**10. Pharmacological activity of curcumin**

Curcumin has been widely regarded as a "wonder drug of the future" due to its exceptional ability in preventing and treating many incurable illnesses, according to several clinical and preclinical studies performed on it over the past decades [121]. Curcumin has been studied for its anticancer properties for the past 50 years. According to some reports, Curcumin was shown to have chemotherapeutic impact on breast cancer [122], colon cancer [123], stomach cancer [124], liver cancer [125], and oral cancer [126]. It's effects on diseases including diabetes [127], Alzheimer [128], gastric ulcer [129], rheumatoid arthritis [130], psoriasis [131], and HIV [132] were studied in other studies, revealing its potential as a therapeutic agent. Curcumin's effects on the cardiovascular system, as well as pulmonary and metabolic disorders, have been studied further [133]. Curcumin's antimicrobial [134], antiviral [135], antioxidant [136], anti-inflammatory [137], and wound healing properties have also been widely recorded [117, 138].

Despite all of curcumin's potential usage in medicine, pharmacological studies have shown a number of disadvantages. Curcumin was discovered to have low absorption, poor solubility, and a low distribution property. As a result, curcumin is poorly absorbed in the body and cannot be used to treat diseases [139, 140]. It has a low bioavailability due to its rapid metabolism, elimination, poor tissue distribution, and low serum concentration [140, 141]. According to studies, curcumin bioavailability varies depending on the route of administration. In *in-vivo* study on mouse sample, it was discovered that when curcumin was administered intravenously, it was absorbed the most in the serum, while when curcumin was given orally, it was absorbed the least [142]. Researchers have been trying to increase the bioavailability of curcumin for the past three decades. They have devised a number of methods to improve the medicinal use of curcumin. Curcumin has been studied in various formulations to see whether they can solve the problem [143]. We have concentrated in this chapter on nanotechnology-based techniques that can aid in the delivery of curcumin and thus alleviate its disadvantages [110].

### **11. Curcumin as a nanoparticle**

Nanoparticles (NPs) are now being researched and used in a variety of medical fields to allow for targeted drug delivery, lower active agent dosing, combination therapy, reduced side effects, and the use of more potent drugs that cannot be clinically used by traditional drug delivery. Because of its many unique characteristics, nanotechnology has become a major area of interest in response to the growing threat of microbial drug resistance. The ability to overcome barriers and gain access to biological molecules and more specifically, microorganisms is enabled by the

physical and chemical properties of NPs including their high surface-to-volume ratio and small size [144]. The mechanisms other than antibiotic arsenal, which has established resistance, this direct association with microbial cell membranes/walls and main proteins/enzymes can both inhibit pathogen growth and/or instigate cell death. Furthermore, the scale, shape, and chemical properties of NPs can be altered to promote these molecular interactions, thereby maximising their ultimate function [144, 145].

Curcumin encapsulation in a nanoparticle platform is a feasible and beneficial method of delivering it. Nanoparticles can pass through the skin barrier and intracellularly due to their small size and high surface-to-volume ratio [146], making them suitable for topical drug delivery. Since the potential maximum volume of substance is never in contact with skin at one time, toxicity is limited by the slow, continuous release of encapsulated contents. Nanoparticles allow the delivery of substances like curcumin that have physicochemical properties that prevent or delay their use in non-encapsulated form. Curcumin nano-formulations have been established for preclinical studies on cancer, inflammation, wound healing, and other conditions, with nano-versus non-encapsulated curcumin demonstrating improved therapeutic efficacy [146, 147]. However, there is minimal evidence in the infection landscape [148], with no *in-vivo* studies reported to date [149].

Nanomaterials have the ability to enhance and change the pharmacodynamic properties of drug molecules with solubility issues, such as curcumin. Curcumin's stability, solubility, and bioavailability can all be improved with nanoparticle-based drug delivery. Physical entrapment, adsorption, and chemical conjugation methods are used to bind drugs to the surface of nanoparticles [140, 143, 150]. Various forms of nanomaterials, such as liposomes, proteins, nano-emulsions, micelles, strong lipid nanoparticles, and polymeric nanoparticles, have been found to be promising carriers for the delivery of curcumin in previous studies. Polymeric nanoparticles are thought to be the most important of all nanoparticle-based delivery methods and are currently being studied for the curcumin delivery [110, 151–153].

## **12. Alginate-curcumin based systems for wound healing**

Acute and chronic wound care is a pressing need, and alginate-based wound dressings provides many benefits over the conventional wound dressings. Alginatebased wound dressings come in a variety of shapes and sizes, including hydrogels, films, foams, nanofibers, membranes, and sponges. Alginate based dressings can absorb wound fluid, resulting in gels that keep the wound site physiologically wet and prevent bacterial infections. Efficacy of these wound dressings has been documented by several researchers [1]. To increase the efficacy of alginate dressing, curcumin was used as a potential antibacterial and ani-inflammatory biomaterial for rapid healing of wounds. In combination with alginate and other biopolymers curcumin increases the potency of wound healing of the wound dressing systems. Many alginate-curcumin systems have been used as drug delivery systems, wound dressing materials, tissue regeneration materials, and other applications in recent years. Curcumin's use in wound healing applications as wound dressing products has been well researched over the last few decades and published in numerous publications [154]. Other than alginate, chitosan was the mostly used biopolymers for preparation of wound care dressing materials. The focused on researches and experiments done with alginate and curcumin and related wound healing dressing systems and summarised in **Table 1**.

There are many attempts to improve the efficiency of wound healing through slow delivery of antioxidants including curcumin from collagen, which also serves as a supporting matrix for the regenerative tissue [167]. In the curcumin


*Curcumin-Alginate Mixed Nanocomposite: An Evolving Therapy for Wound Healing DOI: http://dx.doi.org/10.5772/intechopen.98830*

#### **Table 1.**

*List of experiments on alginate-curcumin nanocomposite wound healing systems.*

incorporated collagen matrix (CICM) group, biochemical parameters and histological analysis revealed increased wound healing, increased cell proliferation and effective free radical scavenging. As compared to standard collagen films, CICM films have a higher shrinkage temperature, implying greater hydrothermal stability. Curcumin was found to be bound to collagen without altering its triple helicity in spectroscopic tests. Curcumin absorbs a lot of light in the wavelength range of 300 to 500 nm. In methanol solution, it has a maximum absorption wavelength of 420 nm, which changes to 430 nm in dimethylformamide. As collagen solution is applied to curcumin, however, the maximum wavelength changes from 420to 429 nm. The change in the absorption shift stabilised and the amplitude of the peak increased with rising curcumin concentration, implying that curcumin is affected by the hydrophobic atmosphere. Further, lipid peroxidation method was used to determine the antioxidant performance of CICM [168]. The CICM's *in-vitro* antioxidant activity was tested by using 2,2-azobisisobutyronitrile antioxidant assay. According to antioxidant research, CICM is more effective at quenching free radicals. This concept supports the topical application of CICM as a viable and effective method for supporting dermal wound healing [167].

A nanocomposite sponge was made out of curcumin-chitosan-gelatine at various ratios of chitosan and gelatine [169], and the chemical structure and morphology were characterised using ATR- FTIR and FE-SEM. The water absorption ability, antibacterial activity, *in-vitro* drug release and *in-vivo* wound healing studies were also performed on these sponges using a rabbit excision wound healing model. The combine form of curcumin, chitosan, and gelatine has shown increase water absorption capacity, antibacterial function and wound closure potency. The cytotoxicity of curcumin sponge tested using the indirect MTT method on mouse fibroblast cells (L929) [170] indicates the controlled release of curcumin increased as the gelatine content of the prepared sponge increased. The drug in the sponge with a higher gelatine content is favoured to be released, instead of being dissolved by the sponge according to the partition ratio between sponge phase and water phase. The findings shows cell viability after 24 hours of incubation period with spongereleased medium. The results show that in the presence of medium containing sponge without curcumin and curcumin sponge, cell viability drops to around 90%. In the *in-vivo* analysis, wounds treated with curcumin-composite sponge closed faster than wounds treated with composite sponge without curcumin. According to the results of curcumin drug release, composite sponges with a higher gelatine content had a faster release activity up to 240 minutes. These composite sponges were also discovered to increase wound healing activity by enhancing collagen production *in-vivo*. These obtained results showed that combination of curcumin, chitosan and gelatine could improve the wound healing activity in comparison to chitosan, and gelatine without curcumin [169].

Hydrogels are most preferable system as their biodegradable and controlled drug delivery systems composed of curcumin loaded micelles are widely applied for cutaneous wound repairing [103]. Curcumin with strong antioxidant and anti-inflammatory properties and having high hydrophobicity was encapsulated in polymeric micelles (CurM) for high drug loading and encapsulation efficiency. To improve cutaneous wound healing, Cur-M loaded thermosensitive hydrogel (Cur-M-H) was prepared and applied as a wound dressing materials. At room temperature, Cur-M-H was a free-flowing solution that transformed into a non-flowing gel at body temperature. Cur-M-H system was found to have good tissue adhesiveness and the ability to release curcumin for a long time in vitro studies. It's *in-vivo* wound healing operation was also assessed using linear incision and full-thickness excision wound models. CureMeH-treated mice had a thicker epidermis and higher tensile strength in an incision model. In an excision model, the CureMeH treated group showed

#### *Curcumin-Alginate Mixed Nanocomposite: An Evolving Therapy for Wound Healing DOI: http://dx.doi.org/10.5772/intechopen.98830*

improved wound closure. This group also had higher collagen content, stronger granulation, higher wound maturity, a drastic decrease in superoxide dismutase, and a small rise in catalase in both models. CureMeH may also improve cutaneous wound healing, according to histopathologic analysis. Thus the combination of curcumin bioactivity and thermosensitive hydrogel in the in-situ gel-forming composite, facilitates tissue reconstruction processes, implying that the CureMeH composite could be used as a wound dressing for cutaneous wound healing [103] .

According to past reports, materials commonly used to treat burn-wound infections are limited by their incomplete microbial coverage, toxicity, insufficient penetration and more resistance to antibiotics. Curcumin is a naturally occurring compound that has antimicrobial, anti-inflammatory and wound-healing properties. Working through a variety of pathways, is less likely than current antibiotics to select for resistant bacteria. But curcumin's weak aqueous solubility and rapid degradation profile make it difficult to use; however, nanoparticle encapsulation solves this problem and allows curcumin to be delivered to the skin for longer periods of time [149]. So, curcumin nanoparticles (Curc-NP) prepared by the modified sol–gel methods [171] is a major step forward in the treatment of contaminated burn wounds, as it reduces bacterial load while also improving wound healing. Curcumin nanoparticles (Curc-NP) inhibited methicillin-resistant *Staphylococcus aureus* (MRSA) and *Pseudomonas aeruginosa* growth *in-vitro* in a dose-dependent manner, and inhibited MRSA growth and improved wound healing in an *in-vivo* murine wound model. The sensitivity of murine PAM212 keratinocytes to curcumin determined using a semiquantitative FDA (fluorescein diacetate) metabolic assay showed no toxicity to the side tissues. These outcomes indicates, Curc-NPs may rise as a novel topical antimicrobial agent over the conventional antibiotics and wound healing adjuvant for the treatment of infected burn-wounds and other cutaneous injuries [149].

A novel collagen scaffold called nanohybrid-scaffold prepared by incorporating curcumin (CUR) in chitosan nanoparticles (CSNPs) to improve the stability and solubility of the scaffold followed by permeation of prepared CUR-CSNPs have shown better tissue regeneration application [172]. This novel nanohybrid collagen scaffold tested for morphology changes, biodegradability, biocompatibility, *in-vitro* drug release and *in-vivo* wound healing studies have shown high potency. *In-vitro*, the nanohybrid scaffold performed well in terms of water absorption, biocompatibility, and long-term drug availability. Whereas, *in in-vivo* wound closure analysis showed that wounds treated with nanohybrid scaffolds contracted substantially faster than wounds treated with control and placebo scaffolds. Thus the study indicate that in the nanohybrid scaffold community, full epithelialization with thick granulation tissue formation occurs, while there was no compact collagen deposition in the placebo scaffold group and the presence of inflammatory cells in the control group. These suggest that, combining CUR (anti-inflammatory and antioxidant), chitosan (sustain drug carrier, wound healing), and collagen (established wound healer as scaffold) is a promising strategy for addressing various pathological manifestations of diabetic wounds and improving wound healing capability [172].

Considering alginate as a vital ingredient and an unavoidable wound dressing system, a lot of steps have been taken place to develop a proper system having high efficiency for wound healing and low toxicity material. Hence, an ethereal, pliable and biodegradable sponge, composed of chitosan (CS) and sodium alginate (SA) in different ratio and curcumin was prepared and its sponginess, chemical composition and morphology characterised using ATR-FTIR and FE-SEM are similar as reported for other materials for wound dressing purpose [120]. The sponges of all kinds had biodegradable quality and the degree of crosslinking influences the

release of curcumin from the sponges. The sponges' water absorption capacity ranged from 10 to 43%. The wound healing test performed on Sprague–Dawley (SD) rats shown that the CA sponges have a continuous release activity for up to 20 days based on the effects of drug release of curcumin. This conclude that the CA sponge acts as an effective drug support for long-term release of curcumin up to 20 days at a time. The collagen bundles in the CA-curcumin sponge-treated wound were thicker than those in the gauze and CA sponge-treated wounds, and they were compact and well-aligned. The developed material, curcumin sponge can promote collagen production, which speeds up the healing process and has a positive impact on wound healing process [120].

Curcumin loaded to alginate foams with low cross-linking was developed based on the previously patented method for the treatment of infected wounds [155, 173]. Curcumin-loaded foam demonstrated a longer hydration time and the amount of curcumin released was adequate, for curcumin-mediated phototoxicity of viable *E. faecalis* cells *in-vitro*. *E. coli*, on the other hand, was less vulnerable to photokilling when curcumin-loaded foams were used, and this was affected by the curcumin solubilizers used in the foams. Only foams containing PEG-400 as the curcumin solubilizer with visible light radiation (29 J/cm<sup>2</sup> ) caused 81% inhibition of the viable *E. coli* cells to be inactivated. When the foams were exposed to the physiological solution, they quickly hydrated and stayed intact after the loaded curcumin was released, implying that they can be withdrawn from the wound site without causing tissue harm prior to irradiation, reducing light attenuation in photodynamic therapy (PDT) [155].

An injectable chitosan and alginate derivates based on hydrogel incorporating nano-curcumin was also prepared in view of a potential wound dressing with enhanced healing efficacy [156]. Nanocurcumin with a particle size of about 40 nm prepared by using methoxy poly(ethylene glycol)-b-poly(−caprolactone) copolymer (MPEG-PCL) as a carrier, followed by a simple nano-precipitation process and integrated into N,O carboxymethyl chitosan/oxidised alginate (CCS-OA) hydrogel shown slowly and continuously release of curcumin from the CCS-OA hydrogel to promote fibroblast proliferation, capillary development, and collagen output, both of which can have a major impact on the healing processes. The encapsulated nanocurcumin shown slowl released from the CCS-OA hydrogel in an *in-vitro* release analysis (with diffusion controllable release at first, followed by the corrosion manner) of hydrogel at terminal phase. According to the histopathology repots, the hydrogels injected into rat dorsal wounds as part of an *in-vivo* wound healing trial has shown significant improve in epidermis re-epithelialization generation and collagen deposition in wound tissue. The measured DNA, protein, and hydroxyproline content of wound tissue indicate that the nano-curcumin and CCS-OA hydrogel together significantly speed up the wound healing process. It was hypothesised that the nano-curcumin/CCS-OA hydrogel have a wide range of applications in wound healing [156].

On the other side a complete investigation of curcumin loaded oleic acid based polymeric bandage and its therapeutic potential in dermal wound healing in a rat model was carried out [157] to show that curcumin has high wound healing potency in various animal models, and a curcumin-loaded oleic acid-based polymeric (COP) bandage was developed to increase curcumin efficacy in the healing region. Due to its effective free radical scavenging properties, biochemical parameters and histological examination showed increased wound reduction and enhanced cell proliferation in COP bandage treated groups. Researchers believe this is due to increased intercellular curcumin retention and, as a result, an improved anti-inflammatory activity by quenching reactive oxygen species (ROS). Early implementation of fibroblasts and differentiation (increased amount of smooth muscle actin) resulted

#### *Curcumin-Alginate Mixed Nanocomposite: An Evolving Therapy for Wound Healing DOI: http://dx.doi.org/10.5772/intechopen.98830*

in a comparative acceleration of wound healing. The COP bandage can effectively quench free radicals, resulting in decreased antioxidative enzyme activity. The mechanism is potent enough to reduce the inflammatory response mediated by the NFB pathway during wound healing, as evidenced from the mRNA and protein levels analysis. In light of this, it's possible that the curcumin-loaded polymeric bandage may have a new therapeutic use in clinical settings for cutaneous wound healing [157].

There are also studies which stated about characterisation and optimisation of different biodegradable and biocompatible formulations of curcumin encapsulated particles, in order to enhance the efficiency of curcumin wound healing effect [166]. The optimised curcumin particles ranged in size from 1286 nm to 1485 nm, with a 75% encapsulation performance. With a Polydispersity Index (PDI) of 0.4, the zeta potential showed values ranging from −7.20 to −7.96. The efficient fabrication and encapsulation of curcumin in the polymeric matrix, which had been fabricated in rod form, was ensured by physical characterisation using HR-TEM imaging. For curcumin particles, the release profile was biphasic, with an initial burst accompanied by a steady release pattern. *In-vitro* cytotoxicity assays and microscopic imaging verified the safety of the curcumin particle concentration used, which was less than 25 g/ml. Furthermore, the findings of a cellular uptake analysis confirmed that curcumin particles were internalised. Overall, the existing biocompatible and biodegradable curcumin encapsulation formulations have the potential to be used as a drug delivery vehicle for curcumin, according to this thesis. More evidence of this curcumin encapsulated particle's ability to improve wound healing is also required [166].

Incorporation of nanoforms of metal oxides into the wound care materials improves their antibacterial efficacy and thus used in wound healing process. This has open up a new window towards the use of metal oxide nanoparticles for therapeutic purpose [165]. Sodium alginate/PVA-titanium dioxide (TiO2) based wound healing patches were synthesised. TiO2 provides characters such as biocompatibility, no toxicity, antibacterial and antifungal etc. [165]. TiO2 NPs and curcumin were incorporated into the polymeric patches and tested for antibacterial activity against *Bacillus subtilis*, *Klebsiella pneumoniae*, *Staphylococcus aureus*, and *Escherichia coli*, as well as antifungal activity against *Candida albicans* and *Aspergillus niger* [92]*.* This provides evidence that both TiO2 nanoparticles and curcumin incorporated SA/PVA patches can be better used in wound healing [165].

Non-biodegradable, opaque and occlusive and low swelling capacity are the vital obstacles of few commercially available wound dressings materials used for clinical performance. Thus to overcome and improve such drawbacks, a novel biodegradable wound dressing material was prepared by using alginate membrane and polycaprolactone (PCL) nanoparticles loaded with curcumin [164]. Curcumin was employed as a model drug due to its important properties in wound healing, including antimicrobial, antifungal, and anti-inflammatory effects. Both, *in-vitro* and *in-vivo* trials were conducted to assess the possible use of this wound dressing material. The novel membrane had a wide range of functional properties that made it suitable for use as a synthetic skin substitute, including a high capacity for swelling and adherence to the skin, evidence of pores to control the loss of trans-epidermal water, clarity for wound monitoring, a high capacity for swelling, controlled drug release and effective adherence to the skin. The use of nanocarriers aids the drug's permeation through various skin layers, resolving curcumin's solubility issues. It also claimed that the clinical implementation of this method would cover large areas of mixed first- and second-degree wounds without the need for removal, reducing patient pain and the risk of changing the formation of the new epithelium tissues [164].

Recently biocompatible polymers are widely used in wound care systems especially for burn wounds as well as skin damages. Polymers such as polyvinyl alcohol and chitosan have been shown to be biocompatible with low toxicity have make them ideal for treating injuries with limited side effects [108]. Curcumin, a key component of turmeric, has anti-inflammatory and antimicrobial effects, but its bioavailability is extremely poor. Curcumin's bioavailability was increased exponentially after it was converted to its nano form, and allowing it to play an important role in wound healing. Considering the biopolymer and dynamic nature of curcumin, polymeric patches were prepared from Polyvinyl alcohol and chitosan with nano-curcumin for wound healing purpose. Slow vaporisation was used to successfully synthesise nano-curcumin, which was then integrated into polyvinyl alcohol and chitosan and obtained as a PVA/Chi/Cur patch using the gel casting process. Different characterisation methods were used to assess the patch: wwelling rate, evaporation rate, blood effect, cell biocompatibility, and antibacterial activity were all investigated. The patch was screened for antibacterial activity against common bacteria present on the wound site (*Escherichia coli*, *Pseudomonas aeruginosa*, *Staphylococcus aureus*, and *Bacillus subtilis*). The study was completed by putting the patch wound healing efficiency to the test on Albino Westar rats for 16 days. The tests were successful and results of cell line experiments and the MTT-assay showed that the PVA/Chi/Cur patch improved cell proliferation. Its antibacterial activity against four major bacterial strains present in wound sites, as well as its water retention, makes it an ideal material for wound healing. Its superiority over commercial ointment was demonstrated in *in-vivo* trials. This procedure for epidermal wounds decreases the number of times the patch has to be replaced and speeds up wound healing [108].

The β-cyclodextrin (CD) is generally used as a good stabilising and solubilising agent for preparation of different pharmaceutical products. It also enhances the water solubility of curcumin by forming β-cyclodextrin (CD)–Cur complex [163]. To facilitate cutaneous wound healing, a composite prepared from curcumin (Cur), chitosan–alginate (CA) and β-cyclodextrin (CD) [163] by adding curcumin to the ring-shaped β-cyclodextrin (CD) to form a β-CD–Cur inclusion complex (CD-Cur) and tested in a skin model to shows higher skin permeability than free Cur [174–176]. These findings indicate that Cur-CD can be an useful component for cutaneous wound healing materials. Animal studies with cutaneous wounds in rats using CA-CD-Cur showed accelerated and better wound closure rates, good histopathological results, and lower SOD, lipid peroxidation, pI3K, and pAkt levels in comparison to other material. Thus, CA-CD-Cur can facilitate cutaneous wound dressing that facilitate faster wound healing process [163].

Another alginate based hydrogel system was developed using curcumin-βcyclodextrin based inclusion complex for wound healing purpose [162]. The fabricated curcumin-β-cyclodextrin inclusion complex loaded sodium alginate/chitosan (CMx-loaded SA/CS) bilayer hydrogels was tested as a better wound healing materials. The improve materials with high CaCl2 content has high tensile strength, percent elongation at split and Young's modulus. The release characteristics of CMx from all hydrogels exhibited a similar pattern of release. Furthermore, the CMxloaded SA/CS bilayer hydrogels inhibited Gram-negative (*Escherichia coli*) as well as Gram-positive bacteria (*Staphylococcus aureus*). Finally, NCTC clone 929 and NHDF (normal human dermal fibroblast) cells were found to be non-toxic to all bilayer hydrogels. Therefore, these CMx loaded SA/CS bilayer hydrogels had the potency for wound healing and can be used as wound dressing materials [162].

As newer technologies are approaching for development of proper wound care management systems, elastin based biomimetics are one of the trending topic for current material development. This concept contributes for the preparation and

#### *Curcumin-Alginate Mixed Nanocomposite: An Evolving Therapy for Wound Healing DOI: http://dx.doi.org/10.5772/intechopen.98830*

characterisation of series of cross-linked films based on the combination of an elastin-derived biomimetic polypeptide [Human Elastin-Like Polypeptide (HELP)] with alginate (ALG) to obtain a composite with enhanced properties [161]. There are a few examples of such elastin-like composites produced to date by combining alginate and HELP to tune the final properties of the resulting material, modulating the delivery of curcumin as a natural molecule used as an antioxidant compound. The existence of HELP in the composite was shown to be useful in controlling the release of the model compound curcumin, resulting in a high antioxidant activity of the material as well as maintaining and improving the final material's cytocompatibility. More research is required to assess the *in-vivo* behaviour of this composite material. However, the current findings showed that combining alginate with HELP to create customizable platforms for drug delivery, wound healing, and tissue regeneration is effective. Finally, HELP-based proteins can be easily customised by molecular fusion of exogenous domains to prepare dynamic biopolymers. These HELP fusion proteins may be used in the future to provide additional flexibility to final composite materials for therapeutic use [161].

Graphene oxide is one of the most preferable material which have characteristics like biocompatibility, greater surface area, high mechanical strength and also antimicrobial activity. *Gymnema sylvestre* is commonly known as "Gumar" plant product also having anti-inflammatory, antimicrobial properties [160]. Fabrication of a novel scaffold was done consisting of curcumin and *Gymnema sylvestre* incorporated graphene oxide polyhydroxy butyrate-sodium alginate (GO-PHB-SA-CUR and GS) composite as an extracellular matrix platform to improve wound healing in normal and diabetic wounds [160]. Curcumin and *Gymnema sylvestre* were integrated into the novel graphene oxide-polyhydroxybutyrate sodium alginate composite scaffold prepared by solution casting to enhance wound healing in regular and diabetic wounds for better tissue regeneration use. The particle size, surface charge (zeta potential), crystalline nature (XRD), and morphology (FE-SEM) content of the GO-PHB-SA-CUR and GS composite were all assessed. The presence of GO-PHB-SA improves wound closure and increases cell viability in both wounded and diabetic wound cells without causing cytotoxicity. The manufacturing of mesoporous composites improves fibroblast cell viability. The composite made from GO-PHB-SA-CUR and GS has been tested as a wound dressing material by clinical trials to validate its future use. *In-vitro* tests with normal and diabetic fibroblast cells indicated that the GO-PHB-SA-CUR and GS composite had strong biocompatibility in terms of increased wound cell migration. As a result the GO-PHB-SA-CUR and GS composite could help regular and diabetic wounds heal faster. According to the findings the GO-PHB-SA-CUR and GS composite scaffold appears to be a promising candidate for a new wound dressing material that is both reliable and affordable. More successful clinical trials of this material will help millions of diabetic patients with improve wound healing capacity and the quality of life they are going through [160].

Multifunctional biopolymer composites comprising mechanically disintegrated bacterial cellulose, alginate, gelatine and curcumin plasticized with glycerol (BCAGG-C) were also successfully made through a simple, naive, cost-supportive mechanical blending and casting method [159]. The composites had a well distributed structure, according to FE-SEM pictures. The water touch angles ranges from 50 to 70 degrees and its permeability value was 300–800 g/m2 /24 hrs, which was equivalent to commercially available dressing products. When the fil was immersion in phosphate buffer solution (PBS) and artificial saliva, no curcumin was released from the films and the fluid uptakes were in the range of 100–700%. Mechanical properties revealed that BCAGG-C films had sufficient strength and versatility to be used as wound dressings. The stretchable film provides adequate

stiffness and long-term deformation. The skin was tightly adhered by hydrated films. Under artificial saliva medium, the *in-vitro* muco-adhesion time was found to be in the range of 0.5–6 hrs using porcine mucosa as a model membrane. Despite being trapped within the biopolymer matrix composite, curcumin could possess useful biological activities. The curcumin-loaded films had successful antibacterial activity against *E. coli* and *S. aureus*. Human keratinocytes and gingival fibroblasts were not harmed by the films, but oral cancer cells displayed potent anticancer activity. As a result, these curcumin-loaded films can be used as leave-on skin applications. These inventive films can be further adapted to meet the needs of local topical patches for wound care, periodontitis, and also for mouth cancer [159].

Taking almost the similar components such as biocompatible biopolymers, sodium alginate and gelatine microfibers are prepared via extrusion-gelation into a physical crosslinking solution [158]. Curcumin, which is an ancient natural bioactive wound healing agent, was loaded into the fibbers. Biopolymers including sodium alginate and gelatine were used to make curcumin-loaded composite microfibers and blank microfibers. The different concentrations of sodium alginate and gelatine in the formulation batches were coded as A1G9-A10G0. The ATR-FTIR was used to describe the molecular transitions inside the composite microfibers, which was then confirmed using molecular dynamic analysis. The mechanical properties such as tensile strength and elongation-at-break (extensibility) were varying between 1.08 ± 0.01 to 3.53 ± 0.41 N/mm<sup>2</sup> and 3.89 ± 0.18% to 0.61 ± 0.03% respectively. The microfibers' formation and fabrication were verified by morphological examination. Physical evaluations, such as matrix degradation and entrapment performance, were also carried out to provide a comparative account of the various formulations. The water uptake ability of the blank and curcumin-loaded composite fibres is found to be 30.77 ± 2.17 to 100.00 ± 5.99 and 22.34 ± 1.11 to 56.34 ± 4.68, respectively. The cumulative release of composite microfibers was 85% in 72 hours, which demonstrating the composite fibres' long-term release capacity. The drug was released in an unusual (non-Fickian) pattern, implying the importance of degradation and diffusion. In an *in-vivo* full-thickness cutaneous wound model, the composite microfibers had higher degree of contraction (96.89 ± 3.76%) than the commercially available lead products such as Vicco turmeric cream. It can be concluded that natural, alginate–gelatine–curcumin composite has the potency to be explored as a cost-effective wound healing product [158].
