The mechanical environment in which a cell finds itself can have a significant impact on its development. Understanding precisely how mechanical forces can be harnessed to direct the fate of a cell is an area of intense research, with tissue engineering heralded as a potential means to treat disease and injury. In a recent review published in Stem Cell Research & Therapy, Christopher O’Conor, Natasha Case and Farshid Guilak from Duke University Medical Center, USA focus on the latest findings into how mechanical stimuli may be used to produce and enhance tissue engineered cartilage replacements for the treatment of osteoarthritis and other articular cartilage diseases. These replacements need to meet several demands that are placed on diarthriodial joints such as the hip and knee joints. Not only must they withstand the stresses of the mechanical environment but they must also distribute loads across the surface of the joint and allow for a near frictionless movement across the tissue surface during joint articulation. In an effort to meet these demands, new avenues of research have opened up, such as the use of multifactorial bioreactors and the roles of individual biophysical factors. Christopher O’Conor explains more about this growing field and the insights drawn from their review.
What is the ultimate goal of this area of research?
The end goal is to develop a cell-based cartilage replacement therapy that can delay or prevent the need for joint replacement surgery. Joint replacements are very effective treatments for osteoarthritis, however these replacements typically last in the order of 15 to 20 years, and revisions can be complicated and carry additional risks. Therefore, tissue engineered cartilage replacement strategies would be an ideal strategy to delay or avoid joint replacement surgery altogether, particularly for younger and more active patients who will outlive currently available artificial joints.
How would findings from this field of research impact on health, and the economic costs of osteoarthritis and other cartilage diseases?
Osteoarthritis (OA) is one of the leading causes of morbidity in the US and abroad due to the pain and loss of mobility associated with the disease. It affects around 630 million people worldwide and is most commonly associated with aging. As people are living longer, there is a growing opportunity to both improve quality of life for millions of people as well as to significantly reduce health care costs by improving osteoarthritis treatments and outcomes. There are also a number of other significant risk factors for OA aside from aging, including obesity, joint trauma (Anterior cruciate ligament (ACL) and meniscal tears), and overuse.
Specifically in the context of the worldwide obesity epidemic, the burden of OA is only expected to increase. In addition, OA and cartilage focal defects that occur in the younger patient population (30s, 40s and 50s) often occurs following joint injury, such as ACL or meniscal tears. It is this younger patient population that would likely benefit the most from cartilage tissue engineering, where it could have the potential to both improve outcomes and allow patients to return to work and other daily activities.
What specific factors need to be considered to produce an effective and stable cartilage tissue replacement from mesenchymal stem cells?
Chondrogenic differentiation of mesenchymal stem cells (MSCs) is a complex process that is still not fully understood. However, generally speaking, we know that stem cell differentiation is influenced by both chemical signals, such as growth factors and cytokines, as well as physical factors, such as the stiffness of the cells physical environment and mechanical stimulation. Chondrogenically differentiated stem cells need to elaborate an extracellular matrix that in combination with any scaffold or other support will perform the mechanical function of the cartilage it is meant to replace. The ideal timing and cocktail of growth factors needed to sufficiently differentiate stem cells into chondrocyte-like cells capable of producing this functional tissue is still be investigated. Furthermore, it is important that the implanted cells stay differentiated once implanted, and do not return to a de-differentiated state or continue through a hypertrophic pathway, which chondrogenically differentiated MSCs typically do during events such as fracture healing. The purpose of this review is to put into context all of the latest findings on how mechanical factors may be able to participate in enhancing and maintaining this differentiated cellular state.
You mention that some researchers are working on models that mimic the forces imposed on joints in vivo. What are the challenges of developing such a model and do you think a realistic model is achievable?
Creating an in vitro environment that precisely recreates all of the biophysical factors that exist in the joint is highly challenging due to the multitude and complexity of these many factors. Engineering a device that could impart all of these forces in controlled manner would be a technical challenge to build and program. However, the latest work in the field has shown that when multiple stimuli are integrated, such as shear plus compression, you can elicit a more chondrogenic response then with either alone. It remains to be seen if adding even more factors to a bioreactor like this, such as osmotic or hydrostatic pressurization or fluid flow, could drive an even stronger chondrogenic phenotype.
You mention a number of potential avenues for further research. Which do you think are the mostly likely to provide the most important or useful insights?
We are very interested in understanding at a mechanistic level mechanotransduction pathways that participate in both chondrogenic differentiation as well as extracellular matrix production. This would allow for both more predicable approaches to tissue engineering, as well as potentially identify novel pathways involved in cartilage mechanoregulation that could then be tested as pharmacologic targets. In the more general area of chondrogenically differentiated stem cells, induced pluriopotent stem cells appear to be an important and emerging enabling technology for this type of research, giving researchers a virtually unlimited supply of chondrogenically-capable cells. This will hopefully lead to, among other things, improved in vitro tissue and disease modeling, which we could use for further understanding cartilage mechanotransduction, as well as high throughput therapeutic drug screening, and even potentially a large pool of autologous pluripotent stem cells for tissue regeneration.
How far away in terms of years do you think this field is from achieving cell-based cartilage replacement therapy?
Autologous chondrocyte implantation, where chondrocytes are removed from a non-weight bearing location, expanded, and placed back into a focal defect, is currently approved and performed in a number of countries. However, the efficacy of these types of treatments still needs to be evaluated. In terms of stem-cell based therapies for articular cartilage replacement, it would not be surprising to see a stem-cell based therapeutic intended for the treatment of OA being submitted to regulators in the next five to ten years. However, it is important to remember that there are further steps in most countries, including animal models, safety, and efficacy, that need to be passed before regulatory approval and clinical adoption.