Interleukin-12 sustained release system promotes hematopoietic recovery after radiation injury.

The continuous production of mature blood cell lineages is maintained by hematopoietic stem cells but they are highly susceptible to damage by ionizing radiation (IR) that induces death. Thus, devising therapeutic strategies that can mitigate hematopoietic toxicity caused by IR would benefit acute radiation syndrome (ARS) victims and patients receiving radiotherapy. Herein, we describe the preparation of an injectable hydrogel formulation based on Arg-Gly-Asp-alginate (RGD-Alg) and Laponite using a simple mixing method that ensured a slow and sustained release of interleukin-12 (IL-12) (RGD-Alg/Laponite@IL-12). The local administration of RGD-Alg/Laponite@IL-12 increased survival rates and promoted the hematopoietic recovery of mice who had received sublethal-dose irradiation. Local intra-bone marrow (intra-BM) injection of RGD-Alg/Laponite@IL-12 hydrogel effectively stimulated IL12 receptor-phosphoinositide 3-kinase/protein kinase B (IL-12R-PI3K/AKT) signaling axis, which promoted proliferation and hematopoietic growth factors secretion of BM mesenchymal stem/stromal cells. This signaling axis facilitates the repair of the hematopoietic microenvironment and plays a pivotal role in hematopoietic reconstitution. In conclusion, we describe a biomaterial-sustained release of IL-12 for the treatment of irradiated hematopoietic injury and provide a new therapeutic strategy for hematopoietic ARS.

Vitamin D3 mitigates autoimmune inflammation caused by activation of myeloid dendritic cells in SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which defective T cells, immune complex deposition and other immune system alterations contribute to pathological changes of multiple organ systems. The vitamin D metabolite c is a critical immunomodulator playing pivotal roles in the immune system. Epidemiological evidence indicates that vitamin D deficiency is correlated with the severity of SLE. Our aim is to investigate the effects of 1,25(OH)2D3 (VitD3) on the activation of myeloid dendritic cells (mDCs) by autologous DNA-containing immune complex (DNA-ICs), and the effects of VitD3 on immune system balance during SLE. We purified DNA-ICs from the serum of SLE patients and isolated mDCs from normal subjects. In vitro studies showed that DNA-ICs were internalized and consumed by mDCs. VitD3 blocked the effects of DNA-ICs on RelB, IL-10 and TNF-α in mDCs. Further analysis indicated that DNA-ICs stimulated histone acetylation in the RelB promoter region, which was inhibited by VitD3. Knockdown of the histone deacetylase 3 gene (HDAC3) blocked these VitD3-mediated effects. Co-culture of mDCs and CD4+ T cells showed that VitD3 inhibited multiple processes mediated by DNA-ICs, including proliferation, downregulation of IL-10, TGF-ß and upregulation of TNF-α. Moreover, VitD3 could also reverse the effects of DNA-IC-induced imbalance of CD4+ CD127- Foxp3+ T cells and CD4+ IL17+ T cells. Taken together, our results indicated that autologous DNA-ICs stimulate the activation of mDCs in the pathogenesis of SLE, and VitD3 inhibits this stimulatory effects of DNA-ICs by negative transcriptional regulation of RelB gene and maintaining the Treg/Th17 immune cell balance. These results suggest that vitamin D may have therapeutic value for the treatment of SLE.

Acoustofluidic Interfaces for the Mechanobiological Secretome of MSCs.

While mesenchymal stem cells (MSCs) have gained enormous attention due to their unique properties of self-renewal, colony formation, and differentiation potential, the MSC secretome has become attractive due to its roles in immunomodulation, anti-inflammatory activity, angiogenesis, and anti-apoptosis. However, the precise stimulation and efficient production of the MSC secretome for therapeutic applications are challenging problems to solve. Here, we report on Acoustofluidic Interfaces for the Mechanobiological Secretome of MSCs: AIMS. We create an acoustofluidic mechanobiological environment to form reproducible three-dimensional MSC aggregates, which produce the MSC secretome with high efficiency. We confirm the increased MSC secretome is due to improved cell-cell interactions using AIMS: the key mediator N-cadherin was up-regulated while functional blocking of N-cadherin resulted in no enhancement of the secretome. After being primed by IFN-γ, the secretome profile of the MSC aggregates contains more anti-inflammatory cytokines and can be used to inhibit the pro-inflammatory response of M1 phenotype macrophages, suppress T cell activation, and support B cell functions. As such, the MSC secretome can be modified for personalized secretome-based therapies. AIMS acts as a powerful tool for improving the MSC secretome and precisely tuning the secretory profile to develop new treatments in translational medicine.

Inhibition of integrin receptors reduces extracellular matrix levels, ameliorating benign prostate hyperplasia.

Although a high prevalence of benign prostate hyperplasia (BPH) has been documented, the risk factors are poorly understood. Metabolic syndrome increases the risk of BPH. Succinylation, a type of posttranslational modification, mostly targets metabolic processes. The level of succinylation was investigated in 4 BPH patients and 4 healthy controls. Additionally, 176 patients with BPH were analyzed by using pan-antisuccinyllysine antibody blotting. TMT-labeling proteomic and sc-RNAseq Cellchat analyses were employed to identify key signaling factors involved in the development of BPH. In vivo and in vitro experiments were used to confirm the role of integrin receptors. The global succinylation level in BPH was higher than that in the healthy prostate. Positive correlations of prostate volume with IHC score sand urodynamics testing were found in large clinical cohorts. The extracellular matrix (ECM), metabolic processes and immune signaling were involved in succinylation in BPH, as indicated by using TMT-labeling proteomic analysis, and this finding was also confirmed by sc-RNAseq CellChat analysis. The proteins upregulated in SIRT5 knockout WPMY-1 cells were also enriched in the extracellular matrix and metabolic processes. More importantly, integrin receptor inhibition in a mouse model of BPH significantly ameliorated prostate hyperplasia. High levels of succinylation modifications were found in BPH, and succinylated proteins influenced the activation of the ECM. Inhibition of ECM signaling further ameliorated prostate hyperplasia in mice.

Corrigendum: Multifunctions of CRIF1 in cancers and mitochondrial dysfunction.

[This corrects the article DOI: 10.3389/fonc.2022.1009948.].

Elimination of methicillin-resistant Staphylococcus aureus biofilms on titanium implants via photothermally-triggered nitric oxide and immunotherapy for enhanced osseointegration.

BACKGROUND: Treatment of methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium (Ti) implants. There is a need to explore more effective approaches for the treatment of MRSA biofilm infections. METHODS: Herein, an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles (PDA), nitric oxide (NO) release donor sodium nitroprusside (SNP) and osteogenic growth peptide (OGP) onto Ti implants, denoted as Ti-PDA@SNP-OGP. The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy, X-ray photoelectron spectroscope, water contact angle, photothermal property and NO release behavior. The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2',7'-dichlorofluorescein diacetate probe, 1-N-phenylnaphthylamine assay, adenosine triphosphate intensity, o-nitrophenyl-ß-D-galactopyranoside hydrolysis activity, bicinchoninic acid leakage. Fluorescence staining, assays for alkaline phosphatase activity, collagen secretion and extracellular matrix mineralization, quantitative real­time reverse transcription­polymerase chain reaction, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells (MSCs), RAW264.7 cells and their co-culture system. Giemsa staining, ELISA, micro-CT, hematoxylin and eosin, Masson's trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms, inhibition of inflammatory response, and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo. RESULTS: Ti-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light irradiation, and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species (ROS)-mediated oxidative stress, destroying bacterial membrane integrity and causing leakage of intracellular components (P < 0.01). In vitro experiments revealed that Ti-PDA@SNP-OGP not only facilitated osteogenic differentiation of MSCs, but also promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype (P < 0.05 or P < 0.01). The favorable osteo-immune microenvironment further facilitated osteogenesis of MSCs and the anti-inflammation of RAW264.7 cells via multiple paracrine signaling pathways (P < 0.01). In vivo evaluation confirmed the aforementioned results and revealed that Ti-PDA@SNP-OGP induced ameliorative osseointegration in an MRSA-infected femoral defect implantation model (P < 0.01). CONCLUSIONS: These findings suggest that Ti-PDA@SNP-OGP is a promising multi-functional material for the high-efficient treatment of MRSA infections in implant replacement surgeries.

Multifunctions of CRIF1 in cancers and mitochondrial dysfunction.

Sustaining proliferative signaling and enabling replicative immortality are two important hallmarks of cancer. The complex of cyclin-dependent kinase (CDK) and its cyclin plays a decisive role in the transformation of the cell cycle and is also critical in the initiation and progression of cancer. CRIF1, a multifunctional factor, plays a pivotal role in a series of cell biological progresses such as cell cycle, cell proliferation, and energy metabolism. CRIF1 is best known as a negative regulator of the cell cycle, on account of directly binding to Gadd45 family proteins or CDK2. In addition, CRIF1 acts as a regulator of several transcription factors such as Nur77 and STAT3 and partly determines the proliferation of cancer cells. Many studies showed that the expression of CRIF1 is significantly altered in cancers and potentially regarded as a tumor suppressor. This suggests that targeting CRIF1 would enhance the selectivity and sensitivity of cancer treatment. Moreover, CRIF1 might be an indispensable part of mitoribosome and is involved in the regulation of OXPHOS capacity. Further, CRIF1 is thought to be a novel target for the underlying mechanism of diseases with mitochondrial dysfunctions. In summary, this review would conclude the latest aspects of studies about CRIF1 in cancers and mitochondria-related diseases, shed new light on targeted therapy, and provide a more comprehensive holistic view.

Multienzyme-like Reactivity Cooperatively Impairs Glutathione Peroxidase 4 and Ferroptosis Suppressor Protein 1 Pathways in Triple-Negative Breast Cancer for Sensitized Ferroptosis Therapy.

Ferroptosis is a recently discovered route of regulated cell death that offers the opportunities for the treatment of chemotherapy-resistant tumor indications, but its efficacy can be affected by the glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) antioxidant mechanisms, posing significant challenges for its clinical translation. In this study, we report a Cu-tetra(4-carboxyphenyl)porphyrin chloride(Fe(III)) (Cu-TCPP(Fe)) metal organic framework (MOF)-based nanosystem for the efficient incorporation of Au nanoparticles (NPs) and RSL3, which can demonstrate enzyme-like activities to universally suppress the antiferroptotic pathways in tumor cells for amplifying ferroptotic damage. Herein, Cu-TCPP(Fe) MOF nanosheets were integrated with Au NPs via in situ nucleation and loaded with RSL3 via π-π stacking, which were eventually modified with polyethylene glycol (PEG) and iRGD for tumor-targeted drug delivery. Specifically, the Au NPs can demonstrate glucose oxidase-like activities for efficient glucose depletion, thus disrupting the pentose phosphate pathway to impede reduced glutathione (GSH) biosynthesis and prevent the recycling of coenzyme Q10 (CoQ10) to CoQ10H2, while Cu species can oxidize GSH into oxidized glutathione (GSSG). These nanocatalytic activities can lead to the simultaneous inhibition of the GPX4/GSH and FSP1/CoQ10H2 pathways and cooperate with the GPX4-deactivating function of RSL3 to cause pronounced ferroptotic damage, thereby providing a strong rationale for the application of ferroptosis therapy in the clinic.

Self-renewal or quiescence? Orchestrating the fate of mesenchymal stem cells by matrix viscoelasticity via PI3K/Akt-CDK1 pathway.

To control the fate of mesenchymal stem cells (MSCs) in a 3D environment by adjusting the mechanical parameters of MSC-loading scaffolds, is one of the hot topics in the field of regenerative biomaterials. However, a thorough understanding of the relevant MSCs behaviors affected by viscoelasticity, a dynamic physical parameter of scaffolds, is still lacking. Herein, we established an alginate hydrogel system with constant stiffness and tunable stress relaxation rate, which is a key parameter for the viscoelastic property of material. MSCs were cultured inside three groups of alginate hydrogels with various stress relaxation rates, and then RNA-seq analysis of cells was performed. Results showed that the change of stress relaxation rates of hydrogels regulated the most of the different expression genes of MSCs, which were enriched in cell proliferation-related pathways. MSCs cultured in hydrogels with fast stress relaxation rate presented a high self-renewal proliferation profile via activating phosphatidylinositol 3- kinase (PI3K)/protein kinase B (Akt) pathway. In contrast, a slow stress relaxation rate of hydrogels induced MSCs to enter a reversible quiescence state due to the weakened PI3K/Akt activation. Combined with a further finite element analysis, we speculated that the quiescence of MSCs could be served as a positive strategy for MSCs to deal with the matrix with a low deformation to keep stemness. Based on the results, we identified that stress relaxation rate of hydrogel was a potential physical factor of hydrogel to regulate the self-renewal or quiescence of MSCs. Thus, our findings provide a significant guiding principle for the design of MSCs-encapsulated biomaterials.

Constructing nanocomplexes by multicomponent self-assembly for curing orthotopic glioblastoma with synergistic chemo-photothermal therapy.

The blood-brain barrier (BBB) is one of the major limitations of glioblastoma therapy in the clinic. Nanodrugs have shown great potential for glioblastoma therapy. Herein, we purposefully developed a multicomponent self-assembly nanocomplex with very high drug loading content for curing orthotopic glioblastoma with synergistic chemo-photothermal therapy. The nanocomplex consisted of self-assembled pH-responsive nanodrugs derived from amino acid-conjugated camptothecin (CPT) and canine dyes (IR783) coated with peptide Angiopep-2-conjugated copolymer of Ang-PEG-g-PLL. Specifically, the carrier-free nanocomplex exhibited a high drug loading content (up to 62%), good biocompatibility, and effective glioma accumulation ability. Moreover, the nanocomplex displayed good stability and pH-responsive behavior ex vivo. Both in vitro and in vivo results revealed that the nanocomplex could effectively cross the BBB and target glioma cells. Furthermore, the combination of chemotherapy and photothermal therapy of the nanocomplex achieved a better therapeutic effect, longer survival time, and minimized toxic side effects in orthotopic glioblastoma tumor-bearing nude mice. Overall, we modified the chemotherapeutic drug CPT so that it could self-assemble with other molecules into nanoparticles, which providing an alternative for the preparation of the carrier-free nanodrugs. The results highlighted the potential of self-assembly nanodrugs as a novel platform for effective glioblastoma therapy.

Mesenchymal Stem Cells Resist Mechanical Confinement through the Activation of the Cortex during Cell Division.

The mechanical properties of the natural extracellular matrix (ECM) change extensively, but these specific properties provide a relatively stable environment for resident cells. Although the effect of matrix stiffness on cell functions has been widely studied, the molecular mechanism was still not fully understood. Matrix stiffening is a common phenomenon in tissue damaging processes. To explore the effect of the increase in local matrix stiffness on cell behaviors, a three-dimensional (3D) cell culture system with a tunable modulus but constant other physical parameters was constructed by the alginate hydrogel with different molecular weights and cross-linking degrees. By using this culture system, the transcriptome response of mesenchymal stem cells (MSCs) to matrix stiffness was explored. Furthermore, a finite element model was developed to simulate the interaction between cells and the matrix. Results revealed that the increased matrix stiffness promoted the proliferation-related signaling of MSCs, and this process depended on the increased cortex tension caused by the activation of RAS and myosin II.

Mitochondrial Metabolism Targeted Nanoplatform for Efficient Triple-Negative Breast Cancer Combination Therapy.

Tumor reprogram pathway of mitochondrial metabolism is an emerging approach for malignant tumor treatment, such as triple-negative breast cancer. In this study, a tumor/mitochondria cascaded targeting, adenosine-triphosphate (ATP) responsive nanocarrier of zeolitic imidazolate framework-90 (ZIF-90) for breast cancer combination therapy is reported. Atovaquone (AVO) and hemin are loaded into ZIF-90, then a peptide iRGD with tumor-targeting ability is modified on the ZIF-90 nanoplatform. Hemin can specifically degrade BTB and CNC homology1 (BACH1), resulting in the changes of mitochondrial metabolism, and AVO acts as the inhibitor of the electron transport chain (ETC). The degradation of BACH1 using hemin can effectively improve the anti-tumor efficiency of mitochondrial metabolism inhibitor AVO, by increasing dependency on mitochondrial respiration. This nanoplatform displays both tumor-targeting and mitochondria-targeting capacity with high level of ATP responsive drug release behavior. The specific characteristic of mitochondria-targeting ability of this nanoplatform can increase the accumulation of AVO in the mitochondria, and in turn, can effectively improve the inhibition of the ETC. Both in vitro and in vivo results reveal that this composite nanocarrier has excellent tumor inhibition ability with limited side effects. Accordingly, this study provides an attractive strategy in the mitochondrial metabolism for cancer targeted therapy.

Engineering of Cascade-Responsive Nanoplatform to Inhibit Lactate Efflux for Enhanced Tumor Chemo-Immunotherapy.

As an increased product of high-rate aerobic glycolysis in tumors, lactate could regulate the immunosuppressive tumor microenvironment (TME). A PEG-CDM surface modified, GSH-dependent responsive hollow mesoporous organosilica nanoplatform loaded with hydroxycamptothecin (HCPT) and siMCT-4 was administrated for synergistic tumor chemo-immunotherapy. The nanoplatform cascaded responded to the weak acid TME and the high level of GSH in tumor cells. HCPT and siMCT-4 were continuously released from the nanoplatform for chemotherapy and inhibiting intracellular lactate efflux. The increased intracellular lactate and HCPT effectively induced tumor cell apoptosis. Moreover, the decreased extracellular lactate polarized tumor-associated macrophages (TAMs) phenotype from M2 type to M1 type and restored CD8+ T cell activity in vivo. The results demonstrated that the nanoplatform effectively removed the immunosuppressive TME, inhibited tumor growth, and suppressed lung metastasis of B16F10 cells and 4T1 cells via the combination of inhibiting lactate efflux and chemotherapy. Accordingly, it suggested a strategy to transform immunosuppressive tumors into "hot" tumors and inhibit the tumor growth with high efficiency in vivo.

A dynamic matrix potentiates mesenchymal stromal cell paracrine function via an effective mechanical dose.

The paracrine function of mesenchymal stromal cells (MSCs) contributes a lot to tissue development, and it is regulated by various physical factors. Moreover, the extracellular matrix (ECM) of MSCs is dynamic, and its remodeling is always occurring. In particular, stiffness changes are prevalent. Accordingly, ECM stiffness changes may affect the paracrine function of MSCs, which has not been investigated much. In this study, for the first time, alginate hydrogels with different stiffening times were used to assess the influence of dynamic ECM stiffness changes on the paracrine function of MSCs. It was found that a stiffer matrix (14.72 ± 1.44 kPa) under static conditions without any additional treatment could significantly potentiate the paracrine function of MSCs compared to a soft matrix (2.44 ± 0.23 kPa). Furthermore, this promotion was regulated by the activation of Yes-associated protein (YAP), which was caused by the polymerization of F-actin. Intriguingly, in a dynamic system, the MSC-encapsulating matrix that stiffened on the third day had stronger YAP activation than the Static-Stiff matrix. However, this activation was weakened when MSCs were cultured in a matrix that stiffened on the fifth day. The results show that an increase in ECM mechanical dosing levels would promote the paracrine function of MSCs. Moreover, an effective mechanical dose that can influence the paracrine function of MSCs indeed exists.

Functionalization of Ti substrate with pH-responsive naringin-ZnO nanoparticles for the reconstruction of large bony after osteosarcoma resection.

After bone tumor resection, the large bony deficits are commonly reconstructed with Ti-based metallic endoprosthesis, which provide immediate stable fixation and allow early ambulation and weight bearing. However, when used in osteosarcoma resection, Ti implant-relative infection and tumor recurrence were recognized as the two critical factors for implantation failure. Hence, in this work, a novel zinc oxide nanoparticle decorating with naringin was prepared and immobilized onto Ti substrate. The drugs delivery profiles proved that in the bacterial infection and Warburg effect of osteosarcoma-induced acidic condition, naringin and Zn2+ can be released easily from the functional Ti substrate. The anti-osteosarcoma and antibacterial assay showed the delivered naringin and Zn2+ can induce a remarkable increase of oxidative stress in bacteria (Escherichia coli and Staphylococcus aureus) and osteosarcoma (Saos-2 cells) by producing reactive oxygen species (ROS). Accumulation of ROS results in damage of bacterial biofilm and bacterial membrane, leading to the leakage of bacterial RNA and DNA. Meanwhile, the increase of ROS induces osteosarcoma cell apoptosis by activating ROS/extracellular signal-regulated kinase signaling pathway. Furthermore, in vitro cellular experiments, including cell viability, alkaline phosphatase activity, collagen secretion, extracellular matrix mineralization level, indicated that the functional Ti substrate exhibited great potential for osteoblasts proliferation and differentiation. Hence, this study provides a simple and promising strategy of developing multifunctional Ti-based implants for the reconstruction of large bony after osteosarcoma resection.

Redox-responsive amphiphilic camptothecin prodrug nanoparticles for targeted liver tumor therapy.

Tumor cell-targeting drug delivery systems are of great importance to anti-tumor therapy in clinics. Owing to the overexpression of the asialoglycoprotein receptor (ASGPR) on the membrane of hepatoma carcinoma cells, the conjugation of lactose on the surface of drug delivery systems has already shown significant advantages for targeting tumor cells. In this study, a disulfide bond-conjugated prodrug targeting delivery system consisting of camptothecin (CPT) and lactose (LA) was synthesized, which was denoted as CPT-S-S-LA. Camptothecin and lactose act as the chemotherapy drug and targeting ligand in the drug delivery system, respectively. Since CPT-S-S-LA is an amphiphilic compound, it can self-assemble into nanoparticles with a diameter of around 110 nm. The CPT-S-S-LA nanoparticles displayed controllable drug release behavior in the physiological environment. Unlike the free CPT, the CPT-S-S-LA nanoparticles firstly assembled at the tumor sites via the enhanced permeability and retention (EPR) effect, and then were phagocytized by the tumor cells with ASGP receptor-mediated endocytosis. Finally, the antitumor agent CPT was released for killing tumor cells, which have a high glutathione (GSH) concentration environment. The nanoparticles displayed favorable ability to target hepatoma carcinoma cells rather than the normal HUVEC cells in vitro. Both the in vitro and in vivo studies demonstrated that the CPT-S-S-LA nanoparticles display enhanced antitumor ability and reduced side effects. Thus, active targeting prodrug delivery systems should be a promising strategy for liver tumor therapy.

Substance P-embedded multilayer on titanium substrates promotes local osseointegration via MSC recruitment.

In this study, the chemokine substance P (SP) was inserted into multilayered systems on titanium (Ti)-based substrates for endogenous mesenchymal stem cell (MSC) recruitment to facilitate bone healing. The multilayer was constructed with cationic chitosan (Chi), SP and anionic gelatin (Gel) via a spin-coater-assisted layer-by-layer (LBL) approach. The characterization results demonstrated that the multilayer system was successfully constructed and was capable of continuously releasing SP for almost 2 weeks. We further confirmed that MSCs grown on SP-modified Ti-based substrates showed improved migration capabilities as well as enhanced secretion of matrix metalloproteinases (MMP2, MMP9), rather than enhanced MSC proliferation and differentiation in vitro. In the CD29+/CD90+ double immunofluorescence assay, the Ti/LBL-SP group showed the highest number of MSCs migrating to the peri-implant area after implantation. Consistently, the Ti/LBL-SP implants also significantly enhanced new bone formation according to the results of micro-CT scanning analysis, H&E staining, Masson's trichrome staining and immunohistochemical staining. The obtained results reveal that SP-modified Ti-based substrates were beneficial for bone formation via recruiting endogenous MSCs.

Regulation of MSC and macrophage functions in bone healing by peptide LL-37-loaded silk fibroin nanoparticles on a titanium surface.

Titanium-based materials have been long regarded as effective bone implants for clinical use, yet the corresponding osteointegration ability needs to be optimized. This challenge can be overcome by fabricating titanium (Ti) materials with physiological functions. In this study, peptide LL-37-loaded silk fibroin nanoparticles (SFNPs) were immobilized on a titanium surface to facilitate osteointegration by regulating the physiological functions of mesenchymal stem cells (MSCs) and macrophages. According to our results, the cell viability, recruitment and paracrine responses of MSCs and macrophages were improved by the modified Ti samples. MSC differentiation was promoted by the macrophages incubated on the modified Ti samples, and the phenotype switch of macrophages was also modulated by the MSCs incubated on the modified Ti samples. In vivo studies proved that the modified Ti implant induced MSC and macrophage recruitments to injury sites and the inflammatory response was positively regulated. Moreover, better bone formation was achieved around the modified Ti implant 28 days after surgery. This suggested that the immobilization of peptide LL-37-loaded SFNPs on a titanium surface improves osteointegration via the regulation of physiological functions of MSCs and macrophages.

Matrix promote mesenchymal stromal cell migration with improved deformation via nuclear stiffness decrease.

Bone marrow derived mesenchymal stromal cells (BMSCs) migration to injury site is a prevalent event in tissue repair process after damage occurrence. The migration process is always accompanied with matrix stiffness change. In this study, sodium alginate hydrogels with different stiffness and Transwell chambers with gradient chemical factors were employed to mimic tissue repair in vivo. In this work, in the stiffness range of 1-20 kPa, BMSCs in stiffer matrix showed higher migration speed compared to those in softer matrix. Moreover, stiffer matrix decreased the nuclear stiffness of BMSCs and reduced the expression of lamin A/C, which playing a main role in the regulation of nuclear stiffness. Furthermore, it was found that BMSCs fitted environment by selecting migration strategy. This study provides a novel platform for the investigation of BMSCs migration to mimic the natural tissue repair process.

Biocompatible MoS2/PDA-RGD coating on titanium implant with antibacterial property via intrinsic ROS-independent oxidative stress and NIR irradiation.

To inhibit bacterial infection in situ and improve osseointegration are essentially important for long-term survival of an orthopedic implant, in particular for infection-associating revision surgery. Herein, we fabricate a functional molybdenum disulfide (MoS2)/polydopamine (PDA)-arginine-glycine-aspartic acid (RGD) coating on titanium (Ti) implant to address above concerns simultaneously. The coating not only improved the osteogenesis of mesenchymal stem cells (MSCs), but also endowed Ti substrates with effective antibacterial ability when exposing to near-infrared (NIR) irradiation. It accelerated glutathione (GSH) oxidation via photothermal energy and induced intrinsic ROS-independent oxidative stress damage deriving from MoS2 nanosheets. The results displayed that RGD-decorated MoS2 nanosheets significantly increased the cellular osteogenic behaviors of MSCs via up-regulating osteogenesis-related genes (ALP, Runx2, Col I and OCN) in vitro. Moreover, the functionalized Ti substrates demonstrated great antibacterial efficiency of over 92.6% inhibition for S. aureus and E. coli under NIR-irradiation. Hyperthermia induced by photothermal effect accelerated the GSH consumption and ROS-independent oxidative stress destroyed the integrity of bacteria membranes, which synergistically led to protein leakage and ATP decrease. Furthermore, co-culture experiment showed that S. aureus contamination was efficiently cleaned from MoS2/PDA-RGD surface after NIR photothermal treatment, while MSCs adhered and proliferated on the MoS2/PDA-RGD surface. In an S. aureus infection model in vivo, MoS2/PDA-RGD modified Ti rods killed bacteria with an efficiency of 94.6% under NIR irradiation, without causing damage to normal tissue. More importantly, the MoS2/PDA-RGD modified Ti implants accelerated new bone formation in comparison with TNT implants in vivo.