Heparin-Based Coacervate of FGF2 Improves Dermal Regeneration by Asserting a Synergistic Role with Cell Proliferation and Endogenous Facilitated VEGF for Cutaneous Wound Healing.

Effective wound healing requires complicated, coordinated interactions and responses at protein, cellular, and tissue levels involving growth factor expression, cell proliferation, wound closure, granulation tissue formation, and vascularization. In this study, we develop a heparin-based coacervate consisting of poly(ethylene argininylaspartate digylceride) (PEAD) as a storage matrix, heparin as a bridge, and fibroblast growth factor-2 (FGF2) as a cargo (namely heparin-FGF2@PEAD) for wound healing. First, in vitro characterization demonstrates the loading efficiency and control release of FGF2 from the heparin-FGF2@PEAD coacervate. The following in vivo studies examine the wound healing efficiency of the heparin-FGF2@PEAD coacervate upon delivering FGF2 to full-thickness excisional skin wounds in vivo, in comparison with the other three control groups with saline, heparin@PEAD as vehicle, and free FGF2. Collective in vivo data show that controlled release of FGF2 to the wounds by the coacervate significantly accelerates the wound healing by promoting cell proliferation, stimulating the secretion of vascular endothelial growth factor (VEGF) for re-epithelization, collagen deposition, and granulation tissue formation, and enhancing the expression of platelet endothelial cell adhesion molecule (CD31) and alpha-smooth muscle actin (α-SMA) for blood vessel maturation. In parallel, no obvious wound healing effect is found for the control, vehicle, and free FGF2 groups, indicating the important role of the coavervate in the wound healing process. This work designs a suitable delivery system that can protect and release FGF2 in a sustained and controlled manner, which provides a promising therapeutic potential for topical treatment of wounds.

Vibrational Characteristics of a Foam-Filled Short Basalt Fiber Reinforced Epoxy Resin Composite Beetle Elytron Plate.

The vibrational properties and mechanism of a foam-filling short basalt fiber reinforced epoxy resin composite beetle elytron plate (EBEPfc) were studied by experiments and the finite element (FE) method in this paper. The experimental results showed that the natural frequencies of the first two modes of the EBEPfc were very close to those of a foam-filling short basalt fiber reinforced epoxy resin composite honeycomb plate (HPfc), while the vibrational response of the EBEPfc was weaker than that of the HPfc, and the damping ratio was improved; the improvement of the second mode was significant. Therefore, the EBEPfc had a better vibration reduction performance and could directly replace the HPfc in engineering applications. The FE results showed that foam filling enhanced the shear stiffness of the whole core structure, and had a more obvious effect on the shear stiffness of the HPfc. Meanwhile, it particularly reduced the shear force proportions and contributed to the protection of the skin and core skeleton. The mechanisms of the vibrational characteristics of these two types of sandwich plates were explored from the perspective of the equivalent cross-sectional area, shear stiffness, shear strain energy per unit volume and friction. These results provide a valuable reference for the promotion and application of EBEPfc in the fields of vibration reduction and seismic resistance.

Utilization of silt, sludge, and industrial waste residues in building materials: A review.

To promote the effective utilization of sludge and slag produced in nature and from human activities, this paper summarizes the research progress in the field of building materials on the basis of expounding their classification and characteristics. (1) Sludge and slag include silt, sludge and industrial waste residues. These three materials are mainly composed of SiO2, which can be used to produce building materials after treatment and can also be used as admixtures, including roadbed admixtures. (2) Silt and sludge are widely used in building wall materials and roadbed materials, etc. Industrial waste residues can be used in the production and processing of green concrete and glass-ceramics. (3) In addition to continuing to use existing utilization methods, key treatment technologies and new treatment devices can be further developed according to the characteristics of sludge and slag. Moreover, observations and mechanistic analysis of the microscopic structure of industrial waste residues and research on strong and weak utilization methods based on the performance of building materials can be carried out, and more efficient and energy-saving excitation or activation technologies will be developed. These efforts will eventually lead to the development of functional building materials with excellent performance and environmentally friendly characteristics to achieve the differentiated utilization of silt, sludge, and industrial waste residues and realize the efficient transformation of resources. This paper provides useful insights for the application of sludge and slag in the field of building materials.

Free vibration and sound transmission properties of beetle elytron plate: structural parametric analysis.

Honeycomb plate (HP), which is a high-strength and lightweight structure, has good vibration characteristics, while beetle elytron plate (BEP) has better mechanical properties. To promote the engineering application of BEPs, the vibration and sound transmission characteristics of aluminium BEPs were investigated in this paper with HP as the comparison object. This paper investigated the effects of the number of trabeculae, the ratio of length and width, skin thickness, core height and core thickness on the first 4 frequencies using finite element method. The results show that (1) the vibration characteristic of BEP is optimal when the number of trabeculae is 6, and its 3rd and 4th modes show mixed mode, i.e., torsion-bending or bending-torsion mode. (2) The frequencies of BEPs are generally lower than those of HPs. Compared with HPs, the ratio of length and width and core thickness have a smaller influence on the mode shapes of BEPs, and the core height has a smaller influence on BEPs' frequencies. When the skin thickness is small, increasing the thickness can effectively change the natural frequencies of BEPs and HPs. (3) Considering the common frequencies of four applications (aircrafts, unmanned aerial vehicles, high-speed trains and automobiles) of sandwich plates, the effects of the abovementioned parameters including the ratio of length and width, skin thickness, core height and core thickness are analysed. (4) Combined with the theoretical calculation formula, the effect of the above structural parameters on the sound transmission characteristic is explored using the index of sound transmission loss, and targeted recommendations are given. This paper progresses the application in engineering.

Tislelizumab-related enteritis successfully treated with adalimumab: A case report.

BACKGROUND: With programmed death-1 (PD-1) inhibitors becoming the standard treatment for lung cancer, PD-1-related adverse reactions and treatment have gradually become prominent. CASE SUMMARY: First reported case of tislelizumab-related enteritis successfully treated with adalimumab 40mg every 2 wk for 3 times in an advanced lung cancer patient who received first-line tislelizumab/pemetrexed/carboplatin for 4 cycles. The patient continued receiving the treatment of pemetrexed/carboplatin after symptoms, abdominal computed tomography and colonoscopy improved, significant diarrhea was not occurred. CONCLUSION: Adalimumab can be an effective treatment option for patients with PD-1 antibody related enteritis if they do not respond well to glucocorticoid treatment.

Evaluation of multiplex ARMS-PCR for detection of Helicobacter pylori mutations conferring resistance to clarithromycin and levofloxacin.

BACKGROUND: Helicobacter pylori bacterium is a major cause of gastritis. With increasing use of antibiotics to treat infections, mutation resistant strains have emerged in most human populations. To effectively treat patients to help resolve infections, the clinician needs information on the antibiotic susceptibility profile of the infection. Therefore, a rapid and accurate test is required to provide this information. To address this issue, we designed and validated a real time multiplex ARMS-PCR assay for rapid detection of highly prevalent H. pylori clarithromycin and levofloxacin resistance mutations. The aim of the study was to evaluate the analytical and diagnostic sensitivity and specificity of ARMS-PCR, using direct Sanger sequencing of the known resistance mutations as the gold standard. RESULTS: In preliminary studies using a defined number of plasmids with clarithromycin and levofloxacin resistance mutations, the analytical sensitivity of our ARMS-PCR assay was 50 plasmid copies, equating to around 50 bacterium in a gastric biopsy sample. In terms of specificity, the assay was highly specific for the targeted resistance mutations. The assay was also able to reliably and efficiently detect heteroresistance of clarithromycin and levofloxacin mutations, even at a disproportional ratio of 1:1000. From the analysis of 192 samples with suspected H. pylori infections, the diagnostic sensitivity and specificity of the assay was very high for detection of clarithromycin resistance (100% and 100%), levofloxacin resistance (98.04% and 95.04%) and clarithromycin and levofloxacin double resistance (100% and 96.91%). Amongst the 74 patients diagnosed antibiotic resistance bacteria, 23 (31.1%) had clarithromycin resistance, 21 (28.4%) had levofloxacin resistance and 30 (40.5%) had double resistance. From sample receipt to results, our single tube assay could be routinely completed in under 2 h. CONCLUSIONS: Our assay demonstrated high diagnostic sensitivity and specificity for detection of clarithromycin and levofloxacin resistant H. pylori. Based on proven accuracy, together with high efficiency, scalability and low cost, our assay has useful clinical utility for rapid diagnosis of clarithromycin and levofloxacin resistant H. pylori infections. Our assay results will provide patients with a clear diagnosis, enabling the treating clinician to administer the most effective antibiotic regimen to help the clear the infection.

Sulfated zwitterionic poly(sulfobetaine methacrylate) hydrogels promote complete skin regeneration.

Skin wound healing is a still long-history challenging problem and impeded by the foreign-body reaction including severe inflammation response, poor neovascularization, incomplete re-epithelialization and defective ECM remodeling. Development of biocompatible polymers, in combination with specific drugs or growth factors, has been considered as a promising strategy to treat skin wounds. Significant research efforts have been made to develop poly(ethylene glycol) PEG-based polymers for wound healing, however less efforts has been paid to zwitterionic materials, some of which have demonstrated their super low-fouling property in vitro and anti-inflammatory property in vivo. Here, we synthesized ultra-low-fouling zwitterionic sulfated poly(sulfobetaine methacrylate) (polySBMA) hydrogels and applied them to full-thickness cutaneous wounds in mice. The healing effects of SBMA hydrogels on the wound closure, re-epithelialization ratio, ECM remodeling, angiogenesis, and macrophage responses during wound healing processes were histologically evaluated by in vivo experiments. Collective results indicate that SBMA hydrogels promote full-thickness excisional acute wound regeneration in mice by enhancing angiogenesis, decreasing inflammation response, and modulating macrophage polarization. Consistently, the incorporation of SBMA into PEG hydrogels also improved the overall wound healing efficiency as compared to pure PEG hydrogels. This work demonstrates zwitterionic SBMA hydrogels as promising wound dressings for treating full-thickness excisional skin wounds. STATEMENT OF SIGNIFICANCE: Development of highly effective wound regeneration system is practically important for biomedical applications. Here, we synthesized ultra-low-fouling zwitterionic sulfated poly(sulfobetaine methacrylate) (polySBMA) hydrogels and applied it to full-thickness cutaneous wounds in mice, in comparison with PEG hydrogels as a control. We are the first to examine and reveal the difference between zwitterionic SBMA hydrogels and PEG hydrogels using a full-thickness excisional mice model. Overall, a series of in vivo systematic tests demonstrated that zwitterionic SBMA hydrogels exhibited superior wound healing property in almost all aspects as compared to PEG hydrogels.

Importance of zwitterionic incorporation into polymethacrylate-based hydrogels for simultaneously improving optical transparency, oxygen permeability, and antifouling properties.

Conventional 2-hydroxyethyl methacrylate (HEMA)-based hydrogels have an inverse relationship between optical transparency (OP) and oxygen permeability (Dk) as a function of water content. While the higher water content favors the oxygen permeability of HEMA-based hydrogels, it also causes poor optical transparency due to the water-induced scattering center effect. Here, we propose and demonstrate that the incorporation of zwitterionic [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide (SBMA) with HEMA hydrogels enables the achievement of both properties (OP = 98% and Dk = 54.7) in hydrogels at high water contents of 84%, and both values are much higher than those of pure HEMA hydrogels (OP = 2.3% and Dk = 17.5 barriers). HEMA-SBMA hydrogels are crosslinked by electrostatic interactions between the zwitterionic SBMA groups and hydrogen bonds between the HEMA groups. The introduction of SBMA into HEMA not only increases the quantity and quality of strongly binding water inside the networks, but also affects the porous structure of the gels, both of which are correlated with OP and Dk. Moreover, hybrid HEMA-SBMA hydrogels demonstrate their excellent antifouling function to prevent nonspecific protein adsorption in vitro, as well as their biocompatibility and hemocompatibility when implanted in mice in vivo. A combination of these excellent properties of HEMA-SBMA hydrogels (high water content, high optical transparency, high oxygen permeability, good antifouling function, and low foreign-body reaction) makes them highly promising for contact lens-based ophthalmic applications. This work, in line with our other HEMA-CBMA hydrogels, offers a new strategy to design hybrid hydrophilic-zwitterionic materials for improving their multi-faceted properties of interest, beyond the conventional designs of hydrophilic-hydrophilic and hydrophilic-hydrophobic materials.

Single injection of a novel nerve growth factor coacervate improves structural and functional regeneration after sciatic nerve injury in adult rats.

The prototypical neurotrophin, nerve growth factor (NGF), plays an important role in the development and maintenance of many neurons in both the central and peripheral nervous systems, and can promote functional recovery after peripheral nerve injury in adulthood. However, repair of peripheral nerve defects is hampered by the short half-life of NGF in vivo, and treatment with either NGF alone or NGF contained in synthetic nerve conduits is inferior to the use of nerve autografts, the current gold standard. We tested the reparative ability of a single local injection of a polyvalent coacervate containing polycation-poly(ethylene argininylaspartate diglyceride; PEAD), heparin, and NGF, in adult rats following sciatic nerve crush injury, using molecular, histological and behavioral approaches. In vitro assays demonstrated that NGF was loaded into the coacervate at nearly 100% efficiency, and was protected from proteolytic degradation. In vivo, the coacervate enhanced NGF bioavailability, leading to a notable improvement in motor function (track walking analysis) after 30days. The NGF coacervate treatment was also associated with better weight gain and reduction in atrophy of the gastrocnemius muscle. Furthermore, light and electron microscopy showed that the number of myelinated axons and axon-to-fiber ratio (G-ratio) were significantly higher in NGF coacervate-treated rats compared with control groups. Expression of markers of neural tissue regeneration (MAP-2, S-100ß, MBP and GAP-43), as well as proliferating Schwann cells and myelin-axon relationships (GFAP and NF200), were also increased. These observations suggest that even a single administration of NGF coacervate could have therapeutic value for peripheral nerve regeneration and functional recovery.

Novel H2S Releasing Nanofibrous Coating for In Vivo Dermal Wound Regeneration.

Hydrogen sulfide (H2S), together with nitric oxide and carbon monoxide, has been recognized as an important gasotransmitter. It plays an essential physiological role in regulating cyto-protective signal process, and H2S-based therapy is considered as the next generation of promising therapeutic strategies for many biomedical applications, such as the treatment of cardiovascular disease. Through electrospinning of polycaprolactone (PCL) containing JK1, a novel pH-controllable H2S donor, nanofibers with H2S releasing function, PCL-JK1, are fabricated. This fibrous scaffold showed a pH-dependent H2S releasing behavior, i.e., lower pH induced greater and faster H2S release. In addition, the H2S release of JK1 was prolonged by the fibrous matrix as shown by decreased releasing rates compared to JK1 in solutions. In addition, in vitro studies indicated that PCL-JK1 exhibited excellent cyto-compatibility, similar to PCL fibers. Finally, we investigated PCL-JK1 as a wound dressing toward a cutaneous wound model in vivo and found that PCL-JK1 could significantly enhance the wound repair and regeneration compared with the control PCL scaffold, likely due to the release of H2S, which results in a broad range of physiologically protective functions toward the wound.

Protein diffusion characteristics in the hydrogels of poly(ethylene glycol) and zwitterionic poly(sulfobetaine methacrylate) (pSBMA).

UNLABELLED: Nonfouling materials such as neutral poly(ethylene glycol) (PEG) and zwitterionic poly(sulfobetaine methacrylate) (pSBMA) are ideal biocompatible materials for drug, especially protein drug delivery. The interaction behavior of protein between the nonfouling materials could cause great impact on their future applications, such as controlled release drug delivery systems. In this work, we investigated the diffusion behavior of the fluorescence-labeled model proteins (bovine serum albumin (BSA) and lysozyme (LYZ)) in nonfouling PEG, pSBMA and mixed PEG-SBMA hydrogels (SBMA:PEG 4:1, SBMA:PEG 1:4). It was observed that these four hydrogels showed varied diffusion behavior for either negatively charged BSA or positively charged LYZ due to protein-polymer interaction and the free water content in hydrogel matrix. The relatively stronger interaction between protein-PEG than protein-pSBMA could increase protein loading efficiency and control release rate by changing ratio of PEG to SBMA in the hybrid hydrogel. Moreover, it is further demonstrated the free water (freezable water) content in low cross-linked hydrogel, not the equilibrium water content (EWC), is a more accurate parameter to reflect the diffusion behavior of protein molecules. Thus, these results together provide new insights of the interactions between protein molecules and nonfouling polymers as well as the bio applications of the nonfouling polymeric hydrogels. STATEMENT OF SIGNIFICANCE: This work shows that the relative stronger interaction between protein-PEG than protein-pSBMA could increase protein loading efficiency and control release rate by the change ratio of PEG to SBMA in the hydrogel, while the free water (freezable water) content in low cross-linked hydrogel, not the equilibrium water content (EWC), is a more accurate parameter to reflect the diffusion behavior of protein molecules. The impact of this work (i) gains some new insights of the interactions between protein molecules and nonfouling polymer matrixes for protein drug delivery; (ii) prompts to apply the weak PEG-protein interactions to protein drug loading and release; (iii) provides a new fundamental understanding of free water in hydrogel for protein diffusion.

Comparative Study of Heparin-Poloxamer Hydrogel Modified bFGF and aFGF for in Vivo Wound Healing Efficiency.

Wound therapy remains a clinical challenge. Incorporation of growth factors (GFs) into heparin-functionalized polymer hydrogel is considered as a promising strategy to improve wound healing efficiency. However, different GFs incorporation into the same heparin-based hydrogels often lead to different wound healing effects, and the underlying GF-induced wound healing mechanisms still remain elusive. Herein, we developed a thermos-sensitive heparin-poloxamer (HP) hydrogel to load and deliver different GFs (aFGF and bFGF) for wound healing in vivo. The resulting GFs-based hydrogels with and without HP hydrogels were systematically evaluated and compared for their wound healing efficiency by extensive in vivo tests, including wound closure rate, granulation formation, re-epithelization, cell proliferation, collagen, and angiogenesis expressions. While all GFs-based dressings with and without HP hydrogels exhibited better wound healing efficacy than controls, both HP-aFGF and HP-bFGF hydrogels demonstrated their superior healing activity to improve wound closure, granulation formation, re-epithelization, and blood vessel density by up-regulation of PCNA proliferation and collagen synthesis, as compared to GF dressings alone. More importantly, HP-aFGF dressings exhibited the higher healing efficacy than HP-bFGF dressings, indicating that different a/bFGF surface properties lead to different binding and release behaviors in HP hydrogels, both of which will affect different wound healing efficiency. On the basis of experimental observations, the working mechanisms of different healing effects of HP-GFs on full skin removal wound were proposed. This work provides different views of the design and development of an effective hydrogel-based delivery system for GFs toward rapid wound healing.

Research Advances in Tissue Engineering Materials for Sustained Release of Growth Factors.

Growth factors are a class of cytokines that stimulate cell growth and are widely used in clinical practice, such as wound healing, revascularization, bone repair, and nervous system disease. However, free growth factors have a short half-life and are instable in vivo. Therefore, the search of excellent carriers to enhance sustained release of growth factors in vivo has become an area of intense research interest. The development of controlled-release systems that protect the recombinant growth factors from enzymatic degradation and provide sustained delivery at the injury site during healing should enhance the growth factor's application in tissue regeneration. Thus, this study reviews current research on commonly used carriers for sustained release of growth factors and their sustained release effects for preservation of their bioactivity and their accomplishment in tissue engineering approaches.