Signaling Pathways Triggering Therapeutic Hydrogels in Promoting Chronic Wound Healing.

In recent years, there has been a significant increase in the prevalence of chronic wounds, such as pressure ulcers, diabetic foot ulcers, and venous ulcers of the lower extremities. The main contributors to chronic wound formation are bacterial infection, prolonged inflammation, and peripheral vascular disease. However, effectively treating these chronic wounds remains a global challenge. Hydrogels have extensively explored as wound healing dressing because of their excellent biocompatibility and structural similarity to extracellular matrix (ECM). Nonetheless, much is still unknown how the hydrogels promote wound repair and regeneration. Signaling pathways play critical roles in wound healing process by controlling and coordinating cells and biomolecules. Hydrogels, along with their therapeutic ingredients that impact signaling pathways, have the potential to significantly enhance the wound healing process and its ultimate outcomes. Understanding this interaction will undoubtedly provide new insights into developing advanced hydrogels for wound repair and regeneration. This paper reviews the latest studies on classical signaling pathways and potential targets influenced by hydrogel scaffolds in chronic wound healing. This work hopes that it will offer a different perspective in developing more efficient hydrogels for treating chronic wounds.

Glucose-Responsive Antioxidant Hydrogel Accelerates Diabetic Wound Healing.

Diabetic complications can be ameliorated by inhibiting excessive oxidative stress with antioxidants. To enhance therapeutic intervention, it is crucial to develop intelligent scaffolds for efficient delivery of antioxidants to diabetic wounds. This study introduces reversible boronic bonds to create an intelligent antioxidant hydrogel scaffold. This study modifies gelatin methacryloyl (GelMA) with 4-carboxyphenyboronic acid (CPBA) to synthesize a derivative of GelMA (GelMA-CPBA), and then photo cross-links GelMA-CPBA with (-)-epigallocatechin-3-gallate (EGCG) to form GelMA-CPBA/EGCG (GMPE) hydrogel. The GMPE hydrogel responds to changes in glucose levels, and more EGCG is released as glucose level increases due to the dissociation of boronic ester bonds. The GMPE hydrogel shows good biocompatibility and biodegradability, and its mechanical property is similar to that of the skin tissue. Both in vitro and in vivo results demonstrate that the GMPE hydrogel scaffolds effectively eliminate reactive oxygen species (ROS), reduce the inflammation, and promote angiogenesis, thereby improve collagen deposition and tissue remodeling during diabetic wound healing. This strategy offers new insight into glucose-responsive scaffolds, and this responsive antioxidan hydrogel scaffold holds great potential for the treatment of chronic diabetic wounds.

Recent Advances in Bioengineered Scaffolds for Cutaneous Wound Healing.

Wound healing is an evolved dynamic biological process. Though many research and clinical approaches have been explored to restore damaged or diseased skin, the current treatment for deep cutaneous injuries is far from being perfect, and the ideal regenerative therapy remains a significant challenge. Of all treatments, bioengineered scaffolds play a key role and represent great progress in wound repair and skin regeneration. In this review, we focus on the latest advancement in biomaterial scaffolds for wound healing. We discuss the emerging philosophy of designing biomaterial scaffolds, followed by precursor development. We pay particular attention to the therapeutic interventions of bioengineered scaffolds for cutaneous wound healing, and their dual effects while conjugating with bioactive molecules, stem cells, and even immunomodulation. As we review the advancement and the challenges of the current strategies, we also discuss the prospects of scaffold development for wound healing.

Engineering Polysaccharides for Tissue Repair and Regeneration.

The success of repair or regeneration depends greatly on the architecture of 3D scaffolds that finely mimic natural extracellular matrix to support cell growth and assembly. Polysaccharides have excellent biocompatibility with intrinsic biological cues and they have been extensively investigated as scaffolds for tissue engineering and regenerative medicine (TERM). The physical and biochemical structures of natural polysaccharides, however, can barely meet all the requirements of tissue-engineered scaffolds. To take advantage of their inherent properties, many innovative approaches including chemical, physical, or joint modifications have been employed to improve their properties. Recent advancement in molecular and material building technology facilitates the fabrication of advanced 3D structures with desirable properties. This review focuses on the latest progress of polysaccharide-based scaffolds for TERM, especially those that construct advanced architectures for tissue regeneration.

Engineering immune-responsive biomaterials for skin regeneration.

The progress of biomaterials and tissue engineering has led to significant advances in wound healing, but the clinical therapy to regenerate perfect skin remains a great challenge. The implantation of biomaterial scaffolds to heal wounds inevitably leads to a host immune response. Many recent studies revealed that the immune system plays a significant role in both the healing process and the outcome. Immunomodulation or immuno-engineering has thus become a promising approach to develop pro-regenerative scaffolds for perfect skin regeneration. In this paper, we will review recent advancements in immunomodulating biomaterials in the field of skin repair and regeneration, and discuss strategies to modulate the immune response by tailoring the chemical, physical and biological properties of the biomaterials. Understanding the important role of immune responses and manipulating the inherent properties of biomaterials to regulate the immune reaction are approaches to overcome the current bottleneck of skin repair and regeneration.

Preparation of gradient-type biological tissue-polymer complex for interlinking device.

The aim of this study was to investigate the monomer absorption behavior of decellularized dermis and prepare a gradient-type decellularized dermis-polymer complex. Decellularized dermis was prepared using sodium dodecyl sulfate, and its monomer absorption behavior was investigated using three types of hydrophobic monomer with different surface free energies. The results show that monomer absorption depends strongly on the tissue structure, regardless of the surface free energy, and the amount of absorbed monomer can be increased by sonication. Based on these results, we prepared a gradient-type decellularized dermis-poly(methyl methacrylate) complex by controlling the permeation time of the methyl methacrylate monomer and polymerization initiator into the decellularized dermis. The mechanical strength of this complex gradually increased from the dermis side to the polymer side, and combined the physical characteristics of the dermis and the polymer.

Construction of vascular graft with circumferentially oriented microchannels for improving artery regeneration.

Design and fabrication of scaffolds with three-dimensional (3D) topological cues inducing regeneration of the neo-tissue comparable to native one remains a major challenge in both scientific and clinical fields. Here, we developed a well-designed vascular graft with 3D highly interconnected and circumferentially oriented microchannels by using the sacrificial sugar microfiber leaching method. The microchannels structure was capable of promoting the migration, oriented arrangement, elongation, and the contractile phenotype expression of vascular smooth muscle cells (VSMCs) in vitro. After implantation into the rat aorta defect model, the microchannels in vascular grafts simultaneously improved the infiltration and aligned arrangement of VSMCs and the oriented deposition of extracellular matrix (ECM), as well as the recruitment and polarization of macrophages. These positive results also provided protection and support for ECs growth, and ultimately accelerated the endothelialization. Our research provides a new strategy for the fabrication of grafts with the capability of inducing arterial regeneration, which could be further extended to apply in preparing other kinds of oriented scaffolds aiming to guide oriented tissue in situ regeneration.

Joint pollution and source apportionment of PM2.5 among three different urban environments in Sichuan Basin, China.

The PM2.5 were sampled in three different urban environments: (city of) Chengdu, Leshan, and Dazhou, which are located in Sichuan Basin. 8 types of water-soluble ion and 25 types of metal element were measured in each PM2.5 sample across the seasons of 2017. The study results suggest that the joint PM2.5 pollution among the three cities mainly occurred in autumn and winter, and the air quality of Chengdu and Leshan was largely affected by Dazhou. Overall, the mass concentrations of PM2.5 of these three cities exhibited no statistically significant differences. However, Leshan had the highest level of ionic pollution, and the dominant form of inorganic compound in ambient PM2.5 was NH4NO3, and a competitive relationship between form of NH4NO3 and (NH4)2SO4 (NH4HSO4) was found as well. High homology between SO42- and NO3- has been observed in all the three cities, and the ratio between [SO42-] and [NO3-] indicated that the stationary source contributed the most to ambient PM2.5 in Dazhou. The mass concentrations of the total metal elements from the three cities exhibited similar levels, nevertheless, Dazhou had the highest mass fraction of total metal elements in PM2.5. The enrichment factor of each element indicated that the natural source was highly contributory to the crustal elements in PM2.5 of all the three cities, whereas Cr, Cu, Se, Mo, Cd, Tl and Bi were primarily originated from anthropogenic source. In addition, the source apportionment of PM2.5 suggest that Dazhou had the different factors and factor-contributions comparing with Chengdu and Leshan.

Ginsenoside Rg3-loaded, reactive oxygen species-responsive polymeric nanoparticles for alleviating myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a serious threat to the health and lives of patients without any effective therapy. Excessive production of reactive oxygen species (ROS) is considered a principal cause of MIRI. Some natural products, including ginsenoside Rg3 (Rg3), exhibit robust antioxidant activity. However, the lack of an effective delivery strategy for this hydrophobic compound hinders its clinical application. In addition, therapeutic targets and molecular mechanisms of Rg3 require further elucidation to establish its mode of action. This study aimed to generate ROS-responsive nanoparticles (PEG-b-PPS) via the self-assembly of diblock copolymers of poly (ethylene glycol) (PEG) and poly (propylene sulfide) (PPS) and use them for Rg3 encapsulation and delivery. We identified FoxO3a as the therapeutic target of Rg3 using molecular docking and gene silencing. In rat ischemia-reperfusion model, an intramyocardial injection of Rg3-loaded PEG-b-PPS nanoparticles improved the cardiac function and reduced the infarct size. The mechanism of action was established as Rg3 targeting of FoxO3a, which inhibited the promotion of oxidative stress, inflammation, and fibrosis via downstream signaling pathways. In conclusion, this approach, involving ROS-responsive drug release, together with the identification of the target and mechanism of action of Rg3, provided an effective strategy for treating ischemic diseases and oxidative stress and could accelerate the implementation of hydrophobic natural products in clinical applications.

A hybrid small-diameter tube fabricated from decellularized aortic intima-media and electrospun fiber for artificial small-diameter blood vessel.

Hybrid small-diameter tubes were fabricated by wrapping decellularized aortic intima-media sheets around a tubular stainless steel mandrel with diameter 4 mm, and then by coating with electrospun segmented polyurethane. The synthetic coat was deposited uniformly to a thickness of about 0.5-3.5 µm depending on the duration of electrospinning. Resistance to luminal pressure, burst strength, and stiffness increased with the thickness of the electrospun coat, suggesting that the synthetic fabric reinforces the reconstructed acellular aortic intima-media. Human umbilical vein endothelial cells seeded on the inner surface acquired flagstone morphology, while normal human dermal fibroblasts seeded on the outer surface proliferated well and partly migrated into deeper layers. Collectively, the data suggest that reinforcing decellularized aortic intima-media with electrospun fibers generates a small-diameter hybrid blood vessel with good biocompatibility and suitable mechanical properties. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1064-1070, 2019.

Bilayered Polymeric Micro- and Nanofiber Vascular Grafts as Abdominal Aorta Replacements: Long-Term in Vivo Studies in a Rat Model.

In vivo long-term evaluation of degradable implants offers valuable information for the further design and optimization of biomaterials. In this study, we prepared one type of bilayer graft, which had an internal layer of oriented elastic degradable poly(l-lactide-ε-caprolactone) (PLCL) microfibers and an external layer of slowly degradable poly-ε-caprolactone (PCL) nanofiber. After in vivo implantation for 18 months, no aneurysm or graft rupture occurred, despite the finding that the mechanical properties of explanted PLCL grafts had decreased due to the degradation of PLCL materials. Explanted grafts maintained complete endothelialization and the degradation of PLCL improved vascular remodeling, which included the formation of a thicker media layer, denser extracellular matrix deposition, and obvious contractile and diastolic functions. Also, we found that the degradation products of PLCL tended to cause calcification, which may limit the return of vascular function to the natural artery level. Taken together, this bilayered graft showed a positive impact on vascular regeneration, while modification of bioactive or anticalcification factors should be considered for incorporation in future designs and the fabrication of small-diameter vascular grafts.

Biodegradable and elastomeric vascular grafts enable vascular remodeling.

Implanted grafts, including vascular substitutes, inevitably experience remodeling by host cells. The design of grafts capable of promoting constructive remodeling remains a challenge within regenerative medicine. Here, we used a biodegradable elastic polymer, poly (l-lactide-co-ε-caprolactone) (PLCL), to develop a vascular graft with circumferentially aligned microfibers. The grafts exhibited excellent handling properties and resistance to deformation. Upon implantation in rat abdominal aorta, graft-guided neoartery regeneration was achieved in a short period (4 weeks) as evidenced by rapid cell infiltration and alignment, and complete endothelialization. During vascular remodeling, a high ratio of M2/M1 macrophage was detected, and the expression of pro-inflammatory and anti-inflammatory cytokines first increased and then decreased to normal level for the follow-up period. By 12 months, the PLCL grafts were almost completely degraded and a well-integrated neoartery was formed with characteristics comparable to native arteries, such as transparent appearance, synchronous pulsation, dense and orderly extracellular matrix (ECM) arrangement, strong and compliant mechanical properties, and vasomotor response to pharmacologic agents. Taken together, our strategy represents a new avenue for guided tissue regeneration by designing the grafts to promote tissue remodeling via controlling structure, degradation and mechanical properties of the scaffolds.

Water absorption by decellularized dermis.

Water absorption by decellularized dermis was investigated and compared with biopolymer and synthetic polymer hydrogels (glutaraldehyde-crosslinked gelatin and crosslinked poly(acrylamide) hydrogel, respectively). Porcine dermis was decellularized in an aqueous sodium dodecyl sulfate (SDS) solution. Histological evaluation revealed that the SDS-treated dermis has much larger gaps between collagen fibrils than non-treated dermis, and that water absorption depends on these gaps. Decellularized dermis has low water absorptivity and the absorption obeys Fick's second law. During absorption, the water diffusion rate decreases with time and occurs in two steps. The first is rapid absorption into the large gaps, followed by slow absorption by the collagen fiber layer. Because of the gaps, decellularized dermis can absorb more water than native dermis and shows different water absorption behavior to glutaraldehyde-crosslinked gelatin and crosslinked poly(acrylamide) hydrogels.

Martrilin-3 (MATN3) Overexpression in Gastric Adenocarcinoma and its Prognostic Significance.

BACKGROUND The aim of this study was to investigate the expression level of martrilin-3 (MATN3) in patients with gastric adenocarcinoma (GAC) and to investigate the prognostic significance of MATN3. MATERIAL AND METHODS Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data were used to predict the expression and prognostic value of MATN3 mRNA in GAC patients. Seventy-six GAC patients had GAC tissue samples and paired adjacent normal tissue samples collected retrospectively to examine the MATN3 protein expression level by immunohistochemical staining. Furthermore, Kaplan-Meier univariate and Cox multivariate analyses were used to verify the correlation between MATN3 expression and clinicopathological parameters of GAC patients and the prognostic significance of MATN3. RESULTS The GEO and TCGA data predicted that MATN3 mRNA levels were significantly higher in GAC tissue compared to normal tissue (all p<0.05). Further survival analyses showed that GAC patients with high mRNA expression of MATN3 had significantly lower disease-free survival (DFS) and overall survival (OS) time than those with low mRNA expression of MATN3 (all p<0.05). Subsequent immunohistochemical staining results confirmed that the MATN3 protein levels in GAC tissues were highly expressed (p=0.000) compared to normal tissues. In addition, GAC patients with high protein expression of MATN3 had remarkably decreased OS compared to patients with low protein expression of MATN3 (p=0.000). Univariate and multivariate survival analyses revealed that MATN3 high expression could be used as an independent predictor of poor prognosis in GAC patients (all p=0.000). CONCLUSIONS This study confirmed that MATN3 protein was highly expressed in GAC patients, and MATN3 overexpression could be used as an independent predictor of poor prognosis in GAC patients.

Decellularized porcine aortic intima-media as a potential cardiovascular biomaterial.

OBJECTIVES: The aim of this research is to investigate the histological and mechanical properties of decellularized aortic intima-media, a promising cardiovascular biomaterial. METHODS: Porcine aortic intima-media was decellularized using two methods: high hydrostatic pressurization (HHP) and sodium dodecyl sulphate (SDS). The histological properties were characterized using haematoxylin and eosin staining and Elastica van Gieson staining. The mechanical properties were evaluated using a tensile strength test. RESULTS: The structure of the HHP-treated samples was unchanged histologically, whereas that of the SDS-treated samples appeared structurally loose. Consequently, with regard to the mechanical properties of SDS-decellularized intima-media, elastic modulus and tensile strength were significantly decreased. CONCLUSIONS: The decellularization method affected the structure and the mechanical properties of the biomaterial. The HHP-treated sample was structurally and mechanically similar to the untreated control. Its mechanical properties were similar to those of human heart valves and the iliac artery and vein. Our results imply that porcine aortic intima-media that is decellularized with HHP is a potential cardiovascular biomaterial.

Relation between the tissue structure and protein permeability of decellularized porcine aorta.

The aim of this study was to assess the suitability of decellularized porcine aorta as a vascular graft material by measuring its permeability to protein. Aorta samples were decellularized by treatment with either high hydrostatic pressurization (HHP) or sodium dodecyl sulfate (SDS). Histological evaluation showed that the structure of an HHP-treated sample was similar to that of an untreated sample, while the structure of an SDS-treated sample was surfactant-damaged. A two-chamber diffusion system was used to measure permeability to lysozyme and bovine serum albumin. The lysozyme and bovine serum albumin mass transfer coefficients calculated for an SDS-treated sample were significantly larger than those calculated for an untreated sample, while the mass transfer coefficients for an HHP-treated sample were similar to those for an untreated sample. The mass transfer coefficients showed very good agreement with the tissue structure characterization, which means that differences in permeability reflected differences in tissue structure.