Botulinum toxin type a intralesional monotherapy for treating human hypertrophic scar in a dose-dependent manner: In an animal model

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Summary

Background

The effect of Botulinum toxin type A (BTX-A) in treating or preventing a hypertrophic scar (HS) had been reported in clinical studies. However, the dose-effect relationship remains unclear.

Objective

To study the dose-effect relationship of BTX-A intralesional monotherapy treating human HS.

Methods

Six HS tissues were collected from six patients. Each tissue was segmented into 24 specimens and split into four groups: negative control (group A), 0.5U BTX-A (group B), 1U BTX-A (group C), and 2U BTX-A (group D). Six nude mice, each was prepared by implanting four specimens (one from each group) into the back for a total of 24 specimens. The process mentioned above were repeated six times. A re-entry operation was performed to obtain the specimens after 8 weeks. The weight of HS, the expression of decorin and TGF-β1, the proliferation, and migration ability of hypertrophic scar fibroblasts (HSFBs) were compared among groups.

Results

The weight of HS, the expression of decorin and TGF-β1, the proliferation, and migration ability of HSFBs showed significant differences in groups C and D as compared to group A; there has been no statistical significance in group B.

Conclusion

BTX-A showed significant therapeutic efficacy when compared with the negative control group in a dose-dependent manner. BTX-A can reduce the weight of HS, upregulate the expression of decorin, downregulate the expression of TGF-β1, and inhibit HSFBs proliferation and migration ability. This study indicates that BTX-A intralesional monotherapy treating HS should reach a threshold dose to achieve an effective treatment, and a high dose of BTX-A is more effective than a low dose.

Introduction

Asians have a tendency to develop hypertrophic scar (HS) after injury due to abnormal collagen deposition and hypertrophic scar fibroblasts (HSFBs) activity, which results in the loss of tissue function, psychological damage, and disfigurement. HS have decreased decorin and increased TGF-β1 expression when compared with healthy skin.1,2 TGF-β1 is the most pivotal profibrotic cytokine related to fibrogenesis, which triggers fibroblasts to overproduce collagen types I, III, and fibronectin.3 Decorin is a member of the small leucine-rich ubiquitous proteoglycan family that is a normal component of the extracellular matrix (ECM). It plays an important role in the regulation of intercellular contact, cell migration, and cell proliferation by the modulation of interactions between cell surface receptors and ECM.4,5 Decorin binds to TGF-β1, thereby inhibiting the biological activity of TGF-β1 and then reducing the fibrous scar.6, 7, 8

There is a wide spectrum of measures to treat HS. Scar revision surgery is considered as a commonly therapy for treating hypertrophic scar,9 but for the patients who wish to take conservative treatment, intralesional injection therapy is an option.10, 11, 12 Triamcinolone is one of the most commonly used steroid for injection treating HS.13,14 However, some complications of applying steroids are hard to accept by patients, such as severe pain during injection, ulcerate in injection-site, hyperpigmentation, telangiectasia, and skin atrophy.15, 16, 17, 18

Botulinum toxin type A (BTX-A) is another option for intralesional injection, with milder complications and less side effects. Botulinum toxin is derived from clostridium botulinum. It is a potent neurotoxin that indirectly blocks neuromuscular transmission. Clinical studies on intralesional injecting BTX-A had indicated that less increase in scar width and improved discoloration of the scar in patients were observed19,20 as well as significant improvement in cosmetic outcomes.21,22 Both observer-dependent qualitative assessments and quantitative measurements were favorable in the BTX-A group. BTX-A could minimize scarring in primates, as it prevents the contraction of muscles and skin during wound healing.23, 24, 25 However, the dose of BTX-A in treating HS in previous studies were mainly established on researchers’ clinical experiment, and no evidence was given on the dose-effect relationship. Therefore, this study aims to compare the effects of different doses of BTX-A in intralesional monotherapy for treating human HS and wish to find a better dose standard for treating HS at the clinic.

Section snippets

HS tissue and nude athymic mouse

HS tissue samples were collected from patients through scar revision surgery. None of these patients presented with a history of intralesional drug injection therapy. The acquisition of the tissues was subject to the consent of the patient. Institutional review board approval and informed consent from the patients were obtained. HS tissues were placed in antiseptic flasks, hydrated in saline solution, and processed within 1 h.

Nude athymic mice (BALB/nu-nu; female; body weight, 25-30 g; and age,

Weight of HS

Measured the weight of harvested HS specimens and calculated the percentage with original weight. Group A (0.9% normal saline) showed no significant reduction when compared with the original. The highest decrease was in group D (2U BTX-A). Significant differences were observed in the weight reduction of the HS specimens among the four groups (group A, 100.67 ± 11.13 percent; group B, 87.67 ± 8.79 percent, p>0.05; group C, 73.67 ± 6.05 percent, p<0.05; and group D, 67.67 ± 1.11 percent, p<0.05) (

Discussion

To our knowledge, this is the first study on dose-effect relationship of BTX-A intralesional monotherapy in the treatment of human HS in an animal model. HS specimens were implanted into a subcutaneous pocket in nude athymic mice that were used to simulate the progression of scar tissue in human patients, which has been previously validated as a reliable model with which to test drug efficacy.28,29 BTX-A was confirmed to reduce the proliferation and migration of human scar fibroblasts.30 In

Conclusions

BTX-A showed significant therapeutic efficacy when compared with the negative control group in a dose-dependent manner. BTX-A can reduce the weight of HS, upregulate the expression of decorin, downregulate the expression of TGF-β1, and inhibit HSFBs proliferation and migration ability. This study indicates that BTX-A intralesional monotherapy treating HS should reach a threshold dose to achieve an effective treatment, and a high dose of BTX-A is more effective than a low dose.

Declaration of Competing Interest

None declared.

Funding

National Natural Science Foundation of China [grant numbers 81671007 and 81870781].

Ethical approval

Approved by Peking University Institutional Review Board (LA2019097).

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