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Neurotoxins and Fillers for Skin Rejuvenation Jessica Mayor, BS1

Lisa Grunebaum, MD2

1 Department of Otolaryngology, University of Miami Miller School of

Medicine, Miami, Florida 2 Division of Facial Plastic and Reconstructive Surgery, University of Miami Miller School of Medicine, Miami, Florida

Address for correspondence Lisa Grunebaum, MD, Division of Facial Plastic and Reconstructive Surgery, University of Miami Miller School of Medicine, Miami, FL 33136 (e-mail: [email protected]).

The ephemeral effects of neurotoxins and fillers are well described for facial remodeling and rejuvenation. Less is known about their long-term effects on skin rejuvenation and neocollagenesis. This article aims to review current available science and literature to support the use of these cosmetic procedures as lasting antiaging treatments.

Abstract Keywords

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fillers neurotoxins rejuvenation antiaging

Facial injections of various substances are increasingly popular cosmetic treatments aimed at improving the appearance of facial lines, folds, and volume depletion associated with aging. For the most part, injectables are considered shortterm solutions and relatively little is known about the potential of these materials in more permanent skin rejuvenation and rhytid improvement. Recently, more research has focused on this aspect. In particular, neocollagenesis as a marker of skin rejuvenation has received attention. This article aims to review available information on injectable materials in this context.

Botulinum Toxin A Food and Drug Administration (FDA) approval of Botox Cosmetic (Allergan, Irvine, CA) for the treatment of glabellar lines was granted in 2002. Botulinum toxin A (BTA) injections have become the most common cosmetic treatment in the United States. According to the American Society of Plastic Surgeons, Botox Cosmetic injections were the most popular minimally invasive procedure in the United States in 2012 with 6.1 million procedures, up 8% from 2011.1 Yet, there are little published data on the effects of BTA in long-term rejuvenation rather than the well described shorter term effects on wrinkle reduction. One study described two patients who had received regular BTA treatments over a 7-year period and noted an improvement in skin quality with effacement of nonreducible forehead lines, suggesting epidermal remodeling over the treatment period.2 In one split-face trial, half

Issue Theme Classical and State-of-theArt Skin Rejuvenation; Guest Editors, Lisa D. Grunebaum, MD, and Noëlle S. Sherber, MD, FAAD

faces were treated with injections of BTA and the other with normal saline; while the BTA side showed a moderate wrinkle soothing effect for at least 8 weeks, histologically, there was slight neocollagen synthesis bilaterally.3 Similarly, a second split-face study with BTA and normal saline found global improvement in skin texture and tightness on both sides; the authors hypothesize that these benefits to neocollagenesis are secondary to the trauma induced by needle pricks, which were equal bilaterally.4 BTA has been examined in several studies for the treatment of excessively oily skin. The majority of patients with oily skin injected with intradermal BTA had reduction in sebum production and pore size with high levels of patient satisfaction.5,6 This preliminary research indicates that there are other possibilities for the use of BTA in the improvement of skin appearance. In the coming years, as more and more patients become long-term BTA users, more data will become available to help increase our understanding of the role BTA has is the reversal of aging.

Alpha Hyaluronic Acid Nonanimal, stabilized α hyaluronic acid (NASHA) is the most commonly used facial filler, accounting for 2 million procedures in 2012.1 In contrast to some of the other materials discussed, there is direct evidence that NASHA increases collagen synthesis in aged skin. Quan et al injected NASHA into the buttock skin of patients older than 70 years of age and

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DOI http://dx.doi.org/ 10.1055/s-0033-1363760. ISSN 0736-6825.

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Neurotoxins and Fillers for Skin Rejuvenation

Poly-L-Lactic Acid In 2004, poly-L-lactic acid (PLLA) was FDA approved for the treatment of human immunodeficiency virus (HIV)-related lipoatrophy. This effect is well described.9 Regarding skin rejuvenation, patients with HIV-related lipoatrophy who received one PLLA injection per month for a total of five injections had an average increase in dermal subcutaneous thickness of 3.5 mm measured 24 weeks after the last treatment.10 Another study found that the increase in skin thickness of 65.1% compared with baseline was maintained over 12 months.11 Valantin et al documented the changes in the effect of four sets of PLLA injections in patients with HIVrelated lipoatrophy over time. The total cutaneous thickness from baseline rises during the first 4 years after treatment, plateaus, and then begins to decline after 8 years.12 This is similar to another study that found three sets of PLLA injections yielded gradual results that take approximately 12 weeks to reach maximum effect.13 The proportion of patients with total cutaneous thickness greater than 10 mm peaked at 4 years posttreatment with 61% of patients; the baseline increase for these patients ranged from 0 to 2.1 mm pretreatment.12 Eight years posttreatment, the effect was maintained in 43% of patients.12 In addition, there is evidence that the effect of PLLA may last longer than other dermal fillers. In a randomized, multicenter, patient-blinded study in immunocompetent patients, effects of PLLA lasted 25 months after treatment, while the effects of collagen disappeared after 13 months; all posttreatment scores were higher in the PLLA group than the collagen group.14 The mechanism by which PLLA contributes to skin rejuvenation has been proposed. As a result of normal foreign body reaction, PLLA particles initiate neocollagenesis; over time, this accumulation of collagen creates volume, while the PLLA is metabolized into carbon dioxide and water.15 In a mouse model, PLLA was injected subcutaneously and later removed surgically; the tissue response was characterized by macrophages, proliferating fibroblasts, and vascularized fibrous capsules.16 Overall, dermal injections of PLLA have produced promising results with few negative side effects and high levels of

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patient satisfaction. However, the majority of the research has been in patients with HIV-related lipoatrophy; therefore, more research needs to be done to evaluate the effects of PLLA injections in normal and aged skin. HIV-positive patients are immunocompromised by definition and the dermal reactions to PLLA may have an immune modulated component.

Calcium Hydroxylapatite Calcium hydroxylapatite (CaHa) is another popular semipermanent filler. Skin biopsies of three subjects injected with CaHa contained evidence of CaHa particles present 6 months posttreatment and of new collagen formation.17 Two large studies show clear patient preference and improved longevity when comparing NASHA to CaHa. The authors entertain the concept that increased longevity may have a greater effect on neocollagenesis and consequently skin rejuvenation; however, this remains unproven.18,19

Autologous Platelet Products Platelet-rich products have the potential to be useful in the reversal of dermal aging. Platelets release growth factors and other substances that promote tissue repair such as vascular endothelial growth factor, TGF-β, and platelet-derived growth factor.20 In animal models, platelet-rich plasma (PRP) has been shown to accelerate epithelial differentiation and regeneration in previously nonhealing wounds in both soft and hard tissues.21,22 In addition, anecdotal evidence exists regarding the use of autologous platelet products in several areas of medicine including orthopedics, ophthalmology, plastic surgery, and dentistry.20 For example, in one study of knee arthroplasty procedures, the use of PRP was associated with better hemostasis of the surgical wound, improved pain control, and shorter hospital stay.23 In full thickness dermal wounds, closure was hastened with the addition topical PRP.24 Therefore, there may be broad potential for various applications of PRP and other platelet-rich products in healing. However, few informative basic science studies have been done investigating the potential effects of platelet-rich products on aged skin. In dermal cell culture, PRP stimulated fibroblast proliferation and increased expression of type I collagen, matrix metalloproteinases, and messenger RNA; this suggests that PRP may have the potential to promote tissue remodeling in aged skin.25 In vivo, injecting PRP into ultraviolet-b–induced skin wrinkles in a murine model was found to thicken the dermis, increase fibroblast proliferation and collagen production, and reduce the appearance of the wrinkles.26 Furthermore, there are a few studied applications of PRP for skin rejuvenation. One study evaluated PRP in combination with laser. Topical application of autologous PRP after erbium fractional laser therapy for facial acne or acne scars resulted in 90.9% of patients with improvements greater than 50% after three treatments.27 In addition, when compared with laser treatment alone, the addition of topical PRP after fractional CO2 resurfacing was found to hasten recovery of Facial Plastic Surgery

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later took biopsies of this skin. They found increased fibroblast proliferation, expanded vasculature, and increased epidermal thickness; they hypothesized that the NASHA stiffens the extracellular matrix, induces fibroblast elongation and activation, and the upregulation of the transforming growth factor (TGF)-β pathway leading to collagen synthesis.7 Injection of cross-linked collagen into aged, photodamaged forearm skin stimulates collagen production; this effect is thought to be at least partially due to mechanical stretching of the dermis and fibroblasts.8 Interestingly, the fibroblasts did not bind to the NASHA, suggesting that the NASHA may not directly stimulatory.8 Perhaps similar to the needle injections of BTA, the mechanical forces created after injection of NASHA may be the stimulus for collagen synthesis rather than a unique property of the NASHA itself.

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transepidermal water loss, thicken collagen bundles, decrease erythema, and reduce signs of postinflammatory hyperpigmentation.28 In another study, patients treated with fractional laser and topical PRP had high scores of patient satisfaction, increased skin elasticity, and decreased erythema index when compared with those patients treated with laser only. Histologically, combination treatment patients had increased amount of collagen, number of fibroblasts, and length of dermoepidermal junction.29 PRP has been used as a combination therapy with laser as an intradermal treatment. In a split-face trial with ablative CO2 fractional laser, the side of the face treated with intradermal injections of PRP after laser treatment was found to resolve edema and erythema faster and reduce posttreatment crusting.30 Although the literature to support its use remains limited, PRP in combination with laser therapy is likely safe and may enhance recovery of laser-treated skin. PRP has been studied as an adjuvant to fat grafting. In rabbits, the injection of the upper lip with fat plus PRP resulted in decreased inflammation, fewer oil cysts, and increased maintenance of the transplanted fat cells.31 In a series of patients with soft tissue deficits of the face, 0.3 to 0.5 mL of PRP mixed with 1 mL of centrifuged fat results were maintained at 18 months posttreatment with high level of patient satisfaction.32 Although these two studies indicate that the combination of PRP with fat may yield better results than fat grafting alone, there is some evidence suggesting that plateletrich fibrin is more effective than PRP; in fact, in a split-face trial, there was greater reabsorption of the grafted fat on the PRPtreated side than on the platelet-rich fibrin side.33 Injection of platelet-rich products into the skin is a third method for the use of these materials. For the treatment of nasolabial folds, long-term diminution of wrinkles measured by the physician wrinkle assessment scale and the patient global aesthetic improvement scale was achieved with the injection of a platelet-rich fibrin matrix into the dermis and subdermis.34 In 23 additional patients, PRP was injected once monthly for three treatments, with satisfactory results with no persistent side effects.35 Because this material is not foreign to the body, it may be a more ideal filler than some of those that are currently on the market; however, there is much to be learned regarding whether there is any reversal of aging occurring as a result of these injections.

large rhytids or facial scars treated with three injections of autologous fibroblasts; histologically, dermal collagen had increased thickness and density.37 These studies demonstrate that the dermal changes induced by autologous fibroblasts are not only evident microscopically but also to the naked eye. In the treatment of nasolabial folds, statistically significant rates of improvement on both subject and evaluator wrinkle assessment scales were recorded in patients treated with autologous fibroblast injections versus placebo.38 Interestingly, Smith et al observed that the time required to see improvements with autologous fibroblast treatments is longer than that for fillers that provide direct volume replacement. Statistically significant changes were seen as early as 2 months after initiating treatment, but the researchers found the greatest rate of improvement between 2 and 6 months following treatment.38 In evaluating autologous fibroblast injections versus placebo injections in the same study, 48% of subjects treated with placebo achieved at least a one-point improvement on the subject assessment at 6 months (p < 0.001), and 64% of subjects treated with autologous fibroblast therapy and 36% of those treated with placebo showed at least a one-point improvement evaluator’s assessment (p < 0.001) The exact mechanism of action of injected autologous fibroblasts has yet to be elucidated; however, it is likely a combination of direct secretion of elastic and collagen, secretion of cofactors, or multiplication of the transplanted fibroblasts.38–40 In addition, again, the authors suggest that the placebo effect may be accounted for simply by the mechanical stretch induced by volumetric injection.

Autologous Fibroblasts

References

Fibroblasts are responsible for the production of dermal constituents, and some work has been done evaluating the effects of autologous fibroblasts on dermal rejuvenation. Autologous fibroblasts have recently been FDA approved under the marketed name LAVIV (Fibrocell Science, Exton, PA). A randomized, double-blind study comparing autologous fibroblast injections versus placebo found statistically significant improvements in appearance of facial contour defects 6 months after treatment with continued benefit at 9 and 12 months posttreatment with no significant adverse effects.36 Using before-and-after silicone molds and optical profilometry, topographical improvements were found in Facial Plastic Surgery

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Conclusion In summary, most of the evidence regarding facial injectables and dermal rejuvenation is preliminary and anecdotal yet shows promise. More research should be done examining each material both in vivo and histologically to determine the potential each has to rejuvenate aged or sun-damaged skin. This research could change the way practitioners and patients view and use dermal injectables. If one or multiple injectable materials are approved for both rhytid effacement and dermal rejuvenation, the market for these procedures will only continue to grow.

1 Reath D. ASPS annual statistics: plastic surgery in 2012. American

Society of Plastic Surgeons. February 19, 2013. 2 Bowler PJ. Dermal and epidermal remodeling using botulinum

toxin type A for facial, non reducible, hyperkinetic lines: two case studies. J Cosmet Dermatol 2008;7(3):241–244 3 Chang SP, Tsai HH, Chen WY, Lee WR, Chen PL, Tsai TH. The wrinkles soothing effect on the middle and lower face by intradermal injection of botulinum toxin type A. Int J Dermatol 2008; 47(12):1287–1294 4 Kapoor R, Shome D, Jain V, Dikshit R. Facial rejuvenation after intradermal botulinum toxin: is it really the botulinum toxin or is it the pricks? Dermatol Surg 2010;36(Suppl 4):2098–2105 5 Shah AR. Use of intradermal botulinum toxin to reduce sebum production and facial pore size. J Drugs Dermatol 2008;7(9): 847–850

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of botulinum toxin for the treatment of oily skin. Dermatol Surg 2013;39(3 Pt 1):443–448 Quan T, Wang F, Shao Y, et al. Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo. J Invest Dermatol 2013;133(3):658–667 Wang F, Garza LA, Kang S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol 2007;143(2):155–163 Fitzgerald R, Vleggaar D. Facial volume restoration of the aging face with poly-l-lactic acid. Dermatol Ther 2011;24(1):2–27 Guaraldi G, Orlando G, De Fazio D, et al. Comparison of three different interventions for the correction of HIV-associated facial lipoatrophy: a prospective study. Antivir Ther 2005;10(6): 753–759 Mest DR, Humble G. Safety and efficacy of poly-L-lactic acid injections in persons with HIV-associated lipoatrophy: the US experience. Dermatol Surg 2006;32(11):1336–1345 Valantin MA, Aubron-Olivier C, Ghosn J, et al. Polylactic acid implants (New-Fill) to correct facial lipoatrophy in HIV-infected patients: results of the open-label study VEGA. AIDS 2003;17(17): 2471–2477 Moyle GJ, Lysakova L, Brown S, et al. A randomized open-label study of immediate versus delayed polylactic acid injections for the cosmetic management of facial lipoatrophy in persons with HIV infection. HIV Med 2004;5(2):82–87 Brandt FS, Cazzaniga A, Baumann L, et al. Investigator global evaluations of efficacy of injectable poly-L-lactic acid versus human collagen in the correction of nasolabial fold wrinkles. Aesthet Surg J 2011;31(5):521–528 Simamora P, Chern W. Poly-L-lactic acid: an overview. J Drugs Dermatol 2006;5(5):436–440 Gogolewski S, Jovanovic M, Perren SM, Dillon JG, Hughes MK. Tissue response and in vivo degradation of selected polyhydroxy acids: polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA). J Biomed Mater Res 1993;27(9):1135–1148 Marmur ES, Phelps R, Goldberg DJ. Clinical, histologic and electron microscopic findings after injection of a calcium hydroxylapatite filler. J Cosmet Laser Ther 2004;6(4):223–226 Anitua E, Andia I, Ardanza B, Nurden P, Nurden AT. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost 2004;91(1):4–15 Moers-Carpi M, Vogt S, Santos BM, Planas J, Vallve SR, Howell DJ. A multicenter, randomized trial comparing calcium hydroxylapatite to two hyaluronic acids for treatment of nasolabial folds. Dermatol Surg 2007;33(Suppl 2):S144–S151 Moers-Carpi MM, Tufet JO. Calcium hydroxylapatite versus nonanimal stabilized hyaluronic acid for the correction of nasolabial folds: a 12-month, multicenter, prospective, randomized, controlled, split-face trial. Dermatol Surg 2008;34(2):210–215 Carter CA, Jolly DG, Worden CE Sr, Hendren DG, Kane CJ. Plateletrich plasma gel promotes differentiation and regeneration during equine wound healing. Exp Mol Pathol 2003;74(3):244–255 Fennis JP, Stoelinga PJ, Jansen JA. Mandibular reconstruction: a clinical and radiographic animal study on the use of autogenous scaffolds and platelet-rich plasma. Int J Oral Maxillofac Surg 2002; 31(3):281–286 Gardner MJ, Demetrakopoulos D, Klepchick PR, Mooar PA. The efficacy of autologous platelet gel in pain control and blood loss in

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total knee arthroplasty. An analysis of the haemoglobin, narcotic requirement and range of motion. Int Orthop 2007;31(3):309–313 Hom DB, Linzie BM, Huang TC. The healing effects of autologous platelet gel on acute human skin wounds. Arch Facial Plast Surg 2007;9(3):174–183 Kim DH, Je YJ, Kim CD, et al. Can platelet-rich plasma be used for skin rejuvenation? Evaluation of effects of platelet-rich plasma on human dermal fibroblast. Ann Dermatol 2011;23(4):424–431 Cho JM, Lee YH, Baek RM, Lee SW. Effect of platelet-rich plasma on ultraviolet b-induced skin wrinkles in nude mice. J Plast Reconstr Aesthet Surg 2011;64(2):e31–e39 Zhu JT, Xuan M, Zhang YN, et al. The efficacy of autologous plateletrich plasma combined with erbium fractional laser therapy for facial acne scars or acne. Mol Med Rep 2013;8(1):233–237 Na JI, Choi JW, Choi HR, et al. Rapid healing and reduced erythema after ablative fractional carbon dioxide laser resurfacing combined with the application of autologous platelet-rich plasma. Dermatol Surg 2011;37(4):463–468 Shin MK, Lee JH, Lee SJ, Kim NI. Platelet-rich plasma combined with fractional laser therapy for skin rejuvenation. Dermatol Surg 2012; 38(4):623–630 Lee JW, Kim BJ, Kim MN, Mun SK. The efficacy of autologous platelet rich plasma combined with ablative carbon dioxide fractional resurfacing for acne scars: a simultaneous split-face trial. Dermatol Surg 2011;37(7):931–938 Rodríguez-Flores J, Palomar-Gallego MA, Enguita-Valls AB, Rodríguez-Peralto JL, Torres J. Influence of platelet-rich plasma on the histologic characteristics of the autologous fat graft to the upper lip of rabbits. Aesthetic Plast Surg 2011;35(4):480–486 Cervelli V, Palla L, Pascali M, De Angelis B, Curcio BC, Gentile P. Autologous platelet-rich plasma mixed with purified fat graft in aesthetic plastic surgery. Aesthetic Plast Surg 2009;33(5):716–721 Keyhan SO, Hemmat S, Badri AA, Abdeshahzadeh A, Khiabani K. Use of platelet-rich fibrin and platelet-rich plasma in combination with fat graft: which is more effective during facial lipostructure? J Oral Maxillofac Surg 2013;71(3):610–621 Sclafani AP. Platelet-rich fibrin matrix for improvement of deep nasolabial folds. J Cosmet Dermatol 2010;9(1):66–71 Redaelli A, Romano D, Marcianó A. Face and neck revitalization with platelet-rich plasma (PRP): clinical outcome in a series of 23 consecutively treated patients. J Drugs Dermatol 2010;9(5): 466–472 Weiss RA, Weiss MA, Beasley KL, Munavalli G. Autologous cultured fibroblast injection for facial contour deformities: a prospective, placebo-controlled, Phase III clinical trial. Dermatol Surg 2007; 33(3):263–268 Watson D, Keller GS, Lacombe V, Fodor PB, Rawnsley J, Lask GP. Autologous fibroblasts for treatment of facial rhytids and dermal depressions. A pilot study. Arch Facial Plast Surg 1999;1(3): 165–170 Smith SR, Munavalli G, Weiss R, Maslowski JM, Hennegan KP, Novak JM. A multicenter, double-blind, placebo-controlled trial of autologous fibroblast therapy for the treatment of nasolabial fold wrinkles. Dermatol Surg 2012;38(7 Pt 2):1234–1243 Lamme EN, Van Leeuwen RT, Brandsma K, Van Marle J, Middelkoop E. Higher numbers of autologous fibroblasts in an artificial dermal substitute improve tissue regeneration and modulate scar tissue formation. J Pathol 2000;190(5):595–603 Spiekstra SW, Breetveld M, Rustemeyer T, Scheper RJ, Gibbs S. Wound-healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes. Wound Repair Regen 2007; 15(5):708–717

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Neurotoxins and Fillers for Skin Rejuvenation

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Neurotoxins and fillers for skin rejuvenation.

The ephemeral effects of neurotoxins and fillers are well described for facial remodeling and rejuvenation. Less is known about their long-term effect...
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