Recent Progress of 3D Printing Bioceramic Scaffolds for Bone Regeneration

Abstract

The reconstruction of critical-sized bone defects remains a challenging clinical problem. At present, the implantation of autogenous and allogeneic grafts is the main clinical treatment strategy but faces some drawbacks, such as inadequate source, donor site-related complications, and immune rejection, driving researchers to develop artificial bone substitutes based on distinct materials and fabrication technologies. Among the bone substitutes, bioceramic-based substitutes exhibit a remarkable biocompatibility, which can also be designed to degrade concomitantly with the formation of new bone. In addition, three-dimensional (3D) printing technologies are frequently used for fabricating personalized 3D bioceramic scaffolds, which can achieve accurate imitation of native bone structures. Especially, bioprinting can produce organoids by integrating cells into scaffolds, which achieves the simultaneous imitation of organ structure and biological function. This review summarizes recent progresses of bioceramic-based materials, including hydroxyapatite, tricalcium phosphate, bioactive glass, calcium silicate, alumina, and zirconia. In addition, the application of 3D printing technologies and bioprinting is also elaborated in this text, offering important reference for future research of 3D-printed bioceramics.

Impact Statement

At present, there are abundant studies on 3D-printed bioceramics. However, bioceramic scaffolds are rarely applied to clinical practice. This review summarizes the bioceramic materials (hydroxyapatite, tricalcium phosphate, bioactive glass, calcium silicate, alumina, and zirconia) and 3D printing technologies (digital light processing, stereolithography, fused deposition modeling, direct ink writing, selective laser sintering, and inkjet printing), especially elaborating the application of bioprinting technology in bone regeneration, with the aim of providing direction for future research and clinical translation of products.

Keywords

3D printing bioceramics bioprinting bone regeneration

Introduction

With the increasing incidence of traffic accidents, bone tumors, etc., the critical-sized bone defects have become a challenging clinical problem, seriously affecting the life quality of patients and increasing social burden.^1–3 The treatment strategies for critical-sized bone defects include autogenous and allogeneic bone transplantation.⁴ Among them, autogenous bones have excellent biocompatibility and no risk of disease metastasis, but their application is limited due to inadequate source and donor site-related complications. Allogeneic bones are relatively easy to obtain, but faced with the problems of immune rejection, infection, and ethics.⁵ Therefore, developing suitable artificial bones to replace autogenous and allogeneic bones is urgent.

Artificial bones mainly include metals, polymers, and bioceramics.⁶ Due to excellent ductility, strength, and fracture toughness, most implants are made of metal materials.⁷ However, metal materials have a higher elastic modulus than native bones, which may lead to insufficient callus formation and delayed fracture healing.⁸ In addition, although polymers such as polyether ether ketone (PEEK) have similar elastic modulus with the native bone, as well as possess the ability of X-ray penetration and anti-infection, the expensive costs of processing and poor biological activity impede the clinical application of PEEK.^9,10

Bioceramics include hydroxyapatite (HA), tricalcium phosphate (TCP), biphasic calcium phosphate (BCP), bioactive glass (BG), calcium silicate (Ca-Si), alumina (Al₂O₃), and zirconia (ZrO₂). Based on the response level of tissues, bioceramics are further divided into bioinert (Al₂O₃, ZrO₂) and bioactive (HA, TCP, BCP, BG, Ca-Si).¹¹ Among them, bioactive ceramics have attracted great interest from researchers due to good biocompatibility.^12–15 By releasing bioactive ions such as Ca²⁺, ${PO}_{4}^{3 -}$ , and Si⁴⁺, bioactive ceramics can exert the effect of inducing osteogenesis. In addition, bioactive ceramics are considered to have osteoconduction property and can guide stem cells and osteoblasts growing into implants.¹⁶ However, the compressive strength of calcium phosphate (CaP, including HA, TCP, and BCP) is less than 3 MPa, which is lower than that of cortical bones (90–230 MPa) and trabecular bones (2–45 MPa).¹⁷ Therefore, except for a few studies using CaP to repair nonload-bearing bone defects, CaP bioceramics are primarily used as coating or filling materials currently.¹⁸ Finally, biomaterials usually need to degrade to avoid secondary surgical removal, and the degradation rate should match the rate of new bone growth. Bioceramics such as TCP, BG, and Ca-Si are considered absorbable bioceramics, while HA exhibits very slow degradation. The comparison results of the characteristics of different bioceramics are summarized in Table 1. It can be drawn as follows: osteogenic vitality: BCP = BG = Ca-Si > HA = TCP > Al₂O₃ = ZrO₂, degradation ability: Ca-Si > BCP = BG > TCP > HA > Al₂O₃ = ZrO₂, and mechanical strength: Al₂O₃ = ZrO₂ > HA = TCP = BCP > BG = Ca-Si.

Table 1.

Comparison of Characteristics of Different Bioceramic Materials

Bioceramic materials	Mechanical properties	Degradation rates	Osteogenic performance	Clinical application
HA	Moderate	Difficult to degrade	Moderate	Oral implantation, repair of periodontal defect, jawbone, ossicle
TCP	Moderate	Biodegradable	Moderate	Bone cement, repair of nonload-bearing bone defects
BCP	Moderate	Biodegradable	Excellent	Repair of periodontal defect, jawbone, ossicle
BG	Low	Biodegradable	Excellent	Repair of periodontal defect, jawbone, ossicle
Ca-Si	Low	Easy to degrade	Excellent	Oral treatment, such as root canal therapy
Al₂O₃	High	Nondegradable	Poor	Repair of load-bearing bone defects
ZrO₂	High	Nondegradable	Poor	Repair of load-bearing bone defects

HA, hydroxyapatite; TCP, tricalcium phosphate; BCP, biphasic calcium phosphate; BG, bioactive glass; Ca-Si, calcium silicate; Al₂O₃, alumina; ZsO₂, zirconia.

Conventional ceramic fabrication methods include slip casting, gel casting, etc. Slip casting manufactures green bodies by pouring slurry into a gypsum mold, which can achieve batch production of complex and large-sized products.¹⁹ Gel casting produces green bodies through adding the organic monomer, initiator, and cast into ceramic slurry with high solid content (volume fraction ≥50%) and low viscosity (<1Pa·s). After heating or cooling, the organic monomer in the slurry can be in situ polymerized into a three-dimensional (3D) network structure, and the green body is shaped. Finally, the green body is demolded, dried, degreased (required for gel casting), and sintered to obtain ceramic products.²⁰ Among them, ceramic sintering is a physicochemical process in which ceramics become dense and hard through material transfer at high temperature. After sintering, ceramics can achieve higher strength by removing pores within them.²¹ Nevertheless, sintering may also lead to cracks and pores of ceramics. In summary, the conventional ceramic fabrication methods have difficulties in forming complex structures. Slip casting requires a long time to dry, and the viscosity of the slurry is too high, which may lead to insufficient filling of the mold. In addition, gel casting can produce a green body with uniform composition, high strength, fewer sintering defects, and realize net-size molding of complex parts. However, gel casting cannot fabricate individualized ceramics.

3D printing, also known as additive manufacturing (AM) technologies, fabricates solid parts by accumulating materials layer by layer, the process is regulated by a computer-aided design model.²² Compared with the conventional fabrication methods, 3D-printed bioceramic scaffolds have some special advantages, such as enhanced bioactivity, a faster degradation rate, and individualized fabrication (Table 2). 3D printing technologies mainly contain digital light processing (DLP), stereolithography (SLA), fused deposition modeling (FDM), direct ink writing (DIW), selective laser sintering (SLS), inkjet printing (IJP), and so forth.²³ In addition, bioprinting, as a kind of new printing technology, can more comprehensively mimic human organs by incorporating cells and bioactive molecules into 3D structures.²⁴ To conclude, 3D printing can precisely regulate the pore shape and size of bioceramics, providing a favorable microenvironment for osteogenesis. However, bioceramic products are not perfect currently, considering the brittleness and ordinary osteogenic effect. Therefore, it is necessary to summarize the recent research on 3D-printed bioceramics, aiming to provide direction for overcoming the defects of bioceramics.

Table 2.

Comparison of Three-Dimensional-Printed and Conventionally Fabricated Bioceramics

Fabrication methods	Mechanical performance	Biological response	Biodegradability	Clinical applicability
Conventional methods (slip casting, gel casting)	High strength	The material has biocompatibility; cells can proliferate and migrate on the surface of material	Long degradation time	Fabrication of hip, knee joint, and artificial tooth root, reinforcement of dental ridge, and maxillofacial reconstruction
3D printing	Lower strength (especially for porous ceramics)	The porous structure can enhance bioactivity, promote cell proliferation and migration, and accelerate the transportation of nutrients and metabolic products	Porous ceramics have a faster degradation rate	Realizing the individualized fabrication of the above application

3D, three-dimensional.

Bioceramic Materials for Repairing Bone Defect

Hydroxyapatite

CaP is the most commonly used bioceramic material in craniomaxillofacial bone reconstruction. It has excellent biocompatibility, osteoinductivity, and osteoconductivity properties.^25,26 According to the Ca/P atomic ratio, CaP can be further classified into HA (Ca:p = 1.67) and TCP (Ca:p = 1.5).

HA (Ca₅(PO₄)₃(OH)) has excellent osseointegration and osteoconductivity properties.^27,28 Table 3 lists some cases of HA bioceramics applied in the field of bone regeneration. It is evident that HA bioceramics exhibit excellent performance in repairing bone defects and enhancing the mechanical strength of the scaffold. It is attributed to the following aspects. First of all, HA can release bioactive Ca²⁺and ${PO}_{4}^{3 -}$ ions, which have a certain osteogenic effect. In addition, the structure and porosity of bioceramic scaffolds are key factors affecting mechanical strength, bioactivity, and osteointegration. Through 3D printing technology, the structure, pore size, porosity, etc. can be precisely designed and printed, thereby enhancing the strength of scaffolds and improving osteogenic properties.

Table 3.

Application and Remarks on Hydroxyapatite in Bone Regeneration

Bioceramics	Fabricating methods and characteristics of scaffolds	Functions of bioceramic scaffolds	Innovation of research	Ref
HA	DLP-printed HA porous bioceramic	Promoting bone regeneration	Preparing a large-scale (length >150 mm), high-precision ceramic scaffold	²⁹
HA	Based on extrusion technology and the rapid gelation properties of guar gum, producing Cu-doped HA scaffolds with pore sizes ranging from 500 μm to nano	Enhanced osteogenic and angiogenic activities due to the presence of copper	Exploring the bioactivity of scaffold with hierarchical pores	³⁰
HA	SLA-printed HA bioceramic scaffolds with different TPMS structures: gyroid, lidinoid, and split-P	The structure with 70% gyroid shell and a solid core achieves the strength of 120 MPa, and promotes cell attachment and differentiation similar to a fully porous structure	Exploring the influence of different TPMS structures on mechanical properties and bioactivity	³¹
HA	DLP-printed HA scaffolds with distinct pore sizes: 400 μm, 600 μm, and 800 μm.	The scaffolds with 600 μm pores promote macrophage M2 polarization by upregulating IFN-β and HIF-1α, augmenting new bone growth, and fostering vascular proliferation	Exploring the influence and mechanism of the scaffold with distinct pore sizes on macrophage polarization	³²
HA	Nanoclusters minimizing light scattering, two-photon polymerization, achieving printing resolution of ≈300 nm	The dimensions of ceramics are reduced to submicron size, achieving flaw-insensitive behavior	The strength of ceramics is approaching the theoretical limit	³³

HA, hydroxyapatite; DLP, digital light processing; SLA, stereolithography; Cu, copper; TPMS, triply periodic minimal surface; IFN-β, interferon-beta; HIF-1α, hypoxia inducible factor-1alpha.

Although HA bioceramic scaffolds have been extensively studied in the field of bone regeneration, HA is more suitable to be used as a bone filler, such as cement and granules or coated on the surface of metallic prostheses, in consideration of the brittleness and poor degradation ability of HA.³⁴ In addition, the strength of porous ceramics is poor, and Ca²⁺and ${PO}_{4}^{3 -}$ ions from HA degradation may cause calcification of surrounding soft tissues, which will impede the regeneration of soft tissues. Finally, the osteogenic and angiogenic activity of pure HA materials is limited, and is often blended with the native organic components of bone or the differentiation-inducing factors to improve bioactivity.

Tricalcium phosphate

TCP [Ca₃(PO₄)₂] includes two forms: α- and β-TCP. α-TCP is easily soluble in aqueous systems and is often used as bone cement.³⁵ While β-TCP has excellent bioactivity, which can be prepared through solid-state reaction or thermal conversion.³⁶ In addition, β-TCP has good degradation performance and is stable under room temperature, which is frequently used for preparing bone scaffolds.³⁷

Table 4 summarizes some application examples of TCP in bone regeneration. It can be seen that TCP bioceramics play an important role in repairing bone defects. It is attributed to the following reasons. On the one hand, by adjusting porosity, pore size, and surface morphology, the optimized scaffold structure enhances the osteogenic effect of TCP ceramics. On the other hand, by affecting Ca/P molar ratio of the ceramic, sintering atmosphere can suppress the process of osteoclastic resorption.

Table 4.

Application and Remarks on Tricalcium Phosphate in Bone Regeneration

Bioceramic	Fabricating methods and characteristics of scaffolds	Functions of bioceramic scaffolds	Innovation of research	Ref
β-TCP	DLP-printed TPMS scaffolds with porosity ranging from 40% to 70%	70% porosity TPMS scaffold showed optimal compressive strength, and notably enhanced osteogenesis and angiogenesis	The influence of TPMS scaffolds with different porosity on osteogenesis and angiogenesis	¹²
β-TCP	Vat-photopolymerization-printed flat-bone-mimetic β-TCP scaffolds	Higher compressive strength and significantly enhanced osteogenic and angiogenic activities compared with cross-hatch scaffolds	The influence of flat-bone-mimetic structure on osteogenesis and angiogenesis	¹³
β-TCP	DLP-printed conch-like scaffolds	Improving osteogenesis, further guiding directional bone growth	The influence of conch-like scaffolds on cell migration and bone regrowth	³⁸
β-TCP	Hierarchical porous scaffolds with macropores (∼400 μm) and micropores (spherical and fibrous) based on DIW and template sacrifice printing methods	Improving cell adhesion, promoting the expression of osteogenic and angiogenetic genes	The influence of rationally designing macro–micro hierarchical structure on bone regeneration	³⁹
β-TCP	Sintering in different atmospheres, including air, annealing at 500°C in air, and a monetite-rich atmosphere	The annealed group with an increase of surface Ca/P molar ratio causes a decrease of osteoclastic resorption	The influence of sintering atmosphere on the physicochemical properties and osteoclastic resorption	⁴⁰
β-TCP	DLP-printed scaffold with microgroove structures of different spacings (0, 25, 50, and 75 μm)	Microgroove structure with large spacing promotes the macrophage M2 polarization and osteoinductive cytokine secretion	The regulation of microgroove structures on macrophage polarization	⁴¹

DLP, digital light processing; TPMS, triply periodic minimal surface; DIW, direct ink writing.

Bioinert ceramics

Al₂O₃, as one kind of bioinert ceramic, is biocompatible and resistant to chemical corrosion, as well as possessing high Young’s modulus and hardness. Al₂O₃ is often used for fabricating cortical bone.⁴² While ZrO₂ has excellent toughness and is often used for constructing artificial load-bearing bone.⁴³ Based on ZrO₂ ceramics, Jiang et al. prepared triply periodic minimal surface (TPMS) structures, which promote bone regeneration by regulating osteogenic immunity and angiogenesis.⁴⁴

Due to high mechanical strength and long-term stability, bioinert ceramics have a special advantage in repairing bone defects of load-bearing areas. However, poor bioactivity and mismatched elastic modulus limit their application in complex stress environments.⁴⁵ Some measures can be taken to overcome the above shortcomings, including surface modification (coated with HA), composite design (ceramic/native polymer), and 3D structure design.

Bioceramic composite materials

HA composite materials

The preparation of conventional ceramic composite materials requires degreasing and sintering steps, leaving only inorganic components. However, many implants currently contain not only inorganic components but also various organic components, which play an important part in bone regeneration. For example, the organic components in bioceramic composites are frequently used for improving osteogenesis and angiogenesis, enhancing the flexibility and plasticity of materials.⁴⁶ Therefore, some composite materials are no longer subjected to high-temperature treatment in the end.

Table 5 illustrates some application examples of HA composite materials in bone regeneration. It is evident that HA composite materials offer stronger bone healing potential and superior mechanical properties. For the synthetic polymers/HA composite materials, synthetic polymers such as polycaprolactone (PCL) and polylactic acid (PLA) have strong hydrophobicity. However, HA possesses high surface energy, which can partially offset the hydrophobicity of the synthesized polymer. Therefore, the composite materials of synthetic polymers and HA exhibit excellent function of cell attraction and adhesion. Besides, the incorporation of synthetic polymers with high elastic modulus may offset the brittleness of bioceramics, improving the mechanical properties of composite materials. Furthermore, most synthetic polymers release acidic products during degradation, which can neutralize the alkalinous ions from bioceramics. Finally, synthetic polymers possess excellent processability, so the mixed slurry composed of synthetic polymers and bioceramics has the potential to be produced into various complex structures compared with pure bioceramic slurry.

Table 5.

Application and Remarks on Hydroxyapatite Composite Materials in Bone Regeneration

Components of materials	Fabricating methods and characteristics of scaffolds	Functions of bioceramic scaffolds	Innovation of research	Ref
HA/Poly (lactide-cotrimethylene carbonate)	Extrusion-based 3D printing scaffolds with different HA ratios: 10%, 30%, and 50%	Scaffolds containing 10% HA exhibit the maximum amount of new bone formation and obvious contact osteogenesis, low rates of Ca release can promote osteoconduction better	Exploring the correlation between Ca release and osteoconduction	⁴⁷
HA/PCL	Eggshell-derived HA microparticles reinforced PCL scaffolds via extrusion-based 3D printing	Enhanced bone formation	Exploring the effect of eggshell derived HA microparticles reinforced PCL scaffolds on bone regeneration	⁴⁸
HA/carbon	DLP-printed HA scaffold containing 0.27 wt.% carbon	Promoting substantial endogenous bone regeneration, achieving the maximum compressive strength of 12.5 MPa under a porosity of 70%	Exploring the effect of graphene oxide and in situ carbon-reinforced HA scaffolds on bone regeneration	⁴⁹
HA/GelMA	SLA-printed porous GelMA/HA scaffolds with gradient porosity and pore sizes	Scaffolds with pore diameters ranging from 50 to 260 μm can promote bone regeneration	The effect of porous GelMA/HA scaffolds with gradient porosity and pore sizes on bone regeneration	⁵⁰
HA/Ce-MBGNs	DLP-printed HA scaffolds incorporated with Ce-MBGNs	Enhanced the mechanical, antioxidant, and osteogenic activities	The influence of Ce-MBGNs incorporation on the mechanical properties and bioactivity of scaffolds	⁵¹

HA, hydroxyapatite; SLA, stereolithography; DLP, digital light processing; PCL, polycaprolactone; GelMA, gelatin methacryloyl; Ce-MBGNs, cerium-containing mesoporous bioactive glass nanoparticles.

TCP composite materials

Table 6 summarizes some application examples of TCP composite materials. It can be seen that the incorporation of osteogenic components can enhance bone regeneration. Osteogenic components, such as differentiation-inducing factors, trace nutrient elements, osteogenic drugs, and bone marrow mesenchymal stem cells (BMSCs), are frequently introduced into materials or modified on the surface of materials to exert the key function of promoting osteogenesis. Nevertheless, there is a potential risk that excessive osteogenic components may lead to side effects, such as heterotopic ossification. Therefore, it is necessary to blend osteogenic components into ceramic slurry or use the chemical networks of hydrogels to wrap them, which can avoid the burst release of osteogenic components, as well as create an environment conducive to the survival of MSCs.

Table 6.

Application and Remarks on Tricalcium Phosphate Composite Materials in Bone Regeneration

Components of materials	Fabricating methods and characteristics of scaffolds	Functions of bioceramic scaffolds	Innovation of research	Ref
β-TCP/Col I/dipyridamole	β-TCP scaffold with surface modification of Col I-loaded dipyridamole	Notably promoting the regeneration of critically sized calvarial defects in the pig model	The repairing effect of Col I-loaded dipyridamole modified bioceramics on calvarial defects	⁵²
Co/ClAP/PLGA	DIW-printed Co-ClAP/PLGA scaffold	Protecting cells from oxidative damage, enhancing the regeneration of cartilage and subchondral bone	Exploring the effect of Co-Incorporated chloroapatite on osteochondral regeneration	⁵³
β-TCP/Mg₃(PO₄)₂	DIW-printed bioceramic scaffold composed of 60 wt% Mg₃(PO₄)₂ and 40 wt% β-Ca₃(PO₄)₂	Compressive strength ranging from 12.7 to 92.4 MPa, stimulating proliferation and osteoblastic differentiation of BMSCs	Exploring the mechanical strength and osteostimulation effect of Ca₃Mg₃(PO₄)₄-based scaffolds	⁵⁴
β-TCP/hADSC-laden hydrogel	β-TCP scaffold with hADSC-laden hydrogel on the top	A certain compressive strength, and promoting the repair of osteochondral defects	Exploring the mechanical strength and bone regeneration effect of the bilayer scaffold	⁵⁵
β-TCP/Zn/Co-MOF	Zn/Co-MOF functionalized β-TCP scaffolds	Excellent antioxidative and anti-inflammatory properties, repairing osteochondral defects under OA environment	Exploring the effect of Zn/Co-MOF functionalized β-TCP bioceramics on repairing osteochondral defects	⁵⁶

Col I, type I bovine collagen; Co, cobalt; ClAP, chloroapatite [Ca₅(PO₄)₃Cl]; PLGA, poly (lactic-coglycolic acid); BMSCs, bone marrow mesenchymal stem cells; hADSCs, human adipose-derived stem cells; Zn, Zinc; MOF, metal organic framework; OA, osteoarthritis.

BCP composite materials

Compared with HA, β-TCP has the advantage of easy degradation, which is an ideal characteristic for implant materials. However, rapid degradation may lead to a decrease in mechanical properties, even implant failure. BCP composite materials, composed of HA and β-TCP in a different ratio, have the advantages of slow degradation and excellent bioactivity.⁵⁷ BCP has been widely explored in the field of bone regeneration. Table 7 illustrates some application examples of BCP bioceramic. It is evident that BCP composite materials have good mechanical properties and osteogenic activity, making them a great potential for future transformation research.

Table 7.

Application and Remarks on Biphasic Calcium Phosphate and Mesoporous Bioactive Glass Composite Materials in Bone Regeneration

Components of materials	Fabricating methods and characteristics of scaffolds	Functions of bioceramic scaffolds	Innovation of research	Ref
HA, β-TCP, BCP	Four different CaP bioceramics, including HA, β-TCP, and BCP with HA:β-TCP = 60/40 and 20/80, respectively	Increased HA reduces osteoclastogenesis, suppresses the expression of positive coupling factors, which in turn modulate osteoblast function	Phase composition of CaP materials affects bone formation by modulating osteoclastogenesis	⁵⁸
BCP	Freeze-casting-based BCP scaffolds with oriented and longitudinal pores ranging from 10 to 20 μm	Exhibiting a flexural strength of 10.6 ± 2.7 MPa, avoiding calcification of the surrounding soft tissues	Assessment on freeze-cast BCP scaffolds with a selective cell ingrowth	⁵⁹
MBG/Cu²⁺/Mg²⁺	Doping Cu²⁺ and Mg²⁺ into MBG	Cu²⁺/Mg²⁺-substituted MBG significantly enhances the proliferation and viability of osteoblast-like MG-63 cells, exhibits antibacterial effects	Exploring the bio-response of Cu²⁺/Mg²⁺-substituted MBG for bone tissue regeneration	⁶⁰
MBGA/PVA	PVA-based 3D printing MBGA, modified with osteostatin and bone marrow aspirate, respectively	Osteostatin group exhibits excellent function of repairing bone defects	Exploring the effect of MBGA scaffold modified with osteostatin or bone marrow aspirate on bone regeneration	⁶¹
MBG/Ag	DIW-printed MBG scaffolds combined with Ag nanoparticles	Antibacterial activity against Staphylococcus aureus and Escherichia coli	Exploring the antibacterial effect of 3D printing MBG scaffolds doped with Ag nanoparticles	⁶²

BCP, biphasic calcium phosphate; HA, hydroxyapatite; CaP, calcium phosphate; MBG, mesoporous bioactive glass; MBGA, 82.5SiO₂–10CaO–5P₂O₅-x2.5SrO; PVA, polyvinyl alcohol; Ag, silver.

BG composite materials

BG [45S5 Bioglass, 45SiO₂–24.5Na₂O–24.5CaO–6P₂O₅ (wt%)], including phosphate-, silicate-, and borate-based glasses, is produced by sol–gel or traditional melting–quenching techniques.^63,64 With the dissolution of Ca²⁺, P⁵⁺, Na⁺, and Si⁴⁺, the surface of BG will form HA, which can help BG bond to tissues tightly.^65,66

Mesoporous bioactive glass (MBG), as one type of BG, has a well-organized mesoporous texture, and the pore sizes of MBG range from 2 to 50 nm.⁶⁷ MBG has a large surface area and pore volume, which facilitate the formation and attachment of HA layer and ensure the excellent bioactivity of MBG.⁶⁸ Currently, many researchers use MBG to deliver drugs, inorganic ions, and organic compounds to the injured sites, further promoting bone regeneration and resisting bacteria.⁶⁹ Table 7 summarizes some application examples of MBG composite materials. It can be seen that MBG is frequently doped with some metal ions such as Cu²⁺, Mg²⁺, and Ag⁺ to promote osteogenesis, as well as to exert antibacterial effects.

Ca-Si composite materials

Ca-Si can significantly promote the repair of bone defects in nonload-bearing areas, and is frequently used as sealers in stomatology, which shows bioactivity by releasing Ca²⁺ and Si⁴⁺. Ca²⁺ is crucial for regulating metabolic processes of bone regeneration,⁷⁰ while Si⁴⁺ can promote cell adhesion and angiogenesis in the early stage of calcification.^71,72 Based on the constituent and property, Ca-Si is divided into monocalcium silicate (CaSiO₃), dicalcium silicate (Ca₂SiO₄), and tricalcium silicate (Ca₃Si₂O₇).⁷³

Ca-Si is often mixed with other components to improve material properties. Table 8 illustrates some application examples of Ca-Si composite materials. It is evident that the composition of Ca-Si with organic polymers (silk fiber/gelatin), metal element Mg²⁺, or inorganic polymers [PCL, polyvinyl alcohol (PVA)] significantly improves material properties. It can be attributed to the following reasons. First, combining Ca-Si with organic polymers such as silk fibroin/gelatin can further reduce immune rejection responses, making Ca-Si ceramics more suitable for tissue repair. Besides, organic polymers generally possess good flexibility and plasticity, which can be used for improving the mechanical properties of Ca-Si ceramics. What is more, most of the native organic polymers have antimicrobial properties, which makes Ca-Si composite materials suitable for an infection environment. Finally, the high degradation rate of Ca-Si may lead to high pH values around the grafts. Acidic products from synthetic polymers can neutralize alkaline ions, further regulating pH values to a normal level.

Table 8.

Application and Remarks on Calcium Silicate Composite Materials in Bone Regeneration

Components of materials	Fabricating methods and characteristics of scaffolds	Functions of bioceramic scaffolds	Innovation of research	Ref
Xonotlite/SF/gelatin	DIW-printed SF/gelatin scaffold mixed with xonotlite nanofiber	Promoting osteogenic and angiogenic differentiation of BMSCs, reprogramming the differentiation of macrophages	The influence of scaffold doped with xonotlite nanofiber on osteo-/angiogenesis and osteoimmune microenvironment	⁷⁴
CaSiO₃/Mg	DLP printing Mg-doped CaSiO₃ bioceramic scaffold	Excellent compressive strength (>30 MPa), mild mechanical decay during in vitro biological dissolution, and inducing apatite remineralization	Exploring the biocompatibility and osteogenic capability of Mg-doped CaSiO₃ scaffolds	⁷⁵
Akermanite	Porous Mg-containing akermanite scaffolds	Enhancing bone regeneration, stimulating exosomal miR-196a-5p secretion, promoting senescent osteogenesis via targeting Hoxa7/MAPK signaling axis	The osteogenic effect and mechanism of Mg-containing akermanite	⁷⁶
BRT	Random morphology (BRT-R) and ordered arrangement structure (BRT-O)	BRT-O scaffolds facilitated the macrophage M2 polarization, promoting osteogenic differentiation of BMSCs	The influence of BRT scaffolds with different morphologies on osteogenic immunity and bone regeneration	⁷⁷
Ca-Si/PCL	Ca-Si/PCL scaffold coated with exosomes	Promoting cell attachment and osteogenic differentiation, recruiting stem cells in situ	The function of the exosome attaching onto Ca-Si/PCL scaffold on enhancing bone regeneration	⁷⁸
Akermanite/ PVA/SF	DIW-printed PVA/SF scaffold with high akermanite ceramic content (66.7 %)	After freeze–thaw cycles, the scaffold becomes flexible and processable	Flexible 3D bioceramic scaffold	⁷⁹

DIW, direct ink writing; DLP, digital light processing; BMSCs, bone marrow mesenchymal stem cells; PVA, polyvinyl alcohol; PCL, polycaprolactone; SF, silk fibroin; xonotlite, Ca₆(Si₆O₁₇) (OH)₂; akermanite, Ca₂MgSi₂O₇; Hoxa7, homeobox A7; MAPK, mitogen-activated protein kinase; BRT, bredigite (Ca₇MgSi₄O₁₆).

3D Printing Technologies for Bioceramic Scaffolds

3D printing technologies for bioceramic scaffolds include DLP, SLA, DIW, FDM, SLS, and IJP (Fig. 1).⁸⁰ Except for the above traditional printing technologies, bioprinting can produce 3D organ structures such as blood vessels and bones, preliminarily by integrating cells, cytokines, etc. into composite scaffolds,⁸¹ which achieves the simultaneous imitation of organ structure and biological function. The characteristics of different 3D printing technologies are summarized in Table 9.

FIG. 1.

Schematic of three-dimensional (3D) printing bioceramic technology. (a) Digital light processing (DLP), (b) stereolithography (SLA), (c) direct ink writing (DIW), (d) fused deposition modeling (FDM), (e) selective laser sintering (SLS), (f) inkjet printing (IJP).

Table 9.

The Comparison of Different Three-Dimensional Printing Technologies

Printing technology	Advantages	Disadvantages	Compatible bioceramics
DLP	High-precision printing, fast speed	Requirement for an appropriate solid content of slurry	CaP, Ca-Si, ZrO₂
SLA	High-precision printing, fast speed	Requirement for removing toxic substances	HA, BCP
FDM	Fast speed, simple operation, no pollution, low cost, and the ability to form complex structures	Material filament limitations, complex postprocessing	HA
DIW	Lower requirement for the precursor ink, multimaterial printing, fast speed	Low printing accuracy	TCP, MBG, Ca-Si
SLS	Reducing usage for raw materials and postprocessing time	Not suitable for printing pour bioceramic scaffolds due to the high melting point of bioceramic powder	CaP, MBG
IJP	Multimaterial printing, low cost, and no need for supporting structures	Requirements for pH value of bioceramic ink, low printing accuracy	HA, BCP
Bioprinting	The simultaneous imitation for organ structure and function	Requirement for ink biocompatibility, the high costs, and risks of abnormal cell proliferation	HA, β-TCP, CaSiO3

DLP, digital light processing; SLA, stereolithography; FDM, fused deposition modeling; DIW, direct ink writing; SLS, selective laser sintering; IJP, inkjet printing; BCP, biphasic calcium phosphate; HA, hydroxyapatite; CaP, calcium phosphate; MBG, mesoporous bioactive glass; TCP, tricalcium phosphate; CaP, calcium phosphate; Ca-Si, calcium silicate; ZrO₂ zirconia.

Digital light processing

DLP printing, as one type of vat photopolymerization technology, uses a high-resolution digital light projector as a light source to sequentially project each layer onto the surface of the slurry, achieving solidification of the slurry. As the platform moves, each solidified layer can combine with the previous layer, producing a 3D structure in the form of “layer-body.”⁸²

Based on DLP printing, Wang et al. prepared CaP ceramic scaffolds with distinct macroporous structures, including simple cube, octet-truss, and inverse face-centered cube. Among them, the structure of inverse face-centered cube shows the largest porosity and compressive strength, as well as the strongest osteoinductivity (Fig. 2).⁸³ Wu et al. fabricated the BCP scaffold with a hexagonal close-packed spherical pore structure, which promotes the expression of osteogenic genes and proteins in MC3T3-E1 cells, and effectively repairs the femoral condyle defects of rabbits.⁸⁴ In addition, TPMS is a kind of structure that has curved pore architectures and fully interconnected pore networks. It has been reported that DLP-printed TPMS structures, such as gyroid and diamond, can notably induce osteogenic differentiation of BMSCs.¹⁴ What is more, the research of Li et al. also demonstrates that TPMS structure has a significant impact on the synthesis of new blood vessels.⁸⁵ In summary, the fine structure of scaffolds will determine the properties of bioceramics. By designing and accurately printing the external shape and internal structure, DLP can obtain bioceramic scaffolds with excellent strength and osteogenic activity.

FIG. 2.

Digital light processing (DLP)-printed calcium phosphate (CaP) bioceramic scaffolds. (a–c) DLP-printed CaP ceramics with distinct macroporous structures, including simple cube, octet-truss, and inverse face-centered cube. (d) SEM images. (e) HE staining. Reproduced with permission.⁸³ Copyright 2022, The Author(s).

DLP technology has the advantages of high precision and short printing time.^86,87 The high solid content of slurry is beneficial for maintaining material density, reducing shrinkage rate, and enhancing mechanical strength of bioceramics. Nevertheless, excessive solid content will lead to the slurry too viscous, even the failure of printing. Therefore, it is necessary to explore a suitable solid content that not only ensures excellent spreading ability, but also increases the density and compressive strength of the scaffolds.

Stereolithography

SLA, as another type of vat photopolymerization technology, uses point scanning of UV light and photopolymerization reaction to solidify slurry. Monomers in the slurry are UV-active and are converted into polymer chains under UV light.⁸⁸ To fabricate bioceramic scaffolds, bioceramic powder needs to be added into the slurry first. Once the photopolymerization reaction occurs, the organic phase will uniformly wrap bioceramic particles in an organic network, and the green bodies of bioceramic scaffolds are established. Furthermore, green bodies need to be sintered under high temperature (>1000°C) to remove organic additives, and improve the density and strength of materials.⁸⁹

The implications of different channel shapes, sizes, and curvatures of scaffolds on bone regeneration are still unclear. A recent study fabricated scaffolds with various shapes (circular vs. rectangular), channel sizes (0.3 to 1.5 mm), and curvatures (concave vs. convex). Among them, channel with a round 0.9 mm diameter notably enhances bone formation, while channel shapes exhibit no significant effect on bone regeneration. Moreover, a concave surface is beneficial for bone tissue growth.¹⁵ Another study shows that the pore diameters ranging from 50 to 260 μm are beneficial for bone regeneration.⁵⁰ In conclusion, there is no standard for what size of pores can best promote osteogenesis currently. However, most research is inclined that the optimal size ranges from 100 to 1000 μm.

To overcome complications, such as inflammation and ectopic calcification brought by the migration of carbonate apatite granules, Hayashi et al. developed SLA-printed carbonate apatite chains (Fig. 3), which can conform to the defect shape and promote bone regeneration without complications.⁹⁰

FIG. 3.

Shapes and structures of granule and stereolithography (SLA)-printed carbonate apatite chain. (a, b) Stereomicroscopic images of carbonate apatite chain. (c, d) SEM images of a carbonate apatite chain. (e) Stereomicroscopic image of a carbonate apatite granule. (f, g) SEM images of a carbonate apatite granule. Reproduced with permission.⁹⁰ Copyright 2024, The Authors.

SLA technology has the advantages of rapid prototyping and high-precision printing.⁹¹ Nevertheless, the photoinitiators, unreacted monomers, etc. may lead to cytotoxicity and affect the synthesis of bone matrix. Therefore, further processing procedures are needed to remove the above toxic substances, such as soaked in deionized water and sintering.

Fused deposition modeling

FDM, as one type of material extrusion technology, uses a nozzle to extrude molten filament onto platform. After that, 3D structures are produced by stacking materials layer by layer.⁹² FDM technology allows for rapid preparation of scaffolds with complex geometries, and has been used for printing multiple-component materials, such as metals, ceramics, and polymers.⁹³

FDM printing technology heavily relies on material filaments. To fabricate ceramic scaffolds based on FDM, the first step is to synthesize filaments containing ceramic components. Recently, FDM-printed scaffolds derived from calcium-deficient HA/PVA filaments,⁹⁴ and PLA/HA filaments⁹⁵ have exhibited excellent biocompatibility and osteogenic activity. In addition, there is also a study attempting to combine FDM with DLP technology to produce ceramic scaffolds with special structures, which undoubtedly extends the application scope of FDM ceramic printing.⁹⁶

To conclude, the advantages of FDM mainly reflect in low cost, simple operation, and the ability to produce complex structures.⁹⁷ However, FDM printing relies on the preparation of filaments, and the composition of filaments determines the composition and function of printed scaffolds. Therefore, it is necessary to develop bioceramic filaments with excellent properties.

Direct ink writing

DIW, as another kind of material extrusion technology, extrudes precursor ink according to the designed paths, constructing 3D structures in the form of “line-lay-body.” The precursor ink, with the character of shear thinning, needs to have a certain storage modulus (G’’) and loss modulus (G’) to achieve excellent rheological properties.⁹⁸

Inspired by spicules of the marine sponge Euplectella aspergillum, Yang et al. prepared flexible bioceramic scaffolds based on DIW, which can be compressed, folded, rolled, twisted, and cut adaptably without the occurrence of fracture.⁹⁹ By polymer dissolving in acetone (15% w/v), another research prepared PLA/β-TCP scaffolds, which exhibit shape memory effect and can be applied for some special bone repair environments.¹⁰⁰ In addition, it has been reported that silk fibroin/gelatin mixed with xonotlite (Ca₆(Si₆O₁₇) (OH)₂) nanofiber can be printed into scaffold via DIW (Fig. 4), and the scaffold exhibits excellent bioactivity and mechanical properties.⁷⁴ Channels in scaffolds facilitate the transport of nutrient and metabolites, DIW printing can produce hollow-strut scaffolds with diverse cross-sectional channels by extruding slurry from customized nozzles.¹⁰¹ In summary, compared with photopolymerization that requires chemical reactions, DIW produces 3D structures through extrusion, which has stronger compatibility with various types of materials. Therefore, DIW-printed structures are more complex and have better properties.

FIG. 4.

Recently, it has been reported that DIW is used to print bioceramic scaffolds in the hydrogel, which utilizes fewer support structures while saving postprocessing time. In addition, scaffolds printed in the sanitizer bath can significantly promote cell growth and osteogenesis.^102,103 Undoubtedly, DIW floating printing provides a new idea for the construction of complex and oblique structures.

DIW has the advantages of high-speed printing and a low requirement for precursor ink components.¹⁰⁴ By introducing binder into precursor ink, bioceramic slurry with high powder content and viscoelasticity can maintain an excellent shape after extrusion. However, DIW-printed bioceramic scaffolds still require solidification and sintering to ensure the scaffolds have a certain mechanical strength.

Selective laser sintering

SLS, as a kind of powder bed fusion technology, uses powder to fabricate 3D structures layer by layer, which is ideal for raw materials with low melting points, such as polymers.¹⁰⁵ With the uninterned powder supporting each layer, SLS printing does not need supporting materials or separate feeders when preparing complex structures, which significantly reduces the usage of raw materials and saves postprocessing time.¹⁰⁶

Ceramics are often combined with synthetic polymers for SLS printing. For example, Feng et al. prepared the composite powder including polydopamine, nano-HA, and PCL, and the printed scaffold derived from the composite powder exhibits excellent tensile and compressive strength, as well as accelerating the formation of apatite layers and promoting adhesion, proliferation, and differentiation of cells.¹⁰⁷ In addition, PVA has a high melting point and crystallinity, which cannot be used for SLS printing. The research by Li et al. indicated that destroying the strong hydrogen bonds of PVA can endow PVA/HA powder with SLS printing property.¹⁰⁸ In conclusion, due to the high melting point of bioceramic powder, the research on SLS bioceramic printing is very limited, and bioceramic powder is commonly mixed with polymer materials as an additive in SLS printing.

Inkjet printing

IJP, as a kind of material jetting technology, sprays ink onto the surface of paper or plastic, manufacturing 3D-printed structures in the form of “points-lines-layers.” IJP includes two modes, continuous mode and drop on demand (DOD) mode. DOD mode adopts piezoelectric effect to control ink extrusion, which has the advantages of accurate droplet controlling and positioning. Based on IJP, Mostofizadeh et al. developed the photocurable and biodegradable phosphoramide-based hydrogel scaffolds added with nano-HA. After the degradation of the hydrogel, phosphates can be produced and exert the effect of promoting osteogenesis.¹⁰⁹

Currently, the application of IJP in bioceramic printing is also limited, and there are some issues that need attention. First, the rheological properties of bioceramic ink are key factors for evaluating whether the ink can be used for high-precision printing. Excessive or insufficient viscosity may lead to the failure of printing.¹¹⁰ Second, the ink needs to maintain an appropriate pH value to prevent the corrosion of the spray system. Third, the mechanical strength of the printed structure is poor. Last, compared with other printing technologies such as DIW and SLA, IJP has a lower printing accuracy.¹¹¹

Bioprinting

Bioprinting can fabricate complex structures containing biomaterials, cells, and bioactive molecules, which has attracted the interest of researchers recently.¹¹² When tissues are damaged due to trauma, chemical, or radiation exposure, bioprinting has the potential to fabricate personalized organoids and solve the problem of donor tissue shortage. 3D bioprinting strategies include the forms of inkjet, laser, and extrusion. Among them, extrusion-based bioprinting is widely used, considering that extrusion printing technologies are suitable for multimaterial printing.¹¹³

Based on decellularized extracellular matrix, HA, and human adipose stem cells, Kim et al. used DIW technology to fabricate engineered tendon-to-bone tissue with biologically graded interface.¹¹⁴ In addition, there is also a study developing a biomimetic scaffold, which includes Mo-containing silicate bioceramic power and tendon/bone-related cells (Fig. 5). The biomimetic scaffold can induce tenogenic and osteogenic differentiation, while enhancing the regeneration of tendon-to-bone interfaces in animal experiments.¹¹⁵

FIG. 5.

Characterization of bioprinted scaffolds containing both tendon stem/progenitor cell (TSPCs) and bone marrow mesenchymal stem cells (BMSCs). (a) Images of biomimetic multicellular scaffolds. (b) After cultured for 1, 4, 7, and 14 days, the confocal laser scanning microscopy photographs of the spatial distribution of BMSCs and TSPCs within the scaffolds. BMSCs show red fluorescence in the lower layer, and TSPCs show green fluorescence in the top layer, which simulates the cellular composition and hierarchical structure of tendon-to-bone interfaces. (c) The morphology images of BMSCs and TSPCs within the scaffolds. The nucleus is blue and cytoskeleton is green. Reproduced with permission.¹¹⁵ Copyright 2023, The Authors.

To enhance the mechanical strength of cell-laden hydrogel, Machour et al. used a novel thermosensitive ink to coprint with cell-laden hydrogel, and the thermosensitive ink can be sintered to form a porous, stiff scaffold at 37°C, which enhances the strength of hydrogel scaffold.¹¹⁶ In addition, it has been reported that with the addition of PCL and nHA, a biomimetic scaffold composed of alginate, nHA-collagen, and human dental pulp stem/stromal cells can obtain excellent mechanical strength.¹¹⁷ To conclude, synthetic polymer can improve the mechanical properties of bioprinted scaffold.

The regeneration of blood vessels and nerves is crucial for bone regeneration. Qin et al. constructed a prevascularization scaffold based on bioprinting technology, which is composed of Li-Mg-Si bioceramics, gelatin methacryloyl (GelMA), and human umbilical vein endothelial cell. The results indicated that the new scaffold has durable angiogenic capability, whether in in vitro or in vivo experiments. What is more, by releasing bioactive ions, the scaffold can promote osteogenic differentiation of MSCs and neurogenic differentiation of neurons.¹¹⁸

In addition, it has been reported that the collagen/HA scaffold derived from whipped bioink has high porosity and cell-laden ability. In vitro experiments showed that the porous scaffold significantly enhances the osteogenic and angiogenic activity of cells.¹¹⁹ Wollastonite, mainly containing CaSiO₃, has the properties of osteoconductivity and mechanical resistance, a promising bone repair material.¹²⁰ Kotlarz et al. prepared apatite–wollastonite bioceramic scaffolds based on binder jet printing technology. After that, they delivered cell-laden hydrogel on the surface of the scaffold. The results showed that with the deposition of hydrogel, cells can penetrate the porous structure and achieve in situ seeding.¹²¹ To conclude, bioprinting can premix bioactive components such as cells into a slurry, which ensures the biological activity of implants, as well as achieving personalized fabrication. Compared with pure material printing, bioprinting can save time for cell migration into the implant, further achieving vascularization and osseointegration of the implant in a shorter time.

Bioprinting is becoming an ideal option for fabricating biomimetic scaffolds. However, bioinks need to simultaneously satisfy printability, cell biocompatibility, and adequate mechanical strength, which existing materials struggle to fully meet.¹²² In addition, the high costs of research and development limit its widespread application currently. Finally, bioprinted organoids may not fully replicate the function of native organs and the existing risks of abnormal cell proliferation.

Clinical Application of Bioceramics in Bone Regeneration

With the advancement of 3D printing technology, 3D-printed bioceramics are gradually entering orthopedics and oral and maxillofacial surgery. For example, a 3D-printed cage composed of PCL and β-TCP in a mass ratio of 1:1 has excellent biodegradability and mechanical strength. Liu et al. used the novel cage to conduct a prospective clinical trial in 22 patients undergoing lumbar interbody fusion. The 12-month follow-up showed that the application of biodegradable PCL/β-TCP cages yields satisfactory results, and the JOABPEQ and visual analogue scale scores are notably improved.¹²³ To reveal the safety and efficacy of 3D-printed PCL/HA scaffolds in cranioplasty surgeries, Babaei et al. selected three clinical cases to carry out a phase 1 clinical trial. The result indicated that the sterilized PCL/HA composite is safe for patients, having the potential to be a substitute for autologous bone in craniomaxillofacial surgery.¹²⁴ In addition, Ca-Si-based bioceramics are frequently applied for endodontic treatment. For example, Wang et al. fabricated a novel material composed of CaO, SiO₂, P₂O₅, and MgO, which can guide bone regeneration and maintain bone volume stability for half a year postgrafting.¹²⁵

Although the application of bioceramic materials in orthopedics and oral and maxillofacial surgery is extensive, there still exist some problems. First, the complexity of operation and potential iatrogenic neurovascular injuries. Second, some complications correlated with degradability, such as implant breakage, damage from degraded debris entering the joint cavity, without the growth of new bone in the residual cavity after implant degradation. Third, inflammatory reactions. Finally, further follow-up is required to reveal long-term therapeutic effects.

Conclusion

3D printing is a promising method to fabricate personalized scaffolds for critical-sized bone defects, which can realize the reconstruction of complex anatomical shapes. At present, researchers are searching for the optimum fabrication parameters for bioceramic scaffolds, including porous structures, porous sizes, and sintering temperature. Meanwhile, by surface functional modification and other ingredients adding, bioceramic-based scaffolds can obtain better performance in mechanical properties, degradability, osteoinduction, and osteoconduction, as well as antitumor, antibacterial, etc.

This review elucidates various bioceramic materials and their applications in bone reconstruction. What is more, 3D printing technologies can prepare personalized bioceramic implants with promising mechanical and biological properties. Although significant advancements have been made in the field of bone repair, some issues still need to be solved.

Mechanical properties: It is difficult for current technologies to produce high-strength, tough, and scalable bioceramic scaffolds. By high-temperature sintering, the strength of bioceramics can be improved. However, porous bioceramic scaffolds have native disadvantages of insufficient toughness and scalability, which cause bioceramic scaffolds to not adapt to complex mechanical environments. In the next research, by mimicking the composition and structures of natural materials such as bone and mussels, modifying sintered ceramics through physical impregnation, or borrowing the dislocations strategy,¹²⁶ composite bioceramics may gain excellent toughness and scalability.

Vascularization challenges: Vascularization of grafts is a critical premise for successful integration and function. After the implantation of pure ceramic scaffolds, it takes plenty of time to achieve vascularization, which impedes the process of bone integration. Bioprinting technology has the potential to fabricate prevascularized bioceramic scaffolds in vitro, which provides a new strategy for accelerating bone regeneration.

Multiple functions: In some clinical cases, bone reconstruction and disease treatment need to be carried out simultaneously. For example, killing residual tumor cells is as important as promoting the regeneration of new bone, blood vessels, and nerves.¹²⁷ Thus, specific drug-laden bioceramic scaffolds are worth further exploration.

Translational barriers: Regulatory approval and requirements for preclinical and clinical validation limit the clinical translation of new products. To solve the above problems, a standardized and simplified protocol for clinical translation of new products needs to be formulated. Meanwhile, strengthening the cooperation between researchers, doctors, regulatory bodies, and companies is crucial. In addition, with the advancement of machine learning and artificial intelligence, the design and function of grafts can be predicted, which will accelerate the clinical translation of new products.¹²⁸

Fine printing: The native bone has a highly complex and ordered microstructure. However, the existing bioceramic scaffolds are rarely able to mimic the fine structures. By attempting a different ratio of slurry composition, regulating sintering temperature, integrating electrospinning or laser engraving with 3D printing technologies, etc., fine structures may be achieved in the future.

Authors’ Contributions

Y.Z.: Writing—original draft. D.L.: Writing—review and editing. L.R.: Conceptualization. X.W.: Conceptualization. D.M.: Conceptualization and writing—review and editing.

Footnotes

Funding Information

The authors greatly appreciate the financial support from the Natural Science Foundation of Gansu Province, China (no. 23JRRA543; no. 24JRRA1124), the Clinical Research on Precise Treatment of Maxillofacial Trauma (no. 2021yxky004), the National Key Research and Development Program of China (2022YFB4600101), the National Natural Science Foundation of China (52175201 and 52205228), and the Research Program of Science and Technology Department of Gansu Province (22JR5RA093 and 22JR5RA107).

Disclosure Statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Wang

, Wu

, Li

, et al. Engineering large-scale self-mineralizing bone organoids with bone matrix-inspired hydroxyapatite hybrid bioinks. Adv Mater, 2024; 36(30):e2309875; doi: 10.1002/adma.202309875

Zhi

, Wang

, Sun

, et al. Optimal regenerative repair of large segmental bone defect in a goat model with osteoinductive calcium phosphate bioceramic implants. Bioact Mater, 2022; 11:240–253; doi: 10.1016/j.bioactmat.2021.09.024

Xiao

, Zhu

, Yu

, et al. Effects of innervation on angiogenesis and osteogenesis in bone and dental tissue engineering. Tissue Eng Part B Rev, 2024; 30(4):477–489; doi: 10.1089/ten.TEB.2023.0267

Chen

, Chen

, Zhang

, et al. 3D-printed dual-bionic scaffolds to promote osteoconductivity and angiogenesis for large segment bone restoration. Adv Funct Materials, 2025; 35(17):2422691; doi: 10.1002/adfm.202422691

, Chen

, Liu

. A review on three-dimensional printed silicate-based bioactive glass/biodegradable medical synthetic polymer composite scaffolds. Tissue Eng Part B Rev, 2023; 29(3):244–259; doi: 10.1089/ten.TEB.2022.0140

Belluomo

, Khodaei

, Yavari

. Additively manufactured Bi-functionalized bioceramics for reconstruction of bone tumor defects. Acta Biomater, 2023; 156:234–249; doi: 10.1016/j.actbio.2022.08.042

Fan

, Chen

, Yang

, et al. Metallic materials for bone repair. Adv Healthc Mater, 2024; 13(3):e2302132; doi: 10.1002/adhm.202302132

, Liu

, Li

, et al. A novel biomimetic trabecular bone metal plate for bone repair and osseointegration. Regen Biomater, 2023; 10:rbad003; doi: 10.1093/rb/rbad003

, Jia

, Han

, et al. Characterization and biocompatibility of a bilayer PEEK-based scaffold for guiding bone regeneration. BMC Oral Health, 2024; 24(1):1138; doi: 10.1186/s12903-024-04909-z

10.

Wei

, Zhou

, Tang

, et al. Magnesium surface-activated 3D printed porous PEEK scaffolds for in vivo osseointegration by promoting angiogenesis and osteogenesis. Bioact Mater, 2023; 20:16–28; doi: 10.1016/j.bioactmat.2022.05.011

11.

de Carvalho

ABG

, Rahimnejad

, Oliveira

, et al. Personalized bioceramic grafts for craniomaxillofacial bone regeneration. Int J Oral Sci, 2024; 16(1):62; doi: 10.1038/s41368-024-00327-7

12.

Zhu

, Wang

, et al. Additively manufactured bioceramic scaffolds based on triply periodic minimal surfaces for bone regeneration. J Tissue Eng, 2024; 15:20417314241244997; doi: 10.1177/20417314241244997

13.

Zhang

, He

, Zhang

, et al. 3D-printed flat-bone-mimetic bioceramic scaffolds for cranial restoration. Research, 2023; 6:e0255; doi: 10.34133/research.0255

14.

Shen

, Li

, Lu

, et al. Bioceramic scaffolds with triply periodic minimal surface architectures guide early-stage bone regeneration. Bioact Mater, 2023; 25:374–386; doi: 10.1016/j.bioactmat.2023.02.012

15.

Entezari

, Wu

, Mirkhalaf

, et al. Unraveling the influence of channel size and shape in 3D printed ceramic scaffolds on osteogenesis. Acta Biomater, 2024; 180:115–127; doi: 10.1016/j.actbio.2024.04.020

16.

Zhang

, Xing

, Chen

, et al. DLP fabrication of customized porous bioceramics with osteoinduction ability for remote isolation bone regeneration. Biomater Adv, 2023; 145:213261; doi: 10.1016/j.bioadv.2022.213261

17.

Abdollahi

, Saghatchi

, Paryab

, et al. Angiogenesis in bone tissue engineering via ceramic scaffolds: A review of concepts and recent advancements. Biomater Adv, 2024; 159:213828; doi: 10.1016/j.bioadv.2024.213828

18.

Zhang

, Wang

, Gui

, et al. 3D-printed bioceramic scaffolds reinforced by the in situ oriented growth of grains for supercritical bone defect reconstruction. Adv Sci (Weinh), 2025; 12(2):e2408459; doi: 10.1002/advs.202408459

19.

Zheng

, Sun

, Li

, et al. Functionally graded composite ceramics: Design, manufacturing, properties and applications. Prog Mater Sci, 2025; 154:101496; doi: 10.1016/j.pmatsci.2025.101496

20.

Babashov

, Varrik

. Gel casting method for producing ceramic materials: A review. Glass Ceram, 2023; 80(1–2):9–16; doi: 10.1007/s10717-023-00547-z

21.

Yin

, Xu

, Ji

, et al. A critical review on sintering and mechanical processing of 3Y-TZP ceramics. Ceram Int, 2023; 49(2):1549–1571; doi: 10.1016/j.ceramint.2022.10.159

22.

Zhao

, Cao

, Wang

, et al. The recent progress of bone regeneration materials containing EGCG. J Mater Chem B, 2024; 12(39):9835–9844; doi: 10.1039/d4tb00604f

23.

Ivanovski

, Breik

, Carluccio

, et al. 3D printing for bone regeneration: Challenges and opportunities for achieving predictability. Periodontol 2000, 2023; 93(1):358–384; doi: 10.1111/prd.12525

24.

, Hwang

, Kim

, et al. Bioprinting-assisted tissue assembly to generate organ substitutes at scale. Trends Biotechnol, 2023; 41(1):93–105; doi: 10.1016/j.tibtech.2022.07.001

25.

Sun

, Zhao

, Qiao

, et al. Injectable periodontal ligament stem cell-metformin-calcium phosphate scaffold for bone regeneration and vascularization in rats. Dent Mater, 2023; 39(10):872–885; doi: 10.1016/j.dental.2023.07.008

26.

Wang

, Xia

, Hao

, et al. A triple-integrated 3D-printed composite scaffold of high-activity peptide-metal ion-bone cement facilitates Osteo-vascular regenerative repair of diabetic bone defects. Adv Funct Mater, 2025:2422950; doi: 10.1002/adfm.202422950

27.

Vitale

, Ligorio

, McAvan

, et al. Hydroxyapatite-decorated Fmoc-hydrogel as a bone-mimicking substrate for osteoclast differentiation and culture. Acta Biomater, 2022; 138:144–154; doi: 10.1016/j.actbio.2021.11.011

28.

Maduka

, Makela

, Tundo

, et al. Regulating the proinflammatory response to composite biomaterials by targeting immunometabolism. Bioact Mater, 2024; 40:64–73; doi: 10.1016/j.bioactmat.2024.05.046

29.

Zhang

, Gui

, Song

, et al. Three-dimensional printing of large-scale, high-resolution Bioceramics with micronano inner porosity and customized surface characterization design for bone regeneration. ACS Appl Mater Interfaces, 2022; 14(7):8804–8815; doi: 10.1021/acsami.1c22868

30.

Yang

, Huang

, Zhu

, et al. Scalable fabrication of freely shapable 3D hierarchical Cu-doped hydroxyapatite scaffolds via rapid gelation for enhanced bone repair. Mater Today Bio, 2024; 29:101370; doi: 10.1016/j.mtbio.2024.101370

31.

Koushik

, Miller

, Antunes

. Graded hydroxyapatite triply periodic minimal surface structures for bone tissue engineering applications. Adv Healthc Mater, 2025:e2402953; doi: 10.1002/adhm.202402953

32.

Xiong

, Zhang

, Zeng

, et al. DLP fabrication of HA scaffold with customized porous structures to regulate immune microenvironment and macrophage polarization for enhancing bone regeneration. Mater Today Bio, 2024; 24:100929; doi: 10.1016/j.mtbio.2023.100929

33.

Roohani

, Wang

, Xu

, et al. Bioinspired nanoscale 3D printing of calcium phosphates using bone Prenucleation clusters. Advanced Materials, 2025; 37(13):2413626; doi: 10.1002/adma.202413626

34.

Dalfino

, Savadori

, Piazzoni

, et al. Regeneration of critical-sized mandibular defects using 3D-printed composite scaffolds: A quantitative evaluation of new bone formation in in vivo studies. Adv Healthc Mater, 2023; 12(21):e2300128; doi: 10.1002/adhm.202300128

35.

Tronco

, Cassel

, Dos Santos

. α-TCP-based calcium phosphate cements: A critical review. Acta Biomater, 2022; 151:70–87; doi: 10.1016/j.actbio.2022.08.040

36.

, Su

, Li

, et al. 3D printed magnesium-doped β-TCP gyroid scaffold with osteogenesis, angiogenesis, immunomodulation properties and bone regeneration capability in vivo. Biomater Adv, 2022; 136:212759; doi: 10.1016/j.bioadv.2022.212759

37.

, Wei

, Liu

, et al. Dynamic degradation patterns of porous polycaprolactone/β-tricalcium phosphate composites orchestrate macrophage responses and immunoregulatory bone regeneration. Bioact Mater, 2023; 21:595–611; doi: 10.1016/j.bioactmat.2022.07.032

38.

Feng

, Zhang

, Qin

, et al. 3D printing of conch-like scaffolds for guiding cell migration and directional bone growth. Bioact Mater, 2023; 22:127–140; doi: 10.1016/j.bioactmat.2022.09.014

39.

Feng

, Liu

, Wang

, et al. Beta-TCP scaffolds with rationally designed macro-micro hierarchical structure improved angio/osteo-genesis capability for bone regeneration. J Mater Sci Mater Med, 2023; 34(7):36; doi: 10.1007/s10856-023-06733-3

40.

Santoni

, Niggli

, Dolder

, et al. Influence of the sintering atmosphere on the physico-chemical properties and the osteoclastic resorption of β-tricalcium phosphate cylinders. Acta Biomater, 2023; 169:566–578; doi: 10.1016/j.actbio.2023.08.012

41.

Hao

, Du

, He

, et al. Bioceramic surface topography regulating immune osteogenesis. BME Front, 2025; 6:e0089; doi: 10.34133/bmef.0089

42.

Zhou

, Su

, Wu

, et al. Additive manufacturing of bioceramic implants for restoration bone engineering: Technologies, advances, and future perspectives. ACS Biomater Sci Eng, 2023; 9(3):1164–1189; doi: 10.1021/acsbiomaterials.2c01164

43.

Jin

, Sun

, Weng

, et al. The effect of GelMA/alginate interpenetrating polymeric network hydrogel on the performance of porous zirconia matrix for bone regeneration applications. Int J Biol Macromol, 2023; 242(Pt 3):124820; doi: 10.1016/j.ijbiomac.2023.124820

44.

Jiang

, Ding

, Zhang

, et al. 3D printed porous zirconia biomaterials based on triply periodic minimal surfaces promote osseointegration in vitro by regulating osteoimmunomodulation and osteo/angiogenesis. ACS Appl Mater Interfaces, 2024; 16(12):14548–14560; doi: 10.1021/acsami.3c18799

45.

Ziąbka

, Wojteczko

, Zagrajczuk

, et al. Biological evaluation of ZrO(2) composites modified with different ceramics additives. Artif Cells Nanomed Biotechnol, 2024; 52(1):551–563; doi: 10.1080/21691401.2024.2422870

46.

Robin

, Mouloungui

, Dali

, et al. Mineralized collagen plywood contributes to bone autograft performance. Nature, 2024; 636(8041):100–107; doi: 10.1038/s41586-024-08208-z

47.

Hassan

, Eltawila

, Mohamed-Ahmed

, et al. Correlation between Ca release and osteoconduction by 3D-printed hydroxyapatite-based templates. ACS Appl Mater Interfaces, 2024; 16(22):28056–28069; doi: 10.1021/acsami.4c01472

48.

Gezek

, Altunbek

, Gouveia

MET

, et al. 3D printed eggshell microparticle-laden thermoplastic scaffolds for bone tissue engineering. ACS Appl Mater Interfaces, 2024; 16(26):32957–32970; doi: 10.1021/acsami.4c02800

49.

Zhao

, Niu

, Wei

, et al. Graphene oxide and in-situ carbon reinforced hydroxyapatite scaffolds via ultraviolet-curing 3D printing technology with high osteoinductivity for bone regeneration. Biofabrication, 2025; 17(2):e025028; doi: 10.1088/1758-5090/adbcdd

50.

Chen

, Zou

, Wang

, et al. SLA-3d printed building and characteristics of GelMA/HAP biomaterials with gradient porous structure. J Mech Behav Biomed Mater, 2024; 155:106553; doi: 10.1016/j.jmbbm.2024.106553

51.

Zhao

, Chen

, et al. Cerium-containing mesoporous bioactive glass nanoparticles reinforced 3D-printed bioceramic scaffolds toward enhanced mechanical, antioxidant, and osteogenic activities for bone regeneration. Adv Healthc Mater, 2025; 14(9):e2404346; doi: 10.1002/adhm.202404346

52.

DeMitchell-Rodriguez

, Shen

, Nayak

, et al. Engineering 3D printed bioceramic scaffolds to reconstruct critical-sized calvaria defects in a skeletally immature pig model. Plast Reconstr Surg, 2023; 152(2):270e–280e; doi: 10.1097/prs.0000000000010258

53.

Shu

, Qin

, Wu

, et al. 3D printing of cobalt-incorporated chloroapatite bioceramic composite scaffolds with antioxidative activity for enhanced osteochondral regeneration. Adv Healthc Mater, 2024; 13(13):e2303217; doi: 10.1002/adhm.202303217

54.

, Rao

, Zhou

, et al. Fabrication of 3D printed Ca3Mg3(PO4)4-based bioceramic scaffolds with tailorable high mechanical strength and osteostimulation effect. Colloids Surf B Biointerfaces, 2023; 229:113472; doi: 10.1016/j.colsurfb.2023.113472

55.

Lee

, Nedunchezian

, Lin

, et al. Bilayer osteochondral graft in rabbit xenogeneic transplantation model comprising sintered 3D-printed bioceramic and human adipose-derived stem cells laden biohydrogel. J Biol Eng, 2023; 17(1):74–24; doi: 10.1186/s13036-023-00389-x

56.

Shu

, Qin

, Chen

, et al. Metal-organic framework functionalized bioceramic scaffolds with antioxidative activity for enhanced osteochondral regeneration. Adv Sci, 2023; 10(13):2206875; doi: 10.1002/advs.202206875

57.

Liu

, Wu

, Liu

, et al. The role of integrin αv83 in biphasic calcium phosphate ceramics mediated M2 Macrophage polarization and the resultant osteoinduction. Biomaterials, 2024; 304:122406; doi: 10.1016/j.biomaterials.2023.122406

58.

Humbert

, Kampleitner

, De Lima

, et al. Phase composition of calcium phosphate materials affects bone formation by modulating osteoclastogenesis. Acta Biomater, 2024; 176:417–431; doi: 10.1016/j.actbio.2024.01.022

59.

Pejchalová

, Pejchal

, Rolecek

, et al. In vivo assessment on freeze-cast calcium phosphate-based scaffolds with a selective cell/tissue ingrowth. ACS Appl Mater Interfaces, 2024; 16(43):58326–58336; doi: 10.1021/acsami.4c12715

60.

Anand

, Kaňková

, Hájovská

, et al. Bio-response of copper-magnesium co-substituted mesoporous bioactive glass for bone tissue regeneration. J Mater Chem B, 2024; 12(7):1875–1891; doi: 10.1039/d3tb01568h

61.

García-Lamas

, Lozano

, Jiménez-Díaz

, et al. Enriched mesoporous bioactive glass scaffolds as bone substitutes in critical diaphyseal bone defects in rabbits. Acta Biomater, 2024; 180:104–114; doi: 10.1016/j.actbio.2024.04.005

62.

Sánchez-Salcedo

, García

, González-Jiménez

, et al. Antibacterial effect of 3D printed mesoporous bioactive glass scaffolds doped with metallic silver nanoparticles. Acta Biomater, 2023; 155:654–666; doi: 10.1016/j.actbio.2022.10.045

63.

Zhu

, Zhang

, Chang

, et al. Bioactive glass in tissue regeneration: Unveiling recent advances in regenerative strategies and applications. Adv Mater, 2025; 37(2):e2312964; doi: 10.1002/adma.202312964

64.

Simila

, Boccaccini

. Sol-gel bioactive glass containing biomaterials for restorative dentistry: A review. Dent Mater, 2022; 38(5):725–747; doi: 10.1016/j.dental.2022.02.011

65.

, Ye

, Liu

, et al. An overview on bioactive glasses for bone regeneration and repair: Preparation, reinforcement, and applications. Tissue Eng Part B Rev, 2025; doi: 10.1089/ten.teb.2024.0272

66.

Zhang

, Zhai

, Ma

, et al. Sequential therapy for bone regeneration by cerium oxide-reinforced 3D-printed bioactive glass scaffolds. ACS Nano, 2023; 17(5):4433–4444; doi: 10.1021/acsnano.2c09855

67.

Cui

, Hong

, Jiang

, et al. Engineering mesoporous bioactive glasses for emerging stimuli-responsive drug delivery and theranostic applications. Bioact Mater, 2024; 34:436–462; doi: 10.1016/j.bioactmat.2024.01.001

68.

Arcos

, Portolés

. Mesoporous bioactive nanoparticles for bone tissue applications. Int J Mol Sci, 2023; 24(4):3249; doi: 10.3390/ijms24043249

69.

Rahimnejad

, Charbonneau

, He

, et al. Injectable cell-laden hybrid bioactive scaffold containing bioactive glass microspheres. J Biomed Mater Res A, 2023; 111(7):1031–1043; doi: 10.1002/jbm.a.37487

70.

Zamparini

, Prati

, Taddei

, et al. Chemical-physical properties and bioactivity of new premixed calcium silicate-bioceramic root canal sealers. Int J Mol Sci, 2022; 23(22):13914; doi: 10.3390/ijms232213914

71.

Yuan

, Zhang

, Mo

, et al. A biomaterial-based therapy for lower limb ischemia using Sr/Si bioactive hydrogel that inhibits skeletal muscle necrosis and enhances angiogenesis. Bioact Mater, 2023; 26:264–278; doi: 10.1016/j.bioactmat.2023.02.027

72.

Xia

, Wu

, Chen

, et al. Silicon-based biomaterials modulate the adaptive immune response of T lymphocytes to promote osteogenesis/angiogenesis via epigenetic regulation. Adv Healthc Mater, 2023; 12(32):e2302054; doi: 10.1002/adhm.202302054

73.

Youness

, Tag El-Deen

, Taha

. A review on calcium silicate ceramics: Properties, limitations, and solutions for their use in biomedical applications. Silicon, 2023; 15(6):2493–2505; doi: 10.1007/s12633-022-02207-3

74.

Yang

, Zhou

, Yu

, et al. A xonotlite nanofiber bioactive 3D-printed hydrogel scaffold based on osteo-/angiogenesis and osteoimmune microenvironment remodeling accelerates vascularized bone regeneration. J Nanobiotechnol, 2024; 22(1):59; doi: 10.1186/s12951-024-02323-9

75.

Wei

, Wang

, Lei

, et al. Appreciable biosafety, biocompatibility and osteogenic capability of 3D printed nonstoichiometric wollastonite scaffolds favorable for clinical translation. J Orthop Translat, 2024; 45:88–99; doi: 10.1016/j.jot.2024.02.004

76.

, Fang

, Yan

, et al. Magnesium-containing bioceramics stimulate exosomal miR-196a-5p secretion to promote senescent osteogenesis through targeting Hoxa7/MAPK signaling axis. Bioact Mater, 2024; 33:14–29; doi: 10.1016/j.bioactmat.2023.10.024

77.

Xuan

, Guo

, Li

, et al. 3D-printed bredigite scaffolds with ordered arrangement structures promote bone regeneration by inducing macrophage polarization in onlay grafts. J Nanobiotechnology, 2024; 22(1):102–111; doi: 10.1186/s12951-024-02362-2

78.

Yun

, Lee

, Yeou

, et al. Electrostatic attachment of exosome onto a 3D-fabricated calcium silicate/polycaprolactone for enhanced bone regeneration. Mater Today Bio, 2024; 29:101283; doi: 10.1016/j.mtbio.2024.101283

79.

, Li

, He

, et al. Flexible biopolymer-assisted 3D printed bioceramics scaffold with high shape adaptability. Int J Biol Macromol, 2024; 265(Pt 1):130919; doi: 10.1016/j.ijbiomac.2024.130919

80.

Yuan

, Zhu

, Yang

, et al. Recent advances in 3D printing of smart scaffolds for bone tissue engineering and regeneration. Adv Mater, 2024; 36(34):e2403641; doi: 10.1002/adma.202403641

81.

van der Heide

, Cidonio

, Stoddart

, et al. 3D printing of inorganic-biopolymer composites for bone regeneration. Biofabrication, 2022; 14(4):e042003; doi: 10.1088/1758-5090/ac8cb2

82.

Hosseinabadi

, Nieto

, Yousefinejad

, et al. Ink material selection and optical design considerations in DLP 3D printing. Appl Mater Today, 2023; 30:101721; doi: 10.1016/j.apmt.2022.101721

83.

Wang

, Tang

, Cao

, et al. Fabrication and biological evaluation of 3D-printed calcium phosphate ceramic scaffolds with distinct macroporous geometries through digital light processing technology. Regen Biomater, 2022; 9:rbac005; doi: 10.1093/rb/rbac005

84.

, Liu

, Feng

, et al. 3D printing calcium phosphate ceramics with high osteoinductivity through pore architecture optimization. Acta Biomater, 2024; 185:111–125; doi: 10.1016/j.actbio.2024.07.008

85.

, Li

, Jiang

, et al. The design of strut/TPMS-based pore geometries in bioceramic scaffolds guiding osteogenesis and angiogenesis in bone regeneration. Mater Today Bio, 2023; 20:100667; doi: 10.1016/j.mtbio.2023.100667

86.

, Zhang

, Li

, et al. Quasi-static compressive and cyclic dynamic impact performances of vat photopolymerization 3D printed Al2O3 triply periodic minimal surface scaffolds and Al2O3/Al hybrid structures: Effects of cell size. J Alloys Compd, 2023; 969:172445; doi: 10.1016/j.jallcom.2023.172445

87.

Zhang

, Wang

, Gui

, et al. 3D printing of customized key biomaterials genomics for bone regeneration. Appl Mater Today, 2022; 26:101346; doi: 10.1016/j.apmt.2021.101346

88.

Chekkaramkodi

, Jacob

, Shebeeb

, et al. Review of vat photopolymerization 3D printing of photonic devices. Addit Manuf, 2024; 86:104189; doi: 10.1016/j.addma.2024.104189

89.

Corrado

, Di Maio

, Palmero

, et al. Vat photo-polymerization 3D printing of gradient scaffolds for osteochondral tissue regeneration. Acta Biomater, 2025; 200:67–86; doi: 10.1016/j.actbio.2025.05.042

90.

Hayashi

, Kishida

, Tsuchiya

, et al. Transformable carbonate apatite chains as a novel type of bone graft. Adv Healthc Mater, 2024; 13(12):e2303245; doi: 10.1002/adhm.202303245

91.

Xing

, Luo

, Lai

, et al. SLA-3D printing and bioactivity enhancement of zirconia anchor screws for temporomandibular joint disc reduction surgery. J Mech Behav Biomed Mater, 2025; 163:106897; doi: 10.1016/j.jmbbm.2025.106897

92.

Sabahi

, Roohani

, Wang

, et al. Material extrusion 3D printing of bioactive smart scaffolds for bone tissue engineering. Addit Manuf, 2025; 98:104636; doi: 10.1016/j.addma.2024.104636

93.

Huang

, Wei

, Li

. Additive manufacturing technologies in the oral implant clinic: A review of current applications and progress. Front Bioeng Biotechnol, 2023; 11:1100155; doi: 10.3389/fbioe.2023.1100155

94.

Thurzo

, Gálfiová

, Nováková

, et al. Fabrication and in vitro characterization of novel hydroxyapatite scaffolds 3D printed using polyvinyl alcohol as a thermoplastic binder. Int J Mol Sci, 2022; 23(23):14870; doi: 10.3390/ijms232314870

95.

Bernardo

, da Silva

BCR

, Hamouda

, et al. PLA/Hydroxyapatite scaffolds exhibit in vitro immunological inertness and promote robust osteogenic differentiation of human mesenchymal stem cells without osteogenic stimuli. Sci Rep, 2022; 12(1):2333; doi: 10.1038/s41598-022-05207-w

96.

Cheng

, Wu

, Tseng

, et al. Development of hybrid 3D printing approach for fabrication of high-strength hydroxyapatite bioscaffold using FDM and DLP techniques. Biofabrication, 2024; 16(2):e025003; doi: 10.1088/1758-5090/ad1b20

97.

Karimi

, Rahmatabadi

, Baghani

. Various FDM mechanisms used in the fabrication of continuous-fiber reinforced composites: A review. Polymers (Basel), 2024; 16(6):831; doi: 10.3390/polym16060831

98.

dos Santos

, Chevalier

, Fredel

, et al. Ceramics and ceramic composites for biomedical engineering applications via Direct Ink Writing: Overall scenario, advances in the improvement of mechanical and biological properties and innovations. Mater Sci Eng R-Rep, 2024; 161:100841; doi: 10.1016/j.mser.2024.100841

99.

Yang

, Xue

, Li

, et al. 3D printing of sponge spicules-inspired flexible bioceramic-based scaffolds. Biofabrication, 2022; 14(3):e035009; doi: 10.1088/1758-5090/ac66ff

100.

Nayak

, Sanjairaj

, Behera

, et al. Direct inkjet writing of polylactic acid/β-tricalcium phosphate composites for bone tissue regeneration: A proof-of-concept study. J Biomed Mater Res B Appl Biomater, 2024; 112(4):e35402; doi: 10.1002/jbm.b.35402

101.

Pang

, Wu

, Gurlo

, et al. Additive manufacturing and performance of bioceramic scaffolds with different hollow strut geometries. Biofabrication, 2023; 15(2):e025011; doi: 10.1088/1758-5090/acb387

102.

Raja

, Park

, Gal

, et al. Support-less ceramic 3D printing of bioceramic structures using a hydrogel bath. Biofabrication, 2023; 15(3):e035006; doi: 10.1088/1758-5090/acc903

103.

Utami

, Raja

, Kim

, et al. Support-less 3D bioceramic/extracellular matrix printing in sanitizer-based hydrogel for bone tissue engineering. Biofabrication, 2025; 17(2):e025017; doi: 10.1088/1758-5090/adb4a3

104.

Zhang

, Li

, Xu

, et al. A review of 3D printed porous ceramics. J Eur Ceram Soc, 2022; 42(8):3351–3373; doi: 10.1016/j.jeurceramsoc.2022.02.039

105.

Azam

, Belyamani

, Schiffer

, et al. Progress in selective laser sintering of multifunctional polymer composites for strain- and self-sensing applications. J Mater Res Technol, 2024; 30:9625–9646; doi: 10.1016/j.jmrt.2024.06.024

106.

, Ding

, Chen

, et al. Synergistic fabrication of micro-nano bioactive ceramic-optimized polymer scaffolds for bone tissue engineering by in situ hydrothermal deposition and selective laser sintering. J Biomater Sci Polym Ed, 2022; 33(16):2104–2123; doi: 10.1080/09205063.2022.2096526

107.

Feng

, Qiu

, Yang

, et al. Polydopamine constructed interfacial molecular bridge in nano-hydroxylapatite/polycaprolactone composite scaffold. Colloids Surf B Biointerfaces, 2022; 217:112668; doi: 10.1016/j.colsurfb.2022.112668

108.

, Peng

, Lv

, et al. SLS 3D printing to fabricate Poly(vinyl alcohol)/hydroxyapatite bioactive composite porous scaffolds and their bone defect repair property. ACS Biomater Sci Eng, 2023; 9(12):6734–6744; doi: 10.1021/acsbiomaterials.3c01014

109.

Mostofizadeh

, Kainz

, Alihosseini

, et al. Phosphoramide hydrogels as biodegradable matrices for inkjet printing and their nano-hydroxyapatite composites. ACS Appl Mater Interfaces, 2024; 16(39):52902–52910; doi: 10.1021/acsami.4c10532

110.

Košir

, Slavič

. Modeling of single-process 3D-printed piezoelectric sensors with resistive electrodes: The low-pass filtering effect. Polymers (Basel), 2022; 15(1):158; doi: 10.3390/polym15010158

111.

Wei

, Khalaf

, Ye

, et al. Therapeutic benefits of pomegranate flower extract: A novel effect that reduces oxidative stress and significantly improves diastolic relaxation in hyperglycemic in vitro in rats. Evid Based Complement Alternat Med, 2022; 2022:4158762; doi: 10.1155/2022/4158762

112.

, He

, Wu

, et al. 3D printing for tissue/organ regeneration in China. Bio-Des Manuf, 2025; 8(2):169–242; doi: 10.1631/bdm.2400309

113.

Chae

, Cho

. Biomaterial-based 3D bioprinting strategy for orthopedic tissue engineering. Acta Biomater, 2023; 156:4–20; doi: 10.1016/j.actbio.2022.08.004

114.

Kim

, Kwon

, Lee

, et al. 3D bioprinted multi-layered cell constructs with gradient core-shell interface for tendon-to-bone tissue regeneration. Bioact Mater, 2025; 43:471–490; doi: 10.1016/j.bioactmat.2024.10.002

115.

, Qin

, Zhang

, et al. Multicellular bioprinting of biomimetic inks for tendon-to-bone regeneration. Adv Sci (Weinh), 2023; 10(21):e2301309; doi: 10.1002/advs.202301309

116.

Machour

, Meretzki

, Haizler

, et al. A stiff bioink for hybrid bioprinting of vascularized bone tissue with enhanced mechanical properties. Biomaterials, 2025; 322:123406; doi: 10.1016/j.biomaterials.2025.123406

117.

Sousa

, Alvites

, Lopes

, et al. Hybrid scaffolds for bone tissue engineering: Integration of composites and bioactive hydrogels loaded with hDPSCs. Biomater Adv, 2025; 166:214042; doi: 10.1016/j.bioadv.2024.214042

118.

Qin

, Zhang

, Chen

, et al. Cell-laden scaffolds for vascular-innervated bone regeneration. Adv Healthc Mater, 2023; 12(13):e2201923; doi: 10.1002/adhm.202201923

119.

Koo

, Lee

, Lim

, et al. Highly porous multiple-cell-laden collagen/hydroxyapatite scaffolds for bone tissue engineering. Int J Biol Macromol, 2022; 222(Pt A):1264–1276; doi: 10.1016/j.ijbiomac.2022.09.249

120.

Wang

, Ye

, Shen

, et al. Core-shell-typed selective-area ion doping wollastonite bioceramic fibers enhancing bone regeneration and repair in situ. Appl Mater Today, 2023; 32:101849; doi: 10.1016/j.apmt.2023.101849

121.

Kotlarz

, Melo

, Ferreira

, et al. Cell seeding via bioprinted hydrogels supports cell migration into porous apatite-wollastonite bioceramic scaffolds for bone tissue engineering. Biomater Adv, 2023; 153:213532; doi: 10.1016/j.bioadv.2023.213532

122.

You

, Xiang

, Hwang

, et al. High cell density and high-resolution 3D bioprinting for fabricating vascularized tissues. Sci Adv, 2023; 9(8):e7923–e13; doi: 10.1126/sciadv.ade7923

123.

Liu

, Wu

, Bao

, et al. Clinical application of 3D-printed biodegradable lumbar interbody cage (polycaprolactone/β-tricalcium phosphate) for posterior lumbar interbody fusion. J Biomed Mater Res B Appl Biomater, 2023; 111(7):1398–1406; doi: 10.1002/jbm.b.35244

124.

Babaei

, Ebrahim-Najafabadi

, Mirzadeh

, et al. A comprehensive bench-to-bed look into the application of gamma-sterilized 3D-printed polycaprolactone/hydroxyapatite implants for craniomaxillofacial defects, an in vitro, in vivo, and clinical study. Biomater Adv, 2024; 161:213900; doi: 10.1016/j.bioadv.2024.213900

125.

Wang

, Fu

, Zhang

, et al. Bioceramics for guided bone regeneration: A multicenter randomized controlled trial. Clin Implant Dent Relat Res, 2025; 27(1):e13437; doi: 10.1111/cid.13437

126.

Dong

, Zhang

, Li

, et al. Borrowed dislocations for ductility in ceramics. Science, 2024; 385(6707):422–427; doi: 10.1126/science.adp0559

127.

, Xu

, He

, et al. 3D-printed biomimetic ceramic scaffolds with photothermal/chemodynamic effects and ionic microenvironment for preventing tumor recurrence and promoting vascularized bone reconstruction. Adv Funct Materials, 2025; 35(25):2418438; doi: 10.1002/adfm.202418438

128.

Liu

, Cao

, Yong

, et al. Optimal structural characteristics of osteoinductivity in bioceramics derived from a novel high-throughput screening plus machine learning approach. Biomaterials, 2025; 321:123348; doi: 10.1016/j.biomaterials.2025.123348