The Stages of Wound Healing

Wound healing is a complex process that occurs in several stages: hemostasis, inflammation, proliferation, and tissue remodeling. Hemostasis involves the immediate response to injury, where blood clotting occurs to prevent excessive bleeding. Subsequently an inflammatory phase follows, which is characterized by the recruitment of immune cells to the wound site and the release of proinflammatory cytokines.

During the proliferative stage, new tissue forms as fibroblasts synthesize collagen and other extracellular matrix components. Finally, in the remodeling stage, the newly formed tissue is reorganized. Strikingly, each stage is tightly regulated, and any disruption can impair the healing process.

How Signaling Molecules Influence Healing

Proinflammatory cytokines play a dual role in wound healing. They are signaling molecules that are released by immune cells in response to infection, injury, or other stressors. Key proinflammatory cytokines include interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). These molecules help to coordinate the immune response, recruit immune cells to the site of injury, and facilitate tissue repair.

Initially, they are critical for clearing debris and pathogens from the wound site. For instance, IL-1 and TNF-alpha promote the migration of immune cells and increase vascular permeability, allowing more immune cells to access the wound.

However, while proinflammatory cytokines are essential for initiating healing, an excessive or prolonged inflammatory response can hinder the healing process. High levels of proinflammatory cytokines can lead to chronic inflammation, impairing fibroblast function and collagen synthesis. This imbalance can result in poor wound healing, increased scar formation, or even chronic wounds. Hence, understanding the balance between their beneficial and detrimental effects is key to optimizing wound healing.

Learning from Fetal Skin

The current knowledge about wound healing comes to a large extent from fetal tissue development and regeneration.

Interestingly, fetal skin is fundamentally different from adult skin in its composition and healing properties. One of the most striking differences is the high concentration of hyaluronic acid found in the extracellular matrix of fetal skin and fetal wound fluid^1,2. This contributes to the fetal skin’s unique ability to heal without forming scars.

Additionally, fetal skin has a higher water content, more collagen, and a different arrangement of collagen fibers compared to adult skin. These factors together create an environment that supports rapid and scarless wound healing.

Hyaluronic Acid: The Key to Scarless Healing

Hyaluronic acid plays a crucial role in the scarless healing observed in fetal wounds³. It modulates various cellular functions, including proliferation, collagen synthesis, and protein synthesis of fibroblasts. By influencing these processes, hyaluronic acid helps regulate how wounds heal and scars form.

In fetal wound healing, the increase in hyaluronic acid content within the extracellular matrix occurs more rapidly than in adult wounds. This rapid increase is crucial for creating an optimal healing environment that prevents scar formation.

Moreover, it has been shown that fetal fibroblasts express more hyaluronic acid receptors compared to adult fibroblasts⁴. These receptors play a critical role in mediating the effects of hyaluronic acid on cellular functions. By binding to these receptors, hyaluronic acid can influence cell proliferation, migration, and differentiation, all of which are essential for effective wound healing.

The increased expression of hyaluronic acid receptors in fetal skin ensures that the cells are more responsive to the presence of hyaluronic acid, thereby optimizing the wound healing process and minimizing scar formation.

Applications in Modern Medicine

Understanding the role of hyaluronic acid in fetal skin and embryonic development had significant implications for modern medicine. Nowadays, hyaluronic-based products for topical and parenteral use for the treatment of chronic and inflammatory diseases are available, which have proven to provide patients with better outcomes and improved quality of life⁵. Further applications include the development of hyaluronic acid-based therapies and biomaterials that take advantage of the biopolymer’s important functions in tissue repair and regeneration.

 

1. Longaker, M. T. et al. Studies in Fetal Wound Healing V. A Prolonged Presence of Hyaluronic Acid Characterizes Fetal Wound Fluid: Ann. Surg. 213, 292–296 (1991).
2. Lawrence Depalma, R. et al. Characterization and Quantitation of Wound Matrix in the Fetal Rabbit. Matrix 9, 224–231 (1989).
3. Nyman, E., Huss, F., Nyman, T., Junker, J. & Kratz, G. Hyaluronic acid, an important factor in the wound healing properties of amniotic fluid: In vitro studies of re-epithelialisation in human skin wounds. J. Plast. Surg. Hand Surg. 47, 89–92 (2013).
4. Alaish, S. M., Yager, D., Diegelmann, R. F. & Cohen, I. K. Biology of fetal wound healing: Hyaluronate receptor expression in fetal fibroblasts. J. Pediatr. Surg. 29, 1040–1043 (1994).
5. Ranawat, A. et al. Health Economic Assessments of Hyaluronic Acid Treatments for Knee Osteoarthritis: A Systematic Review. Adv. Ther. 41, 65–81 (2024).