# 3D Artificial Skin Model As a Novel Strategy for the Detection of Pyroptosis-Cascade Activation in Amyotrophic Lateral Sclerosis

## TL;DR

A 3D artificial skin model is developed to detect pyroptosis activation in ALS, offering a non-invasive alternative to skin biopsies.

## Contribution

A novel 3D artificial skin model is introduced to study pyroptosis in ALS using patient-derived cells.

## Key findings

- 3D artificial skin shows increased TAR DNA-binding protein 43 aggregates and inflammatory markers in ALS patients.
- The model supports standardized experimental conditions and reduces the need for repeated biopsies.
- It enables biomarker research and preclinical drug testing for ALS.

## Abstract

Amyotrophic lateral
sclerosis (ALS) is a severe adult-onset neurodegenerative
disease with limited treatment approaches. Evidence has shown that
degeneration of cutaneous nerves may reflect neurodegenerative processes
occurring within the central nervous system. Although skin biopsy
is widely adopted in clinical practice, the procedure is invasive
and requires multiple patients’ tissue removals. Therefore,
we developed a 3D innervated skin model by combining 3D printing of
methacrylated hyaluronic acid as an innovative tool for better reproducing
the dermis and epidermis and electrospinning of polylactic acid for
mimicking skin innervation. Later, 3D artificial skin was colonized
with a preneuronal cell line (SH-SY5Y) and fibroblasts isolated from
skin biopsy of ALS patients at different disease stages. 3D skin possesses
a porosity suitable for cell colonization and a high stability. Importantly,
biological results reveal an increase of TAR DNA-binding protein 43
aggregates, NOD-like receptor pyrin domain containing protein 3, interleukin
(IL)-18, IL-6, and nitrites in 3D skin of ALS patients, thus indicating
pyroptosis activation linked to neurodegeneration. This physiologically
relevant 3D skin model reduces the need for repeated biopsies, allows
standardized experimental conditions, and supports biomarker research
and preclinical drug testing in ALS.