Current Therapies
Several regenerative medicine therapies are currently approved by the Food and Drug Administration (FDA) and are commercially available. These include biologics, cell-based medical devices and biopharmaceuticals. These treatments are capable of healing at a level similar or better than other standard therapies on the market.
Autologous Cells: Some treatments involve the use of autologous cells harvested from the patient. The FDA recently approved use of Carticel, a treatment for defects in the focal articular cartilage that involves harvesting chondrocytes from the articular cartilage of the patient, culturing and expanding the cells ex vivo, and then implanting them into the site of injury. The treatment results in recovery that is similar to other standard treatments including microfracture and mosaicplasty (Dewan, Gibson, Elisseeff, & Trice, 2014). Some drawbacks to this form of medicine is that it typically creates a new wound and there is a delay in treatment while the cells are expanded in culture.
Allogenic Cells: Other therapies use allogenic cells, or cells from sources other than the patient and that are thus immunologically incompatible. Allogenic cells with low antigenicity tend to be used for these types of treatments. The benefit is that they can be mass produced, while having a low risk of causing an adverse immune reaction. Example of allogenic cell therapies that are currently on the market include GINTUIT and Apligrad, which use human foreskin fibroblasts for wound-healing grafts (Falanga & Sabolinski, 1999).
Biomaterials: Several biomaterials are also used regularly to drive cell behavior. For example, a biomaterial known as matrix induced autologous chondrocyte implantation or MACI is a 3D polymer scaffolds used to promote expansion of chondrocytes in cartilage repair. A similar material called Dermagraft also serves as a scaffold for fibroblasts used to treat venous ulcers (Harding, Sumner, & Cardinal, 2013). Dermapure, decellularized donor tissue, the extracellular matrix of tissue in which the cells were removed that is then used as a scaffold, is used to enhance wound healing (Song & Ott, 2011).
Future Therapies
While there are many effective regenerative medical therapeutics on the market, none of them are capable of fully treating their targeted diseases and injuries. Development of more advanced and sophisticated treatments are still needed. Currently there are multiple strategies under preclinical and clinical investigation to improve regenerative medicine. These include those related to regeneration of tissue and organ structure, integration of grafts with host tissue, and alteration of the host environment to promote therapeutic responses.
Regeneration of Tissue Structure: One strategy currently being used to mimic tissue and organ structure is decellularizing organs and recellularizing them prior to implantation. Decellularization removes all cells including immunogenic cells and molecules from harvested tissue while retaining the extracellular matrix (ECM) (Crapo, Gilbert, & Badylak, 2011; Macchiarini, et al., 2008).
The tissue is then recellularized with cells expanded in the lab. Recellularized tissues have been used in animal models of diseases for various tissues, such as the lungs, kidneys, liver and heart (Nelson & Bissell, 2006; Petersen, et al., 2010; Uygun, et al., 2010; Nakayama, Batchelder, Lee, & Tarantal, 2010; Goh, et al., 2013).
There are still some concerns that need to be addressed before the technology can be used clinically. For one, it is still unknown how the decellularization process will effect the mechanical properties of the tissue or how much of the ECM may be removed during the process. It is also not known how long the recellularized tissue will last following transplantation.
Synthetic scaffolds with properties similar to the targeted tissue are also in development (Yang, Leong, Du, & Chua, 2001). These scaffolds can be generated from a variety of materials such as ECM components, synthetic polymers, or hydrogels (Kim & Mooney, Development of biocompatible synthetic extracellular matrices for tissue engineering, 1998; Drury & Mooney, 2003). Scaffolds are made to be biodegradable to allow them to be replaced by host tissue and grafted cells. Tissue Engineered Vascular Grafts (TEVGs) are currently in clinical trials to treat congenital heart defects (Patterson, et al., 2012).
Strategies to generate tissue without scaffolds are being researched. Cell sheet technology uses confluent sheets of cells from a substrate that maintains cell interactions and cell deposits of ECM components (Okano, Yamada, Sakai, & Sakurai, 1993; Nakajima, et al., 2001). These sheets have been used to successfully recellularize corneas (Nishida, et al., 2004).
Cell self-assembly in the presence of environmental cues and a cellular base to create complex tissues is also under development (Sasai, 2013). In one instance, intestinal structures have been generated from a stem cell in 3D culture in the presence of enhanced Wnt signaling (Sato, et al., 2011).
Graft Tissue Integration: Effective integration of implanted grafts is key to the success of regenerative medicine, specifically for integration with the host vasculature. One method of encouraging graft integration is to promote angiogenesis, or the expansion of blood vessels, through sustained and sequential release of angiogenic growth factors such as vascular endothelial growth factor (VEGF), angiopoietin (Ang), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) (Darland & D’Amore, 1999; Conway, Collen, & Carmeliet, 2001; Richardson, Peters, Ennett, & Mooney, 2001).
Another option to improve graft integration is to prevascularize the graft or the target site prior to implantation. Previous studies have shown that endothelial cells and their precursors can organize into vascular networks on a scaffold (Nör, et al., 2001; Chen, et al., 2009; Fedorovich, Haverslag, Dhert, & Alblas, 2010; Montaño, et al., 2010). When combined with tissue specific cells, a functional vascularized tissue could be generated.
In addition to integration with the host vascular system, the implanted tissue will also need to be effectively innervated by the host for proper tissue function regulation. Similar to tissue vascularization, innervation of implanted tissue can be promoted by release of nerve growth factors (Suuronen, et al., 2004; Carmeliet, 2005).
Promotion of Therapeutic Responses in Host: Implantation and host incorporation of cells is not always necessary to achieve a therapeutic effect. Administered cells can promote healing by secreting factors that influence host cells. For example, injection of umbilical cord blood cells into stroke patients promote angiogenesis resulting in enhanced recovery (Taguchi, et al., 2004).
Transplanted cells can also be utilized to alter the injury site environment to make it more suitable for tissue regeneration through release of ECM components. Researchers and clinicians are becoming increasingly interested in the potential of mesenchymal stem cells (MSCs) for this application.
Administration of MSCs to treat multiple diseases and traumas has resulted in a positive outcome despite poor engraftment, further supporting the beneficial effects of cell administration without incorporation. An obstacle to cell administration is that intravenously injected cells are typically cleared by the body relatively quickly (Kean, Lin, Caplan, & Dennis, 2013). To extend cell residency in the host, immunocloaking strategies are being developed. These strategies, also known as cell painting, involve coating cells in hydrogel alone or in combination with lipidation (with hydrophobic molecules) (Dennis, Cohen, Goldberg, & Caplan, 2004). Another strategy is to genetically modify the implanted cells so that they home to their target to streamline their distribution (Cheng, et al., 2008).
Conclusion
With the potential to use stem cells to generate healthy, personalized, functional tissues and organs to treat disease and injury, regenerative medicine has the potential to revolutionize the medical and research fields. The discovery of stem cells and the development of biomaterials have reinvigorated the field in the last few decades. While great progress has been made, there are still several barriers that need to be crossed in order to reach the full potential of regenerative medicine. However, with the development of novel strategies to surpass immunological issues, cell expansion, and other barriers, treatment of disease and injury with lab generated tissues could be a reality soon.
