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Dermal interstitial fluid (ISF) has emerged as a viable alternative sample for minimally invasive biomacromolecules analysis, containing proteins, immunoglobulins, nucleic acids, and extracellular vesicles that reflect both systemic physiology and local tissue activity. However, effective access to ISF biomacromolecules is constrained by extracellular matrix hindrance, limited accessible volume, slow replenishment, and size- and charge-dependent transport across dermal capillaries. These physiological factors impose fundamental limitations on bulk extraction strategies and complicate quantitative interpretation. Microneedle (MN) technologies offer a controlled and minimally invasive interface to the viable epidermis and superficial dermis, enabling mechanism-specific sampling approaches including passive withdrawal, capillary-driven flow, pressure-gradient extraction, hydrogel swelling, electro-assisted enrichment, and affinity-based capture. This mini review outlines current MN-based platforms for biomacromolecule analysis in dermal ISF, emphasizing how device geometry, material selection, and transport mechanism influence recovery efficiency, sampling bias, and analytical performance. We further discuss quantification strategies, validation challenges, and translational considerations necessary for clinical adoption. A transport-aware and bias-conscious framework is proposed to guide the development of standardised and clinically robust MN-enabled ISF diagnostics.
Malhotra et al. (Fri,) studied this question.