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Bone defects are the second most common tissue grafts after blood. However, bone grafts face several problems, such as bone scaffolds, which have low bioactivity and are prone to corrosion. Much of the current research on bone scaffolds is focused on the mechanical aspects such as structure and strength. Surface modification of the bone scaffold is carried out in terms of the mechanical structure or structural design of the bone scaffold with reference to a bionic structure. However, with the development of mechanical designs, materials science, and medicine, many studies have reported that promoting bone growth by modifying the structure of the scaffold or coating is not possible. Therefore, the application of a bioactive coating to the surface of the bone scaffold is particularly important to generate a synergistic effect between the structure and active coating. In this article, we present several perspectives to improve the bioactivity of bone scaffolds, including corrosion resistance, loading of bioactive coatings or drugs on bone scaffolds, improved adhesion to the surface of the bone scaffolds, immune response modulation, and drawing on bionic structures during manufacturing.

Pulmonary fibrosis (PF) is a chronic progressive disease with an extremely high mortality rate and is a complication of COVID-19. Inhalable microspheres have been increasingly used in the treatment of lung diseases such as PF in recent years. Compared to the direct inhalation of drugs, a larger particle size is required to ensure the sustained release of microspheres. However, the clinical symptoms of PF may lead to the easier deposition of microspheres in the upper respiratory tract. Therefore, it is necessary to understand the effects of PF on the deposition of microspheres in the respiratory tract.In this study, airway models with different degrees of PF in humans and mice were established, and the transport and deposition of microspheres in the airway were simulated using computational fluid dynamics.The simulation results showed that PF increases microsphere deposition in the upper respiratory tract and decreases bronchial deposition in both humans and mice. Porous microspheres with low density can ensure deposition in the lower respiratory tract and larger particle size. In healthy and PF humans, porous microspheres of 10 µm with densities of 700 and 400 kg/m³ were deposited most in the bronchi. Unlike in humans, microspheres larger than 4 µm are completely deposited in the upper respiratory tract of mice owing to their high inhalation velocity. For healthy and PF mice, microspheres of 6 µm with densities of and 100 kg/m³ are recommended.The results showed that with the exacerbation of PF, it is more difficult for microsphere particles to deposit in the subsequent airway. In addition, there were significant differences in the deposition patterns among the different species. Therefore, it is necessary to process specific microspheres from different individuals. Our study can guide the processing of microspheres and achieve differentiated drug delivery in different subjects to maximize therapeutic effects.

Two CFD models A and B were developed based on APV high-pressure homogenizer and it was determined that the mathematical model and analysis method of B were more consistent with the actual homogenization process. The internal flow field of the high-pressure micro-jet homogenizer was simulated using Fluent software. The homogenization pressure, ratio of oil to water, and temperature were investigated. The optimal parameter combination obtained from numerical simulation of orthogonal experiment was 20 °C, 70 MPa, and 1:12. APV high-pressure homogenizer orthogonal experiment was conducted and the optimal experimental parameter combination obtained was 50 °C, 70 MPa, and 1:15. The two groups of optimal parameters were used in the homogeneous experiments. TEM images were used for comparative analysis of the particle size，and the particle size obtained by numerical simulation was slightly larger. A comparison of experimental and numerical simulation results indicate that the single factor experiment and the orthogonal experiment were not entirely chime. The reason for the discrepancy is because the emulsifier was added in the homogeneous experiment such that there were more flow field variation factors in the homogenization process and the numerical process did not define all relevant conditions. However, the highly similar development trend verifies the effectiveness of the B model, which can provide an important reference in the development and use of homogenizers.

Sonodynamic therapy (SDT) has been proposed as a new modality for cancer management through low-intensity ultrasound induced activation of sonosensitizers. Here, we designed a novel redox/enzyme/ultrasound responsive chondroitin sulfate-chlorin e6-lipoic acid nanoplatform loading docetaxel, combining SDT and chemotherapy, for antiproliferation and antimetastasis of melanoma. The reversibly crosslinked and self-assembled nanoparticles possessed monodispersive size distribution, stability in physical conditions, while showing increased uptake with rapid drug release in simulated tumor microenvironment (reductive potentials and degradative hyaluronidase-1). With synthesized ultrasound sensitive polymer backbones, SDT induced the generation of cellular reactive oxygen species and mitochondrial damage, exerting the apoptotic effect through the release of cytochrome C, the expression of cleaved caspase-9 followed by the functional cleaved caspase-3. Chemo-sonodynamic therapy not only inhibited tumor growth and metastasis with reduced metastatic protein expression, but also caused immune response via the release of tumor-associated antigens. It was initially demonstrated that SDT could induce the tumor cell death, therefore having potentials to recruit cytotoxic lymphocytes into tumor sites. Notably, the nanoplatforms exhibited good in vivo stability and blood compatibility, indicating the safety and efficiency in drug delivery. Our work thus presents a convenient approach to fabricate intelligent multifunctional nanoparticles and paves a path for effective cancer therapies.

Immunotherapy has exhibited enormous practice in the treatment of melanoma because of the intrinsic properties of tumor. Tumor can downmodulate immune function via multiple mechanisms such as immune checkpoint pathways. The PD-L1 monoclonal antibodies that block the PD1/PD-L1 pathway, which induced tumor cells to evade an immune attack, can delay tumor growth efficiently with inevitable disadvantages such as low selectivity and systemic toxicity. Nanomedicine is clearly an approach that holds tremendous potential for addressing the shortcomings and assisting delivery of drugs with proper biodistribution. Herein, we developed a smart nanoplatform with precisely active targeting liposome co-loaded chemotherapy and immunotherapy drugs for synergistic antitumor effects while decreasing systemic toxicity. Immunoliposomes have stable pharmaceutical properties and show a significant antitumor effect in vivo and in vitro. Cellular uptake in vitro and biodistribution in vivo demonstrated that immunoliposomes could be delivered and accumulated more in tumor tissues. These immunoliposomes exhibited effective tumor inhibition and prolonged survival time due to activation of tumor-specific CD8+ T cell and highly selective tumor killing. In addition, safety evaluation of liposomes also demonstrated their increased tumor accumulation and decreased systemic toxicity. Hence, this smart pH-sensitive nanoplatform has promising potential for clinical applications and possibly provides a well-controlled design for combination of chemotherapy with various immunotherapies for further exploration.

To realize the controlled mass production of microspheres prepared by a high-pressure homogenizer and solve the problem of protein structure damage caused by very high pressure and overheating. This study established a numerical model based on the high-pressure homogenizer and performed simulation calculations using computational fluid dynamics (CFD). Through multipressure gradient microsphere preparation experiments, the particle size obtained by experiment and numerical calculation were compared and analyzed. According to the principle of conservation of energy, the speed was established as the optimization reference target, the structure of homogenizer was optimized and designed, and the corner spacing, corner radian, and corner taper of the homogeneous cavity were determined as the optimization objects. The ternary and cubic relationship equations of the optimized structure were fitted, and the continuous optimization of multi factor relations were realized. The results show that the optimal structural parameters are 0.496 mm corner spacing, 0.493 mm corner radian and 1.86 degrees corner taper, the fluid motion velocity of the high-pressure homogenizer increases from 234 m/s to 297 m/s under 30 MPa, and the velocity increases by 26.9%, and the particle size of the microsphere reaches the treatment effect of 50 MPa. The increase in kinetic energy indicates that the friction is overcome, the heat generation is reduced. The research has solved the problems of high pressure and overheating encountered in the process of homogeneous production, realized the social needs of efficient and green production, and provided support for the further development of homogenizer technology.

Background and objective Porous bone repair scaffolds are an important method of repairing bone defects. Fluid flow in the scaffold plays a vital role in tissue differentiation and permeability and fluid shear stress (FSS) are two important factors. The differentiation of bone tissue depends on the osteogenic differentiation of cells, FSS affects cell proliferation and differentiation, and permeability affects the transportation of nutrients and metabolic waste. Therefore, it is necessary to better understand and analyze the FSS on the cell surface and the permeability of the scaffold to obtain better osteogenic performance. Methods In this study, computational fluid dynamics (CFD) was used to analyze fluid flow in the scaffold. Three structures and nine scaffold unit cell models were designed and the cell models were loaded onto the scaffold surface. Considering cell deformability, the two-way fluid-structure interaction (FSI) method was used to evaluate the FSS on the cell surface. Results The simulation results showed that as the pore size of the scaffold increases, its permeability increases and the FSS decreases. The FSS received on the cell surface was much larger than scaffold surface. Moreover the FSS on the cell surface was distributed in steps. Conclusions The results showed the permeability of all models matches that of human bone tissue. Based on the cell surface FSS as the criterion, it was found that the spherical-560 scaffold exhibited the best osteogenic performance. This provided a strategy to design a better bone repair scaffold from biological aspects.

In this study, novel prodrug-modified cationic liposome nanocomplexes (Combo NCs) were reported for gemcitabine (GEM) and docetaxel (DTX) co-delivery. This nanoplatform exhibited multiple favorable characteristics, such as a 'green' fabrication with a one-step chemical reaction, appropriate size (∼200nm) and distribution (PDI0.2), low zeta potential (-31.1mv), high drug-loading efficiency (9.3% GEM plus 3.1% DTX, wt%) and pH and enzymatic dual-stimulus-responsive release properties. Immunofluorescence and cellular uptake studies showed that Combo NCs efficiently targeted overexpressed CD44 in MDA-MB-231 carcinoma. In vitro studies revealed that Combo NCs played a critical role in the synergistic induction of cytotoxicity, apoptosis and inhibition of wound healing. Combo NCs were confirmed to exhibit great potency for increasing S phase arrest and remodeling the CDA and dCK balance by decreasing the mRNA expression of CDA down to 0.09-fold and increasing the mRNA expression of dCK by 1.36-fold, remarkably increasing the dCK/CDA ratio to 15.3-fold compared with the blank control. The biodistribution results obtained in vivo revealed an effective accumulation in tumor foci. All of these advantages of Combo NCs contributed to their remarkable anti-tumor efficacy without systemic toxicity as well as their apoptosis-enhancing and anti-proliferative capacities, as determined by TUNEL and Ki67 immunohistochemistry in vivo. Consequently, such a rationally contemplated co-delivery system demonstrated the promising potential of clinical applications for triple-negative breast cancer therapy.The Combo NCs were innovatively applied for co-delivery of hydrophilic GEM and hydrophobic DTX. The ester bond linking and shielding effect of HA-GEM made the carriers achieve synchronous release properties, which was determined in in vitro release study. Due to the HA modification, the vectors own great potency for positive targeting to CD44 overexpressed triple-negative breast cancer cells MDA-MB-231. Cytotoxicity and apoptosis studies confirmed the targeting effect and synergism between two drugs. Interestingly, we found in cell cycle study, drug combinations (free combination or Combo NCs) didn't show a rise in G2M phase, which was significantly higher when treated DTX alone. We further discovered the role of DTX in combinations may involve in modulating GEM associated enzymes thus enhancing the efficacy of GEM. Consequently, this nanoplatform provided a novel solution for achieving targeted co-delivery and potentiating effect in cancer therapy.

Currently, the phosphatidylethanolamine-based, pH-sensitive, liposome drug-delivery system has been widely developed for efficient, targeted cancer therapy. However, the mechanism of pH sensitivity was unclear; it is a main obstacle in controlling the preparation of pH-sensitive liposomes (PSLs).Therefore, our research is aimed at clarifying the pH-response mechanism of the various molecules that compose liposomes. We chose the small pH-sensitive molecules oleic acid (OA), linoleic acid (LA) and cholesteryl hemisuccinate (CHEMS) and the fundamental lipids cholesterol and phosphatidylethanolamine (PE) as test molecules. The PSLs were prepared using the thin-film hydration method and characterized in detail at various pH values (pH 5.0, 6.0 and 7.4), including particle size, ζ-potential, drug encapsulation efficiency and drug loading. The surface structure was observed by transmission electron microscopy (TEM), and the electrical conductivity of the liposome dispersion was also tested. The calorimetric analysis was conducted by Nano-differential scanning calorimetry (Nano-DSC). The in vitro drug release profile showed that PSLs exhibit good pH sensitivity. At neutral pH, the particle size was approximately 150nm, and it dramatically increased at pH 5.0. The ζ-potential increased as the pH decreased. The Nano-DSC results showed that cholesterol and CHEMS can both increase the stability and phase transfer temperature of PSLs. Conductivity increased to a maximum at pH 5.0 and was rather low at pH 7.4. In conclusion, results show that the three kinds of liposomes have pH responsive release characteristics in acidic pH. The OA-PSLs have a pH sensitive point of 5. Since CHEMS has a cholesterol-like structure, it can stabilizes the phospholipid bilayer under neutral conditions as shown in the Nano-DSC data, and because it has a special steroidal rigid structure, it exhibits better pH response characteristics under acidic conditions.

Mounting researches continue to support a favorable role for the drug metal complex against cancer progress and metastasis. However, pharmaceutical barriers were encountered when drug metal complexes needed further pre-clinical and clinical evaluations due to their poor aqueous solubility. In this research, liposomes loaded metal ion as nano-scaled reaction vehicles were used to carry out a synthesis reaction between metal ion and curcumin (Cur) to prepare Cur-metal drug liposomal formulations. The unique flower-like conformation of Cur-M liposomes was observed for the first time and dominated in the Cur-M liposomal formulations system by the cryo-transmission electron microscopy. Different metal ions behaved significant differences in formulations' appearance, release profile, cytotoxic effect against various cell lines, pharmacokinetic profiles, biodistribution and antitumor efficiency. Cur-M liposomes presented enhanced cellular uptake and ROS generation effects, thus augmenting the cytotoxicity of Cur. Superior performances of Cur-copper complexes liposomes were observed in improving Cur stability, promoting apoptosis, inhibiting the proliferation and angiogenesis, therefore enhancing therapeutic effect for primary and metastatic breast cancer. Overall, the current work highlights the potentially significant development value of Cur-M liposomes as an injectable agent for cancer treatment, even superior to the commercial agent Doxil.

The goal of this research was to formulate dual-targeting liposomes (RGD/DTX-PSL) that can selectively release loaded contents in a low pH level environment and to actively target to the tumor using liposomes that had surface arginine-glycine-aspartic (RGD) tripeptides. We investigated whether RGD/DTX-PSL could serve as an effective tumor-targeted nanoparticle that is capable of suppressing tumor growth. The results suggest that DTX is released from liposomes faster at pH 5.0 than pH 7.4, demonstrating their pH sensitivity. RGD/DTX-PSL has a longer blood circulation than Duopafei(®) in rats. The RGD/DTX-PSL formulation displayed stronger antiproliferative effects than DTX alone and the strongest inhibition of tumor growth of the formulations tested, thus expanding therapeutic window of DTX. In conclusion, we established a novel, promising and easy-to-handle liposome formulation that has a considerable antitumor activity in vitro and in vivo. This study provides important prerequisite for the clinical application of dual-targeting liposomes in delivering therapies.

Along with the malignant proliferation of tumor requiring nutrients, the expression of L-type amino acid transporter 1(LAT1) and amino acid transporter B0,+ (ATB0,+) in cancer cells is up-regulated that can be used as new targets for active targeting of tumor. However, since normal cells also express amino acid transporters in small amounts, traditional ligand-exposure drug delivery systems are potentially toxic to the body. Therefore, we designed a smart-response drug delivery system that buries the tyrosine ligand in PEG hydration layer at normal tissues and exposes the ligand by cleaving the pH-sensitive bond of PEG at the tumor site. Irinotecan (CPT-11) is actively loaded into the inner aqueous phase of liposomes via a copper ion gradient mechanism which has high encapsulation efficiency and stable drug release profile. Smart-response liposomes showed the strongest cytotoxicity and the maximum cellular uptake in vitro, the largest amount of tumor site accumulation and the best antitumor effect in vivo, compared with non-targeted liposomes and non-sensitive liposomes. It is worth noting that smart-response liposomes not only achieved enhanced antitumor effect but also attenuated side effects compared to ligand-exposure liposomes. This provides a smart responsive drug delivery system for precise treatment and shows a good application prospect.

3D-QSAR, molecular docking and molecular dynamics (MD) simulations were performed to investigate the mechanism of ACE-inhibitory (ACEi) peptides with tryptophan C-terminal in aqueous solutions. In this work, COMFA (Q2 = 0.85, R2 = 0.993) and COMSIA (Q2 = 0.706, R2 = 0.997) models of di- and tri-peptides were established. Novel tripeptides were predicted by the 3D-QSAR models. Different conformations and interactions between VKW with high activity and GTW with low activity were compared by MD simulation. The results revealed VKW had stronger electrostatic interaction and binding affinity with key residues of ACE. ACE-VKW complex performed more stable than ACE-GTW. Thus, VKW showed a higher activity. Moreover, ACEi tripeptides with Trp C-terminal potentiate the combination with Zn of ACE active pockets.

Background and Objective The process of nanoparticles (NPs) entering blood circulation to actively target tumor cells involves four stages—the transport of NPs in blood vessels, transvascular transport of NPs, transport of NPs in the tumor interstitial matrix and entry of NPs into tumor cells. These four stages are a complex process involving mechanical, physical, biochemical, and biophysical factors, the tumor microenvironment (TME) and properties of NPs play important roles in this process. Because this process involves a large number of factors and is very complex, it is difficult to study with conventional methods. Methods Using mathematical models for simulation is suitable for addressing this complex situation and can describe the complexity well. Results This work focuses on the theoretical simulation of NPs that target tumor cells to illustrate the effects of the abnormal microenvironment of tumors and properties of NPs on the transport process. Mathematical models constructed by different methods are enumerated. Through studying these mathematical models, different methods to overcome nanoparticle (NP) transport obstacles are illustrated. Conclusions It is necessary to construct a theoretical model of active targeting nanodrug delivery under the coupling of micro-flow field and specific binding force field, and to simulate and analyze the delivery process at mesoscopic scale using computational fluid dynamics (CFD) method, so as to reveal the law and characteristics of drug delivery and cell uptake in the micro-environment of tumors in vivo. The methods and techniques discussed can serve as the basis for systematic studies of active targeting of functional nanoparticles to tumor cells.

Plant regeneration via somatic embryogenesis is essential for improvement of vegetatively propagated banana ( Musa spp. AAA) through biotechnological techniques. A systematic comparison of embryogenic cells (ECs) and non-embryogenic cells (NECs) of banana was performed in the present study. Immuno-dot blotting, immunoflourescence labeling, biochemical and ultrastructural analyses were employed to study differences between ECs and NECs. Both immuno-dot analysis and immunofluorescence labeling revealed a higher abundance of fucosylated xyloglucans in cell walls of ECs. Arabinogalactan-protein (AGP) epitopes recognized by LM2 and NH4.3E5 antibodies were more abundant in NECs. On the other hand, AGPs recognized by JIM16, MAC204 and MAC207 antibodies were more abundant in ECs. Biochemical analyses revealed that the content of total soluble sugars and reducing sugars, as well as levels of indole-3-acetic acid, abscisic acid and zeatin riboside were significantly higher in ECs in comparison to NECs. In contrast, NECs showed significantly higher content of gibberellic acid. In addition, NECs were highly vacuolated and contained lipid bodies, prominent mitochondria and plastids, however, endoplasmic reticulum and Golgi bodies were not so abundant when compared to ECs. This study revealed that cell walls of ECs are rich in fucosylated xyloglucan and in AGP epitopes labeled by JIM16, MAC204 and MAC207 antibodies, indicating that these cell wall components together with higher levels of auxin, abscisic acid and zeatin riboside are contributing to the embryogenic competence of banana. In contrast, NECs showed more abundant non-fucosylated and non-XXXG xyloglucans in their cell walls, and higher level of gibberellic acid. This study provides new and useful information about hormonal and cell wall regulation of banana embryogenic competence which contributes to better understanding of this process, and might lead to practical applications in the near future.

To determine the possible involvement of oxidative stress in somatic embryogenesis of banana ( Musa spp.), and provide a means to overcome the recalcitrance in embryogenesis, changes in histology, hydrogen peroxide (H 2 O 2 ) content and antioxidant enzyme activities during banana somatic embryogenesis were investigated. From embryogenic cells (ECs) to early globular embryos, nearly all cells showed typical meristematic characteristics with a high nucleus/cytoplasm ratio. Cells started to lose their meristematic characteristic during later globular stage. Starch granules in cells showed spatial and temporal changes during somatic embryogenesis. POD (E.C.1.11.1.7) activity decreased significantly after transfer of ECs to the embryo regeneration medium which was followed by a significant increase and peaked at the late stages of embryogenesis. CAT (E.C.1.11.1.6) activity showed similar pattern, however its highest activity appeared in the ECs instead of the later embryos. On the contrary, a gradual increase in SOD (E.C.1.15.1.1) activity was observed after inoculation of ECs on embryo regeneration medium until the globular stage. Similarly to SOD activity, the hydrogen peroxide (H 2 O 2 ) content also increased after inoculation of ECs on embryo regeneration medium and it peaked in proembryos, followed by a significant decrease in later embryogenic stages. The H 2 O 2 content as well as activities of all tested antioxidant enzymes were significantly higher in ECs than in non-embryogenic cells. These results suggested that high levels of antioxidant enzyme activity and high H 2 O 2 content were necessary for embryogenic competence of ECs while high H 2 O 2 content played an important role in early development of somatic embryogenesis of banana.

Apparent volumes VΦ of glycylglycine in aqueous NaX (X = F−, Cl−, and Br−) solutions have been obtained from densities of their solutions at 298.15 K and 308.15 K measured by using a precise vibrating-tube digital densimeter. These values have been utilized in conjunction with the values in water to deduce partial molar volumes of transfer Δ trs V Φ ∘ from water to different aqueous NaX solutions. Δ trs V Φ ∘ values are positive. The interpretation is that these results arise from the dominant interaction of the NaX with the charged centers of glycylglycine. The results show that Δ trs V Φ ∘ depend less on the temperature. Hydration numbers and interaction coefficients have been calculated from V Φ ∘ and Δ trs V Φ ∘ values and the values have been interpreted in terms of various interactions.

Densities of binary mixtures of 2-chloroethanol with N , N -dimethylformamide (DMF) and water have been measured over the full range of compositions at various temperatures. From these results, excess molar volumes, V E and excess partial molar volumes at infinite dilution, V¯ i E,0 have been calculated. V E for (DMF + 2-chloroethanol) mixture are positive over the whole mole fraction range and negative values are obtained for (water + 2-chloroethanol) mixture.

Apparent molar volumes V Φ of glycylglycine in aqueous KCl solutions have been obtained from densities at 298.15 and 308.15 K measured with a vibrating-tube densimeter. These data have been used to deduce partial molar volumes of transfer Δ trs V Φ 0 from water to different KCl–water mixtures. Δ trs V Φ 0 values are positive. This result arises from the interaction of KCl with the charged centers of glycylglycine. The results show that Δ trs V Φ 0 depends less on temperature. Hydration numbers are calculated from V Φ 0 data and Δ trs V Φ 0 are interpreted in terms of various interactions.

Enthalpies of solution of glycine, l -alanine, l -serine in water and aqueous solutions of formamide were measured at 298.15 K. Transfer enthalpies of amino acids from water to aqueous solutions of formamide were derived and interpreted qualitatively with hydration co-sphere overlap model. The results show that the structure interaction between formamide and zwitterionic head-group and hydrophilic side chain of amino acids make a negative contribution to transfer enthalpy, while that with the hydrophobic side chain is positive. In the solvent composition range studied, transfer enthalpies decrease overall with the increasing concentration of formamide, with the relative order of l -serine l -alanine.