Connie S. Kwok

Self-assembled molecular structures as ultrasonically-responsive barrier membranes for pulsatile drug delivery

Noninvasive ultrasound has been shown to increase the release rate on demand from drug delivery systems; however, such systems generally suffer from background drug leaching. To address this issue, a drug-containing polymeric monolith coated with a novel ultrasound-responsive coating was developed. A self-assembled molecular structure coating based on relatively impermeable, ordered methylene chains forms an ultrasound-activated on-off switch in controlling drug release on demand, while keeping the drug inside the polymer carrier in the absence of ultrasound. The orderly structure and molecular orientation of these C12 n-alkyl methylene chains on polymeric surfaces resemble self-assembled monolayers on gold. Their preparation and characterization have been published recently (Kwok et al. [Biomacromolecules 2000;1(1):139-148]). Ultrasound release studies showed that a copolymer of 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate (MW 400) coated with such an ultrasound-responsive membrane maintained sufficient insulin for multiple insulin delivery, compared with a substantial burst release during the first 2 h from uncoated samples. With appropriate surface coating coverage, the background leach rate can be precisely controlled. The biological activity of the insulin releasate was tested by assessing its ability to regulate [C14]-deoxyglucose uptake in 3T3-L1 adipocyte cells in a controlled cell culture environment. Uptake triggered by released insulin was comparable to that of the positive insulin control. The data demonstrate that the released insulin remains active even after the insulin had been exposed to matrix synthesis and the methylene chain coating process.

Design of infection-resistant antibiotic-releasing polymers. II. Controlled release of antibiotics through a plasma-deposited thin film barrier.

In the first paper in this series, we described the methods to synthesize an antibacterial polyurethane (PU) incorporating ciprofloxacin as the releasable antibiotic and poly(ethylene glycol) as the pore-forming agent. Here, we report that a thin, RF-plasma-deposited, n-butyl methacrylate (BMA) overlayer on this drug-loaded PU can act as a rate-limiting barrier to achieve a constant, sustained release of ciprofloxacin. Deposition power and deposition time during the coating process were optimized to give an appropriate crosslinked coating barrier that yielded desirable release rates, above the minimum required killing rate, N(kill). Electron spectroscopy for chemical analysis (ESCA), also known as X-ray photoelectron spectroscopy (XPS), was used to characterize the coating, and its crosslinking degree was indirectly related to the C/O ratio. Increasing either deposition power (10-60 W) or duration (5-25 min) resulted in increased C/O ratios and decreased ciprofloxacin release rates. The correlation between increased C/O ratios and reduced release rates is believed to be due to the increased crosslinking, increased hydrophobicity and increased thickness of the coating. The optimal plasma conditions to attain an appropriate crosslinked plasma-deposited film (PDF) required argon etching, pre-treatment of the matrices with an 80W-BMA plasma for 1 min, followed by immediate BMA plasma deposition at 40 W and 150 mT for 20 min. By using these plasma deposition protocols, we eliminated the initial burst effect, significantly reduced the release rates, and closely approached the zero order release kinetics for at least five days. In this study, we also showed that ESCA could be used as a powerful tool to explain the release behavior of molecules through the plasma-deposited films (PDFs).

Plasma-deposited membranes for controlled release of antibiotic to prevent bacterial adhesion and biofilm formation.

Bacterial infection on implanted medical devices is a significant clinical problem caused by the adhesion of bacteria to the biomaterial surface followed by biofilm formation and recruitment of other cells lines such as blood platelets, leading to potential thrombosis and thromboembolisms. To minimize biofilm formation and potential device-based infections, a polyurethane (Biospan) matrix was developed to release, in a controlled manner, an antibiotic (ciprofloxacin) locally at the implant interface. One material set consisted of the polyetherurethane (PEU) base matrix radiofrequency glow discharge plasma deposited with triethylene glycol dimethyl ether (triglyme); the other set had an additional coating of poly(butyl methyacrylate) (pBMA). Triglyme served as a nonfouling coating, whereas the pBMA served as a controlled porosity release membrane. The pBMA-coated PEU contained and released ciprofloxacin in a controlled manner. The efficacy of the modified PEU polymers against Pseudomonas aeruginosa suspensions was evaluated under flow conditions in a parallel plate flow cell. Bacterial adhesion and colonization, if any, to the test polymers were examined by direct microscopic image analysis and corroborated with destructive sampling, followed by direct cell counting. The rate of initial bacterial cell adhesion to triglyme-coated PEU was 0. 77%, and to the pBMA-coated PEU releasing ciprofloxacin was 6% of the observed adhesion rates for the control PEU. However, the rate of adherent cell accumulation due to cell growth and replication was approximately the same for the triglyme-coated PEU and the PEU controls, but was zero for the pBMA-coated PEU releasing ciprofloxacin.

Design of infection-resistant antibiotic-releasing polymers: I. Fabrication and formulation.

Biomaterials-related infections are often observed with prosthetic implants and in many cases result in the failure of the devices. To design a biomedically useful polymer that is intrinsically infection-resistant, we have developed a ciprofloxacin-loaded polyurethane (PU) matrix that releases antibiotic locally at the implant surface, thereby minimizing bacterial accumulation. We report here the methods of fabrication and formulation for making such antibiotic-loaded devices, as well as evidence of their bactericidal properties. Specifically, various pore-forming agents and drug loadings were examined. An optimum formulation consisting of BIOSPAN PU, poly(ethylene glycol) and ciprofloxacin offered the longest effective period of sustained release (5 days). The bactericidal efficacy of the released ciprofloxacin against Pseudomonas aeruginosa (PA) was four times that of the control PU without antibiotics. This bactericidal efficiency was due to an increase in the PA detachment from the surface. These observations suggested that the released ciprofloxacin was biologically active in preventing the bacteria from permanently adhering to the substratum, and thus decreasing the possibility of biofilm-related infection.

Ultrasonic release of insulin from implantable, bio‐compatable polymers coated with self‐assembling membranes

There has been some research in the late 1980s on the development and use of biologically compatable, drug‐carrying polymers for the purpose of subcutaneous release of the drug. In those papers, ultrasound was used to release the drug. This intriguing method for temporally targeted drug release has been hampered by a large, non‐ultrasonic drug release rate. In other words, even without the application of ultrasonic stimulation, an excessive amount of the drug leaches out of the drug‐carrying implant. We have developed a bio‐compatable, drug‐carrying polymer that can release a drug of interest upon ultrasonic stimulation, but whose background leaching rate is negligible. The advance in the present study over previous work is the coating of the drug‐carrying polymer with a self‐assembling membrane (SAM). Before and after the application of ultrasound, the SAM acts as an effective barrier. During and shortly after the application of ultrasound, the SAM transiently disassembles—thereby releasing the drug—then...

Enhanced release of drugs from a novel polymeric film coated with self‐healing, ordered methylene chains induced by hydrodynamic shear

The effect of numerous stimuli upon the release of drugs and other molecules from polymeric substrates has been of great interest in the drug delivery community. Ultrasound has proven to be an effective stimulus for the controlled release of drugs from polymer films. However, the mechanism by which this controlled response occurs has yet to be fully understood. In this study, the ability of shear forces generated by microstreaming around a single ultrasonically stimulated bubble to reversibly increase the release of the drugs from a coated polymer film is demonstrated. The polymer film is loaded with the drug ciprofloxacin and then coated with methylene chains consisting of 12 hydrocarbon chains. The leaching rate of the drug thus depends upon the extent of surface coverage by the methylene chains. A single oscillating bubble in a fluid medium has the capacity to drive streaming at the surface of the polymer film and disrupt the methylene chain coating. An increase of drug concentration in suspension as high as ten times the baseline and controls was achieved, which implies an increase in the leaching rate. After treatment, the leaching rate returns to baseline levels, suggesting the methylene chains reorganize upon the polymer surface.The effect of numerous stimuli upon the release of drugs and other molecules from polymeric substrates has been of great interest in the drug delivery community. Ultrasound has proven to be an effective stimulus for the controlled release of drugs from polymer films. However, the mechanism by which this controlled response occurs has yet to be fully understood. In this study, the ability of shear forces generated by microstreaming around a single ultrasonically stimulated bubble to reversibly increase the release of the drugs from a coated polymer film is demonstrated. The polymer film is loaded with the drug ciprofloxacin and then coated with methylene chains consisting of 12 hydrocarbon chains. The leaching rate of the drug thus depends upon the extent of surface coverage by the methylene chains. A single oscillating bubble in a fluid medium has the capacity to drive streaming at the surface of the polymer film and disrupt the methylene chain coating. An increase of drug concentration in suspension as h...