Performance of Biodegradable Temporizing Matrix vs Collagen-chondroitin Silicone Bilayer Dermal Regeneration Substitutes in Soft Tissue Wound Healing: A Retrospective Analysis

Reconstruction of soft tissue defects is guided by the reconstructive elevator.¹ Autologous split-thickness skin grafts (STSGs) are indicated for wounds with a vascularized wound bed that is free of infection and devitalized tissue.² If skin grafting is not possible, then more complex reconstructive options, including local, regional, or free tissue reconstruction, may be required. Alternatively, artificial dermal substitutes can create a vascularized wound bed in preparation for skin grafting.

The ideal dermal template is shelf-stable, is resistant to infection, yields reliable and cosmetically acceptable results, and is inexpensive.³ The current criterion standard skin substitute is collagen-chondroitin silicone (CCS) bilayer graft (Dermal Regeneration Template; Integra LifeSciences), which is composed of a matrix of bovine collagen crosslinked with glycosaminoglycans covered by a removable silicone layer. For decades, CCS bilayer graft has been widely used in clinical practice, particularly in burn surgery, as a bridge to skin grafting.^4–6 The CCS bilayer graft is approved by the US Food and Drug Administration (FDA) for soft tissue reconstruction for numerous indications, including burns, scar revision, and closure of acute and chronic wounds.⁷ However, use of this graft is limited by its susceptibility to infection, slow production, refrigeration and preparation time, and high cost.⁸ Because of these limitations, other dermal templates have been developed.⁹

One synthetic skin substitute that has been developed is the biodegradable temporizing matrix (BTM; NovoSorb; PolyNovo Ltd), which is made up of biodegradable polyurethane foam and a temporary nonbiodegradable polyurethane seal.^10-12 In clinical and preclinical models, BTM has been shown to form a neodermis as the scaffold integrates into the wound bed and vascularized tissue encloses the edge of the BTM sealing polymer.^13,14 Biodegradable temporizing matrix is FDA approved for indications such as partial- and full-thickness wounds, ulcers, surgical wounds, and trauma.¹⁵ Compared with other dermal templates, the efficacy and cost-effectiveness of BTM are not well established.Case reports have highlighted the ability of BTM to resist infection and effectively integrate into large wound beds resulting from burns, degloving injuries, and necrotizing fasciitis.^13,16,17 The current study is a retrospective comparison of BTM with the criterion standard CCS bilayer graft for soft tissue reconstruction. The safety and outcomes (including reoperation, skin grafting, time to wound closure, and complications) of wound reconstruction with BTM vs CCS bilayer graft are examined. It was hypothesized that BTM would demonstrate similar healing and complication rates compared with CCS in the management of soft tissue defects.

Study population

This retrospective institutional review board (IRB)-approved study evaluated outcomes in patients aged 18 years or older who underwent wound reconstruction with either BTM or CCS bilayer skin substitute between January 1, 2015, and July 31, 2020. Patients were excluded if they died during the study period or were younger than 18 years at the time of dermal template placement, or if multiple or other skin substitutes were applied. Wounds were not excluded based on etiology or anatomic location. Patients were identified using relevant Current Procedural Terminology codes. The decision to use a particular dermal template was at the discretion of the attending surgeon based on the wound and patient-specific qualities. Patient demographics, comorbidities, wound characteristics, and surgical details were collected from electronic medical records. Wounds were classified as infected prior to surgery if a wound culture showed organismal growth. The primary outcome was wound closure, defined as 100% reepithelialization of the wound without drainage or the need for dressing changes. Secondary outcomes included postoperative complications of cellulitis or infection, dehiscence or shear, hematoma, seroma, and time from dermal template placement to complete closure. Infection was defined as any microorganismal growth arising from the template or skin graft and/or clinical signs of infection, such as purulent exudate. Complications involving either the dermal template or skin graft, if present, were assessed individually. Complications were classified as acute if they occurred less than 90 days postoperatively and long term if they occurred 90 days or more postoperatively. Skin graft failure and the number of revision surgeries were recorded.

Patient ethics

This study received MetroHealth IRB approval (IRB number 20-00312). Patient consent was obtained for all photographs.

Statistical analyses

Frequencies and percentages were used to describe categorial factors. The Shapiro-Wilk test was used to determine the normality of continuous measures; normal variables were summarized using mean ± standard deviation, and non-normal variables were summarized using medians and quartiles. Categorical variables were compared using the Fisher exact test. Continuous variables (eg, age, body mass index, time to skin grafting, time to closure) were compared using 2-sample t tests. Univariable and multivariable regression analyses were performed, using the odds of closure as a binary outcome. Cost was reported based on billing information obtained from the authors’ institutions and was not statistically compared. All analyses were performed using R software (version 3.5.0; The R Project for Statistical Computing); a P value less than .05 was considered statistically significant.

A total of 397 patients were initially assessed, and 300 patients were excluded based on age (<18 years), time of surgery, deceased status, or treatment with another type of dermal template (Figure 1). Ninety-seven patients were evaluated and underwent placement of either BTM or CCS bilayer dermal template at the authors’ institution. Of these patients, 51 (52.6%) underwent BTM grafting and 46 (47.4%) underwent CCS bilayer grafting. The demographic characteristics of the study population are provided in Table 1. The mean age ± standard deviation at dermal template placement was 48.2 years ± 18.0 (range, 0–93 years), and 64 patients (66%) were male. The mean age at surgery was significantly higher in the BTM group than in the CCS group (51.6 years ± 18.7 vs. 44.5 years ± 14.3, respectively; P =.037). Sex, smoking status, history of medical comorbidities, radiation history, and anticoagulant use were similar between the groups. Sixty-two patients (63.9%) were current or former smokers at the time of surgery. The median follow-up time was similar between groups, at 9.7 months in the CCS group and 6.4 months in the BTM group (P =.144).

Wound characteristics are shown in Table 2. The indication for dermal template use was significantly different between the groups (P =.006). Most burns were managed with CCS (21/46 [45.7%]) rather than BTM (7/51 [13.7%]), whereas traumatic injuries were treated more often with BTM (24/51 [47.1%]) than with CCS (13/46 [28.3%]). Iatrogenic wounds were more often managed with BTM (10/51 [19.6%]) than with CCS (5/46 [10.9%]). Wound location was also significantly different between the groups; upper extremity wounds were more often treated with BTM, whereas trunk and head and/or neck wounds were more often treated with CCS (P =.012). The overall median defect size was 120 cm² (interquartile range [IQR], 58 cm²–279 cm²) and was similar between groups (P =.308). History of radiation therapy (P ≥.99), wound ischemia (P =.602), and infection (P =.648) before dermal template placement was not significantly different between the groups. Templates were applied at a median of 21 days after wound diagnosis in the CCS group compared with a median of 12 days in the BTM group (P =.075). Prior surgical treatment of the wound site most commonly consisted of sharp surgical debridement, skin grafting, or locoregional or free flap reconstruction, and the number of patients treated with each modality were not different between groups.

Treatment characteristics are shown in Table 3. The median size of the dermal template was similar between groups, with 147 cm² (IQR, 93 cm²–289 cm²) for BTM and 100 cm² (IQR, 152 cm²–479 cm²) for CCS (P =.337). Reapplication of the dermal template was required in 19 patients treated with BTM and 9 treated with CCS (19.6% for each; P ≥.99); most patients underwent 1 template reapplication, except for 1 patient treated with CCS who required 3 reapplications of CCS. Negative pressure wound therapy was applied more frequently in the CCS group than in the BTM group (P =.004). A higher percentage of patients treated with CCS than with BTM underwent concomitant treatment at the wound site (67.4% and 41.2%, respectively; P =.014), including negative pressure wound therapy, locoregional flap reconstruction, and contracture release. Skin grafts were required in 39 patients treated with CCS and in 28 treated with BTM (84.8% and 54.9%, respectively; P =.006). Although the median size of skin graft was similar between treatment groups, the median time between dermal template placement and STSG was longer in the BTM group than in the CCS group (37 days and 16 days, respectively; P <.001). The mean total number of STSGs required after dermal template placement was higher in the CCS group than in the BTM group (1.5 ± 0.9 and 1.1 ± 0.3, respectively; P =.028).

Complication rates between the 2 groups are shown in Table 4. Complications occurred in 13 patients (26%) who underwent BTM grafting and 6 patients (13%) who underwent CCS grafting (P =.217) (Table 5). Template-related infection, defined as collection of purulent fluid below the sealing layer, occurred in 9 patients treated with BTM and 3 patients treated with CCS (17.6% and 6.5%, respectively; P =.127) and was managed with incision and drainage (Figure 2). Skin graft complications occurred in 7 of 28 patients (25%) in the BTM group and 15 of 40 patients in the CCS group (37.5%) (P =.313). Most complications occurred within 90 days of STSG placement. Occurrence of dehiscence and hematoma or seroma after STSG was similar between groups. Infection after skin grafting occurred in 7 of 28 patients in the BTM group (25%) and 6 of 39 in the CCS group (15.4%) (P ≥.99). However, skin graft failure was higher in the CCS group (9/39 [23.1%]) compared with the BTM group (1/28 [3.6%]) (P =.006). The mean number of secondary procedures were higher in the CCS group than in the BTM group (1.9 ± 1.8 vs. 1.0 ± 0.9; P =.002) and consisted primarily of STSG reapplication, which were higher in the CCS group (P =.001), followed by reapplication of the dermal template (P =.800), additional surgical sharp debridement (P =.373), scar release (P =.184), and locoregional (P =.471) or free flap reconstruction (P ≥.99). Definitive closure, including wounds that healed without skin grafting, was achieved in 31 patients treated with BTM and 28 treated with CCS (60.8% and 60.9%, respectively; P =.655). Of the 23 patients in the BTM group who did not undergo STSG, secondary healing was documented in 19 patients (82.6%), and the remaining 4 patients (17.4%) were lost to follow-up. Of the 7 patients treated with CCS who did not undergo STSG, secondary healing occurred in 5 (71.4%), and the other 2 patients were lost to follow-up. In wounds in which final closure was achieved, the mean time from dermal template placement to closure was 5.4 months ± 3.8 after BTM placement and 6.4 months ± 8.9 after CCS placement (P =.591).

On univariable analysis, current smoking status, upper extremity wounds, and use of BTM were associated with lower closure rates, and no individual factors were statistically significant (Table 5). On multivariable analysis, current smoking status and use of CCS were predictors of failure to achieve wound closure but were not significant (Table 5). Representative photographs of the wound healing process for BTM and CCS are shown in Figure 3 and Figure 4, respectively.

Dermal reconstructive matrices are often used for staged reconstruction of soft tissue defects that are not amenable to immediate skin grafting in patients who are not candidates for local, regional, or free flap reconstruction.¹⁸ The CCS bilayer graft is the most common dermal substitute and has a well-established role in reconstruction.^19–22 It has several disadvantages, however, including high cost and associated infection rates.^6,8,23–26 Few randomized controlled trials have compared CCS with alternative skin substitutes, and thus, relative efficacies are not well understood.^27–30 One such alternative, BTM, attained FDA 510(k) approval in December 2015,¹⁵ and early reports have demonstrated favorable outcomes.^{13,16,17,31–37} Similar to CCS, BTM creates a neodermis with integration into wound beds with vascularized tissue at the sealing membrane.^13,14 Preclinical studies have reported improved infection resistance and a more robust vascularization and fibroblast infiltration with BTM compared with CCS.^14,38  However, these studies and clinical reports have lacked a comparison group, thus limiting direct comparisons.^{13,16,17,31–37} The current study was designed to compare outcomes after reconstruction with these 2 templates and evaluate clinical superiority.

This study demonstrates similar rates of definitive wound closure and complications between CCS and BTM, with significantly lower rates of skin graft loss and need for secondary procedures in patients treated with BTM. Although the time to skin grafting was significantly shorter in the CCS group, this was not the result of more rapid incorporation or vascularization of the CCS but rather that BTM anecdotally has a longer window of time in which the substrate is stable before delamination of the sealing layer occurs and skin grafting is performed. Although the difference in template infection rate did not reach statistical significance, infection rates were higher in the BTM group (n = 9 [17.6%]). In a recent case series, Solanki et al³³ reported template infection in 5 of 25 patients treated with BTM. However, unlike with CCS and similar to the experience of the authors of this study, Solanki et al³³ found that in most cases, infected BTM can be salvaged with incision of the sealing layer and drainage of the underlying fluid collection.

One interesting finding in the current study was the decreased need for skin grafting after BTM despite similar wound sizes in the 2 groups, which eliminates the need for a second surgery or skin graft donor site. There was no significant difference in time to complete healing despite allowing for secondary healing. Of the 51 wounds managed with BTM, 23 did not require STSG. An example of wound healing by BTM application and secondary intention is shown in Figure 5. Wound size was smaller in the 23 wounds for which skin grafting was not required (average defect size, 167 cm²) compared with those for which skin grafting was required (average defect size, 320 cm²). Nineteen (82.6%) of these 23 wounds healed secondarily and demonstrated acceptable cosmetic outcomes; the remaining 4 patients were lost to follow-up. In contrast, of 46 wounds managed with CCS, only 7 did not require skin grafting. Of these, 5 wounds (82.6%) underwent secondary healing, and the remaining 2 patients were lost to follow-up. Because of study design, this difference may be a result of the significant differences in anatomic location and indications for the use of dermal substitute between groups; however, the authors of the current study believe this is related to the anecdotal finding based on the authors’ experience that BTM is more stable than CCS and can be left in place for a longer period of time, thereby allowing for secondary healing based on patient or surgeon preference.

Finally, BTM is less expensive at the authors’ institution, where it is billed at $850 per 100 cm² of dermal template, compared with $3150 per 100 cm² of CCS bilayer graft. This cost difference may have influenced the surgeons’ intraoperative decisions on template size; larger template sizes were used with BTM (median, 147 cm² [IQR, 93 cm²–289 cm²]) than with CCS (median, 100 cm² [IQR, 152 cm²–479 cm²]).

This study is not without limitations. The retrospective nature of this study limits the generalizability of the results, which should be confirmed in randomized controlled, ideally multicenter, trials with larger sample sizes. There were significant differences between the 2 groups regarding age, indications for the use of a dermal template, and anatomic location, which may have affected the findings. The median follow-up time in this study was 6.9 months (IQR, 3.2–12.3 months). Longer follow-up is needed to evaluate for and compare any late postoperative complications. Finally, this study did not evaluate other relevant quality-of-life outcomes, including joint and tendon mobility, pain, scarring, and patient satisfaction.

Compared with CCS bilayer graft, BTM has comparable closure rates, time to healing, and complication rates. Wounds managed with BTM required fewer secondary procedures, including skin grafting, and had significantly lower rates of graft failure than those treated with CCS. These findings support consideration of BTM as an alternative to CCS when dermal templates are indicated for soft tissue reconstruction.