Chemical and Physical Chitosan Hydrogels for Drug Delivery (Review) PDF

Journal of Materials Chemistry B...

Journal of Materials Chemistry B View Article Online REVIEW View Journal | View Issue Chemical and physical chitosan hydrogels as prospective carriers for drug delivery: a review Published on 19 October 2020. Downloaded by Brock University on 10/29/2024 9:38:05 AM. Cite this: J. Mater. Chem. B, 2020, 8, 10050 Bingren Tian, †*a Shiyao Hua,†b Yu Tianc and Jiayue Liu *b With the advancement of medical research, the source and preparation of biological materials have gradually attracted attention. Hydrogels prepared from natural polysaccharides have been extensively applied in the medical field. The biocompatibility, excellent degradability and low toxicity of chitosan have favored the use of chitosan hydrogels as prospective carriers for drug delivery. Special chitosan hydrogels that effectively Received 1st August 2020, release target drugs based on different environmental stimuli have also been developed. This article reviews Accepted 22nd September 2020 recent research progress in the development of chemical and physical chitosan hydrogels for drug delivery. DOI: 10.1039/d0tb01869d In particular, preparation methods together with the chemical and physical properties of chitosan hydrogels are summarized. We also discuss multiple mechanisms of drug release from chitosan hydrogels. Finally, we rsc.li/materials-b highlight the future prospects of chitosan hydrogels in medical research. 1. Introduction Recent decades have seen the rapid development of materials science, evidenced by the speedy advancement and production of multiple novel materials.1–4 In particular, good biocompat- ibility allows the use of such materials in medicine.5–7 Among biomaterials, hydrogels have received unrivalled attention due to their excellent biocompatibility, biodegradability and reactivity properties.8 Fig. 1 The structure of chitosan. A hydrogel is a 3D molecule, composed of cross-linked network-like soft materials.9–11 According to current preparation methods, there are two broad classes of hydrogels: physical hydro- aminopolysaccharide with widespread resources and does not gels and chemical hydrogels.12,13 Structurally, physical hydrogels induce acute cytotoxicity.23–25 The large number of amino and mainly display molecular interactions including ionic cross-linking, hydroxyl groups in chitosan provide functional groups for hydrogen bonding and hydrophobic interactions.14,15 In contrast, chemical reactions (Fig. 1).26 Unfortunately, chitosan has poor chemical hydrogels are characterized by covalent bonding between water solubility, but can readily dissolve in acidic solutions, constitutive molecules.16 Importantly, chemical hydrogels cannot because at pH o 6.3, amino groups in the molecule are easily be destroyed by water molecules.17 Overall, hydrogels have good converted into ammonium groups.27,28 This notwithstanding, loading capacity for both small and large molecules. Because chitosan can easily be degraded by various enzymes and then hydrogels are similar to normal tissue in terms of physiological excreted from the body.29,30 Consequently, these excellent charac- activity, they can load and diffuse nutrients under normal teristics make chitosan hydrogels ideal materials for biomedical biological conditions.18–20 applications. Hydrogels can be prepared from synthetic or natural materials Both chemical and physical chitosan hydrogels can be such as chitosan, sodium alginate, hyaluronic acid, cellulose, effectively loaded with multiple drugs owing to their suitable PEG, PVA, etc.12,18,21,22 In particular, chitosan is a natural cavity structure, displaying excellent drug delivery properties, both in vivo and in vitro. In addition, as drug carriers, chitosan a School of Chemical Engineering and Technology, Xinjiang University, hydrogels offer several advantages compared with other drug Urumchi 830046, China. E-mail: [email protected] carriers. For instance, many raw materials for chitosan hydro- b School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China. gels are cheap. In addition, chitosan hydrogels can carry a wide E-mail: [email protected] c School of Computer Science and Engineering, Beihang University, Beijing 100083, range of drug molecules, ranging from small molecules to China proteins. Also, chitosan hydrogels are easily metabolized in † These authors contributed equally to this work. the human body into small molecules without obvious toxic 10050 | J. Mater. Chem. B, 2020, 8, 10050--10064 This journal is © The Royal Society of Chemistry 2020  View Article Online Review Journal of Materials Chemistry B side effects. These key properties make chitosan hydrogels regulating the amount of crosslinking agents (glutaraldehyde prospective carriers for drug delivery. This article reviews the and tripolyphosphate) added to chitosan. Interestingly each cross- applications of both chemical and physical chitosan hydrogels linking agent produces a microphore with unique morphology. for the delivery of different drugs. We also discuss different The aldehyde group of glutaraldehyde reacts with the amino group preparation methods and drug release mechanisms of chitosan of chitosan to form a Schiff base. The microsphere resulting from hydrogels. Most importantly, we highlight the future prospects the crosslinking of the chitosan hydrogel with glutaraldehyde is of chitosan hydrogels with regard to medical applications. spherical with a smooth surface and uniform size. In contrast, tripolyphosphate cross-linked chitosan hydrogel microspheres are structurally loose, rough and spherical, mainly attributed to the 2. Formation of chitosan hydrogels electrostatic attraction between the phosphate and the amino Published on 19 October 2020. Downloaded by Brock University on 10/29/2024 9:38:05 AM. groups of tripolyphosphate and chitosan respectively.42 However, In general, drug carriers and delivery molecules can be pre- glutaraldehyde often causes neurological and other cytotoxicities. pared through multiple methods. With regard to drug Also, excess glutaraldehyde constraints the preparation of the delivery, some properties such as biodegradation and swelling corresponding hydrogel.43 Notably, future research should focus make chitosan hydrogels ideal for such functions. The physical on the metabolism and excretion of glutaraldehyde from the and chemical properties of chitosan hydrogels are inherent to human body. Macromolecules containing aldehydes can be used the different preparation methods.31 For example, the purpose for the preparation of chitosan hydrogels. Here, increasing the for which a chitosan hydrogel is used determines its prepara- concentration of bifunctional PEG acetaldehyde in the hydrogel tion method. Drugs and hydrogels mainly interact through improves the desirable properties of the hydrogel. The maximum covalent and non-covalent bonding (Table 1). This section mechanical strength of a 12% hydrogel is 165.47 Pa, whereas that mainly discusses the two methods used for preparing chitosan of a 3% hydrogel is 6.24 Pa, the latter indicative of insufficient hydrogels. crosslinking. For chemical gels, the storage modulus remains unchanged at strains between 0.1 and 100%, implying that these 2.1. Hydrogels linked by a chemical method types of hydrogels are viscoelastically stable. However, when the Structurally, chitosan has multiple active amino and hydroxyl strain is increased from 1 to 1000%, the storage modulus groups, which can react with other cross-linking agents to form immediately decreases, indicative of a denatured hydrogel stable chemical hydrogels.32,33 Although these hydrogels have many network, but decreasing the strain to 1% restores the initial advantages, some cross-linking agents used in the preparation modulus. Notably, the aldehyde based hydrogel exhibited process are biotoxic. Therefore, use of such agents should be satisfactory recovery performance within 5 cycles.44 George avoided during the preparation of biomedical hydrogels. et al. performed a similar assessment, but using the Schiff Tetrakis-(hydroxymethyl)-phosphonium-chloride (THPC) is one base cross-linking method to prepare a nano-hybrid hydrogel. of the cross-linking agents that reacts with the amino groups of First, chitosan was dissolved in acetic acid solution and then chitosan to form the corresponding hydrogel.34,35 THPC changes the dialdehyde cellulose was added as the cross-linking agent and color of the hydrogel and makes it fragile and brittle. Interestingly, stirred thoroughly to ensure effective bonding. The infrared when the amount of added THPC reaches 36%, the drug release by spectrum revealed covalent bonding between chitosan and the the corresponding hydrogel is impaired.36 interlinking agent. The 3D hydrogel was smooth with clear Aldehydes, epoxy compounds, esters, etc. are the commonly visible pores.45 Meanwhile addition reactions can also be used used chemical crosslinking agents for the preparation of for the preparation of hydrogels. For instance, the Michael hydrogels.37–39 In aqueous solution, aldehydes form an imino addition method involves the reaction between derivatized bond with the amino group of chitosan, to form a bio- trimethyl chitosan and PEG diethyl acrylate to form a local compatible compound. Glutaraldehyde can act as a cross- release injectable hydrogel.46 linking agent, shown to form a homogeneous porous chitosan The corresponding chitosan hydrogel can also be obtained hydrogel.40,41 A chitosan hydrogel is successfully prepared by by free radical polymerization.47–49 Ghaem et al. first added Table 1 Comparison of the properties of chitosan hydrogels loaded with drugs Types of drug Small molecules Small molecules; peptides Small molecules; peptides; proteins Hydrogel formation Physical hydrogels; Physical hydrogels; Physical hydrogels; chemical chemical hydrogels chemical hydrogels hydrogels Drug loading strategies Permeation Entrapment Chemical bonding In situ gelation possible No Yes Yes Drug release speed Rapid Moderate Can be controlled Possible mechanisms Polymer dissolution Polymer dissolution External stimulus; polymer and degradation and degradation dissolution and degradation Duration times Hours to days Days to weeks Days to months Characterization High drug loading effectivity Suitable for hydrophilic and Suitable for hydrophilic drugs; (suitable for hydrophilic drugs); hydrophobic drugs; moderate high probability to change the low chance of drug deactivation chance of drug deactivation structure of the drug This journal is © The Royal Society of Chemistry 2020 J. Mater. Chem. B, 2020, 8, 10050--10064 | 10051  View Article Online Journal of Materials Chemistry B Review acrylic acid and N,N-methylenebisacrylamide in chitosan and stopping any further processes. Therefore, it is necessary to regulate mixed them thoroughly for 30 minutes in the presence of the amount of added small molecules.61 ammonium persulfate as an initiator. Hydrogels were then Freeze-thawing is one of the commonly used methods for prepared at room temperature. The resultant hydrogels had a preparing physical hydrogels.62,63 Research shows that the freezing cavity structure greater than 100 nanometers, ideal for drug process, apart from hydrogen bonding, results in the formation of delivery.50 Reversible addition–fragmentation chain transfer ice crystals in the polymers. Upon melting, the crystals act as holes in polymerization is one of the mainstream methods for polymer the hydrogel network. The physically cross-linked hydrogels pre- synthesis.51,52 Qian and colleagues prepared a hydrogel by first pared by freeze-thawing are non-toxic, non-carcinogenic, have good adding acetic anhydride into chitosan solution to prevent the biocompatibility, high mechanical strength and do not need cross- acetylation of the amino group. They then dissolved acetylated linking agents to initiate the process. Elsewhere, polyvinyl alcohol Published on 19 October 2020. Downloaded by Brock University on 10/29/2024 9:38:05 AM. chitosan in DMF and then added dicyclohexylcarbodiimide, (PVA) and chitosan were dissolved in hot water, then CeO2 nano- 4-(N,N-dimethylamino)pyridine, S-1-dodecyl-S 0 -(a,a 0 -dimethyl- particles were added and the solution was allowed to reach room a00 -acetic acid) and trithiocarbonate for polymerization. The temperature. The solution was thawed several times before the reaction solution was then poured into ice water and filtered formation of the final polymer. The hydrogen bonds between to obtain the product. Notably, this hydrogel was found to have chitosan and PVA resulted in a 3D structure during the nucleation a significant phase transition temperature of 25–34 1C.53 and growth of the polymer interpenetrating network. When the polymer chain freezes, cores form in the polymer solution, but upon 2.2. Hydrogels linked by a physical method thawing, the polymer chain systematically forms a crystal structure Compared with chemical hydrogel preparation, physical cross- near the core. Addition of CeO2 nanoparticles to the hydrogel linking methods offer the advantage of non-use of toxic cross- increased the porosity of the hydrogel, which ranged between 81 linking agents. Here, the respective hydrogels can be obtained by and 90%. The porous structure of the hydrogel enables the adsorp- anion–cation interactions, hydrogen bonding or hydrophobic tion of exudates from the wound surface, which helps in healing.64 bonding.54 Non-toxicity notwithstanding, physical hydrogels also have some deficiencies; they are unstable and have low mechan- ical strength and it is difficult to regulate their pore sizes. 3. Drug release mechanism of Physical hydrogels have been introduced to facilitate effective chitosan hydrogels drug delivery.55–57 Peers et al. prepared liposomes by adding chitosan solution into 1,2-dipalmitoyl-sn-glycero-3-phospho- Several research studies have been conducted on the mechanism of choline. This allowed the production of a chitosan hydrogel with- drug release from chitosan hydrogels.65–67 In fact, drug release out using chemical cross-linking agents or organic solvents (Fig. 4). mechanisms depend on the different physical and chemical prop- Intriguingly, addition of ammonia during the preparation process erties of hydrogels. In general, drug release mechanisms are was found to reduce the apparent charge density of the chitosan broadly divided into two categories: rapid and sustained drug chain, conducive to the formation of hydrogen bonds. Meanwhile, release (Fig. 2). As shown in Table 1, drugs can non-covalently for the first time, Peers et al. showed that drug-loaded liposomes bind to hydrogels, which allows the free movement of the drug in could be incorporated into the hydrogel, without an apparent the hydrogel network. When the hydrogel is implanted in the body, change in the rheological properties of the hydrogel.58 Different the concentration gradient formed between the drug and the hybrid hydrogels exhibiting homogeneous morphology and suitable surrounding environment results in an initial explosive release of consistency have been prepared by mixing lipids and chitosan for the drug. However, the rapid increase in drug concentration in the ionic crosslinking.59 surrounding areas gradually slows down drug release from the Utilizing the conventional film preparation method, casting hydrogel. Unfortunately, the rapid release of some drugs can reduce technology, Di Martino and his collaborators successfully prepared their therapeutic effects or even produce toxic side effects. To this a chitosan–collagen hydrogel. By evaluating the interaction between effect, most drugs are usually covalently or physically attached to the raw materials used for the preparation of the hydrogels using the polymer before gelation. In this way, the hydrogel can effectively FTIR-ATR, it was found that chitosan and collagen react to form regulate the movement of drug molecules in the hydrogel network, hydrogen bonds. The hydrogel reached the swelling equilibrium and thus the drug is released only when the hydrogel network is within a few minutes in relevant swelling experiments. Mechanical destroyed under certain conditions. Polymers that respond to performance experiments further showed that hydrogel films dis- various stimuli can be used to control the rate and time of drug played a good combination of strength and flexibility.60 The classical release. Even so, research on drug release from hydrogels is still in method for preparing hydrogels involves the dissolution of chitosan its infant stage, and therefore it is particularly important to analyze in an appropriate acetic acid solution. The solution is then placed in this process. Drug release models such as Korsmeyer–Peppas and a polystyrene orifice plate (2 mL per well) and cured for 48 h at room Weibull could also improve our understanding of the design of temperature to obtain a columnar hydrogel. Tests revealed that the more advanced and reliable hydrogel drug delivery systems. physical method allows covalent bonding of the free hydroxyl groups At this stage, most of the hydrogel drug loading methods involve of chitosan with an active small molecule (cefuroxime). However, placing the hydrogel in the drug containing medium.68–70 Here, the when the concentration of cefuroxime is increased beyond 20%, the drug slowly diffuses into the hydrogel based on the hydrogel pore solution agglomerates immediately after the addition of chitosan, size and the molecular nature of the drug. Unfortunately, this 10052 | J. Mater. Chem. B, 2020, 8, 10050--10064 This journal is © The Royal Society of Chemistry 2020  View Article Online Review Journal of Materials Chemistry B Published on 19 October 2020. Downloaded by Brock University on 10/29/2024 9:38:05 AM. Fig. 2 (A) Drug loading on chitosan hydrogels; (B) drug release mechanism of chitosan hydrogels. passive diffusion lengthens the drug loading time. However, when possible to achieve the gradual release of the loaded drug after the hydrogel is introduced in a living body, the loaded drug delivery into the appropriate organism, thereby reducing side passively diffuses from the hydrogel to nearby lesions against the effects. Compared to other similar delivery systems, chitosan concentration diffusion gradient. Diffusion is controlled by the hydrogels are the most extensively studied drug delivery vehi- movement of the polymer matrix or the overall breakdown of cles. This section focuses on various types of chitosan hydrogels the hydrogel in the body. This drug loading method is very effective based on the types of delivered drugs. It also explores the future for the delivery of small molecule drugs, but undesirable for large application prospects of chitosan hydrogels. molecule types (peptides and proteins). Drugs that cannot be loaded by this method could be first coupled onto internal carriers 4.1. Antibiotic drugs such as liposomes, micelles, etc. and then encapsulated externally The discovery of antibiotics has almost eliminated the threat on the hydrogel.71,72 posed by bacteria.76–78 However, the indiscriminate use of Thanks to advances in materials preparation, smart chito- antibiotics has led to the emergence or re-emergence of bacterial san hydrogels that release drugs in response to external stimuli resistance, ultimately causing more serious harm to humans.79 signals (pH, temperature, light, etc.) have been developed.73–75 Notably, the sudden release of antibiotics by general drug carriers These smart chitosan hydrogels effectively regulate drug release is inevitably accompanied by several side effects. In order to through their open pore-like structures, in response to different address these shortcomings, chitosan hydrogels have been suc- surrounding stimuli. Stimulus-responsive hydrogels are based cessfully developed, effectively controlling the release of antibiotics on physiological discrepancies between normal and diseased (Table 2). tissues. For example, the pH around cancer tissues is lower Usually, bacteria adhere to the surface of the object, forming than normal tissues. In addition, the two tissues differ with mushroom-like or heap-like microcolonies.80 These pathogens regard to enzymatic signatures. Under the deliberate action of are protected by bacterial membranes, which enable the organ- tumor associated enzymes, chitosan hydrogels can be effec- isms to survive the harsh environment. However, the presence tively ‘‘switched’’ to release the drugs in response to the of bacteria can cause various diseases, which will undoubtedly diseases. Some drug molecules can also be isomerized under increase the already ballooning burden of infectious diseases. various external conditions (factors such as light, heat, etc.), P. aeruginosa is one of the bacteria that forms the bacterial which may have an impact on the therapeutic effect of a drug. membrane. The bacteria are implicated in intestinal infections Based on their unique properties, smart chitosan hydrogels and promote the spread of other diseases as well.81 Although continue to attract research attention with regard to drug these pathogenic bacteria have been well characterized, they delivery. can easily develop drug resistance because of impermeable bacterial membranes.82–84 However, the traditional antibiotic administration method is not precise. Consequently, the 4. Delivery of different drugs by amount of drug that can reach the lesion is way below the chitosan hydrogels therapeutic threshold. Therefore, there is an unmet need to develop drug carriers capable of achieving targeted adminis- Ever since chitosan hydrogels are modified and used as drug tration, which can successfully load and accurately deliver carriers, they have become a common treatment method for antibiotics. A micro-container (hydrogel) prepared from func- some diseases at this stage. Using this system, it has been tionalized PEG and chitosan was tested using ciprofloxacin This journal is © The Royal Society of Chemistry 2020 J. Mater. Chem. B, 2020, 8, 10050--10064 | 10053  View Article Online Journal of Materials Chemistry B Review Table 2 Application of chitosan hydrogels in antibiotic drug delivery Hydrogel Drug Formation materials type Types of cells Summary Ref. Cefuroxime Chitosan; acetic Physical L929 cells; MG63 The drug release studies showed that the release of 61 acid cells; S. aureus the drug was higher in phosphate buffer (pH = 7.4) with the esterase enzyme and alkaline medium (pH = 10) compared to phosphate buffer (pH = 7.4) alone. The prepared hydrogels exhibited good hemocompatibility and cell compatibility. Ciprofloxacin Chitosan; PEG; Chemical E. coli; The drug release from hydrogels was significantly 40 hydrochloride glutaraldehyde B. cereus higher at 24 1C (B51%) than at 37 1C (B15%), which indicates that this hydrogel has the property Published on 19 October 2020. Downloaded by Brock University on 10/29/2024 9:38:05 AM. of being temperature sensitive. The hydrogel exhibited antibacterial activity against both the strains. Ciprofloxacin PEG; chitosan Chemical E. coli; Hydrogels loaded with ciprofloxacin showed efficient 44 hydrochloride NIH-3T3 cells activities (Z80%) against E. coli and the antibacterial activities were sustained for up to 12 h. The cellular uptake experiment showed that hydrogels are nontoxic and cytocompatible with NIH-3T3 cells. Ciprofloxacin Chitosan; Physical P. aeruginosa The hydrogel led to an initial release of the drug 85 hydrochloride acetic acid (25.9  5.6%) after 90 min, followed by a subsequent sustained release with 99.5  9.1% being released after 28 h. Treating a mature cell biofilm with the hydrogel modified with chitosan resulted in the killing of 88.2  5.3% of the biofilm cells after 24 h. Ciprofloxacin Chitosan; acetic acid; Chemical NIH3T3 cells Ciprofloxacin could be sustained- released 6 days after 36 hydrochloride tetrakis-(hydroxymethyl)- immersion. Besides, this hydrogel displayed no phosphonium-chloride cytotoxicity for NIH3T3 cells after 48 h of assay. Ciprofloxacin Chitosan; gelation; Chemical L929 cells; E. coli; This hydrogel exhibited a powerful antibacterial effect 41 hydrochloride glutaraldehyde S. aureus; against E. coli, S. aureus and P. aeruginosa P. aeruginosa (25.8  1.1 mm, 36.2  0.9 mm, and 39.8  2.0 mm in vitro, respectively). The results of the in vitro experiment for biocompatibility evaluation by culturing the L929 cells in the leaching solution of scaffolds indicated that the formation materials have good biocompatibility. Ciprofloxacin Carboxymethyl Chemical E. coli; S. aureus; The hydrogels that acted as wound dressings have 96 hydrochloride; chitosan; collagen P. aeruginosa; satisfactory biocompatibility favorable for HSF cell gentamicin HSF cells growth and proliferation. Besides, the diameters sulfate of inhibition zones of E. coli, S. aureus, and P. aeruginosa were (17.8  1.6 mm), (15.6  0.9 mm), and (12.0  0.8 mm), respectively. Clindamycin Chitosan; poly(ethylene Chemical E. coli; S. aureus; Due to being pH responsive, the degradation 91 glycol)methyl ether MRSA speed was faster at pH = 6.5 than that at pH = 7.4, methacrylate which was related to the hydrolysis of the imine bond. The results showed that the killing rate for both S. aureus and MRSA was over 90%, and for E. coli was over 80%. Diclofenac Chitosan; 2-hydroxy-5- Chemical Polymorphonuclear The hydrogels showed drug release in two steps: a burst 97 sodium salt nitrobenzaldehyde neutrophils; effect in the first 24 h, followed by a slow, continuous lymphocytes; release for 8 days in vitro. The release profile monitored eosinophils; by the in vivo tests on rats indicated that this system monocytes; basophils showed an efficient effect for 5 days. Doxycycline Quaternized chitosan; Chemical MRSA; E. coli; The hydrogel groups exhibited more than 95% killing 88 hydrochloride gelatin methacrylate; S. aureus; L929 ratio against S. aureus and E. coli, and even for MRSA, graphene oxide cells the bacterial killing ratio is higher than 90%. In addition, the hydrogels showed good biocompatibility and biodegradability for wound healing applications. Gentamicin Chitosan; glycerin Physical S. aureus; The study results demonstrate that the hydrogel has 95 P. aeruginosa; superior antimicrobial properties, and as evidenced L929 cells by the viability assay and hemolysis assay of L929 cells the hydrogel is not cytotoxic and has good cytocompatibility and hemocompatibility. Moxifloxacin Chitosan; carbomer Physical S. aureus Animals treated with hydrogels daily during this 98 940; EDTA; boswellia period showed significant contraction of the wound gum as compared with the untreated control group. Rifampicin; Chitosan; acetic acid Physical S. aureus; E. coli The results showed that the antibiotics were released 99 minocycline from the scaffolds easily and that they were 100% effective against bacteria in vitro. Vancomycin; Trimethyl chitosan; Chemical S. aureus; The hydrogel combination has the ability to elute the active 46 amikacin poly(ethylene P. aeruginosa; concentrations of vancomycin and amikacin and exhibit glycol)diacrylate L929 cells cytocompatibility with L929 cells, showing its feasibility as an injectable antimicrobial delivery system. 10054 | J. Mater. Chem. B, 2020, 8, 10050--10064 This journal is © The Royal Society of Chemistry 2020  View Article Online Review Journal of Materials Chemistry B hydrochloride. It was found that when using PEG for regulatory drug delivery, the hydrogel released 31.5% of the drug within 10 minutes, while the amount of drug released from the micro- container without PEG reached 44.7%. However, after 90 minutes, there was no obvious difference between the two delivery systems. This implies that at first, chitosan nanoparticles display sudden drug release behavior, but then maintains a gradual and sustained release. It is worth noting that when a drug is administered by traditional means, only 26.1% of the bacteria can be killed. However, when the same drug and dose is coupled to chitosan Published on 19 October 2020. Downloaded by Brock University on 10/29/2024 9:38:05 AM. hydrogel, it inhibits the growth of 88.2% of the bacteria. Overall, the use of chitosan-containing hydrogels for the treatment of biofilm-associated infections has promising prospects as a new delivery strategy.85 In clinical surgery, nosocomial infections are common. Total joint replacements are also closely associated with such infec- tions. In one study, gelatin and THPC were added to chitosan to prepare a hydrogel that could effectively and gradually release ciprofloxacin. A concentration of THPC of between 12% and 36% in the hydrogel was found to gradually increase the total release of the drug within the same experimental time (duration time = 6 days). In addition, the hydrogel exhibited no cytotoxicity after 48 h of treatment of mouse fibroblasts.36 Fig. 3 (a) Schematic diagram of the synthesis of glycidyl methacrylate functionalized quaternized chitosan; (b) synthesis of gelatin methacrylate Numerous microorganisms in seawater can cause infections and the preparation of the GM/GO mixture; (c) scheme of the QCSG/GM/ to injured or broken skin.86,87 Scaffolds with effective biological GO hydrogel’s network and its applications in sterilization and wound functions are highly desired for the treatment of injuries after healing. QCS: quaternized chitosan; QCSG: glycidyl methacrylate functio- seawater immersion. Fang and colleagues successfully pre- nalized quaternized chitosan. Copyright 2020. Reproduced from American pared composite scaffolds of chitosan/gelatin/gelatin micro- Chemical Society. spheres loading ciprofloxacin hydrochloride, achieving wound healing after seawater immersion. Chitosan and gelatin derived hydrogel microspheres could carry ciprofloxacin hydrochloride. this became apparent at day 7. On the 14th day, the wounds in In subsequent in vitro experiments, it was found that the the hydrogel group had completely healed, converse to the corresponding hydrogel had high water absorption capacity control group. Findings of this study suggest that the multi- (1648.98  111.89%), suitable porosity (92.48  3.71%), good antibacterial injectable gel with good biocompatibility confers a fracture resistance (113.19  0.54 MPa), flexibility (10–15%) good wound healing effect against infectious skin tissue and good biocompatibility. Antibacterial experiments showed defects.88 that drug-loaded hydrogels significantly inhibited E. coli S. aureus infections are common worldwide.89,90 In the (25.8  1.1 mm), S. aureus (36.2  0.9 mm) and P. aeruginosa treatment of the corresponding infection, researchers used (39.8  2.0 mm). In addition, the hydrogels displayed a gradual chitosan to prepare a hyperbranched hydrogel that could carry release of antibiotics (release time exceeded 6 days). A seawater clindamycin. The hydrogel exhibited acidic-responsive, con- immersion animal wound infection model further showed that trolled release of clindamycin (pH = 6.5, release percentage = such scaffolds could accelerate wound healing faster than that 80%, 6 days; pH = 7.4, release percentage = 40%, 6 days). The of the control group.41 A similar study found that an injectable antibacterial study showed that the gel was not only effective antibacterial hydrogel could be obtained by reacting functio- against E. coli and S. aureus, but also displayed good antibac- nalized chitosan, methacrylic acid and graphene oxide (Fig. 3). terial activity against MRSA. Approximately 90% of the bacteria The water absorption of the hydrogel could exceed 10 times its were killed upon contact with the hydrogel. A further in vitro volume. Further in vitro experiments validated the antibacterial cytotoxicity test revealed that the gel displayed good biocom- properties of the polytetracycline loaded hydrogel against patibility (the cell survival rate in vitro was 90%), and therefore E. coli, S. aureus and methicillin-resistant S. aureus (MRSA). it presents great practical application potential.91 Cumulative drug release experiments showed that in the first The skin is the first line of defense against infectious agents. 12 h, the amount of drug released from the hydrogel increased That aside it maintains fluid balance and regulates body rapidly, but then declined gradually, reaching maximum cumu- temperature among other functions.92 However, injuries such lative release after 3 days. In addition, in vivo experiments using as burns destroy this defensive line, where the wound exudates a mouse with full-thickness defect wound induced using MRSA allow microorganisms to grow and reproduce, eventually causing revealed that after 3 days, the hydrogel-attached wounds signifi- inflammation.93,94 In order to solve challenges associated with cantly decreased compared to those of the control group, and skin wound treatment, Yan et al. developed a scald dressing This journal is © The Royal Society of Chemistry 2020 J. Mater. Chem. B, 2020, 8, 10050--10064 | 10055  View Article Online Journal of Materials Chemistry B Review method based on a gentamicin loaded chitosan hydrogel. Safety showed that the hydrogel promotes the synthesis of total protein studies revealed that the concentration of the compatible hydrogel (TP) in the granulation tissue of the skin, increases the amount of reached 1000 mg mL1 and the survival rate of L929 cells remained hydroxyproline (HYP), promotes the formation of collagen fibers, at 79.72% after 3 days of culture. Further rabbit wound healing and reduces the expression of cytokines during the inflammatory studies showed that the skin healing rate was as high as 99.61%. response, which collectively accelerates wound healing.95 In order to further illustrate the impact of the hydrogel on wounds, the researchers assessed the wound tissues at different time 4.2. Anaesthetic and hypotensive drugs periods and found that inflammatory cells gradually decreased over Many patients do not tolerate the pain caused by a disease, time in hydrogel-treated wounds, accompanied by the regeneration necessitating surgical resection of the lesion. Anesthetization is of the wound surface, converse to control groups. In-depth analysis however necessary to allow painless operation. However, since Published on 19 October 2020. Downloaded by Brock University on 10/29/2024 9:38:05 AM. Table 3 Application of chitosan hydrogels in anaesthetic and hypotensive drug delivery Hydrogel Drug Formation materials type Types of cells Summary Ref. Anaesthetic drugs Lidocaine Chitosan; acetic acid Physical Not mentioned Evidence shows that the delayed-release properties of 58 the hydrogel enable it to act as a drug reservoir. Lidocaine Chitosan; hyaluronic Chemical Not mentioned In vitro skin permeation studies and in vivo anesthesia 113 acid effect evaluation illustrated that hydrogels could enhance and prolong the anesthetic effect of lidocaine. Lidocaine; Alginate; xanthan; Chemical 3T3 cells; HaCat The hydrogel was stable (for 6 months under critical 59 prilocaine chitosan cells; VERO conditions), showed suitable mechanical properties to cultured cells be orally administered, was safe, and doubled and quadrupled anesthesia duration in comparison to a control hydrogel formulation (without the nanostructured lipid counterpart) and a commercial cream, respectively. Lidocaine; Chitosan; acetic Physical Human dermal The direct contact with the film induces minimal 60 tetracaine; acid fibroblasts cytotoxicity with the cell viability higher than 80% benzocaine up to 72 h. In the presented work a biodegradable hydrogel film was developed to hold and release a mixture of local anesthetics, lidocaine, benzocaine, and tetracaine in an appropriate ratio within 24 h. Hypotensive drugs Dorzolamide Chitosan; hydroxyethyl Physical Not mentioned The hydrogel released approximately 75% of the drug 111 cellulose during a 3 h period. Besides, other studies revealed that more than 50% of the drug remained in the eye after 18 h administration, while only about 30% of the drug remained in the eye after drop administration. Latanoprost Chitosan; gelatin; Chemical Human corneal The percentage of cumulative release at 1, 7, 14 and 28 days 112 glycerol 2-phosphate epithelial cells was 1.34  0.33, 26.80  5.40, 45.03  2.55 and 67.72  4.25%, disodium salt hydrate; respectively. The results showed no cytotoxic effects of the b-glycerophosphate latanoprost-loaded hydrogel on the cells. Lercanidipine Chitosan; Chemical Not mentioned The aforementioned results indicated the prepared 114 hydrochloride glutaraldehyde hydrogels showed excellent pH sensitivity which indicated higher pH dependent swelling and drug release at pH = 6.8 and 7.4. Nitrendipine Chitosan; acrylamide; Chemical Not mentioned The results indicated the drug release to be at a 109 acetic acid maximum of 38% from nitrendipine-loaded microspheres at pH = 1.2 for 240 min and to be at a maximum of 79% at a pH of 6.8. Interestingly, drug release studies showed the controlled release of drugs for up to 14 h. Pilocarpine Chitosan; poly(N- Chemical HLE-B3 cells; A slow degradation of the drug carrier was also responsible 115 isopropylacrylamide) CRL-11421 cells for the delayed pilocarpine release, which showed that the concentration of released drug could reach a minimum therapeutic level of pilocarpine in the treatment of glaucoma during 42 days of the study. Propranolol Chitosan; gelatin Physical B. subtilis; S. aureus; The presence of higher chitosan amounts in the hydrogel 116 hydrochloride E. coli; P. aeruginosa; resulted in the lowest water-uptake percentage L. acidophilus; (235.1  5.3%) and the highest in vivo residence time B. infantis; in the buccal cavity (240  13 min). Moreover, the C. albicans presence of mannitol in the formulation allowed 80% drug permeation through the porcine buccal mucosa in 5 h. Other interesting aspects of the hydrogel was its compatibility with buccal microflora in the absence of the drug and its ability to cause the growth inhibition of the pathogenic bacteria, but not the probiotic species, when loaded with the drug. 10056 | J. Mater. Chem. B, 2020, 8, 10050--10064 This journal is © The Royal Society of Chemistry 2020  View Article Online Review Journal of Materials Chemistry B the standard time required for different operations is variable, released after 24 h. Elsewhere, after 21 days of MTT experi- chitosan hydrogels have been applied in the gradual delivery of ments, the hydrogel had no significant effect on the survival of anesthetic drugs (Table 3). 3T3, HaCat and VERO cells. In addition, mouse models showed With regard to their chemical structures, local anesthetics that the hydrogel displayed a good local anesthetic effect.59 can be divided into amides and esters.100–102 Amides are Improvement of living standards has been accompanied by however the most commonly used drugs for local anesthesia an increase in fat intake. However, excess metabolic fats are in the clinic. They mainly include lidocaine, levobupivacaine, stored in various parts of the body,106 some of which accumu- bupivacaine, mepivacaine and ropivacaine. On the other hand, late in the inner wall of blood vessels, thus increasing the blood esters mainly include benzocaine, tetracaine and cocaine. In pressure. Currently, the clinical methods against hypertension pharmacological mechanistic research, benzocaine, lidocaine are surgery and antihypertensive therapeutics. However, chit- Published on 19 October 2020. Downloaded by Brock University on 10/29/2024 9:38:05 AM. and tetracaine are often used as model drugs. Among them, osan hydrogels enable the gradual and sustained delivery of benzocaine confers its function by inhibiting the voltage- antihypertensive drugs (Table 2). dependent sodium channels in the neuronal membrane and Hypertension is accompanied by serious societal blocking the propagation of action potentials.103,104 Although morbidities.107,108 In order to prolong the action time of anti- these drugs can exert anesthetic effects, the effective anesthe- hypertensive drugs, Prasanth and colleagues applied a free tization duration is short. Consequently, multiple shots are radical method to prepare acrylamide polymerised chitosan needed for some long operations, a practice that can cause (hydrophilic polymer) encapsulated nitrendipine hydrogel multiple side effects and uncomfortable reactions. In order microspheres. The size of the microspheres before drug loading to achieve controlled release but efficient anesthetization, a ranged between 300 and 350 microns, but after drug loading, hydrogel film made of chitosan and collagen has been devel- the size of the microspheres reduced to 25–30 microns, possibly oped. This film has good swelling performance (the swelling due to the electrostatic interaction between the drug molecules rate could reach more than 500%) and water permeability and the graft copolymer. The drug release experiment showed (6322 mg per day per L), mainly due to the interaction between that at pH = 1.2, the drug release amount of the microspheres –NH2, –OH and –COOH groups which replaces the hydrogen reached 38%, the maximum level, after 240 minutes. At a pH of bonds in the backbone of the biomolecule. The anesthesia 6.8, the drug release reached a maximum of 79% (14 h). could subsequently be induced in either an acidic or an alka- Interestingly, as the polymer concentration increased, drug line environment. Subsequent drug release studies reveal that release decreased. At pH 6.8, the maximum release of conven- the hydrogel film is a pH-dependent release carrier for local tional tablets within 10 h was close to 95%. Compared with anesthetics (lidocaine, benzocaine and tetracaine hydrochloride) commercial tablets, the microspheres showed the highest and the release could be sustained for up to 24 h. Moreover, release rate within 24 h, influenced by the polymer. Nitrendipine, the hydrogel film dissolves completely in the physiological metformin hydrochloride, ciprofloxacin and theophylline could all environment within 24 h and does not leave any toxic metabolites. be released by the acrylamide polymerized chitosan encapsulated A 24 h in vitro cytotoxicity and cell proliferation test on human nitrendipine hydrogel in the same manner.109 dermal fibroblasts showed that the collagen-based hydrogel Antihypertensive drugs can be used against high blood is biocompatible and non-cytotoxic. In conclusion, the collagen- pressure as well as eye diseases (glaucoma).110 Patient compli- based hydrogel film has potential practical applications.60 ance is low with conventional eye drops due to strenuous Dental procedures also require long-lasting local frequent administration and associated systemic side effects. anesthetics.105 Hydrogels for lidocaine and prilocaine delivery Because of these shortcomings, a slow drug release delivery were prepared using alginic acid, xanthan gum and chitosa