With advances in tissue engineering, the possibility of regenerating injured tissue or failing organs has become a realistic prospect for the first time in medical history. Tissue engineering - the combination of bioactive materials with cells to generate engineered constructs that functionally replace lost and/or damaged tissue - is a major strategy to achieve this goal. One facet of tissue engineering is biofabrication, where three-dimensional tissue-like structures composed of biomaterials and cells in a single manufacturing procedure are generated. Cell-laden hydrogels are commonly used in biofabrication and are termed "bioinks". Hydrogels are particularly attractive for biofabrication as they recapitulate several features of the natural extracellular matrix and allow cell encapsulation in a highly hydrated mechanically supportive three-dimensional environment. Additionally, they allow for efficient and homogeneous cell seeding, can provide biologically-relevant chemical and physical signals, and can be formed in various shapes and biomechanical characteristics. However, despite the progress made in modifying hydrogels for enhanced bioactivation, cell survival and tissue formation, little attention has so far been paid to optimize hydrogels for the physico-chemical demands of the biofabrication process. The resulting lack of hydrogel bioinks have been identified as one major hurdle for a more rapid progress of the field. In this review we summarize and focus on the deposition process, the parameters and demands of hydrogels in biofabrication, with special attention to robotic dispensing as an approach that generates constructs of clinically relevant dimensions. We aim to highlight this current lack of effectual hydrogels within biofabrication and initiate new ideas and developments in the design and tailoring of hydrogels. The successful development of a "printable" hydrogel that supports cell adhesion, migration, and differentiation will significantly advance this exciting and promising approach for tissue engineering.

/pdf/25th-anniversary-article-engineering-hydrogels-for-52t0ojjbic.pdf

25th Anniversary Article: Engineering Hydrogels for Biofabrication

As swollen polymer networks in water, hydrogels are usually brittle. However, hydrogels with high toughness play critical roles in many plant and animal tissues as well as in diverse engineering applications. Here we review the intrinsic mechanisms of a wide variety of tough hydrogels developed over the past few decades. We show that tough hydrogels generally possess mechanisms to dissipate substantial mechanical energy but still maintain high elasticity under deformation. The integrations and interactions of different mechanisms for dissipating energy and maintaining elasticity are essential to the design of tough hydrogels. A matrix that combines various mechanisms is constructed for the first time to guide the design of next-generation tough hydrogels. We further highlight that a particularly promising strategy for the design is to implement multiple mechanisms across multiple length scales into nano-, micro-, meso-, and macro-structures of hydrogels.

Multi-scale multi-mechanism design of tough hydrogels: building dissipation into stretchy networks

A new type of physically linked double-network hydrogel is synthesized by a simple, time-saving, facile, easily controlled, one-pot method. The resulting agar/polyacrylamide double-network hydrogels exhibit good mechanical properties, excellent recoverability, and a unique free-shapeable property, which makes them very promising hydrogels for load-bearing soft tissues.

A Robust, One‐Pot Synthesis of Highly Mechanical and Recoverable Double Network Hydrogels Using Thermoreversible Sol‐Gel Polysaccharide

Calcium phosphate cements for bone substitution: chemistry, handling and mechanical properties.

The development of hydrogels for cartilage replacement and soft robotics has highlighted a challenge: load-bearing hydrogels need to be both stiff and tough. Several approaches have been reported to improve the toughness of hydrogels, but simultaneously achieving high stiffness and toughness remains difficult. Here we report that alginate-polyacrylamide hydrogels can simultaneously achieve high stiffness and toughness. We combine short- and long-chain alginates to reduce the viscosity of pregel solutions and synthesize homogeneous hydrogels of high ionic cross-link density. The resulting hydrogels can have elastic moduli of ∼1 MPa and fracture energies of ∼4 kJ m–2. Furthermore, this approach breaks the inverse relation between stiffness and toughness: while maintaining constant elastic moduli, these hydrogels can achieve fracture energies up to ∼16 kJ m–2. These stiff and tough hydrogels hold promise for further development as load-bearing materials.

/pdf/hybrid-hydrogels-with-extremely-high-stiffness-and-toughness-h3kcb8ewf7.pdf

Hybrid Hydrogels with Extremely High Stiffness and Toughness

https://www.tpbin.com/Uploads/Subjects/744676ab-1017-4c72-8100-eee9505c55fb.pdf

Fiber reinforced calcium phosphate cements -- on the way to degradable load bearing bone substitutes?

Hydrogels are fascinating materials with high water content and low surface friction that can be tailored for numerous applications. However, their practical application is often hampered by an intrinsic mechanical weakness. Strategies for mechanically strong hydrogels have been developed, with double network (DN) hydrogels reaching remarkable compression resistance, although so far with loss of these properties under repeated compression. In this study we present DN hydrogels composed of cross-linked six arm star-shaped poly(ethylene oxide-stat-propylene oxide) (sPEOPO) primary networks and polyacrylamide (PAAm) as secondary network. These hydrogels possess high water content (>90 w/w%) and high compression strength of up to 5.6 MPa. Most importantly, they show a fully reversible behaviour in repeated loading–unloading experiments with 1 MPa maximal stress, which we attribute to the partial healing capacity of the primary network and the overall macroporous morphology of the gels.

Mechanically strong hydrogels with reversible behaviour under cyclic compression with MPa loading

Calcium phosphate cements are brittle biomaterials of low bending strength. One promising approach to improve their mechanical properties is reinforcement with fibers. State of the art degradable reinforced composites contain fibers made of polymers, resorbable glass or whiskers of calcium minerals. We introduce a new class of composite that is reinforced with degradable magnesium alloy wires. Bending strength and ductility of the composites increased with aspect ratio and volume content of the reinforcements up to a maximal bending strength of 139±41 MPa. Hybrid reinforcement with metal and polymer fibers (PLA) further improved the qualitative fracture behavior and gave indication of enhanced strength and ductility. Immersion tests of composites in SBF for seven weeks showed high corrosion stability of ZEK100 wires and slow degradation of the magnesium calcium phosphate cement by struvite dissolution. Finally, in vitro tests with the osteoblast-like cell line MG63 demonstrate cytocompatibility of the composite materials.

Strong and tough magnesium wire reinforced phosphate cement composites for load-bearing bone replacement.

Mg-phosphate ceramics have aroused growing interest as bone replacement materials due to their ability to degrade under physiological conditions. To mimic cancelous bone and to promote tissue repair mechanisms a highly macroporous structure with open cells is desired. In this study trimagnesium phosphate (farringtonite, Mg3(PO4)2) and struvite ((NH4)Mg(PO4)·6H2O) scaffolds were developed as open cell foams using the Schwarzwalder-Somers technique and optimized for pore size and mechanical performance. Polyurethane (PU) foam (20-80 ppi) was used as a template. For the optimization of the farringtonite scaffolds, ppi number of the PU foam as well as the technique that was used to remove excess slurry were varied. Sample characterization was done by SEM, XRD and compression testing. For best results were obtained using 60 ppi PU foams leading to a compressive strength of 58 kPa (90 % porosity). Farringtonite scaffolds were modified by either polymer infiltration or transformation into struvite with an ammonium phosphate solution. The pore macrostructure was retained for both of these processes and a reduction of porosity was observed. The microstructure of struvite foams was significantly altered showing larger and more facetted crystals than farringtonite. Mechanical properties substantially improved by transformation into struvite to 730 kPa (68 % porosity). Cytocompatibility was tested using osteoblasts and fibroblasts. Cell number and cell activity (WST) were tested over a period of 3 to 13 days. Farringtonite foams showed a tendency for higher cell numbers than struvite, while the WST activity was similar. Infiltration of farringtonite with PLGA approximately doubled cell number compared to pure farringtonite. In conclusion macroporous Mg-phosphate foams have been successfully produced. Compressive strength of the foams was drastically improved by optimization of pore fineness, transformation to struvite and infiltration with PLGA. The open porous structure was retained and the materials showed good cytocompatibility.

Reinhard Krüger

Papers

Fiber reinforced calcium phosphate cements -- on the way to degradable load bearing bone substitutes?

Mechanically strong hydrogels with reversible behaviour under cyclic compression with MPa loading

Strong and tough magnesium wire reinforced phosphate cement composites for load-bearing bone replacement.

Structural Optimization of Macroporous Magnesium Phosphate Scaffolds and their Cytocompatibility