Monitoring the metabolic phenotype of non-severe burn wound healing in adults: Implications for improving burn wound management

Monique J Ryan

Burn injuries impose a global health burden and present significant challenges to clinicians in achieving successful wound healing. While research focuses on improving clinical management for severe burns, most hospitalised burn injuries are classified as "non-severe", which are burns less than 20% of total body surface area that can still cause substantial physiological damage. The heterogeneity of non-severe burn injuries makes it difficult to predict injury and wound outcomes, relying on subjective visual assessment for clinical classification. Therefore, there is an unmet need for quantitative monitoring tools that can define wound healing parameters and predict patient outcomes to assist in lessening the burden on clinicians. The application of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance spectroscopy (NMR) technologies to metabolic phenotyping applications has emerged as a valuable tool in the identification of dysregulated metabolism that is associated with disease. These techniques have previously been used to establish biomarkers in different inflammatory states, such as sepsis and cardiovascular disease. In recent studies, lipids have been implicated in inflammatory and tissue repair mechanisms and may play a role in burn wound healing. Lipids could shed light on other underlying healing mechanisms and could potentially be involved if impaired wound healing occurs after a non-severe burn. To address this need, a comprehensive lipidomic workflow was developed to detect 1163 lipid species in plasma or serum using LC-MS/MS. The workflow combines stable isotope internal standard dilution, automated sample preparation, and mass spectrometry with polarity switching. It demonstrated robustness against various sources of analytical variation, including choice of blood collection tubes, freeze-thaw cycles, storage stability, extraction technique, and inter-instrumentation variability, as well as achieving a relative standard deviation of <30% for 820 lipids in 1048 replicate quality control plasma samples across 16 independent analytical batches. The optimised lipidomic workflow was then applied to a biological cohort comprising plasma from non-burn controls (n=14) and non-severe burn patients (n=35). Complementary lipoprotein data from 1H NMR to analyse 112 lipoproteins, supramolecular phospholipid composites, and GlycB arising from glycoprotein acetyl residues was added to enrich the dataset. Non-burn control lipid and lipoprotein profiles were compared to non-severe burns at study enrolment and 6 weeks post-injury using orthogonal projections to latent structures discriminant analysis (OPLS-DA) and calculated variable importance in projection (VIP) scores to highlight the key lipids and lipoproteins that differed between the groups. Altered lipoprotein and lipid metabolism, including an increase in GlycB levels, apolipoprotein B100/apolipoprotein A1 ratio (a marker associated with cardiovascular disease risk), decreased anti-inflammatory phospholipids, and increases in pro-atherogenic low-density lipoproteins and monoacylglyceride (20:4) were observed at study enrolment and maintained at the 6-week timepoint in non-severe burn patients, suggesting a potentially heightened risk for cardiovascular disease that warrants additional research. Finally, to evaluate the clinical translation of the protocol, the plasma lipid and lipoprotein profiles of the non-severe burn patients (n=20) were then analysed using the LC-MS/MS method and 1H NMR spectroscopy at study enrolment (within 48 h of hospital admission), day of debridement surgery, 2 days, 2 weeks and 6 weeks post-surgery to monitor the wound healing process. At 2 weeks post-burn surgery, patient burn wounds were assessed for re-epithelisation and dressing removal or dressing continuation until wound closure. The findings revealed that the plasma metabolic phenotype at admission could predict the healing progress of wounds two weeks after surgery. Lipid species within the tri- (TAG) and diacylglyceride (DAG) subclasses and low-density lipoprotein subfractions (p-value <0.02, Cliff’s delta >0.7), were associated with delayed re-epithelisation, while high-density lipoprotein subfractions, phosphatidylinositols, phosphatidylcholines, and phosphatidylserines (p-value <0.01, Cliff’s delta <-0.7) were linked to re-epithelisation. This study demonstrated the clinical potential of early prediction of wound healing outcomes in non-severe burn patients from hospital admission. Further validation of these models will enhance patient stratification and provide an opportunity for early personalised intervention strategies that improve wound healing outcomes. This will in turn reduce the risk of long-term complications following burn injuries.

Monitoring the metabolic phenotype of non-severe burn wound healing in adults: Implications for improving burn wound management

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