Towards the optimization of drug delivery to the cochlear apex: Influence of polymer and drug selection in biodegradable intracochlear implants.

There is growing need for new drug delivery systems for intracochlear application of drugs to effectively treat inner ear disorders. In this study, we describe the development and characterization of biodegradable, triamcinolone-loaded implants based on poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) respectively, prepared by hot-melt extrusion. PEG 1500 was used as a plasticizer to improve flexibility and accelerate drug release. The sterilization process was performed by electron beam irradiation, resulting in minimal but acceptable polymer degradation for PEG-PLGA implants. The implants have been characterized by texture analysis, differential scanning calorimetry and X-ray powder diffraction. Compared to PLGA implants, PEG-PLGA implants offer similar flexibility but with improved mechanical stability, which will ease the handling and intracochlear application. A controlled release over three months was observed for dexamethasone and triamcinolone extrudates (drug load of 10%) with similar release profiles for both drugs. PEG-PLGA implants showed an initial slow release rate over several days regardless of the amount of PEG added. Mathematical simulations of the pharmacokinetics of the inner ear based on the in vitro release kinetics indicate a complete distribution of triamcinolone in the whole human scala tympani, which underlines the high potential of the developed formulation.

Novel biodegradable Round Window Disks for inner ear delivery of dexamethasone.

Drug delivery to the inner ear is an important and very challenging field. The cochlea is protected by several barriers that need to be overcome in the drug delivery process. Local drug delivery can avoid undesirable side effects arising from systemic drug delivery. We developed a biodegradable dexamethasone-loaded Round Window (RW) Disk based on poly(D,L-lactic-co-glycolic acid) (PLGA) for local drug therapy to the inner ear by RW membrane administration by a film-casting method. The optimal drying time was characterized by thermogravimetric analysis and differential scanning calorimetry. In addition, the mass and polymer degradation over time of drug release was measured in vitro showing a total mass loss of 70% after 3 weeks. Dexamethasone release was determined by a RW model setup using a polyethylene terephthalate membrane. We achieved a controlled release over 52 days. Ex vivo implantation of a RW Disk onto a guinea pig RW membrane indicated well-fitting properties of the drug delivery device leading to a close surface contact with the membrane and the successful proof of concept. The developed RW Disks could be new and promising drug delivery device to achieve effective local drug delivery to the inner ear for an extended time.

New E-beam-initiated hyaluronan acrylate cryogels support growth and matrix deposition by dermal fibroblasts.

Cryogels made of components of natural extracellular matrix components are potent biomaterials for bioengineering and regenerative medicine. Human dermal fibroblasts are key cells for tissue replacement during wound healing. Thus, any biomaterial for wound healing applications should enable growth, differentiation and matrix synthesis by these cells. Cryogels are highly porous scaffolds consisting of a network of interconnected pores. Here, we used a novel group of cryogels generated from acrylated hyaluronan where the polymerization was initiated by accelerated electrons (E-beam). This novel procedure omits any toxic polymerization initiators and results in sterile, highly elastic scaffolds with adjustable pore size, excellent swelling and low flow resistance properties. We show that these cryogels are effective 3D-substrates for long-term cultures of human dermal fibroblasts in vitro. The cells proliferate for at least 28days throughout the cryogels and deposit their own matrix in the pores. Moreover, key modulators of dermal fibroblasts during wound healing like TGFß and PDGF efficiently stimulated the expression of wound healing-relevant genes. In conclusion, electron beam initiated cryogels of acrylated hyaluronan represent a functional and cell compatible biomaterial that could be adapted for special wound healing applications by further functionalization.

EPR studies of amine radical cations, part 1: thermal and photoinduced rearrangements of n-alkylamine radical cations to their distonic forms in low-temperature freon matrices.

The thermal and photochemical transformations of primary amine radical cations (n-propyl 1.+, n-butyl 5.+) generated radiolytically in freon matrices have been investigated by using low-temperature EPR spectroscopy. Assignment of the spectra was facilitated by parallel studies on the corresponding N,N-dideuterioamines. The identifications were supported by quantum chemical calculations on the geometry, electronic structure, hyperfine splitting constants and energy levels of the observed transient radical species. The rapid generation of the primary species by a short exposure (1-2 min) to electron-beam irradiation at 77 K allowed the thermal rearrangement of 1.+ to be monitored kinetically as a first-order reaction at 125-140 K by the growth in the well-resolved EPR signal of the distonic radical cation .C(2CH2CH2NH3+. By comparison, the formation of the corresponding .CH2CH2CH2CH2NH3+ species from 5.+ is considerably more facile and already occurs within the short irradiation time. These results directly verify the intramolecular hydrogen-atom migration from carbon to nitrogen in these ionised amines, a reaction previously proposed to account for the fragmentation patterns observed in the mass spectrometry of these amines. The greater ease of the thermal rearrangement of 5.+ is in accordance with calculations on the barrier heights for these intramolecular 1,5- and 1,4-hydrogen shifts, the lower barrier for the former being associated with minimisation of the ring strain in a six-membered transition state. For 1.+, the 1,4-hydrogen shift is also brought about directly at 77 K by exposure to approximately 350 nm light, although there is also evidence for the 1,3-hydrogen shift requiring a higher energy. A more surprising result is the photochemical formation of the H2C=N. radical as a minor product under hard-matrix conditions in which diffusion is minimal. It is suggested that this occurs as a consequence of the beta-fragmentation of 1.+ to the ethyl radical and the CH2=NH2+ ion, followed by consecutive cage reactions of deprotonation and hydrogen transfer from the iminonium group. Additionally, secondary ion-molecule reactions were studied in CFCl2CF2Cl under matrix conditions that allow diffusion. The propane-1-iminyl radical CH3CH2CH=N. was detected at high concentrations of the n-propylamine substrate. Its formation is attributed to a modified reaction sequence in which 1.+ first undergoes a proton transfer within a cluster of amine molecules to yield the aminyl radical CH3CH2CH2N.H. A subsequent disproportionation of these radicals can then yield the propane-1-imine precursor CH3CH2CH=NH, which is known to easily undergo hydrogen abstraction from the nitrogen atom. The corresponding butane-1-iminyl radical was also observed.