A Preliminary Report of the Biochemical and Clinical Effects of 1,4-Diaminobutane on Prevention of Human Hypertrophic Scars

Abstract

Objective evidence for the role of inhibition of collagen cross-linking in human scar using a nontoxic topical inhibitor, 1,4-diaminobutane (1,4 DAB), in patients with scars at risk for hypertrophic scar formation is presented. The authors used a concentration of 1,4 DAB of 0.8% (weight/volume) in a cream base similar to Glaxal Base. Application was once per day at night. The control was treated with cream base alone. In treatment phase studies at 2 months, tissue biopsies were performed and used to determine a therapeutic effect biochemically in paired scars harvested chosen with typical hypertrophic scars at two major treatment centers. Tissue transglutaminase activity revealed a significant reduction of the ε-(γ-glutamyl)lysine cross-links in the treated scars: 7.96 ± 1.51 pmol/µmol amino acid versus 14.78 ± 3.52 pmol/µmol amino acid. A subset of paired scars (n = 15) was also analyzed for soluble procollagen type III amino propeptide. The effect was a significant increase in procollagen type III amino propeptide in the scars treated with 1,4 DAB compared with sham-treated scars: 47.75 ± 4.6 µg/mg wet weight versus 39.08 ± 6.02 µg/mg wet weight, respectively. Levels of tissue 1,4 DAB was found to be twice as high in the presence of the active cream versus in the tissue of the control group. In subsequent prophylaxis studies, the authors treated 44 breast reduction patients prospectively with active cream to one or the other side in a double-blind randomized fashion. Hardness (in grams) measured using a Rex Durometer at 6 and 12 weeks postoperatively along with photographs were analyzed. The mean value ± SD of 24.98 ± 1.2 g on the active side versus 31.76 ± 1.1 g on the sham side was significantly different (p < 0.05). The patient scale scores of the Patient and Observer Scar Assessment Scale were also requested by survey in a responding 27-patient subgroup at a minimum 1 year postoperatively, and the differences between the two sides were found to be statistically significant, where the mean on the active side was 14.07 ± 1.34 and the mean on the sham side was 21.41 ± 1 (p < 0.05). The results are evidence to support the use of this agent in prevention of hypertrophic scars. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, II.

Trial registration: ClinicalTrials.gov NCT03376620.

Figures

Fig. 1.

Early enrolment for biochemical analysis were from two centers. All patients accepted with recent scars were able to be studied in pairs (n = 30). Later, 48 breast reduction patients from one center were enrolled and 44 studied by durometry. Four of the patients enrolled after breast reduction dropped out because of personal reasons. Twenty-seven patients returned Patient and Observer Scar Assessment Scale questionnaires at 1-year follow-up. The total enrollment was 78 patients for both types of analysis. 1,4 DAB, 1,4-diaminobutane; PIIP-RIA, procollagen type III amino propeptide radioimmunoassay; POSAS, Patient and Observer Scar Assessment Scale.

Fig. 2.

High-pressure liquid chromatography: box-and-whisker plot results for 30 paired scar specimens expressed in picomoles of ε-(γ-glutamyl)lysine isopeptide bonds in digests. Kolmogorov-Smirnov test was not normally distributed but applied Mann-Whitney U test was significant (p < 0.05). 1,4 DAB, 1,4-diaminobutane; TGase, tissue transglutaminase.

Fig. 3.

Radioimmunoassay results of 15 paired scar specimens expressed in micrograms of procollagen type III amino propeptide per milligram tissue wet weight after thawing. The insoluble material after exhaustive extraction is compared to the soluble fraction. 1,4 DAB results are also shown as box-and-whisker graphs and show significance (p < 0.05) compared with control-treated scars with respect to soluble procollagen type III amino propeptide only, by Mann-Whitney U test. The Kolmogorov-Smirnov normality test was shown to be valid. PIIIP, procollagen type III amino propeptide; RIA, radioimmunoassay; 1,4 DAB, 1,4-diaminobutane.

Fig. 4.

1,4 DAB content (in nanomoles per milligram wet weight of tissue) after thawing from eight random skin samples harvested in triplicate at the time of elective scar revision at 3 months. Paired scars treated with 1,4 DAB are shown in blue and control-treated scars are shown in pink; t test (p < 0.05) demonstrates twice physiologic levels in active test scars (outside independent laboratory testing performed by industrial partner). 1,4 DAB, 1,4-diaminobutane.

Fig. 5.

Scar hardness in grams using a Rex durometer from 44 paired breast reduction scars. Box plot shows highly significant difference at 12 weeks after run for active side versus sham-treated scars by Mann-Whitney U test (p < 0.00003). The Kolmogorov-Smirnov test is valid.

Fig. 6.

The seven parameters of the 10-point Patient and Observer Scar Assessment Scale is shown (copyright © p.p.m. van zuijlen, beverwijk-nl).

Fig. 7.

Representative result of one breast reduction patient and the relative improvement in the appearance of scars on the treated (left) side versus the sham (right) side at 12 weeks.