Trimethyl Chitosan Research Articles

Coinhibition of S1PR1 and GP130 by siRNA-loaded alginate-conjugated trimethyl chitosan nanoparticles robustly blocks development of cancer cells.

There is an interconnected network between S1P/sphingosine-1-phosphate receptor 1 (S1PR1), IL-6/glycoprotein 130 (GP130), and signal transducer and activator of transcription 3 (STAT3) signaling pathways in the tumor microenvironment, which leads to cancer progression. S1P/S1PR1 and IL-6/GP130 signaling pathways phosphorylate and activate STAT3, and it then induces the expression of S1PR1 and interleukin-6 (IL-6) in a positive feedback loop leading to cancer progression. We hypothesized that blockade of this amplification loop can suppress the growth and development of cancer cells. Therefore, we silenced STAT3 upstream molecules including the S1PR1 and GP130 molecules in cancer cells using small interfering RNA (siRNA)-loaded alginate-conjugated trimethyl chitosan (ATMC) nanoparticles (NPs). The generated NPs had competent properties including the appropriate size, zeta potential, polydispersity index, morphology, high uptake of siRNA, high rate of capacity, high stability, and low toxicity. We evaluated the effects of siRNA loaded ATMC NPs on tumor hallmarks of three murine-derived cancer cell lines, including 4T1 (breast cancer), B16-F10 (melanoma), and CT26 (colon cancer). The results confirmedthe tumor-suppressive effects of combinational targeting of S1PR1 and GP130. Moreover, combination therapy could potently suppress tumor growth as assessed by the chick chorioallantoic membrane assay. In this study, we targeted this positive feedback loop for the first time and applied this novel combination therapy, which provides a promising approach forcancer treatment. The development of a potent nanocarrier system with ATMC for this combination was also another aspect of this study, which should be further investigated in cancer animal models in further studies.

Albumin coated trimethyl chitosan-based targeting delivery platform for photothermal/chemo-synergistic cancer therapy

Current metastatic breast cancer therapies are not only affected by limited drug delivery options, but also restricted to the monotherapies. Here, we synthesized trimethyl chitosan (TMC), loaded it with photosensitizer IR780 or bufalin by ionic gelation, and coated it with human serum albumin (HSA) by electrostatic absorption (designated TIH or TBH, respectively). The near-spherical nanoparticles had a size of approximately 30 nm, exerted strong photothermal effects, and enhanced cellular mitochondrion colocation and phototoxicity. Tumor microenvironments were disrupted by TIH-mediated photothermal effects, which enhanced the accumulation of a second TBH dose in the tumor that promoted deep penetration in the whole tumor mass. After laser irradiation our nanoplatform enhanced cancer tissue accessibility and substantially suppressed tumor growth, and causing a 98.46 % inhibition of lung metastasis. Thus HSA-masked TMC represents a promising tumor-targeted drug delivery strategy with synergistic modality that may improve the therapeutic outcome of metastatic breast cancer.

Optimization of chitosan-based polyelectrolyte nanoparticles for gene delivery, using design of experiment: in vitro and in vivo study.

Gene therapy is a novel approach for cancer treatment and investigation for suitable gene delivery systems is remarkable. Here, preparation of a polyelectrolyte complex containing polysaccharides: trimethyl chitosan (TMC) as the positive and hyaluronate (HA), dextran sulfate and alginate as the negative part was studied. The optimized nanoparticles (TMC: between 0.2 and 0.47mg/ml, HA: 0.35mg/ml (≈131nm, nearly full gene loading)) were obtained via primary screening followed by the D-optimal method. In vitro cellular study on the MCF7 cell line confirmed the non-toxicity and high cellular uptake (>90%) of prepared nanoparticles. Notably, in vivo study indicated noticeable tumor uptake of nanoparticles while low accumulation in vital organs such as heart, liver and lungs. Moreover, although a qualitative variable was considered, the applied method restricted the number of runs by selecting spots from the spherical atmosphere. The prepared nanoparticles could be suggested as an efficient and safe delivery system for cancer gene delivery.

Trimethyl chitosan nanoparticles for ocular baicalein delivery: Preparation, optimization, in vitro evaluation, in vivo pharmacokinetic study and molecular dynamics simulation

To improve ocular bioavailability of baicalein (BAI), trimethyl chitosan coated lipid nanoparticles of baicalein (TMC-BAI-LNPs) were prepared, optimized and characterized. The properties of TMC-BAI-LNPs such as morphology, particle size, zeta potential and fourier transform infrared spectroscopy were investigated. Additionally, molecular dynamics simulation was applied as a new method to evaluate drug-biological membrane interactions. Transmission electron microscopy showed that the LNPs were approximately spherical in shape with a smooth surface. TMC-BAI-LNPs had a particle size of 162.8 nm, a positive surface charge with a zeta potential of 26.6 mV. The entrapment efficiency and drug loading values of BAI in the formulation were 90.65% and 2.04%, respectively. Moreover, in vitro drug release revealed that TMC-BAI-LNPs had a sustained release effect. In vivo studies indicated TMC-BAI-LNPs had no ocular irritation and the AUC of TMC-BAI-LNPs was 3.17-fold than that of the control (p < 0.01). Molecular dynamics simulation data showed that BAI had a poor membrane permeability, which limited the ocular bioavailability. The results indicated that TMC-BAI-LNPs might open up a new avenue for ocular administration. Furthermore, molecular dynamics simulation could predict permeability of drugs.

Codelivery of STAT3 siRNA and BV6 by carboxymethyl dextran trimethyl chitosan nanoparticles suppresses cancer cell progression.

High expression of inhibitor of apoptosis (IAP) molecules in cancer cells promotes cancer cell chemoresistance. Use of BV6, a well-known IAP inhibitor, along with inhibition of signal transducer and activator of transcription 3 (STAT3), which is an important factor in the survival of tumor cells, and NIK as a mediator of BV6 unpredicted side effects, can induce effective apoptosis in tumor cells. The present study has investigated the combination therapy of cancer cells using Carboxymethyl Dextran-conjugated trimethyl chitosan (TMC-CMD) nanoparticles (NPs) loaded with NIK/STAT3-specific siRNA and BV6 to synergistically induce apoptosis in the breast, colorectal and melanoma cancer cell lines. Our results showed that in addition to enhanced pro-apoptotic effects, this combination therapy reduced proliferation, cell migration, colony formation, and angiogenesis, along with expression of factors including IL-10 and HIF in tumor cells. The results indicate the potential of this combination therapy for further investigation in animal models of cancer.

Epoxy Chitosan-Crosslinked Acellular Bovine Pericardium with Improved Anti-calcification and Biological Properties.

Glutaraldehyde (GA) was conventionally used to crosslink bovine pericardium to prepare bioprosthetic heart valves (BHVs), which usually fail within 10 years because of valve deterioration and calcification. To overcome the high cytotoxicity and severe calcification of GA-crosslinked BHVs, a quaternary ammonium salt of epoxy chitosan (epoxy group-modified 3-chlorine-2-hydroxypropyl trimethyl chitosan, abbreviated as "eHTCC") was developed to modify the acellular bovine pericardium to substitute GA and improve its anti-calcification and biocompatible properties. Mechanical test, enzymatic stability test, blood compatibility assay, and cytocompatibility assay were used to investigate its mechanical property and biocompatibility. The anti-calcification effect of the eHTCC-modified bovine pericardium (eHTCC-BP) was assessed by in vitro assay and rat subcutaneous implantation assay. The results showed that eHTCC-BP could improve the mechanical properties and anti-enzymolysis ability of BP, as well as retain the original three-dimensional structure, compared with the uncrosslinked-BP group. Moreover, the in vivo calcification level of the eHTCC-BP group was much lower than that of the GA-BP group, which was 5.1% (2 weeks), 2.3% (4 weeks), and 0.8% (8 weeks) of the GA-BP group. In summary, this study demonstrated that eHTCC could be a potential crosslinking agent for the extracellular matrix for its favorable crosslinking effects, anti-enzymolysis, anti-calcification, and biocompatibility.

New Frontiers in Molecular Imaging with Superparamagnetic Iron Oxide Nanoparticles (SPIONs): Efficacy, Toxicity, and Future Applications.

Supermagnetic Iron Oxide Nanoparticles (SPIONs) are nanoparticles that have an iron oxide core and a functionalized shell. SPIONs have recently raised much interest in the scientific community, given their exciting potential diagnostic and theragnostic applications. The possibility to modify their surface and the characteristics of their core make SPIONs a specific contrast agent for magnetic resonance imaging but also an intriguing family of tracer for nuclear medicine. An example is 68Ga-radiolabeled bombesin-conjugated to superparamagnetic nanoparticles coated with trimethyl chitosan that is selective for the gastrin-releasing peptide receptors. These receptors are expressed by several human cancer cells such as breast and prostate neoplasia. Since the coating does not interfere with the properties of the molecules bounded to the shell, it has been proposed to link SPIONs with antibodies. SPIONs can be used also to monitor the biodistribution of mesenchymal stromal cells and take place in various applications. The aim of this review of literature is to analyze the diagnostic aspect of SPIONs in magnetic resonance imaging and in nuclear medicine, with a particular focus on sentinel lymph node applications. Moreover, it is taken into account the possible toxicity and the effects on human physiology to determine the SPIONs' safety.

Towards the development of Self-Nano-Emulsifying Drug Delivery Systems (SNEDDS) containing trimethyl chitosan for the oral delivery of amphotericin B: In vitro assessment and cytocompatibility studies

In the current study, a self-nanoemulsifying drug delivery system (SNEDDS) containing N-trimethyl chitosan chloride (TMC) was developed and evaluated for its potential to deliver amphotericin B (AmpB) via the gastrointestinal tract. SNEDDS comprising Captex 355, Kolliphor RH40 and Propylene Glycol were optimized and characterized for their formation spontaneity, droplet size and drug loading. Investigations on the effects of the application SNEDDS containing TMC to a model intestinal epithelium (Caco-2 monolayer) indicated the capability of the formulations to induce the transient opening of tight junctions. Caco-2 cell viability studies confirmed the safety of the SNEDDS, whereas in vitro transport studies of AmpB through Caco-2 cell monolayers showed the permeation enhancing ability of TMC. Our results suggest that chitosan derivative TMC combined with a SNEDDS may be used as permeation enhancer to facilitate oral delivery of AmpB.

Bioconjugation of aptamer to fluorescent trimethyl chitosan nanoparticles for bacterial detection

Trimethyl chitosan nanoparticles (TMC NPs), the positively charged chitosan derivative, have been used to deliver medicines to overcome the tissue barrier. Here, fluorescein-labeled TMC NPs were produced by a microemulsion method following the bioconjugation of the single-strand DNA aptamer which can specifically bind to E. coli (DH5α). TMC NPs show uniform spherical particles with an average diameter of 323 ± 10 nm. The large positive zeta potential, 37.1 ± 2.2 mV, indicates the net positive charged surface of TMC NPs which is a suitable carrier for crossing tissue barriers. The linear relationship of the maximum fluorescence intensity of aptamer modified TMC NPs and the concentration of E. coli (DH5α) is obtained. We hope that the fluorescent TMC NPs integrating with a suitable aptamer could be used to understand the pathway of bacteria crossing the host barrier to fight against invasive infections.

Comparison of Magnetically Responsive Trimethyl Chitosan and Chitosan Nanoparticles for Gemcitabine Delivery With in Vitro Studies

Purpose: Gemcitabine is nucleoside analogue and used for various carcinomas like non-small cell lung cancer. Nanoparticle-based therapeutic agents have been developed for use in cancer therapy. Trimethyl chitosan TMC is methylated derivative of chitosan. TMC can be preferable because of the limited solubility of chitosan. Magnetic nanoparticles can be concentrated at cancerous tissue which provide targeted cancer therapy. In this study, we tried to develop and compare magnetically targeted trimethyl chitosan and chitosan nanoparticles for gemcitabine delivery in lung cancer therapy. Methods: Chitosan was trimethylated using methyl iodide. Magnetic nanoparticles were synthesized using co-precipitation method. TMC and chitosan nanoparticles were prepared by cross-linking method with tripolyphosphate. Gemcitabine was loaded onto nanoparticles via adsorption technique. After that characterization studies were performed and in vitro drug release tests were carried out. In order to determine cytotoxicites against A549-luc-C8 and CRL5809 cell lines, MTT assays were performed. Results and conclusion: Trimethylation of chitosan was verified with FTIR analysis. Gemcitabine was loaded with 54.7 and 30.3% on magnetic TMC nanoparticles and chitosan nanoparticles, respectively. According to drug release experiments, both carrier system had controlled drug release profile. IC50 values of gemcitabine loaded magnetic TMC nanoparticles were lower than that of magnetic chitosan nanoparticles. In conclusion, it was suggested that trimethyl chitosan nanoparticles had greater potential than chitosan nanoparticles for further analysis as a magnetically targeted therapy agent for lung cancer.

Trimethyl Chitosan Hydrogel Nanoparticles for Progesterone Delivery in Neurodegenerative Disorders.

Progesterone is a sex hormone which shows neuroprotective effects in different neurodegenerative disorders, including Parkinson’s disease, stroke, and Alzheimer’s disease. However, the pharmacokinetic limitations associated with the peripheral administration of this molecule highlight the need for more efficient delivery approaches to increase brain progesterone levels. Since the nose-to-brain administration of mucoadhesive hydrogel nanoparticles is a non-invasive and convenient strategy for the delivery of therapeutics to the central nervous system, in this work, progesterone-loaded hydrogel nanoparticle formulations have been prepared, characterized, and tested in vivo. Nanoparticles, loaded with different progesterone concentrations, have been obtained by polyelectrolyte complex formation between trimethyl chitosan and sodium alginate, followed by ionotropic gelation with sodium tripolyphosphate as a cross-linking agent. All formulations showed a mean diameter ranging from 200 nm to 236 nm, a polydispersity index smaller than 0.23, and a high progesterone encapsulation efficiency (83–95%). The zeta potential values were all positive and greater than 28 mV, thus ensuring nanoparticles stability against aggregation phenomena as well as interaction with negative sialic residues of the nasal mucosa. Finally, in vivo studies on Sprague–Dawley male rats demonstrated a 5-fold increase in brain progesterone concentrations compared to basal progesterone level after 30 min of hydrogel nanoparticle inhalation.

In-vitro Detection of Phytopathogenic Fungal Cell Wall by Polyclonal Sera Raised Against Trimethyl Chitosan Nanoparticles.

PurposeThe objective of this research was to generate a tool for the first-line detection of fungal infection in plants. Chitin is one of the unique fungal cell wall polysaccharide which is naturally deacetylated to chitosan upon infection. It is said to be involved in the fungal cell wall modulation and plant-pathogen communication. Therefore, detection of chitosan could be potentially helpful in the detection of fungal contamination.MethodsFive different phytopathogenic fungi strains were used for the study. Polyclonal sera were raised in the mice against Trimethylchitosan nanoparticles to generate an enhanced humoral immune response and generate a rich and heterogeneous repertoire of antibodies. The binding affinity of the sera with fungal cell wall was analyzed by ELISA, Langmuir isotherm, confocal microscopy and ITC (Isothermal Calorimetry).ResultsThe raised polyclonal sera could detect chitosan in the fungal cell wall, as analyzed with the different techniques. However, the detection specificity varied among the strains in proportion to the chitin content of their cell wall. Fusarium oxysporum was detected with the highest affinity while Trichoderma reesei was detected with the least affinity by ELISA. Adsorption isotherm, as well as ITC, revealed the specific and high binding capacity. Confocal microscopy also confirmed the detection of all strains used in the study.ConclusionThis novel technique employing TMC nanoparticulate system could be potentially used as a source to raise sera against chitosan in an inexpensive and less laborious manner. Rapid detection of fungal contamination by the polyclonal antibodies could help in devising a quick solution. The polyclonal sera are expected to detect a span of epitopes and provide precise detection. The detection system could be advanced for future applications such as food quality control, crop protection, and human fungal infection detection and treatment.

Lipopeptide-Based Oral Vaccine Against Hookworm Infection.

The human hookworm, Necator americanus, is a parasite that infects almost half a billion people worldwide. Although treatment is available, vaccination is favorable to combat the spread of this parasite due to its wide distribution and continuous reinfection cycle in endemic communities. We have designed a lipopeptide oral delivery system using a B-cell epitope derived from the aspartic protease Na-APR-1 from N americanus, attached to a T-helper epitope. Lipopeptides were self-assembled into nanoparticles or entrapped in liposomes that were electrostatically coated with alginate and trimethyl chitosan polymer shields. The adjuvant-free vaccine candidates were orally administered to mice and generated a humoral immune response against both peptide antigen, and the parent protein in the hookworm gut. The vaccine candidates were evaluated in a rodent hookworm challenge model, resulting in up to 98% and 99% decreases in mean intestinal worm and egg burdens in immunized mice, respectively. Lipopeptide survived the gastrointestinal conditions, induced humoral immune responses and drived protection against parasite challenge infection.

IpaD-loaded N-trimethyl Chitosan Nanoparticles Can Efficiently Protect Guinea Pigs against Shigella flexneri.

Shigella flexneri is a pathogen responsible for shigellosis around the world, especially in developing countries. Many immunogenic antigens have been introduced as candidate vaccines against Shigella, including N-terminal region of IpaD antigen (NIpaD). To evaluate the efficiency of O-metylated free trimethyl chitosan nanoparticles (TMC NPs) in the oral delivery of NIpaD. TMC was synthesized by a two-step method from high molecular weight chitosan. The recombinant NIpaD protein was used as the immunogen. The protein was overexpressed in E. coli BL21 (DE3) and characterized by gel electrophoresis. The NIpaD-loaded TMC NPs were synthesized by ionic gelation method and were characterized by electron microscopy. NPs were orally administered to guinea pigs and specific humoral and mucosal immune responses were assessed by serum IgG and secretory IgA, respectively. The protectivity of the formulation was assessed by keratoconjunctivitis (Sereny) test. The immunized guinea pigs showed a significant raise in rNIpaD-specific serum IgG and faecal IgA titers. Specific secretory IgA was detected in eye-washes. Sereny test results showed that immunized animals vaccinated with IpaD-loaded TMC NPS tolerated the wild type of Shigella flexneri 2a in Sereny test. However, in the group immunized with NIpaD antigen and non-immunized group, no increase was observed in antibody titer against NIpaD. These animals were infected following the challenge with Shigella flexneri 2a (p<0.0152). The recombinant rNIpaD formulated with TMC obtained from high molecular weight chitosan, can be considered as a mucosal vaccine against Shigella flexneri through oral route.

Structure-activity relationship of group A streptococcus lipopeptide vaccine candidates in trimethyl chitosan-based self-adjuvanting delivery system

Synthetic peptide vaccines based on epitopes derived from the conserved region of M-protein are proving to be a realistic option for protection against group A streptococcus (GAS). However, peptide epitopes alone are poorly immunogenic due to lack of pathogen-associated structural patterns. Therefore, we developed a GAS peptide vaccine based on combined lipidic TLR 2 agonist and self-adjuvanting polymers. We synthesized three α-poly-l-glutamic acid (PGA) conjugated lipopeptides composed of 2-amino-d,l-hexadecanoic acid, GAS B-cell peptide epitope J8 (QAEDKVKQSREAKKQVEKALKQLEDKVQ) and universal T-helper epitope PADRE (AKFVAAWTLKAAA) in different spatial arrangements. The anionic lipopeptide conjugates formed nanoparticles via ionic-complexation with a cationic polymer, trimethyl chitosan (TMC). We demonstrated that the spatial arrangement of vaccine components has a significant influence on peptide conformation and particle formation and, as such, contributes to the differential efficacy and opsonin-mediated killing potential of nanovaccines. Nanoparticles carrying branched helical lipopeptide with T-helper epitope on free N-termini (NP3) stimulated the most potent humoral immune responses. Lipopeptides without TMC (LP1-LP3) and TMC nanoparticles of peptide alone (without lipid) NP (P1) were poor inducers of antibody production, indicating that both TMC and lipid are required to induce a strong opsonic immune response.

Carboxymethyl dextran-trimethyl chitosan coated superparamagnetic iron oxide nanoparticles: An effective siRNA delivery system for HIV-1 Nef.

Gene therapy, including small interfering RNA (siRNA) technology, is one of the leading strategies that help to improve the outcomes of the current therapeutic systems against HIV-1 infection. The successful therapeutic application of siRNAs requires their safe and efficient delivery to specific cells. Here, we introduce a superparamagnetic iron oxide nanoparticle (SPION) for delivering siRNA against HIV-1 nef (anti-nef siRNA) into two cell lines, HEK293 and macrophage RAW 264.7. SPIONs were coated with trimethyl chitosan (TMC), and thereafter, different concentrations of SPION-TMC were coated with different ratios of a carboxymethyl dextran (CMD) to modify the physicochemical properties and improve the biological properties of the nanocarriers. The nanoparticles exhibited a spherical shape with an average size of 112 nm. The obtained results showed that the designed delivery route enhanced the uptake of siRNA into both HEK293 and RAW 264.7 cells compared with control groups. Moreover, CMD-TMC-SPIONs containing anti-nef siRNA significantly reduced the expression of HIV-1 nef in HEK293 stable cells. The modified siRNA-loaded SPIONs also displayed no toxicity or apoptosis-inducing effects on the cells. The CMD-TMC-SPIONs are suggested as potential nanocarriers for siRNA delivery in gene therapy of HIV-1 infection.

Self-assembly of trimethyl chitosan and poly(anionic amino acid)-peptide antigen conjugate to produce a potent self-adjuvanting nanovaccine delivery system.

Short peptides derived from virulent pathogen proteins are promising antigens for the development of vaccines against infectious diseases. However, in order to mimic the danger signals associated with natural infection and stimulate an adaptive immune response, peptide antigens must be co-delivered with immune adjuvants. In this study, a group A streptococcus (GAS) M-protein derived B-cell epitope: J8, and universal T-helper epitope P25 containing peptides, were chemically coupled with different anionic amino acid-based polymers. The poly(anionic amino acid)-peptide antigen conjugates were mixed with trimethyl chitosan (TMC) to produce self-adjuvanting nanoparticulate vaccine candidates. TMC from two different sources were used to analyse their effect on immunogenicity. The nanoparticles produced from a peptide modified with 10 residues of polyglutamic acid and fungal TMC (NP5) stimulated production of the highest levels of serum antibodies in outbred mice. These antibodies were opsonic against all clinical GAS isolates tested.

Trimethyl Chitosan/Siloxane-Hybrid Coated Fe3O4 Nanoparticles for the Uptake of Sulfamethoxazole from Water.

The presence of several organic contaminants in the environment and aquatic compartments has been a matter of great concern in the recent years. To tackle this problem, new sustainable and cost-effective technologies are needed. Herein we describe magnetic biosorbents prepared from trimethyl chitosan (TMC), which is a quaternary chitosan scarcely studied for environmental applications. Core@shell particles comprising a core of magnetite (Fe3O4) coated with TMC/siloxane hybrid shells (Fe3O4@SiO2/SiTMC) were successfully prepared using a simple one-step coating procedure. Adsorption tests were conducted to investigate the potential of the coated particles for the magnetically assisted removal of the antibiotic sulfamethoxazole (SMX) from aqueous solutions. It was found that TMC-based particles provide higher SMX adsorption capacity than the counterparts prepared using pristine chitosan. Therefore, the type of chemical modification introduced in the chitosan type precursors used in the surface coatings has a dominant effect on the sorption efficiency of the respective final magnetic nanosorbents.

Systematic optimization of cationic surface engineered mucoadhesive vesicles employing Design of Experiment (DoE): A preclinical investigation.

Fungal keratitis (FK) is treated by topical natamycin (Nat) which is an effective antifungal agent. However, it has numerous therapeutic limitations i.e. toxicity, tolerance, need of frequent dosing and patient incompliance. The aim of the present study was to develop Nat loaded trimethyl chitosan (TMC) coated mucoadhesive cationic niosomes (Muc-Cat-Nios) for prolonged and effective delivery to eyes. Niosomes were prepared using thin film hydration method and optimized using a Box-Behnken design (BBD) with the help of Design-Expert® Software. Three independent variables were considered: amount of Span 60 (X1), amount of Cholesterol [Chol(X2)] and TMC concentration (X3). The encapsulation efficiency (R1: EE%), vesicle size (R2: VS) and Zeta potential (R3: ZP) were selected as dependent variables or responses. The optimized Nios displayed spherical shape, 1034.14 nm vesicle size and 81.76% EE. Nat loaded niosomes were incubated with TMC to get mucoadhesive cationic vesicular system. Uncoated and TMC coated niosomes were characterized for mucoadhesive properties, in vitro drug release, rheological behaviour, and ex vivo permeation studies. Cationic Nios showed greater mucoadhesive potential that provided drug release for a long period of time. The promising outcomes suggest that natamycin delivery using cationic mucoadhesive niosomes could be employed for the effective treatment of fungal keratitis.

Characterization of trimethyl chitosan/polyethylene glycol derivatized chitosan blend as an injectable and degradable antimicrobial delivery system.

Advanced local delivery systems are needed as adjunctive treatments for severe injuries with high infection rates, such as open fractures. Chitosan systems have been investigated as antimicrobial local delivery systems for orthopaedic infection but possess mismatches between elution and degradation properties. Derivatives of chitosan were chosen that have enhanced swelling ratios or tailorable degradation properties. A combination of trimethyl chitosan and poly(ethylene glycol) diacrylate chitosan was developed as an injectable local delivery system. Research objectives were elution of antimicrobials for 7 days, degradation as open fractures heal, and cytocompatibility. The derivative combination eluted increased active concentrations of vancomycin and amikacin compared to the non-derivatized chitosan paste, 6 vs. 5 days and 5 vs. 4 days, respectively. The derivative combination degraded slower than non-derivatized paste in an enzymatic degradation study, 14 vs. 3 days, which increased antimicrobial delivery duration. Cytocompatibility of the combination with fibroblast and pre-osteoblast cells exceeds the cell viability standard set in ISO 10993-5. Combination paste requires an increased ejection force of 9.40 N (vs. 0.64 N), but this force was within an acceptable injection force threshold, 80 N. These preliminary results indicate combination paste should be further developed into a clinically useful adjunctive local delivery system for infection prevention.