Human hypertrophic and keloid scar models: principles, limitations and future challenges from a tissue engineering perspective

Most cutaneous wounds heal with scar formation. Ideally, an inconspicuous normotrophic scar is formed, but an abnormal scar (hypertrophic scar or keloid) can also develop. A major challenge to scientists and physicians is to prevent adverse scar formation after severe trauma (e.g. burn injury) and understand why some individuals will form adverse scars even after relatively minor injury. Currently, many different models exist to study scar formation, ranging from simple monolayer cell culture to 3D tissue-engineered models even to humanized mouse models. Currently, these high-/medium-throughput test models avoid the main questions referring to why an adverse scar forms instead of a normotrophic scar and what causes a hypertrophic scar to form rather than a keloid scar and also, how is the genetic predisposition of the individual and the immune system involved. This information is essential if we are to identify new drug targets and develop optimal strategies in the future to prevent adverse scar formation. This viewpoint review summarizes the progress on in vitro and animal scar models, stresses the limitations in the current models and identifies the future challenges if scar-free healing is to be achieved in the future

Wondgenezing en tissue engineering

Wij beschrijven onze recente vorderingen in de ontwikkeling van huidconstructen voor geavanceerde wondbehandelingen en voor gebruik als alternatief voor dierproeven als in-vitroassays. Voor de behandeling van diepe brandwonden en voor therapieresistente ulcera zijn twee sterk verschillende huidconstructen ontwikkeld die rekening houden met het type wond dat behandeld wordt. Deze beide op autologe huid gebaseerde behandelingen zijn al uitgebreid in fase 1 klinisch onderzoek getest in Nederland. Tevens zijn fysiologisch relevante wondgenezing en littekenmodellen (hypertrofische en keloidlittekens) ontwikkeld om nieuwe medicamenten en behandelstrategieën te kunnen onderzoeken. Momenteel ontwikkelen we een immuuncompetent humaan skin-on-a-chip-model om in de toekomst een persoonlijke medische benadering van huidziekten mogelijk te maken. In this short communication we describe our recent progress in developing skin substitutes for advanced wound healing therapies and for use as an alternative to animal experiments as (in vitro) assays. For healing deep burns and therapy resistant ulcers, two very different skin substitutes have been developed which take into account the differences in the type of wound to be healed. Both of these cell based therapies have undergone extensive Phase 1 clinical testing in The Netherlands. In addition to cell based therapies, human physiologically relevant wound healing and adverse scar models (hypertrophic and keloïd scar) have been developed for identifying novel drug targets and for testing new therapeutic strategies. Currently we are designing a human immune competent skin-on-a-chip-model for a future personalized medical approach to skin disease