Technical feasibility and tissue reaction after silicone-covered biodegradable magnesium stent insertion in the oesophagus: a primary study in vitro and in vivo.

OBJECTIVES: Determine the feasibility of and tissue response to biodegradable magnesium-silicone stent insertion into the oesophagus of rabbits. METHODS: Mechanical compression-recovery and degradation behaviours of the stents were investigated in vitro. Thirty rabbits were randomly divided into a magnesium-silicone stent group (n = 15) that received stent insertion into the lower 1/3 of the oesophagus under fluoroscopic guidance and a control group (n = 15). Oesophagography was performed at 1, 2 and 4 weeks. Five rabbits in each group were euthanized at each time point for histological examination. RESULTS: Magnesium-silicone stents showed good flexibility and elasticity, and degraded more slowly than bare stents at pH 4.0 and 7.4. All stent insertions were well tolerated. The oesophageal diameters at 1, 2 and 4 weeks were 9.7 ± 0.7, 9.6 ± 0.8 and 9.6 ± 0.5 mm, respectively (vs. 9.2 ± 0.8 mm before intervention; P > 0.05). Stent migration occurred in six rabbits (one at 1 week, one at 2 and four at 4). Microscopy demonstrated dilation of the oesophageal wall within 1 week of insertion. Oesophageal injury and collagen deposition following stent insertion were similar to control (P > 0.05). CONCLUSIONS: Oesophageal magnesium-silicone stent insertion was feasible and provided reliable support for 2 weeks without causing oesophageal injury or collagen deposition. KEY POINTS: • Mg stent provided apparently adequate radial force and silicone membrane reduced magnesium biodegradation • Stent insertion provided good support for at least 2 weeks before biodegradation • Stenting effectively resulted in oesophageal wall remodelling, without demonstrable injury.

Quantitative Analysis of Porous Silicon Nanoparticles Functionalization by 1H NMR.

Porous silicon (PSi) nanoparticles have been applied in various fields, such as catalysis, imaging, and biomedical applications, because of their large specific surface area, easily modifiable surface chemistry, biocompatibility, and biodegradability. For biomedical applications, it is important to precisely control the surface modification of PSi-based materials and quantify the functionalization density, which determines the nanoparticle's behavior in the biological system. Therefore, we propose here an optimized solution to quantify the functionalization groups on PSi, based on the nuclear magnetic resonance (NMR) method by combining the hydrolysis with standard 1H NMR experiments. We optimized the hydrolysis conditions to degrade the PSi, providing mobility to the molecules for NMR detection. The NMR parameters were also optimized by relaxation delay and the number of scans to provide reliable NMR spectra. With an internal standard, we quantitatively analyzed the surficial amine groups and their sequential modification of polyethylene glycol. Our investigation provides a reliable, fast, and straightforward method in quantitative analysis of the surficial modification characterization of PSi requiring a small amount of sample.

A pH-Responsive Cluster Metal-Organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect.

As a result of the deficient tumor-specific antigens, potential off-target effect, and influence of protein corona, metal-organic framework nanoparticles have inadequate accumulation in tumor tissues, limiting their therapeutic effects. In this work, a pH-responsive linker (L) is prepared by covalently modifying oleylamine (OA) with 3-(bromomethyl)-4-methyl-2,5-furandione (MMfu) and poly(ethylene glycol) (PEG). Then, the L is embedded into a solid lipid nanoshell to coat apilimod (Ap)-loaded zeolitic imidazolate framework (Ap-ZIF) to form Ap-ZIF@SLN#L. Under the tumor microenvironment, the hydrophilic PEG and MMfu are removed, exposing the hydrophobic OA on Ap-ZIF@SLN#L, increasing their uptake in cancer cells and accumulation in the tumor. The ZIF@SLN#L nanoparticle induces reactive oxygen species (ROS). Ap released from Ap-ZIF@SLN#L significantly promotes intracellular ROS and lactate dehydrogenase generation. Ap-ZIF@SLN#L inhibits tumor growth, increases the survival rate in mice, activates the tumor microenvironment, and improves the infiltration of macrophages and T cells in the tumor, as demonstrated in two different tumor-bearing mice after injections with Ap-ZIF@SLN#TL. Furthermore, mice show normal tissue structure of the main organs and the normal serum level in alanine aminotransferase and aspartate aminotransferase after treatment with the nanoparticles. Overall, this pH-responsive targeting strategy improves nanoparticle accumulation in tumors with enhanced therapeutic effects.

Development of vaccine formulations: past, present, and future.

The current situation, heavily influenced by the ongoing pandemic, puts vaccines back into the spotlight. However, the conventional and traditional vaccines present disadvantages, particularly related to immunogenicity, stability, and storage of the final product. Often, such products require the maintenance of a "cold chain," impacting the costs, the availability, and the distribution of vaccines. Here, after a recall of the mode of action of vaccines and the types of vaccines currently available, we analyze the past, present, and future of vaccine formulation. The past focuses on conventional formulations, the present discusses the use of nanoparticles for vaccine delivery and as adjuvants, while the future presents microneedle patches as alternative formulation and administration route. Finally, we compare the advantages and disadvantages of injectable solutions, nanovaccines, and microneedles in terms of efficacy, stability, and patient-friendly design. Different approaches to vaccine formulation development, the conventional vaccine formulations from the past, the current development of lipid nanoparticles as vaccines, and the near future microneedles formulations are discussed in this review.

Advanced liposome-loaded scaffolds for therapeutic and tissue engineering applications.

Liposome is one of the most commonly used drug delivery systems in the world, due to its excellent biocompatibility, satisfactory ability in controlling drug release, and passive targeting capability. However, some drawbacks limit the application of liposomes in clinical, such as problems in transporting, storing, and difficulties in maintaining the drug concentration in the local area. Scaffolds usually are used as implants to supply certain mechanical supporting to the defective area or utilized as diagnosis and imaging methods. But, in general, unmodified scaffolds show limited abilities in promoting tissue regeneration and treating diseases. Therefore, liposome-scaffold composite systems are designed to take advantages of both liposomes' biocompatibility and scaffolds' strength to provide a novel system that is more suitable for clinical applications. This review introduces and discusses different types of liposomes and scaffolds, and also the application of liposome-scaffold composite systems in different diseases, such as cancer, diabetes, skin-related diseases, infection and human immunodeficiency virus, and in tissue regeneration like bone, teeth, spinal cord and wound healing.

Adhesive nanoparticles with inflammation regulation for promoting skin flap regeneration.

Local drug delivery systems have become an important field of research as locally administration of medications may overcome most of the drawbacks associated with systemic drugs. Still, to assure continuous drug release and therapeutic drug levels, keeping the delivered drug in target area remains a physiological challenge. The aim of this study was to develop novel multipotent flap-protective adhesive mangiferin (MF)-loaded liposomes (A-MF-Lip), bioinspired in mussel architecture, for the promotion of random skin flap regeneration. The long chain 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethyleneglycol)-dopamine (DSPE-PEG-DOPA) was successful combined in liposomes, being dopamine (DOPA) with terminated catechol attached at the end of chain to explore the potential ability in adherence. A-MF-Lip presented a mean particle size of 162 nm, and MF cumulative release reaching 82% up to 72 h. A-MF-Lip adhesive ability was significantly higher compared to non-adhesive mangiferin-loaded liposome (MF-Lip). Moreover, a positive effect of A-MF-Lip on cells proliferation, angiogenesis was observed. And by regulating the PPAR-γ/NF-κB pathway, the A-MF-Lip established a protection effect on hypoxia induced cell apoptosis and inflammation. After locally injection delivery in a Sprague Dawley rat random skin flap model, A-MF-Lip significantly decreased flap necrosis rate and reduced flap inflammation. Therefore, A-MF-Lip is a promising multipotent flap-protective approach for random skin flap regeneration.

Osteogenic and antiseptic nanocoating by in situ chitosan regulated electrochemical deposition for promoting osseointegration.

Ti and titanium alloy have been extensively utilized in the areas of orthopedics and other related fields, however, limited abilities in antibiosis, ossification and vascularization restrict the application of these materials in clinical. In this research, pulse electrochemical deposition was used as a method to make chitosan regulate Ag+ and Ca2+ in situ, achieving ions' dual regulations and coprecipitation of HA nanoparticles (HA-NPs) and Ag nanoparticles (Ag-NPs) on the surface of Ti. The spherical nanoparticles with even distribution were fabricated by optimizing deposition potential and the concentration of Ag+. The physical stabilities of coatings were significantly improved by the chelation among CS, Ag+ and Ca2+ reducing the release rate of Ag+, Ca2+. The coatings also exhibited noticeable abilities in anti-bacteria. Bone marrow mesenchymal stem cells (BMSCs) displayed adhesion, proliferation and differentiation abilities on the surface of coatings, at the same time the composite coatings revealed promising capability in inducing BMSCs differentiation to osteoblast, which is proved by the results of fluorescent dye. Similar results also can be found in investigations about vascular endothelial cells, desirable adhesion between cells and materials and proliferation are able to prove that this kind of materials has outstanding biocompatibility with VECs cells. The animal experiments indicated that the composite coatings were biocompatible with smooth muscle, myocardium and lung with slightly negative impacts on liver and kidney. According to the results of alizarin red staining, the calcified nodules were dyed red, which reveal that this material can promote bone formation. Electrochemical method was utilized in this research to successfully construct multifunctional composite coatings, such as antibiosis, osteogenesis and angiogenesis, on the surface of Ti.

Vascularized 3D printed scaffolds for promoting bone regeneration.

3D printed scaffolds hold promising perspective for bone tissue regeneration. Inspired by process of bone development stage, 3D printed scaffolds with rapid internal vascularization ability and robust osteoinduction bioactivity will be an ideal bone substitute for clinical use. Here, we fabricated a 3D printed biodegradable scaffold that can control release deferoxamine, via surface aminolysis and layer-by-layer assembly technique, which is essential for angiogenesis and osteogenesis and match to bone development and reconstruction. Our in vitro studies show that the scaffold significantly accelerates the vascular pattern formation of human umbilical endothelial cells, boosts the mineralized matrix production, and the expression of osteogenesis-related genes during osteogenic differentiation of mesenchymal stem cells. In vivo results show that deferoxamine promotes the vascular ingrowth and enhances the bone regeneration at the defect site in a rat large bone defect model. Moreover, this 3D-printed scaffold has excellent biocompatibility that is suitable for mesenchymal stem cells grow and differentiate and possess the appropriate mechanical property that is similar to natural cancellous bone. In summary, this 3D-printed scaffold holds huge potential for clinical translation in the treatment of segmental bone defect, due to its flexibility, economical friendly and practicality.

Multifunctional HA/Cu nano-coatings on titanium using PPy coordination and doping via pulse electrochemical polymerization.

The incorporation of hydroxyapatite nanoparticles onto the surface of titanium is an effective method to improve its osteoinductive ability. However, there are still issues with the hydroxyapatite nanoparticle coatings fabricated using current methods, such as particle aggregation and unsatisfactory binding ability with the matrix, in addition to the difficulties in the multi-functionalization of antibacterial, anti-wear and bioinductive ability. In the present study, we propose a strategy to fabricate a refined hydroxyapatite nanoparticles/copper nanoparticles co-deposition titanium matrix by the mediation of pulse electrochemical polymerized pyrrole through its coordination and doping of cations and anions. During this process, PO43- in the electrolyte is doped into the corresponding anion structure in the polypyrrole chain and forms HA with Ca2+ and OH- because of electrostatic interaction. The bioactivity investigation indicates that the composite coatings are able to induce the formation of apatite in supersaturated calcium phosphate solution. Furthermore, the friction and wear tests show that the composite coatings improve the friction properties of the material to a certain extent. The composites also exhibit an antibacterial rate of 97% in the antibacterial test. Finally, in virtue of the dual regulation of polypyrrole by coordination and doping, we successfully fabricate multifunctional hydroxyapatite/copper nano-coatings on titanium surfaces.

Local release of gemcitabine via in situ UV-crosslinked lipid-strengthened hydrogel for inhibiting osteosarcoma.

Osteosarcoma is among the most common malignant bone tumors in human skeletal system. The conventional treatment of osteosarcoma mainly consists of combining neoadjuvant chemotherapy with surgical approach. However, it is crucial to design an artificial implant that possesses excellent biomechanical properties and is capable of sustaining local release of chemotherapeutics. In this study, we envision that the highly efficient combination of gemcitabine (GEM) hydrochloride loaded liposomes with gelatin methacryloyl (GelMA) of in situ photocrosslinkable hydrogel will lead to a multifunctional implant with unique antitumor, mechanical, and biodegradable properties. A sustained controlled release was observed; more specifically, the release of GEM in vitro lasted for 4 days long. Furthermore, its capability in killing MG63 cells was further explored by using the lixivium of GEM-Lip@Gel and GEM-GelMA hydrogel in vitro (composite hydrogel by GEM loaded liposomes blending with GelMA, short for GEM-Lip@Gel), which agreed with the drug release outcome. In addition, these hydrogel showed excellent ability in inhibiting osteosarcoma in vivo by Balb/c mice bearing MG63 cells. Therefore, GEM-loaded lipo-hydrogel certainly has presented itself as a promising strategy for the development of implant in the field of osteosarcoma treatment.

Flexible bipolar nanofibrous membranes for improving gradient microstructure in tendon-to-bone healing.

Enthesis is a specialized tissue interface between the tendon and bone. Enthesis structure is very complex because of gradient changes in its composition and structure. There is currently no strategy to create a suitable environment and to regenerate the gradual-changing enthesis because of the modular complexities between two tissue types. Herein, a dual-layer organic/inorganic flexible bipolar fibrous membrane (BFM) was successfully fabricated by electrospinning to generate biomimetic non-mineralized fibrocartilage and mineralized fibrocartilage in tendon-to-bone integration of enthesis. The growth of the in situ apatite nanoparticle layer was induced on the nano hydroxyapatite-poly-l-lactic acid (nHA-PLLA) fibrous layer in simulated body solution, and the poly-l-lactic acid (PLLA) fibrous layer retained its original properties to induce tendon regeneration. The in vivo results showed that BFM significantly increased the area of glycosaminoglycan staining at the tendon-bone interface and improved collagen organization when compared to the simplex fibrous membrane (SFM) of PLLA. Implanting the bipolar membrane also induced bone formation and fibrillogenesis as assessed by micro-CT and histological analysis. Biomechanical testing showed that the BFM group had a greater ultimate load-to-failure and stiffness than the SFM group at 12weeks after surgery. Therefore, this flexible bipolar nanofibrous membrane improves the healing and regeneration process of the enthesis in rotator cuff repair. STATEMENT OF SIGNIFICANCE: In this study, we generated a biomimetic dual-layer organic/inorganic flexible bipolar fibrous membrane by sequential electrospinning and in situ biomineralization, producing integrated bipolar fibrous membranes of PLLA fibrous membrane as the upper layer and nHA-PLLA fibrous membrane as the lower layer to mimic non-mineralized fibrocartilage and mineralized fibrocartilage in tendon-to-bone integration of enthesis. Flexible bipolar nanofibrous membranes could be easily fabricated with gradient microstructure for enthesis regeneration in rotator cuff tears.

Inorganic Strengthened Hydrogel Membrane as Regenerative Periosteum.

Periosteum plays the pivotal role in neomineralization, vascularization and protection during bone tissue regeneration. However, many artificial periosteum focused only on protection and lacked of the osteogenesis and angiogenesis functional capacity. In this study, we developed a novelty inorganic strengthened gelatin hydrogel membrane via inorganic and organic co-cross-linked double network as artificial periosteum for enhancing the durable angiogenesis and osteogenesis in bone reconstruction. Mesoporous bioactive glass nanoparticles (MBGNs) chemically modified with photo-cross-linkable gelatin derivative (GelMA) were further incorporated into GelMA to fabricate an organic/inorganic co-cross-linked hydrogel membrane (GelMA-G-MBGNs). The GelMA-G-MBGNs hydrogel membrane displayed better mechanical property, durable degradation time, pH stable, biomineralization and long-term ion release. In vitro study demonstrated that, when compared with GelMA or GelMA/MBGNs, the GelMA-G-MBGN membrane significantly promoted osteogenic differentiation while maintaining stable local pH, which is conducive to cell adhesion and proliferation. Finally, the GelMA-G-MBGN membrane shows a superior artificial periosteum with superior capacity in angiogenesis and osteogenesis for accelerating new and mature lamellar bone formation in rat calvarial critical size defect. This co-cross-linked hydrogel membrane implied a promising strategy for the development of advanced periosteum biomaterials with excellent handle and bone repairing properties.

Advances in biomaterials for preventing tissue adhesion.

Adhesion is one of the most common postsurgical complications, occurring simultaneously as the damaged tissue heals. Accompanied by symptoms such as inflammation, pain and even dyskinesia in particular circumstances, tissue adhesion has substantially compromised the quality of life of patients. Instead of passive treatment, which involves high cost and prolonged hospital stay, active intervention to prevent the adhesion from happening has been accepted as the optimized strategy against this complication. Herein, this paper will cover not only the mechanism of adhesion forming, but also the biomaterials and medicines used in its prevention. Apart from acting as a direct barrier, biomaterials also show promising anti-adhesive bioactivity though their intrinsic physical and chemical are still not completely unveiled. Considering the diversity of human tissue organization, it is imperative that various biomaterials in combination with specific medicine could be tuned to fit the microenvironment of targeted tissues. With the illustration of different adhesion mechanism and solutions, we hope this review can become a beacon and further inspires the development of anti-adhesion biomedicines.

Reinforcement of transvaginal repair using polypropylene mesh functionalized with basic fibroblast growth factor.

Numerous modifications have been developed over the past two decades seeking to improve the transvaginal repair in the pelvic organ prolapse (POP) by using polypropylene (PP) mesh implants. The hydrophobicity of PP, however, presents a great hindrance for translating potential technologies into viable clinical applications. In this study, by manipulating self-polymerization and strong adhesive characteristics of dopamine, we developed a facile method to enhance the transvaginal repair by modifying PP meshes with polydopamine (PDA), which allowed easy grafting of basic fibroblast growth factor (bFGF) onto the surface of PP. Such surface modification of PP meshes with bFGF was found to efficiently promote bioactivity without changing the morphology or mechanical properties of the PP meshes. Additionally, bFGF-modified PP meshes significantly promoted cell viability and adhesion compared to the unmodified PP. Ultimately, after three months of implantation, the bFGF-modified PP meshes exhibited improved tissue repair with greater degree of organization of deposited collagen, increased tensile strength and reduced inflammatory response. Overall, the surface-modified PP meshes will be highly practical as templates for transvaginal repair in the POP treatment.