Botulinum Toxin to Minimize Facial Scarring
David A. Sherris, M.D. and Holger G. Gassner, M.D. ABSTRACT
Botulinum toxin injection has been used for a variety of indications in humans, including blepharospasm and hyperfunctional facial lines. This article describes a novel formulation of botulinum toxin, which supplies immediate feedback to the injecting physician. Additionally, recent findings are described that indicate the immediate injection of botulinum toxin into the muscles underlying a wound can improve the cosmetic outcome of the facial cutaneous scar. Future applications of these findings are discussed.
KEYWORDS: Botulinum toxin, scar, wound healing, facial scar
A major goal of elective surgical incision closure and traumatic laceration repair is to minimize the scar. One of the greatest factors determining the final cosmetic appearance of a cutaneous scar is the tension acting on the wound edges during healing. The alignment of the incision on the skin affects the relative amount of tension on the wound. In 1816, Jules Cloquet' reported that contraction of the underlying musculature creates ridges in the skin. Nearly 2 decades later, Guillaume Dupuytren2 observed that circular cutaneous wounds inflicted with a round awl eventuated in linear clefts. Using a similar technique, Karl Langer,' a Viennese professor of anatomy, created a map of natural cutaneous lines in cadavers that reflect the tension created by underlying muscular contraction. The modern concept of relaxed skin tension lines (RSTL) was derived from Borges' work based on that of Langer.4
In general, RSTL lie perpendicular to the tension vector of the underlying muscular contraction. Scars aligned with RSTL are subject to reduced tension and heal well, whereas scars oriented against RSTL are subject to repetitive tension and result in scar hypertrophy.4-8 Often, incisions can be planned parallel to RSTL, thereby improving wound immobilization during the healing phase and resulting in a more esthetic scar. When this is not possible, other techniques can be used to minimize wound tension. The most common of these techniques are skin undermining, use of deep sutures, and flap or graft reconstruction.4-8 Such techniques, however, minimize rather than eliminate the tension that is caused by muscle pull acting on the healing wound. Repeated microtrauma caused by the continuous displacement of injured tissue induces a prolonged inflammatory response and an increased metabolic activity during healing. As a consequence, extracellular deposition of collagen and glycosaminoglycans can intensify and lead to hypertrophic scars.
One way to eliminate the tension caused by local muscle pull would be to denervate the muscles pulling on a wound. Because permanent denervation would be deleterious to function, it is not an option. Yet, temporary denervation with a chemical agent could conceivably be useful to achieve the desired effect of decreasing muscle pull, subsequent microtrauma, and eventual scar hyper-trophy during healing of a wound. This article reviews re-cent research on the application of chemodenervation to improve the cosmetic appearance of scar. A new formulation of botulinum toxin useful for this application is discussed. Animal and human studies of chemodenervation to improve scar appearance are reviewed, and future implications of the findings are discussed.
Botulinum toxin is a potent neurotoxin that produces a flaccid paralysis of striated muscle for 2 to 6 months.' It is derived from Clostridium botulinum and exists in various serotypes (A through F). Both botulinum toxin A and B are available for clinical use in the United States . For more than 20 years, the application of botulinum toxin A has proved safe and effective in the treatment of various disorders, including blepharospasm, spastic dysphonia, and hyperfunctional facial lines.10-12 The maximal dose suggested for administration to one muscle at one injection site is 25 units (U), and the maximal dose suggested per host is 200 U/month.9 In previous primate studies, no systemic side effects were experienced at doses less than 33 U/kg body weight.13 Most authors inject 1.25 to 5.0 U per injection site and thereby effectively chemodenervate the muscle and surrounding area.10-12 When a forehead is treated for hyperfunctioning glabellar and forehead creases, a total dose of 25 to 50 U is effective for treating the entire forehead. Thus, the dose necessary to theoretically immobilize a facial wound would not be expected to exceed 1 U botulinum toxin A/kg body weight.
When side effects of botulinum toxin treatment occur, they are usually related to the transient paralysis of adjacent muscle groups, with a resultant temporary functional deficit, such as lagophthalmos or brow ptosis. To minimize this side effect and maximize the precision of intramuscular injection, electromyographic guidance has been useful. Yet, because of the delayed onset of action of botulinum toxin, follow-up visits and reinjections are frequently necessary to achieve the desired treatment effect. Most patients do not attain full chemodenervation of the treated muscle groups for 48 to 72 hours after injection. To address the lack of immediate feedback when injecting botulinum toxin, we reformulated the medication and did a blinded trial.14 We believe that botulinum toxin, in combination with a local anesthetic with or without a vasoconstrictive agent, is especially useful in wound-healing applications.
REFORMULATION OF BOTULINUM TOXIN
We recently described the simultaneous injection of a botulinum toxin, a local anesthetic, and a vasoconstrictive agent to reduce local diffusion and to provide the physician with immediate feedback on the desired treatment effect.14 The anesthetic agent lidocaine acts by stabilizing the neuronal membrane and inhibiting the ionic fluxes required for the initiation and conduction of neuronal impulses. Through this mechanism, efferent fibers are blocked and muscle paralysis immediately ensues. The vasoconstrictive agent achieves its effect through its sympathomimetic properties, acting on both a- and B-receptors. It thereby reduces local diffusion of the anesthetic agent and of other simultaneously injected agents.
In a randomized and single-blind study in human volunteers, the authors showed that the combination of a botulinum toxin, an anesthetic agent, and a local vasoconstrictive achieves immediate paralysis of the injected muscle One side of the forehead was injected with 20 U of botulinum toxin A reconstituted in 1% lidocaine with 1:100,000 epinephrine, and the contralateral side was injected with 20 U botulinum toxin A reconstituted in 0.9% sodium chloride.
As depicted in Figure 1, paralysis ensued within 5 to 10 minutes after the injection of the experimental drug (botulinum toxin A + lidocaine + epinephrine), whereas no paralysis was noted on the contralateral side of the forehead after injection of the control drug (botulinum toxin A + saline). One week after the injection, symmetric paralysis was present on both the experimental side and the control side of the forehead in all patients (Fig. 2). The blanching effect of the injected epinephrine was noted in all (10 of 10) patients on the experimental side 5 to 10 minutes after the injections, as shown in Figure 1. Symmetric return of muscle function was noted in all patients (10 of 10) 3 months after injection. Thus, all of the separate components of the formulation maintained their function, and no side effects were observed. The anesthetic component, lidocaine, caused immediate paralysis of the injected muscle and thus gave the injecting physician immediate feed-back on the eventual treatment effect. The temporary effect of the lidocaine on paralysis immediately created the level of paralysis eventually seen from the botulinum toxin 3 days later.
Because lidocaine with or without epinephrine is commonly injected before surgical incision or closure of traumatic lacerations, injection of lidocaine and the chemodenervating agent could be done simultaneously to avoid multiple injections. In addition, the proven immediate feedback would be extremely advantageous, especially to less-experienced users of botulinum toxin. This formulation also would be useful in other application sites for the same reasons.
FACIAL WOUND HEALING:
The use of chemodenervation with botulinum toxin to improve cutaneous scar appearance was recently studied in a primate model." Standardized excisions were per-formed in symmetric locations on the forehead of primates, and subsequently the hemiforehead was randomized to botulinum toxin A or placebo injection (Fig. 3). The frontalis muscle underlying each of the cutaneous wounds was injected either with 7 U of botulinum toxin A in 0.9% saline or with 0.9% saline alone. Twenty-one total units of botulinum toxin A was injected into the experimental side of the forehead and resulted in complete paralysis of the side. After the healing phase of 3 months, the scars were evaluated by three blinded servers who used a 10-cm visual analog scale. The botulinum toxin A-treated scars had a significantly superior cosmetic result compared with the respective symmetric control scars (p < 0.01, two-factor analysis of variance; Fig. 4). Consensus scores of rating the scars on either side of the forehead as equal to or better than the scars on the opposite side also resulted in the experimental side having better scars than the control side (p < 0.031, binomial test). Histologic examination revealed that the scars were mature with no ongoing remodeling or inflammatory response present.
FACIAL WOUND HEALING:
HUMAN CASE REPORT
On the basis of the animal studies and the fact that botulinum toxin A is both safe and is approved for many human uses, human trials were indicated. Before we conduct blinded trials we use the agent during scar re-visions in various cases. A typical case is described here. A healthy 27-year-old white man presented with a 15-mm-long scar over the left supraorbital rim (Fig. 5). Its horizontal direction gave it a favorable position relative to the RSTL. The scar had resulted from a wound sustained in a fall at the age of 7; the wound had been closed by an experienced facial plastic surgeon in a tertiary referral center. Five days later the suture material was removed and the entire healing process was uncomplicated. The patient presented to the senior author (D.A.S.) for a revision procedure to improve the cosmetic appearance of the scar. The wound was anesthetized with a local injection of 0.5 ml of 0.5% lidocaine with 1:200,000 epinephrine. In addition to providing pain control, the lidocaine injection caused immediate paralysis of the injected musculature. The scar was excised with standard surgical technique. The frontalis muscle was injected under direct vision with 10 U of botulinum toxin A and the wound was closed with 6-0 polyglactin 910 (Vicryl) buried sutures and 6-0 nylon skin sutures in the standard manner. Because frowning caused distortion of the wound despite the immediate lidocaine-induced paralysis of the musculature adjacent to the wound, another 7.5 U of botulinum toxin A was injected transcutaneously into the procerus and ipsilateral corrugator muscles in the same technique that is used in the treatment of facial rhytids and frown lines.
Twenty-four hours postoperatively, botulinum toxin A-induced paralysis of the injected muscles began to develop. By the third postoperative day the patient had lost the ability to wrinkle the forehead skin in an area of approximately 4 cm in diameter around the excision (Fig. 6). Tension on the wound and distortion of the wound edges were minimal, even during maximal attempts to contract the frontalis muscle. One year after the procedure, the revision scar (Fig. 7) clearly compared favorably with the original scar (Fig. 5).
In our hands, botulinum toxin A has proved to be a safe adjunctive treatment of cutaneous lacerations. The side-effect profile of botulinum toxin A injections, as observed for the treatment of various disorders over many years, is very low. Blinded trials are in development at the Mayo Clinic to assess the efficacy of botulinum toxin treatment for improvement of the esthetic scar result. Because botulinum toxin injection has a positive impact on cutaneous wound healing, other areas likely would heal better if attached muscles were temporarily chemodenervated. For instance, fractured bones and ruptured tendons would likely heal better if the attached muscles and counteracting muscles were temporarily chemodenervated during healing.
Facial skin wounds can be immobilized with the injection of botulinum toxin A. The injection technique resembles that applied to treat age-related rhytids, but it must be tailored appropriately. The method of chemoimmobilization is applicable for both elective and traumatic lacerations. For elective incision, such as lesion excision, scar revisions, or flap reconstruction, injection of the chemodenervating agent can be performed in advance. Injection of traumatic lacerations results in delayed immobilization. For both elective and traumatic lesions, the simultaneous injection of a local anesthetic agent results in immediate paralysis of the injected muscle and thus makes injection of the botulinum toxin more predictable. Further research may well demonstrate the utility of chemodenervation in various wound-healing applications.
- Cloquet JH. Traite d'Anatomie Descriptive. Paris : Libraire de Crochard; 1832:313
- Dupuvtren G. Traite Theorique et Pratique des Armes de Guerre, Vol. 2. Paris : Baillere; 1834:60-66
- Langer K. On the anatomy and physiology of the skin: I. The cleavability of the skin. Br J Plast Surg 1978;31:3
- Borges AF. Elective Incisions and Scar Revision. Boston : Little, Brown; 1973:29
- Larrabee WF Jr, Sherris DA. Principles of Facial Reconstruction. Philadelphia : Lippincott-Raven; 1995:7
- McCarthy JG. Plastic Surgery, Vol. 1. Philadephia: WB Saunders; 1990:43-44
- Courtiss EH, Longacre JJ, DeStafano GA , Loredana B, Holmstrand K. The placement of elective skin incisions. Plast Reconstr Surg 1963;31:31
- Sherris DA, Larrabee WF Jr, Nlurakami CS. Management of scar contractures, hypertrophic scars and keloids. Otolaryngol Clin North Am 1995;28:1057
- Physicians Desk Reference. Montvale , NJ :1V'Iedical Economics; 2000;54:495-497
- Carruthers A, Keine K, Carruthers J. Botulinum A exotoxin use in clinical dermatology. J Am Acad Dermatol 1996;34:788
- Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980; 87:1004-1049
- Hallett, M. One man's poison-clinical applications of botulinum toxin (editorial). N Engl J Med 1999;341:118-120
- Scott AB, Suzuki D. Systemic toxicity of botulinum toxin by intramuscular injection in the monkey. Mov Disord 1988;3: 333-333
- Gassner HG, Sherris DA. Addition of anesthetic agent enhances the predictability of botulinum toxin injections. Mayo Clin Proc 2000;75:701-704
- Karatassas A, Morris RG, Slavotinek AH. The relationship between regional blood flow and absorption of lidocaine. Aust NZ J Surg 1993;63:766-771
- Gassner HG, Sherris DA, Otley CC. Treatment of facial wounds with botulinum toxin A improves cosmetic outcome in primates. Plast Reconstr Surg 2000;105:1948-1953
- Carruthers A, Carruthers J. Aesthetic indications fir botulinum toxin injections. Plast Reconstr Surg 1995;96:437-438