INTRODUCTION:

Skin needs special attention and is considered the largest organ of the body. The skin covers our body and protect us from microbial attack and also helps in maintaining the temperature and fluid balance in the body. Wounds and burns can be major causes of destroying this barrier and seek the attention of the clinician as a terrific health challenge. Chronic and wounds that are nonhealing create physical disability¹ which could disrupt functional continuity and anatomical structure of the injured cells at the sites of injury. "Wound leads to gangrene or septic it may be a cause of patient death"².

Wound healing or repair is a dynamic mechanism in which overlapping phases or inflammation, remodeling cellular proliferation are arranged more slowly to recommence their normal function³. The wound healing starts immediately within zero to 1 hour, or 1 to 24 hours, intermediate time taking such as 1 to 7 days, late healing time more than 7 days, and not heal more than 3 months. The successful wound healing steps are skin refutation, scab development, contraction of a wound, debridement of the wound, wound proliferation, fibroplasia, and collagen creation. Recent updates confirm that approximately 84% (number one cause) of diabetic patients were hospitalized due to foot ulcer issues⁴. First, lifestyle (including smoking and alcoholism) and the age group of the subjects have an immense impact on wound closure (10-14 days). Furthermore, other variables that can hinder wound healing are health disorders of the patient, such as high cholesterol, diabetes, peripheral arterial disease, Ehlers-"Danlos syndrome, Cutis Laxa, hypothyroidism, homocystinuria, and advanced stage of the disease"⁵.

For a successful healing method of wounds number of factors are responsible like wound location and anatomic skin condition, the blood supply into the wound site, the need for nutrition for quick recovery of wound, body and environmental temperature, bacterial infection, hygienic condition, etc. Chronic and nonhealing wounds are cases that often need more attention, and clinicians provide advanced wound care by the development of nanomedicines and improved dressings to keep wounds moist for better wound healing results. The chronic and non-healing nature of wounds creates discomfort ness, pain, and permanent disability in a patient with expensive treatment. Hippocrates suggests the idea of wound cleaning and reduction of wound pH helps in minimizing infections and strengthens the steps of healing procedure⁶. Chronic wounds like pressure ulcers, diabetic wounds, and vascular ulcers in veins and arteries show a major risk factor and lifetime threat for the patient.

Last few decades the act of regular drugs towards the healing of wound gradually improving in many parts of the world relies on the source of treatment such as newly developed drug molecules, an adaptation of new technology, advanced formulations, and targeted delivery systems, improving facilities of treatment and hygienic conditions^7,8. Similarly, current development in medicine, nanotechnology sciences, bioengineering chemistry, and pharmaceutical sciences has brought many new strategies that diminish any complications related to the healing of wounds and improve wound management^9,10.

Nanomedicine is evolving nano range substances (1-100 nm) with high biocompatibility and biodegradability useful in the applications such as oral dosage form, parenteral and topical, etc. provides better diagnosis and therapeutic activity for the diseased condition^11,12. Researchers aimed at the advancement of nanotechnology-based methods and materials towards the topical use of site-specific wound healing treatment. Nanoparticles, dendrimers, ethosomes, niosomes, liposomes are the new formularies that have been designed to focus on drug delivery¹³. This might be a novel method to make a vesicular methodology on a nano-drug delivery system. This system provides a controlled-release on the medication for better treatment of damaged or a complete therapy on topical wound care. This technology is needed for topical treatment application which could prolong the transfer of active drugs keeping in mind to reduce toxicity and side-effect. "This study means to cover different promising factor nano-drug therapy for topical treatment, based on improved nano formulations towards drug conveyance framework and their applications"¹⁴. These outcomes are influenced in the construction of topical skincare which could open a new area for the advancement of novel carriers for active drug towards the faster processing of wound care system.

What Is Wound?

A wound is an injury that breaks the skin as well body tissue represent in Fig. 1. This could be described in many ways by scratches, scrapes, cuts, or punctured skin that happened by an accident. Minor wounds are not serious but proper care and treatment is appropriate for viable, healing¹⁵. Due to wound breakdown of skin and skin function has been taken place which creates damage of stability of epithelium, following an injury underlying tissues/organs¹⁶. Healing of wounds either depend upon sutures that close the wounds or repair naturally, where damaged tissue is restored and gradually formed a connective tissue for regrowth of epithelium¹⁷.

Fig. 1: Schematic representation of various types of wounds.

Wound Healing Phases:

Wound healing involved several steps, which are extraordinary, sophisticated, and it's also vulnerable to interruption thanks to the factors involved locally and systemically, with moistness, contagion, maceration and age nutritious status, somatotype (systemic). The whole process is classically partitioned into four consecutive ways has shown below¹⁸.

1. Phase 1: Hemostasis

2. Phase 2: Inflammation

3. Phase 3: Proliferation

4. Phase 4: Remodelling/Maturation

Hemostasis phase:

In this stage, the draining is constrained by vasoconstriction, which is induced by the sympathetic, later it starts clotting¹⁹. Hemostasis, the primary stage to be healed, started with an injury and the objective is to prevent bleeding. During this stage, the body initiates its crisis fix framework, the blood coagulation framework, and structures a dam to dam the waste. Cells of injured tissue discharge alert signs, chemokines, and development factors that select insusceptible cells from blood flow and animate the multiplication of tissue-inhabitant populaces, bringing about safe cell collection at the injury site²⁰.

Defensive phase/ Phase of inflammation:

In this category Phase, 1 is about coagulation, the subsequent stage, called the defensive/Inflammatory Phase, aimed at killing bacteria and eliminating trash setting up the injury bed for the expansion of the latest tissue. During Phase 2, white blood cells called neutrophils enter the injury to obliterate microbes and take away the debris. Since the macrophages cells leftover by white blood cells reach to continue to remove debris. These cells attract to the systemic cell to ease wound tissue repair responsible for growth and protein supplements. This stage considered as chronic inflammation and lasts for 4 to 6 days and is usually related to erythema, heat, edema, and pain.

Proliferation Phase:

When the injury is wiped out, the injury reaches in 3rd phase where filling and canopy are considered as the main target for the wound. The proliferation stage is portrayed by the arrangement of granulation that comprises recently shaped veins, safe cells, and fibroblasts, and permits skin cell movement on top of this tissue during the process of reepitheliazation²¹. Three different proliferative stages are (1) wound filling; (2) shrinking wound areas and (3) form a thin layer on the wound (epithelialization). The structural arrangement of skin differs in different species which helps in quick healing²². The Proliferative stage mostly continues from 4-24 days.

Remodeling/ Maturation Phase:

At the maturation stage, newly generated tissue gradually gains strength and adaptability. At this point, collagen fibers rearrange the tissue rebuilds and develop, a general increase in lastingness (however maximum strength is limited to 80% of the pre-injured strength). The maturation stage differs significantly between the different wounds, it last about 21days to 2 years.

Wound Treatment by Nano Therapies:

Gradually many products are developing based on nanotechnology, to heal wounds, which is presently under clinical investigation. As previously mentioned, conventional topical delivery having some limitations and compromise the security and effectiveness of the finished product²³. A need for the drug development carrier that may proficiently increase skin penetration activity and produce fewer side effects, toxicity and increase targeted action for topical preparation²⁴. Different formulations based on nano have been developed for better targeted and wound repair activity. Wound care by using nanomaterials which targets to enhance therapeutic efficacy and quick recovery of wounds with the help of delivery vehicles²⁵. The objective of nanoscale approaches was to increase drug therapeutic efficacy by preventing drug degradation, sustained-release action, and enhance tissue repair action. Nano drug delivery as a carrier targeted to a specific localized body part and act as a skin reservoirs²⁶.

Hence the nano-based delivery of drugs mainly focused on its progressive therapeutic effect. Nanoparticles are easily absorbed by cells in a very efficient manner than normal macromolecules and thus, produced more effectiveness in the transportation of drugs to the targeted site. Nano form emphasizes the treatment process in drug delivery by regeneration of skin and helps to keep more potency by sustaining the release rate of the medicaments. Nanoparticles improve the uptake of low soluble drugs to their targeted location^27,28. “The targeted nanoparticles represent as liposomes, polymeric nanoparticles, inorganic nanoparticles, lipid nanoparticles, nanofibrous structures and nano hydrogel”towards a selected site for better drug bioavailability²⁹ , represent in Fig. 2.

Fig. 2: Nanotechnology-based drug designing towards skin regrowth and treatment of wound (reproduced from Ref.)²⁹.

Polymeric nanoparticles:

Polymeric nanoparticles (PNPs) contain biodegradable polymer. Several benefits of PNPs are reported as drug delivery, being the foremost important that they typically increase the steadiness of any volatile pharmaceutical agents which are cost-effectively and have the potency to deliver the active drug to its targeted area^30,31,32. Many biodegradable, non-toxic synthetic, or semi-synthetic polymers have shown a promising effect on topical skin application for the active drug. This includes chitosan, poly (e-caprolactone), polylactic acid (PLA), and poly lactic-co-glycolic acid (PLGA). Fabrication of PLGA NPs is usually done by emulsifying different hydrophobic compounds, with organic solvents and surfactants³³. Natural polymer chitosan has shown several benefits like easy availability, biocompatibility, biodegradability, mucoadhesiveness, non-toxicity, antimicrobial activity, not spreading of infections and low cost³⁴. Chitosan-based PLGA nanoparticles can advance topical delivery by enhancing the lifecycle of macromolecules. In some research studies, it's found that CS NPs are actively used in films and various bandages to offer more mechanical support to treat infected open wound³⁵.

Liposomes:

“Liposomes are two layers of vesicles containing amphiphilic molecules like phospholipids, emerging together of promising nanocarriers for topical application”³⁶. Liposomes are non-toxic, biocompatible, biodegradable to formulate solid lipid nanoparticles (SLNs), hydrophilic Lipid nanoparticles, and nano lipid carriers (NLCs), and capable to hold various active drugs potentially. Liposomes are spherical-shaped bilayer vesicles that contain an aqueous layer covered by a bilayer lipid membrane consist of phospholipids. Liposomal gel plays an efficient role in penetrating because it delivers the therapeutic moiety in a controlled manner for localized drug and produces flexibility in drug administration^37,38. Liposome used in topical application, first made in 1980 by Mezei and Gulasekharam³⁹. From a separate study, it was concluded that di-hydroquercetin loaded liposome has been formulated, which improved the antioxidant property and reduce the necrosis burned area and provide a better scope for skin wound healing⁴⁰.

Niosomes:

A unique technology used for niosomes, which entrapped together hydrophilic and hydrophobic drugs⁴¹. Niosomes are amphiphilic, inside a vesicle active medicaments encapsulated made of a non-ionic surfactant. Niosomes size varies in the range of 10nm-100nm⁴². L'Oreal in 1975, has developed primary niosome formulations and patented. Niosomes are better than liposomes and overcome chemical instability insolubility, low bioavailability, and quick degradation of active drugs. Niosomes can deliver different kinds of drugs like synthetic and herbal, antigens, hormones, etc.⁴³.

Hydrogels:

Hydrogels are hydrophilic, a polymeric network can absorb excessive aqueous fluid from wounds and represent a three-dimensional structure. They are extremely effective in tissue regeneration because of their highly porous nature and soft consistency. It produces a non-adhesive cooling effect onto the targeted area and is considered a suitable material for wound dressing. The polymers like chitosan, PEG, PVA, dextran, and antibiotics when mixed with hydrogel NPs, helps in the regrowth of tissue burn wounds. A study confirms that tetracycline hydrochloride incorporated hydrogel, exhibits an antimicrobial effect for both gram-negative and positive bacteria, and scarring was minimum⁴⁴. A recent study confirms that gelatin-based hydrogels which transport basic fibroblast protein (FP) induces healing without scarring⁴⁵.

Nanohydrogels:

In wound management nano hydrogel as a three-dimensional polymeric network-like structure, enhance the power of fluid absorption and its soft texture provides a comfortable experience within the course of treatment^46,47. Nanohydrogel helps in keeping a moist condition for the wounds by controlling dehydration helps in quick wound healing⁴⁸. Nanohydrogel was introduced as a gellan-cholesterol form for quick recovery of wound⁴⁹. It exhibits viscosity property helps in skin retention for a longer duration, and preferable biocompatibility. The nanohydrogels exhibits optimal results for the entire regrowth of tissue and reduce inflammation confirmed by the in-vivo study. In certain cases, nanohydrogels gradually increase cell adhesion property, spreadability, decrease blood coagulation time, and facilitated in vitro tissue regeneration.

Nanoemulsions:

Nanoemulsions (NE) contain two immiscible liquid substances that can be stabilized by the addition of surfactant. The nanoparticles are stable colloidal small droplets of size from 20-200nm. Nanoemulsions are topically applied on the wounds, where emulsions are penetrated through the skin layer to cure the wound. Nanoemulsions have more lipophilic drug loading ability as compare to microemulsion, which may be beneficial for wound healing⁵⁰. Nanoemulsion-based films consist of essential oil exhibits better antibacterial effect (S. aureus) and non-irritant effect on skin surface⁵¹.

Nanocapsules:

Nanocapsules core consists liquid/solid combination where active drug incorporated at the cavity and covered through polymer containing membrane ranging between 10-1000 nm. They contain a varied different type of natural polymers like albumin, gelatine; synthetic polymers used e.g. polyesters like polycaprolactone (PCL), polycarboxylic acid (PCA). Polymeric nanocapsules are more effective in intracellular and target-based wound treatment. Nanoparticles are often made to succeed in a target site by virtue of their size and surface modification and functionalized^52,53.

Lipid Nanoparticles:

Solid lipid nanoparticles (SLNs) is a solid lipid matrix choose as a carrier for targeted drug delivery. Lipid nanoparticles are divided into two categories like nanostructured particles contain lipid and solid lipid-containing nanoparticles. The surfactants are used to reduce aggregation and provide better stability to dispersed particles. Nanostructured lipid particle and solid-based lipid nanoparticle preferred for topical, oral, inhalational, and parenteral routes drug delivery system. SLNs contain spherical solid lipids with hydrophilic substances like PEG by-products, a different type of surfactants used to stabilize. NLCs are the upgraded group of SLNs, which contain both liquid and solid-based lipid substances. NLC lipid core has shown improved biocompatibility, biodegradability, and potential enough to control drug release. NLCs easily delivered lipophilic drugs into damaged wound tissues and get closely connected to skin layers due to their nano range for better drug permeation. Hence, these carriers deliver the drug for the desired period with less toxicity^54,55.

Inorganic Nanoparticles:

Inorganic nanoparticles play a significant role in the targeted delivery of medicaments because of their distinctive physical characteristics like nano range size reduction, catalytic, magnetic, and electronic characteristics. In a comparison of organic substances, inorganic nanoparticles show less toxicity, more hydrophilic, biocompatible, and more stable. Due to the nano range of particle size, it exerts a larger surface area, multifunctionality characteristics, flexible composition, and precise biological behaviors.

Silver:

Silvers are usually used to treat burn and having well potential for bactericidal activity. For chronic wound management, silver-coated dressing material has been discovered which effectively distributes the active moieties for better management of wound care⁵⁶. By controlling anti-inflammatory cytokine, silver nanoparticles (AgNPs) improves wound healing treatment as dressing materials. AgNPs and collagen synergize combinedly to form more effective wound dressing materials, active against bacterial infection⁵⁷. With the addition of biocompatible material, AgNPs exhibit better wound care by proliferating keratinocytes. As the silver ion gets a discharge, Ag/AgCl nanomaterial produces many oxidative free radicles that help to fight against gram-positive also as gram-negative bacteria and helps in quick recovery of wounds.

Gold:

Chemically stable gold nanoparticles (AuNPs), easy to synthesize and selected as a perfect option for wound therapy⁵⁸. AuNPs having antioxidant properties and significantly increase their activity when incorporated into the polymers which help the rapid recovery of wound⁵⁹. Chitosan-AuNPs significantly increases free radicals which improve hemostasis, re epithelisation, and faster-wound healing rate. AuNPs very effective towards bacterial cell walls or they may bind bacterial DNA, stopping the double-helix and inhibit replication.

Zinc oxide:

A chronic wound can be healed by zinc oxide (ZnO) and considered an important element, especially for its stable inorganic bactericidal activity. In wound care management ZnO significantly reduces inflammation and improving re-epithelialization and regrowth of extracellular matrix. Zinc nanoparticle's efficacy depends on particle range and its concentration. Furthermore, zinc oxide helps in managing auto-phagocytosis and helps to relocate keratinocytes which responsible for tissue repair.

Nanofibers:

Nanofibers (NFs) are nanoscale ranges generally developed from synthetic substances or natural elements, augment drug interaction with scaffolds, and utilize tissue remodeling and antimicrobial drugs. NFs are showing significant importance and are numerously used in the nano range to treat wounds. NFs are fabricated with various pore sizes, densities, and diameters using the electrospinning technique⁶⁰. Thermally-induced phase separation (TIPS) used as fabricating NFs showed more water vapor absorptivity and sustained the release rate of active drug⁶¹. NFs manufactured from gelatine, polyurethane and chitosan produce a higher anti-bacterial effect on P. aeruginosa and E. coli⁶².

Thin Films:

Usually, films are very thin and elastic in nature with a versatile polymer layer known as a thin film (TF)^63,64. Easy acceptance by the patient due to the thin and versatile nature of the films⁶⁵. TF is an excellent carrier for targeting sensitive sites which will not be possible with tablets or capsules⁶⁶. TF has the standard to produce better efficacy, increase therapeutic effectiveness, and reduced dosing frequency⁶⁷. An ideal TF is capable of high drug loading, better drug action at the targeted area with high dissolution property, biodegradable, biocompatible, and better stability, non-toxic in nature^68,69. For the past few years, TF is used widely for the healing of wounds. Also used involved in dressing materials. The benefit of TF is, it allows visual check and adheres topically on the skin surface, not to wounds.

Nanofibrous Scaffolds:

Tissue engineering (TE) a biodegradable and biocompatible scaffold combining with living cells and bioactive moieties has been developed. A Scaffold may be a network-like structure that helps the tissue to regenerate and repair⁷⁰. If wounds are chronic, tissues are unable to regenerate on their own, so a scaffold helps in the natural healing of tissues. As it is highly porous in nature and larger surface area nanofiber helps in better permeability for oxygen and water. Moreover, it adsorbs extrudes, and provides protection to the infected area from bacterial infection. The ideal features of a scaffold, like the optimum shape which provides mechanical support, minimization of immune and inflammatory responses, a bed for tissue growth.

CONCLUSION:

In the treatment of chronic and non-healing wounds, the ulcer is a bigger issue for the researchers and clinicians because current therapies unable to promote better facility for treatment of the wound. Though curing of the wound is a time-consuming process and its etiology should be understood for each wound type, and mainly focused on advancement in drug designing and delivery process. Recently nanotechnology has created attention towards improvising wound healing by prolonging the release rate drug, preventing degradation, improve tissue regrowth and retention. Due to the realization of nano therapy value, various combination of nano-drug delivery is implicated to provide batter physiological and mechanical support to the broken skin for improvising healing activity. Nanotechnology overcomes the limitation of conventional dosage form and also opens up a new era to promote biocompatible, site-specific, increasing drug loading capacity, non-toxicity, improvise drug delivery action, and cost-effective technology in the wound care system. With this review article, we gather information about various nanoparticles and their therapy in the management of the wound. This current article represents valuable information to the researcher and clinician who wants to develop better technology and provide cost-effective treatment for the healing of wounds.

ACKNOWLEDGMENT:

The authors thank the management and pharma faculty, Dr.M.G.R. Educational and research institute, deemed to be University, Chennai for their continuous support and encouragement. The authors also thank Dr. Shaikh Ershadul Haque, Jagan's institute of pharmaceutical sciences, Nellore, Andhra Pradesh, India for proofreading the manuscript.

CONFLICT OF INTEREST:

The authors don't have any conflict of interest.

REFERENCES:

1. Purohit SK, Solanki R, Mathur V, Mathur M. Evaluation of wound healing activity of ethanolic extract of Curcuma longa rhizomes in male albino rats. Asian J Pharm Res. 2013;3(2):79-81.

2. Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C, Chong WH. Fournier Gangrene Associated With Sodium–Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases. Ann Int Med. 2019;170(11):764-69.

3. Gosain A, DiPietro LA. Aging and Wound Healing. World J Surg. 2004;28(3):321-26.

4. Reardon S. WHO warns against'post-antibiotic'era. Nature news. 2014.

5. Kalashnikova I, Das S, Seal S. Nanomaterials for Wound Healing: Scope and Advancement. Nanomedicine. 2015;10(16):2593-612.

6. Daunton C, Kothari S, Smith L, Steele D. A History of Materials and Practices for Wound Management. Wound Practice and Research: J Australian Wound Manag Assoc. 2012;20(4):174.

7. Indalkar YR, Pimpodkar NV, Godase AS, Gaikwad PS. A compressive review on the study of nanotechnology for herbal drugs. Asian J Pharm Res. 2015;5(4):203-7.

8. Senapati S, Mahanta AK, Kumar S, Maiti P. Controlled drug delivery vehicles for cancer treatment and their performance. Signal transduction and targeted therapy. 2018 16;3(1):1-9.

9. Kohane DS, Langer R. Biocompatibility and Drug Delivery Systems. Chem Sci. 2010;1(4):441-46.

10. Mahapatro A, Singh DK. Biodegradable Nanoparticles are Excellent Vehicle for Site Directed In-Vivo Delivery of Drugs and Vaccines. J Nanobiotechnology. 2011;9(1):55.

11. Durgadevi I, Gayathri PK. Polymeric Nano Medicine for Cancer Therapy-Review. Asian J Pharm Res. 2013;4(4):264-67.

12. Moura LI, Dias AM, Leal EC, Carvalho L, de Sousa HC, Carvalho E. Chitosan-Based Dressings Loaded with Neurotensin—An Efficient Strategy to Improve Early Diabetic Wound Healing. Acta Biomater. 2014;10(2):843-57.

13. Singh NK, Singh SK, Dash D, Gonugunta P, Misra M, Maiti P. CNT Induced β-phase in Polylactide: Unique Crystallization, Biodegradation, and Biocompatibility. J Phys Chem C. 2013;117(19):10163-74.

14. Maiti P, Senapati S, Saraf S. Inhibition of Chronic Osteomyelitis using Sustained Release of Drug from Biodegradable Polymeric Chip. Clin. Oncol. 2018;3:1406.

15. Upton D, Solowiej K, Hender C, Woodyatt KY. Stress and Pain Associated with Dressing Change in Patients with Chronic Wounds. J Wound Care. 2012;21:53.

16. Calo E, Khutoryanskiy VV. Biomedical Applications of Hydrogels: A Review of Patents and Commercial Products. Eur Polymer J. 2015;65:252–67.

17. Han G, Ceilley R. Chronic Wound Healing: A Review of Current Management and Treatments. Adv Ther. 2017;34:1–12.

18. Vijayabhaskar K, Sravanprasad M, Venkateshwarlu G, Devi PS, Kumar KH, Sunil J. Wound Healing Activity of Bauhinia purpurea in Albino Wistar Rats. Asian J Pharm Res. 2011;1(2):47-9.

19. Werner S, Grose R. Regulation of Wound Healing by Growth Factors and Cytokines. Physiol Rev. 2003;83:835–870.

20. Phillipson M, Kubes P. The Neutrophil in Vascular Inflammation. Nat Med. 2011;17:1381–1390.

21. Dhalendra G, Satapathy T, Roy A. Animal models for inflammation: A review. Asian J Pharm Res. 2013;3(4):207-12.

22. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound Repair and Regeneration. Nature. 2008;453(7193):314-21.

23. Lademann J, Richter H, Teichmann A, Otberg N, Blume-Peytavi U, Luengo J, Weiss B, Schaefer UF, Lehr CM, Wepf R, Sterry W. Nanoparticles–An Efficient Carrier for Drug Delivery into the Hair Follicles. Eur J Pharm Biopharm. 2007;66(2):159-64.

24. Pople PV, Singh KK. Development and Evaluation of Colloidal Modified Nanolipid Carrier: Application to Topical Delivery of Tacrolimus. Eur J Pharm Biopharm. 2011;79(1):82-94.

25. Tocco, I.; Zavan, B.; Bassetto, F.; Vindigni, V. Nanotechnology- Based Therapies for Skin Wound Regeneration. J. Nanomater. 2012;1−11.

26. Bawarski WE, Chidlowsky E, Bharali DJ, Mousa SA. Emerging Nanopharmaceuticals. Nanomedicine: Nanotech Biology Med. 2008;4(4):273-82.

27. Ould-Ouali L, Noppe M, Langlois X, Willems B, Te Riele P, Timmerman P, Brewster ME, Arien A, Preat V: Self-assembling PEGp (CL-co-TMC) Copolymers for Oral Delivery of Poorly Watersoluble Drugs: A Case Study With Risperidone. J Control Release 2005, 102(3):657-68.

28. Kipp JE: The Role of Solid Nanoparticle Technology in the Parenteral Delivery of Poorly Water-Soluble Drugs. Int J Pharm 2004, 284(1–2):109-122.

29. Chen X, Plasencia C, Hou Y, Neamati N. Synthesis and Biological Evaluation of Dimeric RGD Peptide-Paclitaxel Conjugate as a Model for Integrin-Targeted Drug Delivery. J Med Chem 2005,48:1098-106.

30. Amanat S, Taymouri S, Varshosaz J, Minaiyan M, Talebi A. Carboxymethyl Cellulose-Based Wafer Enriched with Resveratrol-Loaded Nanoparticles for Enhanced Wound Healing. Drug Deliv. Transl. Res. 2020;1-4.

31. Ezhilarasu H, Vishalli D, Dheen ST, Bay BH, Srinivasan DK. Nanoparticle-Based Therapeutic Approach for Diabetic Wound Healing. Nanomaterials. 2020;10(6):1234.

32. Baba R .Patent and Nanomedicine. Nanomedicine 2007; 2(3);351-374.

33. Chereddy KK, Vandermeulen G, Préat V. PLGA Based Drug Delivery Systems: Promising Carriers for Wound Healing Activity. Wound Repair and Regeneration. 2016;24(2):223-36.

34. Haque SE, Sheela A. Miscibility of Eudragit/Chitosan Polymer Blend in Water Determined by Physical Property Measurements. Int J pharm. 2013;441(1-2):648-53.

35. Dai T, Tanaka M, Huang YY, Hamblin MR. Chitosan Preparations for Wounds and Burns: Antimicrobial and Wound-Healing Effects. Expert Review of Anti-Infective Therapy. 2011;9(7):857-79.

36. Chen J, Cheng D, Li J, Wang Y, Guo JX, Chen ZP, Cai BC, Yang T. Influence of Lipid Composition on The Phase Transition Temperature of Liposomes Composed of Both DPPC and HSPC. Drug Dev Ind Pharm. 2013;39:197–204.

37. Gupta M, Goyal AK, Paliwal SR, Paliwal R, Mishra N, Vaidya B, Dube D, Jain SK, Vyas SP. Development and Characterization of Effective Topical Liposomal System for Localized Treatment of Cutaneous Candidiasis. J liposome res. 2010;20(4):341-50.

38. Nikam NR, Patil PR, Vakhariya RR, Magdum CS. Liposomes: A Novel Drug Delivery System: An Overview. Asian Pharm Res. 2020 ;10(1):23-8.

39. Mezei M, Gulasekharam V. Liposomes-A Selective Drug Delivery System for the Topical Route of Administration I. Lotion dosage form. Life Sciences. 1980;26(18):1473-77.

40. Naumov AA, Shatalin YV, Potselueva MM. Effects of A Nanocomplex Containing Antioxidant, Lipid, and Amino Acid on Thermal Burn Wound Surface. Bull. Exp. Biol. Med. 2010;149(1):62.

41. Mujariya RZ, Muzumdar A. Niosomes–An Overview. Res J Pharm Dosage Forms and Tech. 2012;4(4):202-6.

42. Makeshwar KB, Wasankar SR. Niosome: A Novel Drug Delivery System. Asian J. Pharm Res. 2013;3(1):16-20.

43. Sudheer P, Kaushik K. Review on Niosomes- A Novel Approach for Drug Targeting. J Pharm Res. 2015; 1-14.

44. Anjum S, Arora A, Alam MS, Gupta B. Development of Antimicrobial and Scar Preventive Chitosan Hydrogel Wound Dressings. Int j pharm. 2016;508(1-2):92-101.

45. Kuroiwa T, Takada H, Shogen A, Saito K, Kobayashi I, Uemura K, Kanazawa A. Cross-Linkable Chitosan-Based Hydrogel Microbeads with pH-Responsive Adsorption Properties for Organic Dyes Prepared Using Size-Tunable Microchannel Emulsification Technique. Colloids Surf, A Physicochem Eng Asp. 2017;514:69-78.

46. Bhattacharya M, Malinen MM, Lauren P, Lou YR, Kuisma SW, Kanninen L, Lille M, Corlu A, Guguen-Guillouzo C, Ikkala O. Nanofibrillar Cellulose Hydrogel Promotes Three-Dimensional Liver Cell Culture. J Control Release. 2012;164:291–8.

47. Hajimiri M, Shahverdi S, Esfandiari MA, Larijani B, Atyabi F, Rajabiani A, Dehpour AR, Amini M, Dinarvand R. Preparation of Hydrogel Embedded Polymer-Growth Factor Conjugated Nanoparticles as A Diabetic Wound Dressing. Drug Dev Ind Pharm. 2015;42:1.

48. Pachuau L. Recent Developments in Novel Drug Delivery Systems for Wound Healing. Expert Opin Drug Deliv. 2015;12:1895–909.

49. Manconi M, Manca ML, Caddeo C, Cencetti C, Meo CD, Zoratto N, Nacher A, Fadda AM, Matricardi P. Preparation of Gellan-Cholesterol Nanohydrogels Embedding Baicalin and Evaluation of Their Wound Healing Activity. Eur J Pharm Biopharm. 2018;127:244–49.

50. Amminbavi D, Lakshmi NP. Assessment of In vitro wound healing potential of Hibiscus leaf extract Emulgel. Asian J Pharm Res. 2020;10(2) 67-72.

51. Sugumar S, Mukherjee A, Chandrasekaran N. Eucalyptus Oil Nanoemulsion-Impregnated Chitosan Film: Antibacterial Effects Against A Clinical Pathogen, Staphylococcus Aureus, In Vitro. Int J Nanomed. 2015;10(Suppl 1):67.

52. Bechnak L, Khalil C, El Kurdi R, Khnayzer RS, Patra D. Curcumin Encapsulated Colloidal Amphiphilic Block Co-Polymeric Nanocapsules: Colloidal Nanocapsules Enhance Photodynamic and Anticancer Activities of Curcumin. Photochem Photobiol Sci. 2020;19(8):1088-98.

53. Negi P, Sharma G, Verma C, Garg P, Rathore C, Kulshrestha S, Lal UR, Gupta B, Pathania D. Novel Thymoquinone Loaded Chitosan-Lecithin Micelles for Effective Wound Healing: Development, Characterization, and Preclinical Evaluation. Carbohydr Polym. 2020;230:115659.

54. Stecova J, Mehnert W, Blaschke T, Kleuser B, Sivaramakrishnan R, Zouboulis CC, Seltmann H, Korting HC, Kramer KD, Schafer-Korting M. Cyproterone Acetate Loading to Lipid Nanoparticles for Topical Acne Treatment: Particle Characterisation And Skin Uptake. Pharm Res. 2007;24(5):991-1000.

55. Karthick J, Praveen Kumar PK. In-silico analysis of targeted drug delivery to hepatic cells using lipidnano-particles to treat liver diseases. Asian J Pharm Tech. 2013;3:93-7.

56. Hamdan S, Pastar I, Drakulich S, Dikici E, Tomic-Canic M, Deo S, Daunert S. Nanotechnology-Driven Therapeutic Interventions in Wound Healing: Potential Uses And Applications. ACS central sci. 2017;3(3):163-75.

57. Yildirimer L, Thanh NT, Seifalian AM. Skin Regeneration Scaffolds: A Multimodal Bottom-Up Approach. Trends Biotec. 2012;30(12):638-48.

58. Niska K., Zielinska E., Radomski M.W., Inkielewicz-Stepniak I. Metal Nanoparticles in Dermatology and Cosmetology: Interactions With Human Skin Cells. Chem. Biol. Interact. 2018;295:38–51.

59. Mankotia P, Sharma K, Sharma V, Kumar V. Interpenetrating Polymer Networks in Sustained Drug-Releasing. Adv Biopoly Syst Drug Deliv. 2020:195-232.

60. Hromadka M, Collins JB, Reed C, Han L, Kolappa KK, Cairns BA, Andrady T, van Aalst JA. Nanofiber Applications for Burn Care. J Burn Care Res. 2008;29(5):695-703.

61. Li CW, Wang Q, Li J, Hu M, Shi SJ, Li ZW, Wu GL, Cui HH, Li YY, Zhang Q, Yu XH. Silver Nanoparticles/Chitosan Oligosaccharide/Poly (Vinyl Alcohol) Nanofiber Promotes Wound Healing by Activating TGFβ1/Smad Signaling Pathway. Int J Nanomed. 2016;11:373.

62. Tan L, Hu J, Zhao H. Design of Bilayered Nanofibrous Mats for Wound Dressing Using an Electrospinning Technique. Mater letters. 2015;156:46-49.

63. Maniruzzaman M, Boateng JS, Snowden MJ, et al. A Review of Hot-Melt Extrusion: Process Technology to Pharmaceutical Products. ISRN Pharm 2012; 1–9.

64. Haque SE, Sheela A. Development of Polymer-Bound Fast-Dissolving Metformin Buccal Film with Disintegrants. Int J nanomed. 2015;10(Suppl 1):199.

65. Patel VF, Liu F, Brown MB. Advances in Oral Transmucosal Drug Delivery. J Control Release. 2011;153:106–16.

66. Sharma D, Kaur D, Verma S, et al. Fast Dissolving Oral Films Technology: A Recent Trend for an Innovative Oral Drug Delivery System. Int J Drug Deliv. 2015;7:60–75.

67. Borges AF, Silva C, Coelho JF, et al. Oral Films: Current Status and Future Perspectives: I - Galenical Development and Quality Attributes. J Control Release 2015;206:1–19.

68. Barbu E, Verestiuc L, Nevell TG, et al. Polymeric Materials for Ophthalmic Drug Delivery: Trends and Perspectives. J Mater Chem. 2006;16:3439–43.

69. Achouri D, Alhanout K, Piccerelle P, et al. Recent Advances in Ocular Drug Delivery. Drug Dev Ind Pharm. 2013;39:1599– 617.

70. Priyadharshini S, Dhivya B. Application of Nanoscience and Technology in Medicine-Nanomedicine. Res J Eng Tech. 2013;4(4): 300– 305.

Received on 08.03.2021 Modified on 08.06.2021

Research J. Pharm. and Tech. 2022; 15(5):2320-2326.

DOI: 10.52711/0974-360X.2022.00386