Novel Biomaterial Containing Gelatin, Manuka Honey, and Hydroxyapatite Enhanced Secondary Intention Healing Versus Standard Secondary Intention Healing in Mohs Surgical Defects on the Head and Distal Lower Extremities—A Randomized Controlled Trial: Pilot Study

Abstract

BACKGROUND

Randomized, comparative studies evaluating augmented secondary intention healing (SIH) compared with conventional SIH in dermatologic surgery are limited. This study aimed to evaluate whether the use of a novel biomaterial enhances SIH, particularly in shortening time to complete re-epithelialization.

OBJECTIVE

The purpose of this study was to elucidate whether a novel biomaterial containing gelatin, manuka honey, and hydroxyapatite enhances SIH when compared with conventional SIH for surgical defects after Mohs micrographic surgery (MMS) on the head and distal lower extremities.

MATERIALS AND METHODS

Thirty-seven patients were enrolled in this randomized controlled trial. Patients undergoing MMS on the head or distal lower extremities were eligible for recruitment. After clear surgical margins were obtained post-MMS, patients were randomized to receive standard SIH or biomaterial enhanced SIH. Patients had regularly scheduled follow-ups with questionnaires at each visit until complete re-epithelialization was achieved.

RESULTS

Overall, there was no significant difference in time to re-epithelialization between standard SIH and biomaterial-enhanced SIH. However, there was a significant decrease in pain scores and skin thickness in the biomaterial-enhanced SIH group.

CONCLUSION

Biomaterial-enhanced SIH is noninferior to standard SIH and produces less pain and favorable skin thickness compared with standard SIH. ClinicalTrials.gov listing: NCT04545476.

Secondary intention healing (SIH) is often underused and has several advantages compared with primary surgical repair.^1,2 Wound care is minimal although it can be ongoing for months, and risks associated with primary closure (e.g. hematoma, suture granuloma, and graft or flap failure) are nonexistent.³ Importantly, SIH facilitates surveillance of tumor recurrence, whereas flaps and grafts may bury residual tumor.^1,3 When used in appropriate anatomical locations, SIH leads to high patient satisfaction.^1,2,4 However, SIH requires regular wound care that can be cumbersome to patients.^3,5

Previous studies using biologic dressings have shown patients report better quality of life during the postoperative period related to less pain, decreased dressing changes, and faster healing times.^5,6 Biologic dressings provide an alternative to surgical autografts and eliminate the risks associated with graft harvesting (e.g. pain, infection, and scarring).^5,7 For many patients, the cosmetic outcome after healing is important. However, cosmetic outcome with SIH is variable and depends on many factors, namely, location (e.g. concavities favorable), skin laxity, and underlying musculature.^1,2,8 Exuberant granulation tissue, hypopigmented, and telangiectatic scars are the most frequent adverse cosmetic outcomes with SIH.^3,9

The novel APIS biomaterial is an advanced synthesis of gelatin, manuka honey, and hydroxyapatite bioengineered to protect wounds, manage exudate, and maintain a moist environment.¹³ It is FDA cleared (FDA Number K1827250) for wound management across 9 indications including surgical wounds. It has been used successfully in a small case series of 8 patients for postoperative Mohs surgical wounds on the head and distal lower extremities. Time to complete re-epithelialization was 6 weeks (42 days), suggesting a reduction in healing time compared with standard SIH times for the leg and head of 127 and 57 days, respectively.^10,11 Use of this novel biomaterial to enhance SIH is hypothesized to reduce healing times when compared with standard SIH wound care. This provides a useful option to aid SIH in sites such as the lower legs, where healing can be prolonged due to intrinsic factors (e.g., cardiovascular disease, peripheral vascular disease, or diabetes) or extrinsic factors (e.g., increased risk of surgical site infection after dermatologic surgery at sites below the knee).^10,12

Methods

This study was approved by the Institutional Review Board at Vanderbilt University Medical Center and was conducted in accordance with the principles of Good Clinical Practice. This single-center open-label study was conducted at VUMC between October 2019 and February 2022. The primary outcome was time to re-epithelialization of the surgical defect as measured by study personnel. Secondary outcomes included infection rates, difference in pain scores, difference in skin thickness, itching, color, stiffness, irregularity, and overall assessment.

Patients

Patients were enrolled from October 8, 2020, to January 27, 2022. Participants were recruited by their treating Mohs surgeon on the day of Mohs surgery. All participants (1) were older than 17 years, (2) had postoperative wounds after Mohs surgery on the head or distal lower extremities, (3) had a single Mohs postoperative defect, (4) had postoperative wounds greater than 1 cm in width and depth of defect at least to subcutaneous tissue, (5) had the ability to provide their own wound care and were agreeable to regularly scheduled follow-up visits and transmission of photographs through HIPAA-compliant Vanderbilt University Medical Center Box, and (6) were able to provide informed consent. Immunosuppressed and organ transplant patients were excluded from this study.

Study Procedures

In the intervention group, the biomaterial was applied to the clean wound bed followed by a nonstick dressing, gauze, and surgical tape. Patients were instructed to keep this bandage dry and in place until follow-up. At return visits, if the biomaterial had completely resorbed, then another biomaterial was applied to the wound bed. In the control group, standard secondary intention included petrolatum jelly followed by a nonstick dressing, gauze, and surgical tape. Control group patients were instructed to clean their wounds and change their dressing daily. Patients returned at 2-week intervals until complete re-epithelialization was achieved. Skin thickness was assessed by taking measures of the depth of the wound bed at each follow-up appointment. A questionnaire inquiring about ease of wound care, pain, infection, bleeding, and erythema on a scale of 1 to 10 was provided to the patient at each follow-up visit and these scores were recorded.

Trial Design

Sixteen patients with surgical defects on the lower extremities amenable and conducive for SIH were randomized to intervention or control by block randomization. Subjects were randomized in a 1:1 ratio. Twenty-one patients with surgical defects on the head were randomized in the same manner. Patient enrollment occurred at Vanderbilt University Medical Center within the Department of Dermatology Mohs Surgical Unit. All patients eligible for the study according to the inclusion and exclusion criteria mentioned below were considered.

Patients were seen in office 14 days postoperatively, then every 14 days thereafter until complete re-epithelialization was achieved. Photographs of the surgical defects were taken at each follow-up visit until complete re-epithelialization and submitted to a Vanderbilt HIPAA-compliant Box. Time elapsed from surgery date to complete re-epithelialization was noted in days. Using a questionnaire, patients self-reported their surgical site/wound pain, bleeding episodes, and the ease of wound care on a scale of 1 (very easy) to 10 (impossible). In addition, at each follow-up visit, postoperative wounds were assessed for infection.

Randomization

Participants were randomized 1:1 to either the intervention or the control group by block randomization. It was not possible to mask the study coordinators to the study group. Of the 16 patients randomized in the lower extremity group, 8 were allocated to the intervention group and 8 to the control group. Of the 21 randomized in the head group, 11 were randomized to the intervention group and 10 to the control group.

Sample size

Previous studies suggested this biomaterial led to complete re-epithelialization within 42 days, compared with 127 for the leg and 57 for the head for wounds undergoing SIH.^10,11 Based on these estimates, the authors would require 17 patients per treatment group to detect a difference of 15 days with a SD of 15, 1:1 allocation, and 80% power.

Statistical Analysis

The difference in days to complete re-epithelialization between the intervention and control arms was compared using Student’s T-test. Ancillary analyses compared differences in healing time between these groups stratified by body site. Chi-squared tests were used to measure the difference in frequency of postoperative and infection between treatment groups. A two-sided p value <.05 was considered statistically significant. All analyses were conducted between 2/2022 and 3/2022.

Results

Characteristics of the study population are presented in Table 1. Overall, there is no difference in time to complete re-epithelialization between the intervention (45.1 days) and the control groups (47.2 days) (p = .71). There was also no significant difference in healing time when stratified by location, with similar times between groups for head (41.6 vs 43.0, p = .82) or leg (49.5 vs 52.7, p = .76). There were no infections among both the control and biomaterial group. Only 4 patients experienced bleeding complications (3 control, 1 biomaterial, p = .35). Itching, color, stiffness, irregularity, and overall assessment were not significant among the 2 groups (Figures 1 and 2). There was no statistically significant difference in complete re-epithelialization times based on the location (Figure 3).

TABLE 1.

Patient Characteristics

Characteristics	n	Distal Lower Extremities
	Head
Total patients	21	16
Males	18	5
Females	3	11
Age (in years)
Mean	71.4	69.5
Range	35–85	59–92
Tumor type
Basal cell carcinoma	9	2
Squamous cell carcinoma	10	14
Squamous cell carcinoma in situ	2	0

Figure 1.

Assessment of wound in the group. (A), Final wound defect upon clearance of tumor, Day 0. (B) Complete re-epithelialization at Day 47.

Figure 2.

Assessment of wound in the control group. (A) Final wound defect upon clearance of tumor, Day 0. (B) Complete re-epithelialization at Day 34.

Figure 3.

Days to complete re-epithelialization for both head and lower extremities between intervention and control groups.

There were significant differences in pain scores (1.2 biomaterial, 2.0 control, p = .03) and skin thickness (biomaterial 3.33, control 5.0, p = .03) that favored the biomaterial group.

Discussion

In this RCT, there was no significant difference in time to complete re-epithelialization between the control and intervention groups. There was also no difference when stratifying by body location, although the authors were underpowered to test for this. There was a significant difference in pain scores (biomaterial 1.2, control 2.0, p = .03) and skin thickness (biomaterial 3.33, control 50, p = .03). Importantly, these findings demonstrate that this biomaterial is not inferior to standard SIH and may serve as a useful alternative on difficult to heal postoperative wounds on the head and distal lower extremities. Further investigation regarding skin thickness and pain may provide insight that could have clinical impact.

Although not a formal end point of this study, surgeons favored the biomaterial because it was easy for patients to use (e.g. did not require a new bandage change every day) and helped reduce patient discomfort/pain.

Limitations

This study has several limitations. First, although the healing times for the intervention group were very close to expected values, the controls groups had far shorter healing times than previous studies. As a result, the authors were underpowered to detect such small differences. Nevertheless, the consistent small improvements in healing time are encouraging. It was difficult to enroll patients during the COVID-19 pandemic because regular follow-up visits in clinic were required. As a result, the enrollment numbers were lower than initially planned, and the main outcome was determined to be the overall difference in healing time rather than stratified by body site. Of the 21 patients enrolled in the head group, two were lost to follow-up before complete re-epithelialization was achieved. The low infection rate could possibly be attributed to patients with defects on the distal lower extremities receiving prophylactic antibiotics, although it would be difficult to elicit this. In addition, photographs taken at follow-up visits were not taken in standardized format, so the difference in wound healing may not be as evident photographically as it was clinically.

Conclusion

There was no statistical difference in healing time between the experimental group and the control group. However, this study highlights that this novel biomaterial may assist with SIH with less associated pain and favorable skin thickness. Because porcine xenografts can no longer be obtained, this biomaterial may serve as a suitable substitute. Further studies are needed to evaluate the clinical significance of these results.