Dynamic Stomach Model-Capillary Electrophoresis-ICPMS for Evaluation of Release and Transformation Behaviors of Arsenic Species from Microplastics during Digestion.

Microplastics (MPs) can act as carriers of environmental arsenic species into the stomach with food and release arsenic species during digestion, which threatens human health. Herein, an integrated dynamic stomach model (DSM)-capillary electrophoresis-inductively coupled plasma mass spectrometry (CE-ICPMS) is developed for online monitoring of the release and transformation behaviors of arsenic species loaded on MPs (As-MPs) in the simulated human stomach. The 3D-printed DSM with a soft stomach chamber enables the behaviors of gastric peristalsis, gastric and salivary fluid addition, pH adjustment, and gastric emptying (GE) to be controlled by a self-written program after oral ingestion of food with As-MPs. The gastric extract during digestion is introduced into the spiral channel to remove the large particulate impurity and online filtered to obtain the clarified arsenic-containing solution for subsequent speciation analysis of arsenic by CE-ICPMS. The digestion conditions and pretreatment processes of DSM are tracked and validated, and the release rates of As-MPs digested by DSM are compared with those digested by the static stomach model and DSM without GE. The release rate of inorganic arsenic on MPs is higher than that of organic arsenic throughout the gastric digestion process, and 8% of As(V) is reduced to As(III). The detection limits for As(III), DMA, MMA, and As(V) are 0.5-0.9 µg L-1 using DSM-CE-ICPMS, along with precisions of ≤8%. This present method provides an integrated and convenient tool for evaluating the release and transformation of As-MPs during human gastric digestion and provides a reference for exploring the interactions between MPs and metals/metalloids in the human body.

Oral delivery of capsaicin using MPEG-PCL nanoparticles.

AIM: To prepare a biodegradable polymeric carrier for oral delivery of a water-insoluble drug capsaicin (CAP) and evaluate its quality. METHODS: CAP-loaded methoxy poly (ethylene glycol)-poly(ε-caprolactone) nanoparticles (CAP/NPs) were prepared using a modified emulsification solvent diffusion technique. The quality of CAP/NPs were evaluated using transmission electron microscopy, powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared techniques. A dialysis method was used to analyze the in vitro release profile of CAP from the CAP/NPs. Adult male rats were orally administered CAP/NPs (35 mg/kg), and the plasma concentrations of CAP were measured with a validated HPLC method. The morphology of rat gastric mucosa was studied with HE staining. RESULTS: CAP/NPs had an average diameter of 82.54 ± 0.51 nm, high drug-loading capacity of 14.0% ± 0.13% and high stability. CAP/NPs showed a biphasic release profile in vitro: the burst release was less than 25% of the loaded drug within 12 h followed by a more sustained release for 60 h. The pharmacokinetics study showed that the mean maximum plasma concentration was observed 4 h after oral administered of CAP/NPs, and approximately 90 ng/mL of CAP was detected in serum after 36 h. The area under the curve for the CAP/NPs group was approximately 6-fold higher than that for raw CAP suspension. Histological studies showed that CAP/NPs markedly reduced CAP-caused gastric mucosa irritation. CONCLUSION: CAP/NPs significantly enhance the bioavailability of CAP and markedly reduce gastric mucosa irritation in rats.

Economical and green synthesis of bagasse-derived fluorescent carbon dots for biomedical applications.

Carbon quantum dots (CDs) are promising nanomaterials in biomedical, photocatalytical and photoelectronic applications. However, determining how to explore an ideal precursor for a renewable carbon resource is still an interesting challenge. Here, for the first time, we report that renewable wastes of bagasse as a new precursor were prepared for fluorescent CDs by a hydrothermal carbonization (HTC) process. The characterization results show that such bagasse-derived CDs are monodispersed, contain quasi spherical particles with a diameter of about 1.8 nm and exhibit favorable photoluminescence properties, super-high photostability and good dispersibility in water. Most importantly, bagasse-derived CDs have good biocompatibility and can be easily and quickly internalized by living cancer cells; they can also be used for multicolour biolabeling and bioimaging in cancer cells. It is suggested that bagasse-derived CDs might have potential applications in biomedical and photoelectronic fields.

Realveolarization with inhalable mucus-penetrating lipid nanoparticles for the treatment of pulmonary fibrosis in mice.

The stemness loss-associated dysregeneration of impaired alveolar type 2 epithelial (AT2) cells abolishes the reversible therapy of idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 stemness for IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house-made ionizable lipids for high-efficiency pulmonary mucus penetration and codelivery of dual messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 and bone morphogenetic protein 4, respectively. After being inhaled in a bleomycin model, LNPs reverses the mitochondrial dysfunction through ameliorating nicotinamide adenine dinucleotide biosynthesis, which inhibits the accelerated senescence of AT2 cells. Concurrently, pathological epithelial remodeling and fibroblast activation induced by impaired AT2 cells are terminated, ultimately prompting alveolar regeneration. Our data demonstrated that the mRNA-LNP system exhibited high protein expression in lung epithelial cells, which markedly extricated the alveolar collapse and prolonged the survival of fibrosis mice, providing a clinically viable strategy against IPF.

mRNA-Laden Lipid-Nanoparticle-Enabled in Situ CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model.

Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the "superbug" MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials.

Exposure to epoxy-modified nanoplastics in the range of µg/L causes dysregulated intestinal permeability, reproductive capacity, and mitochondrial homeostasis by affecting antioxidant system in Caenorhabditis elegans.

Although surface chemically modified nanopolystyrene (PS) has been reported to have potential toxicity toward organisms, the impact of epoxy modification on the toxicity of PS remains largely unknown. In this study, we first investigated the prolonged exposure effects of epoxy-modified PS (PS-C2H3O) in the range of µg/L on Caenorhabditis elegans (C. elegans) including general toxicity, target organ toxicity, and organelle toxicity. Our data revealed that C. elegans exposed to PS-C2H3O led to the alterations in increased lethality (≥ 1000 µg/L), shortened body length (≥ 100 µg/L), and decreased locomotion capacity (≥ 1 µg/L). In addition, toxicity analysis on target organs and organelles indicated that exposure to PS-C2H3O enhanced intestinal permeability (≥ 100 µg/L) by inhibiting the transcriptional levels of acs-22 (encoding fatty acid transport protein) (≥ 100 µg/L) and hmp-2 (encoding α-catenin) (≥ 1000 µg/L), reduced reproductive capacity (≥ 10 µg/L), and dysregulated mitochondrial homeostasis (≥ 1 µg/L). Moreover, the activation of antioxidant enzyme system could help nematodes against the toxicity caused by PS-C2H3O exposure (≥ 10 µg/L). Furthermore, we also compared the toxicity of PS-C2H3O with other chemically modified derivatives of PS, and the toxicity order was PS-NH2 > PS-SOOOH > PS-C2H3O > PS-COOH > PS > PS-PEG. Our study highlights the potential environmental impact of PS and its derivatives on organisms and suggests that the toxicity of nanoplastics may be charge-dependent.

Cell membrane derived liposomes loaded with DNase I target neutrophil extracellular traps which inhibits colorectal cancer liver metastases.

Neutrophil extracellular traps (NETs) are web-like chromatin structures that are coated with granule proteins and trap microorganisms. However, NETs can damage the host tissue, contribute to the development of autoimmunity and lead to other dysfunctional outcomes in noninfectious diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), diabetes, atherosclerosis, vasculitis, thrombosis, and cancer. As a potential therapeutic approach, targeted ablation of neutrophil extracellular traps is of utmost importance for the treatment of NET-associated diseases. Here, the specific interaction between CCDC25 and NETs was exploited to produce biomimetic CCDC25-overexpressing cell membrane hybrid liposomes capable of targeting NETs in NET-associated diseases. The hybrid liposomes were constructed by fusing cell membrane nanovesicles derived from genetically engineered cells, which stably express CCDC25, and the resulting cell membrane hybrid liposomes exhibited enhanced affinity for NETs in two different NET-associated disease models. Furthermore, after encapsulation of DNase I in the liposomes, the nanoformulation efficiently eliminated NETs and significantly suppressed the recruitment of neutrophils. Overall, we present a bionic nanocarrier that specifically targets NETs in vivo and successfully inhibits colorectal cancer liver metastases; importantly, this could be a promising therapeutic approach for the treatment of NET-associated diseases.

Preparation of polydopamine-functionalized mesoporous silica-coated core/shell magnetic nanocomposite for efficiently extracting five amphetamine-type stimulants from wastewater followed by UPLC-MS/MS determination.

Wastewater-based epidemiology (WBE) was a near-real-time monitoring strategy for illegal drugs. However, solid-phase extraction (SPE) widely used in WBE was time-consuming and labor-intensive to extract ultra-trace target compounds from wastewater. In this study, a convenient magnetic solid-phase extraction (MSPE) approach based on newly designed and synthesized polydopamine functionalized core-shell magnetic mesoporous silica (Fe3O4@nSiO2@mSiO2@PDA) nanocomposite was synthesized and firstly utilized for simultaneously extracting five amphetamine-type stimulants (ATSs) from wastewater samples. Subsequently, ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method coupled with optimal MSPE was developed for determination of ultra-trace ATSs in wastewater. The validation results indicated a favorable linearity ranging from 1 to 200 ng L-1, low limit of detection (0.5-2.5 ng L-1), and qualified recovery (95.1-106.6%) and repeatability (0.6-6.2%). In addition, the Fe3O4@nSiO2@mSiO2@PDA nanoparticles could be reused for at least ten times without significant loss of the adsorption efficiencies of ATSs. Finally, the MSPE-UPLC-MS/MS method was successfully applied to real wastewater samples with the results that the preparation procedure was shrunk from 2 h to 30 min without obvious decline of extraction efficiency compared with the SPE. Hence, based on merits of the novel Fe3O4@nSiO2@mSiO2@PDA nanocomposite, the proposed method is convenient and reliable for determination of ATSs in wastewater.

Synthesis of a novel polydopamine and C18 dual-functionalized magnetic core-shell mesoporous nanocomposite for enrichment and analysis of widely abused illegal drugs in urine samples on site and in the laboratory.

In this study, a novel polydopamine and C18 dual-functionalized magnetic core-shell mesoporous silica (Fe3O4@nSiO2@mSiO2@PDA-C18) nanocomposite was designed and synthesized, which was employed as an adsorbent to extract illegal drugs from urine samples by magnetic solid-phase extraction (MSPE) procedures. The as-prepared nanocomposite was fully characterized and combined with ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to monitor 12 trace illegal drugs and metabolites, including 6-monoacetylmorphine (6-MAM), morphine (MOR), codeine (COD), amphetamine (AMP), methamphetamine (MAMP), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), ketamine (KET), norketamine (NK), cocaine (COC), benzoylecgonine (BZE) and methcathinone (MC). Optimal MSPE procedures were achieved by fully investigating parameters of activation, adsorption, washing and desorption steps. The MSPE-UHPLC-MS/MS method offered high sensitivity with limit of detection (LOD) range of 0.005-0.05 ng mL-1 and good linearity with the concentration of 0.01-1000 ng mL-1. Also, the intra- and inter-day recovery respectively ranged in 90.2-105.0% and 89.8-107.4%, and the intra- and inter-day precision was in the range of 0.5-14.0% and 1.2-10.0%, respectively. By application to real urine samples, the proposed method could not only be equally sensitive for quantifying 12 illegal drugs in urine but also significantly reduce the pretreatment time when comparing with methods based on solid-phase extraction. Furthermore, the designed dual-functionalized adsorbents could also be applied for on-site determination of MAMP in urine coupled with urine test kit, and the detection threshold of MAMP urine test kit remarkably reduced from 1000 ng mL-1 to 50 ng mL-1. Therefore, the present method was a convenient, economic and sensitive approach for determining illegal drugs in urine samples both on site and in the laboratory.

A novel amelogenesis-inspired hydrogel composite for the remineralization of enamel non-cavitated lesions.

Enamel non-cavitated lesions (NCLs) are subsurface enamel porosity from carious demineralization. The developed enamel cannot repair itself once NCLs occurs. The regeneration of mineral crystals in a biomimetic environment is an effective way to repair enamel subsurface defects. Previously, an amelogenin-derived peptide named QP5 was proven to repair demineralized enamel. In this work, inspired by amelogenesis, a novel biomimetic hydrogel composite containing the QP5 peptide and bioactive glass (BG) was designed, in which QP5 could promote enamel remineralization by guiding the calcium and phosphorus ions provided by BG. Also, BG could adjust the mineralization micro-environment to alkalinity, simulating the pH regulation of ameloblasts during enamel maturity. The BQ hydrogel composite showed biosafety and possessed capacity for enamel binding, ion release and pH buffering. Enamel NCLs treated with the BQ hydrogel composite showed a higher reduction in lesion depth and mineral loss both in vitro and in vivo. Moreover, compared to the hydrogels containing only BG or QP5, groups treated with the BQ hydrogel composite attained more surface microhardness recovery and color recovery, exhibiting resistance to erosion and abrasion of the remineralization layer. We envision that the BQ hydrogel composite can provide a biomimetic micro-environment to favor enamel remineralization, thus reducing the lesion depth and increasing the mineral content as a promising biomimetic material for enamel NCLs.

Galectin-1 Inhibited LPS-Induced Autophagy and Apoptosis of Human Periodontal Ligament Stem Cells.

Periodontitis is a widespread human chronic inflammatory disease of the tooth-surrounding tissues, which induces the destruction of periodontium and pathologic loss of teeth among adults. It has been reported that interleukin (IL)-17 was significantly increased in periodontitis patients compared to controls, while galectin-1 (Gal-1) was lower. Interestingly, it is found that Gal-1 treatment reduced systemic IL-17 levels. Hence, the aim of the present study was to explore the effect of Gal-1 on periodontitis development and investigate its underlying mechanism. In this study, Gal-1 was poorly expressed in lipopolysaccharide (LPS)-induced human periodontal ligament stem cells (hPDLSCs), and Gal-1 overexpression attenuated the production of inflammatory cytokines induced by LPS. Moreover, Gal-1 overexpression alleviated LPS-induced cell autophagy and apoptosis and reduced the expressions of IL-17A and IL-17R. Interestingly, IL-17A reversed the effect of Gal-1 on cell autophagy, inflammation, and cell apoptosis induced by the LPS challenge. In conclusion, Gal-1 inhibited LPS-induced autophagy and apoptosis of hPDLSC via regulation of IL-17A expression. Therefore, Gal-1 may have promising potential in regenerating periodontium.

Chemoembolizing hepatocellular carcinoma with microsphere cored with arsenic trioxide microcrystal.

Chemoembolization for hepatocellular carcinoma (HCC) is often suboptimal due to multiple involved signaling and lack of effective drugs. Arsenic trioxide (ATO) is a potent chemotherapeutic agent, which can target multiple signaling and have substantial efficacy on HCC. However, its usage is limited due to systemic toxicity. Using ATO-eluting beads/microspheres for chemoembolization can have locoregional drug delivery and avoid systemic exposure but will require high drug load, which has not been achieved due to low solubility of ATO. Through an innovative approach, we generated the transiently formed ATO microcrystals via micronization and stabilized these microcrystals by solvent exchange. By encapsulating ATO microcrystals, but not individual molecules, with poly(lactide-co-glycolic acid) (PLGA), we developed microspheres cored with extremely high dense ATO. The molar ratio between ATO and PLGA was 157.4:1 and drug load was 40.1%, which is 4-20 fold higher than that of reported ATO nano/microparticles. These microspheres sustainably induced reactive oxygen species, apoptosis, and cytotoxicity on HCC cells and reduced tumor growth by 80% via locoregional delivery. Chemoembolization on mice model showed that ATO-microcrystal loaded microspheres, but not ATO, inhibited HCC growth by 60-75%, which indicates ATO within these microspheres gains the chemoembolizing function via our innovative approach.

In situ tuning proangiogenic factor-mediated immunotolerance synergizes the tumoricidal immunity via a hypoxia-triggerable liposomal bio-nanoreactor.

Rationale: Vascular abnormality stemming from the hypoxia-driven elevation of proangiogenic factors is a hallmark for many solid malignant tumors, including colorectal cancer (CRC) and its liver metastasis. We report a hypoxia-triggered liposome-supported metal-polyphenol-gene bio-nanoreactor to tune the proangiogenic factor-mediated immunotolerance and synergize the elicited tumoricidal immunity for CRC treatment. Methods: With the aid of polyphenol gallic acid, Cu2+ ion-based intracellular bio-nanoreactor was synthesized for the delivery of small interfering RNA targeting vascular endothelial growth factor and then cloaked with a hybrid liposomal membrane that harbored a hypoxia-responsive azobenzene derivative. In hypoxic tumor, the liposomal shell disintegrated, and a shrunk-size bio-nanoreactor was burst released. Intracellularly, Cu2+ from the bio-nanoreactor catalyzed a Fenton-like reaction with glutathione, which efficiently converted H2O2 to •OH and enabled a chemodynamic therapy (CDT) in tumor sites. With the alleviation of proangiogenic factor-mediated immunotolerance and high production of CDT-induced tumor-associated antigens, robust tumoricidal immunity was co-stimulated. Results: With colorectal tumor and its liver metastasis models, we determined the underlying mechanism of proangiogenic factor-mediated immunotolerance and highlighted that the liposomal bio-nanoreactor could create positive feedback among the critical players in the vascular endothelium and synergize the elicited tumoricidal immunity. Conclusion: Our work provides an alternative strategy for exerting efficient tumoricidal immunity in the proangiogenic factor-upregulated subpopulation of CRC patients and may have a wide-ranging impact on cancer immune-anti-angiogenic complementary therapy in clinics.

Targeting Tumor Hypoxia Using Nanoparticle-engineered CXCR4-overexpressing Adipose-derived Stem Cells.

Hypoxia, a hallmark of malignant tumors, often correlates with increasing tumor aggressiveness and poor treatment outcomes. Due to a lack of vasculature, effective drug delivery to hypoxic tumor regions remains challenging. Signaling through the chemokine SDF-1α and its receptor CXCR4 plays a critical role in the homing of stem cells to ischemia for potential use as drug-delivery vehicles. To harness this mechanism for targeting tumor hypoxia, we developed polymeric nanoparticle-induced CXCR4-overexpressing human adipose-derived stem cells (hADSCs). Using glioblastoma multiforme (GBM) as a model tumor, we evaluated the ability of CXCR4-overexpressing hADSCs to target tumor hypoxia in vitro using a 2D migration assay and a 3D collagen hydrogel model. Compared to untransfected hADSCs, CXCR4-overexpressing hADSCs showed enhanced migration in response to hypoxia and penetrated the hypoxic core within tumor spheres. When injected in the contralateral brain in a mouse intracranial GBM xenograft, CXCR4-overexpressing hADSCs exhibited long-range migration toward GBM and preferentially penetrated the hypoxic tumor core. Intravenous injection also led to effective targeting of tumor hypoxia in a subcutaneous tumor model. Together, these results validate polymeric nanoparticle-induced CXCR4-overexpressing hADSCs as a potent cellular vehicle for targeting tumor hypoxia, which may be broadly useful for enhancing drug delivery to various cancer types.

Effect of matrix metalloproteinase-mediated matrix degradation on glioblastoma cell behavior in 3D PEG-based hydrogels.

Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor with median survival of 12 months. To improve clinical outcomes, it is critical to develop in vitro models that support GBM proliferation and invasion for deciphering tumor progression and screening drug candidates. A key hallmark of GBM cells is their extreme invasiveness, a process mediated by matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix. We recently reported the development of a MMP-degradable, poly(ethylene-glycol)-based hydrogel platform for culturing GBM cells. In the present study, we modulated the percentage of MMP-degradable crosslinks in 3D hydrogels to analyze the effects of MMP-degradability on GBM fates. Using an immortalized GBM cell line (U87) as a model cell type, our results showed that MMP-degradability was not required for supporting GBM proliferation. All hydrogel formulations supported robust GBM proliferation, up to 10 fold after 14 days. However, MMP-degradability was essential for facilitating tumor spreading, and 50% MMP-degradable hydrogels were sufficient to enable both robust tumor cell proliferation and spreading in 3D. The findings of this study highlight the importance of modulating MMP-degradability in engineering 3D in vitro brain cancer models and may be applied for engineering in vitro models for other cancer types. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 770-778, 2017.

Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model.

Wear particle-induced osteolysis limits the long-term survivorship of total joint replacement (TJR). Monocyte/macrophages are the key cells of this adverse reaction. Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) is the most important chemokine regulating trafficking of monocyte/macrophages in particle-induced inflammation. 7ND recombinant protein is a mutant of CCL2 that inhibits CCL2 signaling. We have recently developed a layer-by-layer (LBL) coating platform on implant surfaces that can release biologically active 7ND. In this study, we investigated the effect of 7ND on wear particle-induced bone loss using the murine continuous polyethylene (PE) particle infusion model with 7ND coating of a titanium rod as a local drug delivery device. PE particles were infused into hollow titanium rods with or without 7ND coating implanted in the distal femur for 4 weeks. Specific groups were also injected with RAW 264.7 as the reporter macrophages. Wear particle-induced bone loss and the effects of 7ND were evaluated by microCT, immunohistochemical staining, and bioluminescence imaging. Local delivery of 7ND using the LBL coating decreased systemic macrophage recruitment, the number of osteoclasts and wear particle-induced bone loss. The development of a novel orthopaedic implant coating with anti-CCL2 protein may be a promising strategy to mitigate peri-prosthetic osteolysis.

The effect of local IL-4 delivery or CCL2 blockade on implant fixation and bone structural properties in a mouse model of wear particle induced osteolysis.

Modulation of macrophage polarization and prevention of CCL2-induced macrophage chemotaxis are emerging strategies to reduce wear particle induced osteolysis and aseptic total joint replacement loosening. In this study, the effect of continuous IL-4 delivery or bioactive implant coating that constitutively releases a protein inhibitor of CCL2 signaling (7ND) on particle induced osteolysis were studied in the murine continuous femoral intramedullary particle infusion model. Polyethylene particles with or without IL-4 were infused into mouse distal femurs implanted with hollow titanium rods using subcutaneous infusion pumps. In another experimental group, particles were infused into the femur through a 7ND coated rod. After 4 weeks, fixation of the implant was assessed using a pullout test. The volume of trabecular bone and the geometry of the local cortical bone were assessed by µCT and the corresponding structural properties of the cortical bone determined by torsional testing. Continuous IL-4 delivery led to increased trabecular bone volume as well as enhanced local bone geometry and structural properties, while 7ND implant coating did not have effect on these parameters. The results suggest that local IL-4 treatment is a promising strategy to mitigate wear particle induced osteolysis. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2255-2262, 2016.

Winner of the Young Investigator Award of the Society for Biomaterials at the 10th World Biomaterials Congress, May 17-22, 2016, Montreal QC, Canada: Microribbon-based hydrogels accelerate stem cell-based bone regeneration in a mouse critical-size cranial defect model.

Stem cell-based therapies hold great promise for enhancing tissue regeneration. However, the majority of cells die shortly after transplantation, which greatly diminishes the efficacy of stem cell-based therapies. Poor cell engraftment and survival remain a major bottleneck to fully exploiting the power of stem cells for regenerative medicine. Biomaterials such as hydrogels can serve as artificial matrices to protect cells during delivery and guide desirable cell fates. However, conventional hydrogels often lack macroporosity, which restricts cell proliferation and delays matrix deposition. Here we report the use of injectable, macroporous microribbon (µRB) hydrogels as stem cell carriers for bone repair, which supports direct cell encapsulation into a macroporous scaffold with rapid spreading. When transplanted in a critical-sized, mouse cranial defect model, µRB-based hydrogels significantly enhanced the survival of transplanted adipose-derived stromal cells (ADSCs) (81%) and enabled up to three-fold cell proliferation after 7 days. In contrast, conventional hydrogels only led to 27% cell survival, which continued to decrease over time. MicroCT imaging showed µRBs enhanced and accelerated mineralized bone repair compared to hydrogels (61% vs. 34% by week 6), and stem cells were required for bone repair to occur. These results suggest that paracrine signaling of transplanted stem cells are responsible for the observed bone repair, and enhancing cell survival and proliferation using µRBs further promoted the paracrine-signaling effects of ADSCs for stimulating endogenous bone repair. We envision µRB-based scaffolds can be broadly useful as a novel scaffold for enhancing stem cell survival and regeneration of other tissue types. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1321-1331, 2016.

Local delivery of mutant CCL2 protein-reduced orthopaedic implant wear particle-induced osteolysis and inflammation in vivo.

Total joint replacement (TJR) has been widely used as a standard treatment for late-stage arthritis. One challenge for long-term efficacy of TJR is the generation of ultra-high molecular weight polyethylene wear particles from the implant surface that activates an inflammatory cascade which may lead to bone loss, prosthetic loosening and eventual failure of the procedure. Here, we investigate the efficacy of local administration of mutant CCL2 proteins, such as 7ND, on reducing wear particle-induced inflammation and osteolysis in vivo using a mouse calvarial model. Mice were treated with local injection of 7ND or phosphate buffered saline (PBS) every other day for up to 14 days. Wear particle-induced osteolysis and the effects of 7ND treatment were evaluated using micro-CT, histology, and immunofluorescence staining. Compared with the PBS control, 7ND treatment significantly decreased wear particle-induced osteolysis, which led to a higher bone volume fraction and bone mineral density. Furthermore, immunofluorescence staining showed 7ND treatment decreased the number of recruited inflammatory cells and osteoclasts. Together, our results support the feasibility of local delivery of 7ND for mitigating wear particle-induced inflammation and osteolysis, which may offer a promising strategy for extending the life time of TJRs.

Enhanced antitumor efficacy by d-glucosamine-functionalized and paclitaxel-loaded poly(ethylene glycol)-co-poly(trimethylene carbonate) polymer nanoparticles.

The poor selectivity of chemotherapeutics for cancer treatment may lead to dose-limiting side effects that compromise clinical outcomes. To solve the problem, surface-functionalized polymer nanoparticles are regarded as promising tumor-targeting delivery system. On the basis of glucose transporter (GLUT) overexpression on cancer cells, d-glucosamine-conjugated and paclitaxel-loaded poly(ethylene glycol)-co-poly(trimethylene carbonate) copolymer nanoparticles (DGlu-NP/PTX) were developed as potential tumor-targeting drug delivery system in this study. Because of the high affinity between d-glucosamine and GLUT, DGlu-NP/PTX could target to tumor tissue through GLUT-mediated endocytosis to improve the selectivity of PTX. DGlu-NP/PTX was prepared by emulsion/solvent evaporation technique and characterized in terms of morphology, size, and zeta potential. In vitro evaluation of two-dimensional cells and three-dimensional tumor spheroids revealed that DGlu-NP/PTX was more potent than those of plain nanoparticles (NP/PTX) and Taxol. In vivo multispectral fluorescent imaging indicated that DGlu-NP had higher specificity and efficiency on subcutaneous xenografts tumor of mouse. Furthermore, DGlu-NP/PTX showed the greatest tumor growth inhibitory effect on in vivo subcutaneous xenografts model with no evident toxicity. Therefore, these results demonstrated that DGlu-NP/PTX could be used as potential vehicle for cancer treatment.