The Mechanisms of Adipose Stem Cell-Derived Exosomes Promote Wound Healing and Regeneration.

Chronic wound healing is a class of diseases influenced by multiple complex factors, causing severe psychological and physiological impact on patients. It is an intractable clinical challenge and its possible mechanisms are not yet clear. It has been proven that adipose stem cell-derived exosomes (ADSC-Exos) can promote wound healing and inhibit scar formation by regulating inflammation, promoting cell proliferation, migration, and angiogenesis, regulating matrix remodeling, which provides a new approach for wound healing through biological treatment. This review focuses on the mechanism, treatment, and administration methods of ADSC-Exos in wound healing, providing a comprehensive understanding the mechanisms of ADSC-Exos on wound healing. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Layered GelMA/PEGDA Hydrogel Microneedle Patch as an Intradermal Delivery System for Hypertrophic Scar Treatment.

Hypertrophic scar (HS) is an unfavorable skin disorder that typically develops after trauma, burn injury, or surgical procedures and causes numerous physical and psychological issues in patients. Currently, intralesional multi-injection of corticosteroid, particularly compound betamethasone (CB), is one of the most prevalent treatments for HS. However, injection administration could result in severe pain and dose-related side effects. Additionally, the vacuum therapeutic efficacy of this treatment relies on the level of expertise of the healthcare professional. To overcome the limitations of conventional injections, a new method that is convenient, painless, and self-administrable is urgently required. In this study, we developed a methacrylate gelatin (GelMA)/polyethylene glycol diacrylate (PEGDA) double-network hydrogel microneedle patch loaded with CB (CB-HMNP) as an intradermal delivery system for HS treatment. The double-network structure conferred the CB-HMNP with sufficient mechanical properties to successfully penetrate scar tissue while also helping to regulate the drug's sustained release rate. Subsequently, we confirmed that the CB-HMNP had a pronounced inhibitory effect on human HS fibroblasts (hHSFs), whereas drug-free HMNPs had no effect on hHSFs, indicating its high biocompatibility. In order to assess the therapeutic efficacy of CB-HMNPs, HS models of New Zealand rabbit ears were developed. The administration of CB-HMNP three times significantly decreased the scar elevation index (SEI), collagen I/III, and transforming growth factor-ß1 (TGF-ß1) protein. Therefore, the CB-HMNP may offer an administration pathway for the treatment of HS that is less painful, more convenient, less invasive, and sustain-released.

Error assessment and correction for extrusion-based bioprinting using computer vision method.

299Bioprinting offers a new approach to addressing the organ shortage crisis. Despite recent technological advances, insufficient printing resolution continues to be one of the reasons that impede the development of bioprinting. Normally, machine axes movement cannot be reliably used to predict material placement, and the printing path tends to deviate from the predetermined designed reference trajectory in varying degrees. Therefore, a computer vision-based method was proposed in this study to correct trajectory deviation and improve printing accuracy. The image algorithm calculated the deviation between the printed trajectory and the reference trajectory to generate an error vector. Furthermore, the axes trajectory was modified according to the normal vector approach in the second printing to compensate for the deviation error. The highest correction efficiency that could be achieved was 91%. More significantly, we discovered that the correction results, for the first time, were in a normal distribution instead of a random distribution.

Small extracellular vesicles derived from human adipose-derived stem cells regulate energetic metabolism through the activation of YAP/TAZ pathway facilitating angiogenesis.

Recent studies have found small extracellular vesicles (sEVs) that are secreted from human adipose tissue-derived stem cells (hADSCs-sEVs) and contribute to angiogenesis. Glycolysis, the primary energetic pathway of vascular endothelial cells, plays a key role in the process of angiogenesis. However, hADSCs-sEVs' effects on energy metabolism within endothelial cells remain unclear. In our study, we found that hADSCs-sEVs restored glycolytic metabolism suppressed by 3-(pyridinyl)-1-(4-pyridinyl)-2-propen-1-one(3PO), a unique glycolytic inhibitor increasing the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glycolytic gene expression as well as pyruvate, lactate, and ATP production in HUVEC cells. In contrast, hADSCs-sEVs decreased PDH-E1α expression and acetyl-CoA production. The above results indicate that hADSCs-sEVs promote HUVEC angiogenesis via enhancing glycolysis and suppressing mitochondrial oxidative phosphorylation. Furthermore, we found that the YAP/TAZ pathway may play a key role in the effects hADSCs-sEVs have on HUVECs, thus, providing a promising approach for pro-angiogenesis-related regeneration.

Medical high-entropy alloy: Outstanding mechanical properties and superb biological compatibility.

Medical metal implants are required to have excellent mechanical properties and high biocompatibility to handle the complex human environment, which is a challenge that has always existed for traditional medical metal materials. Compared to traditional medical alloys, high entropy alloys (HEAs) have a higher design freedom to allow them to carry more medical abilities to suit the human service environment, such as low elastic modulus, high biocompatible elements, potential shape memory capability. In recent years, many studies have pointed out that bio-HEAs, as an emerging medical alloy, has reached or even surpassed traditional medical alloys in various medical properties. In this review, we summarized the recent reports on novel bio-HEAs for medical implants and divide them into two groups according the properties, namely mechanical properties and biocompatibility. These new bio-HEAs are considered hallmarks of a historic shift representative of a new medical revolution.

Computer Vision-Aided 2D Error Assessment and Correction for Helix Bioprinting.

Bioprinting is an emerging multidisciplinary technology for organ manufacturing, tissue repair, and drug screening. The manufacture of organs in a layer-by-layer manner is a characteristic of bioprinting technology, which can also determine the accuracy of constructs confined by the printing resolution. The lack of sufficient resolution will result in defect generation during the printing process and the inability to complete the manufacture of complex organs. A computer vision-based method is proposed in this study to detect the deviation of the printed helix from the reference trajectory and calculate the modified reference trajectory through error vector compensation. The new printing helix trajectory resulting from the modified reference trajectory error is significantly reduced compared with the original helix trajectory and the correction efficiency exceeded 90%.

Pore Strategy Design of a Novel NiTi-Nb Biomedical Porous Scaffold Based on a Triply Periodic Minimal Surface.

The pore strategy is one of the important factors affecting the biomedical porous scaffold at the same porosity. In this work, porous scaffolds were designed based on the triply periodic minimal surface (TPMS) structure under the same porosity and different pore strategies (pore size and size continuous gradient distribution) and were successfully prepared using a novel Ni46.5Ti44.5Nb9 alloy and selective laser melting (SLM) technology. After that, the effects of the pore strategies on the microstructure, mechanical properties, and permeability of porous scaffolds were systematically investigated. The results showed that the Ni46.5Ti44.5Nb9 scaffolds have a low elastic modulus (0.80-1.05 GPa) and a high ductility (15.3-19.1%) compared with previous works. The pore size has little effect on their mechanical properties, but increasing the pore size significantly improves the permeability due to the decrease in specific surfaces. The continuous gradient distribution of the pore size changes the material distribution of the scaffold, and the smaller porosity structure has a better load-bearing capacity and contributes primarily to the high compression strength. The local high porosity structure bears more fluid flow, which can improve the permeability of the overall scaffold. This work can provide theoretical guidance for the design of porous scaffolds.

TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration.

Despite the widespread observations on the osteogenic effects of magnesium ion (Mg2+), the diverse roles of Mg2+ during bone healing have not been systematically dissected. Here, we reveal a previously unknown, biphasic mode of action of Mg2+ in bone repair. During the early inflammation phase, Mg2+ contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7), and a TRPM7-dependent influx of Mg2+ in the monocyte-macrophage lineage, resulting in the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs). This then triggers the phosphorylation of Histone H3 at serine 10, in a TRPM7-dependent manner at the promoters of inflammatory cytokines, leading to the formation of a pro-osteogenic immune microenvironment. In the later remodeling phase, however, the continued exposure of Mg2+ not only lead to the over-activation of NF-κB signaling in macrophages and increased number of osteoclastic-like cells but also decelerates bone maturation through the suppression of hydroxyapatite precipitation. Thus, the negative effects of Mg2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg2+. Taken together, this study establishes a paradigm shift in the understanding of the diverse and multifaceted roles of Mg2+ in bone healing.

Regulation of extracellular bioactive cations in bone tissue microenvironment induces favorable osteoimmune conditions to accelerate in situ bone regeneration.

The design of orthopedic biomaterials has gradually shifted from "immune-friendly" to "immunomodulatory," in which the biomaterials are able to modulate the inflammatory response via macrophage polarization in a local immune microenvironment that favors osteogenesis and implant-to-bone osseointegration. Despite the well-known effects of bioactive metallic ions on osteogenesis, how extracellular metallic ions manipulate immune cells in bone tissue microenvironments toward osteogenesis and subsequent bone formation has rarely been studied. Herein, we investigate the osteoimmunomodulatory effect of an extracellular bioactive cation (Mg2+) in the bone tissue microenvironment using custom-made poly lactic-co-glycolic acid (PLGA)/MgO-alendronate microspheres that endow controllable release of magnesium ions. The results suggest that the Mg2+-controlled tissue microenvironment can effectively induce macrophage polarization from the M0 to M2 phenotype via the enhancement of anti-inflammatory (IL-10) and pro-osteogenic (BMP-2 and TGF-ß1) cytokines production. It also generates a favorable osteoimmune microenvironment that facilitates the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. The in vivo results further verify that a large amount of bony tissue, with comparable bone mineral density and mechanical properties, has been generated at an early post-surgical stage in rat intramedullary bone defect models. This study demonstrates that the concept of in situ immunomodulated osteogenesis can be realized in a controlled magnesium tissue microenvironment.

Recent Advances in Microfluidic Platforms Applied in Cancer Metastasis: Circulating Tumor Cells' (CTCs) Isolation and Tumor-On-A-Chip.

Cancer remains the leading cause of death worldwide despite the enormous efforts that are made in the development of cancer biology and anticancer therapeutic treatment. Furthermore, recent studies in oncology have focused on the complex cancer metastatic process as metastatic disease contributes to more than 90% of tumor-related death. In the metastatic process, isolation and analysis of circulating tumor cells (CTCs) play a vital role in diagnosis and prognosis of cancer patients at an early stage. To obtain relevant information on cancer metastasis and progression from CTCs, reliable approaches are required for CTC detection and isolation. Additionally, experimental platforms mimicking the tumor microenvironment in vitro give a better understanding of the metastatic microenvironment and antimetastatic drugs' screening. With the advancement of microfabrication and rapid prototyping, microfluidic techniques are now increasingly being exploited to study cancer metastasis as they allow precise control of fluids in small volume and rapid sample processing at relatively low cost and with high sensitivity. Recent advancements in microfluidic platforms utilized in various methods for CTCs' isolation and tumor models recapitulating the metastatic microenvironment (tumor-on-a-chip) are comprehensively reviewed. Future perspectives on microfluidics for cancer metastasis are proposed.

A surface-engineered multifunctional TiO2 based nano-layer simultaneously elevates the corrosion resistance, osteoconductivity and antimicrobial property of a magnesium alloy.

Magnesium biometals exhibit great potentials for orthopeadic applications owing to their biodegradability, bioactive effects and satisfactory mechanical properties. However, rapid corrosion of Mg implants in vivo combined with large amount of hydrogen gas evolution is harmful to bone healing process which seriously confines their clinical applications. Enlightened by the superior biocompatibility and corrosion resistance of passive titanium oxide layer automatically formed on titanium alloy, we employ the Ti and O dual plasma ion immersion implantation (PIII) technique to construct a multifunctional TiO2 based nano-layer on ZK60 magnesium substrates for enhanced corrosion resistance, osteoconductivity and antimicrobial activity. The constructed nano-layer (TiO2/MgO) can effectively suppress degradation rate of ZK60 substrates in vitro and still maintain 94% implant volume after post-surgery eight weeks. In animal study, a large amount of bony tissue with increased bone mineral density and trabecular thickness is formed around the PIII treated group in post-operation eight weeks. Moreover, the newly formed bone in the PIII treated group is well mineralized and its mechanical property almost restores to the level of that of surrounding mature bone. Surprisingly, a remarkable killing ratio of 99.31% against S. aureus can be found on the PIII treated sample under ultra-violet (UV) irradiation which mainly attributes to the oxidative stress induced by the reactive oxygen species (ROS). We believe that this multifunctional TiO2 based nano-layer not only controls the degradation of magnesium implant, but also regulates its implant-to-bone integration effectively. STATEMENT OF SIGNIFICANCE: Rapid corrosion of magnesium implants is the major issue for orthopaedic applications. Inspired by the biocompatibility and corrosion resistance of passive titanium oxide layer automatically formed on titanium alloy, we construct a multifunctional TiO2/MgO nanolayer on magnesium substrates to simultaneously achieve superior corrosion resistance, satisfactory osteoconductivity in rat intramedullary bone defect model and excellent antimicrobial activity against S. aureus under UV irradiation. The current findings suggest that the specific TiO2/MgO nano-layer on magnesium surface can achieve the three objectives aforementioned and we believe this study can demonstrate the potential of biodegradable metals for future clinical applications.

A functionalized TiO2/Mg2TiO4 nano-layer on biodegradable magnesium implant enables superior bone-implant integration and bacterial disinfection.

Rapid corrosion of biodegradable magnesium alloys under in vivo condition is a major concern for clinical applications. Inspired by the stability and biocompatibility of titanium oxide (TiO2) passive layer, a functionalized TiO2/Mg2TiO4 nano-layer has been constructed on the surface of WE43 magnesium implant by using plasma ion immersion implantation (PIII) technique. The customized nano-layer not only enhances corrosion resistance of Mg substrates significantly, but also elevates the osteoblastic differentiation capability in vitro due to the controlled release of magnesium ions. In the animal study, the increase of new bone formation adjacent to the PIII-treated magnesium substrate is 175% higher at post-operation 12 weeks, whereas the growth of new bone on titanium control and untreated magnesium substrate are only 97% and 29%, respectively. In addition, its Young's modulus can be restored to about 82% as compared with the surrounding matured bone. Furthermore, this specific TiO2/Mg2TiO4 layer even exhibits photoactive bacteria disinfection capability when irradiated by ultraviolet light which is attributed to the intracellular reactive oxygen species (ROS) production. With all these constructive observations, it is believed that the TiO2/Mg2TiO4 nano-layer on magnesium implants can significantly promote new bone formation and suppress bacterial infection, while the degradation behavior can be controlled simultaneously.

Precisely controlled delivery of magnesium ions thru sponge-like monodisperse PLGA/nano-MgO-alginate core-shell microsphere device to enable in-situ bone regeneration.

A range of magnesium ions (Mg2+) used has demonstrated osteogenic tendency in vitro. Hence, we propose to actualize this concept by designing a new system to precisely control the Mg2+ delivery at a particular concentration in vivo in order to effectively stimulate in-situ bone regeneration. To achieve this objective, a monodisperse core-shell microsphere delivery system comprising of poly (lactic-co-glycolic acid) (PLGA) biopolymer, alginate hydrogel, and magnesium oxide nano-particles has been designed by using customized microfluidic capillary device. The PLGA-MgO sponge-like spherical core works as a reservoir of Mg2+ while the alginate shell serves as physical barrier to control the outflow of Mg2+ at ∼50 ppm accurately for 2 weeks via its adjustable surface micro-porous network. With the aid of controlled release of Mg2+, the new core-shell microsphere system can effectively enhance osteoblastic activity in vitro and stimulate in-situ bone regeneration in vivo in terms of total bone volume, bone mineral density (BMD), and trabecular thickness after operation. Interestingly, the Young's moduli of formed bone on the core-shell microsphere group have been restored to ∼96% of that of the surrounding matured bone. These findings indicate that the concept of precisely controlled release of Mg2+ may potentially apply for in-situ bone regeneration clinically.

Synthesis of Antioxidative Conductive Copper Inks with Superior Adhesion.

Conductive films have attracted much attention in the printed electronics industry. To date, expensive conductive silver inks have been utilized widely in these conductive films, which ultimately increase the cost. Hence the alternative low-cost copper inks will be of great interest in the future. This paper will present how to synthesize antioxidative conductive copper inks with superior adhesion to FR4 substrates. The antioxidative conductive copper inks were prepared by dispersing the antioxidative copper nanoparticles in diethylene glycol with the bisphenol-F type BEF170 epoxy resin as a binder and the Methyl-5-norbornene-2,3-dicarboxylic anhydride (NMA) as a curing agent, then were coated on FR4 substrates to form the copper films, followed by sintering at 250 °C in nitrogen atmosphere for 20 minutes. We found that the formation of three-dimensional structure between BFE170 binder and curing agent NMA don't affect the conductivities of copper films, and meanwhile can enhance the adhesion strength on FR4 substrates. The lowest resistivity of 158 µΩ · cm determined by using the four-point probe method and the highest adhesion of no peeling after the 10 times peel-off test with 3 M Scotch 600 tape were achieved with the copper ink composed of 1 wt% of BEF170 epoxy resin binder mixed with curing agent NMA in an equivalent ratio of 1:1.

Microstructure evolution and mechanical properties of a Ti-35Nb-3Zr-2Ta biomedical alloy processed by equal channel angular pressing (ECAP).

In this paper, an equal channel angular pressing method is employed to refine grains and enhance mechanical properties of a new ß Ti-35Nb-3Zr-2Ta biomedical alloy. After the 4th pass, the ultrafine equiaxed grains of approximately 300 nm and 600 nm are obtained at pressing temperatures of 500 and 600°C respectively. The SEM images of billets pressed at 500°C reveal the evolution of shear bands and finally at the 4th pass intersectant networks of shear bands, involving initial band propagation and new band broadening, are formed with the purpose of accommodating large plastic strain. Furthermore, a unique herringbone microstructure of twinned martensitic variants is observed in TEM images. The results of microhardness measurements and uniaxial tensile tests show a significant improvement in microhardness and tensile strength from 534 MPa to 765 MPa, while keeping a good level of ductility (~16%) and low elastic modulus (~59 GPa). The maximum superelastic strain of 1.4% and maximum recovered strain of 2.7% are obtained in the billets pressed at 500°C via the 4th pass, which exhibits an excellent superelastic behavior. Meanwhile, the effects of different accumulative deformations and pressing temperatures on superelasticity of the ECAP-processed alloys are investigated.