Advances in the field of polymer chemistry have permitted to prepare polymers of controlled topologies, functionalities and microstructures using various strategies to access complex architectures with a variety of functional groups positioned at well-defined localizations on the polymer chain [1]. This ability to control the architecture and microstructure of polymers along with their functionalities are an asset to adjust the properties of polymers and tune their performances according to the targeted application [2,3]. This presentation will illustrate the ability of macromolecular engineering, especially the topology of polymers, to afford polymers of specific and tunable properties with a focus on biomedical applications through two examples as depicted on Fig. 1. The first part of the presentation will focus the design of comb polymers with peptide sequences as pendent grafts through the macromonomer approach. It will be illustrated through the use of macromonomers with oligoarginine pendent grafts [4]. This polymer exhibited a thermoresponsive behavior in water with a solubilization of the polymer upon increasing the temperature (upper critical solution temperature behavior). In a second part, the preparation of hybrid materials based on upconversion nanoparticles (UCNPs) and polymers will be discussed emphasizing on how the structure of the polymer covalently attached to UCNPs could be designed to fulfil the requirement of theranostics [5,6].

In cellular microenvironment the biochemical, mechanical, and geometrical features of the extracellular matrix (ECM) and of neighboring cells dictate cellular behavior.[1] In polarized cells, like epithelial or muscle cells, these physiochemical cues are received at distinct and spatially segregated cell-matrix and cell-cell interfaces via characteristic adhesion complexes.[2] Despite various synthetic biointerfaces to study cell-matrix and cell-cell interfaces separately, there have been relatively few reports of models that allow the investigation of their cooperative effects.[3] Within this context, we have developed a powerful and generalizable 2.5D synthetic hydrogel microenvironment that offer independent compositions, mechanical properties, and dimensions. In particular, our microenvironment can be fabricated by soft lithography and orthogonal coupling chemistries for selective biofunctionalization with ECM or cadherin ligands resulting in polarized positioning of ligands on the basal and lateral planes.[4,5] Our strategy allows the understanding of implications of a polarized presentation of cell-matrix and cell-cell interfaces for the regulation of myogenic differentiation in myoblasts. Moreover, our platform can be coupled with a traction force microscopy or extended with other functionalities to increase the range and complexity of cues and readouts. Together, our findings establish an exciting biomaterial platform that not only offers independent and polarized presentation of microenvironmental cues at cell-cell and cell-matrix interface but also advances the fundamental understanding of their cooperative roles in developing and maintaining the structural and functional integrity of tissues.

Therapeutic interventions using active pharmaceutical agents continue to pose significant challenges due to ever-increasing complexity of high morbidity rate diseases. Natural and synthetically articulated macromolecules have offered significant potential in developing nanocarriers for drug delivery. Soft nanoparticles provide an ideal platform in overcoming physicochemical obstacles and expediting clinical translation. Despite significant progress, fundamental challenges related to developing macromolecular structure-intended task performance relationships, as well as understanding the role of drug-/carrier-bio interactions in nanocarrier efficacy, still remain. Our group has been working on elaborating the design of polymeric architectures to overcome some of these complex issues and enhance the scope of synthetic macromolecules in nanomedicine. In this presentation, we shall discuss our polymer technology design strategy, and demonstrate how it is helping resolve key problems in nanomedicine.

Particle properties such as size and shape play an important role in the design of polymeric nanocarriers for drug delivery. Worm-like micelles have a higher surface area and aspect ratio compared to their spherical counterparts which may be exploited for improved delivery performance by prolonged blood circulation times or high specificity in targeting and accumulation. However, controlling the dimensions of worm-like micelles remains challenging, hence structure-performance relationships have not yet been fully established. An attractive bottom-up approach to prepare worm-like micelles is polymerization-induced self-assembly (PISA). PISA combines amphiphilic block copolymer synthesis and self-assembly in a one-pot procedure. However, targeting pure worm phases via traditional PISA is challenging. To increase the robustness of the worm synthesis via PISA, Mellot et al. introduced the use of a templating bis-urea sticker to steer the assembly process to favor the worm morphology. While this procedure allows to control the thickness of the worms via the length of the core-forming block, the contour length of the worms remains highly polydisperse. Herein, we investigate two strategies to control the worm length, namely sonication-induced cleavage and shortening of particles with an ‘end-capping’ polymer. With this newly gained access to nanoparticles with varying degrees of anisotropy, nanoparticle-cell interactions are evaluated for three different cell lines under static conditions. Additionally, a perfusion model with human umbilical vein endothelial cells (HUVECs) is used to assess shape-dependent nanoparticle behavior under physiologically more relevant flow conditions. Ultimately, we aim to establish more detailed structure-performance relationships for drug delivery applications.

Muscle tissue engineering aims to replicate the fibrous architecture of skeletal muscle tissue to support the alignment, growth, and differentiation of new muscle cells, necessary for regeneration. Aligned electrospun scaffolds, traditionally prepared from petrochemical-derived starting materials, provide a promising platform for mimicking the mechanical and topological properties of skeletal muscle [1]. The use of proteins presents a sustainable alternative to such traditional synthetic polymers. Electrospinning, a highly scalable fiber fabrication technology, requires a solution with favorable viscoelastic properties for stable fiber formation. While polymer entanglements typically provide this stability, the complex tertiary and quarternary structures of proteins have made it difficult to achieve sufficient spinnability of their solutions [2].
Herein, we fabricate protein-based aligned nanofibrous scaffolds from serum albumin and lysozyme. Electrospinnability is promoted by manipulating the polymer structure for higher solution elasticity, while enhancing thermodynamic stability through introducing cross-β sheet motifs [3]. Furthermore, ordered albumin and lysozyme aggregates were chemically modified to provide bioorthogonal hydrazone cross-linking for in situ rheological enhancement of the polymer jet. The high degree of modification (>30%) allowed significant improvement of the solution viscosity and long-term stability. This approach addresses the long-standing challenge of protein electrospinning, offering a sustainable and functional alternative to synthetic polymers. By bridging the gap between protein-based materials and scalable fabrication, this work advances the development of tailored scaffolds for muscle tissue engineering and other biomedical applications [4].

Discoidal polymeric nanoparticles are positioned as promising candidates for biomedical applications.[1] Their anisotropic geometry promises preferential cell margination and uptake whilst their high surface area promotes cellular interaction, both improving biodistribution. Despite this, accessing such morphologies by direct self-assembly mechanisms is considerably difficult because they exist beyond traditional self-assembly maps. Requiring a balance between a flexible corona with rigidity in core-forming segments, rod-coil polymer architectures are well-positioned as bottom-up self-assembly building blocks.[2,3] This systematic study explores the direct self-assembly of a library of amphiphilic copolymers, namely poly(ethylene glycol)-block–poly(2-(2-Bromoisobutyryloxy)ethyl methacrylate-graft-poly(benzyl methacrylate) (PEG-b-(pBIEM-g-pBzMA)). By independently changing the side chain and backbone lengths, we identify a window where well-defined 2D nanodiscs can be realised, measuring between 50 – 200 nm in diameter, and ~ 7nm in height. This work provides insight into the fundamental polymer design principles for nanodisc formation as a gateway for the advancement of polymeric nanoplatforms for biomedical applications.