Outcomes of Dermal Regeneration Template and Split-Thickness Skin Grafts in Lower Extremity Wound Closure: An 8-Year Retrospective Analysis

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Chronic LE wounds present a major health burden and often lead to severe consequences such as limb loss.^1,2 While free tissue transfer or local flaps are a mainstay for LE reconstruction and limb salvage, their use may be precluded in certain patients due to wound location, tissue availability, or poor baseline health status.^3-5 In these patients, the use of an STSG may be a valuable tool for wound closure.⁶ However, STSG may fail when the wound bed does not have adequate vascularized granulation to support the incorporation of grafted skin.⁷ In addressing this issue, dermal regeneration templates (DRT; Integra Lifesciences, Princeton, NJ) have become a valuable adjunct to STSG. Applied in a separate operation 2 to 3 weeks before STSG inset, DRT augments the uptake of STSG by promoting a vascularized neo-dermis for the STSG to later adhere to.^8-11

Because DRT was originally formulated for the treatment of burns, it has been extensively studied in that patient population and has shown favorable results for wound healing.^12-22 Due to its success, it has also become a valuable tool for the management of chronic, atraumatic LE wounds. Past investigations in this population have demonstrated favorable results for wound healing and 1-year limb salvage, yet the generalizability of these results is questionable due to low sample sizes (13-157 wounds) and the inclusion of only specific demographic groups (patients with diabetes).^23-25 Thus, there is a paucity of literature addressing both short- and long-term efficacy of DRT use in a diverse population of individuals with chronic wounds, which could inform best practices for its clinical use in wound care centers. 

Given the high-volume and varied patient population seen at the authors’ multidisciplinary wound healing center, this review aims to share an 8-year experience with DRT. Based on the clinical experience of the senior authors, they hypothesize that DRT may support both superior graft healing and subsequent limb salvage outcomes in properly selected patients. Thus, this retrospective cohort study compares the short- and long-term outcomes of STSG healing and limb salvage in chronic wounds treated with STSG as the primary intervention, with and without prior DRT treatment. 

Study design

Following Institutional Review Board Approval (STUDY00004145), a retrospective chart review was conducted from December 2014 to December 2022. Patients were included if they (1) were greater than or equal to 18 years and (2) received STSG for a chronic LE wound. Patients were excluded if (1) STSG was used on top of a muscle flap and not applied directly to a wound or (2) they were lost to follow-up. All STSG operations were performed at a single institution by one of 6 senior plastic and podiatric wound surgeons from the authors’ Wound Healing Clinic. Both patient comorbid and vascular abnormalities were optimized preoperatively according to the institution’s “vasculo-plastic” approach to limb salvage, which has been outlined previously.²⁶ 

Study groups

Wounds were stratified by whether or not they were treated with a DRT prior to STSG:

1. DRT Group: The DRT group was treated with a DRT in a separate operation and were debrided serially before DRT placement. Criteria for DRT application were uniform for all surgeons, and included the following considerations: exceptionally large wounds, wounds with exposure of deep structures such as bone or tendon, and wounds in locations subject to sheer or friction forces (eg, mobile areas such as the ankle and natural pressure points such as the plantar heel that create friction with footwear). In these cases, a DRT was applied 2 to 3 weeks before STSG inset. It was then removed and replaced with an STSG once it was well vascularized and salmon pink in color. 

2. Control group (non-DRT group): This group did not receive pre-treatment with a DRT; however, they too underwent serial debridement before STSG placement.

All patients were managed pre- and post-operatively according to the authors’ tertiary wound clinic’s protocol. The only variation in clinical care between groups was DRT placement. All outcomes and follow-up visits are reported in relation to the STSG procedure in both groups (Figure 1). Regardless of DRT treatment, the date of the STSG procedure was considered day 0 for all outcomes. For example, the 30-day follow-up occurred 30 days after STSG placement, not 30 days after DRT placement.

Data collection

EMR were retrospectively reviewed to gather patient demographics, medical history, wound and operative characteristics, and short- and long-term outcomes. Demographic data included patient age, sex, and BMI. Comorbid conditions were determined by the formal diagnosis of any of the following in patient charts prior to surgery: diabetes, peripheral artery disease, neuropathy, history of myocardial infarction, history of stroke, history of malignancy, chronic kidney disease, congestive heart failure, and/or hypertension. Chronic kidney disease was defined as moderate (creatinine >3 mg/dL) or severe (dialysis, status post kidney transplant, uremia) renal disease. Peripheral artery disease was defined as a documented abnormal clinical or arteriographic finding. To quantify comorbidity burden, the CCI was calculated for each patient.²⁷ 

Wound characteristics were defined preoperatively on the day of STSG reconstruction and included wound dimensions, the deepest exposed structure of the wound, and location. Wounds located on the hindfoot were classified into plantar hindfoot (heel) and posterior hindfoot (posterior calcaneus). Ankle wounds were classified separately and were not included in the hindfoot category. All wounds located on the foot were further described by their surface (ie, plantar or dorsal). To better compare DRT and non-DRT wounds, the deepest exposed structure of the wound at original presentation was also recorded. Intraoperative wound swabs of the wound surface were obtained before and after debridement prior to STSG inset, and all wound cultures were processed by the authors’ institution. Incidence of positive culture, microbe species, and bacterial load (qualified as broth, rare, scant/few/light, moderate, and heavy) was recorded. STSG thickness was divided categorically: <0.15 mm, “very thin”; 0.15 to 0.3 mm, “thin”; 0.3 to 0.45 mm, “intermediate”; or 0.45 to 0.6 mm, “thick.”^28-30

Outcome variables and endpoints

After STSG, patients were assessed at postoperative day 30 and 60 (POV-30 and POV-60, respectively). Incidence of infection and binary healing were recorded at these time points. Binary healing was defined as the documentation of a healed STSG by the attending surgeon in clinical notes at follow-up visits. The primary short-term outcome was graft failure, which was defined as complete necrosis or removal of the graft, and time to graft failure was calculated as the days between STSG placement and failure documentation. Ambulation was defined by the first recorded documentation of weight-bearing without presentation to the clinic in a wheelchair or with crutches. If the patient required further surgery before successfully ambulating, the patient was classified as non-ambulatory. 

Long-term outcomes were defined by further interventions taken after STSG reconstruction to heal the wound treated by the STSG. These interventions included the incidence of reoperation on the original wound site, the number of operations required for wound closure, and ipsilateral amputation. Amputation was classified as major (above the ankle) or minor (at or below the level of the ankle). Incidence of postoperative contralateral amputation and mortality were also recorded.  

Statistical analyses

Summary statistics are presented for the overall sample and by study groups as means, medians, standard deviations, minimums, maximums, and proportions (if categorical). Two sample t-tests were employed to examine differences in the averages of continuous variables between groups (DRT vs. non-DRT) when the normality assumption was satisfied. The Wilcoxon rank-sum test was used when the normality assumption was not satisfied. Chi-square and Fisher exact tests (defined as cell counts < 5) were used to investigate differences for categorical variables as appropriate. Patients without follow-up information or sufficient chart documentation regarding graft healing were excluded from the study and thus from analysis. No imputation was performed for missing data. In instances of missing data, the sample size (n) was reported for each variable in the corresponding tables.

To investigate the relationship of plantar location, graft failure, and acellular dermal matrix use, the authors conducted a sub-analysis of plantar wounds only. A univariate linear regression analysis across all collected variables was conducted to evaluate the influence of demographic, wound, and operative characteristics on the incidence of graft failure, infection, reoperation, and ipsilateral amputation. Variables in these univariate regressions that demonstrated statistical significance were included their respective multivariate linear regression analyses to determine independent predictors of graft failure, infection, reoperation, and amputation. Variables with low event counts were omitted from multivariable analysis to avoid unstable estimates and model overfitting. In these cases, the exclusion is noted in the model’s table. 

Statistical significance was defined as P values < .05 for between-group differences, univariate, and multivariate analyses. StataMP Software (StataCorp LLC, College Station, Texas) was used to perform all analyses. Results were reported according to the Strengthening the Reporting of Observational Studies in Epidemiology checklist (STROBE).³¹  

Patient characteristics

Of the 316 patient charts screened, 10 were excluded due to incomplete follow-up information and 45 were excluded due to STSG use over a muscle flap. The remaining cohort included 261 patients with a total of 387 chronic LE wounds. Overall, 44.7% (n=173) of wounds were pre-treated with DRT and 55.3% (n=214) were not (control group, “non-DRT”). Patient demographics and medical history are summarized in Table 1. The study population was predominately male (n=166, 63.6%) with a median age of 63 years (IQR: 12) and BMI of 28.7 kg/m² (IQR: 8.7). The median CCI was 4 (IQR: 3), with diabetes (54.4%), peripheral artery disease (36.8%), and hypertension (79.3%) being prevalent comorbidities. Of the patients with diabetes, 90.2% (n=55) presented with peripheral neuropathy. In the total cohort, 6 patients (1.6%) were paraplegic or hemiplegic. No significant differences were observed in demographic or comorbid conditions between groups.

Wound characteristics

Wound characteristics are summarized in Table 2.

All wounds were chronic, non-healing wounds, and wound etiologies were similar between groups (P = .224). The most common etiologies included diabetic wounds (41.6%, n=161), nonhealing surgical wounds (15.5%, n=60), venous stasis (12.1%, n=47), and arterial (9.3%, n=36). At initial presentation, wounds from both groups demonstrated similar wound depths at the dermis, subcutaneous, fascia, muscle, tendon, and bone levels (P = .402). By the date of STSG reconstruction, the incidence of wounds with deeper structures (fascia, tendon, muscle, and bone) was reduced in both groups. The median wound size (DRT: 29.0 cm² [IQR: 45.5] vs. non-DRT: 27.5 cm² [IQR: 63]; P = .335), location (P = .248), and thickness of STSG used (P = .209) did not differ between groups. Of the foot wounds (n=177), 32.2% (n=57) were located on the plantar surface, with no differences between groups (P = .234). Microbiology results are presented in Table 3. Pre- and post-debridement culture results were available for 272 and 341 wounds, respectively. There were no significant differences in pre- or post-debridement results between groups. Most wounds (80.9%) were contaminated before grafting; after debridement, 68.9% of wounds returned positive cultures. 

Short-term outcomes

Clinical short-term outcomes are presented in Table 4.

The overall graft failure rate was 12.9% (n=50). The DRT group demonstrated significantly less graft failure compared to the non-DRT group (n=9 [5.2%] vs. n=41 [19.2%]; P < .001). Notably, wounds with exposed bone on date of STSG experienced a graft failure rate of 12.5% (n=2/14). Infection at any time (DRT: n=11 [6.4%] vs. non-DRT: n=29 [13.6%]; P = .021) and POV-60 (n=2 [1.4%] vs. n=15 [8.0%]; P = .010) was significantly lower in DRT wounds. Additionally, binary healing at POV-60 was significantly higher in the DRT group (DRT: n=99 [68.8%] vs. non-DRT: n=88 [47.8%]; P < .001). The DRT group demonstrated a significantly higher rate of ambulation within 30 days (n=75 [48.7%] vs. n=71 [36.0%]; P = .040) and within 60 days of STSG (n=98 [63.6%] vs. n=91 [46.2%]; P = .006). Table 5 demonstrates outcomes in plantar wounds only. Graft failure rate in these wounds was higher than the overall population (19.3%) overall. Only 1 (4.2%) plantar DRT wound experienced graft failure, whereas 30.3% (n=10) of non-DRT wounds experienced graft failure (P = .017).  

Long-term outcomes

Long-term complications and amputation outcomes are presented in Table 6. Overall, 38.0% of the total cohort required an additional operation, with no significant differences between DRT and non-DRT groups (n=64 [37.0%] vs. n=83 [38.8%]; P = .718). For these patients, the median number of operations required for wound closure was 3 (IQR: 3). Reoperations included incision and drainage (n=128, 33.1%), debridement (n=99, 25.6%), amputation (n=61, 15.8%), regrafting with STSG (n=38, 9.8%), application of DRT (n=31, 8.0%), and free tissue transfer (n=17, 4.4%). Major ipsilateral amputation occurred in 28 cases (7.2%), with no significant differences between groups (DRT: n=10 [5.8%] vs. non-DRT: n=18 [8.4%]; P = .402). Major ipsilateral amputation occurred at a higher rate among those with plantar wounds (n=10, 17.6%), though the difference between groups was not significant (P = 1.00). Minor ipsilateral amputation occurred in 34 cases (8.8%), with no significant differences between groups (DRT: n=13 [7.5%] vs. non-DRT n=21 [9.8%]; P = .402). The overall limb salvage rate was 91.0%, with no significant differences between groups (P = .419). The DRT group demonstrated a significantly lower rate of contralateral amputation compared to the non-DRT group (n=11 [6.4%] vs. n=29 [13.6%]; P = .021), and mortality trended to be lower in the DRT group (12.4% vs. 18.6%, P = .172).

Univariate and multivariate analyses

Univariate logistic regressions performed on graft failure, infection, reoperation, and amputation are displayed in Supplemental Content, Tables 1-4. Significant co-variates identified in these regressions were included in their respective multivariate regression models displayed in Tables 7-10. DRT remained significantly associated with reduced odds of graft failure (OR: 0.1, CI: [0.0, 0.5], P = .003) and infection (OR: 0.4, CI: [0.2, 0.9], P = .031). Active smoking on the date of surgery also remained significantly associated with higher odds of infection (OR: 1.8, CI: [1.2, 6.4], P = .016). Diabetes (OR: 1.9, CI: [1.3, 2.7], P = .001), chronic kidney disease (OR: 2.4, CI: [1.4, 4.4], P = .003), congestive heart failure (OR: 2.2, CI: [1.0, 4.6], P = .038), and wound etiologies of venous stasis (OR: 4.4, CI: [1.8, 10.7], P = .001) and autoimmune disease (OR: 4.1, CI: [1.1, 15.2], P = .035) remained risk factors for reoperation. Lastly, diabetes (OR: 2.6, CI: [1.3, 5.3], P = .010) and chronic kidney disease (OR: 3.3, CI: [1.6, 6.6], P = .001) independently predicted ipsilateral amputation.  

This retrospective study evaluated 387 LE wounds treated in a tertiary wound center. To the authors’ knowledge, this is the largest and most comprehensive investigation evaluating both short- and long-term outcomes of DRT in this context. As expected, pre-treatment with DRT was significantly associated with lower rates of graft failure and infection as well as higher rates of early ambulation and graft healing. Further sub-analysis and univariate regressions suggest that DRT may be especially valuable to mitigate graft failure in plantar foot wounds. However, prior DRT treatment did not confer benefits for long-term outcomes, as rates of amputation and complications requiring reoperation were similar between both the DRT and non-DRT groups. For these long-term outcomes, patient comorbidities had a more important impact, consistent with previous studies demonstrating the overwhelming and additive impact of comorbidities on limb loss.^32,33 Overall, the current findings emphasize the utility of DRT in improving short-term outcomes in a complex population, but also highlight the importance of managing comorbidities to achieve durable long-term outcomes. 

The role of DRT in promoting healing and ambulation after STSG

In the setting of similar comorbidity and wound profiles, DRT promoted successful STSG outcomes. Notably, the STSG with DRT success rate of 81.9% seen in the current study is relatively higher than the findings reported the current literature.^23,34-36 The most common complication related to DRT use is infection, as the synthetic material tolerates a lower bacterial threshold than native skin.^8,37-40 Consequently, patients who receive a DRT at the authors’ institution undergo a more aggressive debridement preparation to mitigate infection once the DRT is applied, which may have contributed to the current outcomes. Indeed, the univariate regression demonstrated that DRT conferred an 84% reduction in infection at POV-60 and a 57% reduction in overall postoperative infection. Previous work by the current authors has shown the value of a comprehensive debridement approach for STSG, and a rigorous preoperative debridement is recommended to minimize infection risk when using DRT.⁴¹ Additionally, the use of NPWT both during wound bed preparation and after STSG application may be helpful in encouraging granulation formation, reducing wound exudate and inflammation, and possibly controlling infection.⁴² Given the evidence suggesting DRT sensitivity to infection, NPWT use in this setting warrants attention and further investigation. While the current study did not collect data on NPWT use post-application of DRT, the authors’ institution utilizes NPWT as an adjunctive therapy in cases where effective compression is challenging (eg, ankle defects) or in cases of chronic infection. In such situations, NPWT is typically applied for a 2-week period to support DRT vascularization.

The high success rate of the current study is further attributed to the authors’ institution’s hospital-based multidisciplinary wound service that manages patient comorbidities affecting wound healing.^43,44 At the authors’ institution, effective management of STSG take and infection in this population relies on appropriate dressing changes, the use of compression (particularly for venous ulcers), and proper offloading techniques. This model has been previously detailed by the senior author.^43,45-48

Interestingly, univariate analysis demonstrated that plantar wounds were particularly difficult to manage, as they conferred significantly higher risk of graft failure, reoperation, and ipsilateral amputation. Plantar wounds are challenging due to pressure during ambulation and challenges in achieving adequate offloading.⁴⁹ The current sub-analysis of plantar wounds only, while small in sample size, demonstrated an advantage to using DRT particularly in this population.

Parallel to improved healing rates in the immediate postoperative period, DRT patients were able to ambulate sooner and more often than non-DRT patients and also tended to have a lower mortality rate. In the studied population, perhaps the role of DRT is not as a definitive solution to prevent amputation but as a temporizing measure that allows for better functionality after STSG, which is an important consideration in individuals with chronic wounds. Of note, the DRT group conferred lower rates of postoperative contralateral amputations and trended to have lower rates of mortality. It is the senior authors’ hypothesis that early ambulation may have contributed to improved contralateral limb outcomes, though this association warrants further investigation. Nevertheless, the importance of ambulation in this population cannot be understated, given its association with lower rates of mortality.^45,50-52 Consequently, in these patients, a function-focused approach should be taken to achieve early return to ambulation. The current results suggest that the incorporation of DRT could be considered as a means to achieve this goal.

The role of DRT for lower extremity wound closure and reoperation

Despite the DRT’s ability to promote immediately favorable outcomes in the current study’s population, the authors found that a successful STSG after DRT did not affect the need for further reoperations or amputation rates. Rather, comorbid conditions—specifically diabetes and chronic kidney disease—and plantar wound location posed as stronger risk factors for these events. These findings are somewhat in contrast to other publications that report on DRT and “unexpected limb salvage,” with the patients treated with DRT demonstrating significantly lower amputation rates.^20,23,53 While encouraging, these findings are limited by their comparatively small sample size (ranging from 26-154 patients).²⁵ In the current investigation, which evaluates a broad chronic LE wound population, a high limb salvage rate of 91.3% was achieved, regardless of DRT treatment. Whether or not DRT is used, comorbid conditions are important to manage to achieve durable long-term results, which can be optimized by a multidisciplinary team. 

Lastly, it is important to consider these current results in the context that the wounds treated with DRT were likely more complex than those in the control group, given the institution’s clinical considerations for DRT application (Figure 2). The authors hypothesize that the wounds in the DRT group likely had a more complex clinical course that was not captured by the data, perhaps due to factors such as a prolonged history of non-healing, involvement of critical structures, or patient-specific issues (eg, poor adherence to dressing changes or offloading). If evaluating the outcomes through this lens, it may then actually be notable that the long-term results between the 2 groups were similar, suggesting that DRT could be playing a role in equalizing outcomes for more complex wounds. However, this hypothesis warrants further investigation and could be more definitively confirmed through a prospective study.

These findings are limited by the study’s retrospective study design, which relies on the quality of data collected and the accuracy of clinical documentation. Because this study was not randomized, there is potential for selection bias in determining which wounds received DRT and which did not, as previously discussed. This could have impacted the observed outcomes, as the DRT group may have represented more complex wounds that benefited most from this treatment. Additionally, there were no data on specific baseline disease severity, prevalence of Charcot foot deformity, or patient socioeconomic status. 

These findings support the use of DRT in patients with complex wounds as a tool to promote graft take and early postoperative ambulation, but they do not promise long-term wound closure. The incorporation of DRT chronic wound treatment protocols could potentially improve postoperative mobility and impact survival.