offers an alternative approach for the replacement of lost or deficient organs including the bladder. There exists promising research using the foundations of regenerative medicine that have been demonstrated in children with neurogenic bladder caused by myelomeningocele, which is a birth defect in which the spinal canal and backbone do not close.
There are several preclinical experiences with alternatives to enterocystoplasty. Tissue expansion involving the progressive dilation of the bladder with an expansion balloon device has been suggested as a method of bladder augmentation. However, this has not yet been attempted clinically. In preclinical models, tissue expansion increased bladder capacity significantly. Histology of bladder tissue revealed that the bladder compliance was in the normal range. Seromuscular grafts replacing the traditional gastrointestinal segments used for bladder augmentation was another attempted approach. In preclinical models, seromuscular flaps used for bladder augmentation revealed normal re-epithelialization, but the tissue experienced significant shrinkage that severely limited the clinical feasibility of the technique. Using de-epithelialized segments over native tissue was also attempted and revealed little success. In recent years, seromuscular grafts have mostly been abandoned. Extracellular matrices and synthetic grafts for bladder repair have been used to encourage growth of bladder wall segments for partial bladder repair in vivo. These matrices are prepared by mechanical and chemical treatment of native tissue from allogenic or xenogenic donors to remove all the cellular components. In preclinical models of bladder augmentation, small intestine submucosa resulted in bladder wall regeneration in vivo. Bladder repair was shown to be more stabilized when small intestine submucosa was gained from distal ileum.
Regenerative Medicine Strategies Involving Biomaterials
Biomaterials used in regenerative medicine are constructed to support restoration of biological properties of original tissue. Biomaterials may act as a carrier for transplanted cells and provide support for structured tissue formation by endogenous cells. Biomaterials may be synthetic materials, or they may be derived from natural substances. In some instances, both techniques are used. Tissue matrices from naturally derived materials are considered to have biological properties that can mimic native tissue or organ extracellular matrices. Synthetic polymers, naturally derived materials, and acellular tissue matrices are the three primary classes of biomaterials that may be used in regenerative medicine therapies for the bladder and other organs. On the other hand, synthetic scaffolds can be produced on a large scale with controlled properties of strength, microstructure, and degradation rate.
One advantage to using biomaterials is that they can physically control where and when injected cell suspensions localize in the body. Biomaterials can also provide guidance for appropriate development of new tissues. Furthermore, biomaterials are specially designed as artificial extracellular matrices that can deliver growth factor signals to regulate and improve cellular function.
Regenerative Medicine Strategies Involving Cells
Researchers can isolate cells from several sources. Some cells, autologous cells, are isolated from the recipient of the regenerative medicine procedure. In contrast, cells derived from any other human being besides the recipient are allogeneic. Cells obtained from nonhuman origins are called xenogeneic cells. Cells can be applied in different physical states. Cells can be administered in a suspension or attached to a support matrix. The goal of the chosen approach is to repair the tissue and organs with the most native outcome and the fewest complications. One benefit to using autologous homologous cells is rejection is generally not an issue and so avoids the use of immunosuppressant therapies. The cells are also re-implanted into a homologous tissue. When planning regenerative medicine approaches, researchers must consider the condition of the tissue or organ to be replaced. In some cases, diseased organs may not provide suitable cells for regenerative medicine techniques either because of expansion problems or innate qualities that are incompatible with the type of healing process required. For example, re-introducing malignant cells into a scaffold designed to replace tissue or organs removed for cancer treatment would not be a desirable strategy. In some disease states, genetically normal progenitor cells live in the tissue and are reservoirs for new cell formation. These normal progenitor cells are programmed to give rise to normal tissue even if they may reside in a diseased environment. In regenerative medicine, tissue and organ-resident progenitor cells remain a very promising area of ongoing investigation and research.
Regenerative Medicine Strategies Using Progenitor and Stem Cells
The two important characteristics for cells in regenerative medicine therapies are the potential for self-renewal and differentiation. Cells limited in their capacity for self-renewal divide in culture for a finite number of passages. In contrast, cells with unlimited self-renewal may be grown in culture for extended times. Cell differentiation potential can be unipotent, multipotent, or pluripotent. Unipotent cells keep their phenotype. In the bladder, urothelial and bladder smooth-muscle progenitor cells isolated from bladder biopsies are unipotent. Multipotent cells are able to be guided into several phenotypes depending on culture conditions, but the range of possible phenotypic outcomes is more restricted. Bone marrow adipose tissue is a common source of multipotent progenitor cells. These cells can be turned into chondrocytes, adipocytes, or smooth-muscle differentiation pathways. Pluripotent cells have unlimited differentiation potential. Pluripotent cells can become virtually any cell in the body. An example of pluripotent cells are embryonic stem cells. Autologous homologous cells are typically progenitor cells and are usually preferred for regenerative medicine techniques. Sometimes, heterologous cells are used in situations when autologous cells cannot yet be expanded from a particular tissue, such as the pancreas, or are otherwise unavailable for expansion (total-bladder replacements for bladder cancer patients).
Researchers have invested a great deal of time and energy looking into pluripotent stem cells, because of their unlimited self-renewal and plasticity. However, clinical applications remain limited. Pluripotent stem cells are generally allogeneic, and there is a possibility to create immune responses when using them. Furthermore, issues persist with using embryonic stem cells and controlling localization and phenotype for the specific time frames needed for regenerative medicine and tissue-engineering processes. Embryonic stem cells can also form teratomas, which further complicate their implication into clinical procedures. Developers of products using embryonic stem cells will need to address these issues when seeking regulatory approval. Last, many countries have limited or banned clinical use of embryonic cells, because of ethical concerns.
Multiple preclinical studies have demonstrated that bladder implants with progenitor cells elicited superior structure and function when compared with cell-free implants.
Regenerative Medicine Techniques Using Cells Derived From Cloning Techniques
Somatic cell nuclear transfer (SCNT) is being researched as another possible source of pluripotent stem cells for regenerative medicine treatment of the bladder. SCNT involves implanting a nucleus from a donor somatic cell into an unfertilized oocyte and generating embryonic stem cells from the merging of donor genetic material and oocyte cytoplasm. SCNT is different from reproductive cloning in that cells from a SCNT procedure are generally allowed to develop into a blastocyst that is implanted into a pseudopregnant female, giving rise to a baby that is genetically identical to the donor of the nucleus. In regenerative medicine, cells from a SCNT procedure are propagated in cell culture and not as implantable embryos.
In conclusion, there exist a wide variety of regenerative medicine strategies and techniques for the treatment of the human bladder. Current research focuses on the expansion of existing techniques. Further studies may analyze the effectiveness of generated bladders in the long term. Longitudinal studies may prove useful in providing clinicians with effective and safe treatments.
Krishna S. Vyas
University of Kentucky College of Medicine
Shalin Jyotishi
University of Georgia
See Also: Bladder: Stem and Progenitor Cells in Adults; Neural: Development