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SNHS Spotlight: Microcarriers in Regenerative Medicine

Although IHA’s cherished locker-break cookies are earning status as mythological lore with the cafeteria having been closed for so long, humor the scenario that a student consumes one. On a microbiological level, the harvesting of ATP through cellular respiration is constantly occurring as the components of the cookie are broken down, fueling homeostasis, neurological function, and a host of metabolic processes. But in addition to these tasks, collected energy can also be used to sustain cell division. In fact, bionumbers from Harvard University reveal that the human person replaces billions of damaged or dead cells on a daily basis, with most average adults undergoing approximately 1016 cell divisions in their lifetime. The frequency of cell reproduction is easily recognized in the growth of hair and fingernails, in the replenishment of skin and blood cells. Yet, all cells cannot reproduce, and the speed at which cells copy themselves depends on their type. 

Stem cells have the ability to mature into many different cell types. Beginning in an immature state, many of these cells become specialized to a specific function. After development is complete, they may be categorized as skeletal muscle cells, red blood cells, or nerve cells, among others, suited explicitly to a particular function. Fully mature stem cells, known as somatic or adult stem cells, are often incapable of division. So if a young student-athlete experiences severe nerve damage due to a sports injury, or if a middle-aged family member loses cardiac muscle after a heart attack, this inability to heal by regenerating cells has serious consequences. 

Regenerative medicine is working to combat this issue, reducing the threats to life through inherited conditions or external modes of injury. Growing cells in cell culture to form the tissues of artificial organs, bones, or other biological structures, can replace lost body components and counter existing disrepair. Invitrogen’s handbook Cell Culture Basics explains the specific conditions must be met for cells to grow in cell culture environments. In a phenomenon called adherent culture, cells grow in a single layer on an artificial substrate, conforming to the principle of density dependence. In another artificial growth mechanism called suspension culture, cells float freely in the culture medium. Furthermore, anchorage-dependent cells must typically be grown on a tissue-culture treated medium, in which a substrate is modified to be more hydrophilic and enable cell adhesion. 

Scanning Electron Microscope image of an empty Cytopore macroporous microcarrier (GE 20)

General Electric’s department of Healthcare and Life Sciences’s handbook Microcarrier Cell Culture: Principles and Methods details important milestones in the development of microcarriers, which are small biomaterial spheres. In 1967, A. L. Wezel tested the usage of microcarriers as a basis for the growth of anchorage-dependent animal cells in suspension culture. Porous ion exchange medium DEAE SephadexTM A-50, which has a large surface area to volume ratio, provided viable material density as well as ease of observation for Wezel’s initial experiments. Early work showed that these microcarriers could possibly produce human fibroblasts or viruses on a large scale. Eventually, other microcarriers called Cytodex 1 and Cytodex 3 were developed, which utilized denatured collagen to promote adhesion by imitating the surface to which cells attach themselves in vivo (within living organisms). Following this advance, macroporous gelatin microcarriers were developed to increase cell density and protect the cell grown in the microcarrier environment. After this was the formation of new microcarriers for cells grown in fluidized bed cultures (a type of bioreactor-cell manufacturing) that immobilized cells in high density systems for study, along with a host of other developments in microcarrier technology such as Cytopore and Cytoline. 

Microcarrier-based systems have many advantages. These inexpensive surfaces are scalable, host anchorage-dependent cells, facilitate nutrient supply to growing cells, increase yield of products, and occupy minimal space. Microcarrier cell cultures also have an extensive list of applications aside from aiding in the reconstruction of biological tissues, including the creation of vaccines and monoclonal antibodies, the production of viruses and natural proteins, and the study of cell differentiation techniques. 

SMART’s gelatin microcarrier shown dissolving over time in an enzymatic treatment (MIT).

As a new technology, microcarrier advances are abundant. The Singapore-MIT Alliance for Research and Technology (SMART) has developed a new type of gelatin microcarrier that offers a higher yield of cell product and greater scalability in contrast to the extant microcarriers that are popularly used in biotechnology. In particular, SMART’s development will enable a larger-scale production of mesenchymal stromal cells (MSCs), which are isolated from bone marrow and adipose tissue among other sources and retain some cell differentiation capability in vitro (in an artificial environment). MSCs retrieved from mature tissues can be used to treat defects in connective tissues such as bone or cartilage, and the cells can also overcome the body’s rejection of foreign bone-marrow grafts in host cells. The gelatin biomaterial boasts a 90% harvest rate as opposed to the usual 50-60% rate, and the microcarrier’s solubility simplifies the recovery process of manufactured cells. The MSCs cultured by the gelatin-based support matrix also displayed greater balance of multipotency in terms of trilineage, meaning the cells could more successfully differentiate into red blood cells, white blood cells, or platelets. 

Although the aforementioned study focused explicitly on MSCs, the new findings could potentially be applied to the culture of other anchorage-dependent cells. Though it will take extensive breakthroughs in biomedicine and regenerative technology for physical injuries to be a problem of the past, emerging microcarriers hold promise in both the access to and the development of recovery methods. What’s more, large-scale lab-manufactured cell replacement means that injury recovery of any magnitude may not require that IHA cookie after all… though, perhaps you should unleash your inner scientist and obtain that evidence through personal experience. 

(Enjoy the cookie). 

Work Cited:

By: Freya Nair’21, SNHS Member

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