Photoactivated MXene Nanosheets for Integrated Bone-Soft Tissue Therapy: Effect and Potential Mechanism.

The bone defects caused by trauma are inevitably accompanied by soft tissue damage. The development of multifunctional bioactive biomaterials with integrated bone and soft tissue regeneration is necessary and needed urgently in orthopedics. In this work, we found that the photoactivated MXene (Ti3C2Tx) nanosheet showed positive effects on promoting both bone and soft tissue regeneration. We further investigated the detailed effect and potential mechanism of photoactivated MXene on tissue regeneration. Photoactivated MXene shows a good thermal effect and robust antibacterial activity to inhibit the expression of inflammation factors and methicillin-resistant Staphylococcus aureus (MRSA) infection and induces the expression of pro-angiogenic factors and soft tissue wound repair. Photoactivated MXene can also regulate the osteogenic differentiation of adipose-derived stem cells (ADSCs) through the ERK signaling pathway by activating the heat shock protein 70 (HSP70) and enhancing the repair of bone tissue. This work sheds light on the development of bioactive MXene with photothermal activation as an efficient strategy for bone and soft tissue regeneration simultaneously.

Bioactive anti-inflammatory antibacterial metformin-contained hydrogel dressing accelerating wound healing.

Highly efficient wound healing and skin regeneration remain a challenge. Long-term inflammation and bacterial infection can inhibit the healing process and lead to the scar formation. Here, we report a hydrogel (FEM) formed by self-assembly of ε-poly-l-lysine-F127-ε-poly-l-lysine (EPL-F127-EPL) and metformin for wound repair. Especially, the role of metformin-based antibacterial hydrogel in wound healing and repair was investigated for the first time. FEM has inherent multifunctional properties, including controlled metformin release, anti-inflammatory and antibacterial activity, temperature responsiveness, injectable and self-healing capabilities. The in vivo results showed that FEM dressings accelerated the wound healing by stimulating the angiogenesis process of the wound tissue and anti-inflammation. This study shows that the multifunctional metformin-contained hydrogel scaffolds could enhance the wound repair through the anti-inflammation and accelerated angiogenesis, which could also expand the biomedical applications of metformin-based biomaterials.

Multiple Coordination-Derived Bioactive Hydrogel with Proangiogenic Hemostatic Capacity for Wound Repair.

Bioactive hydrogels with multifunctional properties have shown promising potential in promoting wound repair and skin tissue regeneration. The regulation on different stages of skin wound healing (hemostasis and inflammation) is important for wound repair. Herein, a multiple coordination-derived bioactive hydrogel (SGPA) with anti-inflammatory proangiogenic hemostatic capacity for wound repair is reported. The SGPA is prepared through a facile multiple metal coordination action based on the sodium alginate, metal ions (Gd3+ ), and bisphosphate functionalized polycitrate. The SGPA exhibits a large porous structure, good injectability, and self-healing performance, as well as controlled biodegradation. Furthermore, the SGPA has good cytocompatibility and hemocompatibility, and can further promote the migration of endothelial cells. The SGPA hydrogel presents good hemostasis capacity in a liver hemorrhage model in vivo. The full-thickness cutaneous wound model demonstrates that the SGPA hydrogel can effectively accelerate the wound repair through down-regulating the inflammatory factors and stimulating the angiogenesis around the wound beds. This work suggests that the multiple metal-organic coordination may be a good strategy to construct the multifunctional bioactive hydrogel for wound repair.

Bioactive cytomembrane@poly(citrate-peptide)-miRNA365 nanoplatform with immune escape and homologous targeting for colon cancer therapy.

Colon cancer is one of the most common gastrointestinal tumors in the world. Currently, the commonly used methods such as radiotherapy, chemotherapy and drug treatments are often ineffective and have significant side effects. Here we developed a safe and efficient biomaterials based anti-tumor nanoplatform (M@NPs/miR365), which was formed with poly (citrate-peptide) (PCP), miRNA365 mimic and MC38 cancer cell membrane (M). PCP could efficiently deliver miR365 mimic into MC38 cancer cells, promote the apoptosis of MC38 tumor cells and regulate the expression of Bcl2 and Ki67 in vitro. Tumor cell membranes were prepared by a fast and convenient sonication method. This tumor cell membrane-coated drug delivery system M@NPs can effectively reduce macrophage uptake and increase the stability of NPs. And the MC38 tumor model mice experiment showed that M@NPs/miR365 via caudal vein injection effectively inhibit tumor development. Based on the immune escape and homologous targeting of cancer cells and efficient gene transfection ability of NPs, this "Trojan horse" like "Pseudotumor cell" carries the target gene miR365 mimic to the tumor site and realizes cancer therapy. Noteworthy, the drug delivery system has good biocompatibility. Thus, this safe drug delivery strategy mediated by cancer cell membrane and gene therapy may have a certain significance for reducing the gap between nanoplatform and tumor clinical treatment.

Bioactive Anti-Inflammatory Thermocatalytic Nanometal-Polyphenol Polypeptide Scaffolds for MRSA-Infection/Tumor Postsurgical Tissue Repair.

Postsurgical tumor recurrence, infection, and tissue defect are still the challenges in clinical medicine. The development of multifunctional biomaterial scaffolds with a microenvironment-responsive tumor-infection therapy-tissue repair is highly desirable. Herein, we report a bioactive, injectable, adhesive, self-healing, antibacterial, and anti-inflammatory metal-polyphenol polypeptide nanocomposite scaffold (PEAPF) with temporal-spatial-controlled inflammation-triggered therapeutic properties for efficient infection and postsurgical tumor therapy and skin repair. PEAPF scaffolds showed sustained and inherent inflammation-triggered Fenton catalysis and mild thermochemical effect for specifically inhibiting tumor recurrence in vitro and in vivo. The PEAPF scaffolds significantly facilitated skin tissue regeneration in MRSA-infected chronic wounds and postsurgical tissue defects after tumor resection. This study presents the multifunctional scaffold-based safe and efficient therapeutic strategy to prevent local tumor recurrence and enhance postsurgical tissue regeneration.

Li-Doped Bioactive Ceramics: Promising Biomaterials for Tissue Engineering and Regenerative Medicine.

Lithium (Li) is a metal with critical therapeutic properties ranging from the treatment of bipolar depression to antibacterial, anticancer, antiviral and pro-regenerative effects. This element can be incorporated into the structure of various biomaterials through the inclusion of Li chloride/carbonate into polymeric matrices or being doped in bioceramics. The biocompatibility and multifunctionality of Li-doped bioceramics present many opportunities for biomedical researchers and clinicians. Li-doped bioceramics (capable of immunomodulation) have been used extensively for bone and tooth regeneration, and they have great potential for cartilage/nerve regeneration, osteochondral repair, and wound healing. The synergistic effect of Li in combination with other anticancer drugs as well as the anticancer properties of Li underline the rationale that bioceramics doped with Li may be impactful in cancer treatments. The role of Li in autophagy may explain its impact in regenerative, antiviral, and anticancer research. The combination of Li-doped bioceramics with polymers can provide new biomaterials with suitable flexibility, especially as bio-ink used in 3D printing for clinical applications of tissue engineering. Such Li-doped biomaterials have significant clinical potential in the foreseeable future.

Injectable muscle-adhesive antioxidant conductive photothermal bioactive nanomatrix for efficiently promoting full-thickness skeletal muscle regeneration.

The completed skeletal muscle regeneration resulted from severe injury and muscle-related disease is still a challenge. Here, we developed an injectable muscle-adhesive antioxidant conductive bioactive photothermo-responsive nanomatrix for regulating the myogenic differentiation and promoting the skeletal muscle regeneration in vivo. The multifunctional nanomatrix was composed of polypyrrole@polydopamine (PPy@PDA, 342 ± 5.6 nm) nanoparticles-crosslinked Pluronic F-127 (F127)-polycitrate matrix (FPCP). The FPCP nanomatrix demonstrated inherent multifunctional properties including excellent photothermo-responsive and shear-thinning behavior, muscle-adhesive feature, injectable ability, electronic conductivity (0.48 ± 0.03 S/m) and antioxidant activity and photothermal function. The FPCP nanomatrix displayed better photothermal performance with near-infrared irradiation, which could provide the photo-controlled release of protein (91% ± 2.6% of BSA was released after irradiated 3 times). Additionally, FPCP nanomatrix could significantly enhance the cell proliferation and myogenic differentiation of mouse myoblast cells (C2C12) by promoting the expressions of myogenic genes (MyoD and MyoG) and myosin heavy chain (MHC) protein with negligible cytotoxicity. Based on the multifunctional properties, FPCP nanomatrix efficiently promoted the full-thickness skeletal muscle repair and regeneration in vivo, through stimulating the angiogenesis and myotube formation. This study firstly indicated the vital role of multifunctional PPy@PDA nanoparticles in regulating myogenic differentiation and skeletal muscle regeneration. This work also suggests that rational design of bioactive matrix with multifunctional feature would greatly enhance the development of regenerative medicine.

A bioactive injectable self-healing anti-inflammatory hydrogel with ultralong extracellular vesicles release synergistically enhances motor functional recovery of spinal cord injury.

The repair and motor functional recovery after spinal cord injury (SCI) remains a worldwide challenge. The inflammatory microenvironment is one of main obstacles on inhibiting the recovery of SCI. Using mesenchymal stem cells (MSCs) derived extracellular vesicles to replace MSCs transplantation and mimic cell paracrine secretions provides a potential strategy for microenvironment regulation. However, the effective preservation and controlled release of extracellular vesicles in the injured spinal cord tissue are still not satisfied. Herein, we fabricated an injectable adhesive anti-inflammatory F127-polycitrate-polyethyleneimine hydrogel (FE) with sustainable and long term extracellular vesicle release (FE@EVs) for improving motor functional recovery after SCI. The orthotopic injection of FE@EVs hydrogel could encapsulate extracellular vesicles on the injured spinal cord, thereby synergistically induce efficient integrated regulation through suppressing fibrotic scar formation, reducing inflammatory reaction, promoting remyelination and axonal regeneration. This study showed that combining extracellular vesicles into bioactive multifunctional hydrogel should have great potential in achieving satisfactory locomotor recovery of central nervous system diseases.

Injectable self-healing bioactive antioxidative one-component poly(salicylic acid) hydrogel with strong ultraviolet-shielding for preventing skin light injury.

The design and development of one-component temperature-sensitive bioactive hydrogel with multifunctional properties for protecting skin against light injury remain a challenge. Herein, we report a bioactive multifunctional poly(salicylic acid)-F127-poly(salicylic acid) copolymer hydrogel (FPSa) with one-component for potential skin protection applications. The FPSa hydrogel possesses the thermosensitivity (23 °C), injectability, self-healing ability, ultraviolet shielding (shielding the wavelength between 280 and 370 nm), and antioxidation activity (above 70%), and also showed the good cytocompatibility (cell survival rate >90% and hemolysis rate less than 5%) and biodegradability (90% weight loss at 3 days). The in vivo animal model showed that FPSa hydrogel could effectively protect the skin tissue and prevent the ultraviolet induced injury. This study can provide a strategy to design multifunctional bioactive hydrogel with simple composition for disease therapy and regenerative medicine.

Functional Hydrogels as Wound Dressing to Enhance Wound Healing.

Hydrogels, due to their excellent biochemical and mechnical property, have shown attractive advantages in the field of wound dressings. However, a comprehensive review of the functional hydrogel as a wound dressing is still lacking. This work first summarizes the skin wound healing process and relates evaluation parameters and then reviews the advanced functions of hydrogel dressings such as antimicrobial property, adhesion and hemostasis, anti-inflammatory and anti-oxidation, substance delivery, self-healing, stimulus response, conductivity, and the recently emerged wound monitoring feature, and the strategies adopted to achieve these functions are all classified and discussed. Furthermore, applications of hydrogel wound dressing for the treatment of different types of wounds such as incisional wound and the excisional wound are summarized. Chronic wounds are also mentioned, and the focus of attention on infected wounds, burn wounds, and diabetic wounds is discussed. Finally, the future directions of hydrogel wound dressings for wound healing are further proposed.

Silk Polymers and Nanoparticles: A Powerful Combination for the Design of Versatile Biomaterials.

Silk fibroin (SF) is a natural protein largely used in the textile industry but also in biomedicine, catalysis, and other materials applications. SF is biocompatible, biodegradable, and possesses high tensile strength. Moreover, it is a versatile compound that can be formed into different materials at the macro, micro- and nano-scales, such as nanofibers, nanoparticles, hydrogels, microspheres, and other formats. Silk can be further integrated into emerging and promising additive manufacturing techniques like bioprinting, stereolithography or digital light processing 3D printing. As such, the development of methodologies for the functionalization of silk materials provide added value. Inorganic nanoparticles (INPs) have interesting and unexpected properties differing from bulk materials. These properties include better catalysis efficiency (better surface/volume ratio and consequently decreased quantify of catalyst), antibacterial activity, fluorescence properties, and UV-radiation protection or superparamagnetic behavior depending on the metal used. Given the promising results and performance of INPs, their use in many different procedures has been growing. Therefore, combining the useful properties of silk fibroin materials with those from INPs is increasingly relevant in many applications. Two main methodologies have been used in the literature to form silk-based bionanocomposites: in situ synthesis of INPs in silk materials, or the addition of preformed INPs to silk materials. This work presents an overview of current silk nanocomposites developed by these two main methodologies. An evaluation of overall INP characteristics and their distribution within the material is presented for each approach. Finally, an outlook is provided about the potential applications of these resultant nanocomposite materials.

Bioactive biodegradable polycitrate nanoclusters enhances the myoblast differentiation and in vivo skeletal muscle regeneration via p38 MAPK signaling pathway.

Complete skeletal muscle repair and regeneration due to severe large injury or disease is still a challenge. Biochemical cues are critical to control myoblast cell function and can be utilized to develop smart biomaterials for skeletal muscle engineering. Citric acid-based biodegradable polymers have received much attention on tissue engineering, however, their regulation on myoblast cell differentiation and mechanism was few investigated. Here, we find that citrate-based polycitrate-polyethylene glycol-polyethylenimine (POCG-PEI600) nanoclusters can significantly enhance the in vitro myoblast proliferation by probably reinforcing the mitochondrial number, promote the myotube formation and full-thickness skeletal muscle regeneration in vivo by activating the myogenic biomarker genes expression of Myod and Mhc. POCG-PEI600 nanoclusters could also promote the phosphorylation of p38 in MAP kinases (MAPK) signaling pathway, which led to the promotion of the myoblast differentiation. The in vivo skeletal muscle loss rat model also confirmed that POCG-PEI600 nanoclusters could significantly improve the angiogenesis, myofibers formation and complete skeletal muscle regeneration. POCG-PEI600 nanocluster could be also biodegraded into small molecules and eliminated in vivo, suggesting their high biocompatibility and biosafety. This study could provide a bioactive biomaterial-based strategy to repair and regenerate skeletal muscle tissue.

Engineering a Biodegradable Multifunctional Antibacterial Bioactive Nanosystem for Enhancing Tumor Photothermo-Chemotherapy and Bone Regeneration.

The simultaneous therapy of tumors and bone defects resulting from tumor surgery is still a challenge in clinical orthopedics. Few nanomaterial systems simultaneously possess multifunctional capacities, including biodegradability, tumor treatment, and enhanced bone regeneration. Herein, we designed a biodegradable monodispersed bioactive glass nanoparticle (BGN) platform with multifunctional properties for enhanced colon cancer photothermo-chemotherapy and bone repair. The mussel-inspired surface assembly with BGN was established as a stable NIR-excited photothermal nanoplatform (BGN@PDA) for ablating tumors. BGN@PDA shows an ultrahigh anticancer drug (DOX) loading with on-demand (pH/NIR-responsive) drug release behavior and antibacterial activity for enhanced tumor chemotherapy (BGN@PDA-DOX). The growth of colon cancer cells (Hct116 cells) and cervical cancer cells (HeLa cells) was significantly inhibited in vitro, and superior local anticancer efficacy could be achieved by synergic chemo-photothermal therapy in vivo. BGN@PDA underwent a gradual degradation in vivo during 60 days and showed negligible toxic side effects. Meanwhile, BGN@PDA could positively induce the osteogenesis of osteoblasts in vitro and possess excellent in vivo bone repair ability in rat cranial defects. This work presents a distinctive strategy to design a bioactive multifunctional nanoplatform for treating tumor disease-resulted bone tissue regeneration.

Design and evaluation of collagen-inspired mineral-hydrogel nanocomposites for bone regeneration.

Bone loss due to trauma and tumors remains a serious clinical concern. Due to limited availability and disease transmission risk with autografts and allografts, calcium phosphate bone fillers and growth factor-based substitute bone grafts are currently used in the clinic. However, substitute grafts lack bone regeneration potential when used without growth factors. When used along with the added growth factors, they lead to unwanted side effects such as uncontrolled bone growth. Collagen-based hydrogel grafts available on the market fail to provide structural guidance to native cells due to high water-solubility and faster degradation. To overcome these limitations, we employed bioinspired material design and fabricated three different hydrogels with structural features similar to native collagen at multiple length-scales. These hydrogels fabricated using polyionic complexation of oppositely charged natural polysaccharides exhibited multi-scale architecture mimicking nanoscale banding pattern, and microscale fibrous structure of native collagen. All three hydrogels promoted biomimetic apatite-like mineral deposition in vitro elucidating crystalline structure on the surface while amorphous calcium phosphate inside the hydrogels resulting in mineral-hydrogel nanocomposites. When evaluated in a non-load bearing critical size mouse calvaria defect model, chitosan - kappa carrageenan mineral-hydrogel nanocomposites enhanced bone regeneration without added growth factors compared to empty defect as well as widely used marketed collagen scaffolds. Histological assessment of the regenerated bone revealed improved healing and tissue remodeling with mineral-hydrogel nanocomposites. Overall, these collagen-inspired mineral-hydrogel nanocomposites showed multi-scale hierarchical structure and can potentially serve as promising bioactive hydrogel to promote bone regeneration. STATEMENT OF SIGNIFICANCE: Hydrogels, especially collagen, are widely used in bone tissue engineering. Collagen fibrils play arguably the most important role during natural bone development. Its multi-scale hierarchical structure to form fibers from fibrils and electrostatic charges enable mineral sequestration, nucleation, and growth. However, bulk collagen hydrogels exhibit limited bone regeneration and are mostly used as carriers for highly potent growth factors such as bone morphogenic protein-2, which increase the risk of uncontrolled bone growth. Thus, there is an unmet clinical need for a collagen-inspired biomaterial that can recreate structural hierarchy, mineral sequestration ability, and stimulate recruitment of host progenitor cells to facilitate bone regeneration. Here, we propose collagen-inspired bioactive mineral-hydrogel nanocomposites as a growth factor-free approach to guide and enhance bone regeneration.

Engineering multifunctional bioactive citric acid-based nanovectors for intrinsical targeted tumor imaging and specific siRNA gene delivery in vitro/in vivo.

Targeted tumor imaging and efficient specific gene delivery in vivo has been one of the main challenges in gene-based cancer diagnosis and therapy. Herein, we engineered a citric acid-based polymer with intrinsical photoluminescence and gene loading capacity to achieve targeted delivery of siRNA and tumor imaging in vitro and in vivo. The multifunctional platform was formed from the self-assembling of poly (citric acid)-polymine conjugated with folic acid and rhodamine B (PPFR). PPFR showed stable photoluminescent ability and could effectively bind and protect the siRNA against RNase degradation. PPFR also exhibited good blood compatibility and cell compatibility against C2C12, MCF-7 and A549. Compared with commercial transfection agent Lipofectamine™ 2000, PPFR had a high cellular uptake, equivalent transfection efficiency and effectively down-regulated intracellular p65 expression in A549 cancer cells. Importantly, PPFR could efficiently accumulate and label the tumor tissue through the fluorescent imaging, selectively deliver siRNA into tumor tissue in vivo based on the tumor-bearing nude mice model. This work may provide a facile strategy to synthesize multifunctional biocompatible biomaterials for targeted tumor imaging and gene therapy.

Biomimetic elastomeric, conductive and biodegradable polycitrate-based nanocomposites for guiding myogenic differentiation and skeletal muscle regeneration.

Artificial muscle-like biomaterials have gained tremendous interests owing to their broad applications in regenerative medicine, wearable devices, bioelectronics and artificial intelligence. Unfortunately, key challenges are still existed for current materials, including biomimetic viscoelasticity, biocompatibility and biodegradation, multifunctionality. Herein, for the first time, we develop highly elastomeric, conductive and biodegradable poly (citric acid-octanediol-polyethylene glycol)(PCE)-graphene (PCEG) nanocomposites, and demonstrate their applications in myogenic differentiation and guiding skeletal muscle tissue regeneration. In PCEG nanocomposites, PCE provides the biomimetic elastomeric behavior, and the addition of reduced graphene oxide (RGO) endows the enhanced mechanical strength and conductivity. The highly elastomeric behavior, significantly enhanced modulus (400%-800%), strength (200%-300%) of PCEG nanocomposites with controlled biodegradability and electrochemical conductivity were achieved. The myoblasts proliferation and myogenic differentiation were significantly improved by PCEG nanocomposite. Significantly high in vivo biocompatibility of PCEG nanocomposites was observed when implanted in the subcutaneous tissue for 4 weeks in rats. PCEG nanocomposites could significantly enhance the muscle fibers and blood vessels formation in vivo in a skeletal muscle lesion model of rat. This study may provide a novel strategy to develop multifunctional elastomeric nanocomposites with high biocompatibility for potential soft tissue regeneration and stretchable bioelectronic devices.

Photoluminescent arginine-functionalized polycitrate with enhanced cell activity and hemocompatibility for live cell bioimaging.

Development of biodegradable and highly biocompatible polymer with intrinsical photoluminescence and high photostability for real-time live cell bioimaging has attracted much attention recently. Here, a biodegradable and amphiphilic poly (citrate)-co-poly (ethylene glycol) (PEG) grafted with arginine (PCGA) polymer with intrinsical fluorescence was synthesized for targeted live cell bioimaging. The physicochemical structure, photoluminescent properties, hemocompatibility, cytotoxicity, and fluorescent bioimaging studies in live cells were determined in detail. PCGA showed a significantly high hemocompatibility, low cytotoxicity, and excellent photostability, which allows for imaging the live cells attachment and proliferation. Furthermore, PCGA could efficiently enhance cell attachment and proliferation due to the presence of arginine, suggesting their high cellular biocompatibility. Importantly, PCGA could selectively stain the lysosome in cells. Our results demonstrated that the amino acid-based polymer functionalization may be an important strategy to develop multifunctional biomaterials with enhanced biocompatibility for targeted bioimaging, cancer therapy, and regenerative medicine. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3175-3184, 2018.

Polyethylenimine-dermatan sulfate complex, a bioactive biomaterial with unique toxicity to CD146-positive cancer cells.

We report unique bioactivity of a polycation-polyanion complex with potential utility for cancer therapy. A complex of disulfide-crosslinked polyethyleneimine (CLPEI), a polycation used for gene complexation, and dermatan sulfate (DS), an anionic polysaccharide to shield excessive cationic charge of the former, has toxicity to a specific group of cancer cell lines, including B16-F10 murine melanoma, A375SM human melanoma, and PC-3 human prostate cancer cells. These CLPEI-DS-sensitive cells express CD146, which binds to the complex via interaction with DS. There is a positive correlation between toxicity and intracellular level of CLPEI, indicating that the CLPEI-DS-sensitivity is attributable to the increased cellular uptake of CLPEI mediated by the DS-CD146 interactions. In vitro studies show that CLPEI-DS complex causes G0/G1 phase arrest and apoptotic cell death. In syngeneic and allograft models of B16-F10 melanoma, CLPEI-DS complex administered with a sub-toxic level of doxorubicin potentiates the chemotherapeutic effect of the drug by loosening tumor tissues. Given the unique toxicity, CLPEI-DS complex may be a useful carrier of gene or chemotherapeutics for the therapy of CD146-positive cancers.