Table 4.
Summary on the most recent gradient osteochondral scaffolds by additive manufacturing strategies.
| Scaffold composition | Fabrication technique | Established gradients | Main finding | Ref |
|---|---|---|---|---|
| Top: PolyHEMA/HAc Bottom: PolyHEMA/nHA |
Sphere-templating technique | Composition | The integrated bi-layered scaffold could support simultaneous matrix deposition and adequate cell growth of two distinct cell lineages in each layer during four weeks of co-culture in vitro | [29] |
| Porosity | ||||
| Stiffness | ||||
| Top: SF Medium: SF/nHA Bottom: SF/nHA |
Paraffin sphere leaching and modified temperature gradient-guided TIPS technique | Composition Porosity Stiffness |
A chondral layer with a longitudinally oriented microtubular structure, a bony layer with a 3D porous structure and an intermediate layer with a dense structure. The trilayered and integrated osteochondral scaffolds could effectively support cartilage and bone tissue generation in vitro | [68] |
| Top: Col-I/Col-II/HAc (5/15/2) Med: Col-I/Col-II/HA (5/5/2) Bottom: Col-I/HA (1/2) |
Iterative layering freeze-drying | Composition Porosity Stiffness |
The multi-layered scaffold had a seamlessly integrated layer structure, homogeneous cellular distribution throughout the entire construct. Rabbits model: tissue regeneration with a zonal organization |
[54,166] |
| Top: Col-II/(CaP/pTGF-β3/CaP/PEI nanoparticles) Bottom: Col-I/nHA/(CaP/pBMP −2/CaP/PEI nanoparticles) |
3D enzymatic-crosslinked gene-activated | Composition Porosity Stiffness |
The sustained release of incorporated plasmids from bilayer scaffolds promoted long-term transgene expression to stimulate hMSCs differentiation into the osteogenic and chondrogenic lineages by spatial and temporal control, which accelerate healing process | [87] |
| Top: Silicified silk/R5 (1/62.5) Medium: Silicified silk/R5(1/125) Bottom: silicified silk/R5(1/250) |
Sequential laying and then crosslinked | Composition | The gradient silicified silk/R5 composites offers continuous transitions in cytocompatibility and biodegradability, and promoted and regulated osteogenic differentiation of hMSC in an osteoinductive environment | [58] |
| Porosity | ||||
| Stiffness | ||||
| Top: CS/HAc Bottom: CS/SA/HA |
Thermally-induced phase separation (TIPS) | Composition | Cell proliferation and migration to the interface along with increased gene expression associated with relevant markers of osteogenesis and chondrogenesis | [158] |
| Porosity | ||||
| Stiffness | ||||
| Top: PGA/Ly/SA/BC/mHA Bottom: PGA/Ly/SA/BC/nHA |
Three-step crosslinking procedure | Porosity Stiffness |
Rabbits model: good integration between the neo-subchondral bone and the surrounding host bone and the same thickness between the neo-cartilage and the surrounding normal cartilage | [61] |
| Top: GelMA-PDA/TGF-β3 Bottom: GelMA-PDA/HA/BMP-2 |
Simultaneously polymerizing layers using one-pot method | Composition | PDA fix and release proteins or growth factors, which endows the hydrogel with good cartilage and subchondral bone regeneration abilities. | [81] |
| Porosity | ||||
| Stiffness | ||||
| Top: Col-I | Sequentially stacked, crosslinked, and collectively lyophilize | Composition | Rat model: subcutaneous implantation in rats showing the gradient scaffold was significantly colonised by host cells and minimal foreign body reaction, confirmed its in vivo biocompatibility | [55] |
| Medium: HA/Col-I (10/90 and 30/70) | Porosity | |||
| Bottom: HA/Col-I (1/1) | Stiffness | |||
| Top: NC/PdBT Bottom: GHK/PdBT |
Click conjugation of developmentally inspired peptides | Composition | Rabbits model: presentation of the NC peptide and incorporation of MSCs throughout the entire construct enhanced subchondral bone filling and the degree of bone bonding with adjacent tissue | [59] |
| Top: PEGDA Bottom: low-molecular-weight gels (LMWGs) |
Assembly/disassembly of LMWGs inside the network by photopolymerization | Composition Porosity Stiffness |
Each domain had an individual capacity to spatially control the differentiation of MSCs toward osteoblastic lineage and chondrocytic lineage. Rabbits model: the multi-domain gels distinctly improved the regeneration of subchondral bone and cartilage tissues | [85] |
| Top: ChS-NPs/SA/PVA Bottom: n-HA/SA/PVA |
Injectable semi-interpenetrating | Composition | Rabbits model: the engineered osteochondral mimetic injectable hydrogel with spatial variation, deep mineralized zone and gradient interface showed accelerated osteochondral tissue regeneration | [62] |
| Porosity | ||||
| Stiffness | ||||
| Top: TGF-β1/PLGA NPs | Table-top stereolithography 3D printing | Composition Porosity | Scaffolds with a highly interconnected microporous calcified transitional and subchondral region were created which facilitated cell adhesion, proliferation, and cellular activities | [167] |
| Medium: 10%nHA | ||||
| Bottom: 20%nHA | ||||
| Top: GelMA-PEGDA/TGF-β1-PLGA NPs | 3D stereolithography printing | Composition Stiffness |
Scaffold promoted osteogenic and chondrogenic differentiation of hMSCs, as well as enhanced gene expression associated with both osteogenesis and chondrogenesis alike | [43] |
| Bottom: GelMA-PEGDA/nHA | ||||
| Top: PCL | ||||
| Bottom: PCL/HA | Selective laser sintering technique | Composition Stiffness | Rabbit model: Scaffolds induced cartilage formation by accelerating the early subchondral bone regeneration, and the newly formed tissues could well integrate with the native tissues | [7] |
| Top: PNAGA-PTHMMA/TGF-β1 Bottom:PNAGA-PTHMMA/β-TCP |
Thermal-assisted extrusion printing | Composition | Rat model: 3D-printed biohybrid gradient hydrogel scaffolds significantly accelerate simultaneous regeneration of cartilage and subchondral bone | [42] |
| Porosity | ||||
| Stiffness | ||||
| Top: PACG-GelMA/Mn2+ Bottom: PACG-GelMA/BG | Low-temperature receiver assisted 3D-Printing | Composition Stiffness | Scaffold enhances gene expression of chondrogenic-related and osteogenic-related differentiation of hBMSC. Rat model: significantly facilitates concurrent regeneration of cartilage and subchondral bone | [86] |
| Top: PCL/PDA/TGF-β1 Bottom: PCL/nHA |
Fused deposition modeling 3D printing and casting | Composition | 3D printed constructs with nHA and bioactive cues have improved mechanical properties and enhanced hMSC adhesion, growth, and differentiation | [72] |
| Porosity | ||||
| Stiffness | ||||
| Top: Peptide/TCP/PLGA Bottom: P(DLLA-TMC)/Col-I |
Cryogenic 3D printing | Composition | High viability and proliferation at both subchondral-and cartilage layer. Moreover, gradient rBMSC osteogenic/chondrogenic differentiation was obtained in the osteochondral scaffolds | [78] |
| Porosity | ||||
| Stiffness | ||||
| Top: PCL Bottom: PCL/nHA |
Multi-material extrusion 3D printing | Composition | The fabricated scaffolds incorporate porosity changes similar to those found in the native osteochondral unit as well as compressive properties in the range of human trabecular bone | [73] |
| Porosity | ||||
| Stiffness | ||||
| Top: PCL | Multi-nozzle 3D printer | Composition | More cells attached and grew vigorously on the sintered HA layers and PCL layers, and proliferated very fast with days | [71] |
| Bottom: HA | Stiffness | |||
| Top: HAc/KGN hydrogel Bottom: HA/ALN | 3D-printing and semi-immersion | Composition | Rat model: Scaffold had sufficient anchoring strength to maintain stable binding of the two layers, and strong promotions of cartilage or bone regeneration in the respective layers | [139] |
| Porosity | ||||
| Drug-factor | ||||
| Top: fibrin Bottom: CS-Mg8 | Porogen-leaching method and 3D printing | Composition | Rabbit model: the biphasic scaffold could achieve simultaneous regeneration of cartilage and subchondral bone, the neo-tissue was well connected to the host tissue, and the tidemark was obvious in the neo-tissue | [168] |
| Porosity | ||||
| Stiffness |