TY - JOUR
T1 - A Humanized In Vitro Model of Innervated Skin for Transdermal Analgesic Testing
AU - Malheiro, Afonso
AU - Thon, Maria
AU - Lourenço, Ana Filipa
AU - Gamardo, Adrián Seijas
AU - Gibbs, Susan
AU - Wieringa, Paul
AU - Moroni, Lorenzo
N1 - Funding Information:
A.C. contributed with rheology tests done in revision. The authors would like to acknowledge Irit Vahav (Amsterdam UMC) for assisting in skin model construction. The authors would like to thank the Dutch province of Limburg for the project funding. This work was partly supported by the research program VENI 2017 STW‐ project 15900 financed by the Dutch Research Council (NWO).
Funding Information:
A.C. contributed with rheology tests done in revision. The authors would like to acknowledge Irit Vahav (Amsterdam UMC) for assisting in skin model construction. The authors would like to thank the Dutch province of Limburg for the project funding. This work was partly supported by the research program VENI 2017 STW- project 15900 financed by the Dutch Research Council (NWO).
Publisher Copyright:
© 2022 The Authors. Macromolecular Bioscience published by Wiley-VCH GmbH.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - 3D in vitro model
KW - biofabrication
KW - electrospinning
KW - innervation
KW - skin
U2 - 10.1002/mabi.202200387
DO - 10.1002/mabi.202200387
M3 - Article
C2 - 36222273
SN - 1616-5187
VL - 23
JO - Macromolecular Bioscience
JF - Macromolecular Bioscience
IS - 1
M1 - e2200387
ER -