Introduction: Parathyroid transplantation is a cornerstone treatment for permanent hypoparathyroidism following thyroidectomy. However, autotransplantation faces limitations in tissue availability, while allogeneic transplantation is hindered by immune rejection (e.g., CD3+ T-cell infiltration). To address these challenges, parathyroid organoids (PTOs) have emerged as a promising alternative, leveraging their 3D structural and functional similarity to native tissue. This study reviews recent advances in PTO research and systematizes fabrication strategies.
Methods:
Human Parathyroid Stem Cell-Derived PTOs: Hyperplastic parathyroid tissues were enzymatically digested using collagenase II and cultured in 3D Matrigel with conditioned media for four passages.
Human-Induced Pluripotent Stem Cell (iPSC)-Derived PTOs: Skin-derived fibroblasts were reprogrammed into iPSCs, followed by a 20-day differentiation protocol to generate organoids.
Tonsil-Derived Mesenchymal Stem Cell (TMSC)-Based PTOs: TMSCs were differentiated into parathyroid-like cells and cultured in a microfluidic chip-based "parathyroid-on-a-chip" system.
Results:

• Self-Renewal Capacity: Patient-derived PTOs maintained self-renewal through four passages (p1: 100% → p4: 18%) and showed a 31.3% reduction in PTH secretion under high calcium (3.4 mM, p=0.015).
• Drug Responsiveness: Cinacalcet (a calcimimetic) induced significant changes in calcium and phosphate levels.
• Chip Model Functionality: The parathyroid-on-a-chip system regulated PTH secretion in response to calcium fluctuations.
• Limitations: Lack of vascularization and extracellular matrix (ECM) components reduced long-term viability.

Conclusions: Parathyroid organoids demonstrate functional mimicry and potential as drug screening platforms. However, the absence of native tissue microenvironment components remains a critical barrier. Future studies should prioritize co-culture with endothelial cells and CRISPR-Cas9-based editing to enhance survival post-transplantation in non-human primates.