The most striking and general property of the biological fibrous architectures in the extracellular matrix (ECM) is the strong and directional interaction between biologically active protein ...subunits. These fibers display rich dynamic behavior without losing their architectural integrity. The complexity of the ECM taking care of many essential properties has inspired synthetic chemists to mimic these properties in artificial one-dimensional fibrous structures with the aim to arrive at multi-component biomaterials. Due to the dynamic character required for interaction with natural tissue, supramolecular biomaterials are promising candidates for regenerative medicine. Depending on the application area, and thereby the design criteria of these multi-component fibrous biomaterials, they are used as elastomeric materials or hydrogel systems. Elastomeric materials are designed to have load bearing properties whereas hydrogels are proposed to support
in vitro
cell culture. Although the chemical structures and systems designed and studied today are rather simple compared to the complexity of the ECM, the first examples of these functional supramolecular biomaterials reaching the clinic have been reported. The basic concept of many of these supramolecular biomaterials is based on their ability to adapt to cell behavior as a result of dynamic non-covalent interactions. In this review, we show the translation of one-dimensional supramolecular polymers into multi-component functional biomaterials for regenerative medicine applications.
This review features the translation of supramolecular fibers into elastomers and hydrogels for regenerative medicine.
Hydrogels were prepared with physical cross-links comprising 2-ureido-41H-pyrimidinone (UPy) hydrogen-bonding units within the backbone of segmented amphiphilic macromolecules having hydrophilic ...poly(ethylene glycol) (PEG). The bulk materials adopt nanoscopic physical cross-links composed of UPy–UPy dimers embedded in segregated hydrophobic domains dispersed within the PEG matrix as comfirmed by cryo-electron microscopy. The amphiphilic network was swollen with high weight fractions of water (w H2O ≈ 0.8) owing to the high PEG weight fraction within the pristine polymers (w PEG ≈ 0.9). Two different PEG chain lengths were investigated and illustrate the corresponding consequences of cross-link density on mechanical properties. The resulting hydrogels exhibited high strength and resilience upon deformation, consistent with a microphase separated network, in which the UPy–UPy interactions were adequately shielded within hydrophobic nanoscale pockets that maintain the network despite extensive water content. The cumulative result is a series of tough hydrogels with tunable mechanical properties and tractable synthetic preparation and processing. Furthermore, the melting transition of PEG in the dry polymer was shown to be an effective stimulus for shape memory behavior.
Nanocomposite hydrogels based on carbon nanotubes (CNTs) are known to possess remarkable stiffness, electrical, and thermal conductivity. However, they often make use of CNTs as fillers in covalently ...cross‐linked hydrogel networks or involve direct cross‐linking between CNTs and polymer chains, limiting processability properties. Herein, nanocomposite hydrogels are developed, in which CNTs are fillers in a physically cross‐linked hydrogel. Supramolecular nanocomposites are prepared at various CNT concentrations, ranging from 0.5 to 6 wt%. Incorporation of 3 wt% of CNTs leads to an increase of the material's toughness by over 80%, and it enhances electrical conductivity by 358%, compared to CNT‐free hydrogel. Meanwhile, the nanocomposite hydrogels maintain thixotropy and processability, typical of the parent hydrogel. The study also demonstrates that these materials display remarkable cytocompatibility and support cell growth and proliferation, while preserving their functional activities. These supramolecular nanocomposite hydrogels are therefore promising candidates for biomedical applications, in which both toughness and electrical conductivity are important parameters.
Supramolecular nanocomposite hydrogels are fabricated starting from a hydrophobically assembled physical gel and multi‐walled carbon nanotubes. Prepared nanocomposites are characterized by improved tensile toughness and electrical conductivity, due to dispersed nanotubes. Moreover, these supramolecular nanocomposites are fully processable and recoverable. Being also cytocompatible and able to support cell growth and proliferation, these gels are suitable for biomedical applications.
Structural and kinetic exchange properties of supramolecular polymers composed of mono- and bivalent ureidopyrimidinone-based monomers are investigated in aqueous solutions. It is shown that exchange ...dynamics can be controlled by mixing different types of monomers. This tunability widens the scope in their design as biomaterials.
Benzene-1,3,5-tricarboxamide (BTA) glyco-monomers containing one, two or three mannose units are synthesized and formulated into differently patterned supramolecular glycopolymers through ...homo-assembly or co-assembly with non-functionalized BTAs. Unfortunately, no cellular activity could be detected. Excitingly, these glyco-BTA monomers could be formulated into hydrogels, paving the way for (immune) cell culture.
Mannose patterning is introduced into benzene-1,3,5-tricarboxamide (BTA)-based supramolecular assemblies through copolymerization of fully mannosylated
M3 BTA
with non-functionalized
nBTA
, and compared to their asymmetric homopolymer counterparts (
M1
and
M2 BTA
).
Abstract The creation of a living heart valve is a much-wanted alternative for current valve prostheses that suffer from limited durability and thromboembolic complications. Current tissue ...engineering strategies to create such valves, however, require the use of cells for in vitro culture, or decellularized human- or animal-derived donor tissue for in situ engineering. Here, we propose and demonstrate proof-of-concept of in situ heart valve tissue engineering using a synthetic approach, in which a cell-free, slow biodegrading elastomeric valvular implant is populated by endogenous cells to form new valvular tissue inside the heart. We designed a fibrous valvular scaffold, fabricated from a novel supramolecular elastomer that enables endogenous cells to enter and produce matrix. Orthotopic implantations as pulmonary valve in sheep demonstrated sustained functionality up to 12 months, while the implant was gradually replaced by a layered, collagen and elastic matrix in pace with cell-driven polymer resorption. These results offer new perspectives for endogenous heart valve replacement starting from a readily-available synthetic graft that is compatible with surgical and transcatheter implantation procedures.
Minimally invasive intervention strategies after myocardial infarction use state‐of‐the‐art catheter systems that are able to combine mapping of the infarcted area with precise, local injection of ...drugs. To this end, catheter delivery of drugs that are not immediately pumped out of the heart is still challenging, and requires a carrier matrix that in the solution state can be injected through a long catheter, and instantaneously gelates at the site of injection. To address this unmet need, a pH‐switchable supramolecular hydrogel is developed. The supramolecular hydrogel is switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1‐m long catheter while rapidly forming a hydrogel in contact with tissue. The hydrogel has self‐healing properties taking care of adjustment to the injection site. Growth factors are delivered from the hydrogel thereby clearly showing a reduction of infarct scar in a pig myocardial infarction model.
A supramolecular hydrogel system is reported that can be quickly switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1‐m long catheter while rapidly forming a hydrogel in contact with myocardial tissue. The hydrogel has self‐healing properties taking care of adjustment to the injection site. Hydrogel delivery of growth factors shows a clear reduction of infarct scar collagen in a pig myocardial infarction model.
The extracellular microenvironment is an important regulator of cell functions. Numerous structural cues present in the cellular microenvironment, such as ligand distribution and substrate ...topography, have been shown to influence cell behavior. However, the roles of these cues are often studied individually using simplified, single-cue platforms that lack the complexity of the three-dimensional, multi-cue environment cells encounter in vivo. Developing ways to bridge this gap, while still allowing mechanistic investigation into the cellular response, represents a critical step to advance the field. Here, we present a new approach to address this need by combining optics-based protein patterning and lithography-based substrate microfabrication, which enables high-throughput investigation of complex cellular environments. Using a contactless and maskless UV-projection system, we created patterns of extracellular proteins (resembling contact-guidance cues) on a two-and-a-half-dimensional (2.5D) cell culture chip containing a library of well-defined microstructures (resembling topographical cues). As a first step, we optimized experimental parameters of the patterning protocol for the patterning of protein matrixes on planar and non-planar (2.5D cell culture chip) substrates and tested the technique with adherent cells (human bone marrow stromal cells). Next, we fine-tuned protein incubation conditions for two different vascular-derived human cell types (myofibroblasts and umbilical vein endothelial cells) and quantified the orientation response of these cells on the 2.5D, physiologically relevant multi-cue environments. On concave, patterned structures (curvatures between κ = 1/2500 and κ = 1/125 μm–1), both cell types predominantly oriented in the direction of the contact-guidance pattern. In contrast, for human myofibroblasts on micropatterned convex substrates with higher curvatures (κ ≥ 1/1000 μm–1), the majority of cells aligned along the longitudinal direction of the 2.5D features, indicating that these cells followed the structural cues from the substrate curvature instead. These findings exemplify the potential of this approach for systematic investigation of cellular responses to multiple microenvironmental cues.
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