Since it is an architecturally and functionally complex organ, the HF is much more difficult to regenerate or reconstruct than many other organs. Due to this limitation, HF regeneration is still far from clinical transformation. (1) The sources of potential cells are still poor, largely because of cell ageing in vitro culture and inefficient reprogramming, so there is still a need to optimize the in vitro culture system. (2) The mechanism of hair cycling is very complex, and it is extremely difficult to identify the key molecules. (3) Current strategies simulating EMI are still insufficient. Both cell transplantation and organoid architecture lack the microenvironment of connective tissue, blood vessels and immune cells, which is still quite different from the physiological environment of normal tissues and organs. (4) It is unknown how many new HFs can be regenerated from biomaterials and tissue engineering. Do they allow other essential cells to be recruited to the new follicle? If so, do the attracted cells have the ability to affect organogenesis overall? 5) The cellular reprogramming techniques that contribute to HF regeneration still have low efficiency in vitro. (6) The 3D regeneration of HFs depends on biomaterials that need better external security, controllability and internal stability. Ideal biomaterials need to be safe and nontoxic. Under normal metabolism in the body, they can be kept in a stable state without biological degeneration, and the metabolism or degradation products are harmless and easily metabolized. (7) Whether the regenerated HFs function normally and how long they can last in vivo are less mentioned in past studies.
In summary, at the current stage, various attempts are only imitating a partial structure and/or function regeneration of HFs. The combination of different technologies and methodologies will hopefully lead to new progress.
