Organoid-loaded Core-Shell Cryomicroneedles Induce Biomimetic Follicular Units and Hair Regeneration

Tissue-engineered hair follicle regeneration offers a promising method for increasing hair follicle count, yet it faces challenges such as difficulty with hair emergence through the skin and the potential for clustered and disordered growth. Achieving biomimetic regeneration of single or double hair follicular units is therefore essential. Microneedle arrays (MNs) can mimic natural hair density, enabling controlled hair regeneration in direction and density. However, most MNs for hair regeneration are designed for drug delivery, which can only modulate the hair cycle of existing follicles and cannot generate de novo hair follicles in bald areas. MNs designed for tissue-engineered hair follicle delivery are rare and face challenges in sustaining cellular vitality and achieving epidermal breakthrough. Thus, a novel approach based on core-shell MN technology and hair follicle organoids (HFOs) culture was developed for hair follicle unit regeneration. In this study, degradable core-shell cryomicroneedles (CryoMNs) with uniform walls and multiple small channels were loaded with HFOs. When applied to nude mice, the core-shell CryoMNs supported biomimetic follicular unit growth, mimicking natural hair regeneration. Controllably degradable core-shell CryoMNs offer nutrient channels for HFOs and cutaneous channels for hair growth, controlling hair growth direction and spacing, and enabling orderly follicular unit regeneration in patients with baldness. This study introduces novel ideas and strategies for the subcutaneous delivery of organoids and the systematic regeneration of tissue-engineered hair follicles.