Christian Wischke

Shape-memory polymers as a technology platform for biomedical applications

Polymeric materials are clinically required for medical devices, as well as controlled drug delivery systems. Depending on the application, the polymer has to provide suitable functionalities, for example, mechanical functions or the capability to actively move, so that an implant can be inserted in a compact shape through key-hole incisions and unfold to its functional shape in the body. Shape-memory polymers, as described herein regarding their general principle, compositions and architectures, have developed to a technology platform that allows the tailored design of such multifunctionality. In this way, defined movements of implants triggered either directly or indirectly, tailored mechanical properties, capability for sterilization, biodegradability, biocompatibility and controlled drug release can be realized. This comprehensive review of the scientific and patent literature illustrates that this technology enables the development of novel medical devices that will be clinically evaluated in the near future.

Evaluation of a degradable shape-memory polymer network as matrix for controlled drug release.

Degradable shape-memory polymers are multifunctional materials with broad applicability for medical devices. They are designed to acquire their therapeutically relevant shape and mechanical properties after implantation. In this study, the potential of a completely amorphous shape-memory polymer matrix for controlled drug release was comprehensively characterized according to a four step general strategy which provides concepts for validating multifunctional materials for pharmaceutical applications. Independent functionalities are thereby crucial for fully exploiting the potential of the materials. The copolyester urethane network was synthesized by crosslinking star-shaped tetrahydroxy telechelics of oligo[(rac-lactide)-co-glycolide] with an aliphatic diisocyanate. In step 1 of the four step characterization procedure, this material showed the thermal and mechanical properties, which are required for the shape-memory effect under physiological conditions. Shape recovery could be realized by a one-step or a multi-step methodology. In step 2, feasibility of drug loading of pre-formed shape-memory networks has been demonstrated with drugs of different hydrophobicities. The presence of drugs did not disturb the materials functionalities directly after loading (step 3) and under release conditions (step 4). A predictable release of about 90% of the payload in 80 days was observed. Overall, the synthesized amorphous polymer network showed three independent functionalities, i.e., a shape-memory effect combined with biodegradability and controlled drug release.

Poly(I:C) coated PLGA microparticles induce dendritic cell maturation.

Microparticles from poly(D,L-lactic-co-glycolic acid) [PLGA] are of steadily rising interest for the delivery of antigens to immune cells and the induction of a long-lasting immune response for vaccination or immunological tumor therapy. However, if the desired vaccine contains only weak antigens and fails to activate the antigen presenting cells (APC), the opposite effect, i.e., the induction of immunotolerance may be observed. Therefore, it was the aim of this study to show the ability of protein loaded PLGA microparticles to additionally carry a specific, surface-coated maturation signal to human dendritic cells (DC), i.e., the most potent APC. Polyinosine-polycytidylic acid [poly(I:C)], a ligand of Toll-like receptor (TLR) 3, was efficiently bound either in a single layer or a multilayer attempt to the surface of diethylaminoethyl dextran modified PLGA microparticles. These particles were effectively phagocytized by DC ex vivo and induced a maturation similar to that achieved with a cytokine cocktail or higher concentrations of soluble poly(I:C). In conclusion, the concept of surface coating of biodegradable microparticles with selected TLR ligands might successfully be used in DC-based cell therapies for cancer or in vaccination trials to induce DC maturation and specifically amplify the immunological response to encapsulated antigens.

Preparation and biological evaluation of multifunctional PLGA-nanoparticles designed for photoacoustic imaging

UNLABELLED Nanoparticulate contrast agents for molecular imaging have attracted widespread interest for diagnostic applications with high resolution in medicine. Here we introduce polymer-based multifunctional nanoparticles exhibiting a near-infrared absorption in the range of the Nd:YAG laser wavelength of 1064 nm as a novel resorbable photoacoustic (PA) contrast system and report about their biological evaluation. Submicron-sized spherical nanoparticles with a high encapsulation efficiency (>87%) were created by incorporation of near-infrared dyes (IR5/IR26) in poly[(rac-lactide)-co-glycolide] (PLGA) with 50 mol% glycolide content via a specific spray-drying process in good yield (>75%). Subsequent application of a centrifugation protocol produced two different size fractions with diameters in the ranges 445-540 nm and 253-305 nm; these were further used for investigation of PA properties and cytotoxic effects. The prepared PLGA nanoparticles exhibited PA properties using a Nd:YAG laser-based system. After exposure of particle concentrations up to 10 μg·ml(-1) for 2 days no effects on viability, mitochondrial activity and proliferation, and cell death of human hepatocarcinoma cells and monkey kidney cells were observed. The excellent PA properties in combination with the positive biological results qualify the dye-loaded PLGA particles as promising candidates for a resorbable PA contrast system. FROM THE CLINICAL EDITOR Photoacoustics (PA), a new modality, in which laser light is shined into tissue and absorbed by inherent proteins or synthetic particles is reflected back and received as ultrasound. This technique was shown to be effective with an erodible polymer particle containing near infrared dyes. In vitro, the PA properties of the PLGA particles persisted for 2 days in cell culture.

A thermosensitive morphine-containing hydrogel for the treatment of large-scale skin wounds.

PURPOSE Topically applied opioids are an option to induce efficient analgesia in patients with severe skin wounds. For ongoing pain reduction, the vehicle should provide sustained drug release in order to increase the intervals during the regular wound dressing changes. In addition, the formulation should not impair wound healing. Hydrogels provide a moist wound environment, which is known to facilitate the healing process. METHODS AND RESULTS Investigating poloxamer hydrogels as a carrier system for morphine in terms of release behavior and (per-)cutaneous absorption, poloxamer 407 25wt.% hydrogel sustained morphine release up to 24h. The drug release rate decreased with increasing concentration of the gel forming triblock copolymer. Poloxamer 407 25wt.% hydrogel retarded morphine uptake into reconstructed human skin and percutaneous drug absorption compared to a hydroxyethyl cellulose reference gel. CONCLUSIONS The results of our in vitro study indicate that the thermosensitive poloxamer 407 25wt.% hydrogel is an appropriate carrier system for the topical application of morphine with regard to sustained drug release and ongoing analgesia.

Shape-Memory Polymers as Drug Carriers—A Multifunctional System

Along with the progress in surgical techniques, especially in minimally invasive surgery (MIS) (1), the requirements for the functionality of implants becomes more complex. Smart materials are demanded to enable the insertion of a bulky device in the body through a small keyhole incision in a temporarily fixed, compressed shape. After precise positioning by the surgeon, such intelligent implants gain their application-relevant shape on demand. An example is intravascular stents, whose unfolding from a compact shape requires well-controlled forces applied against the vessel wall. Therefore, suitable materials should store stress and enable predefined, directional changes of the implant shape. Moreover, often a combination of tailored mechanical properties and functions, such as controlled drug release and suitability for implantation by MIS, is envisioned, leading to multifunctional implants. Establishing parenteral drug carriers which exhibit multifunctionality has been an aim of research on controlled drug release from biodegradable polymers from its very beginning. Multifunctionality is understood as the combination of different predefined functions in a material system, which preferentially is necessary to meet a specific requirement of an application, here to reach a certain therapeutic aim. Multifunctionality may be accomplished under conditions of or in its interaction with a biological system. Known drug-loaded implants from biodegradable polymers are two-component systems (drug+polymer), which typically exhibit two functionalities: the capability of drug molecules to gradually escape from the matrix for a controlled release and the ability of the matrix to subsequently degrade for complete excretion from the body. So far, multifunctionality of devices was often achieved by combining materials, as in the case of drug-eluting stents: metal for mechanical strength, polymer coatings for hemocompatibility, and drug to be released for prevention of restenosis. A challenge arising from the addition of novel functionalities to such multi-material systems is the possibility to impair previously established capabilities. While this issue can be solved in many cases by a suitable design of the multicomponent systems, certain functionalities, like degradability, cannot be achieved by addition of a component. For this purpose, one-component multifunctional materials were envisioned. An example is the matrix for modern implants for MIS, which preferentially should be biodegradable and capable of incorporating/releasing drugs without adverse effects on other functionalities.

Controlled Drug Release from Biodegradable Shape-Memory Polymers

Biodegradable shape-memory polymers (SMPs) have attracted significant interest for biomedical applications. Modern concepts for biofunctional implants often comprise the controlled release of bioactive compounds to gain specific biofunctionalities. Therefore, a general strategy has been suggested for polymer systems combining degradability and shape-memory capability with controlled release of drugs. This chapter provides a detailed description of the molecular basis for such multifunctional SMPs including the selection of building blocks, the polymer morphology, and the three dimensional architecture. Moreover, drug loading and release, drug effects on thermomechanical properties of SMPs, and drug release patterns in a physiological environment are described and potential applications in minimally-invasive surgery are discussed.

Shape-Memory Hydrogels: Evolution of Structural Principles To Enable Shape Switching of Hydrophilic Polymer Networks

The ability of hydrophilic chain segments in polymer networks to strongly interact with water allows the volumetric expansion of the material and formation of a hydrogel. When polymer chain segments undergo reversible hydration depending on environmental conditions, smart hydrogels can be realized, which are able to shrink/swell and thus alter their volume on demand. In contrast, implementing the capacity of hydrogels to switch their shape rather than volume demands more sophisticated chemical approaches and structural concepts. In this Account, the principles of hydrogel network design, incorporation of molecular switches, and hydrogel microstructures are summarized that enable a spatially directed actuation of hydrogels by a shape-memory effect (SME) without major volume alteration. The SME involves an elastic deformation (programming) of samples, which are temporarily fixed by reversible covalent or physical cross-links resulting in a temporary shape. The material can reverse to the original shape when these molecular switches are affected by application of a suitable stimulus. Hydrophobic shape-memory polymers (SMPs), which are established with complex functions including multiple or reversible shape-switching, may provide inspiration for the molecular architecture of shape-memory hydrogels (SMHs), but cannot be identically copied in the world of hydrophilic soft materials. For instance, fixation of the temporary shape requires cross-links to be formed also in an aqueous environment, which may not be realized, for example, by crystalline domains from the hydrophilic main chains as these may dissolve in presence of water. Accordingly, dual-shape hydrogels have evolved, where, for example, hydrophobic crystallizable side chains have been linked into hydrophilic polymer networks to act as temperature-sensitive temporary cross-links. By incorporating a second type of such side chains, triple-shape hydrogels can be realized. Considering the typically given light permeability of hydrogels and the fully hydrated state with easy permeation by small molecules, other types of stimuli like light, pH, or ions can be employed that may not be easily used in hydrophobic SMPs. In some cases, those molecular switches can respond to more than one stimulus, thus increasing the number of opportunities to induce actuation of these synthetic hydrogels. Beyond this, biopolymer-based hydrogels can be equipped with a shape switching function when facilitating, for example, triple helix formation in proteins or ionic interactions in polysaccharides. Eventually, microstructured SMHs such as hybrid or porous structures can combine the shape-switching function with an improved performance by helping to overcome frequent shortcomings of hydrogels such as low mechanical strength or volume change upon temporary cross-link cleavage. Specifically, shape switching without major volume alteration is possible in porous SMHs by decoupling small volume changes of pore walls on the microscale and the macroscopic sample size. Furthermore, oligomeric rather than short aliphatic side chains as molecular switches allow stabilization of the sample volumes. Based on those structural principles and switching functionalities, SMHs have already entered into applications as soft actuators and are considered, for example, for cell manipulation in biomedicine. In the context of those applications, switching kinetics, switching forces, and reversibility of switching are aspects to be further explored.

Shape‐Memory Effect of Micro‐/Nanoparticles from Thermoplastic Multiblock Copolymers

The miniaturization and retained full shape-memory functionality with particle switching to different predefined shapes is reported for semi-crystalline multiblock copolymer matrices with all dimensions in the low micrometer-range. A matrix size-induced reduction of crystallinity suggests limitations of functionality in the low nanometer range. Applications as actuators in microdevices or as microcarriers with switchable shapes for modulated biorecognition are suggested.

Comparing techniques for drug loading of shape-memory polymer networks: effect on their functionalities

A family of oligo[(epsilon-caprolactone)-co-glycolide]dimethacrylate (oCG-DMA) derived networks of different glycolide contents as well as precursor molecular weights has been synthesized by crosslinking oCG-DMA, providing matrices of different hydrophilicity, network density, and morphology at body temperature. Such networks were loaded with a hydrophilic model drug, ethacridine lactate, either before crosslinking or afterwards by swelling in drug solution. Disadvantageous alterations of the shape-memory functionality and degradation characteristics were observed only in few loaded materials. Loading by swelling generally resulted in low payloads, which slightly increased for more hydrophilic polymer networks, and a substantial burst and fast subsequent release for all investigated materials. Loading before crosslinking gave almost no burst and higher subsequent release rates over longer periods of time. Overall, depending on the needs of a specific application, a material from this polymer family with the desired mechanical properties, shape-memory functionality, and degradation pattern can be selected and combined with drugs when considering that (i) loading by swelling is best suited for applications that require high initial doses and (ii) loading before crosslinking allows easy variation of payloads and low burst release for therapeutics that are non-sensitive to chemical alterations during crosslinking.