The Ying of wound healing - chronic wounds
Insufficient healing causes a high level of mortality and morbidity and is an important cost factor for the global health care system. Chronic wounds are present in 2% of the patients in Western countries and 1% worldwide. Chronic wounds particular affect diabetics, physically disabled, elderly and patients with vascular diseases, as was shown in a cross-sectional study performed in India. Finding effective treatments to restore normal healing in chronic wounds and measuring the outcomes are major challenges for clinical therapies, which was discussed in several talks. Risk factors include smoking, whereas smoking cessation and nicotine replacement therapy was shown to improve healing. Other treatments include negative pressure wound therapy (NPWT), and platelet-rich fibrin for general regeneration support.
One major complication in chronic wounds is bacterial infection. Mouse models demonstrate a systemic negative effect of local sepsis on the inflammatory response. Different concepts were presented to target/prevent bacterial infection and biofilm formation, including treatment with local polyhexamethylene biguanidine antiseptics. It was postulated that in some cases, adequately used local antiseptics could prevent the need for systemic antibiotics. Novel concepts involve the use of dextrin-colistin polymers to interfere with biofilm growth and stability and to deliver GFs to the wound bed. Other innovative systems that may improve chronic wound healing include a non-viral piggyback transposon system for gene delivery and nanostructured polymer containers constructed of magnetic nanoparticles to deliver GFs. Such GFs may include Epidermal GF (EGF) to support re-epithelialization or tumor necrosis factor α to control ECM reorganization by matrix metalloproteinases.
Chronic wound healing is often associated with ischemia and with low levels of tissue O2 (hypoxia); hypoxia is accepted to be one of the main risk factors for chronic wounds. One session focused on the molecular mechanisms of angiogenesis as targets to support tissue oxygenation. Several biomolecules were addressed, including anti-angiogenic molecules such as advanced glycation end products and pro-angiogenic molecules such as vascular endothelial GF (VEGF), nucleolin, talin and epoxyeicosatrienoic acids. The role of Interleukin-10 was discussed in a talk given by Swati Balaji (Cincinnati Children’s Hospital Medical Center, Cincinnati, OH), the Young Investigator Award winner of the Wound Healing Society’s 2012 Annual Meeting.
The Yang of wound healing - fibrosis and contractures
Excessive healing involves the excessive and persistent accumulation of ECM, inflammatory cells and reparative cells, which are common in organ fibrosis and skin hypertrophic scarring, such as after large area burns. According to the American Burn Association, approximately 45% of patients with burn wounds died in the period 2001 to 2010 when more than 50% of the skin surface was destroyed. Hypertrophic scars arise from imperfect dermis regeneration and can immobilize digits and limbs; furthermore, the poor esthetics of the scar enormously impact on the patient’s quality of life. A workshop organized by Integra presented ECM restoration strategies to support the formation of a neo-dermis in burns and in post-traumatic and post-surgical wounds.
A number of talks discussed the molecular mechanisms of fibrosis development in other organs and conditions. Deciphering common traits in the pathophysiological processes will be beneficial to develop novel anti-fibrosis strategies. Such approaches include systems biology (for example, gene array meta-analysis of human keloid scars and control tissue, data analysis from a longitudinal human platform to model processes and pathways in variety of pathologies including wound healing). A workshop organized by Bruker informed researchers of the use, principles and instrumentation of proteomic analysis for wound healing research. To identify processes involved in airway scarring, ex vivo organ cultures of early non-scarring and late developmental stage scarring fetal rat airways were presented as another model for detecting patterns of pro-fibrotic gene clusters. In-depth analysis of selected pathways and molecules was presented for the pro-fibrotic/wound healing supporting roles of TAK1, a downstream effector of non-Smad transforming GF β1 (TGFβ1) signaling, the β2 adrenoceptor, Trefoil family factor 2 (TFF2) and CCN2 (Connective tissue growth factor, CTGF). The pro-fibrotic cytokine TGFβ was shown to play a major role in normal adult lung repair, whereas Bone morphogenetic protein (BMP) is prevalent during development. The data suggested that during lung injury, BMP is expressed by cells with stem cell characteristics whereas TGFβ hallmarks differentiated cells.
Inflammation plays a role in chronic wound healing and fibrosis
Inflammatory cells can be both beneficial and detrimental to the outcome of tissue and organ repair. The inflammatory response and the hepatic regeneration potential were compared in animal models of open and laparoscopic left partial hepatectomy. The open surgical procedure resulted in a higher systemic inflammatory response and improved liver regeneration. Viral overexpression of Activin A in mouse lungs leads to chronic inflammation and generates a phenotype that resembles human acute respiratory stress syndrome (ARDS). In another study, histatins were presented to supporting re-epithelialization and wound healing, possibly by modulating the inflammatory response. In chronic wounds, macrophage polarization was presented as a critical event in wound healing. Whereas the pro-inflammatory macrophage M1 type prevails in chronic wounds, a switch to the M2 macrophage appears to improve healing. This switch can be induced by delivered mesenchymal progenitor cells (MSCs).