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Cellular microstructures form naturally in many living organisms (e.g., flowers and leaves) to provide vital functions in synthesis, transport of nutrients, and regulation of growth. Although heterogeneous cellular microstructures are believed to play pivotal roles in their three-dimensional (3D) shape formation, programming 3D curved mesosurfaces with cellular designs remains elusive in man-made systems. We report a rational microlattice design that allows transformation of 2D films into programmable 3D curved mesosurfaces through mechanically guided assembly. Analytical modeling and a machine learning–based computational approach serve as the basis for shape programming and determine the heterogeneous 2D microlattice patterns required for target 3D curved surfaces. About 30 geometries are presented, including both regular and biological mesosurfaces. Demonstrations include a conformable cardiac electronic device, a stingray-like dual mode actuator, and a 3D electronic cell scaffold.

Nerve guidance conduits with hollow lumen fail to regenerate critical-sized peripheral nerve defects (15 mm in rats and 25 mm in humans), which can be improved by a beneficial intraluminal microenvironment. However, individual cues provided by intraluminal filling materials are inadequate to eliminate the functional gap between regenerated nerves and normal nerves. Herein, an aligned fibrin/functionalized self-assembling peptide (AFG/fSAP) interpenetrating nanofiber hydrogel that exerting synergistic topographical and biochemical cues for peripheral nerve regeneration is constructed via electrospinning and molecular self-assembly. The hydrogel possesses an aligned structure, high water content, appropriate mechanical properties and suitable biodegradation capabilities for nerve repair, which enhances the alignment and neurotrophin secretion of primary Schwann cells (SCs) in vitro, and successfully bridges a 15-mm sciatic nerve gap in rats in vivo. The rats transplanted with the AFG/fSAP hydrogel exhibit satisfactory morphological and functional recovery in myelinated nerve fibers and innervated muscles. The motor function recovery facilitated by the AFG/fSAP hydrogel is comparable with that of autografts. Moreover, the AFG/fSAP hydrogel upregulates the regeneration-associated gene expression and activates the PI3K/Akt and MAPK signaling pathways in the regenerated nerve. Altogether, the AFG/fSAP hydrogel represents a promising approach for peripheral nerve repair through an integration of structural guidance and biochemical stimulation., Graphical abstract Image 1, Highlights • A novel aligned interpenetrating nanofiber hydrogel is first constructed for peripheral nerve regeneration. • The aligned hydrogel presents synergistic topographical and biochemical cues for peripheral nerve regeneration. • Nerve conduits filled with the aligned hydrogel can repair the long-distance sciatic nerve defects in 12 weeks. • The function recovery facilitated by the aligned hydrogel is comparable with that of autografts. • The aligned hydrogel upregulates regeneration-related genes and activates the PI3K/Akt and MAPK signaling pathways.

Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic–tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans. A functional interfacial material has been developed for soft integration of bioelectronic devices with biological tissues. This has been applied in battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy as well as wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays.

3D, hierarchical micro/nanostructures formed with advanced functional materials are of growing interest due to their broad potential utility in electronics, robotics, battery technology, and biomedical engineering. Among various strategies in 3D micro/nanofabrication, a set of methods based on compressive buckling offers wide-ranging material compatibility, fabrication scalability, and precise process control. Previously reports on this type of approach rely on a single, planar prestretched elastomeric platform to transform thin-film precursors with 2D layouts into 3D architectures. The simple planar configuration of bonding sites between these precursors and their assembly substrates prevents the realization of certain types of complex 3D geometries. In this paper, a set of hierarchical assembly concepts is reported that leverage multiple layers of prestretched elastomeric substrates to induce not only compressive buckling of 2D precursors bonded to them but also of themselves, thereby creating 3D mesostructures mounted at multiple levels of 3D frameworks with complex, elaborate configurations. Control over strains used in these processes provides reversible access to multiple different 3D layouts in a given structure. Examples to demonstrate these ideas through both experimental and computational results span vertically aligned helices to closed 3D cages, selected for their relevance to 3D conformal bio-interfaces and multifunctional microsystems.

Description, Mechanically guided assembly techniques yield complex 3D microvascular networks with multifunctional characteristics., Microfluidic technologies have wide-ranging applications in chemical analysis systems, drug delivery platforms, and artificial vascular networks. This latter area is particularly relevant to 3D cell cultures, engineered tissues, and artificial organs, where volumetric capabilities in fluid distribution are essential. Existing schemes for fabricating 3D microfluidic structures are constrained in realizing desired layout designs, producing physiologically relevant microvascular structures, and/or integrating active electronic/optoelectronic/microelectromechanical components for sensing and actuation. This paper presents a guided assembly approach that bypasses these limitations to yield complex 3D microvascular structures from 2D precursors that exploit the full sophistication of 2D fabrication methods. The capabilities extend to feature sizes

A hierarchically aligned fibrin hydrogel (AFG) that possesses soft stiffness and aligned nanofiber structure has been successfully proven to facilitate neuroregeneration in vitro and in vivo. However, its potential in promoting nerve regeneration in large animal models that is critical for clinical translation has not been sufficiently specified. Here, the effects of AFG on directing neuroregeneration in canine hemisected T12 spinal cord injuries were explored. Histologically obvious white matter regeneration consisting of a large area of consecutive, compact and aligned nerve fibers is induced by AFG, leading to a significant motor functional restoration. The canines with AFG implantation start to stand well with their defective legs from 3 to 4 weeks postoperatively and even effortlessly climb the steps from 7 to 8 weeks. Moreover, high-resolution multi-shot diffusion tensor imaging illustrates the spatiotemporal dynamics of nerve regeneration rapidly crossing the lesion within 4 weeks in the AFG group. Our findings indicate that AFG could be a potential therapeutic vehicle for spinal cord injury by inducing rapid white matter regeneration and restoring locomotion, pointing out its promising prospect in clinic practice.

Liquid crystal elastomers (LCEs) are a class of soft active materials of increasing interest, because of their excellent actuation and optical performances. While LCEs show biomimetic mechanical properties (e.g., elastic modulus and strength) that can be matched with those of soft biological tissues, their biointegrated applications have been rarely explored, in part, due to their high actuation temperatures (typically above 60 °C) and low biaxial actuation performances (e.g., actuation strain typically below 10%). Here, unique mechanics-guided designs and fabrication schemes of LCE metamaterials are developed that allow access to unprecedented biaxial actuation strain (-53%) and biaxial coefficient of thermal expansion (-33 125 ppm K-1 ), significantly surpassing those (e.g., -20% and -5950 ppm K-1 ) reported previously. A low-temperature synthesis method with use of optimized composition ratios enables LCE metamaterials to offer reasonably high actuation stresses/strains at a substantially reduced actuation temperature (46 °C). Such biocompatible LCE metamaterials are integrated with medical dressing to develop a breathable, shrinkable, hemostatic patch as a means of noninvasive treatment. In vivo animal experiments of skin repair with both round and cross-shaped wounds demonstrate advantages of the hemostatic patch over conventional strategies (e.g., medical dressing and suturing) in accelerating skin regeneration, while avoiding scar and keloid generation.

Background Long non-coding RNAs (lncRNAs) have been certified to play vital biological functions in glioma and have received considerable attention in the recent literature. Nonetheless, the role of LINC01158 in glioma remains to be elucidated. Methods qRT-PCR, western blot and GEPIA database were applied for reporting the expression of CENPK and LINC01158 in glioma and the correlation between LINC01158 and CENPK expression. EdU, colony formation, CCK-8, caspase-3 activity and TUNEL assays probed the impacts of LINC01158 on glioma cell growth. Subcellular fractionation and FISH assays revealed the cellular distribution of LINC01158. Luciferase reporter and RIP assays examined ceRNA network of LINC01158, CENPK and miR-6734-3p. Results LINC01158 and CENPK were both overexpressed in glioma and a positive regulation of LINC01158 on CENPK was corroborated. LINC01158 served a pro-proliferative and anti-apoptotic part in glioma by sponging miR-6734-3p to augment CENPK. Conclusion LINC01158 enhances CENPK by serving as sponge for miR-6734-3p to facilitate glioma development, proposing LINC01158 as a new player in glioma.

Minimally invasive methods for temperature sensing and thermal modulation in living tissues have extensive applications in biological research and clinical care. As alternatives to bioelectronic devices for this purpose, functional nanomaterials that self-assemble into optically active microstructures offer important features in remote sensing, injectability, and compact size. This paper introduces a transient, or bioresorbable, system based on injectable slurries of well-defined microparticles that serve as photopumped lasers with temperature-sensitive emission wavelengths (>4-300 nm °C-1). The resulting platforms can act as tissue-embedded thermal sensors and, simultaneously, as distributed vehicles for thermal modulation. Each particle consists of a spherical resonator formed by self-organized cholesteric liquid crystal molecules doped with fluorophores as gain media, encapsulated in thin shells of soft hydrogels that offer adjustable rates of bioresorption through chemical modification. Detailed studies highlight fundamental aspects of these systems including particle sensitivity, lasing threshold, and size. Additional experiments explore functionality as photothermal agents with active temperature feedback (ΔT = 1 °C) and potential routes in remote evaluation of thermal transport properties. Cytotoxicity evaluations support their biocompatibility, and ex vivo demonstrations in Casper fish illustrate their ability to measure temperature within biological tissues with resolution of 0.01 °C. This collective set of results demonstrates a range of multifunctional capabilities in thermal sensing and modulation.

Extensive tissue engineering studies have supported the enhanced spinal cord regeneration by implantable scaffolds loaded with bioactive cues. However, scaffolds with single-cue delivery showed unsatisfactory effects, most likely due to the complex nature of hostile niches in the lesion area. In this regard, strategies of multi-modal delivery of multiple heterogeneous cell-regulatory cues are unmet needs for enhancing spinal cord repair, which requires a thorough understanding of the regenerative niche associated with spinal cord injury. Here, by combining hierarchically aligned fibrin hydrogel (AFG) and functionalized self-assembling peptides (fSAP), a novel multifunctional nanofiber composite hydrogel AFG/fSAP characterized with interpenetrating network is designed. Serving as a source of both biophysical and biochemical cues, AFG/fSAP can facilitate spinal cord regeneration via guiding regenerated tissues, accelerating axonal regrowth and remyelination, and promoting angiogenesis. Giving the synergistic effect of multiple cues, AFG/fSAP implantation contributes to anatomical, electrophysiological, and motor functional restorations in rats with spinal cord hemisection. This study provides a novel multi-modal approach for regeneration in central nervous system, which has potentials for clinical practice of spinal cord injury.

Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic-tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans.

The repair of infective bone defects is a great challenge in clinical work. It is of vital importance to develop a kind of bone scaffold with good osteogenic properties and long-term antibacterial activity for local anti-infection and bone regeneration. A porous mineralized collagen (MC) scaffold containing poly(d,l-lactide-co-glycolic acid) (PLGA) microspheres loaded with two antibacterial synthetic peptides, Pac-525 or KSL-W was developed and characterized via scanning electron microscopy (SEM), porosity measurement, swelling and mechanical tests. The results showed that the MC scaffold embedded with smooth and compact PLGA microspheres had a positive effect on cell growth and also had antibacterial properties. Through toxicity analysis, cell morphology and proliferation analysis and alkaline phosphatase evaluation, the antibacterial scaffolds showed excellent biocompatibility and osteogenic activity. The antibacterial property evaluated with Staphylococcus aureus and Escherichia coli suggested that the sustained release of Pac-525 or KSL-W from the scaffolds could inhibit the bacterial growth aforementioned in the long term. Our results suggest that the antimicrobial peptides-loaded MC bone scaffold has good antibacterial and osteogenic activities, thus providing a great promise for the treatment of infective bone defects.

Titanium (Ti) implants with TiO2 nanotubular arrays on the surface could regulate cells adhesion, proliferation and differentiation to determine the bone integration. Additionally, the regulation of immune cells could improve osteogenesis or lead in appropriate immune reaction. Thus, we evaluate the behavior of RAW264.7 macrophages on TiO2 nanotubular arrays with a wide range diameter (from 20 to 120 nm) fabricated by an electrochemical anodization process. In this work, the proliferation, cell viability and cytokine/chemokine secretion were evaluated by CCK-8, live/dead staining and ELISA, respectively. SEM and confocal microscopy were used to observe the adhesion morphology. Results showed that the small size nanotube surface was benefit for the macrophages adhesion and proliferation, while larger size surface could reduce the inflammatory response. These findings contribute to the design of immune-regulating Ti implants surface that supports successful implantation.

Spinal cord injuries (SCI) normally disrupt the long axonal tracts of the spinal cord and cause permanent neurological deficits, for which there is currently a lack of effective therapeutic methods. Biomaterial-based regenerative medicine is a pivotal strategy to induce axonal regeneration through delivery of biophysical and/or biochemical regulatory cues by biomaterials. We previously fabricated a hierarchically aligned fibrin hydrogel (AFG) that could promote neurogenic differentiation of stem cells in vitro and has been successfully applied for peripheral nerve and spinal cord regeneration in rats. In this study, AFG was used to repair a canine lumbar segment 2 hemisection spinal cord injury, and the consistency of histological, imageological and behavioral results was compared. AFG was used to construct an aligned fiber bridge that supported cell adhesion in vitro and rapidly facilitated tissue invasion along the long axis of fibers in vivo, Moreover, in vivo results demonstrated regrowth of axons in an oriented pattern connecting the rostral and caudal stumps. Consistent results were confirmed by diffusion tensor imaging, which allowed successful tracing of reconnected nerve fibers across the defect. As a result, directional axonal regrowth contributed to significantly improved recovery of motor functional behavior of SCI canines with AFG implantation. Our results suggest that AFG has great promise for rapidly directing axonal regrowth for nerve regeneration.

Titanium and its alloys have been extensively used as implant materials due to their excellent mechanical properties, adequate corrosion resistance and good biocompatibility. In this study, an interconnected 3D TiO 2 structure on Ti implants is fabricated via anodization method in a fluoride-containing electrolyte with water content larger than 50%. The pore size ranges from 30 to 200 nm with the current density increased from 50 to 100 mA·cm 2 . Compared with other kinds of porous TiO 2 layers, which were fabricated by the same method with different electrolyte composition, the prepared 3D TiO 2 structure shows the highest hardness and apparent Young's modulus, which are over 4 times higher than that of the TiO 2 nanotube arrays. Moreover, the 3D TiO 2 possess the highest adhesion strength as the critical load for the delamination occurred is 0.7 N, while for the nanotube-structured layer and the transition structure, the load are 0.2 and 0.4 N, respectively. Additionally, the 3D TiO 2 structure also shows better corrosion resistance than the others. Titanium with 3D oxide layer has also shown good performance in osteogenic cells culturing, since in the cell viability assay, the cells adhered on the 3D oxide layer spread extensively and showed a spindle shape while on the TiO 2 nanotube arrays or titanium with transition structure the cells were unfavorable to spread. This work can provide guidelines for improving structural and environmental conditions responsible for modification of Ti surfaces for biomedical applications.

The development of modern therapeutics has raised the requirement for controlled drug delivery system which is able to efficiently encapsulate bioactive agents and achieve their release at a desired rate satisfying the need of the practical system. In this study, two kind of aqueous model drugs with different molecule weight, Congo red and albumin from bovine serum (BSA) were nano-encapsulated in poly (dl-lactic-co-glycolic acid) (PLGA) microspheres by emulsion electrospray. In the preparation process, the aqueous phase of drugs was added into the PLGA chloroform solution to form the emulsion solution. The emulsion was then electrosprayed to fabricate drug-nanoencapsulated PLGA microspheres. The morphology of the PLGA microspheres was affected by the volume ratio of aqueous drug phase and organic PLGA phase (Vw/Vo ) and the molecule weight of model drugs. Confocal laser scanning microcopy showed the nanodroplets of drug phase were scattered in the PLGA microspheres homogenously with different distribution patterns related to Vw/Vo . With the increase of the volume ratio of aqueous drug phase, the number of nanodroplets increased forming continuous phase gradually that could accelerate drug release rate. Moreover, BSA showed a slower release rate from PLGA microspheres comparing to Congo red, which indicated the drug release rate could be affected by not only Vw/Vo but also the molecule weight of model drug. In brief, the PLGA microspheres prepared using emulsion electrospray provided an efficient and simple system to achieve controlled drug release at a desired rate satisfying the need of the practices.

Structured surfaces with both anti-bacterial capability and biocompatibility are essential to medical devices including orthopedic implants. Over the past few years, numerous studies indicated that nanostructures such as nanotubes, nanowires, nano-pillars and nano-ripples were capable of repelling or killing bacteria, while the morphology and dimensions of the nanostructures showed essential influence on the adhesion and proliferation of cells. The long-term functionalities of implants depend on their reliable anti-bacterial performance at the same time enhanced biocompatibility. However, researches covering both these two aspects are still very limited. In this paper, we applied one-step femtosecond laser irradiation to produce three types of nano-ripples, and to investigate their anti-bacterial behavior and their biocompatibility. Our results demonstrate that all the three types of nano-ripples are capable of preventing bacterial colonization and biofilm formation, with their anti-bacteria rates towards E. coli respectively 43%, 49% and 56%. Meanwhile, the femtosecond laser induced nano-ripples exhibit good rat mesenchymal stem cells (MSCs) proliferation capacity and spreading performance, and the nano-ripples affect significantly the orientation of MSCs. The results offer valuable information and potentials on the anti-bacteria and biocompatibility of nanostructures.

Shenglian Yao,1,2 Shukui Yu,3 Zheng Cao,2 Yongdong Yang,2,4 Xing Yu,4 Hai-Quan Mao,5 Lu-Ning Wang,1 Xiaodan Sun,2 Lingyun Zhao,2 Xiumei Wang2 1School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, China; 2Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing, China; 3Department of Otolaryngology-Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China; 4Department of Orthopedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; 5Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA Background: Designing novel biomaterials that incorporate or mimic the functions of extracellular matrix to deliver precise regulatory signals for tissue regeneration is the focus of current intensive research efforts in tissue engineering and regenerative medicine. Methods and results: To mimic the natural environment of the spinal cord tissue, a three-dimensional hierarchically aligned fibrin hydrogel (AFG) with oriented topography and soft stiffness has been fabricated by electrospinning and a concurrent molecular self-assembling process. In this study, the AFG was implanted into a rat dorsal hemisected spinal cord injury model to bridge the lesion site. Host cells invaded promptly along the aligned fibrin hydrogels to form aligned tissue cables in the first week, and then were followed by axonal regrowth. At 4 weeks after the surgery, neurofilament (NF)-positive staining fibers were detected near the rostral end as well as the middle site of defect, which aligned along the tissue cables. Abundant NF- and GAP-43-positive staining indicated new axon regrowth in the oriented tissue cables, which penetrated throughout the lesion site in 8 weeks. Additionally, the abundant blood vessels marked with RECA-1 had reconstructed within the lesion site at 4 weeks after surgery. Basso-Beattie-Bresnahan scoring showed that the locomotor performance of the AFG group recovered much faster than that of blank control group or the random fibrin hydrogel (RFG) group from 2 weeks after surgery. Furthermore, diffusion tensor imaging tractography of MRI confirmed the optimal axon fiber reconstruction compared with the RFG and control groups. Conclusion: Taken together, our results suggested that the AFG scaffold provided an inductive matrix for accelerating directional host cell invasion, vascular system reconstruction, and axonal regrowth, which could promote and support extensive aligned axonal regrowth and locomotor function recovery. Keywords: spinal cord injury, nerve regrowth, fibrin hydrogel, aligned structure, soft stiffness

Titanium (Ti) with nanoscale structure on the surface exhibits excellent biocompatibility and bone integration. Once implanted, the surgical implantation may lead to bacterial infection and inflammatory reaction, which cause the implant failure. In this work, irregular and nanorod-shaped ZnO nanoparticles were doped into TiO

Fibrin plays a crucial role in peripheral nerve regeneration, which could occur spontaneously in the format of longitudinally oriented fibrin cables during the initial stage of nerve regeneration. This fibrin cable can direct migration and proliferation of Schwann cells and axonal regrowth, which is very important to nerve regeneration. In the present study, we prepared a three-dimensional hierarchically aligned fibrin nanofiber hydrogel (AFG) through electrospinning and molecular self-assembly to resemble the architecture and biological function of the native fibrin cable. The AFG displayed a hierarchically aligned topography as well as low elasticity (∼1.5 kPa) that were similar to nerve extracellular matrix (ECM) and the native fibrin cable. Rapid, directional cell adhesion and migration of Schwann cells (SCs) and dorsal root ganglions were observed in vitro . The AFG was then used as a potential intraluminal substrate in a bioengineered chitosan tube to bridge a 10-mm-long sciatic nerve gap in rats. We found that the AFG served as a beneficial microenvironment to support SCs cable formation and axonal regrowth within 2 weeks. Further histological and morphological analyses as well as electrophysiological and functional examinations were performed after AFG implantation for up to 12 weeks. The results from morphological analysis and electrophysiological examination indicated that regenerative outcomes achieved by our developed graft were close to those by an autologous nerve graft, but superior to those by hollow chitosan tubes (hCST) and random fibrin nanofiber hydrogel (RFG). Our results demonstrate that the AFG creates an instructive microenvironment by mimicking the native fibrin cable as well as the oriented and soft features of nerve ECM to accelerate axonal regrowth, thus showing great promising potential for applications in neural regeneration. Statement of Significance In peripheral nervous system defect repair, a wide variety of strategies have been proposed for preparing functionalized nerve guidance conduits (NGC) with more complex configurations to obtain optimal repair effects. Longitudinally oriented fibrin cables were reported to form spontaneously during the initial stages of peripheral nerve regeneration in an empty NGC, which can direct the migration and proliferation of Schwann cells and promote axonal regrowth. Therefore, based on the biomimetic idea, we prepared a three-dimensional hierarchically aligned fibrin nanofiber hydrogel (AFG) through electrospinning and molecular self-assembly, resembling the architecture and biological function of the native fibrin cable and serving as an intraluminal filling to accelerate axon regeneration. We found that the AFG was a beneficial microenvironment to support SCs cable formation and accelerate axonal regrowth with improved motor functional recovery.

This study examined sustained co-delivery of vascular endothelial growth factor (VEGF), angiopoietin-1 and basic fibroblast growth factor (bFGF) encapsulated in angiogenic microspheres. These spheres were delivered to sites of spinal cord contusion injury in rats, and their ability to induce vessel formation, neural regeneration and improve hindlimb motor function was assessed. At 2–8 weeks after spinal cord injury, ELISA-determined levels of VEGF, angiopoietin-1, and bFGF were significantly higher in spinal cord tissues in rats that received angiogenic microspheres than in those that received empty microspheres. Sites of injury in animals that received angiogenic microspheres also contained greater numbers of isolectin B4-binding vessels and cells positive for nestin or β III-tubulin (P P

Some studies have reported that scaffold or cell-based transplantation may improve functional recovery following SCI, but no imaging information regarding regeneration has been provided to date. This study used tractography to show the regenerating process induced by a new biomaterial-aligned fibrin hydrogel (AFG). A total of eight canines subjected to SCI procedures were assigned to the control or the AFG group. AFG was implanted into the SCI lesion immediately after injury in 5 canines. A follow-up was performed at 12 weeks to evaluate the therapeutic effect including the hindlimb functional recovery, anisotropy and continuity of fibers on tractography. Using tractography, we found new fibers running across the SCI in three canines of the AFG group. Further histological examination confirmed limited glial scarring and regenerated nerve fibers in the lesions. Moreover, Repeated Measures Analysis revealed a significantly different change in fractional anisotropy (FA) between the two groups during the follow-up interval. An increase in FA during the post injury time interval was detected in the AFG group, indicating a beneficial effect of AFG in the rehabilitation of injured axons. Using tractography, AFG was suggested to be helpful in the restoration of fibers in SCI lesions, thus leading to promoted functional recovery.

Neural stem cells (NSCs) have been a promising candidate for stem cell-based nerve tissue regeneration. Therefore, the design of idea biomaterials that deliver precise regulatory signals to control stem cell fate is currently a crucial issue that depends on a profound understanding of the interactions between NSCs with the surrounding micro-environment. In this work, self-assembled monolayers of alkanethiols on gold with different chemical groups, including hydroxyl (-OH), amino (-NH2), carboxyl (-COOH) and methyl (-CH3), were used as a simple model to study the effects of surface chemistry on NSC fate decisions. Contact angle measurement and x-ray photoelectron spectroscopy (XPS) examination implied that all types of alkanethiols self-assembled on gold into a close-packed phase structure with similar molecular densities. In this study, we evaluated NSC adhesion, migration and differentiation in response to different chemical functional groups cultured under serum-free conditions. Our studies showed that NSCs exhibited certain phenotypes with extreme sensitivity to surface chemical groups. Compared with other functional groups, the SAMs with hydroxyl end-groups provided the best micro-environment in promoting NSC migration and maintaining an undifferentiated or neuronal differentiation state. -NH2 surfaces directed neural stem cells into astrocytic lineages, while NSCs on -COOH and -CH3 surfaces had a similar potency to differentiate into three nerve lineages. To further investigate the possible signaling pathway, the gene expression of integrin β1 and β4 were examined. The results indicated that a high expression of β1 integrin would probably have a tight correlation with the expression of nestin, which implied the stemness of NSCs, while β4 integrin seemed to correspond to the differentiated NSCs. The results presented here give useful information for the future design of biomaterials to regulate the preservation, proliferation and differentiation of NSCs for central nervous tissue engineering.

Guided bone regeneration (GBR) technique is widely used in the treatment of bone defects caused by peri-implantitis, periodontal disease, etc. However, the GBR membranes commonly used in clinical treatments currently have no antibacterial activity. Therefore, in this study, sequential layer-by-layer electrospinning and electrospraying techniques were utilized to prepare a gelatin (Gln) and chitosan (CS) composite GBR membrane containing hydroxyapatite nanoparticles (nHAp) and antimicrobial peptide (Pac-525)-loaded PLGA microspheres (AMP@PLGA-MS), which was supposed to have osteogenic and antibacterial activities. The scanning electron microscope (SEM) observation showed that the morphology of the nanofibers and microspheres could be successfully produced. The diameters of the electrospun fibers with and without nHAp were 359 ± 174 nm and 409 ± 197 nm, respectively, and the mechanical properties of the membrane were measured according to the tensile stress-strain curve. Both the involvement of nHAp and the chemical crosslinking were able to enhance their tensile strength. In vitro cell culture of rat bone marrow mesenchymal stem cells (rBMSCs) indicated that the Gln/CS composite membrane had an ideal biocompatibility with good cell adhesion, spreading, and proliferation. In addition, the Gln/CS membrane containing nHAp could promote osteogenic differentiation of rBMSCs. Furthermore, according to the in vitro drug release assay and antibacterial experiments, the composite GBR membrane containing AMP@PLGA-MS exhibited a long-term sustained release of Pac-525, which had bactericidal activity within one week and antibacterial activity for up to one month against two kinds of bacteria, S. aureus and E. coli. Our results suggest that the antimicrobial peptide-loaded Gln/CS composite membrane (AMP@PLGA-MS@Gln/CS/nHAp) has a great promise in bone generation-related applications for the unique functions of guiding bone regeneration and inhibiting bacterial infection as well.

Titanium (Ti) with nanoscale structure on the surface exhibits excellent biocompatibility and bone integration. Once implanted, the surgical implantation may lead to bacterial infection and inflammatory reaction, which cause the implant failure. In this work, irregular and nanorod-shaped ZnO nanoparticles were doped into TiO2 nanotubes (TNTs) with inner diameter of about 50 nm by electro-deposition. The antibacterial properties of ZnO incorporated into TiO2 nanotubes (TNTs/ZnO) were evaluated using Staphylococcus aureus (S. aureus). Zn ions released from the nanoparticles and the morphology could work together, improving antibacterial effectiveness up to 99.3% compared with the TNTs. Macrophages were cultured on the samples to determine their respective anti-inflammatory properties. The proliferation and viability of macrophages were evaluated by the CCK-8 method and Live&Dead stain, and the morphology of the cells was observed by scanning electron microscopy. Results indicated that TNTs/ZnO has a significant inhibitory effect on the proliferation and adhesion of macrophages, which could be used to prevent chronic inflammation and control the inflammatory reaction. Besides, the release of Zn ions from the ZnO nanoparticles is a long-term process, which could be beneficial for bone integration. Results demonstrate that ZnO deposited into TNTs improved the antibacterial effectiveness and weakened the inflammatory reaction of titanium-based implants, which is a promising approach to enhance their bioactivity.

To declare the mechanisms of neural stem cells (NSCs) in response to material surface chemistry, NSCs were exposed to the self-assemble monolayers of alkanethiolates on gold surfaces terminated with amine (NH2), hydroxyl (OH) and methyl (CH3) for analysis. The morphological responses of NSCs were recorded; the gene expression profilings were detected by genechips; the gene expressions data of NSCs responded to different chemical groups were declared through the gene ontology term and pathway analyses. It showed that cells behaved dissimilar on the three chemical groups, the adhesion, proliferation and migration were easier on the NH2 and OH groups; the gene expressions of NSCs were induced differently, either, involved in several functional processes and signaling pathways. CH3 group induced genes enriched much in chemistry reactions and death processes, whereas many genes of cellular nucleotide metabolism were down-regulated. NH2 group induced NSCs to express many genes of receptors on membrane, and participated in cellular signal transduction of cell adhesion and interactions, or associated with axon growth. OH group was similar to NH2 group to induce the membrane response, but it also down regulated metabolism of cells. Therefore, it declared the chemical groups affected NSCs through inner way and the NH2, OH and CH3 groups triggered the cellular gene expression in different signaling pathways.

Nanofibers exist ubiquitously in natural extracellular matrix (ECM) of all kinds of human tissues forming hydrated interwoven network. Electrospinning nanotechnology has been proven to be a powerful technique to fabricate controllable nanofibers mimicking the natural ECM structures. Hyaluronic acid (HA), as a critical component of natural ECM, has been widely used in tissue engineering and regenerative medicine. In this study, pure HA nanofibers with average diameter of 33 +/- 5 nm, 59 +/- 12 nm, 79 +/- 12 nm and 113 +/- 19 nm were successfully prepared using different electrospinning parameters. The effect of the ambient relative humidity on HA electrospinnability was investigated for the first time in detail, which was proven to be one of the most important factors to control the morphology of HA nanofibers beside the solution properties. A critical value of humidity for a defined HA solution was observed, only below which HA nanofibers with similar diameters and morphologies could be successfully obtained. When the ambient relative humidity was higher than the critical value, the HA nanofibers started dissolving at the cross points and even fused together forming a spreading layer. Moreover, only a small amount of N, N-Dimethylformamide (DMF) was found to be required to promote the electrospinnability of HA solution by mixing with water as solvents. With the increase in the DMF content, the surface tension of the solution decreased significantly, which was thought to be benefit for the stable Taylor cone and fluid jet formation in electrospinning. At the same time, it should be noted that the conductivity of the solution also decreased with the increase of DMF content in the solution, which was believed to be responsible for the increasing diameters of HA nanofibers corresponding to higher DMF content. Controllable HA nanofibers with diameter below 100 nm have great promising for developing novel nanobiomaterials applied in tissue engineering and regenerative medicine.

The discovery of neural stem cells (NSCs), which have the ability to self-renew and differentiate into all types of neural lineages, offers promising prospect for the treatment of brain neurological disorders such as stroke/cerebral ischemia, traumatic brain injury and neurodegenerative disorders. However, only limited number of NSCs could survive or propagate due to tissue inflammation or blood–brain barrier. Therefore, it is necessary to develop an appropriate culture system that highly mimics the natural NSCs niche to direct stem cell fate and behavior for nerve regeneration. Both biophysical and biochemical properties of the NSC niche, including topology, mechanical properties, bioactive molecules, and their spatial and temporal presentations should be considered for the design of functionalized scaffolds, which could not only serve as the delivery vehicles of NSCs but also stimulate specific cellular responses at the molecular level, such as support endogenous or exogenous cells proliferation, migration and homing, even promote the growth of axon at the injured brain site. This review attempts to outline the varieties of biomaterial parameters that are applied as biophysical and biochemical signals to direct neural stem cell fate and behavior. The understanding on the interaction of NSCs decision and biomaterial parameters is helping to advance NSCs-based clinical approaches for nerve tissue regeneration and repair.