Bioengineered Wound Healing Skin Models: The Role of Immune Response and Endogenous ECM to Fully Replicate the Dynamic of Scar Tissue Formation In Vitro

Abstract

The healing of deep skin wounds is a complex phenomenon evolving according with a fine spatiotemporal regulation of different biological events (hemostasis, inflammation, proliferation, remodeling). Due to the spontaneous evolution of damaged human dermis toward a fibrotic scar, the treatment of deep wounds still represents a clinical concern. Bioengineered full-thickness skin models may play a crucial role in this direction by providing a deep understanding of the process that leads to the formation of fibrotic scars. This will allow (i) to identify new drugs and targets/biomarkers, (ii) to test new therapeutic approaches, and (iii) to develop more accurate in silico models, with the final aim to guide the closure process toward a scar-free closure and, in a more general sense, (iv) to understand the mechanisms involved in the intrinsic and extrinsic aging of the skin. In this work, the complex dynamic of events underlaying the closure of deep skin wound is presented and the engineered models that aim at replicating such complex phenomenon are reviewed. Despite the complexity of the cellular and extracellular events occurring during the skin wound healing the gold standard assay used to replicate such a process is still represented by planar in vitro models that have been largely used to identify the key factors regulating the involved cellular processes. However, the lack of the main constituents of the extracellular matrix (ECM) makes these over-simplistic 2D models unable to predict the complexity of the closure process. Three-dimensional bioengineered models, which aim at recreating the closure dynamics of the human dermis by using exogenous biomaterials, have been developed to fill such a gap. Although interesting mechanistic effects have been figured out, the effect of the inflammatory response on the ECM remodelling is not replicated yet. We discuss how more faithful wound healing models can be obtained by creating immunocompetent 3D dermis models featuring an endogenous ECM.

Full Skin Equivalent Models for Simulation of Burn Wound Healing, Exploring Skin Regeneration and Cytokine Response

“…However, such scratch models rely on a single type of cell, usually keratinocytes or fibroblasts [ 15 ]. Alternatively, 3D culture models can be used to study skin diseases [ 12 , 13 , 14 , 16 , 17 , 18 , 19 ]. 3D culture models resemble a more natural and complete environment for cells; however, they are often produced from hydrogels and seeded with immortalized cell lines or animal cells instead of primary isolated human cells.…”

Chronic Wound Healing Models

“…Interestingly, the regrowth of the destructed cells can be predicted in real-time by measuring the electrical impulses of the cells instead of using the conventional microscopy method to evaluate the healing potential. However, the attachment of cells to the electrodes and the need for a very precise protocol are expected downsides …”

“…However, the attachment of cells to the electrodes and the need for a very precise protocol are expected downsides. 116 The 2D cell monolayer model provides an effective means to analyze numerous physiological processes involved in the wound repair process, including cellular proliferation, differentiation and viability, 117 cell migration, 118 angiogenesis, 119 and gene expression and protein production. 120 The 2D cell monolayer models may use dermal fibroblasts which are involved in extracellular matrix production.…”

“…139 The constructed full-skin model generally comprises a scaffold of fibroblast layer representing the dermal structure enclosed by another layer of keratinocytes to constitute the epidermis-like layer and epidermal bilayer structure. 140 It is crucial to indicate here that the constructed skin could be exogenous or endogenous in terms of its origin; the former includes an exogenous scaffold to accommodate the skin cells, while in the endogenous model, skin cells are induced to synthesize their own ECM matrices. 140 Wounding of 3D models is commonly conducted using typical techniques or punch biopsies.…”

In-vitro and in-vivo wound healing studies of Ag@TiO2NRs/GG hydrogel film for skin tissue regeneration

“…As a result, wound management, including repair and treatment, has emerged as a global medical issue that must be addressed. It entails a series of highly controlled and complex reactions that are triggered by tissue destruction to restore the functionality and integrity of the damaged tissues [3,4]. Around 2 million people in Europe alone receive treatment for acute or chronic wounds.…”