Abstract
BackgroundRegeneration of articular cartilage poses a tremendous challenge due to its limited self-repair capability and inflammation at the damaged site. To generate the desired structures that mimic the structure of native tissue, microtissues with repeated functional units such as cell aggregates have been developed. Multicellular aggregates of mesenchymal stem cells (MSCs) can be used as microscale building blocks of cartilage due to their potential for cell-cell contact, cell proliferation, and differentiation.MethodsChondrogenic microtissues were developed through incorporation of kartogenin-releasing poly (lactic-co-glycolic acid) (PLGA) microparticles (KGN-MP) within the MSC aggregates. The chondrogenic potential of KGN-MP treated MSC aggregates was proven in vitro by studying the chondrogenic markers at the RNA level and histological analysis. In order to address the inflammatory responses at the defect site, the microtissues were delivered in vivo via an injectable, anti-inflammatory hydrogel that contained gelatin methacryloyl (GelMA) loaded with curcumin (Cur).ResultsThe KGN-MPs were fabricated to support MSCs during cartilage differentiation. According to real-time RT-PCR analysis, the presence of KGN in the aggregates led to the expression of cartilage markers by the MSCs. Both toluidine blue (TB) and safranin O (SO) staining demonstrated homogeneous glycosaminoglycan production throughout the KGN-MP incorporated MSC aggregates. The curcumin treatment efficiently reduced the expressions of hypertrophy markers by MSCs in vitro. The in vivo results showed that implantation of chondrogenic microtissues (KGN-MP incorporated MSC aggregates) using the curcumin loaded GelMA hydrogel resulted in cartilage tissue regeneration that had characteristic features close to the natural hyaline cartilage according to observational and histological results.ConclusionsThe use of this novel construct that contained chondrogenic cell blocks and curcumin is highly desired for cartilage regeneration.Graphical abstract
Highlights
Regeneration of articular cartilage poses a tremendous challenge due to its limited self-repair capability and inflammation at the damaged site
Fabrication and characterization of the KGN-loaded poly (PLGA) microparticles (MPs) The KGN-loaded PLGA MPs were fabricated by a single emulsion/solvent evaporation method
According to the scanning electron microscopy (SEM) images, the particles had an average diameter of 11 ± 5.5 μm, which was in the range of the previously reported MPs for incorporation within cell spheroids [24, 25]
Summary
Regeneration of articular cartilage poses a tremendous challenge due to its limited self-repair capability and inflammation at the damaged site. Multicellular aggregates of mesenchymal stem cells (MSCs) can be used as microscale building blocks of cartilage due to their potential for cell-cell contact, cell proliferation, and differentiation. Tissue engineering is a promising way to improve the cartilage function or replace the damaged tissues. A bottom-up tissue engineering approach has been suggested to rebuild high-cell-density and efficient three-dimensional tissues. In this approach, a tissue is created from a gathering of microtissues or cellular building blocks [3, 4]. Despite the advantages of cell aggregates, both limited diffusion of nutrients and GFs decrease both cell viability and differentiation, especially in the center of the structure. Several methods have been devised to circumvent the limited diffusion of GFs by incorporating GF-releasing polymer microparticles (MPs) or GF-encoded gene bounded MPs within the cell aggregates [7,8,9,10]
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