Correction: A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration.

Correction for 'A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration' by Shang Lyu et al., Mater. Horiz., 2024, https://doi.org/10.1039/D3MH01910A.

A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration.

Microneedles for skin regeneration are conventionally restricted by uncontrollable multi-drug release, limited types of drugs, and poor wound adhesion. Here, a novel core-shell microneedle patch is developed for scarless skin repair, where the shell is composed of hydrophilic gelatin methacryloyl (GelMA) loaded with mangiferin, an anti-inflammatory small molecule, and the core is composed of hydrophobic poly (lactide-co-propylene glycol-co-lactide) dimethacrylates (PGLADMA) loaded with bioactive macromolecule and human mesenchymal stromal cell (hMSC)-derived exosomes. This material choice provides several benefits: the GelMA shell provides a swelling interface for tissue interlocking and rapid release of mangiferin at an early wound healing stage for anti-inflammation, whereas the PGLADMA core offers long-term encapsulation and release of exosomes (30% release in 3 weeks), promoting sustained angiogenesis and anti-inflammation. Our results demonstrate that the core-shell microneedle possesses anti-inflammatory properties and can induce angiogenesis both in vitro in terms of macrophage polarization and tube formation of human umbilical vein endothelial cells (HUVECs), and in vivo in terms of anti-inflammation, re-epithelization, and vessel formation. Importantly, we also observe reduced scar formation in vivo. Altogether, the degradation dynamics of our hydrophilic/hydrophobic materials enable the design of a core-shell microneedle for differential and prolonged release, promoting scarless skin regeneration, with potential for other therapies of long-term exosome release.

Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice.

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

Mechanical characterization and design of biomaterials for nucleus pulposus replacement and regeneration.

Biomaterials for nucleus pulposus (NP) replacement and regeneration have great potential to restore normal biomechanics in degenerated intervertebral discs following nucleotomy. Mechanical characterizations are essential for assessing the efficacy of biomaterial implants for clinical applications. While traditional compression tests are crucial to quantify various modulus values, relaxation behaviors and fatigue resistance, rheological measurements should also be conducted to investigate the viscoelastic properties, injectability, and overall stability upon deformation. To recapitulate the physiological in vivo environment, the use of spinal models is necessary to evaluate the risk of implant extrusion and the restoration of biomechanics under different loading conditions. When designing devices for NP replacement, injectable materials are ideal to fully fill the nucleus cavity and prevent implant migration. In addition to achieving biocompatibility and desirable mechanical characteristics, biomaterial implants should be optimized to avoid implant extrusion or re-herniation post-operatively. This review discusses the most commonly used testing protocols for assessing mechanical properties of biomaterial implants and serves as reference material for enabling researchers to characterize NP implants through a unified approach whereby newly developed biomaterials may be compared and contrasted to existing devices.

A new osteogenic protein isolated from Dioscorea opposita Thunb accelerates bone defect healing through the mTOR signaling axis.

Delayed bone defect repairs lead to severe health and socioeconomic impacts on patients. Hence, there are increasing demands for medical interventions to promote bone defect healing. Recombinant proteins such as BMP-2 have been recognized as one of the powerful osteogenic substances that promote mesenchymal stem cells (MSCs) to osteoblast differentiation and are widely applied clinically for bone defect repairs. However, recent reports show that BMP-2 treatment has been associated with clinical adverse side effects such as ectopic bone formation, osteolysis and stimulation of inflammation. Here, we have identified one new osteogenic protein, named 'HKUOT-S2' protein, from Dioscorea opposita Thunb. Using the bone defect model, we have shown that the HKUOT-S2 protein can accelerate bone defect repair by activating the mTOR signaling axis of MSCs-derived osteoblasts and increasing osteoblastic biomineralization. The HKUOT-S2 protein can also modulate the transcriptomic changes of macrophages, stem cells, and osteoblasts, thereby enhancing the crosstalk between the polarized macrophages and MSCs-osteoblast differentiation to facilitate osteogenesis. Furthermore, this protein had no toxic effects in vivo. We have also identified HKUOT-S2 peptide sequence TKSSLPGQTK as a functional osteogenic unit that can promote osteoblast differentiation in vitro. The HKUOT-S2 protein with robust osteogenic activity could be a potential alternative osteoanabolic agent for promoting osteogenesis and bone defect repairs. We believe that the HKUOT-S2 protein may potentially be applied clinically as a new class of osteogenic agent for bone defect healing.

Probiotic-based nanoparticles for targeted microbiota modulation and immune restoration in bacterial pneumonia.

While conventional bacterial pneumonia mainly centralizes avoidance of bacterial colonization, it remains unclear how to restore the host immunity for hyperactive immunocompetent primary and immunocompromised secondary bacterial pneumonia. Here, probiotic-based nanoparticles of OASCLR were formed by coating chitosan, hyaluronic acid and ononin on living Lactobacillus rhamnosus. OASCLR nanoparticles could effectively kill various clinic common pathogens and antibacterial efficiency was >99.97%. Importantly, OASCLR could modulate lung microbiota, increasing the overall richness and diversity of microbiota by decreasing pathogens and increasing probiotic and commensal bacteria. Additionally, OASCLR could target inflammatory macrophages by the interaction of OASCLR with the macrophage binding site of CD44 and alleviate overactive immune responses for hyperactive immunocompetent pneumonia. Surprisingly, OASCLR could break the state of the macrophage's poor phagocytic ability by upregulating the expression of the extracellular matrix assembly, immune activation and fibroblast activation in immunocompromised pneumonia. The macrophage's phagocytic ability was increased from 2.61% to 12.3%. Our work provides a potential strategy for hyperactive immunocompetent primary and immunocompromised secondary bacterial pneumonia.

Realizing Highly Efficient Sonodynamic Bactericidal Capability through the Phonon-Electron Coupling Effect Using Two-Dimensional Catalytic Planar Defects.

Conferring catalytic defects in sonosensitizers is of paramount importance in reinforcing sonodynamic therapy. However, the formation of such 0D defects is governed by the Schottky defect principle. Herein, 2D catalytic planar defects are designed within Ti3 C2  sheets to address this challenge. These specific planar slip dislocations with abundant Ti3+ species (Ti3 C2 -SD(Ti3+ )) can yield surface-bound O due to the effective activation of O2 , thus resulting in a substantial amount of 1 O2  generation and the 99.72% ± 0.03% bactericidal capability subject to ultrasound (US) stimulation. It is discovered that the 2D catalytic planar defects can intervene in electron transfer through the phonon drag effect-a coupling effect between surface electrons and US-triggered phonons-that simultaneously contributes to a dramatic decrease in O2  activation energy from 1.65 to 0.06 eV. This design has achieved a qualitative leap in which the US catalytic site has transformed from 0D to 2D. Moreover, it is revealed that the electron origin, electron transfer, and visible O2  activation pathway triggered by US can be attributed to the phonon-electron coupling effect. After coating with neutrophil membrane (NM) proteins, the NM-Ti3 C2 -SD(Ti3+ ) sheets further demonstrate a 6-log10  reduction in methicillin-resistant Staphylococcus aureus burden in the infected bony tissue.

Gaussian curvature-driven direction of cell fate toward osteogenesis with triply periodic minimal surface scaffolds.

Leaf photosynthesis, coral mineralization, and trabecular bone growth depend on triply periodic minimal surfaces (TPMSs) with hyperboloidal structure on every surface point with varying Gaussian curvatures. However, translation of this structure into tissue-engineered bone grafts is challenging. This article reports the design and fabrication of high-resolution three-dimensional TPMS scaffolds embodying biomimicking hyperboloidal topography with different Gaussian curvatures, composed of body inherent ß-tricalcium phosphate, by stereolithography-based three-dimensional printing and sintering. The TPMS bone scaffolds show high porosity and interconnectivity. Notably, compared with conventional scaffolds, they can reduce stress concentration, leading to increased mechanical strength. They are also found to support the attachment, proliferation, osteogenic differentiation, and angiogenic paracrine function of human mesenchymal stem cells (hMSCs). Through transcriptomic analysis, we theorize that the hyperboloid structure induces cytoskeleton reorganization of hMSCs, expressing elongated morphology on the convex direction and strengthening the cytoskeletal contraction. The clinical therapeutic efficacy of the TPMS scaffolds assessed by rabbit femur defect and mouse subcutaneous implantation models demonstrate that the TPMS scaffolds augment new bone formation and neovascularization. In comparison with conventional scaffolds, our TPMS scaffolds successfully guide the cell fate toward osteogenesis through cell-level directional curvatures and demonstrate drastic yet quantifiable improvements in bone regeneration.

SARS-CoV-2 infection induces inflammatory bone loss in golden Syrian hamsters.

Extrapulmonary complications of different organ systems have been increasingly recognized in patients with severe or chronic Coronavirus Disease 2019 (COVID-19). However, limited information on the skeletal complications of COVID-19 is known, even though inflammatory diseases of the respiratory tract have been known to perturb bone metabolism and cause pathological bone loss. In this study, we characterize the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on bone metabolism in an established golden Syrian hamster model for COVID-19. SARS-CoV-2 causes significant multifocal loss of bone trabeculae in the long bones and lumbar vertebrae of all infected hamsters. Moreover, we show that the bone loss is associated with SARS-CoV-2-induced cytokine dysregulation, as the circulating pro-inflammatory cytokines not only upregulate osteoclastic differentiation in bone tissues, but also trigger an amplified pro-inflammatory cascade in the skeletal tissues to augment their pro-osteoclastogenesis effect. Our findings suggest that pathological bone loss may be a neglected complication which warrants more extensive investigations during the long-term follow-up of COVID-19 patients. The benefits of potential prophylactic and therapeutic interventions against pathological bone loss should be further evaluated.

Microwave assisted antibacterial action of Garcinia nanoparticles on Gram-negative bacteria.

Owing to the existence of the outer membrane barrier, most antibacterial agents cannot penetrate Gram-negative bacteria and are ineffective. Here, we report a general method for narrow-spectrum antibacterial Garcinia nanoparticles that can only be effective to kill Gram-positive bacteria, to effectively eliminate Gram-negative bacteria by creating transient nanopores in bacterial outer membrane to induce drug entry under microwaves assistance. In vitro, under 15 min of microwaves irradiation, the antibacterial efficiency of Garcinia nanoparticles against Escherichia coli can be enhanced from 6.73% to 99.48%. In vivo, MV-assisted GNs can effectively cure mice with bacterial pneumonia. The combination of molecular dynamics simulation and experimental results reveal that the robust anti-E. coli effectiveness of Garcinia nanoparticles is attributed to the synergy of Garcinia nanoparticles and microwaves. This work presents a strategy for effectively treating both Gram-negative and Gram-positive bacteria co-infected pneumonia using herbal medicine nanoparticles with MV assistance as an exogenous antibacterial auxiliary.

2D MOF Periodontitis Photodynamic Ion Therapy.

Traditional surgical intervention and antibiotic treatment are poor and even invalid for chronic diseases including periodontitis induced by diverse oral pathogens, which often causes progressive destruction of tissues, even tooth loss, and systemic diseases. Herein, an ointment comprising atomic-layer Fe2O3-modified two-dimensional porphyrinic metal-organic framework (2D MOF) nanosheets is designed by incorporating a polyethylene glycol matrix. After the atomic layer deposition surface engineering, the enhanced photocatalytic activity of the 2D MOF heterointerface results from lower adsorption energy and more charge transfer amounts due to the synergistic effect of metal-linker bridging units, abundant active sites, and an excellent light-harvesting network. This biocompatible and biodegradable 2D MOF-based heterostructure exhibits broad-spectrum antimicrobial activity (99.87 ± 0.09%, 99.57 ± 0.21%, and 99.03 ± 0.24%) against diverse oral pathogens (Porphyromonas gingivalis, Fusobacterium nucleatum, and Staphylococcus aureus) by the synergistic effect of reactive oxygen species and released ions. This photodynamic ion therapy exhibits a superior therapeutic effect to the reported clinical periodontitis treatment owing to rapid antibacterial activity, alleviative inflammation, and improved angiogenesis.

Enhanced Near-Infrared Photocatalytic Eradication of MRSA Biofilms and Osseointegration Using Oxide Perovskite-Based P-N Heterojunction.

Methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections after orthopedic implant increase the risk of failure and potentially cause amputation of limbs or life-threatening sepsis in severe cases. Additionally, satisfactory bone-implant integration is another important indicator of an ideal implant. Here, an antibiotic-free antibacterial nanofilm based on oxide perovskite-type calcium titanate (CTO)/fibrous red phosphorus (RP) on titanium implant surface (Ti-CTO/RP) in which the P-N heterojunction and internal electric field are established at the heterointerface, is designed. Near-infrared light-excited electron-hole pairs are effectively separated and transferred through the synergism of the internal electric field and band offset, which strongly boosts the photocatalytic eradication of MRSA biofilms by reactive oxygen species with an efficacy of 99.42% ± 0.22% in vivo. Additionally, the charge transfer endows the heterostructure with hyperthermia to assist biofilm eradication. Furthermore, CTO/RP nanofilm provides a superior biocompatible and osteoconductive platform that enables the proliferation and osteogenic differentiation of mesenchymal stem cells, thus contributing to the subsequent implant-to-bone osseointegration after eradicating MRSA biofilms.

Interfacial engineering of Bi2S3/Ti3C2Tx MXene based on work function for rapid photo-excited bacteria-killing.

In view of increasing drug resistance, ecofriendly photoelectrical materials are promising alternatives to antibiotics. Here we design an interfacial Schottky junction of Bi2S3/Ti3C2Tx resulting from the contact potential difference between Ti3C2Tx and Bi2S3. The different work functions induce the formation of a local electrophilic/nucleophilic region. The self-driven charge transfer across the interface increases the local electron density on Ti3C2Tx. The formed Schottky barrier inhibits the backflow of electrons and boosts the charge transfer and separation. The photocatalytic activity of Bi2S3/Ti3C2Tx intensively improved the amount of reactive oxygen species under 808 nm near-infrared radiation. They kill 99.86% of Staphylococcus aureus and 99.92% of Escherichia coli with the assistance of hyperthermia within 10 min. We propose the theory of interfacial engineering based on work function and accordingly design the ecofriendly photoresponsive Schottky junction using two kinds of components with different work functions to effectively eradicate bacterial infection.

Photo-controlled degradation of PLGA/Ti3C2 hybrid coating on Mg-Sr alloy using near infrared light.

A PLGA/Ti3C2 hybrid coating was successfully deposited on the surface of magnesium-strontium (Mg-Sr) alloys. Compared with the corrosion current density (i corr ) of the Mg-Sr alloy (7.13 × 10-5 A/cm2), the modified samples (Mg/PLGA/Ti3C2) was lower by approximately four orders of magnitude (7.65 × 10-9 A/cm2). After near infrared 808 nm laser irradiation, the i corr of the modified samples increased to 3.48 × 10-7 A/cm2. The mechanism is that the local hyperthermia induced the free volume expansion of PLGA, and the increase in intermolecular gap enhanced the penetration of electrolytes. Meanwhile, the cytotoxicity study showed that the hybrid coating endowed the Mg-Sr alloy with enhanced biocompatibility.

Antibacterial Hybrid Hydrogels.

Bacterial infectious diseases and bacterial-infected environments have been threatening the health of human beings all over the world. In view of the increased bacteria resistance caused by overuse or improper use of antibiotics, antibacterial biomaterials are developed as the substitutes for antibiotics in some cases. Among them, antibacterial hydrogels are attracting more and more attention due to easy preparation process and diversity of structures by changing their chemical cross-linkers via covalent bonds or noncovalent physical interactions, which can endow them with various specific functions such as high toughness and stretchability, injectability, self-healing, tissue adhesiveness and rapid hemostasis, easy loading and controlled drug release, superior biocompatibility and antioxidation as well as good conductivity. In this review, the recent progress of antibacterial hydrogel including the fabrication methodologies, interior structures, performances, antibacterial mechanisms, and applications of various antibacterial hydrogels is summarized. According to the bacteria-killing modes of hydrogels, several representative hydrogels such as silver nanoparticles-based hydrogel, photoresponsive hydrogel including photothermal and photocatalytic, self-bacteria-killing hydrogel such as inherent antibacterial peptides and cationic polymers, and antibiotics-loading hydrogel are focused on. Furthermore, current challenges of antibacterial hydrogels are discussed and future perspectives in this field are also proposed.

Ultrasonic Interfacial Engineering of Red Phosphorous-Metal for Eradicating MRSA Infection Effectively.

Sonodynamic therapy (SDT) is considered to be a potential treatment for various diseases including cancers and bacterial infections due to its deep penetration ability and biosafety, but its SDT efficiency is limited by the hypoxia environment of deep tissues. This study proposes creating a potential solution, sonothermal therapy, by developing the ultrasonic interfacial engineering of metal-red phosphorus (RP), which has an obviously improved sonothermal ability of more than 20 °C elevation under 25 min of continuous ultrasound (US) excitation as compared to metal alone. The underlying mechanism is that the mechanical energy of the US activates the motion of the interfacial electrons. US-induced electron motion in the RP can efficiently transfer the US energy into phonons in the forms of heat and lattice vibrations, resulting in a stronger US absorption of metal-RP. Unlike the nonspecific heating of the cavitation effect induced by US, titanium-RP can be heated in situ when the US penetrates through 2.5 cm of pork tissue. In addition, through a sonothermal treatment in vivo, bone infection induced by multidrug-resistant Staphylococcus aureus (MRSA) is successfully eliminated in under 20 min of US without tissue damage. This work provides a new strategy for combating MRSA by strong sonothermal therapy through US interfacial engineering.

Engineered probiotics biofilm enhances osseointegration via immunoregulation and anti-infection.

Preventing multidrug-resistant bacteria-related infection and simultaneously improving osseointegration are in great demand for orthopedic implants. However, current strategies are still limited to a combination of non-U.S. Food and Drug Administration-approved antibacterial and osteogenic agents. Here, we develop a food-grade probiotic-modified implant to prevent methicillin-resistant Staphylococcus aureus (MRSA) infection and accelerate bone integration. Lactobacillus casei is cultured on the surface of alkali heat-treated titanium (Ti) substrates and inactivated by ultraviolet irradiation to avoid sepsis induced by viable bacteria. This inactivated L. casei biofilm shows excellent 99.98% antibacterial effectiveness against MRSA due to the production of lactic acid and bacteriocin. In addition, the polysaccharides in the L. casei biofilm stimulate macrophages to secrete abundant osteogenic cytokines such as oncostatin M and improve osseointegration of the Ti implant. Inactivated probiotics modification can be a promising strategy to endow implants with both excellent self-antibacterial activity and osteointegration ability.

Photoelectrons Mediating Angiogenesis and Immunotherapy through Heterojunction Film for Noninvasive Disinfection.

A light-inspired hydroxyapatite (Hap)/nitrogen-doped carbon dots (NCDs) modified graphene oxide (GO) heterojunction film is developed, which shows a promoted separation of interfacial electrons and holes and an inhibited recombination efficiency via hole depletion. The metabolism of bacteria on this film is significantly inhibited under light irradiation, due to the enhanced photocatalytic and photothermal effects. In addition, the electron transfer from the plasmonic membrane to the GO/NCD/Hap film further inhibits the adenosine triphosphate process of bacteria, thus leading to the synergetic antibacterial efficacy. Meanwhile, the electron transfer between film and cell membrane induces the Ca2+ flow after irradiation, which can promote the migration and proliferation of cells and alkaline phosphatase enhancement, thus favoring the tissue reconstruction. An in vivo test discloses that the vascular injury repair is achieved through the Ca2+-activated PLCγ1/ERK pathway, identified by the enhanced CD31 expression. Moreover, the increased CD4+/CD8+ lymphocytes are ameliorative by activating the PI3K/P-AKT pathway. Consequently, the electron transfer boosts the synergic photodynamic and photothermal therapeutic effects for bacterial infection by Ca2+ flow for immunotherapy. This mild phototherapy approach with GO/NCDs/Hap, which can simultaneously repair injured vessels and relieve inflammation reactions, will increase the clinical application of noninvasive phototherapy in the near future.