Wound Healing, Tissue Repair, and Regeneration in Diabetes

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 Cover WOUND HEALING, TISSUE REPAIR, AND REGENERATION IN DIABETES Copyright Dedication Contributors About the authors Preface Part 1: Background and overview 1 The diabetic foot Introduction Clinical classification Definition Risk factors Etiology Epidemiology The complicated diabetic foot Vascular Neural Skin and soft tissue Bone Infection Care and management Treatment Other factors Prevention Conclusion References 2 Role of oxidants and antioxidants in diabetic wound healing Introduction Oxidative stress and wound healing Antioxidants and wound healing Examples of enzymatic antioxidants SOD, GSTs, GPx, NADPH Heme-oxygenase 1 (HO-1) Peroxiredoxins and thioredoxins Nonenzymatic antioxidants Vitamin C Vitamin E Vitamin D Alpha-lipoic acid (α-LA) and its reduced form of dihydrolipoic acid (DHLA) N-acetyl-cysteine (NAC) Other small molecules Herbal extracts Curcumin Honey Factor-E2-related factor (Nrf2) Diabetes, oxidative stress, and impaired/chronic wounds OS and the triggering of wound chronicity Conclusions References Further reading 3 Chronic infection and inflammation: Hallmarks of diabetic foot ulcers Background Chronicity of wound infection Antibiotic resistance (ABR) Biofilm infection Novel approaches for therapeutics Electroceuticals Bacteriophage Dysregulated resolution of wound inflammation miRNA Macrophage function and phenotypes Efferocytosis Conclusion References 4 Diabetic peripheral neuropathy: An insight into the pathophysiology, diagnosis, and therapeutics Introduction Neuropathy Peripheral neuropathy Cranial neuropathy Autonomic neuropathy Focal neuropathy Mononeuropathy Polyneuropathy Experimental mouse models for DPN Diet-induced DPN mouse model Chemically induced DPN mouse model Genetically modified DPN mouse model Nociception assays Mechanical stimuli The manual von Frey test The electronic von Frey Randall-Selitto test Heat stimuli The tail-flick test Hot plate test Hargreaves test Thermal probe test Cold stimuli Cold plate test Acetone evaporation test Cold plantar assay Temperature preference test Nonstimulus evoked nociception Grimace scales Burrowing Weight-bearing and gait analysis Automated behavioral analysis Diabetic neuropathy clinical research trials Nutrition for diabetic neuropathy Vitamin B12 Alpha-lipoic acid Acetyl-l-carnitine Clinical assays for diagnosis of DPN Neurology exam questions Neurological function test Diagnostic testing Electromyogram NCV test Biopsies Spinal tap Blood test Peripheral neuropathy and wound healing Neuroregeneration in DPN Gene therapy NTFs delivery Stem cell-based strategies Alternative RNA splicing Noncoding RNAs Electrical stimulation Summary and future perspective References Part 2: Molecular mechanisms in diabetic wounds 5 Dysregulated inflammation in diabetic wounds Introduction Normal wound healing Diabetic wound healing Platelets Neutrophils Monocytes/macrophages T cells Epigenetics and immune cell function Macrophage phenotype is epigenetically regulated in diabetic wounds Neutrophil inflammatory activity is epigenetically regulated Summary References 6 Angiogenic response in wound healing Introduction Angiogenesis and vasculogenesis Wound healing Hemostasis Inflammation Neutrophils Macrophage Proliferation Endothelial cells From bench to bed Current practice Future potential therapy Cell therapy microRNAs Conclusion References 7 Fibrosis and diabetes: Chronic hyperglycemia triggers organ-specific fibrotic mechanisms Introduction Normal cutaneous wound-healing pathogenesis Mechanisms which take place in response to hyperglycemia Protein glycation The renin-angiotensin-aldosterone system Growth factors Matrix metalloproteinases Organs The eye The kidney The heart Blood vessels The liver The lung Concluding remarks References Further reading 8 miRNAs in diabetic wound healing Introduction miRNAs involved in regular skin function Expression pattern of miRNAs in diabetic skin Exploring the functions of miRNAs in diabetic wound healing Inflammation phase Angiogenesis phase Reepithelialization phase Remodeling (maturation) phase Advantage of miRNAs as therapeutic target to improve diabetic wound healing Conclusions References 9 Epigenetics of diabetic wound healing Diabetic wounds: Introduction and burden Epigenetics fundamentals DNA methylation DNMTs: Writers for DNA methylation Ten-eleven translocation (Tet) enzymes: The erasers of DNA methylation The 5-methylcytosine binding domain (MBD) family: Readers of DNA methylation Histone modifications Epigenetics of type 2 diabetes (T2D) Epigenetic dysregulations in diabetic wound healing impairment Macrophages Fibroblasts Endothelial cells Therapeutic strategies targeting epigenetics for diabetes and diabetic wound healing impairment Conclusion References 10 Role of lipid mediators in diabetic wound healing Introduction Fatty acyls Prostaglandins Leukotrienes and cytochrome p450 metabolites Endocannabinoids Glycerolipids Glycerophospholipids Phosphatidylinositol phosphates Lysophosphatidic acid Sphingolipids Ceramides and their phosphates Sphingosine-1-phosphate Gangliosides Sterol lipids References 11 Role of cytokines and chemokines in wound healing Introduction Chemokine classification and function Cytokine and chemokine expression during acute vs diabetic wound healing Insult before injury The AGE of ruin A spoonful of sugar does not help the medicine Impact of diabetes on fibroblasts Impact of diabetes on endothelial and endothelial progenitor cells Impact of diabetes on keratinocytes Impact of diabetes on immune cells and cytokines Hemostasis Inflammatory stage of wound healing: Damnation by perpetuation The neutrophil influx When 2 does not follow 1 (macrophages) Mast cells and lymphocytes Proliferation and remodeling stages of wound healing Granulation tissue deposition Neovascularization Re-epithelialization Remodeling Diabetic challenges and potential therapeutic opportunities Biofilms Cytokines/chemokines that may alleviate diabetic wounds Mesenchymal stromal cells Biomaterials Conclusion References 12 The wound microbiome Introduction From contamination to infection: The wound infection continuum Culture-based insights into wound microbes Culture-independent profiling of the DFU microbiome Who are the members of the DFU microbiome? Temporal stability of the DFU microbiome A focus on methodology: High-throughput sequencing approaches to characterize the diabetic wound microbiota Amplicon-based sequencing approaches Experimental bias, statistical corrections, and normalization Current utility and future prospects for amplicon-based microbiome studies of diabetic wound Whole metagenomic shotgun sequencing Experimental limitations and computational challenges Functional characterization of DFU microbiota using gene-level metagenomic profiles Future directions Microbial lifestyles: Impact of biofilms From microbial census to gene expression Harnessing the therapeutic potential of the microbiome Summary References 13 Downregulation of hexose sugar metabolism in diabetes decreases the rate of wound healing Introduction Hemostasis Inflammation Proliferation Remodeling Influence of diabetes on functions of neutrophils Hindrance in energy supply Involvement of polyol pathway Disrupted bactericidal activity Inhibition of chemotaxis Influence of diabetes on functions of keratinocytes Impaired migration Impaired angiogenesis Influence of diabetes on apoptosis Contribution of AGEs Apoptosis of fibroblasts Conclusion References Further reading Part 3: Emerging therapeutics in diabetic wound care 14 Biomaterials for diabetic wound-healing therapies Introduction Successes and challenges in the use of biomaterials for the management of diabetic wounds Biomaterials for dermal tissue engineering and regeneration Acellular biomaterials Synthetic polymeric biomaterials Poly (-caprolactone) Poly (lactic-co-glycolic acid) Polylactic acid Polyurethane Natural animal-derived polymers used as biomaterials Collagen Hyaluronic acid Gelatin Chitosan Alginate Self-assembling peptides Cell-based skin substitutes Cellular skin substitutes based in a combination of natural and synthetic biomaterials Cellular skin substitutes from human amniotic membrane Cellular skin substitutes from human cadaver skin Cellular skin substitutes based on combined human and animal sources Stem-cell-based substitutes for regenerative healing of diabetic wounds Induced pluripotent stem cells Mesenchymal stem cells Embryonic stem cells Emerging biomaterial technologies for treatment of diabetic wounds Conclusions References 15 Photobiomodulation therapy in diabetic wound healing Light as a therapeutic intervention Mechanisms of photobiomodulation therapy Energizing the powerhouse-The mitochondria: The performance mechanism Lighting up beacons-Photosensitive membrane receptors and channels: Analgesia mechanism Harnessing endogenous stem cells for regeneration-TGF-β activation: Healing mechanism PBM therapy in diabetic wound healing PBM and redox modulation in diabetic wounds Optimizing PBM treatments to dysregulated signaling pathways in diabetic wound healing JAK/STAT signaling Interleukins, bFGF, and TNFα VEGF and SDF-1α TGF-β PI3K/AKT signaling via mTOR and GSK-3β Implications for PBM therapy in diabetes wounds and associated fibrosis and cancers References 16 Therapeutic benefits of treating chronic diabetic wounds with placental membrane allografts History of placental tissue in wound repair Preservation techniques of placental membranes for commercial use Benefits of placental allografts in chronic wound repair Experimental evidence of wound repair by placental membrane in animal models Clinical evidence for efficacy of placental membranes in diabetic foot ulcer patients References 17 Debridement and negative pressure wound therapy Introduction Debridement Medical management and vascular status Literature review Types of debridement Endpoint and biopsies Applications for the diabetic foot Negative-pressure wound therapy Background Mechanism of action Description/function Applications for the diabetic foot Unique clinical usage and future applications Safety and conclusion References 18 Protease technology in wound repair Diabetes, wound prevalence, and health economics Risk factors for primary and recurrent DFUs Dynamics of wound repair and tissue regeneration Protease therapy Protease therapy for DFUs Nonhealing wounds: Chronic inflammation impedes or stalls wound repair and regeneration Role of protease in wound infection Mechanisms of action Proteases as activators of wound healing: Creation of bioactive peptides in situ Effect of collagenase on cells Next frontier: Emerging uses of protease therapy Protease therapy for acute wounds Effects of plant proteases on inflammation Angiogenesis and antiinflammation effects of proteases on wound repair and regeneration Effect on antimicrobial peptides in skin Emerging protease technologies for treatment of fibrosis Emerging technologies for treatment of biofilm Emerging protease-inspired therapies and cancer diagnostics Conclusions References 19 Collagen in diabetic wound healing Introduction Collagen in diabetic wounds Diabetic-wound-infection-induced collagen dysfunction Applications of collagen in wound healing References 20 Nutrition and diabetic wound healing Introduction Dysregulated wound inflammation during diabetes Nutrition in diabetic wound healing Carbohydrates Fats and fatty acids Proteins and amino acids Vitamins Minerals Other nutritional interventions Papaya: A natural remedy for diabetic wounds Conclusion References Part 4: Nanotechnology and nanocarriers in wound healing 21 Nanotechnology in diabetic wound healing Diabetic wounds-An overview Applications of nanotechnology in wound healing and management Nanosensors Nanoparticles Nanofibers Nanotransfection Strategies of nanotechnology applications Hemostasis Cell proliferation and skin remodeling Antiinflammatories Antimicrobial activity Concerns regarding nanotechnology in medicine Future perspectives References 22 Drug-delivery nanocarriers for skin wound-healing applications Skin wound healing Nanotechnology and nanomedicine to address challenges in skin wound healing Nanotechnology and drug delivery Nanocarriers for drug delivery in wound healing Nanomaterials for drug delivery in skin wound healing Polymeric-based nanomaterials Dendrimers Polymeric micelles Polymeric nanoparticles Polymersomes Lipid-based nanocarriers Liposomes Niosomes Transfersomes Ethosomes Metallic nanoparticles Pure metal nanoparticles Metal oxide nanoparticles Bimetallic nanoparticles Carbon-based nanomaterials Carbon nanotubes Graphene-based nanomaterials Fullerene Nanodiamonds Conclusion and future directions References Part 5: Biomarkers in wound healing 23 Volatile organic compounds: Potential biomarkers for improved diagnosis and monitoring of diabetic wounds Introduction How wounds produce VOCs Role of VOCs in diabetes wound formation Quantitative collection and processing of VOCs from wounds Analytical and statistical methods for analyzing VOCs Bacterial VOCs In vitro In vivo VOCs produced by biofilms Classification of bacterial VOCs by functional groups Hydrocarbons Alcohols Aldehydes Acids Esters Phenyl groups and other cyclics Sulfur-containing compounds VOCs produced in humans due to diabetes Acetone Isopropanol Ethanol Isoprene Current status of E-noses and other devices for wound diagnosis and monitoring Conclusion References Further reading Part 6: Novel concepts in diabetic wound healing 24 Tissue regeneration and reprogramming Introduction Cells of tissue regeneration Platelets Keratinocytes Fibroblasts Immune cells Bone-marrow-derived stem cells Epidermal stem cells Role of ECM in tissue regeneration Epigenetics of tissue regeneration Tissue regeneration in diabetes Conclusion References 24 Bone marrow monopoiesis and wound healing in diabetes Introduction Function of wound Mphi in normal skin wound healing Mo/Mphi dysregulation and impaired wound healing in diabetes Ontogeny of tissue mononuclear phagocytes and blood Mo in homeostasis Origin of wound Mphi Tissue injury and monopoiesis Enhanced monopoiesis in diabetes Diabetes-induced HSPC modifications Potential mechanisms underlying HSPC alterations in diabetic bone marrow Signaling pathways involved in obesity and diabetes-associated increases in monopoiesis Effect of diabetes on skin wounding-induced monocyte expansion in bone marrow Conclusions, implications, and future directions References 26 Role of mesenchymal stem cells in diabetic wound healing Introduction Mesenchymal stem cells MSCs and their dysregulation in diabetes MSCs in normal tissue repair Use of MSCs in tissue regeneration and wound healing MicroRNAs in diabetes MSC modulation of miRNA in diabetic complications Diabetic neuropathy MSCs and diabetic nephropathy MSCs and diabetic retinopathy MSCs and diabetic cardiomyopathy MiRNA in skin physiology Application of MSCs in correcting dysregulated wound healing Inflammation Angiogenesis MSC correction of ECM remodeling MSC correction of re-epithelialization Future directions References Further reading 27 Fetal wound healing Introduction Fetal wound healing: Historical perspective Contributions of the local wound environment Inflammation Extracellular matrix Collagen Hyaluronic acid Fibromodulin Importance of fetal fibroblasts Fetal wound healing and diabetes Conclusions References Index Back Cover