Tissue Repair, Wound Healing and Cytoprotection Research Group, Biomedical Research Direction, Center for Genetic Engineering and Biotechnology, Playa, Havana 10600, Cuba.
Int J Mol Sci. 2023 Jun 15;24(12):10170. doi: 10.3390/ijms241210170.
An impaired healing response underlies diabetic foot wound chronicity, frequently translating to amputation, disability, and mortality. Diabetics suffer from underappreciated episodes of post-epithelization ulcer recurrence. Recurrence epidemiological data are alarmingly high, so the ulcer is considered in "remission" and not healed from the time it remains epithelialized. Recurrence may result from the combined effects of behavioral and endogenous biological factors. Although the damaging role of behavioral, clinical predisposing factors is undebatable, it still remains elusive in the identification of endogenous biological culprits that may prime the residual scar tissue for recurrence. Furthermore, the event of ulcer recurrence still waits for the identification of a molecular predictor. We propose that ulcer recurrence is deeply impinged by chronic hyperglycemia and its downstream biological effectors, which originate epigenetic drivers that enforce abnormal pathologic phenotypes to dermal fibroblasts and keratinocytes as memory cells. Hyperglycemia-derived cytotoxic reactants accumulate and modify dermal proteins, reduce scar tissue mechanical tolerance, and disrupt fibroblast-secretory activity. Accordingly, the combination of epigenetic and local and systemic cytotoxic signalers induce the onset of "at-risk phenotypes" such as premature skin cell aging, dysmetabolism, inflammatory, pro-degradative, and oxidative programs that may ultimately converge to scar cell demise. Post-epithelialization recurrence rate data are missing in clinical studies of reputed ulcer healing therapies during follow-up periods. Intra-ulcer infiltration of epidermal growth factor exhibits the most consistent remission data with the lowest recurrences during 12-month follow-up. Recurrence data should be regarded as a valuable clinical endpoint during the investigational period for each emergent healing candidate.
慢性糖尿病足溃疡的根本原因是愈合反应受损，这通常会导致截肢、残疾和死亡。糖尿病患者经常经历上皮化后溃疡复发而未被充分认识。复发的流行病学数据非常高，因此，从溃疡仍然上皮化开始，就被认为处于“缓解”状态而未愈合。复发可能是行为和内源性生物学因素共同作用的结果。虽然行为、临床诱发因素的破坏性作用是不可否认的，但仍难以确定可能使残余瘢痕组织易于复发的内源性生物学罪魁祸首。此外，溃疡复发的事件仍有待确定分子预测指标。我们提出溃疡复发受到慢性高血糖及其下游生物学效应器的严重影响，这些效应器起源于表观遗传驱动因素，将异常的病理表型强加给真皮成纤维细胞和角质形成细胞作为记忆细胞。高血糖衍生的细胞毒性反应物积累并修饰真皮蛋白，降低瘢痕组织的机械耐受性，并破坏成纤维细胞的分泌活性。因此，表观遗传和局部及全身细胞毒性信号的联合作用会引发“高危表型”的发生，如皮肤细胞过早衰老、代谢紊乱、炎症、促降解和氧化程序，这些程序最终可能导致瘢痕细胞死亡。在具有良好声誉的溃疡愈合疗法的临床研究中，缺乏上皮化后复发率的数据。在 12 个月的随访中，表皮生长因子在溃疡内的渗透显示出最一致的缓解数据和最低的复发率。在每个新兴愈合候选物的研究期间，复发数据应被视为有价值的临床终点。
