Uncontrolled and sustained inflammation disrupts the wound-healing process and produces excessive reactive oxygen species, resulting in chronic or impaired wound closure. Natural antioxidants such as plant-based extracts and natural polysaccharides have a long history in wound care. However, they are hard to apply to wound beds due to high levels of exudate or anatomical sites to which securing a dressing is difficult. Therefore, we developed a complex coacervate-based drug carrier with underwater adhesive properties that circumvents these challenges by enabling wet adhesion and controlling inflammatory responses. This resulted in significantly accelerated wound healing through balancing the pro- and anti-inflammatory responses in macrophages. In brief, we designed a complex coacervate-based drug carrier (ADC) comprising oligochitosan and inositol hexaphosphate to entrap and release antioxidant proanthocyanins (PA) in a sustained way. The results from in vitro experiments demonstrated that ADC is able to reduce LPS-stimulated pro-inflammatory responses in macrophages. The ability of ADC to reduce LPS-stimulated pro-inflammatory responses in macrophages is even more promising when ADC is encapsulated with PA (ADC-PA). Our results indicate that ADC-PA is able to polarize macrophages into an M2 tissue-healing phenotype via up-regulation of anti-inflammatory and resolution of inflammatory responses. Treatment with ADC-PA around the wound beds fine-tunes the balance between the numbers of inducible nitric oxide synthase-positive (iNOS+) and mannose receptor-negative (CD206-) M1 and iNOS-CD206+ M2 macrophages in the wound microenvironment compared to controls. Achieving such a balance between the numbers of iNOS+CD206- M1 and iNOS-CD206+ M2 macrophages in the wound microenvironment has led to significantly improved wound closure in mouse models of diabetes, which exhibit severe impairments in wound healing. Together, our results demonstrate for the first time the use of a complex coacervate-based drug delivery system to promote timely resolution of the inflammatory responses for diabetic wound healing by fine-tuning the functions of macrophages.

The generation of hepatic spheroids is beneficial for a variety of potential applications, including drug development, disease modeling, transplantation, and regenerative medicine. Natural hydrogels are obtained from tissues and have been widely used to promote the growth, differentiation, and retention of specific functionalities of hepatocytes. However, relying on natural hydrogels for the generation of hepatic spheroids, which have batch to batch variations, may in turn limit the previously mentioned potential applications. For this reason, we researched a way to establish a three-dimensional (3D) culture system that more closely mimics the interaction between hepatocytes and their surrounding microenvironments, thereby potentially offering a more promising and suitable system for drug development, disease modeling, transplantation, and regenerative medicine. Here, we developed self-assembling and bioactive hybrid hydrogels to support the generation and growth of hepatic spheroids. Our hybrid hydrogels (PC4/Cultrex) inspired by the sandcastle worm, an Arg-Gly-Asp (RGD) cell adhesion sequence, and bioactive molecules derived from Cultrex BME (Basement Membrane Extract). By performing optimizations to the design, the PC4/Cultrex hybrid hydrogels can enhance HepG2 cells to form spheroids and express their molecular signatures (e.g., Cyp3A4, Cyp7a1, A1at, Afp, Ck7, Ck1, and E-cad). Our study demonstrated that this hybrid hydrogel system offers potential advantages for hepatocytes in proliferating, differentiating, and self-organizing to form hepatic spheroids in a more controllable and reproducible manner. In addition, it is a versatile and cost-effective method for 3D tissue cultures in mass quantities. Importantly, we demonstrate that it is feasible to adapt a bioinspired approach to design biomaterials for 3D culture systems, which accelerates the design of novel peptide structures and broadens our research choices on peptide-based hydrogels.

Increasing clinical evidence supports the use of direct oral anticoagulants (DOACs) as a potential new therapeutic option for patients suffering from cancer-associated thromboembolism. However, the clinical impact of DOACs compared with traditional anticoagulants on the survival of patients with head and neck cancer has not been well studied. A total of 1025 patients diagnosed as having head and neck cancer, including 92 DOAC users, 113 warfarin users, and 820 nonusers of anticoagulants, were selected from the Chang Gung Research Database between January 2001 and December 2019. The patients were matched using the propensity-score method. The survival rates were estimated among the three groups using the Kaplan–Meier method. The protective effects and side effects of the two anticoagulants were compared using the chi-square test. The death rate (18 patients, 19.57%) in patients using DOACs was significantly lower than that in patients using warfarin (68 patients, 60.18%) and those not using any anticoagulant (403 patients, 49.15%). DOAC users had significantly better disease-specific survival (DSS) than warfarin users (p = 0.019) and those who did not use any anticoagulant (p = 0.03). Further, DOAC users had significantly higher overall survival (OS) rates than warfarin users and those who did not use any anticoagulant (p = 0.003). Patients with oropharyngeal and laryngeal cancer and DOAC users had a significantly lower hazard ratio for survival, whereas patients with American Joint Committee on Cancer stage IV disease and those receiving multidisciplinary treatment (e.g., surgery with radiotherapy or concurrent radiochemotherapy) had a significantly higher hazard ratio for survival. Among them, patients with laryngeal cancer (HR = 0.47, 95% CI = 0.26–0.86, p = 0.0134) and DOAC users (HR = 0.53, 95% CI = 0.29–0.98, p = 0.042) had the lowest hazard ratio from DSS analysis. Similarly, patients with laryngeal cancer (HR = 0.48, 95% CI = 0.30–0.76, p = 0.0018) and DOAC users (HR = 0.58, 95% CI = 0.36–0.93, p = 0.0251) had the lowest hazard ratio from OS analysis. As for the protective effects or side effects of anticoagulants, there were no significant differences in the occurrence rate of bleeding or ischemic events between DOAC and warfarin users. In our study, DOACs were found to be better than warfarin in terms of survival in patients with head and neck cancer. As regards thromboembolism prevention and side effects, DOACs were comparable to warfarin in our patients. DOACs can be a treatment choice or prophylaxis for tumor emboli in head and neck cancer patients and they might be a better choice than traditional anticoagulants according to the results of our study.

Background: Incidence of fungal rhinosinusitis has increased in recent few years. We investigated the differences in microbiological findings between patients with fungal and non-fungal rhinosinusitis by growing microbiological cultures from samples obtained from sinus surgery. Methods: Using the Chang Gung Research Database, we enrolled all chronic rhinosinusitis (CRS) patients who had ever undergone sinus surgery from 2001 to 2019 and had microbiological culture during sinus surgery. Enrolled patients were divided into fungal and non-fungal groups, based on fungal culture and surgical pathology. Results: A total of 898 patients were diagnosed with fungal rhinosinusitis and 2884 with non-fungal rhinosinusitis. The fungal group had a higher age distribution (56.9 ± 13.1 vs. 47.0 ± 14.9), a larger proportion of females (62.4% vs. 37.0%), more unilateral lesions (80.4% vs. 41.6%), a lower incidence of the need for revision surgery (3.6% vs. 6.0%, p = 0.004), and a higher proportion of Pseudomonas aeruginosa in the culture (14.3% vs. 4.6%, p < 0.001). Conclusions: This large-scale study showed that Pseudomonas aeruginosa are more commonly found in patients with fungal rhinosinusitis and in patients who needed revision surgery, suggesting that efforts aimed at eliminating Pseudomonas are needed in order to improve the disease outcomes of patients with fungal rhinosinusitis.