Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers

*Pawandeep Kaur and Diptiman Choudhury*

### **Abstract**

About 5% of the world population is diabetic and are at a risk of slow nonrecoverable wound formation. Estimated 15–25% of diabetic patients develop foot ulcers, 6% among them needing clinical attention among which 15–20% will need an amputation. This counts for around 50% of all traumatic amputation. Wound leads to activation of dynamic inflammatory cascade responsible for the healing process. But in diabetes, a persistent rise of pro-inflammatory cytokines and low anti-inflammatory cytokines blocks the dynamic cascade. Wounding induces various pro-inflammatory cytokines such as IL-1, IL-6, IL-12, IL-18, IFN-γ, and TNFs causing accumulation of free radicals leading to inflammation which become persistent in diabetes. Inhibition of proinflammatory cytokines drives the equilibrium towards the expression of anti-inflammatory cytokines such as IL4, IL-10, IL-11, IL-13, IFN-α, and TGF-β, which is necessary for the wound recovery process. Here in this chapter, the inflammatory modulatory roles of different drugs/formulations have been discussed to unravel their significance to promote wound recovery.

**Keywords:** diabetic wound, tissue inflammation, pro-inflammatory cytokines, anti-inflammatory cytokines, nanoformulation for wound recovery

### **1. Introduction**

Over the last 25 years, there has been found a four-fold increase in the number of diabetes mellitus cases commonly called diabetes [1]. 422 million people worldwide in 2016 have been reported to have diabetes mellitus. Diabetes in the year 2012 was a cause of 1.5 million deaths worldwide; according to WHO (World Health Organization), diabetes becomes the 8th leading cause of death [2]. Diabetes mellitus is mainly identified by the presence free glucose at high or the chronic level in the body fluids like sweat, urine, blood, etc. [3]. The major reason for diabetes mellitus among others was the hormone-mediated metabolism regulation failure. Hormones like glucagon and insulin play an important role in regulating the level of blood sugar or maintaining its balance [4]. The sugar balance in blood is important for perfect functioning of human body [5]. High/chronic level of glucose in body fluids is responsible for different pathological conditions like infection susceptibility, leading to various diseases such as arthritis, hypertension, cardiovascular problems, cataract, retinopathy, neuropathy, damage of kidneys, damaging of blood vesicles, wound healing delay, etc. (**Figure 1**) [5, 6]. Due to the linkage of diabetes mellitus with other different diseases, the International Diabetes Foundation (IDF), in 2014, recorded that the 4.9 million lives loss and ~1.25% dead were diabetic patients, either directly by diabetes mellitus or indirectly through other diseases [7]. All these diseases are linked causing various effects on different body organs with various pathways; pathological/hyperglycemic conditions are linked with the inflammation of tissue [8]. Diabetes is responsible for lower gradation inflammation in a systemic way and leads to the promotion of different diseases like arthritis, retinopathy, etc. [9, 10].

One of the major problems associated with diabetes mellitus is inflammation in wounds and results in wound recovery delay [11]. The chronic wounds in diabetes mainly show the persistent increase in the level of pro-inflammatory cytokine and the absence of the signals, which are responsible for signals in the damaged tissues [12]. The treatments used in diabetes mellitus are also helpful in controlling the level of glucose blood and helps in delaying the further progression of other diseases linked with diabetes mellitus, like retinopathy, contract, arthritis, neuropathy, retinopathy, etc., but very less is known in the literature about diabetes mellitus treatment's effects on diabetic wound recovery [13]. Wound results in release of the pro-inflammatory cytokines such as interleukin-6 (IL-6), IL-1, IL-12, IL-18, and tumor necrosis factors (TNFs) and interferon-gamma (IFN-γ), which results in inflammation of tissues [14]. Pro-inflammatory cytokines like IL-6 and IL-1β are released from the macrophages and monocytes in the wound and result in pain responses by signaling the neurons [15]. IFN-γ, IL-1β, and TNF-α induce apoptosis and pyroptosis mediated by the activation of innate immunity and oxidative stress [16]. IFN-γ is an activator; it activates macrophages by stimulating STAT1 expression in order to activate the defense mechanism against the pathogens in the infected area [17]. IL-12 stimulates TNF-α and IFN-γ production and reduces the expression of IL-4, an anti-inflammatory cytokine, and negatively controls the expression of IFN-γ; IL-4 also through the activation of STAT-3 signaling inhibits IFN- γ [18]. IL-18 for defense against pathogens activates T cells and natural killer

#### **Figure 1.**

*M1 macrophages (also known as classically activated), such as IL-12, IL-1β, IL-10, STAT1, TNF-α, and NFkβP50/P65, are leads to wound inflammation. Alternatively, active, that is, M2 macrophages, such as STAT3, HIF-α, PKC, NFkβP50/P50, etc., help in healing of the wound by decreasing inflammation. People having diabetes show prolonged M1 macrophage expression in wounds in comparison to nondiabetic wounds that delay M1 to M2 macrophage transition.*

**55**

administrated systematically.

**2. Activation of anti-inflammatory cytokines and increased differentiation of cells by signaling through insulin**

Insulin, released from pancreatic gland produced in its beta cells of the islets of Langerhans is a peptide hormone. Insulin precursor is proinsulin in humans, is

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers*

To start and control the wound healing mechanism, the inflammation is most important. In the nondiabetic wounds, anti-inflammatory cytokines like IL-4, IL-10, IL-13, IL-11, and transforming growth factor-beta (TGF-β) and interferon-alpha (IFN-α) play an important role in the wound healing process [24]. At the initial stage of wound recovery, TLR-9 induces the instant expression of pro-inflammatory signals like TNF-α through the increase in expression of mitogen-activated protein kinase (MAPK)/p38 and c-Jun N-terminal kinase (JNK) pathway [25]. In nondiabetic wounds, MAPK activation is prolonged and leads to MAPK phosphatase enzyme activation, which works as a negative regulator of JNK and MAPK/p38 pathways, resulting in the negative regulation of TNF-α production. The de-phosphorylation of MAPK/p38 leads to more expression of anti-inflammatory cytokines such as IL-10 a homodimeric cytokine, which is produced by the macrophages, monocytes and induce signaling of TGF-β, and can enhance the division of cells [26]. Cytokines like IL-4, IL-13, and IL-10 can stimulate extracellular matrix and fibrinogen, mainly collagen synthesis. IL-4, cytokines secreted by macrophages, mast cells and inflamed T cells activate the Janus kinase/signal transducer and transcription-6 (Jak/STAT6) pathway activator which promotes the wound repairing [27]. IL-4 is responsible for the extracellular matrix synthesis, mainly collagen which gives the physical support for the healing of the wound [28]. Another kind of cytokine, L-1RA, secreted from immune cells, adipocytes cells and cells of epithelia, leads the inhibition of pro-inflammatory IL1β cytokine effect by binding with the (IL-1R) interleukin-1 receptor. On the other hand, deregulation of TNF-α and IL-1β prolongs the phase of inflammation phase and leads to delay in wound healing [29]. IL-11 released from cells of bone marrow expresses anti-inflammatory effect. IL-11 inhibits the synthesis of IL-1 and TNF-α synthesis by the inhibition of NFkβP50/P65 with increasing the expression of inhibitory NFkβP50/P50 synthesis in monocytes/macrophage cells [30]. Transition between cytokines of pro and anti-inflammatory is balanced in nondiabetic wounds but in case of diabetic wounds, it gets impaired (**Figure 1**). For the type-1 diabetes treatment or insulin-dependent diabetes, insulin is

(NK) cells and promotes the expression of of IFN-γ cytokines at the wound site [19]. However, the prolonged expression of inflammatory cytokines leads the damage of tissues, which results in a delay in the repairing process of wounds. IL-1 is a TNF activator and is responsible for the damaging of cells. IL-1β overproduction is responsible for neuronal tissue inflammation, leads to damage of neuro-muscular junctions and ultimately leads to delaying in wound healing [20]. In the presence of pathogens, the macrophages secrete IL-6 which in turn increases Toll like receptor expression (TLR)-9 response-mediated defense for killing foreign particles. In case of prokaryotes, unmethylated DNA activates the TLR-9 pathway and helps in killing the pathogen at the wound site; mitochondrial DNA spillage, essentially the unmethylated DNA, triggers similar kind of responses in the tissue of wound [21]. In tissues, the angiogenesis is inhibited by IL-12 by overexpression of IFN-γmediated interferon-gamma-induced protein 10 (CXCL-10 or IP-10) [22]. Vascular endothelial growth factor (VEGF) expression is negatively controlled by IL-18, essential for the development of new blood vessels at the wound site and is essential

*DOI: http://dx.doi.org/10.5772/intechopen.92096*

for the growth and repair at wound tissue [23].

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers DOI: http://dx.doi.org/10.5772/intechopen.92096*

(NK) cells and promotes the expression of of IFN-γ cytokines at the wound site [19]. However, the prolonged expression of inflammatory cytokines leads the damage of tissues, which results in a delay in the repairing process of wounds. IL-1 is a TNF activator and is responsible for the damaging of cells. IL-1β overproduction is responsible for neuronal tissue inflammation, leads to damage of neuro-muscular junctions and ultimately leads to delaying in wound healing [20]. In the presence of pathogens, the macrophages secrete IL-6 which in turn increases Toll like receptor expression (TLR)-9 response-mediated defense for killing foreign particles. In case of prokaryotes, unmethylated DNA activates the TLR-9 pathway and helps in killing the pathogen at the wound site; mitochondrial DNA spillage, essentially the unmethylated DNA, triggers similar kind of responses in the tissue of wound [21]. In tissues, the angiogenesis is inhibited by IL-12 by overexpression of IFN-γmediated interferon-gamma-induced protein 10 (CXCL-10 or IP-10) [22]. Vascular endothelial growth factor (VEGF) expression is negatively controlled by IL-18, essential for the development of new blood vessels at the wound site and is essential for the growth and repair at wound tissue [23].

To start and control the wound healing mechanism, the inflammation is most important. In the nondiabetic wounds, anti-inflammatory cytokines like IL-4, IL-10, IL-13, IL-11, and transforming growth factor-beta (TGF-β) and interferon-alpha (IFN-α) play an important role in the wound healing process [24]. At the initial stage of wound recovery, TLR-9 induces the instant expression of pro-inflammatory signals like TNF-α through the increase in expression of mitogen-activated protein kinase (MAPK)/p38 and c-Jun N-terminal kinase (JNK) pathway [25]. In nondiabetic wounds, MAPK activation is prolonged and leads to MAPK phosphatase enzyme activation, which works as a negative regulator of JNK and MAPK/p38 pathways, resulting in the negative regulation of TNF-α production. The de-phosphorylation of MAPK/p38 leads to more expression of anti-inflammatory cytokines such as IL-10 a homodimeric cytokine, which is produced by the macrophages, monocytes and induce signaling of TGF-β, and can enhance the division of cells [26]. Cytokines like IL-4, IL-13, and IL-10 can stimulate extracellular matrix and fibrinogen, mainly collagen synthesis. IL-4, cytokines secreted by macrophages, mast cells and inflamed T cells activate the Janus kinase/signal transducer and transcription-6 (Jak/STAT6) pathway activator which promotes the wound repairing [27]. IL-4 is responsible for the extracellular matrix synthesis, mainly collagen which gives the physical support for the healing of the wound [28]. Another kind of cytokine, L-1RA, secreted from immune cells, adipocytes cells and cells of epithelia, leads the inhibition of pro-inflammatory IL1β cytokine effect by binding with the (IL-1R) interleukin-1 receptor. On the other hand, deregulation of TNF-α and IL-1β prolongs the phase of inflammation phase and leads to delay in wound healing [29]. IL-11 released from cells of bone marrow expresses anti-inflammatory effect. IL-11 inhibits the synthesis of IL-1 and TNF-α synthesis by the inhibition of NFkβP50/P65 with increasing the expression of inhibitory NFkβP50/P50 synthesis in monocytes/macrophage cells [30]. Transition between cytokines of pro and anti-inflammatory is balanced in nondiabetic wounds but in case of diabetic wounds, it gets impaired (**Figure 1**).

For the type-1 diabetes treatment or insulin-dependent diabetes, insulin is administrated systematically.

### **2. Activation of anti-inflammatory cytokines and increased differentiation of cells by signaling through insulin**

Insulin, released from pancreatic gland produced in its beta cells of the islets of Langerhans is a peptide hormone. Insulin precursor is proinsulin in humans, is

*Wound Healing*

retinopathy, neuropathy, damage of kidneys, damaging of blood vesicles, wound healing delay, etc. (**Figure 1**) [5, 6]. Due to the linkage of diabetes mellitus with other different diseases, the International Diabetes Foundation (IDF), in 2014, recorded that the 4.9 million lives loss and ~1.25% dead were diabetic patients, either directly by diabetes mellitus or indirectly through other diseases [7]. All these diseases are linked causing various effects on different body organs with various pathways; pathological/hyperglycemic conditions are linked with the inflammation of tissue [8]. Diabetes is responsible for lower gradation inflammation in a systemic way and leads to the promotion of different diseases like arthritis, retinopathy, etc. [9, 10]. One of the major problems associated with diabetes mellitus is inflammation in wounds and results in wound recovery delay [11]. The chronic wounds in diabetes mainly show the persistent increase in the level of pro-inflammatory cytokine and the absence of the signals, which are responsible for signals in the damaged tissues [12]. The treatments used in diabetes mellitus are also helpful in controlling the level of glucose blood and helps in delaying the further progression of other diseases linked with diabetes mellitus, like retinopathy, contract, arthritis, neuropathy, retinopathy, etc., but very less is known in the literature about diabetes mellitus treatment's effects on diabetic wound recovery [13]. Wound results in release of the pro-inflammatory cytokines such as interleukin-6 (IL-6), IL-1, IL-12, IL-18, and tumor necrosis factors (TNFs) and interferon-gamma (IFN-γ), which results in inflammation of tissues [14]. Pro-inflammatory cytokines like IL-6 and IL-1β are released from the macrophages and monocytes in the wound and result in pain responses by signaling the neurons [15]. IFN-γ, IL-1β, and TNF-α induce apoptosis and pyroptosis mediated by the activation of innate immunity and oxidative stress [16]. IFN-γ is an activator; it activates macrophages by stimulating STAT1 expression in order to activate the defense mechanism against the pathogens in the infected area [17]. IL-12 stimulates TNF-α and IFN-γ production and reduces the expression of IL-4, an anti-inflammatory cytokine, and negatively controls the expression of IFN-γ; IL-4 also through the activation of STAT-3 signaling inhibits IFN- γ [18]. IL-18 for defense against pathogens activates T cells and natural killer

*M1 macrophages (also known as classically activated), such as IL-12, IL-1β, IL-10, STAT1, TNF-α, and NFkβP50/P65, are leads to wound inflammation. Alternatively, active, that is, M2 macrophages, such as STAT3, HIF-α, PKC, NFkβP50/P50, etc., help in healing of the wound by decreasing inflammation. People having diabetes show prolonged M1 macrophage expression in wounds in comparison to nondiabetic wounds* 

**54**

**Figure 1.**

*that delay M1 to M2 macrophage transition.*

encoded by the INS gene and is a single polypeptide; after processing of proinsulin, two secretory proteins are produced, one chain having two chains namely A (21 amino acids) and B (30 amino acids), which forms mature insulin, and the second is C-chain known as C-peptide having 31 amino acids [31, 32]. Chain "A" is more compact having (2 small) α-helix region; on other hand, B chain has 1 such region. Two disulfide bonds between A20-B19 and A7-B7 hold chain A and chain B together; in addition to this, there is a disulfide bridge between A7-A11 cys amino acids of chain A. In the presence of Zn2+ and at ~6.0 favorable insulin pH, it folds to hexameric forms and is stored in pancreas. After diffusion of insulin in blood, with change in the pH, the hexameric insulin form changes to its monomeric form and shows binding with the insulin receptor [33]. The insulin binding with receptors depends on the regions present in the insulin monomeric form. The binding regions are present on the surface of insulin receptors; the changes or mutations in the binding regions reduce the insulin binding affinity [34]. The regions are located at TyrA19, AsnA21, CysA20, on the "A" chain C-terminus, IleA2, GlyA1, GluA4, ValA3, on the N terminus and at PheB24, GlyB23, TyrB26, and PheB25 at B" chain C-terminus (**Figure 2**) [35].

The insulin is found only in the humans, but peptides which are like insulin are also present in invertebrates like insects and molasses. Insulin-like peptides are having growth-related functions, and it indicates that the insulin is not only involved in metabolism of glucose but has other functions as well [37]. Drugs which can balance between the pro-inflammatory and anti-inflammatory cytokines can also be helpful for the treatment of other insulin-independent or dependent diabetes mellitus and its linked disease conditions. Using insulin as a wound-healing agent, very few studies have been found.

The anti-inflammatory effect by insulin is shown by activating the cytokine expression that can decrease the inflammation and help in recovery of the wound. Through metabolism and synthesis activities, insulin shows its effect on the differentiation and survival of cells. Insulin promotes NF-kβP50/P50 upregulation by the suppression of TNF-α and p65 expression. NF-kβP50/P65 expression suppression leads to decrease in expression of proinflammatory cytokines like IL-12, IL-1β, IL-6, and TNF-α cytokines at the site of wound [38]. Proinflammatory cytokine inhibition shifts the equilibrium towards the anti-inflammatory cytokine expression, like

#### **Figure 2.**

*Insulin structure (a) showing the sequence of amino acids present in insulin protein (b) showing the 3-D model of insulin [36].*

**57**

**Figure 3.**

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers*

IL-4, IL-10, and VEGF, etc., inhibits the apoptosis of cells, and increases proliferation of cell similarly like IGF [39]. Below sections show the regulation of cytokine dynamics by the insulin: (a) Inactivation of NFkβp50/p65 by insulin results in decrease in inflammation by inducing uptake of glucose uptake, (b) biosynthesis of fatty acid induction by insulin and inactivation through TNF-α, (c) role of insulin in cell differentiation and growth by synthesis of protein and inhibition of proteolysis by inactivation of FOXO to promote the survival of cell, (d) insulin functions like IGF and activates the same signaling pathway and reduces inflammation, and (e) anti-inflammatory action of insulin by reduction in proinflammatory cytokines

and increased expression of the anti-inflammatory cytokines (**Figure 3**).

*2.1.1 Inactivation of NFkβp50/p65 by insulin results in decrease in inflammation* 

The presence of high concentration of glucose at the wound site promotes microbial growth and leads to inflammatory signaling activation. The main function of insulin in the body is regulation of blood glucose level. It helps in the utilization of the glucose present in the blood through activation of glucose transporters and stored in glycogen form in the cells. The glycogen stored in the tissue of muscles behaves as a source of energy and gets used aerobically [40]. Wounds mainly in peripheral nerves, renal cortex, and retina are results from microcirculatory damage mainly due to increment in consumption of wound by the inflammatory cells, which leads to switch from aerobic glycolytic to anaerobic glycolytic [41]. The direct result of this is the lactic acid formation as the end glycolysis product. In addition to this, other resources of anaerobic glycolysis are the wound-proliferating cells, which are showing anaerobic respiration in the muscle cells [42]. In the blood, the lactic

Lactate converts into pyruvate and nicotinamide adenine dinucleotide (NADH);

NADH behaves as a substrate for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and helps in the formation of reactive species of oxygen (ROS) induced by lactate [43]. Due to more NADPH synthesis, NADPH to NAD+ ratio

*Insulin plays an important role as an anti-inflammatory agent and helps in the survival of cells by synthesis and metabolic pathways. Glucose metabolism activates NFk-β, and biosynthesis of fatty acids leads to TNF-ɑ activation which can inactivate the inflammatory signaling. By this signaling, insulin helps in the survival of cells and synthesis of protein. Along with this, the insulin activates the Akt pathway and can increase mTOR, MMPs, and eNOS expression leading to the formation of new blood vessels. Insulin can also decrease the NFkβP50/P65 expressions by the ERK and MEK pathways like the pathway for glucose uptake.*

*DOI: http://dx.doi.org/10.5772/intechopen.92096*

**2.1 Role of insulin to promote wound recovery**

*by inducing uptake of glucose*

acid gets used in the liver to form glucose.

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers DOI: http://dx.doi.org/10.5772/intechopen.92096*

IL-4, IL-10, and VEGF, etc., inhibits the apoptosis of cells, and increases proliferation of cell similarly like IGF [39]. Below sections show the regulation of cytokine dynamics by the insulin: (a) Inactivation of NFkβp50/p65 by insulin results in decrease in inflammation by inducing uptake of glucose uptake, (b) biosynthesis of fatty acid induction by insulin and inactivation through TNF-α, (c) role of insulin in cell differentiation and growth by synthesis of protein and inhibition of proteolysis by inactivation of FOXO to promote the survival of cell, (d) insulin functions like IGF and activates the same signaling pathway and reduces inflammation, and (e) anti-inflammatory action of insulin by reduction in proinflammatory cytokines and increased expression of the anti-inflammatory cytokines (**Figure 3**).

#### **2.1 Role of insulin to promote wound recovery**

*Wound Healing*

very few studies have been found.

encoded by the INS gene and is a single polypeptide; after processing of proinsulin, two secretory proteins are produced, one chain having two chains namely A (21 amino acids) and B (30 amino acids), which forms mature insulin, and the second is C-chain known as C-peptide having 31 amino acids [31, 32]. Chain "A" is more compact having (2 small) α-helix region; on other hand, B chain has 1 such region. Two disulfide bonds between A20-B19 and A7-B7 hold chain A and chain B together; in addition to this, there is a disulfide bridge between A7-A11 cys amino acids of chain A. In the presence of Zn2+ and at ~6.0 favorable insulin pH, it folds to hexameric forms and is stored in pancreas. After diffusion of insulin in blood, with change in the pH, the hexameric insulin form changes to its monomeric form and shows binding with the insulin receptor [33]. The insulin binding with receptors depends on the regions present in the insulin monomeric form. The binding regions are present on the surface of insulin receptors; the changes or mutations in the binding regions reduce the insulin binding affinity [34]. The regions are located at TyrA19, AsnA21, CysA20, on the "A" chain C-terminus, IleA2, GlyA1, GluA4, ValA3, on the N terminus and at PheB24, GlyB23, TyrB26, and PheB25 at B" chain C-terminus (**Figure 2**) [35]. The insulin is found only in the humans, but peptides which are like insulin are also present in invertebrates like insects and molasses. Insulin-like peptides are having growth-related functions, and it indicates that the insulin is not only involved in metabolism of glucose but has other functions as well [37]. Drugs which can balance between the pro-inflammatory and anti-inflammatory cytokines can also be helpful for the treatment of other insulin-independent or dependent diabetes mellitus and its linked disease conditions. Using insulin as a wound-healing agent,

The anti-inflammatory effect by insulin is shown by activating the cytokine expression that can decrease the inflammation and help in recovery of the wound. Through metabolism and synthesis activities, insulin shows its effect on the differentiation and survival of cells. Insulin promotes NF-kβP50/P50 upregulation by the suppression of TNF-α and p65 expression. NF-kβP50/P65 expression suppression leads to decrease in expression of proinflammatory cytokines like IL-12, IL-1β, IL-6, and TNF-α cytokines at the site of wound [38]. Proinflammatory cytokine inhibition shifts the equilibrium towards the anti-inflammatory cytokine expression, like

*Insulin structure (a) showing the sequence of amino acids present in insulin protein (b) showing the 3-D model* 

**56**

**Figure 2.**

*of insulin [36].*

### *2.1.1 Inactivation of NFkβp50/p65 by insulin results in decrease in inflammation by inducing uptake of glucose*

The presence of high concentration of glucose at the wound site promotes microbial growth and leads to inflammatory signaling activation. The main function of insulin in the body is regulation of blood glucose level. It helps in the utilization of the glucose present in the blood through activation of glucose transporters and stored in glycogen form in the cells. The glycogen stored in the tissue of muscles behaves as a source of energy and gets used aerobically [40]. Wounds mainly in peripheral nerves, renal cortex, and retina are results from microcirculatory damage mainly due to increment in consumption of wound by the inflammatory cells, which leads to switch from aerobic glycolytic to anaerobic glycolytic [41]. The direct result of this is the lactic acid formation as the end glycolysis product. In addition to this, other resources of anaerobic glycolysis are the wound-proliferating cells, which are showing anaerobic respiration in the muscle cells [42]. In the blood, the lactic acid gets used in the liver to form glucose.

Lactate converts into pyruvate and nicotinamide adenine dinucleotide (NADH); NADH behaves as a substrate for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and helps in the formation of reactive species of oxygen (ROS) induced by lactate [43]. Due to more NADPH synthesis, NADPH to NAD+ ratio

#### **Figure 3.**

*Insulin plays an important role as an anti-inflammatory agent and helps in the survival of cells by synthesis and metabolic pathways. Glucose metabolism activates NFk-β, and biosynthesis of fatty acids leads to TNF-ɑ activation which can inactivate the inflammatory signaling. By this signaling, insulin helps in the survival of cells and synthesis of protein. Along with this, the insulin activates the Akt pathway and can increase mTOR, MMPs, and eNOS expression leading to the formation of new blood vessels. Insulin can also decrease the NFkβP50/P65 expressions by the ERK and MEK pathways like the pathway for glucose uptake.*

reduces, which leads to the VEGF activation and angiogenesis. NADPH and pyruvate, both lead to the formation of new blood vessels and collagen through the inactivation of prolyl hydroxylase hypoxia inducible factor (HIF PHD) [44].

HIF causes the damage of tissue and inflammation at the wound [45]. Hypoxia is also responsible for the damage of peripheral blood vessels and also causes activates NADP oxidase (NOX) to generate oxidative stress in the wound, regulating key factor in the process of wound recovery and leading to inter-cellularly ROS overexpression [46]. High ROS level induces oxidation of protein and peroxidation of lipid, which causes apoptosis of cells [47]. The production of ROS leads to accumulation of NFkβP50/ P65 and inhibits HIF1 α and mTOR expression. In addition to mTOR and HIF1 inhibition, NFkβp50/NFkβp65 induces resistin expression, and both are responsible for intercellular insulin resistance [48]. The resistin leads to the activation of vicious cycle through p65 overexpression [49]. P65 activation shifts the equilibrium from NFκβp50/p50 to NFκβp50/p65 and results in insulin resistance generation [50]. It also induces mTOR and HIF1, by activation of the AKT pathway and inhibition of TNFα [51]. HIF1 activation shifts back to NFκβp50/p65 to NFκβp50/p50 equilibrium. The blood glucose normalization is possible with insulin proper functioning and also by the effective reduction of NFkβP50/P65 expression [52]. NFkβP50/P50 activation reduces expression of proinflammatory cytokines like IL-6 and IL-1β, induces high anti-inflammatory cytokine expression, leads to reduction in inflammation stage, and enhances repairing of tissue [50].

Pyruvate and NADPH inactivate the expression of HIF PHDs, by the oxidation of ascorbic acid and Fe (II). HIF PHDs are the dioxygenase and are 2-oxoglutarate and Fe (II)-dependent and require ascorbic acid. In lactate presence, ascorbic acid and Fe (II) get oxidized and inhibit damage of tissue and increase IL-8release, basal fibroblast growth factor (bFGF) and NF-kβP50/P50 activation [53]. Lactate also upregulates the expression of NF-kβP50/P50 by suppressing the formation of NF-kβP50/P65 and results in reduction of expression of IL-12, IL-1β, TNF-α, and IL-6 cytokines. This pathway ultimately results in more cell viability. Also, ROS-dependent IkBɑ expression inhibition and VEGF receptors are responsible for synthesis of collagen and angiogenesis [54]. IkBɑ helps in NFkβ translocation from nucleus, and p65 gene expression in turn is responsible for inflammation [55]. Along with this, NF-kβP50/P65 expression suppression happens through the phosphorylation of ERK through signaling of insulin [56]. In contrast to these findings, the lactate formed in skeletal muscles impairs the signaling of insulin and results in glucose metabolism inhibition [57]. Glucose metabolism signaling of insulin occurs through 6-phosphofructo-1-kinase (PFK-1), which in turn is formed by pyruvate dehydrogenase (PDH) and fructose-2, 6-biphosphate and used for the conversion pyruvate to oxaloacetate. This signaling of insulin is inhibited by lactate through the production of more citrate and reducing fructose-2, 6-biphosphate, and inhibits and promotes PFK-1 expression, respectively. Inhibition of PDH by rising ratio of NADH to NAD ultimately stops the pyruvate to oxaloacetate transformation [58]. This negative effect of lactate on glucose metabolism shows that it acts as an glycolysis inhibitor and results in increase in concentration of glucose in the blood serum [59]. The glucose high concentration in the blood leads to long-time expression of the inflammation cytokines at the wound site (**Figure 4**).

#### *2.1.2 Fatty acid biosynthesis induction by insulin and inactivation through TNF-α pathway*

Insulin also plays different other functions like it can stimulate the synthesis of protein and lipogenesis, as well as differentiation and growth of cells [60]. The lipogenesis is the fatty acid synthesis process which converts acetyl-CoA

**59**

**Figure 4.**

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers*

Fatty acids, mainly polyunsaturated, play an important role in the formation of cell membrane. Cell membrane composition affects the absorption of enzymes which are responsible for cell phosphatidylinositol 4-kinase (PI4K) proper functioning; membrane associated phosphatidylinositol kinase shows an important role in signaling of cell [64]. The fat metabolism products activate PI4K, which in turn regulates the Protein Kinase C (PKC) functioning and controls proinflammatory cytokine TNF-ɑ signaling [65]. PKC also induces inflammation through increasing the NFkβ and p38MAPK expression. In PI4K presence, the activity of PKC is inhibited, which leads to the reduction of proinflammatory cytokine (TNF-ɑ) release [66]. The free fatty acid component plays an important role in the wound recovery

*Transition pathway from M1 to M2 macrophages. TNF ɑ and IFN ϒ activate NFk β, STAT1, and IRF-3 at the wound site and help in the release of IL-10, IL-12, NFkβP50/P65, TNF-α, IL-1β, and STAT-1 leading to inflammation. M1 to M2 transition is important for wound recovery. IL-10, IL-4, IL-13, VEGF, insulin, and IGF can activate HIF-α, STAT3, and NFkβP50/P50 cytokines to activate the anti-inflammatory action.*

to triglycerides [61]. Lipogenesis is stimulated by insulin through two types of enzyme activation, PDH (pyruvate dehydrogenase), responsible for pyruvate conversion to acetyl CoA and another acetyl CoA carboxylase helps in conversion of acetyl to malonyl CoA. In the cytoplasm, Malonyl CoA gives 2-C building blocks, used for larger fatty acid synthesis [62]. Transportation of acetyl CoA from mitochondria to cytoplasm occurs by tricarboxylate translocase enzyme, after formation of citrate by reaction with oxaloacetate. The glucose shows a role in increasing

*DOI: http://dx.doi.org/10.5772/intechopen.92096*

the release of both citrate and insulin [63].

process (**Figure 4**).

#### *Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers DOI: http://dx.doi.org/10.5772/intechopen.92096*

to triglycerides [61]. Lipogenesis is stimulated by insulin through two types of enzyme activation, PDH (pyruvate dehydrogenase), responsible for pyruvate conversion to acetyl CoA and another acetyl CoA carboxylase helps in conversion of acetyl to malonyl CoA. In the cytoplasm, Malonyl CoA gives 2-C building blocks, used for larger fatty acid synthesis [62]. Transportation of acetyl CoA from mitochondria to cytoplasm occurs by tricarboxylate translocase enzyme, after formation of citrate by reaction with oxaloacetate. The glucose shows a role in increasing the release of both citrate and insulin [63].

Fatty acids, mainly polyunsaturated, play an important role in the formation of cell membrane. Cell membrane composition affects the absorption of enzymes which are responsible for cell phosphatidylinositol 4-kinase (PI4K) proper functioning; membrane associated phosphatidylinositol kinase shows an important role in signaling of cell [64]. The fat metabolism products activate PI4K, which in turn regulates the Protein Kinase C (PKC) functioning and controls proinflammatory cytokine TNF-ɑ signaling [65]. PKC also induces inflammation through increasing the NFkβ and p38MAPK expression. In PI4K presence, the activity of PKC is inhibited, which leads to the reduction of proinflammatory cytokine (TNF-ɑ) release [66]. The free fatty acid component plays an important role in the wound recovery process (**Figure 4**).

#### **Figure 4.**

*Wound Healing*

reduces, which leads to the VEGF activation and angiogenesis. NADPH and pyruvate, both lead to the formation of new blood vessels and collagen through the inactivation of prolyl hydroxylase hypoxia inducible factor (HIF PHD) [44].

reduction in inflammation stage, and enhances repairing of tissue [50].

the inflammation cytokines at the wound site (**Figure 4**).

*2.1.2 Fatty acid biosynthesis induction by insulin and inactivation through TNF-α*

Insulin also plays different other functions like it can stimulate the synthesis of protein and lipogenesis, as well as differentiation and growth of cells [60]. The lipogenesis is the fatty acid synthesis process which converts acetyl-CoA

Pyruvate and NADPH inactivate the expression of HIF PHDs, by the oxidation of ascorbic acid and Fe (II). HIF PHDs are the dioxygenase and are 2-oxoglutarate and Fe (II)-dependent and require ascorbic acid. In lactate presence, ascorbic acid and Fe (II) get oxidized and inhibit damage of tissue and increase IL-8release, basal fibroblast growth factor (bFGF) and NF-kβP50/P50 activation [53]. Lactate also upregulates the expression of NF-kβP50/P50 by suppressing the formation of NF-kβP50/P65 and results in reduction of expression of IL-12, IL-1β, TNF-α, and IL-6 cytokines. This pathway ultimately results in more cell viability. Also, ROS-dependent IkBɑ expression inhibition and VEGF receptors are responsible for synthesis of collagen and angiogenesis [54]. IkBɑ helps in NFkβ translocation from nucleus, and p65 gene expression in turn is responsible for inflammation [55]. Along with this, NF-kβP50/P65 expression suppression happens through the phosphorylation of ERK through signaling of insulin [56]. In contrast to these findings, the lactate formed in skeletal muscles impairs the signaling of insulin and results in glucose metabolism inhibition [57]. Glucose metabolism signaling of insulin occurs through 6-phosphofructo-1-kinase (PFK-1), which in turn is formed by pyruvate dehydrogenase (PDH) and fructose-2, 6-biphosphate and used for the conversion pyruvate to oxaloacetate. This signaling of insulin is inhibited by lactate through the production of more citrate and reducing fructose-2, 6-biphosphate, and inhibits and promotes PFK-1 expression, respectively. Inhibition of PDH by rising ratio of NADH to NAD ultimately stops the pyruvate to oxaloacetate transformation [58]. This negative effect of lactate on glucose metabolism shows that it acts as an glycolysis inhibitor and results in increase in concentration of glucose in the blood serum [59]. The glucose high concentration in the blood leads to long-time expression of

HIF causes the damage of tissue and inflammation at the wound [45]. Hypoxia is also responsible for the damage of peripheral blood vessels and also causes activates NADP oxidase (NOX) to generate oxidative stress in the wound, regulating key factor in the process of wound recovery and leading to inter-cellularly ROS overexpression [46]. High ROS level induces oxidation of protein and peroxidation of lipid, which causes apoptosis of cells [47]. The production of ROS leads to accumulation of NFkβP50/ P65 and inhibits HIF1 α and mTOR expression. In addition to mTOR and HIF1 inhibition, NFkβp50/NFkβp65 induces resistin expression, and both are responsible for intercellular insulin resistance [48]. The resistin leads to the activation of vicious cycle through p65 overexpression [49]. P65 activation shifts the equilibrium from NFκβp50/p50 to NFκβp50/p65 and results in insulin resistance generation [50]. It also induces mTOR and HIF1, by activation of the AKT pathway and inhibition of TNFα [51]. HIF1 activation shifts back to NFκβp50/p65 to NFκβp50/p50 equilibrium. The blood glucose normalization is possible with insulin proper functioning and also by the effective reduction of NFkβP50/P65 expression [52]. NFkβP50/P50 activation reduces expression of proinflammatory cytokines like IL-6 and IL-1β, induces high anti-inflammatory cytokine expression, leads to

**58**

*pathway*

*Transition pathway from M1 to M2 macrophages. TNF ɑ and IFN ϒ activate NFk β, STAT1, and IRF-3 at the wound site and help in the release of IL-10, IL-12, NFkβP50/P65, TNF-α, IL-1β, and STAT-1 leading to inflammation. M1 to M2 transition is important for wound recovery. IL-10, IL-4, IL-13, VEGF, insulin, and IGF can activate HIF-α, STAT3, and NFkβP50/P50 cytokines to activate the anti-inflammatory action.*

*2.1.3 Role of insulin in cell differentiation and growth by synthesis of protein and proteolysis inhibition by the inactivation of FOXO to enhance the survival of the cell and tissue*

Insulin stimulates the synthesis of protein in different cells and tissues. In muscle tissues, insulin affects the flow of blood and amino acids uptake by the tissues of muscle and helps in anabolism in the muscles [67]. It has been studied that insulin systematic uptake loses the muscle volume, which mainly happens due to insulin systematic infusion and results in the reduction of the amount of free amino acids in blood and plays an important role in the anabolism in muscles [68]. The deficiency of insulin can be overcome by systematically giving insulin exogenously [69]. Essential protein formation is stimulated by promoting the concentration of RNA contents in the cells and tissues by the insulin functioning pathway through the translocation of the mRNA by the phosphoinositide-3-kinase (PI3K) pathway [70]. By the PI3K pathway, an Akt inhibits the tuberous sclerosis protein ½ (TSC1/2) functioning and behaves like an inhibitor of the mechanistic target of rapamycin (mTOR) and in the end by phosphorylation of 4E Binding protein (4EBP-1leads it activates the eukaryotic initiation factor (eIF4B)). The eukaryotic 20 structured mRNA 5'end eIF4B binds. During the synthesis of protein, eIF4B binds with subunits of eIF4A and eIF4G, further binding with ribosome 40S, and it has RNA helicase absent or low results in impairment in the synthesis of protein. The mTOR activation leads to proteolysis inhibition by MAPox activation [71]. High concentration of insulin in the muscle cells inhibits the protein degradation and leads to muscle cell and tissue expansion [72]. Due to inhibition of protein degradation, the insulin ultimately leads to reduce the blood amino acids concentration [73]. This amino acid concentration regulation of insulin clearly indicates that insulin plays a very important part in the diabetic wound healing condition when the patients are on systemic treatment of insulin (**Figure 4**).

#### *2.1.4 Insulin behaves the same as insulin-like growth factor and can also activate similar pathway to decrease the inflammation*

Insulin-like growth factor (IGF) is composed of two IGF ligands such as IGF-I and II. At the time of embryogenesis, IGF are the proteins that regulate development and growth, tissue differentiation in adults and show anti-inflammatory actions through the activation of anti-inflammatory cytokines. Insulin shows antiinflammatory effect by increasing release of IL-10 and IL-13/4. By decreasing proinflammatory cytokines release (IFN-ϒ) [74]. IGFs show binding with the insulin receptor (IR), insulin-related receptor, and IGF receptor (IGF-1 and IGF-2). Main functions of IGF-I and II are mediated by Insulin Growth Factor Insulin receptor (IGF-IR) [75]. IGF-I is an important growth factor produced by the macrophages, fibroblast keratinocyte, and platelets. It enhances endothelial cell migration into the wound site. It enhances the mitosis and fibroblast cell proliferation for the new blood vessel formation and extracellular matrix and activation of protein kinase B signaling. In addition to this, it also enhances the synthesis of protein and blocks the muscles atrophy in order to skeletal hypertrophy catalysis [76].

Upon binding with receptor, the IGF-I activates the insulin receptor substrate-1 (IRS-1) which in turn by phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) phosphorylates the protein kinase B (Akt). Phosphorylated Akt activates the mTOR; PI3K-related kinase controls the proliferation of the cells [77]. Also, IGF-I enhances cell growth by activating the mitogen-activated protein kinase/extracellular signal regulated kinase/MAPK/ERK pathway through RAF/RAS kinase phosphorylation of [78]. Along with this, IGF-I binding of receptor enhances the

**61**

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers*

The decrease in action of insulin may be due to resistance of insulin or due to the insufficient insulin release, and it ultimately results in diabetes mellitus. The functioning of insulin either reduces due to the β-cells functioning loss or due to the improper functioning of insulin receptors or due to the kidney disease [79]. The insulin treatment systemically is already taken by 6 million people of America, and it keeps on increasing to control high blood glucose condition. High blood glucose concentration leads to the tissue damage by the oxidative stress through increasing flux of other sugars and glucose by the polyol pathway and also enhances the expression end products of advanced glycation and it's activating ligand receptors and through the overexpression of the pathway of hexosamine and activation of protein kinase. The mechanisms mainly take place by the overexpression of mitochondrial ROS [80]. In the polyol pathway, due to more NADPH consumption in the glucose transport pathway, more redox stress is generated and remains insufficient to form the scavengers of ROS that is GSH reduced form advanced glycinated product precursor formation modifies the proteins of plasma that can bind with the receptors of the advanced glycination product present on the surface of macrophages, smooth cells and vascular endothelial cells. This activation of NFkβ transcription factor, in turns activates HIF-ɑ and results in hypoxia stimulated chemokines production through the ROS production [81]. In the presence of high glucose, the protein kinase enzyme shows hyperactivity and stimulates the expression of eNOS in the smooth muscles cells and leads to the destruction of tissue. Increased ROS expression shows the activation of different proinflammation pathways and helps in generating the epigenetic changes, which can result in the prolonged expression of the proinflammatory genes during the wound recovery. Matrix metalloproteinase (MMP-2, 4) excessive production impairs the recovery process of wound and results in extracel-

secretion of anti-inflammatory cytokine such as IL-10 activates Akt by AMPK signaling. Likewise, such as IL-4 and IL-10 can also bind with Akt and plays role in

M2 macrophages infiltration at the site of wound (**Figure 4**).

*2.1.5 The anti-inflammatory action of insulin through a reduction in pro-inflammatory cytokine expression enhances the formation of* 

lular matrix protein breakdown such as vitronectin and fibronectin [82].

In nondiabetic wounds, the wound healing process involves the activation of the series of different physiological events for wound recovery like inflammation at wound site, cell proliferation, epithelisation of cells, vascularisation, maturation, and re-modeling at the site of wound [83]. Macrophages play an important role in the whole healing process. At early wound phase, in the wound recovery process, macrophages function by the cytokine release and activation of leucocytes, which leads to the production of inflammatory response at the site of the wound [84]. The infiltration of the macrophage at the wound site takes place by the effect of chemotaxis which induces the factors like Toll-like receptor (TLR) ligand, PAMP (pathogen-associated molecular patterns), LPS (lipopolysaccharide), PDGF, and IFN-gamma (IFN-ϒ) [85]. M1 macrophages lead to high level secretion of STAT1 and expression of TNF-α or IFN-β. By the activation of the Akt/PI3 pathway, insulin stimulates STAT3, which inhibits STAT1 formation and activates the transition from M1 macrophages to M2 macrophages for the repairing of wound and tissue repairing. M2 macrophages can help in the production of polyamines and ornithine by the pathway of arginase enzyme and anti-inflammatory pathway IL-10, IL-13and IL-4 cytokines [86]. Insulin along with M2 macrophages activates the anti-inflammatory cytokines by Akt, or IP3K pathway activates biosynthesis of protein to induce fatty acid and blood vessel formation and division and migration of cells, to increase

*DOI: http://dx.doi.org/10.5772/intechopen.92096*

*anti-inflammatory cytokines*

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers DOI: http://dx.doi.org/10.5772/intechopen.92096*

secretion of anti-inflammatory cytokine such as IL-10 activates Akt by AMPK signaling. Likewise, such as IL-4 and IL-10 can also bind with Akt and plays role in M2 macrophages infiltration at the site of wound (**Figure 4**).

### *2.1.5 The anti-inflammatory action of insulin through a reduction in pro-inflammatory cytokine expression enhances the formation of anti-inflammatory cytokines*

The decrease in action of insulin may be due to resistance of insulin or due to the insufficient insulin release, and it ultimately results in diabetes mellitus. The functioning of insulin either reduces due to the β-cells functioning loss or due to the improper functioning of insulin receptors or due to the kidney disease [79]. The insulin treatment systemically is already taken by 6 million people of America, and it keeps on increasing to control high blood glucose condition. High blood glucose concentration leads to the tissue damage by the oxidative stress through increasing flux of other sugars and glucose by the polyol pathway and also enhances the expression end products of advanced glycation and it's activating ligand receptors and through the overexpression of the pathway of hexosamine and activation of protein kinase. The mechanisms mainly take place by the overexpression of mitochondrial ROS [80]. In the polyol pathway, due to more NADPH consumption in the glucose transport pathway, more redox stress is generated and remains insufficient to form the scavengers of ROS that is GSH reduced form advanced glycinated product precursor formation modifies the proteins of plasma that can bind with the receptors of the advanced glycination product present on the surface of macrophages, smooth cells and vascular endothelial cells. This activation of NFkβ transcription factor, in turns activates HIF-ɑ and results in hypoxia stimulated chemokines production through the ROS production [81]. In the presence of high glucose, the protein kinase enzyme shows hyperactivity and stimulates the expression of eNOS in the smooth muscles cells and leads to the destruction of tissue. Increased ROS expression shows the activation of different proinflammation pathways and helps in generating the epigenetic changes, which can result in the prolonged expression of the proinflammatory genes during the wound recovery. Matrix metalloproteinase (MMP-2, 4) excessive production impairs the recovery process of wound and results in extracellular matrix protein breakdown such as vitronectin and fibronectin [82].

In nondiabetic wounds, the wound healing process involves the activation of the series of different physiological events for wound recovery like inflammation at wound site, cell proliferation, epithelisation of cells, vascularisation, maturation, and re-modeling at the site of wound [83]. Macrophages play an important role in the whole healing process. At early wound phase, in the wound recovery process, macrophages function by the cytokine release and activation of leucocytes, which leads to the production of inflammatory response at the site of the wound [84].

The infiltration of the macrophage at the wound site takes place by the effect of chemotaxis which induces the factors like Toll-like receptor (TLR) ligand, PAMP (pathogen-associated molecular patterns), LPS (lipopolysaccharide), PDGF, and IFN-gamma (IFN-ϒ) [85]. M1 macrophages lead to high level secretion of STAT1 and expression of TNF-α or IFN-β. By the activation of the Akt/PI3 pathway, insulin stimulates STAT3, which inhibits STAT1 formation and activates the transition from M1 macrophages to M2 macrophages for the repairing of wound and tissue repairing. M2 macrophages can help in the production of polyamines and ornithine by the pathway of arginase enzyme and anti-inflammatory pathway IL-10, IL-13and IL-4 cytokines [86]. Insulin along with M2 macrophages activates the anti-inflammatory cytokines by Akt, or IP3K pathway activates biosynthesis of protein to induce fatty acid and blood vessel formation and division and migration of cells, to increase

*Wound Healing*

*the cell and tissue*

*2.1.3 Role of insulin in cell differentiation and growth by synthesis of protein and proteolysis inhibition by the inactivation of FOXO to enhance the survival of* 

it activates the eukaryotic initiation factor (eIF4B)). The eukaryotic 20

on systemic treatment of insulin (**Figure 4**).

*similar pathway to decrease the inflammation*

muscles atrophy in order to skeletal hypertrophy catalysis [76].

mRNA 5'end eIF4B binds. During the synthesis of protein, eIF4B binds with subunits of eIF4A and eIF4G, further binding with ribosome 40S, and it has RNA helicase absent or low results in impairment in the synthesis of protein. The mTOR activation leads to proteolysis inhibition by MAPox activation [71]. High concentration of insulin in the muscle cells inhibits the protein degradation and leads to muscle cell and tissue expansion [72]. Due to inhibition of protein degradation, the insulin ultimately leads to reduce the blood amino acids concentration [73]. This amino acid concentration regulation of insulin clearly indicates that insulin plays a very important part in the diabetic wound healing condition when the patients are

*2.1.4 Insulin behaves the same as insulin-like growth factor and can also activate* 

Insulin-like growth factor (IGF) is composed of two IGF ligands such as IGF-I and II. At the time of embryogenesis, IGF are the proteins that regulate development and growth, tissue differentiation in adults and show anti-inflammatory actions through the activation of anti-inflammatory cytokines. Insulin shows antiinflammatory effect by increasing release of IL-10 and IL-13/4. By decreasing proinflammatory cytokines release (IFN-ϒ) [74]. IGFs show binding with the insulin receptor (IR), insulin-related receptor, and IGF receptor (IGF-1 and IGF-2). Main functions of IGF-I and II are mediated by Insulin Growth Factor Insulin receptor (IGF-IR) [75]. IGF-I is an important growth factor produced by the macrophages, fibroblast keratinocyte, and platelets. It enhances endothelial cell migration into the wound site. It enhances the mitosis and fibroblast cell proliferation for the new blood vessel formation and extracellular matrix and activation of protein kinase B signaling. In addition to this, it also enhances the synthesis of protein and blocks the

Upon binding with receptor, the IGF-I activates the insulin receptor substrate-1 (IRS-1) which in turn by phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) phosphorylates the protein kinase B (Akt). Phosphorylated Akt activates the mTOR; PI3K-related kinase controls the proliferation of the cells [77]. Also, IGF-I enhances cell growth by activating the mitogen-activated protein kinase/extracellular signal regulated kinase/MAPK/ERK pathway through RAF/RAS kinase phosphorylation of [78]. Along with this, IGF-I binding of receptor enhances the

Insulin stimulates the synthesis of protein in different cells and tissues. In muscle tissues, insulin affects the flow of blood and amino acids uptake by the tissues of muscle and helps in anabolism in the muscles [67]. It has been studied that insulin systematic uptake loses the muscle volume, which mainly happens due to insulin systematic infusion and results in the reduction of the amount of free amino acids in blood and plays an important role in the anabolism in muscles [68]. The deficiency of insulin can be overcome by systematically giving insulin exogenously [69]. Essential protein formation is stimulated by promoting the concentration of RNA contents in the cells and tissues by the insulin functioning pathway through the translocation of the mRNA by the phosphoinositide-3-kinase (PI3K) pathway [70]. By the PI3K pathway, an Akt inhibits the tuberous sclerosis protein ½ (TSC1/2) functioning and behaves like an inhibitor of the mechanistic target of rapamycin (mTOR) and in the end by phosphorylation of 4E Binding protein (4EBP-1leads

structured

**60**

wound recovery. With resistance of insulin in diabetic condition, there is constant increase in concentration of proinflammatory cytokines TNFα and IL-6 have been shown in the figure. In the non-diabetic/normal glycemic condition, cytokines are produced by adipocytes such as IL-13, which can promote the M2 activation or alternative macrophages. Alternatively, M2 or activated macrophages are important for the expression of anti-inflammatory cytokine secretion such as IL-10 and PPAR-ϒ (Peroxisome Proliferator-Activated Receptor Gamma) and insulinsensitizing factors, forming a vicious circle for the functionality of insulin. PPAR-ϒ also activates anti-inflammatory IL-10 cytokine [87] (**Figure 4**).

In the glycemic condition, there is an excessive proinflammatory macrophage expression of cytokines like TNF-α and IL-1β leading to impaired wound recovery. Overactivation of cytokines like IL-17, TNF-α or IL-1β reduces expression of inflammatory cytokines and upregulates genes responsible for wound healing and increases the healing process [86]. In the blood and adipose tissue, the high TNF-α cytokine concentration and TNF-α neutralization improve the insulin sensitivity in the humans or animals. High glucose condition stimulates changes in the gene expression and adipocyte metabolism and lipolysis increment and synthesis of fatty acids (FFAs) and proinflammatory cytokines induces the expressions of macrophages, like tumor necrosis factor α (TNF-α) and monocyte chemotactic protein-1 (MCP-1). M1 macrophage activation produces an excessive concentration of cytokines responsible for inflammation such as TNFα, resistin, and IL-1β, which can act on the cells of adipocyte to make them insulin-resistant. This signaling pathway forms the feedback loop which can increase the resistance to insulin and inflammation [88].

TNF-α, an inflammatory cytokine, performs role in the healing of nondiabetic wound process, but activation of TNF-α for a long time leads to enhancing enzymatic activity of protease enzyme. In human diabetic wounds, MMPs are found in very high amount. In chronic or diabetic wounds, there is imbalance in the expression of cytokines causes proinflammation and their proteases, inhibitors, and their ant protease expression [89].

The switching of macrophages in the high glucose condition gets delayed due to MMPs, IL-1β, IL-6, and ROS cytokine oxidative stress (**Figures 5** and **6**). This leads to delay in M1 to M2 transition and is responsible for the inflammation for long time and leads to delay in the wound recovery [90, 91]. The insulin role in the switching from inflammatory state to anti-inflammatory state is shown in **Figure 5**.

#### *2.1.6 The insulin-like activity of C-peptide*

C-peptide consists of only 31 amino acids, is a short peptide and has glycine amino acid-rich regions and behaves like a linker between the two peptides of proinsulin A and B [93]. By ERK1/2 activation and Akt phosphorylation, C-peptide shows angiogenesis. The angiogenesis signaling pathway shows similarity with the VEGF pathway and leads to the formation of nitric oxide by eNOS activation. C-peptide plays a curious role in the cell mitogenesis like insulin, by the same signaling pathway as the insulin protein [94]. C-peptide shows binding to the insulin receptor (IR) and results in intracellular substrate phosphorylation in Ras/MAPK. The PI3K/Akt signaling results in cell division and mitogenesis. Along with the abovementioned two functions, C-peptide also shows its antiinflammatory effect. C-peptide shows MIP-1ɑ, IL-8, MIP-1β, and IL-6 expression inhibition and other pro-inflammatory cytokine expression [95]. Like insulin, C-peptide can also reduce the problems linked with diabetes, such as vascular inflammation, neuropathy, and nephropathy, in diabetes case especially type 1 diabetes case [96].

**63**

**Figure 6.**

*around 22 ± 2 to 1.96 ± 0.1 nm. Scale bar: 50 nm [40].*

**Figure 5.**

*and help in wound healing.*

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers*

*Effect of insulin on switching of M1 to M2 macrophages. In insulin presence, (AMPK, Akt, STAT3, PKC, HIF-α, PI3K, NFkβP50/P50, and ERK) M2 macrophage expression increases show an anti-inflammatory effect* 

The C-peptide level rises in the blood during diabetic mellitus type 2, which is due to resistance of insulin [97]. At this time, endothelial dysfunction initiated led by the C-peptide deposition in the blood vessel intima walls. The C-peptide deposition causes more inflammation in the blood vessels of the aortic arch and promotes atherosclerotic lesions. The inflammation effect of C-peptide is shown due to C-peptide chemotactic behaviour towards macrophages responsible for inflammation. Monocytes/T-lymphocytes/macrophages migrate through the vessel walls and then release TNF-ɑ, IL-6, and MIF etc., pro-inflammatory cytokines and chemo-

*TEM micrographs of AgNPs and IAgNPs shown with insulin protein coating; the size of AgNPs shifts from* 

kines and nitric oxide, and activates intracellular signaling pathway [98].

*DOI: http://dx.doi.org/10.5772/intechopen.92096*

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers DOI: http://dx.doi.org/10.5772/intechopen.92096*

#### **Figure 5.**

*Wound Healing*

wound recovery. With resistance of insulin in diabetic condition, there is constant increase in concentration of proinflammatory cytokines TNFα and IL-6 have been shown in the figure. In the non-diabetic/normal glycemic condition, cytokines are produced by adipocytes such as IL-13, which can promote the M2 activation or alternative macrophages. Alternatively, M2 or activated macrophages are important for the expression of anti-inflammatory cytokine secretion such as IL-10 and PPAR-ϒ (Peroxisome Proliferator-Activated Receptor Gamma) and insulinsensitizing factors, forming a vicious circle for the functionality of insulin. PPAR-ϒ

In the glycemic condition, there is an excessive proinflammatory macrophage expression of cytokines like TNF-α and IL-1β leading to impaired wound recovery. Overactivation of cytokines like IL-17, TNF-α or IL-1β reduces expression of inflammatory cytokines and upregulates genes responsible for wound healing and increases the healing process [86]. In the blood and adipose tissue, the high TNF-α cytokine concentration and TNF-α neutralization improve the insulin sensitivity in the humans or animals. High glucose condition stimulates changes in the gene expression and adipocyte metabolism and lipolysis increment and synthesis of fatty acids (FFAs) and proinflammatory cytokines induces the expressions of macrophages, like tumor necrosis factor α (TNF-α) and monocyte chemotactic protein-1 (MCP-1). M1 macrophage activation produces an excessive concentration of cytokines responsible for inflammation such as TNFα, resistin, and IL-1β, which can act on the cells of adipocyte to make them insulin-resistant. This signaling pathway forms the feedback

also activates anti-inflammatory IL-10 cytokine [87] (**Figure 4**).

loop which can increase the resistance to insulin and inflammation [88].

from inflammatory state to anti-inflammatory state is shown in **Figure 5**.

ant protease expression [89].

*2.1.6 The insulin-like activity of C-peptide*

TNF-α, an inflammatory cytokine, performs role in the healing of nondiabetic wound process, but activation of TNF-α for a long time leads to enhancing enzymatic activity of protease enzyme. In human diabetic wounds, MMPs are found in very high amount. In chronic or diabetic wounds, there is imbalance in the expression of cytokines causes proinflammation and their proteases, inhibitors, and their

The switching of macrophages in the high glucose condition gets delayed due to MMPs, IL-1β, IL-6, and ROS cytokine oxidative stress (**Figures 5** and **6**). This leads to delay in M1 to M2 transition and is responsible for the inflammation for long time and leads to delay in the wound recovery [90, 91]. The insulin role in the switching

C-peptide consists of only 31 amino acids, is a short peptide and has glycine

amino acid-rich regions and behaves like a linker between the two peptides of proinsulin A and B [93]. By ERK1/2 activation and Akt phosphorylation, C-peptide shows angiogenesis. The angiogenesis signaling pathway shows similarity with the VEGF pathway and leads to the formation of nitric oxide by eNOS activation. C-peptide plays a curious role in the cell mitogenesis like insulin, by the same signaling pathway as the insulin protein [94]. C-peptide shows binding to the insulin receptor (IR) and results in intracellular substrate phosphorylation in Ras/MAPK. The PI3K/Akt signaling results in cell division and mitogenesis. Along with the abovementioned two functions, C-peptide also shows its antiinflammatory effect. C-peptide shows MIP-1ɑ, IL-8, MIP-1β, and IL-6 expression inhibition and other pro-inflammatory cytokine expression [95]. Like insulin, C-peptide can also reduce the problems linked with diabetes, such as vascular inflammation, neuropathy, and nephropathy, in diabetes case especially type 1

**62**

diabetes case [96].

*Effect of insulin on switching of M1 to M2 macrophages. In insulin presence, (AMPK, Akt, STAT3, PKC, HIF-α, PI3K, NFkβP50/P50, and ERK) M2 macrophage expression increases show an anti-inflammatory effect and help in wound healing.*

#### **Figure 6.**

*TEM micrographs of AgNPs and IAgNPs shown with insulin protein coating; the size of AgNPs shifts from around 22 ± 2 to 1.96 ± 0.1 nm. Scale bar: 50 nm [40].*

The C-peptide level rises in the blood during diabetic mellitus type 2, which is due to resistance of insulin [97]. At this time, endothelial dysfunction initiated led by the C-peptide deposition in the blood vessel intima walls. The C-peptide deposition causes more inflammation in the blood vessels of the aortic arch and promotes atherosclerotic lesions. The inflammation effect of C-peptide is shown due to C-peptide chemotactic behaviour towards macrophages responsible for inflammation. Monocytes/T-lymphocytes/macrophages migrate through the vessel walls and then release TNF-ɑ, IL-6, and MIF etc., pro-inflammatory cytokines and chemokines and nitric oxide, and activates intracellular signaling pathway [98].

### **3. Insulin encapsulated mettalic nanoformulations for wound recovery**

Nanoparticles of metals such as silver nanoparticles can be used for the delivery of insulin at the site of a wound. Silver nanoparticles have clinical applications due to its antibacterial, anti-inflammatory, and wound healing role. Due to the presence of charge on the surface of metal nanoparticle surface, they are highly reactive and can be surfaces modified by adsorbing different molecules or drugs. The drugs having thiol or amine can easily adsorb on the surface of silver nanoparticles, and due to this, it can help as a drug delivery agent. The anti-inflammatory effect and wound healing (non-diabetic and diabetic) efficiency of silver nanoparticles can be improved by encapsulating the insulin with silver nanoparticles [99, 100].

#### **3.1 Synthesis and characterization of metal insulin nanoparticles**

It is very easy to synthesize silver nanoparticles by using reducing and stabilizing agents. Plant extracts like tulsi leaf extract may be used as both reducing and stabilizing agents. The tulsi (*Ocimum tenuiflorum*) aqueous extract of leaves (ATE) was extracted by boiling 3 g of tulsi leaves in water (100 ml for 2 h). After extraction, the extract was allowed to cool and filtered, and the pH of the extract was adjusted to 7.4, and the pH adjusted extract was stored at 4°C for further use. AgNP synthesis was performed by using ATE as a reducing and capping agent. AgNO3 240 μM was added in ATE (5000 μl) and for 10 min was kept under sunlight. The solution color changed from faint light yellow to reddish brown in the presence of sunlight. After this, AgNPs were incubated with insulin at physiological conditions, the temperature being 37°C for an hour in an incubator in order to produce insulinprotected AgNPs (IAgNPs).

Surface plasmon of nanoparticles with or without protein was monitored using a UV–visible spectrophotometer equipped with Peltier, which showed a resonance peak observed at 352 nm due to the silver nitrate reduction by ATE in sunlight. After incubation with insulin, a blue shift (3 nm) with almost peak intensity double was observed, and λmax was obtained at 349 nm due to the formation of monodispersed IAgNPs. The hydrodynamic size of 22 ± 2 and 42 ± 2 nm (approximately diameter) are observed for AgNPs and IAgNPs, respectively. The Zeta potential showed an increment in the potential values from −12.4 to −15.1 mV due to the conversion of AgNPs to IAgNPs. TEM micrographs showed that both AgNPs and IAgNPs are similar in shape (spherical in shape). AgNP have a size ranging between 20 ± 4 nm, and further, it received a cap of 2 ± 0.5 nm when coated with insulin (IAgNPs) as shown in **Figure 6**.

#### **3.2 Metallic insulin nanoformulation wound healing and anti-inflammatory effect**

Wound recovery is promoted by both insulin and IAgNPs in hyperglycemic/diabetic and normal/nondiabetic animal conditions. In both in vivo and in vitro cases, the insulin promotes the wound healing in hyperglycemic and normal conditions. With IAgNPs 12 and 20%, faster wound recovery on treatment's 5th day of the wound was found for nondiabetic and diabetic rats in comparison to the untreated control. Whereas in relation to the IAgNPs, faster wound recovery was shown by free insulin with lesser efficiency with an enhanced rate of 7.27 and 4.67%, respectively, for the normoglycemic and diabetic rate in comparison to untreated rats. The % was 60.0 and 73.33% and with IAgNPs and 33.33 and 40% with only insulin in nondiabetic and diabetic models, respectively, on the 11th day, in comparison to the untreated controls as shown in **Figure 7**.

**65**

**Figure 7.**

*11th day [40].*

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers*

The quantification of serum showed an increase in anti-inflammatory cytokine percentage and reduction in the expression of inflammatory cytokines in diabetic and normal/normoglycemic animals after treatment with insulin and IAgNPs in comparison to their respective controls. On 5th day, in diabetic rats, the IL-6 concentration was 25%, and TNF-α is in double higher concentration than the normoglycemic control. With treatment of IAgNPs, 50% inhibition of expression of cytokine is much higher than free insulin in both the groups. On the 11th day, IL-6 expression and TNF-α was 30% and 50%, respectively, in control than in normal models, which reduces to 45% in both hyperglycemic and normal animals after treatment with free insulin, and with IAgNPs, the inhibition was around 30% in TNF-α and 40% in IL-6. In addition to reduction in inflammatory cytokine expression, the anti-inflammatory cytokine percentage (IL-10) increases after treating with free insulin and IAgNPs. On the 5th day, IAgNP-treated rats showed that IL-10 increased 50% in diabetic rats and 70% in normal and similarly showed increment in IL-10 concentration of 30% and 45% in diabetic and normal models, respectively, in free insulin-treated groups in comparison to control. On 11th day with IAgNPs anti-inflammatory cytokine concentration was increased by 50 and 65% and with insulin slightly less in both hyperglycemic and normal animals models, respectively. On the 5th and 11th days, the histological evaluations significantly decreased leukocyte infiltration level; faster collagen deposition and fast re-epithelization were

observed with insulin and IAgNPs in relation with sub-group (**Figure 8**).

*Wound healing rate of AgNP, ATE-insulin and IAgNP treatment in both hyperglycemic and normal animals on 5th day and 11th day. (A) Wound contraction physical observation in various treatment and control groups. (B) Percentage of closure of wound in different treated groups (AgNPs, ATE-insulin, and IAgNPs) and respective controls of hyperglycemic and normal animals until complete healing of wound takes place. (C) Percentage of contraction of wound in four subgroups of hyperglycemic and normal animals on 5th day. (D) Percentage of contraction of wound in all the four subgroups of hyperglycemic and normal animals on the* 

*DOI: http://dx.doi.org/10.5772/intechopen.92096*

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers DOI: http://dx.doi.org/10.5772/intechopen.92096*

The quantification of serum showed an increase in anti-inflammatory cytokine percentage and reduction in the expression of inflammatory cytokines in diabetic and normal/normoglycemic animals after treatment with insulin and IAgNPs in comparison to their respective controls. On 5th day, in diabetic rats, the IL-6 concentration was 25%, and TNF-α is in double higher concentration than the normoglycemic control. With treatment of IAgNPs, 50% inhibition of expression of cytokine is much higher than free insulin in both the groups. On the 11th day, IL-6 expression and TNF-α was 30% and 50%, respectively, in control than in normal models, which reduces to 45% in both hyperglycemic and normal animals after treatment with free insulin, and with IAgNPs, the inhibition was around 30% in TNF-α and 40% in IL-6. In addition to reduction in inflammatory cytokine expression, the anti-inflammatory cytokine percentage (IL-10) increases after treating with free insulin and IAgNPs. On the 5th day, IAgNP-treated rats showed that IL-10 increased 50% in diabetic rats and 70% in normal and similarly showed increment in IL-10 concentration of 30% and 45% in diabetic and normal models, respectively, in free insulin-treated groups in comparison to control. On 11th day with IAgNPs anti-inflammatory cytokine concentration was increased by 50 and 65% and with insulin slightly less in both hyperglycemic and normal animals models, respectively. On the 5th and 11th days, the histological evaluations significantly decreased leukocyte infiltration level; faster collagen deposition and fast re-epithelization were observed with insulin and IAgNPs in relation with sub-group (**Figure 8**).

#### **Figure 7.**

*Wound Healing*

protected AgNPs (IAgNPs).

(IAgNPs) as shown in **Figure 6**.

untreated controls as shown in **Figure 7**.

**effect**

**3. Insulin encapsulated mettalic nanoformulations for wound recovery**

improved by encapsulating the insulin with silver nanoparticles [99, 100].

**3.1 Synthesis and characterization of metal insulin nanoparticles**

Nanoparticles of metals such as silver nanoparticles can be used for the delivery of insulin at the site of a wound. Silver nanoparticles have clinical applications due to its antibacterial, anti-inflammatory, and wound healing role. Due to the presence of charge on the surface of metal nanoparticle surface, they are highly reactive and can be surfaces modified by adsorbing different molecules or drugs. The drugs having thiol or amine can easily adsorb on the surface of silver nanoparticles, and due to this, it can help as a drug delivery agent. The anti-inflammatory effect and wound healing (non-diabetic and diabetic) efficiency of silver nanoparticles can be

It is very easy to synthesize silver nanoparticles by using reducing and stabilizing agents. Plant extracts like tulsi leaf extract may be used as both reducing and stabilizing agents. The tulsi (*Ocimum tenuiflorum*) aqueous extract of leaves (ATE) was extracted by boiling 3 g of tulsi leaves in water (100 ml for 2 h). After extraction, the extract was allowed to cool and filtered, and the pH of the extract was adjusted to 7.4, and the pH adjusted extract was stored at 4°C for further use. AgNP synthesis was performed by using ATE as a reducing and capping agent. AgNO3 240 μM was added in ATE (5000 μl) and for 10 min was kept under sunlight. The solution color changed from faint light yellow to reddish brown in the presence of sunlight. After this, AgNPs were incubated with insulin at physiological conditions, the temperature being 37°C for an hour in an incubator in order to produce insulin-

Surface plasmon of nanoparticles with or without protein was monitored using a UV–visible spectrophotometer equipped with Peltier, which showed a resonance peak observed at 352 nm due to the silver nitrate reduction by ATE in sunlight. After incubation with insulin, a blue shift (3 nm) with almost peak intensity double was observed, and λmax was obtained at 349 nm due to the formation of monodispersed IAgNPs. The hydrodynamic size of 22 ± 2 and 42 ± 2 nm (approximately diameter) are observed for AgNPs and IAgNPs, respectively. The Zeta potential showed an increment in the potential values from −12.4 to −15.1 mV due to the conversion of AgNPs to IAgNPs. TEM micrographs showed that both AgNPs and IAgNPs are similar in shape (spherical in shape). AgNP have a size ranging between 20 ± 4 nm, and further, it received a cap of 2 ± 0.5 nm when coated with insulin

**3.2 Metallic insulin nanoformulation wound healing and anti-inflammatory** 

Wound recovery is promoted by both insulin and IAgNPs in hyperglycemic/diabetic and normal/nondiabetic animal conditions. In both in vivo and in vitro cases, the insulin promotes the wound healing in hyperglycemic and normal conditions. With IAgNPs 12 and 20%, faster wound recovery on treatment's 5th day of the wound was found for nondiabetic and diabetic rats in comparison to the untreated control. Whereas in relation to the IAgNPs, faster wound recovery was shown by free insulin with lesser efficiency with an enhanced rate of 7.27 and 4.67%, respectively, for the normoglycemic and diabetic rate in comparison to untreated rats. The % was 60.0 and 73.33% and with IAgNPs and 33.33 and 40% with only insulin in nondiabetic and diabetic models, respectively, on the 11th day, in comparison to the

**64**

*Wound healing rate of AgNP, ATE-insulin and IAgNP treatment in both hyperglycemic and normal animals on 5th day and 11th day. (A) Wound contraction physical observation in various treatment and control groups. (B) Percentage of closure of wound in different treated groups (AgNPs, ATE-insulin, and IAgNPs) and respective controls of hyperglycemic and normal animals until complete healing of wound takes place. (C) Percentage of contraction of wound in four subgroups of hyperglycemic and normal animals on 5th day. (D) Percentage of contraction of wound in all the four subgroups of hyperglycemic and normal animals on the 11th day [40].*

#### **Figure 8.**

*Histological evaluation (40×) wound site of different groups (a and B, respectively). On the 5th and 11th day of post-treatment, infiltration of leukocyte, formation of exudates and deposition of collagen are denoted by red, yellow and white arrows respectively. Each micrograph represents an overall pattern of a 6-rats group. (C–E). Pro-inflammatory cytokines such as IL-6 and TNF-ɑ and the anti-inflammatory cytokines like IL-10 concentration in all sub-groups of hyperglycemic/and normal animals at 5th and 11th day. TNF-ɑ and IL-6 results show a significant reduction and IL-10 increment by IAgNP treatment in comparison to control, AgNPs, and ATE-insulin-treated animals of both sets on the 5th and 11th day, respectively. Values are shown by the average ± SD of group of six rats [40].*

### **4. Conclusions**

Insulin, a hormone which shows the various multiple functions in the body like controlling the inflammation, enhancing the differentiation of cells, biosynthesis of protein and lipid, etc., in addition to controlling the level of glucose in blood through metabolism of glucose. By the metabolism of glucose, the NFkβP50/P50 and IL-8 get activated, causing an inactivation of the IL-1β, TNF-α, NFkβP50/P65, IL-6, resistin IFN- ϒ, and NOX pro-inflammatory cytokines. The metabolism of fat by insulin through inactivating TNF-ɑ mediated pathway also inactivates the pro-inflammatory cytokines. The synthesis of protein gets induced by insulin through Akt; PI3K pathway helps in survival of the cell through the formation of 4EBPI, ribosomal protein S6 (rpS6). This indicates that along with maintaining the blood glucose level, the insulin also shows its anti-inflammatory effect, though the mechanistic aspects of the insulin's anti-inflammatory role is still remained to be elucidated and understood. In addition to biosynthesis and metabolism, insulin pathways have the similarity in structure with IGF-I, can also bind with receptor of IGF and can shows anti-inflammatory activity through PI3K and Akt signaling pathway, which leads to the activation of the

**67**

**Author details**

Pawandeep Kaur and Diptiman Choudhury\*

provided the original work is properly cited.

\*Address all correspondence to: diptiman@thapar.edu

fellowship under inspire scheme (Award No. IF160636).

The authors declare that there is no conflict of interest.

Technology, Patiala, Punjab, India

School of Chemistry and Biochemistry, Thapar Institute of Engineering and

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers*

pro-inflammatory cytokines such as STAT-3 and can activate Akt again and promote the formation of blood vessels and increases the eNOS production. Likewise, due to similarity in structure, insulin can bind with the receptors of IGF and activate the same pathway as GF/IGF-I, necessitating further studies on insulin, IGFs and their role in anti- response of inflammation (**Figure 5**). About 5% of the world population is diabetic and are in the risk of nonrecoverable or slow wound recovery. The insulin can increase the recovery of wound by inflammatory dynamics modulating, therefore insulin-like inflammatory modulators (such as IGF) or insulin novel formulations based on and have a huge potential for the different clinical applications such as including the diabetic care and should be explored for the beneficiary purposes.

Inflammatory regulation is one of the most important factors for wound recovery which caught attention lately. Here in this chapter, the authors have discussed the role of inflammatory regulators in controlling wound recovery taking insulin as an example and model drug for diabetes treatment where wound recovery get delayed to prolonged inflammation. Macrophages in the wound tissue play a critical role in controlling the wound recovery process. Macrophage plasticity is curtailed in the initiation of tissue regeneration, tissue remodeling, and epithelization. Anti-inflammatory activators which can promote M1 to M2 Macrophage transition have a great influence in the promotion of wound recovery. Therefore, anti-inflammatory molecules can be

Diptiman Choudhury is thankful to the DST/SERB project (ECR/2016/000486) for funding. Pawandeep Kaur is thankful to DST inspire, Govt of India, for inspire

of great virtue for designing advanced wound recovery agents in the future.

*DOI: http://dx.doi.org/10.5772/intechopen.92096*

**5. Future perspective**

**Acknowledgements**

**Conflict of interest**

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers DOI: http://dx.doi.org/10.5772/intechopen.92096*

pro-inflammatory cytokines such as STAT-3 and can activate Akt again and promote the formation of blood vessels and increases the eNOS production. Likewise, due to similarity in structure, insulin can bind with the receptors of IGF and activate the same pathway as GF/IGF-I, necessitating further studies on insulin, IGFs and their role in anti- response of inflammation (**Figure 5**). About 5% of the world population is diabetic and are in the risk of nonrecoverable or slow wound recovery. The insulin can increase the recovery of wound by inflammatory dynamics modulating, therefore insulin-like inflammatory modulators (such as IGF) or insulin novel formulations based on and have a huge potential for the different clinical applications such as including the diabetic care and should be explored for the beneficiary purposes.

### **5. Future perspective**

*Wound Healing*

**66**

**4. Conclusions**

*average ± SD of group of six rats [40].*

**Figure 8.**

Insulin, a hormone which shows the various multiple functions in the body like controlling the inflammation, enhancing the differentiation of cells, biosynthesis of protein and lipid, etc., in addition to controlling the level of glucose in blood through metabolism of glucose. By the metabolism of glucose, the NFkβP50/P50 and IL-8 get activated, causing an inactivation of the IL-1β, TNF-α, NFkβP50/P65, IL-6, resistin IFN- ϒ, and NOX pro-inflammatory cytokines. The metabolism of fat by insulin through inactivating TNF-ɑ mediated pathway also inactivates the pro-inflammatory cytokines. The synthesis of protein gets induced by insulin through Akt; PI3K pathway helps in survival of the cell through the formation of 4EBPI, ribosomal protein S6 (rpS6). This indicates that along with maintaining the blood glucose level, the insulin also shows its anti-inflammatory effect, though the mechanistic aspects of the insulin's anti-inflammatory role is still remained to be elucidated and understood. In addition to biosynthesis and metabolism, insulin pathways have the similarity in structure with IGF-I, can also bind with receptor of IGF and can shows anti-inflammatory activity through PI3K and Akt signaling pathway, which leads to the activation of the

*Histological evaluation (40×) wound site of different groups (a and B, respectively). On the 5th and 11th day of post-treatment, infiltration of leukocyte, formation of exudates and deposition of collagen are denoted by red, yellow and white arrows respectively. Each micrograph represents an overall pattern of a 6-rats group. (C–E). Pro-inflammatory cytokines such as IL-6 and TNF-ɑ and the anti-inflammatory cytokines like IL-10 concentration in all sub-groups of hyperglycemic/and normal animals at 5th and 11th day. TNF-ɑ and IL-6 results show a significant reduction and IL-10 increment by IAgNP treatment in comparison to control, AgNPs, and ATE-insulin-treated animals of both sets on the 5th and 11th day, respectively. Values are shown by the* 

Inflammatory regulation is one of the most important factors for wound recovery which caught attention lately. Here in this chapter, the authors have discussed the role of inflammatory regulators in controlling wound recovery taking insulin as an example and model drug for diabetes treatment where wound recovery get delayed to prolonged inflammation. Macrophages in the wound tissue play a critical role in controlling the wound recovery process. Macrophage plasticity is curtailed in the initiation of tissue regeneration, tissue remodeling, and epithelization. Anti-inflammatory activators which can promote M1 to M2 Macrophage transition have a great influence in the promotion of wound recovery. Therefore, anti-inflammatory molecules can be of great virtue for designing advanced wound recovery agents in the future.

### **Acknowledgements**

Diptiman Choudhury is thankful to the DST/SERB project (ECR/2016/000486) for funding. Pawandeep Kaur is thankful to DST inspire, Govt of India, for inspire fellowship under inspire scheme (Award No. IF160636).

### **Conflict of interest**

The authors declare that there is no conflict of interest.

### **Author details**

Pawandeep Kaur and Diptiman Choudhury\* School of Chemistry and Biochemistry, Thapar Institute of Engineering and Technology, Patiala, Punjab, India

\*Address all correspondence to: diptiman@thapar.edu

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[59] Guo X et al. Glycolysis in the control of blood glucose homeostasis.

[60] Saltiel AR et al. Insulin signalling pathways regulating translocation of GLUT4. Nature. 2005;**5**:159-165

[61] Wu M et al. Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse model of diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2011;**108**:5378-5383

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[61] Wu M et al. Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse model of diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2011;**108**:5378-5383

[62] Murphy MP. Modulating mitochondrial intracellular location as a redox signal. Science Signaling. 2012;**5**:39

[63] Ellen L et al. Selective superoxide generation within mitochondria by the targeted redox cycler mitoparaquat. Free Radical Biology and Medicine. 2015;**89**:883-889

[64] James S et al. Fluid shear stress inhibits TNF-α activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among MAPK family members. Proceedings of the National Academy of Sciences of the United States of America. 2011;**98**:6476-6481

[65] Adolfo RAP et al. c-Fos activates and physically interacts with specific enzymes of the pathway of synthesis of polyphosphoinositides. Molecular Biology of the Cell. 2011;**22**:4716-4725

[66] Laurence H et al. Signaling pathways involved in LPS induced TNFalpha production in human adipocytes. Journal of Inflammation Research. 2010;**7**:1

[67] Greenhaff PL et al. Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle. American Journal of Physiology. Endocrinology and Metabolism. 2008;**295**(3):595-604

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[74] Higashi Y et al. IGF-1, oxidative stress and atheroprotection. Trends in Endocrinology and Metabolism. 2010;**21**:245-254

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#### *Wound Healing*

[76] Ando Y et al. Epidermal growth factor and insulin like growth factor I enhance keratinocyte migration. Journal of Investigative Dermatology. 1993;**100**:633-639

[77] Burks DJ, White MF. Beta cell and function in type 2 diabetes. Diabetes. 2001;**50**:140

[78] Yamada Y et al. Activation of the AktmTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors. Cancer. 2014;**120**:864-876

[79] Cefalu WT. Insulin resistance: Cellular and clinical concepts. Experimental Biology and Medicine. 2001;**226**:13-26

[80] Vatankhah N et al. Effect of systematic insulin treatment on diabetic wound healing. Wound Repair and Regeneration. 2017;**25**:288-291

[81] Novak ML, Koh TJ. Macrophage phenotypes during tissue repair. Journal of Leukocyte Biology. 2013;**93**:875-881

[82] Falanga V. Advanced treatments for non healing chronic wounds. EWMAJ. 2004;**4**:11-13

[83] McCormick SM et al. Regulation of macrophage, dendritic cell, and microglial phenotype and function by the SOCS proteins. Frontiers in Immunology. 2015;**6**(6):549

[84] Guo SA et al. Factors affecting wound healing. Journal of Dental Research. 2010;**89**:219-229

[85] Thomsen LH et al. Polarization of macrophages in metabolic diseases. Cellular Immunology. 2015;**6**(6):2

[86] Wang N et al. Molecular mechanisms that influence the macrophage M1–M2 polarization balance. Frontiers in Immunology. 2014;**5**:614

[87] Ferreira AE et al. PPAR-g/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. Journal of Immunology. 2014;**192**:2357-2365

[88] Chandirasegaran G et al. Diabetes millerus induced oxidative stress, inflammation and apoptosis: A concise review. ECDMR. 2009;**1**:10-17

[89] Zhu X et al. Micro environment and intra cellular metabolism modulation of adipose tissue macrophage polarization in relation to chronic inflammatory diseases. Diabetes/ Metabolism Research and Reviews. 2018;**34**:e2993

[90] Wetzler C et al. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: Prolonged persistence of neutrophils and macrophages during the late phase of repair. Journal of Investigative Dermatology. 2000;**115**:245-253

[91] Kasuya A et al. Attempts to accelerate wound healing. Journal of Dermatological Science. 2014;**76**:169-172

[92] Porta C et al. Molecular and epigenetic basis of macrophage polarized activation. Seminars in Immunology. 2015;**27**:237-248. DOI: 10.1016/j.smim.2015.10.003

[93] Jornvall H et al. Oligomerization and insulin interactions of pro-insulin C-peptide: Three folds relationships to properties of insulin. Biochemical and Biophysical Research Communications. 2010;**391**:1561-1566

[94] Bhatt MP et al. C-peptide replacement as an emerging strategy for preventing diabetic vasculopathy. Cardiovascular Research. 2014;**104**:234-244

[95] Haidet J et al. C-peptide reduces pro-inflammatory cytokine secretion

**73**

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers*

*DOI: http://dx.doi.org/10.5772/intechopen.92096*

in LPS-stimulated U937 monocytes in condition of hyperglycemia. Inflammation Research. 2012;**61**:27-35

[96] Bloomgarden ZT. Diabetes complications. Diabetes Care.

[97] Hills CE et al. Cellular and physiological effects of C-peptide. Clinical Science. 2009;**116**:565-574

[99] Gunasekaran T et al. Silver nanoparticles as real topical bullets for wound healing. The Journal of the American College of Certified Wound

Specialists. 2012;**3**:82-96

2008;**68**:1970-1978

[100] Patra CR et al. Targeted

delivery of gemcitabine to pancreatic adenocarcinoma using cetuximab as a targeting agent. Cancer Research.

[98] Walcher D, Marx N. C-peptide in the veaael wall. The Review of Diabetic

2004;**27**:1506-1514

Studies. 2009;**6**:180

*Modulation of Inflammatory Dynamics by Insulin to Promote Wound Recovery of Diabetic Ulcers DOI: http://dx.doi.org/10.5772/intechopen.92096*

in LPS-stimulated U937 monocytes in condition of hyperglycemia. Inflammation Research. 2012;**61**:27-35

[96] Bloomgarden ZT. Diabetes complications. Diabetes Care. 2004;**27**:1506-1514

*Wound Healing*

1993;**100**:633-639

2001;**50**:140

2001;**226**:13-26

2013;**93**:875-881

2004;**4**:11-13

[76] Ando Y et al. Epidermal growth factor and insulin like growth factor I enhance keratinocyte migration. Journal of Investigative Dermatology. [87] Ferreira AE et al. PPAR-g/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. Journal of Immunology.

[88] Chandirasegaran G et al. Diabetes millerus induced oxidative stress, inflammation and apoptosis: A concise

[89] Zhu X et al. Micro environment and intra cellular metabolism modulation of adipose tissue macrophage polarization in relation to chronic inflammatory diseases. Diabetes/ Metabolism Research and Reviews. 2018;**34**:e2993

review. ECDMR. 2009;**1**:10-17

[90] Wetzler C et al. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: Prolonged persistence of neutrophils and macrophages during the late phase of repair. Journal of Investigative Dermatology. 2000;**115**:245-253

[91] Kasuya A et al. Attempts to accelerate wound healing. Journal of Dermatological Science.

[92] Porta C et al. Molecular and epigenetic basis of macrophage polarized activation. Seminars in Immunology. 2015;**27**:237-248. DOI:

[93] Jornvall H et al. Oligomerization and insulin interactions of pro-insulin C-peptide: Three folds relationships to properties of insulin. Biochemical and Biophysical Research Communications.

10.1016/j.smim.2015.10.003

[94] Bhatt MP et al. C-peptide replacement as an emerging strategy for preventing diabetic

vasculopathy. Cardiovascular Research.

[95] Haidet J et al. C-peptide reduces pro-inflammatory cytokine secretion

2010;**391**:1561-1566

2014;**104**:234-244

2014;**76**:169-172

2014;**192**:2357-2365

[77] Burks DJ, White MF. Beta cell and function in type 2 diabetes. Diabetes.

[78] Yamada Y et al. Activation of the AktmTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumors. Cancer. 2014;**120**:864-876

[79] Cefalu WT. Insulin resistance: Cellular and clinical concepts. Experimental Biology and Medicine.

[80] Vatankhah N et al. Effect of

systematic insulin treatment on diabetic wound healing. Wound Repair and Regeneration. 2017;**25**:288-291

[81] Novak ML, Koh TJ. Macrophage phenotypes during tissue repair. Journal of Leukocyte Biology.

[82] Falanga V. Advanced treatments for non healing chronic wounds. EWMAJ.

[83] McCormick SM et al. Regulation of macrophage, dendritic cell, and microglial phenotype and function by the SOCS proteins. Frontiers in Immunology. 2015;**6**(6):549

[84] Guo SA et al. Factors affecting wound healing. Journal of Dental Research. 2010;**89**:219-229

[85] Thomsen LH et al. Polarization of macrophages in metabolic diseases. Cellular Immunology. 2015;**6**(6):2

[86] Wang N et al. Molecular mechanisms that influence the macrophage M1–M2 polarization balance. Frontiers in Immunology.

**72**

2014;**5**:614

[97] Hills CE et al. Cellular and physiological effects of C-peptide. Clinical Science. 2009;**116**:565-574

[98] Walcher D, Marx N. C-peptide in the veaael wall. The Review of Diabetic Studies. 2009;**6**:180

[99] Gunasekaran T et al. Silver nanoparticles as real topical bullets for wound healing. The Journal of the American College of Certified Wound Specialists. 2012;**3**:82-96

[100] Patra CR et al. Targeted delivery of gemcitabine to pancreatic adenocarcinoma using cetuximab as a targeting agent. Cancer Research. 2008;**68**:1970-1978

**75**

**Chapter 5**

Ulcers

*and Rita Morais*

**Abstract**

burden

**1. Introduction**

Managing Patients with Pressure

This study describes care for the person and the informal caregiver with pressure ulcers. The qualitative methodological approach was used, and case study research and the data collection techniques used were the semi-structured interview and the questionnaire. The following scales were applied to the patient: Braden Pressure Ulcer Risk Assessment, Resvesch 2.0, Malnutrition Universal Screening Nutritional Assessment. Modified Barthel and direct observation of wounds, use of the acronym Tissues, Inflammation/infection, Moisture, Edges/Epithelium. The nursing intervention at the patient's home was positive in the evolution of the pressure ulcer healing and in the management of the caregiver's emotions. Providing nursing home care to the injured person is a balm for patients and caregivers. It is an excellent response to aging and consequent complications, for example, wounds. They promote gains in health and in the management of human and economic resources.

**Keywords:** pressure ulcers, home care nursing, caregiver and informal, caregiver

The technological and scientific development of medicine has increased the average life expectancy. Today, living more years is not synonymous with quality of life. Society's increased concern with the perception of the quality of life is not

Health is a state of balance between the physical and the mental, without discomfort and suffering, which enables the individual to function as effectively as possible in the environment, and a change in this balance causes malaise [1]. Nowadays, health policies favor homecare for dependent people [2]. The Development Plan of the National Network for Integrated Continuous Care [RNCCI] reinforces this concept by stating that the community is the most privileged place for patient care and that each person is responsible for their life and their family as a socio-family reference; therefore, home is a key aspect in health care [3]. With the increase in the population age as well as the need for care, new health requirements emerge. The RNCCI has formed Integrated Continuing Care [ECCI] to provide homecare, focusing on dependent people whose situation does not require hospitalization but who cannot move independently and where the focus of

consensual, but its association with health is unanimous.

*Eglantina Afonso, Dina Borges, Kátia Furtado,* 

*Maria do Céu Marques, Margarida Pedro, Inês Reis* 

### **Chapter 5**

## Managing Patients with Pressure Ulcers

*Eglantina Afonso, Dina Borges, Kátia Furtado, Maria do Céu Marques, Margarida Pedro, Inês Reis and Rita Morais*

### **Abstract**

This study describes care for the person and the informal caregiver with pressure ulcers. The qualitative methodological approach was used, and case study research and the data collection techniques used were the semi-structured interview and the questionnaire. The following scales were applied to the patient: Braden Pressure Ulcer Risk Assessment, Resvesch 2.0, Malnutrition Universal Screening Nutritional Assessment. Modified Barthel and direct observation of wounds, use of the acronym Tissues, Inflammation/infection, Moisture, Edges/Epithelium. The nursing intervention at the patient's home was positive in the evolution of the pressure ulcer healing and in the management of the caregiver's emotions. Providing nursing home care to the injured person is a balm for patients and caregivers. It is an excellent response to aging and consequent complications, for example, wounds. They promote gains in health and in the management of human and economic resources.

**Keywords:** pressure ulcers, home care nursing, caregiver and informal, caregiver burden

#### **1. Introduction**

The technological and scientific development of medicine has increased the average life expectancy. Today, living more years is not synonymous with quality of life. Society's increased concern with the perception of the quality of life is not consensual, but its association with health is unanimous.

Health is a state of balance between the physical and the mental, without discomfort and suffering, which enables the individual to function as effectively as possible in the environment, and a change in this balance causes malaise [1]. Nowadays, health policies favor homecare for dependent people [2]. The Development Plan of the National Network for Integrated Continuous Care [RNCCI] reinforces this concept by stating that the community is the most privileged place for patient care and that each person is responsible for their life and their family as a socio-family reference; therefore, home is a key aspect in health care [3].

With the increase in the population age as well as the need for care, new health requirements emerge. The RNCCI has formed Integrated Continuing Care [ECCI] to provide homecare, focusing on dependent people whose situation does not require hospitalization but who cannot move independently and where the focus of care is centered on the patient and the informal caregiver, who are equally involved. This informal care is the care given to dependent people by their family, friends and neighbors [4]. The informal caregiver is undoubtedly a valuable aspect not only for patient care but also for the health teams provided by the state. This alliance requires the informal caregiver to be available as well as to develop caregiving skills. Given this scenario, the challenge of health policies will be to strike a balance between self-care, informal support and care provided by professionals [5].

Despite the growing interest in the positive aspects of care given by the caregiver, there is still some predominance of negative impacts. Home nursing care is a difficult task influenced by different factors [6]. Thus, it is intended that the benefits become the core of the issue. Stimulating the role of the informal caregiver is essential to keep the patient at home, to optimize his quality of life and avoid his institutionalization [7].

Nursing as a science that takes care of the human being is committed to educating and guiding [8], as one of the competences of the general care nurse. As mentioned in article 5, it is the nurse's responsibility to guide and supervise, transmitting information to the patient aiming at changing behaviors for the acquisition of healthy lifestyles or health recovery, following this process and introducing the necessary adjustments [9]. The community nurse has the role of educating by promoting adequate education as well as information and training.

One of the reasons for admitting patients to ECCI is the treatment of pressure ulcers [PUs] and/or wounds, the admission criterion being the existence of an informal caregiver as a help from the home care team, so that continuity of care is guaranteed and to achieve the goals in the prevention and treatment of complex wounds.

Physical dependence leads to long periods of immobility, endangering skin integrity, leading to the appearance of PUs [1]. PUs represent a public health problem, both nationally and internationally. These entail marked economic burdens for a country, hence the growing political and economic concern [10], and are considered the third or fourth most expensive pathology in the world [11]. PUs are an indicator of the quality of health care provided. The personal suffering caused by this pathology affects the quality of life of patients and caregivers, which can lead to death in extreme situations [12].

The European Pressure Ulcer Advisory Panel [EPUAP] in 2014 defined PU as a localized lesion on the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure or a combination of torsion forces [13]. This entity classifies PUs according to their stage of evolution into six categories/grades, as follows: Category/Grade I: non-blanching erythema; Category/Grade II: partial loss of skin thickness; Category/Grade III: total loss of skin thickness; Category/Grade IV: total loss of tissue thickness; non-gradable/unclassifiable: indeterminate depth; and suspected deep tissue injury: indeterminate depth [13].

The appearance of a PU is largely due to an association of the following risk factors, such as immobilization, nutritional status, skin integrity, age and blood oxygenation level. PUs do not only occur in the geriatric population, but they can also occur in any individual who has one or more of the risk factors mentioned [14]. Demographic changes, such as the growth of the elderly population with multiple co-morbidities, lead to an increase in the number of people with injuries [15]; hence, the prevention and treatment are a challenge for health professionals, especially, nurses. According to the DGS Guideline, 95% of PUs are preventable by early identification of the degree of risk [12]. Therefore, the assessment and management of the risk of developing PUs require a general and multidisciplinary approach to the person [16].

This study aims to describe care for the person and informal caregiver with pressure ulcers.

**77**

*Managing Patients with Pressure Ulcers DOI: http://dx.doi.org/10.5772/intechopen.91034*

This study consists of qualitative research, more specifically a case study, with a central focus on the user and the caregiver, who are provided nursing care by the

After selecting the patient for the study, informed consent was requested from the legal representative, his wife, since the patient presented changes regarding his orientation of time and space, as evidenced by the application of the Mini-Mental State scale. The study was submitted to the Ethics Committee of the Baixo Alentejo

This type of study seeks to relate the evolution of a phenomenon associated with an intervention. For this, the following resources were used: data collection through semi-structured interviews with the informal caregiver and application of the Informal Caregiver Burden Assessment Questionnaire [QASCI]. Regarding the patient, the following were used: application of the Pressure Ulcer Risk Assessment Scale: Braden Scale [12]; application of the Resvech 2.0 Scale; application of the Malnutrition Universal Screening Nutritional Assessment Scale [MUST] [17]; application of the Barthel Modified Scale [18] and direct observation of the PU, through photographic recording and based on the acronym Tissues, Inflammation/infection, Moisture, Edges/Epithelium [TIME]; the data collection through the clinical process of the patient and the diagnostic evaluation according to the life activities following the Roper-Logan-Tierney theoretical model [19], related to the changed daily living activities [DLA] in the patient. For the elaboration of the diagnostic judgments, the language of the International Classification

for Nursing Practice [ICNP] [20] was used, based on the Nursing Interventions Classification [NIC 2010] and the Nursing Outcomes Classification [NOC 2010].

retired, married, and living with his wife and a daughter.

did not have the expected evolution, despite its smaller size.

The case study was carried out to the AF patient, male, 70 years old, Caucasian, Portuguese nationality, who lives in Beja, with an Elementary School Education,

*Personal history*: hypertension; depressive syndrome; ethanolic habits, cerebral vascular accident (CVA) in 2013 with left hemiparesis, senile dementia, vascular epilepsy, venous insufficiency of the lower limbs, inguinal hernioplasty, pneumonia, acute cholecystitis and urinary tract infection. Once part of the ECCI, the patient presented with four PUs, with three of them already cicatrized (sacred, left

*Daily medication*: ®baclofen 50 mg at breakfast and bedtime; ®warfarin 1.25 mg

After the CVA in 2013, the patient started at RNCCI, having integrated three units. On August 11 of 2016, he was admitted in ECCI, referenced by the family health team for wound care at home. During a home visit, on August 12, 2016, four PUs were found instead of one (information given on the first day). For the healing of the sacred PU, there was a need for constant articulation with the family health team and surgery team. During the 27 months with the ECCI, the left trochanter PU

The patient presents with total dependence on ADL, as demonstrated by the Barthel Modified Scale Assessment with a zero score, with ankylosis of the joints, which makes hygiene care and mobilization difficult, maintains home support

at 7 pm; ®pantoprazole 40 mg before meal; ®sertraline 50 mg at breakfast; ®enalapril 20 mg at breakfast and ®sodium valproate 500 mg every 8 h.

Integrated Continuous Care Team of a city in southern Portugal.

**2. Methodology**

Local Health Unit.

**3. Results**

**3.1 Appreciation**

shoulder and right trochanter).

### **2. Methodology**

*Wound Healing*

institutionalization [7].

death in extreme situations [12].

care is centered on the patient and the informal caregiver, who are equally involved. This informal care is the care given to dependent people by their family, friends and neighbors [4]. The informal caregiver is undoubtedly a valuable aspect not only for patient care but also for the health teams provided by the state. This alliance requires the informal caregiver to be available as well as to develop caregiving skills. Given this scenario, the challenge of health policies will be to strike a balance

between self-care, informal support and care provided by professionals [5].

Despite the growing interest in the positive aspects of care given by the caregiver, there is still some predominance of negative impacts. Home nursing care is a difficult task influenced by different factors [6]. Thus, it is intended that the benefits become the core of the issue. Stimulating the role of the informal caregiver is essential to keep the patient at home, to optimize his quality of life and avoid his

Nursing as a science that takes care of the human being is committed to educating and guiding [8], as one of the competences of the general care nurse. As mentioned in article 5, it is the nurse's responsibility to guide and supervise, transmitting information to the patient aiming at changing behaviors for the acquisition of healthy lifestyles or health recovery, following this process and introducing the necessary adjustments [9]. The community nurse has the role of educating by

One of the reasons for admitting patients to ECCI is the treatment of pressure ulcers [PUs] and/or wounds, the admission criterion being the existence of an informal caregiver as a help from the home care team, so that continuity of care is guaranteed and to achieve the goals in the prevention and treatment of complex wounds.

Physical dependence leads to long periods of immobility, endangering skin integrity, leading to the appearance of PUs [1]. PUs represent a public health problem, both nationally and internationally. These entail marked economic burdens for a country, hence the growing political and economic concern [10], and are considered the third or fourth most expensive pathology in the world [11]. PUs are an indicator of the quality of health care provided. The personal suffering caused by this pathology affects the quality of life of patients and caregivers, which can lead to

The European Pressure Ulcer Advisory Panel [EPUAP] in 2014 defined PU as a localized lesion on the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure or a combination of torsion forces [13]. This entity classifies PUs according to their stage of evolution into six categories/grades, as follows: Category/Grade I: non-blanching erythema; Category/Grade II: partial loss of skin thickness; Category/Grade III: total loss of skin thickness; Category/Grade IV: total loss of tissue thickness; non-gradable/unclassifiable: indeterminate depth;

The appearance of a PU is largely due to an association of the following risk factors, such as immobilization, nutritional status, skin integrity, age and blood oxygenation level. PUs do not only occur in the geriatric population, but they can also occur in any individual who has one or more of the risk factors mentioned [14]. Demographic changes, such as the growth of the elderly population with multiple co-morbidities, lead to an increase in the number of people with injuries [15]; hence, the prevention and treatment are a challenge for health professionals, especially, nurses. According to the DGS Guideline, 95% of PUs are preventable by early identification of the degree of risk [12]. Therefore, the assessment and management of the risk of developing PUs require a general and multidisciplinary approach to

This study aims to describe care for the person and informal caregiver with

promoting adequate education as well as information and training.

and suspected deep tissue injury: indeterminate depth [13].

**76**

the person [16].

pressure ulcers.

This study consists of qualitative research, more specifically a case study, with a central focus on the user and the caregiver, who are provided nursing care by the Integrated Continuous Care Team of a city in southern Portugal.

After selecting the patient for the study, informed consent was requested from the legal representative, his wife, since the patient presented changes regarding his orientation of time and space, as evidenced by the application of the Mini-Mental State scale. The study was submitted to the Ethics Committee of the Baixo Alentejo Local Health Unit.

This type of study seeks to relate the evolution of a phenomenon associated with an intervention. For this, the following resources were used: data collection through semi-structured interviews with the informal caregiver and application of the Informal Caregiver Burden Assessment Questionnaire [QASCI]. Regarding the patient, the following were used: application of the Pressure Ulcer Risk Assessment Scale: Braden Scale [12]; application of the Resvech 2.0 Scale; application of the Malnutrition Universal Screening Nutritional Assessment Scale [MUST] [17]; application of the Barthel Modified Scale [18] and direct observation of the PU, through photographic recording and based on the acronym Tissues, Inflammation/infection, Moisture, Edges/Epithelium [TIME]; the data collection through the clinical process of the patient and the diagnostic evaluation according to the life activities following the Roper-Logan-Tierney theoretical model [19], related to the changed daily living activities [DLA] in the patient. For the elaboration of the diagnostic judgments, the language of the International Classification for Nursing Practice [ICNP] [20] was used, based on the Nursing Interventions Classification [NIC 2010] and the Nursing Outcomes Classification [NOC 2010].

### **3. Results**

### **3.1 Appreciation**

The case study was carried out to the AF patient, male, 70 years old, Caucasian, Portuguese nationality, who lives in Beja, with an Elementary School Education, retired, married, and living with his wife and a daughter.

*Personal history*: hypertension; depressive syndrome; ethanolic habits, cerebral vascular accident (CVA) in 2013 with left hemiparesis, senile dementia, vascular epilepsy, venous insufficiency of the lower limbs, inguinal hernioplasty, pneumonia, acute cholecystitis and urinary tract infection. Once part of the ECCI, the patient presented with four PUs, with three of them already cicatrized (sacred, left shoulder and right trochanter).

*Daily medication*: ®baclofen 50 mg at breakfast and bedtime; ®warfarin 1.25 mg at 7 pm; ®pantoprazole 40 mg before meal; ®sertraline 50 mg at breakfast; ®enalapril 20 mg at breakfast and ®sodium valproate 500 mg every 8 h.

After the CVA in 2013, the patient started at RNCCI, having integrated three units. On August 11 of 2016, he was admitted in ECCI, referenced by the family health team for wound care at home. During a home visit, on August 12, 2016, four PUs were found instead of one (information given on the first day). For the healing of the sacred PU, there was a need for constant articulation with the family health team and surgery team. During the 27 months with the ECCI, the left trochanter PU did not have the expected evolution, despite its smaller size.

The patient presents with total dependence on ADL, as demonstrated by the Barthel Modified Scale Assessment with a zero score, with ankylosis of the joints, which makes hygiene care and mobilization difficult, maintains home support

#### *Wound Healing*

three times a day (hygiene and transfers). The equipment that exists in the patient's home is an alternating pressure mattress and a shower chair. The patient gets up daily to an armchair and sleeps in a double bed with inadequate equipment. The patient presents with incoherent speech, hydrated and flushed skin and mucous membranes, normal nutritional status, with a body mass index [BMI] of 23.1. The patient has as an informal caregiver his wife, who is less than two years old than the patient, manifesting difficulties in taking care of her husband, presenting with physical and mental stress overload.

To describe the ADL, the theoretical model previously mentioned was used. Regarding his breathing and controlling body temperature, it remained unchanged. Mobilization is compromised in bedridden and ankylosing patients, and they are dependent on transfers and positions. The patient was not supported by the team's physiotherapist since he was already in a rehabilitation unit. His work and leisure time are compromised, due to his illness and dependence. Regarding the alimentation, it is his wife who prepares and feeds him soft diet meals and protein supplements, using a syringe. His wife is concerned about his well-being and quite motivated by the food aspects, which manifest with increased concern.

Personal hygiene and dressing are compromised, being performed by the home support team, with the supervision of the caregiver. Elimination is compromised but without alteration of the bladder and intestinal pattern. Regarding the following: his sleep, sleep habits are maintained; sensations, the patient presented on the observer scale, without pain; integument, compromised with the presence of PU in the left trochanter; memory, patient is disoriented in space, time and himself.

#### **3.2 Analysis and discussion of results**

PUs are lesions that require prolonged and difficult treatment. It depends not only on the therapeutic care provided, such as the frequency of treatment and the suitability of the dressing material, but also on the general condition of the patient and the care provided to him or her by the informal caregiver, such as the frequency of positioning/repositioning; adaptive equipment; pressure reduction and relief. Based on the recommendations of NPUAP/EPUAP & PPPIA [13], the supporting surfaces are essential and should be chosen according to the pressure redistribution needs and other therapeutic functions of the individual.

Based on the diagnosis of needs, it is essential to define intervention strategies, to plan the nursing interventions appropriate to the individual, using appropriate assessment instruments.

Concerning the degree of risk of developing PU according to the Braden Scale, the patient's FA has a total score of 13, which represents a high risk, since DGS [12] reports that a score less than or equal to 16 is high risk. According to the DGS [12], the assessment of the risk of developing PU is fundamental for planning and implementing PU prevention and treatment measures. From the application of the instrument to the patient, it is verified that the mobilization and the friction and sliding forces are the most relevant factors that condition the healing of the wounds and the reappearance of new injuries, despite the intervention with the caregiver through the transmitted information and the results and lessons learned: wheelchair acquisition, viscoelastic cushion, articulated bed and correct positioning techniques, and the informal caregiver due to individual and cultural factors did not adhere to the intervention proposals planned by health professionals. The patient has an alternating pressure mattress in the bed and the caregiver positions it without collaboration, however, and uses incorrect positioning techniques, causing

**79**

**Figure 1.**

*Left trochanter November 2016, own source.*

*Managing Patients with Pressure Ulcers DOI: http://dx.doi.org/10.5772/intechopen.91034*

ering the guidelines of health professionals.

tion of the MUST instrument, the assessment is low risk.

consultation, having attended only one consultation.

peutic adjustment of the anticoagulant.

damage to tissue already regenerated, as occurred in the sacred region, not consid-

The informal caregiver demonstrates physical and psychological overload, proven by the application of the QASCI instrument (in October and December 2018). Given the scores, it is noteworthy that the caregiver presents instability in the performance of her role as a caregiver. The caregiver's condition worsened in November 2018, when she initiated restrictions on her health, through non-adherence to the therapeutic regimen for arterial hypertension, dental abscesses and osteoarticular pain. The caregiver's imbalance in biological, psychological and social factors has repercussions on the care she gives. ECCI's multidisciplinary team from Beja articulated with the caregiver and family team referring her to a psychiatry

When the patient had a stroke in 2013, PU appeared, and there was a need for nursing intervention and entry into the ECCI. In the beginning, the left trochanter PU was grade I, and it was aggravated due to the number of hours that the patient remained in the left lateral decubitus, to relieve the existing PU. In the beginning, the treatment applied was once a day with ®hyperoxygenated fatty acid and protection with polyurethane foam with ®sodium carboxymethylcellulose. On September 19, 2016, the UP presented: devitalized tissue, bleeding tissue, without smell, bounded edges, with a dimension of 5 cm [cm] long by 3 cm wide. The treatment applied daily was enzymatic debridement due to the risk of hemorrhage, with irrigation with a solution of ®polyhexamethylene guanidine [PHMB], ®calcium alginate with silver and foam ®polyurethane with ®sodium carboxymethylcellulose. Articulation with the family team was carried out for close control of the international normalized ratio [INR] and respective thera-

On November 14, 2016, the wound presented: hemorrhage in the wound bed,

devitalized tissue, granulation tissue and odor. Despite being referred to the emergency department and a surgery doctor, his wife refused to go. Gelatin sponge dressing, pads and patching, dressing and treatment were initiated twice a day, as well as antibiotic therapy after medical observation. On November 20, 2016 (**Figure 1**), there was PU with devitalized granulation tissue, without bleeding, with inflammatory signs (redness and erythema) and without odor. The treatment applied was saline [S], ®carboxymethylcellulose single fibers, polyurethane

Regarding the patient alimentation, the caregiver is concerned about the food and water intake of the patient and makes daily protein supplements. In the applica-

#### *Managing Patients with Pressure Ulcers DOI: http://dx.doi.org/10.5772/intechopen.91034*

*Wound Healing*

physical and mental stress overload.

**3.2 Analysis and discussion of results**

assessment instruments.

needs and other therapeutic functions of the individual.

increased concern.

himself.

three times a day (hygiene and transfers). The equipment that exists in the patient's home is an alternating pressure mattress and a shower chair. The patient gets up daily to an armchair and sleeps in a double bed with inadequate equipment. The patient presents with incoherent speech, hydrated and flushed skin and mucous membranes, normal nutritional status, with a body mass index [BMI] of 23.1. The patient has as an informal caregiver his wife, who is less than two years old than the patient, manifesting difficulties in taking care of her husband, presenting with

To describe the ADL, the theoretical model previously mentioned was used. Regarding his breathing and controlling body temperature, it remained unchanged. Mobilization is compromised in bedridden and ankylosing patients, and they are dependent on transfers and positions. The patient was not supported by the team's physiotherapist since he was already in a rehabilitation unit. His work and leisure time are compromised, due to his illness and dependence. Regarding the alimentation, it is his wife who prepares and feeds him soft diet meals and protein supplements, using a syringe. His wife is concerned about his well-being and quite motivated by the food aspects, which manifest with

Personal hygiene and dressing are compromised, being performed by the home support team, with the supervision of the caregiver. Elimination is compromised but without alteration of the bladder and intestinal pattern. Regarding the following: his sleep, sleep habits are maintained; sensations, the patient presented on the observer scale, without pain; integument, compromised with the presence of PU in the left trochanter; memory, patient is disoriented in space, time and

PUs are lesions that require prolonged and difficult treatment. It depends not only on the therapeutic care provided, such as the frequency of treatment and the suitability of the dressing material, but also on the general condition of the patient and the care provided to him or her by the informal caregiver, such as the frequency of positioning/repositioning; adaptive equipment; pressure reduction and relief. Based on the recommendations of NPUAP/EPUAP & PPPIA [13], the supporting surfaces are essential and should be chosen according to the pressure redistribution

Based on the diagnosis of needs, it is essential to define intervention strategies, to plan the nursing interventions appropriate to the individual, using appropriate

Concerning the degree of risk of developing PU according to the Braden Scale, the patient's FA has a total score of 13, which represents a high risk, since DGS [12] reports that a score less than or equal to 16 is high risk. According to the DGS [12], the assessment of the risk of developing PU is fundamental for planning and implementing PU prevention and treatment measures. From the application of the instrument to the patient, it is verified that the mobilization and the friction and sliding forces are the most relevant factors that condition the healing of the wounds and the reappearance of new injuries, despite the intervention with the caregiver through the transmitted information and the results and lessons learned: wheelchair acquisition, viscoelastic cushion, articulated bed and correct positioning techniques, and the informal caregiver due to individual and cultural factors did not adhere to the intervention proposals planned by health professionals. The patient has an alternating pressure mattress in the bed and the caregiver positions it without collaboration, however, and uses incorrect positioning techniques, causing

**78**

damage to tissue already regenerated, as occurred in the sacred region, not considering the guidelines of health professionals.

Regarding the patient alimentation, the caregiver is concerned about the food and water intake of the patient and makes daily protein supplements. In the application of the MUST instrument, the assessment is low risk.

The informal caregiver demonstrates physical and psychological overload, proven by the application of the QASCI instrument (in October and December 2018). Given the scores, it is noteworthy that the caregiver presents instability in the performance of her role as a caregiver. The caregiver's condition worsened in November 2018, when she initiated restrictions on her health, through non-adherence to the therapeutic regimen for arterial hypertension, dental abscesses and osteoarticular pain. The caregiver's imbalance in biological, psychological and social factors has repercussions on the care she gives. ECCI's multidisciplinary team from Beja articulated with the caregiver and family team referring her to a psychiatry consultation, having attended only one consultation.

When the patient had a stroke in 2013, PU appeared, and there was a need for nursing intervention and entry into the ECCI. In the beginning, the left trochanter PU was grade I, and it was aggravated due to the number of hours that the patient remained in the left lateral decubitus, to relieve the existing PU. In the beginning, the treatment applied was once a day with ®hyperoxygenated fatty acid and protection with polyurethane foam with ®sodium carboxymethylcellulose. On September 19, 2016, the UP presented: devitalized tissue, bleeding tissue, without smell, bounded edges, with a dimension of 5 cm [cm] long by 3 cm wide. The treatment applied daily was enzymatic debridement due to the risk of hemorrhage, with irrigation with a solution of ®polyhexamethylene guanidine [PHMB], ®calcium alginate with silver and foam ®polyurethane with ®sodium carboxymethylcellulose. Articulation with the family team was carried out for close control of the international normalized ratio [INR] and respective therapeutic adjustment of the anticoagulant.

On November 14, 2016, the wound presented: hemorrhage in the wound bed, devitalized tissue, granulation tissue and odor. Despite being referred to the emergency department and a surgery doctor, his wife refused to go. Gelatin sponge dressing, pads and patching, dressing and treatment were initiated twice a day, as well as antibiotic therapy after medical observation. On November 20, 2016 (**Figure 1**), there was PU with devitalized granulation tissue, without bleeding, with inflammatory signs (redness and erythema) and without odor. The treatment applied was saline [S], ®carboxymethylcellulose single fibers, polyurethane

**Figure 1.** *Left trochanter November 2016, own source.*

foam and ®hydrocolloid plate. For a long period, the PU did not evolve, despite vacuum therapy being applied for 1 month, without favorable results due to caregiver resistance. On September 18, 2018, the patient began treatment with honey, ®carboxymethylcellulose single fibers and ®hydrocolloid plaque. In October 2018, the wound did not heal and presented with: devitalized tissue, increased exudate and purulent characteristics, inflammatory signs, and bad smell, the non-healing mnemonics was applied, increased exudate, red and bleeding surface tissue, Dobris [NERDS]. The use of honey was suspended due to the rejection of the informal caregiver; therefore, irrigation with PHMB and carboxymethylcellulose fibers with silver, calcium alginate, polyurethane foam and ®hydrocolloid plate were restarted.

On November 20, 2018, the wound presented: fibrin that was removed, granulation tissue and devitalized, odorless. The treatment was warm saline, ®carboxymethylcellulose single fibers, polyurethane foam and ®hydrocolloid plate (**Figure 2**). Due to acute illness on December 15, 2018 (**Figure 3**), hospitalized patient referred to the unit. He was discharged on January 10, 2019, continuing with ECCI support. On January 23, 2019, PU with granulation and devitalized tissue, macerated and thickened edges, applied with warm saline and

#### **Figure 2.**

*Evolution with acronym TIME November 2018, own source.*

**81**

practice.

bed preparation.

**4. Final considerations**

*Managing Patients with Pressure Ulcers DOI: http://dx.doi.org/10.5772/intechopen.91034*

September 19, 2016

November 14, 2016

November 20, 2018

January 23, 2019

*Own source.*

**Table 1.**

**Date TIME**

Necrotic tissue (10%), devitalized tissue (40%) and granulation tissue (50%)

Granulation tissue (95%) and devitalized tissue (5%)

Granulation tissue (80%), epithelialization tissue (15%) and fibrin (5%)

Granulation tissue (80%) and devitalized tissue (20%)

*Preparation of the wound bed, comparison from August 2016 to January 2019.*

**T I M E**

– Moderated serous

Serous hematic and purulent exudate

Considerable sanguineous exudate

drainage

Moderated serous drainage

Delimited edges and macerated perilesional skin

Delimited edges

Delimited, thickened, whitish and macerated edges

Delimited, thickened and macerated edges

Pain, redness and edema

> Light redness, odor and pain

Edema, erythema, no odor or pain

®carboxymethylcellulose single fibers, polyurethane foam and ®hydrocolloid plate. For a better understanding, **Table 1** represents the comparison regarding PU

We can conclude that a correct diagnosis in favor of the needs felt by the informal caregiver and the patient is crucial in the planning of nursing interventions and the result of health gains for both the patient and those who take care. The positive aspects of the present study were the commitment of the caregiver together with the professionals in self-care in hygiene/comfort and nutrition, leading to the healing of three initial PUs. However, something remained to be done, the barriers created by the caregiver to the management of the physical space, the non-healing of the left trochanter PU and constant maceration of the sacred region, the care inherent in positioning/repositioning avoiding friction and sliding forces, despite the intervention through the teachings done over time. Taking care of a patient is not easy, and the nurse has to know the entire biopsychosociocultural context of the patient and the caregiver, to give the appropriate response to the detected needs. Homecare nurses can promote interventions aimed at favoring and promoting conditions so that the patient and the informal caregiver can transform the negative aspects into positive ones, as a way to achieve a quality of life. What makes the difference is people, for that it is necessary to rethink strategies and put them into

**Figure 3.** *Left trochanter December 2018, own source.*

*Managing Patients with Pressure Ulcers DOI: http://dx.doi.org/10.5772/intechopen.91034*


**Table 1.**

*Wound Healing*

foam and ®hydrocolloid plate. For a long period, the PU did not evolve, despite vacuum therapy being applied for 1 month, without favorable results due to caregiver resistance. On September 18, 2018, the patient began treatment with honey, ®carboxymethylcellulose single fibers and ®hydrocolloid plaque. In October 2018, the wound did not heal and presented with: devitalized tissue, increased exudate and purulent characteristics, inflammatory signs, and bad smell, the non-healing mnemonics was applied, increased exudate, red and bleeding surface tissue, Dobris [NERDS]. The use of honey was suspended due to the rejection of the informal caregiver; therefore, irrigation with PHMB and carboxymethylcellulose fibers with silver, calcium alginate, polyurethane foam and ®hydrocolloid plate were restarted. On November 20, 2018, the wound presented: fibrin that was removed, granulation tissue and devitalized, odorless. The treatment was warm saline, ®carboxymethylcellulose single fibers, polyurethane foam and ®hydrocolloid plate (**Figure 2**). Due to acute illness on December 15, 2018 (**Figure 3**), hospitalized patient referred to the unit. He was discharged on January 10, 2019, continuing with ECCI support. On January 23, 2019, PU with granulation and devitalized tissue, macerated and thickened edges, applied with warm saline and

**80**

**Figure 3.**

**Figure 2.**

*Left trochanter December 2018, own source.*

*Evolution with acronym TIME November 2018, own source.*

*Preparation of the wound bed, comparison from August 2016 to January 2019.*

®carboxymethylcellulose single fibers, polyurethane foam and ®hydrocolloid plate. For a better understanding, **Table 1** represents the comparison regarding PU bed preparation.

### **4. Final considerations**

We can conclude that a correct diagnosis in favor of the needs felt by the informal caregiver and the patient is crucial in the planning of nursing interventions and the result of health gains for both the patient and those who take care. The positive aspects of the present study were the commitment of the caregiver together with the professionals in self-care in hygiene/comfort and nutrition, leading to the healing of three initial PUs. However, something remained to be done, the barriers created by the caregiver to the management of the physical space, the non-healing of the left trochanter PU and constant maceration of the sacred region, the care inherent in positioning/repositioning avoiding friction and sliding forces, despite the intervention through the teachings done over time. Taking care of a patient is not easy, and the nurse has to know the entire biopsychosociocultural context of the patient and the caregiver, to give the appropriate response to the detected needs. Homecare nurses can promote interventions aimed at favoring and promoting conditions so that the patient and the informal caregiver can transform the negative aspects into positive ones, as a way to achieve a quality of life. What makes the difference is people, for that it is necessary to rethink strategies and put them into practice.

### **Author details**

Eglantina Afonso1 , Dina Borges2 , Kátia Furtado3 , Maria do Céu Marques4 \*, Margarida Pedro5 , Inês Reis1 and Rita Morais6

1 Unidade de Cuidados na Comunidade de Beja, Beja, ULSBA, EPE, Portugal

2 Departamento de Enfermagem, Universidade de Évora, Évora, Portugal

3 José Maria Grande Hospital, ULSNA, EPE, Portugal

4 Departamento de Enfermagem, Comprehensive Health Research Centre, Universidade de Évora, Évora, Portugal

5 Vila Real Santo Antonio Community Care Unit, Vila Real de Santo António, Portugal

6 Orthopaedics and Rheumatology Unit, Queen Alexandra Hospital, UK

\*Address all correspondence to: mcmarques@uevora.pt

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**83**

*Managing Patients with Pressure Ulcers DOI: http://dx.doi.org/10.5772/intechopen.91034*

[1] Augusto B, Almeida Z. Preservar a integridade Cutânea uma prioridade? In: Ribeiro F, Costa R, Augusto B, Almeida Z, Durão A, Dinis A, Neto I, editors. Feridas e Úlceras Cutâneas. Coimbra: Edições Formasau, Formação enfermagem e orientando o familiar cuidador. Maringá. 2007;**29**(2):85-89

Regulamento do Exercício Profissional dos enfermeiros e Estatuto da Ordem dos Enfermeiros. Lisboa: Ordem dos Enfermeiros; 2012. Available from: http://www.ordemenfermeiros.pt/ publicacoes/documents/repe\_vf.pdf

[10] Ferreira PL, Miguéns C, Gouveia J, Furtado K. Risco de desenvolvimento de Úlceras de Pressão: Implementação Nacional da Escala de Braden. Lisboa:

[11] Menoita EC. Gestão de Feridas Complexas. Lisboa: Lusodidacta; 2017

[12] Direção Geral da Saúde. Escala de Braden: Versão Adulto e Pediátrica (Braden Q ). Lisboa, Portugal: Ministério da Saúde; 2011. Available from: https://

www.dgs.pt/departamento-daqualidade-na-saude/ficheiros-anexos/ orientacao\_ulceraspdf-pdf.aspx

pt/documentos/Prevencao\_e\_

Tratamento\_de\_Ulceras\_Por\_Pressao-Guia\_de\_Referencia\_Rapido.pdf

[15] Parreira A, Marques R. Feridas— Manual de boas práticas. Lisboa: Lidel;

2017

[14] Ministério da Saúde. Plano Nacional para a Segurança dos Doentes 2015- 2020. Diário da República, 2.ª série N° 28, de 10 de fevereiro de 2018 (Despacho n° 1400-A/2015). Lisboa: Ministério da Saúde; 2015. Available from: https:// www.dgs.pt/.../plano-nacional-para-aseguranca-dos-doentes-2015-2020-pdf

[13] National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance. In: Haesler E, editor. Prevention and Treatment of Pressure Ulcers: Quick Reference Guide. Osborne Park, Western Australia: Cambridge Media; 2014. Available from: https://sociedadeferidas.

[9] Ordem dos Enfermeiros.

Lusociência; 2007

[2] Andrade FO. Cuidador Informal à Pessoa Idosa Dependente em Contexto Domicílio: Necessidades Educativas do Cuidador Principal (dissertação de mestrado). Universidade do Minho, Instituto de Educação e Psicologia; 2009. Available from: http://repositorium.sdum.uminho. pt/bitstream/1822/10460/1/ Disserta%C3%A7%C3%A3o\_ Mestrado\_Fernanda\_%20Andrade-

**References**

e Saúde, Lda; 1999

Vers%C3%A3o\_final.pdf

[3] República Portuguesa. Plano de Desenvolvimento da RNCCI 2016-2019. Ministério da Saúde e Ministério do Trabalho, Solidariedade e Segurança Social; 2016. Available from: https://www.sns.gov.pt/

desenvolvimento-da-RNCCI.pdf

Solidariedade e Segurança Social e Saúde, Portugal. Diário da República. 1.ª Série (N° 24). de 2 de fevereiro de 2017

[5] Lopes L. Envelhecimento Activo: Uma Via para o Bem-Estar. Fórum Sociológico. 2007;**II**(17):65-68

[6] Rice R. Prática de Enfermagem nos Cuidados Domiciliários. Conceitos e aplicações. Lusodidacta: Lisboa; 2004

[8] Lise F, Silva L. Prevenção de úlceras por pressão: Instrumentalizando a

[7] Cruz D, Loureiro H, Silva M, Fernandes M. As vivências do cuidador

informal do idoso dependente. Revista de Enfermagem Referencia.

2010;**III**(2):127-136

[4] Ministério do Trabalho,

wp-content/uploads/2016/02/Plano-de-

*Managing Patients with Pressure Ulcers DOI: http://dx.doi.org/10.5772/intechopen.91034*

### **References**

*Wound Healing*

**Author details**

Eglantina Afonso1

Margarida Pedro5

, Dina Borges2

3 José Maria Grande Hospital, ULSNA, EPE, Portugal

\*Address all correspondence to: mcmarques@uevora.pt

, Inês Reis1

Universidade de Évora, Évora, Portugal

provided the original work is properly cited.

, Kátia Furtado3

and Rita Morais6

2 Departamento de Enfermagem, Universidade de Évora, Évora, Portugal

4 Departamento de Enfermagem, Comprehensive Health Research Centre,

5 Vila Real Santo Antonio Community Care Unit, Vila Real de Santo António,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

6 Orthopaedics and Rheumatology Unit, Queen Alexandra Hospital, UK

1 Unidade de Cuidados na Comunidade de Beja, Beja, ULSBA, EPE, Portugal

, Maria do Céu Marques4

\*,

**82**

Portugal

[1] Augusto B, Almeida Z. Preservar a integridade Cutânea uma prioridade? In: Ribeiro F, Costa R, Augusto B, Almeida Z, Durão A, Dinis A, Neto I, editors. Feridas e Úlceras Cutâneas. Coimbra: Edições Formasau, Formação e Saúde, Lda; 1999

[2] Andrade FO. Cuidador Informal à Pessoa Idosa Dependente em Contexto Domicílio: Necessidades Educativas do Cuidador Principal (dissertação de mestrado). Universidade do Minho, Instituto de Educação e Psicologia; 2009. Available from: http://repositorium.sdum.uminho. pt/bitstream/1822/10460/1/ Disserta%C3%A7%C3%A3o\_ Mestrado\_Fernanda\_%20Andrade-Vers%C3%A3o\_final.pdf

[3] República Portuguesa. Plano de Desenvolvimento da RNCCI 2016-2019. Ministério da Saúde e Ministério do Trabalho, Solidariedade e Segurança Social; 2016. Available from: https://www.sns.gov.pt/ wp-content/uploads/2016/02/Plano-dedesenvolvimento-da-RNCCI.pdf

[4] Ministério do Trabalho, Solidariedade e Segurança Social e Saúde, Portugal. Diário da República. 1.ª Série (N° 24). de 2 de fevereiro de 2017

[5] Lopes L. Envelhecimento Activo: Uma Via para o Bem-Estar. Fórum Sociológico. 2007;**II**(17):65-68

[6] Rice R. Prática de Enfermagem nos Cuidados Domiciliários. Conceitos e aplicações. Lusodidacta: Lisboa; 2004

[7] Cruz D, Loureiro H, Silva M, Fernandes M. As vivências do cuidador informal do idoso dependente. Revista de Enfermagem Referencia. 2010;**III**(2):127-136

[8] Lise F, Silva L. Prevenção de úlceras por pressão: Instrumentalizando a

enfermagem e orientando o familiar cuidador. Maringá. 2007;**29**(2):85-89

[9] Ordem dos Enfermeiros. Regulamento do Exercício Profissional dos enfermeiros e Estatuto da Ordem dos Enfermeiros. Lisboa: Ordem dos Enfermeiros; 2012. Available from: http://www.ordemenfermeiros.pt/ publicacoes/documents/repe\_vf.pdf

[10] Ferreira PL, Miguéns C, Gouveia J, Furtado K. Risco de desenvolvimento de Úlceras de Pressão: Implementação Nacional da Escala de Braden. Lisboa: Lusociência; 2007

[11] Menoita EC. Gestão de Feridas Complexas. Lisboa: Lusodidacta; 2017

[12] Direção Geral da Saúde. Escala de Braden: Versão Adulto e Pediátrica (Braden Q ). Lisboa, Portugal: Ministério da Saúde; 2011. Available from: https:// www.dgs.pt/departamento-daqualidade-na-saude/ficheiros-anexos/ orientacao\_ulceraspdf-pdf.aspx

[13] National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance. In: Haesler E, editor. Prevention and Treatment of Pressure Ulcers: Quick Reference Guide. Osborne Park, Western Australia: Cambridge Media; 2014. Available from: https://sociedadeferidas. pt/documentos/Prevencao\_e\_ Tratamento\_de\_Ulceras\_Por\_Pressao-Guia\_de\_Referencia\_Rapido.pdf

[14] Ministério da Saúde. Plano Nacional para a Segurança dos Doentes 2015- 2020. Diário da República, 2.ª série N° 28, de 10 de fevereiro de 2018 (Despacho n° 1400-A/2015). Lisboa: Ministério da Saúde; 2015. Available from: https:// www.dgs.pt/.../plano-nacional-para-aseguranca-dos-doentes-2015-2020-pdf

[15] Parreira A, Marques R. Feridas— Manual de boas práticas. Lisboa: Lidel; 2017

#### *Wound Healing*

[16] Alves P. Úlceras por Pressão: da Ciência Básica à Prática Clínica. In: Parreira A, Feridas MR, editors. Manual de boas práticas. Lisboa: Lidel; 2017

[17] British Association for Parenteral and Enteral Nutrition. Malnutrison Universal Screening Tool. 2010. Available from: http://www.bapen.org.uk

[18] Direção Geral da Saúde. Acidente Vascular Cerebral: Prescrição de Medicina Física e Reabilitação. Lisboa, Portugal: Ministério da Saúde; 2011. Available from: http://www.dgs. pt/directrizes-da-dgs/normas-ecirculares-normativas/norma-n-0542011-de-27122011.aspx

[19] Roper N, Logan W, Tierney AJ. O Modelo de Enfermagem Roper–Logan– Tierney. Lisboa: Climepsi; 2001

[20] Ordem dos Enfermeiros. Classificação Internacional para a Prática de enfermagem; 2010. Available from: http://ordemenfermeirospt/ browserCIPE/BrowserCIPE.aspx

**85**

Section 2

Hypertrophic Scarring

Section 2
