Regenerative Medicine Meets Gynecology

Elizabeth A. McGee., M.D.

Regenerative medicine is a relatively new term generally applied to the multidisciplinary approach to disease management encompassing tissue and organ culture, bioengineering, and the use of natural and engineered tissues to repair or regenerate human tissues or to enhance function of existing tissues or organs. Discussion of regenerative medicine typically leads to mention of artificial livers, heart bypass pumps, or limb regeneration. However, gynecology is also rich with examples of modern regenerative medicine. The lives of some our patients are even now being touched by these new technologies, and the future of patient-specific stem cell therapies, organ culture, sperm sorting, egg selection, and even organ repair and replacement with bioengineered tissues is no longer only in the realm of science fiction.

The acquisition of male and female gametes is a major part of modern fertility techniques. Germ cell culture and manipulation is also critical for successful fertility treatments. Although artificial reproductive technologies have been used in patients since Steptoe and Edwards and the birth of Louise Brown, there are many limitations and consequences of in vitro fertilization (IVF). Improved gamete microculture and facilitation of healthy germ cell selection will begin to ameliorate some of these problems. If healthy eggs and sperm can be more readily identified and embryos can be effectively evaluated noninvasively, then single embryo transfers become much more accessible and acceptable to infertility patients. Thus reducing or eliminating the dire consequences of multiple gestations as well as reducing the incidence of pregnancy loss due to embryo or egg quality issues becomes feasible. Gary Smith and colleagues introduce a fascinating microfluidics culture system in the first article in this issue that has great potential to fill these needs. The possibility of “ART lab-on-a-Chip” is very real and may advance the IVF field enormously with better gamete handling as well as new platforms for research of embryo secretome applications for reproductive biology.

In vitro culture of intact ovarian follicles has been studied for > 20 years, and investigators have continued to use several different organ culture techniques to try to produce mature oocytes from immature follicles from many species. Eppig reported live birth from in vitro–derived mouse oocytes in 1989 and Spears in 1994. In this issue, Marie McLaughlin and Evelyn Telfer review the two decades of progress in this field and also describes their major advances in culturing human follicles. There are special challenges in the culture of species with larger follicles than mice, and this article describes a multistep process to address stage-specific requirements of folliculogenesis.

The endgame of folliculogenesis is the production of a healthy mature oocyte. Smitz and colleagues have described a new approach to in vitro oocyte maturation of the immature oocytes that are often obtained during IVF procedures. Their approach centers on slowing down nuclear maturation and focusing on the synchronous maturation of both the nucleus and cytoplasm, and it recognizes a key role for the cumulus complex in the process.

As regenerative medicine techniques are increasingly applied to assisted reproductive techniques, gametogenesis, and reproductive biology, there will likely be new, safer ways to treat female infertility as well as to preserve fertility in patients with cancer and autoimmune diseases.

In the near future our patients will also have access to improved alternatives for tissues for vaginal repairs and neovaginal construction as well as bladder reconstruction. Vaginal repair tissues and techniques are described in articles by Dr. DeFilippo and Dr. Panici and their respective colleagues. In the first article a description of a novel bioresorbable scaffold for expanding mucosal tissues is discussed and the histological properties of these engineered replacements are extensively described and compared with normal vaginal mucosa. In vivo studies demonstrated excellent long-term survival of these vaginal replacements with biomechanical properties comparable with native vaginal tissues as well as the presence of an intact neurotransmitter pathway.

Dr. Panici et al review the condition of vaginal agenesis and the many types of repairs and tissues that have historically been used to create neovaginas. They also describe their group's successful use of a biopsy of vaginal mucosa with dispersion and expansion in cell culture followed by mounting the resulting cultured tissue on a hyaluronic acid–embedded gauze for use with a classical McIndoe mold in the creation of a neovagina in a patient. Although further studies of long-term survival of vaginal replacement and characterization of the properties of these various replacement tissues are going to be necessary, these two reports make it clear that the time of using intestinal mucosa or skin grafts for vaginal replacement may be passing rapidly. These new methods of vaginal replacement also have great possibilities for applications in repair or replacement of both congenital malformations and diseased vaginal tissues.

In the article that follows, Del Priore and colleagues describe the body of work in animal models of uterine transplant and also the technical and ethical challenges in moving toward uterine replacement treatments for humans.

In the final selection in this issue, Nikolavasky and colleagues describe their very exciting use of patient-specific adult stem cells to treat urinary incontinence. Autologous muscle–derived stem cells can be obtained from a simple muscle biopsy of the patient. The biopsy is sent to a laboratory for expansion and selection of the muscle-derived stem cells, which are subsequently injected back into the patient's midurethral region of the rhabdosphincter. Initial studies were very encouraging in the restoration of continence, and multicenter trials of this minimally invasive approach to treating stress incontinence are ongoing.

These articles are just a sample of the diverse body of work applying regenerative medicine principles to gynecologic problems. The world of artificial organs and in vitro solutions for human disease is only just beginning. The ethical and logistical need to keep up with technology will be accelerating as the science progresses. Although these emerging technologies have great potential to alleviate suffering and diminish disease effects, gynecologists need to be aware of the advancements to incorporate them safely and acceptably into clinical practice. Clinicians need to be ready to answer their patients' questions and also participate in the ongoing discussions of ethics, patient needs, and acceptable use that will inevitably follow these technological advancements.