Herein we designed and characterized films composed of naturally derived materials for controlled release of proteins. Traditional drug delivery strategies rely on synthetic or semi-synthetic materials, or utilize potentially denaturing assembly conditions that are not optimal for sensitive biologics. Layer-by-Layer (LbL) assembly of films uses benign conditions and can generate films with various release mechanisms including hydrolysis-facilitated degradation. These use components such as synthetic polycations that degrade into non-natural products. Herein we report the use of a naturally-derived, biocompatible and degradable polyanion, poly(β-l-malic acid), alone and in combination with chitosan in an LbL film, whose degradation products of malic acid and chitosan are both generally recognized as safe (GRAS) by the FDA. We have found that films based on this polyanion have shown sustained release of a model protein, lysozyme that can be timed from tens of minutes to multiple days through different film architectures. We also report the incorporation and release of a clinically used biologic, basic fibroblast growth factor (bFGF), which demonstrates the use of this strategy as a platform for controlled release of various biologics.
Long-term, localized delivery of small molecules from a biodegradable thin film is challenging owing to their low molecular weight and poor charge density. Accomplishing highly extended controlled release can facilitate high therapeutic levels in specific regions of the body while significantly reducing the toxicity to vital organs typically caused by systemic administration and decreasing the need for medical intervention because of its longlasting release. Also important is the ability to achieve high drug loadings in thin film coatings to allow incorporation of significant drug amounts on implant surfaces. Here we report a sustained release formulation for small molecules based on a soluble charged polymer-drug conjugate that is immobilized into nanoscale, conformal, layer-by-layer assembled films applicable to a variety of substrate surfaces. We measured a highly predictable sustained drug release from a polymer thin film coating of 0.5-2.7 μm that continued for more than 14 mo with physiologically relevant drug concentrations, providing an important drug delivery advance. We demonstrated this effect with a potent small molecule nonsteroidal anti-inflammatory drug, diclofenac, because this drug can be used to address chronic pain, osteoarthritis, and a range of other critical medical issues.NSAID | polyelectrolyte multilayers | polymer prodrug
Uncontrolled bleeding and infection are the major causes of death and morbidity from traumatic wounds during military conflicts, disasters, and accidents. Because immediate treatment is critical to survival, it is desirable to have a lightweight and rapidly applicable bandageone capable of delivering a hemostat that can quickly resolve bleeding while addressing infection over short and longer time frames. It is challenging to design thin film coatings capable of multidrug release, particularly when the drugs are quite different in nature (biologic versus small molecule, charged versus neutral) and the desired release profiles are different for each drug. Herein we have adopted a layer-by-layer film assembly technique to create a linear combination of two independently functional films capable of rapidly releasing thrombin within minutes while sustaining vancomycin elution for more than 24 h. By conjugating vancomycin to a hydrolytically degradable polyacid, poly(β-L-malic acid), we were able to create a robust thin film with loading and release kinetics that remain unaffected by the additional deposition of a thrombin-based film, demonstrating the possibility for future multitherapeutic films with independently tunable release kinetics.
Multidrug regimens can sometimes treat recalcitrant diseases when single-drug therapies fail. Recapitulating complex multidrug administration from controlled release films for localized delivery remains challenging because their release kinetics are frequently intertwined and an initial burst release of each drug is usually uncontrollable. Herein we demonstrate kinetic control over protein release by crosslinking Layer-by-Layer films during the assembly process. We used biodegradable and naturally derived components and relied on copper-free click chemistry for bioorthogonal covalent crosslinks throughout the film that entrap, but do not modify the embedded protein. We found that this strategy restricted the interdiffusion of protein while maintaining its activity. By depositing a barrier layer and a second protein-containing layer atop this construct, we generated well-defined sequential protein release with minimal overlap that follows their spatial distribution within the film.
ABSTRACT:The speed and scalability of film fabrication can dictate the translation of technologies from the laboratory scale to industrial level mass production. Spray-assisted layer-by-layer (LbL) film assembly enables the rapid coating of geometrically complex and porous substrates with functional polyelectrolyte multilayers. Unfortunately, the encapsulation efficiency can be as low as one percent, making this technique prohibitively costly with even modestly priced materials. Herein, we used containment chambers to separately capture the aerosolized solutions for each step in the spray-LbL process and analyzed the effect of recycling on multilayer film assembly. With potential biomedical applications, we studied the controlled release films of (Poly 2/heparin/lysozyme/heparin) n films and tracked the distribution of lysozyme after film assembly. In a "Conventional" Spray-LbL protocol, only 6% of the aerosolized lysozyme is incorporated into the film. By collecting and returning the expended solutions to their respective reservoirs (Recycle SprayLbL), we increased this efficiency to 15%. We also tuned the final distribution of lysozyme by adjusting the spray times (Optimized Spray-LbL), which minimized the amount of lysozyme lost to non-specific adsorption and reduced the fraction of lysozyme lost to the wash step from 30% and 75% (Conventional and Recycle Spray-LbL, respectively) to 13%. Despite the changes in film assembly parameters, each film demonstrated similar controlled release properties. With the inherent limitations of time and cost facing Dip and Conventional Spray-LbL technologies, respectively, the implementation of recycling to the latter demonstrates improvements in efficiency and time that may make it more attractive for the manufacture of biomedical coatings.
Multidrug regimens can sometimes treat recalcitrant diseases when single-drug therapies fail. Recapitulating complex multidrug administration from controlled release films for localized delivery remains challenging because their release kinetics are frequently intertwined and an initial burst release of each drug is usually uncontrollable. Herein we demonstrate kinetic control over protein release by crosslinking Layer-by-Layer films during the assembly process.
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