New advances in widespread/burn scar management

Keywords::

• hypertrophic scar
• mechanotransduction
• myofibroblasts
• neurogenic inflammation
• pruritis
• silicone

Burn injury outcome has improved significantly in recent years in relation to survival and patient rehabilitation. However, scarring and its accompanying aesthetic and functional sequelae still remain a major problem. Hypertrophic scarring can functionally and symptomatically (pruritis, pain) impact on the patients’ quality of life. The identification of molecular events occurring in the evolution of the burn scar has increased our knowledge of this aspect of the injury; however, as yet this has not translated into significant effective burn scar limitation modalities. The incidence of hypertrophic scar (HTS) occurrence following burn injuries has been reported in a range varying from 32 to 94% [1–3]. HTSs usually develop within one to three months after injury, usually manifesting about four weeks from complete re-epithelialization [1]. Treatment of these cases was estimated to cost at least US$4 billion per annum in the USA alone in 2005 [3,4]. The philosophy of widespread scar management differs from incisional scar management, not only in relation to the extent of the scar, but also with respect biomechanical and neurogenic influences particular to this type of injury.

Pathophysiology

The pathophysiologic background of most cases of HTS involves an overactive proliferative phase of wound healing [5–9]. The stage is set for HTS during the phase of conversion from immature healing provisional extracellular matrix (ECM) to the mature healed scar. During this process, the interaction of cellular components of the healing wound and the structural components of the ECM determine the scar outcome. These interactions are well described and may be influenced by mechanical factors, bacterial bioburden, inflammatory stimulation and the ongoing signaling between keratinocytes, fibroblasts, collagen, fibronectin and the various combinations of integrins and ligands [5–9].

The principles previously published relating to the management of incisional scars – mechanotension, inflammation, hydration and influencing scar remodeling and maturation [9,10] – clearly have significance but certain nuances related to the nature of the burn injury have added relevance.

Widespread scar nuances

Itch/pruritis

Burn therapists’ analysis of burn patient symptomatology revealed that the most common and distressful complications in burn patients were abnormal appearance (75.2%), itch (73.3%) and pain (67.6%) [11]. Itching usually begins at the time of wound closure with maximal intensity at three months often continuing over a year or more with significant impairment of quality of life. Through the years, we have accepted that itching/pruritis is an accompaniment of the healing process. However, it has become apparent, particularly in extensive scar areas, that pruritis needs to be controlled, not only to alleviate discomfort but also to halt a cellular/molecular process that can contribute significantly to and as part of the HTS scenario.

Peripheral nerve damage may be central to the burn injury itch syndrome and HTS. Activation of peripheral sensory nerves causes the release of neuropeptides and neurotrophins, which are capable of activating mast cells [12], which initiate or exaggerate neurogenic inflammation [13,14]. The interaction of neuropeptides with mast cells and leukocytes release histamine and various inflammatory mediators [14]. It is likely that excessive neurogenic inflammation results in increased cellular proliferation, cytokine and growth factor stimulation and excess ECM deposition. Additionally the neuropeptide release results in hyperemia and pruritis [13,14].

Treatment of severe pruritus in patients with HTSs is still unsatisfactory. Antihistamines, opiod antagonists [12] and moisturizing lotions have had varied results. Itching may be a manifestation of neuropeptide release in relation to neurogenic inflammation from exposed nerve endings – protecting these exposed nerves by stabilizing the wound environment from dressing interface movement, biomechanical forces and sweating would decrease neuropeptide release and may prevent or alleviate itching symptoms.

Mechanotension & cell signaling

Mechanotransduction describes the phenomenon whereby mechanical signals are converted into biochemical responses [9,15]. Scar tissue collagen and ECM ground substance is influenced by external vector forces that impact on collagen bundle size and directionality [11,16]. By controlling the biomechanics of the wound environment, new design dressings will have the capacity to improve healing and reduce scar formation [11,15,17–19]. By significantly reducing tension in widespread healing wounds, scarring can be minimized [20].

One important area for tension reception is the keratinocyte. Mechanoreceptors in these cells (or neuropeptide receptors in nerve cells) initiate the transmission of intercellular and cellular matrix signals. The sensitivity to mechanical tension transmits to the fibroblast cell via signaling to glycoproteins, primarily fibronectin and collagen, which attach to integrins transmitting the signal from the ECM into the cytosol [9]. The message from this union is transferred into the cell cytoplasm where phosphorylation of Smad2, 3 units amalgamates with Smad4 and translocates into the nucleus. Here they bring about transcription and message encoding relaying new instructions via integrins and ligands, primarily TGF-β (reinforced by CTGF) to stimulate procollagen formation, collagen formation, fibroblast differentiation to myofibroblast and wound contraction with excess collagen. If the cycle is repeated sufficient times, particularly intermittently, the physical representation that results is the HTS [9].

In summary, maintaining stability of the healing wound and evolving scar tissue by counteracting the external deforming forces initiating skin stress may keep the biological processes of repair and collagen formation in check. Stabilizing tensile dressing devices are an important advance in this regard and likely to dominate the burns (or other extensive scar) market in the near future.

Hydration/occlusion

An occluded wound environment is thought to decrease the stimulation of damaged nerves (free nerve endings) and their neuropeptide release, whereas a dry and unoccluded wound is more likely to be painful stimulating nociceptive nerve fibers releasing neuropeptides mediators [14]. This is the basis of the use of long-term occlusive material such as silicone gel sheeting as a ‘sensory isolation’ to the scar surface – decreasing neurogenic inflammation, leading to a reduction in scar tissue [14]. Alternatively Akaishi et al. [20] demonstrated on a computerized model that silicone gel sheeting reduced the tension at the border between the scar and normal skin - this tension was transferred to lateral edge of the silicone gel sheet. Silicone gel sheet with the hardness of normal skin was the most effective [20]. It is likely that both effects (tension relief and sensory protection) are synergistic - decreasing neuropeptide release and neurogenic inflammation [14].

Possible solutions

Current therapy (aside from silicone sheeting) has had limited success in widespread scar management. Once healing has occurred, massage, pressure therapies, steroids, laser therapy and silicone dressings are frequently used to manage the scar burden in burn patients [1,3–6]. Unfortunately current modes of extensive scar management are lacking in efficacy.

From the nuances particular to the burn injury wound, it is evident that multiple processes are occurring concurrently and that therapy directed at just one process is unlikely to be successful. Most of the present attempts at scar control are directed at one aspect or mediator and it is unlikely that this approach will succeed. We have previously described multimodal scar management regimens but these are primarily directed at incisional wounds or smaller open wound [9,10]. The burn injury, however, presents unique pathophysiologic characteristics that warrant consideration when designing a scar management device.

From the discussion, earlier, it is apparent that successful management of the burn scar would need to accomplish the following ideals:

• • sensory protection of exposed nerve endings and surface hydration;

• • itch prevention or control;

• • stability of the wound/scar from mechanoreceptor stimulation or blocking of various signals in the TGF/smad pathway.

The first pre-requisite for such a device would involve a hydrative/occlusive material such as silicone [14] but one which has the necessary inherent tension and elasticity to stabilize the area of the scar surface. This would fulfill the criteria of sensitivity protection, hydration and tension relief.

Possible extensions may include substance impregnated material (hydrogel, silicone, etc.) into the device described earlier that would include substances able to interact at a molecular level influencing cellular signaling, inflammatory mediators and growth factor activity such as relaxin; osteopontin inhibitors; halofuginone (HF) [16,21–23]; extracts of centella asiatica, bulbine frutescens [9,10]; interferon; 5-Fluorouracil; bleomycin; anti-TGF antibodies; TGF-β receptor inhibitors; gapapentin; angiogenin inhibitors [16,21–23]. For various reasons including drug interactions, sensitivities, timing and absorption uncertainties, this strategy may be less important than efficient wound stabilization, protection and hydration achieved by a tensile silicone-based occlusive support dressing.

Conclusion

The burn injury is characterized by unique differences in the nature of tissue trauma, the pathophysiologic response to that trauma and the molecular events that impact on the evolution of scar formation in these injuries. The areas that have been highlighted have direct influence on scar outcome but have not been concentrated on in the past when designing treatment regimens for scar control. These include the exposed nerve endings, stimulation of neuropeptide mediators, neurogenic inflammation, pruritis, mechanotension signaling and hydration. The TGF/smad pathway appears to be a common sequence for scar formation that is influenced by the factors described earlier. A composite device for scar control in burn injuries should involve a multimodal approach that incorporates strategies for control of these contributing factors. A tension relieving, protective, substance impregnated dressing/device would satisfy many of the required criteria.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.