Stéphane Bernhard

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Bernhard

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Stéphane

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0000-0002-6534-6905

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Publications 1 - 10 of 12

Reinforced Polymer-Nanoparticle Hydrogels for Subcutaneous and Sustained Delivery of Trastuzumab
Bovone, Giovanni; Bernhard, Stéphane; Jacquot, Guillaume; et al. (2025)
Advanced Healthcare Materials
In oncology, the advent of monoclonal antibody (mAb) therapeutics represents a breakthrough in various cancer diseases. However, these therapies often necessitate iterative hospital visits for intravenous infusion that alter patient quality of life and contribute to the chronic saturation of hospitals. Subcutaneous formulations of mAbs offer a promising alternative facilitating faster administration compared with traditional intravenous methods, while still maintaining the same dosing schedule and providing time-saving advantages. Here, an injectable mAb delivery platform using alpha-cyclodextrin (alpha CD)-reinforced polymer-nanoparticle hydrogels to perform subcutaneous mAb depots and delay their release is developed. By leveraging mAb-polymer electrostatic complexation, hyaluronic acid- and alginate-based injectable drug depots are formulated by simply mixing components that are generally regarded as safe. Trastuzumab is included as a clinically relevant therapeutic antibody. These formulations delayed mAb release both in vitro and in vivo mice models, with a similar pharmacokinetic performance to the clinically approved Herceptin SC (Roche) formulation composed of trastuzumab with recombinant human hyaluronidase (rHuPH20).
Dual carbon sequestration with photosynthetic living materials
Dranseike, Dalia; Cui, Yifan; Ling, Andrea S.; et al. (2025)
Nature Communications
Natural ecosystems efficiently sequester CO2 but containing and controlling living systems remains challenging. Here, we engineer a photosynthetic living material for dual CO2 sequestration that leverages biomass production and insoluble carbonate formation via microbially induced carbonate precipitation (MICP). To achieve this, we immobilize photosynthetic microorganisms within a printable polymeric network. Digital design and fabrication of the living structures ensure sufficient light access and nutrient supply to encapsulated cyanobacteria, enabling long-term culture for over a year. We showcase that photosynthetic living materials are able to sequester 2.2 ± 0.9 mg of CO2 per gram of hydrogel material over 30 days and 26 ± 7 mg of CO2 over 400 days. These findings highlight the potential of photosynthetic living materials for scalable, low-maintenance carbon sequestration with applications in carbon-neutral infrastructure and CO2 mitigation.
Driving electrochemical reactions at the microscale using CMOS microelectrode arrays
Duru, Jens; Rüfenacht, Arielle; Löhle, Josephine; et al. (2023)
Lab on a Chip
Precise control of pH values at electrode interfaces enables the systematic investigation of pH-dependent processes by electrochemical means. In this work, we employed high-density complementary metal-oxide-semiconductor (CMOS) microelectrode arrays (MEAs) as miniaturized systems to induce and confine electrochemical reactions in areas corresponding to the pitch of single electrodes (17.5 mu m). First, we present a strategy for generating localized pH patterns on the surface of the CMOS MEA with unprecedented spatial resolution. Leveraging the versatile routing capabilities of the switch matrix beneath the CMOS MEA, we created arbitrary combinations of anodic and cathodic electrodes and hence pH patterns. Moreover, we utilized the system to produce polymeric surface patterns by additive and subtractive methods. For additive patterning, we controlled the in situ formation of polydopamine at the microelectrode surface through oxidation of free dopamine above a threshold pH > 8.5. For subtractive patterning, we removed cell-adhesive poly-L-lysine from the electrode surface and backfilled the voids with antifouling polymers. Such polymers were chosen to provide a proof-of-concept application of controlling neuronal growth via electrochemically-induced patterns on the CMOS MEA surface. Importantly, our platform is compatible with commercially available high-density MEAs and requires no custom equipment, rendering the findings generalizable and accessible.
Modular and Photoreversible Polymer-Nanoparticle Hydrogels via Host-Guest Interactions
Bernhard, Stéphane; Ritter, Lauritz; Müller, Marco; et al. (2024)
Small
Polymer-nanoparticle (PNP) hydrogels are a class of nanocomposite materials showing potential as injectable platforms for biomedical applications. Their design is limited by incomplete knowledge of how the binding motif impacts the viscoelastic properties of the material and is generally constrained to non-responsive supramolecular interactions. Expanding the scope of available interactions and advancing the understanding of how defined interactions influence network formation would accelerate PNP hydrogel design. To address this gap in the design of PNP hydrogels, the study designs and investigates a tunable platform based on beta-cyclodextrin (beta CD) host-guest cross-links between functionalized polymers and nanoparticles. A host-functionalized polymer (beta CD hyaluronic acid) and guest harboring block co-polymer (poly(ethylene glycol)-b-poly(lactic acid)) NPs are synthesized. The presence and accessibility for binding of the host and guest moieties are characterized via isothermal titration calorimetry. PNP hydrogels with varying concentrations of functionalized polymer and NPs reveal a limited window of concentrations for gelation. It is hypothesized that network formation is governed by the capacity of polymer chains to effectively bridge NPs, which is related to the host-guest ratios present in the system. Further, photo-responsive guests are incorporated to engineer photoreversible gelation of PNP hydrogels via exposure to specific wavelengths of light.
Polymer functionalization of inorganic nanoparticles for biomedical applications
Komsthöft, Tobias; Bovone, Giovanni; Bernhard, Stéphane; et al. (2022)
Current Opinion in Chemical Engineering
Inorganic nanoparticles (NPs) are useful materials in the chemical, physical, biological, and medical sciences. Biomedical applications require inorganic NPs to be stable in hydrophilic environments and to avoid premature biodegradation or clearance by the immune system. For this, the NP surface is engineered to enable NP colloidal stability, biocompatibility, and biomedical function. In this review, we present recent advances in polymer coatings of inorganic NPs focusing on polymer composition, ligand architecture, and the resulting coating properties. Further, we discuss how engineering of the polymer coatings governs the NP physicochemical and biological properties, enabling biomedical use as therapeutics, diagnostics, biosensors, and building blocks for material assembly.
Hierarchical biomaterials via photopatterning-enhanced direct ink writing
Guzzi, Elia A.; Bischof, Raffaele; Dranseikiene, Dalia; et al. (2021)
Biofabrication
Recent advances in additive manufacturing (AM) technologies provide tools to fabricate biological structures with complex three-dimensional (3D) organization. Deposition-based approaches have been exploited to manufacture multimaterial constructs. Stimulus-triggered approaches have been used to fabricate scaffolds with high resolution. Both features are useful to produce biomaterials that mimic the hierarchical organization of human tissues. Recently, multitechnology biofabrication approaches have been introduced that integrate benefits from different AM techniques to enable more complex materials design. However, few methods allow for tunable properties at both micro- and macro-scale in materials that are conducive for cell growth. To improve the organization of biofabricated constructs, we integrated direct ink writing (DIW) with digital light processing (DLP) to form multimaterial constructs with improved spatial control over final scaffold mechanics. Polymer-nanoparticle hydrogels were combined with methacryloyl gelatin (GelMA) to engineer dual inks that were compatible with both DIW and DLP. The shear-thinning and self-healing properties of the dual inks enabled extrusion-based 3D printing. The inclusion of GelMA provided a handle for spatiotemporal control of cross-linking with DLP. Exploiting this technique, complex multimaterial constructs were printed with defined mechanical reinforcement. In addition, the multitechnology approach was used to print live cells for biofabrication applications. Overall, the combination of DIW and DLP is a simple and efficient strategy to fabricate hierarchical biomaterials with user-defined control over material properties at both micro- and macro-scale.
Poly(Ethylene Glycols) to Facilitate Celloidin Removal for Immunohistochemical Studies on Archival Human Brain and Temporal Bone Sections
Bächinger, David; O'Malley, Jennifer T.; Wolf, Morris; et al. (2024)
Journal of Histochemistry & Cytochemistry
Pathology repositories worldwide store millions of celloidin-processed human brain and temporal bone (TB) sections vital for studying central nervous system diseases and sensory organs. However, accessing these sections for modern molecular-pathological research, like immunohistochemistry, is hindered by the challenge of removing celloidin without damaging tissue. In this study, we explored the use of polyethylene glycols (PEGs), a class of non-hazardous, ethylene glycol oligomers, combined with an improved section mounting technique, to gently and effectively dissolve celloidin from sections archived for up to 40 years. Optimizing our protocol involved exploring celloidin dissolution kinetics in PEGs of varying molecular weights and terminations, as well as different temperatures. Low molecular weight PEGs, particularly PEG 200, were the most efficient celloidin solvent. Nuclear magnetic resonance (NMR) spectroscopy of celloidin-PEG 200 dissolution products revealed no chemical alterations, suggesting pure solvation without chemical modification. Because the solvation of celloidin in PEG was inhibited by proteins, we further developed a protein-free mounting protocol allowing complete celloidin removal in 30 to 60 minutes by immersing in PEG 200. In summary, our approach overcomes major methodological hurdles, rendering decades-old archival celloidin sections viable for immunohistochemical and other molecular biological techniques, while enhancing safety and workflow efficiency.
Supramolecular Reinforcement of Polymer – Nanoparticle Hydrogels for Modular Materials Design
Bovone, Giovanni; Guzzi, Elia A.; Bernhard, Stéphane; et al. (2022)
Advanced Materials
Moldable hydrogels are increasingly used as injectable or extrudable materials in biomedical and industrial applications owing to their ability to flow under applied stress (shear-thin) and reform a stable network (self-heal). Nanoscale components can be added to dynamic polymer networks to modify their mechanical properties and broaden the scope of applications. Viscoelastic polymer–nanoparticle (PNP) hydrogels comprise a versatile and tunable class of dynamic nanocomposite materials that form via reversible interactions between polymer chains and nanoparticles. However, PNP hydrogel formation is restricted to specific interactions between select polymers and nanoparticles, resulting in a limited range of mechanical properties and constraining their utility. Here, a facile strategy to reinforce PNP hydrogels through the simple addition of α-cyclodextrin (αCD) to the formulation is introduced. The formation of polypseudorotoxanes between αCD and the hydrogel components resulted in a drastic enhancement of the mechanical properties. Furthermore, supramolecular reinforcement of CD–PNP hydrogels enabled decoupling of the mechanical properties and material functionality. This allows for modular exchange of structural components from a library of functional polymers and nanoparticles. αCD supramolecular binding motifs are leveraged to form CD–PNP hydrogels with biopolymers for high-fidelity 3D (bio)printing and drug delivery as well as with inorganic NPs to engineer magnetic or conductive materials.
Supramolecular engineering of hydrogels for drug delivery
Bernhard, Stéphane; Tibbitt, Mark W. (2021)
Advanced Drug Delivery Reviews
Supramolecular binding motifs are increasingly employed in the design of biomaterials. The ability to rationally engineer specific yet reversible associations into polymer networks with supramolecular chemistry enables injectable or sprayable hydrogels that can be applied via minimally invasive administration. In this review, we highlight two main areas where supramolecular binding motifs are being used in the design of drug delivery systems: engineering network mechanics and tailoring drug–material affinity. Throughout, we highlight many of the established and emerging chemistries or binding motifs that are useful for the design of supramolecular hydrogels for drug delivery applications.
Design of modular and responsive hydrogels for drug delivery using supramolecular interactions
Bernhard, Stéphane (2024)
Currently, therapeutics delivery relies heavily on systemic oral or intravenous administration to the patient. To reduce off-site effects and possible premature degradation of the therapeutics, drug delivery platforms are being engineered to enable local, sustained and controlled delivery of therapeutics. Hydrogels have shown their potential as drug delivery platforms because of their biocompatibility, high water content, and ease of therapeutic encapsulation. To allow for simple administration, physical hydrogels leveraging supramolecular interactions as crosslinks are promising. Indeed, the reversible interactions forming the polymer network enable local injection. Of interest, polymer–nanoparticle (PNP) hydrogels are a class of injectable nanocomposite based on reversible interactions between polymer and nanoparticles, which have sown potential drug delivery platforms. Current design of PNP hydrogels is, however, limited to few supramolecular motifs and our understanding of the impact of the crosslinking interactions on the macroscopic properties of the hydrogels is incomplete. In this thesis, we expanded our understanding of how to leverage supramolecular interactions for the rational design of modular nanoparticulate hydrogels by relating molecular interactions, microarchitecture and mechanical properties. We first leveraged a simple supramolecular motif based on α-cyclodextrin (αCD) for the reinforcement of PNP hydrogels. The simple addition of αCD resulted in a concentration dependent increase in mechanical properties through increased polypseudorotaxane formation. Furthermore, the supramolecular motif resulted in increased nanoparticle–nanoparticle interactions, enabling the decoupling of the mechanical properties from the building blocks, allowing the use of interchangeable building blocks from a wide range of biopolymer and nanoparticles. Nonetheless, the origin of the emerging mechanical properties of PNP hydrogel remained poorly described. Building upon this strategy, we engineered a PNP hydrogel using host–guest crosslinks for the investigation of the impact of the supramolecular interactions that form the network on the macroscopic properties of the system. By combining molecular analysis with rheological characterization, we shed light on several underlying mechanisms governing the emergence of the macroscopic properties of PNP hydrogel. Namely, we elucidated the dominant contribution of nanoparticles in network formation, while the polymer mostly provided the required viscosity for gelation. In addition, we leveraged fluorescent and super resolution optical microscopy for the visualization of PNP hydrogel microstructure. We were able to resolve the nanoparticle distribution and investigated the impact of αCD addition on the microarchitecture of the hydrogel. Lastly, we incorporated responsive interactions in the design of a nanogel drug delivery system for the selective delivery of therapeutics upon internalization of the nanocarrier. Through rational chemical design, coupling to protein could be achieved in mild aqueous condition while enabling the chemical-free release of the therapeutic upon exposure to a biological stimulus. Overall, we investigated and leveraged supramolecular and responsive interactions for the design of nanoparticulate-hydrogels targeted to drug delivery application. This work advances the field of supramolecular hydrogel design by creative utilization and extended understanding of the impact of supramolecular interaction on the micro and macro scale properties.

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