Neonatal Skin Physiology. Marty Visscher, PhD, Skin Sciences Program Cincinnati Children s Hospital Medical Center May 2011

Transcription

1 Neonatal Skin Physiology Marty Visscher, PhD, Skin Sciences Program Cincinnati Children s Hospital Medical Center May 2011

2 Change the Outcome

3 Why Study Infant Skin? Skin contact is important for the development and care of premature infants.

4 At Birth The infant moves rapidly from a warm, wet, safe womb to a cooler, dry nursery environment. The baby must breathe, eat and maintain body temperature.

5 Roles of the Skin at Birth 1. Protection - barrier to water loss, light and irritants 2. Infection control and immunosurveillance 3. Resilience to mechanical trauma 4. Sensation and tactile discrimination 5. Thermal regulation 6. Acid mantle formation

6 Stratum Corneum Viable Epidermis Dermis Melanocyte Blood Supply Langerhans Cell Stratum Corneum: Physical barrier to irritants Tactile discrimination Acid mantle formation Viable Epidermis: Physical barrier Tactile discrimination Sensation Acid mantle formation Dermis: Resilient foundation Thermal regulation Sensation Blood supply Melanocyte: Protection light Color Langerhans Cell: Barrier - immunological

7 Pigmentary System Melanocytes In lower epidermis basal layer Produce melanin Determine inherent skin color Become activated when the skin is exposed to sunlight (ultraviolet radiation) Transport melanin to shield the living epidermal cells, protecting the DNA. Darkening (tanning) is a result of this process.

8 Pigmentary System The pigmentary system is affected by irritation and inflammation, e.g., from ultraviolet light, chemical irritants, burns, wounds. It may respond by producing more pigmentation (skin darkening) or less pigmentation (skin lightening).

9 Langerhans Cells Located in the viable epidermis below the stratum corneum (SC) Also called antigen presenting cells Part of the immune system and Line of defense if the SC is breached

10 Stratum Corneum Cells corneocytes Lipid bilayers Cells connected by desmosomes, molecular rivets Formed by the viable epidermis Replaced every 14 days

11 Stratum Corneum Has ~ 16 cell layers Thickness microns, about 1/5 as thick as paper Variable thickness depending on body site Mechanically tough, difficult to penetrate Contains antimicrobials lysozyme, lactoferrin, etc. From: The Epidermis, ed. W. Montagna, W.C. Lobitz

12 Stratum Corneum Formation

13 Transepidermal Water Loss (TEWL) Water of respiration normally moves through the stratum corneum from below. The rate of transepidermal water loss (TEWL, g/m 2 /hr) is a measure of skin barrier integrity TEWL is higher (faster) when the barrier is damaged.

14 Full Term Infant Skin Healthy infants Well-formed stratum corneum..note multiple layers Thick epidermis Structural proteins present in the dermis

15 Full-Term Newborn SC Barrier TEWL very low at birth 4-6 g/m 2 /hr remains low over month 1 lower than adult values of 6-8 g/m 2 /hr TEWL, g/m 2 /hr Day 1 Day 7 Day 28 Adult

16 Biological Question How does the infant develop excellent skin while soaking in water and urine before birth?

17 Long-Term Water Exposure Water Immersion Foot: Skin Damage from Long- Term Water Exposure Newborn Infant: Exquisite Skin

18 SC Damage from Water Exposure Water exposure disrupts the lipid bilayers between the corneocytes. Holes or defects are created and damage continues. SC formation or repair of damage cannot occur.

19 SC Formation The stratum corneum forms during the last trimester. Infants born too early, at 23 or 24 weeks, have little if any SC. Their TEWL is very high, ~ 75 g/m 2 /hr, similar to values with no barrier

20 SC Formation Dry Conditions When the epidermis (no SC) is exposed to dry conditions, e.g., normal humidity, the stratum corneum formation process is triggered. New SC forms to cover the epidermis and eventually has ~ 16 layers. This process occurs for premature infants without a SC.

21 How Does This Occur??? Somehow, the full term infant is born with a welldeveloped and fully functional stratum corneum in a water environment. Consider Vernix Caseosa

22 Vernix Composition Water: 80.5% Proteins: 10.3% Lipids: 9.1% Other lipids: 6.4% Barrier lipids: 2.7% Pickens WL, et. al. J Invest Dermatol (2000) 115(5): Hoeger PH, et. al. Br J Dermatol (2002) 146(2):

23 Vernix Structure Corneocytes imbedded in an amorphous lipid matrix. Corneocytes are swollen with lower keratin density than adult cells. No desmosomes are observed between the corneocytes Fluid, not rigid like SC Pickens WL, et. al. J Invest Dermatol (2000) 115(5): Hoath SB et al. Int J Cosmet Sci (2006) 28(5):

24 Vernix Lipids Vernix contains non-polar and polar lipids: triglycerides, sterol esters, wax esters, squalene, cholesterol, free fatty acids, ceramides Lipid compositions of vernix and SC are shown in b with the ceramides in c Rissman R, et. al. J Invest Dermatol (2006) 126(8):

25 Ontogeny of Vernix During gestation, vernix starts to appear on the brow around the hair. Full term newborns are often covered with vernix at birth.

26 Infant Skin in Utero Stratum corneum not yet formed Hair Follicle Sebaceous Gland

27 Vernix Production in Utero Vernix caseosa coats the epidermis in utero starting around the hair follicle. Over time, the SC continues to form Then, it spreads over the epidermal surface between the individual hairs.

28 Vernix Research Findings Native vernix is a multifunctional skin cream with the following properties Skin moisturizer Anti-infective Anti-oxidant Skin cleanser Skin repair and wound healing, semipermeable Barrier protectant, e.g. against enzymes

29 Vernix Retained Skin was: Moisture Accumulation Rate (cru/sec) Under Probe Occlusion p < 0.05 * Initial Vernix OFF: Back Vernix ON: Back * p < hours 1..more hydrated Skin Erythema Grade Vernix ON Back at Birth Chest at Birth * * Vernix OFF 2. less erythematous Vernix OFF: Back Vernix ON: Back 3..of lower skin ph Skin Surface ph p < 0.05 * p < 0.05 * Visscher, Hoath, et al., J Perinatology, 2005; 25: Initial 24 hours

30 Vernix: Cleanser Finger and forearm skin was soiled (top row). Treatment with vernix was effective for removing the soil particularly from ridges, furrows and hair follicles. Moraille R, et. al., Biol Neonate (2005) 87:8-14.

31 Vernix: SC Barrier Repair Wounds were made at 25 microns of laser energy. Vernix and petrolatumbased cream (PBC) had greater recovery than no treatment, day 2 (p < 0.05). PBC had directionally faster recovery than both others on day 7 (p = 0.06). Visscher M, et. al. Skin Physiol Pharmacol (In Press).

32 Vernix: SC Barrier Repair Vernix contains fatty acids, including oleic, linoleic and long chain species. Fatty acids, particularly linoleic, activate peroxisome proliferator-activated receptor-a (PPARa) which increases the rate of SC barrier formation. Linoleic acid has anti-inflammatory properties which may favorably impact SC repair or development. Tollin M., et. al. Cell Mol Life Sci. 2005;62(19-20): Rissmann R., et. al. J Invest Dermatol. 2006;126(8): Darmstadt G., et. al. Acta Paediatr. 2002;91(5): Schurer N. Contact Dermatitis. 2002;47(4):

33 Vernix: Enzyme Penetration Films of vernix impeded the penetration of the exogenous enzyme chymotrypsin (found in meconium, similar proteolytic enzymes present in feces) in vitro. Additionally, vernix films maintained the activity of native enzymes which are necessary for epidermal development. Tansirikongkol A, et. al. Pediatr Res 2007;62:49-53

34 Implications Overall, vernix facilitates SC development in normal, full term infanst through a variety of protective and adaptive mechanisms. The findings provide support for the practice of vernix retention at birth. The World Health Organization recommends that vernix be retained and bathing delayed for at least 6 hours.

35 What Happens After Birth???? Full Term Infants Premature Infants

36 Full-Term Skin Adaptation The SC undergoes a rapid transition at birth. The water handling behavior changes significantly over the first month. By one month, the moisture accumulation rate is significantly higher for the infant vs. mother. Visscher, Hoath, et al., Pediatr Dermatol, 2000; 17(1):45-51.

37 Full-Term Skin Adaptation Newborn skin has significantly lower hydration than infants at 1, 2 and 6 months and their mothers. The changes in hydration and water binding indicates that the skin is adapting to the new environment. Nikolovski J, et. al. J Invest Dermatol (7):

38 Importance of Hydration Adequate stratum corneum hydration is essential for plasticity and flexibility during movement to prevent cracking for desquamation of the outermost layer Blank. J Invest Dermatol. 1952;18: Gloor M. et. al. Hautarzt. 1998;49(1):6-9.

39 Low Skin Hydration: Potential Explanations 1. Rapid change from high to low humidity at birth may initiate changes such as the proteolysis of filaggrin to natural water binding molecules known as moisturizing factor (NMF). 2. Extensive exposure to amniotic fluid may extract water binding molecules (NMF) from newborn skin. Robinson M.,et. al. Journal of Cosmetic Science. 2010;62: Visscher M, et. al. Pediatr Dermatol. 2002;19(6). Scott I., et. al. Dev Biol. 1986;115(1):84-92.

40 Water Binding Free Amino Acids Free amino acid (FAA) levels are very low at birth and then increase significantly over the first month (p < 0.05). FAAs are substantially lower in infants at one month of age than in adults (p < 0.05). Visscher, et al., Pediatr Dermatol, 2011; 28(2):

41 Free Amino Acids: Effect of Vernix Vernix retention resulted in significantly higher FAA levels after birth versus infants with it removed. Free amino acids in vernix retained skin appear to originate from vernix itself. Visscher, et al., Pediatr Dermatol, 2011; 28(2):

42 Summary 1. FAA production may be initiated with high-tolow humidity transition in the neonatal period. 2. The low levels of FAA in neonatal foreskin is consistent with reports that 100% humidity blocks filaggrin proteolysis (animals). 3. Retention of FAA containing vernix appears to facilitate increased hydration and ph reduction at birth. Visscher, et al., Pediatr Dermatol, 2011; 28(2): Scott I., et. al. Dev Biol. 1986;115(1):84-92.

43 Newborn Skin Adaptation: ph Skin ph nearly neutral at birth. Rapid decrease during first 4 days. Regional differentiation with lower ph for nondiaper site. Visscher, Hoath, et al., Pediatr Dermatol, 2000; 17(1):45-51.

44 Importance of an Acidic SC ph An acidic ph is required for SC cell cohesion contributes to the SC innate immune function by inhibiting colonization of pathogens, e.g., S. aureus. is necessary for the effective functioning of enzymes in SC formation and integrity, i.e.: lipid metabolism, bilayer structure, ceramide synthesis, desquamation Schmid-Wendtner, et. al., Skin Pharmacol Physiol, 2006, 19: Rippke F, et. al., Am J Clin Dermatol 2002, 3: Fluhr, et al, J Invest Dermatol. 2001, 117: Elias, PM, Semin Immunopathol. 2007, 29:3-14.

45 Premature Infant Skin

46 Premature Infant Skin Stratum corneum poorly developed or absent Thin epidermis Dermis not fully formed and deficient of structural proteins

47 Significance 1. NICU patients at risk for skin breakdown Prematurity, irritants (e.g., feces), stress 2. Epidermis is less well developed in premature vs full term neonates 3. Skin breakdown can result in Infection, fluid loss, discomfort, stress, delay in start of oral feeding, anxiety for caregivers and families

48 Premature SC Barrier Premature infant skin barrier integrity varies greatly with gestational age. TEWL for wks gestation is very high, comparable to epidermis without a SC barrier. Premature Infants Sedin et al., Acta Paediatr Scand Suppl, 1983, 305:

49 Hydration Premature SC Development Premature infants experience high fluid loss, thermal instability, electrolyte imbalance. However, the SC barrier forms rapidly after birth. Surface hydration decreases over a few days. Okah, Wickett, Pickens, Hoath, Pediatrics, 1995, 96(4):

50 Premature SC Barrier Development At one month post birth, TEWL is significantly higher for the preterm infant than for the full term newborn. May lead to increased susceptibility to infection and penetration of exogenous agents. Agren et al, Acta Paediatr Scand, 1999, 72(5):

51 Premature Barrier Development Effect of humidity Premature infants wks GA Incubator at ~80% RH for first week Randomized to 75% or 50% thereafter SC barrier maturation was more rapid at 50% vs 75% RH Agren et al, J Pediatrics, 2006, 148:613-7.

52 TEWL (g/m2/hr) Premature Barrier Maturation Case study report on 10 infants aged wks at birth GA = 23 weeks TEWL decreased and conductance increased over time. Proposed a maturation time of 9 weeks TEWL for Full Term Infants Postnatal Age (days) Kalia et al., J Invest Dermatol, 1998, 111:

53 Premature Skin Adaptation: ph Skin ph profile for the mature infant varies with gestational age. Initial ph drop was observed in both groups. Smaller babies have a higher ph for a longer time. Fox, et al, J Perinatology, 1998, 18(4):

54 Chest Skin ph: Adaptation Chest Skin ph Over Time Chest skin ph decreased significantly over 14 days. Skin ph over time was influenced by age at birth and time from birth. Neonatal skin continues to change long after birth, presumably as it adapts to the dry environment. Chest Skin ph * Day of Study Indicates difference for day 1 versus day 14 by paired t-test Total Group * * * All Infants in trial for 14 days GA < 38 At Start < 38 GA < 38 At Start > 38 Day 1 Day 14 p = p = p = GA > 38 At Start > 38 Subgroup by GA Birth and Age at Start (wks) Visscher, Odio et al. Neonatology (2009) 96:

55 Involucrin pg/mg protein Keratin 1,10,11 ng/mg protein Biomarkers of Innate Immunity ** * * Adult Full Term Infant Premature Infant 0 Adult Full Term Infant Premature Infant Involucrin was higher in Preterms than full terms both infant groups versus adults. Keratin 1,10,11 higher in adults than infants Narendran, Hendrix, et al., Pediatric Research, 2010;67:382-6.

56 Cytokine Level pg/ug protein Cytokine Level pg/ug protein Biomarkers of Innate Immunity IL6 IL8 * # * # # IL1a TNFa X Adult Full Term Preterm 0 Adult Full Term Preterm IL6 and IL8 were higher in preterms than full terms IL1a was higher in both infant groups than adults and may be a marker of barrier maturation. Narendran, Hendrix, et al., Pediatric Research, 2010;67:382-6.

57 Skin Integrity in NICU Patients

58 Skin Compromise Damaged Barrier Irritants Have Entered Irritants act on living cells Mediators increase erythema via vasculature Cells release mediators of inflammation

59 Skin Compromise Skin barrier with defects Water & cleansers disrupt lipid structure Irritants can penetrate Microorganisms can enter to reach the Langerhans cells and epidermis

60 Diaper Skin Compromise Diaper skin can be damaged by: over-hydration urine feces friction increased skin ph diet medications Fecal enzymes can degrade SC proteins and cause inflammation

61 Stratum corneum: cells, lipids, rivets Skin Compromise Water, harsh cleansers damage lipids 1 4 Enzymes: Degrade SC proteins Prematurity: fewer SC layers Excess rubbing strips skin Net: Irritants penetrate to the epidermis and cause inflammation

62 Skin Barrier Repair after Damage Normal Skin Barrier Uniform size Regular structure Cells connected Abnormal Skin Barrier Defective formed too fast Dry with large scales

63 Skin Compromise: Stress Stress Reduced integrity due to decreased cell proliferation: fewer layers lipid synthesis desmosomes (cell connections) Decreased antimicrobial agents Increased skin infection Delayed barrier recovery & wound healing Choi, et. al. J Invest Dermatol (2005);124: Aberg, et al. J Clin Invest (2007);117(11):

64 The Skin Brain Connection 1. Skin and brain are both derived from ectoderm during gestation 2. Evidence for a brain-skin axis Mast cells, substance P, nerve growth factor An HPA axis within the skin that makes: CRH, ACTH, Cortisol 3. A. Slominski: The skin runs the brain. Paus, et al. Trends Immunol (2006);27(1): Ito, et al. FASEB J (2005);19(10: Slominski, et al. FESB Lett (1995);374(1):113-6.

65 Skin Nerve Response Physical stimuli Trauma, mechanical, heat, cold Osmotic changes, hydration changes Hydration changes Chemical stimuli Irritants, toxins, allergens, microbes Enzymes Inflammatory mediators ph changes Responses Pain, Burning, Stinging, Itch

66 Cutaneous Nerve Endings Note that the nerve endings are not exposed to the environment. Sensory signal receptors are expressed in the keratinocytes. Denda M, et al. Experimental Dermatology (2007);16:

67 Keratinocyte Response Damaged Barrier Heat activates receptors TRPV1 delays barrier repair TRPV4 enhances repair Net, cells (keratinocytes) sense and respond to environmental, i.e., threatening, effects the communicate to the nervous system Denda M, et al. Experimental Dermatology (2007);16:

68 Questions????????