Sustained Release Kinetics Research Articles

Incorporation of doxorubicin in different polymer nanoparticles and their anticancer activity.

Background: Nanoparticles are under investigation as carrier systems for anticancer drugs. The expression of efflux transporters such as the ATP-binding cassette (ABC) transporter ABCB1 is an important resistance mechanism in therapy-refractory cancer cells. Drug encapsulation into nanoparticles has been shown to bypass efflux-mediated drug resistance, but there are also conflicting results. To investigate whether easy-to-prepare nanoparticles made of well-tolerated polymers may circumvent transporter-mediated drug efflux, we prepared poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and PEGylated PLGA (PLGA-PEG) nanoparticles loaded with the ABCB1 substrate doxorubicin by solvent displacement and emulsion diffusion approaches and assessed their anticancer efficiency in neuroblastoma cells, including ABCB1-expressing cell lines, in comparison to doxorubicin solution.Results: The resulting nanoparticles covered a size range between 73 and 246 nm. PLGA-PEG nanoparticle preparation by solvent displacement led to the smallest nanoparticles. In PLGA nanoparticles, the drug load could be optimised using solvent displacement at pH 7 reaching 53 µg doxorubicin/mg nanoparticle. These PLGA nanoparticles displayed sustained doxorubicin release kinetics compared to the more burst-like kinetics of the other preparations. In neuroblastoma cells, doxorubicin-loaded PLGA-PEG nanoparticles (presumably due to their small size) and PLGA nanoparticles prepared by solvent displacement at pH 7 (presumably due to their high drug load and superior drug release kinetics) exerted the strongest anticancer effects. However, nanoparticle-encapsulated doxorubicin did not display increased efficacy in ABCB1-expressing cells relative to doxorubicin solution.Conclusion: Doxorubicin-loaded nanoparticles made by different methods from different materials displayed substantial discrepancies in their anticancer activity at the cellular level. Optimised preparation methods resulted in PLGA nanoparticles characterised by increased drug load, controlled drug release, and high anticancer efficacy. The design of drug-loaded nanoparticles with optimised anticancer activity at the cellular level is an important step in the development of improved nanoparticle preparations for anticancer therapy. Further research is required to understand under which circumstances nanoparticles can be used to overcome efflux-mediated resistance in cancer cells.

Nanohybrid Scaffold of Chitosan and Functionalized Graphene Oxide for Controlled Drug Delivery and Bone Regeneration.

Nanohybrid scaffolds of chitosan have been designed for controlled drug delivery and bone regeneration. Sulfonated graphene oxide has been used to develop the nanohybrids. Nanohybrid scaffolds show highly hydrophilic character and greater mechanical strength as compared to pure chitosan. Nanohybrid scaffolds show an interconnected uniform porous network structure exhibiting sustained release kinetics of the antibacterial drug, tetracycline hydrochloride. Nanohybrids are found to be highly biocompatible in nature and are able to support and proliferate MG63 osteoblast cells and thereby induce bone tissue regeneration. The in-vivo bone healing study shows that the developed nanohybrid scaffolds have the potential to regenerate the bone faster without any side effects as compared to pure scaffolds. Hence, the developed nanohybrid scaffold has good potential as a controlled drug delivery vehicle and in bone tissue engineering for faster healing.

Covalent Poly(lactic acid) Nanoparticles for the Sustained Delivery of Naloxone.

The opioid epidemic currently plaguing the United States has been exacerbated by an alarming rise in fatal overdoses as a result of the proliferated abuse of synthetic mu opioid receptor (MOR) agonists, such as fentanyl and its related analogues. Attempts to manage this crisis have focused primarily on widespread distribution of the clinically approved opioid reversal agent naloxone (Narcan); however, due to the intrinsic metabolic lability of naloxone, these measures have demonstrated limited effectiveness against synthetic opioid toxicity. This work reports a novel polymer-based strategy to create a long-acting formulation of naloxone with the potential to address this critical issue by utilizing covalent nanoparticle (cNP) drug delivery technology. Covalently loaded naloxone nanoparticles (Nal-cNPs) were prepared via the naloxone-initiated, ring-opening polymerization (ROP) of l-lactide in the presence of a bifunctional thiourea organocatalyst with subsequent precipitation of the resulting naloxone-poly(l-lactic acid) polymer. This protocol afforded well-defined nanoparticles possessing a drug loading of approximately 7% w/w. The resulting Nal-cNPs demonstrated excellent biocompatibility, while exhibiting sustained linear release kinetics in vitro and blocking the effects of high dose (10 mg/kg) acute morphine for up to 98 h in an in vivo rodent model of neuropathic pain.

Temperature‐sensitive polyurethane (TSPU) film incorporated with carvacrol and cinnamyl aldehyde: antimicrobial activity, sustained release kinetics and potential use as food packaging for Cantonese‐style moon cake

SummaryTemperature‐sensitive polyurethane (TSPU) films incorporated with carvacrol and cinnamyl aldehyde were prepared for the potential use of food packaging. The antimicrobial properties and sustained release kinetics of carvacrol and cinnamyl aldehyde in TSPU film were investigated. Results indicated that cinnamyl aldehyde and carvacrol had favourable antimicrobial properties at relatively low addition ratio. The diffusion and release of carvacrol were linearly related to temperature and its addition ratio. The release rates of carvacrol from TSPU film increased from 0.6% to 2.2% with the increase of addition ratio and temperature. The first‐order kinetic equation could be used to describe its diffusion and sustained release process. TSPU films could significantly prolong the shelf life of Cantonese‐style moon cakes by effectively inhibiting microbial growth and decreasing lipid oxidation comparing with commonly used polyethylene food packaging. Results obtained in the present work can provide technical guide of sustained release food packaging films with antimicrobial properties.

Biodegradable Poly(Acetonide Gluconic Acid) for Controlled Drug Delivery.

We report here on the synthesis, characterization, degradation, and drug release of acetal-protected gluconic acid-based poly(α-hydroxy ester). This polyester was synthesized by ring-opening polymerization of O-carboxyanhydride of acetal-protected gluconic acid. The polymer undergoes hydrolytic degradation under mild acidic media, whereas minimal degradation takes place under physiological pH. Under acidic conditions, the acetal-protecting groups are hydrolyzed, resulting in a water-soluble polyester with saccharide side chains that erodes from the surface, leaving the bulk of the polymer matrix intact. At pH 3.5, zero-order kinetics was maintained for 50 days accounting for ∼75% drug release. These biodegradable, pH-responsive, sustained zero-order release kinetics of the polymer have application as drug carriers for oral drug delivery or medical implants or also for nonmedical applications.

Functional N-Substituted N-Thiocarboxyanhydrides as Modular Tools for Constructing H2S Donor Conjugates.

We report a synthetic route toward a family of functional COS/H2S-releasing N-substituted N-thiocarboxyanhydrides (NTAs) with functionalities to accommodate popular conjugation reactions, including olefin cross metathesis, thiol-ene, and copper-catalyzed azide-alkyne cycloaddition. The N-substituted NTAs were attached to small molecules, polymers, and a protein to synthesize novel H2S donors convergently. All conjugates showed sustained H2S release kinetics.

Gradiently degraded electrospun polyester scaffolds with cytostatic for urothelial carcinoma therapy.

Kidney-sparing surgery is the preferred treatment strategy for low-risk upper tract urothelial carcinoma (UTUC). However, after this procedure, prevention of the carcinoma recurrence in the ureter and supporting the ureter with a ureteral stent are necessary. Biodegradable drug-loaded ureteral scaffolds are able to maintain their long-term effective drug concentrations in the lesion sites without the defects of traditional ureteral stents, which may address both issues simultaneously. The purpose of this study was to reveal the possibility of the controlled delivery of epirubicin (EPI) via gradiently degraded electrospun poly(ε-caprolactone) (PCL)/poly(lactide-co-glycolide) (PLGA) scaffolds to evaluate their antitumor activity against UTUC. The degradable PCL/PLGA scaffolds containing 15.0 and 25.0 wt% PCL and loading of 0, 5.0, and 10.0 wt% EPI were successfully fabricated via electrospinning. In addition, the PCL/PLGA scaffolds showed sustained and controlled degradation and drug release kinetics, that is, their degradation and drug release rates slowed with an increase in the ratio of PCL. The EPI-loaded PCL/PLGA scaffolds showed excellent antitumor activities both in vitro and in vivo without apparent systemic toxicity. Overall, the gradiently-degraded EPI-loaded electrospun polyester scaffolds are potential ureteral stent tubes for the local inhibition of the recurrence of UTUC, where the continued release of EPI can prevent the subsequent proliferation of residual tumor cells, and the gradient degradation is consistent with the repair of the ureter.

Iodine binding and release from antimicrobial hemostatic polymer foams

Hemostatic macroporous polymer foams synthesized via high internal phase emulsion (HIPE) templating were loaded with iodine to impart broad-spectrum antimicrobial activity. The effects of kaolin loading and iodine content on structure and antimicrobial activity were identified. ATR-FTIR, Raman, and XRD provided detailed insight into the complexation of iodine with the cross-linked PEG-NaAA-PEG macroporous polymer matrix. Iodine was found to incorporate into the foams exclusively as triiodide (I3−) ion coordinated to the various carbonyls throughout the polymer structure. Continued, sustained release kinetics of iodine over 48 h was achieved at high iodine loading, while low iodine yielded burst release kinetics. Broad spectrum antimicrobial activity dependent on iodine loading was demonstrated with significant zone of inhibition against E. coli, K. pneumoniae, P. aeruginosa, and S. aureus. This represents the first report of detailed complexation and sustained release of antimicrobial iodine into highly absorbent, hemostatic, and biocompatible polymeric wound dressing material with potential to combat bacterial resistance in infected wounds.

Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection.

BackgroundInfluenza virus infections are a major public health concern worldwide. Conventional treatments against the disease are designed to target viral proteins. However, the emergence of viral variants carrying drug-resistant mutations can outpace the development of pathogen-targeting antivirals. Diphyllin and bafilomycin are potent vacuolar ATPase (V-ATPase) inhibitors previously shown to have broad-spectrum antiviral activity. However, their poor water solubility and potential off-target effect limit their clinical application.MethodsIn this study, we report that nanoparticle encapsulation of diphyllin and bafilomycin improves the drugs’ anti-influenza applicability.ResultsUsing PEG-PLGA diblock copolymers, sub-200 nm diphyllin and bafilomycin nanoparticles were prepared, with encapsulation efficiency of 42% and 100%, respectively. The drug-loaded nanoparticles have sustained drug release kinetics beyond 72 hours and facilitate intracellular drug delivery to two different influenza virus-permissive cell lines. As compared to free drugs, the nanoparticulate V-ATPase inhibitors exhibited lower cytotoxicity and greater in vitro antiviral activity, improving the therapeutic index of diphyllin and bafilomycin by approximately 3 and 5-fold, respectively. In a mouse model of sublethal influenza challenge, treatment with diphyllin nanoparticles resulted in reduced body weight loss and viral titer in the lungs. In addition, following a lethal influenza viral challenge, diphyllin nanoparticle treatment conferred a survival advantage of 33%.ConclusionsThese results demonstrate the potential of the nanoparticulate V-ATPase inhibitors for host-targeted treatment against influenza.

PH Responsive 5-Fluorouracil Loaded Biocompatible Nanogels For Topical Chemotherapy of Aggressive Melanoma.

Combating melanoma via topical route is a highly challenging task due to low selectivity, poor efficacy and impeding biological environment of the skin. In the present study, we engineered a chitosan based pH responsive biodegradable nanogel (FCNGL), encapsulated with 5-FU that was effective even at very low drug doses (0.2% w/v) against melanoma. The FCNGL was synthesized by ion gelation technique exhibited nano-size particle distribution and sustained drug release kinetics. Hemolysis and coagulation analysis revealed high safety whereas MTT and apoptosis assays exhibited the efficacy of FCNGL. DMBA-Croton oil Swiss albino mice model was employed for in vivo assessment followed by gamma scintigraphic screening. Tumor burden and pharmacokinetic antioxidant stress levels along with whole-body gamma scintigraphy imaging using 99 mTc labelled nanogel exhibited selective accumulation in melanoma tumor nodules. The pH responsive behaviour of the nanogels resulted in triggered release of 5-FU in slightly acidic microenvironment, resulting in selective drug accumulation at the melanoma site. Immunohistochemistry (IHC) analysis of tumor showed improvement of subcutaneous layer alignment and regeneration of the epithelial skin layer when compared with standard 5% 5-FU and control mice group. Overall our preclinical data using the FCNGL portends to be a promising platform for efficient and sustained delivery of 5-FU for topical chemotherapy that can result in high efficacy, patient compliance and safety in the clinical set up.

Enhanced Skull Bone Regeneration by Sustained Release of BMP-2 in Interpenetrating Composite Hydrogels.

Direct administration of bone morphogenetic protein-2 (BMP-2) for bone regeneration could cause various clinical side effects such as osteoclast activation, inflammation, adipogenesis, and bone cyst formation. In this study, thiolated gelatin/poly(ethylene glycol) diacrylate (PEGDA) interpenetrating (IPN) composite hydrogels were developed for guided skull bone regeneration. To promote bone regeneration, either polycation-based coacervates (Coa) or gelatin microparticles (GMPs) were incorporated within IPN gels as BMP-2 carriers. Both BMP-2 loaded Coa and BMP-2 loaded GMPs showed significantly enhanced in vitro alkaline phosphate (ALP) activity of human mesenchymal stem cells (hMSCs) than non-BMP-2 treated control. Moreover, BMP-2 loaded GMPs group exhibited statistically increased ALP activity compared to both bolus BMP-2 administration and BMP-2 loaded Coa group, indicating that our carriers could protect and maintain biological activity of cargo BMP-2. Sustained release kinetics of BMP-2 from IPN composite hydrogels could be controlled by different formulations. For in vivo bone regeneration, various IPN gel formulations (i.e., (1) control, (2) only hydrogel, (3) hydrogel with bolus BMP-2, (4) hydrogel with BMP-2-loaded Coa, and (5) hydrogel with BMP-2-loaded GMPs) were bilaterally implanted into 5 mm-sized rat calvarial defects. After 4 weeks, micro-CT and histological analysis were performed to evaluate new bone formation. Significantly higher scores for bony bridging and union were observed in BMP-2-loaded Coa and BMP-2-loaded GMP groups as compared to other formulations. In addition, rats treated with BMP-2-loaded GMPs showed a significantly higher ratio of bone volume/total volume and lower trabecular separation scores than others. Finally, rats treated with either Coa or GMP groups exhibited a significant increase in bone formation area, as assessed via histomorphometric analysis. Taken together, it could be concluded that Coa and GMPs were effective carriers to maintain the bioactivity of cargo BMP-2 during its sustained release. Consequently, our IPN composite hydrogel system that combines such BMP-2 carriers could effectively promote skull bone regeneration.

Glutathione-loaded solid lipid nanoparticles based on Gelucire® 50/13: Spectroscopic characterization and interactions with fish cells

A characterization of solid lipid nanoparticles (SLN) produced starting from an emulsion prepared in acidic or neutral medium and based on Gelucire® 50/13 as lipid phase was performed by X-Ray Photoelectron Spectroscopy Analysis (XPS). The smallest particle size and the highest peptide content were observed for GSH-SLN produced in acidic medium [GSH-SLN(HAc)]. XPS analysis demonstrate the absence of GSH from the surface of the SLN and, combined with the observed sustained release kinetics, allowed us to propose the peptide GSH localization within the lipid nanoparticles. Differential Scanning Calorimetry thermograms of the GSH loaded SLN revealed the absence of the melting point peak at 193 °C attributable to the peptide, suggesting the decreased crystallinity of GSH in the lipid Gelucire® 50/13 forming the SLN matrix. SAF-1 cells (fibroblast-like cells derived from the fin) and gilthead seabream leukocytes were incubated in the presence of FITC-SLN. However, confocal microscopy confirmed that both types of cells were unable to internalize SLN. This result may be ascribed to the slightly negative surface-charge of labelled particles which is unfavorable for effective interactions of these essentially neutral particles with fish cells, suggesting, in perspective, the need to modify the carrier system surface in order to target cell fish.

Therapeutic Nanotechnology for Bone Infection Treatment - State of the Art.

Despite extended, aggressive use of conventional antibiotics, drug treatment of bone infections frequently fails as a combined result of the widespread of drug-resistant bacteria, poor accessibility of many antimicrobials to the deeper portion of the bones, the ease of biofilm formation on the bone surface, and high risk of drug toxicity. Emerging therapeutic nanotechnology offers potential solutions to these issues. In recent years, a number of nanoantimicrobials, i.e. nanoscale devices with intrinsic antibacterial activities or capacity for delivering antibiotics, have been developed for the treatment and prevention of bone infections. These nanoantimicrobials can be designed to have controlled and sustained drug release kinetics, surface-modifications for bone or bacteria targeting, and increased affinity for biofilms. Given the potential value of nanoantimicrobials, clinical application of nanoantimicrobials for bone infection treatment remains scant when compared with the number of ongoing research. It is, therefore, a good time to carefully examine this promising yet relatively uncharted area. This review will extensively discuss the development and state of the art of different classes of nanoantimicrobials for bone infections with emphasis on the treatment aspect and identify the factors that prevent the clinical translation of nanoantimicrobial therapy from bench to bedside.

Local sustained delivery of bupivacaine HCl from a new castor oil-based nanoemulsion system.

Bupivacaine HCl (1-butyl-2',6'-pipecoloxylidide hydrochloride), an amide local anesthetic compound, is a local anesthetic drug utilized for intraoperative local anesthesia, post-operative analgesia and in the treatment of chronic pain. However, its utility is limited by the relative short duration of analgesia after local administration (approximately 9h after direct injection) and risk for side effects. This work is aimed to develop a nanoemulsion of bupivacaine HCl with sustained local anesthetics release kinetics for improved pain management, by exhibiting extended analgesic action and providing reduced peak levels in the circulation to minimize side effects. Herein, biodegradable oils were evaluated for use in nanoemulsions to enable sustained release kinetics of bupivacaine HCl. Only with castor oil, a clear and stable nanoemulsion was obtained without the occurrence of phase separation over a period of 3months. High loading of bupivacaine HCl into the castor oil-based nanoemulsion system was achieved with about 98% entrapment efficiency and the resulting formulation showed high stability under stress conditions (accelerated stability test) regarding changes in visual appearance, drug content, and droplet size. We show herein that the in vitro release and in vivo pharmacokinetic profiles as well as pharmacodynamic outcome (pain relief test) after subcutaneous administration in rats correlate well and clearly demonstrate the prolonged release and extended duration of activity of our novel nanoformulation. In addition, the lower Cmax value achieved in the blood compartment suggests the possibility that the risk for systemic side effects is reduced. We conclude that castor oil-based nanomulsion represents an attractive pain treatment possibility to achieve prolonged local action of bupivacaine HCl.

Effect of the adhesion of Ag coatings on the effectiveness and durability of antibacterial properties

The adhesion force between metal-based antibacterial coatings and polymer substrate decides the effectiveness and durability of antibacterial performance. In this study, the silicone rubber substrate was modified by molecular bridge, i.e., polyvinylpyrrolidone, chitosan and (3-mercaptopropyl) trimethoxysilane, to provide “anchors” which captured Ag+ during electroless plating, and Ag coatings were resultantly produced. Different molecular bridge offered different adhesion. The spread plate counting, fluorescent staining assay and bacterial growth kinetics test showed that the antibacterial and anti-biofilm performance against Escherichia coli and Staphylococcus aureus was directly related to coating–substrate adhesion strength. A relative weaker adhesion resulted in rapid bactericidal and bacteria growth inhibition effect, and vice versa. The inductively coupled plasma atomic emission spectrometry indicated that relative weak adhesion provided fast Ag+ release, and strong adhesion gave lower Ag+ cumulative concentration, which may be attributed to different bonding strength. The coatings displayed sustained-release kinetics with the maximum cumulative Ag+ concentration of only 0.45 mg/L after 45 days of immersion in PBS solution, which was far below the human cell toxicity concentration. Nevertheless, all tested Ag coatings exhibited effective and long-lasting antibacterial properties. The tailored adhesion and consequent different antibacterial effect provided a choice for clinical applications.

Chitosan-stablized bovine serum albumin nanoparticles having ability to control the release of NELL-1 protein

The study was designed to prepare and evaluate chitosan stabilized-albumin nanoparticles as NELL-1 protein carriers(Chi/NNPs). The Chi/NNPs were prepared by desolvation method and then stabilized by chitosan through electrostatic interaction. The Chi/NNPs were characterized for drug loading efficiency, surface morphology, particle size, surface charge. Fluorescein isothiocyanate-labeled chitosan was used to confirm the homogeneity of chitosan coating on the BSA nanoparticles. The NELL-1 bioactivity of Chi/NNPs and the release kinetics were investigated in vitro. It was observed that the mean particle size with chitosan (0.075 wt%,0.15 wt%, 0.3 wt%, respectively) and the surface charge were 368.663 ± 15.470 nm, 382.881 ± 18.767 nm, 390.480 ± 11.465 nm and +25.03 ± 1.42 mV, +30.27 ± 1.80 mV, +31.03 ± 2.05 mV respectively. Drug entrapment efficiency ranged from 87.83% to 89.30%. The Chi/NNPs prepared with the 0.15 wt% chitosan were able to successfully control the release of NELL-1 and maintain a sustained release for up to 8 days. Furthermore, more than 82.67 ± 8.74% of the loaded protein’s bioactivity was preserved in Chi/NNPs over the period of the investigation. Our findings suggest that Chi/NNPs as promising protein delivery nanocarriers have the ability to maintain sustained release kinetics and to preserve the bioactivity of released NELL-1.

Design and characterization of calcium-free in-situ gel formulation based on sodium alginate and chitosan

The aim of this study was to prepare and evaluate calcium-free sustained release drug delivery systems, based on the in-situ gelation of oral suspensions containing chitosan, sodium alginate and Ranitidine as drug model. The combined effects of polymer concentrations and their interactions on the rheological characteristics of both gels and suspensions and, on the kinetics of drug release were evaluated by using a central composite face-centered design. Rheological analysis showed that suspensions were potentially stable, with a viscosity increased by 1000 times compared to that of water. In addition, the obtained gels were consistent; their storage modulus could reach values close to 50 kPa when alginate concentration was greater than 7.5 g/100 mL and chitosan was fixed to 0.5 g/100 mL. In these conditions gels should have a higher gastric residence time, in comparison to the standard gastric emptying time (∼2 h). Evaluation of the in-vitro release kinetics of Ranitidine showed that the association of the lowest concentration of chitosan (0.5 g/100 mL) with higher alginate concentrations generates sustained release kinetics profiles. The time corresponding to 63% of release was found close to 1.5 h, in which case the process is governed by Fickian diffusion. Finally, calcium-free alginate-chitosan based on the in-situ gelation of suspensions is advantageous as a drug delivery system for sustained-release.

Stent-based delivery of adeno-associated viral vectors with sustained vascular transduction and iNOS-mediated inhibition of in-stent restenosis.

In-stent restenosis remains an important clinical problem in the era of drug eluting stents. Development of clinical gene therapy protocols for the prevention and treatment of in-stent restenosis is hampered by the lack of adequate local delivery systems. Herein we describe a novel stent-based gene delivery platform capable of providing local arterial gene transfer with adeno-associated viral (AAV) vectors. This system exploits the natural affinity of protein G (PrG) to bind to the Fc region of mammalian IgG, making PrG a universal adaptor for surface immobilization of vector-capturing antibodies (Ab). Our results: 1) demonstrate the feasibility of reversible immobilization of AAV2 vectors using vector tethering by AAV2-specific Ab appended to the stent surface through covalently attached PrG, 2) show sustained release kinetics of PrG/Ab-immobilized AAV2 vector particles into simulated physiological medium in vitro and site-specific transduction of cultured cells, 3) provide evidence of long-term (12 weeks) arterial expression of luciferase with PrG/Ab-tethered AAV2Luc, and 4) show anti-proliferative activity and anti-restenotic efficacy of stent-immobilized AAV2iNOS in the rat carotid artery model of stent angioplasty.

Dual growth factor loaded nonmulberry silk fibroin/carbon nanofiber composite 3D scaffolds for invitro and invivo bone regeneration.

In recent years the potential application of nanocomposite biomaterials in tissue engineering field is gaining importance because of the combined features of all the individual components. A bottom-up approach is acquired in this study to recreate the bone microenvironment. The regenerated silk protein fibroin obtained from nonmulberry tropical tasar Antheraea mylitta species is reinforced with functionalized carbon nano fiber (CNF) and the composite sponges are fabricated using facile green aqueous based method. Biophysical investigations show that the matrices are porous and simultaneously bioactive when incubated in simulated body fluid. The reinforcement of CNF influences the mechanical property of the matrices by increasing the compressive modulus up to 46.54MPa (∼4.3 times of the control fibroin sponge) in hydrated state, which is higher than the minimum required human trabecular bone modulus (10MPa). The composite matrices are found to be non-hemolytic as well as cytocompatible. The growth factors (BMP-2 and TGF-β1) loaded composites show sustained release kinetics and an early attachment, growth, proliferation, and osteogenic differentiation of the osteoblasts and mesenchymal stem cells. The matrices are immunocompatible as evidenced by minimal release of pro-inflammatory cytokines both invitro and invivo. In order to support the invitro study, invivo analysis of new bone formation within the implants is performed through radiological, μ-CT, fluorochrome labeling and histological analysis, which show statistically better bone formation on growth factor loaded composite scaffolds. The study clearly shows the potential attributes of these composite matrices as an extra cellular matrix for supporting successful osseointegration process.

Vancomycin-loaded HPMC microparticles embedded within injectable thermosensitive chitosan hydrogels

Antibiotic use is an essential method for the treatment of bacterial infections. In certain cases, antibiotics are not effective because of the distribution problems caused by physiological barriers in the body. Such problems are thought to be minimized by development of sustained release systems which involve implantation of antibiotic loaded polymeric systems directly to the site of infection. In this work, a new composite vancomycin hydrochloride release system based on HPMC microparticles and chitosan/glycerophosphate (Ch/Gp) thermosensitive hydrogel was designed for the aim of local treatment of osteomyelitis. Vancomycin-loaded HPMC microparticles (Van-HPMCs) were prepared by spray drying method. The SEM results showed that these particles had a mean diameter of 1.5–6.4 μm with a narrow size distribution and homogeneous particle production. Their drug encapsulation efficiency was 72.6%. The Van-HPMCs were embedded in an injectable Ch/Gp solution to introduce a composite drug release platform (Van/HPMC-Ch/Gp). In vitro release studies indicated that inclusion of the Van-HPMCs into the Ch/Gp hydrogel caused a reduction in both the release rate and total amount of vancomycin release, which suggests that HPMC microparticles entrapped into the Ch/Gp hydrogels showed more suitable sustained release kinetics for local antibiotics delivery.