Sustained Local Drug Delivery Research Articles

In vivo validation of a mechanically adaptive microfluidic intracortical device as a platform for sustained local drug delivery

Introduction: Intracortical microelectrodes (IME) are vital to properly functioning brain-computer interfacing (BCI). However, the recording electrodes have shown a steady decline in performance after implantation, mainly due to chronic inflammation. Compliant materials have been explored to decrease differential strain resulting in lower neural inflammation. We have previously developed a fabrication method for creating mechanically adaptive microfluidic probes made of a cellulose nanocrystal (CNC) polymer nanocomposite material that can become compliant after implantation. Here, we hypothesized that our device, would have a similar tissue response to the industry standard, allowing drug delivery therapeutics to improve neural inflammation in the future.Methods: RNA expression analysis was performed to determine the extent of neural inflammation and oxidative stress in response to the device compared to controls and to naïve shame tissue.Results: Results presented for both four- and eight-weeks post-implantations suggest that our device offers a promising platform technology that can be used to deliver therapeutic strategies to improve IME performance.

Biodegradable gemcitabine-loaded microdevice with sustained local drug delivery and improved tumor recurrence inhibition abilities for postoperative pancreatic tumor treatment

At present, the 10-year survival rate of patients with pancreatic cancer is still less than 4%, mainly due to the high cancer recurrence rate caused by incomplete surgery and lack of effective postoperative adjuvant treatment. Systemic chemotherapy remains the only choice for patients after surgery; however, it is accompanied by off-target effects and server systemic toxicity. Herein, we proposed a biodegradable microdevice for local sustained drug delivery and postoperative pancreatic cancer treatment as an alternative and safe option. Biodegradable poly(l-lactic-co-glycolic acid) (P(L)LGA) was developed as the matrix material, gemcitabine hydrochloride (GEM·HCl) was chosen as the therapeutic drug and polyethylene glycol (PEG) was employed as the drug release-controlled regulator. Through adjusting the amount and molecular weight of PEG, the controllable degradation of matrix and the sustained release of GEM·HCl were obtained, thus overcoming the unstable drug release properties of traditional microdevices. The drug release mechanism of microdevice and the regulating action of PEG were studied in detail. More importantly, in the treatment of the postoperative recurrence model of subcutaneous pancreatic tumor in mice, the microdevice showed effective inhibition of postoperative in situ recurrences of pancreatic tumors with excellent biosafety and minimum systemic toxicity. The microdevice developed in this study provides an option for postoperative adjuvant pancreatic treatment, and greatly broadens the application prospects of traditional chemotherapy drugs.

Branched PCL-Based Thermogelling Copolymers: Controlling Polymer Architecture to Tune Drug Release Profiles

Temperature-responsive hydrogels, or thermogels, are a unique class of biomaterials that show facile and spontaneous transition from solution to gel when warmed. Their high biocompatibility, and ease of formulation with both small molecule drugs and biologics have made these materials prime candidates as injectable gel depots for sustained local drug delivery. At present, controlling the kinetics and profile of drug release from thermogels is achieved mainly by varying the ratio of hydrophobic: hydrophilic composition and the polymer molecular weight. Herein, we introduce polymer branching as a hitherto-overlooked polymer design parameter that exhibits profound influences on the rate and profile of drug release. Through a family of amphiphilic thermogelling polymers with systematic variations in degree of branching, we demonstrate that more highly-branched polymers are able to pack less efficiently with each other during thermogel formation, with implications on their physical properties and stability towards gel erosion. This in turn resulted in faster rates of release for both encapsulated small molecule hydrophobic drug and protein. Our results demonstrate the possibility of exploiting polymer branching as a hitherto-overlooked design parameter for tailoring the kinetics and profile of drug release in injectable thermogel depots.

Formulation and Optimization of Biodegradable Periodontal Chips Containing Metronidazole and Levofloxacin

This research aimed to developintrapocket,biodegradablechips ofpoly(d,l-lactide-co-glycolide) (PLGA) loaded with Metronidazole (MZ) and levofloxacin (LF),for sustained release local drug delivery in periodontal pocket to treat periodontitis. Metronidazole and levofloxacin are widely employed for the treatment of periodontitis,but high oral dose and resistance development after long-term oral administration limit their use, hence local delivery is a good approach. The chips were prepared by solvent casting technique using diethyl phthalate as plasticizer. Their physical characteristics, such as drug content,surface pH, swelling index, and folding endurance, exhibited results within limit. Further, FTIR and DSCstudies revealed stability of chips and compatibility between drugs and excipients.In vitro release in McIlvainebuffer pH 7.8 was of sustained nature assisted by the burst effect. Design-Expert® (11.0.4) software was used to study the effect of polymer & plasticizer on release of drugs Polymer concentrationsnegatively affected drug release and positively affected T90 (time for releasing 90% of the drug) due toaltered matrix density. In contrast, the plasticizer concentration increases membrane permeability andhence increased drug release, lowering T90. Forvarious response variables,polynomial mathematical models were generated usingmultiple regression analysis, and found to be statistically significant (????<0.05).The antibacterial efficacy of films was tested on Pseudomonas spp. Bacteroides spp., indicatinggood antibacterial activity. Optimized formulations were further used for preparing optimized biodegradable, Metronidazole-Levofloxacin sustained release chip. Conclusively, the films of MZ and LF were successful tools for the management ofperiodontitis.

A porous collagen-based hydrogel and implantation method for corneal stromal regeneration and sustained local drug delivery

Biomaterials designed to replace the diseased cornea could be used to treat corneal blindness where human donor tissue is in short supply, but challenges are the integration of biomaterials with host tissue and cells, avoiding a rapid material degradation and maintaining corneal transparency. Additionally, implantation surgery often triggers an aggressive wound healing response that can lead to corneal thinning and opacity. Here, we report a collagen-based hydrogel with transparency and mechanical properties suitable for replacing a substantial portion of a damaged or diseased corneal stroma. The porous hydrogel permitted migration and population by host cells while maintaining transparency and thickness six months after surgical implantation in an in vivo model of human corneal surgery. With a novel hybrid surgical implantation technique inspired by LASIK refractive surgery, rapid wound healing occurred around implants to maintain biomaterial integrity, transparency and function. Host stromal cell repopulation and regeneration of host epithelium and nerves were observed, as necessary steps towards corneal regeneration. Finally, as a proof-of-principle, the hydrogel loaded with a neuroregenerative drug achieved sustained slow-release drug delivery in vitro. The proposed hydrogel and novel implantation technique together represent a therapeutic approach with translational potential for replacing and regenerating diseased corneal stromal tissue.

Evaluation of Drug Delivery and Efficacy of Ciprofloxacin-Loaded Povidone Foils and Nanofiber Mats in a Wound-Infection Model Based on Ex Vivo Human Skin.

Topical treatment of wound infections is often a challenge due to limited drug availability at the site of infection. Topical drug delivery is an attractive option for reducing systemic side effects, provided that a more selective and sustained local drug delivery is achieved. In this study, a poorly water-soluble antibiotic, ciprofloxacin, was loaded on polyvinylpyrrolidone (PVP)-based foils and nanofiber mats using acetic acid as a solubilizer. Drug delivery kinetics, local toxicity, and antimicrobial activity were tested on an ex vivo wound model based on full-thickness human skin. Wounds of 5 mm in diameter were created on 1.5 × 1.5 cm skin blocks and treated with the investigated materials. While nanofiber mats reached the highest amount of delivered drug after 6 h, foils rapidly achieved a maximum drug concentration and maintained it over 24 h. The treatment had no effect on the overall skin metabolic activity but influenced the wound healing process, as observed using histological analysis. Both delivery systems were efficient in preventing the growth of Pseudomonas aeruginosa biofilms in ex vivo human skin. Interestingly, foils loaded with 500 µg of ciprofloxacin accomplished the complete eradication of biofilm infections with 1 × 109 bacteria/wound. We conclude that antimicrobial-loaded resorbable PVP foils and nanofiber mats are promising delivery systems for the prevention or topical treatment of infected wounds.

Liposomal doxorubicin loaded PLGA-PEG-PLGA based thermogel for sustained local drug delivery for the treatment of breast cancer

The aim of this research is to utilize a hybrid system of liposomal doxorubicin (DOX-Lip) loaded thermogel (DOX-Lip-Gel) to realize the steady sustained delivery of doxorubicin (DOX), a small hydrophilic drug, for the treatment of breast cancer locally. Herein, liposomal doxorubicin was prepared via the traditional film dispersion method with the particle size of 75 nm and drug entrapment efficiency of 86%. And, the triblock copolymer of poly (D, L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D, L-lactide -co-glycolide) (PLGA-PEG-PLGA) was synthesized via ring-opening polymerization to prepare the thermosensitive hydrogel through dissolving the polymers in DOX-Lip solution. The liposome loaded hydrogel was in a sol state at room temperature and converted into the gel state at body temperature and would degrade gradually during the time in vivo. The drug release of DOX out of DOX-Lip-Gel could be in a steady sustained manner up to 11 days without significant burst release as compared to that of DOX-loaded hydrogel (DOX-Gel). An orthotopic breast cancer model was adopted to evaluate the in vivo antitumor efficacy. And, the results revealed DOX-Lip-Gel had better antitumor efficiency as well as lower side effects.

Fabrication of Mucoadhesive-Dendrimers as Solid Dosage Forms.

Mucoadhesion has a potential role in the delivery of pharmaceutical medicaments via various routes of administration, viz. oral, nasal, vaginal, and buccal. Mucoadhesion provides controlled drug delivery, sustained drug delivery, and local or site-specific drug delivery. This chapter focuses on the mechanism of bio-adhesion to glycoprotein layer of mucosal membrane. Some of the gastric mucoadhesive solid dosage forms of nanocarrier, viz. nanoparticle, microsphere, and nanofibers, undergo evaluation of mucoadhesive parameters. That includes mucoadhesive strength, tensile strength, swelling index, stability studies, in vivo study, etc. The oral route is the most desirable way among intravenous, subcutaneous, intramuscular, intranasal, intravaginal, etc. for drug delivery and because of patient compliance. One of the novel approaches is where nanocarrier is loaded in the solid dosage form for effective drug action and enhanced local delivery of a drug. Mainly this chapter explains about dendrimer-based oral solid dosage form (tablet) employing mucoadhesive polymers with an aim to improve retention time of drug at desired sites. Dendrimer-loaded mucoadhesive tablets promise controlled drug delivery with a gastro-retentive property, higher drug incorporation, ease of formulation development, and accessible absorption, owing to adjacent interaction with a biological membrane and prolonged retention to mucosa providing higher bioavailability of drugs.

Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer

Conventional systemic immunotherapy administration often results in insufficient anti-tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit efficient anti-tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic-based device for intratumoral drug delivery called the nanofluidic drug-eluting seed (NDES). The NDES is inserted intratumorally using a minimally invasive trocar method similar to brachytherapy seed insertion and offers a clinical advantage of drug elution. Drug diffusion from the NDES is regulated by physical and electrostatic nanoconfinement, thereby resulting in constant and sustained immunotherapeutic delivery without the need for injections or clinician intervention. In this study, the NDES was used to deliver immunotherapeutics intratumorally in the 4 T1 orthotopic murine mammary carcinoma model, which recapitulates triple negative breast cancer. We demonstrated that NDES-mediated intratumoral release of agonist monoclonal antibodies, OX40 and CD40, resulted in potentiation of local and systemic anti-tumor immune response and inhibition of tumor growth compared to control mice. Further, mice treated with NDES-CD40 demonstrated minimal liver damage compared to systemically treated mice. Collectively, our study highlights the NDES as an effective platform for sustained intratumoral immunotherapeutic delivery. The potential clinical impact is tremendous given that the NDES is applicable to a broad spectrum of drugs and solid tumors.

Abstract 1708: Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer

Abstract Conventional systemic immunotherapy administration often results in insufficient anti-tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit robust anti-tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic-based device for intratumoral drug delivery called the nanofluidic drug-eluting seed (NDES). The NDES is inserted intratumorally using a minimally invasive trocar method similar to brachytherapy seed insertion and offers a clinical advantage of intratumoral drug elution. Drug diffusion from the NDES is regulated by physical and electrostatic nanoconfinement, thereby resulting in constant and sustained immunotherapeutic delivery without the need for repeated injections or clinician intervention. In this study, the NDES was utilized to deliver immunotherapeutics intratumorally in the 4T1 orthotopic murine mammary carcinoma model, which recapitulates triple negative breast cancer. We demonstrated that NDES-mediated intratumoral release of agonist immunotherapeutic monoclonal antibodies, OX40 and CD40, resulted in potentiation of local and systemic anti-tumor immune response and significant inhibition of tumor growth compared to control mice. Further, mice treated with NDES-CD40 demonstrated minimal liver damage compared to systemically treated mice. Collectively, our study highlights the NDES as an effective platform for sustained intratumoral immunotherapeutic delivery. The potential clinical impact is tremendous given that the NDES is applicable to a broad spectrum of drugs and solid tumors. Citation Format: Corrine Ying Xuan Chua, Priya Jain, Marco Folci, Andrea Ballerini, Jessica Rhudy, April Gilbert, Shail Shaibala, Giacomo Bruno, Carly S. Filgueira, Cassian Yee, E. Brian Butler, Alessandro Grattoni. Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1708.

Drug-Free ROS Sponge Polymeric Microspheres Reduce Tissue Damage from Ischemic and Mechanical Injury.

The inherent antioxidant function of poly(propylene sulfide) (PPS) microspheres (MS) was dissected for different reactive oxygen species (ROS), and therapeutic benefits of PPS-MS were explored in models of diabetic peripheral arterial disease (PAD) and mechanically induced post-traumatic osteoarthritis (PTOA). PPS-MS (∼1 μm diameter) significantly scavenged hydrogen peroxide (H2O2), hypochlorite, and peroxynitrite but not superoxide in vitro in cell-free and cell-based assays. Elevated ROS levels (specifically H2O2) were confirmed in both a mouse model of diabetic PAD and in a mouse model of PTOA, with greater than 5- and 2-fold increases in H2O2, respectively. PPS-MS treatment functionally improved recovery from hind limb ischemia based on ∼15-25% increases in hemoglobin saturation and perfusion in the footpads as well as earlier remodeling of vessels in the proximal limb. In the PTOA model, PPS-MS reduced matrix metalloproteinase (MMP) activity by 30% and mitigated the resultant articular cartilage damage. These results suggest that local delivery of PPS-MS at sites of injury-induced inflammation improves the vascular response to ischemic injury in the setting of chronic hyperglycemia and reduces articular cartilage destruction following joint trauma. These results motivate further exploration of PPS as a stand-alone, locally sustained antioxidant therapy and as a material for microsphere-based, sustained local drug delivery to inflamed tissues at risk of ROS damage.

Preparation of HCPT-Loaded Nanoneedles with Pointed Ends for Highly Efficient Cancer Chemotherapy

The high-aspect-ratio nanoparticles were proved to be internalized much more rapidly and efficiently by cancer cells than the nanoparticles with an equal aspect ratio. Herein, a kind of high-aspect ratio, pointed-end nanoneedles (NDs) with a high drug loading (15.04 %) and the prolonged drug release profile were fabricated with an anti-tumor drug—10-hydroxycamptothecin (HCPT)—via an ultrasound-assisted emulsion crystallization technique. It is surprising to see that the cellular internalization of NDs with an average length of 5 μm and an aspect ratio of about 12:1 was even much faster and higher than that of nanorods with the same size and the nanospheres with a much smaller size of 150 nm. The results further validated that cellular internalization of the nanoparticles exhibited a strong shape-dependent effect, and cellular uptake may favor the particles with sharp ends as well as a high-aspect ratio instead of particle size. The NDs with enhanced cytotoxicity would lead to a promising sustained local drug delivery system for highly efficient anticancer therapy. More importantly, the fabrication of NDs opens a door to design new formulations of nanoneedle drug delivery systems for highly efficient cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s11671-016-1491-9) contains supplementary material, which is available to authorized users.

Sustained Pulmonary Delivery of a Water-Soluble Antibiotic Without Encapsulating Carriers.

Traditional polymeric nanoparticle formulations for prolonged local action during inhalation therapy are highly susceptible to muco-ciliary clearance. In addition, polymeric carriers are typically administered in high doses due to finite drug loading. For toxicological reasons, these carriers and their degradation byproducts are undesirable for inhalation therapy, particularly for chronic use, due to potential lung accumulation. We synthesized a novel, insoluble prodrug (MRPD) of a time-dependent β-lactam, meropenem, and formulated MRPD into mucus-penetrating crystals (MRPD-MPCs). After characterizing their mucus mobility (in vitro) and stability, we evaluated the lung pharmacokinetics of intratracheally-instilled MRPD-MPCs and a meropenem solution in guinea pigs. Meropenem levels rapidly declined in the lungs of guinea pigs receiving meropenem solution compared to those given MRPD-MPCs. At 9h after dosing, drug levels in the lungs of animals that received meropenem solution dropped to 12ng/mL, whereas those that received MRPD-MPCs maintained an average drug level of ≥1,065ng/mL over a 12-h period. This work demonstrated that the combination of prodrug chemistry and mucus-penetrating platform created nanoparticles that produced sustained levels of meropenem in guinea pig lungs. This strategy represents a novel approach for sustained local drug delivery to the lung without using encapsulating matrices.

Integration of an anti-tumor drug into nanocrystalline assemblies for sustained drug release.

Delicate mesoscopic architectures, bearing complex forms with multiple hierarchy levels, lead to significant functions in biogenic minerals. Herein, a bio-inspired approach was developed to fabricate comet-shaped assemblies of an anti-tumor drug - 10-hydroxycamptothecin (HCPT). The anti-solvent co-precipitation of HCPT and the excipient - PEG-b-PLGA - within the emulsifier leads to the immediate nucleation of comet bundles, followed by a secondary nucleation to generate the comet head, which is an assembly of nanofibers aligned almost in parallel. The continuous manufacturing furnishes drug-excipient hybrid particles with high drug-loading and a sustained drug release profile. This simple and efficient bio-inspired approach led to a promising sustained local drug delivery system, and could be extended to the fabrication of other functional organic materials bearing mesoscopic structural units.

Evaluation of sorption capacity of antibiotics and antibacterial properties of a cyclodextrin-polymer functionalized hydroxyapatite-coated titanium hip prosthesis

Infection still present as one of common complications after total hip replacement (∼2.5%), which may cause serious outcomes. For preventing such risk, loading antibiotics onto implants for increasing local drug concentration at targeted sites could be a solution. This study aims at modifying the surface of hydroxyapatite (HA) coated titanium hip implant material (Ti–HA) with polymer of cyclodextrin (polyCD) for loading antibiotics, to achieve a sustained local drug delivery. Two widely applied antibiotics (tobramycin and rifampicin) in orthopedic surgery were loaded alone or in combination. The drug adsorption isotherm, drug release kinetics and drug’s efficacy were thoroughly investigated. The results proved that polyCD coating significantly improved the affinity of both drugs to Ti–HA surface, while the mechanism of drug–polyCD interaction varies from the nature of drug, courtesy of the structural complex of polyCD. The advantage of dual-drug loading was highlighted by its strong efficacy against both Staphylococcus aureus and Enterobacter cloacae, which overcomes the limitation of mono-drug loading for an effective treatment against both bacterial strains. The prolonged antibacterial activity of antibiotic loaded Ti–HA-polyCD samples confirmed that polyCD could be a promising drug-delivery system, for sustained antibiotics release or other potential applications e.g., antimitotic agent release.

Combination of doxorubicin-based chemotherapy and polyethylenimine/p53 gene therapy for the treatment of lung cancer using porous PLGA microparticles

In this study, porous PLGA microparticles for the co-delivery of doxorubicin and PEI25K/p53 were successfully prepared by the water–oil–water emulsion solvent evaporation method, using ammonium bicarbonate as a porogen. The porous microparticles were obtained with a mean diameter of 22.9±11.8μm as determined by laser scattering particle size analysis. The particles’ surface porous morphology and distributions of doxorubicin and p53 were systematically characterized by scanning electron microscopy, flow cytometry, fluorescence microscopy and confocal laser scanning microscopy, revealing that doxorubicin and the plasmid were successfully co-encapsulated. Encapsulation efficiencies of 88.2±1.7% and 36.5±7.5% were achieved for doxorubicin and the plasmid, respectively, demonstrating that the porous structure did not adversely affect payload encapsulation. Microparticles harboring both doxorubicin and PEI25K/p53 exhibited enhanced tumor growth inhibition and apoptosis induction compared to those loaded with either agent alone in A549 human lung adenocarcinoma cells. Overall, the porous PLGA microparticles provide a promising anticancer delivery system for combined chemotherapy and gene therapy, and have great potential as a tool for sustained local drug delivery by inhalation.

Periodontal Debridement: Still the Treatment of Choice

Periodontal debridement (PD) remains a gold standard for the treatment of inflammatory periodontitis. Background/PurposeThe evidence base regarding the causal relationship between oral biofilm and the host inflammatory response to the etiology of periodontal disease has substantially increased over the years. What has not changed significantly during that time is the conservative manner in which the disease can be treated with periodontal debridement (PD). Since dental hygienists, in particular, specialize in providing these procedures it is important to evaluate the evidence that supports periodontal debridement as a primary and fundamental treatment modality. MethodAn extensive narrative literature review that included systematic reviews, examined traditional PD, the use of adjuncts to enhance PD and newer PD procedures to determine what are the best practices for achieving optimal clinical outcomes. ConclusionCompared to surgical therapy, PD results in maintenance of attachment levels over time, but is not as effective in the initial reduction of probing depths in deep pockets. Sustained release local drug delivery agents have some modest adjunctive effects when used with PD, as do systemic antibiotics in aggressive periodontitis cases. Reported analyses of the long term effects of chemotherapeutic agents usually do not extend beyond a few months to a year. While laser therapy is still under investigation it remains as a potential PD therapy. New instruments being refined to better visualize the root surface either non-surgically or with mini papilla reflection flaps, hold promise for the future when they become more affordable and accessible. Despite the development of new technology, it still appears that periodontal debridement (PD) remains the gold standard for the treatment of inflammatory periodontitis.

Avidin as a model for charge driven transport into cartilage: relevance to osteoarthritis drug delivery

Purpose: There is an unmet need for effective ways to locally and safely introduce DMOADs into cartilage, to minimize systemic adverse effects and to increase drug specificity for targets in the tissue. Several studies have focused on drug-encapsulating polymeric particles whose effectiveness depends on their ability to enter the dense cartilage ECM and to be retained over time. Our recent studies using solutes having a wide size range (1-15nm diameter) revealed that nanoparticles with diameter <10nm could penetrate into and diffuse throughout cartilage while larger solutes became trapped within the superficial zone. We now confirmed this size limitation using NeutrAvidin, a globular protein (diam∼7nm, 60kDa, electrically neutral). While nanoparticle transport is size and shape dependent, surface charge can greatly affect their binding within ECM. Therefore, we compared the binding and transport properties of NeutrAvidin to Avidin, a highly positively charged protein of similar MW and size. Methods: Cartilage disks (6mm diam, 1mm thick) were harvested from the femoropatellar grooves of 1-2 week old bovine calf knee joints. Transport and binding properties of FITC-labeled NeutrAvidin (pI∼7) and Avidin (pI∼10.5) were measured. A transparent PMMA transport chamber (Fig 1F) allowed diffusion of solutes from only one side (superficial zone) of the disk. Half-cylindrical disks were placed within slots in the middle of the chambers. The chamber side facing the superficial zone was filled with ∼45μl solution of solute in 1X-PBS; the other side was filled with 1X PBS. The chamber was placed on a low-speed rocker inside a 37-deg incubator. At selected times, samples were removed from the chamber and gently rinsed. A full-thickness slice was cut from the center of the sample and imaged using a confocal microscope at 10X magnification. For desorption studies, the solute solution was removed from the chamber and replaced with 1X or 10X PBS. Results: Figs 1A, B, C along with their fluorescence intensity-vs-depth graphs show increasing penetration of NeutrAvidin at 1, 2 and 4 days from the superficial zone (denoted by arrows). Fluorescence intensity is plotted vs distance from the left edge of the images. Figs. 1D, E show explants after 24h desorption of NeutrAvidin in 1X and 10X PBS respectively, suggesting that most NeutrAvidin diffused out similarly by 24h. In contrast, Avidin completely penetrated and diffused throughout the cartilage within 24h (Fig 2A). While some Avidin diffused out of the explants after 24h in 1XPBS (Fig 2B), significantly more Avidin diffused out in 10X PBS. Explants within the chamber (Fig. 1F) show visual evidence of significantly higher uptake of Avidin compared to NeutrAvidin in 24h (i.e., cartilage fluorescence staining). Conclusions: Our results suggest that the transport and binding of Avidin into bovine cartilage is driven by strong electrostatic interactions. Despite their similar sizes, Avidin penetrated through the full thickness (1mm) of cartilage in 24h, while it took 4 days for NeutrAvidin to penetrate half the thickness. A 400-times greater uptake was measured for Avidin compared to NeutrAvidin in 24h. NeutrAvidin diffused out in both 1X and 10X PBS while Avidin remained bound in 1X PBS but diffused out in 10X PBS. We hypothesize that Avidin binds to negatively charged GAG chains in the cartilage: both Avidin and NeutrAvidin exhibited identical absorption and desorption properties in GAG-depleted cartilage explants (data not shown), further confirming the effects of electrostatic interactions. Using principles of Donnan equilibrium, we calculated a net charge of approx. +15 on Avidin. This work suggests that polymeric particles mimicking the structure of Avidin (i.e., ∼7nm diameter with high positive charge) might facilitate higher and faster uptake into cartilage from the surrounding synovial fluid, and also bind within the tissue, thereby providing sustained local drug delivery.

Development andIn VitroCharacterization of Hyaluronic Acid-Based Coatings for Implant-Associated Local Drug Delivery Systems

The development of drug-eluting coatings based on hyaluronic acid (HA) is especially promising for implant-associated local drug delivery (LDD) systems, whose implantation provokes high insertion forces, as, for instance, cochlear implants or drug-coated balloons (DCB). The lubricious character of HA can then reduce the coefficient of friction and serve as drug reservoir simultaneously. In this context, we investigated several plasma- and wet-chemical methods for the deposition of HA-based coatings with LDD function on polyamide 12 as a model implant surface, conventionally used for DCB. In contrast to aminosilane, epoxy silane surface layers allowed the covalent attachment of a smooth and uniform HA base layer, which provided good adherence of further HA layers deposited by manual dip coating at a subsequent processing stage. The applied HA-crosslinking procedure during dip coating influences the transfer and release of paclitaxel, which could be reproducibly incorporated via infiltration. While crosslinking with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride provided HA coatings on DCB, which allowed for an efficient paclitaxel transfer upon expansion in a vessel model, crosslinking with glutardialdehyde resulted in a slower drug release being more appropriate for implants with longer residence time in the body. The developed HA coating is hence well suited for spontaneous and sustained LDD.

Laponite clay as a carrier for in situ delivery of tetracycline

Although smectite clays have gained much interest in recent years as potential sustained local drug delivery vehicles, they have not been yet utilized or assessed as a local drug delivery device for treatment of periodontal disease. In this paper we showed that unique nanostructure and gel-formation ability of clay holds great promise as an effective drug carrier. In particular, we demonstrated the feasibility of using laponite XLG, a smectite clay, as a carrier for in situ delivery of tetracycline that can potentially be used in the treatment and prevention of periodontal disease. The intercalation of tetracycline between the layers of laponite at different acidic pHs and different concentrations of tetracycline was examined. The laponite–tetracycline composite was characterized using X-ray diffraction (XRD), Fourier transformed infrared spectroscopy (FT-IR) and differential thermal analysis (DTA). The results showed that, in a pH and concentration dependent manner, tetracycline can be intercalated between the layers of laponite nanoparticles. The release study in a simulated saliva solution demonstrated a sustained release of tetracycline from laponite over a 72 hour period. The antimicrobial activity of the released tetracycline was maintained and was not affected by the intercalation of tetracycline into the carrier (laponite) and its release from the carrier.