Significance: When a cutaneous injury occurs, the wound heals via a dynamic series of physiological events, including coagulation, granulation tissue formation, re-epithelialization, and extracellular matrix (ECM) remodeling. The final stage can take many months, yet the new ECM forms a scar that never achieves the flexibility or strength of the original tissue. In certain circumstances, the normal scar is replaced by pathological fibrotic tissue, which results in hypertrophic or keloid scars. These scars cause significant morbidity through physical dysfunction and psychological stress. Recent Advances and Critical Issues: The cutaneous ECM comprises a complex assortment of proteins that was traditionally thought to simply provide structural integrity and scaffolding characteristics. However, recent findings show that the ECM has multiple functions, including, storage and delivery of growth factors and cytokines, tissue repair and various physiological functions. Abnormal ECM reconstruction during wound healing contributes to the formation of hypertrophic and keloid scars. Whereas adult wounds heal with scarring, the developing foetus has the ability to heal wounds in a scarless fashion by regenerating skin and restoring the normal ECM architecture, strength, and function. Recent studies show that the lack of inflammation in fetal wounds contributes to this perfect healing. Future Directions: Better understanding of the exact roles of ECM components in scarring will allow us to produce therapeutic agents to prevent hypertrophic and keloid scars. This review will focus on the components of the ECM and their role in both physiological and pathological (hypertrophic and keloid) cutaneous scar formation.

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Extracellular Matrix Reorganization During Wound Healing and Its Impact on Abnormal Scarring

Hypertrophic scarring: the greatest unmet challenge after burn injury.

Fibrosis is a pathological scarring process that leads to destruction of organ architecture and impairment of organ function. Chronic loss of organ function in most organs, including bone marrow, heart, intestine, kidney, liver, lung, and skin, is associated with fibrosis, contributing to an estimated one third of natural deaths worldwide. Effective therapies to prevent or to even reverse existing fibrotic lesions are not yet available in any organ. There is hope that an understanding of common fibrosis pathways will lead to development of antifibrotic therapies that are effective in all of these tissues in the future. Here we review common and organ-specific pathways of tissue fibrosis.

https://www.physiology.org/doi/pdf/10.1152/ajpcell.00328.2012

Cellular Mechanisms of Tissue Fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis

Burn injury is a severe form of trauma affecting more than 2 million people in North America each year Burn trauma is not a single pathophysiological event but a devastating injury that causes structural and functional deficits in numerous organ systems Due to its complexity and the involvement of multiple organs, in vitro experiments cannot capture this complexity nor address the pathophysiology In the past two decades, a number of burn animal models have been developed to replicate the various aspects of burn injury, to elucidate the pathophysiology, and to explore potential treatment interventions Understanding the advantages and limitations of these animal models is essential for the design and development of treatments that are clinically relevant to humans This review aims to highlight the common animal models of burn injury in order to provide investigators with a better understanding of the benefits and limitations of these models for translational applications While many animal models of burn exist, we limit our discussion to the skin healing of mouse, rat, and pig Additionally, we briefly explain hypermetabolic characteristics of burn injury and the animal model utilized to study this phenomena Finally, we discuss the economic costs associated with each of these models in order to guide decisions of choosing the appropriate animal model for burn research

/pdf/animal-models-in-burn-research-nz02qb9v61.pdf

Animal models in burn research

Chronic wounds are a tremendous burden on the healthcare system and lead to significant patient morbidity and mortality. Normal cutaneous wound healing occurs through an intricate and delicate interplay between the immune system, keratinocytes, and dermal cells. Each cell type contributes signals that drive the normal phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This paper reviews how various immunological cell types and signaling molecules influence the way wounds develop, persist, and heal. Concurrent with the achievement of hemostasis, neutrophils are the first cells to migrate to the wound bed, brought in by pro-inflammatory signals including IL-8. Their apoptosis and engulfment by macrophages (efferocytosis) provides a key signal to the local immune milieu, including macrophages, to transition to an anti-inflammatory, pro-repair state, where angiogenesis occurs and granulation tissue is laid down. Myofibroblasts, activated through contractile forces and signaling molecules, then drive remodeling, where granulation tissue becomes scar. Unchecked inflammation at this stage can result in abnormal scar formation. Although the derangement of immune signals at any stage can result in impaired wound healing, recent research has shown that the key transition point lies between the inflammatory and the proliferative phases. This review summarizes the events that facilitate this transition and discusses how this process can be disrupted, leading to chronic, non-healing wounds.

/pdf/immunology-of-wound-healing-37roe1d272.pdf

Immunology of Wound Healing

Excessive scars form as a result of aberrations of physiologic wound healing and may arise following any Insult to the deep dermis. By causing pain, pruritus and contractures, excessive scarring significantly affects the patient’s quality of life, both physically and psychologically. Multiple studies on hypertrophic scar and keloid formation have been conducted for decades and have led to a plethora of therapeutic strategies to prevent or attenuate excessive scar formation. However, most therapeutic approaches remain clinically unsatisfactory, most likely owing to poor understanding of the complex mechanisms underlying the processes of scarring and wound contraction. In this review we summarize the current understanding of the pathophysiology underlying keloid and hypertrophic scar formation and discuss established treatments and novel therapeutic strategies.

Tatiana Pavicic

Papers

Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies