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Review
. 2024 May 30;10(1):39.
doi: 10.1038/s41405-024-00219-2.

Bioprinting salivary gland models and their regenerative applications

Jutapak Klangprapan  1 , Glauco R Souza  2 , João N Ferreira  3
Affiliations
Review

Bioprinting salivary gland models and their regenerative applications

Jutapak Klangprapan et al. BDJ Open. .

Abstract

Objective: Salivary gland (SG) hypofunction is a common clinical condition arising from radiotherapy to suppress head and neck cancers. The radiation often destroys the SG secretory acini, and glands are left with limited regenerative potential. Due to the complex architecture of SG acini and ducts, three-dimensional (3D) bioprinting platforms have emerged to spatially define these in vitro epithelial units and develop mini-organs or organoids for regeneration. Due to the limited body of evidence, this comprehensive review highlights the advantages and challenges of bioprinting platforms for SG regeneration.

Methods: SG microtissue engineering strategies such as magnetic 3D bioassembly of cells and microfluidic coaxial 3D bioprinting of cell-laden microfibers and microtubes have been proposed to replace the damaged acinar units, avoid the use of xenogeneic matrices (like Matrigel), and restore salivary flow.

Results: Replacing the SG damaged organ is challenging due to its complex architecture, which combines a ductal network with acinar epithelial units to facilitate a unidirectional flow of saliva. Our research group was the first to develop 3D bioassembly SG epithelial functional organoids with innervation to respond to both cholinergic and adrenergic stimulation. More recently, microtissue engineering using coaxial 3D bioprinting of hydrogel microfibers and microtubes could also supported the formation of viable epithelial units. Both bioprinting approaches could overcome the need for Matrigel by facilitating the assembly of adult stem cells, such as human dental pulp stem cells, and primary SG cells into micro-sized 3D constructs able to produce their own matrix and self-organize into micro-modular tissue clusters with lumenized areas. Furthermore, extracellular vesicle (EV) therapies from organoid-derived secretome were also designed and validated ex vivo for SG regeneration after radiation damage.

Conclusion: Magnetic 3D bioassembly and microfluidic coaxial bioprinting platforms have the potential to create SG mini-organs for regenerative applications via organoid transplantation or organoid-derived EV therapies.

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Conflict of interest statement

The authors declare no competing interests.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical approval and consent were not applicable since this manuscript is a narrative review of the existing literature.

Figures

Fig. 1
Fig. 1. Comparison of 2D and 3D cell culture.
This highlights the differences in cell behavior and constraints between 2D and 3D environments, embedded in Matrigel/hydrogels or other ECM proteins. Created with BioRender.com
Fig. 2
Fig. 2. Classification of biomaterials for 3D scaffold preparation in salivary tissue engineering.
The diagram illustrates three main categories of biomaterials used in the construction of 3D scaffolds: naturally-derived scaffold biomaterials, synthetic scaffold polymers, and hybrid scaffold materials. Created with BioRender.com
Fig. 3
Fig. 3. SG organoid biofabrication workflow utilizing two different magnetic 3D bioassembly platforms.
Human dental pulp stem cells (hDPSC) or salivary gland (SG) primary cells were magnetized with magnetic nanoparticle (MNP), also referred to as Nanoshuttle. Subsequently, the cells were detached and seeded into an ultra-low attachment 96-well plate. Bioprinting refers to when a plate with cells is placed on top of a magnetic field (with magnet dots), and levitation is when the magnets are positioned on top of the plate, both of which induced cell aggregation. Created with BioRender.com
Fig. 4
Fig. 4. Flowchart outlining EV-based strategies for SG epithelial repair using hDPSC cultures and SG organoids prepared via M3DB.
hDPSC and SG primary cells were assembled into organoids using a magnetic drive in a 96-well ultra-low attachment plate. Then, EV was extracted from conditioned media and identified as exosomes. Magnetic bioassembly of hDPSC-derived and SG organoid-derived exosomes (100% extract) was then administered into SG growth media to treat epithelial repair in irradiated (IR) SG models. Created with BioRender.com
Fig. 5
Fig. 5. Potential therapeutic applications of organoids manufactured by M3DB.
This M3DB platform has demonstrated the ability to generate organoids from mimicking various tissues, including lung, aortic valve, adipose tissue, and cancers such as breast, pancreatic and glioblastoma. These printing capabilities and prototyping make it crucial for drug discovery, disease modeling, and regenerative medicine applications. Created with BioRender.com
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References

    1. Mody MD, Rocco JW, Yom SS, Haddad RI, Saba NF. Head and neck cancer. Lancet. 2021;398:2289–99. doi: 10.1016/S0140-6736(21)01550-6. - DOI - PubMed
    1. Gluck C, Min S, Oyelakin A, Smalley K, Sinha S, Romano RA. RNA-seq based transcriptomic map reveals new insights into mouse salivary gland development and maturation. BMC Genom. 2016;17:923. doi: 10.1186/s12864-016-3228-7. - DOI - PMC - PubMed
    1. Hauser BR, Aure MH, Kelly MC, Hoffman MP, Chibly AM. Generation of a single-cell RNAseq atlas of murine salivary gland development. iScience. 2020;23:101838. doi: 10.1016/j.isci.2020.101838. - DOI - PMC - PubMed
    1. Miyajima H, Matsumoto T, Sakai T, Yamaguchi S, An SH, Abe M, et al. Hydrogel-based biomimetic environment for in vitro modulation of branching morphogenesis. Biomaterials. 2011;32:6754–63. doi: 10.1016/j.biomaterials.2011.05.072. - DOI - PubMed
    1. Soscia DA, Sequeira SJ, Schramm RA, Jayarathanam K, Cantara SI, Larsen M, et al. Salivary gland cell differentiation and organization on micropatterned PLGA nanofiber craters. Biomaterials. 2013;34:6773–84. doi: 10.1016/j.biomaterials.2013.05.061. - DOI - PMC - PubMed