Some inflammation is needed for wound healing.  However, excess inflammation on a wound surface will retard healing by several mechanisms.

1. Problem of excess neutrophils and byproducts

By products of dead and dying neutrophils releasing toxins damaging to local cells impair the healing process. Typically when neutrophils die, in the process of necrosis or exudates formation, proteases and oxidants are released.  The controlled cell death known as APOPTOSIS occurs without cell rupture.  Increasing the process of apoptosis in neutrophils would be a protective advantage to the wound bed. 

2. What are Metalloproteases (MMP’s) and How do they alter Healing?

The Metalloproteases are a family of proteases (enzymes which break down tissue) characterized by:

• Dependence of the metal zinc for activation

• Present in wounds where their role is to break down damaged tissue, denatured protein and matrix, in order to make way for new tissue initiated by growth factors
• Sulfur content including sulfhydryl and disulfide bonds
• present in highest concentration on the wound surface and in matrix
• Can inactivate growth factors

The wound healing process is recognized to be a dynamic balance between growth factors, or the synthetic aspects, and proteases, which produce tissue breakdown and remodeling.

These proteases therefore break down the elements of a wound namely collagen, elastin, and matrix.  In addition, these proteases will inactivate growth factors if present in excess as in a chronic wound or an acute burn wound.

There is present a counteraction system to maintain optimum balance in the wound called endogenous tissue inhibitors of MMP’s or TIMP’s.

There are a number of TIMP’s, released by macrophages and fibroblasts, in response to MMP production which protect tissue from protease breakdown by a competitive binding to tissue protease sites.

This system is limited to a finite production, which can be overwhelmed by the greater potential for protease production with inflammation.  At present, considerable research is underway to increase TIMP’s activity.  Presently, there are no clinically available protease inhibitors.

There are several types of wounds where there is a recognized MMP imbalance:

• Infected wound logically because bacterial promotes inflammation

• The acute burn wound likely due to the massive tissue insult (mostly seen in the partial thickness burn)

• The chronic non-healing wound where excess inflammation is known to be the cause of the lack of healing

There are many documented mechanisms for the excess MMP’s produced by:

• increased tissue neutrophils

• increased neutrophils, macrophage and fibroblast gene expression for MMP’s
• oxidant and other mediator induced increase in MMP production by all wound cell types
• increase in pro-inflammatory cytokines

• Collagenase (MMP-1, MMP-8)

• Gelantinases (MMP-2, MMP-9)
• Elastase (MMP-13)

• Breakdown collagen, elastin and matrix
• Should be in balance with natural inhibitors and Growth factors
• Can degrade growth factors and also wound tissue if in excess
• Dependent on zinc to activate
• Need sulfhydryl bonds

Immediately after initial cleaning

Presence of inflammation induced pseudo eschar.

3. Anti-inflammatory Properties of Silver Released from Nanocrystals (Acticoat™)

Silver from Acticoat, has been shown to decrease wound surface inflammation by at least two known mechanisms.  The first is by a decrease in excess surface MMP’s.  The nanocrystal silver has been shown to decrease MMP activity in an in vitro model as well as on the surface of non-healing wounds (in animals and man).

In the first five days after wounding, the wounds were dressed daily and the dressing materials from each of the experimental groups and the controls were collected and the wound fluid extracted for analysis.  The wounds covered with inactive control and silver-nitrate-soaked dressings (4 to 6) reached high levels of MMP activity from day 3 onwards which were maintained throughout the duration of the experiment.  The wound-fluid samples were assayed for total MMP activity.  The Acticoat™ wound MMP levels of activity remained steady.  More rapid healing and reduced inflammation was also noted.

The levels of total proteases mirrored those of the MMP’s.  Of particular importance was the observation that MMP levels in wounds dressed with the Acticoat™ nanocrystalline silver dressings were normalized but did not fall to zero.  Total inhibition of MMP activity might delay healing. 

Patient with chronic wound treated with nanocrystalline silver.

In addition to MMP suppression the Acticoat silver was shown to increase wound surface neutrophil apoptosis.  Apoptosis is a programmed form of cell death in which cells are fragmented into membrane-bound particles that are then eliminated through phagocytosis, avoiding the necrotic pathway and reducing inflammation.  This response of silver would also protect the wound from damage by excess neutrophil products.

Overall, the reduced inflammation in the wounds treated with Acticoat™ contributed to more rapid healing.  This was demonstrated by the marked decrease in time to develop granulation tissue.

Increased healing rate in an experimental wound using the Acticoat^TM silver.