Three-Dimensional Bioprinting of Articular Cartilage: A Systematic Review

Abstract

Objective: Treatment of chondral injury is clinically challenging. Available chondral repair/regeneration techniques have significant shortcomings. A viable and durable tissue engineering strategy for articular cartilage repair remains an unmet need. Our objective was to systematically evaluate the published data on bioprinted articular cartilage with regards to scaffold-based, scaffold-free and in situ cartilage bioprinting.

Design: We performed a systematic review of studies using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and ScienceDirect databases were searched and all articles evaluating the use of 3-dimensional (3D) bioprinting in articular cartilage were included. Inclusion criteria included studies written in or translated to English, published in a peer-reviewed journal, and specifically discussing bioinks and/or bioprinting of living cells related to articular cartilage applications. Review papers, articles in a foreign language, and studies not involving bioprinting of living cells related to articular cartilage applications were excluded.

Results: Twenty-seven studies for articular cartilage bioprinting were identified that met inclusion and exclusion criteria. The technologies, materials, cell types used in these studies, and the biological and physical properties of the created constructs have been demonstrated.

Conclusion: These 27 studies have demonstrated 3D bioprinting of articular cartilage to be a tissue engineering strategy that has tremendous potential translational value. The unique abilities of the varied techniques allow replication of mechanical properties and advances toward zonal differentiation. This review demonstrates that bioprinting has great capacity for clinical cartilage reconstruction and future in vivo implantation.

Keywords: articular cartilage; bioprinting; scaffold-free; tissue engineering; zonal structure.

Figure 1.

Search methodology for selection of studies.

Figure 2.

Bioprinted constructs using EBB, DBB, and LBB. (A) Three-dimensional illustration of hydrogel fibers deposition in EBB (adapted with permission from [ref 15]). (B) Three-dimensional printed construct using alginate with GelMA (adapted with permission from [ref 15]). (C) Three-dimensional printed porous constructs based on M₁₀P₁₀ blended with HAMA (adapted with permission from [ref 17]). (D) Three-dimensional printed sheep meniscus with bioink of nanofibrillated cellulose and alginate (scale bar = 2 mm) (adapted with permission from [ref 20]). (E) Three-dimensional bioprinted hybrid constructs with PCL supporting structure and the cell-laden alginate hydrogel (adapted with permission from [ref 22]). (F) A schematic of DBB with simultaneous photopolymerization process (adapted with permission from [ref 27]). (G) A printed PEG hydrogel construct with 4 mm in diameter and 4 mm in height (scale bar = 2 mm) (adapted with permission from [ref 27]). (H) Multiple-layered printed construct which was composed of layers of electrospun PCL fibers and layers of cell-laden fibrin-collagen matrix printed by DBB (scale bar = 100 μm) (adapted with permission from [ref 31]). (I) A schematic illustration of LBB for cartilage (adapted from [ref 68]). (J) Live-dead staining of MSCs within 5% PEGDA/GelMA bioprinted construct after culturing (adapted with permission from [ref 32]). EBB = extrusion-based bioprinting; DBB = droplet-based bioprinting; LBB = laser-based bioprinting; MSCs = mesenchymal stem cells; GelMA = gelatin-metacryloyl methacrylate; PEGMA = poly(ethylene glycol) methyl ether methacrylate; HAMA = hyaluronic acid methacrylate; PCL = polycaprolactone

Figure 3.

(A) Bioprinted cartilage constructs with the Pluronic frame (A1), which was bioprinted with MSCs in the middle/deep layer and ACPCs in the superficial layer. Histological staining after 56 days of culture for (A2) sulfated GAGs and (A3) collagen type II (scale bar = 1 mm) (adapted with permission from [ref 34]). (B) Bioprinting setup with detachable nozzle assembly for tissue strand bioprinting (B1). Positive COL II (B2), aggrecan (B3), and safranin-O staining (B4) was obtained in tissue strands. (B5) A bioprinted cartilage tissue patch showed sulphated GAG deposition throughout the entire construct (adapted from [ref 37]). (C) The biopen with 2 separate chambers. Insert showed that 2 chambers are connected to the printing nozzle (insert), which allows the coaxial printing of the 2 different bioinks in a core/shell distribution (C1). (C2) Intraoperative bioprinting using the biopen for treatment of a full-thickness chondral defect in a sheep. (C3) Macroscopic appearance of the treated defect at 8 weeks after implantation (adapted with permission from [ref 40]).