Almost exactly a year ago, I wrote in the introduction to an article on skin rejuvenation1 that topical growth factors were all the rage as far as the cosmeceuticals industry and the media were concerned. What was true then is even more so now, as progressively more skin creams containing growth factors become available for in office dispensing. As I wrote then, the challenge we face as clinicians is to separate the wheat from the chaff and to offer our patients something more than the “promise in a jar” that they may have already obtained many times over from drugstores and department store beauty counters prior to consulting with us.

Our current understanding of skin aging is that ithas an extrinsic component that is primarily due toultraviolet (UV) light exposure, and an intrinsic componentdue to the inherent oxidative metabolism ofskin cells [Fig. 1]. The rationale for applying growthfactors to the skin is to replenish natural levels ofgrowth mediators, which tend to decline with age,and to increase the production of extracellularmatrix (ECM). Antioxidants, peptides, and retinoidsmay be added to synergistically augment the effects.Antioxidants prevent free radical (reactive oxygenspecies) overload and provide anti-inflammatory,anti-matrix metalloproteinase (MMP) and anti-glycationeffects. Peptides induce ECM production andhave signaling and mimicking functions. Retinoidsinduce the production of ECM and increase cellturnover. In selecting effective skin rejuvenation formulationsfor our patients, it is helpful to considersome strategies for scientific selection of these antiagingactives.

Strategy 1: Know How Your Growth factors Are Made
Growth factor mixtures may be harvested aftersecretion by cultured fibroblasts into the medium inwhich they are grown. Alternatively, they may beharvested by lysis of fibroblasts. A third manufacturingmethod is to utilize recombinant technology tosynthesize individual growth factors that may thenbe used alone or in combination. Given the complexityof growth factor signaling pathways [Fig. 2],it seems logical that a product containing a physiologicallybalanced mixture of growth factors—in proportions that approximate what is found in livingskin—would be more effective than a product containinga single, synthetic growth factor. The idealmanufacturing method should optimize the in vivoactivity of growth factors. It should also producegrowth factors in a high enough concentration thatthey can penetrate the uppermost layers of the epidermisand bind to growth factor receptors on keratinocytes,2 causing them to secrete endogenousgrowth factors that in turn can stimulate dermalfibroblasts.2-4 Highly concentrated growth factorsalso tend to be more stable at room temperature.

Strategy 2: Multi-Task With Antioxidants
Antioxidants may be hydrophilic and protectthe ECM (e.g. green tea polyphenols),or lipophilic and protect the cell membrane(e.g. vitamin E and vitamin C esters). It isbeneficial to combine hydrophilic andlipophilic antioxidants. Many antioxidantshave additional effects that enhance theiroverall benefits. For example, blackberryleaf extract is both a free radical fighter inthe water phase and a MMP Inhibitor.Green tea extract is a water-based free radicalfighter and also has anti-inflammatoryeffects. A number of methods are availableto assay anti-oxidant activity. The ORACscore is an in vitro evaluation that determinesthe maximum possible chemicalantioxidant activity, but this may not correspondto in vivo activity. Assays performedwith artificial skin constructs provide ameasure of biologically active antioxidantcapacity and can measure multiple targeteffects simultaneously. However, the physiologicalrelevance of this assay is questionable.The most physiologically relevantmethod of determining antioxidant activitymay be to measure protection of the skinfrom UV-induced erythema. This is a noninvasive,in vivo clinical evaluation thatmeasures the diminishing or blocking ofreactive oxygen species after test skin sitesthat are either untreated or treated with atopical antioxidant formulation are exposedto UVA and UVB radiation. This radiation is suppliedby an artificial source with UV range comparable tothat of natural sunlight.1

Strategy 3: Choose Less Irritating Retinoids
The biological activity of retinoids is mediated via several pathways, including the stimulation of collagengene expression in skin,5 increased cellturnover via retinoid binding to the nuclearPPARβ/δ receptor, and decreased cell proliferationvia the nuclear RAR receptor. Retinoic acid hasbeen shown to reverse UV-mediated loss of procollagen, most probably via the activation or stimulationof TGFβ-mediated pathways which induceexpression of collagen genes.5,7 The retinoic acidanalog, all-trans retinoic acid (tretinoin) is the primaryretinoid used for skin repair. It binds directlyto intracellular retinoic acid receptors, as doother retinoic acid analogs such as adapalene andtazarotene. Retinoids including beta carotene,retinol, retinyl palmitate, retinyl acetate and retinaldehydeare metabolized to retinoic acid, whichthen binds to intracellular retinoic acid receptors[Fig. 3].

Retinoids all have similar end results, but thespeed of results and associated skin irritation vary.Many patients seeking topical rejuvenative therapiesmay not be able to tolerate prescriptionstrength retinoids. Thus a sustained release, lowconcentration tretinoin (e.g. 0.02%) or slow actingretinol esters (e.g. retinyl palmitate or encapsulatedretinol) may be better for daily cosmetic use.The activity of retinol and retinyl esters is about10 percent of that of tretinoin. However, a 10-foldhigher level of retinol is more tolerable for dailycosmetic use. It is postulated that long term use of0.2% retinol may produce a clinical effect that issimilar to 0.02% tretinoin, but with a lower risk ofskin irritation. Clinical improvement in skin dryness,roughness, fine lines, skin texture and skinlaxity has been demonstrated after application of a0.15% retinol cream for three months.6

Next month: Picking proven peptides, knowing when to lumpand when to split, and considering the whole formulation.