What are MSC Spheroids, Why it Matters, & How to Culture It for Regenerative Medicine Studies?

What are MSC Spheroids, Why it Matters, & How to Culture It for Regenerative Medicine Studies?

What are MSC Spheroids, Why it Matters, & How to Culture It for Regenerative Medicine Studies?

Stem Cells Application in Cell Therapy

Stem cell therapy is one of the most promising approaches in the field of regenerative medicine. It is to promote the repair response of the diseased or injured tissue to restore the lost function. Many diseases can be targeted by cell therapy. These include blood-related diseases, neuronal degenerative diseases, ischemic and cardiovascular disorders, bone and cartilage diseases, wound healing, etc.

Several types of stem cells can be used in stem cell therapy, such as pluripotent stem cells, multipotent adult stem cells, and cancer stem cells. Some cell therapies have been established and approved for clinical use. The most well-established cell therapy treatment is the bone marrow transplant for the treatment of blood diseases.

MSCs – A Therapeutic Target for Cell Therapy in Regenerative Medicine

There has been a tremendous interest in using human mesenchymal stem cells (MSC) in stem cell therapy. MSCs are a type of adult stem cell that have the ability to differentiate into various cell types, for example, bone, cartilage, skin, muscle, and fat cells. They are found in various tissues in the body, such as bone marrow, adipose tissue, Wharton’s jelly, amniotic fluid, umbilical cord, and dental pulp. 


What makes MSCs an attractive source for cell therapy? MSCs can be easily isolated, rapidly expanded on a large scale, and able to migrate to the injured tissue through chemo-attraction. MSCs are also shown to have immunomodulatory and anti-inflammatory properties, which reduce immune response and inflammation to prevent the rejection of transplanted cells/tissues and promote tissue repair. They also replenish the lost/injured cells and promote the regeneration of impaired tissues by modulating the immune responses.  

Because of their ability to differentiate into multiple cell types, MSCs have been studied as a potential treatment for a wide range of diseases and injuries in regenerative medicine.  Some of the diseases that have been studied include osteoarthritis, wound healing, cartilage repair, heart disease, lung disease, diabetes, and neurological disorders such as multiple sclerosis and spinal cord injury.

Effect of bone marrow MSC-based regenerative medicine
Credit: Margiana, R., Markov, A., Zekiy, A.O. et al. https://doi.org/10.1186/s13287-022-03054-0 reproduced under the Creative Commons license


Therapeutic Potential of MSCs Spheroids

Generally, monodispersed cells are transplanted into the patients. However, this strategy has limited success, as the majority of cells transplanted into an injury site lose their viability after a few days due to the harsh microenvironment and limited cell-cell and cell-matrix interactions.


Spheroids represent one approach to overcoming the limitation of transplanting monodispersed cells. Spheroids are aggregates of cells that mimic the in vivo environment. Spheroids facilitate cell-cell and cell-matrix interactions, improve viability and proliferation, promote stemness marker expression, maintain intrinsic phenotypic properties, and secrete cytokines and chemokines, providing a more relevant model for disease research and drug testing, as well as tissue engineering and stem cell research.


Owing to the therapeutic potential of MSCs, the approach of using MSCs spheroids in cell therapies is particularly promising. Many studies were initiated to investigate the use of MSC spheroids in preclinical studies. MSC spheroids have been employed for in vivo cartilage and bone regeneration, wound healing, inflammation and autoimmune diseases, neurological disorders, cardiovascular diseases, diabetes, and liver diseases.



Atlantis Bioscience’s Solutions to Reproducible and Large-Scale Production of Spheroids

At Atlantis Bioscience, we discovered two solutions to circumvent the limitations of uniformly sized, spherical-shaped, and large-scale production of spheroids.

CellHD-256 Hanging Drop Spheroid Cell Culture Chip

CellHD-256 is a unique microfluidic-based hanging drop chip for the generation of spheroids.  The chip is simple to use and enables high throughput generation of 256 uniform spheroids. It is based on the principle of the hydraulic difference to form hanging drops in the chip. Due to gravity, the cells will concentrate at the bottom of the drop and form a spheroid.


Easy generation of spheroids

CellHD-256 enables long-term cultivation of spheroids, with easy medium exchange without disturbing the spheroids. As CellHD-256 is microfluidic-based, reagent consumption is minimal. Spheroids can also be stained and observed under high-resolution microscopy.

Images of MCF7 cells on Day 4 stained with Calcein AM (live cell stain)
and Ethidium Homodimer (dead cell stain)

CellHD-256 represents a superior alternative to the conventional hanging drop method in the generation of a large number of spheroids with ease and convenience.  

SphericalPlate 5D – A Platform Technology Enabling Advanced 3D culture

3D culture geometry is important for communication between cells and affects their early differentiation, a prerequisite for regenerative medicine applications. In order to achieve this communication, the shape and size of the 3D culture are critical, which leads to the development of the SphericalPlate 5D (SP5D)



SP5D is a 3D cell culture plate for the formation of uniform, and size-controlled spheroids in high quality and yield. Its special geometry and nanocoating hinder cells from attaching to the surface and enable the effortless upscaling of 9000 cell spheroids without losing control over cell differentiation and spheroid size. Its rounded bottoms also ensure uniformly sized spheroids allowing equal fate decisions and avoiding the formation of necrotic cores.


SP5D is ready-to-use and user-friendly. The cultivation does not require any pre-treatment or centrifugation steps after seeding your cells. Changing the media is also particularly convenient by simple pipetting, as the height of the microwells has been designed to retain cell spheroids. In addition, the platform is compatible with standard automation units and the plate also allows real-time imaging and monitoring within the platform.

Our Technology – SphericalPlate 5D

Currently, the SP5D is for research use only, however, medical device certification for cell therapy purposes is under preparation. This will be an excellent platform for the easy and scalable production of spheroids for translation into diagnostic or clinical applications. 

Future Perspective of MSCs Therapies

At present, there are no FDA-approved MSC therapies for general use. However, there are several products that have been granted regulatory approval in other countries. The use of 3D cultures further enhances the applicability of stem cells making it a more attractive therapy strategy than the traditional monolayer culture. Nevertheless, thorough preclinical and clinical studies are warranted to ensure the safety, compatibility, and efficacy of using MSCs as an effective treatment option for a variety of diseases. 



Jovic D, Yu Y, Wang D, Wang K, Li H, Xu F, Liu C, Liu J, Luo Y. A Brief Overview of Global Trends in MSC-Based Cell Therapy. Stem Cell Rev Rep. 2022 Jun;18(5):1525-1545. doi: 10.1007/s12015-022-10369-1. Epub 2022 Mar 28. PMID: 35344199; PMCID: PMC8958818.

Margiana, R., Markov, A., Zekiy, A.O. et al. Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review. Stem Cell Res Ther 13, 366 (2022). https://doi.org/10.1186/s13287-022-03054-0

Petrenko Y, Syková E, Kubinová Š. The therapeutic potential of three-dimensional multipotent mesenchymal stromal cell spheroids. Stem Cell Res Ther. 2017;8(1):94. Published 2017 Apr 26. doi:10.1186/s13287-017-0558-6

Sa S, Nguyen D, Pegan J, Khine M, McCloskey K. Round-bottomed Honeycomb Microwells: Embryoid body shape correlates with stem cell fate. J Dev Biol Tissue Eng. 2012; 5(2): 12. Published 2012 May 31. doi: 10.5897/JDBTE11.025

Zhou T, Yuan Z, Weng J, et al. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol. 2021;14(1):24. Published 2021 Feb 12. doi:10.1186/s13045-021-01037-x

Tags: #regenerative medicine, #spheroid, #tissue regeneration, #cell therapy, #stem cell therapy #MSC, #cancer spheroid #tissue engineering, #drug screening #3D culture # Mesenchymal stromal cell 



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