Functionalized PLGA Microsphere Loaded with Fusion Peptide for Therapy of Bone Defects.

The challenges in the treatment of extensive bone defects are infection control and bone regeneration. Bone tissue engineering is currently one of the most promising strategies. In this study, a short biopeptide with specific osteogenic ability is designed by fusion peptide technology and encapsulated with chitosan-modified poly(lactic acid-glycolic acid) (PLGA) microspheres. The fusion peptide (FP) mainly consists of an osteogenic functional sequence (P-15) and a bone-specific binding sequence (Asp-6), which can regulate bone formation accurately and efficiently. Chitosan-modified PLGA with antimicrobial and pro-healing effects is used to achieve the sustained release of fusion peptides. In the early stage, the antimicrobial and soft tissue healing effects can stop the wound infection as soon as possible, which is relevant for the subsequent bone regeneration process. Our data show that CS-PLGA@FP microspheres have antibacterial and pro-cell migration effects in vitro and excellent pro-wound-healing effects in vivo. In addition, CS-PLGA@FP microspheres promote the expression of osteogenic-related factors and show excellent bone regeneration in a rat defect model. Therefore, CS-PLGA@FP microspheres are an efficient biomaterial that can accelerate the recovery of bone defects.

Functionalized 3D Hydroxyapatite Scaffold by Fusion Peptides-Mediated Small Extracellular Vesicles of Stem Cells for Bone Tissue Regeneration.

3D printing technology offers extensive applications in tissue engineering and regenerative medicine (TERM) because it can create a three-dimensional porous structure with acceptable porosity and fine mechanical qualities that can mimic natural bone. Hydroxyapatite (HA) is commonly used as a bone repair material due to its excellent biocompatibility and osteoconductivity. Small extracellular vesicles (sEVs) derived from bone marrow mesenchymal stem cells (BMSCs) can regulate bone metabolism and stimulate the osteogenic differentiation of stem cells. This study has designed a functionalized bone regeneration scaffold (3D H-P-sEVs) by combining the biological activity of BMSCs-sEVs and the 3D-HA scaffold to improve bone regeneration. The scaffold utilizes the targeting of fusion peptides to increase the loading efficiency of sEVs. The composition, structure, mechanical properties, and in vitro degradation performance of the 3D H-P-sEVs scaffolds were examined. The composite scaffold demonstrated good biocompatibility, substantially increased the expression of osteogenic-related genes and proteins, and had a satisfactory bone integration effect in the critical skull defect model of rats. In conclusion, the combination of EVs and 3D-HA scaffold via fusion peptide provides an innovative composite scaffold for bone regeneration and repair, improving osteogenic performance.

A Surface Matrix of Au NPs Decorated Graphdiyne for Multifunctional Laser Desorption/Ionization Mass Spectrometry.

The development of the valid strategy to enhance laser desorption/ionization efficiency gives rise to widespread concern in surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) technology. Herein, a hybrid of Au NP-decorated graphdiyne (Au/GDY) was fabricated and employed as the SALDI-MS matrix for the first time, and a mechanism based on photothermal and photochemical energy conversions was proposed to understand LDI processes. Given theoretical simulations and microstructure characterizations, it was revealed that the formation of a coupled thermal field and internal electric field endow the as-prepared Au/GDY matrix with superior desorption and ionization efficiency, respectively. Moreover, laser-induced matrix ablation introduced strain and defect level into the Au/GDY hybrid, suppressing the recombination of charge carriers and thereby facilitating analyte ionization. The optimized Au/GDY matrix allowed for reliable detection of trace sulfacetamide and visualization of exogenous/endogenous components in biological tissues. This work offers an integrated solution to promote LDI efficiency based on collaborative photothermal conversion and internal electric field, and may inspire the design of novel semiconductor-based surface matrices.

Correction: Synergetic osteogenesis of extracellular vesicles and loading RGD colonized on 3D-printed titanium implants.

Correction for 'Synergetic osteogenesis of extracellular vesicles and loading RGD colonized on 3D-printed titanium implants' by Shiqing Ma et al., Biomater. Sci., 2022, 10, 4773-4784, https://doi.org/10.1039/D2BM00725H.

A Bone Targeting Nanoparticle Loaded OGP to Restore Bone Homeostasis for Osteoporosis Therapy.

Restoring bone homeostasis is the key to the treatment of osteoporosis. How to increase osteogenic ability or inhibit osteoclast activity has always been a topic of great concern. In recent years, short peptides with biological activity have received great attention in bone repair. However, the application of short peptides is still limited due to the lack of a stable and targeted delivery system. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles modified by alendronate (AL) to transport osteogenic peptides (OGP) (AL-PLGA@P NPs) are designed. Benefiting from the high affinity of AL for hydroxyapatite, AL-PLGA@P NPs have the ability to target bone. In this delivery system, OGP that promotes osteogenesis synergizes with AL, which inhibits osteoclasts, to regulate bone homeostasis, which gives them more advantages in the treatment of osteoporosis. The data shows that nanoparticles can selectively deliver peptides to the bone surface without systemic toxicity. Moreover, nanoparticles can upregulate osteogenesis-related factors (ALP, Runx-2, and BMP2) and downregulate osteoclast-related factors (TRAP and CTSK) in vitro. With AL-PLGA@P NPs, bone microarchitecture and bone mass are improved in ovariectomized osteoporosis rats. Therefore, this study proposes a novel osteoporosis-based drug system that effectively improves bone density.

Intracavity adaptive correction of an unstable standing-wave resonator based on reconstruction matrix optimization.

Due to the existence of the expanding beam portion in the positive branch confocal unstable resonator, the laser passes through the intracavity deformable mirror (DM) twice with different apertures, which makes it complicated to calculate the required compensation surface of the DM. In this paper, an adaptive compensation method for intracavity aberrations based on reconstruction matrix optimization is proposed to solve this problem. A collimated probe laser of 976 nm and a Shack-Hartmann wavefront sensor (SHWFS) are introduced from the outside of the resonator to detect intracavity aberrations. The feasibility and effectiveness of this method are verified by numerical simulations and the passive resonator testbed system. By adopting the optimized reconstruction matrix, the control voltages of the intracavity DM can be directly calculated from the SHWFS slopes. After compensation by the intracavity DM, the beam quality ß of the annular beam coupled out from the scraper is improved from 6.2 times diffraction limit to 1.6 times diffraction limit.

A pH-Responsive Asymmetric Microfluidic/Chitosan Device for Drug Release in Infective Bone Defect Treatment.

Bacterial infection is currently considered to be one of the major reasons that leads to the failure of guided bone regeneration (GBR) therapy. Under the normal condition, the pH is neutral, while the microenvironment will become acid at the sites of infection. Here, we present an asymmetric microfluidic/chitosan device that can achieve pH-responsive drug release to treat bacterial infection and promote osteoblast proliferation at the same time. On-demand release of minocycline relies on a pH-sensitive hydrogel actuator, which swells significantly when exposed to the acid pH of an infected region. The PDMAEMA hydrogel had pronounced pH-sensitive properties, and a large volume transition occurred at pH 5 and 6. Over 12 h, the device enabled minocycline solution flowrates of 0.51-1.63 µg/h and 0.44-1.13 µg/h at pH 5 and 6, respectively. The asymmetric microfluidic/chitosan device exhibited excellent capabilities for inhibiting Staphylococcus aureus and Streptococcus mutans growth within 24 h. It had no negative effect on proliferation and morphology of L929 fibroblasts and MC3T3-E1 osteoblasts, which indicates good cytocompatibility. Therefore, such a pH-responsive drug release asymmetric microfluidic/chitosan device could be a promising therapeutic approach in the treatment of infective bone defects.

Modification of the small intestinal submucosa membrane with oligopeptides screened from intrinsically disordered regions to promote angiogenesis and accelerate wound healing.

A slow vascularization rate is considered one of the major disadvantages of biomaterials used for accelerating wound healing. Several efforts, including cellular and acellular technologies, have been made to facilitate biomaterial-induced angiogenesis. However, no well-established techniques for promoting angiogenesis have been reported. In this study, a small intestinal submucosa (SIS) membrane modified by an angiogenesis-promoting oligopeptide (QSHGPS) screened from intrinsically disordered regions (IDRs) of MHC class II was used to promote angiogenesis and accelerate wound healing. Because the main component of SIS membranes is collagen, the collagen-binding peptide sequence TKKTLRT and the pro-angiogenic oligopeptide sequence QSHGPS were used to construct chimeric peptides to obtain specific oligopeptide-loaded SIS membranes. The resulting chimeric peptide-modified SIS membranes (SIS-L-CP) significantly promoted the expression of angiogenesis-related factors in umbilical vein endothelial cells. Furthermore, SIS-L-CP exhibited excellent angiogenic and wound-healing abilities in a mouse hindlimb ischaemia model and a rat dorsal skin defect model. The high biocompatibility and angiogenic capacity of the SIS-L-CP membrane make it promising in angiogenesis- and wound healing-related regenerative medicine.

A Lead-Free 0D/2D Cs3Bi2Br9/Bi2WO6 S-Scheme Heterojunction for Efficient Photoreduction of CO2.

Photocatalytic reduction of CO2 into valuable hydrocarbon fuels is one of the green ways to solve the energy problem and achieve carbon neutrality. Exploring photocatalyst with low toxicity and high-efficiency is the key to realize it. Here we report a lead-free halide perovskite-based 0D/2D Cs3Bi2Br9/Bi2WO6 (CBB/BWO) S-scheme heterojunction for CO2 photoreduction, prepared by a facile electrostatic self-assembly approach. The CBB/BWO shows superior photoreduction of CO2 under visible light with CO generation rate of 220.1 µmol·g-1·h-1, which is ∼115.8 and ∼18.5 times higher than that of Cs3Bi2Br9 perovskite quantum dots (CBB PQDS) and Bi2WO6 nanosheets (BWO NS), respectively. The improved photocatalytic activity can be attributed to the tight 0D/2D structure and S-scheme charge transfer pathway between the Cs3Bi2Br9 PQDS and atomic layers of the Bi2WO6 NS, which shortens transmission distance of photogenerated carriers and boosts efficient separation and transfer of the carriers. This work provides insight in manufacturing potential lead-free perovskite-based photocatalysts for achieving carbon neutrality.

SIS membrane modification to improve antimicrobial and osteogenic properties for guide bone regeneration.

The guided bone regeneration (GBR) technique is the most common and durable approach to repairing bone defects in periodontal surgery. However, membrane exposure causes bacterial infiltration, which lowers the functional integrity of the barrier membrane and destroys bone repair. Here, an antibacterial peptide-modified small intestinal submucosa (SIS) membrane is used as a new GBR membrane for effective bone regeneration. The peptide JH8194 was placed into chitosan microspheres to preserve its stability and allow for sustained release, which realizes rapid and efficient functional modification of the SIS membrane. Biocompatibility and certain antibacterial activities were found in the modified SIS membrane (SIS@CS-JH8194). Additionally, in vitro experiments showed that SIS@CS-JH8194 promoted the expression of osteogenic-related factors and decreased the secretion of inflammatory factors in rat bone mesenchymal stem cells. In vivo experiments showed that SIS@CS-JH8194 could effectively promote bone regeneration in rat skull defects. In this work, we created a new antibacterial GBR membrane to help avoid postoperative infection and improve bone tissue regeneration.

A drug delivery system constructed by a fusion peptide capturing exosomes targets to titanium implants accurately resulting the enhancement of osseointegration peri-implant.

BACKGROUND: Exosomes derived from bone marrow mesenchymal stem cells (BMSC-exos) have been shown triggering osteogenic differentiation and mineralization of MSCs, but exosomes administered via bolus injections are rapidly sequestered and cleared. Therefore, we considered the implant as a new organ of patient's body and expected to find a method to treat implant with BMSC-exos in vivo directly. METHODS: A fusion peptide (PEP), as a drug delivery system (DDS) which contained a titanium-binding peptide (TBP) possessing the ability to selectively bind to the titanium surface and another peptide CP05 being able to capture exosomes expertly, is constructed to modify the titanium surface. RESULTS: Both in vitro and in vivo experiments prove PEP retains the ability to bind titanium and exosome simultaneously, and the DDS gain the ability to target exosomes to titanium implants surface following enhancing osseointegration post-implantation. Moreover, the DDS constructed by exosomes of diverse origins shows the similar combination rate and efficiency of therapy. CONCLUSION: This drug delivery system demonstrates the concept that EXO-PEP system can offer an accurate and efficient therapy for treating implants with long-term effect.

An Asymmetric Microfluidic/Chitosan Device for Sustained Drug Release in Guided Bone Regeneration Applications.

One of the major challenges of guided bone regeneration (GBR) is infections caused by pathogen colonization at wound sites. In this paper, an asymmetric microfluidic/chitosan device was developed to release drugs to inhibit infections and to ensure that guided bone regeneration can be realized. The microfluidic technique was introduced into the GBR membrane for the first time, which demonstrated more controllable drug release, more flexible clinical use and had a lower cost compared with surface treatments and embedded nanoparticles. Based on the theory of diffusion and Fick's first law, the contact area and concentration gradient were adjusted to realize sustained drug release. The standard deviation of minocycline release over 5 days was only 12.7%, which was lower than the joint effect of porous chitosan discs and nanospheres. The in vitro experiments against E. coli and Streptococcus mutans showed the excellent antibacterial performance of the device (>95%). The in vitro experiments for fibroblasts at the microfluidic side and osteoblasts at the chitosan side showed the satisfactory biocompatibility and the ability of the device to enhance bone regeneration. Therefore, this microfluidic/chitosan device is a promising therapeutic approach to prevent infection and guide bone regeneration.

An injectable multifunctional thermo-sensitive chitosan-based hydrogel for periodontitis therapy.

Bacteria are recognized as the driving factors of periodontitis. However, excessive reactive oxygen species (ROS) can harm periodontal tissue while also causing an uncontrolled inflammatory response. Hence, eliminating excessive ROS and blocking ROS-induced abnormal inflammatory response by antioxidants are achieving remarkable results in periodontitis therapy. Moreover, influenced by the deep and irregular periodontal pockets, injectable thermo-sensitive chitosan-based hydrogels have attracted a lot of attention. This study aimed to formulate an antibacterial and antioxidant therapeutic regimen by incorporating antimicrobial peptides (Nal-P-113) and/or antioxidants (polydopamine nanoparticles, PDNPs) into chitosan-based hydrogels. The hydrogel was characterized in vitro and finally examined in rats using the experimental periodontitis model. The release kinetics showed that the hydrogel could stably release Nal-P-113 and PDNPs for up to 13 days. The scavenging activity of the hydrogel against DPPH was about 80 % and the antibacterial ratio against Streptococcus gordonii (S. gordonii), Fusobacterium nucleatum (F. nucleatum) and Porphyromonas gingivalis (P. gingivalis) was about 99 %. Importantly, it was examined that the hydrogel had the ability to prevent periodontal tissue damage. Thus, chitosan-based hydrogels may provide a basis for designing multifunctional local drug delivery biomaterials for the treatment of periodontitis.

Microsphere-Gel Composite System with Mesenchymal Stem Cell Recruitment, Antibacterial, and Immunomodulatory Properties Promote Bone Regeneration via Sequential Release of LL37 and W9 Peptides.

Various types of biomaterials have been widely used to treat complex bone defects. However, potential infection risks and inappropriate host immune responses induced by biomaterials can adversely affect the final bone repair outcome. Therefore, the development of novel bone biomaterials with antibacterial and immunomodulatory capabilities is conducive to achieving a good interaction between the host and material, thereby creating a local microenvironment favorable for osteogenesis and ultimately accelerating bone regeneration. In this study, we fabricated a porcine small intestinal submucosa (SIS) hydrogel containing LL37 peptides and polylactic-glycolic acid (PLGA) microspheres encapsulated with WP9QY(W9) peptide (LL37-W9/PLGA-SIS), which can fill irregular bone defects and exhibits excellent mechanical properties. In vitro experiments showed that the microsphere-gel composite system had sequential drug release characteristics. The LL37 peptide released first had good antibacterial performance and BMSC recruitment ability, which could prevent infection at an early stage and increase the number of BMSCs at the injured site. In addition, it also has immunomodulatory properties, showing both pro-inflammatory and anti-inflammatory activities, but its early pro-inflammatory properties are more inclined to activate the M1 phenotype of macrophages. Moreover, the subsequently released W9 peptide not only reduced the expression of pro-inflammatory genes to alleviate inflammation and induced more macrophages to convert to M2 phenotypes but also promoted the osteogenic differentiation of BMSCs. This finely regulated immune response is considered to be more closely related to the physiological bone healing process. When studying the interaction between macrophages and BMSCs mediated by the material, it was found that the immunomodulatory and osteogenic effects were enhanced. In vivo experiments, we constructed rat skull defect models, which further proved that LL37-W9/PLGA-SIS gel can properly regulate the immune response, and has a good ability to promote osteogenesis in situ. In conclusion, the LL37-W9/PLGA-SIS hydrogel has great application prospects in immune regulation and bone therapy.

Mechanically active small intestinal submucosa hydrogel for accelerating chronic wound healing.

The treatment of chronic wounds is still a challenge worldwide. Here, inspired by mechanically induced embryonic wound healing, we design a mechanically active small intestinal submucosa based hydrogel (SIS-PNIPAm). The mechanical activity, biocompatibility, and bioactivity (angiogenesis and immunoregulation) of the SIS-PNIPAm hydrogel enable the fast healing of diabetic rat full-thickness wounds.

Synergetic osteogenesis of extracellular vesicles and loading RGD colonized on 3D-printed titanium implants.

Titanium (Ti) and its alloys have been universally used as surgical implants, and the clinical need for modifying titanium surfaces to accelerate early stage osseointegration and prevent implant loosening is in huge demand. 3D printing technology is an accurate and controllable method to create titanium implants with complex nanostructures, which provide enough space to react and fit in the microenvironment of cells. Recently, extracellular vesicles (EVs) have attracted attention in promoting osteogenesis. The vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) have been proved to pack osteogenic-relative RNAs thereby regulating the osteogenic differentiation and mineralization of the target BMSCs. Arg-Gly-Asp (RGD)-derived peptides are typical peptides used to improve cell attachment and proliferation in bone tissue engineering. A novel strategy is proposed to load RGD-derived peptides on EVs with a fusion peptide (EVsRGD) and colonize EVsRGD on the titanium surface via a specific bonding peptide. In this study, we verify that the presence of EVsRGD enables the realization of the synergetic effect of EVs and RGD, enhancing the osteogenic differentiation and mineralization of BMSCs in vitro, resulting in satisfactory osseointegration around implants in vivo.