Development and in-vivo characterization of supramolecular hydrogels for intrarenal drug delivery.

Intrarenal drug delivery from a hydrogel carrier implanted under the kidney capsule is an innovative way to induce kidney tissue regeneration and/or prevent kidney inflammation or fibrosis. We report here on the development of supramolecular hydrogels for this application. We have synthesized two types of supramolecular hydrogelators by connecting the hydrogen bonding moieties to poly(ethylene glycols) in two different ways in order to obtain hydrogels with different physico-chemical properties. Chain-extended hydrogelators containing hydrogen bonding units in the main chain, and bifunctional hydrogelators end-functionalized with hydrogen bonding moieties, were made. The influence of these hydrogels on the renal cortex when implanted under the kidney capsule was studied. The overall tissue response to these hydrogels was found to be mild, and minimal damage to the cortex was observed, using the infiltration of macrophages, formation of myofibroblasts, and the deposition of collagen III as relevant read-out parameters. Differences in tissue response to these hydrogels could be related to the different physico-chemical properties of the three hydrogels. The strong, flexible and slow eroding chain-extended hydrogels are proposed to be suitable for long-term intrarenal delivery of organic drugs, while the weaker, soft and fast eroding bifunctional hydrogel is eminently suitable for short-term, fast delivery of protein drugs to the kidney cortex. The favourable biological behaviour of the supramolecular hydrogels makes them exquisite candidates for subcapsular drug delivery, and paves the way to various opportunities for intrarenal therapy.

Chemical and biological properties of supramolecular polymer systems based on oligocaprolactones.

We show that materials with a diverse range of mechanical and biological properties can be obtained using a modular approach by simply mixing different ratios of oligocaprolactones that are either end-functionalized or chain-extended with quadruple hydrogen bonding ureido-pyrimidinone (UPy) moieties. The use of two UPy-synthons allows for easy synthesis of UPy-modified polymers resulting in high yields. Comparison of end-functionalized UPy-polymers with chain-extended UPy-polymers shows that these polymers behave distinctively different regarding their material and biological properties. The end-modified UPy-polymer is rather stiff and brittle due to its high crystallinity. Disks made of this material fractures after subcutaneous implantation. The material shows a low inflammatory response which is accompanied by the formation of a fibrous capsule, reflecting the inertness of the material. The chain-extended UPy-material on the contrary is practically free of crystalline domains and shows clear flexible properties. This material deforms after in-vivo implantation, accompanied with cellular infiltration. By mixing both polymers, materials with intermediate properties concerning their mechanical and biological behaviour can be obtained. Surprisingly, a 20:80 mixture of both polymers with the chain-extended UPy-polymer in excess shows flexible properties without visible deformation upon implantation for 42 days. This mixture, a blend formed by intimate mixing through UPy-UPy interaction, also shows a mild tissue response accompanied with the formation of a thin capsule. The material does not become more crystalline upon implantation. Hence, this mixture might be an ideal scaffold material for soft tissue engineering due to its flexibility and diminished fibrous tissue formation, and illustrates the strength of the modular approach.