Putting science into practice earns Young Investigator Award for Chu
By Sally Chapralis
The 2007 Kappa Delta Young Investigator Award has been presented to Constance R. Chu, MD, of the department of orthopaedic surgery at the University of Pittsburgh, for her manuscript, “Integrating Bench to Operating Room: Journey of a Clinician-Scientist.”
Dr. Chu’s paper explains how her efforts as a clinician scientist have had a direct impact on the clinical practice of orthopaedic surgery, particularly in the identification and treatment of osteochondral defects.
Moving between the orthopaedic and scientific communities has enabled Dr. Chu to, as she said, “approach new technologies both as someone who understands [their] laboratory applications and as a potential clinical end-user.” Her manuscript outlines how she used this understanding and flexibility to apply a novel imaging technology—optical coherence tomography (OCT)—to arthroscopic evaluation of articular cartilage.
Dr. Chu’s scientific and clinical interest in arthroscopic OCT is the latest step in her ongoing research into the preservation of articular cartilage and chondrocyte viability.
“The quest for a biologic solution to joint replacement led me to study cartilage homeostasis at cellular and molecular levels, to develop new scaffolds for cartilage repair and to genetically engineer bone marrow stem cells for mechanistic in vivo study of chondrogenesis,” she wrote. “In turn, lessons learned from and collaborations with basic scientists specializing in these areas permitted me to answer clinically driven questions.”
This first investigation increased the understanding of cell-polymer constructs and the effects of perichondrial cells seeded with porous polylactic acid scaffolds both in vitro and in vivo. Further clinical study of fresh osteochondral allografts contributed to their use for treatment of focal cartilage defects.
Other studies (in which Dr. Chu served as principal or co-principal investigator) focused on maintaining optimal chondrocyte viability during cold storage. Because cold storage and pH changes increased chondrocyte necrosis and apoptosis, the shelf life of commercial allografts has been reduced to 30 days. In addition, transplanting fresh osteochondral allografts is now recommended to take place as soon as possible after microbial studies have been completed.
Another study addressed the issue of oxidative stress. It found that “loss of the articular surface through injury or degeneration alters the physiological oxygen gradient and disturbs chondrocyte homeostatis, especially in the deeper zones of articular cartilage.” As a result of these findings, new therapies could “protect deep zone chondrocytes from oxidative stress….restore homeostatis and delay progressive cartilage loss.”
Dr. Chu and her colleagues then addressed radiofrequency energy (RFE) probes and thermal stress. They showed that the radiofrequency probe setting, speed and distance to the articular cartilage changed the biological effects of these instruments, thus suggesting the importance of both probe design and surgical technique.
The results of these translational studies were used by several RFE probe manufacturers “to modify [and improve] probe design and treatment protocols to fall within temperature ranges and probe use techniques shown in our work to permit chondrocyte survival and recovery of metabolic function.”
Dr. Chu also led studies that addressed the chondrotoxicity of bupivacaine and contributed to the abandonment of routine continuous infusion protocols and intra-articular use of 0.5 percent bupivacaine. Because current methodologies may not be sensitive enough to detect early stage chondrocyte loss and cartilage degeneration, she then evaluated a prototype handheld confocal microscopy. Research revealed the “potential use of confocal microscopy in the operating room for cellular imaging heretofore possible only in the laboratory.”
Improving cartilage repair
In conjunction with efforts at chondroprotection, Dr. Chu continued work on improving “the cartilage repair potential of bone marrow cells with the long-term goal of enhancing in vivo cartilage repair.” Research on the TGF-b1 and chondrogenesis of human bone marrow stem cells (hBMSC) increased researchers’ understanding of its application.
Using a novel polyethylene glycol crosslined with genipin (PEG-genipin) resulted in a “smart polymer” that could be used for controlled in vivo release of growth factors. The study also demonstrated that the degradation of the smart polymer release system within osteochondral defects could be controlled by changing the concentration of genepin.
By 2003, this research led Dr. Chu to investigate the use of optical coherence tomography. This new imaging technology—initially introduced to image the eye—offered “nondestructive optical biopsies that are similar to low-power histology without touching or damaging the [articular cartilage] tissue.”
In considering clinical applications, Dr. Chu wanted to develop an OCT probe that could be used with an arthroscope. First, she and her colleagues assembled a handheld OCT probe that could be sterilized and inserted into joints to permit real-time cross-sectional imaging. Once the in vivo application to porcine articular cartilage proved effective, Dr. Chu studied its use in human joints to “determine whether OCT images of human cartilage could be acquired arthroscopically and whether the resulting images correlated with histopathology.”
Research, which included identification of a unique banding pattern called cartilage OCT form birefringence, demonstrated that OCT did identify “early structural changes in human cartilage with intact articular surfaces that were predictive of early metabolic changes that have been implicated in the pathogenesis of osteoarthritis.” Subsequent independent data confirmed that OCT scanning and grading are reproducible.
Dr. Chu’s first clinical in vivo arthroscopic OCT (Imalux) “was for in situ evaluation of an autologous chondrocyle implantation (ACI) graft after knee trauma.” The research, examinations and subsequent findings “show that OCT can be used arthroscopically in the clinical setting to identify details of cartilage surface topography and cartilage OCT form birefringence previously demonstrated in the laboratory to be predictive of early dengneration.” The process also “illustrates the central role of the clinician scientist as a vital link between new discoveries and the patient.”
As a result of her studies, it is evident that OCT has the potential to enhance the sensitivity and specificity of arthroscopic diagnosis of early cartilage degenerative processes in the clinical setting. “Because we also showed that these early metabolic changes are potentially reversible,” wrote Dr. Chu, “this diagnostic potential may have profound clinical implications for efforts to prevent or delay the onset of osteoarthritis through early disease-modifying treatments.”
Dr. Chu has received her first National Institutes of Health (NIH) R01 Research Project Grant to complete a 5-year translational project for this purpose. As principal investigator, she received funding from the NIH, the Department of Defense, the Arthritis Foundation, the Pittsburgh Foundation, the Pittsburgh Tissue Engineering Initiatives, and the University of Pittsburgh’s Competitive Medical Research Fund.