Research topic: Investigating whether biodegradable polymer scaffolds enhanced with cells and growth factors are a viable option for developing ACL reconstruction grafts
Research results: Data that support the use of tissue-engineered grafts in ACL reconstruction
Patient care application of results: Tissue-engineered grafts that would allow orthopaedic surgeons to reconstruct the ACL without the disadvantages of autografts or allografts.
Simplified patient care application: Better grafting options with fewer risks for patients undergoing treatment for ACL disruptions.
Reconstructing the ACL
OREF-funded study looks at a novel tissue-engineered graft
The anterior cruciate ligament (ACL) is a major stabilizer of the knee, enabling not only sports activities but also many of the activities of daily living. More than 200,000 patients are diagnosed each year in the United States with ACL disruptions.1 As many as 175,000 of those cases require surgery.
Natalie L. Leong, MD, is a resident in the Department of Orthopaedic Surgery at the University of California, Los Angeles. In 2013, she received an Orthopaedic Research and Education Foundation (OREF) Resident Clinician Scientist Training Grant to design and evaluate novel tissue-engineered ACL constructs in an in vivo rat model. Dr. Leong hypothesized that constructs seeded with human foreskin fibroblasts—treated with basic fibroblast growth factor and conditioned with mechanical loading in the in vivo setting—would have superior biologic and biomechanical properties as measured through histology and mechanical testing.
The success of this project could lead to developing a new treatment strategy for ACL reconstruction that does not require the use of autografts (with possible donor-site morbidity) or the use of allografts (with possible supply constraints or disease transmission). Moreover, the project could help translate current technologies in tissue engineering to the operating room by bringing a polymer scaffold augmented with human cells and growth factor into use in ACL reconstruction surgery.
Working with tissue-engineered grafts
Describing her research, Dr. Leong said, “My OREF grant allowed me to investigate a novel tissue-engineered graft for ACL replacement. We started with an electrospun polymer, and then added human foreskin fibroblasts along with growth factor. We implanted these grafts into rat knees and grew them for several months. Then we tested them for mechanical properties and looked at histology to see how close we were to native ligament.”
Dr. Leong and her research team obtain human foreskin fibroblasts from cell banks that meet stringent regulatory standards. She said that she uses ligament fibroblasts derived from foreskin tissue because they are similar to the collagen-producing fibrolasts found in healthy ACLs.
Favorable in vivo data are a prerequisite to human trials and eventual approval for use in ACL reconstruction surgery. If approved, the procedure would represent a new treatment option for ACL rupture patients that would circumvent the concerns of donor site morbidity or the use of cadaver tissue. It would also avoid issues of wear and chronic inflammation when synthetic materials are used as ACL substitutes.
This study would directly benefit sports medicine surgeons and arthroscopy specialists. Strategies derived from this line of study could be directly applied to the development of a tissue-engineered ACL grafts that could be used in reconstruction surgery without disadvantages that come with autografts or cadaver allografts.
In addition, the basic tendon and ligament engineering strategies developed and evaluated in this project can be applied to rotator-cuff injuries in the shoulder, quadriceps and patellar tendon ruptures in the knee, and in many other common connective tissue problems.
Research funding for better treatment options
Dr. Leong has long had an interest in sports medicine, with particular focus on clinical problems that disproportionately affect women, such as ACL rupture. She also cites the strong patient interest in ACL. “Patients come to sports medicine clinics asking about their options,” she said. “I have to tell them, ‘Right now, the options are an autograft, which means harvesting your own tissues; your other option is an allograft.’ But patients often balk at the idea of cadaver tissue in their knee. So they keep asking whether there’s anything beyond that on the horizon. I tell them we’re working on all these things in the lab, and I hope that someday there will be other options available.”
She also appreciates the funding that makes her research possible. “OREF is unique in the way it funds new researchers, even those at the resident level like me. Also OREF doesn’t restrict funding based on what type of research you’re doing in orthopaedic surgery. It supports many different avenues of investigation.”
She continued, “Without OREF grants, it would have been impossible to do the substantial amount of work we’ve done so far. Animal surgery is very expensive, but the grant allows us to plan experiments without as many resource limitations.” She’s also grateful that OREF funding allows her to write manuscripts and present her work at conferences such as the Orthopaedic Research Society and AAOS Annual Meetings. “That’s where I can meet people who are interested in our research and collaborate with them to develop new ideas.
For Dr. Leong, research also brings substantial personal rewards. “It’s the best feeling in the world when you have a hypothesis, you do the research, and the data actually work out. There are so many disappointments in research; it takes so much effort, so many tries. When something actually works and makes sense, it’s great to know that it will eventually translate into helping patients.”
1Fetto, J.F. and J.L. Marshall, The natural history and diagnosis of anterior cruciate ligament insufficiency. Clin Orthop. 1980(147): p. 29-38.
2Matava MJ. Boden BP, eds. AOSSM initiates multi-center ACL revision study. Sports Medicine Update 2005:5. Available from: http://www.sportsmed.org/tabs/resources/smupdate.aspx. Accessed September 2012.