The Probleme Of Slow Wound Closure

Injury brings misery. When we wound ourselves, we endure that nasty pain during a bath, troublesome dressing procedures and the irksome itch when it’s finally healing... simply nightmarish. Fortunately for us, scientists from Sweden’s Uppsala University and SLU have discovered a method that accelerates wound healing in mice by using special bacteria to deliver a protein to the wound site, giving us a gleam of hope for less dreadful experiences next time we injure ourselves.

Slow wound closure is a serious medical problem that poses great financial burden on the healthcare system as constant treatment is required. Standard care for wounds is a tedious process that includes repeated dressing changes, antibiotic administrations and possibly even surgical removal of dead tissues.

This problem is intensified by a globally aging population and increasing prevalence of chronic diseases like diabetes, both of which are factors that slow healing. Therefore, a method that enhances wound recovery exerts major importance.“We have developed a drug candidate, a next-generation biologic medical product,” said Mia Phillipson, Professor at Uppsala University, where “wound healing was strongly accelerated in mice”. The “fantastic results” obtained strongly enhanced the prospects of developing a practical treatment which speeds up healing in humans.

Wound healing is a complex process. Injured cells release important CXCL12 signalling proteins that act as SOS signals, summoning immune cells like white blood cells (WBCs) to the wound area for help. Besides fighting harmful micro-organisms, WBCs fuel the healing process by releasing even more of these signalling proteins, promoting tissue restitution. However, these signals can be futile attempts as they are spontaneously degraded by an enzyme naturally present in humans – CD26. This enzyme isn’t intentionally an antagonist as it actually helps to regulate other immune responses, but in wound healing, it is a real troublemaker that has hindered previous attempts to enhance healing.

To curb the drop in CXCL12 levels, the scientists employed a special deliveryman – Lactobacillus. In this study, L. reuteri, a type of Lactobacillus, is responsible for delivering CXCL12 to the wound. By genetic modification, they are groomed to mass produce CXCL12 directly at the wound when administered.Besides directly delivering CXCL12, L. reuteri raises CXCL12 levels by reducing its degradation rate. This is possible as the activity of troublemaker CD26 is pH-dependent, being efficient at more alkaline pH but almost completely inactive at acidic pH. By altering pH, unnecessary troublemakers at wound site can be incapacitated for good.

As the adage goes, “one man's trash is another man's treasure”, lactic acid released by Lactobacilli as a waste product is in turn essential for accelerating healing in mice as it acidifies pH at the wound. This inhibits troublemakers CD26 and consequently enhanced effectiveness of the delivered CXCL12. A delivery like no others, this is truly a special delivery.The experiment was conducted on healthy mice, small-scaled healthy human skin disks and diabetic mice. Wounds of half a centimetre in length were made on the limb of anesthetized mice by removing its surface skin. For two weeks, the wounds are administered several times daily with CXCL12-expressing L. reuteri. These are found to heal within a shorter time than those untreated, and those treated only once daily.

Evidently, administration of CXCL12-expressing L. reuteri heals wounds faster. However, it is not all convenient in using this method, as it is necessary for sustained administration of L. reuteri each day, just like how an infant needs constant attention growing up. We cannot feed the infant only once daily, but several times. Likewise, persistent administration is the only way to enhance the healing environment for best results.

This result is mirrored by the diabetic mice and human skin models, potentiating the use of this method on actual patients, whether they are healthy or diabetic.While this method is promising, it is important to note that it still has many clinical trials to undergo. For instance, it is noteworthy that the inhibition of troublemaker CD26 may harm other immune responses. Further research will access this and attempt to reduce any negative impacts.

In addition, although safety studies have shown that the Lactobacilli used are non-invasive to other parts of the body, it remains a possibility that these bacteria can break free from the wound site and be circulated around the body, causing infections elsewhere.

Finally, it remains to be explored the application of this method in humans. This is something worth anticipating as now that scientists have developed and understood this concept using a mice model, Professor Phillipson says that “the next step is a study in a pig model”– a step closer to a study in humans and a step closer to shortened dreadful healing experiences for us.