• Connective Tissue
• Epithelial Tissue
• Muscle Tissue
• Nervous Tissue

1. What Is a Connective Tissue?

Connective tissue provides structure, support, protection, and connection to other tissues and organs of the body [1].

1.1. What Are the 3 Types of Connective Tissue?

Connective tissue is made of fibers, gelatinous-like substances, and cells, and is divided into 3 types of tissues: loose connective tissue, dense connective tissue, and specialized connective tissue.

1.1.1. Where Is Loose Connective Tissue Found and What Is Its Function?

Loose connective tissue is found in almost every part of the body where it maintains organs in place.

It is made of an extracellular matrix and fibers of collagen, elastin, and reticulum.

• What Is Extracellular Matrix?

The extracellular matrix (ECM) is a complex network made of macromolecules and minerals, including collagen, elastin, glycoproteins, laminin, fibronectin, hydroxyapatite, and enzymes [2].

The extracellular matrix is found between the different cells of the body where it works as a structural scaffold and serves as membranous support where cells stand.

Glycoproteins are a type of protein involved in the interactions between and within cells.

Laminin is made of glycoproteins and collagen that form a membrane where the cells stand. This type of membrane is known as the basement membrane.

Fibronectin is a glycoprotein that works like a biological glue that connects the cells to the extracellular matrix through its interaction with proteins known as integrins found on the surface of cells.

Hydroxyapatite is also known as the bone mineral is made of calcium and phosphorus. It is mostly found in the bone and teeth connective tissues.

Enzymes are proteins that work as a catalyst through reactions that produce products necessary for the function of cells and tissues.

What Are Collagen Fibers?

Collagen is made by cells known as fibroblasts and is assembled into fibrils that make the collagen fibers.

Collagen fibers provide structural support for the cells of the extracellular matrix.

What Are Collagen Fibers?

What Are Elastin Fibers?

Elastin fibers are fibers that provide elasticity to the tissues.

What Are Reticular Fibers?

Reticular fibers are a type of collagen made by reticular cells. They form a supportive network for soft tissues such as the liver, bone marrow, and lymphatic system.

1.1.2. Where Is Dense Connective Tissue Found and What Is Its Function?

Dense Connective Tissue is what makes the tendons and ligaments. It also provides structure, support, protection, and connectivity.

Dense Connective Tissue is also made of extracellular matrix and fibers of collagen, elastin, and reticulum.

1.1.3. What Is Specialized Connective Tissue and What Is Its Function?

Specialized connective tissues include the blood, bone, cartilage, and adipose tissue.

Blood is a bodily fluid that provides oxygen and nutrients to tissues and organs of the body. It also collects metabolic waste away from the cells. It is made of red blood cells and plasma.

The bone is a hard connective tissue (support and connect tissues) that contains a honey-comb shaped structure made of a mineralized matrix and bone cells.

Cartilage is a gelatinous-like substance that is found in body parts such as joints, rib cage, ears, nose, intervertebral discs, and bronchial tubes.

The Adipose tissue is a specialized tissue that stores fat and insulates the body.

2. What Is Epithelial Tissue?

Epithelial tissue or epithelium is made of one or more sheets of interconnected cells, known as epithelial cells, that cover the surface of organs and vessels and internal cavities of the body [3].

The epithelium is also part of the endocrine and exocrine glands that produce hormones and other substances and is the main component of the skin epidermis.

The epithelial cells have no blood vessels, and therefore, oxygen and nutrients are provided by the conjunctive tissue through basement membranes.

2.1. Epithelial Tissue Types

There are 8 different types of epithelial tissues according to their functions, morphologies, and localization in the body:

• Simple Squamous Epithelium
• Simple Cuboidal Epithelium
• Simple Columnar Epithelium
• Pseudostratified Columnar Epithelium
• Stratified Squamous tissue
• Stratified Cuboidal Epithelium
• Stratified Columnar Epithelium
• Transitional Epithelium

2.1.1. Where Is Simple Squamous Epithelium Found in the Body?

The simple squamous epithelium is made of flat epithelial cells that are found in the lining of vessels, heart, lungs, and lymphatic vessels.

The simple squamous epithelium is permeable which allows the diffusion and filtration of small molecules.

2.1.1. Where Is Simple Cuboidal Epithelium Found in the Body?

The simple cuboidal epithelium is made of cuboidal (cube-like shape) epithelial cells found in the kidneys and small glands. It is involved in absorption and secretion.

2.1.1. Where Is Simple Columnar Epithelium Found in the Body?

The simple columnar epithelium is made of ciliated epithelial cells that are shaped like columns, and that is found in bronchi, digestive tissue, and uterus.

2.1.1. Where Is Pseudostratified Columnar Epithelium Found in the Body?

The pseudostratified columnar epithelium is also made of ciliated epithelial cells that are shaped like columns.

However, their nuclei are found in different areas within each cell which makes them different from the simple columnar epithelial cells that have the nucleus at the bottom of the cells.

The pseudostratified columnar epithelium is found in the upper respiratory tract where they secrete and move mucus along the tract through cilia.

2.1.1. Where Is Stratified Squamous Epithelium Found in the Body?

The stratified squamous epithelium is made of layers of flat epithelial cells found in the mouth, esophagus, and vagina where it protects against abrasion.

2.1.1. Where Is Stratified Cuboidal Epithelium Found in the Body?

The stratified cuboidal epithelium is made of layers of cuboid epithelial cells found in mammary glands, salivary glands, and sweat glands where it acts as a protective tissue.

2.1.1. Where Is Stratified Columnar Epithelium Found in the Body?

The stratified columnar epithelium is made of layers of non-ciliated column-shaped epithelial cells found in male urethra and ducts of some glands where they are involved in secretion and have a

2.1.1. Where Is Transitional Epithelium Found in the Body?

The transitional epithelium is made of layers of epithelial cells that have different shapes and that are found in the bladder, urethra, and ureters where they allow these organs to stretch.

3. What Is Muscle Tissue?

The muscle tissue is made of cells and contractile proteins that allow the contraction and relaxation of muscles.

There are 3 types of muscle tissues according to their functions and localization in the body:

• Skeletal Muscle Tissue
• Smooth Muscle Tissue
• Cardiac Muscle Tissue

3.1. What Is Skeletal Muscle Tissue?

The skeletal or striatal muscle is made of elongated cylindrical muscle cells known as muscle fibers (myofibers) that are attached to bones through tendons [4].

Examples of skeletal muscles are the muscles of the arms and legs.

Each muscle fiber is a bundle of fibers arranged in parallel, known as myofibrils, and that are surrounded by collagen.

Myofibrils can be made of thin filaments containing actin or thick filaments made of myosin.

The filaments are known as myofilaments which are arranged in such a way that it alternate light and dark bands, hence the striatal aspect of the muscle.

3.2. What Is Smooth Muscle Tissue?

The smooth muscle tissue is made of smooth muscle cells known as myocytes.

Myocytes are elongated cells with a wide middle and contain proteins such as actin and myosin responsible for their contraction and relaxation.

Smooth muscle tissue is found in organs such as the intestines, stomach, bladder, uterus, and blood vessels.

3.3. What Is Cardiac Muscle Tissue?

The cardiac muscle tissue is what makes the myocardium of the heart, a muscle that is found between the endocardium (inner layer) and the epicardium (outer layer).

The cardiac muscle tissue is made of cardiac cells known as cardiomyocytes that provide the contraction and relaxation of the heart.

Some of the cardiomyocytes, known as peacemaker cells, are responsible for maintaining heartbeats and are found in the atria of the heart.

4. What Is Nervous Tissue?

The nervous tissue is the tissue that makes the nervous system including the peripheral and central nervous systems [5].

The central nervous system (CNS) includes the brain and the spinal cord, while the peripheral nervous system (PNS) includes the branching nerves that are outside the brain and the spinal cord.

The nervous tissue is made of neurons that transmit nerves impulses and neuroglia cells that provide support to neurons.

4.1. What Are Neurons and Their Functions?

Neurons are highly specialized cells that transmit nerve impulses (action potentials).

They are made of a cell body, an axon, and an axon terminal.

The cell body contains cell projections known as dendrites.

The axon extends from the cell body and all the way to the axon terminals which are cell projections.

Axons are covered by a sheet made of a fatty substance known as myelin sheet that protects the axon and helps with the transmission of nerve impulses.

Neurons are interconnected through gaps, known as synapses, that are found between a dendrite of one neuron and an axon terminal of another neuron.

Nerve impulses are transmitted from one neuron to another using neurotransmitters that are released from one neuron axon terminal to a dendrite of the following neuron through the synapses.

A neurotransmitter that is released in the synapse by the axon terminal of a neuron is captured by receptors that are specific to the neurotransmitter and that are found on the dendrite of the following neuron.

Once the dendrite of a neuron receives the neurotransmitter, there is a start of a nerve impulse (action potential) that is transmitted along the axon and all the way to the axon terminal where it is transferred to the next neuron.

This process of nerve transmission is known as neurotransmission.

Based on their function, neurons are classified as sensory, motor, or interneurons.

• What Are Sensory Neurons?

Sensory neurons or afferent neurons are neurons that transmit information (e.g., tactile, gustatory, visual, or auditory) from the different organs of the body to the central nervous system.

• What Are Motor Neurons?

Motor neurons or efferent neurons are neurons that transmit information from the nervous central nervous to different organs of the body to initiate an action (e.g., muscle).

• What Are Interneurons?

As their name indicates, interneurons are neurons that serve as neuronal bridges between neurons, such as between sensory or motor neurons and the central nervous system.

4.2. What Are Neuroglia Cells and Their Functions?

Neuroglia cells are not neurons but different types of cells that provide support to neurons and include microglia, astrocytes, oligodendrocytes, Schwann cells, and enteric glia [6].

• What are Microglia Cells?

Macroglia cells are macrophages that contribute to the immunity of the central nervous system.

• What Are Astrocytes?

Astrocytes or astroglia are star-shaped cells that have many functions such as providing nutrients to the nervous tissue, repair, and scarification of the brain and spinal cord, support of endothelial cells involved in the blood-brain barrier.

• What Are Oligodendrocytes?

Oligodendrocytes are cells that make the myelin sheet and provide insulation and support for neurons.

• What Are Schwann Cells?

Schwann cells are cells that make the myelin sheet and provide insulation and support for neurons in the peripheral nervous system.

• What Are Enteric Glia Cells?

Enteric glial cells are cells found in the enteric nervous system (gut nervous system) where they may play a role in neurotransmission [7].

In the central nervous system, the brain tissue can also be classified as grey matter and white matter

• What Is Grey Matter?

The grey matter is made of the neurons’ cell bodies, neurons’ unmyelinated axons, neurons’ dendrites, astrocytes, oligodendrocytes, synapses, and blood capillaries.

• What Is White Matter?

The white matter is mostly made of myelinated axons of neurons is found in a brain structure known as the corpus callosum which is a tract of fibers located under the cerebral cortex.

Conclusion

Tissues are what make the body, and therefore, taking care of our tissues through a healthy diet, exercise, and a healthy environment can only improve their function and health which will increase the potential of a healthier and longer life.

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1- What Are cytokines?

Cytokines are small proteins that are produced by white blood cells, such as lymphocytes T and lymphocytes B, and endothelial cells, mast cells, fibroblasts, and mesenchymal cells.

In the nervous system, cytokines are produced by microglia, astrocytes, endothelial cells, and macrophages [1].

• Lymphocytes T

Lymphocytes T are immune cells involved in the killing of viruses and cancer cells.

• Lymphocytes B

Lymphocytes B are immune cells that produce antibodies against viruses, bacteria, and cancer cells. Anomalies in the recognition of the body’s own antigens lead to autoimmune diseases.

• Endothelial Cells

Endothelial cells are the building block of vessels.

• Mesenchymal Cells

Mesenchymal Cells are cells that generate connective tissues.

• Fibroblasts

Fibroblasts are cells found in connective tissues where they produce collagen and are also involved in wound healing.

• Mast Cells

Mast cells are found in connective tissues where they produce histamine (neurotransmitter) and heparin (anticoagulant).

• Macrophages

Macrophages are a type of white cells that are responsible for engulfing and digesting viruses, microbes, cancer cells, debris of cells, and foreign substances.

• Microglia

Microglia are non-neuronal cells that are specifically found in the brain and the spinal cord where they play an essential role in the immune response.

• Astrocytes

Astrocytes are also non-neuronal cells responsible for providing nutrients to the nervous system and support the activity of the nervous system endothelial cells in forming the blood-brain barrier.

2- What Are Chemokines?

Chemokines are also cytokines that control the movement of lymphocytes in response to inflammation, infection, or cancer.

3- What Are Secondary Messengers?

When a ligand such as a growth factor, binds to a receptor on the surface of cells in the body there is a transmission of information within the cells by small molecules and ions that promote the expression of proteins necessary for the function of the cell.

4- What Are Reactive Oxygen Species (ROS)?

Reactive oxygen species (ROS) are produced by the metabolism of oxygen (O2) in the body’s cells. An excess of ROS (e.g., free radicals) can damage the DNA of the cells causing their death or mutations that can lead to cancer.

5- What Causes Neuroinflammation?

• Traumatic Brain Injury

A traumatic brain injury can be mechanical such as a blow to the brain or spinal cord leading to tissue damage, or pathological due to tissue damage caused by excitotoxicity (excessive excitation of neurotransmitters), ischemic injury, or alterations in mitochondria function [2].

• Spinal Cord Injury

A spinal injury is due to an acute or localized (focal) trauma, a reduced blood supply (ischemia), or excitotoxicity.

• Infection

The most known infection of the central nervous system (CNS) is due to Mycobacterium tuberculosis (tuberculosis), but there are other infections such as Plasmodium falciparum (malaria), Rickettsia conorii (Boutonneuse fever), Trypanosoma cruzi (Chagas disease) [3].

These infections cause inflammation by altering the function of the CNS vessels.

• Autoimmunity

Autoimmunity is due to the production of antibodies by lymphocytes B against antigens that are expressed by normal cells, including cells of the brain and spinal cord.

These antibodies are known as autoantibodies and attack the body’s cells and tissues causing their damage and inflammation.

• Toxic Metabolites

Alterations in CNS metabolites (Neurometabolites) such as N-acethylaspartate (NAA), creatine, and glutamine can cause injuries or death of neurons in the central nervous system leading to inflammation.

• Aging

Although the mechanisms are not known, there is an increase in proinflammatory cytokines and a decrease in anti-inflammatory cytokines in the aged central nervous system.

6- What Are the Symptoms of Neuroinflammation?

The symptoms of neuroinflammation depend on the injured part of the central nervous and the type of injury; however, some of the common symptoms are pain, depression, and fatigue.

7- What Mechanisms Mediate Inflammation in the Brain?

The immune response and inflammation in the brain and spinal cord are mainly mediated by microglia and astrocytes but also endothelial cells, and macrophages.

The brain and spinal cord are closed environments due to the presence of the blood-brain barrier (BBB), therefore, not all the cells of the immune system can enter [4].

Following the damage of the brain or spinal cord, microglia are activated and secrete cytokines and chemokines that recruit other cell types such as astrocytes, endothelial cells, and macrophages to repair the damage.

However, during the early stage of spinal injury, there is an infiltration of other immune cells, such as neutrophils, and monocytes. Lymphocytes also contribute to inflammation at a later stage of the injury [1].

9- How Does Neuroinflammation Contribute to Neurodegeneration?

Although the mechanisms are not well known, neuroinflammation has been implicated in the pathogenesis of dementia through its role in cerebral small vessel disease (SVD)-vascular dementia [5].

Neuroinflammation contributes to multiple sclerosis through the disruption of the blood-brain barrier resulting in the recruitment of immune cells and the secretion of proinflammatory factors and antibodies against the myelin sheath.

It was suggested that neuroinflammation also contributes to Alzheimer’s disease through the incapacity of microglia to eliminate amyloid-beta plaques [6].

10- How Is Neuroinflammation Treated?

For multiple sclerosis, a monoclonal antibody (rituximab) has been successfully used to target lymphocytes B responsible for the production of antibodies against the myelin sheet.

However, this treatment has also a potential risk of inducing a rare disease known as progressive multifocal leukoencephalopathy that causes damage to the white matter in multiple parts of the brain [7].

For Alzheimer’s disease and Parkinson’s disease, there are several ongoing clinical trials using inhibitors that regulate the function of microglia and astrocytes which are involved in the pathogenesis of AD and PD [7].

Conclusion

Neuroinflammation is a natural response of the brain and spinal cord to injuries, autoimmunity, infection, toxic metabolites, and aging.

Although its role is to promote the repair of tissues’ damage, proinflammatory cytokines can also result in the recruitment of other types of cells, such as immune cells, fibroblasts, and lymphocytes that can lead to additional and indirect tissue damage resulting in neurodegenerative diseases such as dementia, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.

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1. What Are the Stages of Wound Healing?

Homeostasis Phase

This phase involves blood vessels’ vasoconstriction (tightening) and platelet aggregation to stop blood loss at the injured site.  Platelet aggregation, also known as coagulation, relies on a primary homeostasis stage and a secondary homeostasis stage [2].

In the first stage, platelets aggregate to form a plug that prevents bleeding, and in the second. In the second stage, intrinsic and extrinsic coagulation pathways are activated through a series of clotting factors.

Intrinsic coagulation factors are activated by the wound-exposed endothelial collagen and include factors I (fibrinogen), II (Prothrombin), IX (Christmas factor), X (Stuart-Prower factor), XI (Plasma Thromboplastin), and XII (Hageman factor).

Extrinsic factors, also named stable factors are activated by tissue factors released by damaged endothelial cells and include factors I, II, VII, and X.

Inflammatory Response Phase

After coagulation, the vasoconstriction that characterizes the homeostasis phase is replaced by vasodilation (opening) that promotes the recruitment of inflammatory cells (neutrophils, monocytes, and endothelial cells) to the site of injury and their binding to the scaffolding that was constructed by the platelets’ aggregation.

Once on-site, neutrophils initiate the phagocytosis and killing of pathogens to decontaminate the wound, while also promoting cell proliferation and angiogenesis.

Besides their direct role in the phagocytosis and killing of pathogens, Monocytes which become macrophages, also remove apoptotic cells and support cell proliferation and tissue restoration following injury.

Endothelial cells are the building blocks for vessels, and during wound healing, these cells generate new vessels (angiogenesis) to satisfy the metabolic demands of the highly proliferative healing tissue. 

 Proliferation Phase

In this phase, keratinocytes, fibroblasts, macrophages, and endothelial cells are extensively activated to contribute to the closure, matrix deposition, and angiogenesis at the wound site [3]. 

keratinocytes in the surroundings of the wound migrate across the wound to reform the epidermal layer through a process known as epithelialization [4]. During this process, hair follicle stem cells are also activated to generate hair on the newly healed skin tissue.

While the epithelialization is ongoing, fibroblasts proceed to the breakdown of the fibrin clot and the deposition of a new extracellular matrix (ECM) and collagen to build structures that support the effective wound-healing effort of the other cells [5].

Although macrophages play a role during the inflammatory response phase, their functions during the proliferation phase are also critical in guiding the proper formation of vessels and in supporting fibroblasts in the breakdown of fibrin [6].

Remodeling Phase

This process is associated with the deposition of collagen by fibroblasts to replace the initial fibrin clot. Although collagen deposition contributes to the scarification of the wound, this deposited collagen is different from the one that was initially present in the unwounded tissue and will only confer for up to 80% of pre-wounding strength [7].

Other components that are required for the remodeling phase include myofibroblasts that secrete alpha-smooth muscle actin (α-SMA), necessary for the generation of strong contractile forces and focal adhesions, and elastin that provide skin elasticity to the healed wound.

2. What Slowdown Wound Healing?

Diabetes and Wound Healing

During the inflammatory response phase, vasodilation of the blood vessels is necessary for the recruitment of inflammatory cells (neutrophils, monocytes, and endothelial cells) to the site of injury.

However, due to the high levels of glucose in the blood of diabetics, the arteries are thickened, resulting in vasoconstriction of the blood vessels which slows down wound healing. 

Another pathological process that can slow down wound healing in diabetics is associated with nerve damage that is caused by high levels of glucose which leads to poor blood circulation.

Malnutrition and wound healing

Micronutrients (minerals and vitamins) and macronutrients (Proteins, lipids, and carbohydrates) are required for effective wound healing. For instance, proteins are necessary for the production of enzymes, collagen, and connective tissue during the remodeling phase of wound healing.  

Neutrophils, monocytes, fibroblasts, endothelial cells, and myofibroblasts require glucose to generate energy for their activity during wound healing. Lipids are necessary for the generation of new cellular membranes.

In addition, vitamin A enhances the early inflammatory response phase and promotes epithelial cell differentiation, and vitamin C promotes the migration of neutrophils and is necessary for the production of collagen.

Finally, zinc is required for DNA and protein synthesis, and cell division during the proliferation stage of wound healing [8].

Smoking and Wound Healing

Clinically, it is well accepted that cigarette smoking delays wound healing as the toxic constituents of cigarette smoke such as nicotine, carbon monoxide, and hydrogen cyanide can affect nutritional blood flow to the skin, which impairs healing of the injured tissue.

Carbon monoxide is known to reduce oxygen transport and metabolism’ while hydrogen cyanide is also a known inhibitor of enzymatic systems required for cellular oxidative metabolism and oxygen transport [9]. 

3. How to Improve Wound Healing?

The consumption of the following foods can improve wound healing:

• – Drinking plenty of water for hydration (if recommended).
• – Proteins (e.g., in lean meat, beans, lentils, and dairy products).
• –  Carbohydrates (e.g., in whole-grain bread and cereals, potatoes, and rice)
• – Vitamins and minerals: vitamin A (e.g., in the liver, milk, eggs, and leafy greens), vitamin C (e.g., in broccoli, strawberries, tomatoes, and kiwi), and Zinc (e.g., in seafood, beans, lentils, and whole-grain bread).

4. Frequently Asked Questions about What Are the Mechanisms of Wound Healing?

What are the stages of wound healing?

Wound healing typically progresses through three main stages: inflammation, proliferation, and remodeling.

What happens during the inflammation stage of wound healing?

During inflammation, the body’s immune response is activated to clear debris and prevent infection. Blood vessels constrict to reduce bleeding, followed by dilation to increase blood flow, bringing white blood cells to the wound site.

What occurs during the proliferation stage of wound healing?

In the proliferation stage, new tissue is formed to repair the wound. This involves the proliferation of fibroblasts, which produce collagen, as well as the formation of new blood vessels (angiogenesis) to supply nutrients to the healing tissue.

What is the role of fibroblasts in wound healing?

Fibroblasts are key cells involved in wound healing. They produce collagen, which provides structural support to the healing tissue, and they also help to contract the wound, reducing its size.

What is angiogenesis and why is it important in wound healing?

Angiogenesis is the formation of new blood vessels. It is crucial in wound healing because it ensures that the healing tissue receives an adequate blood supply, delivering oxygen and nutrients necessary for repair.

How does the remodeling stage contribute to wound healing?

During the remodeling stage, the newly formed tissue undergoes maturation and remodeling. Collagen fibers reorganize to increase tissue strength, and excess scar tissue may be broken down.

This stage can last for months to years, gradually improving the strength and appearance of the healed wound.

What factors can affect the wound healing process?

Various factors, including age, underlying health conditions (such as diabetes or immunodeficiency), nutritional status, medications (such as steroids or chemotherapy), and the presence of infection, can influence the speed and effectiveness of wound healing.

How can I promote optimal wound healing?

To support wound healing, it’s essential to maintain good overall health, including adequate nutrition, hydration, and hygiene.

Following medical advice regarding wound care, avoiding smoking, managing chronic conditions, and protecting the wound from further injury can also facilitate healing.

Conclusion

Wound healing involves the participation of different cells, cytokines, mediators, and the vascular system to repair the damaged tissue. However, to fuel this amazing repair machinery, an appropriate diet that provides proteins, lipids, carbohydrates, vitamins, and minerals is necessary for effective wound healing.

References

[1] Wallace, H.A., Basehore, B.M. and Zito, P.M., 2017. Wound healing phases.

[2] Chaudhry, R., Usama, S.M. and Babiker, H.M., 2018. Physiology, coagulation pathways.

[3] Wilkinson, H.N. and Hardman, M.J., 2020. Wound healing: Cellular mechanisms and pathological outcomes. Open biology, 10(9), p.200223.

[4] Santoro, M.M. and Gaudino, G., 2005. Cellular and molecular facets of keratinocyte reepithelization during wound healing. Experimental cell research, 304(1), pp.274-286.

[5] Driskell, R.R., Lichtenberger, B.M., Hoste, E., Kretzschmar, K., Simons, B.D., Charalambous, M., Ferron, S.R., Herault, Y., Pavlovic, G., Ferguson-Smith, A.C. and Watt, F.M., 2013. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature, 504(7479), pp.277-281.

[6] Willenborg, S., Lucas, T., Van Loo, G., Knipper, J.A., Krieg, T., Haase, I., Brachvogel, B., Hammerschmidt, M., Nagy, A., Ferrara, N. and Pasparakis, M., 2012. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood, The Journal of the American Society of Hematology, 120(3), pp.613-625.

[7] Young, A. and McNaught, C.E., 2011. The physiology of wound healing. Surgery (Oxford), 29(10), pp.475-479.

[8] MacKay, D.J. and Miller, A.L., 2003. Nutritional support for wound healing. Alternative medicine review, 8(4).

[9] Silverstein, P., 1992. Smoking and wound healing. The American journal of medicine, 93(1), pp.S22-S24.

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