Orthopaedic Research Activities
Our mission is to inspire colleagues to create new knowledge, to communicate knowledge through medical education, and to provide superior and compassionate health care in a collegial atmosphere. Basic, clinical and translational research in Orthopaedic science is an integrated part of our graduate medical education. Thus, in addition to the clinical and educational commitments, our faculty is actively involved in a broad range of research on bone and musculoskeletal diseases, which have been highlighted in the following areas.
The Orthopaedic Biomedical Imaging Institute
As the Director of The Orthopaedic Biomedical Imaging Institute at Weiss Memorial Hospital in affiliation with the University of Chicago, Dr. John Martell continues to develop collaborations with implant manufactures and individual investigators. Dr. Martell’s research has been funded by grants from The Harris Foundation, NIH/NIAMS, Smith & Nephew, Stryker, Biomet and Zimmer. The Orthopaedic Biomedical Imaging Institute is known nationally and internationally as a resource for the design and implementation of polyethylene wear studies and has been involved in the analysis of cross-linked polyethylene.
Dr. Martell accommodates requests from academic joint replacement programs to observe the techniques that are used in processing and analyzing films. The Orthopaedic Biomedical Imaging Institute has become a world-class resource for the analysis of polyethylene wear in total hip arthroplasty. The Institute has furthered its commitment to orthopaedic research by sponsoring the Geraldine Mary Maley Research Award, an annual research award for projects developed by faculty/residents in the Section of Orthopaedic Surgery at the University of Chicago or Weiss Memorial Hospital.
Dr. Martell has recently developed several important and innovative biomedical imaging tools. First, mechanical analysis software allows investigators to estimate the joint reaction force and stress in normal and prosthetic hips. Using the joint stress as a predictor variable in combination with patient activity indicators (speed of walking, UCLA score, or pedometer data) he has developed a multiple logistic regression model that can identify patients with total hips that are at risk for high wear and osteolysis in the long term. This model is now 87% accurate and has no false negatives in a series of 300 hips with minimum 8 year follow-up.
Dr. Martell has partnered with Dr. Christian Heisel at Heidelberg University in Germany to investigate the biomechanical factors predisposing women to hip arthritis. Preliminary results show a significantly higher contact stress in the native hips of women patients compared to men. Factors that play a role in this finding are: a wider female pelvis, causing the body weight moment arm to be larger, smaller femoral offset in women and smaller femoral heads, which increases contact stress. Dr. Martell is also working with Dr. William Walters from Australia to investigate the biomechanics of ceramic total hip arthroplasty to identify factors leading to squeaking in ceramic total hip arthroplasty.
As an extension of the mechanical analysis software, Dr. Martell developed preoperative templating software which allows the surgeon to template pre-operatively using knowledge of the impact choices for keyboard, stress and wear performance of the implanted prosthetic hip joint. This identifies reconstructive options that put the patient at risk for high wear, and assists the surgeon in choosing prosthetic position and designs to minimize this significant complication. Another modification of the mechanical analysis software allows the estimation of shear forces in the capitol femoral epiphysis that predispose to slipped capitol femoral epiphysis in children. These shear forces, in conjunction with the skeletal age of the pelvis; have a predictive value of 90% for the risk of SCFE.
Dr Martell has partnered with the Argonne National Laboratories, and has received $20,000 through the BIASE initiative to fund a pilot project to develop a visual-tactile feedback system for use in minimally invasive robotic surgery. Preliminary testing of this video processing image analysis system has shown the capability to detect real time suture strain rates that are 100 times lower than the strain to failure. Work now continues on perfecting the video processing, including and on measuring strains in sutures from archived clinical videos.
Tendon and Ligament Injury Repair
Drs. Daniel Mass, Sherwin Ho, Lewis L. Shi, and Jovito Angeles, in collaboration with Dr. T.-C. He, are investigating possible gene therapy approaches to enhancing tendon and ligament healing using recombinant adenoviral vectors expressing BMPs and/or other biological factors. They have demonstrated that BMP-13 can significantly improve the biomechanical properties of lacerated flexor tendons in a rabbit model while BMP-14 is also shown to significantly improve the biomechanical properties of lacerated flexor tendons in a rabbit model. Based on time-course studies of gene expression after tendon injury, they identified several factors that may work alongside BMP-13 and BMP-14 at different stages of tendon healing. Dr. Lewis L Shi Is also investigating biological factors that may improve the healing of rotator cuff injuries.
Dr. Lewis L Shi is leading an active should research program, with multiple clinical and translational projects. In collaboration with Dr. T.-C. He, he is investigating biological factors that may improve the healing of rotator cuff injuries. He has an on-going IRB approved study examining patients undergoing shoulder arthroscopy, correlating the growth factors of the subacromial milieu to the condition and chronicity of cuff tears. The ultimate goal is to identify potential pharmacologic treatment to augment rotator cuff repairs in human patients.
Dr. Shi is leading several multi-centered shoulder clinical outcome studies. These are prospective randomized control trials studying the optimal methods of treatment for rotator cuff tears, biceps tendonitis, and labrum tears. He is also conducting several studies using the Marketscan, a national insurance claims database, to examine the patterns, complications, and the cost of shoulder surgery in the last decade.
Dr. Shi continues his collaborations with the several prestigious orthopaedic hospitals in China. In this past year he has co-authored several papers in PLoS One and Genet Test Mol Biomarkers on ankylosing spondylitis with investigators in 301 Military Hospital in Beijing. Additionally his work on vascularized fibula graft with the Shanghai Sixth People’s Hospital has generated multiple podium presentations at international conferences and will be published soon.
Foot and Ankle Research
Dr. Brian Toolan has focused on several clinical projects related to foot and ankle disorders. In the past, he studied the effects of acquired flatfoot deformity on tibiotalar contact pressures in a cadaveric model, and performed a follow-up study on the effects of UCBL orthotics and surgical techniques on joint contact characteristics in the same model. Both of these studies were published in Foot & Ankle International. He recently published a retrospective study in Foot & Ankle International comparing lateral column lengthening to a medial calcaneal osteotomy in the treatment of adult acquired flatfoot. He is currently conducted a similar comparison in a prospective clinical study that is currently ongoing. Lastly, he is retrospectively evaluating the results of a new procedure for salvaging malunited ankle fractures with chronic syndesmotic disruption using a distal fibular arthrodesis and soft tissue reconstructions.
In addition to his interests on flatfoot deformity, Dr. Brian Toolan is interested developing a better understanding of ruptured Achilles tendon healing process and potentially developing new means in treating patients with this injury. Achilles tendon ruptures are common injuries and both surgical and non-surgical treatments have frequent complications such as wound dehiscence and re-rupture. Therefore, Dr. Toolan, in collaboration with Drs. He, has used a rat model to investigate the effects of BMP-14 and other factors on Achilles tendon healing, finding a 70% increase in tensile strength at two weeks.
Articular Cartilage Regeneration and Anterior Cruciate Ligament Repair
The Sports Medicine Services, consisting of Drs. Sherwin Ho, Martin Leland, and Richard Kang, has been intensively investigating the biological processes in articular cartilage regeneration, anterior cruciate ligament repair, and rotator cuff tear repair. Articular cartilage has little intrinsic capacity to repair itself after injury, prompting many researchers to explore new methods to facilitate and augment cartilage regeneration. Currently, a variety of approaches have been developed, including chondroplasty, osteochondral transfer procedures (autologous and allograft procedure), microfracture and autologous cultured chondrocyte implant (ACCI). Each of these techniques is useful when utilized in appropriate conditions; however, a significant cohort of patients still fail to achieve good to excellent results even when surgical, pharmacologic and physical therapy are optimal by current standards. These clinical failures suggest that new biologic strategies, including gene therapy, may be a useful adjunct to current treatments to further improve clinical outcome.
Drs. Sherwin Ho, Martin Leland and Richard Kang are investigating the possible use of Sox9 and/or other biofactors to facilitate articular cartilage regeneration. Previously, Drs. T.-C. He and Rex Haydon successfully transduced intervertebral disc cells with Sox9, a transcription factor necessary for chondrogenesis and Type II collagen synthesis. They observed that human degenerative intervertebral disc cells transfected with Sox9 genes led to chondrocyte proliferation with increased production of Type II collagen (Spine 28: 755-763). Currently, Drs. Ho, Leland and Kang are investigating whether exogenous expression of Sox9 in articular cartilage cells or in mesenchymal stem cells will augment articular cartilage repair in a rabbit model. This research has included experiments comparing different man-made scaffolds that can be used to implant these genetically altered cartilage cells back into the host knee defects (J Biomed Mater Res A. 2013, 101(12):3542-50). In addition, Drs. Ho, Leland, and Kang are investigating the potential use of BMP-13 and/or PRP (platelet-rich plasma) for rotator cuff tears using a rat model, as possible treatment options for patellar tendonitis, and a unique approach to rehabilitation following ACL reconstruction surgery.
The Sports Medicine Service has developed a surgical skills laboratory for medical students, residents, and fellows to develop their arthroscopic and minimally-invasive surgical skills using a state-of-the-art virtual reality arthroscopy simulator (MIST) developed by the Spanish aerospace company, GMV based in Madrid, as well as with cadavers. Such virtual and simulated surgery represents important new educational tools for training medical students, residents and fellows. A study to quantitate the learning of these skills was presented at the Arthroscopy Association of North America’s Annual Meeting in San Francisco this year, as well as at the Mid-America Orthopaedic Society’s Annual Meeting in Marcos Island, Florida and has been submitted for publication.
Dr. Reider is also engaged in an ongoing clinical prospective cohort study of possible links between knee proprioception in collegiate soccer and basketball players. Dr. Reider’s previous research has shown that athletes with ACL tears have abnormal proprioception of the knee that returns to normal after ACL reconstruction. The current project prospectively measures proprioception in a large number of healthy athletes to see if those who go on to tear their ACL’s have deficient proprioception prior to the injury. Dr. Reider has also completed a study of degenerative meniscal tears, which has been submitted for publication.
Osteosarcoma is a “Differentiation Disease”
Under the direction of T.-C. He, M.D., Ph.D., Rex C. Haydon, M.D., Ph.D., and Hue H. Luu, M.D. the Molecular Oncology Laboratory has focused on the molecular aspects of bone and soft tissue tumors through collaborations with Drs. Michael A. Simon, and Anthony Montag. They previously found that b-catenin signaling is activated in approximately 70% of human osteosarcoma samples, suggesting that deregulation of b-catenin may play a role in the development of human osteosarcoma. They examined the expression of the S100A6 in human osteosarcoma, and found that approximately 84% of the analyzed osteosarcoma specimens stained positive for S100A6. Thus, their findings suggest that S100A6 may be associated with the pathogenesis of osteosarcoma (International Journal of Cancer 102:338-342; Clin Orthop Relat Res 466: 2060-2070, and Cancer Letters 229: 135-148). More recently, Drs. Haydon, Luu and He found that, while in mesenchymal stem cells BMP-2 and BMP-9 induce osteogenic differentiation, osteosarcoma cells are refractory to BMP-induced bone formation with increased increased cell proliferation, suggesting that blocks to normal BMP-induced differentiation must exist. Downstream targets of the osteogenic BMPs include several key inhibitors of differentiation that are commonly expressed in human tumors. They hypothesize that that osteosarcoma may represent a “disease of differentiation”, possibly caused by the defects in the terminal differentiation pathway of pre-osteoblast and/or osteoblasts (Laboratory Investigation 88:1264-1277; Clinical Orthopaedics and Related Research 466: 2114–2130; Clinical Orthopaedics and Related Research 454: 237-246; Clinical Cancer Research 16; 2235–2245, Clinical Cancer Research 8: 1288-1294). They are attempting to reconstruct osteosarcoma-like cells from mesenchymal stem cells by disrupting the differentiation pathway and enhancing proliferation activity of the progenitors. Consistent with “disease of differentiation” model, generic differentiation agents, such as PPARg agonists and retinoic acids were shown to promote osteogenic differentiation and inhibit osteosarcoma tumor growth (Clinical Cancer Research 16; 2235–2245; PPAR Research 2010: 956427; PLoS ONE 5: e11917).
Drs. He, Haydon and Luu developed a novel orthotopic tumor model for osteosarcoma progression and pulmonary metastasis (Clin Exp Metastasis. 22: 319-329). This model highlights different stages of primary bone tumor progression and the eventual development of pulmonary metastasis. They are currently using this model to investigate several genes for their role in controlling bone tumorigenesis and metastasis. Meanwhile, they have conducted gene profiling analysis of gene expression patterns between non-metastatic and highly metastatic osteosarcoma cells, and have identified several promising candidate genes associated with pulmonary metastasis of osteosarcoma. Further functional characterization of these target genes is currently ongoing (Clinical & Experimental Metastasis 26:599–610). They have recently reported that insulin-like growth factor binding protein 5 (IGFBP5) suppresses tumor growth and metastasis of human osteosarcoma (Oncogene 30(37):3907-17).
Effects of natural products and herbal extracts on cancer cells and stem cell differentiation: As natural products and herbs represent a great deal of resources for drug discovery, we have collaborated with Dr. Chun-Su Yuan of the Tang Center for Herbal Medicine Research and investigated the effect of several herbal products, such as Berberine and ginseng extracts, on cancer growth and proliferation, as well as on stem cell differentiation. Dr. He was one of the PIs on a P01 grant from the NIH to study the role of herbal products in cancer (International Journal of Oncology 32: 975-983; Oncol Rep 22: 943-952; Biol Pharm Bull 32: 1552-1558; Cancer Lett 289: 62-70; Mol Pharmacol 79(2):211-9).
Molecular Biology of Bone Formation
Identification of BMP-9 as the most osteogenic BMP in vitro and in vivo. Although several BMPs (mostly BMP-2 and BMP-7) have been shown to induce bone formation, it is unclear whether the ones currently used represent the most osteogenic BMPs. Through a comprehensive analysis of the 14 types of human BMPs, the He, Haydon, and Luu lab previously demonstrated that BMP-2, BMP-6, and BMP-9 are the most potent osteogenic BMPs in osteoblastic progenitor cells in vitro, which was published in the Journal of Bone and Joint Surgery with over 500 citations so far. They have concluded several rounds of in vivo studies and found that BMP-2, BMP-6 and BMP9 are the most potent osteogenic BMPs at inducing orthotopic bone formation in athymic mice (Gene Theraoy 11: 1312-1320; J Orthop Res 25: 665-677; and Front Biosci 13: 2001-2021). Interestingly, they have also found that osteogenic BMPs can induce adipogenic differentiation of mesenchymal stem cells (Stem Cells and Development 18: 545-559). They have demonstrated that TGFbeta/BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells (J Biol Chem. 285(38): 29588-98.).
To identify potentially important mediators of BMP-induced osteogenic signaling, Drs. He, Haydon and Luu determined the transcriptional differences between three osteogenic BMPs (i.e., BMP2, 6, and 9) and two inhibitory/non-osteogenic BMPs (i.e., BMP3 and 12). Through the microarray analysis in pre-osteoblast progenitor cells, they found that expression level of 203 genes (105 up-regulated and 98 down-regulated) was altered >2-fold upon osteogenic BMP stimulation. Gene ontology analysis revealed that osteogenic BMPs, but not inhibitory/non-osteogenic BMPs, activate genes involved in the proliferation of pre-osteoblast progenitor cells towards osteoblastic differentiation, and simultaneously inhibit myoblast-specific gene expression. Their findings are consistent with the notion that osteogenesis and myogenesis are two divergent processes (Journal of Cellular Biochemistry 90: 1149-1165). The Molecular Oncology Lab identified several potentially signaling mediators of BMP-induced osteogenesis. Several such downstream targets are the Inhibitors of DNA binding/Differentiation helix-loop-helix (a.k.a., Id proteins), Connective Tissue Growth Factor (a.k.a., CTGF), Hey1, and growth hormone. Their studies thus far have demonstrated that both Ids, CTGF, Hey1, and growth hormone play an important role in BMP-9 induced osteogenic signaling (Journal of Biological Chemistry 279: 32941-32949; Journal of Biological Chemistry 279: 55958-55968; Journal of Biological Chemistry 284: 649-659; and J Bone Miner Res. 2012, 27(7):1566-75).
Role of Wnt/b-catenin signaling in osteogenic differentiation of mesenchymal stem cells: The He, Haydon and Luu group previously demonstrated that Wnt/beta-catenin signaling is de-regulated in over 70% of human osteosarcomas. He, Haydon, and Luu lab have demonstrated that normal Wnt/b-catenin signaling is required for BMP9 signaling in MSCs (Journal of Cellular and Molecular Medicine 13:2448-2464). They have completed a microarray analysis on the genes regulated by Wnt3A in mesenchymal stem cells, and found that CTGF is also highly regulated by Wnt. They have recently finished a study, in which they demonstrate that CTGF is a mutual target of Wnt and BMP-9 and play an important role in regulating osteogenic differentiation (Journal of Biological Chemistry 279: 55958-55968; Molecular and Cellular Biology 26: 2955–2964. Furthermore, Drs. He, Haydon and Luu have recently investigated the potential synergistic effect of other factors on BMP9-mediated osteogenic differentiation and bone formation. Such factors include retinoid receptors and IGFs (PLoS ONE 5: e11917 and Journal of Bone and Mineral Research 25:2447-59).
Recipient of Orthopaedic Research and Education Foundation $100,000 Grant in Total Ankle Arthroplasty as Writer, Study Coordinator, and Co-Investigator, 2015.
Schipper ON, Denduluri S, Zhou Y, Haddad SL. Effect of Obesity on Total Ankle Arthroplasty. Foot Ankle Int. 2016 Jan. Vol. 37(1): 1-7. DOI: 10.1177/1071100715604392.