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EFFECT OF ALOE GEL IN ENHANCING DIABETIC WOUND HEALING

EFFECT OF ALOE GEL IN ENHANCING DIABETIC WOUND HEALING. Djanggan Sargowo, Yudha Handaya, Askandar Tjokroprawiro. Brawijaya Medical School Malang. BACKGROUNDS. WAGNER CLASSIFICATION. Grade 0 pre-ulcerative lesion, healed ulcers, presence of bony deformity

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EFFECT OF ALOE GEL IN ENHANCING DIABETIC WOUND HEALING

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  1. EFFECT OF ALOE GEL IN ENHANCING DIABETIC WOUND HEALING Djanggan Sargowo, Yudha Handaya, Askandar Tjokroprawiro Brawijaya Medical School Malang

  2. BACKGROUNDS

  3. WAGNER CLASSIFICATION Grade 0pre-ulcerative lesion, healed ulcers, presence of bony deformity Grade 1superficial ulcer without subcutaneous tissue involvement Grade 2penetration through the subcutaneous tissue (may expose bone, tendon, ligament or joint capsule) Grade 3osteitis, abscess, or osteomyelitis Grade 4gangrene on the forefoot Grade 5 gangrene on the entire foot

  4. WOUND HEALING DISORDERS

  5. DMHyperglycemia↑ ROS  ↑ apoptosisangiogenesis dysfunction (#tube formation)  ↓ WH↑ diabetic foot ulcers (DFU) progression amputation (David et al2002,Heshamet al2006 ,Beem 2007, Tjokropawiro 2010) DM↓ VEGF  ↓ Ca cytosolic activity + ↓eNOS↓Homing EPC ↓ Angiogensis # WHulkus DM (Costanza et al 2002,Pradhanet al 2007,Singhan et al 2007) DFU proper management  Herbal therapy enhance angiogenesis (Larijaniet al 2008)

  6. HYPERGLYCEMIA HIPERGLIKEMIA (DM) SCHIFF BASE <1 day AMADORI 1-7 days P A H A b↑AGE >1 week ↑AR ↑HEKSOSAMINE PATWAY (H) ↑PKC ↑ROS ↑TNF ↑NFκB ↓NO GFAT ↑OH+ ↑TNFα ↑NFκB, ↓eNO, ↑TGFβ ↑NAD(P)H OXIDASE ↑ET-1, ↑PAI-1, ↑VEGF ↑SORBITOL ↓GSH ↑TNFα ↑TGFβ,↑MMPs ↓CELL PROLIFERATION INSULIN SENSITIVITY STRESS OXIDATIVE Β-CELL FUNCTION “PAHAM”:PKC,AGE,HEKSOSAMINE,AR,MITOCONDRIAL DYSFUNCTION MIKROANGIOPATI & MAKROANGIOPATI NEUROPATHY TRAUMA VASCULOPATHY MOTORIC SENSORY AUTONOM MICROPATHY MACROPATHY BM CAPILLARY THICKENNING A-V SHUNT ↑BLOOD FLOW EDEMA NEUROPATHY ATEROSCLEROSIS ISCHEMIA WEAKNESS ATROPHY DEFORMITY ↑PLANTAR PRESSURE CLAVUS ↓PROTECTION ↓SENSATION ANHIDROSIS DRY SKIN FISSURE ↑SYMPATHY PRESSURE ↓NUTRITION ↓CAPILLARY BLOOD FLOW ↓RESPONSE TO INFECTION OSTEOARTHROPATHY ENDOTHELIAL DYSFUNCTION # ANGIOGENESIS ↓KERATINOCYTES ↓PROLIFERATION #INFLAMMATION ↓NEUTROPHIL ↓MONOCYTE ↓FIBROBLAST ↓GF ↓CITOKINES HEMOSTASIS 1 HOUR #INFLAMMATION 2-7 DAYS #REMODELLING 6WEEK-3 MONTHS #PROLIFERATIOM 2-20 DAYS AMPUTASI AMPUTASI GAMGGUAN PENYEMBUHAN ULKUS KAKI DM OXIDATIVE STRESS MACRO-MICROANGIOPATHY AMPUTATION AMPUTATION # WOUND HEALING Gambaran Kegagalan Patofisiologi Ulkus diabetes dan Patologi Penyembuhan ulkus diabetes (Robert et al 2006, Gugliucci 2007, Pradhan et al 2007, Tjokroprawiro 2010).

  7. CONCEPTUAL THEORY ALOE GEL VEGF  eNOS CEC  ERK-1/2 EPC  ANGIOGENESIS  Cellular proliferation  DIABETIC WOUND HEALING 

  8. Hipotesis wound diameter Dose of 30,60,120 (mg/day) Aloe gel Angiogenesis Diabetic wound healing VEGF, eNOS,EPC ,CEC , Rasio EPC/CEC Expression and amount

  9. MATERIALS AND METHODS

  10. VEGF :Vascular Endothelial Growth Factor eNOS :endothelial Nitric Oxide Synthase EPC :Endothelial Progenitor Cells CEC :Circulating Endothelial Cells A : NORMAL RATS B : UNTREATED RATS C : DIABETIC RATS+TREATMENT D : DIABETIC RATS+TREATMENT E : DIABETIC RATS+TREATMENT PRE-STUDY: 0-14 days bedore treatment STUDY : 0-14 hari after treatment Ale gel : glycoprotein and polysacchaarides aloe vera SCHEME OF STUDY PROTOCOL (ROCKET SYSTEM MODIFICATION, TJOKROPRAWIRO, 1978) S T R A I N W I S T A R + A L O E G E L DAY 14 0 14 0 VEGF,eNOS, EPC,CEC Ø WOUND PRA PENELITIAN PRE- STUDY STUDY PENELITIAN NON DM A0 WOUND n:3 A14 DATA D A T A A N A L Y S I S A N A L I S I S D A T A R E P O R T DM 0 B14 B0 WOUND n:3 DATA RANDOM HASIL RESULT DM 30 C14 N:15 C0 WOUND + ALOE GEL 30 MG n:3 DATA DM 60 D0 WOUND + ALOE GEL 60 MG n:3 D14 DATA DM120 E0 WOUND + ALOE GEL 120 MG n:3 E14 DATA VEGF,eNOS, EPC,CEC Ø WOUND PRE- STUDY STUDY 0 14 28 DAY MAIN PARAMETER PARAMETER DATA ANALYSIS MAKING OF DIABETIC RATS VEGF : immunohistochemistry eNOS : immunohistochemistry EPC : CD34 (Flowcitometri) CECs : CD45(FITC)+CD146(PE) (Flowcitometri) Ø wound : wound dimeter Anova (simple anova) Linear Regression Injection of STZ 60mg/kg (IP) for 14 days (2 weeks) Diabetes if blood glucose level >200mg/dl MAKING OF WOUND SAMPLE POPULATION p ketamin (10mg/kg/iv) Wound diameter 2,5 cm depth 0,2 cm Wash the wound with Nacl 0,9% (t-1)(r-1)≥ 15 t=±treatment r=±repetition

  11. STUDY TIMELINE

  12. RESULTS • 14th Day, measurement of : • Wound diameter • Immunohistochemistry of dermal tissue • Blood for Flowcitometry

  13. Measurement of Wound Diameter Normal Rats Diabetic rats DM + 30 mg DM + 60 mg DM + 120 mg p = 0.000

  14. Vascular Endothelial Growth Factor (VEGF) Expression Normal Rats Diabetic Rats DM+30mg DM+60mg DM+120mg p = 0.676

  15. Endothelial Nitric Oxide Synthase (eNOS) Expression Normal Rats Diabetic rats DM + 30 mg DM + 60 mg DM + 120 mg p = 0.000

  16. Amount of Endothelial Progenitor Cells (EPCs) CD 34 Normal Rats Diabetic rats DM + 30 mg DM + 60 mg DM + 120 mg n kelompok = 3 p = 0.457

  17. Amount ofCirculating Endothelial Cells (CECs) CD 45 Normal Rats Diabetic rats DM + 30 mg DM + 60 mg DM + 120 mg p = 0.000

  18. PATH ANALYSIS

  19. DISCUSSION

  20. Effect administration ofAloe gel onwound diameter  Wound diameter Dosis (mg/day) Diabetic wound healing Aloe gel ↑ wound contraction • Anti inflammatory • fibroblast proliferation • collagen dan glycosaminoglikan synthesis (Heggers 1993; Jia et al 2008;Kwack et al 2009 ,;Liu et al., 2010; Fernanda et al., 2009;Jettanacheawchankit et al 2009)

  21. Effect administration ofAloe gel onExpression of VEGF and eNOS Dermal Tissue  Wound diameter Dosis (mg/day) Diabetic wound healing Aloe gel ↑ Angiogenesis VEGF eNOS EPC mobilization (Heggers 1993; Choi et al 2002; Tanimoto et al 2002;Duda et al 2004; Young et al 2004;Kim et al 2007;Pradhan et al. 2007; Beemet al. 2007; Singhan et al 2007; Chen et al 2007).

  22. Effect administration of Aloe gel on amount ofEPCs and CECs circulation Wound diameter Dosis (mg/day) ↑ Angiogenesis Diabetic wound healing Aloe gel migration /Homing EPC CECs • Spinetti et al. 2008;Albieroet al., 2011;Orenet al., 2010;McClunget al2005;Fiorina et al. 2010;Sibalet al2009;Spinetti et al2008;Nababanet al., 2007;Boos et al 2006

  23. EPC/CEC RATIO AFTER ADMINISTRATIONOF ALOE GEL aloe gel  herbal pro-angiogenickeepsurvival EPCs during mobilizationandhoming into woundincreaseamount of EPCs to damage endothelial cells from vascular wall (CECs).

  24. conclusion wound diameter cm2 Dose 120(mg) Aloe gel Angiogenesis wound healing • Hipotesis statistically proved (P<0,05) Ratio EPC/CEC VEGF, eNOS,EPC ,CEC • EPC/CEC ratio • Novel (new) • Base of therapy • Prognostic factor Exresion (ng/ml) and amount

  25. Terima kasih

  26. THE ROLES OF HSP 70 / HSP 72 on Wound Healing HEALTHY WOUND IMPROVED BY HBO THERAPY DIABETIC WOUND DM WITH 5 DYSFUNCTION : KERATINOCYTE, PLATELET, ENDOTHELIUM, MACROPHAGE, MYOFIBROBLAST c-myc -catenin Mekanisme Penyembuhan luka Normal dibanding Diabetes (Beemet al 2007, Tjokropawiro 2011) VEGF LIMITED NEOVASCULOGENESIS AND WOUND HEALING LIMITED EPC HOMING IMPROVED BY LOCAL SDF-1 INJECTION Blood Glukose Should be < 200 Decreased eNOS Activation

  27. Conceptual Theory Vascular Complication of Diabetes Ischemia/hypoxia VEGF VEGFR-2 ROS PLC-γ DAG IP3 cSrc FAK PKC Ca2+ CaM Raf-1 eNOS PI3K MEK p38MAPK Calpain PIP3 ERK1/2 HSP27 Akt/PKB NO HIF-1α, AP-1, NFκB, Ets-1 Paxillin Migration vascular permeability EPC Homing, CEC ↓ MMPs, uPA, PAI-1 proliferation Angiogenesis Diabetic wound healing

  28. Active Compound of Aloe Gel (Hamman, 2008)

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