Salivary Gland Tissue Engineering Approaches: State of the Art and Future Directions

Abstract

Salivary gland regeneration is important for developing treatments for radiation-induced xerostomia, Sjögren’s syndrome, and other conditions that cause dry mouth. Culture conditions adopted from tissue engineering strategies have been used to recapitulate gland structure and function to study and regenerate the salivary glands. The purpose of this review is to highlight current trends in the field, with an emphasis on soluble factors that have been shown to improve secretory function in vitro. A PubMed search was conducted to identify articles published in the last 10 years and articles were evaluated to identify the most promising approaches and areas for further research. Results showed increasing use of extracellular matrix mimetics, such as Matrigel®, collagen, and a variety of functionalized polymers. Soluble factors that provide supportive cues, including fibroblast growth factors (FGFs) and neurotrophic factors, as well as chemical inhibitors of Rho-associated kinase (ROCK), epidermal growth factor receptor (EGFR), and transforming growth factor β receptor (TGFβR) have shown increases in important markers including aquaporin 5 (Aqp5); muscle, intestine, and stomach expression 1 (Mist1); and keratin (K5). However, recapitulation of tissue function at in vivo levels is still elusive. A focus on identification of soluble factors, cells, and/or matrix cues tested in combination may further increase the maintenance of salivary gland secretory function in vitro. These approaches may also be amenable for translation in vivo to support successful regeneration of dysfunctional glands.

Encapsulation of Primary Salivary Gland Acinar Cell Clusters and Intercalated Ducts (AIDUCs) within Matrix Metalloproteinase (MMP)‐Degradable Hydrogels to Maintain Tissue Structure and Function

“…[69,70] Suppression of acinar-to-ductal metaplasia using functional molecules to block specific signaling pathways, such as EGFR, TGF-𝛽1 receptor, and ROCK may also prove useful to maintain salivary gland acinar cell phenotype and function in vitro. [68,[71][72][73] Further studies can be undertaken to further engineer the hydrogel matrix to enhance maintenance of the acinar cell phenotype and to suppress acinar-to-ductal metaplasia. For example, the mode of hydrogel degradation has a significant impact on the organization and phenotype maintenance of SGm.…”

“…[40,45,74,75] SGCs cultured on fibrin hydrogel surfaces in the presence of laminin-111 protein and peptide derivatives, such as YIGSR, A99, RGD, and KP24, promoted salivary gland growth, lumen formation, and expression of secretory proteins. [24,[76][77][78][79] Soluble factors, including neurotrophic factors (neurturin and glial derived growth factor) [80][81][82][83][84] and FGFs (FGF2, FGF7, and FGF10), [11,73,[85][86][87] have been reported to prevent stress responses and promote salivary gland development and acinar cell phenotype maintenance. Additionally, the study of matrix cues to maintain salivary gland function will be another topic of future investigations.…”

“…[ 69,70 ] Suppression of acinar‐to‐ductal metaplasia using functional molecules to block specific signaling pathways, such as EGFR, TGF‐ β 1 receptor, and ROCK may also prove useful to maintain salivary gland acinar cell phenotype and function in vitro. [ 68,71–73 ]…”

Bioengineering in salivary gland regeneration

“…The currently available treatments for xerostomia (stimulant medications or secretagogues, salivary substitutes, or artificial saliva) only provide temporary relief without offering a permanent solution [ 41 ]. Therefore, in search for potential and promising ways to permanently restore SG secretory function in patients with SG hypofunction, three main avenues have been considered: gene therapy [ 18 , 51 ], stem cell therapies [ 16 , 17 , 19 , 45 , 52 ], and SG bioengineered models [ 9 , 33 , 53 ].…”

“…Single cells [ 135 ] or cells retaining their 3D in vivo spatial organization can be obtained following SG dissociation [ 136 ]. Single cells can be sorted into specific parenchymal and stromal subpopulations using flow cytometry and/or selective enhancement during in vitro culture [ 53 ]. The challenge lies in assembling implantable and secretory tissue models by mixing stem/progenitor cells from adult SG with a biocompatible and biodegradable 3D scaffold.…”