Strategies to capitalize on cell spheroid therapeutic potential for tissue repair and disease modeling

Abstract

Cell therapies offer a tailorable, personalized treatment for use in tissue engineering to address defects arising from trauma, inefficient wound repair, or congenital malformation. However, most cell therapies have achieved limited success to date. Typically injected in solution as monodispersed cells, transplanted cells exhibit rapid cell death or insufficient retention at the site, thereby limiting their intended effects to only a few days. Spheroids, which are dense, three-dimensional (3D) aggregates of cells, enhance the beneficial effects of cell therapies by increasing and prolonging cell–cell and cell–matrix signaling. The use of spheroids is currently under investigation for many cell types. Among cells under evaluation, spheroids formed of mesenchymal stromal cells (MSCs) are particularly promising. MSC spheroids not only exhibit increased cell survival and retained differentiation, but they also secrete a potent secretome that promotes angiogenesis, reduces inflammation, and attracts endogenous host cells to promote tissue regeneration and repair. However, the clinical translation of spheroids has lagged behind promising preclinical outcomes due to hurdles in their formation, instruction, and use that have yet to be overcome. This review will describe the current state of preclinical spheroid research and highlight two key examples of spheroid use in clinically relevant disease modeling. It will highlight techniques used to instruct the phenotype and function of spheroids, describe current limitations to their use, and offer suggestions for the effective translation of cell spheroids for therapeutic treatments.

Skeletal Muscle Spheroids as Building Blocks for Engineered Muscle Tissue

“…Spheroid diameter regulates nutrient availability to the aggregate core due to gradients within the spheroid and can have important implications on spheroid function. 10,43 We did not observe differences in the spheroid metabolic activity with diameters below 250 μm. However, previous studies demonstrated that smaller mesenchymal stromal cell (MSC) spheroids exhibit higher levels of proliferation and metabolic activity due to greater nutrient availability, while slightly larger spheroids can secrete higher levels of trophic factors.…”

“…Spheroids are dense cellular aggregates that are promising building blocks for tissue engineering due to their increased cell–cell interactions, upregulated cytokine production, retention of endogenous ECM, as well as enhanced cell survival in vitro and in vivo compared to monodisperse cells. ,− Spheroids have been fabricated from a variety of cell types, ,, yet literature on skeletal muscle spheroids is sparse . Aggregation of muscle cells into spheroids has largely focused on understanding the behavior of primary muscle cells, − but the application of this approach in tissue engineering lags behind other tissue types such as bone, , cardiac, and adipose, , among others.…”

Nanofabrication Technologies to Control Cell and Tissue Function in Three-Dimension

“…The use of spheroids is currently under investigation for many cell types. To improve the therapeutic effect of cell spheroids even further, various biomaterials (e.g., fibers and hydrogels) have been developed for spheroid engineering [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]. Note that hydrogels, as artificial 3D cell scaffolds, have attracted great attention in recent years because of their ability to reproduce the biological environment, with their inherent biochemical and physicochemical properties, such as cell adhesion, degradation, and viscoelasticity ( Figure 1 ) [ 1 ].…”

In Vitro Tumor Mimetic Spheroid Model: Void Space within a Self-Detachable Cross-Linked Hydrogel

“…However, techniques based on this method require specialized training, resulting in a lack of reproducible results. In addition, the formed spheroids pose challenges in immunostaining, imaging, retrieval, and storage. , …”

“…In addition, the formed spheroids pose challenges in immunostaining, imaging, retrieval, and storage. 16,17 Sodium alginate has been used as a biocompatible polymer material to support cell growth in 3D scaffolds. 18,19 Alginate scaffolds have demonstrated several advantages for 3D cell culture, including their ability to support cell growth and function and mimic many tissues' extracellular matrix (ECM).…”