Adrenal insufficiency requires lifelong corticoid replacement therapies. However, current therapies are not able to replace the physiological circadian pattern of the adrenal cortex and are associated with many metabolic, vascular, neuroendocrine, and mental perturbations. Therefore, regenerative and more curative strategies would be desirable. In the current perspective, we describe emerging new regenerative therapies for the treatment of adrenal insufficiency. In particular, we discuss gene therapy and cell replacement strategies. Furthermore, we discuss how adrenal cells might be used as a source for regenerative therapies of nonadrenal neurodegenerative diseases such as Parkinson disease.

Macroencapsulation systems for pancreatic islet delivery are an emerging strategy for cell replacement therapy in type 1 diabetes, aimed at eliminating systemic immunosuppression and enabling the use of alternative cell sources. A critical design challenge is to achieve high packing densities while maintaining sufficient oxygen and nutrient supply to ensure islet viability and function. This design-focused study presents a one-step method for the simultaneous and defined formation and spatial arrangement of uniformly sized pancreatic pseudoislets using high-density concave microwell arrays with potential for future integration into macroencapsulation devices. Microwells with diameters between 130 and 200 µm were arranged in a hexagonal pattern with inter-well spacings of 50 or 100 µm to maximize the packing density while maintaining separation between clusters. The effects of microwell depth, diameter, and inter-well spacing on pseudoislet size, morphology, viability, and glucose-stimulated insulin secretion were systematically evaluated using reaggregated rat islet cells as a standardized and well-characterized model system under normoxic and hypoxic conditions. The optimized microwell configuration enabled efficient pseudoislet formation with a tailorable, uniform size, high viability, and preserved insulin secretory function, even at high densities. This scalable microwell array technology addresses key limitations of current pseudoislet culture and transplantation methods, thus providing a base for improved macroencapsulation device design in diabetes cell therapy.