactide-co-glycolide)-co-polyetherimide with abundant entrapped and continuously released BMP2 for in vivo stem cell-capture and in situ osteogenic induction,avoiding the use of exogenous cells.The optimized bioactive osteo-polyester scaffold(BOPSC),i.e.SBMP-10SC,had a high BMP2 entrapment efficiency of 95.35%.Due to its higher porosity of 83.42%,higher water uptake ratio of 850%,and sustained BMP2 release with polymer degradation,BOPSCs were demonstrated to support excellent in vitro capture,proliferation,migration and osteogenic differentiation of mouse adipose derived mesenchymal stem cells(mADSCs),and performed much better than traditional BMP-10SCs with unmodified BMP2 and single polyester scaffolds(10SCs).Furthermore,in vivo capture and migration of stem cells and differentiation into osteoblasts was observed in mice implanted with BOPSCs without exogenous cells,which enabled allogeneic bone formation with a high bone mineral density and ratios of new bone volume to existing tissue volume after 6 months.The BOPSC is an advanced 3D cell-free platform with sustained BMP2 supply for in situ stem cell capture and osteoinduction in bone tissue engineering with potential for clinical translation.