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Cell and tissue stiffness is an important biomechanical signalling parameter for dynamic biological processes; responsive polymeric materials conferring responsive functionality are therefore appealing for in vivo implants. We have developed thermoresponsive poly(urea-urethane) nanohybrid scaffolds with 'stiffness memory' through a versatile 3D printing-guided thermally induced phase separation (3D-TIPS) technique. 3D-TIPS, a combination of 3D printing with phase separation, allows uniform phase-separation and phase transition of the polymer solution at a large interface of network within the printed sacrificial preform, leading to the creation of full-scale scaffolds with bespoke anatomical complex geometry. A wide range of hyperelastic mechanical properties of the soft elastomer scaffolds with interconnected pores at multi-scale, controlled porosity and crystallinity have been manufactured, not previously achievable via direct printing techniques or phase-separation alone. Semi-crystalline polymeric reverse self-assembly to a ground-stated quasi-random nanophase structure, throughout a hierarchical structure of internal pores, contributes to gradual stiffness relaxation during in vitro cell culture with minimal changes to shape. This 'stiffness memory' provides initial mechanical support to surrounding tissues before gradually softening to a better mechanical match, raising hopes for personalized and biologically responsive soft tissue implants which promote human fibroblast cells growth as model and potential scaffold tissue integration. STATEMENT OF SIGNIFICANCE: Biological processes are dynamic in nature, however current medical implants are often stronger and stiffer than the surrounding tissue, with little adaptability in response to biological and physical stimuli. This work has contributed to the development of a range of thermoresponsive nanohybrid elastomer scaffolds, with tuneable stiffness and hierarchically interconnected porous structure, manufactured by a versatile indirect 3D printing technique. For the first time, stiffness memory of the scaffold was observed to be driven by phase transition and a reverse self-assembly from a semicrystalline phase to a quasi-random nanostructured rubber phase. Early insight into cell response during the stiffness relaxation of the scaffolds in vitro holds promise for personalized biologically responsive soft implants.

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Cardiovascular implants must resist infection and thrombosis. A nanocomposite polymeric material [polyhedral-oligomeric-silsesquioxane-poly(carbonate-urea)urethane; POSS-PCU] demonstrates ideal properties for cardiovascular applications. Silver nanoparticles or nanosilver (NS) are recognized for efficient antibacterial properties. This study aims to determine the influence of NS integrated POSS-PCU on thrombogenicity. Silver nitrate was reduced with dimethylformamide and stabilized by the inclusion of fumed silica nanoparticles to prevent aggregation of NS and were incorporated into POSS-PCU to form a range of POSS-PCU-NS concentrations (by weight); 0.20% (NS16), 0.40% (NS32), 0.75% (NS64), and 1.50% (NS128). Surface wettability was determined with sessile-drop water contact angles. Platelets were introduced onto test samples and Alamar Blue (AB), mitochondrial-activity assay, quantified the degree of platelet adhesion whilst platelet-factor-4 (PF4) ELISA quantified the degree of platelet activation. Thromboelastography (TEG) determined the profiles of whole blood kinetics while hemolysis assay demonstrated the degree of blood compatibility. Increasing levels of NS induced greater hydrophilicity. A concentration dependant decrease in platelet adhesion and activation was observed with AB and PF4 readings, respectively. TEG demonstrated that the antithrombogenic properties of POSS-PCU were retained with POSS-PCU-NS16, and enhanced with POSS-PCU-NS32, but was reduced with POSS-PCU-NS64 and POSS-PCU-NS128. POSS-PCU-NS64 and POSS-PCU-NS128 demonstrated a hemolytic tendency, but no hemolysis was observed with POSS-PCU-NS16 and POSS-PCU-NS32. Overall, POSS-PCU-NS32 rendered potent antithrombogenic properties.

With the continuous and expanding use of implantable biomaterials in a clinical setting, this study aims to elucidate the influence of sterilization techniques on the material surface and bulk properties of two polyurethane nanocomposite biomaterials. Both solid samples and porous membranes of nondegradable polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) and a biodegradable poly(caprolactone-urea) urethane (POSS-PCL) were examined. Sterilization techniques included conventional steam sterilization (autoclaving), gamma irradiation, and disinfection via incubating with ethanol (EtOH) for 10 min or 24 h. After treatment, the samples were examined using gel permeation chromatography (GPC), attenuated total reflectance Fourier transform infrared spectroscopy, and tensiometry. Cytotoxicity was evaluated through the culture of endothelial progenitor cells and the efficacy of sterilization method was determined by incubating each sample in tryptone soya broth and fluid thioglycollate medium for cultivation of microorganisms. Although EtOH did not affect the material properties in any form, the samples were found to be nonsterile with microbial growth detected on each of the samples. Gamma irradiation was not only effective in sterilizing both POSS-PCU and POSS-PCL but also led to minor material degradation and displayed a cytotoxic effect on the cultured cells. Autoclaving was found to be the optimal sterilization technique for both solid and porous membranes of the nondegradable POSS-PCU samples as it was successful in sterilizing the samples, displayed no cytotoxic side effects and did not degrade the material. However, the biodegradable POSS-PCL was not able to withstand the harsh environment during autoclaving, resulting in it losing all structural integrity.

Our group has developed a non-biodegradable nanocomposite based on POSS (polyhedral oligomeric silsesquioxane) nanocages with PCU [poly(carbonate urethane)] and previous studies have shown good cell-compatibility and antithrombogenic properties. The latest biodegradable formulation is a POSS-modified poly(hexanolactone/carbonate)urethane/urea containing 80% hexanolactone (caprolactone) with the tradename UCL-NanoBio. The direct effect of the polymer on cells was investigated by seeding stem cells on to circular discs of the polymer in 24-well plates; these discs were prepared mainly by electrohydrodynamic jetting. To assess the indirect effect of the polymer, various concentrations of the polymer powder were added to CCM (cell culture medium) and left on a shaker for 10 days. The precipitate was then removed and the CCM was used for culturing the cells seeded on to 24-well plates. Cell viability and growth at 48 and 96 h were assessed using Alamar Blue and lactate dehydrogenase, and morphology was studied by scanning electron microscopy. Cells were shown to adhere well to the polymer, with cell metabolism being comparable with that found on TCP (tissue-culture plastic). Indirect assessment demonstrated some decrease in cell viability with high concentrations of polymer, but showed no difference in cell death between polymer concentrations. The viability of cells seeded on to the polymer was comparable with that of those seeded on to TCP. Cell viability was comparable on both electrosprayed and electrospun scaffolds, but infiltration into the scaffold was much more evident on the electrospun scaffolds. It can be concluded that this new nanocomposite can support the growth and viability of stem cells and that scaffolds of this polymer nanocomposite fabricated by electrohydrodynamic jetting routes have potential use for tissue engineering in the future.

Number-average molecular weight; b) Weight-average molecular weight; c) Molecular weight of highest peak; d) Dispersion index.