Hydrogels for Salivary Gland Tissue Engineering

Abstract

Mimicking the complex architecture of salivary glands (SGs) outside their native niche is challenging due their multicellular and highly branched organization. However, significant progress has been made to recapitulate the gland structure and function using several in vitro and ex vivo models. Hydrogels are polymers with the potential to retain a large volume of water inside their three-dimensional structure, thus simulating extracellular matrix properties that are essential for the cell and tissue integrity. Hydrogel-based culture of SG cells has seen a tremendous success in terms of developing platforms for cell expansion, building an artificial gland, and for use in transplantation to rescue loss of SG function. Both natural and synthetic hydrogels have been used widely in SG tissue engineering applications owing to their properties that support the proliferation, reorganization, and polarization of SG epithelial cells. While recent improvements in hydrogel properties are essential to establish more sophisticated models, the emphasis should still be made towards supporting factors such as mechanotransduction and associated signaling cues. In this concise review, we discuss considerations of an ideal hydrogel-based biomaterial for SG engineering and their associated signaling pathways. We also discuss the current advances made in natural and synthetic hydrogels for SG tissue engineering applications.

Bioengineered Salivary Gland Microtissues─A Review of 3D Cellular Models and their Applications

“…The matrix stiffness, architecture, and degradation properties of hydrogels should be tuned to match the features of the native SG tissue microenvironment. 34 These are crucial parameters that affect the maintenance of the secretory cell phenotype and function in long-term 3D cultures. Several studies have documented the approximate stiffness values of normal (∼9−33 kPa) and radiation-injured (mean ∼23 kPa) human SG tissues using shear wave elastography (SWE) techniques.…”

“…However, while hydrogel-based ECMs are attractive options to culture SG cells in 3D, the biomechanical properties of these ECM analogues need optimization. The matrix stiffness, architecture, and degradation properties of hydrogels should be tuned to match the features of the native SG tissue microenvironment . These are crucial parameters that affect the maintenance of the secretory cell phenotype and function in long-term 3D cultures.…”

“…18,28,32 A variety of natural, synthetic, and composite biomaterials have been employed to support SG cell growth in three-dimensional (3D) culture for extended periods and for use as transplantation scaffolds. 14,33,34 These advancements have also enhanced our understanding of the various SG cell types, including the diversity of stem/progenitor cell populations, which are crucial as treatment targets or for use in stem cell therapy. 35−37 Furthermore, efforts have been directed toward comprehending how ECM remodelling and the physicochemical properties of biomaterials influence the SG phenotype and secretory functions, which are paramount for successful clinical applications.…”

“…Efforts to address salivary gland hypofunction and xerostomia have led to the emergence of three interdisciplinary research focus areas: bioengineering of an artificial SG gland, − use of SG and non-SG stem cell therapy, − and delivery of gene therapy. − A substantial body of research has concentrated on the first two aspects, aiming to restore and regenerate the lost gland function. Various research groups have undertaken the challenge of optimizing the SG cell culture, facing inherent difficulties due to the slow proliferation potential and dynamic phenotypic characteristics in vitro. − To address challenges associated with two-dimensional (2D) culture systems, researchers have turned to the development and utilization of innovative biomaterials to mimic and serve as the native extracellular matrix (ECM). ,, A variety of natural, synthetic, and composite biomaterials have been employed to support SG cell growth in three-dimensional (3D) culture for extended periods and for use as transplantation scaffolds. ,, These advancements have also enhanced our understanding of the various SG cell types, including the diversity of stem/progenitor cell populations, which are crucial as treatment targets or for use in stem cell therapy. − Furthermore, efforts have been directed toward comprehending how ECM remodelling and the physicochemical properties of biomaterials influence the SG phenotype and secretory functions, which are paramount for successful clinical applications. ,, Clinical trials, on the other hand, have centered on delivering stem cells and their derivatives from different sources to alleviate xerostomia. In recent times, a handful of human clinical trials have demonstrated the promising potential of autologous mesenchymal stem cells (MSCs) in the treatment of radiation-injured salivary glands. − However, these studies are ongoing and are constrained by several limitations until they are made clinically available.…”

“…35−37 Furthermore, efforts have been directed toward comprehending how ECM remodelling and the physicochemical properties of biomaterials influence the SG phenotype and secretory functions, which are paramount for successful clinical applications. 34,38,39 Clinical trials, on the other hand, have centered on delivering stem cells and their derivatives from different sources to alleviate xerostomia. In recent times, a handful of human clinical trials have demonstrated the promising potential of autologous mesenchymal stem cells (MSCs) in the treatment of radiation-injured salivary glands.…”