Point-Counterpoint: Extracellular Matrices: Are They Worth It?

Steven R. Kravitz, DPM, Khurram Khan, DPM, and Lawrence Harkless, DPM

Yes. By Dr. Steven R. Kravitz, DPM. This author says podiatrists should consider extracellular matrix enhancement for chronic, complex wounds that do not respond to standard of care therapy.

Over the past 10 years, there have been paradigm shifts in intervention for chronic non-healing wounds. There has been an increased emphasis on moist wound healing,wound bed preparation and managing the wound microenvironment through bone factor enhancement, matrix metalloprotease (MMP) management and bioload reduction.
There has also been a new emphasis on extracellular matrix (ECM) enhancement. In past years, the prevailing thinking on extracellular matrix was that it was primarily structural relative to its involvement with wound healing. However, researchers have demonstrated increasing evidence that the ECM also plays an important regulatory role in the wound healing process.
There are distinct differences in the biochemical interactions that occur between healing and non-healing wounds. Healing wounds provide increased cellular mitosis, a tight regulation on pro-inflammatory cytokines, tight regulation of matrix metalloproteases, and the release of growth factors, which ultimately provide normal extracellular matrix formation.
In contrast, non-healing wounds demonstrate decreased cellular mitoses or the complete absence of cellular mitoses with quiescent cells in the Go (pronounced “Jee–Oh”) phase. There is an increased abundance of both pro-inflammatory cytokines and MMPs, and a decrease in growth factors, all of which lead to abnormal extracellular matrix formation and delayed epithelialization.
All chronic wounds contain significant necrosis, which is essentially premature cell death, and quiescent cells that are in a Go phase and non-mitotic. Stating that these cells are senescent is a common misstatement in wound care literature. Senescence occurs before cellular apoptosis, which is normal cell death due to maturity. Both senescence and apoptosis are irreversible, and accordingly cannot be the objectives of a wound care regimen.
In contrast, quiescence and necrosis are both reversible. Therefore, addressing these cells is the goal of all treatment for chronic wounds. Treatment that replaces or, in another matter, addresses the extracellular matrix is an effective method of decreasing cellular necrosis and converting cells from a quiescent Go phase into actively mitotic cells. Stopping necrosis and enhancing mitosis are the essential goals to converting a chronic wound into one that is actively healing.
Non-healing wounds are in a cyclical phase of degradation.This cycle starts with any one or more of the following factors: repeated trauma, local tissue ischemia, edema, maceration and desiccation with tissue breakdown (necrosis) and an associated increase in bioburden.The result of all this is prolonged inflammation with inflammatory white cells. There is activation of macrophages with an increased release of MMPs. This results in impaired connective tissue deposition and degradation of the extracellular matrix.

How The Extracellular Matrix Affects The Wound Healing Process

As stated above, the extracellular matrix acts as a scaffold to support cellular migration and production, and angiogenesis. It also serves as an active director and coordinator to the wound healing cascade. It activates receptor mediated bonding sites, and regulates the release and activation of growth factors. Molecular composition of the extracellular matrix includes:

• structural proteins (collagen and elastin);
• specialized proteins (fibronectin and fibrillin);
• proteoglycans (long chain glycosaminoglycans attached to a protein core); and
• integrins (adhesive molecules).

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