Seong Keun Kwon

Radiation therapy for head and neck cancer often causes xerostomia, a chronic salivary gland (SG) dysfunction driven by excessive reactive oxygen species (ROS), severely impacting the quality of life of patients. Existing treatments, such as artificial saliva or SG stimulants, offer only temporary relief. We developed a novel therapeutic system combining glutathione (GSH)-conjugated gelatin (Gel) hybrid protein-based cell carrier (GC) with adipose-derived mesenchymal stem cell (AdMSC) spheroids. This hybrid protein carrier (GC) extended the antioxidant activity of GSH by overcoming its short half-life and enabled efficient encapsulation and delivery of AdMSC spheroids to irradiation (IR)-damaged SGs. The 3D spheroids enhanced vascular endothelial growth factor (VEGF) expression through hypoxic core formation, promoting angiogenesis. In an IR-damaged mouse model, spheroid-encapsulated GC increased SOD2 expression and decreased 8-OHdG and NOX4 levels, effectively mitigating oxidative stress, fibrosis, and apoptosis, while accelerating angiogenesis. SG structural regeneration and functional recovery were confirmed using histological and immunohistochemical analyses following spheroid-encapsulating GC treatment. These results demonstrate the synergistic effects of ROS-scavenging activity from GC and paracrine signaling from AdMSC spheroids. This groundbreaking spheroid-encapsulating GC improves SG regeneration and functional recovery by integrating antioxidant activity with angiogenic effects, offering a paradigm-shifting solution for other oxidative stress-mediated tissue disorders.

For the treatment of dysphonia and aspiration induced by presbylaryngis, injection laryngoplasty is widely conducted. Here, the feasibility of carboxymethyl cellulose hydrogel modified with pyrogallol (CMC‐PG) is checked for injection laryngoplasty. CMC‐PG, owing to its low viscosity, is easily injectable in liquid form and can self‐polymerize into a hydrogel without the need for oxidative cross‐linking agents. Moreover, the CMC‐PG hydrogel demonstrates improved stability, tissue adhesiveness, and elastic modulus, compared to a commercial product currently being used for injection laryngoplasty. CMC‐PG hydrogel has high binding affinity to various functional moieties and can maintain its structure under swelling condition for an extended period, thereby enabling sustained release of growth factors. CMC‐PG is highly biocompatible both in vitro and in vivo, and it does not induce fibrosis or immunogenic responses. Injection of CMC‐PG hydrogel encapsulating basic fibroblast growth factor (bFGF) regenerates both the lamina propria and the muscle layer in the vocal folds of an aged rat model, showing increased hyaluronic acids layer and muscle density, enhanced angiogenesis, and modulated immunogenicity. Importantly, bFGF‐loaded CMC‐PG hydrogel facilitates functional restoration of the aged vocal folds. This study offers clinical potential of CMC‐PG hydrogel for injection laryngoplasty for the treatment of presbylaryngis.

The relationship between tumor microenvironments (TMEs) of regional lymph node metastases (LNMs) and primary tumors in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study compared tumor-infiltrating lymphocytes (TILs) and the immune phenotype (IP), characterized by spatial TIL distribution, between primary tumors and LNMs. Twenty-one HNSCC patients with regional LNM who received immune checkpoint inhibitors (ICIs) were included. A paired comparative analysis of TIL densities and IP between primary tumors and LNMs revealed no significant difference or correlation between TIL densities in primary tumors and LNMs. Their IPs were discordant in 12 patients (57.1%). Patients with high intratumoral TIL exhibited longer progression-free survival (PFS) than those with low intratumoral TIL in both primary tumors (median, 5.2 vs. 1.3 months, p = 0.003) and LNMs (median, 30.2 vs. 1.3 months, p = 0.012). Patients with inflamed IP exhibited longer PFS than those with non-inflamed IP in both primary tumors (median, 4.5 vs. 1.3 months, p = 0.043) and LNMs (median, 4.1 vs. 1.3 months, p = 0.037). Given the lack of correlation in TIL densities, the discrepancies in IP, and the predictive value of both TMEs, evaluating the TMEs of both primary tumors and LNMs may be beneficial for the precise use of ICIs in HNSCC. There was a significant discordance between the TME of primary tumors and LNMs, with implications in survival outcomes. Therefore, evaluating the TME of both the primary tumor and LNM could be beneficial for the precise use of ICIs in HNSCC.