As individuals grow older and lead more active lifestyles, orthopaedic surgeons are increasingly being called on to use their surgical techniques to improve patients’ quality of life. Earlier solutions to orthopaedic disorders required the use of instrumentation to improve the mechanical environment for orthopaedic tissues. Newer research has aimed to improve the biologic environment for healing.

One area that has shown a promising future is the use of stem cells to regenerate or repair tissues. This article will briefly review the science of stem cells and current research using these cells.

Basic science
Stem cells, in broad terms, are any cells that can self-replicate and differentiate into any cell line in the body. Stem cells may be pluripotent (able to differentiate into any tissue type), or multipotent (able to differentiate into limited tissue types). The three main sources of stem cells are embryos, adults, and umbilical cords.

In general, embryonic stem cells are pluripotent, and adult or umbilical cord stem cells are multipotent. Mesenchymal stem cells (MSC) are nonhematopoietic cells, derived from the mesoderm layer of humans, that are generally committed to differentiating into muscle, bone, ligaments, tendons, fat, etc. Depending on their environment, MSCs can differentiate into a variety of cell lineages. Most orthopaedic research has been conducted using adult MSCs to treat musculoskeletal disorders.

Fracture healing
Fracture healing occurs through an organized process in which osteoblasts lay down bone that is reorganized by osteoclasts. In certain traumatic situations, the defects are extensive and cannot be healed via the normal biologic process.

Several researchers have been able to isolate and purify MSCs from bone marrow and use them to heal these defects. Autologous MSCs have been used to heal segmental defects (> 4 cm) in limited numbers of patients,¹ and critically sized femoral defects in rats have been healed using transplanted rat bone marrow-derived cells with bone morphogenetic protein.²

Intervertebral disk
Disorders of the back result in significant morbidity and loss of productivity to our society. Most therapeutic solutions rely on conservative or nonsurgical treatment. In certain situations, removal of the degenerated intervertebral disk (IVD) and fusion can lead to a successful result.

Understanding the causes of degeneration and developing treatments to regenerate the IVD may help prevent these problems. When autologous MSCs were transplanted into a rabbit model of degenerative disk disease, the treated rabbits achieved 91 percent of the height of their disks 24 weeks after transplantation; the control group achieved only 67 percent of disk height. Laboratory analysis also demonstrated the restoration of proteoglycans accumulation.³ Research in using this technology for humans has been limited thus far.

Sports medicine
Injuries related to disruption of ligaments or tendons are common and can result in significant morbidity to the active individual. The healing of these disrupted tissues results in an inferior-quality tissue. Cell-based therapy is actively being investigated as a new method of treating these injuries.

MSCs transplanted into a 1-cm defect within a rabbit Achilles tendon resulted in greater cross-sectional surface area as well as better-aligned collagen tissue when compared to controls.⁴

MSCs have also been studied in the repair of meniscal injuries. Tears in the inner third of the avascular region of the meniscus have a limited capability to heal. Scientists have been employing a broad-based strategy to repair these defects. A recent study found that MSCs transplanted into this region of the meniscus in a pig can result in tissue with better bonding capabilities.⁵ New studies are beginning to examine whether these same techniques can be used to improve the results of human meniscal repair.

Federal and state research funding
Much of the research being conducted on stem cells occurs in private institutions or public universities that do not rely on federal funding. In 2001, President Bush signed legislation that prohibited destroying embryos to obtain stem cells. The legislation did allow for continued research on embryonic cell lines that were obtained prior to 2001 that were held at the National Institutes of Health. In addition, the legislation allowed for continued federal funding on cell lines from umbilical cord, placenta, adults, and animals.⁶

Although Congress attempted to overturn this policy in both 2006 and 2007 by passing legislation allowing for federally funded research on stem cells, both bills were vetoed by the president.

Some states have appropriated funds for conducting research on stem cells. California has taken the most advanced position. In 2004, Californians approved Proposition 71, which allocated $295 million a year for 10 years for grants to conduct research on cell lines obtained from 5-day-old embryos.

Although other states have similar proposals on the table, none has received as broad approval as the California position. In Massachusetts, the governor recently proposed a plan for raising $1.25 billion to fund research within the state. The governors of New York and New Jersey also have similar proposals.⁷

As we orthopaedic surgeons attempt to improve patients’ quality of life, we will need to expand the techniques we use. In the past, surgeons used a combination of instrumentation and surgical technique to maximize results. As we improve our understanding of the biology of degenerative processes, we may turn to newer agents and sophisticated techniques to improve both outcomes and quality of life.

The Washington Health Policy Fellows include Ryan M. Nunley, MD; Alok D. Sharan, MD; Samir Mehta, MD; James W. Genuario, MD; Aaron Covey, MD; Sharat K. Kusuma, MD; Anil Ranawat, MD; John Flint, MD; and Alex Jahangir, MD.

References

1. Quarto R, Mastrogiacomo M, Cancedda T, et al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N Eng J Med 2001; 344: 385-6.
2. Leiberman JR, Le LQ, Wu L, et al. Regional Gene Therapy with a BMP-2 producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. J Orthop Res 1998; 16:330-9.
3. Sakai D, Mochida J, Iwashina T, et al: Regenerative effects of transplanting mesenchymal stem cells embedded in atelocollagen to the degenerated intervertebral disc. Biomaterials 27: 335–345, 2006
4. Young RG, Butler DL, Weber W, et al. Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair. J Orthop Res 1998;16:406-13.
5. Dutton A, Hui JPP, Lee EH, Goh J. Enhancement of meniscal repair using Mesenchymal stem cells in a porcine model. Procs 5th Combined Meeting of the Orthopaedic Research Societies of USA, Canada, Japan & Europe, 2004.
6. http://stemcells.nih.gov/policy
7. “Massachusetts Proposes Stem Cell Research Grants.” New York Times 9 May 2007.

Did you know?

• 5: The number of states that have established independent funding for embryonic stem cell research (New Jersey, California, Connecticut, Illinois, Maryland)
• 21: The number of independent, fully developed stem cell lines available for distribution at the NIH
• 23: The number of nations that permit some type of research on embryonic stem cells (excludes the United States)
• 1998: The year that Dr. James Thomson from the University of Wisconsin, Madison, was able to isolate the first human embryonic stem cell