Most existing bioadhesives, even those showing superiority in wound closure effectiveness, do not assist in the post‐wound closure process. A bioinspired, in situ formed, double‐dynamic‐bond ...crosslinked hydrogel bioadhesive that is capable of efficiently closing open wounds and enabling post‐wound closure care is reported. Catechol‐modified ε‐poly‐l‐lysine and oxidized dextran are employed as natural polymer backbones and they are in situ crosslinked using Schiff's base dynamic bond and catecholFe coordinate dynamic bond through a process inspired by that used to cure marine mussel glue, forming a hydrogel bioadhesive. The unique double‐dynamic‐bond crosslinked structure endows the bioadhesive with higher mechanical and adhesive strength while retaining quick dissociation and good self‐healing capacities. Accordingly, the bioadhesive can exhibit multiple desirable functions, such as dissolution on demand, repeatable adhesiveness, adhesive and mechanical strength sufficient for wound closure, injectability, and good biocompatibility (DREAMING). After efficiently closing skin incisions, the bioadhesive can be facilely removed or repeatedly close the reopened wounds, thus enabling post‐wound closure care. On the basis of favorable functions in wound closure and the ability to enable post‐wound closure care, the bioadhesive demonstrates great potential in dealing with skin wounds.
A double‐dynamic‐bond crosslinked bioadhesive with DREAMING functions such as dissolution on demand, repeatable adhesiveness, adhesive and mechanical strength sufficient for wound closure, injectability, and good biocompatibility is presented. The adhesive, synthesized by mimicking the adhesion and curing process of marine mussel glue, is designed for efficient wound closure and post‐wound closure care.
Bone‐implant‐associated infections are common after orthopedic surgery due to impaired host immune response around the implants. In particular, when a biofilm develops, the immune system and ...antibiotic treatment find it difficult to eradicate, which sometimes requires a second operation to replace the infected implants. Most strategies have been designed to prevent biofilms from forming on the surface of bone implants, but these strategies cannot eliminate the biofilm when it has been established in vivo. To address this issue, a nonsurgical, noninvasive treatment for biofilm infection must be developed. Herein, a red‐phosphorus–IR780–arginine–glycine–aspartic‐acid–cysteine coating on titanium bone implants is prepared. The red phosphorus has great biocompatibility and exhibits efficient photothermal ability. The temperature sensitivity of Staphylococcus aureus biofilm is enhanced in the presence of singlet oxygen (1O2) produced by IR780. Without damaging the normal tissue, the biofilm can be eradicated through a safe near‐infrared (808 nm) photothermal therapy at 50 °C in vitro and in vivo. This approach reaches an antibacterial efficiency of 96.2% in vivo with 10 min of irradiation at 50 °C. Meanwhile, arginine–glycine–aspartic‐acid–cysteine decorated on the surface of the implant can improve the cell adhesion, proliferation, and osteogenic differentiation.
A red‐phosphorus–IR780–arginine–glycine–aspartic‐acid–cysteine film with photothermal and photodynamic properties is prepared on a bone implant. The susceptibility of bacteria to heat is enhanced in the presence of 1O2. This study presents a practicable and noninvasive strategy for rapid in situ biofilm eradication on bone implants in vivo under near‐infrared irradiation.
Interfacial characteristics play an important role in infection prevention and osteointegration of artificial bone implants. In this work, both Ag nanoparticles (AgNPs) and ZnO NPs are incorporated ...into hydroxyapatite (HA) nanopowders and deposited onto Ti6Al4V (Ti6) implants by laser cladding. The composite coatings possess a hierarchical surface structure with homogeneous distributions of Ag and ZnO. The Ag and ZnO NPs that are immobilized by laser cladding ensure long-term and gradual release of Ag and Zn ions at low cumulative concentrations of 36.2 and 56.4 μg/L after immersion for 21 days. A large concentration of Ag released initially increases the cytotoxicity but the large initial ZnO content enhances the cell viability and osteogenetic ability. The nano Ag/ZnO-embedded HA coating (Ag/ZnO/HA = 7:3:90 wt %, namely Ag7ZnO3HA) exhibits optimal antibacterial efficacy and osteogenetic capability, as exemplified by the broad spectrum antibacterial efficacy of 96.5 and 85.8% against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), respectively, together with enhanced osteoinductivity with higher alkaline phosphatase (ALP) activity of 134.60 U/g protein compared to 70.79 U/g protein for the untreated implants after culturing for 7 days. The rabbit femoral implant model further confirms that the optimized composite coating accelerates the formation of new bone tissues indicating 87.15% of the newly formed bone area and osteointegration showing 83.75% of the bone–implant contact area even in the presence of injected S. aureus. The laser-cladded Ag7ZnO3HA composite coatings are promising metallic implants with excellent intrinsic antibacterial activity and osteointegration ability.
In situ hydrogel has attracted widely attention in hemostasis due to its ability to match irregular defects, but its application is limited by insufficient mechanical strength and long gelation time. ...Although some specifical in situ chemically cross-linked hydrogels could be fast formed and exhibit high mechanical strength, they unable to absorb blood. Hence their applications were further limited in emergency hemostasis usage. In this study, a robust hydrogel formed by hydration of powders was developed using multiple hydrogen bonds crosslinking. Here, catechol groups modified ε-polylysine (PL-CAT) and polyacrylamide (PAAM) were used to construct the PL-CAT/PAAM hydrogel. This hydrogel could be formed within 7 s to adhere and seal bleeding sites. The catechol groups endowed the hydrogel outstanding adhesive strength, which was 3.5 times of fibrin glue. Besides, the mechanical performance of in-situ PL-CAT/PAAM hydrogel was explored and the results showed that the hydrogel exhibited high compressive strength (0.47 MPa at 85% strain). Most importantly, the blood loss of wound treated with PL-CAT/PAAM hydrogel powders was 1/7 of untreated group, indicating the hydrogel's excellent hemostatic effect. And the cytotoxicity studies indicated that the PL-CAT/PAAM hydrogel had low toxicity. To summarize, this hydrogel could be a potential hemostatic material in emergency situations.
The hydrogel was reformed by rehydration of powders within 7 s. Firstly, the water/blood was absorbed by the hydrogel powders, then the powders swelled and the hydrogel was reformed by hydrogen bonds recombination. The mechanical strength was improved by multiple hydrogen bond interactions and the adhesion strength was 3.5 times of that of fibrin glue due to the introduction of catechol group. Besides, the hemostasis effect was better than other reported hemostatic agents. The blood loss of wound treated with hydrogel powder was 1/7 of that of untreated group. Display omitted
•In situ forming PL-CAT/PAAM hydrogel was formed by hydrogen bonds combination with in 7 s.•The hydrogel exhibited high mechanical and adhesion properties.•PL-CAT/PAAM hydrogel powders had effective hemostatic ability.
Abstract The combined treatment of chemotherapeutant and microRNA (miR) has been proven to be a viable strategy for enhancing chemosensitivity due to its synergistic effect for tumor therapy. ...However, the co-delivery of drugs and genes remains a major challenge as they lack efficient co-delivery carriers. In this study, three amphiphilic star-branched copolymers comprising polylactic acid (PLA) and polydimethylaminoethyl methacrylate (PDMAEMA) with AB3 , (AB3 )2 ,and (AB3 )3 molecular architectures were synthesized respectively by a combination of ring-opening polymerization, atom transfer radical polymerization, and click chemistry via an “arm-first” approach. The star copolymers possessed a low critical micelle concentration (CMC) and formed nano-sized micelles with positive surface charges in water as well as exhibiting a much lower cytotoxicity than PEI 25 kDa. Nevertheless, their gene transfection efficiency and tumor inhibition ability showed a remarkable dependence on their molecular architecture. The (AB3 )3 architecture micelle copolymer exhibited the highest transfection efficiency, about 2.5 times higher than PEI. In addition, after co-delivering DOX and miR-21 inhibitor (miR-21i) into LN229 glioma cells, the micelles could mediate escaping miR-21i from lysosome degradation and the release of DOX to the nucleus, which significantly decreased the miR-21 expression. Moreover, co-delivery of DOX and miR-21i surprisingly exhibited an anti-proliferative efficiency compared with DOX or the miR-21i treatment alone. These results demonstrated that amphiphilic star-branched copolymers are highly promising for their combinatorial delivery of genes and hydrophobic therapeutants.
Bacterial infection and associated complications are threats to human health especially when biofilms form on biomedical devices and artificial implants. Herein, a hybrid polydopamine ...(PDA)/Ag3PO4/graphene oxide (GO) coating is designed and constructed to achieve rapid bacteria killing and eliminate biofilms in situ. By varying the amount of GO in the hybrid coating, the bandgap can be tuned from 2.52 to 2.0 eV so that irradiation with 660 nm visible light produces bacteria-killing effects synergistically in concert with reactive oxygen species (ROS). GO regulates the release rate of Ag+ to minimize the cytotoxicity while maintaining high antimicrobial activity, and a smaller particle size enhances the yield of ROS. After irradiation with 660 nm visible light for 15 min, the antimicrobial rates of the PDA/Ag3PO4/GO hybrid coating against Escherichia coli and Staphylococcus aureus are 99.53% and 99.66%, respectively. In addition, this hybrid coating can maintain a repeatable and sustained antibacterial efficacy. The released Ag+ and photocatalytic Ag3PO4 produce synergistic antimicrobial effects in which the ROS increases the permeability of the bacterial membranes to increase the probability of Ag+ to enter the cells to kill them together with ROS synergistically.
Monoclonal antibodies have been used in many diseases, but how to improve their delivery efficiency is still a key issue. As the modification of zwitterionic polymers can maintain the stability and ...biological activity of monoclonal antibodies, in this study, zwitterionic monomers, sulfobetaine methacrylate (SBMA), and 3-2-(methacryloyloxy) ethyl dimethylammonio propionate (CBMA) were used to prepare monoclonal antibody-loaded zwitterionic nanoparticles with the aid of the crosslinker of MMP-2 enzyme-responsive peptide which was a rapid synthesis process under mild conditions. The results from dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM) indicated that a series of zwitterionic nanoparticles had been successfully prepared by the
in situ
free radical polymerization using the MMP-2 enzyme-responsive peptide as the cross-linking agent. These nanoparticles were spherical with the sizes of (18.7±1.9) nm (SBMA nanoparticle) and (18.2±2.1) nm (CBMA nanoparticle), and the surface contained zwitterionic polymers. It was revealed that they had no cytotoxicity, could be released in tumor microenvironment by enzyme to inhibit the growth of tumor cells, and was able to effectively penetrate endothelial cells (> 2%) by transwell. Therefore, the development of this strategy has a great prospect for the delivery of monoclonal antibodies.
The healing of osteoporotic fractures in the elderly patients is a difficult clinical problem. Currently, based on the internal fixation of fractures, the available drug treatments mainly focus on ...either inhibiting osteoclast function, such as bisphosphonate, calcitonin, oestrogen or promoting osteogenesis, such as parathyroid hormones. However, the availability of current antiosteoporotic drugs in promoting osteoporotic fracture healing is limited. The objective of the present study was to investigate the ability of the MiR-21/nanocapsule to enhance the early bone repair of osteoporotic fractures.
Based on the presence of matrix metalloproteinases that are overexpressed at the fracture site, we designed the matrix metalloproteinase–sensitive nanocapsules which were formed by in situ free radical polymerisation on the surface of MiR-21 with 2-(methacryloyloxy) ethyl phosphorylcholine and the bisacryloylated VPLGVRTK peptide. The MiR-21/nanocapsule n (miR-21) and O-carboxymethyl chitosan (CMCS) were mixed until they formed a gel-like material CMCS/n (miR-21) with good fluidity and injectability. Thirty elderly Sprague Dawley (SD) rats (female, 14-month-old, 380 ± 10 g) were subjected to bilateral removal of the ovaries (ovariectomised). All rats were subjected to bilateral bone defects (2 mm diameter) of the proximal tibia and randomly divided into three groups (groups A, B, and C): separately injected with CMCS/n (miR-21), CMCS/n (NC-miR), and saline. Micro-computed tomography (CT) imaging was performed to evaluate newly formed bone volume and connectivity. Nondecalcified histology and toluidine blue staining were performed to measure the effects of CMCS/n (miR-21) on bone repair. In vitro, the effect of n (miR-21) on osteogenic differentiation to bone marrow mesenchymal stem cells (BMSCs) which derived from the ovariectomised rat model was observed.
The morphology of n (miR-21) was a regular spherical nanocapsule with a uniform small size (25–35 nm). The results confirmed that n (miR-21) could be efficiently phagocytosed by BMSCs and released in the cytoplasm to promote osteogenesis. The expression level of alkaline phosphatase and Runt-related transcription factor 2 mRNA in the n (miR-21) group was higher than that in the n (NC-miR) group. Animal experiments proved that CMCS/n (miR-21) produced better bone repair compared with the CMCS/n (NC-miR) group in the early stages of fracture healing at 4 weeks. In the late stage of fracture healing (8 weeks), micro-CT quantitative analysis showed that the new bone trabeculae in the CMCS/n (miR-21) group has decreased compared with the CMCS/n (NC-miR) group. In the CMCS/n (miR-21) group, the new cancellous bone had been absorbed, and the process of bone healing was almost completed. In contrast, the new bone in the CMCS/n (NC-miR) and the control groups was still in the healing process.
The cytological tests confirmed that n (miR-21) can promote osteogenic differentiation of BMSCs derived from the osteoporosis rat model. Furthermore, the results of animal tests demonstrated that local injection of CMCS/n (miR-21) promoted the early healing of osteoporotic bone defects. Consequently CMCS/n (miR-21) promoted the bone repair process to enter the moulding phase earlier.
CMCS/n (miR-21) can be widely applied to elderly patients with osteoporotic fractures. This method can help patients with osteoporotic fractures recover earlier and avoid serious complications. It provides a potential approach for the clinical treatment of osteoporotic fractures in the elderly.
Blood transferrin receptor-positive (TfR+) exosomes are a kind of optimized drug delivery vector compared with other kinds of exosomes due to their easy access and high bio-safety. Their application ...facilitates the translation from bench to bedside of exosome-based delivery vehicles.
In this study, a pH-responsive superparamagnetic nanoparticles cluster (denoted as SMNC)-based method was developed for the precise and mild separation of blood TfR+ exosomes. Briefly, multiple superparamagnetic nanoparticles (SPMNs) labeled with transferrins (Tfs) could precisely bind to blood TfR+ exosomes to form an exosome-based cluster due to the specific recognition of TfR by Tf. They could realize the precise magnetic separation of blood TfR+ exosomes. More importantly, the pH-responsive dissociation characteristic of Tf and TfR led to the mild collapse of clusters to obtain pure blood TfR+ exosomes.
Blood TfR+ exosomes with high purity and in their original state were successfully obtained through the pH-responsive SMNC-based method. These can load Doxorubicin (DOX) with a loading capacity of ~10% and dramatically increase the tumor accumulation of DOX in tumor-bearing mice because of their innate passive-targeting ability. In addition, blood TfR+ exosomes changed the biodistribution of DOX leading to the reduction of side effects. Compared with free DOX, DOX-loaded blood TfR+ exosomes showed much better tumor inhibition effects on tumor-bearing mice.
Taking advantage of the pH-responsive binding and disaggregation characteristics of Tf and TfR, the SMNC-based method can precisely separate blood TfR+ exosomes with high purity and in their original state. The resulting blood TfR+ exosomes showed excellent bio-safety and enable the efficient delivery of chemotherapeutics to tumors, facilitating the clinical translation of exosome-based drug delivery systems.
•Dopamine-modified hyaluronic acid (DHA) was synthesized.•DHA possessed strong adhesion and negative charge.•DHA/chitosan (CHI) multilayers were created on Ti–24Nb–2Zr (TNZ) alloys.•DHA/CHI ...multilayers fabricated through layer-by-layer assembly.•DHA/CHI multilayers enhanced the osteoblast proliferation on TNZ alloys.
The bare inert surface of titanium (Ti) alloy typically causes early failures in implants. Layer-by-layer self-assembly is one of the simple methods for fabricating bioactive multilayer coatings on titanium implants. In this study, a dopamine-modified hyaluronic acid/chitosan (DHA/CHI) bioactive multilayer was built on the surface of Ti–24Nb–2Zr (TNZ) alloy. Zeta potential oscillated between −2 and 17mV for DHA- and CHI-ending layers during the assembly process, respectively. The DHA/CHI multilayer considerably decreased the contact angle and dramatically improved the wettability of TNZ alloy. Atomic force microscopy results revealed a rough surface on the original TNZ alloy, while the surface became smoother and more homogeneous after the deposition of approximately 5 bilayers (TNZ/(DHA/CHI)5). X-ray photoelectron spectroscopy analysis indicated that the TNZ/(DHA/CHI)5 sample was completely covered by polyelectrolytes. Pre-osteoblast MC3T3-E1 cells were cultured on the original TNZ alloy and TNZ/(DHA/CHI)5 to evaluate the effects of DHA/CHI multilayer on osteoblast proliferation in vitro. The proliferation of osteoblasts on TNZ/(DHA/CHI)5 was significantly higher than that on the original TNZ alloy. The results of this study indicate that the proposed technique improves the biocompatibility of TNZ alloy and can serve as a potential modification method in orthopedic applications.
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