Lei Tan

Balancing Bacteria–Osteoblast Competition through Selective Physical Puncture and Biofunctionalization of ZnO/Polydopamine/Arginine-Glycine-Aspartic Acid-Cysteine Nanorods

Bacterial infection and lack of bone tissue integration are two major concerns of orthopedic implants. In addition, osteoinductivity often decreases and toxicity may arise when antibacterial agents are introduced to increase the antibacterial ability. Here hybrid ZnO/polydopamine (PDA)/arginine-glycine-aspartic acid-cysteine (RGDC) nanorod (NR) arrays are designed and prepared on titanium (Ti) implants to not only enhance the osteoinductivity but also effectively kill bacteria simultaneously, which are ascribed to the selective physical puncture and the biofunctionalization of ZnO/PDA/RGDC nanorods during the competition between bacteria and osteoblasts. That is, owing to the much larger size of osteoblasts than bacteria, the hybrid NRs can puncture bacteria but not damage osteoblasts. Meanwhile, the cytocompatibility can be enhanced through the suppression of both reactive oxygen species and higher Zn2+ concentration by the covering of PDA and RGDC. The in vitro results confirm the selective puncture of the bacterial membrane and the better osteoinductivity. In vivo tests also show much higher antibacterial efficacy of the hybrid NRs with far less amounts of lobulated neutrophils and adherent bacteria in the surrounding tissues. In addition, the hybrid NRs also accelerate formation of new bone tissues (20.1% higher than pure Ti) and osteointegration between implants and newly formed tissues (32.0% higher than pure Ti) even in the presence of injected bacteria. This work provides a surface strategy for designing implants with desirable ability of osseointegration and infection prevention simultaneously, which will exhibit tremendous clinical potential in orthopedic and dental applications.

Porous Iron-Carboxylate Metal–Organic Framework: A Novel Bioplatform with Sustained Antibacterial Efficacy and Nontoxicity

Sustained drug release plays a critical role in targeting the therapy of local diseases such as bacterial infections. In the present work, porous iron-carboxylate metal-organic framework [MOF-53(Fe)] nanoparticles (NPs) were designed to entrap the vancomycin (Van) drugs. This system exhibited excellent chemical stability under acidic conditions (pH 7.4, 6.5, and 5.5) and much higher drug-loading capability because of the high porosity and large surface area of MOF NPs. The results showed that the drug-loading ratio of Van could reach 20 wt % and that the antibacterial ratio of the MOF-53(Fe)/Van system against Staphylococcus aureus could reach up to 90%. In addition, this MOF-53(Fe)/Van system exhibited excellent biocompatibility because of its chemical stability and sustained release of iron ions. Hence, these porous MOF NPs are a promising bioplatform not only for local therapy of bacterial infections but also for other biomedical therapies for tissue regeneration.

In Situ Disinfection through Photoinspired Radical Oxygen Species Storage and Thermal‐Triggered Release from Black Phosphorous with Strengthened Chemical Stability

Photodynamic therapy (PDT) utilizing light-induced reactive oxygen species (ROS) is a promising alternative to combat antibiotic-resistant bacteria and biofilm. However, the photosensitizer (PS)-modified surface only exhibits antibacterial properties in the presence of light. It is known that extended photoirradiation may lead to phototoxicity and tissue hypoxia, which greatly limits PDT efficiency, while ambient pathogens also have the opportunity to attach to biorelevant surfaces in medical facilities without light. Here, an antimicrobial film composed of black phosphorus nanosheets (BPSs) and poly (4-pyridonemethylstyrene) endoperoxide (PPMS-EPO) to control the storage and release of ROS reversibly is introduced. BPS, as a biocompatible PS, can produce high singlet oxygen under the irradiation of visible light of 660 nm, which can be stably stored in PPMS-EPO. The ROS can be gradually thermally released in the dark. In vitro antibacterial studies demonstrate that the PPMS-EPO/BPS film exhibits a rapid disinfection ability with antibacterial rate of 99.3% against Escherichia coli and 99.2% against Staphylococcus aureus after 10 min of irradiation. Even without light, the corresponding antibacterial rate reaches 76.5% and 69.7%, respectively. In addition, incorporating PPMS significantly improves the chemical stability of the BPS.

Construction of N-halamine labeled silica/zinc oxide hybrid nanoparticles for enhancing antibacterial ability of Ti implants

The traditional antibiotic treatment for bacterial infections often induces antibiotic resistance in bacteria. In this work, we developed hybrid nanoparticles (NPs) with a self-antibacterial ability on Ti implants using monodispersed polystyrene-acrylic acid (PSA) nanoparticles as colloidal templates followed by the electrostatic adsorption of zinc oxide (ZnO) and the subsequent deposition of silica (SiO2) membrane on the outside. These synthesized PSA-ZnO-SiO2 NPs were pretreated by 5,5-dimethylhydantoin (DMH) before chlorination in a diluted NaClO solution. These nanoparticles (PSA-ZnO-SiO2-DMH) were subsequently labeled by N-halamines and then immobilized on the surface of titanium plates through hydrogen bonding. Field emission scanning electron microscopy (FE-SEM) and X-ray photoelectron spectroscopy (XPS) were utilized to characterize the modified surface. Antibacterial tests disclosed that the PSA-ZnO-SiO2-DMH-Cl NPs modified surface exhibited excellent antibacterial activity against both Pseudomonas aeruginosa (P.au), Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In vitro cell culture results revealed that PSA-ZnO-SiO2-DMH-Cl had no obvious cytotoxicity for an MC3T3-E1 preosteoblast. This novel surface system provides a promising self-antibacterial bioplatform for metallic implants without using antibiotics.

Electrophoretic Deposited Stable Chitosan@MoS2 Coating with Rapid In Situ Bacteria‐Killing Ability under Dual‐Light Irradiation

Developing in situ disinfection methods in vivo to avoid drug-resistant bacteria and tissue toxicity is an urgent need. Here, the photodynamic and photothermal properties of the chitosan-assisted MoS2 (CS@MoS2 ) hybrid coating are simultaneously inspired to endow metallic Ti implants with excellent surface self-antibacterial capabilities. This coating, irradiated by only 660 nm visible light (VL) for 10 min, exhibits an antibacterial efficacy of 91.58% and 92.52% against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), respectively. The corresponding value is 64.67% and 57.44%, respectively, after irradiation by a single 808 nm near infrared light for the same amount of time. However, the combined irradiation using both lights can significantly enhance the efficiency up to 99.84% and 99.65% against E. coli and S. aureus, respectively, which can be ascribed to the synergistic effects of photodynamic and photothermal actions. The former produces single oxygen species under 660 nm VL while the latter induces a rise in temperature of implants, which can inhibit the growth of both E. coli and S. aureus. The introduction of CS can also promote the biocompatibility of implants, which provides a facile, rapid, and safe in situ bacteria-killing method in vivo without needing a second surgery.

Rapid Biofilm Eradication on Bone Implants Using Red Phosphorus and Near‐Infrared Light

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 (1 O2 ) 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.

Tuning the Bandgap of Photo-Sensitive Polydopamine/Ag3PO4/Graphene Oxide Coating for Rapid, Noninvasive Disinfection of Implants

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.

Construction of perfluorohexane/IR780@liposome coating on Ti for rapid bacteria killing under permeable near infrared light

Near infrared (NIR) light induced photodynamic antibacterial therapy (PDAT) is a promising antibacterial technique in rapid in situ disinfection of bacterially infected artificial implants due to its penetration ability into tissues. However, the lower oxygen content in vivo may restrict the yields of reactive oxygen species (ROS), thus reducing the antibacterial efficacy of PADT significantly. Herein, liposome encapsulated photosensitizers (PS), IR780 and perfluorohexane (PFH), have been constructed on the surface of Ti implants via a covalent linkage to overcome this issue. Thanks to the high oxygen capacity of PFH, more ROS can be generated during NIR irradiation regardless of the low content of oxygen in vivo. As a result, in vitro tests demonstrated that 15 minutes of 808 nm near-infrared irradiation could achieve a high antibacterial efficacy of 99.62% and 99.63% on the implant surface against Escherichia coli and Staphylococcus aureus, respectively. By contrast, the PDAT system without PFH modification shows a lower antibacterial efficacy (only 66.54% and 48.04%, respectively). In addition, this enhanced PDAT system also possesses great biocompatibility based on the in vitro and in vivo subcutaneous assays. This surface system makes it possible for rapid bacteria-killing in artificial implants that have been implanted in vivo under local conditions with lower oxygen content.

Controlled-temperature photothermal and oxidative bacteria killing and acceleration of wound healing by polydopamine-assisted Au-hydroxyapatite nanorods

Since skin wounds are subject to bacterial infection and tissue regeneration may be impeded, there is demand for biomaterials that possess rapid bactericidal and tissue repair capability. Herein we report in situ promotion of wound healing by a photothermal therapy (PTT) assisted nanocatalytic antibacterial system utilizing a polydopamine (PDA) coating on hydroxyapatite (HAp) incorporated with gold nanoparticles (Au-HAp). The PDA@Au-HAp NPs produce hydroxyl radicals (OH) via catalysis of a small concentration of H2O2 to render bacteria more vulnerable to the temperature change. The antibacterial efficacy against Escherichia coli and Staphylococcus aureus is 96.8% and 95.2%, respectively, at a controlled photo-induced temperature of 45 °C that causes no damage to normal tissues. By combining catalysis with near-infrared (NIR) photothermal therapy, the PDA@Au-HAp NPs provide safe, rapid, and effective antibacterial activity compared to OH or PTT alone. In addition, this system stimulates the tissue repairing-related gene expression to facilitate the formation of granulation tissues and collagen synthesis and thus accelerate wound healing. After the 10-day treatment of skin wounds in vivo, PDA@Au-HAp group exhibits quicker recovery than the control group and both sterilization and healing are completed after the 10-day treatment. STATEMENT OF SIGNIFICANCE This study presents in situ promotion of wound healing by a low-temperature photothermal therapy (PTT) assisted nanocatalytic antibacterial system utilizing a polydopamine (PDA) coating on hydroxyapatite (HAp) incorporated with gold nanoparticles (Au-HAp). The PDA@Au-HAp NPs produce hydroxyl radicals (OH) via catalysis of a small concentration of H2O2 to render bacteria more vulnerable to temperature change. After irradiation by 808 nm laser, the antibacterial efficacy against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) is 96.8% and 95.2%, respectively, at a low photo-induced temperature of 45 °C which causes no damage to normal tissues. In addition, this system stimulates the tissue repairing-related gene expression to facilitate the formation of granulation tissues and collagen synthesis and accelerate wound healing.