Armin Arshi, medical student, performs a cell culture under the watchful eyes of Natalie L. Leong, MD (center), and bioengineering graduate student Azadeh Nazemi (right).
Courtesy of OREF


Published 1/1/2015
Catherine Rategan

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, and as many as 175,000 of those cases require surgery.

Natalie L. Leong, MD, a resident in the Department of Orthopaedic Surgery at the University of California, Los Angeles, has an interest in sports medicine, particularly those clinical problems that disproportionately affect women, such as ACL rupture. 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.

Under the guidance of her mentor, David McAllister, MD, chief of sports medicine service and professor of orthopaedic surgery at UCLA, Dr. Leong hypothesized that constructs seeded with human foreskin fibroblasts would have superior biologic and biomechanical properties as measured through histology and mechanical testing.

Favorable in vivo data are a prerequisite to human trials and eventual approval for use in ACL reconstruction surgery. The success of this 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.

If approved, this new treatment strategy would not require autograft (with possible donor-site morbidity) or allograft tendons (with possible supply constraints or disease transmission). Moreover, the project could help avoid issues of wear and chronic inflammation that arise when synthetic materials are used as ACL substitutes.

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 uses fibroblasts derived from foreskin tissue because they are similar to the collagen-producing fibroblasts found in healthy ACLs.

Additional applications
The basic tendon and ligament engineering strategies developed and evaluated in Dr. Leong’s project can be applied to rotator-cuff injuries in the shoulder, quadriceps and patellar tendon ruptures in the knee, and many other common connective tissue problems.

Armin Arshi, medical student, performs a cell culture under the watchful eyes of Natalie L. Leong, MD (center), and bioengineering graduate student Azadeh Nazemi (right).
Courtesy of OREF
Dr. Natalie Leong inspects a histology slide while testing her theory that tissue-engineered ACL 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.
Courtesy of OREF

Research funding for better treatment options
Patients have a strong interest in ACL treatment alternatives, according to Dr. Leong.

“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.”

Dr. Leong 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. OREF also doesn’t restrict funding based on the type of orthopaedic research. 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.”

Dr. Leong is also grateful that OREF funding enables her to write manuscripts and present her work at conferences such as the Orthopaedic Research Society and AAOS Annual Meetings. “I can meet people who are interested in our research and collaborate with them to develop new ideas,” she said.

For Dr. Leong, research also brings substantial personal rewards. “It’s very rewarding 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.”

Catherine Rategan is a contributing writer for OREF and can be reached at


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  2. Matava MJ,. Boden BP, eds: AOSSM initiates multi-center ACL revision study. Sports Medicine Update 2005:5.