An Updated Review on Mechanism of Novel Carrier System for Wound Healing

 

Pooja Sahu, Rajendra Jangade*

University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G)

 

ABSTRACT:

Novel carrier system are conventional dosage form provide drug release for immediately and it causes fluctuation of drug level in blood. Therefore to maintain the drug concentration within the therapeutically effective range needs novel carrier system. Novel carrier systems have emerged as a major platform to treat acute and chronic wounds. Many of the nanotechnology based drug delivery systems have been proposed manifesting with numerous functions and unique properties associated with mechanism of wound healing. Wound is an injury of damage including an outer or inner break in body tissue. Wound healing is a natural and well body structured process, where several factors reduced in the phases of healing process. The repair of wounds through collective movement of epithelial cells is a fundamental process in multicellular organisms, which is mainly involve in three processes such as inflammation, proliferation, and maturation. This minimum review focus on the current trends and applications of nanotechnology to promote wound healing process.

 

 

 

1. INTRODUCTION:

Wound

A wound is damage and break of internal and external surface of body skin or tissues

 

An injury is damage including an outer or inner break in body tissue, generally including the skin. Almost everybody will encounter an injury sooner or later in their life. Most injuries are minor and can be deal with at home. Falls, mishaps with sharp questions or apparatuses, and auto crashes are the most widely recognized reasons for wounds [1].

 

 

1.1 Skin:

The human skin is the natural covering and first line defence of the body. Skin plays an important role in immunity to protecting the body against pathogens and excessive water loss. Its other functions are maintaining body temperature, sensation, synthesis of vitamin D, and the protection of vitamin B folate [2].

 

1.2 Wound Healing:

A wound is a break in the integrity of the skin or tissue often which may be associated with disruption of the structure and function caused by the external force. Healing is the response of system to injury in an attempt to restore normal structure and function of membrane [3].

 

 

Figure. 1.Process of Wound Healing

 

1. Novel Carrier System:

Novel carrier systems is to provide a therapeutic amount of drug to the appropriate site in the body to accomplish promptly and then maintain the desired drug concentration. They reach the target site with little or no side effects. They reduced drug degradation and loss. They increase bioavailability of the drug and the fraction of the drug absorbed in the required site[4].

 

Figure. 2. Classification of novel carrier system

 

General mechanism of novel carrier systems on wound healing:

In present days, Chronic wound and infected wounds are a major burden. Novel carrier systems of wound healing drugs are more convenient than systemic administration on wound areas. These are directly delivered to the desired area in a sustained manner [5]. They have the potential of providing optimum environmental conditions to help in wound healing. While reduced or carry off frequent changes of dressing [6].

 

2.1 Nanoparticles:

‘Nanoparticles are sub-Nanosized colloidal structures composed of synthetic or semisynthetic polymers carrying drugs or proteinaceous substances’. There sizes ranges from 10-1000 nm. The drug is dissolved, entrapped, encapsulated are atteched to the nanoparticles[7].

 

Figure. 3.  Nanoparticles

 

Mechanism of action - Main mechanism of nanoparticles into membranes is to increase the mechanical and thermal stability along with swelling capacity and water vapour transmission of infected membranes. Depending upon the size of nanoparticles and polymer content, body systems exhibited different secretion release, and degree of retention by their administration of nanoparticles [8].

 

2.1.1 Metal nanoparticles

Metal nanoparticles refers is used to describe nano sized metals which ranges are 1-100nm.

(In which their size, length, width or thickness all occurs within nano sized ranges [9].)

 

 

 

 

Mechanism of action –Metal nanoparticles exhibit a range of properties, such as enhancing mechanical strength, controlled release, and antibacterial activity against both bacteria and fungi, which make them excellent candidates for topical use in wound healing [10].

 

Silver Nanoparticles -

ilver has been commonly used as an anti-bacterial agent for the treatment for the, open wound and several infected wounds. Silver nanoparticles in burn wounds could improve thehealing of initially on the basis of the known Antimicrobial property of silver [11].

 

 

Figure 4. Silver NPs

 

Figure. 5. The Remarkable Properties of Silver Nanoparticles Bring the Wound Closer to the Normal Skin. Silver nanoparticles play a distinct role in preventing infection, decreasing bacterial load in the wound by their broad-spectrum antimicrobial properties, and their surface modification properties provide easy incorporation of Nano silver into cotton fabrics and drugs to improve the wound-healing treatment.

Mechanism of action:

It is believed that silver ions interact with 3 main components of the bacterial cell to produce a bactericidal effect:

·         The peptidoglycan cell wall and plasma membrane,

·         Bacterial (cytoplasmic) DNA and bacterial proteins, and Especially enzymes involved in vital cellular processes such as the electrons transport chain [12, 13].

 

2.1.1.1.1. Poly (e- caprolactone) loaded silver nanoparticles:

Poly(e-caprolactone) (PCL) has been suggested for wide range of biomedical applications, such asElectro spinning is an first class technique for the fabrication of thin membranes for wound coverage applications with barrier property against microbes [14].

 

Mechanism of action:

They have manifested that these scaffolds were effective against both Gram-positive and Gram-negative bacteria without affecting endothelial cell proliferation. Anti-inflammatory property also promote wound healing by reducing cytokine release, decreasing lymphocyte and mast cell infiltration [15].

 

2.1.1.2.    Gold nanoparticles:

Gold nanoparticles occurs as clusters of gold atoms up to 100nm in diameter. Nanogold has ususal visible properties as the particles are small enough to scatter visible light. Mass gold reflects light. Gold nanoparticles appears deep red to black in solution colour depends on size of nanoparticles. Gold nanoparticles shows chemically inert property. These have biological compatible [16].

 

Figure. 6. Gold Nanoparticles

 

Mechanism of action:

Combining AuNPs with antioxidants rich compounds (Epigallocatechin gallate and alpha lipoic acid) significantly accelerated wound healing. AuNPs have been shown to be capable of opening of stratum corneum and penetrating the skin barrier [17]. They also accelerates wound healing by increasing proliferation and migration of epidermal cells [18].

 

Figure. 7.Types of gold nanoparticles

 

2.1.1.2.1 AuNPs With Antioxidants Epigallocatechin Gallate (EGCG) And Alpha Lipoic Acid (ALA):

These are topically applied gold nanoparticles loaded with epigallocatechin gallate (EGCG) and alpha lipoic acid (ALA) have shown antioxidattive effect and could help in the healing of wound. In which epigallocatechin gallate and alpha lipoic acid are act in antioxidant agent [19].

 

2.1.1.3 Copper (Cu), Titaniumdioxide (Tio2) And Zinc Oxide (Zno)Nanoparticles:

Copper can damage proteins (especially lipoproteins) can cause rapid oxidation reactions in unsaturated lipids. Titanium dioxide and zinc oxide nanoparticles are widely used in the cosmetic and pharmaceutical industry as UV protectors and also as a wound healing material [20]. Zinc oxide nanoparticles have been incorporated formerly PVA chitosan membranes and PVA alginates nanofibers mates using physical blending [21].

 

2.1.1.4 Antioxidantcontaining Nanoparticles:

Nitric Oxide Nanoparticles:

NO is an antibacterial agent effective against a broad range of bacteria, including biofilm forming microorganisms, through an oxidation process involving free radical superoxide (O2*−) to form peroxynitrite (−OONO).NO also using nanoscale delivery systems [22].

 

2.1.1.5 Chitosan Nanoparticles:

Chitosan demonstrated higher antibacterial activity against Gram-positive bacteria than Gram-negative Bacteria. Chitosan showing a molecular weight – dependent negative effects on cell viability and proliferation [23]. Chitosan with high Degree of deacetylation strongly stimulated proliferation [24].

 

2.1.1.6 Curcumin Encapsulated Nanoparticles:

Curcumin nanoparticle inhibit planktonic growth of gram – positive and gram negative organisms [25]. The antimicrobial activity of curcumin is not completely characterized but by interacting with many of the molecular targets and transduction pathways, it employs a multi-mechanistic anti-infective strategy [26].

 

2.1.1.7 Antibiotics Loaded Nanoparticles:

There has been a recent research in advanced therapeutics targeting the multidrug – resistant microbes using antibiotics linked to Nano particles, commonly referred to as nanobiotics. These nanobiotics significantly greater increased antimicrobial activity of the antibiotics than the non-conjugated antibiotics formulations [27].

 

2.1.1.8 Ceremic Nanoparticles:

Targeted ceramic NPs have been explored as potential carriers for drugs, genes, proteins, imaging agents and photosensitizers in a broad span range of biomedical applications. Ceramic NPs have also been utilized as drug delivery platforms to enhance antimicrobial activity against pathogens [28].

 

2.2 Solid Lipid Based Nanoparticles:

SLBNs have been administered as potential drug delivery systems (DDSs)That could be topically administered to the skin and eyes, or else delivered by parenteral, oral, and inhalational routes. SLBNs can be divided into two main categories including solid lipid NPs (SLNs) and nanostructured lipid carriers (NLCs) [29].

 

2.2.1 Solid Lipid Nanoparticles:

Solid lipid nanoparticles are submicron systems ranging in size from 50-1000nm.Drug loaded with solid lipid nanoparticles demonstrated significantly improved permeation and retention of the drug in both barrier impaired and intact skin signifying in drug reservoir effect in the epidermis [29].

 

Figure 8: Solid Lipid Nanoparticles

 

Mechanism of Action:

They increased cell migration and improved wound closure rates. The coating solid lipid nanoparticles with hydrophilic agents enhances their plasma stability and improves the bioactivity of the drug [30].

 

2.2.1.2 Silver Sulfadiazine:

SSD-loaded-SLNs were tested for prolonged release of the cargo, andto reduce the pain in serious skinwounds In addition, the use of SLNs acceleratecellmigration and better wound closure rates [31].

 

Mechanism of Action:

Silver sulfadiazine appeared to disrupted cytokine activity, suppress macrophage recruitment, and inhibit collagen deposition and re epithelialization with full thickness. Silver sulfadiazine is broad spectrum antimicrobial used widely for treating second and third degree burn wounds [31].

 

2.2.2 Nanostructured Lipid Carriers:

Nanostructured lipid carriers are composed of low toxicity physiological and biodegradable lipids which due to nanosize showed large surface area in close proximity of stratum corneum increasing the amount of drug penetrating into the skin [32].

 

Mechanism of Action:

This reduce systemic absorption, and when drug produces irritation in high concentrations. NLC have been shown to exhibit a controlled release behaviour for various active ingredients such as ascorbyl palmitate, clotrimazole, ketoconazole, and other antifungal agents [33].

 

2.2.2.1 Miconazole Nanostructured Lipid Carriers:

Miconazole encapsulated nanostructured lipid carriers were recently used to enhance Miconazole activity (a poorly –water soluble antifungal agents). Miconazole topically prevents fungus from developing on your skin. Disrupted cytokine activity, suppress macrophage recruitment, and inhibit collagen deposition and re epithelialization with full thickness [34].

 

2.3 Nanoemulsion:

Emulsion droplet that are extremely small in size, ranging from 20-200 nm, are called nanoemulsion. Nanoemulsions (NEs) are prepared by oil-based and aqueous solutions [35]. Generally NMs are made of amphiphilic molecules that follow a spherical form in aqueous solutions. They contain a hydrophobic core as well as a hydrophilic coating [36].

 

Figure 9: Nanoemulsion

 

Mechanism of Action:

Release from nanoemulsion in controlled by the interactions between drugs and surfactant or partitioning of drug between oil and water phase.The carrier has utilized for delivery of drugs with possible role in wound healing. these are Enhanced the proliferation and reduced the tissue inflammation [37].

 

 

2.3.1 Chlorhexidine Acetate Nanoemulsion:

These was used against a methicillin resistant S.aureous (MRSA) infection to a skin wound model [38]. they disrupted MRSA cell walls, lead to increased leakage of DNA, protein, Mg2+, K+ and alkaline phosphates out of the cells [39].

 

2.3.2 Nanoemulsions Encapsulating Eucalyptus Oil:

Chitosan film was impregnated with Nanoemulsions encapsulating eucalyptus oil, which showed a good antibacterial effect against S.aureus. The mechanism of action of this eucalyptus oil NE-NS film was attributed to cell membrane damage, and wound healing efficacy to a non-irritant activity in the wounds [40].

 

2.4 Liposomes:

Liposomes are versatile drug delivery system due to their ease of protein delivery, biocompatibility, and intracellular delivery, modulation of size, charge, and surface properties [41] Liposomes are bilayered phospholipid vesicular structures enveloping an aqueous volume. Liposomes are suitable for containing both hydrophilic (in aqueous core) and lipophilic drugs (in lipid bilayer) due to its amphiphilic nature [42].

 

Figure 10. Liposomes

 

Mechanism of Action:

Liposomes act by penetrating the epidermal layers releasing drug into the skin. They lose their bilayer membrane during the penetration and thus, these lipids penetrate into the stratum corneum by adhering to the skin surface and finally fasing with the lipid matrix and releasing the drug enclosed in it [43].

 

2.4.1 Anti – Gal / Alpha Gal Liposome:

Anti – gal / alpha – gal liposome interaction showed rapid enlisting and activation of macrophages by accelerates wound healing. their application in wound results in rapid local recruitment of neutrophils and macrophages. The novel aspects in alpha gal liposome treatment versus other wound healing treatments are the harnessing of at least two immunological mechanisms for accelerating the healing process [44].

 

 

2.4.2 Corneal Epithelial Wound Healing Promoted by Verbasconide – Based Liposomal Eye drops:

Verbasconide was administered in the form of tiny capsules of lipids for effectively protecting the antioxidants. Neutral or slightly positive surface charge with liposome interact very well with the cornea [45].

 

Mechanism of Action:

Epidermal growth factor (EGF), keratinocyte growth factor, platelet derived growth factor (PDGF) and vascular endothelial factor (VEGF)are some of the growth factors known to stimulate corneal wound healing. These factors promotes corneal epithelial cell migration and wound closure. they penetrate into the stratum corneum by adhering to the skin surface and finally fasing with the lipid matrix and releasing the drug enclosed in it [46].

 

2.4.3 Povidone Iodine Liposome Hydrogel:

Povidone iodine is active in broad spectrum. They have penetrate biofilms. They have lack of associated resistance, anti-inflammatory properties, low cytotoxicity and good tolerability. The microbicide combines novel PVP – I liposome hydrogel and activities of wound healing resulting in enhanced epithelization [47].

 

2.5 Hydrogels:

Hydrogels are hydrophilic, three-dimensional with polymeric networks that are capable of imbibing large amounts of water or biological fluids.These networks are composed of a single polymers or copolymers, which are insoluble due to the presence of physical crosslinks or chemical crosslinks, either as entanglements or crystallites [48].

 

Mechanism of Action:

These hydrogels exhibit a thermodynamic compatibility with water which makes them to swell in aqueous media. Hydrogels absorb and imbibe water in their network structure and thus act as a moist wound dressing material and thus retain the wound exudates along with the foreign bodies, such as bacteria. Hydrogels also promote the fibroblast proliferation and protect the wound from external noxae necessary for rapid healing of the wound [48].

 

2.5.1 Tetracycline Hydrochloride Loaded Hydrogel:

Tetracycline hydrochloride was prepared in the hydrogel. They improved antimicrobial effect of the dressings against both Gram-positive and Gram-negative bacteria, and minimal scarring when the dressing was applied to wounds [49]. A 3D network-like matrix composed of hydrogel behaves more like naturalstructures [50].

 

2.5.2Liposomal Hydrogels:

Hydrogel containing liposomes that are covalently linked to the hydrogel network [51]. The hydrogel formulation not only preserves the structural integrity of the nanoparticles stabilized liposomes, but also allow for controllable viscoelasticity and tenable liposome release rate [52].

 

 

Figure 11. Liposome Loaded Hydrogels

 

Mechanism of Action:

They increases the drug concentration locally and decreases systemic drug concentration and hydrogels combine the features of moist wound healing with good fluid absorbance. And against bacteria and oxygen permeability they work as a barriers, it is easy to handle, hence it is useful as a moist wound dressing material [53].

 

2.6 Dendrimers:

Dendrimers are a type of nano-scale (1–10 nm) polymeric macromolecule with a homogeneous and Monodisperse structure, which have applications in both diagnosis and therapy. Dendrimers possess a symmetric core, an inner shell and an outerShell. Dendrimers can be prepared from phenyl acetylene subunits [54].

 

Figure12. Dendrimers

 

Mechanism of Action:

The surface functional groups of dendrimers can act as antibacterial agents themselves (especially if cationic). Disturbance of the bacterial structure and function are resulted from the interaction of the positively charged group of a dendrimers (quaternary ammonium groups) and the negatively charged groups of the bacterial cell wall. Example – Polyamidoamine based dendrimers are loaded with the Nadifloxacin and Prolifloxacin [55].

 

2.7 Microspheres:

Microspheres are also termed as micro particles. Microspheres are spherical polymer matrix systems with size in micron range normally 1 -1000 micro meter. Microspheres provide steady and sustained release reducing the dosing frequency with improved therapeutic effect and patient compliance [56].

 

Figure 13. Types of Microspheres

 

Mechanism of Action:

Microsphere provide sustained drug delivery with reduced patient compliance. They have the potential to accelerate the drug targeting specificity. They enhanced therapeutic effectiveness for prolonged period of times [56].

 

2.7.1 PLGA Microspheres:

Microspheres with high peptide internalisation efficiency which can be prepared from low molecular weight and hydrophilic Acid ended PLGA polymers [57]. Generally, PLGA microspheres are prepared using a water-in-oil-in water Double-emulsion technique [58].

 

Mechanism of Action:

They showed antimicrobial activity against the targeted microorganism Staphylococcus epidermidis. This provides a platform for a continued and sustained release of the loaded drug to increase bioavailability, inhibit systemic absorption, and the need for frequent administration leading to improved patient compliance [59].

 

2.7.2 Polyheal’s Microsphere:

Polyheal’s wound healing technology is based on the principle of triggering the suffered person’s own cells to regenerate the deteriorated tissue of chronic wound. Polyheal’s findings show that its charged microspheres have a therapeutic effect on wound healing, by their activation of different types of cells in wound space (inflammatory cells, fibroblasts and keratinocytes). The microsphere with specially designed physical – chemical features designed to optimize the therapeutic process [60].

 

Table 1. – Mechanism of Novel Carrier Systems

S. No	Novel Carriers	Mechanism on Wound Healing	References.
1.	Nanoparticles	Increase the mechanical and thermal stability along with swelling capacity and water vapour transmission of infected membranes. Depending upon the size of nanoparticles and polymer content, body systems exhibited different secretion release, and degree of retention by their administration of nanoparticles. They do not contain biodegradability property, thus their usage in only for superficial and thin wound as in wound dressing field.	[61]
1.1	Metal NPs	Metal nanoparticles exhibit a range of properties, such as enhancing mechanical strength, controlled release, and antibacterial activity against both bacteria and fungi, which make them excellent candidates for topical use in wound healing.	[62]
1.1.1	Silver NPs	Silver nanoparticles exhibit antibacterial effects against a large number of bacterial species, such as strains of B.subtilis, E.coliTh, and S.aureus. Silver ions interact with 3 main components of the bacterial cell to produce a bactericidal effect: ·    The peptidoglycan cell wall and plasma membrane, ·    Bacterial (cytoplasmic) DNA and bacterial proteins, and Especially enzymes involved in vital cellular processes such as the electrons transport chain. Silver nanoparticles reduced mitochondrial activity without activating cell death mechanisms, as well in vitro results showed AgNPs were localized in the cytoplasm of fibroblast with no cytotoxicity evident. AgNPs interact with sulphur containing proteins of the bacterial membranes, as well as with phosphorus containing compounds such as DNA, to inhibit replication. Anti-inflammatory property of silver nanoparticles also promote wound healing by reducing cytokine release, decreasing lymphocyte and mast cell infiltration.	[63] [64]
1.1.1.1	Poly (e-caprolactone) loaded AgNPs	It Efficacious against both Gram negative and gram positive bacteria. these not affecting proliferation of endothelial cell. Provide a promising biomaterial for wound dressing applications due to the antibacterial properties of silver nanoparticles.	[65]
1.1.2	Gold NPs	They have good biocompatibility high mechanical strength, enhances stability against enzymatic degradation and hydrolytic activity. AuNPs have been shown to be capable of opening of stratum corneum and penetrating the skin barrier. They also accelerates wound healing by increasing proliferation and migration of epidermal cells. AuNPs also effectively accelerated wound healing and enhanced the restoration of normal dermal and epidermal tissue structures in wound area.	[66] [67]
1.1.2.1	AuNPs With EGCG and ALA	These are topically applied gold nanoparticles loaded with epigallocatechin gallate (EGCG) and alpha lipoic acid (ALA) have shown antioxidattive effect and could help in the healing of wound. Topical application of antioxidant in cutaneous wound is most suitable for fast healing. In which epigallocatechin gallate and alpha lipoic acid are act in antioxidant agent.	[68]
1.1.2.2	AuNPs Conjugated to SiRNA based nucleic acid	SNA-NCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis. Gold nanoparticles conjugated to SiRNA based spherical nucleic acids (SRNAs) have been used for wounds with ganglioside – monosialic acid 3 synthase (GM3S) knockdown. GM3S is an enzyme that is over expressed in diabetic patient and may cause insulin resistance and reduced wound healing. They effectively accelerated wound healing and enhanced the restoration of normal dermal and epidermal tissue structures in wound area.	[69]
1.1.3	Copper, Titanium dioxide, and zinc oxide NPs	CuNPs are effective against E.coli and S.aureus. CuNPs is considered to possess a broad spectrum antimicrobial activity against, Bacteria, Yeast as well as Viruses. Copper can damage proteins (especially lipoproteins) can cause rapid oxidation reactions in unsaturated lipids. Copper causing cytotoxicity and tissue damage. and initiated to tissue healing through the cell proliferation and restoration of the wound. Titanium dioxide and zinc oxide nanoparticles are widely used in the cosmetic and pharmaceutical industry as UV protectors and also as a wound healing material. Zinc oxide nanoparticles have been incorporated formerly PVA chitosan membranes and PVA alginates nanofibers mates using physical blending. Topical zinc may stimulate healing by enhancing re–epithelisation, decreasing inflammation and bacterial growth.	[70] [71] [72]
1.1.4	Thrombin conjugated to iron oxide NPs	Combined thrombin greater wound healing activity as compared to free thrombin. They promote to close the incisional wounds. These may stimulate healing by enhancing re–epithelisation, decreasing inflammation and bacterial growth. Restoration of tissue are facilitated ultimately and promote to the closure of wound surfaces.	[73]
1.1.5	Magnesium fluoride NPs	The antimicrobial activity was dependent on the size of the nanoparticles. They can inhibit the bacterial colonization of surfaces. Magnesium fluoride NPs attach to the bacterial cell and penetrate into the cell. These NPs caused a disruption in the membrane potential. The MgF2 nanoparticles also induced membrane lipid peroxidation and once internalized can interact with chromosomal DNA. The possibility of using the MgF2 nanoparticles to coat surfaces and inhibit biofilm formation	[74]
1.2	Antioxidant containing NPs
1.2.1	Nitric oxide NPs	NO is an antibacterial agent effective against a broad range of bacteria, including biofilm forming microorganisms, through an oxidation process involving free radical superoxide (O2*−) to form peroxynitrite (−OONO). Low cytotoxicity.	[75] [76]
1.2.2	Cerium oxide NPs	Accelerates the healing of full – thickness dermal wounds. The strong antioxidant properties of cerium oxide nanoparticles.  Nanoceria trigger cell death, they trigger pro oxidative effect due to reactive oxygen species ( ROS) which cause damage to the infected cell and healing may be occurred.	[77] [78]
1.3	Chitosan NPs	Antibacterial activity against Gram-positive bacteria while little activity against Gram-negative Bacteria. The treatment with nanoparticles carriers effectively showed controlled Trans epidermal water loss, erythema intensity, dermatitis index and skin thickness significantly. Nanoparticles exhibited anti-fibrotic and anti-inflammatory activity against the lesion of atopic dermatitis	[79] [80][81]
1.4	Poly caprolactone NPs	These are cause complete disruption, necrosis, and disorganized inflammation of epidermis, subepidermis, and dermis layers. Increase the proliferation.	[82]
1.5	Gelatin NPs	Drugs can be effectively incorporated or attached to the surface of the nanoparticle matrix.  Its proteinaceous origin has raised specific interest, due to the presence of different accessible functional groups. They Have great impact on the healing process.  In these gelatin nanoparticles are attached to the cell surface and target them, and then killed it.	[83] [84]
1.6	Curcumin NPs	Curcumin nanoparticles disrupt MRSA cellular structure. Curcumin nanoparticles reduce bacterial burden in MRSA-infected burn wounds. Curcumin nanoparticles treated wounds displayed more well-formed granulation tissue and reepithelialised early. Curcumin nanoparticles enhance granulation tissue formation, collagen deposition, and new vessel formation. Curcumin nanoparticle do not influence keratinocyte migration. Curcumin is interacting with numerous molecular targets and transduction pathways, it employs a multi-mechanistic anti-infective strategy.	[85]
1.7	Antibiotic loaded NPs	Increased antimicrobial activity of the antibiotics in comparison to the non-conjugated antibiotics formulations.	[86]
1.7.1	Polyacrylate NPs	These are capable of solubilising lipophilic antibiotics for systemic administration. The activity of drug against resistant microbes such as MRSA. These easily penetrating the cell surface and disrupted them. they firstly kill the nucleic material of the cell. and then restoration may occur.  By these, healing process are occur very rapidly, by their antibiotic actions.	[86]
1.7.2	Vincomycin modified NPs	Fast and effective interactions between the nanoparticles and pathogen cell wall surface and only one orientation in a series of modified nanoparticles leads to the efficient and reproducible capture of several important pathogenic bacteria
1.7.3	Gentamycin loaded NPs	Regeneration rapidly occurred and microbial growth reduced.
1.7.4.	Folic acid tagged chitosan NPs	Bacterial cells are efficiently kill. The need for therapies targeting gram – negative bacteria has become urgent matter with the rise in antibiotic resistant drugs,
1.8	Ceremic NPs	Targeted ceramic NPs have been showed potent carriers for drugs, genes, proteins, imaging agents and photosensitizers in a broad span range of biomedical applications. Antimicrobial activity against pathogens are increased.	[88] [89]
1.9	Polymeric NPs	Antibacterial activity, and high swelling properties.  high moisture vapour transmission rate, hydrophilicnature, biocompatibility, wound appearance, and enhanced wound closure rate.	[90] [91]
2.	Solid lipid based NPs
2.1	Soli d lipid NPs	They increased cell migration and improved wound closure rates. The coating solid lipid nanoparticles with hydrophilic agents enhances their plasma stability and improves the bioactivity of the drug.	[92]
2.1.1	Silver sulfadiazine	Impaired re epithelialization may occurs. Silver sulfadiazine appeared to disrupted cytokine activity, suppress macrophage recruitment, and inhibit collagen deposition and re epithelialization with full thickness.	[93]
2.2	NanoStructured Lipid carriers	This reduce systemic absorption, and when drug produces irritation in high concentrations, NLCs have been shown to exhibit a controlled release behaviour for various active ingredients such as ascorbyl palmitate, clotrimazole, ketoconazole, and other antifungal agents. They have also act on – ·    Increased dispersability in an aqueous medium, ·    High entrapment of lipophilic drugs and hydrophilic drugs, ·    Increase of skin occlusion, ·    An advanced and efficient carrier system in particular for substances, Extended release of the drug.	[94][95]
2.2.1	Miconazole NSLCs	Miconazole is a most widely used antifungal agent. But it have less aqueous solubility, which requires the development of drug delivery systems able to improve its therapeutic activity. Topically miconazole prevents fungus growing on your skin. Disrupted cytokine activity, suppress macrophage recruitment, and inhibit collagen deposition and re epithelialization with full thickness	[96]
2.2.2	Recombinant human EGF loaded NSLCs	These indicate to improve wound healing. Its stimulate fibroblast expansion and collagen production. They reduced the duration of healing in addition to providing excellent quality of wound healing and reepithelization	[97]
3	Nanoemulsion	Release from nanoemulsion in controlled by the interactions between drugs and surfactant or partitioning of drug between oil and water phase. The carrier has utilized for delivery of drugs with possible role in wound healing. These are Enhanced the proliferation and reduced the tissue inflammation	[98]
3.1	Chlorhexidine acetate NEs	It directly inhibited bacteria those systemically spreading and also prevented the penetration. These was used against a methicillin resistant S.aureous (MRSA) infection to a skin wound model. The nanoemulsion showed effective and rapid activity against MRSA in-vitro and in-vivo and hindered formation of biofilm, disrupted MRSA cell walls, led to increased leakage of DNA, protein, Mg2+, K+ and alkaline phosphates out of the cells.	[99] [100] [101]
3.2	Eucalyptus oil NEs	Have antibacterial effect and mainly acts against S.aureus. Eucalyptus oil NE-NS film was attributed to cell membrane damage, and wound healing efficacy to a non-irritant activity in the wounds	[102]
4	Liposomes	Liposomes act by penetrating the epidermal layers releasing drug into the skin. They lose their bilayer membrane during the penetration. Lipids penetrate into the stratum corneum by adhering to the skin surface and finally fasing with the lipid matrix and releasing the drug enclosed in it. effective is the formation of a protective film on the tissue surface. Liposomes might enhance the barrier properties of a dysfunctional urothelium and increase the resistance to irritant penetration.	[103] [104]
4.1	Anti-gal/alpha gal liposomes	Neutrophils and macrophages are rapidly enlisting. Recruited macrophages are pivotal for healing of wound occurs by the burns because they secrete cytokines/growth factors. Epidermis regenerated and tissue repair occur. For accelerating the healing process Tackle of at least two immunological mechanisms.	[105]
4.2	Verbasconide based liposomal eye drops	Verbasconide was administered in the form of tiny capsules of lipids for effectively protecting the antioxidants. Verbasconide promotes skin repair and ameliorates skin inflammation.	[106]
4.3	Povidone iodine liposome hydrogel	Povidone iodine is active in broad spectrum. They have penetrate biofilms. They have lack of associated resistance, anti-inflammatory properties, low cytotoxicity and good tolerability. For wound healing activities necessary its combination with microbicidal, resulting in enhanced epithelisation.	[107]
4.4	Collagen liposome	These applied to the superficial wounds. Another potential means of liposome – collagen matrix is capable of protecting the active ingredient from the enzymes in tears and epithelium, Efficacy of drug delivery accelerated.	[108]
4.5	Dihydro - Quercetin	The necrotic area in burned skin are reduced. Rapid healing occur.	[109]
5	Hydrogels	Exhibit a thermodynamic compatibility with water which makes them to swell in aqueous media. Retain the wound release along with the foreign bodies, such as bacteria. Hydrogels also promote the fibroblast proliferation which is necessary for complete epithelialization of the wound by reducing the fluid loss from the wound surface and protect the wound from external noxae necessary for rapid healing of the wound	[110]
5.1	Tetracycline Hydrochloride Hydrogel	Antimicrobial effect of the dressings improved which occurs against both Gram-positive and Gram-negative bacteria, and minimal scarring. Tissue regeneration. Release various bioactive molecules such as antibacterial agents, growth factors, and cytokinesin tissue damage site.	[111] [112]
5.2	Liposomal hydrogels	Provides a barrier against contamination of the wound. Against bacteria, oxygen permeability act as a barrier. it is easily handled, hence it is useful as a moist wound dressing material. They enhance the skin retention of drugs, a higher drug concentrations in the skin and at the same time slow down the systemic absorption of drugs. Act as a drug depot and provide a sustained localized drug delivery and liposomal hydrogels deliver adequate amount of drugs for their therapeutic activity.	[113] [114]
5.3	L-glutamic acid hydrogels	Increased the collagen content and crosslinking in diabetic wounds. Improve the angiogenic process by formation of blood capillaries and microvasculature, and maturation of blood vessels in diabetic wounds decreased macrophage count in the maturation phase had no significant effect on wound closure.	[115] [116]
6	Dendrimers	The surface functional groups of dendrimers can act as antibacterial agents themselves (especially if cationic). Interaction of the positively charged group of a dendrimers (quaternary ammonium groups) and the negatively charged groups of the bacterial cell wall. Water soluble dendrimers loaded with water insoluble antibiotics, leads to increases their bioavailability and their antibacterial properties.	[117] [118]
7	Microspheres	Microsphere provide sustained drug delivery. They have increase the drug targeting specificity. They enhanced therapeutic effectiveness for prolonged period of times.	[119]
7.1	PLGA microspheres	They showed antimicrobial activity against the targeted microorganism Staphylococcus epidermidis. Increased bioavailability. Systemic absorption reduced, and the need for frequent administration leading to improved patient compliance .	[120]
7.2	Sonochemical Proteinaceous Microspheres	Reduce the activity of human neutrophil elastrase (HNE) . The ability of these devices to inhibit HNE was evaluated using porcine pancreatic elastrase (PPE) solution as wound exudates.	[121]
7.3	Polyheal’s Microspheres	Triggering the patient’s own cells to regenerate the deteriorated tissue of chronic wound. Polyheal’s shows activation of different types of cells in wound space (inflammatory cells, fibroblasts and keratinocytes).	[122]
7.4	RHEGF loaded PLGA alginate Microspheres	Accelerates wound closure . Inflammatory process resolved.	[123]

 

CONCLUSION:

Wound healing research are promote the complete reformation and renovation of the skin structure and function, remains with no or minimum scarring. Novel pharmaceuticals carriers have the great ability on the wound healing process to deliver drugs such as antibiotics, antimicrobials, nanoparticles and human EGFs etc. [124]. Thus offering a possible platform to get over the limitations of established wound dressing [125]. This review will describe various techniques such as nanoparticles, liposomes, dendrimers, microspheres, hydrogels, solid lipid based nanoparticles, and nanoemulsion, that are successfully applied as carriers for wound healing drugs. Novel drug delivery of wound healing drugs to the wounds is more convenient than others. In systemic administration as higher concentrations of the medication are delivered directly to the desired area in a sustained manner [126]. They are providing optimum environmental conditions to facilitate wound healing while eliminating the need for frequent changes of dressings. People suffering from chronic wound are increased therefore, novel carriers agents used due to its enormous potential for patient friendly in wound management [127].

 

ACKNOWLEDGEMENT:

The authors are thankful to Director, University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh, India, 492010 for providing necessary infrastructure. The authors would like to thank and acknowledge SERB EEQ/2017/000294 for providing financial support for this work.

 

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Received on 17.06.2019                    Accepted on 16.09.2019

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