Photo-Crosslinked Pro-Angiogenic Hydrogel Dressing for Wound Healing.

Severe burns are one of the most devastating injuries, in which sustained inflammation and ischemia often delay the healing process. Pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) have been widely studied for promoting wound healing. However, the short half-life and instability of VEGF limit its clinical applications. In this study, we develop a photo-crosslinked hydrogel wound dressing from methacrylate hyaluronic acid (MeHA) bonded with a pro-angiogenic prominin-1-binding peptide (PR1P). The materials were extruded in wound bed and in situ formed a wound dressing via exposure to short-time ultraviolet radiation. The study shows that the PR1P-bonded hydrogel significantly improves VEGF recruitment, tubular formation, and cell migration in vitro. Swelling, Scanning Electron Microscope, and mechanical tests indicate the peptide does not affect the overall mechanical and physical properties of the hydrogels. For in vivo studies, the PR1P-bonded hydrogel dressing enhances neovascularization and accelerates wound closure in both deep second-degree burn and full-thickness excisional wound models. The Western blot assay shows such benefits can be related to the activation of the VEGF-Akt signaling pathway. These results suggest this photo-crosslinked hydrogel dressing efficiently promotes VEGF recruitment and angiogenesis in skin regeneration, indicating its potential for clinical applications in wound healing.

ZIF-8-modified hydrogel sequentially delivers angiogenic and osteogenic growth factors to accelerate vascularized bone regeneration.

To realize high-quality vascularized bone regeneration, we developed a multifunctional hydrogel (SHPP-ZB) by incorporating BMP-2@ZIF-8/PEG-NH2 nanoparticles (NPs) into a sodium alginate/hydroxyapatite/polyvinyl alcohol hydrogel loaded with PDGF-BB, allowing for the sequential release of angiogenic and osteogenic growth factors (GFs) during bone repair. ZIF-8 served as a protective host for BMP-2 from degradation, ensuring high encapsulation efficiency and long-term bioactivity. The SHPP-ZB hydrogel exhibited enhanced mechanical strength and injectability, making it suitable for complex bone defects. It provided a swelling interface for tissue interlocking and the early release of Zn2+ and tannin acid (TA) to exert antioxidant and antibacterial effects, followed by the sequential release of angiogenic and osteogenic GFs to promote high-quality vascularized bone regeneration. In vitro experiments demonstrated the superior angiogenic and osteogenic properties of SHPP-ZB compared to other groups. In vivo experiments indicated that the sequential delivery of GFs via SHPP-ZB hydrogel could improve vascularized bone regeneration. Further, RNA sequencing analysis of regenerative bone tissue revealed that SHPP-ZB hydrogel promoted vascularized bone regeneration by regulating JUN, MAPK, Wnt, and calcium signaling pathways in vivo. This study presented a promising approach for efficient vascularized bone regeneration in large-scale bone defects.

Cu-MOF loaded chitosan based freeze-dried highly porous dressings with anti-biofilm and pro-angiogenic activities accelerated Pseudomonas aeruginosa infected wounds healing in rats.

Metal-organic frameworks (MOFs)-based therapy opens a new area for antibiotic-drug free infections treatment. In the present study, chitosan membranes (CS) loaded with two concentrations of copper-MOF 10 mg/20 ml (Cu-MOF10/CS) & 20 mg/20 ml (Cu-MOF20/CS) were prepared by a simple lyophilization procedure. FTIR spectra of Cu-MOF10/CS and Cu-MOF20/CS dressings confirmed absence of any undesirable chemical changes after loading Cu-MOF. The SEM images of the synthesized materials (CS, Cu-MOF10/CS & Cu-MOF20/CS) showed interconnected porous structures. Cytocompatibility of the materials was confirmed by fibroblasts cells culturing and the materials were hemocompatible, with blood clotting index <5 %. Cu-MOF20/CS showed comparatively higher effective antibacterial activity against the tested strains; E. coli (149.2 %), P. aeruginosa (165 %) S. aureus (117.8 %) and MRSA (142 %) as compared to Amikacin, CS and Cu-MOF10/CS membranes. Similarly, Cu-MOF20/CS dressing significantly eradicated the biofilms; P. aeruginosa (37 %) and MRSA (52 %) respectively. In full thickness infected wound rat model, on day 23, Cu-MOF10/CS and Cu-MOF20/CS promoted wound healing up to 87.7 % and 82 % respectively. H&E staining of wounded tissues treated with Cu-MOF10/CS & Cu-MOF20/CS demonstrated enhanced neovascularization and re-epithelization along-with reduced inflammation, while trichrome staining exhibited increased collagen deposition. Overall, this study declares Cu-MOFs loaded chitosan dressings a multifunctional platform for the healing of infected wounds.

Characterization of a polysaccharide from Amauroderma rugosum and its proangiogenic activities in vitro and in vivo.

Amauroderma rugosum (AR), also known as "Blood Lingzhi" in Chinese, is a basidiomycete belonging to the Ganodermataceae family. Four polysaccharide fractions were systematically isolated and purified from AR. Subsequently, their compositions were examined and analyzed via high-performance gel permeation chromatography (HPGPC), analysis of the monosaccharide composition, Fourier-transform infrared spectroscopy (FT-IR), and 1H nuclear magnetic resonance (NMR). The zebrafish model was then used to screen for proangiogenic activities of polysaccharides by inducing vascular insufficiency with VEGF receptor tyrosine kinase inhibitor II (VRI). The third fraction of AR polysaccharides (PAR-3) demonstrated the most pronounced proangiogenic effects, effectively ameliorating VRI-induced intersegmental vessel deficiency in zebrafish. Concurrently, the mRNA expression levels of vascular endothelial growth factor (VEGF)-A and VEGF receptors were upregulated by PAR-3. Moreover, the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) were also stimulated by PAR-3, consistently demonstrating that PAR-3 possesses favorable proangiogenic properties. The activation of the Akt, ERK1/2, p38 MAPK, and FAK was most likely the underlying mechanism. In conclusion, this study establishes that PAR-3 isolated from Amauroderma rugosum exhibits potential as a bioresource for promoting angiogenesis.

Deferoxamine-Loaded Injectable Chitosan-Grafted Chlorogenic Acid/Oxidized Hyaluronic Acid Hybrid Hydrogel with Antibacterial, Anti-inflammatory, and Angiogenesis-Promoting Properties for Diabetic Wound Repair.

Diabetic chronic wounds are notoriously difficult to heal as a result of their susceptibility to infection. To address this issue, we constructed an innovated and adaptable solution in the form of injectable chitosan (CS) hydrogel, denoted as CCOD, with enhanced antibacterial and anti-inflammatory properties. This hydrogel is created through a Schiff base reaction that combines chitosan-grafted chlorogenic acid (CS-CGA) and oxidized hyaluronic acid (OHA) with deferoxamine (DFO) as a model drug. The combination of CS and CGA has demonstrated excellent antibacterial and anti-inflammatory properties, while grafting played a pivotal role in making these positive effects stable. These unique features make it possible to customize injectable hydrogel and fit any wound shape, allowing for more effective and personalized treatment of complex bacterial infections. Furthermore, the hydrogel system is not only effective against inflammation and bacterial infections but also possesses antioxidant and angiogenic abilities, making it an ideal solution for the repair of chronic wounds that have been previously thought of as unmanageable.

Mechanically reinforced hydrogel vehicle delivering angiogenic factor for beta cell therapy.

Type 1 diabetes mellitus (T1DM) is a chronic disease affecting millions worldwide. Insulin therapy is currently the golden standard for treating T1DM; however, it does not restore the normal glycaemic balance entirely, which increases the risk of secondary complications. Beta-cell therapy may be a possible way of curing T1DM and has already shown promising results in the clinic. However, low retention rates, poor cell survival, and limited therapeutic potential are ongoing challenges, thus increasing the need for better cell encapsulation devices. This study aimed to develop a mechanically reinforced vascular endothelial growth factor (VEGF)-delivering encapsulation device suitable for beta cell encapsulation and transplantation. Poly(l-lactide-co-ε-caprolactone) (PLCL)/gelatin methacryloyl (GelMA)/alginate coaxial nanofibres were produced using electrospinning and embedded in an alginate hydrogel. The encapsulation device was physically and biologically characterised and was found to be suitable for INS-1E beta cell encapsulation, vascularization, and transplantation in terms of its biocompatibility, porosity, swelling ratio and mechanical properties. Lastly, VEGF was incorporated into the hydrogel and the release kinetics and functional studies revealed a sustained release of bioactive VEGF for at least 14 days, making the modified alginate system a promising candidate for improving the beta cell survival after transplantation.

Yttrium Oxide Nanoparticle-Loaded, Self-Assembled Peptide Gel with Antibacterial, Anti-Inflammatory, and Proangiogenic Properties for Wound Healing.

Chronic wounds are a major healthcare challenge owing to their complex healing mechanism and number of impediments to the healing process, like infections, unregulated inflammation, impaired cellular functions, poor angiogenesis, and enhanced protease activity. Current topical care strategies, such as surgical debridement, absorption of exudates, drug-loaded hydrogels for infection and inflammation management, and exogenous supply of growth factors for angiogenesis and cell proliferation, slow the progression of wounds and reduce patient suffering but suffer from low overall cure rates. Therefore, we have developed a proteolytically stable, multifunctional nanoparticle loaded-peptide gel with inherent anti-inflammatory, antibacterial, and pro-angiogenic properties to provide a favorable wound healing milieu by restoring impaired cellular functions. We have fabricated a self-assembled, lauric acid-peptide conjugate gel, LA-LLys-DPhe-LLys-NH2, loaded with yttrium oxide (Y2O3) nanoparticles (NLG). Gel formed a nanofibrous structure, and nanoparticles were passively entrapped within the network. The surface morphology, stability, viscoelastic, and self-healing characteristics of gels were characterized. It showed a high stability against degradation by proteolytic enzymes and highly potent antibacterial activities against E. coli and S. aureus due to the presence of positively charged side chains of lysine in the peptide chain. It also exhibited an excellent antioxidant activity as well as ability to stimulate cell proliferation in murine fibroblast (L929) cells and human umbilical vein endothelial cells (HUVECs). The incorporation of nanoparticles promoted angiogenesis by upregulating pro-angiogenic genes, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF2), and epidermal growth factor (EGFR), and the gel caused complete wound closure in cells. In summary, the Y2O3 nanoparticle-loaded lauric acid-peptide conjugate gel is able to elicit the desired tissue regeneration responses and, therefore, has a strong potential as a matrix for the treatment of chronic wounds.

Angiogenic Hyaluronic Acid Hydrogels with Curcumin-Coated Magnetic Nanoparticles for Tissue Repair.

Angiogenic magnetic hydrogels are attractive for tissue engineering applications because their integrated properties can improve angiogenesis while providing magnetic guidance and stimulation for tissue healing. In this study, we synthesized magnetic nanoparticles (MNPs) with curcumin as an angiogenic agent, referred to as CMNPs, via a one-pot coprecipitation method. We dispersed CMNPs in hyaluronic acid (HyA) to create angiogenic magnetic hydrogels. CMNPs showed a slightly reduced average diameter compared to that of MNPs and a curcumin content of 11.91%. CMNPs exhibited a sustained slow release of curcumin when immersed in a revised simulated body fluid (rSBF). Both CMNPs and MNPs showed a dose-dependent cytocompatibility when cultured with bone marrow-derived mesenchymal stem cells (BMSCs) using the direct exposure culture method in vitro. The average BMSC density increased when the concentrations of CMNPs or MNPs increased from 100 to 500 µg/mL, but the cell density decreased when the nanoparticle concentration reached 1000 µg/mL. CMNPs showed a weaker magnetic response than MNPs both in air and in water immediately after synthesis but retained the magnetism better than MNPs when embedded in the HyA hydrogel because of less oxidation. CMNPs were able to respond to magnetic guidance even when the porcine skin or muscle tissues were placed in between the nanoparticles and external magnet. The magnetic hydrogels of HyA_CMNP and HyA_MNP promoted the adhesion of BMSCs in a direct exposure culture. The HyA_CMNP group also showed the highest secretion of the vascular endothelial growth factor with the release of curcumin in vitro. Overall, our magnetic hydrogels integrated the desirable properties of cytocompatibility and angiogenesis with magnetic guidance, thus proving to be promising for improving tissue regeneration.

Discovery of Salidroside-Derivated Glycoside Analogues as Novel Angiogenesis Agents to Treat Diabetic Hind Limb Ischemia.

Therapeutic angiogenesis is a potential therapeutic strategy for hind limb ischemia (HLI); however, currently, there are no small-molecule drugs capable of inducing it at the clinical level. Activating the hypoxia-inducible factor-1 (HIF-1) pathway in skeletal muscle induces the secretion of angiogenic factors and thus is an attractive therapeutic angiogenesis strategy. Using salidroside, a natural glycosidic compound as a lead, we performed a structure-activity relationship (SAR) study for developing a more effective and druggable angiogenesis agent. We found a novel glycoside scaffold compound (C-30) with better efficacy than salidroside in enhancing the accumulation of the HIF-1α protein and stimulating the paracrine functions of skeletal muscle cells. This in turn significantly increased the angiogenic potential of vascular endothelial and smooth muscle cells and, subsequently, induced the formation of mature, functional blood vessels in diabetic and nondiabetic HLI mice. Together, this study offers a novel, promising small-molecule-based therapeutic strategy for treating HLI.

Developing Wound Dressings Using 2-deoxy-D-Ribose to Induce Angiogenesis as a Backdoor Route for Stimulating the Production of Vascular Endothelial Growth Factor.

2-deoxy-D-Ribose (2dDR) was first identified in 1930 in the structure of DNA and discovered as a degradation product of it later when the enzyme thymidine phosphorylase breaks down thymidine into thymine. In 2017, our research group explored the development of wound dressings based on the delivery of this sugar to induce angiogenesis in chronic wounds. In this review, we will survey the small volume of conflicting literature on this and related sugars, some of which are reported to be anti-angiogenic. We review the evidence of 2dDR having the ability to stimulate a range of pro-angiogenic activities in vitro and in a chick pro-angiogenic bioassay and to stimulate new blood vessel formation and wound healing in normal and diabetic rat models. The biological actions of 2dDR were found to be 80 to 100% as effective as VEGF in addition to upregulating the production of VEGF. We then demonstrated the uptake and delivery of the sugar from a range of experimental and commercial dressings. In conclusion, its pro-angiogenic properties combined with its improved stability on storage compared to VEGF, its low cost, and ease of incorporation into a range of established wound dressings make 2dDR an attractive alternative to VEGF for wound dressing development.

Angiogenic Aptamer-Modified Tetrahedral Framework Nucleic Acid Promotes Angiogenesis In Vitro and In Vivo.

In a search for a solution to large-area soft and hard tissue defects, whether or not tissue regeneration or tissue-substitutes transplantation is used, the problems with angiogenesis need to be solved urgently. Thus, a new and efficient proangiogenic approach is needed. Nanoengineering systems have been considered one of the most promising approaches. In this study, we modify the tetrahedral framework nucleic acid (tFNA) for the first time with two different angiogenic DNA aptamers to form aptamer-tFNA nanostructures, tFNA-Apt02 and tFNA-AptVEGF, and the effects of them on angiogenesis both in vitro and in vivo are investigated. We develop new nanomaterials for enhancing angiogenesis to solve the problem of tissue engineering vascularization and ischemic diseases. The results of our study confirm that tFNA-Apt02 and tFNA-AptVEGF has a stronger ability to accelerate endothelial cell proliferation and migration, tubule formation, spheroid sprouting, and angiogenesis in vivo. We first demonstrate that the engineered novel tFNA-Apt02 and tFNA-AptVEGF have promoting effects on angiogenesis both in vitro and in vivo and provide a theoretical basis and opportunity for their application in tissues engineering vascularization and ischemic diseases.

Angiogenic potential of airbrushed fucoidan/polycaprolactone nanofibrous meshes.

Implantation of biomaterials and hybrid constructs in tissue engineering approaches presents major limitations such as inflammatory reaction and the lack of vasculature integration. Therefore, new strategies are needed to enhance implant function, immune protection, and revascularization. In this work, we developed fibrous meshes composed of fucoidan (Fu), a sulfated polysaccharide extracted from brown algae, and polycaprolactone (PCL), a synthetic biodegradable polymer, using the airbrush technique. The chemical characterization by FTIR, EDS, and XPS confirmed the presence of the two polymers in the structure of airbrushed nanofibrous meshes (ANFM). Moreover, these nanofibrous exhibited good wettability and mechanical properties envisaging their application as templates for biomaterials and cell culture. The developed ANFM were directly cultured with human pulmonary microvascular endothelial (HPMEC-ST1.6R) cells for up to 7 days. Biological results demonstrated that ANFM comprising Fu promoted cellular attachment, spreading, and proliferation of human endothelial cells. The angiogenic potential of ANFM was further evaluated by onplantation of PCL and PCL/Fu ANFM in chick chorioallantoic membrane (CAM). In ovo and ex ovo results showed that the incorporation of Fu increased the pro-angiogenic potential of ANFM. Altogether, the results suggest that airbrush biocomposite meshes could be used as a biomaterial substrate to promote vascularization.

Characterisation of Novel Angiogenic and Potent Anti-Inflammatory Effects of Micro-Fragmented Adipose Tissue.

Adipose tissue and more specifically micro-fragmented adipose tissue (MFAT) obtained from liposuction has recently been shown to possess interesting medicinal properties whereby its application supports pain reduction and may enhance tissue regeneration particularly in osteoarthritis. Here we have characterised samples of MFAT produced using the Lipogems® International Spa system from eight volunteer individuals in order to understand the critical biological mechanisms through which they act. A variation was found in the MFAT cluster size between individual samples and this translated into a similar variation in the ability of purified mesenchymal stem cells (MSCs) to form colony-forming units. Almost all of the isolated cells were CD105/CD90/CD45+ indicating stemness. An analysis of the secretions of cytokines from MFAT samples in a culture using targeted arrays and an enzyme-linked immunosorbent assay (ELISA) showed a long-term specific and significant expression of proteins associated with anti-inflammation (e.g., interleukin-1 receptor alpha (Il-1Rα) antagonist), pro-regeneration (e.g., hepatocyte growth factor), anti-scarring and pro-angiogenesis (e.g., transforming growth factor beta 1 and 2 (TGFß1/2) and anti-bacterial (e.g., chemokine C-X-C motif ligand-9 (CXCL-9). Angiogenesis and angiogenic signalling were notably increased in primary bovine aortic endothelial cells (BAEC) to a different extent in each individual sample of the conditioned medium whilst a direct capacity of the conditioned medium to block inflammation induced by lipopolysaccharides was shown. This work characterises the biological mechanisms through which a strong, long-lasting, and potentially beneficial effect can be observed regarding pain reduction, protection and regeneration in osteoarthritic joints treated with MFAT.

Separation, identification and cardiovascular activities of phospholipid classes from the head of Penaeus vannamei by lipidomics and zebrafish models.

Phospholipids not only have high nutritional value, but also have a positive effect on cardiovascular disease, cancer and nervous system diseases. However, the activity of individual phospholipid classes of shrimp phospholipids is rarely studied. This paper researched phospholipids in the by-products of Penaeus vannamei processing. The phospholipid classes of the head from P. vannamei (PV) were separated by column chromatography, analyzed with UHPLC-Q-Exactive HF/MS, and quantified using ammonium ferrothiocyarate spectrophometry. In addition, their cardiovascular activities in zebrafish models were evaluated. A total of 5 phospholipid classes were obtained, including PV-PC, PV-PE, PV-PI, PV-PS and PV-SM, and identified as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS) and sphingomyelin (SM), respectively. In the phospholipid profiling analysis, PV-PC (308 molecules) had the highest proportion with 85.24%, followed by PV-PE (139 types) with 9.32%, PV-SM (41 structures) with 4.75%, PV-PS (24 types) with 0.16%, and PV-PI (6 molecules) with 0.03%. In the quantitative analysis, the content of PV was 45.7%, and the purity of phospholipid classes was 75.5-88.1%. In the cardiovascular activity assays, the effects of different phospholipid classes were different. For example, PV-PC groups had strong angiogenesis activity, but PV-PE groups showed the opposite property. Our comprehensive profiling analysis and in vivo bioactivity evaluation of phospholipids from the head of P. vannamei can provide evidence for their targeted applications in the future.

Buxuhuayu decoction accelerates angiogenesis by activating the PI3K-Akt-eNOS signalling pathway in a streptozotocin-induced diabetic ulcer rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Buxuhuayu decoction (BXHYD) has been frequently used to treat patients with diabetic ulcers (DUs), without notable adverse reactions. However, the related molecular mechanism remains unelucidated. AIM OF THE STUDY: This study assessed the potential mechanism of BXHYD against DUs by using network pharmacology and animal experiments. MATERIALS AND METHODS: First, high-performance liquid chromatography (HPLC) was used for quality control of BXHYD. Further, the hub compounds and targets were screened from the Active Compound-Targets (ACT) network and the protein and protein interaction (PPI) network. Enrichment analysis was performed using DAVID, and molecular docking technology was used to identify active compounds that may play a key role in pub targets. Finally, a DUs animal model was established and used to elucidate the effect of BXHYD on the PI3K/Akt/eNOS signalling pathway. RESULTS: (1) Calycosin-7-glucoside, amygdalin, and tanshinone iiA were detected in the freeze-dried powder of BXHYD. (2) Twelve hub compounds and eight hub targets were screened using the ACT and PPI networks. Through molecular docking, it was found that the four hub targets (TP53, IL6, VEGFA, and AKT1) binds luteolin and quercetin more tightly. (3) BXHYD is most likely to promote angiogenesis and wound healing by activating the PI3K/Akt/eNOS signalling pathway. CONCLUSIONS: This research revealed that BXHYD might activate the PI3K/Akt/eNOS signalling pathway to promote DUs healing. These findings support the clinical use of BXHYD and provide the foundation for its subsequent studies.

Study of injectable PNIPAAm hydrogels containing niosomal angiogenetic drug delivery system for potential cardiac tissue regeneration.

Nowadays, heart disease, especially myocardial infarction, is one of the most astoundingly unfortunate causes of mortality in the world. That is why special attention has been paid toward tissue engineering techniques for curing and regeneration of heart tissue. In this study, poly(N-isopropyl acrylamide) (PNIPAAm), a temperature-sensitive injectable hydrogel, was selected as a minimally invasive scaffold to accommodate, carry, and release of niosomal rosuvastatin to the inflicted area for inducing angiogenesis and thus accelerating the healing process. The characteristics of PNIPAAm were studied by scanning electron microscopy, rheology tests, and Fourier transform infrared spectroscopy. The properties of the niosomal rosuvastatin release system, including particle size distribution, zeta potential, encapsulation efficiency (EE), and drug release, were also studied. The results showed that niosomes (358 nm) had a drug EE of 78% and a loading capacity of 53%. The drug was sustainably released from the system up to about 54% in 5 d. Cellular studies showed no toxicity to the endothelial cell lines, and the niosomal drug with a concentration of 7.5 nM enhanced cell proliferation, and cell migration increased from 72% to 90% compared to the control sample. Therefore, the controlled-release of niosomal rosuvastatin enhanced angiogenesis in a dose-dependent manner. Taken together, these advantages suggest that PNIPAAm-based niosomal hydrogel provides a promising candidate as an angiogentic injectable scaffold for potential cardiac tissue regeneration.

Nanotized praseodymium oxide collagen 3-D pro-vasculogenic biomatrix for soft tissue engineering.

The current study explores development of highly vascularizable biomatrix scaffold containing rare-earth metal praseodymium oxide nanoadditives for angiogenic and soft tissue regenerative applications. The therapeutic potential of praseodymium oxide nanoparticles rendered excellent endothelial cell differentiation for inducing pro angiogenic microenvironment by eliciting VE-Cadherin expression in the biomatrix scaffold. The nanoparticles were incorporated into bio-macromolecule collagen which aided in stabilization of collagen by maintaining the structural integrity of collagen and showed less susceptibility towards protease enzymes, high cyto-compatibility and high hemo-compatibility. The scaffold provided 3-dimensional micro-environments for the proliferation of endothelial cells and fibroblast cells promoting the wound healing process in an orchestrated fashion. Biological signal modulatory property of rare earth metal is the unexplored domains that can essentially bring significant therapeutic advancement in engineering advanced biological materials. This study opens potential use of nano-scaled rare earth metals in biomaterial application for tissue regeneration by modulating the pro-angiogenesis and anti-proteolysis properties.

A non-anticoagulant heparin-like snail glycosaminoglycan promotes healing of diabetic wound.

Diabetic foot ulcer (DFU) is a common high-risk complication in patients with diabetes mellitus, but current drugs and therapies in management of this disease cannot meet the urgent clinical needs. In this study, a snail glycosaminoglycan (SGAG) from the cultured China white jade snail was purified and structurally clarified. This snail glycosaminoglycan is a regular sulfated polysaccharide, composed of iduronic acid (IdoA) and N-acetyl-glucosamine (GlcNAc) with the repeating sequence of →4)-α-GlcNAc (1→4)-α-IdoA2S (1→. The biological assays showed that SGAG had no anticoagulant activity for lacking specific heparin pentasaccharide sequence. The pharmacological experiments suggested that SGAG markedly accelerated the healing of full-thickness wounds in diabetic mice skin. Histologic and immunohistochemical analysis revealed that SGAG treatment alleviated the inflammation and dermal edema, and promoted angiogenesis. This is the first report applying the snail glycosaminoglycan to favor diabetic wound healing.

Attenuation of cadmium-induced vascular toxicity by pro-angiogenic nanorods.

Cadmium (Cd) is a common heavy metal that causes major environmental pollution with adverse effects on human health and well-being. Exposure to Cd is known to exhibit detrimental consequences on all the vital organ systems of the body, especially the vascular system. Certain approaches using anti-oxidants and chelating agents have been demonstrated previously to mitigate Cd-induced toxicity. However, these approaches are associated with their own limitations. In this context, there is a critical need for the development of alternative treatment strategies to address the conditions associated with Cd-poisoning. One such novel approach is the application of nanomedicine which is well-known to resolve several health complications by improving disease therapy. Recently, our group demonstrated the role of europium hydroxide nanorods (EHN) in promoting vascular growth using in vitro and in vivo assay systems. Therefore, in the present study, we have evaluated the effect of EHN on health of endothelial cells (EA.hy926) and fibroblasts (NIH 3T3) intoxicated by Cd. The results revealed that EHN significantly improved the viability of EA.hy926 and NIH 3T3 cells, reduced apoptotic cell population, increased nitric oxide (NO) production and promoted blood vasculature development in the chick embryo model, which were hampered due to Cd insult. Molecular studies demonstrated the reduced expression of tumor suppressor (p53) and elevated anti-apoptotic protein (Bcl-xL) levels along with enhanced NO production through endothelial nitric oxide synthase (eNOS) activation as the plausible mechanisms underlying protective role of EHN against Cd-induced vascular toxicity. Considering the above observations, we strongly believe that EHN could be a potential nanomedicine approach for overcoming Cd-induced toxicity by improving vascular health and functioning.

An alginate/poly(N-isopropylacrylamide)-based composite hydrogel dressing with stepwise delivery of drug and growth factor for wound repair.

Anti-inflammation and angiogenesis play an essential role in wound healing. In this study, we developed a composite hydrogel dressing with stepwise delivery of diclofenac sodium (DS) and basic fibroblast growth factor (bFGF) in the inflammation stage and new tissue formation stage respectively for wound repair. Sodium alginate (SA) crosslinked by calcium ion acted as the continuous phase, and thermosensitive bFGF-loaded poly(N-isopropylacrylamide) nanogels (pNIPAM NGs, LCST1 ~33 °C) and DS-loaded p(N-isopropylacrylamide-co-acrylic acid) nanogels [p(NIPAM-co-AA) NGs, LCST2 ~40 °C] acted as the dispersed phase. The synthesized SA/bFGF@pNIPAM/DS@p(NIPAM-co-AA) hydrogel presented a desirable storage modulus of ~4500 Pa, a high water equilibrium swelling ratio of ~90, an appropriate water vapor transmission rate of ~2300 g/m2/day, and nontoxicity to human skin fibroblasts. The in vitro thermosensitive cargo delivery of this hydrogel showed that 92% of DS was sustainably delivered at 37 °C within the early three days mimicking the inflammation stage, while 80% of bFGF was controlled released at 25 °C within the later eight days mimicking new tissue formation stage. The in vivo wound healing of rats showed that this composite hydrogel presented a better healing effect with a wound contraction of 96% at 14 d, less inflammation and higher angiogenesis, than all control groups. These findings indicate SA/bFGF@pNIPAM/DS@p(NIPAM-co-AA) composite hydrogel is a potential dressing for wound repair.