Bioinspired Multiscale Mineralization: From Fundamentals to Potential Applications.

The wondrous and imaginative designs of nature have always been an inexhaustible treasure trove for material scientists. Throughout the long evolutionary process, biominerals with hierarchical structures possess some specific advantages such as outstanding mechanical properties, biological functions, and sensing performances, the formation of which (biomineralization) is delicately regulated by organic component. Provoked by the subtle structures and profound principles of nature, bioinspired functional minerals can be designed with the participation of organic molecules. Because of the designable morphology and functions, multiscale mineralization has attracted more and more attention in the areas of medicine, chemistry, biology, and material science. This review provides a summary of current advancements in this extending topic. The mechanisms underlying mineralization is first concisely elucidated. Next, several types of minerals are categorized according to their structural characteristic, as well as the different potential applications of these materials. At last, a comprehensive overview of future developments for bioinspired multiscale mineralization is given. Concentrating on the mechanism of fabrication and broad application prospects of multiscale mineralization, the hope is to provide inspirations for the design of other functional materials.

Self-Adhesive, Strong Antifouling, and Mechanically Reinforced Methacrylate Hyaluronic Acid Cross-Linked Carboxybetaine Zwitterionic Hydrogels.

Hyaluronic acid and zwitterionic hydrogels are soft materials with poor mechanical properties. The unique structures and physiological properties make them attractive candidates for ideal hydrogel dressings, but the crux of lacking satisfying mechanical strengths and adhesive properties is still pendent. In this study, the physical cross-linking of dipole-dipole interactions of zwitterionic pairs was utilized to enhance the mechanical properties of hydrogels. The hydrogels have been prepared by copolymerizing methacrylate hyaluronic (HAGMA) with carboxybetaine methacrylamide (CBMAA) (the mass ratio of [HAGMA]/[CBMAA] is 2:5, 1:5, 1:10, or 1:20), obtaining HA-CB2.5, HA-CB5.0, HA-CB10.0, or HA-CB20.0 hydrogel. Therein, the HA-CB20.0 hydrogel with a high CBMAA content can generate a strong dipole-dipole interaction to form internal physical cross-links, exhibit stretchability and low elastic modulus, and withstand 99% compressive deformation and cyclic compression under strain at 90%. Moreover, the HA-CB20.0 hydrogel is adhesive to diverse substrates, including skin, glass, stainless steel, and plastic. The synergistic effect of HAGMA and CBMAA shows strong anti-biofouling, high water absorption, biodegradability under hyaluronidase, and biocompatibility.

Light and Magnetism Orchestrating Aquatic Pollutant-Degradation Robots in Programmable Trajectories.

Interfacial floating robots have promising applications in carriers, environmental monitoring, water treatment, and so on. Even though, engineering smart robots with both precisely efficient navigation and elimination of water pollutants in long term remains a challenge, as the superhydrophobicity greatly lowers resistance for aquatic motion while sacrificing chemical reactivity of the surface. Here, a pollutant-removing superhydrophobic robot integrated with well-assembled iron oxide-bismuth sulfide heterojunction composite minerals, which provide both light and magnetic propulsion, and the ability of catalytic degradation, is reported. The motion velocity of the robot reaches up to 51.9 mm s-1 within only 300 ms of acceleration under the orchestration of light, and brakes rapidly (≈200-300 ms) once turn off the light. And magnetism extends the robot to work in broad range of surface tensions in any programmable trajectory. Besides, purification of polluted water is efficiently achieved in situ and the degradation efficiency exhibits eightfold enhancements under the effect of light-triggered photothermal behavior coupled with magnetic induction, overcoming the dilemma of efficient motion with catalytic superhydrophobicity. This strategy developed here provides guidelines for the explorations of high-performance smart devices.

Supramolecular Self-Healing Antifouling Coating for Dental Materials.

In orthodontic treatment, orthodontic appliances are prone to bacterial infections, which pose a risk to oral health. Surface modification of orthodontic appliances has been explored to improve their antifouling properties and impart antibacterial capabilities, inhibiting initial bacterial adhesion and biofilm formation. However, coatings are susceptible to damage in the complex oral environment, leading to a loss of functionality. Here, we have prepared an antifouling self-healing coating based on supramolecular bonding by employing a simple spin coating method. The presence of the hydrophilic zwitterionic trimethylamine N-oxide (TMAO) and the hydrophobic antimicrobial moieties triclosan acrylate (TCSA) imparts to the polymers an amphiphilic structure and enhances the interaction with bacteria, resulting in excellent antimicrobial activity and surface antifouling properties. The multiple hydrogen bonds of ureido-pyrimidinone methacrylate (UPyMA) and ionic interactions contained in the polymers not only increased the adhesion of the coating to the material substrate (approximately 3 times) but also endowed the coating with the intrinsic self-healing ability to restore the antibiofouling properties at oral temperature and humidity. Finally, the polymer coating is biologically safe both in vitro and in vivo, showing no cytotoxic effects on cells and tissues. This research offers a promising avenue for improving the performance of orthodontic appliances and contributes to the maintenance and treatment of oral health.

Mimicking Antioxidases and Hyaluronan Synthase: A Zwitterionic Nanozyme for Photothermal Therapy of Osteoarthritis.

Restoring joint homeostasis is crucial for relieving osteoarthritis (OA). Current strategies are limited to unilateral efforts in joint lubrication, inhibition of inflammation, free radicals scavenging, and cartilage regeneration. Herein, by modifying molybdenum disulfide (MoS2 ) with Mg2+ -doped polydopamine and coating with polysulfobetaines, a dual-bionic photothermal nanozyme (MPMP) is constructed to mimic antioxidases/hyaluronan synthase for OA therapy. Photothermally enhanced lubrication lowers the coefficient of friction (0.028) in the early stage of OA treatment. The antioxidases-mimicking properties of MPMP nanozyme contribute to eliminating reactive oxygen and nitrogen species (ROS/RNS) (over 90% of scavenging ratio for H2 O2 /·OH/O· 2 - /DPPH/ABTS+ ) and supplying O2 . With NIR irradiation, the MPMP nanozyme triggers thermogenesis (upregulating HSP70 expression) and Mg2+ release, which promotes the chondrogenesis in inflammatory conditions by deactivating NF-κB/IL-17 signaling pathways and enhancing MAPK signaling pathway. Benefiting from HSP70 and Mg2+ , MPMP-NIR shows HAS-mimicking activity to increase the intracellular (twofold) and extracellular (3.12-fold) HA production. Therefore, MPMP-NIR demonstrates superior spatiotemporally therapeutic effect on OA in mice model, in terms of osteophytes (83.41% of reduction), OARSI scores (88.57% of reduction), and ACAN expression (2.70-fold of increment). Hence, insights into dual-bionic nanozymes can be a promising strategy for OA therapy or other inflammation-related diseases.

A cyclic brush zwitterionic polymer based pH-responsive nanocarrier-mediated dual drug delivery system with lubrication maintenance for osteoarthritis treatment.

Enhanced joint synergistic lubrication combined with anti-inflammatory therapy is an effective strategy to delay the progression of early osteoarthritis (OA) but has been rarely reported. The hydration lubrication of zwitterions and inherent super-lubrication properties of the cyclic brush, as well as the enhancement of the steric stability of the cyclic topology, can effectively improve the drug loading and utilization; herein we report a pH-responsive cyclic brush zwitterionic polymer (CB) with SBMA and DMAEMA as brushes and a cyclic polymer (c-P(HEMA)) as the core template, possessing a low coefficient of friction (0.017). After loading with hydrophobic curcumin and hydrophilic loxoprofen sodium it demonstrates high drug-loading efficiency. In vitro and in vivo experiments confirmed the triple function of the CB on superlubrication, sequence controlled release and anti-inflammatory effects demonstrated by Micro CT, histological analysis and qRT-PCR. Overall, the CB is a promising long-acting lubricating therapeutic agent, with potential for OA treatment or other diseases.

Hexapeptide decorated ß-cyclodextrin delivery system for targeted therapy of bone infection.

Successfully treating bone infections is a major orthopedic challenge. Clinically, oral, intravenous, or intramuscular injections of drugs are usually used for direct or complementary treatment. However, once the drug enters the system, it circulates throughout the body, leading to an insufficient local dose and limiting the therapeutic effect because of the lack of targeting in the drug system. In this study, ß-cyclodextrin, modified with poly (ethylene glycol) [PEG] and aspartic acid hexapeptide (Asp6-ß-CD), was used to specifically target the hydroxyapatite (HA) component of the bone. It was then loaded with norfloxacin (NFX) to treat bone infections. The antibacterial ability of NFX was enhanced by loading it into Asp6-ß-CD, because the solubility of Asp6-ß-CD@NFX increased significantly. Moreover, Asp6-ß-CD could target bone tissue in nude mice and showed significantly enhanced accumulation (10 times) than the unmodified ß-CD. In addition, in a rat model of osteomyelitis, Asp6-ß-CD@NFX targeted HA well and exerted its antibacterial activity, which reduced inflammation and promoted bone tissue repair. This study indicates that the Asp6-ß-CD based drug delivery system can efficiently target bone tissue to enable potential applications for treating bone-related diseases.

Chitosan based photothermal scaffold fighting against bone tumor-related complications: Recurrence, infection, and defects.

After bone tumor resection, the severe complications including cancer recurrence, infection and extensive bone loss are still a challenge. To address this problem, a chitosan/hydroxypropyltrimethyl ammonium chloride chitosan/hydroxyapatite/black phosphorus (CS/HC/HA/BP) hybrid photothermal scaffold with a multistage photothermal strategy was developed. HC-stabilized BP endowed the scaffold with simultaneous antitumor/antibacterial properties under photothermal stimulation of <50 °C. Subsequently, excellent osteogenesis could be achieved with mild hyperthermia stimulation (∼42 °C) through up-regulating the expressions of heat shock proteins. Under NIR irradiation, the scaffold could eliminate 95 % of osteosarcoma cells as well as 97 % of E. coli and 92 % of S. aureus. The osteogenic gene expressions of ALP, COL 1A1, and OCN in photothermal group were 1.64, 1.31 and 1.27 folds higher than that of non-photothermal group in vivo, respectively. Therefore, the obtained scaffold synergized with multistage photothermal strategy was effective and a reference for the treatment of other complex diseases.

Recent advancements in wound management: Tailoring superwettable bio-interfaces.

Skin tissue suffering from severe damages fail in self-regeneration. Proper wound dressings are highly demanded to protect the wound region and accelerate the healing process. Although large efforts have been devoted, there still exist disturbing dilemmas for traditional dressings. The exquisite design of bio-interface upon superwettable materials opens new avenues and addresses the problems perfectly. However, the advancements in this area have rarely been combed. In light of this, this minireview attempts to summarize recent strategies of superwettable bio-interfaces for wound care. Concentrating on the management of biofluids (blood and exudate), we described superwettable hemostatic bio-interfaces first, and then introduced the management of exudates. Finally, the perspective of this area was given. This minireview gives a comprehensive outline for readers and is believed to provide references for the design of superwettable materials in biomedical area.

Chloroplast-inspired Scaffold for Infected Bone Defect Therapy: Towards Stable Photothermal Properties and Self-Defensive Functionality.

Bone implant-associated infections induced by bacteria frequently result in repair failure and threaten the health of patients. Although black phosphorus (BP) material with superior photothermal conversion ability is booming in the treatment of bone disease, the development of BP-based bone scaffolds with excellent photothermal stability and antibacterial properties simultaneously remains a challenge. In nature, chloroplasts cannot only convert light into chemical energy, but also hold a protective and defensive envelope membrane. Inspired by this, a self-defensive bone scaffold with stable photothermal property is developed for infected bone defect therapy. Similar to thylakoid and stroma lamella in chloroplasts, BP is integrated with chitosan and polycaprolactone fiber networks. The mussel-inspired polydopamine multifunctional "envelope membrane" wrapped above not only strengthens the photothermal stability of BP-based scaffolds, but also realizes the in situ anchoring of silver nanoparticles. Bacteria-triggered infection of femur defects in vivo can be commendably inhibited at the early stage via these chloroplast-inspired implants, which then effectively promotes endogenous repair of the defect area under mild hyperthermia induced by near-infrared irradiation. This chloroplast-inspired strategy shows outstanding performance for infected bone defect therapy and provides a reference for the functionality of other biomedical materials.

Polylactic acid film surface functionalized by zwitterionic poly[2-(methacryloyloxy)ethyl choline phosphate] with improved biocompatibility.

Polylactic acid (PLA) is a non-toxic, biodegradable biological material that is widely used in tissue engineering and regenerative medicine. PLA is easy to adsorb non-specific proteins and lacks cell adhesion after implantation. Choline phosphate (CP) is a novel zwitterion with a reverse structure of phosphate choline (PC) on the cell membrane that can form a specific "CP-PC" interaction to promote cell adhesion. In our previous work, modification of choline phosphate polymers (PMCP) onto the PLA film surface improved the hydrophilicity and degradation properties. In this study, we further investigated the biocompatibility of PLA-PMCP films from protein adsorption, cell adhesion and proliferation, bacterial adhesion, blood compatibility, and inflammation in vivo. The PLA-PMCP surface can resist protein adsorption and bacterial adhesion due to the anti-fouling properties of the zwitterion PMCP. Meanwhile, the PLA-PMCP surface promotes the adhesion and proliferation of BMSCs due to the specific "CP-PC" effect. In addition, the PLA-PMCP film has good blood compatibility as well as the PLA film. During in vivo experiments, biocompatibility was improved and the inflammatory response and immune rejection of PLA-PMCP films were reduced compared to those of the original PLA film. Therefore, the PMCP-modified PLA film resists protein adsorption and bacterial adhesion, promotes cell adhesion and proliferation, and has good hemocompatibility and histocompatibility. This brings a significant potential for application in the fields of tissue engineering and regenerative medicine.

Zwitterionic choline phosphate conjugated folate-poly (ethylene glycol): a general decoration of erythrocyte membrane-coated nanoparticles for enhanced tumor-targeting drug delivery.

Erythrocyte membrane nanosystems have become one of the important research directions of disease treatment, especially for tumor treatment, and can enhance the long circulation time of anti-cancer drugs in vivo, and penetrate and accumulate in the tumor site effectively. However, erythrocyte membranes lack targeting properties and it is necessary to provide tumor-targeting function by modifying erythrocyte membranes. In this study, we report on a novel modification method of an erythrocyte membrane nanosystem to target tumors. Specifically, the tumor-targeting molecule folate-poly (ethylene glycol) (FA-PEG) was modified with a zwitterionic 2-(methyl acryloyoxy) ethyl choline phosphate (MCP) by the Michael addition reaction to obtain MCP-modified FA-PEG (MCP-PEG-FA). Based on the strong "N-P" tetravalent electrostatic interaction between MCP and phosphatidyl choline on the erythrocyte membranes, MCP-PEG-FA can be modified on the erythrocyte membrane encapsulated doxorubicin (DOX) loaded poly(lactic-co-glycolic acid) (PLGA) nanosystem to form a tumor-targeting erythrocyte membrane nanosystem (FA-RBC@PLGA-DOX). The results show that MCP-PEG-FA was synthesized and successfully bonded to the erythrocyte membrane nanosystem, and the FA-RBC@PLGA-DOX nanosystem had a better tumor-targeting function and tumor killing effect compared with those of the nanosystems without FA ligand modification. The universal modification method of erythrocyte membranes is successfully provided and can be applied to the treatment of various diseases.

Heterogenous hydrogel mimicking the osteochondral ECM applied to tissue regeneration.

Inspired by the intricate extracellular matrix (ECM) of natural cartilage and subchondral bone, a heterogenous bilayer hydrogel scaffold is fabricated. Gelatin methacrylate (GelMA) and acryloyl glucosamine (AGA) serve as the main components in the upper layer, mimicking the chondral ECM. Meanwhile, vinylphosphonic acid (VPA) as a non-collagen protein analogue is incorporated into the bottom layer to induce the in situ biomineralization of calcium phosphate. The two heterogenous layers are effectively sutured together by the inter-diffusion between the upper and bottom layer hydrogels, together with chelation between the calcium ions and alginate added to separate layers. The interfacial bonding between the two different layers was thoroughly investigated via rheological measurements. The incorporation of AGA promotes chondrocytes to produce collagen type II and glycosaminoglycans and upregulates the expression of chondrogenesis-related genes. In addition, the minerals induced by VPA facilitate the osteogenesis of bone marrow mesenchymal stem cells (BMSCs). In vivo evaluation confirms the biocompatibility of the scaffold with minor inflammation and confirms the best repair ability of the bilayer hydrogel. This cell-free, cost-effective and efficient hydrogel shows great potential for osteochondral repair and inspires the design of other tissue-engineering scaffolds.

Zwitterionic PMCP-functionalized titanium surface resists protein adsorption, promotes cell adhesion, and enhances osteogenic activity.

Titanium (Ti) has excellent biocompatibility and corrosion resistance and is widely used as a biomedical material for orthopedic implants. However, the bare Ti surface limits cell adhesion without biological activity and promotes unnecessary protein adsorption, which can activate the coagulation pathway with blood-contacting devices. To improve the antifouling and biological activity of Ti, zwitterionic poly[2-(methacryloyloxy)ethyl choline phosphate] (PMCP) was used to modify the Ti surface via surface-initiated atom transfer radical polymerization. The Ti-PMCP surface reduced bovine serum albumin and fibrinogen adsorption owing to the zwitterionic antifouling property. Ti-PMCP is involved in the unique interaction between PMCP on the Ti surface and phosphate choline on cell membranes, and therefore, the Ti-PMCP surface can promote the adhesion and proliferation of MC3T3-e1 cells and bone marrow mesenchymal cells (BMSCs). In addition, the Ti-PMCP surface was effective in promoting the osteogenic differentiation of MC3T3-e1 cells and BMSCs because the phosphate group in MCP can stimulate osteogenic signaling pathways. Therefore, the PMCP-modified Ti surface can resist protein adsorption and promote the adhesion, proliferation, and differentiation of osteoblast-related cells and has great potential in bone tissue engineering.

Cell-Membrane-Targeted Drug Delivery System Based on Choline-Phosphate-Functionalized ß-Cyclodextrin.

In this study, a novel cyclodextrin derivative, i.e., zwitterionic choline phosphate (CP)-functionalized ß-cyclodextrin (CP-ß-CD) is successfully synthesized by click chemistry reaction. CP-ß-CD has excellent cell-membrane-targeted ability because of the CP group can bind to phosphate choline (PC) in the cell membrane and promote the cellular uptake. Due to the introduction of CP group on ß-CD, it disrupts the hydrogen network between natural ß-CD molecules. Meanwhile, the water solubility of CP-ß-CD is improved dramatically to 816 mg mL-1 , which is 440 times as that of unmodified ß-CD. Apatinib, a small molecular inhibitor, is used as a model of hydrophobic drug and loaded into CP-ß-CD to study the solubilization effect and the anti-angiogenisis activity. In addition, the cytotoxicity of CP-ß-CD is also studied, and it is demonstrated that CP-ß-CD is nontoxic. These results indicate that the apatinib can be transported into cell interior and play an excellent anti-angiogenisis activity after being loaded into CP-ß-CD drug delivery system. This work suggests that the water soluble CP-ß-CD with excellent cell internalization efficiency has a potential application prospect in the field of drug delivery.

Poly[2-(methacryloyloxy)ethyl choline phosphate] functionalized polylactic acid film with improved degradation resistance both in vitro and in vivo.

In this study, the surface-initiated atom transfer radical polymerization (SI-ATRP) of 2-(methacryloyloxy) ethyl choline phosphate (MCP) was successfully carried out via the ATRP initiator immobilized on the surfaces of polylactic acid (PLA) films. Different amounts of PMCP polymer brushes were constructed on the PLA surface to investigate the effects of the biological and degradation properties before and after modification. The results showed that the hydrophilicity of the surface of PLA were improved by MCP modification. In addition, there are no significant influence on the structure and crystallinity of the film before and after modification, except for the increased slightly thermal stability. Since the PMCP polymer brush forms a "protection" effect on the surface, the films showed an excellent property of resistant to hydrolysis even with obviously improved hydrophilicity. Furthermore, with the increase of the amount of introduced MCP monomer, the hydrophilicity and degradation resistance have been further improved. The in vivo animal experiment also verified this degradation resistance. Thereby, this strategy can be used to modulate the degradation rate of degradable polymers via surface modification.