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Review

Polysaccharide-Based Transdermal Drug Delivery

1
Marine College, Shandong University, Weihai 264209, China
2
SDU-ANU Joint Science College, Shandong University, Weihai 264209, China
3
Weihai Changqing Ocean Science Technology Co., Ltd., Weihai 264209, China
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2022, 15(5), 602; https://doi.org/10.3390/ph15050602
Submission received: 14 April 2022 / Revised: 10 May 2022 / Accepted: 11 May 2022 / Published: 14 May 2022
(This article belongs to the Special Issue Polysaccharide-Based Nanoparticles for Theranostic Nanomedicine)

Abstract

:
Materials derived from natural plants and animals have great potential for transdermal drug delivery. Polysaccharides are widely derived from marine, herbal, and microbial sources. Compared with synthetic polymers, polysaccharides have the advantages of non-toxicity and biodegradability, ease of modification, biocompatibility, targeting, and antibacterial properties. Currently, polysaccharide-based transdermal drug delivery vehicles, such as hydrogel, film, microneedle (MN), and tissue scaffolds are being developed. The addition of polysaccharides allows these vehicles to exhibit better-swelling properties, mechanical strength, tensile strength, etc. Due to the stratum corneum’s resistance, the transdermal drug delivery system cannot deliver drugs as efficiently as desired. The charge and hydration of polysaccharides allow them to react with the skin and promote drug penetration. In addition, polysaccharide-based nanotechnology enhances drug utilization efficiency. Various diseases are currently treated by polysaccharide-based transdermal drug delivery devices and exhibit promising futures. The most current knowledge on these excellent materials will be thoroughly discussed by reviewing polysaccharide-based transdermal drug delivery strategies.

Graphical Abstract

1. Introduction

Transdermal drug delivery has many advantages over conventional administration, including avoiding the first-pass effect in the liver, reduced side effects, and improved patient compliance [1]. However, due to the “brick and mortar” structure of the stratum corneum, drugs cannot effectively cross the skin barrier. To surmount the cutaneous obstacle for more effective topical drug delivery, natural polymeric polysaccharides played an essential role in transdermal delivery as drug or drug delivery carriers and traditional methods such as ultrasound [2] and electrical conduction [3].
Compared with traditional carriers such as polylactic acid (PLA), poly (lactic-co-glycolic acid) (PLGA), and polyvinyl pyrrolidone (PVP), naturally derived polymeric polysaccharides performed well as drug delivery carriers with high water retention, non-toxicity, good biocompatibility, biodegradability, and many other critical biological properties. For example, chitosan (CS) has significant slow-release properties for drug delivery [4]; hyaluronic acid (HA) can increase skin hydration and involve cell signaling to promote tissue regeneration and wound healing [5]; sodium alginate could be applied for drug encapsulation by cross-linking with metal ions to prepare nanoparticles and therefore enhance skin penetration of drugs [6], etc. Further, the cross-linking or functional group modification of natural polysaccharides can change their surface properties, including hydrophilicity, hydrophobicity, mechanical strength, etc., and endow them with new functions. In addition, naturally derived polymeric polysaccharides have various pharmacological properties such as antitumor, anticoagulant, immunomodulatory, antioxidant, and anti-inflammatory. For example, Bletilla striata polysaccharides (BSP) have wound healing, anti-allergic, and antibacterial effects [7]; Panax notoginseng polysaccharides (PNPS) promote the activation of skin dendritic cells (DCs) [8]; and Centella asiatica polysaccharides have antibacterial and anti-inflammatory effects [9].
Polymeric polysaccharides play an influential role in treating scars, psoriasis, acne, and other skin diseases. There is an excellent potential for naturally derived polymeric polysaccharides in transdermal delivery, but a systematic summary is lacking. In this case, this review specifically presents the application of polysaccharides based on natural sources (plant, marine, microbial) as drug or drug delivery vehicles for transdermal delivery, including hydrogel, film, microneedle (MN), tissue scaffolds, and polysaccharide-based nanoparticles are developed for their targeting and good penetration ability. Diseases that require therapeutic measures, such as psoriasis, skin cancer, hypertrophic scars (HSs), etc., treated by polysaccharide-based transdermal drug delivery, are also discussed.

2. Polysaccharide

Polysaccharides have received increasing attention as an essential natural bioactive substance with the advantages of safety, stability, and biodegradability. They have demonstrated their unique gifts in antiviral, immunomodulatory, antioxidant, and other aspects [10,11]. In addition, the multifunctional group properties of polysaccharides make them susceptible to being modified and demonstrate more applications. Polysaccharides are broadly present in animals, plants, microorganisms, and algae. The following section will focus on several commonly used polysaccharides.

2.1. Herbal Polysaccharide

Herbal polysaccharides are explored to be medicines to treat various diseases due to their excellent performance in treating diabetes, hypertension, malaria, and other diseases [12,13,14]. However, traditional herbal medicines are mainly applied externally and administrated orally, limiting their therapeutic effects for these skin diseases. In this case, today, herbal medicines are investigated for transdermal drug delivery systems. Polysaccharides extracted from herbs are of increasing interest due to their extensive range of pharmacological applications, including acting on antitumor, immunomodulatory, antioxidant, and anti-inflammatory [15,16,17,18].

2.1.1. Bletilla Striata Polysaccharide

BSP is the main active ingredient of Bletilla striata, with a relative molecular mass size of 1.35 × 105 [19]. BSP was used as a cosmetic additive to treat cracked skin and promote skin recovery [20], which had the functions of promoting wound healing [21], anti-aging [22], and antibacterial qualities [23]. BSP was used to treat chapped skin and ulcerative carbuncle acknowledged by the human body and comparatively painless to satisfy the diverse requirements in pharmacology.

2.1.2. Panax Notoginseng Polysaccharide

PNPS is mainly found in saponin, the main active ingredient of Panax notoginseng. PNPS is obtained by grinding the plant and extracting it with ethanol, and a large amount of PNPS remains in the residue, accounting for about 3–5% of the extract. It is of great interest for various biological properties such as immunomodulatory, antitumor, antioxidant, anti-aging, and neuroprotective effects and has been used in the treatment of diseases [24,25].

2.1.3. G. lucidum Polysaccharides

Ganoderma lucidum, known as “Lingzhi”, is a renowned traditional Chinese herb with a history of more than 2000 years. G. lucidum polysaccharides (GLPs) are highly abundant in G. lucidum cells and are used for their anti-inflammatory [26], immunomodulatory [27], and antitumor qualities [28]. In addition, GLPs have been used in combination with doxorubicin (DOX) as an additive that enhances the effectiveness of medical treatment in cancer [29].

2.1.4. Others

BSP, PNPS, and GLPs, Plantaginis Semen polysaccharide (PSP), derived from the herb Plantaginis Semen, were combined with titanium dioxide nanoparticles as a new promising immune adjuvant to prevent infectious laryngotracheitis (ILT) [30]. Radix Hedysari polysaccharides (HPS), derived from Radix Hedysari, have been proved to have antitumor and antidiabetic effects [31]. Lycium barbarum polysaccharides (LBPs), obtained from Lycium barbarum L., have also been widely discussed for their anticancer effects [32]. The efficacy of more and more herbal polysaccharides is being discovered, providing good prospects for future drug therapy.

2.2. Marine Polysaccharide

Polysaccharides extracted from marine organisms have been extensively investigated over the last few years because they can be easily extracted from marine organisms and exhibit anti-inflammatory and antibacterial properties in drug delivery [33]. Moreover, marine polysaccharides show unique advantages in transdermal drug delivery owing to their good targeting and readiness to be modified.

2.2.1. Chitosan

CS is among the most broadly employed polymers in numerous biomedical applications and has seen increased research in recent years. It is derived from chitin and is available by partial deacetylation of chitin [34]. The molecular weight of CS is between 300 and 1000 kDa. CS is the only positively charged polysaccharide in natural polysaccharides, and protonated CS can cooperate with the negative charge of the stratum corneum to improve drug penetration. The hydroxyl groups at the C-3 and C-6 positions and amino groups at the C-2 position are easily modified and facilitate various reactions [35]. The modifiability of the functional groups leads to their ability to be tailored to the desired mechanical strength and functionality. Many pH-responsive compounds based on CS are extensively applied in transdermal drug delivery [36,37]. In addition, it is considered a potential antifungal drug because of its biocompatibility, biodegradability, non-toxicity, hemostatic activity, and antibacterial and antimycotic properties [38,39,40].

2.2.2. Hyaluronic Acid

HA is a linear glycosaminoglycan (GAG) consisting of N-acetyl-d-glucosamine and d-glucuronic acid. HA derived from rooster comb [41], microbial source [5]. HA was first isolated from the vitreous humor of bovine eyes. Studies suggest that HA may be the most widely used marine polymer in transdermal drug delivery systems [42]. HA is one of the essential components of human skin and is detected in extracellular tissues in different body parts [43,44]. HA has the properties of non-toxic, non-immunogenic, biocompatible, and high-water affinity [45]. HA is also used in various biomedical applications, such as cartilage regeneration [46], ophthalmology [47], and cancer therapy [48]. It could interact with the stratum corneum barrier to promote drug penetration. HA could also target CD44 fibroblasts, and cancer therapy with HA as a vehicle is evolving [49]. HA has been authorized by the Food and Drug Administration (FDA) as a dermal filler, showing great promise in drug delivery [50].

2.2.3. Alginate

Alginate is a natural, biodegradable anionic polysaccharide, and sodium alginate is the most commonly employed one. Alginate consists of different ratios of β-Dmannuronic acid (M-blocks) and α-l-guluronic acid (G-blocks). The mannuronic blocks/guluronic acid block (M/G) ratio predominantly affects the properties of alginate [51]. Alginate with a high M/G ratio can promote chronic wound healing by producing cytokine production through human monocytes [52]. In addition, alginate also binds to metal ions through electrostatic and ionic interactions. In transdermal drug delivery systems, alginate is mainly utilized to prepare MNs [53] and nanoparticles [54]. Alginate-based MNs were used to load vaccines and deliver macromolecules such as bovine serum proteins and insulin [55,56]. Alginate was combined with CS to prepare nanoparticles possessing anti-inflammatory activity and antibacterial for the targeted therapy of cutaneous pathogens [57].

2.2.4. Ulvan Polysaccharide

Ulvan polysaccharide is a biologically active natural sulfated polysaccharide with excellent properties such as antibacterial [58], antioxidant [59], antiviral [60], and hypolipidemic activity [61]. Ulvan polysaccharide mainly consists of rhamnose 3-sulfate, xylose-2-sulfate, and glucuronic acid, and is widely used as a raw material for the preparation of hydrogels [62]. Ulvan polysaccharide contains hydroxyl groups that can form hydrogen bonds, producing gel-like properties [63]. In the presence of boric acid and divalent cations, thermally reversible hydrogels can be formed [64]. Composite hydrogels prepared using ulvan polysaccharide and CS exhibited excellent cell proliferation [65].

2.3. Exopolysaccharide

EPSs are currently considered helpful in dealing with cancer, tumors, ulcers, etc. [66]. A fungal homopolymer, schizophyllan, produced by schizophyllum commune, has been used to treat cancer, demonstrating excellent therapeutic efficacy when present in the triple-helical form [67]. Xanthan gum (XG), produced by Xanthomonas campestre, is considered the most commercially available EPSs and has been prepared as hydrogels [68]. Notably, extreme environments tend to harbor specific microorganisms that secrete substances, which often have high temperature, alkali, and acid resistance in some respects. Proteins and microbial EPSs collected from these extremophiles are currently used industrially [69,70]. In this case, polysaccharides secreted by such microorganisms are to be expected.

3. Polysaccharide-Based Vehicles

Compared with traditional polymers, polysaccharides are biodegradable and non-toxic, making them widely employed in transdermal drug delivery. Polysaccharide-based transdermal drug delivery system is also evolving, as shown in Figure 1. For example, the polysaccharide-based hydrogel shows advantages in wound dressings due to their good swelling and high hydrophilia properties; the polysaccharide-based films enable continuous drug release due to their good elasticity and breathability; the polysaccharide-based MNs have good mechanical strength and can smoothly penetrate the skin stratum corneum, and the biodegradability of polysaccharides makes MNs more biocompatible; the polysaccharide-based tissue scaffolds show unique biomimetic potential due to its good biocompatibility. The polysaccharide-based transdermal drug delivery vehicles are discussed in detail in the following section.

3.1. Polysaccharide-Based Hydrogels

Hydrogels are three-dimensional, hydrophilic, and polymeric networks with the ability to absorb large quantities of water. Hydrogels have received heaps of attention as outstanding candidates for bioadhesion, controlled release, and targeted therapeutic agent devices in drug delivery systems. Hydrogels prepared from conventional materials such as hydroxyethyl methacrylate are not soluble for the existence of chemical cross-linking or physical cross-linking [71]. Polysaccharide-based hydrogels are soluble and have good water retention ability and antibacterial advantages. Highly absorbent hydrogel materials prepared by cross-linking carboxymethyl agarose (CMA) and polyacrylamide (PAm) can absorb an aqueous solution hundreds of times heavier than its weight [72]. The hydrogel of BSP combined with Carbopol 940 has good viscoelasticity and physical strength and can be used in wound dressing to promote plasma coagulation and facilitate wound healing [73,74]. Polysaccharide-based hydrogels are also adopted for the delivery of macromolecules. Polysaccharide transparent hydrogel patches were used to improve the permeability of proteins to the skin. Gold nanorods are placed on the surface of the HA-based hydrogel. The temperature of the skin was raised by irradiating the gold nanorods with a laser to promote protein penetration through the skin [75].
Some “smart” hydrogels are continuously researched for the controlled release of drugs according to changing external conditions. Common ones are pH/temperature-sensitive hydrogels. pH-sensitive hydrogels made from hydroxyethyl cellulose (HEC)/HA complex loaded with isoliquiritigenin (ILTG) were used to treat skin disorders caused by pH imbalance [76]. Hydrogels that can be regulated by pH and temperature have also been prepared. Pluronic F-127 based pH and temperature dual-responsive hydrogels prepared with nano-conjugate of HA and CS oligosaccharide lactate were loaded with gallic acid (GA) in treating atopic dermatitis [77]. The cost-effective and versatile dual dynamic cross-linking hydrogels have been studied to facilitate wound healing and prevent infection. The hydrogels composed of oxidized Bletilla striata polysaccharide (OBSP), GA-grafted CS, and pyrogallol-Fe3+, and Schiff base influenced its cross-linking form (Figure 2). The photothermal effect and polysaccharide combination enabled the hydrogels to degrade and accelerate the gelation on demand. The cross-linking of GA with Fe3+ made the hydrogel have good photothermal properties. The gelation time of the hydrogel under NIR radiation was 1/2–1/3 of that without radiation. The NIR irradiation made the temperature of the hydrogel rise, and by adjusting the irradiation time and IR intensity, the antibacterial activity can be satisfied without burning the skin. The photothermal effect also accelerated the degradation of the hydrogel. NIR radiation for 20 min allowed complete decomposition of the hydrogel in 2% acetic acid solution, providing a convenient way to observe the wound. The potential antibacterial activity of GA and Fe3+ and the increase in the number of CS naked amine groups allowed the hydrogel to exhibit good antibacterial effects. It created a long-lasting antibacterial environment that persisted to a large extent until wound healing, showing good promise in clinical practice [78].
To summarize, hydrogels corresponding to external stimuli are constantly developing and becoming smarter. They have good prospects in transdermal drug delivery in the future.

3.2. Polysaccharide-Based Films

Polymeric films have attracted interest as an alternative to patches because they are transparent, flexible, non-occlusive, and easy to administer while prolonging the drug retention time in the skin [79]. The films demonstrate greater drug loading and better drug release than ointment [80]. The film-forming ability of polysaccharides and their unique adhesion properties have attracted widespread attention. In this case, the polysaccharide-based films emerge as a candidate for transdermal drug delivery vehicles.
Films prepared with two or more polysaccharides tend to exhibit better properties. Nifedipine (NFD) polysaccharide-based transdermal films with sodium alginate and pectin as matrix polymers were developed to provide their long-term plasma concentrations [81]. CS-based films containing methyl salicylate (MS) nanoemulsions (NE) were prepared in some studies. NE-film demonstrated good MS release volume compared to the physical mixture (Figure 3). TGA and FTIR results confirmed that the encapsulation of MS into NE made the oily drugs fully integrated into the hydrophilic CS films, which increased the stability of the film [82]. Loading rifampicin into alginate and gelatin fiber-based film showed good wound healing effects [83].
New composite membrane formulations are also being investigated. Multilayer films by electrostatic interactions using alginate/CS/alginate-modified silica nanocapsules (SNCs) and CS biopolymers were prepared. They encapsulated Fulvestrant, a selective estrogen receptor downregulator, in SNC and then incorporated it into the film. The effectiveness of the film was releasing the drug influenced by the external pH. At pH 7.4, the film can entrap Fulvestrant well, while at pH 5.0, it releases the drug rapidly. The rate of drug release can be changed continuously according to the external pH change [84]. In the following study, HA and temperature-responsive micelles were used to prepare a sandwich-like membrane that utilized the protonation and deprotonation reactions of the micelle core for the controlled release of anticancer drugs osimertinib [85]. A layer-by-layer self-assembly method using sodium cellulose sulfate (NaCS), chitosan hydrochloride (CHC), and sodium tripolyphosphate (STPP) was used to prepare “sandwich structure” hydrogel film for loading ibuprofen (IBU). The results showed that the film penetrated the skin of mice with good controlled drug release [86]. Tri-layers prepared from sodium alginate and poly (4-vinyl pyridine) can be stabilized in an acidic buffer at pH 4.2 and used for skin wound healing under acidic conditions [87]. Ternary blend films of CS, polyethylene oxide (PEO), and levan prepared by the solution casting method demonstrated better biocompatibility than the CS-PEO binary films [88]. The weight ratio of different polysaccharides in films also affects the release of drugs [89].

3.3. Polysaccharide-Based Microneedles

MNs technology has attracted the attention of researchers as a minimally and efficient invasive way of drug delivery. Traditional MNs made from solids, such as silicon and metals, typically create microchannels on the skin surface where the drug enters, limiting the drug utilization [90]. Polysaccharides have the biodegradability advantage and are similar to the components of the extracellular matrix [91]. In this case, soluble MNs with polysaccharides as raw materials are continuously studied and used to enhance MN biocompatibility and improve patient compliance. The recent examples of polysaccharide-based MNs are listed in Table 1, including the basic components, pharmaceutical ingredients, and applications.
Some natural polysaccharides such as HA [92], carboxymethyl cellulose [93], alginate, maltose, and CS [94] are widely used to prepare soluble MNs. Calcium ion cross-linking alginate/maltose composite MNs loaded with insulin had a significant hypoglycemic effect compared with traditional transdermal injection [56]. Bacillus Calmette–Guérin polysaccharide nucleic acid MN patches (BCG-PSN MNP) were prepared by incorporating the ribonucleic acid fraction of the BCG vaccine into a sodium hyaluronate (HNA) based MN patch and were used for immunotherapeutic treatment. The BCG-PSN MNP exhibited increased IFN-c and TNF-a production in peripheral blood CD4+T cells [95].
Most herbal medicines have the inherent properties of promoting wound healing, and antiseptic and anti-inflammatory properties. Combined with this feature, MNs based on herbal polysaccharides have been continuously investigated in recent years. In 2018, BSP was used for the first time in the preparation of MNs [96], and BSP MN (BMN) containing Rhodamine B (RB) demonstrated good mechanical strength and a desirable cumulative penetration rate. Subsequently, BMN was used to deliver vaccines (Figure 4). The process of preparing MNs has two steps. First, the OVA/BSP solution is poured into the mold and centrifuged to form the MN tip, and then the remaining solution is removed. The BSP solution (15% w/v) was poured, centrifuged, and dried to form the BMN substrate. The BSP in the tip gave the BMN a mechanical strength of 0.63 N/needle and enabled it to penetrate the stratum corneum. The BSP in the substrate relied on its specific anti-inflammatory and antibacterial activity to promote the healing of the microchannels caused by the BMN. BMN was cytocompatible, less irritating to the skin, promoted cell growth to a certain extent, and had good low hygroscopicity. The OVA of 76.74% was released within three hours, and BMN loaded with antigen ovalbumin (OVA) maintained an intact secondary structure within 21 days [97].
Table 1. Some latest polysaccharide-based MNs.
Table 1. Some latest polysaccharide-based MNs.
CompositionPharmaceutical
Active Ingredient
ApplicationMain AchievementRef.
BSPOVAInfectious diseasesBetter mechanical strength and stability than HA-MNs and PVA-MNs, well-reserved OVA at 4 °C for 21 days[97]
CD-MOF,
QUE, BSP
HSF membraneHypertrophic ScarsThe combination of bio nanoparticles and soluble MNs inhibited collagens I and III expressions[98]
BSPRBDrug deliveryThe transdermal effect was more effective than the patch, had better mechanical strength, and promoted wound healing[96]
PNPSDox, 5-FuSkin dendritic cell
activation
It targeted skin dendritic cells, activated immune cells, and triggered T cell immune response mediated by DCs[99]
DCSDCSHemostasisPagoda-like shape, the insect-foot-inspired multilayer structure helped MNs adhere to the bleeding area[100]
CSmeloxicamPain management
for cattle
Indicated for pain control in cattle after routine surgery[101]
CSInsulin in a macroporous
alumina core
Diabetes mellitusThe dissolution of the gel Intelligent controlled the release of insulin according to in vivo glucose level, and kept normoglycemia stable for 5 h[102]
CSMg, PNSChronic woundsIt promoted neovascularization in chronic wounds and regulated macrophage phenotype conversion to reduce inflammation[103]
HA, PVPPropranolol
Hydrochloride
IHAbout 100% propranolol hydrochloride was released in 20 min[104]
HA, CuS
into ZIF-8
CPTMelanomaAchieve long-lasting enrichment at the tumor site, and the scab disappeared within 7–10 days[105]
HAShikoninHSsHA MNs markedly reduced the proliferation and viability of HSF and downregulated fibrotic-related genes such as TGF-β1, FAP-α, and COL1A1[106]
HAMXDAlopeciaHA and MXD had a synergistic effect in treating alopecia, which maximized the effectiveness of the treatment and minimized the side effects of MXD for alopecia[107]
Alg-ABA, chondroitin sulfateMineralized insulin particles, GODDiabetes mellitusThe H+ produced by the reaction of GOD with glucose gradually dissolved mineralized insulin particles, leading to the self-adjustable release of insulin[108]
UlvanFITC-BSA, R6GDrug deliveryEnhance the cumulative release of FITC-BSA and biocompatibility, and it dissolved in only 2 min in porcine skin[109]
BSP: Bletilla striata polysaccharide; OVA: Ovalbumin; CD-MOF: The cyclodextrin metal-organic framework; QUE: Quercetin; HSF: Hypertrophic scar fibroblast; RB: Rhodamine B; PNPS: Panax notoginseng polysaccharide; DOX: Doxorubicin; 5-Fu: 5-fluorouracil; DCS: Dodecyl-modified chitosan; CS: Chitosan; PNS: Panax notoginseng saponins; HA: Hyaluronic acid; PVP: Polyvinyl pyrrolidone; PVA: Polyvinyl alcohol; IH: Infantile hemangioma; ZIF-8: Zeolitic imidazolate framework-8; CPT: Camptothecin; HSs: Hypertrophic scars; MXD: Minoxidil; Alg-ABA: 3-amino-phenylboronic acid-modified alginate; GOD: Glucose oxidase; FITC-BSA: Bovine serum albumin–fluorescein isothiocyanate conjugate; R6G: Rhodamine 6G.

3.4. Polysaccharide-Based Tissue Scaffolds

Polysaccharides have been widely used for tissue scaffolds due to their good biocompatibility and biodegradability [110]. In bone tissue engineering field, different polysaccharides exhibit different excellent properties. CS can promote the attachment, proliferation, and mineralization of osteoblasts in vitro and activate endogenous bone regeneration [111,112]; cross-linking modified HA can increase the porosity to meet different strengths of bone tissue scaffolds, HA-based scaffolds show a synergistic effect with stem cells in tissue engineering [113], alginate is more suitable for cell attachment by modification of chemical bonds [114], and XG also shows a unique bionic potential in bone tissue engineering applications [115]. Nano hydroxyapatite particles (nHAP) modulate the biomineralization process of inorganic nanoparticles inside bone by functionalizing CS with a graphene oxide (GO) network matrix, which crystallizes in situ into a graphene oxide/chitosan/nHAP (GO/CS/nHAP) scaffold. The scaffolds exhibit good cell proliferation capacity and bioactivity and are considered an approach for endogenous bone repair [112].
Polysaccharides allow scaffolds to exhibit better performance and provide a good framework for drug release. Hydrogels are widely used as scaffolds for tissue engineering. Composite scaffolds prepared from alginate-based hydrogels and gelatin-based electrospun mats exhibited better mechanical strength and controlled drug release [114]. Epigallocatechin-3-gallate (EGCG) has the ability to enhance the differentiation of mesenchymal stem cells (MSCs) into osteoblasts, and pour EGCG is easily metabolized by cells and reduces bioavailability. EGCG-loaded CS nanoparticles were encapsulated into CS/alginate (CS/Alg) scaffolds (CS/Alg-ECN) to improve the utilization of EGCG. CS/Alg-ECN can activate the Wnt/β-catenin signaling pathway to promote the differentiation of osteoblasts [116]. Hydrogels made from combinations of different ratios of polysaccharides can be used as a base material for skin scaffolds and show efficient osteoinduction [117,118].

4. Polysaccharide-Based Penetration

The barrier effect of the stratum corneum is the key problem faced by transdermal drug delivery, and how to enhance drug penetration is the main obstacle that affects the development of transdermal drug delivery. Physical methods have been used to enhance drug penetration, but their effectiveness is limited and may lead to skin damage; in addition, physical methods often require additional equipment, resulting in poor patient compliance. Polysaccharides exhibit unique advantages in promoting drug penetration, such as charge effect, and hydration effect. Both polysaccharide permeation enhancers and polysaccharide-related nanotechnology have promoted drug penetration.

4.1. Penetration Enhancers

The primary problem faced by transdermal drug delivery is the stratum corneum barrier. In addition to physical penetration methods such as ultrasound, temperature, electricity, and magnetic fields [119], chemical penetration enhancers are also used to promote drug penetration into the stratum corneum, such as fatty alcohols and fatty acids [120]. Chemical penetration enhancers display some skin irritation, possibly leading to the development of inflammation and erythema [121,122]. In this case, polysaccharide-based penetration enhancers are continuously used in transdermal drug delivery systems. CS, the only positively charged polysaccharide among natural polysaccharides, is bound tightly to the negatively charged sites on the epithelial cell membrane. Its positive charge leads to the depolymerization of F-actin and the dissolution of the tight junction protein ZO-1, thereby promoting penetration [123]. HA improves the hydration of the stratum corneum, promoting penetration [124]. The high moisturizing properties of XG promote the drug’s hair follicle penetration [125]. The mucilage polysaccharide extracted from Hibiscus rosa–Sinensis L. forms non-covalent bonds with skin tissues, affecting drug penetration [126]. Thiolated CS opens tight junctions through interaction with the thiol groups of cysteine-containing membrane receptors [127].

4.2. Polysaccharide-Based Nanoparticles

Nanotechnology mainly refers to controlling the particle size of the drug at the nanoscale, which has the advantages of improving drug solubility and stability and enhancing the curative efficacy [128]. Based on the advantages of polysaccharides’ natural targeting, hydration function, and charge interaction with the skin, polysaccharide-based nanoparticles show a better prospect than ordinary nanoparticles. A diversity of methods using nanotechnologies has been investigated to optimize the efficiency of transdermal drug delivery, and several currently used methods are described below.

4.2.1. Emulsion

The polysaccharide-based emulsion is a thermodynamically stable colloidal system composed of the oil phase and water phase and stabilized by surfactants or cosurfactants. The pro-permeation effect of NE was used to deliver a hypoglycemic drug, Glimepiride (GMP). The NE was prepared from clove oil, Tween-80, and PEG-400, gelated with XG. It improved skin permeability and hypoglycemic activity, providing a new option for the treatment of diabetes (Figure 5) [129]. The ratio of polymer to surfactant has been proved to influence the permeation effect. Researchers prepared a microemulsion of HA and collagen and found that the molecular weight of collagen and HA did not affect the delivery efficiency [130].
Some polysaccharides with natural pharmacological activity are combined with NE to load drugs. The antifungal properties of CS were combined with the antifungal drug Fluconazole (FZ), essential oils, and sucrose fatty acid esters to prepare gel microemulsions for the treatment of mycoses [131]. CS emulsions loaded with 5-fluorouracil (5-FU) are considered a promising method for delivering 5-FU. CS facilitates the movement of 5-FU through the stratum corneum by altering the arrangement of phospholipids in the epithelial cell membrane [132]. Pickering emulsions stabilized by CS/collagen peptides nanoparticles were penetrated into the deeper stratum corneum due to the interaction of protonated CS with the negatively charged sites of the stratum corneum [133]. NE containing HNA and indomethacin (Ind) demonstrated better skin penetration and drug deposition than the HNA-Ind solution. In addition, it had an anti-inflammatory effect on ear edema in mice to a certain extent [134].

4.2.2. Ethosomes

Similar to liposomes, ethosomes (ES) have a phospholipid bilayer. In addition, ES have unique properties such as high deformability and fluidity due to their relatively high concentration of ethanol (20–45%) [135,136,137], exhibiting a better effect in promoting penetration than traditional liposomes [138]. However, the promotion of permeation also leads to the problem of easy drug leakage. In this case, polysaccharides are chosen to combine with ES to enhance the stability of the formulation.
Polysaccharides are used to modify ES to improve their susceptibility to drug leakage. HA-modified ES (HA-ES) formed a hydrogel network on the surface of ES to reduce drug leakage, and HA-ES loaded with eugenol (EUG), and cinnamaldehyde ([EUG/CAH]) (volatile oil medicines) demonstrated better encapsulation ability and better stability compared to ES. Pharmacokinetics showed that EUG and cinnamic acid (CA) concentrations in subcutaneous tissues were considerably higher in the HA-ES group than in the ES group. In addition, the moisturizing ability of HA enhanced the hydration of the stratum corneum and facilitated transdermal drug delivery [139]. HA/ES-aminolevulinic acid (ALA) (HA/ES-ALA) with a synergistic effect was prepared by combining HA gels and ES of 5-ALA (ES-ALA). HA/ES-ALA protected ES-ALA during permeation, then HA/ES-ALA actively aggregated on the hypertrophic scar fibroblast (HSF) surface using HA receptors to release ES-ALA, and finally, ES-ALA on the surface of HSF delivered ALA into HSF through the membrane fusion mechanism [140]. HA was combined with glycol-based ES to prepare a drug carrier, HA-ES, to transport curcumin (Figure 6). The HA gel network on the surface reduced curcumin leakage, and its eight-hour cumulative transdermal volume was 1.6 times higher than that of ES. Due to the specific targeting of HA-ES on CD44 exhibited higher intradermal drug accumulation, and the levels of TNF-α, IL-17A mRNA, and CCR-6 protein were also reduced [141].

4.2.3. Lipid Nanoparticles

Lipid nanoparticles (LNPs) consist of a monolayer of surfactants with a lipophilic nucleus, which is different from liposomes. At present, there are three types of LNP used for drug delivery: lipid nano-emulsions (LNE), solid lipid nanoparticles (SLN), and nano-lipid carriers (NLC). They can enhance drug permeability and have a good retention effect [142]. Bilosomes (BLS) are novel lipid nanocarriers composed mainly of amphiphilic bile salts (ABS). CS-modified bilosomes containing terbutaline sulfate (TBN) exhibited good encapsulation efficiency, with an approximately 2.33-fold increase in bioavailability compared to oral solutions [143]. However, the LNP aqueous dispersions exhibit unsuitable rheological properties. In this case, some studies combined LNP with other substances to modify this property, such as LNP-hydrogel systems. Lipophilic drugs can be efficiently loaded into the LNP, encapsulating LNP in a hydrogel network [144].
XG was added to the LNP-poloxamer hydrogel to enhance the mucoadhesive properties during the synthesis of poloxamers [145]. CS-LNPs loaded with IBU were packed into the hydrogel for the transdermal delivery of IBU. CS interacted with negatively charged IBU to form drug-polymer complexes, and in addition, the bioadhesive nature of CS improved the residence time of IBU at the application site [146]. This form of double encapsulation strategy provides better control of drug release. Although the LNP-hydrogel system shows great promise, the mechanism of drug release needs to be further investigated.

4.2.4. Nanoassemblies

Due to the potential applications of nanoscale polymer in the biomedical field, many efforts have been committed to designing nanoscale polymer assemblies. The currently commonly used self-assembly method of amphiphilic copolymers usually leads to the ability of core/shell nanostructures to carry dipolar drugs in their dipolar cores [147].
Self-assembled polysaccharide-based nanoassemblies were prepared using N-alkylaminated chitosan (NACs) to deliver the anti-inflammatory drug Voltaren. The modified NACs had amphiphilic characteristics and could voluntarily assemble into nanoaggregates at particular concentrations because of the added hydrophobic aliphatic side chains of CS. The capacity of NACs to load diclofenac under a lipid environment was verified by adding almost insoluble diclofenac into paraffin oil. The solubility of diclofenac in an aqueous solution was improved by NACs [148]. Negatively charged lecithin and positively charged CS interacted electrostatically to form nanoparticles for coating drugs and achieve self-assembly at the supramolecular level forming lecithin-CS hybrid nanoparticles, thereby enhancing drug penetration to treat psoriasis. The positive charge on the surface of CS increased the deposition of nanoparticles in the skin. Compared to commercially available products, lecithin-CS hybrid nanoparticles showed faster control of psoriasis [149]. Lecithin/CS nanoparticles (LCNs) were also used to load baicalein-phospholipid complexes to form BPC-LCNs. Phospholipids combined with baicalein to form a complex and enhance the solubility of baicalein, which is encapsulated into lecithin/CS nanoparticles to enhance skin penetration [150]. Polyunsaturated fatty acids (PUFAs) and the photosensitizer chlorin e6 (Ce6) were self-assembled into nanoassemblies to prepare L-Ce6 NAs and incorporated into fast-dissolving oligo-HA MN patches to prepare L-Ce6 MNs. Combining the tumor-targeting function of HA with photodynamic therapy (PDT) allowed L-Ce6 MNs loaded with very low doses of photosensitizers to show promising results in melanoma treatment [151].

4.2.5. Omniphilic Nanocarriers

The main problem with drug delivery is that it is often necessary to transfer from one phase to another, such as the transfer between the aqueous phase and lipid phase. This situation would affect the delivery of medications. Therefore, researchers were investigating if it is possible to develop a nanoparticle carrier that can deliver drugs in different phases without affecting too many properties of the drug. In this case, the concept of the omniphilic nanocarrier was proposed. These nanocarriers are named “omniphilic”, meaning “like everything”, to illustrate their ability to accommodate all kinds of molecules and adapt to solvent environments.
Nanocarriers based on the biopolymer CS encapsulate both hydrophilic and hydrophobic drugs and convey them into lipid or aqueous environments. The results exhibited that omniphilic polysaccharide-based nanocarriers (OPNs) showed excellent self-regulation ability in media with different polarities and successfully encapsulated different guest molecules in lipid or water environments, making it possible to cross the barriers between different phases. In addition, OPNs exhibited structural plasticity and adaptiveness, which allowed them to actively load drugs and achieve cross-phase transport. Based on the advantages of OPNs, for fields where nanoparticles can be used, such as the cosmetic industry, agriculture, and transdermal delivery of drugs, the combination of OPNs allows for a better performance of delivering drug molecules to the site of action and improved drug utilization [152].

5. Polysaccharide Based Drug Delivery for Diseases Therapeutics

Transdermal drug delivery systems allow a controlled release rate of drugs [153], and they have prospective applications in personalized medicine, matching each patient to the most appropriate medical regimen [154]. Polysaccharides are natural polymers with targeting, modifiable, inherent antibacterial, antioxidant, and other properties. These properties make them desirable compounds for biomedical applications. When drug delivery systems are modified by polysaccharides, receptors on target cells trigger phagocytosis, producing active targeting effects [155]. Polysaccharide-based transdermal drug delivery systems are now widely used in the medical field and in combination with other drugs to address therapeutic diseases, such as immunotherapy [156], diabetes [56], psoriasis [157], etc. They are described in more detail in the following sections.

5.1. Vaccination

Polysaccharides were used in vaccine development fifty or sixty years ago, and the capsular polysaccharide vaccine was used to prepare of anti-streptococcus pneumoniae at that time. It has become common sense to construct polysaccharide-based antimicrobial vaccines and commercialize several polysaccharide-based vaccines. For example, Ac Vax®, Pneumovaxll®, and Typhim Vi® were respectively formulated against Neiseria meningitidis, Streptococcus pneumoniae, and Salmonella typhi [158,159]. In order to overcome poor immunogenicity, polysaccharides were coupled to immunogenic protein carriers and acted as part of the vaccine formulation [160]. The immunogenicity of the conjugated polysaccharide vaccine was related to the length of the polysaccharide, and the length of the Vi polysaccharide has a direct effect on the secretion of anti-Vi lgG [161]. In addition, polysaccharides with unique properties are also used in the vaccine field. For example, trimethyl chitosan, a derivative of CS, was regarded as an adjuvant for vaccine delivery owing to its advantages of high aqueous solubility and high charge density [162].
CS MNs were used as intradermal delivery tools for vaccination (Figure 7). CS MNs have good mechanical strength, and the entire needle tip could reach the deep dermis. In addition to providing good mechanical strength, CS acts as an adjuvant to facilitate antigen uptake and presentation [163]. A composite MN with HA tip and CS base has also been used for long-lasting vaccine release. The fast release of antigen from the HA tip upon entry into the skin and the slow release of antigen from CS enhances the immunogenicity of the antigen. It produces a stable level of lgG antibodies for at least 16 weeks [164]. The dry-coated MN vaccine formulations reduce the demand for expensive cold-chain processes and facilitate the transmission of vaccines to rural areas [165].

5.2. Wound Healing

Wound healing is a sophisticated process, encompassing inflammatory, proliferative, and remodeling phases, involving good interactions between complex tissues and cells [166]. Polysaccharides exhibit unique advantages in promoting wound healing. In the early stages of inflammation, BSP stimulates the accumulation of inflammatory factors and exerts a healing effect on the wound. BSP could activate the expression of pro-inflammatory cytokines in M2 macrophages [167]. A BSP of 80 μg/mL induces human umbilical vascular endothelial cell proliferation and enhances VEGF and EGF expression [168]. CS could increase the level of anti-inflammatory factors (IL-10, TGF-β1) and decrease the level of pro-inflammatory factors [169]. Alginate could cause cytokine to arise produced by human monocytes, which facilitates tissue repair and promotes chronic wound healing [170].
Polysaccharides also act as delivery vehicles for active drugs to promote wound healing. Maltose MNs loaded with myrsinoside B exhibited good antioxidant and anti-inflammatory effects [171]. HA MNs loaded with green tea extraction (tea polyphenols) showed good antibacterial activity against Gram-positive and Gram-negative bacteria [172]. Pectin-rich Premna microphylla and Asiatic acid (AA), an extract of CentellaaAsiatica, have the abilities of anti-bacterial activity, and were utilized together to prepare the Chinese herb MN (CHMN) (Figure 8). The CHMN showed a better wound healing effect. Due to the good repair capacity of AA, the thickness of regenerated granulation tissue was up to 0.96 ± 0.12 mm, becoming the highest in the three experimental groups. CHMN significantly promoted the formation of new blood vessels and collagen in the wound [21].

5.3. Hypertrophic Scars

HSs are mainly due to the excessive collagen deposition of dermal fibroblasts, which often occur after wound healing. Shikonin, an active component extracted from Arnebiae Radix, was added to MN, which was made from soluble HA. Shikonin HA-MN was used to treat HSs. The results showed that Shikonin HA-MN had local therapeutic effects and was beneficial for local scar treatment in clinical practice. In addition, Shikonin HA-MN inhibited the expression of scar-related genes (TGF-β1, FAP-α, and COL1A1), providing a new approach to treating HSs [106]. Soluble HA MNs loaded bleomycin were also used to treat HSs [173]. Hydroxypropyl β-cyclodextrin (HP-β-CD) encapsulated with triamcinolone acetonide (TA) was co-loaded with verapamil (VRP) into carboxymethyl chitosan (CMCH), and BSP based MNs. The MN decreased the expression of the transforming growth factor-beta 1 (TGF-β1) and hydroxyproline (HYP) in HSs. The combination of TA and VRP showed a synergistic effect on the treatment of HSs [174].
The MN-mediated biomimetic transdermal system shown in Figure 9 was designed with a cyclodextrin metal-organic framework cross-linking with diphenyl carbonate (CDF). Quercetin (QUE) was loaded into the cyclodextrin metal-organic framework (CD-MOF) to prepare QUE-loaded CDF (QUE@CDF) and then coated with an HSF membrane (QUE@HSF/CDF). Then, QUE@HSF/CDF was dispersed in BSP-based MN to achieve targeted delivery. BSP showed synergistic effects, and the mechanical strength was superior to HA-based MN. This system reduced the expression of collagens I and III in HSs to improve the treatment efficacy of HSs, and MNs prepared in this way had better mechanical strength than HA-based MNs [98].

5.4. Psoriasis

Psoriasis is a chronic degenerative inflammatory disease with multiple signs caused by a mixture of genetic and environmental factors [175]. There are many therapies available for psoriasis. Methotrexate (MTX) is the most commonly adopted drug for psoriasis treatment. Side effects such as stomatitis and gastrointestinal discomfort may occur when MTX is administered orally or through the parenteral route. The high molecular weight and hydrophilic nature of MTX make it less effective in passively diffusing through the stratum corneum. To overcome this problem, the MTX-HA MN was prepared. The good hydration ability of HA allows MTX to stay in the epidermis and reduces penetration into the deeper skin [176]. The overexpression of CD44 protein in psoriatic skin is used as a potential target to treat psoriasis. CS/HA nanogels loaded with MTX and ALA (MTX-ALA NGs) exhibited good synergistic therapeutic effects (Figure 10).
On the one hand, CS and HA enabled the nanogels to have cellular uptake enhancement and targeting ability for psoriasis. On the other hand, the nanogels exhibited characteristics shared by nanoparticles and hydrogels, enhanced drug penetration, and high loading capacity. MTX-ALA NGs effectively downregulated the pro-inflammatory cytokines of IL-17A and TNF-α, reduced the side effects of oral MXT, and enhanced MXT and ALA penetration and deposition in the skin [177]. CS nanoparticles loaded with tacrolimus utilized the positive charge of CS to combine with the negative charge sites of the skin, enhancing the deposition rate of tacrolimus in the skin, with 82.0% ± 0.6 of the drugs retained in the skin. Its therapeutic efficacy is superior to commercially available tacrolimus® ointment [157].

5.5. Skin dendritic Cell Activation

Immune effector DCs are important antigen-presenting cells (APC) that are associated with adaptive and innate immunity and target cancer immunotherapy and vaccine adjuvants [178]. Mature DCs are the only cells that can directly communicate with T cells and trigger their proliferation to generate cellular immunity. The skin contains quantities of epidermal DCs, which recognize and deliver antigens to lymph nodes, thereby triggering a response. Skin DCs activation is of great immunological importance. PNPS, isolated from the traditional Chinese herb Panax notoginseng, significantly induces the maturation of bone-marrow-derived DCs (BMDCs). The PNPS MN was prepared for delivery of PNPS (Figure 11). PNPS MNs could easily cross the stratum corneum and diffuse to the depth of 450 µm, allowing good targeting of skin DCs. In addition, PNPS with biological activity could identify and target skin DC through Toll-like receptor 2 (TLR2)/Toll-like receptor 4 (TLR4) and trigger the maturation of DC. Administration via PNPS MNs demonstrated a higher ratio of CD11c+/FTSC+ DCs cells, 7 and 2.5 times that of PNPS solutions and dextran MNs [99].

5.6. Insulin

Insulin is the most powerful drug for regulating the level of blood glucose in patients with type I diabetes. However, the transdermal route has become the favored insulin administration due to the low absorption or enzymatic degradation of insulin in the liver. Usually, insulin is administered through a transdermal needle, but this is painful and inconvenient, often causing poor patient compliance [179]. Therefore, polysaccharide-based MN systems have been used to deliver insulin, such as HA [180], alginate [181], and maltose [56]. Insulin MN patches prepared from gelatin and starch have sufficient mechanical strength and dissolve completely after five minutes of insertion into the skin [179]. Pullulan polysaccharide (PL), a non-ionic natural occurring exopolysaccharide produced by yeasts, was adopted to prepare PL microneedle (PLMN) for insulin delivery. It can be stored at 4, 20, and 40 °C for at least one month to ensure insulin activity, which enables insulin to be preserved for a long time and is of great significance for the use of insulin in remote areas [182].
In addition to enhancing insulin preservation time in vitro, smart insulin MN patches are also being developed. An MN patch that allowed visualization and quantification of blood glucose and self-regulation of insulin release was investigated (Figure 12). MNs were prepared by cross-linking chondroitin sulfate and 3-aminophenyl boronic acid (ABA)-modified sodium alginate, loaded with mineralized glucose oxidized (GOD) and insulin particles. H+ produced by the catalytic reaction of GOD with glucose progressively dissolved mineralized insulin particles, leading to the self-regulated release of insulin. The increasing level of H2O2 resulted in a visible color change, which allowed for a reading of the glucose content changes [108]. The dynamically capped hierarchically porous MNs, which utilized the dissolution of CS hydrogels, allowed for the intelligent release of insulin [102]. Smart MN patches offer a new perspective in the self-adjustable insulin release field. To prevent hypoglycemia caused by the overuse of insulin, methacrylate hyaluronic acid (MeHA)-based smart insulin MNs were used to automatically deliver glucagon at low glucose concentrations. This smart MN patch shifts the treatment of hypoglycemia from emergency treatment to a preventive measure, enhancing patient safety [183].

5.7. Immunotherapy

Transdermal immunotherapy exhibits better results than oral administration and injection due to a large number of APCs in the skin. Polysaccharides have certain specific target cells that show unique advantages in immunotherapy. The main mechanism by which polysaccharides perform immunomodulation is usually considered to be through activation of the body’s immune response [184]. Polysaccharides could activate immune cells such as T lymphocytes and macrophages to exert immune activity [185]. HA with galactosylated chitosan (GC) modified ES (Eth-HA-GC) was loaded on silk fibroin (SF) nanofiber mats (Eth HA-GC/SF) to perform transdermal immunization (Figure 13). Galactosyl is thought to be able to target DCs [186]. Eth-HA-GC/SF can target and induce DCs maturation. Eth-HA-GC/SF loaded with OVA can increase the expression of marker molecules (CD80, CD86) associated with DCs maturation in BMDCs and improve the expression of IFN-γ and IL-6 in spleen cells. Eth-HA-GC/SF is considered to have the good immunotherapeutic potential [187]. Chemically modified polysaccharides often exhibit immunomodulatory capabilities. Sulfated polysaccharides can promote interleukin secretion by macrophages [188], acetylated polysaccharides can enhance antioxidant properties [189], and carboxymethylated polysaccharides can enhance the ability to induce maturation of DCs [190]. In general, polysaccharides show promising potential in immunotherapy.

5.8. Skin Cancer

Malignant melanoma is a fatal type of skin cancer. To reduce the side effects caused by the systemic application of anticancer drugs, polysaccharide-based transdermal drug delivery systems provide a new tactic for the effective treatment of skin cancer. Astragalus polysaccharide was shown to treat melanoma by inducing programmed death-ligand 1 (PD-L1) downregulation [191]. DOX, an anthracycline drug, has been successfully used to treat several cancers. Carboxymethylcellulose (CMC), a cellulose polysaccharide derivative, formed nanocomplexes with DOX. The electrostatic interactions stabilized the anionic carboxylate group of CMCs and the cationic amino group of DOX. The degree of substitution of CMC was shown to influence the DOX release. The CMC-DOX nanocomplexes with citric acid hydrogels could control the drug release [192]. A multifunctional nanoparticle-integrated soluble MN, called CPT-CuS-ZIF-8@HA@MN, was prepared for the treatment of malignant melanoma (Figure 14). Nanoparticles were prepared by adding a photothermal agent (CuS) to Zeolitic imidazolate framework-8 functionalized (ZIF-8) by HA. ZIF-8, a promising drug carrier for tumor therapy, could be modified to enhance active targeting capability [193]. HA itself could target CD44, and ZIF-8, modified by HA, could specifically gift down cellular uptake to enhance therapeutic efficacy. The MNs could be loaded with multiple drugs simultaneously, improving the specificity of targeting tumors and overcoming the limitation of monotherapy [105].

5.9. Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects the joints. Polysaccharides and polysaccharides-based nanoparticles have been widely researched in RA treatment [194]. Dendrobium huoshanense stem polysaccharide treats RA by inhibiting inflammatory signaling pathways [195]. Berberine encapsulated in CS, a surface-modified bilosome nanogel (BER-CTS-BLS), was used for the treatment of RA. BER-CTS-BLS has a size of 202.3 nm and has high drug encapsulation and good stability. The positive charge and bioadhesive properties of BER-CTS-BLS allowed the permeability coefficient of BER-CTS-BLS to be 1.5 times higher than that of BER solution, achieving better drug diffusion. BER-CTS-BLS gel significantly decreased the swelling percentage of rat paw edema after 12 h, providing a new therapeutic approach for the treatment of RA [196]. Cationic starch and poly (vinyl alcohol) (PVA)-based films loaded with MTX were used for the treatment of RA, avoiding the intestinal side effects caused by MTX. The films demonstrated good drug distribution and drug loading ability (>68.4%) [197].
Acid-responsive nanoparticles could enhance the transdermal treatment of RA. PEGylated star-shaped PLGA, hybridized by the calcium carbonate, formed nanoparticles [6 s-NPs (CaCO3)], which increase the loading of tetrandrine (Tet). Peach gum polysaccharides (GPs) secreted from peach trees exhibit good antioxidant and antibacterial activities. The [6s-NPs (CaCO3)] were loaded into MN prepared from GPs (GP-MN). GP-MN exhibited good transdermal effects and better mechanical strength than HA-MN (Figure 15). This delivery method increases Tet’s synovial uptake and improves the regulation of the VEGF, JAK2/p-JAK2, and STAT3/p-STAT3 pathways [198].

5.10. Others

In addition to the aforementioned disease treatment, polysaccharides are extensively employed in treating various illnesses for their distinctive advantages. Pectin-based silver nanocomposite films loaded with donepezil were used to treat Alzheimer’s disease, where nanosilver and pectin were compounded to improve the absorption and release of the drug, exhibiting good antibacterial properties [199]. Sodium carboxymethylcellulose (SCMC)-based MNs loaded with calcitonin gene-related peptide (CGRP), a neuropeptide released from sensory nerve terminals, were used as a safe and convenient way to treat neuropathic pain [200]. Trimethyl CS/sodium alginate multilayer nanomembranes encapsulating pentoxifylline (PTX) were used as a new modality to treat chronic venous ulceration [201]. In terms of disease treatment, polysaccharide-based transdermal drug delivery demonstrates its unique advantages and provides a new approach to disease treatment.

6. Conclusions

Polysaccharides, as natural polymers, have been extensively employed in transdermal drug delivery systems. Polysaccharides derived from herbal, marine, and microbial sources show unique advantages, such as antibacterial, biodegradable, anti-inflammatory, antioxidant, and non-toxic. On top of reducing gastrointestinal side effects, avoiding hepatic first-pass metabolism, and improving patient compliance, polysaccharide-based transdermal drug delivery systems show improved drug targeting, safety, and biocompatibility.
Polysaccharide-based vehicles also demonstrate better properties than traditional polymers, including (1) better hydrophilicity and swelling properties, stimulus-responsive hydrogel shows better therapeutic results; (2) better tensile strength, and polysaccharide-based composite films exhibit better biocompatibility and drug synergy effects; (3) enhanced mechanical strength and controlled drugs release by cross-linking and modification of polysaccharides-based MNs; (4) reduce the hindrance of the “brick and mortar” structure of the stratum corneum by hydration and charge effects and therefore improve the drug penetration efficiency. In addition, polysaccharide-based nanoparticles have shown advantages in the treatment of diseases, including (1) natural targeting ability. They can be used to target specific receptors and deliver drugs to the treatment site ((2) improve penetration ability). They act as a carrier to help deliver drugs to the site of action, improving the utilization of the drug ((3) natural pharmaceutical activity). Some polysaccharides exhibit natural an-bacterial and anti-inflammatory ability in the treatment of skin diseases; ((4) better patient compliance). Polysaccharides are biodegradable, which greatly improves patient compliance.
It Is foreseeable that polysaccharides-based transdermal drug delivery systems will become a promising way to deliver drugs. They are combining with nanotechnology to prepare “smart” formulations. In the future, as an alternative to the oral route, improving portability and acceptability for patients will be essential for further development.

Author Contributions

Conceptualization, J.L., Q.Z. and X.M.; methodology, J.L. and X.M.; validation, J.L. and X.M.; investigation, J.L. and H.X.; writing—original draft preparation, J.L., H.X. and X.M.; writing—review and editing, J.L., H.X., Q.Z. and X.M.; visualization, J.L., Q.Z. and H.X.; supervision, X.M.; project administration, X.M.; funding acquisition, X.M. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by Key Laboratory of Earth and Planetary Physics, Institute of Geology and Geophysics, Chinese Academy of Sciences, DQXX2021-07.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank Tongkai Chen of Guangzhou University of Chinese Medicine for technical support on the reviewing and editing contribution. Thank for to Holly in Shandong University for the help of image design and language polish.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Neupane, R.; Boddu, S.H.S.; Renukuntla, J.; Babu, R.J.; Tiwari, A.K. Alternatives to Biological Skin in Permeation Studies: Current Trends and Possibilities. Pharmaceutics 2020, 12, 152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Azagury, A.; Khoury, L.; Enden, G.; Kost, J. Ultrasound mediated transdermal drug delivery. Adv. Drug Deliv. Rev. 2014, 72, 127–143. [Google Scholar] [CrossRef] [PubMed]
  3. Watanabe, S.; Takagi, S.; Ga, K.; Yamamoto, K.; Aoyagi, T. Enhanced transdermal drug penetration by the simultaneous application of iontophoresis and sonophoresis. J. Drug Deliv. Sci. Technol. 2009, 19, 185–189. [Google Scholar] [CrossRef]
  4. Abd El-Hack, M.E.; El-Saadony, M.T.; Shafi, M.E.; Zabermawi, N.M.; Arif, M.; Batiha, G.E.; Khafaga, A.F.; Abd El-Hakim, Y.M.; Al-Sagheer, A.A. Antimicrobial and antioxidant properties of chitosan and its derivatives and their applications: A review. Int. J. Biol. Macromol. 2020, 164, 2726–2744. [Google Scholar] [CrossRef]
  5. Zhu, J.; Tang, X.; Jia, Y.; Ho, C.-T.; Huang, Q. Applications and delivery mechanisms of hyaluronic acid used for topical/transdermal delivery—A review. Int. J. Pharm. 2020, 578, 119127. [Google Scholar] [CrossRef]
  6. Jadach, B.; Swietlik, W.; Froelich, A. Sodium Alginate as a Pharmaceutical Excipient: Novel Applications of a Well-known Polymer. J. Pharm. Sci. 2022, 111, 1250–1261. [Google Scholar] [CrossRef]
  7. Ji, X.L.; Yin, M.S.; Nie, H.; Liu, Y.Q. A Review of Isolation, Chemical Properties, and Bioactivities of Polysaccharides from Bletilla striata. Biomed Res. Int. 2020, 2020, 5391379. [Google Scholar] [CrossRef]
  8. Qi, H.; Zhang, Z.; Liu, J.; Chen, Z.; Huang, Q.; Li, J.; Chen, J.; Wang, M.; Zhao, D.; Wang, Z.; et al. Comparisons of Isolation Methods, Structural Features, and Bioactivities of the Polysaccharides from Three Common Panax Species: A Review of Recent Progress. Molecules 2021, 26, 4997. [Google Scholar] [CrossRef]
  9. Win, Y.Y.; Charoenkanburkang, P.; Limprasutr, V.; Rodsiri, R.; Pan, Y.; Buranasudja, V.; Luckanagul, J.A. In Vivo Biocompatible Self-Assembled Nanogel Based on Hyaluronic Acid for Aqueous Solubility and Stability Enhancement of Asiatic Acid. Polymers 2021, 13, 4071. [Google Scholar] [CrossRef]
  10. Karki, S.; Kim, H.; Na, S.-J.; Shin, D.; Jo, K.; Lee, J. Thin films as an emerging platform for drug delivery. Asian J. Pharm. Sci. 2016, 11, 559–574. [Google Scholar] [CrossRef] [Green Version]
  11. Kim, H.; Seong, K.-Y.; Lee, J.H.; Park, W.; Yang, S.Y.; Hahn, S.K. Biodegradable Microneedle Patch Delivering Antigenic Peptide-Hyaluronate Conjugate for Cancer Immunotherapy. Acs Biomater. Sci. Eng. 2019, 5, 5150–5158. [Google Scholar] [CrossRef] [PubMed]
  12. Maxmen, A. Slew of trials launch to test coronavirus treatments in china. Nature 2020, 578, 347–348. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Cyranoski, D. The big push for chinese medicine for the first time, the World Health Organization will recognize traditional medicine in its influential global medical compendium. Nature 2018, 561, 448–450. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Liu, Z.-Q. Chemical Insights into Ginseng as a Resource for Natural Antioxidants. Chem. Rev. 2012, 112, 3329–3355. [Google Scholar] [CrossRef]
  15. Peng, B.; Luo, Y.; Hu, X.; Song, L.; Yang, J.; Zhu, J.; Wen, Y.; Yu, R. Isolation, structural characterization, and immunostimulatory activity of a new water-soluble polysaccharide and its sulfated derivative from Citrus medica L. var. sarcodactylis. Int. J. Biol. Macromol. 2019, 123, 500–511. [Google Scholar] [CrossRef]
  16. Hui, X.; Jia-qing, Z.; Yu-fei, L.; Bo-si, Z.; Liu-fang, W.; Ming-hao, F. Study on Insulation Failure Time and Failure Temperature of the Aged Cables under External Heating. Procedia Eng. 2018, 211, 1012–1017. [Google Scholar] [CrossRef]
  17. Wang, C.; Xu, L.; Guo, X.; Cui, X.; Yang, Y. Optimization of the extraction process of polysaccharides from Dendrobium officinale and evaluation of the in vivo immunmodulatory activity. J. Food Processing Preserv. 2018, 42, e13598. [Google Scholar] [CrossRef]
  18. Olatunji, O.J.; Feng, Y.; Olatunji, O.O.; Tang, J.; Wei, Y.; Ouyang, Z.; Su, Z. Polysaccharides purified from Cordyceps cicadae protects PC12 cells against glutamate-induced oxidative damage. Carbohydr. Polym. 2016, 153, 187–195. [Google Scholar] [CrossRef]
  19. Kong, L.S.; Yu, L.; Feng, T.; Yin, X.J.; Liu, T.J.; Dong, L. Physicochemical characterization of the polysaccharide from Bletilla striata: Effect of drying method. Carbohydr. Polym. 2015, 125, 1–8. [Google Scholar] [CrossRef]
  20. Liu, G.B.; Huang, Z.; Huang, C.G. Functions and application in cosmetics of Bletilla striata (Thunb) Reichb.f. Deterg. Cosmet 2005, 28, 22–24. [Google Scholar]
  21. Chi, J.J.; Sun, L.Y.; Cai, L.J.; Fan, L.; Shao, C.M.; Shang, L.R.; Zhao, Y.J. Chinese herb microneedle patch for wound healing. Bioact. Mater. 2021, 6, 3507–3514. [Google Scholar] [CrossRef] [PubMed]
  22. Zhang, Y.S.; Lv, T.; Li, M.; Xue, T.; Liu, H.; Zhang, W.M.; Ding, X.Y.; Zhuang, Z.H. Anti-aging effect of polysaccharide from Bletilla striate on nematode Caenorhabditis elegans. Pharmacogn. Mag. 2015, 11, 449–454. [Google Scholar] [CrossRef] [PubMed]
  23. Li, Q.; Li, K.; Huang, S.S.; Zhang, H.L.; Diao, Y.P. Optimization of Extraction Process and Antibacterial Activity of Bletilla striata Polysaccharides. Asian J. Chem. 2014, 26, 3574–3580. [Google Scholar] [CrossRef]
  24. Feng, S.; Cheng, H.; Xu, Z.; Yuan, M.; Huang, Y.; Liao, J.; Yang, R.; Zhou, L.; Ding, C. Panax notoginseng polysaccharide increases stress resistance and extends lifespan in Caenorhabditis elegans. J. Funct. Foods 2018, 45, 15–23. [Google Scholar] [CrossRef]
  25. Jia, D.; Deng, Y.; Gao, J.; Liu, X.; Chu, J.; Shu, Y. Neuroprotective effect of Panax notoginseng plysaccharides against focal cerebral ischemia reperfusion injury in rats. Int. J. Biol. Macromol. 2014, 63, 177–180. [Google Scholar] [CrossRef]
  26. Chung, D.-J.; Yang, M.-Y.; Li, Y.-R.; Chen, W.-J.; Hung, C.-Y.; Wang, C.-J. Ganoderma lucidum repress injury of ethanol-induced steatohepatitis via anti-inflammation, anti-oxidation and reducing hepatic lipid in C57BL/6J mice. J. Funct. Foods 2017, 33, 314–322. [Google Scholar] [CrossRef]
  27. Wang, C.; Shi, S.; Chen, Q.; Lin, S.; Wang, R.; Wang, S.; Chen, C. Antitumor and Immunomodulatory Activities of Ganoderma lucidum Polysaccharides in Glioma-Bearing Rats. Integr. Cancer Ther. 2018, 17, 674–683. [Google Scholar] [CrossRef] [Green Version]
  28. Kladar, N.V.; Gavaric, N.S.; Bozin, B.N. Ganoderma: Insights into anticancer effects. Eur. J. Cancer Prev. 2016, 25, 462–471. [Google Scholar] [CrossRef]
  29. Xu, F.; Li, X.; Xiao, X.; Liu, L.-f.; Zhang, L.; Lin, P.-p.; Zhang, S.-l.; Li, Q.-s. Effects of Ganoderma lucidum polysaccharides against doxorubicin-induced cardiotoxicity. Biomed. Pharmacother. 2017, 95, 504–512. [Google Scholar] [CrossRef]
  30. Ren, Z.; Yu, R.; Meng, Z.; Sun, M.; Huang, Y.; Xu, T.; Guo, Q.; Qin, T. Spiky titanium dioxide nanoparticles-loaded Plantaginis Semen polysaccharide as an adjuvant to enhance immune responses. Int. J. Biol. Macromol. 2021, 191, 1096–1104. [Google Scholar] [CrossRef]
  31. Mo, X.; Guo, D.; Jiang, Y.; Chen, P.; Huang, L. Isolation, structures and bioactivities of the polysaccharides from Radix Hedysari: A review. Int. J. Biol. Macromol. 2022, 199, 212–222. [Google Scholar] [CrossRef] [PubMed]
  32. Xiao, Z.; Deng, Q.; Zhou, W.; Zhang, Y. Immune activities of polysaccharides isolated from Lycium barbarum L. What do we know so far? Pharmacol. Ther. 2022, 229, 107921. [Google Scholar] [CrossRef] [PubMed]
  33. Barbosa, A.I.; Coutinho, A.J.; Costa Lima, S.A.; Reis, S. Marine Polysaccharides in Pharmaceutical Applications: Fucoidan and Chitosan as Key Players in the Drug Delivery Match Field. Mar. Drugs 2019, 17, 654. [Google Scholar] [CrossRef] [Green Version]
  34. Dabholkar, N.; Gorantla, S.; Waghule, T.; Rapalli, V.K.; Kothuru, A.; Goel, S.; Singhvi, G. Biodegradable microneedles fabricated with carbohydrates and proteins: Revolutionary approach for transdermal drug delivery. Int. J. Biol. Macromol. 2021, 170, 602–621. [Google Scholar] [CrossRef] [PubMed]
  35. Kaczmarek, M.B.; Struszczyk-Swita, K.; Li, X.; Szczesna-Antczak, M.; Daroch, M. Enzymatic Modifications of Chitin, Chitosan, and Chitooligosaccharides. Front. Bioeng. Biotechnol. 2019, 7, 243. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Moniz, T.; Costa Lima, S.A.; Reis, S. Marine polymeric microneedles for transdermal drug delivery. Carbohydr. Polym. 2021, 266, 118098. [Google Scholar] [CrossRef]
  37. Chatterjee, S.; Hui, P.C.-l.; Siu, W.S.; Kan, C.-w.; Leung, P.-C.; Chen, W.; Chiou, J.-C. Influence of pH-responsive compounds synthesized from chitosan and hyaluronic acid on dual-responsive (pH/temperature) hydrogel drug delivery systems of Cortex Moutan. Int. J. Biol. Macromol. 2021, 168, 163–174. [Google Scholar] [CrossRef]
  38. Luo, Y.; Wang, Q. Recent development of chitosan-based polyelectrolyte complexes with natural polysaccharides for drug delivery. Int. J. Biol. Macromol. 2014, 64, 353–367. [Google Scholar] [CrossRef]
  39. Menchicchi, B.; Hensel, A.; Goycoolea, F.M. Polysaccharides as Bacterial Antiadhesive Agents and “Smart” Constituents for Improved Drug Delivery Systems Against Helicobacter pylori Infection. Curr. Pharm. Des. 2015, 21, 4888–4906. [Google Scholar] [CrossRef]
  40. Qin, Y.K.; Li, P.C.; Guo, Z.Y. Cationic chitosan derivatives as potential antifungals: A review of structural optimization and applications. Carbohydr. Polym. 2020, 236, 116002. [Google Scholar] [CrossRef]
  41. Gottschalk, J.; Assmann, M.; Kuballa, J.; Elling, L. Repetitive Synthesis of High-Molecular-Weight Hyaluronic Acid with Immobilized Enzyme Cascades. Chemsuschem 2021, 15, e202101071. [Google Scholar] [CrossRef] [PubMed]
  42. Kim, K.S.; Kim, H.; Park, Y.; Kong, W.H.; Lee, S.W.; Kwok, S.J.J.; Hahn, S.K.; Yun, S.H. Noninvasive Transdermal Vaccination Using Hyaluronan Nanocarriers and Laser Adjuvant. Adv. Funct. Mater. 2016, 26, 2512–2522. [Google Scholar] [CrossRef] [PubMed]
  43. Mero, A.; Campisi, M. Hyaluronic Acid Bioconjugates for the Delivery of Bioactive Molecules. Polymers 2014, 6, 346–369. [Google Scholar] [CrossRef] [Green Version]
  44. Collins, M.N.; Birkinshaw, C. Hyaluronic acid based scaffolds for tissue engineering-A review. Carbohydr. Polym. 2013, 92, 1262–1279. [Google Scholar] [CrossRef]
  45. Highley, C.B.; Prestwich, G.D.; Burdick, J.A. Recent advances in hyaluronic acid hydrogels for biomedical applications. Curr. Opin. Biotechnol. 2016, 40, 35–40. [Google Scholar] [CrossRef]
  46. Tan, H.; Chu, C.R.; Payne, K.A.; Marra, K.G. Injectable in situ forming biodegradable chitosan-hyaluronic acid based hydrogels for cartilage tissue engineering. Biomaterials 2009, 30, 2499–2506. [Google Scholar] [CrossRef] [Green Version]
  47. Zhang, Z.; Suner, S.S.; Blake, D.A.; Ayyala, R.S.; Sahiner, N. Antimicrobial activity and biocompatibility of slow-release hyaluronic acid-antibiotic conjugated particles. Int. J. Pharm. 2020, 576, 119024. [Google Scholar] [CrossRef]
  48. Hu, Z.; Wang, S.; Dai, Z.; Zhang, H.; Zheng, X. A novel theranostic nano-platform (PB@FePt-HA-g-PEG) for tumor chemodynamic-photothermal co-therapy and triple-modal imaging (MR/CT/PI) diagnosis. J. Mater. Chem. B 2020, 8, 5351–5360. [Google Scholar] [CrossRef]
  49. Misra, S.; Heldin, P.; Hascall, V.C.; Karamanos, N.K.; Skandalis, S.S.; Markwald, R.R.; Ghatak, S. Hyaluronan-CD44 interactions as potential targets for cancer therapy. Febs J. 2011, 278, 1429–1443. [Google Scholar] [CrossRef] [Green Version]
  50. Becker, L.C.; Bergfeld, W.F.; Belsito, D.V.; Klaassen, C.D.; Marks, J.G., Jr.; Shank, R.C.; Slaga, T.J.; Snyder, P.W.; Andersen, F.A.; Cosmetic Ingredient Review, E. Final Report of the Safety Assessment of Hyaluronic Acid, Potassium Hyaluronate, and Sodium Hyaluronate. Int. J. Toxicol. 2009, 28, 5–67. [Google Scholar] [CrossRef]
  51. Varaprasad, K.; Jayaramudu, T.; Kanikireddy, V.; Toro, C.; Sadiku, E.R. Alginate-based composite materials for wound dressing application:A mini review. Carbohydr. Polym. 2020, 236, 116305. [Google Scholar] [CrossRef] [PubMed]
  52. Del Gaudio, P.; Amante, C.; Civale, R.; Bizzarro, V.; Petrella, A.; Pepe, G.; Campiglia, P.; Russo, P.; Aquino, R.P. In situ gelling alginate-pectin blend particles loaded with Ac2-26: A new weapon to improve wound care armamentarium. Carbohydr. Polym. 2020, 227, 115305. [Google Scholar] [CrossRef] [PubMed]
  53. Wu, M.X.; Zhang, Y.J.; Huang, H.; Li, J.W.; Liu, H.Y.; Guo, Z.Y.; Xue, L.J.; Liu, S.; Lei, Y.F. Assisted 3D printing of microneedle patches for minimally invasive glucose control in diabetes. Mater. Sci. Eng. C-Mater. Biol. Appl. 2020, 117, 111299. [Google Scholar] [CrossRef] [PubMed]
  54. Ahmad, Z.; Sharma, S.; Khuller, G.K. Chemotherapeutic evaluation of alginate nanoparticle-encapsulated azole antifungal and antitubercular drugs against murine tuberculosis. Nanomed.-Nanotechnol. Biol. Med. 2007, 3, 239–243. [Google Scholar] [CrossRef]
  55. Arshad, M.S.; Fatima, S.; Nazari, K.; Ali, R.; Farhan, M.; Muhammad, S.A.; Abbas, N.; Hussain, A.; Kucuk, I.; Chang, M.W.; et al. Engineering and characterisation of BCG-loaded polymeric microneedles. J. Drug Target. 2020, 28, 525–532. [Google Scholar] [CrossRef]
  56. Zhang, Y.; Jiang, G.H.; Yu, W.J.; Liu, D.P.; Xu, B. Microneedles fabricated from alginate and maltose for transdermal delivery of insulin on diabetic rats. Mater. Sci. Eng. C-Mater. Biol. Appl. 2018, 85, 18–26. [Google Scholar] [CrossRef]
  57. Friedman, A.J.; Phan, J.; Schairer, D.O.; Champer, J.; Qin, M.; Pirouz, A.; Blecher-Paz, K.; Oren, A.; Liu, P.T.; Modlin, R.L.; et al. Antimicrobial and Anti-Inflammatory Activity of Chitosan Alginate Nanoparticles: A Targeted Therapy for Cutaneous Pathogens. J. Investig. Dermatol. 2013, 133, 1231–1239. [Google Scholar] [CrossRef] [Green Version]
  58. Thi Thanh Van, T.; Hai Bang, T.; Nguyen Ha Vy, T.; Thi Minh Thu, Q.; Thi Nu, N.; Minh Ly, B.; Yoshiaki, Y.; Thi Thu Thuy, T. Structure, conformation in aqueous solution and antimicrobial activity of ulvan extracted from green seaweed Ulva reticulata. Nat. Prod. Res. 2018, 32, 2291–2296. [Google Scholar] [CrossRef]
  59. Li, W.; Jiang, N.; Li, B.; Wan, M.; Chang, X.; Liu, H.; Zhang, L.; Yin, S.; Qi, H.; Liu, S. Antioxidant activity of purified ulvan in hyperlipidemic mice. Int. J. Biol. Macromol. 2018, 113, 971–975. [Google Scholar] [CrossRef]
  60. Shi, Q.; Wang, A.; Lu, Z.; Qin, C.; Hu, J.; Yin, J. Overview on the antiviral activities and mechanisms of marine polysaccharides from seaweeds. Carbohydr. Res. 2017, 453–454, 1–9. [Google Scholar] [CrossRef]
  61. Kalita, P.; Ahmed, A.B.; Sen, S.; Chakraborty, R. A comprehensive review on polysaccharides with hypolipidemic activity: Occurrence, chemistry and molecular mechanism. Int. J. Biol. Macromol. 2022, 206, 681–698. [Google Scholar] [CrossRef] [PubMed]
  62. Colodi, F.G.; Ducatti, D.R.B.; Noseda, M.D.; de Carvalho, M.M.; Winnischofer, S.M.B.; Duarte, M.E.R. Semi-synthesis of hybrid ulvan-kappa-carrabiose polysaccharides and evaluation of their cytotoxic and anticoagulant effects. Carbohydr. Polym. 2021, 267, 118161. [Google Scholar] [CrossRef] [PubMed]
  63. Ren, Y.; Aierken, A.; Zhao, L.; Lin, Z.; Jiang, J.; Li, B.; Wang, J.; Hua, J.; Tu, Q. hUC-MSCs lyophilized powder loaded polysaccharide ulvan driven functional hydrogel for chronic diabetic wound healing. Carbohydr. Polym. 2022, 288, 119404. [Google Scholar] [CrossRef]
  64. Beaumont, M.; Tran, R.; Vera, G.; Niedrist, D.; Rousset, A.; Pierre, R.; Shastri, V.P.; Forget, A. Hydrogel-Forming Algae Polysaccharides: From Seaweed to Biomedical Applications. Biomacromolecules 2021, 22, 1027–1052. [Google Scholar] [CrossRef] [PubMed]
  65. Mariia, K.; Arif, M.; Shi, J.; Song, F.; Chi, Z.; Liu, C. Novel chitosan-ulvan hydrogel reinforcement by cellulose nanocrystals with epidermal growth factor for enhanced wound healing: In vitro and in vivo analysis. Int. J. Biol. Macromol. 2021, 183, 435–446. [Google Scholar] [CrossRef] [PubMed]
  66. Raveendran, S.; Palaninathan, V.; Nagaoka, Y.; Fukuda, T.; Iwai, S.; Higashi, T.; Mizuki, T.; Sakamoto, Y.; Mohanan, P.V.; Maekawa, T.; et al. Extremophilic polysaccharide nanoparticles for cancer nanotherapy and evaluation of antioxidant properties. Int. J. Biol. Macromol. 2015, 76, 310–319. [Google Scholar] [CrossRef]
  67. Giese, E.C.; Dekker, R.F.H.; Barbosa, A.M.; da Silva, R. Triple helix conformation of botryosphaeran, a (1 -> 3;1 -> 6)-beta-D-glucan produced by Botryosphaeria rhodina MAMB-05. Carbohydr. Polym. 2008, 74, 953–956. [Google Scholar] [CrossRef]
  68. Sethi, S.; Saruchi; Kaith, B.S.; Kaur, M.; Sharma, N.; Kumar, V. Cross-linked xanthan gum-starch hydrogels as promising materials for controlled drug delivery. Cellulose 2020, 27, 4565–4589. [Google Scholar] [CrossRef]
  69. Wang, J.; Goh, K.M.; Salem, D.R.; Sani, R.K. Genome analysis of a thermophilic exopolysaccharide-producing bacterium—Geobacillus sp. WSUCF1. Sci. Rep. 2019, 9, 1608. [Google Scholar] [CrossRef] [Green Version]
  70. Wang, J.; Salem, D.R.; Sani, R.K. Extremophilic exopolysaccharides: A review and new perspectives on engineering strategies and applications. Carbohydr. Polym. 2019, 205, 8–26. [Google Scholar] [CrossRef]
  71. Peppas, N.A.; Bures, P.; Leobandung, W.; Ichikawa, H. Hydrogels in pharmaceutical formulations. Eur. J. Pharm. Biopharm. 2000, 50, 27–46. [Google Scholar] [CrossRef]
  72. Khan, H.; Chaudhary, J.P.; Meena, R. Anionic carboxymethylagarose-based pH-responsive smart superabsorbent hydrogels for controlled release of anticancer drug. Int. J. Biol. Macromol. 2019, 124, 1220–1229. [Google Scholar] [CrossRef] [PubMed]
  73. Cui, X.; Zhang, X.; Yang, Y.; Wang, C.; Zhang, C.; Peng, G. Preparation and evaluation of novel hydrogel based on polysaccharide isolated from Bletilla striata. Pharm. Dev. Technol. 2017, 22, 1001–1011. [Google Scholar] [CrossRef] [PubMed]
  74. Cheng, J.Y.; Liu, J.H.; Li, M.; Liu, Z.Y.; Wang, X.; Zhang, L.C.; Wang, Z. Hydrogel-Based Biomaterials Engineered from Natural-Derived Polysaccharides and Proteins for Hemostasis and Wound Healing. Front. Bioeng. Biotechnol. 2021, 9, 1608. [Google Scholar] [CrossRef] [PubMed]
  75. Haine, A.T.; Koga, Y.; Hashimoto, Y.; Higashi, T.; Motoyama, K.; Arima, H.; Niidome, T. Enhancement of transdermal protein delivery by photothermal effect of gold nanorods coated on polysaccharide-based hydrogel. Eur. J. Pharm. Biopharm. 2017, 119, 91–95. [Google Scholar] [CrossRef] [PubMed]
  76. Kwon, S.S.; Kong, B.J.; Park, S.N. Physicochemical properties of pH-sensitive hydrogels based on hydroxyethyl cellulose-hyaluronic acid and for applications as transdermal delivery systems for skin lesions. Eur. J. Pharm. Biopharm. 2015, 92, 146–154. [Google Scholar] [CrossRef]
  77. Chatterjee, S.; Hui, P.C.-l.; Wat, E.; Kan, C.-w.; Leung, P.-C.; Wang, W. Drug delivery system of dual-responsive PF127 hydrogel with polysaccharide-based nano-conjugate for textile-based transdermal therapy. Carbohydr. Polym. 2020, 236, 116074. [Google Scholar] [CrossRef]
  78. Chen, C.H.; Zhou, P.; Huang, C.; Zeng, R.; Yang, L.; Han, Z.; Qu, Y.; Zhang, C. Photothermal-promoted multi-functional dual network polysaccharide hydrogel adhesive for infected and susceptible wound healing. Carbohydr. Polym. 2021, 273, 118557. [Google Scholar] [CrossRef]
  79. Tripathi, K.; Singh, A. Chitin, Chitosan and their Pharmacological Activities: A review. Int. J. Pharm. Sci. Res. 2018, 9, 2626–2635. [Google Scholar] [CrossRef]
  80. Abramov, E.; Schwob, O.; Benny, O. Film- and ointment-based delivery systems for the transdermal delivery of TNP-470. Polym. Adv. Technol. 2019, 30, 2586–2595. [Google Scholar] [CrossRef]
  81. Bektas, A.; Cevher, E.; Gungor, S.; Ozsoy, Y. Design and Evaluation of Polysaccharide-Based Transdermal Films for the Controlled Delivery of Nifedipine. Chem. Pharm. Bull. 2014, 62, 144–152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. da Silva, T.N.; Reynaud, F.; de Souza Picciani, P.H.; de Holanda e Silva, K.G.; Barradas, T.N. Chitosan-based films containing nanoemulsions of methyl salicylate: Formulation development, physical-chemical and in vitro drug release characterization. Int. J. Biol. Macromol. 2020, 164, 2558–2568. [Google Scholar] [CrossRef] [PubMed]
  83. Sharma, A.; Puri, V.; Kumar, P.; Singh, I. Rifampicin-Loaded Alginate-Gelatin Fibers Incorporated within Transdermal Films as a Fiber-in-Film System for Wound Healing Applications. Membranes 2021, 11, 7. [Google Scholar] [CrossRef] [PubMed]
  84. Xu, L.; Chu, Z.; Wang, H.; Cai, L.; Tu, Z.; Liu, H.; Zhu, C.; Shi, H.; Pan, D.; Pan, J.; et al. Electrostatically Assembled Multilayered Films of Biopolymer Enhanced Nanocapsules for on-Demand Drug Release. Acs Appl. Bio. Mater. 2019, 2, 3429–3438. [Google Scholar] [CrossRef] [PubMed]
  85. Xu, L.; Wang, H.; Chu, Z.; Cai, L.; Shi, H.; Zhu, C.; Pan, D.; Pan, J.; Fei, X.; Lei, Y. Temperature-Responsive Multilayer Films of Micelle-Based Composites for Controlled Release of a Third-Generation EGFR Inhibitor. Acs Appl. Polym. Mater. 2020, 2, 741–750. [Google Scholar] [CrossRef]
  86. Wang, X.H.; Su, T.; Zhao, J.; Wu, Z.; Wang, D.; Zhang, W.N.; Wu, Q.X.; Chen, Y. Fabrication of polysaccharides-based hydrogel films for transdermal sustained delivery of Ibuprofen. Cellulose 2020, 27, 10277–10292. [Google Scholar] [CrossRef]
  87. Alshhab, A.; Yilmaz, E. Sodium alginate/poly(4-vinylpyridine) polyelectrolyte multilayer films: Preparation, characterization and ciprofloxacin HCl release. Int. J. Biol. Macromol. 2020, 147, 809–820. [Google Scholar] [CrossRef]
  88. Bostan, M.S.; Mutlu, E.C.; Kazak, H.; Keskin, S.S.; Oner, E.T.; Eroglu, M.S. Comprehensive characterization of chitosan/PEO/levan ternary blend films. Carbohydr. Polym. 2014, 102, 993–1000. [Google Scholar] [CrossRef]
  89. Yuan, X.X.; Liu, R.; Zhang, W.C.; Song, X.Q.; Xu, L.; Zhao, Y.; Shang, L.; Zhang, J.S. Preparation of carboxylmethylchitosan and alginate blend membrane for diffusion-controlled release of diclofenac diethylamine. J. Mater. Sci. Technol. 2021, 63, 210–215. [Google Scholar] [CrossRef]
  90. Serrano-Castaneda, P.; Escobar-Chavez, J.J.; Rodriguez-Cruz, I.M.; Melgoza-Contreras, L.M.; Martinez-Hernandez, J. Microneedles as Enhancer of Drug Absorption Through the Skin and Applications in Medicine and Cosmetology. J. Pharm. Pharm. Sci. 2018, 21, 73–93. [Google Scholar] [CrossRef] [Green Version]
  91. Shelke, N.B.; James, R.; Laurencin, C.T.; Kumbar, S.G. Polysaccharide biomaterials for drug delivery and regenerative engineering. Polym. Adv. Technol. 2014, 25, 448–460. [Google Scholar] [CrossRef]
  92. Kim, S.; Lee, J.; Shayan, F.L.; Kim, S.; Huh, I.; Ma, Y.H.; Yang, H.S.; Kang, G.; Jung, H. Physicochemical study of ascorbic acid 2-glucoside loaded hyaluronic acid dissolving microneedles irradiated by electron beam and gamma ray. Carbohydr. Polym. 2018, 180, 297–303. [Google Scholar] [CrossRef] [PubMed]
  93. Loizidou, E.Z.; Williams, N.A.; Barrow, D.A.; Eaton, M.J.; McCrory, J.; Evans, S.L.; Allender, C.J. Structural characterisation and transdermal delivery studies on sugar microneedles: Experimental and finite element modelling analyses. Eur. J. Pharm. Biopharm. 2015, 89, 224–231. [Google Scholar] [CrossRef] [PubMed]
  94. Bhatnagar, S.; Chawla, S.R.; Kulkarni, O.P.; Venuganti, V.V.K. Zein Microneedles for Transcutaneous Vaccine Delivery: Fabrication, Characterization, and in Vivo Evaluation Using Ovalbumin as the Model Antigen. Acs Omega 2017, 2, 1321–1332. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Yan, Q.Y.; Liu, H.M.; Cheng, Z.G.; Xue, Y.; Cheng, Z.D.; Dai, X.Y.; Shan, W.S.; Chen, F. Immunotherapeutic effect of BCG-polysaccharide nucleic acid powder on Mycobacterium tuberculosis-infected mice using microneedle patches. Drug Deliv. 2017, 24, 1648–1653. [Google Scholar] [CrossRef] [Green Version]
  96. Hu, L.; Liao, Z.; Hu, Q.; Maffucci, K.G.; Qu, Y. Novel Bletilla striata polysaccharide microneedles: Fabrication, characterization, and in vitro transcutaneous drug delivery. Int. J. Biol. Macromol. 2018, 117, 928–936. [Google Scholar] [CrossRef]
  97. Zhou, P.; Zhao, S.; Huang, C.; Qu, Y.; Zhang, C. Bletilla striata polysaccharide microneedle for effective transdermal administration of model protein antigen. Int. J. Biol. Macromol. 2022, 205, 511–519. [Google Scholar] [CrossRef]
  98. Wu, T.; Hou, X.; Li, J.; Ruan, H.; Pei, L.; Guo, T.; Wang, Z.; Ci, T.; Ruan, S.; He, Y.; et al. Microneedle-Mediated Biomimetic Cyclodextrin Metal Organic Frameworks for Active Targeting and Treatment of Hypertrophic Scars. Acs Nano 2021, 15, 20087–20104. [Google Scholar] [CrossRef]
  99. Wang, C.X.; Liu, S.N.; Xu, J.W.; Gao, M.J.; Qu, Y.; Liu, Y.; Yang, Y.; Cui, X.M. Dissolvable microneedles based on Panax notoginseng polysaccharide for transdermal drug delivery and skin dendritic cell activation. Carbohydr. Polym. 2021, 268, 118211. [Google Scholar] [CrossRef]
  100. Zhang, X.X.; Chen, G.P.; Cai, L.J.; Wang, Y.T.; Sun, L.Y.; Zhao, Y.J. Bioinspired pagoda-like microneedle patches with strong fixation and hemostasis capabilities. Chem. Eng. J. 2021, 414, 128905. [Google Scholar] [CrossRef]
  101. Castilla-Casadiego, D.A.; Carlton, H.; Gonzalez-Nino, D.; Miranda-Munoz, K.A.; Daneshpour, R.; Huitink, D.; Prinz, G.; Powell, J.; Greenlee, L.; Almodovar, J. Design, characterization, and modeling of a chitosan microneedle patch for transdermal delivery of meloxicam as a pain management strategy for use in cattle. Mater. Sci. Eng. C-Mater. Biol. Appl. 2021, 118, 111544. [Google Scholar] [CrossRef] [PubMed]
  102. Gholami, S.; Zarkesh, I.; Ghanian, M.H.; Hajizadeh-Saffar, E.; Hassan-Aghaei, F.; Mohebi, M.M.; Baharvand, H. Dynamically capped hierarchically porous microneedles enable post-fabrication loading and self-regulated transdermal delivery of insulin. Chem. Eng. J. 2021, 421, 127823. [Google Scholar] [CrossRef]
  103. Ning, T.Q.; Yang, F.H.; Chen, D.L.; Jia, Z.Z.; Yuan, R.Q.; Du, Z.Q.; Liu, S.Y.; Yu, Y.; Dai, X.C.; Niu, X.F.; et al. Synergistically Detachable Microneedle Dressing for Programmed Treatment of Chronic Wounds. Adv. Healthc. Mater. 2022, 2102180. [Google Scholar] [CrossRef] [PubMed]
  104. He, J.; Zhang, Z.; Zheng, X.; Li, L.; Qi, J.; Wu, W.; Lu, Y. Design and Evaluation of Dissolving Microneedles for Enhanced Dermal Delivery of Propranolol Hydrochloride. Pharmaceutics 2021, 13, 579. [Google Scholar] [CrossRef]
  105. Zhao, Y.; Zhou, Y.; Yang, D.; Gao, X.; Wen, T.; Fu, J.; Wen, X.; Quan, G.; Pan, X.; Wu, C. Intelligent and spatiotemporal drug release based on multifunctional nanoparticle-integrated dissolving microneedle system for synergetic chemo-photothermal therapy to eradicate melanoma. Acta Biomater. 2021, 135, 164–178. [Google Scholar] [CrossRef]
  106. Ning, X.; Wiraja, C.; Chew, W.T.S.; Fan, C.; Xu, C. Transdermal delivery of Chinese herbal medicine extract using dissolvable microneedles for hypertrophic scar treatment. Acta Pharm. Sin. B 2021, 11, 2937–2944. [Google Scholar] [CrossRef]
  107. Kim, M.J.; Seong, K.-Y.; Kim, D.S.; Jeong, J.S.; Kim, S.Y.; Lee, S.; Yang, S.Y.; An, B.-S. Minoxidil-loaded hyaluronic acid dissolving microneedles to alleviate hair loss in an alopecia animal model. Acta Biomater. 2022, 143, 189–202. [Google Scholar] [CrossRef]
  108. Sun, X.T.; Ji, W.W.; Zhang, B.; Ma, L.J.; Fu, W.J.; Qian, W.H.; Zhang, X.Y.; Li, J.T.; Sheng, E.Z.; Tao, Y.; et al. A theranostic microneedle array patch for integrated glycemia sensing and self-regulated release of insulin. Biomater. Sci. 2022, 10, 1209–1216. [Google Scholar] [CrossRef]
  109. Don, T.-M.; Chen, M.; Lee, I.C.; Huang, Y.-C. Preparation and characterization of fast dissolving ulvan microneedles for transdermal drug delivery system. Int. J. Biol. Macromol. 2022, 207, 90–99. [Google Scholar] [CrossRef]
  110. Tchobanian, A.; Van Oosterwyck, H.; Fardim, P. Polysaccharides for tissue engineering: Current landscape and future prospects. Carbohydr. Polym. 2019, 205, 601–625. [Google Scholar] [CrossRef]
  111. Bose, S.; Koski, C.; Vu, A.A. Additive manufacturing of natural biopolymers and composites for bone tissue engineering. Mater. Horiz. 2020, 7, 2011–2027. [Google Scholar] [CrossRef]
  112. Zhao, Y.; Chen, J.; Zou, L.; Xu, G.; Geng, Y. Facile one-step bioinspired mineralization by chitosan functionalized with graphene oxide to activate bone endogenous regeneration. Chem. Eng. J. 2019, 378, 122174. [Google Scholar] [CrossRef]
  113. Agarwal, G.; Agiwal, S.; Srivastava, A. Hyaluronic acid containing scaffolds ameliorate stem cell function for tissue repair and regeneration. Int. J. Biol. Macromol. 2020, 165, 388–401. [Google Scholar] [CrossRef] [PubMed]
  114. Zare, P.; Pezeshki-Modaress, M.; Davachi, S.M.; Zare, P.; Yazdian, F.; Simorgh, S.; Ghanbari, H.; Rashedi, H.; Bagher, Z. Alginate sulfate-based hydrogel/nanofiber composite scaffold with controlled Kartogenin delivery for tissue engineering. Carbohydr. Polym. 2021, 266, 118123. [Google Scholar] [CrossRef]
  115. Patel, J.; Maji, B.; Moorthy, N.S.H.N.; Maiti, S. Xanthan gum derivatives: Review of synthesis, properties and diverse applications. Rsc Adv. 2020, 10, 27103–27136. [Google Scholar] [CrossRef]
  116. Wang, J.; Sun, Q.; Wei, Y.; Hao, M.; Tan, W.-S.; Cai, H. Sustained release of epigallocatechin-3-gallate from chitosan-based scaffolds to promote osteogenesis of mesenchymal stem cell. Int. J. Biol. Macromol. 2021, 176, 96–105. [Google Scholar] [CrossRef]
  117. Malhotra, D.; Pan, S.; Ruether, L.; Schlippe, G.; Voss, W.; Germann, N. Polysaccharide-based skin scaffolds with enhanced mechanical compatibility with native human skin. J. Mech. Behav. Biomed. Mater. 2021, 122, 104607. [Google Scholar] [CrossRef]
  118. Pan, P.; Chen, X.; Xing, H.; Deng, Y.; Chen, J.; Alharthi, F.A.; Alghamdi, A.A.; Su, J. A fast on-demand preparation of injectable self-healing nanocomposite hydrogels for efficient osteoinduction. Chin. Chem. Lett. 2021, 32, 2159–2163. [Google Scholar] [CrossRef]
  119. Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 2013, 12, 991–1003. [Google Scholar] [CrossRef]
  120. Laubach, J.; Joseph, M.; Brenza, T.; Gadhamshetty, V.; Sani, R.K. Exopolysaccharide and biopolymer-derived films as tools for transdermal drug delivery. J. Control. Release 2021, 329, 971–987. [Google Scholar] [CrossRef]
  121. Prausnitz, M.R.; Langer, R. Transdermal drug delivery. Nat. Biotechnol. 2008, 26, 1261–1268. [Google Scholar] [CrossRef] [PubMed]
  122. Alkilani, A.Z.; McCrudden, M.T.C.; Donnelly, R.F. Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum. Pharmaceutics 2015, 7, 438–470. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Al-Kassas, R.; Wen, J.; Cheng, A.E.-M.; Kim, A.M.-J.; Liu, S.S.M.; Yu, J. Transdermal delivery of propranolol hydrochloride through chitosan nanoparticles dispersed in mucoadhesive gel. Carbohydr. Polym. 2016, 153, 176–186. [Google Scholar] [CrossRef] [PubMed]
  124. Jeon, S.; Yoo, C.Y.; Park, S.N. Improved stability and skin permeability of sodium hyaluronate-chitosan multilayered liposomes by Layer-by-Layer electrostatic deposition for quercetin delivery. Colloids Surf. B-Biointerfaces 2015, 129, 7–14. [Google Scholar] [CrossRef] [PubMed]
  125. Pelikh, O.; Eckert, R.W.; Pinnapireddy, S.R.; Keck, C.M. Hair follicle targeting with curcumin nanocrystals: Influence of the formulation properties on the penetration efficacy. J. Control. Release 2021, 329, 598–613. [Google Scholar] [CrossRef]
  126. Saidin, N.M.; Anuar, N.K.; Tin Wui, W.; Meor Mohd Affandi, M.M.R.; Wan Engah, W.R. Skin barrier modulation by Hibiscus rosa-sinensis L. mucilage for transdermal drug delivery. Polym. Bull. 2021, 79, 3099–3115. [Google Scholar] [CrossRef]
  127. Federer, C.; Kurpiers, M.; Bernkop-Schnurch, A. Thiolated Chitosans: A Multi-talented Class of Polymers for Various Applications. Biomacromolecules 2021, 22, 24–56. [Google Scholar] [CrossRef]
  128. Matalqah, S.M.; Aiedeh, K.; Mhaidat, N.M.; Alzoubi, K.H.; Bustanji, Y.; Hamad, I. Chitosan Nanoparticles as a Novel Drug Delivery System: A Review Article. Curr. Drug Targets 2020, 21, 1613–1624. [Google Scholar] [CrossRef]
  129. Razzaq, F.A.; Asif, M.; Asghar, S.; Iqbal, M.S.; Khan, I.U.; Khan, S.U.D.; Irfan, M.; Syed, H.K.; Khames, A.; Mahmood, H.; et al. Glimepiride-Loaded Nanoemulgel; Development, In Vitro Characterization, Ex Vivo Permeation and In Vivo Antidiabetic Evaluation. Cells 2021, 10, 2404. [Google Scholar] [CrossRef]
  130. Szumala, P.; Jungnickel, C.; Kozlowska-Tylingo, K.; Jacyna, B.; Cal, K. Transdermal transport of collagen and hyaluronic acid using water in oil microemulsion. Int. J. Pharm. 2019, 572, 118738. [Google Scholar] [CrossRef]
  131. Vlaia, L.; Olariu, I.; Mut, A.M.; Coneac, G.; Vlaia, V.; Anghel, D.F.; Maxim, M.E.; Stanga, G.; Dobrescu, A.; Suciu, M.; et al. New, Biocompatible, Chitosan-Gelled Microemulsions Based on Essential Oils and Sucrose Esters as Nanocarriers for Topical Delivery of Fluconazole. Pharmaceutics 2022, 14, 75. [Google Scholar] [CrossRef] [PubMed]
  132. Khan, T.A.; Azad, A.K.; Fuloria, S.; Nawaz, A.; Subramaniyan, V.; Akhlaq, M.; Safdar, M.; Sathasivam, K.V.; Sekar, M.; Porwal, O.; et al. Chitosan-Coated 5-Fluorouracil Incorporated Emulsions as Transdermal Drug Delivery Matrices. Polymers 2021, 13, 3345. [Google Scholar] [CrossRef] [PubMed]
  133. Sharkawy, A.; Barreiro, M.F.; Rodrigues, A.E. New Pickering emulsions stabilized with chitosan/collagen peptides nanoparticles: Synthesis, characterization and tracking of the nanoparticles after skin application. Colloids Surf. A-Physicochem. Eng. Asp. 2021, 616, 126327. [Google Scholar] [CrossRef]
  134. Guermech, I.; Lassoued, M.A.; Abdelhamid, A.; Sfar, S. Development and Assessment of Lipidic Nanoemulsions Containing Sodium Hyaluronate and Indomethacin. Aaps Pharmscitech 2019, 20, 330. [Google Scholar] [CrossRef] [PubMed]
  135. Verma, P.; Pathak, K. Therapeutic and cosmeceutical potential of ethosomes: An overview. J. Adv. Pharm. Technol. Res. 2010, 1, 274–282. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Cristiano, M.C.; Froiio, F.; Spaccapelo, R.; Mancuso, A.; Nistico, S.P.; Udongo, B.P.; Fresta, M.; Paolino, D. Sulforaphane-Loaded Ultradeformable Vesicles as A Potential Natural Nanomedicine for the Treatment of Skin Cancer Diseases. Pharmaceutics 2020, 12, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Fu, X.; Shi, Y.; Wang, H.; Zhao, X.; Sun, Q.; Huang, Y.; Qi, T.; Lin, G. Ethosomal Gel for Improving Transdermal Delivery of Thymosin beta-4. Int. J. Nanomed. 2019, 14, 9275–9284. [Google Scholar] [CrossRef] [Green Version]
  138. Paiva-Santos, A.C.; Silva, A.L.; Guerra, C.; Peixoto, D.; Pereira-Silva, M.; Zeinali, M.; Mascarenhas-Melo, F.; Castro, R.; Veiga, F. Ethosomes as Nanocarriers for the Development of Skin Delivery Formulations. Pharm. Res. 2021, 38, 947–970. [Google Scholar] [CrossRef]
  139. Zhang, Y.; Zhang, H.; Zhang, K.; Li, Z.; Guo, T.; Wu, T.; Hou, X.; Feng, N. Co-hybridized composite nanovesicles for enhanced transdermal eugenol and cinnamaldehyde delivery and their potential efficacy in ulcerative colitis. Nanomed. -Nanotechnol. Biol. Med. 2020, 28, 102212. [Google Scholar] [CrossRef]
  140. Chen, Y.; Zhang, Z.; Xin, Y.; Zhou, R.; Jiang, K.; Sun, X.; He, D.; Song, J.; Zhang, Y. Synergistic transdermal delivery of nanoethosomes embedded in hyaluronic acid nanogels for enhancing photodynamic therapy. Nanoscale 2020, 12, 15435–15442. [Google Scholar] [CrossRef]
  141. Zhang, Y.; Xia, Q.; Li, Y.; He, Z.; Li, Z.; Guo, T.; Wu, Z.; Feng, N. CD44 Assists the Topical Anti-Psoriatic Efficacy of Curcumin-Loaded Hyaluronan-Modified Ethosomes: A New Strategy for Clustering Drug in Inflammatory Skin. Theranostics 2019, 9, 48–64. [Google Scholar] [CrossRef] [PubMed]
  142. Maeda, H. Polymer therapeutics and the EPR effect. J. Drug Target. 2017, 25, 781–785. [Google Scholar] [CrossRef] [PubMed]
  143. El Menshawe, S.F.; Aboud, H.M.; Elkomy, M.H.; Kharshoum, R.M.; Abdeltwab, A.M. A novel nanogel loaded with chitosan decorated bilosomes for transdermal delivery of terbutaline sulfate: Artificial neural network optimization, in vitro characterization and in vivo evaluation. Drug Deliv. Transl. Res. 2020, 10, 471–485. [Google Scholar] [CrossRef] [PubMed]
  144. Din, F.U.; Kim, D.W.; Choi, J.Y.; Thapa, R.K.; Mustapha, O.; Kim, D.S.; Oh, Y.K.; Ku, S.K.; Youn, Y.S.; Oh, K.T.; et al. Irinotecan-loaded double-reversible thermogel with improved antitumor efficacy without initial burst effect and toxicity for intramuscular administration. Acta Biomater. 2017, 54, 239–248. [Google Scholar] [CrossRef]
  145. Lee, M.H.; Shin, G.H.; Park, H.J. Solid lipid nanoparticles loaded thermoresponsive pluronic-xanthan gum hydrogel as a transdermal delivery system. J. Appl. Polym. Sci. 2018, 135, 46004. [Google Scholar] [CrossRef]
  146. Mahmood, S.; Almurisi, S.H.; Al-Japairai, K.; Hilles, A.R.; Alelwani, W.; Bannunah, A.M.; Alshammari, F.; Alheibshy, F. Ibuprofen-Loaded Chitosan-Lipid Nanoconjugate Hydrogel with Gum Arabic: Green Synthesis, Characterisation, In Vitro Kinetics Mechanistic Release Study and PGE2 Production Test. Gels 2021, 7, 254. [Google Scholar] [CrossRef]
  147. Harada, A.; Kataoka, K. Supramolecular assemblies of block copolymers in aqueous media as nanocontainers relevant to biological applications. Prog. Polym. Sci. 2006, 31, 949–982. [Google Scholar] [CrossRef]
  148. Cohen, Y.; Rutenberg, R.; Cohen, G.; Veltman, B.; Gvirtz, R.; Fallik, E.; Danino, D.; Eltzov, E.; Poverenov, E. Aminated Polysaccharide-Based Nanoassemblies as Stable Biocompatible Vehicles Enabling Crossing of Biological Barriers: An Effective Transdermal Delivery of Diclofenac Medicine. Acs Appl. Bio. Mater. 2020, 3, 2209–2217. [Google Scholar] [CrossRef]
  149. Fereig, S.A.; El-Zaafarany, G.M.; Arafa, M.G.; Abdel-Mottaleb, M.M.A. Self-assembled tacrolimus-loaded lecithin-chitosan hybrid nanoparticles for in vivo management of psoriasis. Int. J. Pharm. 2021, 608, 121114. [Google Scholar] [CrossRef]
  150. Dong, W.; Ye, J.; Wang, W.; Yang, Y.; Wang, H.; Sun, T.; Gao, L.; Liu, Y. Self-Assembled Lecithin/Chitosan Nanoparticles Based on Phospholipid Complex: A Feasible Strategy to Improve Entrapment Efficiency and Transdermal Delivery of Poorly Lipophilic Drug. Int. J. Nanomed. 2020, 15, 5629–5643. [Google Scholar] [CrossRef]
  151. Bian, Q.; Huang, L.L.; Xu, Y.H.; Wang, R.X.; Gu, Y.T.; Yuan, A.R.; Ma, X.L.; Hu, J.Y.; Rao, Y.F.; Xu, D.H.; et al. A Facile Low-Dose Photosensitizer-Incorporated Dissolving Microneedles-Based Composite System for Eliciting Antitumor Immunity and the Abscopal Effect. Acs Nano 2021, 15, 19468–19479. [Google Scholar] [CrossRef] [PubMed]
  152. Rutenberg, R.; Galaktionova, D.; Golden, G.; Cohen, Y.; Levi-Kalisman, Y.; Cohen, G.; Kral, P.; Poverenov, E. Omniphilic Polysaccharide-Based Nanocarriers for Modular Molecular Delivery in a Broad Range of Biosystemsn. Acs Appl. Mater. Interfaces 2018, 10, 36711–36720. [Google Scholar] [CrossRef] [PubMed]
  153. Shim, G.; Ko, S.; Kim, D.; Quoc-Viet, L.; Park, G.T.; Lee, J.; Kwon, T.; Choi, H.-G.; Kim, Y.B.; Oh, Y.-K. Light-switchable systems for remotely controlled drug delivery. J. Control. Release 2017, 267, 67–79. [Google Scholar] [CrossRef] [PubMed]
  154. Biswas, S.; Das, J.; Barman, S.; Shah, S.S.; Gangopadhyay, M.; Maiti, T.K.; Singh, N.D.P. Single component image guided ’On-demand’ drug delivery system for early stage prostate. Sens. Actuators B-Chem. 2017, 244, 327–333. [Google Scholar] [CrossRef]
  155. Huang, S.; Huang, G. The dextrans as vehicles for gene and drug delivery. Future Med. Chem. 2019, 11, 1659–1667. [Google Scholar] [CrossRef] [PubMed]
  156. Chen, M.-C.; Lai, K.-Y.; Ling, M.-H.; Lin, C.-W. Enhancing immunogenicity of antigens through sustained intradermal delivery using chitosan microneedles with a patch-dissolvable design. Acta Biomater. 2018, 65, 66–75. [Google Scholar] [CrossRef] [PubMed]
  157. Fereig, S.A.; El-Zaafarany, G.M.; Arafa, M.G.; Abdel-Mottaleb, M.M.A. Tacrolimus-loaded chitosan nanoparticles for enhanced skin deposition and management of plaque psoriasis. Carbohydr. Polym. 2021, 268, 118238. [Google Scholar] [CrossRef]
  158. Huo, Z.; Miles, J.; Harris, T.; Riches, P. Effect of Pneumovax (R) II vaccination in high-risk individuals on specific antibody and opsonic capacity against specific and non-specific antigen. Vaccine 2002, 20, 3532–3534. [Google Scholar] [CrossRef]
  159. Zimmer, S.M.; Stephens, D.S. Meninglococcal conjugate vaccines. Expert Opin. Pharmacother. 2004, 5, 855–863. [Google Scholar] [CrossRef]
  160. Lin, L.; Qiao, M.; Zhang, X.; Linhardt, R.J. Site-selective reactions for the synthesis of glycoconjugates in polysaccharide vaccine development. Carbohydr. Polym. 2020, 230, 115643. [Google Scholar] [CrossRef]
  161. Arcuri, M.; Di Benedetto, R.; Cunningham, A.F.; Saul, A.; MacLennan, C.A.; Micoli, F. The influence of conjugation variables on the design and immunogenicity of a glycoconjugate vaccine against Salmonella Typhi. PLoS ONE 2017, 12, e0189100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Malik, A.; Gupta, M.; Gupta, V.; Gogoi, H.; Bhatnagar, R. Novel application of trimethyl chitosan as an adjuvant in vaccine delivery. Int. J. Nanomed. 2018, 13, 7959–7969. [Google Scholar] [CrossRef] [Green Version]
  163. Chen, Y.-H.; Lai, K.-Y.; Chiu, Y.-H.; Wu, Y.-W.; Shiau, A.-L.; Chen, M.-C. Implantable microneedles with an immune-boosting function for effective intradermal influenza vaccination. Acta Biomater. 2019, 97, 230–238. [Google Scholar] [CrossRef]
  164. Chiu, Y.-H.; Chen, M.-C.; Wan, S.-W. Sodium Hyaluronate/Chitosan Composite Microneedles as a Single-Dose Intradermal Immunization System. Biomacromolecules 2018, 19, 2278–2285. [Google Scholar] [CrossRef] [PubMed]
  165. Mistilis, M.J.; Bommarius, A.S.; Prausnitz, M.R. Development of a Thermostable Microneedle Patch for Influenza Vaccination. J. Pharm. Sci. 2015, 104, 740–749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Aragona, M.; Dekoninck, S.; Rulands, S.; Lenglez, S.; Mascre, G.; Simons, B.D.; Blanpain, C. Defining stem cell dynamics and migration during wound healing in mouse skin epidermis. Nat. Commun. 2017, 8, 14684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Chen, Z.Y.; Cheng, L.Z.; He, Y.C.; Wei, X.L. Extraction, characterization, utilization as wound dressing and drug delivery of Bletilla striata polysaccharide: A review. Int. J. Biol. Macromol. 2018, 120, 2076–2085. [Google Scholar] [CrossRef]
  168. Wang, C.M.; Sun, J.T.; Luo, Y.; Xue, W.H.; Diao, H.J.; Dong, L.; Chen, J.N.; Zhang, J.F. A polysaccharide isolated from the medicinal herb Bletilla striata induces endothelial cells proliferation and vascular endothelial growth factor expression in vitro. Biotechnol. Lett. 2006, 28, 539–543. [Google Scholar] [CrossRef]
  169. Shen, S.H.; Chen, X.W.; Shen, Z.W.; Chen, H. Marine Polysaccharides for Wound Dressings Application: An Overview. Pharmaceutics 2021, 13, 1666. [Google Scholar] [CrossRef]
  170. Park, G.Y.; Yeum, J.H.; Yang, D.J.; Park, G.O.; Kim, Y.H.; Jeon, S.; Kim, T.J.; Oh, E.J.; Chung, H.Y.; Choi, J.H. Moisture Wound Healing Characteristics of Alginate Sponge and Hydrogel. Polym. Korea 2018, 42, 112–118. [Google Scholar] [CrossRef]
  171. Fibrich, B.; Gao, X.Y.; Puri, A.; Banga, A.K.; Lall, N. In Vitro Antioxidant, Anti-Inflammatory and Skin Permeation of Myrsine africana and Its Isolated Compound Myrsinoside B. Front. Pharmacol. 2020, 10, 1410. [Google Scholar] [CrossRef] [PubMed]
  172. Park, S.Y.; Lee, H.U.; Lee, Y.C.; Kim, G.H.; Park, E.C.; Han, S.H.; Lee, J.G.; Choi, S.; Heo, N.S.; Kim, D.L.; et al. Wound healing potential of antibacterial microneedles loaded with green tea extracts. Mater. Sci. Eng. C-Mater. Biol. Appl. 2014, 42, 757–762. [Google Scholar] [CrossRef] [PubMed]
  173. Xie, Y.; Wang, H.; Mao, J.Z.; Li, Y.C.; Hussain, M.; Zhu, J.J.; Li, Y.; Zhang, L.B.; Tao, J.; Zhu, J.T. Enhanced in vitro efficacy for inhibiting hypertrophic scar by bleomycin-loaded dissolving hyaluronic acid microneedles. J. Mater. Chem. B 2019, 7, 6604–6611. [Google Scholar] [CrossRef] [PubMed]
  174. Zhang, N.; Xue, L.P.; Younas, A.; Liu, F.F.; Sun, J.H.; Dong, Z.L.; Zhao, Y.X. Co-delivery of triamcinolone acetonide and verapamil for synergistic treatment of hypertrophic scars via carboxymethyl chitosan and Bletilla striata polysaccharide-based microneedles. Carbohydr. Polym. 2022, 284, 119219. [Google Scholar] [CrossRef] [PubMed]
  175. Bejarano, J.J.R.; Valdecantos, W.C. Psoriasis as Autoinflammatory Disease. Dermatol. Clin. 2013, 31, 445–460. [Google Scholar] [CrossRef]
  176. Du, H.Y.; Liu, P.; Zhu, J.J.; Lan, J.J.; Li, Y.; Zhang, L.B.; Zhu, J.T.; Tao, J. Hyaluronic Acid-Based Dissolving Microneedle Patch Loaded with Methotrexate for Improved Treatment of Psoriasis. Acs Appl. Mater. Interfaces 2019, 11, 43588–43598. [Google Scholar] [CrossRef] [PubMed]
  177. Wang, Y.X.; Fu, S.J.; Lu, Y.; Lai, R.R.; Liu, Z.Y.; Luo, W.X.; Xu, Y.H. Chitosan/hyaluronan nanogels co-delivering methotrexate and 5-aminole-vulinic acid: A combined chemo-photodynamic therapy for psoriasis. Carbohydr. Polym. 2022, 277, 118819. [Google Scholar] [CrossRef]
  178. Banchereau, J.; Briere, F.; Caux, C.; Davoust, J.; Lebecque, S.; Liu, Y.T.; Pulendran, B.; Palucka, K. Immunobiology of dendritic cells. Annu. Rev. Immunol. 2000, 18, 265–267. [Google Scholar] [CrossRef]
  179. Ling, M.H.; Chen, M.C. Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to diabetic rats. Acta Biomater. 2013, 9, 8952–8961. [Google Scholar] [CrossRef]
  180. Liu, S.; Jin, M.N.; Quan, Y.S.; Kamiyama, F.; Katsumi, H.; Sakane, T.; Yamamoto, A. The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin. J. Control. Release 2012, 161, 933–941. [Google Scholar] [CrossRef]
  181. Yu, W.J.; Jiang, G.H.; Zhang, Y.; Liu, D.P.; Xu, B.; Zhou, J.Y. Polymer microneedles fabricated from alginate and hyaluronate for transdermal delivery of insulin. Mater. Sci. Eng. C-Mater. Biol. Appl. 2017, 80, 187–196. [Google Scholar] [CrossRef] [PubMed]
  182. Fonseca, D.F.S.; Costa, P.C.; Almeida, I.F.; Dias-Pereira, P.; Correia-Sa, I.; Bastos, V.; Oliveira, H.; Duarte-Araujo, M.; Morato, M.; Vilela, C.; et al. Pullulan microneedle patches for the efficient transdermal administration of insulin envisioning diabetes treatment. Carbohydr. Polym. 2020, 241, 116314. [Google Scholar] [CrossRef] [PubMed]
  183. GhavamiNejad, A.; Li, J.; Lu, B.; Zhou, L.; Lam, L.; Giacca, A.; Wu, X.Y. Glucose-Responsive Composite Microneedle Patch for Hypoglycemia-Triggered Delivery of Native Glucagon. Adv. Mater. 2019, 31, 1901051. [Google Scholar] [CrossRef]
  184. Yu, Y.; Shen, M.Y.; Song, Q.Q.; Xie, J.H. Biological activities and pharmaceutical applications of polysaccharide from natural resources: A review. Carbohydr. Polym. 2018, 183, 91–101. [Google Scholar] [CrossRef] [PubMed]
  185. Chen, F.; Huang, G.L. Preparation and immunological activity of polysaccharides and their derivatives. Int. J. Biol. Macromol. 2018, 112, 211–216. [Google Scholar] [CrossRef] [PubMed]
  186. Jiang, P.-L.; Lin, H.-J.; Wang, H.-W.; Tsai, W.-Y.; Lin, S.-F.; Chien, M.-Y.; Liang, P.-H.; Huang, Y.-Y.; Liu, D.-Z. Galactosylated liposome as a dendritic cell-targeted mucosal vaccine for inducing protective anti-tumor immunity. Acta Biomater. 2015, 11, 356–367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  187. Yang, X.; Wang, X.; Hong, H.; Elfawal, G.; Lin, S.; Wu, J.; Jiang, Y.; He, C.; Mo, X.; Kai, G.; et al. Galactosylated chitosan-modified ethosomes combined with silk fibroin nanofibers is useful in transcutaneous immunization. J. Control. Release 2020, 327, 88–99. [Google Scholar] [CrossRef]
  188. Kim, J.-K.; Cho, M.L.; Karnjanapratum, S.; Shin, I.-S.; You, S.G. In vitro and in vivo immunomodulatory activity of sulfated polysaccharides from Enteromorpha prolifera. Int. J. Biol. Macromol. 2011, 49, 1051–1058. [Google Scholar] [CrossRef]
  189. Chen, Y.; Zhang, H.; Wang, Y.X.; Nie, S.P.; Li, C.; Xie, M.Y. Acetylation and carboxymethylation of the polysaccharide from Ganoderma atrum and their antioxidant and immunomodulating activities. Food Chem. 2014, 156, 279–288. [Google Scholar] [CrossRef]
  190. Mandal, A.; Boopathy, A.V.; Lam, L.K.W.; Moynihan, K.D.; Welch, M.E.; Bennett, N.R.; Turvey, M.E.; Thai, N.; Van, J.H.; Love, J.C.; et al. Cell and fluid sampling microneedle patches for monitoring skin-resident immunity. Sci. Transl. Med. 2018, 10, eaar2227. [Google Scholar] [CrossRef]
  191. Gong, Q.; Yu, H.; Ding, G.; Ma, J.; Wang, Y.; Cheng, X. Suppression of stemness and enhancement of chemosensibility in the resistant melanoma were induced by Astragalus polysaccharide through PD-L1 downregulation. Eur. J. Pharmacol. 2022, 916, 174726. [Google Scholar] [CrossRef] [PubMed]
  192. Carvalho, S.M.; Mansur, A.A.P.; Capanema, N.S.V.; Carvalho, I.C.; Chagas, P.; de Oliveira, L.C.A.; Mansur, H.S. Synthesis and in vitro assessment of anticancer hydrogels composed by carboxymethylcellulose-doxorubicin as potential transdermal delivery systems for treatment of skin cancer. J. Mol. Liq. 2018, 266, 425–440. [Google Scholar] [CrossRef]
  193. He, L.Z.; Huang, G.N.; Liu, H.X.; Sang, C.C.; Liu, X.X.; Chen, T.F. Highly bioactive zeolitic imidazolate framework-8-capped nanotherapeutics for efficient reversal of reperfusion-induced injury in ischemic stroke. Sci. Adv. 2020, 6, eaay9751. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Allawadhi, P.; Singh, V.; Govindaraj, K.; Khurana, I.; Sarode, L.P.; Navik, U.; Banothu, A.K.; Weiskirchen, R.; Bharani, K.K.; Khurana, A. Biomedical applications of polysaccharide nanoparticles for chronic inflammatory disorders: Focus on rheumatoid arthritis, diabetes and organ fibrosis. Carbohydr. Polym. 2022, 281, 118923. [Google Scholar] [CrossRef]
  195. Shang, Z.-Z.; Qin, D.-Y.; Li, Q.-M.; Zha, X.-Q.; Pan, L.-H.; Peng, D.-Y.; Luo, J.-P. Dendrobium huoshanense stem polysaccharide ameliorates rheumatoid arthritis in mice via inhibition of inflammatory signaling pathways. Carbohydr. Polym. 2021, 258, 117657. [Google Scholar] [CrossRef]
  196. Elkomy, M.H.; Alruwaili, N.K.; Elmowafy, M.; Shalaby, K.; Zafar, A.; Ahmad, N.; Alsalahat, I.; Ghoneim, M.M.; Eissa, E.M.; Eid, H.M. Surface-Modified Bilosomes Nanogel Bearing a Natural Plant Alkaloid for Safe Management of Rheumatoid Arthritis Inflammation. Pharmaceutics 2022, 14, 563. [Google Scholar] [CrossRef]
  197. Nornberg, A.B.; Martins, C.C.; Cervi, V.F.; Sari, M.H.M.; Cruz, L.; Luchese, C.; Wilhelm, E.A.; Fajardo, A.R. Transdermal release of methotrexate by cationic starch/poly(vinyl alcohol)-based films as an approach for rheumatoid arthritis treatment. Int. J. Pharm. 2022, 611, 121285. [Google Scholar] [CrossRef]
  198. Hu, H.; Ruan, H.; Ruan, S.; Pei, L.; Jing, Q.; Wu, T.; Hou, X.; Xu, H.; Wang, Y.; Feng, N.; et al. Acid-responsive PEGylated branching PLGA nanoparticles integrated into dissolving microneedles enhance local treatment of arthritis. Chem. Eng. J. 2022, 431, 134196. [Google Scholar] [CrossRef]
  199. Kodoth, A.K.; Ghate, V.M.; Lewis, S.A.; Prakash, B.; Badalamoole, V. Pectin-based silver nanocomposite film for transdermal delivery of Donepezil. Int. J. Biol. Macromol. 2019, 134, 269–279. [Google Scholar] [CrossRef]
  200. Xie, X.; Pascual, C.; Lieu, C.; Oh, S.; Wang, J.; Zou, B.; Xie, J.; Li, Z.; Xie, J.; Yeomans, D.C.; et al. Analgesic Microneedle Patch for Neuropathic Pain Therapy. Acs Nano 2017, 11, 395–406. [Google Scholar] [CrossRef]
  201. Stana, J.; Stergar, J.; Gradisnik, L.; Flis, V.; Kargl, R.; Froehlich, E.; Kleinschek, K.S.; Mohan, T.; Maver, U. Multilayered Polysaccharide Nanofilms for Controlled Delivery of Pentoxifylline and Possible Treatment of Chronic Venous Ulceration. Biomacromolecules 2017, 18, 2732–2746. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Four types of polysaccharide-based vehicles in transdermal drug delivery.
Figure 1. Four types of polysaccharide-based vehicles in transdermal drug delivery.
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Figure 2. A schematic diagram of the dual network polysaccharide hydrogel and photothermal effect accelerated the gelation and degradation rate of the hydrogel and gallic acid with Fe3+ showed good antibacterial properties. OBSP: oxidized Bletilla striata polysaccharide; GA-CS: gallic acid grafted chitosan [66]. Reproduced with permission from Chonghao Chen, Carbohydrate Polymers; published by Elsevier, 2021.
Figure 2. A schematic diagram of the dual network polysaccharide hydrogel and photothermal effect accelerated the gelation and degradation rate of the hydrogel and gallic acid with Fe3+ showed good antibacterial properties. OBSP: oxidized Bletilla striata polysaccharide; GA-CS: gallic acid grafted chitosan [66]. Reproduced with permission from Chonghao Chen, Carbohydrate Polymers; published by Elsevier, 2021.
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Figure 3. Schematic diagram of the process of nanoemulsions (NE)-film and the size and PDI analysis of formulation for three months after ultrasonication process and the release effect compared with a physical mixture for 24 h [82]. Reproduced with permission from Talita Nascimento daSilva, International Journal of Biological Macromolecules; published by Elsevier, 2020.
Figure 3. Schematic diagram of the process of nanoemulsions (NE)-film and the size and PDI analysis of formulation for three months after ultrasonication process and the release effect compared with a physical mixture for 24 h [82]. Reproduced with permission from Talita Nascimento daSilva, International Journal of Biological Macromolecules; published by Elsevier, 2020.
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Figure 4. Schematic diagram of the preparation process and ovalbumin (OVA) delivery condition. (a) Two-step preparation of Bletilla striata polysaccharide (BSP) microneedle (MN) (BMN). (b) Transdermal drug delivery of the OVA-loaded BMN system and the release of the drug can be triggered by the dissolving of BSP in the skin interstitial fluid [97]. Reproduced with permission from Ping Zhou, International Journal of Biological Macromolecules; published by Elsevier, 2022.
Figure 4. Schematic diagram of the preparation process and ovalbumin (OVA) delivery condition. (a) Two-step preparation of Bletilla striata polysaccharide (BSP) microneedle (MN) (BMN). (b) Transdermal drug delivery of the OVA-loaded BMN system and the release of the drug can be triggered by the dissolving of BSP in the skin interstitial fluid [97]. Reproduced with permission from Ping Zhou, International Journal of Biological Macromolecules; published by Elsevier, 2022.
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Figure 5. Schematic diagram of the preparation of the NE and its hypoglycemic effect, skin irritation, and in vivo antidiabetic evaluation [129]. Reproduced with permission from Fizza Abdul Razzaq, Cells; published by MDPI, 2021.
Figure 5. Schematic diagram of the preparation of the NE and its hypoglycemic effect, skin irritation, and in vivo antidiabetic evaluation [129]. Reproduced with permission from Fizza Abdul Razzaq, Cells; published by MDPI, 2021.
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Figure 6. Schematic illustration of the curcumin-loaded HA-ES targeted CD44 protein and reduced the level of TNF-α, IL-17A, IL-17F mRNA, etc., and lowered the expression of CCR-6 protein [141]. Reproduced with permission from Yongtai Zhang, THERANOSTICS; published by Ivyspring International, 2019.
Figure 6. Schematic illustration of the curcumin-loaded HA-ES targeted CD44 protein and reduced the level of TNF-α, IL-17A, IL-17F mRNA, etc., and lowered the expression of CCR-6 protein [141]. Reproduced with permission from Yongtai Zhang, THERANOSTICS; published by Ivyspring International, 2019.
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Figure 7. Schematic representation of the chitosan (CS) MNs for influenza vaccination delivery. The CS MN is easy to implant in the skin for sustained release of vaccines and immune activation [163]. Reproduced with permission from Yu-Hung Chen, Acta Biomaterialia; published by Elsevier, 2019.
Figure 7. Schematic representation of the chitosan (CS) MNs for influenza vaccination delivery. The CS MN is easy to implant in the skin for sustained release of vaccines and immune activation [163]. Reproduced with permission from Yu-Hung Chen, Acta Biomaterialia; published by Elsevier, 2019.
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Figure 8. A schematic diagram exhibiting the application of Chinese herb MN (CHMN) patch made from Premna microphylla and Centella Asiatica extractions for wound healing [21]. Reproduced with permission from Junjie Chi, Bioactive Materials; published by KEAI, 2021.
Figure 8. A schematic diagram exhibiting the application of Chinese herb MN (CHMN) patch made from Premna microphylla and Centella Asiatica extractions for wound healing [21]. Reproduced with permission from Junjie Chi, Bioactive Materials; published by KEAI, 2021.
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Figure 9. Schematic diagram of the administration of BSP-MNs-QUE@HSF/CDF, which can make active targeting hypertrophic scars (HSs). The HSs treatment efficacy was improved by reducing the expression of collagen I and III in HSs and regulating the pathways of β-catenin and STAT3 [98]. Reproduced with permission from Tong Wu, ACS nano; published by American Chemical Society, 2022.
Figure 9. Schematic diagram of the administration of BSP-MNs-QUE@HSF/CDF, which can make active targeting hypertrophic scars (HSs). The HSs treatment efficacy was improved by reducing the expression of collagen I and III in HSs and regulating the pathways of β-catenin and STAT3 [98]. Reproduced with permission from Tong Wu, ACS nano; published by American Chemical Society, 2022.
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Figure 10. Schematic diagram of combined chemical-photodynamic treatment of psoriasis with MTX and ALA loaded CS/HA nanogels (NGs). MTX-ALA NGs promoted the penetration of both ALA and MTX into the skin, synergistically enhancing the local treatment of psoriasis and reducing the toxicity and pain associated with the photodynamic therapy of ALA and oral MTX [177]. Reproduced with permission from Yixuan Wang, Carbohydrate Polymers; published by Elsevier, 2022.
Figure 10. Schematic diagram of combined chemical-photodynamic treatment of psoriasis with MTX and ALA loaded CS/HA nanogels (NGs). MTX-ALA NGs promoted the penetration of both ALA and MTX into the skin, synergistically enhancing the local treatment of psoriasis and reducing the toxicity and pain associated with the photodynamic therapy of ALA and oral MTX [177]. Reproduced with permission from Yixuan Wang, Carbohydrate Polymers; published by Elsevier, 2022.
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Figure 11. Schematic diagram of the preparation of the dissolved Panax notoginseng polysaccharides MN (PNPS MNs) and in vivo activation process. (a) The preparation process of PNPS MNs loaded with the model drugs. (b) PNPS MNs dissolved and activated skin dendritic cells and triggered DC-initiated T cell immune response for transcutaneous immunization [99]. Reproduced with permission from Chengxiao Wang, Carbohydrate Polymers; published by Elsevier, 2021.
Figure 11. Schematic diagram of the preparation of the dissolved Panax notoginseng polysaccharides MN (PNPS MNs) and in vivo activation process. (a) The preparation process of PNPS MNs loaded with the model drugs. (b) PNPS MNs dissolved and activated skin dendritic cells and triggered DC-initiated T cell immune response for transcutaneous immunization [99]. Reproduced with permission from Chengxiao Wang, Carbohydrate Polymers; published by Elsevier, 2021.
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Figure 12. Schematic diagram of glucose responsiveness that triggers the self-adjustable release of insulin and perception of blood glucose in real-time. (a) Insulin mineralization under Ca2+. (b) Dual-functional MN prepared by cross-linking and micro-molding. (c) Self-regulated release of insulin is triggered by glucose responsiveness and real-time glucose sensing [108]. Reproduced with permission from Xuetong Sun, Biomaterials Science; published by The Royal Society of Chemistry, 2022.
Figure 12. Schematic diagram of glucose responsiveness that triggers the self-adjustable release of insulin and perception of blood glucose in real-time. (a) Insulin mineralization under Ca2+. (b) Dual-functional MN prepared by cross-linking and micro-molding. (c) Self-regulated release of insulin is triggered by glucose responsiveness and real-time glucose sensing [108]. Reproduced with permission from Xuetong Sun, Biomaterials Science; published by The Royal Society of Chemistry, 2022.
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Figure 13. A schematic diagram of the preparation of the Eth-HA-GC/SF loaded OVA, causing cellular and humoral immune responses in the mouse model [187]. Reproduced with permission from Xingxing Yang, Journal of Controlled Release; published by Elsevier, 2020.
Figure 13. A schematic diagram of the preparation of the Eth-HA-GC/SF loaded OVA, causing cellular and humoral immune responses in the mouse model [187]. Reproduced with permission from Xingxing Yang, Journal of Controlled Release; published by Elsevier, 2020.
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Figure 14. Schematic representation of (a) the preparation of CPT-CuS-ZIF-8@HA and (b) multifunctional nanoparticle-integrated DMNs for transdermal drug delivery, smart drug release, targeted delivery, and synergistic chemotherapy-photothermal therapy in melanoma [105]. Reproduced with permission from Yiting Zhao, Acta Biomaterialia; published by Elsevier, 2021.
Figure 14. Schematic representation of (a) the preparation of CPT-CuS-ZIF-8@HA and (b) multifunctional nanoparticle-integrated DMNs for transdermal drug delivery, smart drug release, targeted delivery, and synergistic chemotherapy-photothermal therapy in melanoma [105]. Reproduced with permission from Yiting Zhao, Acta Biomaterialia; published by Elsevier, 2021.
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Figure 15. Schematic representation of the preparation of acid-responsive released [6s-NPs (CaCO3)] MN and the in vivo regulation of the VEGF, JAK2, and STAT3 pathways for the treatment of Rheumatoid Arthritis (RA) [198]. Reproduced with permission from Hu, Hongmei, Chemical Engineering Journal; published by Elsevier, 2022.
Figure 15. Schematic representation of the preparation of acid-responsive released [6s-NPs (CaCO3)] MN and the in vivo regulation of the VEGF, JAK2, and STAT3 pathways for the treatment of Rheumatoid Arthritis (RA) [198]. Reproduced with permission from Hu, Hongmei, Chemical Engineering Journal; published by Elsevier, 2022.
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MDPI and ACS Style

Li, J.; Xiang, H.; Zhang, Q.; Miao, X. Polysaccharide-Based Transdermal Drug Delivery. Pharmaceuticals 2022, 15, 602. https://doi.org/10.3390/ph15050602

AMA Style

Li J, Xiang H, Zhang Q, Miao X. Polysaccharide-Based Transdermal Drug Delivery. Pharmaceuticals. 2022; 15(5):602. https://doi.org/10.3390/ph15050602

Chicago/Turabian Style

Li, Jingyuan, Hong Xiang, Qian Zhang, and Xiaoqing Miao. 2022. "Polysaccharide-Based Transdermal Drug Delivery" Pharmaceuticals 15, no. 5: 602. https://doi.org/10.3390/ph15050602

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