Early identification of delayed wound healing in complex diabetic foot ulcers treated with a dermal regeneration template: a novel clinical target and its risk factors

Abstract

Background: The dermal regeneration template (DRT), a tissue-engineered skin substitute composing a permanent dermal matrix and an upper temporary silicone layer that serves as the epidermis, has demonstrated efficacy in treating uncomplicated diabetic foot ulcers (DFUs). Our institution has obtained good outcomes with DRT in patients with more complicated DFUs. Because of its chronicity, the authors are working to identify a clinical target that anticipates delayed healing early in the treatment in addition to determining the risk factors linked to this endpoint to increase prevention.

Materials and methods: This retrospective single-center study analyzed patients with DFUs who underwent wound reconstruction using DRT between 2016 and 2021. The patients were categorized into poor or good graft-take groups based on their DRT status on the 21st day after the application. Their relationship with complete healing (CH) rate at day 180 was analyzed. Variables were collected for risk factors for poor graft take at day 21. Independent risk factors were identified after multivariable analysis. The causes of poor graft take were also reported.

Results: This study examined 80 patients (38 and 42 patients in the poor and good graft-take groups, respectively). On day 180, the CH rate was 86.3% overall, but the poor graft-take group had a significantly lower CH rate (76.3 vs. 95.2%, P =0.021) than the good graft-take group. Our analysis identified four independent risk factors: transcutaneous oxygen pressure less than 30 mmHg (odds ratio, 154.14), off-loading device usage (0.03), diabetic neuropathy (6.51), and toe wound (0.20). The most frequent cause of poor graft take was infection (44.7%), followed by vascular compromise (21.1%) and hematoma (15.8%).

Conclusion: Our study introduces the novel concept of poor graft take at day 21 associated with delayed wound healing. Four independent risk factors were identified, which allows physicians to arrange interventions to mitigate their effects or select patients more precisely. DRT represents a viable alternative to address DFUs, even in complicated wounds. A subsequent split-thickness skin graft is not always necessary to achieve CH.

Graphical abstract

Figure 1

Poor and good graft take. Case A and B are good graft takes, showing well-adhered dermal regeneration templates (DRT) with different degrees of neovascularization and granulation. In cases with good graft take, the wounds usually present colors from light yellow and pink to red when the upper silicone layer is removed. However, if the graft was poorly taken, the wound will present colors in gray, pale, thick, and cloudy yellow and there may be massive drainage, pus, or hematoma under DRT. Cases C, D, and E are all poor graft takes. In the case of C, pus formation was found a few days after the application of DRT (C1). It was then removed to allow better pus drainage and infection control; however, slough and some pus could still be noted three weeks after the application (C2). Case D was a patient with a TcPO₂ level of 19 mmHg before applying DRT. Although the wound was completely debrided, the tissue became progressively necrotized after DRT was applied. The compromised vasculature was thought to be the main cause of persistent infection and poor graft take. Case E showed the presence of hematoma after removing the silicone sheet, causing poor graft take, especially at the hematoma site.

Figure 2

Complete healing after the application of dermal regeneration template at different wound locations and severity. In the three cases presented here, the final wound photographs all demonstrate thorough reepithelialization without drainage, aligning with our definition of complete healing (CH). Case A shows a 4 cm² wound with joint exposure on the left second toe. After the application of Terudermis, it achieved CH on day 57. Case B shows a 24 cm² wound with bone exposure on the left lateral heel. After the application of Integra, it achieved CH on day 112. Case C shows a 77 cm² wound on the left medial malleolus with initial necrotizing fasciitis and tendon exposure. After the application of Integra, it achieved CH on day 245.

Figure 3

Study protocol, including the standard of care in treating patients with diabetic foot ulcers, the number of patients enrolled in the analysis and each group, and the outcomes of our study. DRT, dermal regeneration template; DFU, diabetic foot ulcer; D14, day 14; D21, day 21; D180, day 180.

Figure 4

Kaplan–Meier curve for complete wound healing after dermal regeneration template in the two groups (with P-value <0.001 in the log-rank test). The mean time to complete healing was 119.2 days overall, 157 days in the poor graft-take group, and 85 days in the good graft-take group. D21, the 21st day after applying the dermal regeneration template; GT, graft take.

Figure 5

Distribution of the causes for poor graft take. Nine main causes of poor graft take were concluded in our study, which were: 1) residual necrotic tissue, 2) hematoma, 3) seroma, 4) mechanical shearing, 5) excessive pressure, 6) other surgeon error, 7) infection, 8) vascular compromise, and 9) systemic complication. The figure demonstrates the distribution of the causes, and the top three causes in our cohort were infection (44.7%), vascular compromise (21.1%), and hematoma (15.8%).