Wound Healing, Tissue Repair, and Regeneration in Diabetes

Description

Wound Healing, Tissue Repair and Regeneration in Diabetes explores a wide range of topics related to wound healing, tissue repair and regeneration, putting a special focus on diabetes and obesity. The book addresses the molecular and cellular pathways involved in the process of wound repair and regeneration. Other sections explore a wide spectrum of nutritional supplements and novel therapeutic approaches, provide a comprehensive overview, present various types of clinical aspects related to diabetic wounds, including infection, neuropathy, and vasculopathy, provide an exhaustive review of various foods, minerals, supplements and phytochemicals that have been proven beneficial, and assess future directions.

This book is sure to be a welcome resource for nutritionists, practitioners, surgeons, nurses, wound researchers and other health professionals.

Explains diabetic wounds and their complications
Assesses the role of nutraceuticals, herbal supplements and other modalities for use in treating diabetic wounds
Provides protocols for diabetic wound management

Front Cover 2
Wound Healing, Tissue Repair, and Regeneration in Diabetes 5
Copyright 6
Dedication 7
Contents 9
Contributors 19
About the authors 27
Preface 29
Part 1: Background and overview 31
- Chapter 1: The diabetic foot 33
  - 2. Clinical classification 33
    - 2.1. Definition 33
    - 2.3. Etiology 34
  - 1. Introduction 33

Front Cover 2
Wound Healing, Tissue Repair, and Regeneration in Diabetes 5
Copyright 6
Dedication 7
Contents 9
Contributors 19
About the authors 27
Preface 29
Part 1: Background and overview 31
- Chapter 1: The diabetic foot 33
  - 2. Clinical classification 33
    - 2.1. Definition 33
    - 2.3. Etiology 34
    - 2.4. Epidemiology 34
    - 2.2. Risk factors 34
  - 1. Introduction 33
  - 3. The complicated diabetic foot 34
    - 3.1. Vascular 34
    - 3.3. Skin and soft tissue 35
    - 3.2. Neural 35
    - 3.4. Bone 36
    - 3.5. Infection 36
  - 4. Care and management 36
    - 4.1. Treatment 36
      - 4.1.1. Other factors 37
    - 4.2. Prevention 37
  - 5. Conclusion 37
  - References 38
- Chapter 2: Role of oxidants and antioxidants in diabetic wound healing 43
  - 1. Introduction 43
  - 2. Oxidative stress and wound healing 45
  - 3. Antioxidants and wound healing 46
    - 3.1. Examples of enzymatic antioxidants 46
      - 3.1.1. SOD, GSTs, GPx, NADPH 48
      - 3.1.2. Heme-oxygenase 1 (HO-1) 48
      - 3.1.3. Peroxiredoxins and thioredoxins 49
    - 3.2. Nonenzymatic antioxidants 49
      - 3.2.1. Vitamin C 50
      - 3.2.4. Alpha-lipoic acid (α-LA) and its reduced form of dihydrolipoic acid (DHLA) 51
      - 3.2.2. Vitamin E 51
      - 3.2.3. Vitamin D 51
      - 3.2.5. N-acetyl-cysteine (NAC) 52
    - 3.4. Herbal extracts 53
      - 3.4.1. Curcumin 54
      - 3.4.2. Honey 54
    - 3.3. Other small molecules 53
    - 3.5. Factor-E2-related factor (Nrf2) 55
  - 4. Diabetes, oxidative stress, and impaired/chronic wounds 56
  - 5. OS and the triggering of wound chronicity 60
  - 6. Conclusions 61
  - References 63
  - Further reading 68
- Chapter 3: Chronic infection and inflammation: Hallmarks of diabetic foot ulcers 69
  - 2. Chronicity of wound infection 69
    - 2.2. Biofilm infection 70
    - 2.1. Antibiotic resistance (ABR) 70
    - 2.3. Novel approaches for therapeutics 71
      - 2.3.2. Bacteriophage 71
      - 2.3.1. Electroceuticals 71
    - 3. Dysregulated resolution of wound inflammation 72
      - 3.1. miRNA 72
      - 3.2. Macrophage function and phenotypes 73
      - 3.3. Efferocytosis 73
    - 4. Conclusion 74
    - References 74
  - 1. Background 69
  - Chapter 4: Diabetic peripheral neuropathy: An insight into the pathophysiology, diagnosis, and therapeutics 79
    - 1. Introduction 79
    - 2. Neuropathy 82
      - 2.2. Cranial neuropathy 82
      - 2.3. Autonomic neuropathy 82
      - 2.1. Peripheral neuropathy 82
      - 2.4. Focal neuropathy 83
        
        2.4.1. Mononeuropathy 83
        
        2.4.2. Polyneuropathy 83
      - 3. Experimental mouse models for DPN 84
        
        3.1. Diet-induced DPN mouse model 84
        
        3.2. Chemically induced DPN mouse model 84
        
        3.3. Genetically modified DPN mouse model 85
      - 4. Nociception assays 85
        
        4.1. Mechanical stimuli 85
        
        4.1.1. The manual von Frey test 85
        
        4.1.3. Randall-Selitto test 87
        
        4.1.2. The electronic von Frey 87
        
        4.2. Heat stimuli 87
        
        4.2.2. Hot plate test 87
        
        4.2.1. The tail-flick test 87
        
        4.2.4. Thermal probe test 88
        
        4.2.3. Hargreaves test 88
        
        4.3. Cold stimuli 88
        
        4.3.1. Cold plate test 88
        
        4.3.2. Acetone evaporation test 89
        
        4.3.3. Cold plantar assay 89
        
        4.3.4. Temperature preference test 89
        
        5. Nonstimulus evoked nociception 89
        
        5.2. Burrowing 90
        
        5.1. Grimace scales 90
        
        5.3. Weight-bearing and gait analysis 91
        
        5.4. Automated behavioral analysis 91
        
        6. Diabetic neuropathy clinical research trials 91
        
        7. Nutrition for diabetic neuropathy 91
        
        7.2. Alpha-lipoic acid 95
        
        7.3. Acetyl-l-carnitine 95
        
        7.1. Vitamin B12 95
        
        8. Clinical assays for diagnosis of DPN 96
        
        8.3. Diagnostic testing 96
        
        8.3.3. Biopsies 97
        
        8.3.1. Electromyogram 97
        
        8.3.4. Spinal tap 97
        
        8.3.2. NCV test 97
        
        8.1. Neurology exam questions 96
        
        8.2. Neurological function test 96
        
        8.4. Blood test 98
        
        9. Peripheral neuropathy and wound healing 98
        
        10. Neuroregeneration in DPN 99
        
        10.1. Gene therapy 100
        
        10.2. NTFs delivery 100
        
        10.4. Alternative RNA splicing 101
        
        10.3. Stem cell-based strategies 101
        
        10.6. Electrical stimulation 102
        
        10.5. Noncoding RNAs 102
        
        11. Summary and future perspective 102
        
        References 103
      - Part 2: Molecular mechanisms in diabetic wounds 109
        
        Chapter 5: Dysregulated inflammation in diabetic wounds 111
        
        1. Introduction 111
        
        2. Normal wound healing 112
        
        3. Diabetic wound healing 114
        
        3.1. Platelets 114
        
        3.2. Neutrophils 115
        
        3.3. Monocytes/macrophages 115
        
        3.4. T cells 116
        
        4. Epigenetics and immune cell function 116
        
        5. Macrophage phenotype is epigenetically regulated in diabetic wounds 117
        
        6. Neutrophil inflammatory activity is epigenetically regulated 119
        
        References 120
        
        7. Summary 120
        
        Chapter 6: Angiogenic response in wound healing 127
        
        2. Angiogenesis and vasculogenesis 127
        
        1. Introduction 127
        
        3. Wound healing 129
        
        3.1. Hemostasis 129
        
        3.2. Inflammation 130
        
        3.2.1. Neutrophils 130
        
        3.2.2. Macrophage 133
        
        3.3. Proliferation 135
        
        3.3.1. Endothelial cells 135
        
        4. From bench to bed 136
        
        4.1. Current practice 136
        
        4.2. Future potential therapy 138
        
        4.2.1. Cell therapy 138
        
        4.2.2. microRNAs 140
        
        5. Conclusion 143
        
        References 143
        
        Chapter 7: Fibrosis and diabetes: Chronic hyperglycemia triggers organ-specific fibrotic mechanisms 151
        
        1. Introduction 151
        
        2. Normal cutaneous wound-healing pathogenesis 151
        
        3. Mechanisms which take place in response to hyperglycemia 156
        
        3.3. Growth factors 157
        
        3.1. Protein glycation 157
        
        3.2. The renin-angiotensin-aldosterone system 157
        
        3.4. Matrix metalloproteinases 158
        
        4. Organs 158
        
        4.1. The eye 158
        
        4.2. The kidney 161
        
        4.3. The heart 163
        
        4.4. Blood vessels 164
        
        4.5. The liver 165
        
        4.6. The lung 167
        
        5. Concluding remarks 167
        
        References 168
        
        Further reading 177
        
        Chapter 8: miRNAs in diabetic wound healing 179
        
        1. Introduction 179
        
        1.1. miRNAs involved in regular skin function 180
        
        1.2. Expression pattern of miRNAs in diabetic skin 181
        
        2. Exploring the functions of miRNAs in diabetic wound healing 183
        
        2.1. Inflammation phase 183
        
        2.2. Angiogenesis phase 186
        
        2.3. Reepithelialization phase 189
        
        2.4. Remodeling (maturation) phase 190
        
        3. Advantage of miRNAs as therapeutic target to improve diabetic wound healing 191
        
        4. Conclusions 192
        
        References 192
        
        Chapter 9: Epigenetics of diabetic wound healing 197
        
        1. Diabetic wounds: Introduction and burden 197
        
        3. DNA methylation 198
        
        3.1. DNMTs: Writers for DNA methylation 199
        
        3.2. Ten-eleven translocation (Tet) enzymes: The erasers of DNA methylation 200
        
        3.3. The 5-methylcytosine binding domain (MBD) family: Readers of DNA methylation 201
        
        2. Epigenetics fundamentals 198
        
        4. Histone modifications 201
        
        5. Epigenetics of type 2 diabetes (T2D) 202
        
        6. Epigenetic dysregulations in diabetic wound healing impairment 203
        
        6.1. Macrophages 203
        
        6.2. Fibroblasts 204
        
        6.3. Endothelial cells 204
        
        7. Therapeutic strategies targeting epigenetics for diabetes and diabetic wound healing impairment 205
        
        8. Conclusion 206
        
        References 207
        
        Chapter 10: Role of lipid mediators in diabetic wound healing 211
        
        1. Introduction 211
        
        2. Fatty acyls 213
        
        2.1. Prostaglandins 213
        
        2.2. Leukotrienes and cytochrome p450 metabolites 215
        
        2.3. Endocannabinoids 215
        
        3. Glycerolipids 216
        
        4. Glycerophospholipids 217
        
        4.1. Phosphatidylinositol phosphates 217
        
        4.2. Lysophosphatidic acid 218
        
        5. Sphingolipids 218
        
        5.1. Ceramides and their phosphates 219
        
        5.2. Sphingosine-1-phosphate 219
        
        5.3. Gangliosides 220
        
        6. Sterol lipids 220
        
        References 221
        
        Chapter 11: Role of cytokines and chemokines in wound healing 227
        
        1. Introduction 227
        
        2. Chemokine classification and function 228
        
        3. Cytokine and chemokine expression during acute vs diabetic wound healing 232
        
        3.1. Insult before injury 235
        
        3.1.1. The AGE of ruin 235
        
        3.1.2. A spoonful of sugar does not help the medicine 238
        
        3.1.2.1. Impact of diabetes on fibroblasts 238
        
        3.1.2.2. Impact of diabetes on endothelial and endothelial progenitor cells 239
        
        3.1.2.3. Impact of diabetes on keratinocytes 240
        
        3.1.2.4. Impact of diabetes on immune cells and cytokines 240
        
        3.2. Hemostasis 242
        
        3.3. Inflammatory stage of wound healing: Damnation by perpetuation 243
        
        3.3.1. The neutrophil influx 243
        
        3.3.2. When 2 does not follow 1 (macrophages) 245
        
        3.3.3. Mast cells and lymphocytes 248
        
        3.4. Proliferation and remodeling stages of wound healing 250
        
        3.4.1. Granulation tissue deposition 250
        
        3.4.2. Neovascularization 251
        
        3.4.3. Re-epithelialization 252
        
        3.4.4. Remodeling 253
        
        4. Diabetic challenges and potential therapeutic opportunities 253
        
        4.1. Biofilms 253
        
        4.3. Mesenchymal stromal cells 254
        
        4.2. Cytokines/chemokines that may alleviate diabetic wounds 254
        
        4.4. Biomaterials 256
        
        References 258
        
        5. Conclusion 258
        
        Chapter 12: The wound microbiome 267
        
        1. Introduction 267
        
        2. From contamination to infection: The wound infection continuum 268
        
        3. Culture-based insights into wound microbes 269
        
        4. Culture-independent profiling of the DFU microbiome 271
        
        4.1. Who are the members of the DFU microbiome? 271
        
        4.2. Temporal stability of the DFU microbiome 274
        
        5. A focus on methodology: High-throughput sequencing approaches to characterize the diabetic wound microbiota 275
        
        5.1. Amplicon-based sequencing approaches 275
        
        5.1.2. Current utility and future prospects for amplicon-based microbiome studies of diabetic wound 277
        
        5.1.1. Experimental bias, statistical corrections, and normalization 277
        
        5.2. Whole metagenomic shotgun sequencing 278
        
        5.2.1. Experimental limitations and computational challenges 279
        
        5.2.2. Functional characterization of DFU microbiota using gene-level metagenomic profiles 280
        
        6. Future directions 281
        
        6.1. Microbial lifestyles: Impact of biofilms 281
        
        6.2. From microbial census to gene expression 282
        
        6.3. Harnessing the therapeutic potential of the microbiome 283
        
        7. Summary 283
        
        References 284
        
        Chapter 13: Downregulation of hexose sugar metabolism in diabetes decreases the rate of wound healing 289
        
        1. Introduction 289
        
        1.1. Hemostasis 289
        
        1.2. Inflammation 290
        
        1.3. Proliferation 290
        
        1.4. Remodeling 290
        
        2. Influence of diabetes on functions of neutrophils 291
        
        2.1. Hindrance in energy supply 291
        
        2.2. Involvement of polyol pathway 292
        
        2.3. Disrupted bactericidal activity 293
        
        2.4. Inhibition of chemotaxis 294
        
        3. Influence of diabetes on functions of keratinocytes 294
        
        3.1. Impaired migration 294
        
        3.2. Impaired angiogenesis 296
        
        4. Influence of diabetes on apoptosis 296
        
        4.1. Contribution of AGEs 296
        
        4.2. Apoptosis of fibroblasts 297
        
        5. Conclusion 298
        
        References 298
        
        Further reading 300
        
        Part 3: Emerging therapeutics in diabetic wound care 301
        
        Chapter 14: Biomaterials for diabetic wound-healing therapies 303
        
        1. Introduction 303
        
        2. Successes and challenges in the use of biomaterials for the management of diabetic wounds 305
        
        3. Biomaterials for dermal tissue engineering and regeneration 306
        
        3.1. Acellular biomaterials 307
        
        3.1.1. Synthetic polymeric biomaterials 307
        
        3.1.1.1. Poly (-caprolactone) 309
        
        3.1.1.2. Poly (lactic-co-glycolic acid) 309
        
        3.1.1.4. Polyurethane 310
        
        3.1.1.3. Polylactic acid 310
        
        3.1.2. Natural animal-derived polymers used as biomaterials 311
        
        3.1.2.1. Collagen 312
        
        3.1.2.2. Hyaluronic acid 314
        
        3.1.2.4. Chitosan 315
        
        3.1.2.3. Gelatin 315
        
        3.1.2.5. Alginate 316
        
        3.1.2.6. Self-assembling peptides 316
        
        3.2. Cell-based skin substitutes 320
        
        3.2.1. Cellular skin substitutes based in a combination of natural and synthetic biomaterials 320

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