Injectable decellularized extracellular matrix hydrogel promotes salivary gland regeneration via endogenous stem cell recruitment and suppression of fibrogenesis.

Saliva is key to the maintenance of oral homeostasis. However, several forms of salivary gland (SG) disorders, followed by hyposalivation, often result in dental caries, oral infection, and decreased taste, which dramatically affect the quality of patient's life. Functional biomaterials hold great potential for tissue regeneration in damaged or dysfunctional SGs and maintaining the good health of oral cavity. Herein, we prepared an injectable hydrogel derived from decellularized porcine submandibular glands (pDSG-gel), the material and biological properties of the hydrogel were systematically investigated. First, good biocompatibility and bioactivities of the pDSG-gel were validated in 2D and 3D cultures of primary submandibular gland mesenchymal stem cells (SGMSCs). Especially, the pDSG-gel effectively facilitated SGMSCs migration and recruitment through the activation of PI3K/AKT signaling pathway, suggested by transcriptomic analysis and immunoblotting. Furthermore, proteomic analysis of the pDSG revealed that many extracellular matrix components and secreted factors were preserved, which may contribute to stem cell homing. The recruitment of endogenous SG cells was confirmed in vivo, upon in situ injection of the pDSG-gel into the defective SGs in rats. Acinar and ductal-like structures were evident in the injury sites after pDSG-gel treatment, suggesting the reconstruction of functional SG units. Meanwhile, histological characterizations showed that the administration of the pDSG-gel also significantly suppressed fibrogenesis within the injured SG tissues. Taken together, this tissue-specific hydrogel provides a pro-regenerative microenvironment for endogenous SG regeneration and holds great promise as a powerful and bioactive material for future treatments of SG diseases. STATEMENT OF SIGNIFICANCE: Decellularized extracellular matrix (dECM) has been acknowledged as one of the most promising biomaterials that recapitalizes the microenvironment in native tissues. Hydrogel derived from the dECM allows in situ administration for tissue repair. Herein, a tissue-specific dECM hydrogel derived from porcine salivary glands (pDSG-gel) was successfully prepared and developed for functional reconstruction of defective salivary gland (SG) tissues. The pDSG-gel effectively accelerated endogenous SG stem cells migration and their recruitment for acinar- and ductal-like regeneration, which was attributed to the activation of PI3K/AKT signaling pathway. Additionally, the introduction of the pDSG-gel resulted in highly suppressed fibrogenesis in the defective tissues. These outcomes indicated that the pDSG-gel holds great potential in clinical translation toward SG regeneration through cell-free treatments.

The contralateral-based submental artery island flap: feasibility and oncological safety in oral cancer-related defect reconstruction.

OBJECTIVES: Oncologic risk is a serious concern of submental artery island flaps. Here, we introduce the contralateral-based submental artery island flap (C-SAIF) and demonstrate its feasibility and long-term oncological safety in reconstructing oral cancer-related defects. METHODS: An anatomical study was performed concentrating on the pedicle length in seven cadavers. Then, a retrospective study was carried out on C-SAIF patients operated on by a single team. The standard surgical technique of C-SAIF was conducted. Outcomes including operative time, length of hospital stay, volume of intraoperative blood loss, and scores of the Multidisciplinary Salivary Gland Society (MSGS) questionnaire were compared with a similar cohort reconstructed with anterolateral thigh free flap (ALTF). In addition, oncological outcomes were evaluated by the 5-year cumulative survival rate between C-SAIF and ALTF patients. RESULTS: The pedicle length of C-SAIF was sufficient for the flap to be extended to the contralateral oral cavity. Fifty-two patients were included in the retrospective study, and nineteen of them underwent reconstruction with C-SAIF. The operative time of C-SAIF was shorter (p = 0.003), and the intraoperative blood loss was less (p = 0.004) than that of ALTF. There was no difference in MSGS scores. The results of survival analysis revealed comparable survival curves for the two groups in terms of overall survival, disease-specific survival, and disease-free survival. CONCLUSION: C-SAIF is a feasible and reliable flap for reconstructing oral cancer-related defects. Moreover, it is an effective island flap to preserve the perforator and pedicle without compromising oncological safety.