Intelligente Drug-Delivery-Systeme zur Vermeidung Implantat-assoziierter Infektionen

All medical devices and implants are made of synthetic or natural, but usually not endogenous, materials. Implantation of such devices, into living tissue, is therefore subject to the risk of nosocomial infections, biofilm formation and may cause implant-associated infections. Microorganisms (including bacteria) that grow in biofilms and cause chronic inflammation are the typical source of these infections. Subsequently, they can lead to implant failure, requiring further surgical treatments. To prevent this, this study investigated and presented enzymatically degradable drug delivery systems that enable encapsulation and targeted release of an antibacterial agent triggered by an infection. To achieve this, the dissertation focused on the fabrication, characterization of suitable nanocarriers and their immobilization on implant surfaces such as titanium. To build a stable and degradable encapsulation system, different steps were established: 1) the integration of an enzyme-labile model peptide into two different polymer-based systems 2) generation of particles 3) coating of titanium surfaces with the particles 4) investigation of stability and degradability of those systems 5) the release of ciprofloxacin as a model substance. For this, two approaches have been tested. The first approach included the synthesis of chitosan‐g‐[peptide‐poly‐L‐caprolactone] and its self‐assembly into polymeric vesicles by the solvent shift method. For the second approach, nanogels dispersions were prepared by ionotropic gelation of the alginate with the poly-L-lysine, which was conjugated with ciprofloxacin via a copper-free 1,3-dipolar cycloaddition (click reaction).Alle medizinischen Geräte und Implantate bestehen aus synthetischen oder natürlichen, jedoch in der Regel aus nicht endogenen Materialien. Die Implantation solcher Geräte in lebendes Gewebe unterliegt daher dem Risiko nosokomialer Infektionen und der Bildung von Biofilmen und kann implantatassoziierte Infektionen verursachen. Mikroorganismen (einschließlich Bakterien), die in Biofilmen wachsen und chronische Entzündungen verursachen, sind die typische Quelle dieser Infektionen. Anschließend können sie zu einem Implantatversagen führen, was weitere chirurgische Behandlungen erforderlich macht. Um dies zu verhindern, untersuchte und ergab diese Studie enzymatisch abbaubare Arzneimittelabgabesysteme, die die Einkapselung und gezielte Freisetzung eines durch eine Infektion ausgelösten antibakteriellen Mittels ermöglichen. Um dies zu erreichen, konzentrierte sich die Dissertation auf die Herstellung und Charakterisierung geeigneter Nanoträger sowie deren Immobilisierung auf Implantatoberflächen wie Titan. Um ein stabiles und abbaubares Einkapselungssystem aufzubauen, wurden verschiedene Schritte festgelegt: 1) Integration eines enzymlabilen Modellpeptids in zwei verschiedene Systeme auf Polymerbasis 2) Erzeugung von Partikeln 3) Beschichtung von Titanoberflächen mit den Partikeln 4) Untersuchung von Stabilität und Abbaubarkeit dieser Systeme 5) Freisetzung von Ciprofloxacin als Modellsubstanz. Hierzu wurden zwei Ansätze getestet. Der erste Ansatz umfasste die Synthese von Chitosan-g-[Peptid-Poly-ε-Caprolacton] und dessen Selbstorganisation zu polymeren Vesikeln durch das Lösungsmittel-Verschiebungsverfahren. Für den zweiten Ansatz wurden Nanogeldispersionen durch ionotrope Gelierung des Alginats mit dem Poly-L-Lysin hergestellt, das über eine kupferfreie 1,3-dipolare Cycloaddition (Klickreaktion) mit Ciprofloxacin konjugiert wurde

Optimization of Critical Parameters for Carbodiimide Mediated Production of Highly Modified Chitosan

An optimization of the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and hydroxy benzotriazole mediated conjugation of the polysaccharide chitosan with functional carboxylic acids was shown. Optimal parameters that enable resource-efficient synthesis of highly functionalized chitosan were identified. In particular, use of only catalytic instead of stoichiometric amounts of hydroxy benzotriazole and tight control of pH in reaction mixture resulted in highly efficient incorporation of the desired moieties as side chains in chitosan. As a result, the model reactant 4-azidobenzoic acid was incorporated resulting in a degree of substitution of over 30% with very high coupling efficacy of up to 90%. Similar results were obtained with other carboxylic acids such as methacrylic acid, 3-(2-furyl) propionic acid and 3-maleimido propionic acid, highlighting the broad applicability of our findings for the functionalization of chitosan

Enzyme-Responsive Nanoparticles and Coatings Made from Alginate/Peptide Ciprofloxacin Conjugates as Drug Release System

Infection-controlled release of antibacterial agents is of great importance, particularly for the control of peri-implant infections in the postoperative phase. Polymers containing antibiotics bound via enzymatically cleavable linkers could provide access to drug release systems that could accomplish this. Dispersions of nanogels were prepared by ionotropic gelation of alginate with poly-l-lysine, which was conjugated with ciprofloxacin as model drug via a copper-free 1,3-dipolar cycloaddition (click reaction). The nanogels are stable in dispersion and form films which are stable in aqueous environments. However, both the nanogels and the layers are degraded in the presence of an enzyme and the ciprofloxacin is released. The efficacy of the released drug against Staphylococcus aureus is negatively affected by the residues of the linker. Both the acyl modification of the amine nitrogen in ciprofloxacin and the sterically very demanding linker group with three annellated rings could be responsible for this. However the basic feasibility of the principle for enzyme-triggered release of drugs was successfully demonstrated