A Humanized In Vitro Model of Innervated Skin for Transdermal Analgesic Testing |
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Authors: | Afonso Malheiro Maria Thon Ana Filipa Lourenço Adrián Seijas Gamardo Amit Chandrakar Susan Gibbs Paul Wieringa Lorenzo Moroni |
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Institution: | 1. MERLN Institute for Technology-Inspired Regenerative Medicine, Complex Tissue Regeneration Department, Maastricht University, Universiteitssingel 40, Maastricht, 6229ER The Netherlands;2. Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centre, Amsterdam Infection and Immunity Institute, Vrije Universiteit Amsterdam, Amsterdam, 1081HV The Netherlands;3. Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centre, Amsterdam Infection and Immunity Institute, Vrije Universiteit Amsterdam, Amsterdam, 1081HV The Netherlands
Department of Oral Cell Biology, Academic Centre for Dentistry (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, 1182DB The Netherlands |
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Abstract: | 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. |
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Keywords: | 3D in vitro model biofabrication electrospinning innervation skin |
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