Trends in Double Networks as Bioprintable and Injectable Hydrogel Scaffolds for Tissue Regeneration

Additive manufacturing and injection are essential tools in the rapidly developing field of personalized medicine and are particularly promising for applications in regenerative medicine. One of the biggest challenges in this vibrant research domain remains the processing of complex formulations with robust mechanical properties. Mimicking the native extracellular matrix associated with many tissues requires materials that have high degrees of functionality for performing the complex array of functions within the cellular environment. Furthermore, native tissues often possess outstanding mechanical properties, particularly in connective tissues. These exceptional mechanics are a challenge to emulate in their own right, especially considering the accompanying demands for additional functionality. Double-network hydrogels have emerged as strong candidates for tissue engineering because of the impressive mechanics and versatility in terms of chemical makeup. Combining advances in processing (i.e., additive manufacturing and injection) with dual-network hydrogel formulations has led to an impressive collection of results, making great strides toward systems capable of addressing the demanding environment surrounding tissues while being amenable to personalized fabrication techniques. This review provides a brief summary of the most contemporary trends collected from the literature describing dual-network hydrogels being demonstrated in additive manufacturing and injectable applications

The effect of pendant benzene-1,3,5-tricarboxamides in the middle block of ABA triblock copolymers : synthesis and mechanical properties

The synthesis and mechanical properties of ABA triblock copolymers containing benzene-1,3,5-tricarboxamide (BTA) moieties in the middle block are described. The triblock architecture was achieved by sequential polymerization of different monomers by atom-transfer radical polymerization (ATRP). The ABA triblock copolymer has a soft-hard-soft block sequence, in which the "A" block consists of soft poly(methyl acrylate), while the "B" block is a random copolymer of isobornyl methacrylate with 20 mol% of propargyl methacrylate partially functionalized with peripheral BTA groups. The pendent BTAs self-assemble into helical aggregates through lateral hydrogen-bond formation. Thermal and mechanical analyses indicated that the Young's modulus is enhanced by the BTAs. AFM images revealed that BTA self-assembly has dramatic influence on the nanoscopic ordered structure. The morphology of the triblock copolymer without BTAs consisted of hard, isolated domains embedded in a soft matrix. The copolymer containing BTAs appears as a continuous, disorganized morphology with nanoscopic domain sizes. This morphological difference presumably influences the Young's modulus. Ductility (i.e., necking) was only observed in the polymer containing BTAs. From these investigations, we conclude that introducing BTA in the hard-midblock results in intermolecular physical crosslinks, and the morphological characteristics translate to improved strength as reflected by the modulus. This journal is © The Royal Society of Chemistry

Nanostructured supramolecular block copolymers based on polydimethylsiloxane and polylactide

Hierarchical self-assembly has been demonstrated with diblock copolymers comprising poly(dimethylsiloxane) (PDMS) and poly(lactide) (PLA) with supramolecular, 4-fold hydrogen-bonding junctions. PDMS with a single ureidoguanosine unit at the end was synthesized by a postpolymerization strategy. PLA with a single 1,7-diamidonaphthyridine was synthesized by ring-opening polymerization from the appropriate functional initiator. Selective association of the end groups to form distinct, noncovalent connections between the respective homopolymers in blends was established by H-1 NMR spectroscopy. The orthogonal self-assembly of the resulting pseudoblock copolymer, driven by immiscibility between the polymer constituents was demonstrated. Bulk polymer blends were prepared that have approximately symmetric composition and a 1:1 end-group stoichiometry. Small angle X-ray scattering combined with differential scanning calorimetry and transmission electron microscopy provide unambiguous evidence for the adoption of a lamellar morphology having long-range order, nanoscopic domain dimensions (20 nm pitch), and a sharp domain interface defined by the supramolecular building blocks

Nanostructured supramolecular block copolymers based on polydimethylsiloxane and polylactide

Hierarchical self-assembly has been demonstrated with diblock copolymers comprising poly(dimethylsiloxane) (PDMS) and poly(lactide) (PLA) with supramolecular, 4-fold hydrogen-bonding junctions. PDMS with a single ureidoguanosine unit at the end was synthesized by a postpolymerization strategy. PLA with a single 1,7-diamidonaphthyridine was synthesized by ring-opening polymerization from the appropriate functional initiator. Selective association of the end groups to form distinct, noncovalent connections between the respective homopolymers in blends was established by H-1 NMR spectroscopy. The orthogonal self-assembly of the resulting pseudoblock copolymer, driven by immiscibility between the polymer constituents was demonstrated. Bulk polymer blends were prepared that have approximately symmetric composition and a 1:1 end-group stoichiometry. Small angle X-ray scattering combined with differential scanning calorimetry and transmission electron microscopy provide unambiguous evidence for the adoption of a lamellar morphology having long-range order, nanoscopic domain dimensions (20 nm pitch), and a sharp domain interface defined by the supramolecular building blocks

Well-organized dense arrays of nanodomains in thin films of poly(dimethylsiloxane)-b-poly(lactide) diblock copolymers

Thin films with well-organized arrays of densely packed nanodomains were fabricated from poly(dimethylsiloxane)-b-poly(DL-lactide) (DL) diblock copolymers. As a consequence of the unusually large Flory-Huggins interaction parameter between these repeat units, domains with sizes similar to 10 nm are routinely generated using low molar mass diblock copolymers. Different morphologies are easily accessible by judiciously adjusting the block composition, garnering dot patterns (from spheres) and line patterns (from parallel cylinders) in a facile manner. The strong incompatibility also allows retention of order at relatively low molar mass even with high degrees of compositional asymmetry (e.g., f(L) similar to 0.15). Block copolymers with various compositions are shown to form well-organized morphologies on various substrates and thermal annealing readily enhanced long-range order. All block copolymers were prepared on a >10 g scale, and the processing conditions are compatible with the current infrastructure of the microelectronics industry, demonstrating a strong potential for commercial relevance

Tough stimuli-responsive supramolecular hydrogels with hydrogen-bonding network junctions

Hydrogels were prepared with physical cross-links comprising 2-ureido-4[1H]-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 (wH2O ˜ 0.8) owing to the high PEG weight fraction within the pristine polymers (wPEG ˜ 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

Well-organized dense arrays of nanodomains in thin films of poly(dimethylsiloxane)-b-poly(lactide) diblock copolymers

Thin films with well-organized arrays of densely packed nanodomains were fabricated from poly(dimethylsiloxane)-b-poly(DL-lactide) (DL) diblock copolymers. As a consequence of the unusually large Flory-Huggins interaction parameter between these repeat units, domains with sizes similar to 10 nm are routinely generated using low molar mass diblock copolymers. Different morphologies are easily accessible by judiciously adjusting the block composition, garnering dot patterns (from spheres) and line patterns (from parallel cylinders) in a facile manner. The strong incompatibility also allows retention of order at relatively low molar mass even with high degrees of compositional asymmetry (e.g., f(L) similar to 0.15). Block copolymers with various compositions are shown to form well-organized morphologies on various substrates and thermal annealing readily enhanced long-range order. All block copolymers were prepared on a >10 g scale, and the processing conditions are compatible with the current infrastructure of the microelectronics industry, demonstrating a strong potential for commercial relevance

Biomimetic double network hydrogels: Combining dynamic and static crosslinks to enable biofabrication and control cell-matrix interactions

Hydrogels are promising candidates for recapitulation of the native extracellular matrix (ECM), yet recreating molecular and spatiotemporal complexity within a single network remains a challenge. Double network (DN) hydrogels are a promising step towards recapitulating the multicomponent ECM and have enhanced mechanical properties. Here, we investigate DNs based on dynamic covalent and covalent bonds to mimic the dynamicity of and enable biofabrication. We also investigate the spatiotemporal molecular attachment of a bioactive adhesive peptide within the networks. Using oxidized alginate (dynamic network, Schiff base) and polyethylene glycol diacrylate (static network, acrylate polymerization) we find an optimized procedure, where the dynamic network is formed first, followed by the static network. This initial dynamically cross-linked hydrogel imparts self-healing, injectability, and 3D printability, while the subsequent DN hydrogel improves the stability of the 3D gels and imparts toughness. Rheology and compression testing show that the toughening is due to the combination of energy dissipation (dynamic network) and elasticity (static network). Furthermore, where we place adhesive sites in the network matters; we find distinct differences when tripeptide Arg-Gly-Asp (RGD) is attached to the different networks. This DN strategy bring us closer to understanding and recreating the complex multicomponent ECM-pushing us past a materials view of cell adhesion-while enabling injectabiltiy and printing of tough hydrogels

Ring-opening metathesis polymerization of a diolefinic [2]-catenane-copper(i) complex: an easy route to polycatenanes

A dilute (30 mM) dichloromethane solution of the copper(I) complex 1·Cu+ of a [2]-catenane composed of two identical 28-membered macrocyclic alkenes featuring a phenanthroline moiety in the backbone was subjected to ring-opening metathesis polymerization (ROMP) with second-generation Grubbs catalyst. Shortly after mixing of reactants, the dark red solution transformed into a gel. The bis(phenanthroline)copper(I) units were effectively preserved during ROMP, as evinced by spectroscopic analysis. This implies that the putative metal alkylidene pseudorotaxane intermediates did not undergo dethreading processes but were involved in ring-chain equilibria strongly biased toward the ring products at the low monomer concentration employed in the ROMP reactions. MALDI-TOF mass spectra of the reaction mixtures obtained at an early stage of the reaction revealed a distribution of interlocked oligomers (1·Cu+)n(PF6 -)n-1 with n up to 7, with no traces of peaks ascribable to open chain species. Rheological and mechanical analyses of the gel products provided independent evidence in support of the conclusion that the fraction of linear species in the polymer is negligible. Indications were obtained that the major portion of the polymeric material is composed of fully interlocked species