Smart Bandage Containing Herbal hydro Gel for Controlled Drug Release wound healing.

Revolutionary biomedical uses, especially in wound care, have recognized hydrogels as essential components due to their adjustable characteristics that help maintain a moist environment and support cellular regeneration. The of hydrogels dates to the 1960s when Wycherley and Lim created crosslinked poly (2-hydroxyethyl methacrylate) hydrogels specifically for contact lenses. As a result, hydrogels have been formulated from a wide range of materials, including synthetic polymers, natural biopolymers, and hybrid systems, each offering distinct properties suited for Partula clinical uses.[1] The complex process of skin wound healing involves a series of precisely coordinated biological activities, including haemostasis, inflammation, proliferation, and remuddling of the wound, which take place simultaneously. The precise mechanisms behind slow skin wound healing have not yet been completely understood. Treatments aimed at essential biochemical processes like cell growth, inflammation, bacterial infection, and tissue remodelling have demonstrated encouraging outcomes in speeding up wound healing.[2] The skin is a large and intricate organ that plays a crucial role in safeguarding the body and maintaining homeostasis. The outermost layer, known as the epidermis, acts as a barrier against external stressors, while the dermis, the inner layer, contains fat and contributes to the skin's elasticity. As skin ages, its ability to repair itself diminishes, leading to a slower rate of wound healing, which can promote the formation of chronic wounds, particularly in individuals with pre-existing chronic conditions. Additionally, dry skin and itching can lead to wounds, and when combined with reduced vascularization and innervation, healing may be further delayed. A hydrogel is a type of hydrophilic polymeric gel that can be physically or chemically crosslinked, maintaining its structural integrity when hydrated. Typically, hydrogels do not adhere to the wound site, alleviate pain, promote autolytic debridement, and possess various properties that make them ideal for use as dressings.[3] Smart bandages represent a significant advancement in the area of wound care for individuals with different injuries and medical conditions. These intelligent systems facilitate real-time observation of wound characteristics and the swift provision of healthcare. A notable example is the development of ultra-low-power systems integrated with machine learning algorithms to create an edge computing framework for smart bandages, which provides precise and energy-efficient anomaly detection, as discussed in RealTime Anomaly Detection on Smart Bandages.[4] Chronic wounds have been estimated to affect 2–4.5 million people in the US and to cost the US economy $25 billion per year. This burden is increasing due to rising healthcare cost, an aging population, and greater incidence of comorbidities such as diabetes. Wound healing occurs through sequential and carefully synchronized biological events that are dysregulated in chronic wounds. Various local and systemic factors can negatively affect successful wound healing, including infection, chronic inflammation, low nutrition content, increased local pressure, and poor perfusion [5] The skin is the body's most vital organ, serving as an active immune organ and the primary barrier between the external environment and internal organs. Damage to the skin or organs, which can occur due to various factors such as domestic accidents, sports injuries, or military-related incidents, is referred to as wounds. These wounds can result from mechanical, thermal, chemical, or radiogenic trauma to the skin. Although human skin possesses the ability to self-heal, the lengthy repair process and the potential for pathogenic effects, including inflammation and secondary damage—in the case of extensive full-particularly thickness wounds—impose significant challenges on the design and application of wound dressings. [6]

5. The need for smart bandages in wound care:

Chronic wounds arise from a variety of causes and therefore exhibit different biological and clinical characteristics. Even though they vary at both the molecular and clinical levels, they are generally classified into three primary types: venous leg ulcers (VLUs), diabetic foot ulcers (DFUs), and pressure ulcers (PUs)[7].

Various types of wound dressings have been designed to suit wound conditions, such as whether the wound is dry or producing fluid, shallow or deep, and clean or infected. However, these dressings come with certain limitations. As  understanding of the wound healing process continues to improve, there is increasing interest in advanced systems capable of precisely controlling when and where therapeutic agents are released, which could significantly enhance the effectiveness of wound care treatments.[8]

Fig no 1:

(a) Skin structure, (b) conventional wound dressing, (c) wound structure, (d) types of wounds and curing system, (e) VAT polymerization 3D printing system, and the produced hydrogel wound dressing.

Phases of Wound Healing:

Four stages of wound healing process that naturally occur in immune system

• Haemostasis

 Process of vasoconstriction (decrease in size of blood vessel), formation of clotting to stop the bleeding released by platelets and cytokines initiates the repairing process.

• Inflammation

 The body responses by involvement of macrophages and neutrophils to remove the debris and pathogens in wound area.

•  Proliferation

Formation of new tissues includes granulation tissue and capillaries in the wound by cells such as fibroblasts, keratinocytes and endothelial cells.

•  Remodelling

 Remodelled extracellular matrix to improve tensile strength over time and collagen Fibers are reorganized [9,10]

Fig no 2

5. HYDROGEL:

Hydrogels are three-dimensional, water-attracting polymers known as hydrophilic compounds. These polymer networks possess the ability to retain significant amounts of water within their structure while also preserving mechanical properties, making them particularly useful in biomedical applications such as wound healing. Hydrogels can be classified as natural, synthetic, or semi-synthetic, each exhibiting specific functionalities such as high-water content, biocompatibility, and a soft, flexible nature that allows them to respond to environmental stimuli like ionic strength, temperature, and pH. Among various polymers, hydrogels are especially fevered for wound healing due to their capacity for maintaining a moist wound environment, enhancing autolytic debridement, and promoting cell motility. Hydrogels possess unique characteristics that specifically address wound treatment and sustain the wound environment. Additionally, hydrogels can be tailored to suit different types of injuries.[11]

Classification of Hydrogels

1.Classification Based on Source (Origin)

a) Natural Hydrogel

These are derived from natural polymers.

Examples: alginate, gelatine, collagen, chitosan

Advantages: Biocompatible, biodegradable, non-toxic

Disadvantages: Poor mechanical strength, less controllable properties

b) Synthetic Hydrogels

Prepared from synthetic polymers.

Examples: polyacrylamide (PAM), polyethylene glycol (PEG), polyvinyl alcohol (PVA)

Advantages: High strength, tenable properties, reproducibility

Disadvantages: May lack biocompatibility in some cases

c) Hybrid (Semi-synthetic) Hydrogels

Combination of natural and synthetic polymers.

Example: PEG + collagen

Advantage: Combines biocompatibility with mechanical strength

2.. Classification Based on Polymer Composition

a) Homopolymer Hydrogels

Made from a single type of monomer

Example: Polyacrylamide hydrogel

b) Copolymeric Hydrogels

Made from two or more different monomers

Arranged randomly, in blocks, or alternately

c) Interpenetrating Polymer Networks (IPN)

Two independent polymer networks interlaced but not covalently bonded

Semi-IPN: One polymer is crosslinked, the other is linear

3. Classification Based on Cross-Linking

a) Physically Crosslinked Hydrogels

Formed by weak interactions (hydrogen bonding, ionic interactions, van der Waals forces)

Reversible and stimuli-sensitive

Example: Gelatine gel

b) Chemically Crosslinked Hydrogels

Formed by covalent bonds

Permanent and stable

Example: Crosslinked polyacrylamide

4. Classification Based on Configuration (Structure)

a) Amorphous Hydrogels

Randomly arranged polymer chains

b) Crystalline Hydrogels

Ordered structure with high mechanical strength

c) Semi-crystalline Hydrogels

Combination of amorphous and crystalline regions

5. Classification Based on Physical Appearance

a) Matrix (Bulk) Hydrogels

Continuous polymer network

b) Film Hydrogels

Thin sheet-like structures

c) Microspheres / Nanogels

Small-sized hydrogel particles used in drug delivery

6. Classification Based on Charge (Ionic Nature)

a) Neutral Hydrogels

No charge on polymer chains

b) Ionic Hydrogels

Carry charged groups

Cationic: Positively charged

Anionic: Negatively charged

c) Amphoteric Hydrogels

Contain both positive and negative charges

d) Zwitterionic Hydrogels

Equal positive and negative charges → overall neutral

 7. classification Based on Responsiveness (Stimuli-Sensitive Hydrogels)

These hydrogels respond to environmental changes:

a) pH-sensitive hydrogels

Swell or shrink depending on pH

b) Temperature-sensitive hydrogels

Example: Poly(N-isopropylacrylamide) (PNIPAM)

c) Light-sensitive hydrogels

d) Electric or magnetic field-sensitive hydrogels

e) Enzyme-sensitive hydrogels

8. Classification Based on Biodegradability

a) Biodegradable Hydrogels

Break down naturally in biological environments

b) Non-biodegradable Hydrogels

Remain stable for long durations [12,13]

Multiple functions of hydrogel-based Bandage

Hydrogels were first used as wound dressings to offer physical seclusion and maintain a moist atmosphere. However, with the advent of difficult non-healing wounds in the healthcare setting and the growing desire for successful wound healing, both medical professionals and patients are looking for improved performance from hydrogel-based dressings. As a result, there has been an increase in the development of hydrogel-based dressings that serve several purposes. In this review, we will present a comprehensive review of the numerous functions of hydrogel-containing dressings that help to encourage wound healing.

1]Adhesive property

Sutures and staples, while regarded as the "gold standard" for wound closure, could not be appropriate for all types of wounds. These traditional closure procedures have limitations, including a greater chance of subsequent tissue injury and infection, which can hamper effective wound healing.65 Adhesive hydrogels have gained popularity in the field of wound healing due to their less intrusive and more effective nature. Currently, a variety of sticky hydrogels have been synthesised, divided into nature-inspired adhesive hydrogels and supramolecular-based adhesive hydrogels, with the goal of improving the interfacial interaction between hydrogels and tissue. Nature-inspired adhesive hydrogels are mostly modelled after structures and ingredients found in molluscs, such as mussels, and marine creatures, such as sandcastle worms. In contrast, supramolecular-type sticky hydrogels aim to improve the relationship between the surfaces between hydrogels and tissues. Nature-derived adhesive hydrogels are mostly modelled after structures and ingredients found in molluscs, such as mussel, and aquatic organisms, such as sandcastle worms. In contrast, supramolecular-based adhesive hydrogels primarily rely on mechanisms such as bonds of hydrogen, host-guest interactions, or molecular topologies. However, one disadvantage of sticky hydrogels is their low mechanical strength, which leads to diminished cohesion and limits their potential use in wound healing. To solve this issue, researchers created novel hydrogels that have improved mechanical performance and adhesive properties. Dopamine (DA) is a molecule that contains several catechol (catechol groups, which have been discovered as important factors in generating quick and robust adhesion to moist tissues. Researchers created a gelatine-DA conjugated hydrogel and discovered that its sticky characteristic.

Fig no 3

2] Antibacterial efficacy:

In simple terms, when skin tissue is damaged for a variety of reasons, it loses its normal barrier function, making the human body vulnerable to the invasion of numerous harmful microorganisms from the external environment, such as bacteria, fungus, or viruses. Wound infections generated by a variety of pathogenic bacteria greatly hinder the natural wound healing process. In severe situations, these infections can spread to other organs, causing significant damage to the overall well-being of the human body. Antibacterial hydrogels have demonstrated extraordinary performance in both infection prevention and wound healing. Antibacterial hydrogels are categorised into three categories based on their raw materials, antibacterial agents, and mechanisms of action: intrinsic antibacterial hydrogel, antibacterial agent-containing hydrogel, and environmentally stimuli-responsive antibacterial hydrogel [16].

3] Inherent antibacterial hydrogel:

Hydrogel wound dressings with intrinsic antibacterial properties can be made from a variety of natural polymer ingredients. Chitosan, antibacterial peptide organic acids, and plant essential oils are commonly used to make antimicrobial hydrogels because of their biocompatibility and degradability.80 The presence of functional groups within the molecular structure of natural polymers adds to their antibacterial properties, which are required for the development and performance of antibacterial hydrogel wound dressings. As a result, these inherent antibacterial hydrogels can demonstrate long-term antibacterial action.81 Tavakolian et al. produced a carboxyl-modified cellulosic hydrogel as an example of such a material. Bioconjugation was used to covalently link ε-poly-L-lysine, a natural polyamide with antibacterial characteristics, to the hydrogel. he antibacterial activity of this hydrogel was tested against Staphylococcus aureus and Pseudomonas aeruginosa. The antibacterial activity trial revealed significant efficacy, as the antimicrobial hydrogel eliminated nearly 99% of Staphylococcus aureus and Pseudomonas aeruginosa following a three-hour exposure time. However, it is crucial to note that hydrogels derived from natural antibacterial agents have some limits in their application. The antibacterial effect of these hydrogels is typically based on a process that disrupts bacterial cell membranes. While this can be helpful, it may result in a relatively poor sterilisation efficiency in certain instances Therefore, it is critical to analyse the specific requirements of the wound and carefully evaluate the antimicrobial activity of natural antibacterial hydrogels to verify their acceptability for use in wound dressing [16] [17][18]

Fig no 4

5. Application of hydrogel-based dressings in different types of wounds

cutaneous wounds are grouped into two types: acute wounds and chronic wounds, each having particular features. The unique features of each wound type highlight the need for hydrogel-derived dressing that are tailored to meet their requirements. In this section, we will look at the obstacles that arise throughout the wound healing process for various wound types, as well as an overview of recent advances in the use of hydrogel-based dressings for different types of wound treatment (Table 1). Furthermore, an increasing number of researchers have worked to produce new hydrogel dressings that can monitor the wound healing process, and we will be conducting a comprehensive review of these inventive hydrogels as well.[19]

Fig no 5

1. Acute wound

An acutely wound is a skin injury created by surgical incisions, burns, sips, deep wounds, or abrasions. Acute wounds have the inherent ability to heal spontaneously through a well-organized and predictable process, even without external interventions.4 The average recovery time for acute wounds is 8 to 12 weeks. Acute injuries heal with modest amounts of microorganisms, cytokines that are inflammatory, proteases in particular and oxygen species that are reactive. In addition, they preserve an intact functioning matrix, as well as increased mitotic activity and cell proliferation. Researchers have examined the effects of acute wound fluid from split-thickness skin graft patients on the in vitro growth of human dermal fibroblasts and umbilical vein endothelial cells; the results showed a stimulating effect of acute wound fluid on the growth of both cell types, suggesting that the molecular environment of acute wounds promotes cellular proliferation. In scientific studies, the safety and efficacy of wound dressings in promoting the healing of rats or pigs. The incisional simulation is a commonly used experimental method where surgical wounds are created on the skin of animals, typically rats or swine, using sharp surgical blades. This approach allows for the controlled creation of skin incisions with minimal accompanied damage to tissues. However, conventional suturing methods used to close these wounds have drawbacks such as secondary tissue damage, increased risk of infection, and discomfort during a stitch removal. In comparison with surgical sutures, hydrogel-derived dressings have evolved as a less intrusive and more successful method of wound healing. To close incision wounds quickly, achieve good haemostasis, and avoid wound infections, use hydrophilic dressings with adhesive characteristics, antibacterial efficacy, haemostatic capabilities, and healing abilities to aid in wound repair. Zhao et al. developed a unique injection self-healing hydrogel adhesive. The hydrogel-based adhesive was constructed up of two components: a catechol-Fe3+ coordination -cross-linked poly (glycerol subacute) and co-poly (ethylene glycol)-g-catechol and quadruple hydrogen bonding cross-linked ureido-pyrimidinone modified gelatine. In vivo investigations found that this hydrogel has significant haemostatic capacities for treating skin damage and was highly effective in eliminating methicillin-resistant MRSA infections. Moreover, compared with professional glue and surgical sutures.[19]

Fig no 6

B)Chronic wound

Chronic wounds are distinguished by their inability to proceed through the normal healing procedure within 12 weeks or longer, and they frequently reoccur. These wounds face challenges during the healing process due to physiological conditions such as bacterial infections and associated pathologies. A variety for variables may complicate the typical course of wound healing, including inadequate primary care, bacterial infections, diabetes, and vascular disorders. Chronic wounds include a range of disorders, including venous ulcers, diabetic foot ulcers, arterial ulcers, ischaemic ulcers, and pressure ulcers. Some of these wounds, like acute wounds, could have been produced by traumatic situations. The existence of these related factors delays the healing process, lowers healing quality, and extends overall healing time. Chronic wounds cause severe physical and mental stress in patients, resulting in ongoing pain and discomfort. Due to the availability of diabetic wound models, research on chronic wounds has concentrated mainly on diabetic wounds. In this part, we will look at improvements in the use of hydrogels in diabetic wound healing. Diabetes mellitus is a chronic medical disorder characterised by chronically high blood sugar levels caused by the body's failure to produce or utilise insulin. Diabetic individuals frequently develop leg and foot ulcers; however, damage can occur anywhere on the body. These ulcers provide major healing issues due to decreased circulation, his renders them more susceptible to infections and raises the likelihood of amputation. An increasing number of researchers contend that the healing of diabetic wounds is intricately linked to the biological and pathological aspects of diabetes. Diabetes causes a variety of inherent pathophysiological alterations in tissues and cells responsible for regeneration and repair, as well as affecting wound healing procedures. Diabetes' systemic high blood sugar has the potential to cause protein glycosylation, which leads to an increase in pro-inflammatory cytokines, peroxide-induced damage, and ECM changes. The high concentration of ROS in diabetic wounds is known to cause a strong inflammatory response by inhibiting the migration of indigenous stem cells, phagocytes, and macrophage.[19][20]

Fig no 7