Botulinum toxin type-A (BTX-A), a subtype from known seven types of botulinum neurotoxin (serotype A-G), is produced by a gram-positive bacterium, Clostridium botulinum. The toxin is now widely and efficiently used in treating a plethora of diverse symptoms and conditions. Recent evidence in the literature also shows that BTX-A exhibits a wide range of effects on non-neuronal cells. Its potential has markedly expanded to clinical applications other than the treatment of neurological and muscular conditions that are characterized by neuronal hyperactivity. A number of studies have shown BTX-A to improve the quality of scar outcome and prevent the formation of keloids and HTS. Although the mechanism of action of BTX-A on wound healing is still not clearly understood, lately there has been extensive research to grasp the underlying mechanisms of this multifunctional toxin. BTX-A seems to affect wound healing by a number of mechanisms that include action on tensile forces, inhibition of fibroblasts differentiation, downregulation of TGF-β1 and collagen expression. This review will explore the responses of Botulinum toxin type-A on wound healing and preventing pathological scars like HTS and keloids, and comprehend the overall effect BTX-A has on wound healing.
References
[1]
Ziade, M., et al. (2013) Use of Botulinum Toxin Type A to Improve Treatment of Facial Wounds: A Prospective Randomised Study. Journal of Plastic, Reconstructive & Aesthetic Surgery, 66, 209-214. https://doi.org/10.1016/j.bjps.2012.09.012
[2]
Zhang, D.Z., et al. (2016) Botulinum Toxin Type A and the Prevention of Hypertrophic Scars on the Maxillofacial Area and Neck: A Meta-Analysis of Randomized Controlled Trials. PLoS ONE, 11, e0151627. https://doi.org/10.1371/journal.pone.0151627
[3]
Leventhal, D., Furr, M. and Reiter, D. (2006) Treatment of Keloids and Hypertrophic Scars: A Meta-Analysis and Review of the Literature. Archives of Facial Plastic Surgery, 8, 362-368. https://doi.org/10.1001/archfaci.8.6.362
[4]
Kerner, J.A.C. (1820) Neue Beobachtungen über die in Württemberg so häufig vorfallenden tödlichen Vergiftungen durch den Genuss geräucherter Würste.
[5]
Kerner, J.A.C. (1822) Das Fettgift, oder die Fettsa\0308ure und ihre Wirkungen auf den thierischen Organismus, etc.
[6]
Hagenah, R., Benecke, R. and Wiegand, H. (1977) Effects of Type a Botulinum Toxin on the Cholinergic Transmission at Spinal Renshaw Cells and on the Inhibitory Action at Ia Inhibitory Interneurones. Naunyn-Schmiedeberg’s Archives of Pharmacology, 299, 267-272. https://doi.org/10.1007/BF00500319
Ashkenazi, A. and Silberstein, S. (2008) Botulinum Toxin Type A for the Treatment of Headache: Why We Say Yes. Archives of Neurology, 65, 146-149. https://doi.org/10.1001/archneurol.2007.20
[9]
Wheeler, T. (2012) Sweat and Tears: Treating the Patient with Primary Hyperhidrosis. British Journal of Nursing, 21, 408, 410-412. https://doi.org/10.12968/bjon.2012.21.7.408
[10]
Santos-Silva, A., da Silva, C.M. and Cruz, F. (2013) Botulinum Toxin Treatment for Bladder Dysfunction. International Journal of Urology, 20, 956-962. https://doi.org/10.1111/iju.12188
[11]
Beer, K. and Waibel, J. (2007) Botulinum Toxin Type A Enhances the Outcome of Fractional Resurfacing of the Cheek. Journal of Drugs in Dermatology, 6, 1151-1152.
[12]
Lee, H., Saladi, R.N. and Fox, J.L. (2008) Cohort Study on Patient Response to Botulinum Toxin Cosmetic Therapy. Journal of Cosmetic Dermatology, 7, 39-42. https://doi.org/10.1111/j.1473-2165.2008.00359.x
[13]
Egan, M. (2014) Botox Maker Bought for $66 Billion in Biggest Deal of 2014. http://money.cnn.com/2014/11/17/investing/allergan-actavis-merger-boom
[14]
Allergan (2015) Actavis plc Is Now Allergan plc.
[15]
Felber, E.S. (2006) Botulinum Toxin in Primary Care Medicine. The Journal of the American Osteopathic Association, 106, 609-614.
[16]
Li, B., et al. (2010) Small Molecule Inhibitors as Countermeasures for Botulinum Neurotoxin Intoxication. Molecules, 16, 202-220. https://doi.org/10.3390/molecules16010202
[17]
Montecucco, C. and Molgo, J. (2005) Botulinal Neurotoxins: Revival of an Old Killer. Current Opinion in Pharmacology, 5, 274-279. https://doi.org/10.1016/j.coph.2004.12.006
[18]
Pirazzini, M., et al. (2017) Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology. Pharmacological Reviews, 69, 200-235. https://doi.org/10.1124/pr.116.012658
[19]
Lacy, D.B., et al. (1998) Crystal Structure of Botulinum Neurotoxin Type A and Implications for Toxicity. Nature Structural Biology, 5, 898-902. https://doi.org/10.1038/2338
[20]
de Paiva, A., et al. (1999) Functional Repair of Motor Endplates after Botulinum Neurotoxin Type A Poisoning: Biphasic Switch of Synaptic Activity between Nerve Sprouts and Their Parent Terminals. Proceedings of the National Academy of Sciences of the United States of America, 96, 3200-3205. https://doi.org/10.1073/pnas.96.6.3200
[21]
Davies, J.R., et al. (2018) High Resolution Crystal Structures of Clostridium botulinum Neurotoxin A3 and A4 Binding Domains. Journal of Structural Biology, 202, 113-117. https://doi.org/10.1016/j.jsb.2017.12.010
[22]
Rossetto, O., Pirazzini, M. and Montecucco, C. (2014) Botulinum Neurotoxins: Genetic, Structural and Mechanistic Insights. Nature Reviews Microbiology, 12, 535-349. https://doi.org/10.1038/nrmicro3295
[23]
Montecucco, C. (1986) How Do Tetanus and Botulinum Toxins Bind to Neuronal Membranes? Trends in Biochemical Sciences, 11, 314-317. https://doi.org/10.1016/0968-0004(86)90282-3
[24]
Brunger, A.T. and Rummel, A. (2009) Receptor and Substrate Interactions of Clostridial Neurotoxins. Toxicon, 54, 550-560. https://doi.org/10.1016/j.toxicon.2008.12.027
[25]
Zhang, Y., et al. (2012) Simultaneous and Sensitive Detection of Six Serotypes of Botulinum Neurotoxin Using Enzyme-Linked Immunosorbent Assay-Based Protein Antibody Microarrays. Analytical Biochemistry, 430, 185-192. https://doi.org/10.1016/j.ab.2012.08.021
[26]
Pellett, S., et al. (2018) The Light Chain Defines the Duration of Action of Botulinum Toxin Serotype A Subtypes. mBio, 9, pii: e00089-18. https://doi.org/10.1128/mBio.00089-18
[27]
Pirazzini, M., et al. (2015) The Thioredoxin Reductase—Thioredoxin Redox System Cleaves the Interchain Disulphide Bond of Botulinum Neurotoxins on the Cytosolic Surface of Synaptic Vesicles. Toxicon, 107, 32-36. https://doi.org/10.1016/j.toxicon.2015.06.019
[28]
Arnon, S.S., et al. (2001) Botulinum Toxin as a Biological Weapon: Medical and Public Health Management. JAMA, 285, 1059-1070. https://doi.org/10.1001/jama.285.8.1059
[29]
Flanagan, M. (2013) Wound Healing and Skin Integrity: Principles and Practice. John Wiley and Sons Ltd., Hoboken.
[30]
Gauglitz, G.G., et al. (2011) Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies. Molecular Medicine, 17, 113-125. https://doi.org/10.2119/molmed.2009.00153
[31]
Roberts, A.B. and Sporn, M.B. (1993) Physiological Actions and Clinical Applications of Transforming Growth Factor-Beta (TGF-Beta). Growth Factors, 8, 1-9. https://doi.org/10.3109/08977199309029129
[32]
Biernacka, A., Dobaczewski, M. and Frangogiannis, N.G. (2011) TGF-Beta Signaling in Fibrosis. Growth Factors, 29, 196-202. https://doi.org/10.3109/08977194.2011.595714
[33]
Mayrand, D., et al. (2012) Angiogenic Properties of Myofibroblasts Isolated from Normal Human Skin Wounds. Angiogenesis, 15, 199-212. https://doi.org/10.1007/s10456-012-9253-5
[34]
Pastar, I., et al. (2014) Epithelialization in Wound Healing: A Comprehensive Review. Advances in Wound Care (New Rochelle), 3, 445-464. https://doi.org/10.1089/wound.2013.0473
[35]
Su, W.H., et al. (2010) Nonsteroidal Anti-Inflammatory Drugs for Wounds: Pain Relief or Excessive Scar Formation? Mediators of Inflammation, 2010, Article ID: 413238. https://doi.org/10.1155/2010/413238
[36]
Butzelaar, L., et al. (2016) Currently Known Risk Factors for Hypertrophic Skin Scarring: A Review. Journal of Plastic, Reconstructive & Aesthetic Surgery, 69, 163-169. https://doi.org/10.1016/j.bjps.2015.11.015
[37]
Jeong, H.S., et al. (2015) Effect of Botulinum Toxin Type A on Differentiation of Fibroblasts Derived from Scar Tissue. Plastic and Reconstructive Surgery, 136, 171e-178e. https://doi.org/10.1097/PRS.0000000000001438
[38]
Oh, S.H., et al. (2012) The Potential Effect of Botulinum Toxin Type A on Human Dermal Fibroblasts: An in Vitro Study. Dermatologic Surgery, 38, 1689-1694. https://doi.org/10.1111/j.1524-4725.2012.02504.x
[39]
Xiao, Z. and Qu, G. (2012) Effects of Botulinum Toxin Type a on Collagen Deposition in Hypertrophic Scars. Molecules, 17, 2169-2177. https://doi.org/10.3390/molecules17022169
[40]
Xiao, Z., et al. (2011) Botulinum Toxin Type a Inhibits Connective Tissue Growth Factor Expression in Fibroblasts Derived from Hypertrophic Scar. Aesthetic Plastic Surgery, 35, 802-807. https://doi.org/10.1007/s00266-011-9690-3
[41]
Wang, L., Tai, N.Z. and Fan, Z.H. (2009) Effect of Botulinum Toxin Type A Injection on Hypertrophic Scar in Rabbit Ear Model. Chinese Journal of Plastic Surgery, 25, 284-287.
[42]
Xiao, Z., et al. (2010) Effect of Botulinum Toxin Type A on Transforming Growth Factor Beta1 in Fibroblasts Derived from Hypertrophic Scar: A Preliminary Report. Aesthetic Plastic Surgery, 34, 424-427. https://doi.org/10.1007/s00266-009-9423-z
[43]
Zhibo, X. and Miaobo, Z. (2009) Intralesional Botulinum Toxin Type A Injection as a New Treatment Measure for Keloids. Plastic and Reconstructive Surgery, 124, 275e-277e. https://doi.org/10.1097/PRS.0b013e3181b98ee7
[44]
Xiao, Z., Zhang, F. and Cui, Z. (2009) Treatment of Hypertrophic Scars with Intralesional Botulinum Toxin Type A Injections: A Preliminary Report. Aesthetic Plastic Surgery, 33, 409-412. https://doi.org/10.1007/s00266-009-9334-z
[45]
Zhibo, X. and Miaobo, Z. (2008) Botulinum Toxin Type A Affects Cell Cycle Distribution of Fibroblasts Derived from Hypertrophic Scar. Journal of Plastic, Reconstructive & Aesthetic Surgery, 61, 1128-1129. https://doi.org/10.1016/j.bjps.2008.05.003
[46]
Hao, R., et al. (2018) Efficacy and Possible Mechanisms of Botulinum Toxin Type A on Hypertrophic Scarring. Journal of Cosmetic Dermatology, 17, 340-346. https://doi.org/10.1111/jocd.12534
[47]
Chen, M., et al. (2016) Botulinum Toxin Type A Inhibits alpha-Smooth Muscle Actin and Myosin II Expression in Fibroblasts Derived From Scar Contracture. Annals of Plastic Surgery, 77, e46-e49. https://doi.org/10.1097/SAP.0000000000000268
[48]
Raghow, R., et al. (1987) Transforming Growth Factor-Beta Increases Steady State Levels of Type I Procollagen and Fibronectin Messenger RNAs Posttranscriptionally in Cultured Human Dermal Fibroblasts. Journal of Clinical Investigation, 79, 1285-1288. https://doi.org/10.1172/JCI112950
[49]
Chen, M.A. and Davidson, T.M. (2005) Scar Management: Prevention and Treatment Strategies. Current Opinion in Otolaryngology & Head and Neck Surgery, 13, 242-247. https://doi.org/10.1097/01.moo.0000170525.74264.f8
[50]
Fujiwara, M., Muragaki, Y. and Ooshima, A. (2005) Keloid-Derived Fibroblasts Show Increased Secretion of Factors Involved in Collagen Turnover and Depend on Matrix Metalloproteinase for Migration. British Journal of Dermatology, 153, 295-300. https://doi.org/10.1111/j.1365-2133.2005.06698.x
[51]
Tanriverdi-Akhisaroglu, S., Menderes, A. and Oktay, G. (2009) Matrix Metalloproteinase-2 and -9 Activities in Human Keloids, Hypertrophic and Atrophic Scars: A Pilot Study. Cell Biochemistry and Function, 27, 81-87. https://doi.org/10.1002/cbf.1537
[52]
Babalola, O., et al. (2013) The Role of microRNAs in Skin Fibrosis. Archives of Dermatological Research, 305, 763-776. https://doi.org/10.1007/s00403-013-1410-1
[53]
Wolfram, D., et al. (2009) Hypertrophic Scars and Keloids—A Review of Their Pathophysiology, Risk Factors, and Therapeutic Management. Dermatologic Surgery, 35, 171-181. https://doi.org/10.1111/j.1524-4725.2008.34406.x
[54]
Shah, M., Foreman, D.M. and Ferguson, M.W. (1995) Neutralisation of TGF-beta 1 and TGF-beta 2 or Exogenous Addition of TGF-beta 3 to Cutaneous Rat Wounds Reduces Scarring. Journal of Cell Science, 108, 985-1002.
[55]
Shi, Y. and Massague, J. (2003) Mechanisms of TGF-beta Signaling from Cell Membrane to the Nucleus. Cell, 113, 685-700. https://doi.org/10.1016/S0092-8674(03)00432-X
[56]
Lee, S.D., et al. (2016) The Effect of Botulinum Neurotoxin Type A on Capsule Formation around Silicone Implants: The in Vivo and in Vitro Study. International Wound Journal, 13, 65-71. https://doi.org/10.1111/iwj.12228
[57]
Kim, S., et al. (2016) Effect of Botulinum Toxin Type A on TGF-beta/Smad Pathway Signaling: Implications for Silicone-Induced Capsule Formation. Plastic and Reconstructive Surgery, 138, 821e-829e. https://doi.org/10.1097/PRS.0000000000002625
[58]
Gabbiani, G., Ryan, G.B. and Majne, G. (1971) Presence of Modified Fibroblasts in Granulation Tissue and Their Possible Role in Wound Contraction. Experientia, 27, 549-550. https://doi.org/10.1007/BF02147594
[59]
Gabbiani, G. (2003) The Myofibroblast in Wound Healing and Fibrocontractive Diseases. The Journal of Pathology, 200, 500-503. https://doi.org/10.1002/path.1427
[60]
Hinz, B., et al. (2007) The Myofibroblast: One Function, Multiple Origins. The American Journal of Pathology, 170, 1807-1816. https://doi.org/10.2353/ajpath.2007.070112
[61]
Darby, I.A. and Hewitson, T.D. (2007) Fibroblast Differentiation in Wound Healing and Fibrosis. International Review of Cytology, 257, 143-179. https://doi.org/10.1016/S0074-7696(07)57004-X
[62]
Tanaka, J., et al. (1993) Morphological and Biochemical Analyses of Contractile Proteins (Actin, Myosin, Caldesmon and Tropomyosin) in Normal and Transformed Cells. Journal of Cell Science, 104, 595-606.
[63]
Bond, J.E., et al. (2011) Temporal Spatial Expression and Function of Non-Muscle Myosin II Isoforms IIA and IIB in Scar Remodeling. Laboratory Investigation, 91, 499-508. https://doi.org/10.1038/labinvest.2010.181
[64]
Vicente-Manzanares, M., et al. (2009) Non-Muscle Myosin II Takes Centre Stage in Cell Adhesion and Migration. Nature Reviews Molecular Cell Biology, 10, 778-790. https://doi.org/10.1038/nrm2786
[65]
Tomasek, J.J., et al. (2002) Myofibroblasts and Mechano-Regulation of Connective Tissue Remodelling. Nature Reviews Molecular Cell Biology, 3, 349-363. https://doi.org/10.1038/nrm809
[66]
Zaleskas, J.M., et al. (2001) Growth Factor Regulation of Smooth Muscle Actin Expression and Contraction of Human Articular Chondrocytes and Meniscal Cells in a Collagen-GAG Matrix. Experimental Cell Research, 270, 21-31. https://doi.org/10.1006/excr.2001.5325
[67]
Arno, A.I., et al. (2014) New Molecular Medicine-Based Scar Management Strategies. Burns, 40, 539-551. https://doi.org/10.1016/j.burns.2013.11.010
[68]
Berman, B., Maderal, A. and Raphael, B. (2017) Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment. Dermatologic Surgery, 43, S3-S18. https://doi.org/10.1097/DSS.0000000000000819
[69]
Jumper, N., Paus, R. and Bayat, A. (2015) Functional Histopathology of Keloid Disease. Histology and Histopathology, 30, 1033-1057.
[70]
Roh, T.S., et al. (2013) The Effects of Botulinum Toxin A on Collagen Synthesis, Expression of MMP (Matrix Metalloproteinases)-1,2,9 and TIMP (Tissue Inhibitors of Metalloproteinase)-1 in the Keloid Fibroblasts. Archives of Aesthetic Plastic Surgery, 19, 114-119. https://doi.org/10.14730/aaps.2013.19.2.114
[71]
Fanous, A., et al. (2019) Treatment of Keloid Scars with Botulinum Toxin Type A versus Triamcinolone in an Athymic Nude Mouse Model. Plastic and Reconstructive Surgery, 143, 760-767. https://doi.org/10.1097/PRS.0000000000005323
[72]
Liu, D.Q., Li, X.J. and Weng, X.J. (2017) Effect of BTXA on Inhibiting Hypertrophic Scar Formation in a Rabbit Ear Model. Aesthetic Plastic Surgery, 41, 721-728. https://doi.org/10.1007/s00266-017-0803-5
[73]
Lee, B.J., et al. (2009) Effect of Botulinum Toxin Type a on a Rat Surgical Wound Model. Clinical and Experimental Otorhinolaryngology, 2, 20-27. https://doi.org/10.3342/ceo.2009.2.1.20
[74]
Niessen, F.B., et al. (1999) On the Nature of Hypertrophic Scars and Keloids: A Review. Plastic and Reconstructive Surgery, 104, 1435-1458. https://doi.org/10.1097/00006534-199910000-00031
[75]
Grotendorst, G.R. (1997) Connective Tissue Growth Factor: A Mediator of TGF-β Action on Fibroblasts. Cytokine & Growth Factor Reviews, 8, 171-179. https://doi.org/10.1016/S1359-6101(97)00010-5
[76]
Duncan, M.R., et al. (1999) Connective Tissue Growth Factor Mediates Transforming Growth Factor Beta-Induced Collagen Synthesis: Down-Regulation by cAMP. The FASEB Journal, 13, 1774-1786. https://doi.org/10.1096/fasebj.13.13.1774
[77]
Weston, B.S., Wahab, N.A. and Mason, R.M. (2003) CTGF Mediates TGF-Beta-Induced Fibronectin Matrix Deposition by Upregulating Active Alpha5beta1 Integrin in Human Mesangial Cells. Journal of the American Society of Nephrology, 14, 601-610. https://doi.org/10.1097/01.ASN.0000051600.53134.B9
[78]
Abreu, J.G., et al. (2002) Connective-Tissue Growth Factor (CTGF) Modulates Cell Signalling by BMP and TGF-Beta. Nature Cell Biology, 4, 599-604. https://doi.org/10.1038/ncb826
[79]
Igarashi, A., et al. (1996) Connective Tissue Growth Factor Gene Expression in Tissue Sections from Localized Scleroderma, Keloid, and Other Fibrotic Skin Disorders. Journal of Investigative Dermatology, 106, 729-733. https://doi.org/10.1111/1523-1747.ep12345771
[80]
Lasky, J.A., et al. (1998) Connective Tissue Growth Factor mRNA Expression Is Upregulated in Bleomycin-Induced Lung Fibrosis. American Journal of Physiology, 275, L365-L371. https://doi.org/10.1152/ajplung.1998.275.2.L365
[81]
Paradis, V., et al. (1999) Expression of Connective Tissue Growth Factor in Experimental Rat and Human Liver Fibrosis. Hepatology, 30, 968-976. https://doi.org/10.1002/hep.510300425
[82]
Chen, S.J., et al. (1999) Stimulation of Type I Collagen Transcription in Human Skin Fibroblasts by TGF-Beta: Involvement of Smad 3. Journal of Investigative Dermatology, 112, 49-57. https://doi.org/10.1046/j.1523-1747.1999.00477.x
[83]
Uzel, M.I., et al. (2001) Connective Tissue Growth Factor in Drug-Induced Gingival Overgrowth. Journal of Periodontology, 72, 921-931. https://doi.org/10.1902/jop.2001.72.7.921
[84]
Leask, A., Holmes, A. and Abraham, D.J. (2002) Connective Tissue Growth Factor: A New and Important Player in the Pathogenesis of Fibrosis. Current Rheumatology Reports, 4, 136-142. https://doi.org/10.1007/s11926-002-0009-x
[85]
Mustoe, T.A., et al. (2002) International Clinical Recommendations on Scar Management. Plastic and Reconstructive Surgery, 110, 560-571. https://doi.org/10.1097/00006534-200208000-00031
[86]
Derderian, C.A., et al. (2005) Mechanical Strain Alters Gene Expression in an in Vitro Model of Hypertrophic Scarring. Annals of Plastic Surgery, 55, 69-75. https://doi.org/10.1097/01.sap.0000168160.86221.e9
[87]
Ogawa, R. (2008) Keloid and Hypertrophic Scarring May Result from a Mechanoreceptor or Mechanosensitive Nociceptor Disorder. Medical Hypotheses, 71, 493-500. https://doi.org/10.1016/j.mehy.2008.05.020
[88]
Wipff, P.J., et al. (2007) Myofibroblast Contraction Activates Latent TGF-beta1 from the Extracellular Matrix. Journal of Cell Biology, 179, 1311-1323. https://doi.org/10.1083/jcb.200704042
[89]
Kuang, R., et al. (2015) Influence of Mechanical Stimulation on Human Dermal Fibroblasts Derived from Different Body Sites. International Journal of Clinical and Experimental Medicine, 8, 7641-7647.
[90]
Shu, M.G., Han, Y., Yang, L., Zhang, L.X., Xia, W.S., Liu, D. and Guo, S.Z. (2008) The Effect of Mechanical Stress on the Expression of Growth Factor in Human Skin Fibroblasts. Chinese Journal of Aesthetic Medicine, 17, 689-691.
[91]
Carruthers, A. and Carruthers, J. (2001) Botulinum Toxin Type A: History and Current Cosmetic Use in the Upper Face. Seminars in Cutaneous Medicine and Surgery, 20, 71-84. https://doi.org/10.1053/sder.2001.25138
[92]
Silberstein, E., et al. (2018) Effect of Botulinum Toxin A on Muscle Healing and Its Implications in Aesthetic and Reconstructive Surgery. Aesthetic Surgery Journal, 38, 557-561. https://doi.org/10.1093/asj/sjx207
[93]
Gassner, H.G., Sherris, D.A. and Otley, C.C. (2000) Treatment of Facial Wounds with Botulinum Toxin A Improves Cosmetic Outcome in Primates. Plastic and Reconstructive Surgery, 105, 1948-1953. https://doi.org/10.1097/00006534-200005000-00005
[94]
Gassner, H.G. and Sherris, D.A. (2003) Chemoimmobilization: Improving Predictability in the Treatment of Facial Scars. Plastic and Reconstructive Surgery, 112, 1464-1466. https://doi.org/10.1097/01.PRS.0000081073.94689.DB
[95]
Gassner, H.G., et al. (2006) Botulinum Toxin to Improve Facial Wound Healing: A Prospective, Blinded, Placebo-Controlled Study. Mayo Clinic Proceedings, 81, 1023-1028. https://doi.org/10.4065/81.8.1023
[96]
Gassner, H.G., Sherris, D.A. and Friedman, O. (2009) Botulinum Toxin-Induced Immobilization of Lower Facial Wounds. Archives of Facial Plastic Surgery, 11, 140-142. https://doi.org/10.1001/archfacial.2009.3
[97]
Tollefson, T.T., et al. (2006) Botulinum Toxin to Improve Results in Cleft Lip Repair. Archives of Facial Plastic Surgery, 8, 221-222. https://doi.org/10.1001/archfaci.8.3.221
[98]
Choi, J.C., Lucarelli, M.J. and Shore, J.W. (1997) Use of Botulinum A Toxin in Patients at Risk of Wound Complications Following Eyelid Reconstruction. Ophthalmic Plastic and Reconstructive Surgery, 13, 259-264. https://doi.org/10.1097/00002341-199712000-00006
