Foam replica method

The foam replica method (FRM) for the fabrication of ceramic foams was patented in 1963. ^{Reference Schwartzwalder and Somers16} In 2006, ^{Reference Chen, Thompson and Boccaccini17} the technique was developed for the first time for the fabrication of bioactive glass-ceramic scaffolds based on 45S5 bioactive glass. Scaffolds produced by this technique are a positive replica of an open-cell porous template, which is usually a polyurethane foam ( Figure 1a). After coating with a bioactive glass or bioactive glass-ceramic slurry, the template is burned out and the bioactive glass is sintered at high temperature, which, in the case of 45S5 bioactive glass, leads to crystallization. ^{Reference Chen, Thompson and Boccaccini17,Reference Lefebvre, Gremillard, Chevalier, Zenati and Bernache-Assolant18} The resulting 3D structures are characterized by an open and interconnected porous network that mimics the architecture of trabecular bone, ^{Reference Chen, Thompson and Boccaccini17,Reference Bretcanu, Samaille and Boccaccini19,Reference Vitale-Brovarone, Baino and Verne20} however, it is at the expense of a relatively low compressive strength of the structures. ^{Reference Gerhardt and Boccaccini3} Using this technique, foams with graded porosity can also be obtained. ^{Reference Bretcanu, Samaille and Boccaccini19}

Figure 1.

Flowchart for the production of bioactive glass (BG) and bioactive glass-ceramic (BGC) scaffolds via foam replica method. ^{Reference Schwartzwalder and Somers16,Reference Chen, Thompson and Boccaccini17} (a) Polyurethane foam (45 ppi, [pores per inch]) and (b) natural marine sponge used to produce (c–d) bioactive glass-ceramic scaffolds of crystallized 45S5 (45SiO₂-24.5CaO-24.5Na₂O-6P₂O₅, wt%) bioactive glass composition. Micrographs courtesy of Friedrich-Alexander-Universität Erlangen-Nürnberg, Institute of Biomaterials.

Baino et al. ^{Reference Baino, Minguella, Kirk, Montealegre, Fiaschi, Korkusuz, Orlygsson and Vitale-Brovarone21,Reference Baino, Marshall, Kirk and Vitale-Brovarone22} recently developed a hemispheric highly porous bioactive glass-ceramic shell as a trabecular-like coating for the bioceramic acetabular cup (the semispherical component of a hip implant that allows movement inside the joint) in hip-replacement devices that demonstrates the versatility of the FRM. Moreover, the use of different templates, including marine sponges, ^{Reference Boccardi, Philippart, Juhasz-Bortuzzo, Novajra, Vitale-Brovarone and Boccaccini23} has been shown to lead to increased mechanical properties, especially the compressive strength, by a reduction of the total porosity of the scaffolds, without affecting the pore interconnectivity (Figure 1b,d).

The bioactivity of crystallized 45S5-based bioactive glass-ceramic scaffolds has been proven, ^{Reference Chen, Thompson and Boccaccini17} confirming earlier studies ^{Reference Peitl, Zanotto and Hench24} that had shown that crystallization of bioactive glass reduces, but does not eliminate, the bioactive character of the 45S5 bioactive glass composition. It is also well known that bioactive glasses and bioactive glass-ceramics can be doped with a variety of metallic ions to enhance their biological activity ^{Reference Hoppe, Güldal and Boccaccini12,Reference Salinas and Vallet-Regí25} ( Figure 2 Footnote *).

Figure 2.

Selected examples of the biologically active ions being investigated to enhance the performance of bioactive glasses and bioactive glass-ceramics. ^{Reference Hoppe, Güldal and Boccaccini12,Reference Salinas and Vallet-Regí25}

FRM is also versatile in terms of the type of starting slurry suitable for producing foams. Zhu et al. ^{Reference Zhu, Wu, Ramaswamy, Kockrick, Simon, Kaskel and Zreiqat26} proposed using a sol-gel synthesis solution to coat the sacrificial template. Cabañas-Polo et al. ^{Reference Cabañas-Polo, Philippart, Boccardi, Hazur and Boccaccini27} applied electrophoretic deposition of a sol-gel solution in combination with FRM, accelerating the scaffold production time. Bioactive glass-ceramic scaffolds made by FRM have also been coated with ordered mesoporous silica particles, ^{Reference Boccardi, Philippart, Juhasz-Bortuzzo, Beltrán, Novajra, Vitale-Brovarone, Spiecker and Boccaccini28} biodegradable polymers, ^{Reference Desimone, Li, Roether, Schubert, Crovace, Rodrigues, Zanotto and Boccaccini29} and polymer microspheres, ^{Reference Li, Nooeaid, Roether, Schubert and Boccaccini30} transforming them in local drug delivery systems. In addition, polymer coatings on bioactive glass-ceramic foams usually lead to enhanced mechanical properties. ^{Reference Desimone, Li, Roether, Schubert, Crovace, Rodrigues, Zanotto and Boccaccini29,Reference Philippart, Boccaccini, Fleck, Schubert and Roether31,Reference Yunos, Bretcanu and Boccaccini32}

The versatility and simplicity of FRM as well as the high reproducibility of the microstructure of the scaffolds produced explain the popularity of this method. A critical FRM challenge is to produce a uniform coating of the sacrificial template, which can be achieved by using slurries of suitable viscosity; the incomplete removal of excess slurry could lead to the presence of closed pores in the final bioactive glass-ceramic scaffolds, decreasing pore interconnectivity. ^{Reference Colombo33}

Foaming techniques

Highly porous bioactive glass and bioactive glass-ceramic scaffolds can be produced by directly foaming a colloidal sol or a powder suspension, followed by a solidification treatment. The resulting foams exhibit a hierarchical structure with interconnected macropores (ranging from ∼20 µm to 1–2 mm). ^{Reference Jones and Hench34} The main challenge is to prevent the foam struts from collapsing, which may result from the loss of the cellular shape of the bubbles. For this reason, a surfactant is used to stabilize the bubbles.

One of the most successful foaming methods is gel casting, ^{Reference Sepulveda, Jones and Hench35} in which in situ polymerization of monomers can be initiated, forming a 3D polymeric network, a gel, which produces mechanically stable structures. ^{Reference Jones and Hench34} The samples are then sintered to provide mechanical strength. The total porosity and the pore size can be controlled by the surfactant concentration. A further development of this technique is sol-gel foaming. ^{Reference Sepulveda, Jones and Hench35} In this method, a sol-gel glass synthesis solution is prepared and a surfactant is added, the foam is generated by vigorous agitation, the sol is transferred to a mold for aging, and finally, the porous body is heat-treated. ^{Reference Sepulveda, Jones and Hench35}

A more recent technology developed for bioactive glass-ceramic foams involves the use of polymer-derived ceramics. ^{Reference Elsayed, Zocca, Franchin, Bernardo and Colombo36} In this approach, metal oxide precursors in the form of micro- or nano-sized particles are added to a polymeric precursor (e.g., a silicone resin), allowing the production of silicate bioceramics ( Figure 3 ). The foaming is obtained by water release from specific hydrated fillers. The foams are then sintered. Fiocco et al. ^{Reference Fiocco, Elsayed, Daguano, Soares and Bernardo37,Reference Fiocco, Elsayed, Ferroni, Gardin, Zavan and Bernardo38} showed the possibility of obtaining wollastonite-diopside (CaSiO₃-CaMgSi₂O₆) foams with 77% porosity and compressive strength of 1.8 ± 0.3 MPa.

Figure 3.

Schematic diagram of the production of wollastonite-diopside (CaSiO₃-CaMgSi₂O₆) polymer derived glass-ceramic foams, using sodium hydrate phosphate filler (Na-Ph hydrate). The process leads to the fabrication of highly porous glass-ceramic foams by mixing preceramic polymers (e.g., silicone resins that act as a silica precursor) and powdered metal oxide precursors. ^{Reference Fiocco, Elsayed, Ferroni, Gardin, Zavan and Bernardo38}

The quality of the obtained porous scaffolds can be improved by selecting different silicon precursors (e.g., polysiloxane) and by using CO₂-assisted extrusion. Another approach to produce porous bioactive glass-ceramics involves a powder-metallurgy technique. ^{Reference Auguilar-Reyes, León-Patiño, Jacinto-Díaz, Perdomo-Cervantes and Lefebvre39} In this method, bioactive glass powder is dry mixed with a solid polymeric binder and a foaming agent. The mixture is then molded and heat-treated. ^{Reference Aguilar-Reyes, León-Patiño, Jacinto-Diaz and Lefebvre40} The resulting scaffolds showed compressive strength values in the range of 5–40 MPa (i.e., in the upper range of values reported so far for this type of porous materials). The scaffolds exhibited highly interconnected pore structure and tunable porosity (55–77%), and they retained satisfactory compressive strength after immersion for one month in simulated body fluid (6 MPa). ^{Reference Boccardi, Melli, Catignoli, Altomare, Jahromi, Cerruti, Lefebvre and De Nardo41}

The major drawback of this method is that the process could yield a structure with unconnected pores that are essential for bone integration and vascularization. ^{Reference Zhu, Chen and Pignatello42} Interconnected porosity is a key property required in bone-tissue engineering scaffolds as it is essential to enhance cell invasion and new tissue growth. In addition, the ability of these scaffolds to promote vascularization has not been yet investigated, as opposed to bioactive glass-ceramics produced by FRM. ^{Reference Arkudas, Balzer, Buehrer, Arnold, Hoppe, Detsch, Newby, Fey, Greil, Horch, Boccaccini and Kneser43}

Additive manufacturing technologies

Additive manufacturing technology (AMT) is the usual term given to fabrication processes where 3D structures are fabricated layer by layer without any specific tooling to obtain the targeted geometry. ^{Reference Bose, Vahabzadeh and Bandyopadhyay44,Reference Gmeiner, Deisinger, Schönherr, Lechner, Detsch, Boccaccini and Stampfl45} Of relevance for bone-tissue engineering, these methods allow for the customization the final cellular scaffolds from the patient-specific (bone) defect using a computer-aided design file. ^{Reference Gmeiner, Deisinger, Schönherr, Lechner, Detsch, Boccaccini and Stampfl45}

Tesavibul et al. ^{Reference Tesavibul, Felzmann, Gruber, Liska, Thompson, Boccaccini and Stampfl46} were the first to process 45S5 bioactive glass powder, obtaining porous bioactive glass-ceramic scaffolds with 50% porosity through stereolithography ceramic manufacturing (SLCM). SLCM starts with a layer-by-layer buildup of a photoreactive polymer filled with bioactive glass or bioactive glass-ceramic powders. ^{Reference Gmeiner, Deisinger, Schönherr, Lechner, Detsch, Boccaccini and Stampfl45} Gmeiner et al. ^{Reference Gmeiner, Mitteramskogler, Stampfl and Boccaccini47} recently demonstrated the possibility of processing different bioactive glasses and bioactive glass-ceramics by SLCM using raw materials with specific particle sizes (0.16–4.3 µm). ^{Reference Gmeiner, Deisinger, Schönherr, Lechner, Detsch, Boccaccini and Stampfl45} They succeeded in reproducing the microstructure of a human femoral bone with a precision of micrometers. The authors also reported the possibility to increase the structural strength ^{Reference Gmeiner, Deisinger, Schönherr, Lechner, Detsch, Boccaccini and Stampfl45} of these scaffolds by adding artificial support structures (e.g., barrel rings, shifted honeycomb structure). The strength values were increased by a factor of three. ^{Reference Gmeiner, Deisinger, Schönherr, Lechner, Detsch, Boccaccini and Stampfl45,Reference Gmeiner, Mitteramskogler, Stampfl and Boccaccini47}

Three-dimensional printing has mainly been used for the production of bioactive glass-ceramic composite scaffolds. ^{Reference Suwanprateeb, Sanngam, Suvannapruk and Panyathanmaporn48,Reference Shao, He, Fu, He, Yang, Xie, Yao, Ye, Xu and Gou49} A liquid binder is printed onto a powder bed layer by layer, gluing the powder together in the desired areas until the 3D structure is completely printed. ^{Reference Gmeiner, Deisinger, Schönherr, Lechner, Detsch, Boccaccini and Stampfl45} Zocca et al. ^{Reference Zocca, Gomes, Bernardo, Müller, Günster and Colombo50} developed 3D printed Li-aluminosilicate crystallized scaffolds characterized by 60% porosity and 15 MPa maximum compressive strength. More recently, a nonsacrificial preceramic binder (e.g., silicon resin), combined with reactive fillers (e.g., calcium carbonate, CaCO₃, and bioactive glasses) was used to produce complex porous wollastonite 3D printed structures. ^{Reference Zocca, Elsayed, Bernardo, Gomes, Lopez-Heredia, Knabe, Colombo and Günster51} The resin plays a dual role: first, as a binder during the printing process, and second, as a reactive phase to form the desired bioceramic during the thermal treatment. Highly porous (80%) structures exhibiting a compressive strength of 1.0 ± 0.3 MPa were produced.

Lee et al. ^{Reference Lee, Barlow, Marcus, Beaman, Barlow, Bourell and Crawford52} proposed in early investigations the selective laser sintering (SLS) technique for the development of ceramic porous structures. This technique is analogous to 3D printing, consisting of a free-flowing powder fused by a laser in defined areas. ^{Reference Gmeiner, Deisinger, Schönherr, Lechner, Detsch, Boccaccini and Stampfl45,Reference Lusquiños, del Val, Arias-González, Comesaña, Quintero, Riveiro, Boutinguiza, Jones, Hill and Pou53} Liu et al. ^{Reference Liu, Hu, Li, Shuai and Peng54} showed that the processing of 45S5 bioactive glass by SLS led to the same crystalline phases obtained in conventionally sintered 45S5 bioactive glass, namely combeite (Na₂Ca₂Si₃O₉) as the main phase and rhenanite (NaCaPO₄) as the secondary phase, which confirms SLS as a suitable alternative method to fabricate this type of scaffold.

The dispense plotting technique, also known as direct ink writing or robocasting, is a method in which a paste-like material is extruded through a nozzle onto a building platform. ^{Reference Fu, Saiz and Tomsia55} Eqtesadi et al. ^{Reference Eqtesadi, Motealleh, Miranda, Pajares, Lemos and Ferreira56} fabricated 45S5 bioactive glass-based scaffolds with 60–80% porosity and compressive strength of 2–13 MPa by this technique. Shao et al. ^{Reference Shao, Yang, He, Fu, Liu, Ma, Zhang, Yang, Gao and Gou57} reported a study on low-melting-point bioactive glass evaluating the effect of pore morphology on the mechanical properties of the scaffolds (compressive strength of 48 MPa and porosity of 60%). Pierin et al. ^{Reference Pierin, Grotta, Colombo and Mattevi58} used the same technique and produced for the first time a porous bioactive glass-ceramic scaffold using an ink made of a pure preceramic polymer ([CH₃]_0.96 [OR]_0.04 SiO_1.5)_n (where the cross-linking groups [OR] are –OH and –OC₂H₅) with 64% porosity and compressive strength of 2.5 MPa, which increased to 3.1 MPa with the addition of 0.1 wt% graphene oxide.

While AMTs for bioactive glass-ceramics continue to be developed, novel combinations of bioactive amorphous and crystalline phases are expected, which should enhance the biological activity of the scaffolds without compromising their mechanical stability. However, the main disadvantage of the techniques involving organic inks and resins is the difficulty in removing unprocessed powders trapped in the pores of the scaffolds, which requires optimized heat treatment in each case. ^{Reference Thavornyutikarn, Chantarapanick, Sitthiseripratip, Thouas and Chen59}

Freeze casting

Freeze casting generally involves freezing a ceramic slurry, inducing the formation of ice crystals along the freezing direction and agglomeration of bioactive glass or bioactive glass-ceramic particles between the crystals. ^{Reference Deville, Saiz and Tomsia60} The obtained structure undergoes sublimation to remove the ice. The obtained green body is then thermally treated to consolidate the structure. ^{Reference Gaudillere and Serra61} Similar methods have been used for the production of porous polymeric composite scaffolds containing bioactive glass and bioactive glass-ceramic as the filler. ^{Reference Roether, Gough, Boccaccini, Hench, Maquet and Jérôme62,Reference Pourhaghgouy, Zamanian, Shahrezaee and Masouleh63} Limited work has been reported in the literature on bioactive glass-ceramic scaffolds developed by this method, and the resulting foams are mainly characterized by relatively small pores (≤100 µm). ^{Reference Mallick64,Reference Song, Koh, Kim, Li and Bahn65} Thus, a drawback of this technique is the presence of small pores in the final structure and the long processing time required to produce scaffolds of relevant dimensions. ^{Reference Subia, Kundu, Kundu and Eberli66}

Table I ^{Reference Kokubo and Takadama67–Reference Wu, Hill, Yue, Nightingale, Lee and Jones80} lists a summary of the latest achievements in the field of 3D bioactive glass-ceramic scaffolds, reporting the fabrication techniques used and the main properties of the scaffolds.

Table I.

Summary of the latest achievements in the field of 3D bioactive glass-ceramic scaffolds, including processing method used and main properties obtained. (*Bioactivity test performed without following the proposed standard in References Reference Kokubo and Takadama67 and Reference Cerruti, Greenspan and Powers68.)

Note: HCA, hydrocarbonate apatite; FRM, foam replica method; BG, bioactive glass; BGC, bioactive glass-ceramic; CEL2, 45SiO₂-26CaO-15Na₂O-3P₂O₅-4K₂O-7MgO mol%; SCNA, 57SiO₂-34CaO-6Na₂O-3Al₂O₃ mol%; PCL, polycaprolactone; MBG, mesoporous bioactive glass; MCM, mobil composition of matter; HA/A-W hydroxyapatite/apatite-wollastonite; 6P53B, 52.7SiO₂, 10.3Na₂O, 2.8K₂O, 10.2MgO, 18.0CaO, 6.0P₂O₅ (wt%); SLCM, stereolithography ceramic manufacturing; SBF, simulated body fluid; TRIS, tris-(hydroxymethyl) aminomethane; T _sint, sintering temperature; 45S5, 45SiO_2–24.5CaO-24.5Na₂O-6P₂O₅, in wt%.