clinical trials involving 240 patients in multiple states for the use of this treatment on patients with heart failure. Clinical trials were also carried out at 40 hospitals in Europe and Israel.
Researchers and physicians engaged in stem cell research and therapies continue to perform groundbreaking work in the supportive environment of Belgium. The willingness of Belgian researchers to collaborate with other scientists in Europe and North America has resulted in increased knowledge of the ways that stem cell research can be used to save and improve human lives.
Elizabeth Rholetter Purdy
Independent Scholar
See Also: Mayo Clinic; Minnesota; University of Cambridge; University of Minnesota.
Further Readings
Banchoff, Thomas F. Embryo Politics: Ethics and Policy in Atlantic Democracies. Ithaca, NY: Cornell University Press, 2011.
“Belgian Scientists Repair Bones With New Stem Cell Technique.” http:/www.cbsnews.com/news/belgian-scientists-repair-bones-with-new-stem-cell-technique (Accessed March 2014).
Cardio3 Biosciences. http:/www.c3bs.com/en (Accessed March 2014).
Cedric Blanpain Lab. http://blanpainlab.ulb.ac.be/research_main.html (Accessed March 2014).
Moran, Mark. “Historical Concept of Brain Death Still Makes Waves Today.” Neurology Today, v.5/7 (July 2008).
“The Reality of Human Stem Cell Research in Europe.” http:/www.esf.org/media-centre/ext-single-news/article/the-reality-of-human-stem-cell-research-in-europe-621.html (Accessed March 2014).
Steinhoff, Gustav, ed. Regenerative Medicine From Protocol to Patient. New York: Springer, 2011.
Vermylen, C., et al. “Haematopoietic Stem Cell Transplantation for Sickle Cell Anemia: The First 50 Patients Transplanted in Belgium.” Bone Marrow Transplantation, v.221 (1998).
Vlaams Instituut voor Biotechnologie. http:/www.vib.be/en/pages/default.aspx (Accessed March 2014).
Bioreactors
Bioreactors
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Bioreactors
Bioreactors are controlled, closed systems used for the creation of cultures. They have many uses, ranging from the production of beer to more refined purposes such as creating large batches of stem cells of uniformly high quality. Microfluidic devices are another recent development similar to microbioreactors. Microfluidic devices and microbioreactors allow tight control and management of throughputs for better understanding of niches and more efficient drug screening. They also reveal paracrine/autocrine factors for enhanced control of differentiation. Both allow manipulation of the microenvironment through adjustment of cytokine gradients and flow rate.
Bioreactors have long been used in large-scale animal cell production, and converting them to stem cell generation is a matter of process engineering. Bioreactor engineering enables better modification and management of niches for maximum expansion, differentiation, and application of new cell-based medicines. Critical parameters include oxygen tension; 3-D scaffolds; physical forces such as mechanical, electrical, hydrodynamic force or strain; and flow shear. Different process outcomes and tissue-specific cell types require different bioreactor designs. What works for beer does not necessarily work for stem cells, regardless of type.
Stem cells are of two main types: pluripotent stem cells and adult stem cells. The pluripotent stem cells include both embryonic and induced pluripotent stem cells. Embryonic stem cells are pluripotent and can develop into all types of cells. This reprogramming of somatic cells is what causes them to become pluripotent. Adult stem cells, such as hematopoietic, neural, and mesenchymal stem cells, have a more limited differentiation potential and can only generate a subset of cells.
Stem cells hold great potential for biomedical applications across a wide spectrum, among them regenerative medicine, drug discovery, and cell therapy. Unfortunately, the current static tissue culture vessels, the Petri dish, can produce only small numbers of cells. Stem cell use is exceeding generation capacity of static vessels with cell counts reaching 1010–1012. Bioreactors need to be scalable and capable of quickly shifting the number and volume of cells they grow in order to provide the large numbers of stem cells that researchers need.
Stem cells require a regulated environment to grow properly. Because cells may be cultured either as free cells or aggregates fixated to solid substrates (such as the wall of the container) or in suspension, different bioreactor configurations are desirable. Bioreactors provide the necessary niche factors for proper growth into the appropriate cell configuration, regulating parameters such as oxygen, synthetic and decellularized extracellular matrix, paracrine/autocrine signaling, and physical forces such as mechanical and electrical forces and flow shear. The appropriate bioreactor offers precise control and recreation of niche factors by means of modulating or regulation of operation parameters. In this environment, the stem cells can expand and differentiate.
Stirred tank bioreactors produce free cells in suspension. This system is easy to scale up, provides a homogeneous culture environment, and is suitable for aggregate culture. However, it is subject to high shear stress. Another bioreactor type useful for cells or clusters in suspension is the rotary cell culture system (RCCS). The RCCS provides good mass transfer, controlled oxygenation, and low shear stress. However, the limited volume generated by the RCCS is relatively small and potentially inadequate for stem cell research. The wave bioreactor is suitable for hematopoietic stem cell culture and offers low shear stress, easy scalability, and gentle mixing, but it can be quite expensive.
For adherent cells, the microcarrier-based bioreactor may be either the stirred tank or the 4-D rotary cell culture system manufactured by Synthecon. The rotating wall bioreactor is a National Aeronautics and Space Administration (NASA) development to simulate the microgravity of space for cell growth. The bioreactor and inner cartridge rotate at the same angular rate, producing microgravity and low fluid shear. Cells grow as they would in vivo, and the RCCS allows mass transfer and efficient oxygenation through a permeable membrane. Rotating wall bioreactors were first used for bone marrow stem cell research and then expanded into other types of stem cells. However, rotating wall bioreactors are hard to scale up.
Adherent cell bioreactors regulate cell growth and differentiation, allow high-density cell culture, serve as delivery systems, and are easy to scale up. Cell harvest is difficult, however. Another option is a bioreactor with immobilized cells on a fixed or fluid 3-D scaffold. Tissue scaffolds (synthetic extracellular matrices) may be constructed of natural or synthetic materials such as Matrigel, alginate, collagen, hyaluronic acid, polyethylene terephthalate, and self-assembling peptide gels. Surface topology and tensile strength are among the factors that can alter cell adhesion, proliferation, and differentiation. The type of material used in constructing the scaffold depends on tissue. For instance, human embryonic stem cell cultures and soft tissues have worked with hydrogels with tunable properties while the engineering of bone and heart muscle requires a stronger and more porous material such as mineralized silk. Pore size affects the type of engineered bone tissue. The microencapsulation-based stirred tank and RCCS protect from shear stress and offer a 3-D environment, allow spatial organization, and regulate proliferation and tissue formation, but cells need to be released from the hydrogels and harvest is difficult.
The hollow-fiber membrane reactor provides low shear stress in a close approximation to the natural cell environment