Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care

Abstract

This is the first installment of 2 articles that discuss the biology and pathophysiology of wound healing, review the role that growth factors play in this process, and describe current ways of growth factor delivery into the wound bed. Part 1 discusses the latest advances in clinicians' understanding of the control points that regulate wound healing. Importantly, biological similarities and differences between acute and chronic wounds are considered, including the signaling pathways that initiate cellular and tissue responses after injury, which may be impeded during chronic wound healing.

Figure 1. MECHANISMS OF NORMAL WOUND HEALING

Normal wound healing processes can be divided into 4 overlapping phases: coagulation (not shown), inflammatory phase (A), proliferative phase/granulation tissue formation (B), and remodeling phase (C). During coagulation and inflammatory phases (A) of the healing, blood-borne cells—neutrophils, macrophages, as well as platelets—play critical roles. These cells provide growth factors and provisional matrices that are necessary for recruitment of epidermal and dermal cells into the wound bed. The proliferative phase (B) starts at approximately 3 days after injury and is characterized by increased levels of keratinocyte and fibroblast proliferation, migration, and ECM synthesis in response to autocrine, paracrine, and juxtacrine growth factors. Angiogenesis/neovascularization also occurs during this phase. Because of the presence of blood vessels, the tissue has a granular appearance (granulation tissue). Finally, at approximately 1 to 2 weeks after injury, differentiated fibroblastic cells (myofibroblasts) that present within the granulation tissue begin to remodel extracellular matrix (C). Extracellular matrix remodeling followed by apoptosis of resident cells leads to the formation of an acellular scar.

Figure 2. NORMAL VERSUS CHRONIC WOUND HEALING

Microenvironment within a normal wound bed (left) is characterized by the presence of numerous growth factors, a well-organized ECM, and responsive cell populations. Matrix synthesis, here, exceeds its degradation, and MMP activity is regulated by the presence of MMP inhibitors (TIMPs). Angiogenesis and neovascularization of normal wounds proceed in a timely manner via well-regulated sprouting of existing blood vessels and recruitment of endothelial progenitor cells (EPC), respectively. Finally, unlike their chronic counterparts, acute wounds are generally characterized by low bacterial burden. Chronic wounds (right) often have high incidence of bacterial biofilms, leading to persistent inflammation, excessive proteolysis, and degradation of critical growth factors, receptors, and/or ECM. Cells residing within these wounds are unable to proliferate and/or migrate effectively perhaps because of the absence of functional receptors or appropriate promigratory matrix substrates. Impaired angiogenesis and neovascularization, both hallmarks of chronic wounds, result in insufficient oxygen and nutrient supply for the cells residing within the wound bed, which leads to further wound bed mutilation and impaired healing.

Figure 3. PHYSIOLOGIC IMBALANCE: A KEY FEATURE OF CHRONIC WOUNDS

Inflammation, MMP production, matrix degradation, and cell senescence/apoptosis are all elevated in chronic wounds. These processes cannot be overcome because of insufficient levels of cell proliferation, ECM synthesis, production of TIMPs, and impaired angiogenesis/ neovascularization. This imbalance leads to inability of chronic wounds to heal.

Figure 4. CHRONIC WOUND CONUNDRUM

Diagrammatic representation of those physiologic functions that are perturbed or disequilibrated during chronic wound healing.

Figure 5. CONTROL OF WOUND HEALING: A ROLE FOR BACTERIAL COLLAGENASE?

Bacterial collagenase clinically used for wound debridement stimulates both endothelial and epithelial responses to injury. Degradation of the ECM in close proximity to the cells’ enzyme allows for efficient cell migration. The release of growth factors and liberation of biologically active matrix fragments that can interact with and activate cellular receptors increase the motogenic and mitogenic potential of the cells within the wound bed, promoting the healing responses. Similar to naturally occurring ECM fragments released by bacterial collagenase in vivo, synthetic matrix-derived peptides identified and tested in the laboratory can enhance cellular responses to injury. Therefore, the authors propose that the peptides could be used in combination or as an alternative to the bacterial products, which foster wound healing in vivo.