Dynamic Cross-Linking, Self-Healing, Antibacterial Hydrogel for Regenerating Irregular Cranial Bone Defects.

Given the widespread clinical demand, addressing irregular cranial bone defects poses a significant challenge following surgical procedures and traumatic events. In situ-formed injectable hydrogels are attractive for irregular bone defects due to their ease of administration and the ability to incorporate ceramics, ions, and proteins into the hydrogel. In this study, a multifunctional hydrogel composed of oxidized sodium alginate (OSA)-grafted dopamine (DO), carboxymethyl chitosan (CMCS), calcium ions (Ca2+), nanohydroxyapatite (nHA), and magnesium oxide (MgO) (DOCMCHM) was prepared to address irregular cranial bone defects via dynamic Schiff base and chelation reactions. DOCMCHM hydrogel exhibits strong adhesion to wet tissues, self-healing properties, and antibacterial characteristics. Biological evaluations indicate that DOCMCHM hydrogel has good biocompatibility, in vivo degradability, and the ability to promote cell proliferation. Importantly, DOCMCHM hydrogel, containing MgO, promotes the expression of osteogenic protein markers COL-1, OCN, and RUNX2, and stimulates the formation of new blood vessels by upregulating CD31. This study could provide meaningful insights into ion therapy for the repair of cranial bone defects.

Strongly Adhesive, Self-Healing, Hemostatic Hydrogel for the Repair of Traumatic Brain Injury.

With wide clinical demands, therapies for traumatic brain injury (TBI) are a major problem in surgical procedures and after major trauma. Due to the difficulty in regeneration of neurons or axons after injury, as well as the inhibition of blood vessel growth by the formation of neural scars, existing treatment measures have limited effectiveness in repairing brain tissue. Herein, the biomultifunctional hydrogels are developed for TBI treatment based on the Schiff base reaction of calcium ion (Ca2+)-cross-linked oxidized sodium alginate (OSA) and carboxymethyl chitosan (CMCS). The obtained COCS hydrogel exhibits excellent adhesion to wet tissues, self-repair capability, and antimicrobial properties. What's particularly interesting is that the addition of Ca2+ increases the hydrogel's extensibility, enhancing its hemostatic capabilities. Biological assessments indicate that the COCS hydrogel demonstrates excellent biocompatibility, hemostatic properties, and the ability to promote arterial vessel repair. Importantly, the COCS hydrogel promotes the growth of cerebral microvessels by upregulating CD31, accelerates the proliferation of astrocytes, enhances the expression of GFAP, and stimulates the expression of neuron-specific markers such as NEUN and ß-tubulin. All of these findings highlight that the strongly adhesive, self-healing, hemostatic hydrogel shows great potential for the repair of traumatic brain injury and other tissue repair therapy.

Cathepsins in oral diseases: mechanisms and therapeutic implications.

Cathepsins are a type of lysosomal globulin hydrolase and are crucial for many physiological processes, including the resorption of bone matrix, innate immunity, apoptosis, proliferation, metastasis, autophagy, and angiogenesis. Findings regarding their functions in human physiological processes and disorders have drawn extensive attention. In this review, we will focus on the relationship between cathepsins and oral diseases. We highlight the structural and functional properties of cathepsins related to oral diseases, as well as the regulatory mechanisms in tissue and cells and their therapeutic uses. Elucidating the associated mechanism between cathepsins and oral diseases is thought to be a promising strategy for the treatment of oral diseases and may be a starting point for further studies at the molecular level.

Porous gelatin microsphere-based scaffolds containing MC3T3-E1 cells and calcitriol for the repair of skull defect.

There is an increasing demand for biomaterials with skull regeneration for clinical application. However, most of the current skull repair materials still have limitations, such as inadequate sources, poor cell adherence, differentiation, tissue infiltration, and foreign body sensation. Therefore, this study developed porous microsphere-based scaffolds containing mouse embryonic osteoblast precursor cells (MC3T3-E1 cells) and calcitriol (Cal) using gelatin and gelatin/hydroxyapatite through green freeze-crosslinking and freeze-drying. Gelatin was employed to prepare porous microspheres with a particle size of 100-300 µm, containing open pores of 2-70 µm and interconnected paths. Furthermore, the addition of Cal to porous gelatin microsphere-based scaffolds containing MC3T3-E1 cells (PGMSs-MC) and porous gelatin/hydroxyapatite composite microspheres containing MC3T3-E1 cells (HPGMSs-MC) improved their osteoinductivity and cell proliferation and promoted the formation of mature and well-organized bone. The developed Cal-HPGMSs-MC and Cal-PGMSs-MC displayed a good porous structure and cytocompatibility, histocompatibility, osteoconductivity, and osteoinduction. Thus, the designed scaffolds provide a promising prospect for tissue-engineered constructs with skull growth and integration, laying a foundation for further research on the reconstruction of skull defects.

Progress of gelatin-based microspheres (GMSs) as delivery vehicles of drug and cell.

Gelatin has various attractive features as biomedical materials, for instance, biocompatibility, low immunogenicity, biodegradability, and ease of manipulation. In recent years, various gelatin-based microspheres (GMSs) have been fabricated with innovative technologies to serve as sustained delivery vehicles of drugs and genetic materials as well as beneficial bacteria. Moreover, GMSs have exhibited promising potentials to act as both cell carriers and 3D scaffold components in tissue engineering and regenerative medicine, which not only exhibit excellent injectability but also could be integrated into a macroscale construct with the laden cells. Herein, we aim to thoroughly summarize the recent progress in the preparations and biomedical applications of GMSs and then to point out the research direction in future. First, various methods for the fabrication of GMSs will be described. Second, the recent use of GMSs in tumor embolization and in the delivery of cells, drugs, and genetic material as well as bacteria will be presented. Finally, several key factors that may enhance the improvement of GMSs were suggested as delivery vehicles.

A biodegradable antibacterial alginate/carboxymethyl chitosan/Kangfuxin sponges for promoting blood coagulation and full-thickness wound healing.

Conventional wound-dressing materials with structural and functional deficiencies are not effective in promoting wound healing. The development of multifunctional wound dressings is emerging as a promising strategy to accelerate blood coagulation, inhibit bacterial infection, and trigger full-thickness wound into a regenerative process. Herein, multifunctional composite sponges were developed by incorporation of traditional Chinese medicine Kangfuxin (KFX) into alginate (AG)/carboxymethyl chitosan (CMC) via green crosslinking, electrostatic interaction, and freeze-drying methods. It is demonstrated that the AG/CMC/KFX (ACK) sponges exhibit a highly interconnected and porous structure, suitable water vapor transmittance, excellent elastic properties, antibacterial behavior, cytocompatibility, and rapid hemostasis. Further, in a rat full-thickness wounds model, the ACK sponge containing 10% KFX (ACK-10) significantly facilitates wound closure compared to the AC group and ACK sponge containing 5% and 15% KFX. Thus, the multifunctional ACK-10 composite sponge has great promise for the application of full-thickness wound healing.

Corrigendum: Development and Validation of a Prognostic Nomogram to Predict Cancer-Specific Survival in Adult Patients With Pineoblastoma.

[This corrects the article DOI: 10.3389/fonc.2020.01021.].

Development and Validation of a Prognostic Nomogram to Predict Cancer-Specific Survival in Adult Patients With Pineoblastoma.

Pineoblastoma (PB) is a rare neoplasm of the central nervous system. This analysis aimed to identify factors and establish a predictive model for the prognosis of adult patients with PB. Data for 213 adult patients with PB (Surveillance, Epidemiology, and End Results database) were randomly divided into primary and validation cohorts. A predictive model was established and optimized based on the Akaike Information Criterion and visualized by a nomogram. Its predictive performance (concordance index and receiver operating characteristic curve) and clinical utility (decision curve analyses) were evaluated. We internally and externally validated the model using calibration curves. Multivariate Cox regression analysis identified age, year of diagnosis, therapy, tumor size, and tumor extension as independent predictors of PB. The model exhibited great discriminative ability (concordance index of the nomogram: 0.802; 95% confidence interval: 0.78-0.83; area under the receiver operating characteristic curve: ranging from 0.7 to 0.8). Calibration plots (probability of survival) showed good consistency between the actual observation and the nomogram prediction in both cohorts, and the decision curve analyses demonstrated great clinical utility of the nomogram. The nomogram is a useful and practical tool for evaluating prognosis and determining appropriate therapy strategies.

A Transcriptome Sequencing Study on Genome-Wide Gene Expression Differences of 3D Cultured Chondrocytes in Hydrogel Scaffolds with Different Gel Density.

Hydrogel is considered as a promising cell delivery vehicle in cartilage tissue engineering, whose tunable microenvironments may influence the function and fate of encapsulated chondrocytes. Here, the transcriptomes of chondrocytes that are encapsulated and cultured in hydrogel constructs respectively made of 0.8% and 4% alginate solution are investigated. Differences in chondrocyte transcriptome are detected via RNA-sequencing from these two cultural conditions. The differentially expressed genes (DEGs) are reflected in extracellular matrix (ECM) secretion, cell cycle, proliferation, cartilage development, and so on. Significantly, the expression of DEGs associated with cartilage ECM and cell proliferation are upregulated in 0.8% constructs; whilst the expressions of DEGs involved in cell cycle and matrix degradation are upregulated in 4% constructs. Moreover, interestingly, the expressions of chondrocyte hypertrophy markers are upregulated in 0.8% constructs; while 4% constructs seemingly favor the long-term maintenance of chondrocyte phenotype. Taken together, this study confirms on transcriptomic level that gel density affects gene expression and phenotype of the encapsulated chondrocytes; therefore, it may provide guidance for future design and fabrication of cartilage tissue engineering scaffolds.

Cross-linked gelatin microsphere-based scaffolds as a delivery vehicle of MC3T3-E1 cells: in vitro and in vivo evaluation.

Scaffolding plays a crucial role in bone tissue engineering by not only providing interfaces for cell adhesion, proliferation, and differentiation but also guiding neotissue formation. For this purpose, microspheres (MSs) are being increasingly used alone or in combination with other scaffolds. However, few researchers have used MSs to prepare 3D scaffolds by culture with delivered cells. In this study, we have developed covalent cross-linked gelatin MSs (ccG-MSs) (average diameter = 100-300 µm) to load mouse osteoblast MC3T3-E1 cells, which exhibit attachment and spreading on surfaces of ccG-MSs after co-culture. Significantly, the ccG-MSs can be integrated into a macroscopic construct with MC3T3-E1 cells after 5 days of cultivation. The MC3T3-E1 cells within ccG-MSs constructs show a higher viability and proliferation activity than those in the micro-cavitary gelatin gel (MCG) constructs. Calcium deposition, alkaline phosphatase activity as well as osteocalcin secretion within both ccG-MSs and MCG constructs have been evaluated in vitro and in vivo, respectively. Compared to MCG scaffolds, ccG-MS-based scaffolds can provide better cellular microenvironments for cell proliferation and osteogenic differentiation. Our findings will lay the foundation for understanding cellular behaviors in MS-based 3D constructs and help in designing MS-based bone tissue engineering scaffolds.