Bioreactor based cancer therapy
Introduction
In the field of cell-based medicine, bioreactors have evolved into essential tools. To maintain carefully regulated microenvironments to govern cell proliferation, differentiation, and tissue development, many types of bioreactors are used. They are necessary to generate physiologically accurate in vitro models for pharmacologic agent testing or to provide standardized, repeatable cell-based products for regenerative medicine applications. Cell expansion bioreactors, tissue engineering bioreactors, and lab-on-a-chip systems are the three primary groups of bioreactors that are covered in this blog.
The following new concerns influence the commercialization and clinical application of bioreactors:
The requirement to scale up to larger graft sizes and cell volumes,
Making in vivo systems simpler so they can operate without foreign stem cells, growth factors, or both
Tighter regulation of miniature system production and maintenance to better capture intricate tissue and organ function.
How Bioreactors help??
Due to the lack of standardized and trustworthy characterization methodologies and models, the development of pharmaceuticals is a difficult, expensive, and time-consuming procedure. Drug screening has historically involved in vitro study utilising two-dimensional (2D) cell cultures, followed by in vivo testing on animals. Sadly, approximately 90% of the time, applying the results to humans fails. To produce more trustworthy results, it is crucial to create and enhance cell-based systems that can replicate in vivo-like circumstances.
In this blog, we describe the design and evaluation of a unique, user-friendly perfusion bioreactor system for single-use applications in tissue engineering, drug screening for cancer, anti-cancer medication response studies, and cancer research. The perfusion bioreactor's straightforward design allows for direct medium flow at physiological speeds (100-250 mu ms(-1)) through samples of various sizes and shapes. In short-term cultivation investigations using cervical cancer SiHa cells trapped in alginate microfibers under continuous medium flow, the bioreactor's biocompatibility was proven. After which the cell viability was retained, suggesting that the perfusion bioreactor might be employed in conjunction with alginate hydrogels as cell carriers to conduct controlled anti-cancer drug screening in a three-dimensional setting.
"A bioreactor offers the perfect sterile setting for cell growth while preventing cross-contamination. The bioreactor gives us the ability to manage the temperature, maintain pH, make sure there is a sufficient gas supply, and add nutrients without interfering with or contaminating the process. Bioreactors can only do this effectively when the conditions are correct.
To affect cell growth, differentiation, and tissue creation, bioreactors supply nutrients and biomimetic stimuli under regulated conditions. They have been widely utilized to encourage the growth of mesenchymal stem cells, induced pluripotent stem cells, CAR-T cells, and red blood cells. Additionally, being able to control the spatiotemporal delivery of the biological, biochemical, and biophysical signals that control tissue development confers several benefits for engineering 3D tissues in comparison to standard cell culture techniques by offering precisely controlled conditions to control cell behaviour.
These advantages include:
Improved standardization and reproducibility
Increase the size to more clinically significant tissue grafts or cell expansion scales.
Superior functionality in comparison to 3D grafts grown in tissue culture flasks,
Better methods for evaluating how cells react to various experimental conditions. The number of applications has grown as the area of regenerative medicine has developed, and the functions that bioreactors provide in facilitating the commercialization and clinical translation of stem cell-based technologies have been more clearly defined.
In this blog, we will give a critical overview of bioreactor applications in the biomedical field and talk about recent trends and developments that support the use of bioreactor technologies for the fabrication of engineered tissue grafts, single-cell manufacturing, and drug screening.
Bioreactors for cell proliferation and differentiation
The necessity for a cell-manufacturing industry to supply therapeutic allogeneic cells has been prompted by the therapeutic potential of stem cell-based technologies for the treatment of disorders ranging from hair loss1 to blindness2. The cost will likely be too high for conventional hospitals and treatment centres and will instead take the form of centralized facilities that specialize in providing high-quality cells with verifiable characteristics due to the extensive infrastructure requirements and stringent standards set by regulatory agencies. Yet, for cell-based therapies to be effective, enormous amounts of cells (108 -1010) must be used.
A practical restriction results from the prohibitive amount of room needed to cultivate these significant numbers of cells using conventional cell culture equipment. To produce homogeneous populations of stem or lineage-specific cells, this has led to a demand for bioreactors that can support industrial-scale, ultra-high-density cell suspension cultures with controlled microenvironments, standardization, and uniformity of culture conditions.
Many different bioreactor types have been used to produce sizable populations of phenotypically distinct cells. Various designs have been used to account for changes in cellular responses to microenvironmental signals and for adherent versus non-adherent cells.
Advances in Tissue Engineering Bioreactor
Tissue engineering bioreactors have aided in the generation of substantial 3D tissue grafts, as opposed to bioreactors that produce single cells. These systems frequently use convective flow to provide essential mass transport regimes, overcome the diffusional limitations of nutrients and oxygen, and prevent the accumulation of metabolic waste products that would otherwise cause starvation and death of the cells in the inner regions of the construct. This allows them to produce large (centimeter-sized) viable grafts. Using physiological stimuli that mimic natural physiological processes as well as the incorporation of sensors that provide real-time feedback on culture conditions, tissue engineering bioreactors can also improve the functionality of grafts.
The mature, functional cellular constructions can be transplanted in vivo to repair damaged tissues after incubation. With the potential automation, engineered grafts will probably play a big part in the translation of engineered grafts to the clinic since mass production for larger patient populations is feasible and the potential automation makes designed grafts economically efficient.
Recently, it was shown that it was possible to culture a 200 cm3 cell-based construct in vitro without the development of necrotic centres. In this method, mesenchymal stem cells from bone marrow were put in a tubular perfusion bioreactor and enclosed in hydrogel beads. The flow through the hydrogel beads was controlled using anatomically formed three-dimensionally printed moulds. The stem cells were able to remain alive and undergo osteogenic differentiation because the spacing between the hydrogel beads improved mass transport to the cells across the entire construct.
While being a significant step forward in the growth of clinically sized structures, this method is still constrained using hydrogel beads, which reduce cell-cell contacts and impede paracrine signalling between cells, both of which are crucial for bone formation. In contrast, adipose-derived stem cells were directly seeded into the pore spaces of pig temporomandibular joint scaffolds that were anatomically formed.
In-Vivo Bioreactor
Not with standing the intrinsic benefits of growing whole grafts in tissue engineering bioreactors that are prepared for implantation into defect locations, there are several real-world obstacles to clinical translation that are connected to extended ex vivo culture. One significant drawback is that the huge, volumetric grafts frequently don't have a complete vasculature, which hinders their post-transplant survivability.
In vivo bioreactors, a different strategy, have been used to get around these restrictions. Despite the name "bioreactor" being used, the in vivo bioreactor does not apply sound design principles or brand-new machinery like the systems mentioned above. There is no hardware, and surgical skill and manipulation are crucial to the strategy's success.
It mostly refers to a compartment inside the body where biomaterials or immature tissue-engineered constructions are surgically inserted and cultured for a long time. The grafts utilize the body's ability to regenerate within these pockets (such as an omentum or muscle flap) to properly vascularize. The presence of cytokines and other naturally occurring substances, the development of neovasculature and nerve tissue inside the implant, and immunological compatibility are some of the major benefits of this technique.
The in vivo bioreactor principle has primarily been used to create bone grafts of crucial size. The use of prefabricated bone grafts that are either incubated in situ, vascularized by prolonged implantation in muscle or omentum, or anastomosed with large arteries has been demonstrated in several recent studies and may be feasible even without the use of transplanted stem cells or growth factors.
Closure
In the commercialization and clinical translation of cell-based medicines and drug-testing platforms, bioreactors play a crucial role. Trends today point to a greater focus on manufacturing requirements. This includes expanding suspension culture bioreactors to industrial scales and altering tissue engineering bioreactors to allow the creation of patient-specific grafts with therapeutically useful sizes. Regulatory requirements may prove to be substantial obstacles to these systems' clinical implementation despite their considerable scientific and technological benefits.
Major developments in monitoring, controlling, and fabrication methods are leading to increasingly complicated systems for lab-on-a-chip systems that more accurately imitate human physiology and record the interactions of various organs. The development of low-cost platforms will significantly improve disease modelling and medication testing in the future.
“The difficulty lies in developing a culture method that can generate enough blood cells. The research team has progressed closer to producing the enormous number of red blood cells required for a single transfusion, which would help save lives, thanks to tests with nine days of growth in our AppliFlex bioreactors. The bioreactor industry is seeing rapid growth, which is exciting”.
"Cancer merely a word itself scares people, there isn't any promising drug for its treatment yet. Many scientists are continuously working hard for understanding it and seeking for ways to treat this disease. Every Biotechnologist manifests to develop some method or create some drug for it still there's none promising way. They need all the help they can get to overcome the disease and Amerging Technologies is contributing in this research by putting all its effort and ensures that they shouldn't be lacking in their resources to work on, providing them with the desired types of bioreactors to produce any type of cell lines and whatever amount they need".
Reference:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931275/