Search

The erosion of tooth enamel is a common oral disease. The erosion pattern and location and the effects of nanoscale chemical composition on the erosion susceptibility of enamel have been well documented. However, the enamel remineralization accompanied by erosion and its underlying physicochemical mechanisms still remain poorly understood. Here, using rat molars selected for its good relevancy to human teeth, we investigated the remineralization behavior of the outermost enamel surface at the nanoscale level during erosion in diluted hydrochloric acid solutions. While particles on the outermost enamel surface that represent the termination of crystallites protruding to the surface from the near-surface core eroded by acid-attack, the lateral-growth of the particles (i.e., the main remineralization picture of the surface enamel) occurred concurrently. Ionic analyses indicate that the particle growth is driven by the local increase in pH near the eroding enamel surface as a result of the combination of the PO

Polymeric hydrogels are fascinating platforms as 3D scaffolds for tissue repair and delivery systems of therapeutic molecules and cells. Among others, methacrylated gelatin (GelMA) has become a representative hydrogel formulation, finding various biomedical applications. Recent efforts on GelMA-based hydrogels have been devoted to combining them with bioactive and functional nanomaterials, aiming to provide enhanced physicochemical and biological properties to GelMA. The benefits of this approach are multiple: i) reinforcing mechanical properties, ii) modulating viscoelastic property to allow 3D printability of bio-inks, iii) rendering electrical/magnetic property to produce electro-/magneto-active hydrogels for the repair of specific tissues (e.g., muscle, nerve), iv) providing stimuli-responsiveness to actively deliver therapeutic molecules, and v) endowing therapeutic capacity in tissue repair process (e.g., antioxidant effects). The nanomaterial-combined GelMA systems have shown significantly enhanced and extraordinary behaviors in various tissues (bone, skin, cardiac, and nerve) that are rarely observable with GelMA. Here we systematically review these recent efforts in nanomaterials-combined GelMA hydrogels that are considered as next-generation multifunctional platforms for tissue therapeutics. The approaches used in GelMA can also apply to other existing polymeric hydrogel systems., Graphical abstract Image 1, Highlights • Physicochemical properties of GelMA hydrogel. • Role of nanomaterials for engineering bio-functional GelMA hydrogel. • Diverse biomedical applications of nanostructured GelMA hydrogel. • Promising directions for nano-inspired GelMA bioink formulation. • Applications and challenges of advanced GelMA-nanomaterial platforms.

Background Astrocyte is a key regulator of neuronal activity and excitatory/inhibitory balance via gliotransmission. Recently, gliotransmission has been identified as a novel target for neurological diseases. However, using the properties of nanomaterials to modulate gliotransmission has not been uncovered. Results We prepared non-invasive CNT platforms for cells with different nanotopography and properties such as hydrophilicity and conductivity. Using CNT platforms, we investigated the effect of CNT on astrocyte functions participating in synaptic transmission by releasing gliotransmitters. Astrocytes on CNT platforms showed improved cell adhesion and proliferation with upregulated integrin and GFAP expression. In addition, intracellular GABA and glutamate in astrocytes were augmented on CNT platforms. We also demonstrated that gliotransmitters in brain slices were increased by ex vivo incubation with CNT. Additionally, intracellular resting Ca2+ level, which is important for gliotransmission, was also increased via TRPV1 on CNT platforms. Conclusion CNT can improve astrocyte function including adhesion, proliferation and gliotransmission by increasing resting Ca2+ level. Therefore, our study suggests that CNT would be utilized as a new therapeutic platform for central nervous system diseases by modulating gliotransmission. Graphical Abstract

Cell–material interactions are regulated by mimicking bone extracellular matrix on the surface of biomaterials. In this regard, reproducing the extracellular conditions that promote integrin and growth factor (GF) signaling is a major goal to trigger bone regeneration. Thus, the use of synthetic osteogenic domains derived from bone morphogenetic protein 2 (BMP-2) is gaining increasing attention, as this strategy is devoid of the clinical risks associated with this molecule. In this work, the wrist and knuckle epitopes of BMP-2 are screened to identify peptides with potential osteogenic properties. The most active sequences (the DWIVA motif and its cyclic version) are combined with the cell adhesive RGD peptide (linear and cyclic variants), to produce tailor-made biomimetic peptides presenting the bioactive cues in a chemically and geometrically defined manner. Such multifunctional peptides are next used to functionalize titanium surfaces. Biological characterization with mesenchymal stem cells demonstrates the ability of the biointerfaces to synergistically enhance cell adhesion and osteogenic differentiation. Furthermore, in vivo studies in rat calvarial defects prove the capacity of the biomimetic coatings to improve new bone formation and reduce fibrous tissue thickness. These results highlight the potential of mimicking integrin-GF signaling with synthetic peptides, without the need for exogenous GFs.

We propose an ex vivo T cell expansion system that mimics natural antigen-presenting cells (APCs) for adoptive cell therapy (ACT). Microfiber scaffolds coated with dendritic cell (DC) membrane replicate physicochemical properties of dendritic cells specific for T cell activation such as rapid recognition by T cells, long duration of T cell tethering, and DC-specific co-stimulatory cues. The DC membrane-coated scaffold is first surface-immobilized with T cell stimulatory ligands, anti-CD3 (αCD3) and anti-CD28 (αCD28) antibodies, followed by adsorption of releasable interleukin-2 (IL-2). The scaffolds present both surface and soluble cues to T cells ex vivo in the same way that these cues are presented by natural APCs in vivo. We demonstrate that the DC-mimicking scaffold promotes greater polyclonal expansion of primary human T cells as compared to αCD3/αCD28-functionalized Dynabead. More importantly, major histocompatibility complex molecules derived from the DC membrane of the scaffold allow antigen-specific T cell expansion with target cell-specific killing ability. In addition, most of the expanded T cells (∼97%) can be harvested from the scaffold by density gradient centrifugation. Overall, the DC-mimicking scaffold offers a scalable, modular, and customizable platform for rapid expansion of highly functional T cells for ACT.

Novel polycaprolactone-based polyurethane (PCL-PU) copolymers with hyperelasticity, shape-memory, and ultra-cell-adhesion properties are reported as clinically applicable tissue-regenerative biomaterials. New isosorbide derivatives (propoxylated or ethoxylated ones) were developed to improve mechanical properties by enhanced reactivity in copolymer synthesis compared to the original isosorbide. Optimized PCL-PU with propoxylated isosorbide exhibited notable mechanical performance (50 MPa tensile strength and 1150% elongation with hyperelasticity under cyclic load). The shape-memory effect was also revealed in different forms (film, thread, and 3D scaffold) with 40%-80% recovery in tension or compression mode after plastic deformation. The ultra-cell-adhesive property was proven in various cell types which were reasoned to involve the heat shock protein-mediated integrin (α5 and αV) activation, as analyzed by RNA sequencing and inhibition tests. After the tissue regenerative potential (muscle and bone) was confirmed by the myogenic and osteogenic responses in vitro

Osteoporosis causes severe bone damage, posing potential risks to human health, patient quality of life, and society. Calcium has been widely shown to enhance bone density and prevent osteoporosis-related bone fractures. Here, we focused on calcium salt formulations containing natural substances and their possible therapeutic effects on osteoporosis. In particular, we developed a nanoscale calcium salt of natural origin and formulated nanocomposite tablets supplemented with vitamin D (Vit D), herb Rhodiola rosea (R. rosea) and natural mineral Shilajit that are known to be antiosteoporotic. The calcium salt nanocomposites exhibited no toxicity, and particularly the formulation containing R. rosea stimulated osteogenic differentiation. The calcium salt nanocomposites inhibited osteoclastic activity, including RANKL expression, as shown by a decrease in tartrate-resistant acid phosphatase (TRAP)-positive cells. When administered orally to osteoporotic rats for 45 days, the calcium salt nanocomposites reduced bone resorption, as evidenced by the significantly higher bone volume and density, increase in osteoblasts and decrease in osteoclasts compared to those in nontreated control rats. Systemic administration of the nanocomposites caused no severe stomach toxicity or damage over the test period, during which no renal stone growth was observed. On the basis of their significant bilateral effects in stimulating osteoblasts and inhibiting osteoclasts and the resultant efficacy in an osteoporotic model, the nanocomposite tablets composed of a calcium salt and natural products can be considered novel nanotherapeutics for osteoporosis treatment.

Tailoring the surface of biomaterial scaffolds has been a key strategy to modulate the cellular interactions that are helpful for tissue healing process. In particular, nanotopological surfaces have been demonstrated to regulate diverse behaviors of stem cells, such as initial adhesion, spreading and lineage specification. Here, we tailor the surface of biopolymer nanofibers with carbon nanotubes (CNTs) to create a unique bi-modal nanoscale topography (500 nm nanofiber with 25 nm nanotubes) and report the performance in modulating diverse in vivo responses including inflammation, angiogenesis, and bone regeneration. When administered to a rat subcutaneous site, the CNT-coated nanofiber exhibited significantly reduced inflammatory signs (down-regulated pro-inflammatory cytokines and macrophages gathering). Moreover, the CNT-coated nanofibers showed substantially promoted angiogenic responses, with enhanced neoblood vessel formation and angiogenic marker expression. Such stimulated tissue healing events by the CNT interfacing were evidenced in a calvarium bone defect model. The in vivo bone regeneration of the CNT- coated nanofibers was significantly accelerated, with higher bone mineral density and up-regulated osteogenic signs (OPN, OCN, BMP2) of in vivo bone forming cells. The in vitro studies using MSCs could demonstrate accelerated adhesion and osteogenic differentiation and mineralization, supporting the osteo-promoting mechanism behind the in vivo bone forming event. These findings highlight that the CNTs interfacing of biopolymer nanofibers is highly effective in reducing inflammation, promoting angiogenesis, and driving adhesion and osteogenesis of MSCs, which eventually orchestrate to accelerate tissue healing and bone regeneration process. Statement of significance Here we demonstrate that the interfacing of biopolymer nanofibers with carbon nanotubes (CNTs) could modulate multiple interactions of cells and tissues that are ultimately helpful for the tissue healing and bone regeneration process. The CNT-coated scaffolds significantly reduced the pro-inflammatory signals while stimulating the angiogenic marker expressions. Furthermore, the CNT-coated scaffolds increased the bone matrix production of bone forming cells in vivo as well as accelerated the adhesion and osteogenic differentiation of MSCs in vitro. These collective findings highlight that the CNTs coated on the biopolymer nanofibers allow the creation of a promising platform for nanoscale engineering of biomaterial surface that can favor tissue healing and bone regeneration process, through a series of orchestrated events in anti-inflammation, pro-angiogenesis, and stem cell stimulation.

Nanomaterials combined with phototherapy and multimodal imaging are promising for cancer theranostics. Our aim is to develop fluorescent mesoporous bioglass nanoparticles (fBGn) based on carbon dots (CD) with delivery, triple-mode imaging, and photothermal (PTT) properties for cancer theranostics. A direct and label-free approach was used to prepare multicolor fluorescent fBGn with 3-aminopropyl triethoxysilane as the surface-functionalizing agent. The calcination at 400 °C provided fBGn with high fluorescence intensity originating from the CD. In particular, a triple-mode emission [fluorescence imaging, two-photon (TP), and Raman imaging] was observed which depended on CD nature and surface properties such as surface oxidation edge state, amorphous region, nitrogen passivation of surface state, and crystalline region. The fBGn also exhibited phototherapeutic properties such as photodynamic (PDT) and PTT effects. The antitumor effect of the combined PDT/PTT therapy was significantly higher than that of individual (PDT or PTT) therapy. The fBGn, due to the mesoporous structure, the anticancer drug doxorubicin could be loaded and released in a pH-dependent way to show chemotherapy effects on cancer cells. The in vivo imaging and biocompatibility of fBGn were also demonstrated in a nude mouse model. The fBGn, with the combined capacity of anticancer delivery, triple-mode imaging, and PTT/PDT therapy, are considered to be potentially useful for cancer theranostics.

Rigidity (or stiffness) of materials and extracellular matrix has proven to be one of the most significant extracellular physicochemical cues that can control diverse cell behaviors, such as contractility, motility, and spreading, and the resultant pathophysiological phenomena. Many 2D materials engineered with tunable rigidity have enabled researchers to elucidate the roles of matrix biophysical cues in diverse cellular events, including migration, lineage specification, and mechanical memory. Moreover, the recent findings accumulated under 3D environments with viscoelastic and remodeling properties pointed to the importance of dynamically changing rigidity in cell fate control, tissue repair, and disease progression. Thus, here we aim to highlight the works related with material/matrix-rigidity-mediated cell and tissue behaviors, with a brief outlook into the studies on the effects of material/matrix rigidity on cell behaviors in 2D systems, further discussion of the events and considerations in tissue-mimicking 3D conditions, and then examination of the

Designing various transplantable biomaterials, especially nanoscale matrixes for bone regeneration, involves precise tuning of topographical features. The cellular fate on such engineered surfaces is highly influenced by many factors imparted by the surface modification (hydrophilicity, stiffness, porosity, roughness, ROS responsiveness). Herein, hybrid matrixes of gelatin methacryloyl (GelMA) decorated with uniform layers of nanoceria (nCe), called Ce@GelMA, were developed without direct incorporation of nCe into the scaffolds. The fabrication involves a simple base-mediated in situ deposition in which uniform nCe coatings were first made on GelMA hydrogels and then nCe layered GelMA scaffolds were made by cryodesiccation. In this hybrid platform, degradable GelMA biopolymer provides the porous microstructure and nCe provides the nanoscaled biointerface. The surface morphology and elemental composition of the matrixes analyzed by field emission scanning electron microscopy (FE-SEM) and energy-dispersive spectroscopy (EDS) show uniform nCe distribution. The surface nanoroughness and chemistry of the matrixes were also characterized using atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). The presence of nCe on GelMA enhanced its mechanical properties as confirmed by compressive modulus analysis. Substantial bonelike nanoscale hydroxyapatite formation was observed on scaffolds after simulated body fluid (SBF) immersion, which was confirmed by SEM, X-ray diffraction (XRD), and Fourier transform infrared (FT-IR) spectroscopy. Moreover, the developed scaffolds could also be used as an antioxidant matrix owing to the reactive oxygen species (ROS) scavenging property of nCe as assessed by 3,3',5,5'-tetramethylbenzidine (TMB) assay. The enhanced proliferation and viability of rat bone marrow mesenchymal stem cells (rMSCs) on the scaffold surface after 3 days of culture ensures the biocompatibility of the proposed material. Considering all, it is proposed that the micro/nanoscaled matrix could mimic the composition and function of hard tissues and could be utilized as degradable scaffolds in engineering bones.

Providing appropriate biophysical and biochemical cues to the interface is a facile strategy to enhance the osteogenic ability of metallic implants. Here we exploited this through the incorporation of mesoporous bioactive glass nanoparticles (MBGN) at a high content (1:1 by weight) to a biopolymer chitosan in the electrodeposition process of titanium. The MGBN/chitosan layer thickness, tunable by electrodeposition parameters, exhibited an accelerated ability of apatite mineral induction in a body simulating medium. Of note, the involvement of MBGN could generate nanoscale roughness in a unique range of 10-25 nm. Moreover, the layer showed a slowly releasing profile of ions (calcium and silicate) over weeks at therapeutically relevant doses. The ion-releasing nanotopological surface was demonstrated to alter the preosteoblasts responses in a way favorable for osteogenic differentiation. The combinatory cues of nanotopology (25 nm roughness) and ion release enabled highly accelerated cellular anchorage with somewhat limited spreading area at initial periods. The subsequent osteoblastic differentiation behaviors on the engineered surface, as examined up to 21 days, showed significantly enhanced alkaline phosphate activity and up-regulated expression of bone-associated genes (ALP, Col I, OPN, and OCN). These results indicate that the combinatory cues provided by nanotopology (25 nm roughness) and ions released from MBGN are highly effective in stimulating osteoblastic differentiation and suggest that the MBGN/chitosan may serve as a potential composition for bone implant coatings.

The eggshell membrane (ESM) is an abundant resource with innate complex structure and composition provided by nature. With at least 60 million tonnes of hen eggs produced globally per annum, utilisation of this waste resource is highly attractive in positively impacting sustainability worldwide. Given the morphology and mechanical properties of this membrane, it has great potential as a biomaterials for wound dressing. However, to date, no studies have demonstrated nor reported this application. As such, the objective of this investigation was to identify and optimise a reproducible extraction protocol of the ESM and to assess the physical, chemical, mechanical and biological properties of the substrate with a view to use as a wound dressing. ESM samples were isolated by either manual peeling (ESM-strip) or via extraction using acetic acid [ESM-A0.5] or ethylenediaminetetraacetic acid, EDTA [ESM-E0.9]. Energy dispersive X-ray spectroscopy (EDS) confirmed that there were no traces of calcium residues from the extraction process. Fourier transform infrared (FTIR) spectroscopy revealed that the extraction method (acetic acid and EDTA) did not alter the chemical structures of the ESM and also clarified the composition of the fibrous proteins of the ESM. Scanning electron microscopy (SEM) analyses revealed a three-layer composite structure of the ESM: an inner layer as continuous, dense and non-fibrous (limiting membrane), a middle layer with a network of fibres (inner shell membrane) and the outer layer (outer shell membrane) of larger fibres. Material properties including optical transparency, porosity, fluid absorption/uptake, thermal stability, mechanical profiling of the ESM samples were performed and demonstrated suitable profiles for translational applications. Biological in vitro studies using SV40 immortalised corneal epithelial cells (ihCEC) and corneal mesenchymal stromal cells (C-MSC) demonstrated excellent biocompatibility. Taken together, these results document the development of a novel sustainable biomaterial that may be used for ophthalmic wounds and/or other biomedical therapies.

Neural stem cells (NSC) have tremendous potential for therapeutic regeneration of diseased or traumatized neural tissues, including injured spinal cord. However, transplanted NSC suffer from low cell survival and uncontrolled differentiation, limiting in vivo efficacy. Here, this issue is tackled by delivery through silk-collagen protein hydrogels that are stiffness-matched, stress-relaxing, and shear-thinning. The mechanically-tuned hydrogels protect NSC reprogrammed from fibroblasts (iNSC) initially from injection shear-stress, and enhance long-term survival over 12 weeks. Hydrogel-iNSC treatment alleviates neural inflammation, with reduced inflammatory cells and lesions than NSC-only. The iNSC migrate from the hydrogel into surrounding tissues, secrete up-regulated neurotrophic factors, and differentiate into neural cell subtypes, forming synapses. More serotonergic axons are observed in the lesion cavity, and locomotor functions are improved in hydrogel-iNSC than in iNSC-only. This study highlights the ability of mechanically-tuned protein hydrogels to protect iNSC from the injection stress and severe inflammatory environment, allowing them to differentiate and function to recover the injured spinal cord.

The aim of this study was to compare the performance of a deep-learning convolutional neural network (Faster R-CNN) model to detect imaging findings suggestive of idiopathic Parkinson’s disease (PD) based on [18F]FP-CIT PET maximum intensity projection (MIP) images versus that of nuclear medicine (NM) physicians. The anteroposterior MIP images of the [18F]FP-CIT PET scan of 527 patients were classified as having PD (139 images) or non-PD (388 images) patterns according to the final diagnosis. Non-PD patterns were classified as overall-normal (ONL, 365 images) and vascular parkinsonism with definite defects or prominently decreased dopamine transporter binding (dVP, 23 images) patterns. Faster R-CNN was trained on 120 PD, 320 ONL, and 16 dVP pattern images and tested on the 19 PD, 45 ONL, and seven dVP patterns images. The performance of the Faster R-CNN and three NM physicians was assessed using receiver operating characteristics curve analysis. The difference in performance was assessed using Cochran’s Q test, and the inter-rater reliability was calculated. Faster R-CNN showed high accuracy in differentiating PD from non-PD patterns and also from dVP patterns, with results comparable to those of NM physicians. There were no significant differences in the area under the curve and performance. The inter-rater reliability among Faster R-CNN and NM physicians showed substantial to almost perfect agreement. The deep-learning model accurately differentiated PD from non-PD patterns on MIP images of [18F]FP-CIT PET, and its performance was comparable to that of NM physicians.

Introducing new generations of injectable bioactive types of cement that fulfill excellent injectability, rapid self-setting, high bioactivity, proper biodegradability, and fast therapeutic ion-releasing capability is highly demanded for tooth and bone regeneration. Here, we announce therapeutic fast ion-releasing nanobiocements (NBCs) based on sol-gel-processed calcium silicate mesoporous nanobioactive glass with or without strontium (NBC, Sr-free and Sr-NBC, Sr-doped). The stimulating role of Sr ions in odontogenesis of stem cells derived from dental pulp (DPSCs) and in in vivo dentin formation has been investigated. The nanobiocement was formulated through the mixing of bioactive glass nanopowder with a phosphate-buffered saline (P/L = 0.5 g/mL) to form a soft cement paste that hardens within 5-10 min in the ambient environment. The self-setting originated from a setting reaction involving the deposition of hydroxyapatite as evidenced from X-ray diffraction. Both nanobiocements showed the rapid release of therapeutic ions with biologically effective doses, including strontium (Sr), calcium (Ca), or silicon (Si). In vitro cell cultures with DPSCs showed excellent biocompatibility and high odontogenic potential, especially from Sr-NBC. In an in vivo study, Sr-NBC showed more new dentin formation compared to that of NBC, revealed by two different animal models (odontogenesis in subcutaneous and natural tooth environment). Also, NBCs showed high loading capacities of simvastatin used as a model drug. Taken together, Sr-NBC could be considered as a multifunctional nanobiocement with high bioactivity, excellent biodegradability, fast therapeutic ion release, and high drug loading capability, which potentiates its application in dentin-pulp complex regeneration therapy.

Although biopolymers are widely used in biomedical fields, the issue of poor antimicrobial properties remains unsolved, leading to a potential increase in infections. Here, ceria nanoparticles (CNPs) were incorporated into a representative biopolymer, poly(methyl methacrylate) (PMMA), for drug-free antimicrobial properties. After characterizing the CNPs and surface/mechanical properties of the CNP-PMMA nanocomposite, antiadhesive effects against Candida albicans, the most common fungal species responsible for fungal infections, were determined using metabolic activity assays, and the underlying microbial antiadhesive mechanism was revealed. Hydrothermally fabricated CNPs showed a size of ∼20 nm with a zeta potential of 12 ± 2.3 mV and showed catalytic properties as a ROS modulator. Successful incorporation of CNPs into PMMA up to 2 wt % was confirmed by EDS analysis. The surface roughness and mechanical properties such as flexural strength and modulus were relatively unchanged up to 2 wt %. In contrast, the surface energy increased, and the Vickers hardness decreased in the 2 wt % PMMA compared with the control. A drop of up to 90% of adherent Candida albicans was observed in CNP-incorporated PMMA, which was confirmed and quantified via fungus staining images. The antiadhesive mechanism was revealed from the direct antimicrobial effects of CNP via the upregulation of the intracellular ROS level. Taken together, the antimicrobial-adhesive properties of the CNP-PMMA nanocomposite suggest the potential usefulness of CNP as a promising drug-free antimicrobial ingredient for biopolymers, which could lead to the prevention of microbial-induced complications in clinical settings.

Current gold standard to treat soft tissue injuries caused by trauma and pathological condition are autografts and off the shelf fillers, but they have inherent weaknesses like donor site morbidity, immuno-compatibility and graft failure. To overcome these limitations, tissue-engineered polymers are seeded with stem cells to improve the potential to restore tissue function. However, their interaction with native tissue is poorly understood so far. To study these interactions and improve outcomes, we have fabricated scaffolds from natural polymers (collagen, fibrin and elastin) by custom-designed processes and their material properties such as surface morphology, swelling, wettability and chemical cross-linking ability were characterised. By using 3D scaffolds, we comprehensive assessed survival, proliferation and phenotype of adipose-derived stem cells in vitro. In vivo, scaffolds were seeded with adipose-derived stem cells and implanted in a rodent model, with X-ray microtomography, histology and immunohistochemistry as read-outs. Collagenbased materials showed higher cell adhesion and proliferation in vitro as well as higher adipogenic properties in vivo. In contrast, fibrin demonstrated poor cellular and adipogenesis properties but higher angiogenesis. Elastin formed the most porous scaffold, with cells displaying a non-aggregated morphology in vitro while in vivo elastin was the most degraded scaffold. These findings of how polymers present in the natural polymers mimicking ECM and seeded with stem cells affect adipogenesis in vitro and in vivo can open avenues to design 3D grafts for soft tissue repair. info:eu-repo/semantics/publishedVersion

Ulceration of the oral mucosa is common, can arise at any age and as a consequence of the pain lessens enjoyment and quality of life. Current treatment options often involve the use of topical corticosteroids with poor drug delivery systems and inadequate contact time. In order to achieve local controlled delivery to the lesion with optimal adhesion, we utilized a simple polydopamine chemistry technique inspired by mussels to replicate their adhesive functionality. This was coupled with production of a group of naturally produced polymers, known as polyhydroxyalkanoates (PHA) as the delivery system. Initial work focused on the synthesis of PHA using Pseudomonas mendocina CH50; once synthesized and extracted from the bacteria, the PHAs were solvent processed into films. Polydopamine coating was subsequently achieved by immersing the solvent cast film in a polymerized dopamine solution. Fourier Transform Infrared Spectroscopy (FTIR) spectroscopy confirmed functionalization of the PHA films via the presence of amine groups. Further characterization of the samples was carried out via surface energy measurements and Scanning Electron Microscopy (SEM) micrographs for surface topography. An adhesion test via reverse compression testing directly assessed adhesive properties and revealed an increase in polydopamine coated samples. To further identify the effect of surface coating, LIVE/DEAD imaging and Alamar Blue metabolic activity evaluated attachment and proliferation of fibroblasts on the biofilm surfaces, with higher cell growth in favor of the coated samples. Finally, in vivo biocompatibility was investigated in a rat model where the polydopamine coated PHA showed less inflammatory response over time compared to uncoated samples with sign of neovascularization. In conclusion, this simple mussel inspired polydopamine chemistry introduces a step change in bio-surface functionalization and holds great promise for the treatment of oral conditions., Graphical Abstract Illustration of PHA synthesis followed by a simple muscle inspired chemistry polydopamine coating.

Glial cell alignment in tissue engineered constructs is essential for achieving functional outcomes in neural recovery. While gelatin methacrylate (GelMA) hydrogel offers superior biocompatibility along with permissive structure and tailorable mechanical properties, phosphate glass fibers (PGFs) can provide physical cues for directionality of neural growth. Aligned PGFs were fabricated by a melt quenching and fiber drawing method and utilized with synthesized GelMA hydrogel. The mechanical properties of GelMA and biocompatibility of the GelMA-PGFs composite were investigated in vitro using rat glial cells. GelMA with 86% methacrylation degree were photo-crosslinked using 0.1%wt photo-initiator (PI). Photocrosslinking under UV exposure for 60 s was used to produce hydrogels (GelMA-60). PGFs were introduced into the GelMA before crosslinking. Storage modulus and loss modulus of GelMA-60 was 24.73 ± 2.52 and 1.08 ± 0.23 kN/m2 , respectively. Increased cell alignment was observed in GelMA-PGFs compared with GelMA hydrogel alone. These findings suggest GelMA-PGFs can provide glial cells with physical cues necessary to achieve cell alignment. This approach could further be used to achieve glial cell alignment in bioengineered constructs designed to bridge damaged nerve tissue.

Brain diseases and damages come in many forms such as neurodegenerative diseases, tumors, and stroke. Millions of people currently suffer from neurological diseases worldwide. While Challenges of current diagnosis and treatment for neurological diseases are the drug delivery to the central nervous system. The Blood-Brain Barrier (BBB) limits the drug from reaching the targeted site thus showing poor effects. Nanoparticles that have advantage of the assembly at the nanoscale of available biomaterials can provide a delivery platform with potential to raising brain levels of either imaging therapeutic drugs or imaging. Therefore, successful modeling of the BBB is another crucial factor for the development of nanodrugs. In this review, we analyze the in vitro and in vivo findings achieved in various models, and outlook future development of nanodrugs for the successful treatment of brain diseases and damages.

Extracellular vesicles (EVs), including exosomes, carry the genetic packages of RNA, DNA, and proteins and are heavily involved in cell-cell communications and intracellular signalings. Therefore, EVs are spotlighted as therapeutic mediators for the treatment of injured and dysfunctional tissues as well as biomarkers for the detection of disease status and progress. Several key issues in EVs, including payload content and bioactivity, targeting and bio-imaging ability, and mass-production, need to be improved to enable effective therapeutics and clinical translation. For this, significant efforts have been made recently, including genetic modification, biomolecular and chemical treatment, application of physical/mechanical cues, and 3D cultures. Here we communicate those recent technological advances made mainly in the biogenesis process of EVs or at post-collection stages, which ultimately aimed to improve the therapeutic efficacy in tissue healing and disease curing and the possibility of clinical translation. This communication will help tissue engineers and biomaterial scientists design and produce EVs optimally for tissue regenerative therapeutics.

Although emergence of bone tissue engineering techniques has revolutionized the field of maxillofacial reconstruction, the successful translation of such products, especially concerning larger sized defects, still remains a significant challenge. Light-curable methacrylate-based polymers have ideal properties for bone repair. These materials are also suitable for 3D printing which can be applicable for restoration of both function and aesthetics. The main objective of this research was to synthesize a mechanically stable and biologically functional polymer for reconstruction of complex craniofacial defects. The experimental work initially involved synthesis of (((3R,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl)bis(oxy))bis(ethane-2,1-diyl)bis((4-methyl-3-oxopent-4-en-1-yl)carbamate), CSMA-1, and ((((((((((((3R,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl)bis(oxy))bis(ethane-2,1 diyl))bis(oxy))bis(carbonyl))bis(azanediyl))bis(methylene))bis(3,3,5-trimethylcyclohexane-5,1-diyl))bis(azanediyl))bis(carbonyl))bis(oxy))bis(ethane-2,1-diyl)bis(2-methylacrylate), CSMA-2; nuclear magnetic resonance analysis confirmed formation of the monomers, and composite samples were fabricated respectively by exposing 11 mm diameter discs to blue light. Modulus of elasticity was determined using a biaxial flexural test and the values were found to be between 1 and 3 GPa in CSMA-1, CSMA-2, and their composites. In vitro cell culture, using human bone marrow-derived mesenchymal stem cells, confirmed nontoxicity of the samples and finally 3D printing allowed direct photo-polymerization and setting of the bio ink into a 3D construct.

The cellular microenvironment plays an important role in regulating cancer progress. Cancer can physically and chemically remodel its surrounding extracellular matrix (ECM). Critical cellular behaviors such as recognition of matrix geometry and rigidity, cell polarization and motility, cytoskeletal reorganization, and proliferation can be changed as a consequence of these ECM alternations. Here, we present an overview of cancer mechanobiology in detail, focusing on cancer microenvironmental sensing of exogenous cues and quantification of cancer-substrate interactions. In addition, mechanics of metastasis classified with tumor progression will be discussed. The mechanism underlying cancer mechanosensation and tumor progression may provide new insights into therapeutic strategies to alleviate cancer malignancy.

Using microspherical scaffolds as building blocks to repair bone defects of specific size and shape has been proposed as a tissue engineering strategy. Here, phosphate glass (PG) microcarriers doped with 5 mol % TiO2 and either 0 mol % CoO (CoO 0%) or 2 mol % CoO (CoO 2%) were investigated for their ability to support osteogenic and vascular responses of human mesenchymal stem cells (hMSCs). Together with standard culture techniques, cell-material interactions were studied using a novel perfusion microfluidic bioreactor that enabled cell culture on microspheres, along with automated processing and screening of culture variables. While titanium doping was found to support hMSCs expansion and differentiation, as well as endothelial cell-derived vessel formation, additional doping with cobalt did not improve the functionality of the microspheres. Furthermore, the microfluidic bioreactor enabled screening of culture parameters for cell culture on microspheres that could be potentially translated to a scaled-up system for tissue-engineered bone manufacturing.

Angiogenesis (or the development of new blood vessels) is a key event in tissue engineering and regenerative medicine; thus, a number of biomaterials have been developed and combined with stem cells and/or bioactive molecules to produce three-dimensional (3D) pro-angiogenic constructs. Among the various biomaterials, electrospun nanofibrous scaffolds offer great opportunities for pro-angiogenic approaches in tissue repair and regeneration. Nanofibers made of natural and synthetic polymers are often used to incorporate bioactive components (e.g., bioactive glasses (BGs)) and load biomolecules (e.g., vascular endothelial growth factor (VEGF)) that exert pro-angiogenic activity. Furthermore, seeding of specific types of stem cells (e.g., endothelial progenitor cells) onto nanofibrous scaffolds is considered as a valuable alternative for inducing angiogenesis. The effectiveness of these strategies has been extensively examined both in vitro and in vivo and the outcomes have shown promise in the reconstruction of hard and soft tissues (mainly bone and skin, respectively). However, the translational of electrospun scaffolds with pro-angiogenic molecules or cells is only at its beginning, requiring more research to prove their usefulness in the repair and regeneration of other highly-vascularized vital tissues and organs. This review will cover the latest progress in designing and developing pro-angiogenic electrospun nanofibers and evaluate their usefulness in a tissue engineering and regenerative medicine setting.

Three-dimensional (3D) printing enhances the production of on-demand fabrication of patient-specific devices as well as anatomically fitting implants with high complexity in a cost-effective manner. Additive systems that employ vat photopolymerisation such as stereolithography (SLA) and digital light projection (DLP) are used widely in the field of biomedical science and engineering. However, additive manufacturing methods can be limited by the types of materials that can be used. In this study, we present an isosorbide-based formulation for a polymer resin yielding a range of elastic moduli between 1.73 GN/mm2 dependent on the photoinitiator system used as well as the amount of calcium phosphate filler added. The monomer was prepared and enhanced for 3D-printing using an SLA technique that delivered stable and optimized 3D-printed models. The resin discussed could potentially be used following major surgery for the correction of congenital defects, the removal of oral tumours and the reconstruction of the head and neck region. The surgeon is usually limited with devices available to restore both function and appearance and with the ever-increasing demand for low-priced and efficient facial implants, there is an urgent need to advance new manufacturing approaches and implants with a higher osseointegration performance.

Therapeutic options are quite limited in clinics for the successful repair of infected/degenerated tissues. Although the prevalent treatment is the complete removal of the whole infected tissue, this leads to a loss of tissue function and serious complications. Herein the dental pulp infection, as one of the most common dental problems, was selected as a clinically relevant case to regenerate using a multifunctional nanotherapeutic approach. For this, a mesoporous bioactive glass nano-delivery system incorporating silicate, calcium, and copper as well as loading epidermal growth factor (EGF) was designed to provide antibacterial/pro-angiogenic and osteo/odontogenic multiple therapeutic effects. Amine-functionalized Cu-doped bioactive glass nanospheres (Cu-BGn) were prepared to be 50–60 nm in size, mesoporous, positive-charged and bone-bioactive. The Cu-BGn could release bioactive ions (copper, calcium and silicate ions) with therapeutically-effective doses. The Cu-BGn treatment to human umbilical vein endothelial cells (HUVEC) led to significant enhancement of the migration, tubule formation and expression of angiogenic gene (e.g. vascular endothelial growth factor, VEGF). Furthermore, the EGF-loaded Cu-BGn (EGF@Cu-BGn) showed pro-angiogenic effects with antibacterial activity against E. faecalis, a pathogen commonly involved in the pulp infection. Of note, under the co-culture condition of HUVEC with E. faecalis, the secretion of VEGF was up-regulated. In addition, the osteo/odontogenic stimulation of the EGF@Cu-BGn was evidenced with human dental pulp stem cells. The local administration of the EGF@Cu-BGn in a rat molar tooth defect infected with E. faecalis revealed significant in vivo regenerative capacity, highlighting the nanotherapeutic uses of the multifunctional nanoparticles for regenerating infected/damaged hard tissues., Graphical abstract Image 1, Highlights • EGF/Cu releasing nanotherapeutics demonstrated promising angiogenic/antibacterial and osteogenic/odontogenic effects. • In vitro study involving HUVECs/bacteria co-cultures revealed remarkable angiogenic and antibacterial activities. • In vivo study in bacterial infected pulp tissue of rat molar teeth unveiled the high efficacy of EGF/Cu nanotherapeutics.

Cancer stem cells have been shown to be important in tumorigenesis processes, such as tumor growth, metastasis, and recurrence. As such, many three-dimensional models have been developed to establish an ex vivo microenvironment that cancer stem cells experience under in vivo conditions. Cancer stem cells propagating in three-dimensional culture systems show physiologically related signaling pathway profiles, gene expression, cell–matrix and cell–cell interactions, and drug resistance that reflect at least some of the tumor properties seen in vivo. Herein, we discussed the presently available Cancer stem cell three-dimensional culture models that use biomaterials and engineering tools and the biological implications of these models compared to the conventional ones.

In this communication we report that anchoring avß3 or a5ß1 integrin-selective RGD peptidomimetics to titanium efficiently tunes mesenchymal stem cell response in vitro and bone growth in rat calvarial defects. Our results demonstrate that this molecular chemistry-derived approach could be successful to engineer instructive coatings for orthopedic applications.

Promoting angiogenesis is a key strategy for stimulating the repair of damaged tissues, including bone. Among other proangiogenic factors, ions have recently been considered a potent element that can be incorporated into biomaterials and then released at therapeutic doses. Silicate-based biomaterials have been reported to induce neovascularization through vascular endothelial growth factor signaling pathway, potentiating acceleration of bone regeneration. Here, we designed a silicate-shelled hydrogel fiber scaffold with a hard/soft layered structure to investigate the possibility of silicate coating on biopolymer for enhancing biological properties. An alginate hydrogel was injected to form a fiber scaffold with shape-tunability that was then coated with a thin silicate layer with various sol-gel compositions. The silicate/alginate scaffold could release calcium and silicate ions, and in particular, silicate ion release was highly sustainable for over one week at therapeutically relevant levels. The ionic release was highly effective in stimulating the mRNA expression of angiogenic markers (VEGF, KDR, eNOS, bFGF, and HIF1-α) in endothelial cells (HUVECs). Moreover, the in vitro tubular networking of cells was significantly enhanced (1.5 times). In vivo implantation in subcutaneous tissue revealed more pronounced blood vessel formation around the silicate-shelled scaffolds than around silicate-free scaffolds. The presence of a silicate shell was also shown to accelerate acellular mineral (hydroxyapatite) formation. The cellular osteogenesis potential of the silicate/alginate scaffold was further proven by the enhanced expression of osteogenic genes (Col1a1, ALP and OCN). When implanted in a rat calvarium defect, the silicate-shelled scaffold demonstrated significantly improved bone formation (2-3 times higher in bone volume and density) with a concurrent sign of proangiogenesis. This work highlights that the surface-layering of silicate composition is an effective approach for improving the bone regeneration capacity of polymeric hydrogel scaffolds by stimulating ion-induced angiogenesis and providing bone bioactivity to the surface.

Tissue engineering provides great possibilities to manage tissue damages and injuries in modern medicine. The involvement of hard biocompatible materials in tissue engineering-based therapies for the healing of soft tissue defects has impressively increased over the last few years: in this regard, different types of bioceramics were developed, examined and applied either alone or in combination with polymers to produce composites. Bioactive glasses, carbon nanostructures, and hydroxyapatite nanoparticles are among the most widely-proposed hard materials for treating a broad range of soft tissue damages, from acute and chronic skin wounds to complex injuries of nervous and cardiopulmonary systems. Although being originally developed for use in contact with bone, these substances were also shown to offer excellent key features for repair and regeneration of wounds and "delicate" structures of the body, including improved cell proliferation and differentiation, enhanced angiogenesis, and antibacterial/anti-inflammatory activities. Furthermore, when embedded in a soft matrix, these hard materials can improve the mechanical properties of the implant. They could be applied in various forms and formulations such as fine powders, granules, and micro- or nanofibers. There are some pre-clinical trials in which bioceramics are being utilized for skin wounds; however, some crucial questions should still be addressed before the extensive and safe use of bioceramics in soft tissue healing. For example, defining optimal formulations, dosages, and administration routes remain to be fixed and summarized as standard guidelines in the clinic. This review paper aims at providing a comprehensive picture of the use and potential of bioceramics in treatment, reconstruction, and preservation of soft tissues (skin, cardiovascular and pulmonary systems, peripheral nervous system, gastrointestinal tract, skeletal muscles, and ophthalmic tissues) and critically discusses their pros and cons (e.g., the risk of calcification and ectopic bone formation as well as the local and systemic toxicity) in this regard. STATEMENT OF SIGNIFICANCE: Soft tissues form a big part of the human body and play vital roles in maintaining both structure and function of various organs; however, optimal repair and regeneration of injured soft tissues (e.g., skin, peripheral nerve) still remain a grand challenge in biomedicine. Although polymers were extensively applied to restore the lost or injured soft tissues, the use of bioceramics has the potential to provides new opportunities which are still partially unexplored or at the very beginning. This reviews summarizes the state of the art of bioceramics in this field, highlighting the latest evolutions and the new horizons that can be opened by their use in the context of soft tissue engineering. Existing results and future challenges are discussed in order to provide an up-to-date contribution that is useful to both experienced scientists and early-stage researchers of the biomaterials community.

The dissolution of fluoride-containing bioactive glasses critically affects their biomedical applications. Most commercial fluoride-releasing bioactive glasses have been designed in the soda-lime-silica system. However, their relatively slow chemical dissolution and the adverse effect of fluoride on their bioactivity are stimulating the study of alternative biodegradable materials with higher biodegradability, such as biodegradable phosphate-based bioactive glasses, which can be a good candidate for applications where a fast release of active ions is sought. In order to design new biomaterials with controlled degradability and high bioactivity, it is essential to understand the connection between chemical composition, molecular structure, and solubility in physiological fluids. Accordingly, in this work we have combined the strengths of various experimental techniques with Molecular Dynamics (MD) simulations, to elucidate the impact of fluoride ions on the structure and chemical dissolution of bioactive phosphate glasses in the system: 10Na2O-(45 -x)CaO-45P2O5-xCaF2, where x varies between 0-10 mol%. NMR and MD data reveal that the medium-range atomic-scale structure of these glasses is dominated by Q2 phosphate units followed by Q1 units, and the MD simulations further show that fluoride tends to associate with network modifier cations to form alkali/alkaline-earth rich ionic aggregates. The impact of fluoride on chemical dissolution of glasses has been studied in deionized water, acidic (pH = 3.0), neutral (pH = 7.4) and basic (pH = 9.0) buffer solutions, while the bioactivity and cytotoxicity of glasses has been studied in vitro through their apatite-forming ability in simulated body fluid (SBF) and cell culture tests on mesenchymal stem cells (MSCs), respectively. The macroscopic trends observed from various chemical dissolution and bioactivity studies are discussed on the basis of the effect of fluoride on the atomistic structure of glasses, such as F-induced phosphate network re-polymerization, in an attempt to establish composition-structure-property relationships for these biomaterials.

Injectable calcium phosphate cements (CPCs) with strong mechanical properties and improved biological performance have the potential to be extensively used for bone regeneration. Although many additive materials have been incorporated into CPCs in order to achieve improvements in their mechanical and biological properties, somehow the results have not been fully satisfactory. Here we focus on using the nanoparticle form of mesoporous bioactive glasses (mBGn) as additive nano-components for alpha-tricalcium phosphate-based CPCs. The effects of mBGn incorporated up to 10 wt% into CPCs were examined in depth with respect to the setting time, morphology, injectability, wash-out properties, consistency, ionic release, pH change, and mechanical strength. The addition of mBGn significantly increased the surface area (for both the as-cemented and the hydrated compositions) and also significantly accelerated the setting reaction of CPCs. The injectability and the anti-washout property of CPCs were remarkably enhanced with the addition of mBGn. In striking contrast to the case of pure CPCs, the morphological changes observed in simulated body fluid (SBF) revealed a spherical development of apatite crystals, replicating the nanospherical morphology of the mBGn and consequently resulting in a nano-micro-roughened surface. The mechanical compressive strength substantially increased after SBF immersion and significantly higher values were recorded for mBGn/CPC as compared to pure CPCs. The ion release, including that of calcium, phosphate, and silicon, was recorded at substantial levels during the test period, and the addition of mBGn caused changes in the pH towards less acidic. The in vivo study of the mBGn/CPCs in rat subcutaneous tissue confirmed excellent tissue compatibility with little evidence of inflammatory reactions while exhibiting viable fibroblastic cells with a substantial presence of mature endothelial cells surrounding the cements. When implanted in a rat calvarium defect, a substantial degradation of the samples was noticed in the interfacial region. The proposed mBGn/CPC is a novel, promising cement formulation for the repair and regeneration of bone due to setting characteristics, physico-chemical and mechanical properties, and excellent in vivo tissue compatibility and bioactivity.

Biocompatible and multifunctional nanocarriers significantly improve the therapeutic and diagnostic efficacy of the cargo molecules. Here we report a novel biocompatible apatite nanocrystal-based delivery system with in situ imaging capacity. A nanorod (40 nm × 10 nm) produced by a citrate-involved sol–gel process expressed a strong blue emission at 427 nm under fluorescence microscopy. The CO2˙− radical impurities present in the apatite crystal lattice account for the fluorescent behavior. The fluorescent nanorods exhibited excellent cell viability (over 90% up to ∼100 μg ml−1 concentration for both osteoblasts and osteoclasts). The nanorods loaded alendronate drug at a high efficiency (10%) and released over 3 days, while enabling in situ fluorescence imaging within the cells. The fluorescent apatite was further hybridized onto the surface of mesoporous nanospheres, aimed at improving the drug-delivery capacity. Small interfering RNA (siRNA) gene, encoding Plekho-1, was effectively loaded to the hybrid nanocarrier, and was sustainably released over 5 days. The siRNA-loaded nanocarrier exhibited excellent osteoblastic uptake (96% efficiency) and gene-silencing effect, suppressing Plekho-1 down to ∼18%, while preserving intracellular fluorescence signals. Taken as a whole, the self-fluorescent nature of apatite nanorods is believed to find potential and versatile applications as biocompatible drug-delivery and in situ imaging systems.

In this brief review, basic principles and recent progresses on the development of therapeutic substitutes for major blood components are briefly discussed with primary focus on the red cell substitutes.

Objective Titanium and its alloys are widely used for dental and medical biomaterials due to their excellent mechanical and biological advantages. After the introduction of direct laser metal sintering (DLMS) 3D printing technology and its use over conventional machine-cut processes, questions remain regarding whether 3D-printed titanium (alloy) devices have similar biological properties to machine-cut counterparts for dental applications. Thus, this work focuses on comparing the biological activities of machine-cut and 3D-printed specimens after optimizing the DLMS 3D-printing conditions in terms of the mechanophysical characteristics. Methods The DLMS 3D-printing (as a function of the laser spacing from 30–100 μm) and post-surface treatment (as-given or sand-blasted) conditions were optimized using medical-grade Ti-6Al-4V powders in terms of the inner pore amount, mechanical properties, roughness and hydrophilicity. Then, the initial cell adhesion of the optimized DLMS 3D-printed Ti-6Al-4V specimen was compared with that of the machine-cut Ti-6Al-4V specimen against human dermal fibroblasts (hDFs) and mesenchymal stem cells (hMSCs), which are representative of direct-contact cell types of orofacial mucosa and bone, respectively. hMSC differentiation on the specimens was conducted for up to 21 days to measure the osteogenic gene expression and biomineralization. Results Laser spacings of 30–40 μm had fewer inner defects and consequently a higher three-point flexural strength and elastic modulus compared to other larger laser spacings. Depending on the span width (0.3–1 mm) in the lattice architecture, the elastic modulus of the 3D-printed cuboid specimen can be further controlled (up to ∼30 times). The sand-blasted specimens after 3D printing revealed lower surface roughness and higher hydrophilicity compared to the as-3D printed specimen, which were considered optimal conditions for biological study. Initial hDF and hMSC adhesion for 12 hr and hMSC differentiation on the surface were comparable between the sand-blasted 3D-printed and machine-cut specimens in terms of adherent cell numbers, vinculin intensity, osteogenic gene expression and biomineralization. Significance The optimized DLMS 3D-printed Ti-6Al-4V specimen had similar biological properties to those of the machine-cut counterpart, suggesting the potential usefulness of 3D printing technology for a wide range of dental applications.

The control of bacterial infections is of particular importance in the field of tissue engineering. Recently, much attention has been addressed toward the use of mesoporous bioactive glasses (MBGs) for antibacterial strategies, primarily because of their capability of acting as carriers for the local release of antimicrobial agents. The incorporation of antibacterial metallic ions including silver (Ag+), zinc (Zn2+), copper (Cu+ and Cu2+), cerium (Ce3+ and Ce4+), and gallium (Ga3+) cations into the MBG structure and their controlled release is proposed as one of the most attractive strategies for inhibiting bacterial growth and reproduction. Moreover, the possibility of loading and delivering various antibacterial biomolecules (e.g., antibiotics) through the porous structure of MBGs makes them as ideal candidates for antibacterial applications. In this review, we aim to present a comprehensive evaluation of MBG potential regarding antibacterial activities. For this purpose, different types of antibacterial ion-doped and drug-loaded MBGs are introduced and discussed in the light of existing knowledge, along with the significant challenges ahead. Statement of significance Prevention and treatment of infections is one of the today’s greatest challenges in medical sciences, also considering the well-known issues related to increased bacterial resistance to antibiotics. The advent of mesoporous glasses led to the birth of a new class of multifunctional biomaterials acting as bioactive platforms for the local release of organic or inorganic agents eliciting an antimicrobial effect. This reviews summarizes the state of the art of MBGs in this field, highlighting the latest evolutions and the specific role played by metallic antimicrobial ions that can be incorporated in the glass composition and then properly released. Perspective for tissue engineering applications are also discussed to provide an up-to-date contribution that is useful to both experienced scientists and early-stage researchers.

Cell encapsulating hydrogels with tunable mechanical and biological properties are of special importance for cell delivery and tissue engineering. Silk fibroin and collagen, two typical important biological proteins, are considered potential as cell culture hydrogels. However, both have been used individually, with limited properties (e.g., collagen has poor mechanical properties and cell-mediated shrinkage, and silk fibroin from Bombyx mori (mulberry) lacks cell adhesion motifs). Therefore, the combination of them is considered to achieve improved mechanical and biological properties with respect to individual hydrogels. Here, we show that the cell-encapsulating hydrogels of mulberry silk fibroin / collagen are implementable over a wide range of compositions, enabled simply by combining the different gelation mechanisms. Not only the gelation reaction but also the structural characteristics, consequently, the mechanical properties and cellular behaviors are accelerated significantly by the silk fibroin / collagen hybrid hydrogel approach. Of note, the mechanical and biological properties are tunable to represent the combined merits of individual proteins. The shear storage modulus is tailored to range from 0.1 to 20 kPa along the iso-compositional line, which is considered to cover the matrix stiffness of soft-to-hard tissues. In particular, the silk fibroin / collagen hydrogels are highly elastic, exhibiting excellent resistance to permanent deformation under different modes of stress; without being collapsed or water-squeezed out (vs. not possible in individual proteins) – which results from the mechanical synergism of interpenetrating networks of both proteins. Furthermore, the role of collagen protein component in the hybrid hydrogels provides adhesive sites to cells, stimulating anchorage and spreading significantly with respect to mulberry silk fibroin gel, which lacks cell adhesion motifs. The silk fibroin / collagen hydrogels can encapsulate cells while preserving the viability and growth over a long 3D culture period. Our findings demonstrate that the silk / collagen hydrogels possess physical and biological properties tunable and significantly improved (vs. the individual protein gels), implying their potential uses for cell delivery and tissue engineering. Statement of Significance Development of cell encapsulating hydrogels with excellent physical and biological properties is important for the cell delivery and cell-based tissue engineering. Here we communicate for the first time the novel protein composite hydrogels comprised of ‘Silk’ and ‘Collagen’ and report their outstanding physical, mechanical and biological properties that are not readily achievable with individual protein hydrogels. The properties include i) gelation accelerated over a wide range of compositions, ii) stiffness levels covering 0.1 kPa to 20 kPa that mimic those of soft-to-hard tissues, iii) excellent elastic behaviors under various stress modes (bending, twisting, stretching, and compression), iv) high resistance to cell-mediated gel contraction, v) rapid anchorage and spreading of cells, and vi) cell encapsulation ability with a long-term survivability. These results come from the synergism of individual proteins of alpha-helix and beta-sheet structured networks. We consider the current elastic cell-encapsulating hydrogels of silk-collagen can be potentially useful for the cell delivery and tissue engineering in a wide spectrum of soft-to-hard tissues.

Dysfunction in the olfactory system of a person can have adverse effects on their health and quality of life. It can even increase mortality among individuals. Olfactory dysfunction is related to many factors, including post-viral upper respiratory infection, head trauma, and neurodegenerative disorders. Although some clinical therapies such as steroids and olfactory training are already available, their effectiveness is limited and controversial. Recent research in the field of therapeutic nanoparticles and stem cells has shown the regeneration of dysfunctional olfactory systems. Thus, we are motivated to highlight these regenerative approaches. For this, we first introduce the anatomical characteristics of the olfactory pathway, then detail various pathological factors related to olfactory dysfunctions and current treatments, and then finally discuss the recent regenerative endeavors, with particular focus on nanoparticle-based drug delivery systems and stem cells. This review offers insights into the development of future therapeutic approaches to restore and regenerate dysfunctional olfactory systems.

Healing and repair of damaged bones with various geometries are challenging issues in personalized regenerative medicine. Herein, we examine if the engineered electroblown scaffolds can be suitable to this purpose with the ability to shape and fill defects, populate stem cells, and stimulate the regeneration process of defected bone. The electroblowing method could generate bioactive nanocomposite scaffolds made of poly(caprolactone) and bioactive glass nanoparticles, of which the macrostructure is highly spaced and fibrous networked. The scaffolds were easily formable to different shapes with space filling ability, and were hydrophilic to soak water and blood rapidly. Multipotent stem cells from dental pulp effectively infiltrated the scaffold networks, anchored the fiber surface within few hours, proliferated actively over weeks, and were stimulated to differentiate into osteogenic cells. The cell/scaffold constructs, implanted to tooth-extracted, irregular-shaped alveolar bone defects, were shown to fit the defect and to stimulate early new bone formation. Taken together, the electroblown bioactive fibrous scaffolds and their constructs with multipotent dental stem cells may be useful as a potential 3D platform for future personalized bone tissue engineering.

Synthetic nanocarriers continue to play an important role in nanomedicine as the next generation of therapeutics demands effective intracellular delivery. Better understanding of the extra- and intra-cellular fate of the nanocarriers in relation with biological environments in vitro and in vivo is essential for the progress of nanocarrier-based therapeutics. As nanocarriers come into contact with biological fluid, interactions with various biomolecules alter their initial physicochemical status. Such dynamic modifications influence their interactions with cells and the subsequent endocytic process. Upon cellular uptake, intracellular machineries control their trafficking, release and degradation of cargoes, and exocytosis. In this Review, we highlight the navigation of nanocarriers through various extra- and intra-cellular barriers, with an emphasis on how dynamic interactions with biological components alter their fate and performance.

Even though roughened titanium (Ti) and Ti alloys have been clinically used as dental implant, they encourage bacterial adhesion, leading to failure of the initial stability. Here, the non-thermal atmospheric pressure plasma jet (NTAPPJ) functionalized Ti and Ti alloy were investigated to promote cellular activities but inhibit the initial attachment of the adherent pioneer bacterium, Streptococcus sanguinis, without topographical changes.After the produced radicals from NTAPPJ were characterized, bacterial adhesion to specimens was assessed by PrestoBlue assay and live-dead staining with or without the NTAPPJ functionalizing. After the surface was characterized using optical profilometry, X-ray photoelectron spectroscopy and contact angle analysis, the ions released from the specimens were investigated. In vitro initial cell attachment (4h or 24h) with adhesion images and alkaline phosphatase activity (ALP, 14 days) measurements were performed using rat bone marrow-derived mesenchymal stem cells.The initial bacterial adhesion to the Ti and Ti alloy was significantly inhibited after NTAPPJ functionalizing (p0.05) compared to those without NTAPPJ functionalizing. The bacterial adhesion-resistance effect was induced by carbon cleaning, which was dependent on the working gas used on the Ti specimens (nitrogenammonia and air, p0.05). The initial cell adhesion with well-developed vinculin localization and consequent ALP activity at 14days to the NTAPPJ-functionalized specimens were superior to the non-treated specimens.For the promising success of dental implants, NTAPPJ functionalizing is suggested as a novel surface modification technique; this technique can help ensure the success of integration between the dental implants and bone tissues with less concern of inflammation.

Cerium oxide nanomaterials (CeNMs), due to their excellent scavenging properties of reactive oxygen species (ROS), have gained great promise for therapeutic applications. A high level of ROS often degrades the potential of stem cells in terms of survivability, maintenance and lineage differentiation. Here we hypothesize the CeNMs may play an important role in protecting the capacity of stem cells against the oxidative insult, and the suppression mechanism of ROS level may depend on the internalization of CeNMs. We synthesized CeNMs with different directional shapes (aspect ratios) by a pH-controlled hydrothermal method, and treated them to stem cells derived from human dental pulp at various doses. The short CeNMs (nanoparticles and nanorods) were internalized rapidly to cells whereas long CeNMs (nanowires) were slowly internalized, which led to different distributions of CeNMs and suppressed the ROS levels either intracellularly or extracellularly under the H 2 O 2 -exposed conditions. Resultantly, the stem cells, when dosed with the CeNMs, were rescued to have excellent cell survivability; the damages in intracellular components including DNA fragmentation, lipid rupture and protein degradation were significantly alleviated. The findings imply that the ROS-scavenging events of CeNMs need special consideration of aspect ratio-dependent cellular internalization, and also suggest the promising use of CeNMs to protect stem cells from the ROS-insult environments, which can ultimately improve the stem cell potential for tissue engineering and regenerative medicine uses. Statement of Significance Oxidative stress governs many stem cell functions like self-renewal and lineage differentiation, and the biological conditions involving tissue repair and disease cure where stem cell therapy is often needed. Here we demonstrate the unique role of cerium oxide nanomaterials (CeNMs) in rescuing stem cell survivability, migration ability, and intracellular components from oxidative stress. In particular, we deliver a novel finding that nano-morphologically varied CeNMs show different mechanisms in their scavenging reactive oxygen species either intracellularly or extracellularly, and this is related with their different cellular internalizations. We used human dental pulp stem cells for the model study and proved the CeNMs were effective in controlling ROS level by means of scavenging intracellularly or extracellularly, which ultimately led to improving the intact therapeutic potential of stem cells. This work touches an important biological issue of nanomaterial interactions with stem cells under the conditions related with oxidative stress and the resultant damage. The correlation of shape factor in therapeutic nanomaterials with stem cell interaction and the oxidative stress-related functions will provide informative ideas in the design of CeNMs for cellular therapy.

Angiogenic capacity of biomaterials is a key asset to drive vascular ingrowth during tissue repair and regeneration. Here we design a unique angiogenic microcarrier based on sol-gel derived mesoporous silica. The microspheres offer a potential angiogenic stimulator, Si ion, 'intrinsically' within the chemical structure. Furthermore, the highly mesoporous nature allows the loading and release of angiogenic growth factor 'extrinsically'. The Si ion is released from the microcarriers at therapeutic ranges (over a few ppm per day), which indeed up-regulates the expression of hypoxia inducing factor 1α (HIF1α) and stabilizes it by blocking HIF-prolyl hydroxylase 2 (PHD2) in HUVECs. This in turn activates the expression of a series of proangiogenic molecules, including bFGF, VEGF, and eNOS. VEGF is incorporated effectively within the mesopores of microcarriers and is then released continuously over a couple of weeks. The Si ion and VEGF released from the microcarriers synergistically stimulate endothelial cell functions, such as cell migration, chemotactic homing, and tubular networking. Furthermore, in vivo neo-blood vessel sprouting in chicken chorioallantoic membrane model is significantly promoted by the Si/VEGF releasing microcarriers. The current study demonstrates the synergized effects of Si ion and angiogenic growth factor through a biocompatible mesoporous microsphere delivery platform, and the concept provided here may open the door to a new co-delivery system of utilizing ions with growth factors for tissue repair and regeneration.

A xerogel was interfaced onto biopolymer nanofibers though a core–shell electrospinning design for bone regeneration. The xerogel-interfaced biopolymer nanofibrous matrix was bioactive and highly hydrophilic, with a significant decrease in the water contact angle. The matrix showed excellent in vitro responses of primary osteoblasts in terms of adhesion, proliferation, and migration. Furthermore, the osteoblastic differentiation of cells, including alkaline phosphatase activity, mineralization, and gene expression, was significantly upregulated by the xerogel interface. In vivo animal tests in a critical-sized calvarial defect confirmed the new bone formation ability of the xerogel-surfaced nanofiber matrices. The underlying signaling mechanisms of the stimulation were implied to be integrin and bone morphogenetic protein (BMP) pathways, as demonstrated by the activation of integrin (α2β1) and downstream signaling molecules (FAK, paxillin, RhoA, MAPK, and NF-κB), as well as the BMPs and the downstream transcription factor Smad1/5/8. Taking these findings together, the xerogel-surfaced biopolymer nanofibers are proposed to be a promising scaffold candidate for bone regeneration.

For skeletal muscle engineering, scaffolds that can stimulate myogenic differentiation of cells while possessing suitable mechanical properties (e.g. flexibility) are required. In particular, the elastic property of scaffolds is of importance which helps to resist and support the dynamic conditions of muscle tissue environment. Here, we developed highly flexible nanocomposite nanofibrous scaffolds made of polycarbonate diol and isosorbide-based polyurethane and hydrophilic nano-graphene oxide added at concentrations up to 8%. The nano-graphene oxide incorporation increased the hydrophilicity, elasticity, and stress relaxation capacity of the polyurethane-derived nanofibrous scaffolds. When cultured with C2C12 cells, the polyurethane–nano-graphene oxide nanofibers enhanced the initial adhesion and spreading of cells and further the proliferation. Furthermore, the polyurethane–nano-graphene oxide scaffolds significantly up-regulated the myogenic mRNA levels and myosin heavy chain expression. Of note, the cells on the flexible polyurethane–nano-graphene oxide nanofibrous scaffolds could be mechanically stretched to experience dynamic tensional force. Under the dynamic force condition, the cells expressed significantly higher myogenic differentiation markers at both gene and protein levels and exhibited more aligned myotubular formation. The currently developed polyurethane–nano-graphene oxide nanofibrous scaffolds, due to their nanofibrous morphology and high mechanical flexibility, along with the stimulating capacity for myogenic differentiation, are considered to be a potential matrix for future skeletal muscle engineering.

Spinal cord injury (SCI) is a devastating lesion lacking effective treatment options currently available in clinics. The inflammatory process exacerbates the extent of the lesion through a secondary injury mechanism, where proinflammatory classically activated macrophages (M1) are prevalent at the lesion site. However, the polarized alternatively activated anti-inflammatory macrophages (M2) are known to play an important role in wound healing and regeneration following SCI. Herein, we introduce porcine brain decellularized extracellular matrix (dECM) to modulate the macrophages in the injured spinal cord. The hydrogels with collagen and dECM at various dECM concentrations (1, 5, and 8 mg/ml) were used to cultivate primary macrophages and neurons. The dECM hydrogels were shown to promote the polarization of macrophages toward M2 phase and the neurite outgrowth of cortical and hippocampal neurons. When the dECM hydrogels were applied to rat SCI models, the proportion of M1 and M2 macrophages in the injured spinal cord was substantially altered. When received dECM concetration of 5 mg/ml, the expression of molecules associated with M2 (CD206, arginase1, and IL-10) was significantly increased. Consistently, the population of total macrophages and cavity area were substantially reduced in the dECM-treated groups. As a result, the locomotor functions of injured spinal cord, as assessed by BBB and ladder scoring, were significantly improved. Collectively, the porcine brain dECM with optimal concentration promotes functional recovery in SCI models through the activation of M2 macrophages, suggesting the promising use of the engineered hydrogels in the treatment of acute SCI. Statement of significance Spinal cord injury (SCI) is a devastating lesion, lacking effective treatment options currently available in clinics. Here we delineated that the treatment of injured spinal cord with porcine brain decellularized matrix-based hydrogels for the first time, and could modulate the macrophage polarization and the ultimate functional recovery. When appropriate formulations were applied to a contused spinal cord model in rats, the decellularized matrix hydrogels shifted the macrophages to polarize to pro-regenerative M2 phenotype, decreased the size of lesion cavity, and finally promoted the locomotor functions until 8 weeks following the injury. We consider this work can significantly augment the matrix(biomaterial)-based therapeutic options, as an alternative to drug or cell-free approaches, for the treatment of acute injury of spinal cord.