A Humanized In Vitro Model of Innervated Skin for Transdermal Analgesic Testing

Afonso Malheiro, Maria Thon, Ana Filipa Lourenço, Adrián Seijas Gamardo, Susan Gibbs, Paul Wieringa, Lorenzo Moroni*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Sensory innervation of the skin is essential for its function, homeostasis, and wound healing mechanisms. Thus, to adequately model the cellular microenvironment and function of native skin, in vitro human skin equivalents (hSE) containing a sensory neuron population began to be researched. In this work, a fully human 3D platform of hSE innervated by induced pluripotent stem cell-derived nociceptor neurospheres (hNNs), mimicking the native mode of innervation, is established. Both the hSE and nociceptor population exhibit morphological and phenotypical characteristics resembling their native counterparts, such as epidermal and dermal layer formation and nociceptor marker exhibition, respectively. In the co-culture platform, neurites develop from the hNNs and navigate in 3D to innervate the hSE from a distance. To probe both skin and nociceptor functionality, a clinically available capsaicin patch (Qutenza) is applied directly over the hSE section and neuron reaction is analyzed. Application of the patch causes an exposure time-dependent neurite regression and degeneration. In platforms absent of hSE, axonal degeneration is further increased, highlighting the role of the skin construct as a barrier. In sum, an in vitro tool of functional innervated skin with high interest for preclinical research is established.

Original languageEnglish
Article numbere2200387
Number of pages11
JournalMacromolecular Bioscience
Issue number1
Early online date12 Oct 2022
Publication statusPublished - Jan 2023


  • 3D in vitro model
  • biofabrication
  • electrospinning
  • innervation
  • skin


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