title: Rebuild, restore, reinnervate: do human tissue engineered dermo-epidermal skin analogs attract host nerve fibers for innervation?
abstract: OBJECTIVE
  Tissue engineered skin substitutes are a promising tool to cover large skin defects, but little is known about reinnervation of transplants. In this experimental study, we analyzed the ingrowth of host peripheral nerve fibers into human tissue engineered dermo-epidermal skin substitutes in a rat model. Using varying cell types in the epidermal compartment, we wanted to assess the influence of epidermal cell types on reinnervation of the substitute.
  
  
  METHODS
  We isolated keratinocytes, melanocytes, fibroblasts, and eccrine sweat gland cells from human skin biopsies. After expansion, epidermal cells were seeded on human dermal fibroblast-containing collagen type I hydrogels as follows: (1) keratinocytes only, (2) keratinocytes with melanocytes, (3) sweat gland cells. These substitutes were transplanted into full-thickness skin wounds on the back of immuno-incompetent rats and were analyzed after 3 and 8 weeks. Histological sections were examined with regard to myelinated and unmyelinated nerve fiber ingrowth using markers such as PGP9.5, NF-200, and NF-145.
  
  
  RESULTS
  After 3 weeks, the skin substitutes of all three epidermal cell variants showed no neuronal ingrowth from the host into the transplant. After 8 weeks, we could detect an innervation of all three types of skin substitutes. However, the nerve fibers were restricted to the dermal compartment and we could not find any unmyelinated fibers in the epidermis. Furthermore, there was no distinct difference between the constructs resulting from the different cell types used to generate an epidermis.
  
  
  CONCLUSIONS
  Our human tissue engineered dermo-epidermal skin substitutes demonstrate a host-derived innervation of the dermal compartment as early as 8 weeks after transplantation. Thus, our substitutes apparently have the capacity to attract nerve fibers from adjacent host tissues, which also grow into grafts and thereby potentially restore skin sensitivity.
authors.affiliation: Tissue Biology Research Unit, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Biedermann
authors.forename: Sophie
authors.initials: S
authors.lastname: Böttcher-Haberzeth
authors.forename: Agnieszka S
authors.initials: AS
authors.lastname: Klar
authors.forename: Luca
authors.initials: L
authors.lastname: Pontiggia
authors.forename: Clemens
authors.initials: C
authors.lastname: Schiestl
authors.forename: Claudia
authors.initials: C
authors.lastname: Meuli-Simmen
authors.forename: Ernst
authors.initials: E
authors.lastname: Reichmann
authors.forename: Martin
authors.initials: M
authors.lastname: Meuli
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020405:Dermis; D004817:Epidermis; D006801:Humans; D009412:Nerve Fibers; D051381:Rats; D012867:Skin / Q000294:innervation*; D017768:Skin, Artificial; D023822:Tissue Engineering