Biomimetic Bone-Like Composite Hydrogel Scaffolds Composed of Collagen Fibrils and Natural Hydroxyapatite for Promoting Bone Repair.

Bone is a complex organic-inorganic composite tissue composed of ∼30% organics and ∼70% hydroxyapatite (HAp). Inspired by this, we used 30% collagen and 70% HAp extracted from natural bone using the calcination method to generate a biomimetic bone composite hydrogel scaffold (BBCHS). In one respect, BBCHS, with a fixed proportion of inorganic and organic components similar to natural bone, exhibits good physical properties. In another respect, the highly biologically active and biocompatible HAp from natural bone effectively promotes osteogenic differentiation, and type I collagen facilitates cell adhesion and spreading. Additionally, the well-structured porosity of the BBCHS provides sufficient growth space for bone marrow mesenchymal stem cells (BMSCs) while promoting substance exchange. Compared to the control group, the new bone surface of the defective location in the B-HA70+Col group is increased by 3.4-fold after 8 weeks of in vivo experiments. This strategy enables the BBCHS to closely imitate the chemical makeup and physical structure of natural bone. With its robust biocompatibility and osteogenic activity, the BBCHS can be easily adapted for a wide range of bone repair applications and offers promising potential for future research and development.

Multifunctional nanomaterials via cell cuproptosis and oxidative stress for treating osteosarcoma and OS-induced bone destruction.

Reactive Oxygen Species (ROS) refers to a highly reactive class of oxidizing species that have the potential to induce cellular apoptosis and necrosis. Cuproptosis, a type of cell death, is primarily associated with the effects of copper ions. However, the specific relationship between ROS, cuproptosis, and osteosarcoma (OS) remains relatively unexplored. Additionally, there is limited research on the use of cuproptosis in conjunction with oxidative stress for treating OS and inhibiting tumor-induced bone destruction. To address these gaps, a novel treatment approach has been developed for OS and neoplastic bone destruction. This approach involves the utilization of glutathione (GSH) and pH-responsive organic-inorganic mesoporous silica nanoparticles@Cu2S@oxidized Dextran (short for MCD). The MCD material demonstrates excellent cytocompatibility, osteogenesis, tumor suppression, and the ability to inhibit osteoclast formation. The specific mechanism of action involves the mitochondria of the MCD material inhibiting key proteins in the tricarboxylic acid (TCA) cycle. Simultaneously, the generation of ROS promotes this inhibition and leads to alterations in cellular energy metabolism. Moreover, the MCD biomaterial exhibits promising mild-temperature photothermal therapy in the second near-infrared (NIR-II) range, effectively mitigating tumor growth and OS-induced bone destruction in vivo.

The transformation of multifunctional bio-patch to hydrogel on skin wounds for efficient scarless wound healing.

Hydrogels have been widely used in various biomedical applications, including skin regeneration and tissue repair. However, the capability of certain hydrogels to absorb exudate or blood from surrounding wounds, coupled with the challenge in their long-term storage to prevent bacterial growth, can pose limitations to their efficacy in biological applications. To address these challenges, the development of a multifunctional aloin-arginine-alginate (short for 3A) bio-patch capable of transforming into a hydrogel upon absorbing exudate or blood from neighboring wounds for cutaneous regeneration is proposed. The 3A bio-patch exhibits outstanding features, including an excellent porous structure, swelling properties, and biodegradability. These characteristics allow for the rapid absorption of wound exudates and subsequent transformation into a hydrogel that is suitable for treating skin wounds. Furthermore, the 3A bio-patch exhibits remarkable antibacterial and anti-inflammatory properties, leading to accelerated wound healing and scarless repair in vivo. This study presents a novel approach to the development of cutaneous wound dressing materials.

Size- and Dose-Dependent Body-Wide Organ Transcriptomic Responses to Calcium Phosphate Nanomaterials.

Nanomaterials are widely used in clinical practice. There are potential risks of body-wide infiltration due to their small size; however, the body-wide reliable risk assessment of nanoparticle infiltration is not fully studied and established. In this study, we demonstrated the size- and dose-dependent body-wide organ transcriptomic responses to calcium phosphate nanomaterials in vivo. In a mice model, a calcium phosphate nanocluster (amorphous calcium phosphate, ACP, ∼1 nm in diameter) and its crystallization product (ACP-M, ∼10 nm in diameter) in a series of doses was administrated systematically; multiorgan transcriptomics were then performed with tissues of heart, liver, spleen, lung, kidney, and brain to investigate the systematic effect of dose and size of nanomaterials on the whole body. The results presented gene expression trajectories correlated with the dose of the nanomaterials and tissue-specific risk effects in all detected tissues. For the dose-dependent tissue-specific risk effects, lung tissue exhibited the most significant risk signatures related to apoptosis, cell proliferation, and cell stress. The spleen showed the second most significant risk signatures associated with immune response and DNA damage. For the size-dependent tissue-specific risk effects, ACP nanomaterials could increase most of the tissue-specific risk effects of nanomaterials in multiple organs than larger calcium phosphate nanoparticles. Finally, we used the size- and dose-dependent body-wide organ transcriptomic responses/risks to nanomaterials as the standards and built up a risk prediction model to evaluate the risk of the local nanomaterials delivery. Thus, our findings could provide a size- and dose- dependent risk assessment scale of nanoparticles in the transcriptomic level. It could be useful for risk assessment of nanomaterials in the future.

A nano-conductive osteogenic hydrogel to locally promote calcium influx for electro-inspired bone defect regeneration.

Conductive nano-materials and electrical stimulation (ES) have been recognized as a synergetic therapy for ordinary excitable tissue repair. It is worth noting that hard tissues, such as bone tissue, possess bioelectrical properties as well. However, insufficient attention is paid to the synergetic therapy for bone defect regeneration via conductive biomaterials with ES. Here, a novel nano-conductive hydrogel comprising calcium phosphate-PEDOT:PSS-magnesium titanate-methacrylated alginate (CPM@MA) was synthesized for electro-inspired bone tissue regeneration. The nano-conductive CPM@MA hydrogel has demonstrated excellent electroactivity, biocompatibility, and osteoinductivity. Additionally, it has the potential to enhance cellular functionality by increasing endogenous transforming growth factor-beta1 (TGF-ß1) and activating TGF-ß/Smad2 signaling pathway. The synergetic therapy could facilitate intracellular calcium enrichment, resulting in a 5.8-fold increase in calcium concentration compared to the control group in the CPM@MA ES + group. The nano-conductive CPM@MA hydrogel with ES could significantly promote electro-inspired bone defect regeneration in vivo, uniquely allowing a full repair of rat femoral defect within 4 weeks histologically and mechanically. These results demonstrate that our synergistic strategy effectively promotes bone restoration, thereby offering potential advancements in the field of electro-inspired hard tissue regeneration using novel nano-materials with ES.

WISP2 downregulation inhibits the osteogenic differentiation of BMSCs in congenital scoliosis by regulating Wnt/ß-catenin pathway.

OBJECTIVES: Bone marrow mesenchymal stem cells (BMSCs) are instrumental in bone development, metabolism, and marrow microenvironment homeostasis. Despite this, the relevant effects and mechanisms of BMSCs on congenital scoliosis (CS) remain undefined. Herein, it becomes our focus to reveal the corresponding effects and mechanisms implicated. METHODS: BMSCs from CS patients (hereafter referred as CS-BMSCs) and healthy donors (NC-BMSCs) were observed and identified. Differentially expressed genes in BMSCs were analyzed utilizing scRNA-seq and RNA-seq profiles. The multi-differentiation potential of BMSCs following the transfection or infection was evaluated. The expression levels of factors related to osteogenic differentiation and Wnt/ß-catenin pathway were further determined as appropriate. RESULTS: A decreased osteogenic differentiation ability was shown in CS-BMSCs. Both the proportion of LEPR+ BMSCs and the expression level of WNT1-inducible-signaling pathway protein 2 (WISP2) were decreased in CS-BMSCs. WISP2 knockdown suppressed the osteogenic differentiation of NC-BMSCs, while WISP2 overexpression facilitated the osteogenesis of CS-BMSCs via acting on the Wnt/ß-catenin pathway. CONCLUSIONS: Our study collectively indicates WISP2 knockdown blocks the osteogenic differentiation of BMSCs in CS by regulating Wnt/ß-catenin signaling, thus providing new insights into the aetiology of CS.

Guanidine-modified nanoparticles as robust BTZ delivery carriers and activators of immune responses.

Dendritic cells (DCs), the primary antigen-presenting cells in the immune system, play a critical role in regulating tumor immune responses. However, the tumor immunosuppressive microenvironment severely impedes the process of antigen-presenting and DC maturation, thereby limiting the efficacy of cancer immunotherapy. In this work, a pH-responsive polymer nanocarrier (PAG) modified with aminoguanidine (AG) was constructed for the efficient delivery of bortezomib (BTZ) through bidentate hydrogen bonds and electrostatic adsorption formed between guanidine groups of PAG and boronic acid groups of BTZ. The obtained PAG/BTZ nanoparticles exhibited pH-responsive release of BTZ and AG in the acidic tumor microenvironment. On the one hand, BTZ induced potent immune activation by eliciting immunogenic cell death (ICD) and releasing damage-associated molecular patterns. On the other hand, the cationic AG significantly promoted antigen uptake by DCs and activated DC maturation. As a result, PAG/BTZ significantly stimulated tumoral infiltration of cytotoxic T lymphocytes (CTLs) and triggered robust antitumor immune responses. Thus, it showed potent antitumor efficacy when synergizing with an immune checkpoint-blocking antibody.

Synergistic Effect of Magneto-Mechanical Bioengineered Stem Cells and Magnetic Field to Alleviate Osteoporosis.

Therapeutic bioengineering based on stem cell therapy holds great promise in biomedical applications. However, the application of this treatment is limited in orthopedics because of their poor survival, weak localization, and low cell retention. In this work, magneto-mechanical bioengineered cells consisting of magnetic silica nanoparticles (MSNPs) and mesenchymal stem cells (MSCs) are prepared to alleviate osteoporosis. The magneto-mechanical bioengineered MSCs with spatial localization, cell retention, and directional tracking capabilities could be mediated by a guided magnetic field (MF) in vitro and in vivo. Furthermore, high uptake rates of the MSNPs ensure the efficient construction of magnetically controlled MSCs within 2 h. In conjunction with external MF, the magneto-mechanical bioengineered MSCs have the potential for the activation of the YAP/ß-catenin signaling pathway, which could further promote osteogenesis, mineralization, and angiogenesis. The synergistic effects of MSNPs and guided MF could also decline bone resorption to rebalance bone metabolism in bone loss diseases. In vivo experiments confirm that the functional MSCs and guided MF could effectively alleviate postmenopausal osteoporosis, and the bone mass of the treated osteoporotic bones by using the bioengineered cells for 6 weeks is nearly identical to that of the healthy ones. Our results provide a new avenue for osteoporosis management and treatment, which contribute to the future advancement of magneto-mechanical bioengineering and treatment.

A Bispecific Peptide-Polymer Conjugate Bridging Target-Effector Cells to Enhance Immunotherapy.

Peptide-based immune checkpoint inhibitors exhibit remarkable therapeutic benefits although their application is hindered by quick blood clearance and low affinity with receptors. The modification of the peptides into artificial antibodies is an ideal platform to solve these problems, and one of the optional pathways is the conjugation of peptides with a polymer. More importantly, the bridging effect, mediated by bispecific artificial antibodies, could promote the interaction of cancer cells and T cells, which will benefit cancer immunotherapy. Herein, a bispecific peptide-polymer conjugate (octa PEG-PD1-PDL1) is prepared by simultaneously conjugating PD1-binding and PDL1-binding peptides onto 8-arm-PEG. octa PEG-PD1-PDL1 bridges T cells and cancer cells and thus enhances T cell-mediated cytotoxicity against cancer cells. Meanwhile, the tumor-targeting octa PEG-PD1-PDL1 increases the infiltration of cytotoxic T lymphocytes in tumors and reduces their exhaustion. It effectively activates the tumor immune microenvironment and exerts a potent antitumor effect against CT26 tumor models with a tumor inhibition rate of 88.9%. This work provides a novel strategy to enhance tumor immunotherapy through conjugating bispecific peptides onto a hyperbranched polymer to effectively engage target-effector cells.

Highly Sensitive Imaging of Tumor Metastasis Based on the Targeting and Polarization of M2-like Macrophages.

Tumor-associated macrophages, especially M2-like macrophages, are extensively involved in tumor growth and metastasis, suppressing the innate immunity to help tumor cells escape and reshaping the microenvironment to help metastatic cells grow. However, in vivo, real-time visualized migration of M2-like macrophages has never been explored to monitor the tumor metastasis process. Herein, we prepared an M2-like macrophage-targeting nitric oxide (NO)-responsive nanoprobe (NRP@M-PHCQ) consisting of an amphiphilic block copolymer with mannose and hydroxychloroquine (HCQ) moieties (denoted as M-PHCQ) and a NO-responsive NIR-II probe (denoted as NRP). The mannose moieties provided M2-like macrophage-targeting capacity, and the HCQ moieties polarized M2-like macrophages to M1-like ones with enhanced NO secretion. Consequently, NRP@M-PHCQ was lit up by the secreted NO to visualize the migration and polarization of M2-like macrophages in real time. In vivo metastasis imaging with NRP@M-PHCQ successfully tracked early tumor metastasis in the lymph nodes and the lungs with high sensitivity, even superior to Luci-labeled bioluminescence imaging, suggesting the extensive distribution and critical role of M2-like macrophages in tumor metastasis. In general, this work provided a new strategy to sensitively image metastatic tumors by tracking the polarization of M2-like macrophages and visually disclosed the critical role of M2-like macrophages in early tumor metastasis.

Real-Time Objective Evaluation of the Ischemic Stroke through pH-Responsive Fluorescence Imaging.

A rapid and comprehensive assessment of ischemic stroke (IS) is critical for clinicians to take the most appropriate treatment. Currently, IS assessment is mainly carried out by computed tomography and magnetic resonance imaging in combination with observing the clinical symptoms and inquiring about contraindications. However, they cannot diagnose pathological conditions and judge the microenvironment in real-time. Near-infrared fluorescence imaging has advantages for IS imaging, such as high sensitivity, high spatiotemporal resolution, and straightforward real-time operation. Herein, a pH-responsive fluorescent liposomal probe (BOD@Lip) is prepared for in vivo real-time visualization of the degree of IS based on the different acid microenvironments in the progression of the disease. The fluorescence imaging with BOD@Lip shows the degree of IS, and the correlation between fluorescence signals and the neurological deficit scores is established for the first time. This work provides a new method to objectively evaluate the degree of IS through a visualized route and a new insight into the relationship between the acidic microenvironment and the progression of IS.

Smart pH-responsive polyhydralazine/bortezomib nanoparticles for remodeling tumor microenvironment and enhancing chemotherapy.

The clinical translation of nanomedicines has been impeded by the unfavorable tumor microenvironment (TME), particularly the tortuous vasculature networks, which significantly influence the transport and distribution of nanomedicines into tumors. In this work, a smart pH-responsive bortezomib (BTZ)-loaded polyhydralazine nanoparticle (PHDZ/BTZ) is presented, which has a great capacity to augment the accumulation of BTZ in tumors by dilating tumor blood vessels via specific release of vasodilator hydralazine (HDZ). The Lewis acid-base coordination effect between the boronic bond of BTZ and amino of HDZ empowered PHDZ/BTZ nanoparticles with great stability and high drug loading contents. Once triggered by the acidic tumor environment, HDZ could be released quickly to remodel TME through tumor vessel dilation, hypoxia attenuation, and lead to an increased intratumoral BTZ accumulation. Additionally, our investigation revealed that this pH-responsive nanoparticle dramatically suppressed tumor growth, inhibited the occurrence of lung metastasis with fewer side effects and induced immunogenic cell death (ICD), thereby eliciting immune activation including massive cytotoxic T lymphocytes (CTLs) infiltration in tumors and efficient serum proinflammatory cytokine secretion compared with free BTZ treatment. Thus, with efficient drug loading capacity and potent immune activation, PHDZ nanoparticles exhibit great potential in the delivery of boronic acid-containing drugs aimed at a wide range of diseases.

Injectable Dual-Dynamic-Bond Cross-Linked Hydrogel for Highly Efficient Infected Diabetic Wound Healing.

Diabetic wound is a significant challenge for clinical treatment with high morbidity and mortality. Plenty of hydrogels with good biocompatibility have been widely used in diabetic wound healing. However, most of them cannot be directly absorbed and utilized by the wounds, which prolongs the regeneration time. Here a new type of healing hydrogel is developed that is based on histidine, a natural dietary essential amino acid that is significant for tissue formation. The amino acid is cross-linked with zinc ions (Zn2+ ) and sodium alginate (SA) via dynamic coordinate and hydrogen bonds, respectively, forming a histidine-SA-Zn2+ (HSZH) hydrogel with good injectable, adhesive, biocompatible, and antibacterial properties. Application of this dual-dynamic-bond cross-linked HSZH hydrogel accelerates the migration and angiogenesis of skin-related cells in vitro. Furthermore, it significantly promotes the healing of infected diabetic wounds in vivo and uniquely allows a full repair of wounds within ≈13 days, while ≈27 days are required for the healing process of the control group. This work provides a new strategy for designing wound dressing materials, that weakly cross-linked material based on tissue-friendly micromolecules can heal the wounds more efficiently than highly cross-linked materials based on long-chain polymers.

Persistent ferroptosis promotes cervical squamous intraepithelial lesion development and oncogenesis by regulating KRAS expression in patients with high risk-HPV infection.

Cervical squamous cell carcinoma (CSCC) is a type of female cancer that affects millions of families worldwide. Human papillomavirus (HPV) infection is the main reason for CSCC formation, and squamous intraepithelial lesions (SILs) induced by high-risk HPV (HR-HPV) infection are considered precancerous lesions. A previous study reported that HPV-infected cancer cells were able to counteract lipid peroxidation for survival. Recent research has reported that ferroptosis acts in an iron-dependent lipid peroxidation manner to kill cancer cells, and it is proposed as a new approach for female cancer therapy. Here, we investigated the role of ferroptosis throughout SIL development into CSCC. We found that ferroptosis occurred in SIL, but anti-ferroptosis emerged in CSCC. Our data further indicated that an antiferroptotic effect was formed in response to persistent ferroptosis and then promoted oncogenesis. Altogether, we provide novel insight into ferroptosis in cervical SIL development and suggest a potential therapeutic target for the treatment of CSCC.

Systemic and single cell level responses to 1 nm size biomaterials demonstrate distinct biological effects revealed by multi-omics atlas.

Although ultra-small nanoclusters (USNCs, < 2 nm) have immense application capabilities in biomedicine, the investigation on body-wide organ responses towards USNCs is scant. Here, applying a novel strategy of single-cell mass cytometry combined with Nano Genome Atlas of multi-tissues, we systematically evaluate the interactions between the host and calcium phosphate (CaP) USNCs at the organism level. Combining single-cell mass cytometry, and magnetic luminex assay results, we identify dynamic immune responses to CaP USNCs at the single cell resolution. The innate immune is initially activated and followed by adaptive immune activation, as evidenced by dynamic immune cells proportions. Furthermore, using Nano Genome Atlas of multi-tissues, we uncover CaP USNCs induce stronger activation of the immune responses in the cartilage and subchondral bone among the five local tissues while promote metabolic activities in the liver and kidney. Moreover, based on the immunological response profiles, histological evaluation of major organs and local tissue, and a body-wide transcriptomics, we demonstrate that CaP USNCs are not more hazardous than the Food and Drug Administration-approved CaP nanoparticles after 14 days of injection. Our findings provide valuable information on the future clinical applications of USNCs and introduce an innovative strategy to decipher the whole body response to implants.

A tyrosinase-responsive tumor-specific cascade amplification drug release system for melanoma therapy.

Tumor-selective drug delivery could enhance anticancer efficacy and avoid drug side effects. However, because of tumor heterogeneity, current nanoparticle-based drug delivery systems rarely improve clinical outcomes significantly, commonly only reducing systemic toxicity. In this work, a new tumor-specific, tyrosinase-responsive cascade amplification release nanoparticle (TR-CARN) was developed to fulfill the needs for tumor-specific drug delivery and high efficacy cancer treatment. Tyrosinase (Tyr) is specifically expressed in melanomas and can catalyze acetaminophen (APAP) to increase reactive oxygen species (ROS). It was therefore utilized here to initiate the ROS amplification procedure. In TR-CARN, a ROS-responsive prodrug BDOX was loaded into an amphiphilic polymer, and APAP was linked to the polymer through a ROS-cleavable thioether bond. TR-CARN caused reduced side effects during the delivery because of the low toxicity of BDOX. Once TR-CARN entered into the tumor, endogenous ROS triggered initial APAP and BDOX release. Tyr-mediated ROS synthesis by APAP then accelerated APAP and BDOX release and toxification. Consequently, TR-CARN achieved melanoma-specific treatment of high efficacy through the cascade amplification strategy with enhanced biosafety.

miR-21-5p targets SKP2 to reduce osteoclastogenesis in a mouse model of osteoporosis.

Osteoporosis results from an imbalance between bone formation and bone resorption. Traditional drugs for treating osteoporosis are associated with serious side effects, and thus, new treatment methods are required. This study investigated the role of differentially expressed microRNAs during osteoclast differentiation and osteoclast activity during osteoarthritis as well as the associated underlying mechanisms. We used a microarray to screen microRNAs that decreased in the process of osteoclast differentiation and verified miR-21-5p to decrease significantly using RT-qPCR. In follow-up experiments, we found that miR-21-5p targets SKP2 to regulate osteoclast differentiation. In vivo, ovariectomized mice were used to simulate perimenopausal osteoporosis induced by estrogen deficiency, and miR-21-5p treatment inhibited bone resorption and maintained bone cortex and trabecular structure. These results suggest that miR-21-5p is a new therapeutic target for osteoporosis.

The oncogenic and prognostic role of PDK1 in the progression and metastasis of ovarian cancer.

Ovarian cancer (OC) is the most lethal of gynecological tumors in women. Tumor metabolism has become a new opportunity in the treatment of tumors. Pyruvate dehydrogenase kinase 1 (PDK1), as a key regulatory enzyme implicated in metabolic reprogramming of tumors, abnormally high expressed in various tumors and involved in the regulation of tumor cell biological behavior. However, the role of PDK1 in the occurrence and development of ovarian cancer remains unclear. Our team identified the expression of PDK1 in ovarian cancer cell lines and tissues through RT-PCR and immunohistochemical staining and evaluated the correlation of PDK1 expression with clinicopathologic features of patients and survival analyses. We used a variety of in vitro experiments to explore the influence of PDK1 on proliferation, invasion, migration, colony formation, apoptosis and the cell cycle of ovarian cancer cell lines CAOV3 and SKOV3. PDK1 was highly expressed in ovarian cancer cell lines and OC tissues. High expression of PDK1 was closely correlated to tumor size, FIGO stage, extraovarian metastases status and distribution. Univariate and multivariate Cox regression analysis identified that PDK1 was an independent prognostic factor for overall survival. Moreover, PDK1 was a superior predictor in prognosis of ovarian cancer and the incorporation of CA125 into PDK1 generated a predictive combination that displayed better predictive accuracy for overall survival. Downregulation of PDK1 suppressed the biological behavior of ovarian cancer cells due to S phase arrest and cellular apoptosis. PDK1 may serve as a novel prognostic biomarker, even a promising antineoplastic target of ovarian cancer.

Clinical laboratory features of Meigs' syndrome: a retrospective study from 2009 to 2018.

Meigs' syndrome (MS), a rare complication of benign ovarian tumors, is easily misdiagnosed as ovarian cancer (OC). We retrospectively reviewed the clinical laboratory data of patients diagnosed with MS from 2009 to 2018. Serum carbohydrate antigen 125 and HE4 levels were higher in the MS group than in the ovarian thecoma-fibroma (OTF) and healthy control groups (all P < 0.05). However, the serum HE4 levels were lower in the MS group than in the OC group (P < 0.001). A routine blood test showed that the absolute counts and percentages of lymphocytes were significantly lower in the MS group than in the OTF and control groups (all P < 0.05). However, these variables were higher in the MS group than in the OC group (both P < 0.05). The neutrophil-to-lymphocyte ratio (NLR) was also significantly lower, whereas the lymphocyte-to-monocyte ratio was higher in the MS group than in the OC group (both P < 0.05). The NLR, platelet-to-lymphocyte ratio, and systemic immune index were significantly higher in the MS group than in the OTF and control groups (all P < 0.05). The hypoxia-inducible factor-1 mRNA levels were also significantly higher, whereas the glucose transporter 1, lactate dehydrogenase, and enolase 1 mRNA levels were lower in peripheral CD4+ T cells obtained preoperatively in a patient with MS than those in patients with OTF, patients with OC, and controls (all P < 0.05). The expression of these four glucose metabolism genes was preferentially restored to normal levels after the tumor resection of MS (P < 0.001). These clinical laboratory features can be useful in improving the preoperative diagnostic accuracy of MS.

Biomimetic remineralization of artificial caries dentin lesion using Ca/P-PILP.

OBJECTIVE: To assess the ultrastructural change of demineralized dentin collagen during calcium phosphate polymer-induced liquid precursor (Ca/P-PILP) mediated remineralization process and to evaluate the biomimetic remineralization potential of high concentration Ca/P-PILP at demineralized artificial caries dentin lesion, additionally to investigate the bond interfacial integrity as well as the bonding strength of the biomimetic remineralized artificial caries dentin lesion. METHODS: Demineralized dentin collagen of 5 µm thick was biomimetically remineralized with low, medium concentration Ca/P-PILP for 10 days and high concentration Ca/P-PILP for 10, 15, 20 days. Artificial caries dentin lesion at a thickness of 150 ± 50 µm was biomimetically remineralized with high concentration Ca/P-PILP for 20 days. The biomimetic remineralization of demineralized dentin collagen was observed by scanning electron microscopy (SEM). The biomimetic remineralization intensity and depth of artificial caries dentin lesion was assessed by Electron Probe Micro Analyzer (EPMA). The bonding interfacial integrity between remineralized artificial caries dentin and composite resin was observed by Swept-source optical coherence tomography (SS-OCT) and the bonding strength of remineralized artificial caries dentin was evaluated by micro-tensile bond strength analysis (µTBS). RESULTS: Solely PAA-PASP solution and solely saturated Ca/P solution can't achieve dentin collagen remineralization. Increased concentration of Ca/P-PILP and prolonged remineralization time can enhance the biomimetic remineralization intensity of demineralized dentin collagen. After treating with high concentration Ca/P-PILP, a 150 ± 50 µm thick layer of demineralized artificial caries dentin lesion was not fully remineralized, and the biomimetic remineralization intensity reached up to 88.0%. Furthermore, a better bonding interfacial integrity with less microgap and increased bond strength at both baseline level and aging level were observed when artificial caries dentin lesion was biomimetically remineralized with high concentration Ca/P-PILP. SIGNIFICANCE: Biomimetic remineralization of demineralized caries dentin lesion promotes its clinical properties for resin composited adhesive restoration.