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HYPOTHESIS: Injectable hydrogels are important in situ forming implants for tissue regeneration at damaged sites. Understanding the behavior of these systems in a complex in vivo environment remains a challenge. Ultrathin films as 2D model systems are expected to provide fundamental insights into formation and (bio)degradation at material-liquid interfaces, and are also applicable as bioresponsive coatings. EXPERIMENTS: Hydrogel ultrathin films are prepared by covalently cross-linking four-arm PEG macromers with maleimide end-groups (PEG4MAL) at alkaline pH using two different types of dithiol-bearing cross-linkers - thio-depsipeptide (TDP) or 3,6-Dioxa-1,8-octanedithiol (DODT). This thiol-Michael addition "click" reaction is carried out at the air-water interface using the Langmuir technique. Morphological observation in real time is carried out by Brewster angle microscopy (BAM) and in coatings using atomic force microscopy (AFM). Stability against enzymatic and oxidative degradation is evaluated in the same setup. FINDINGS: Non-cross-linked PEG or PEG incubated with cross-linkers at slightly acidic pH desorbs from the interface over time. Cross-linking of PEG at alkaline pH renders 2D hydrogel networks (thickness <1 nm) that are stable against desorption. They are easily transferrable onto solid mica surfaces, forming homogenous coatings as revealed by AFM. The type of dithiol cross-linker used to form the branching centers influences the degradability of these 2D hydrogel networks in the presence of lipase, peroxides, or bases. For example, enzymatic degradation of the 2D hydrogel networks can be switched "on" or "off" depending on the cleavable sites in the cross-linkers.

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Hydroxyl terminated oligo(ε-caprolactone) (OCL) monolayers were reversibly cross-linked forming two dimensional networks (2D) at the air-water interface. The equilibrium reaction with glyoxal as the cross-linker is pH-sensitive. Pronounced contraction in the area of the prepared 2D OCL films in dependence of surface pressure and time revealed the process of the reaction. Cross-linking inhibited crystallization and retarded enzymatic degradation of the OCL film. Altering the subphase pH led to a cleavage of the covalent acetal cross-links. The reversibility of the covalent acetal cross-links was proved by observing an identical isotherm as non-cross-linked sample. Besides as model systems, these customizable reversible OCL 2D networks are intended for use as pH responsive drug delivery systems or functionalized cell culture substrates.

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Chronic inflammatory responses after implantation of biomaterials can lead to fibrotic encapsulation and failure of implants. The present study was designed to reduce the inflammatory responses to biomaterials by assembling polyelectrolyte multilayers (PEMs) composed of glycosaminoglycans (GAGs) and chitosan (Chi) on glass as model surfaces through layer-by-layer (LBL) technique. Surface plasmon resonance (SPR) and water contact angle (WCA) investigations confirmed the multilayer build-up with alternating deposition of GAGs and Chi layers, while zeta potential measurements showed significant negative charges after multilayer deposition, which further proved the PEM formation. Macrophage adhesion, macrophage spreading morphology, foreign body giant cell (FBGC) formation, as well as ß1 integrin expression and interleukin-1ß (IL-1ß) production were all significantly decreased by GAG-Chi multilayer deposition in comparison to the primary poly (ethylene imine) (PEI) layer. Thereby, the type of GAGs played a pivotal role in inhibiting the inflammatory responses to various extents. Especially heparin (Hep)-Chi multilayers hindered all inflammatory responses to a significantly higher extent in comparison to hyaluronic acid (HA)-Chi and chondroitin sulfate (CS)-Chi multilayer systems. Overall, the present study suggests a great potential of GAG-Chi multilayer coating on implants, particularly the Hep-Chi based systems, to reduce the inflammatory responses.

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