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Bioprinting of osteochondral tissues: A perspective on current gaps and future trends

spheroids (also known as chondrospheres [43] ) self- laser-based bioprinting (LBB)—the detailed mechanisms
assemble into articular cartilage when implanted into of which are available at several sources [55,56] . The
the lesion, and has been under investigation in a phase- bioprinting techniques offer several advantages for
[44]
III controlled clinical trial in Europe . Chondrospheres engineering of osteochondral tissue constructs. Bio-
have similar properties to native cartilage and can printing allows for precise mimicking of the native
be engineered by altering their cellular density, self- heterogeneous, anisotropic tissue architectures. Most
assembly and culture condition. bioprinting techniques presently have the capability to
process several different types of cells and biomaterials,
1.2 Three­dimensional (3D) Printing for rendering unique potentiality to tune structural and
Osteochondral Defect Healing mechanical properties as per the requirement of specific
Attempts to create bi-layered grafts for osteochondral tissue-type. In the case of osteochondral tissue, wherein
tissue regeneration have been further boosted by the mechanical and compositional requirements are
the development of three-dimensional (3D) printing different for cartilage and bone tissues, bioprinting can
technology. Initially, 3D printing was used in conjunction thus be advantageous. Moreover, the ability to precisely
with conventional scaffold fabrication techniques, such control the patterning of cells and biological materials
as particulate leaching, to obtain bi-layered structures. enables the fabrication of zonal variations seen in
In most such cases, polymeric scaffolds have been osteochondral tissue. Interestingly, all the processing
selected to mimic the cartilage tissue, whereas a ceramic and fabrication of labile biological materials, such as
phase is usually chosen to represent the subchondral genes, growth factors and cells, through bioprinting can
bone. For example, hydroxyapatite has been printed be achieved under physiologically ambient conditions. It
with a porous polylactide (PLA) scaffold to mimic the has been thus observed that bioprinted constructs allow
osteochondral tissue composition and in vivo results for precise facilitation of cell–cell interactions, which
exhibited osteogenic and chondrogenic markers in both is critical to fabricate a composite tissue [57–61] . Thus,
[45]
respective layers . Similarly, stereolithography process bio printing has attracted the attention of researchers
has been used to fabricate osteochondral constructs with working with the quest to devise improved solutions for
polyethylene glycol and beta (β)-tricalcium phosphate, osteochondral healing.
which showed encouraging results in a year-long One of the early osteochondral tissue bioprinting
[46]
follow-up study in a rabbit critical-size defect model . efforts was attempted with EBB of two different cell
Using fused deposition modeling, Cao et al. fabricated types: mesenchymal stem cells with osteoinductive
a honey-comb-like PCL scaffold with 0°/60°/120° calcium phosphate particles, and chondrocytes on
lay-down pattern to create anisotropic structures [47] . two sides of an alginate mesh scaffold [62] . After ap-
Using 3D printing technology, tissue constructs with pro ximately three weeks in culture as well as in vivo
porosity gradient with embedded nanomaterials have experimentation, functional markers and ECM cha-
been demonstrated for osteochondral healing [48,49] . racteristics of both osteogenic and chondrogenic diffe-
Furthermore, MSCs and chondrocytes cultured on such rentiation were observed indicating the formation of
scaffolds showed different tissue morphologies over interfacial composite tissue. Later research has shown
[48]
time . Similar experiments using fibrin glue to mimic that bioprinting of cells with an appropriate hydrogel can
the cartilage tissue have also been reported [50,51] . 3D be used to direct differentiation into desired tissue. In
printing using selective laser sintering is also a facile these studies, collagen type-I or polycaprolactone (PCL)
technique to create gradient porosity [52,53] . Though was found to be suitable for bone tissue formation, and
3D printing techniques allow for creating different hyaluronic acid or alginate was suitable for cartilage
mechanical and porosity properties, inferior cell– tissue formation . As depicted in Figure 2A, a separate
[63]
cell interactions and inhomogeneous cell growth and study has shown that droplet-based bioprinting can be
differentiation amongst the scaffold remain the barriers effectively used to obtain composite tissue, where human
for effective clinical translation. mesenchymal stem cells (hMSCs) were bioprinted
on patterned bone morphogenetic protein-2 (BMP-
1.3 Bioprinting for Osteochondral Engineer ing 2) committed to osteoblast formation, while MSCs
Bioprinting is a process by which living cells and bio- were bioprinted on patterned TGF-β1 committed to
®
materials can be deposited precisely in a layer-by-layer chondrocyte differentiation [64] . Using a Bioscaffolder ,
manner as per a prescribed computer-aided design for a potential method to generate osteochondral models
[54]
the fabrication of engineered tissue constructs . Based of clinically-relevant sizes using poly(lactic acid)
[65]
upon the mechanism of deposition, bioprinting can be microcarriers has been developed . This study explored
defined in three broad categories—extrusion-based the fabrication of a bilayered graft in which cartilage
bioprinting (EBB), droplet-based bioprinting (DBB), and region was printed with gelatin methacrylate-gellan gum
112 International Journal of Bioprinting (2017)–Volume 3, Issue 2