Solid freeform-fabricated scaffolds designed to carry multicellular mesenchymal stem cell spheroids for cartilage regeneration

Abstract

Three-dimensional (3D) cellular spheroids have recently emerged as a new trend to replace suspended single cells in modern cell-based therapies because of their greater regeneration capacities in vitro. They may lose the 3D structure during a change of microenvironment, which poses challenges to their translation in vivo. Besides, the conventional microporous scaffolds may have difficulty in accommodating these relatively large spheroids. Here we revealed a novel design of microenvironment for delivering and sustaining the 3D spheroids. Biodegradable scaffolds with macroporosity to accommodate mesenchymal stem cell (MSC) spheroids were made by solid freeform fabrication (SFF) from the solution of poly(D,L-lactide-co-glycolide). Their internal surface was modified with chitosan following air plasma treatment in order to preserve the morphology of the spheroids. It was demonstrated that human MSC spheroids loaded in SFF scaffolds produced a significantly larger amount of cartilage-associated extracellular matrix in vitro and in NOD/SCID mice compared to single cells in the same scaffolds. Implantation of MSC spheroid-loaded scaffolds into the chondral defects of rabbit knees showed superior cartilage regeneration. This study establishes new perspectives in designing the spheroid-sustaining microenvironment within a tissue engineering scaffold for in vivo applications.

Self‐assembled adult adipose‐derived stem cell spheroids combined with biomaterials promote wound healing in a rat skin repair model

“…In previous literature, it was found that proliferation, differentiation, and migration potential of MSCs were raised when MSCs were cultured as spheroids. 16,37 In addition, the formation of MSC spheroids could increase cytokine release and thus possibly enhance the paracrine effect, 15,40 which was important for MSCs on wound healing as previously described. Previous studies also suggested that preservation of MSCs as spheroids was essential for beneficial properties of MSC spheroids.…”

“…Previous studies also suggested that preservation of MSCs as spheroids was essential for beneficial properties of MSC spheroids. It was demonstrated that embedding spheroids in HA gel loaded in a chitosan‐grafted scaffold assisted to maintain spheroid morphology . These were the reasons why we made an attempt to utilize MSC spheroids rather than single cells in HA gel combined with the chitosan membrane for wound healing studies.…”

Spreading of Tissue Spheroids on an Electrospun Polyurethane Matrix

“…Fusion of tissue spheroids occurs, however, only if they are held in direct contact with each other. To hold tissue spheroids next to each other at a predetermined position in a 3D space, 3D printed synthetic scaffolds [4,5], dif ferent hydrogels [6], and even metal rods [7] are used, with varying degrees of effectiveness.…”

Patterning of tissue spheroids biofabricated from human fibroblasts on the surface of electrospun polyurethane matrix using 3D bioprinter

“…Thus, to enable post-printed tissue spheroids fusion it 3 is necessary to keep them close to each other in threedimensional space. Several different approaches have been developed to enable controllable tissue spheroids fusion, which include placing tissue sphe-roids inside 3D printed synthetic scaffolds [11][12][13] , using bioprintable hydrogel [14,15] and even metallic rods [16] . The search for the effective methods to keep tissue spheroids close to each other during 3D bioprinting continues and one of the possible perspective approaches is an application of nanotechnology.…”