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

Abstract

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.

Keywords: hypertrophic; in vitro; keloid; organ-on-a-chip; organotypic; scar.

Figure 1

Macroscopic photographs of different scar tissues. (a) Normotrophic scar developed after incision wound (breast). (b) Hypertrophic scar developed after incision wound (abdomen). (c) Hypertrophic scar developed after extreme 3rd degree burn injury (hand). (d) Keloid scar formed from pustule (sternum) (e) In vitro hypertrophic scar model: skin equivalent of reconstructed epidermis on adipose-tissue-derived mesenchymal stem cells populated matrix. Bars = 1 cm.