Wound Care Demystified: A Comprehensive Review Of Types, Pathophysiology, Global Burden, Therapies, And Future Directions

Abstract

The body reacts to the dissipated cells following any type of severe injury through the intricate process of wound healing, which is a type of tissue regeneration. Non-healing wounds and diabetes are regarded as unmet clinical needs. Nowadays, a variety of strategic approaches are frequently employed in the management of acute and chronic wounds, which can involve the use of an instrument, cell therapy, tissue transplantation, and wound dressings, among other things. Although a lot of literature has been written about this subject, finding the best clinical treatment is still difficult. In order to deliver medication, autologous stem cells, or growth factors from the blood, the wound dressing uses a scaffold, typically made of biomaterials. In order to prevent infection and hasten wound healing, antibacterial and anti-inflammatory medications are also utilized. There is an urgent need to enhance the current treatment approaches because diabetes and related cutaneous wounds are becoming more common as the population ages. This study critically examines the most recent developments in clinical and therapeutic strategies for tissue regeneration and wound healing. Recent clinical trial results indicate that the simplest, most affordable, and most accessible method of treating chronic wounds is to use contemporary dressings and skin substitutes. Materials science advancements like graphene as a 3D scaffold and biomolecules hold great promise. The annual market value for successful wound treatment exceeds over $50 billion US dollars, and this will encourage industries as well as academics to investigate the application of emerging smart materials for modern dressings and skin substitutes for wound therapy.

Keywords

Introduction

Structure of skin

The largest organ in the human body, the skin has an average surface area of 1.85 m² and makes up 16% of the body weight. Skin serves as a barrier of defense against the outside world in addition to being essential for preserving homeostasis. setting to stop fluid loss and infections ^[1,2]. The epidermis, dermis, and hypodermis are the three separate layers that make up the skin, which is the largest organ in the human body. Anisotropic collagenous extracellular matrix (ECM) also contains over 50 different cell types ^[3]. The primary roles of skin include preventing water loss from the body, regulating body temperature, promoting metabolic processes (vitamin D synthesis), and providing adequate protection against external factors (ultraviolet light, microbes, chemical, thermal, etc.). The two primary structural layers of skin, the epidermis and dermis, are joined by the basement membrane. Adipose tissue and the third layer, the hypodermis, are subcutaneous layers that sit beneath these layers (Figure 1). The outermost waterproof layer of skin is made up of the epidermis, an avascular keratinized stratified squamous epithelium that is essential for regulating the body's moisture intake ^[4]. The diffusion of intercellular fluids originating from the dermal vasculature typically provides nourishment to the epidermis layer. Numerous specialized cells, including keratinocytes, Merkel cells, melanocytes, and antigen-presenting dendritic Langerhans cells, make up the epidermis layer. About 90% of the cell population is made up of keratinocytes, the predominant epidermal cells found in the epidermis layer. Keratinocytes are the main cell type found in the epidermis layer, and they are primarily involved in water transport and epidermal healing. Keratinocytes secrete a range of currently recognized growth factors, chemokines, and cytokines to control immunological and inflammatory responses in pathological skin conditions ^[5,6]. The brain receives touch information in the form of pressure and texture from Merkel cells, which are non-epithelial cells. Keratinocytes receive melanin, the pigment that makes up skin, which is secreted by melanocytes. Antimicrobial peptides secreted by Langerhans cells promote both innate and adaptive immunity ^[7]. The stratum corneum, stratum granulosum, stratum spinosum, stratum lucidum, and stratum basale are additional components of the epidermis. Keratinocytes are essentially produced from stem cells found in the skin's basal layer, which differentiate for three to six weeks before becoming corneocytes and finally forming the stratum corneum layer ^[8]. Keratin, which is a key structural component of the stratum corneum, is one of the many proteins that keratinocytes synthesize. The stratum corneum's complex lipids and cell membranes, in addition to proteins, offer a significant barrier of defense against bacteria and dehydration. The migration of fully differentiated cuboidal basal keratinocytes with large nuclei, phospholipid membranes, and organelles starts from the basal layer about every 28 days ^[9].

Figure no 1 Structure of skin

An increased buildup of lipids and keratin takes place during this turnover process, and it eventually differentiates into stratum corneum. The basement membrane known as the dermo-epidermal junction, to which the hemidesmosomes, which are molecules that bind cells together, separates the epidermal and dermal layers. Keratinocytes from the basal layer, ECM constituents, basal lamina, filaments, and anchoring fibrils make up the intricate dermo-epidermal junction structure ^[10]. To reduce the chance of the epidermis separating from the dermis layer during the wound healing process, the dermo-epidermal junction must be restored. About 90% of the skin's weight is made up of the dermis, the innermost layer, which is located above the hypodermis and beneath the epidermal layer. Vascular endothelial cells, fibroblasts, Schwann cells, mast cells, sweat glands, blood vessels, hair follicles, and both free and encapsulated nerve endings make up the dermal layer, which is a connective tissue. Fibroblasts and thick collagen fibers, respectively, are found in the superficial (papillary dermis) and deep (reticular dermis) layers that make up the dermal layer. Fibroblasts are the primary dermal cells that give the skin its elasticity and mechanical strength by secreting collagen, elastin, and glycosaminoglycans. Because of its structural characteristics, the dermal layer which houses the skin's neural, vascular, and lymphatic systems provides the epidermal layer with mechanical and metabolic support. The hypodermis is the subcutaneous tissue layer beneath the dermis that joins the skin's dermal layer to other structures, such as muscles or bone. The loose connective tissue, adipocytes, fluid that absorbs proteoglycan and glycosaminoglycan, blood vessels, and nerves make up the hypodermis layer. The hypodermal layer's primary roles include controlling body temperature and storing fat ^[1].

WOUNDS, ITS TYPES AND PHYSIOLOGY OF WOUND HEALING

Injuries or any conditions that impair the integrity of the skin's structure and are brought on by external factors (cuts, burns, pressure), surgery, or pathological conditions like diabetes or vascular diseases are referred to as wounds ^[11]. Based on the length of time and the healing process, wounds are divided into two categories: Acute and Chronic

Acute wounds are diverse injuries brought on by a variety of factors, including chemicals, radiation, and abrupt temperature changes. Acute wounds can be further divided into superficial, deep dermal, or full thickness wounds based on their size and depth ^[12]. Through a systematic, conventional wound healing process, acute wounds typically heal in 4-12 weeks, restoring the functional and anatomical integrity of the skin ^[13].

Chronic wounds, on the other hand, are challenging to heal because of underlying medical conditions like diabetes, autoimmune diseases, or venous stasis. Chronic wounds can also result from previous infections, inflammations, tumors, or other physical agents. Low mitogenic activity, elevated cytokine and protease levels, low growth factor secretion, excessive reactive oxygen species (ROS) and matrix metalloproteases (MMPs) production, inhibited angiogenesis, fibrosis, and ECM degradation are all traits of chronic wounds ^[14]. In contrast to acute wounds, chronic wounds take longer to heal more than 12 weeks which increases the risk of infection. The optimal and functional restoration of skin integrity is further impeded by the delayed healing process in chronic wounds. In order to speed up the healing process of wounds, especially those that are chronic, it is imperative that newer techniques and strategies be developed ^[15].

The four phases of wound healing are hemostasis, inflammatory, proliferation, and remodelling.

1. Hemostasis phase

The hemostasis phases this early stage aims to stop the bleeding and minimize haemorrhage. It involves vasoconstriction in addition to primary and secondary hemostasis. Because they encourage the deposition of collagen by fibroblasts and epithelial cells, biomolecules are crucial at this stage.

2. Inflammatory phase

Inflammation typically begins immediately after an accident and lasts for three days. Platelet degranulation causes vasodilation, increased vascular permeability, and the release of inflammatory mediators. Following that, macrophages eliminate neutrophils, reducing inflammation and halting tissue degradation.

3. Proliferation phase

During the course of the wound healing process, neovascularization and re-epithelialization occur over a few weeks. Neovascularization includes both vasculogenic, which is the process by which endothelial progenitor cells create new arteries to ensure tissue nutrition uptake, and angiogenesis, which is the process by which new blood vessels grow from pre-existing arteries. Epithelialization reduces the size of wounds by forming a thin layer of epithelial cells that gradually thickens. M2 phenotype macrophages release anti-inflammatory mediators that promote angiogenesis, fibroblast proliferation, and collagen deposition. In addition to revascularization, the wound widens and fibroplasia advances as collagen fibres replace the fibrin mixture. Low oxygen tension, lactic acid, biogenic amines, and cytokines from platelets, macrophages, and lymphocytes all contribute to the proliferation and migration of capillary buds into the wound. Growth factors (FGF, TGF-β, and VEGF) and the environment (low pH, low oxygen, and high lactate) encourage endothelial cell adhesion to the extracellular matrix and promote healing, which in turn encourages the formation of new blood vessels.

4. Remodelling phase

The final stage of wound healing is remodelling, which restores the healthy tissue's original collagen structure. Extracellular matrix and matrix metal proteinases, which promote wound contraction, reduce epithelialization, and prevent scarring, are produced by fibroblasts. To create scar tissue with mechanical properties similar to the tissue prior to damage, an ordered extracellular matrix takes the place of the granulation tissue. The density of blood vessels in granulation tissue returns to normal. To produce a more robust structure, fibroblasts use matrix metalloproteinases to break down collagen. Type I to type III collagen ratios progressively approach normal skin levels, suggesting that collagen arrangement influences healing. Over time, collagen fbrils enlarge and begin to resemble a healthy dermis. Compared to collagen type I bundles in healthy skin, those in scar tissue are mainly parallel and less flexible ^[16,17].

Figure no 2 Four phases of wound healing a) Hemostasis b) Inflammation c) Proliferation d) Remodelling

Table no 1 Factors influencing wound healing process

TREATMENT OF WOUNDS

1. Skin Transplantation or stem cell/ cell

This tactic relies on the regeneration of tissue through the transplantation of either skin, cells, or stem cells and their derivatives. Patients with severe burns and other wounds are the main candidates for skin transplants.

a) Skin transplantation

Due to keratinocyte deficiencies, epithelial repair in deep skin wounds occurs slowly; therefore, autograft, allograft, or xenograft transplantation is advised for tissue regeneration, replacement, or repair in an emergency ^[20]. The usual course of treatment for severe burns, including early wound debridement and incisions, has been proposed to be autograft ^[21]. Autografts, however, cannot be used for severe burns because of limited access and potential scarring from the absence of dermis. A dermatome separates the donor area from the wound site and applies a thin layer of skin a split-thickness graft that contains the entire epidermis and a portion of the dermis. Autograft wound treatment is dependent on dermal thickness; the thicker the dermis, the faster the wound heals and the less scarring occurs. There is no chance of rejection because this transplant is made from the patient's own tissue ^[21]. In many burn centers worldwide, the skin of cadavers is frequently used to treat burn wounds. Furthermore, live donors can provide skin grafts. Due to the potential for viral transmission and immunogenic rejection by the host's immune system, the primary disadvantage of allograft transplantation is that this replacement is only temporary.

b) Stem cell or cell therapy

Removing necrotic tissue and sealing the wound bed as quickly as possible are crucial in wounds like burns essential. There is an urgent need to remove the burned area and replace it with other skin tissue. However, because large burns lack healthy skin, this is not possible. In order to address this issue, a portion of the patient's own skin is separated, and after being cultured for a few weeks, the epidermis cells are applied to the patient's injured skin.

Because of the expense and skill needed for cell proliferation, as well as the possibility of infection, the procedure is primarily used in teaching hospitals and is not routine. The cost of this procedure is very high ($800 per 50 cm2). For patients with severe burns who lack sufficient autologous viable skin, this procedure is advised. Using "minced micrograft" on the injured area is an additional option. Using this technique, a tiny patch of the patient's healthy skin (dermis and epidermis) measuring roughly 2 cm2 is cut into tiny pieces, combined with hydrogel, and applied to the wound site. This straightforward and inexpensive technique can replicate the skin's geometry ^[22,23]. Another treatment option is the skin graft meshing technique. This technique involves using a dermatome to isolate a tiny portion of skin, which is then prepared and applied to the wound area. Typically, the meshed grafts grow up to four times their initial size. The mesh graft has a higher cell density and a higher chance of success the smaller its extent. Additionally, the risk of scarring increases with the size of the damaged area because it will take longer for the wound to close ^[24,25].

c) Platelet therapy

Megakaryocytes in the bone marrow are the source of platelets, which are components of blood. These cells are crucial for inflammation, thrombosis, primary hemostasis, and wound healing. Alpha granules, which are secretory organelles found in platelets, have the ability to release growth factors, cytokines, and ECM modulators. These elements have the potential to accelerate wound healing by promoting fibroblast migration, proliferation, and activation, mesenchymal stem cell differentiation into particular tissue cell types, revascularization of damaged tissue, and connective tissue repair. In addition to the aforementioned, platelets protect against microorganisms by releasing cytokines and chemokines, which stimulate immune cells, as well as kinocidins and other microbicide proteins ^[26,27]. The use of platelet therapy offers an alternative approach to wound care. Platelets are found in plasma, which makes up a significant portion of blood.
Growth factors that control homeostasis, fibrin clot formation, and tissue repair are found in platelets, which have a unique function in blood coagulation ^[28]. Depending on the type of leukocytes trapped in the fibrin mesh, the density and number of platelets, and the release of active molecules at the injury sites, the prepared platelet concentrates promote the regeneration process ^[29]. Centrifugation of blood is used to create platelet concentrates, which can be either first generation (platelet-rich plasma, or PRP) and platelet-poor plasma, or second generation (platelet-rich fibrin, or PRF), leukocyte-platelet-rich fibrin, or advanced platelet-rich fibrin, or A-PRF), depending on the preparation protocol ^[30].

2. Wound dressings

The most popular approach to wound care involves applying various kinds of dressings based on the size, location, depth, and type of the wound. Generally speaking, a dressing serves as a physical barrier between the wound and the outside world, preventing additional harm and microbes while also hastening the healing process. The wound healing process is slowed down and disrupted when microorganisms are present and enter the wound. In order to avoid wound infection and the development of bacterial biofilm, an ideal wound dressing should have antibacterial qualities. By preventing bacteria and other microorganisms from penetrating the wound site, an antibacterial wound dressing can promote the body's natural healing process (Figure 3). The ideal characteristics of a wound dressing product are highlighted in Table 2.

Table no 2 Ideal characteristics of wound dressing product

Figure no 3 Process of antibacterial wound dressings

1. Common materials for wound healing constructs

It is possible to create appropriate wound dressings using both natural and synthetic polymers. However, because of their structural resemblance to the extracellular matrix (ECM), natural biopolymers are more appealing for use as wound dressings due to their high degree of biomimicry, biocompatibility, and biodegradability as well as their favorable physicochemical characteristics. Physiological healing and the release of active agents must be guaranteed in biopolymer-based wound dressings, and the degree of degradation should be tracked by the dynamics of the wound healing process. Furthermore, it is important to take into account the mechanical characteristics of an appropriate wound dressing. Tensile strength, elastic modulus, stiffness, stress stiffening effects, stress relaxation rate, and viscoelasticity are a few of these ^[31].

2. Nanomaterials

Because of their special qualities, such as their high surface energy and extremely large specific surface area, nanomaterials are used extensively today. Generally speaking, during the wound healing process, nanomaterials can actively participate in hemostasis, inflammation, proliferation, and antimicrobial inhibition. Silver, gold, zinc, and other metal nanoparticles are among the substances that have long been utilized in wound dressings to speed up wound healing and stop bacterial infections. Also, in many studies, the use of liposomes, mesoporous silica and drugcontaining nanomaterials have shown promising results. The use of carbon nanomaterials with special physicochemical properties, such as graphene, carbon nanotubes, and graphene oxide (GO), in contemporary wound dressings has recently been studied; these are covered in brief below ^[32,33,34].

3. Graphene and GO

Because of structural alterations and the presence of oxygen groups, graphene oxide (GO) is one of the graphene-based materials with lower thermal and electrical conductivity than graphene. Because GO has carboxyl, hydroxyl, and carbonyl groups, it can interact with a variety of materials, including polymers. Antibacterial activity, improved mechanical qualities, wound moisture retention, biocompatibility, and the promotion of cell proliferation, adhesion, differentiation, and growth are some of the main uses for wound dressings containing graphene-based nanomaterials. Additionally, graphene-based nanomaterials have been employed as drug carriers in a number of studies, either alone or in conjunction with biopolymers ^[35].

3. Instrumental Method

1. Negative pressure wound therapy

A sponge, a semi-occlusive barrier, and a fluid collection system that applies consistent negative pressure to the wound surface make up the negative pressure wound therapy (NPWT) system. This technique speeds up wound healing through a number of mechanisms, such as enhancing local blood flow, causing macrodeformation, triggering granulation and angiogenesis, lowering bacterial colonization, and decreasing oedema ^[36]. By eliminating fluid from the exudate, the NPWT stops infection and cross-contamination (Figure 4).

Figure no 4 negative pressure wound therapy

Additionally, this technique lessens edema, encourages angiogenesis, keeps the wound moist, and eventually encourages the edges of the wound to contract. This method has been used to treat burns, diabetic wounds, open wounds, acute and chronic wounds, as well as venous and arterial wounds ^[37]. Overall, there is no hard proof that NPWT is noticeably superior to conventional therapy, despite the fact that many patients including those at our own institution, the Royal Free Hospital in London have received treatment with it. A multicentre, carefully planned clinical trial is required to confirm the efficacy of the NPWT as a wound-healing tool because the previous clinical trials were inconclusive.

2. Hyperbaric oxygen therapy

An important factor in the healing of chronic wounds is the presence of oxygen. The foundation of the non-invasive and generally safe hyperbaric oxygen therapy (HOT) treatment approach is the delivery of 100% pure oxygen in a completely sealed chamber at a pressure of roughly three times the ambient pressure. Using HOT has been shown to produce a number of beneficial physiological changes, including increased angiogenesis, improved collagen deposition, leukocyte activation, and decreased edema. Hyperbaric oxygen (HBO) was used in a large clinical study involving 6259 patients, but the results indicated that the treatment neither accelerated wound healing nor stopped amputation ^[38].

CONCLUSION

Wound healing, particularly in chronic and non-healing wounds associated with conditions like diabetes, remains a critical challenge in modern medicine. Despite extensive research and the development of various treatment strategies including surgical intervention, skin grafting, stem cell therapy, and advanced wound dressings the search for an ideal, universally effective, and affordable solution continues. Among the current approaches, modern wound dressings and bioengineered skin substitutes have demonstrated significant promise due to their accessibility, cost-effectiveness, and ability to enhance the wound microenvironment. The integration of biocompatible scaffolds, such as those based on natural polymers and smart nanomaterials like graphene and graphene oxide, is reshaping the landscape of regenerative wound therapy. These materials offer unique properties, including antimicrobial activity, moisture retention, and enhanced cellular interactions, which collectively support rapid tissue regeneration. Concurrently, innovations like platelet-rich therapies and negative pressure wound therapy further accelerate the healing process by modulating inflammation and promoting angiogenesis.

FUTURE PROSPECT

Looking forward, the convergence of biomaterials science, nanotechnology, stem cell biology, and precision medicine is expected to revolutionize wound care. Future research should focus on:

• Personalized wound care, using patient-specific factors (e.g., genetic profile, wound etiology) to tailor treatment modalities.
• Development of multifunctional, stimuli-responsive wound dressings capable of controlled drug release, real-time monitoring of wound status, and targeted therapy.
• Cost-effective production and scalability of advanced therapies, particularly for use in low-resource settings.
• Enhanced understanding of wound pathophysiology through molecular and systems biology approaches to identify novel therapeutic targets.
• Clinical translation and regulatory standardization of next-generation therapies to bridge the gap between bench and bedside.

The global wound care market, valued at over $50 billion annually, underscores the high demand and potential impact of such advancements. As the aging population and prevalence of chronic diseases continue to rise, the need for innovative, effective, and accessible wound healing solutions has never been more urgent. Through continued interdisciplinary collaboration between academia, industry, and healthcare providers, the next generation of wound healing technologies holds the promise of transforming patient outcomes and setting new standards in regenerative medicine.

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