Injectable conductive hydrogel remodeling microenvironment and mimicking neuroelectric signal transmission after spinal cord injury.

Severe spinal cord injury (SCI) leads to dysregulated neuroinflammation and cell apoptosis, resulting in axonal die-back and the loss of neuroelectric signal transmission. While biocompatible hydrogels are commonly used in SCI repair, they lack the capacity to support neuroelectric transmission. To overcome this limitation, we developed an injectable silk fibroin/ionic liquid (SFMA@IL) conductive hydrogel to assist neuroelectric signal transmission after SCI in this study. The hydrogel can form rapidly in situ under ultraviolet (UV) light. The mechanical supporting and neuro-regenerating properties are provided by silk fibroin (SF), while the conductive capability is provided by the designed ionic liquid (IL). SFMA@IL showed attractive features for SCI repair, such as anti-swelling, conductivity, and injectability. In vivo, SFMA@IL hydrogel used in rats with complete transection injuries was found to remodel the microenvironment, reduce inflammation, and facilitate neuro-fiber outgrowth. The hydrogel also led to a notable decrease in cell apoptosis and the achievement of scar-free wound healing, which saved 45.6 ± 10.8 % of spinal cord tissue in SFMA@IL grafting. Electrophysiological studies in rats with complete transection SCI confirmed SFMA@IL's ability to support sensory neuroelectric transmission, providing strong evidence for its signal transmission function. These findings provide new insights for the development of effective SCI treatments.

A nano-composite hyaluronic acid-based hydrogel efficiently antibacterial and scavenges ROS for promoting infected diabetic wound healing.

Diabetic wound infection brings chronic pain to patients and the therapy remains a crucial challenge owing to the disruption of the internal microenvironment. Herein, we report a nano-composite hydrogel (ZnO@HN) based on ZnO nanoparticles and a photo-trigging hyaluronic acid which is modified by o-nitrobenzene (NB), to accelerate infected diabetic wound healing. The diameter of the prepared ZnO nanoparticle is about 50 nm. X-ray photoelectron spectroscopy (XPS) analysis reveals that the coordinate bond binds ZnO in the hydrogel, rather than simple physical restraint. ZnO@HN possesses efficient antioxidant capacity and it can scavenge DPPH about 40 % in 2 h and inhibit H2O2 >50 % in 8 h. The nano-composite hydrogel also exhibits satisfactory antibacterial capacity (58.35 % against E. coli and 64.03 % against S. aureus for 6 h). In vitro tests suggest that ZnO@HN is biocompatible and promotes cell proliferation. In vivo experiments reveal that the hydrogel can accelerate the formation of new blood vessels and hair follicles. Histological analysis exhibits decreased macrophages, increased myofibroblasts, downregulated TNF-α expression, and enhanced VEGFA expression during wound healing. In conclusion, ZnO@HN could be a promising candidate for treating intractable infected diabetic skin defection.

Fabrication of an Adhesive Small Intestinal Submucosa Acellular Matrix Hydrogel for Accelerating Diabetic Wound Healing.

The treatment of diabetic skin defects comes with enormous challenges in the clinic due to the disordered metabolic microenvironment. In this study, we therefore designed a novel composite hydrogel (SISAM@HN) with bioactive factors and tissue adhesive properties for accelerating chronic diabetic wound healing. Hyaluronic acid (HA) modified by N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide (NB) held the phototriggering tissue adhesive capacity. Decellularized small intestinal submucosa (SIS) was degreased and digested to form the acellular matrix, which facilitated bioactive factor release. The results of the burst pressure test demonstrated that the in situ formed hydrogel possessed a tissue adhesive property. In vitro experiments, based on bone marrow stromal cells, revealed that the SIS acellular matrix-containing hydrogel contributed to promoting cell proliferation. In vivo, a diabetic mouse model was created and used to evaluate the tissue regeneration function of the obtained hydrogel, and our results showed that the synthesized hydrogel could assist collagen deposition, attenuate inflammation, and foster vascular growth during the wound healing process. Overall, the SIS acellular matrix-containing HA hydrogel was able to adhere to the wound sites, promote cell proliferation, and facilitate angiogenesis, which would be a promising biomaterial for wound dressing in clinical therapy of diabetic skin defects.

A multi-functional double cross-linked chitosan hydrogel with tunable mechanical and antibacterial properties for skin wound dressing.

Chitosan hydrogels with essential antibacterial properties and biocompatibility have great potential in tissue engineering and regeneration medicine. However, pure chitosan hydrogel could be limited by insufficient mechanical properties. In this work, we designed a multi-functional chitosan hydrogel based on the combination of chitosan methacrylate (CTSMA) and sulfhydrated chitosan (CTSSH), which is cross-linked simultaneously by free-radical polymerization reaction and Thiol-ene reaction. The CTSMA/CTSSH (CMS) hydrogels displayed superior tissue adhesive and mechanical properties when compared to pure CTSMA hydrogel. Additionally, the resulting hydrogels exhibited potent antimicrobial effects against both E. coli and S. aureus. Besides, the CMS hydrogels exhibited good biocompatibility as demonstrated by cytotoxicity and cell proliferation experiments using fibroblasts cells (L929) and adipose-derived stem cells (ADSCs). In vivo experiment, the repairing effect of hydrogels on full-thickness skin defect model in rats was studied. Histological and immunohistochemical staining results showed that CMS hydrogels promoted angiogenesis, dermal repair and epidermal regeneration. Overall, the study highlights the potential of the CMS hydrogels as a promising biomaterial in wound healing applications.

Case Report: Complete pathological remission of human chorionic gonadotrophin-producing gallbladder carcinoma with multiple liver metastases after treatment with chemotherapy plus an immune checkpoint inhibitor.

Background: Gallbladder carcinoma (GBC) producing human chorionic gonadotrophin (HCG) is an extremely rare and highly invasive tumor with a poor prognosis. This unfavorable clinical outcome is partly due to the aggressive nature of the tumor and its insensitivity to chemotherapy. Case presentation: We herein report a case of primary GBC producing HCG with liver metastases in a 58-year-old woman. The patient presented with a markedly elevated ß-HCG level and a mass in the gallbladder with multiple liver metastases. A definitive diagnosis was obtained after a needle biopsy of the liver metastases, showing poorly differentiated carcinoma with large-scale necrosis and strong positivity of immunostaining for HCG in tumor cells. The patient received chemotherapy (gemcitabine plus capecitabine) combined with carrellizumab, an immune checkpoint inhibitor (ICI). Pathological complete response was achieved after eight courses of combined therapy, which was confirmed by pathological analysis of resected specimens. After surgery, two courses of chemotherapy plus ICIs were adopted again. Complete response remained for approximately 1 year up to the present. Tumor tissue was collected to perform immunostaining of PD-L1, whole-exome sequencing, and RNA-seq. Low-TMB (1.51 mut/Mb), MSS, and high PD-L1 expression (TPS ≥ 50%) were observed in the tumor. Besides, the dominant types of infiltrating immune cells were macrophage and CD4+ T cells. Compared to other gallbladder adenocarcinoma without HCG, the proportion of M1 macrophage was at a higher level and the gene sets of MYC targets v1 and PI3K/AKT/mTOR signaling were highly expressed in our case. To the best of our knowledge, this is the first case report of complete remission of HCG-producing gallbladder carcinoma with liver metastases after chemotherapy combined with an immune checkpoint inhibitor. Furthermore, this is also the first report that described the tumor genetic feature and tumor immune microenvironment atlas of HCG-producing GBC. Conclusion: chemotherapy plus an immune checkpoint inhibitor may provide a potentially curative option for gallbladder carcinoma with HCG production.

The molecular feature of abnormal fetal neuromuscular development after maternal use of telbivudine or tenofovir during pregnancy in rodent model.

AIMS: Maternal treatment with nucleoside analogues such as telbivudine (LdT) and tenofovir disoproxil fumarate (TDF) has been applied worldwide. However, administration of LdT or TDF during pregnancy may affect the fetal neuromuscular development. We conducted the current study to investigate the histological pathology and transcriptomic changes pertaining to the neuromuscular system of the newborn exposed to LdT or TDF during pregnancy in rodent model. MAIN METHODS: Pregnant C57/BL6 mice were randomly divided into three arms and administered either with LdT solution (0.1 ml, 78 mg/kg/d), TDF solution (0.1 ml, 39 mg/kg/d) or normal saline solution (0.1 ml). Pups in each arm were weighed and sacrificed after birth. Both sides of quadriceps femoris muscle of the newborn were obtained. The histological observation was conducted under light microscope. The transcriptional profiling was analyzed with RNA sequencing (RNA seq). KEY FINDINGS: Four types of morphological abnormalities of the newborn neuromuscular system, being clusters of rhabdomyoblasts, skeletal muscle fibrosis, rhabdomyolysis and necrosis and immature muscle fiber bundles, were noted in both LdT group and TDF group. Moreover, both groups showed significantly decreased gross cross-sectional area of muscle fiber and significantly increased percentage of muscle lesion area. RNA seq identified a total of 164 differentially expressed genes (DEGs) essential to fetal neuromuscular development. These DEGs were involved in calcium regulation, phospholipid activity, muscle cell development, the functioning of mitochondria/endoplasmic reticulum/lysosome/cytoskeleton, the regulation of arachidonic acid and the development of nervous system. SIGNIFICANCE: Our findings suggest maternal administration of LdT or TDF lead to abnormal neuromuscular development in offspring mice. Further study should be encouraged to investigate the down-stream signaling pathways.

A Dual-Crosslinked Hydrogel Based on Gelatin Methacryloyl and Sulfhydrylated Chitosan for Promoting Wound Healing.

The skin is the largest organ of the human body. Skin injuries, especially full-thickness injuries, are a major treatment challenge in clinical practice. Therefore, wound dressing materials with therapeutic effects have great practical significance in healthcare. This study used photocrosslinkable gelatin methacryloyl (GelMA) and sulfhydrylated chitosan (CS-SH) to design a double-crosslinked hydrogel for wound dressing. When crosslinked together, the resulting hydrogels showed a highly porous inner structure, and enhanced mechanical properties and moisture retention capacity. The compression modulus of the GelMA/CS-SH hydrogel (GCH) reached up to about 40 kPa and was much higher than that of pure GelMA hydrogel, and the compression modulus was increased with the amount of CS-SH. In vitro study showed no cytotoxicity of obtained hydrogels. Interestingly, a higher concentration of CS-SH slightly promoted the proliferation of cells. Moreover, the double-crosslinked hydrogel exhibited antibacterial properties because of the presence of chitosan. In vivo study based on rats showed that full-thickness skin defects healed on the 15th day. Histological results indicate that the hydrogel accelerated the repair of hair follicles and encouraged the orderly growth of collagen fibers in the wound. Furthermore, better blood vessel formation and a higher expression of VEGFR were observed in the hydrogel group when compared with the untreated control group. Based on our findings, GCH could be a promising candidate for full-thickness wound dressing.

Retrorectal mucinous adenocarcinoma arising from a tailgut cyst: A case report and review of literature.

BACKGROUND: Tailgut cysts are defined as congenital cysts that develop in the rectosacral space from the residue of the primitive tail. As a congenital disease, caudal cysts are very rare, and their canceration is even rarer, which makes the disease prone to misdiagnosis and delayed treatment. We describe a case of caudal cyst with adenocarcinogenesis and summarize in detail the characteristics of cases with analytical value reported since 1990. CASE SUMMARY: A 35-year-old woman found a mass in her lower abdomen 2 mo ago. She was asymptomatic at that time and was not treated because of the coronavirus disease 2019 pandemic. Two weeks ago, the patient developed abdominal distension and right waist discomfort and came to our hospital. Except for the high level of serum carcinoembryonic antigen, the medical history and laboratory tests were not remarkable. Magnetic resonance imaging showed a well-defined, slightly lobulated cystic-solid mass with a straight diameter of approximately 10 cm × 9 cm in the presacral space, slightly high signal intensity on T2-weighted imaging, and moderate signal intensity on T1-weighted imaging. The mass was completely removed by laparoscopic surgery. Histopathological examination showed that the lesion was an intestinal mucinous adenocarcinoma, and the multidisciplinary team decided to implement postoperative chemotherapy. The patient recovered well, the tumor marker levels returned to normal, and tumor-free survival has been achieved thus far. CONCLUSION: The case and literature summary can help clinicians and researchers develop appropriate examination and therapeutic methods for diagnosis and treatment of this rare disease.

A photo-triggering double cross-linked adhesive, antibacterial, and biocompatible hydrogel for wound healing.

Full-thickness wounds, lacking the epidermis and entire dermis and extending into subcutaneous fat, represent a common treatment challenge. Due to the loss of adnexal structures as a source of keratinocytes, full-thickness wounds healing can only be achieved by re-epithelialization from the wound edge and contraction. Here, we developed a hydrogel composed of chitosan methacrylate (CSMA) and o-nitrosobenzaldehyde-modified gelatin (GelNB) for promoting full-thickness wound healing. The CSMA/GelNB (CM/GN) hydrogels exhibited superior mechanical and adhesive properties than that of pure CSMA hydrogel. In vivo experiments confirmed that CM/GN could promote wound healing by generating more hair follicles and mutual blood vessels, high fibroblasts density, and thicker granulation tissue thickness. In addition, reduced secretions of tumor necrosis factor-α (TNF-α) and enhanced secretions of vascular endothelial growth factor (VEGF) could be observed in regenerated tissues after CM/GN treatment. These results suggested that CM/GN hydrogels could be promising candidates to promote wound healing.

Surgically treated rare intestinal bleeding due to submucosal hematoma in a patient on oral anticoagulant therapy: A case report.

RATIONALE: Bleeding in the gastrointestinal tract is a common complication of oral anticoagulant therapy (AT), and it usually appears as mucosal erosion or ulcer; however, intestinal submucosal hematoma (ISH) is an uncommon cause of hemorrhage. PATIENT CONCERNS: This report presents the case of a 70-year-old woman with acute hematochezia induced by AT. She underwent computed tomography and endoscopy. DIAGNOSES: Colon submucosal hematoma. INTERVENTIONS: Conservative treatment had no effect, and the patient underwent emergency surgery. OUTCOMES: Surgical resection showed hemorrhage and necrosis in the left colon, and the patient recovered 24 hours after surgery and continued AT. LESSONS: The present case indicates that the ISH should be kept in mind as a complication of AT. It can be managed conservatively in some stable patients, but emergency surgery may be needed in some serious situations.

Efficacy and safety of mTOR inhibitor therapy in patients with early-stage autosomal dominant polycystic kidney disease: a meta-analysis of randomized controlled trials.

BACKGROUND: The objective of this study was to conduct a meta-analysis of randomized controlled trials (RCTs) to present a profound review and an objective appraisal of the efficacy and safety of the mammalian target of rapamycin (mTOR) inhibitor therapy in patients with autosomal dominant polycystic kidney disease (ADPKD). METHODS: RCTs involving the mTOR inhibitor therapy in patients with ADPKD are included. The data of studies and major outcomes include changes in patients' glomerular filtration rate (GFR), urinary protein, total kidney volume (TKV), cyst volume, parenchymal volume, and lipid profile and the frequency of adverse events. Review Manager 5.0 for meta-analysis was used in this study. RESULTS: Up to January 31, 2011, 4 RCTs (with a total of 564 patients) were included. The mTOR inhibitor therapy group had smaller TKV than the control group [weighted mean difference (WMD) of TKV after treatment: -318.45, P = 0.04]. The mTOR inhibitor treatment does not necessarily slow down the aggravation of renal function in patients with ADPKD (WMD of GFR after therapy: 5.55, P < 0.01; at 6-month analyses = -0.97, P = 0.56). Side effects could occur during the mTOR inhibitor therapy, but the severities can be controlled by the appropriate use of drug. CONCLUSIONS: Based on the current limited clinical trials, this study suggests that short-duration mTOR inhibitor therapy is relatively safe to slow down the increase in kidney volume in patients with early-stage ADPKD, but it has limited impact on slowing down the decrease in GFR.

Urinary proteome analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry with magnetic beads for identifying the pathologic presentation of clinical early IgA nephropathy.

IgA nephropathy is the most common type of chronic glomerulonephritis which leads eventually to end-stage renal disease (ESRD). The duration of clinical early stage IgA nephropathy to ESRD varies a lot. The pathologic presentation may have detrimental effect on outcome. But the renal biopsy is a high-risk invasive operation not able to be accepted by all patients. In this study, we tried to find biomarkers in urine as a non-invasive approach to diagnose different pathologic presentations of clinical early stage IgA nephropathy. A total of 56 patients with IgA nephropathy were included in this study, with 23 patients having severe pathologic presentation and the other 33 having mild ones. The control group consisted of 14 normal subjects. The urinary proteomic spectra from those three groups were generated by Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with weak cationic exchange magnetic beads. The total experiment data was handled by the Zhejiang University ProteinChip Data Analysis System. We found that the urine protein/peptide spectra patterns could be established to distinguish severe IgA nephropathy from the mild IgA nephropathy group and the normal group. Several potential biomarkers were found and the diagnostic system could distinguish between severe IgA nephropathy from the mild IgA nephropathy with a sensitivity of 90.48% and specificity of 96.77%. We conclude that, using MALDI-TOF-MS with magnetic beads to detect urine proteomic patterns shows great potential in identifying early IgA nephropathy with different pathologic prognosis.