Dynamic hydrogel-metal-organic framework system promotes bone regeneration in periodontitis through controlled drug delivery.

Periodontitis is a prevalent chronic inflammatory disease, which leads to gradual degradation of alveolar bone. The challenges persist in achieving effective alveolar bone repair due to the unique bacterial microenvironment's impact on immune responses. This study explores a novel approach utilizing Metal-Organic Frameworks (MOFs) (comprising magnesium and gallic acid) for promoting bone regeneration in periodontitis, which focuses on the physiological roles of magnesium ions in bone repair and gallic acid's antioxidant and immunomodulatory properties. However, the dynamic oral environment and irregular periodontal pockets pose challenges for sustained drug delivery. A smart responsive hydrogel system, integrating Carboxymethyl Chitosan (CMCS), Dextran (DEX) and 4-formylphenylboronic acid (4-FPBA) was designed to address this problem. The injectable self-healing hydrogel forms a dual-crosslinked network, incorporating the MOF and rendering its on-demand release sensitive to reactive oxygen species (ROS) levels and pH levels of periodontitis. We seek to analyze the hydrogel's synergistic effects with MOFs in antibacterial functions, immunomodulation and promotion of bone regeneration in periodontitis. In vivo and in vitro experiment validated the system's efficacy in inhibiting inflammation-related genes and proteins expression to foster periodontal bone regeneration. This dynamic hydrogel system with MOFs, shows promise as a potential therapeutic avenue for addressing the challenges in bone regeneration in periodontitis.

pH-responsive cinnamaldehyde-TiO2 nanotube coating: fabrication and functions in a simulated diabetes condition.

Current evidence has suggested that diabetes increases the risk of implanting failure, and therefore, appropriate surface modification of dental implants in patients with diabetes is crucial. TiO2 nanotube (TNT) has an osteogenic nanotopography, and its osteogenic properties can be further improved by loading appropriate drugs. Cinnamaldehyde (CIN) has been proven to have osteogenic, anti-inflammatory, and anti-bacterial effects. We fabricated a pH-responsive cinnamaldehyde-TiO2 nanotube coating (TNT-CIN) and hypothesized that this coating will exert osteogenic, anti-inflammatory, and anti-bacterial functions in a simulated diabetes condition. TNT-CIN was constructed by anodic oxidation, hydroxylation, silylation, and Schiff base reaction to bind CIN, and its surface characteristics were determined. Conditions of diabetes and diabetes with a concurrent infection were simulated using 22-mM glucose without and with 1-µg/mL lipopolysaccharide, respectively. The viability and osteogenic differentiation of bone marrow mesenchymal stem cells, polarization and secretion of macrophages, and resistance to Porphyromonas gingivalis and Streptococcus mutans were evaluated. CIN was bound to the TNT surface successfully and released better in low pH condition. TNT-CIN showed better osteogenic and anti-inflammatory effects and superior bacterial resistance than TNT in a simulated diabetes condition. These findings indicated that TNT-CIN is a promising, multifunctional surface coating for patients with diabetes needing dental implants. Graphical abstract.

Nanoparticles of deoxycholic acid, polyethylene glycol and folic acid-modified chitosan for targeted delivery of doxorubicin.

Chitosan (CS) was first modified hydrophobically with deoxycholic acid (DCA) and then with polyethylene glycol (PEG) to obtain a novel amphiphilic polymer (CS-DCA-PEG). This was covalently bound to folic acid (FA) to develop nanoparticles (CS-DCA-PEG-FA) with tumor cell targeting property. The structure of the conjugates was characterised using Fourier transform infrared and (1)H nuclear magnetic resonance spectroscopy and X-ray diffraction. Based on self-aggregation, the conjugates formed nanoparticles with a low critical aggregation concentration of 0.035 mg/ml. The anti-cancer drug doxorubicin (DOX) was encapsulated into the nanoparticles with a drug-loading capacity of 30.2 wt%. The mean diameter of the DOX-loaded nanoparticles was about 200 nm, with a narrow size distribution. Transmission electron microscopy images showed that the DOX-loaded nanoparticles were spherical. The drug release was studied under different conditions. Furthermore, the cytotoxic activities of DOX in CS-DCA-PEG-FA nanoparticles against folate receptor (FR)-positive HeLa cells and FR-negative fibroblast 3T3 cells were evaluated. These results suggested that the CS-DCA-PEG-FA nanoparticles may be a promising vehicle for the targeting anticancer drug to tumor cells.

In Situ Rapid-Formation Sprayable Hydrogels for Challenging Tissue Injury Management.

Rapid-acting, convenient, and broadly applicable medical materials are in high demand for the treatment of extensive and intricate tissue injuries in extremely medical scarcity environment, such as battlefields, wilderness, and traffic accidents. Conventional biomaterials fail to meet all the high criteria simultaneously for emergency management. Here, a multifunctional hydrogel system capable of rapid gelation and in situ spraying, addressing clinical challenges related to hemostasis, barrier establishment, support, and subsequent therapeutic treatment of irregular, complex, and urgent injured tissues, is designed. This hydrogel can be fast formed in less than 0.5 s under ultraviolet initiation. The precursor maintains an impressively low viscosity of 0.018 Pa s, while the hydrogel demonstrates a storage modulus of 0.65 MPa, achieving the delicate balance between sprayable fluidity and the mechanical strength requirements in practice, allowing flexible customization of the hydrogel system for differentiated handling and treatment of various tissues. Notably, the interactions between the component of this hydrogel and the cell surface protein confer upon its inherently bioactive functionalities such as osteogenesis, anti-inflammation, and angiogenesis. This research endeavors to provide new insights and designs into emergency management and complex tissue injuries treatment.

Biomineralization-Inspired Anti-Caries Strategy Based on Multifunctional Nanogels as Mineral Feedstock Carriers.

Background: Dentin caries remains a significant public concern, with no clinically viable material that effectively combines remineralization and antimicrobial properties. To address this issue, this study focused on the development of a bio-inspired multifunctional nanogel with both antibacterial and biomineralization properties. Methods: First, p(NIPAm-co-DMC) (PNPDC) copolymers were synthesized from N-isopropylacrylamide (NIPAm) and 2-methacryloyloxyethyl-trimethyl ammonium chloride (DMC). Subsequently, PNPDC was combined with γ-polyglutamic acid (γ-PGA) through physical cross-linking to form nanogels. These nanogels served as templates for the mineralization of calcium phosphate (Cap), resulting in Cap-loaded PNPDC/PGA nanogels. The nanogels were characterized using various techniques, including TEM, particle tracking analysis, XRD, and FTIR. The release properties of ions were also assessed. In addition, the antibacterial properties of the Cap-loaded PNPDC/PGA nanogels were evaluated using the broth microdilution method and a biofilm formation assay. The remineralization effects were examined on both demineralized dentin and type I collagen in vitro. Results: PNPDC/PGA nanogels were successfully synthesized and loaded with Cap. The diameter of the Cap-loaded PNPDC/PGA nanogels was measured as 196.5 nm at 25°C and 162.3 nm at 37°C. These Cap-loaded nanogels released Ca2+ and PO43- ions quickly, effectively blocking dental tubules with a depth of 10 µm and promoting the remineralization of demineralized dentin within 7 days. Additionally, they facilitated the heavy intrafibrillar mineralization of type I collagen within 3 days. Moreover, the Cap-loaded nanogels exhibited MIC50 and MIC90 values of 12.5 and 50 mg/mL against Streptococcus mutans, respectively, with an MBC value of 100 mg/mL. At a concentration of 50 mg/mL, the Cap-loaded nanogels also demonstrated potent inhibitory effects on biofilm formation by Streptococcus mutans while maintaining good biocompatibility. Conclusion: Cap-loaded PNPDC/PGA nanogels are a multifunctional biomimetic system with antibacterial and dentin remineralization effects. This strategy of using antibacterial nanogels as mineral feedstock carriers offered fresh insight into the clinical management of caries.

Development of an Antiswelling Hydrogel System Incorporating M2-Exosomes and Photothermal Effect for Diabetic Wound Healing.

Diabetic wounds represent a persistent global health challenge with a substantial impact on patients' health and overall well-being. Herein, a hydrogel system that integrates functionalized gold nanorods (AuNRs) and M2 macrophage-derived exosomes (M2-Exos) was developed to achieve an efficient and synergistic therapy for diabetic wounds. We introduced an ion-cross-linked dissipative network into a prefabricated covalent cross-linked network (long-chain polymer network), which was prepared using AuNRs as a specific cross-linker. The ion network was then cross-linked with the long-chain polymer in situ to form a specific network structure, imparting antiswelling and photothermal effects to the hydrogel. This integrated hydrogel system effectively scavenged reactive oxygen species levels, inhibited inflammation, promoted angiogenesis, and stimulated photothermal antibacterial activity through near-infrared (NIR) irradiation. To demonstrate the potential of the hydrogel, we established experimental animal models of oral mucosa ulceration and full-thickness skin defects. In vivo results confirmed that M2-Exos released from the hydrogels played a crucial role in wound closure. Furthermore, the synergistic effect of AuNRs and NIR photothermal effects eradicated bacterial infections in the wound area. Overall, our integrated hydrogel system is a promising tool for accelerating chronic diabetic wound healing and tissue regeneration. This study highlights the potential benefits of combining bioactive M2-Exos and the photothermal effect of AuNRs into an antiswelling hydrogel platform to achieve satisfactory wound healing in patients with diabetes.

A bi-layered membrane with micro-nano bioactive glass for guided bone regeneration.

Guided bone regeneration (GBR) is widely used to treat oral bone defects. However, the osteogenic effects are limited by the deficiency of the available barrier membranes. In this study, a novel bi-layer membrane was prepared by solvent casting and electrospinning. The barrier layer made of poly (lactic-co-glycolic acid) (PLGA) was smooth and compact, whereas the osteogenic layer consisting of micro-nano bioactive glass (MNBG) and PLGA was rough and porous. The mineralization evaluation confirmed that apatite formed on the membranes in simulated body fluid. Immersion in phosphate-buffered saline led to the degradation of the membranes with proper pH changes. Mechanical tests showed that the bi-layered membranes have stable mechanical properties under dry and wet conditions. The bi-layered membranes have good histocompatibility, and the MNBG/PLGA layer can enhance bone regeneration activity. This was confirmed by cell culture results, expression of osteogenic genes, and immunofluorescence staining of RUNX-related transcription factor 2 and osteopontin. Therefore, the bi-layered membranes could be a promising clinical strategy for GBR surgery.

Superhydrophobic hierarchical fiber/bead composite membranes for efficient treatment of burns.

One of the current challenges in burn wound care is the development of multifunctional dressings that can protect the wound from bacteria or organisms and promote skin regeneration and tissue reconstitution. To this end, we report the design and fabrication of a composite electrospun membrane, comprised of electrospun polylactide: poly(vinyl pyrrolidone)/polylactide: poly(ethylene glycol) (PLA:PVP/PLA:PEG) core/shell fibers loaded with bioactive agents, as a functionally integrated wound dressing for efficient burns treatment. Different mass ratios of PLA:PVP in the shell were screened to optimize mechanical, physicochemical, and biological properties, in addition to controlled release profiles of loaded antimicrobial peptides (AMPs) from the fibers for desirable antibacterial activity. Fibroblasts were shown to readily adhere and proliferate when cultured on the membrane, indicating good in vitro cytocompatibility. The introduction of PLA beads by electrospraying on one side of the membrane resulted in biomimetic micro-nanostructures similar to those of lotus leaves. This designer structure rendered the composite membranes with superhydrophobic property to inhibit the adhesion/spreading of exogenous bacteria and other microbes. The administration of the resulting composite fibrous membrane on burnt skin in an infected rat model led to faster healing than a conventional product (sterile silicone membrane) and control detailed herein. These composite fibrous membranes loaded with bioactive drugs provide an integrated strategy for promoting burn wound healing and skin regeneration. STATEMENT OF SIGNIFICANCE: To address an urgent need in complex clinical requirements on developing a new generation of wound dressings with integrated functionalities. This article reports research work on a hierarchical fiber/bead composite membranes design, which combines a lotus-leaf-like superhydrophobic surface with drugs preloaded in the core and shell of fibers for effective burn treatment. This demonstrates a balance between simplified preparation processes and increased multifunctionality of the wound dressings. The creation of hierarchically structured surfaces can be readily achieved by electrospinning, and the composite dressings possessed a considerable mechanical strength, effective wound exudate absorption and permeability, good biocompatibility, broad antibacterial ability and promoting wound healing etc. Thus, our work unveils a promising strategy for the development of functionally integrated wound dressings for burn wound care.

Microparticle templating as a route to nanoscale polymer vesicles with controlled size distribution for anticancer drug delivery.

Polymer vesicles are self-assembled shells of amphiphilic block copolymers (BCPs) that have attracted tremendous interest due to their encapsulation ability and intracellular delivery of therapeutic agents. However, typical processes for the formation of polymer vesicles lead to ensembles of structures with a broad size distribution (from nanometer to micrometer scale) which result in a limitation for efficient cellular uptake. In this study, we present a simple and efficient approach for the fabrication of polymer vesicles with uniform nanoscale dimensions from template formation of electrosprayed particles in a high throughput manner. First, electrospraying was applied to produce micrometer-sized templates of a block copolymer before polymer vesicles were formed from the pre-prepared microparticles via rehydration. Four different biocompatible diblock and triblock copolymers were used to successfully fabricate polymer vesicles with uniform size around 150nm using this approach. Furthermore, we encapsulate anticancer drug doxorubicin (DOX) within the polymer vesicles via this method. The kinetics of cellular uptake (HeLa cell) and intracellular distribution of DOX-loaded polymer vesicles have been quntified and monitored by flow cytometry and confocal microscopy, respectively. The results show that our new method provides a promising way to fabricate drug-loaded polymer vesicles with controllable nanoscale size for intracellular anticancer drug delivery.

Glucosamine-modified polyethylene glycol hydrogel-mediated chondrogenic differentiation of human mesenchymal stem cells.

Glucosamine (GA) is an important cartilage matrix precursor for the glycosaminoglycan biochemical synthesis, and has positive effects on cartilage regeneration, particularly in osteoarthritis therapy. However, it has not been used as a bioactive group in scaffolds for cartilage repair widely. In this study, we synthesized modified polyethylene glycol (PEG) hydrogel with glucosamine and then encapsulated human bone mesenchymal stem cells (hBMSCs) in the hydrogel to induce the differentiation of hBMSCs into chondrocytes in three-dimensional culture. The GA-modified PEG hydrogels promoted the chondrogenesis of hBMSCs, particularly in the concentration of 5mM and 10mM. The subcutaneous transplantation of 10mM GA-modified hydrogels with hBMSCs formed cartilage-like blocks in vivo for 8weeks. Importantly, with glucosamine increase, the modified hydrogels down-regulated the fibrosis and hypertrophic cartilage markers in protein level. Therefore, glucosamine modified PEG hydrogels facilitated the chondrogenesis of hBMSCs, which might represent a new method for cartilage repair using a tissue-engineering approach.

Novel ß-TCP/PVA bilayered hydrogels with considerable physical and bio-functional properties for osteochondral repair.

Cartilage repairing grafts have been widely studied, and osteochondral replacement hydrogels have proven to be an excellent method in research and clinical fields. However, it has been difficult to simultaneously solve three main issues in osteochondral replacement preparation: surface lubrication, overall mechanical support and good simulations of cell regeneration. A novel integrated bilayered hydrogel osteochondral replacement was constructed by blending polyvinyl alcohol (PVA) and ß-tricalcium phosphate (ß-TCP) in this study. Separated nano-ball milling with ultrasound dispersion prepared ß-TCP demonstrated suitable properties of tiny particle size, high purity and ideal distribution, improving the mechanical properties of the novel integrated hydrogel, and providing a cartilage-like lubrication effect and high biocompatibility, including cytocompatibility and osteogenesis. The reinforcement of ß-TCP and integrated molding technology enabled the hydrogel to demonstrate excellent component compatibility and good bonding between the two layers, which promoted the strengthening of the compression modulus and tensile modulus up to three times by mechanical testing. The surface lubrication properties of the novel osteochondral hydrogel were similar to the natural cartilage by friction coefficient characterization. The two layers of the novel integrated graft provided a considerable bio-function by co-culturing with chondrocytes and synovium mesenchymal stem cells: chondrocytes promoted adherence achieved by the upper density layer and better osteogenesis performance of the porous lower layer. The design of the bilayered ß-TCP/PVA osteochondral hydrogel is promising for use in articular cartilage repair.

In vitro and in vivo evaluation of a novel collagen/cellulose nanocrystals scaffold for achieving the sustained release of basic fibroblast growth factor.

Tissue-engineered dermis is thought to be the best treatment for skin defects; however, slow vascularization of these biomaterial scaffolds limits their clinical application. Exogenous administration of angiogenic growth factors is highly desirable for tissue regeneration. In this study, biodegradable gelatin microspheres (GMs) containing basic fibroblast growth factor (bFGF) were fabricated and incorporated into a porous collagen/cellulose nanocrystals (CNCs) scaffold, as a platform for long-term release and consequent angiogenic boosting. The physicochemical properties of these scaffolds were examined and the in vitro release pattern of bFGF from scaffolds was measured by ELISA. Collagen/CNCs scaffolds with and without bFGF-GMs were incubated with human umbilical vein endothelial cells for 1 week, results showed that the scaffolds with bFGF-GMs significantly augmented cell proliferation. Then, four different groups of scaffolds were implanted subcutaneously into Sprague-Dawley rats to study angiogenesis in vivo via macroscopic observation, and hematoxylin and eosin and immunohistochemical staining. The results suggested that the collagen/CNCs/bFGF-GMs scaffolds had a significantly higher number of newly formed and mature blood vessels, and the fastest degradation rate. This study demonstrated that collagen/CNCs/bFGF-GMs scaffolds have great potential in skin tissue engineering.

Collagen based film with well epithelial and stromal regeneration as corneal repair materials: Improving mechanical property by crosslinking with citric acid.

Corneal disease can lead to vision loss. It has become the second greatest cause of blindness in the world, and keratoplasty is considered as an effective treatment method. This paper presents the crosslinked collagen (Col)-citric acid (CA) films developed by making use of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS). The results showed that the Col-CA films had necessary optical performance, water content. The collagenase resistance of CA crosslinked films was superior to that of EDC crosslinked films. And CA5 film (Col:CA:EDC:NHS=60:3:10:10) had the best mechanical properties. Cell experiments showed that CA5 film was non-cytotoxic and human corneal epithelial cells could proliferate well on the films. Lamellar keratoplasty showed that the CA5 film could be sutured in the rabbit eyes and was epithelialized completely in about 10 days, and the transparency was restored quickly in 30±5 days. No inflammation and corneal neovascularization were observed at 6 months. Corneal stroma had been repaired; stromal cells and neo-stroma could be seen in the area of operation from the hematoxylin-eosin stained histologic sections and anterior segment optical coherence tomography images. These results indicated that Col-CA films were highly promising biomaterials that could be used in corneal tissue engineering and a variety of other tissue engineering applications.

Preparation and properties of cellulose nanocrystals reinforced collagen composite films.

Collagen films have been widely used in the field of biomedical engineering. However, the poor mechanical properties of collagen have limited its application. Here, rod-like cellulose nanocrystals (CNCs) were fabricated and used to reinforce collagen films. A series of collagen/CNCs films were prepared by collagen solution with CNCs suspensions homogeneously dispersed at CNCs: collagen weight ratios of 1, 3, 5, 7, and 10. The morphology of the resulting films was analyzed by scanning electron microscopy (SEM), the enhancement of the thermomechanical properties of the collagen/CNCs composites were demonstrated by thermal gravimetric analysis (TGA) and mechanical testing. Among the CNCs contents used, a loading of 7 wt % led to the maximum mechanical properties for the collagen/CNCs composite films. In addition, in vitro cell culture studies revealed that the CNCs have no negative effect on the cell morphology, viability, and proliferation and possess good biocompatibility. We conclude that the incorporation of CNCs is a simple and promising way to reinforce collagen films without impairing biocompatibility. This study demonstrates that the composite films show good potential for use in the field of skin tissue engineering.

Fabrication and characterization of chitosan-collagen crosslinked membranes for corneal tissue engineering.

This article describes a chitosan-collagen composite membrane as corneal tissue-engineering biomaterials. The membrane was prepared by dissolving the chitosan into collagen with the weight ratio of 0, 15, 30, 45, 60, and 100%, followed by crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. Mechanical properties, contact angles, and optical transmittance were determined and compared between chitosan membrane and crosslinking composite membrane. As a result, the optical transparency and mechanical strength of the chitosan-collagen membranes were significantly better than that of the sample of chitosan. In addition, in vitro cell culture studies revealed that the collagen has no negative effect on the cell morphology, viability, and proliferation and possess good biocompatibility. Overall, the dendrimer crosslinked chitosan-collagen composite membranes showed promising properties that suggest that these might be suitable biomaterials for corneal tissue-engineering applications.