Dr. Constance R. Chu is Professor and Vice Chair Research, in the Department of Orthopedic Surgery at Stanford University. She is also Director of the Joint Preservation Center and Chief of Sports Medicine at the VA Palo Alto. Previously, she was the Albert Ferguson Endowed Chair and Professor of Orthopaedic Surgery at the University of Pittsburgh. She is a clinician-scientist who is both principal investigator of several projects funded by the National Institutes of Health and who has been recognized as a Castle-Connelly/US News and World Report “Top Doctor” in Orthopedic Surgery as well as on Becker’s list of Top Knee Surgeons in the United States. Her clinical practice focuses on the knee: primarily restoration and reconstruction of the ACL, menisci and cartilage. She graduated from the U.S. Military Academy at West Point and earned her medical degree from Harvard Medical School.

As Director of the multi-disciplinary Joint Preservation Center structured to seamlessly integrate the latest advances in biologics, mechanics, and imaging with comprehensive patient centered musculoskeletal and orthopedic care, Dr. Chu aims to develop a new model for health care delivery, research and education with an emphasis on health promotion and prevention. Cornerstones of this program include teamwork and a focus on personalized medicine. A central goal is to transform the clinical approach to osteoarthritis from palliation to prevention. In addition to optimizing clinical operations, outstanding research is critical to developing more effective new treatments. Towards this end, Dr. Chu is leading innovative translational research from bench to bedside in three main areas: quantitative imaging and biomarker development for early diagnosis and staging of joint and cartilage injury and degeneration; cartilage tissue engineering and stem cell based cartilage repair; and molecular and biological therapies for joint restoration and joint rejuvenation. Her research efforts have led to more than 30 professional awards and honors to include a Kappa Delta Award, considered to be the highest research honor in Orthopedic Surgery.

Dr. Chu also regularly holds leadership and committee positions in major professional organizations such as the American Association of Orthopedic Surgeons (AAOS) and the American Orthopedic Association (AOA). In her subspecialty of Orthopedic Sports Medicine, she is a past President of the Forum Sports Focus Group, a member of the Herodicus Society of leaders in Sports Medicine, and immediate past Chair of the American Orthopedic Society for Sports Medicine (AOSSM) Research Council. She is alumnus of the AOA American, British, Canadian (ABC) and the AOSSM Traveling Fellowships.

Clinical Focus

  • Orthopaedic Surgery
  • Sports Medicine and Arthroscopy
  • ACL, Cartilage and Meniscus Repair

Academic Appointments

Administrative Appointments

  • Director, Joint Preservation Center, VA Palo Alto (2013 - Present)
  • Chief, Sports Medicine, VA Palo Alto (2013 - Present)
  • Vice Chair Research, Stanford Orthopedic Surgery (2013 - Present)

Professional Education

  • Board Certification: Orthopaedic Surgery, American Board of Orthopaedic Surgery (2002)
  • Medical Education:Harvard Medical School (1992) MA
  • Fellowship, Drexel University, Executive Leadership in Academic Medicine (2012)
  • Certificate, University of Pittsburgh Katz Business School, Physician Leadership and Management (2011)
  • Fellowship:Brigham and Women's Hospital Harvard Medical School (1999) MA
  • Residency:UCSD Medical Center (1998) CA
  • Internship:UCSD Medical Center (1993) CA
  • Undergraduate, US Military Academy at West Point (1983)


2017-18 Courses

Stanford Advisees

Graduate and Fellowship Programs

  • PM& R Sports Medicine (Fellowship Program)
  • Sports Medicine (Fellowship Program)


All Publications

  • Dance between biology, mechanics, and structure: A systems-based approach to developing osteoarthritis prevention strategies JOURNAL OF ORTHOPAEDIC RESEARCH Chu, C. R., Andriacchi, T. P. 2015; 33 (7): 939-947


    Osteoarthritis (OA) is a leading cause of human suffering and disability for which disease-modifying treatments are lacking. OA occurs through complex and dynamic interplays between diverse factors over long periods of time. The traditional research and clinical focus on OA, the end stage disease, obscured understanding pathogenesis prior to reaching a common pathway defined by pain and functional deficits, joint deformity, and radiographic changes. To emphasize disease modification and prevention, we describe a multi-disciplinary systems-based approach encompassing biology, mechanics, and structure to define pre-osteoarthritic disease processes. Central to application of this model is the concept of "pre-osteoarthritis," conditions where clinical OA has not yet developed. Rather, joint homeostasis has been compromised and there are potentially reversible markers for heightened OA risk. Key messages from this perspective are (i) to focus research onto defining pre-OA through identifying and validating biological, mechanical, and imaging markers of OA risk, (ii) to emphasize multi-disciplinary approaches, and (iii) to propose that developing personalized interventions to address reversible markers of OA risk in healthy joints may be the key to prevention. Ultimately, a systems-based analysis of OA pathogenesis shows potential to transform clinical practice by facilitating development and testing of new strategies to prevent or delay the onset of osteoarthritis.

    View details for DOI 10.1002/jor.22817

    View details for Web of Science ID 000355333600001

    View details for PubMedID 25639920

  • The Challenge and the Promise of Bone Marrow Cells for Human Cartilage Repair CARTILAGE Chu, C. R. 2015; 6 (2): 36S-45S
  • Effects of high heel wear and increased weight on the knee during walking. Journal of orthopaedic research Titchenal, M. R., Asay, J. L., Favre, J., Andriacchi, T. P., Chu, C. R. 2015; 33 (3): 405-411


    Knee osteoarthritis (OA), a leading cause of disability, is more prevalent in women than men. Wearing high heeled shoes has been implicated as a potential contributing factor for the higher lifetime risk of osteoarthritis in women. This study tests the hypotheses that changes to knee kinematics and kinetics observed during high heeled walking increase in magnitude with increasing heel height and are accentuated by a 20% increase in weight. Fourteen healthy females were tested using marker-based gait analysis in combinations of footwear (flat athletic shoe, 3.8 cm and 8.3 cm heeled shoes) and weight (with and without 20% bodyweight vest). At preferred walking speed, knee flexion angle at heel-strike and midstance increased with increasing heel height and weight. Maximum knee extension moment during loading response decreased with added weight; maximum knee extension moment during terminal stance decreased with heel height; maximum adduction moments increased with heel height. Many of the changes observed with increasing heel height and weight were similar to those seen with aging and OA progression. This suggests that high heel use, especially in combination with additional weight, may contribute to increased OA risk in women. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:???-???, 2015.

    View details for DOI 10.1002/jor.22775

    View details for PubMedID 25532875

  • Quantitative Magnetic Resonance Imaging UTE-T2* Mapping of Cartilage and Meniscus Healing After Anatomic Anterior Cruciate Ligament Reconstruction. American journal of sports medicine Chu, C. R., Williams, A. A., West, R. V., Qian, Y., Fu, F. H., Do, B. H., Bruno, S. 2014; 42 (8): 1847-1856


    BACKGROUND:An anterior cruciate ligament (ACL) injury greatly increases the risk for premature knee osteoarthritis (OA). Improved diagnosis and staging of early disease are needed to develop strategies to delay or prevent disabling OA. PURPOSE:Novel magnetic resonance imaging (MRI) ultrashort echo time (UTE)-T2(*) mapping was evaluated against clinical metrics of cartilage health in cross-sectional and longitudinal studies of human participants before and after ACL reconstruction (ACLR) to show reversible deep subsurface cartilage and meniscus matrix changes. STUDY DESIGN:Cohort study (diagnosis/prognosis); Level of evidence, 2. METHODS:Forty-two participants (31 undergoing anatomic ACLR; 11 uninjured) underwent 3-T MRI inclusive of a sequence capturing short and ultrashort T2 signals. An arthroscopic examination of the medial meniscus was performed, and modified Outerbridge grades were assigned to the central and posterior medial femoral condyle (cMFC and pMFC, respectively) of ACL-reconstructed patients. Two years after ACLR, 16 patients underwent the same 3-T MRI. UTE-T2(*) maps were generated for the posterior medial meniscus (pMM), cMFC, pMFC, and medial tibial plateau (MTP). Cross-sectional evaluations of UTE-T2(*) and arthroscopic data along with longitudinal analyses of UTE-T2(*) changes were performed. RESULTS:Arthroscopic grades showed that 74% (23/31) of ACL-reconstructed patients had intact cMFC cartilage (Outerbridge grade 0 and 1) and that 90% (28/31) were Outerbridge grade 0 to 2. UTE-T2(*) values in deep cMFC and pMFC cartilage varied significantly with injury status and arthroscopic grade (Outerbridge grade 0-2: n = 39; P = .03 and .04, respectively). Pairwise comparisons showed UTE-T2(*) differences between uninjured controls (n = 11) and patients with arthroscopic Outerbridge grade 0 for the cMFC (n = 12; P = .01) and arthroscopic Outerbridge grade 1 for the pMFC (n = 11; P = .01) only and not individually between arthroscopic Outerbridge grade 0, 1, and 2 of ACL-reconstructed patients (P > .05). Before ACLR, UTE-T2(*) values of deep cMFC and pMFC cartilage of ACL-reconstructed patients were a respective 43% and 46% higher than those of uninjured controls (14.1 ± 5.5 vs 9.9 ± 2.3 milliseconds [cMFC] and 17.4 ± 7.0 vs 11.9 ± 2.4 milliseconds [pMFC], respectively; P = .02 for both). In longitudinal analyses, preoperative elevations in UTE-T2(*) values in deep pMFC cartilage and the pMM in those with clinically intact menisci decreased to levels similar to those in uninjured controls (P = .02 and .005, respectively), suggestive of healing. No decrease in UTE-T2(*) values for the MFC and new elevation in UTE-T2(*) values for the submeniscus MTP were observed in those with meniscus tears. CONCLUSION:This study shows that novel UTE-T2(*) mapping demonstrates changes in cartilage deep tissue health according to joint injury status as well as a potential for articular cartilage and menisci to heal deep tissue injuries. Further clinical studies of UTE-T2(*) mapping are needed to determine if it can be used to identify joints at risk for rapid degeneration and to monitor effects of new treatments to delay or prevent the development of OA.

    View details for DOI 10.1177/0363546514532227

    View details for PubMedID 24812196

  • Quantitative Magnetic Resonance Imaging UTE-T2*Mapping of Cartilage and Meniscus Healing After Anatomic Anterior Cruciate Ligament Reconstruction AMERICAN JOURNAL OF SPORTS MEDICINE Chu, C. R., Williams, A. A., West, R. V., Qian, Y., Fu, F. H., Do, B. H., Bruno, S. 2014; 42 (8): 1847-1856
  • Osteoarthritis: From Palliation to Prevention: AOA Critical Issues. The Journal of bone and joint surgery. American volume 2014; 96 (15): e130


    Osteoarthritis is a leading cause of disability. The traditional focus on late-stage osteoarthritis has not yielded effective disease-modifying treatments. Consequently, current clinical care focuses on palliation until joint replacement is indicated. A symposium format was used to examine emerging strategies that support the transformation of the clinical approach to osteoarthritis from palliation to prevention. Central to this discussion are concepts for diagnosis and treatment of pre-osteoarthritis, meaning joint conditions that increase the risk of accelerated development of osteoarthritis. The presentation of translational and clinical research on three common orthopaedic conditions-anterior cruciate ligament tear, intra-articular fracture, and hip dysplasia-were used to illustrate these ideas. New information regarding the use of novel quantitative magnetic resonance imaging (MRI) in the form of ultrashort echo time enhanced T2* (UTE-T2*) mapping to evaluate the potential for articular cartilage to heal subsurface damage in a mechanically sound environment was presented. These data indicate that improved diagnostics can both identify cartilage at risk and evaluate the effectiveness of early treatment strategies. With use of a new mouse model for intra-articular fracture, it was shown that inflammation correlated to fracture severity and that super-healer mice avoided early posttraumatic osteoarthritis in part through an enhanced ability to dampen inflammation. These findings suggest that there is a role for acute and sustained anti-inflammatory treatment in the prevention of osteoarthritis. For long-term treatment, contemporary gene-therapy approaches may offer an effective means for sustained intra-articular delivery of anti-inflammatory and other bioactive agents to restore joint homeostasis. To illustrate the potential of early treatment to prevent or delay the onset of disabling osteoarthritis, the positive clinical effects on articular cartilage and in long-term clinical follow-up after operative correction of structural abnormalities about the hip highlight the role for targeting mechanical factors in delaying the onset of osteoarthritis. Given that orthopaedic surgeons treat the full spectrum of joint problems, ranging from joint trauma to pre-osteoarthritic conditions and end-stage osteoarthritis, an awareness of the paradigm shift toward the prevention of osteoarthritis is critical to the promotion of improved clinical care and participation in clinical research involving new treatment strategies.

    View details for DOI 10.2106/JBJS.M.01209

    View details for PubMedID 25100783

  • Persistence, Localization, and External Control of Transgene Expression After Single Injection of Adeno-Associated Virus into Injured Joints HUMAN GENE THERAPY Lee, H. H., O'Malley, M. J., Friel, N. A., Payne, K. A., Qiao, C., Xiao, X., Chu, C. R. 2013; 24 (4): 457-466


    A single intra-articular injection of adeno-associated virus (AAV) results in stable and controllable transgene expression in normal rat knees. Because undamaged joints are unlikely to require treatment, the study of AAV delivery in joint injury models is crucial to potential therapeutic applications. This study tests the hypotheses that persistent and controllable AAV-transgene expression are (1) highly localized to the cartilage when AAV is injected postinjury and (2) localized to the intra-articular soft tissues when AAV is injected preinjury. Two AAV injection time points, postinjury and preinjury, were investigated in osteochondral defect and anterior cruciate ligament transection models of joint injury. Rats injected with AAV tetracycline response element (TRE)-luciferase received oral doxycycline for 7 days. Luciferase expression was evaluated longitudinally for 6 months. Transgene expression was persistent and controllable with oral doxycycline for 6 months in all groups. However, the location of transgene expression was different: postinjury AAV-injected knees had luciferase expression highly localized to the cartilage, while preinjury AAV-injected knees had more widespread signal from intra-articular soft tissues. The differential transgene localization between preinjury and postinjury injection can be used to optimize treatment strategies. Highly localized postinjury injection appears advantageous for treatments targeting repair cells. The more generalized and controllable reservoir of transgene expression following AAV injection before anterior cruciate ligament transection (ACLT) suggests an intriguing concept for prophylactic delivery of joint protective factors to individuals at high risk for early osteoarthritis (OA). Successful external control of intra-articular transgene expression provides an added margin of safety for these potential clinical applications.

    View details for DOI 10.1089/hum.2012.118

    View details for Web of Science ID 000317826200010

    View details for PubMedID 23496155

  • Early diagnosis to enable early treatment of pre-osteoarthritis ARTHRITIS RESEARCH & THERAPY Chu, C. R., Williams, A. A., Coyle, C. H., Bowers, M. E. 2012; 14 (3)


    Osteoarthritis is a prevalent and disabling disease affecting an increasingly large swathe of the world population. While clinical osteoarthritis is a late-stage condition for which disease-modifying opportunities are limited, osteoarthritis typically develops over decades, offering a long window of time to potentially alter its course. The etiology of osteoarthritis is multifactorial, showing strong associations with highly modifiable risk factors of mechanical overload, obesity and joint injury. As such, characterization of pre-osteoarthritic disease states will be critical to support a paradigm shift from palliation of late disease towards prevention, through early diagnosis and early treatment of joint injury and degeneration to reduce osteoarthritis risk. Joint trauma accelerates development of osteoarthritis from a known point in time. Human joint injury cohorts therefore provide a unique opportunity for evaluation of pre-osteoarthritic conditions and potential interventions from the earliest stages of degeneration. This review focuses on recent advances in imaging and biochemical biomarkers suitable for characterization of the pre-osteoarthritic joint as well as implications for development of effective early treatment strategies.

    View details for DOI 10.1186/ar3845

    View details for Web of Science ID 000314972600066

    View details for PubMedID 22682469

  • Donor sex and age influence the chondrogenic potential of human femoral bone marrow stem cells OSTEOARTHRITIS AND CARTILAGE Payne, K. A., Didiano, D. M., Chu, C. R. 2010; 18 (5): 705-713


    Damaged articular cartilage does not heal well and can progress to osteoarthritis (OA). Human bone marrow stem cells (BMC) are promising cells for articular cartilage repair, yet age- and sex-related differences in their chondrogenesis have not been clearly identified. The purpose of this study is to test whether the chondrogenic potential of human femoral BMC varies based on the sex and/or age of the donor.BMC were isolated from 21 males (16-82 years old (y.o.)) and 20 females (20-77 y.o.) during orthopaedic procedures. Cumulative population doubling (CPD) was measured and chondrogenesis was evaluated by standard pellet culture assay in the presence or absence of transforming growth factor beta 1 (TGFbeta1). Pellet area was measured, and chondrogenic differentiation was determined by Toluidine blue and Safranin O-Fast green histological grading using the Bern score and by glycosaminoglycan (GAG) content.No difference in CPD was observed due to donor sex or age. The increase in pellet area with addition of TGFbeta1 and the Bern score significantly decreased with increasing donor age in male BMC, but not in female BMC. A significant reduction in GAG content per pellet was also observed with increasing donor age in male BMC. This was not observed in female BMC.This study showed an age-related decline in chondroid differentiation with TGFbeta1 stimulation in male BMC, but not in female BMC. Understanding the mechanisms for these differences will contribute to improved clinical use of autologous BMC for articular cartilage repair, and may lead to the development of customized age- or sex-based treatments to delay or prevent the onset of OA.

    View details for DOI 10.1016/j.joca.2010.01.011

    View details for Web of Science ID 000278175600016

    View details for PubMedID 20171308

  • CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis ANNALS OF THE RHEUMATIC DISEASES Raghu, H., Lepus, C. M., Wang, Q., Wong, H. H., Lingampalli, N., Oliviero, F., Punzi, L., Giori, N. J., Goodman, S. B., Chu, C. R., Sokolove, J. B., Robinson, W. H. 2017; 76 (5)
  • Gait mechanics 2 years after anterior cruciate ligament reconstruction are associated with longer-term changes in patient-reported outcomes JOURNAL OF ORTHOPAEDIC RESEARCH Erhart-Hledik, J. C., Chu, C. R., Asay, J. L., Andriacchi, T. P. 2017; 35 (3): 634-640

    View details for DOI 10.1002/jor.23317

    View details for Web of Science ID 000397594300026

  • Early articular cartilage MRI T2 changes after anterior cruciate ligament reconstruction correlate with later changes in T2 and cartilage thickness JOURNAL OF ORTHOPAEDIC RESEARCH Williams, A., Winalski, C. S., Chu, C. R. 2017; 35 (3): 699-706

    View details for DOI 10.1002/jor.23358

    View details for Web of Science ID 000397594300034

  • Early Changes in Knee Center of Rotation During Walking After Anterior Cruciate Ligament Reconstruction Correlate With Later Changes in Patient-Reported Outcomes AMERICAN JOURNAL OF SPORTS MEDICINE Titchenal, M. R., Chu, C. R., Erhart-Hledik, J. C., Andriacchi, T. P. 2017; 45 (4): 915-921
  • Environmental durability of protected silver mirrors prepared by plasma beam sputtering APPLIED OPTICS Folgner, K. A., Chu, C., Lingley, Z. R., Kim, H. I., Yang, J., Barrie, J. D. 2017; 56 (4): C75-C86


    Various overcoat layers have been developed to protect silver mirrors from tarnish and corrosion. However, the mechanisms by which these protective layers improve mirror durability are not fully understood. Mixed flowing gas exposure was used to investigate the corrosion behavior of plasma beam sputtered silver mirrors with different adhesion layer materials. A small amount of nickel in the adhesion layer had a significant impact on the silver-dielectric interface. Additionally, lateral transport of silver was found to be an important factor in the corrosion process. Better stability at all layer interfaces is suggested to improve mirror durability.

    View details for DOI 10.1364/AO.56.000C75

    View details for Web of Science ID 000394309200013

    View details for PubMedID 28158059

  • Effects of active feedback gait retraining to produce a medial weight transfer at the foot in subjects with symptomatic medial knee osteoarthritis. Journal of orthopaedic research Erhart-Hledik, J. C., Asay, J. L., Clancy, C., Chu, C. R., Andriacchi, T. P. 2017


    This study aimed to determine if active feedback gait retraining to produce a medial weight transfer at the foot significantly reduces the knee adduction moment in subjects with medial compartment knee osteoarthritis. Secondarily, changes in peak knee flexion moment, frontal plane knee and ankle kinematics, and center of pressure were investigated. Ten individuals with medial compartment knee osteoarthritis (9 males; age: 65.3 ± 9.8 years; BMI: 27.8 ± 3.0 kg/m(2) ) were tested at self-selected normal and fast speeds in two conditions: Intervention, with an active feedback device attached to the shoe of their more affected leg, and control, with the device de-activated. Kinematics and kinetics were assessed using a motion capture system and force plate. The first peak, second peak, and impulse of the knee adduction moment were significantly reduced by 6.0%, 13.9%, and 9.2%, respectively, at normal speed, with reductions of 10.7% and 8.6% in first peak and impulse at fast speed, respectively, with the active feedback system, with no significant effect on the peak knee flexion moment. Significant reductions in peak varus knee angle and medialized center of pressure in the first half of stance were observed, with reductions in peak varus knee angle associated with reductions in the knee adduction moment. This study demonstrated that active feedback to produce a medial weight-bearing shift at the foot reduces the peaks and impulse of the knee adduction moment in patients with medial compartment knee osteoarthritis. Future research should determine the long-term effect of the active feedback intervention on joint loading, pain, and function. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

    View details for DOI 10.1002/jor.23527

    View details for PubMedID 28120496

  • CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis. Annals of the rheumatic diseases Raghu, H., Lepus, C. M., Wang, Q., Wong, H. H., Lingampalli, N., Oliviero, F., Punzi, L., Giori, N. J., Goodman, S. B., Chu, C. R., Sokolove, J. B., Robinson, W. H. 2016


    While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains.Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA.Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.

    View details for DOI 10.1136/annrheumdis-2016-210426

    View details for PubMedID 27965260

  • Early Changes in Knee Center of Rotation During Walking After Anterior Cruciate Ligament Reconstruction Correlate With Later Changes in Patient-Reported Outcomes. American journal of sports medicine Titchenal, M. R., Chu, C. R., Erhart-Hledik, J. C., Andriacchi, T. P. 2016


    Altered knee kinematics after anterior cruciate ligament injury and reconstruction (ACLR) have been implicated in the development of posttraumatic osteoarthritis (PTOA), leading to poor long-term clinical outcomes.This study was conducted to determine (1) whether the average knee center of rotation (KCOR), a multidimensional metric of knee kinematics, of the ACL-reconstructed knee during walking differs from that of the uninjured contralateral knee; (2) whether KCOR changes between 2 and 4 years after surgery; and (3) whether early KCOR changes predict patient-reported outcomes 8 years after ACLR.Descriptive laboratory study.Twenty-six human participants underwent gait analysis with calculation of bilateral KCOR during walking at 2 and 4 years after unilateral ACLR. Knee injury and Osteoarthritis Outcome Score (KOOS) and Lysholm score results were collected at 2, 4, and 8 years after ACLR in 13 of these participants.The ACL-reconstructed knee showed greater medial compartment motion because of pivoting about a more lateral KCOR ( P = .03) than the contralateral knee at 2 years. KCOR became less lateral over time ( P = .047), with values approaching those of the uninjured knee by 4 years ( P = .55). KCOR was also more anterior in the ACL-reconstructed knee at 2 years ( P = .02). Between 2 and 4 years, KCOR moved posteriorly in 16 (62%) and anteriorly in 10 (38%) participants. Increasing the anterior position of KCOR in the ACL-reconstructed knee from 2 to 4 years correlated with worsening clinical outcomes at 4 years (KOOS-Quality of Life, R(2) = 0.172) and more strongly at 8 years (Lysholm score, R(2) = 0.41; KOOS-Pain, R(2) = 0.37; KOOS-Symptoms, R(2) = 0.58; and KOOS-Quality of Life, R(2) = 0.50).The observed changes to KCOR during walking between 2 and 4 years after ACLR show progressive improvement toward kinematic symmetry over the 2-year follow-up. The correlation between increasingly abnormal kinematics and worsening clinical outcomes years later in a subset of participants provides a potential explanation for the incidence of PTOA after ACLR.

    View details for PubMedID 27881382

  • Early articular cartilage MRI T2 changes after anterior cruciate ligament reconstruction correlate with later changes in T2 and cartilage thickness. Journal of orthopaedic research Williams, A., Winalski, C. S., Chu, C. R. 2016


    Anterior cruciate ligament (ACL) injury is a known risk factor for future development of osteoarthritis (OA). This human clinical study seeks to determine if early changes to cartilage MRI T2 maps between baseline and 6 months following ACL reconstruction (ACLR) are associated with changes to cartilage T2 and cartilage thickness between baseline and 2 years after ACLR. Changes to T2 texture metrics and T2 mean values in medial knee cartilage of 17 human subjects 6 months after ACLR were compared to 2-year changes in T2 and in cartilage thickness of the same areas. T2 texture and mean assessments were also compared to that of 11 uninjured controls. In ACLR subjects, six-month changes in mean T2 correlated to 2-year changes in mean T2 (R = 0.80, p = 0.0001), and 6-month changes to T2 texture metrics, but not T2 mean, correlated with 2-year changes in medial femoral cartilage thickness in 9 of the 20 texture features assessed (R = 0.48-0.72, p ≤ 0.05). Both mean T2 and texture differed (p < 0.05) between ALCR subjects and uninjured controls.These results show that short-term longitudinal evaluation of T2 map and textural changes may provide early warning of cartilage at risk for progressive degeneration after ACL injury and reconstruction. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:699-706, 2017.

    View details for DOI 10.1002/jor.23358

    View details for PubMedID 27381512

  • AAOS Research Symposium Updates and Consensus: Biologic Treatment of Orthopaedic Injuries JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LaPrade, R. F., Dragoo, J. L., Koh, J. L., Murray, I. R., Geeslin, A. G., Chu, C. R. 2016; 24 (7): E62-E78


    Strategies that seek to enhance musculoskeletal tissue regeneration and repair by modulating the biologic microenvironment at the site of injury have considerable therapeutic potential. Current and emerging biologic approaches include the use of growth factors, platelet-rich plasma, stem cell therapy, and scaffolds. The American Academy of Orthopaedic Surgeons hosted a research symposium in November 2015 to review the current state-of-the-art biologic treatments of articular cartilage, muscle, tendon, and bone injuries and identify knowledge gaps related to these emerging treatments. This review outlines the findings of the symposium and summarizes the consensus reached on how best to advance research on biologic treatment of orthopaedic injuries.

    View details for DOI 10.5435/JAAOS-D-16-00086

    View details for Web of Science ID 000383728900002

    View details for PubMedID 27227987

  • Gait mechanics 2 years after anterior cruciate ligament reconstruction are associated with longer-term changes in patient-reported outcomes. Journal of orthopaedic research Erhart-Hledik, J. C., Chu, C. R., Asay, J. L., Andriacchi, T. P. 2016


    This study tested the hypothesis that side-to-side differences in knee gait mechanics 2 years after anterior cruciate ligament (ACL) reconstruction are associated with long-term (∼8 years post-reconstruction) changes in patient-reported outcome scores. Sixteen subjects (5 males; age: 29.1 ± 7.1 years) with primary unilateral ACL reconstruction were gait tested at baseline (2.2 ± 0.3 years post-ACL reconstruction) and filled out KOOS and Lysholm surveys. At long-term follow-up (7.7 ± 0.7 years post-ACL reconstruction), the same subjects completed KOOS and Lysholm surveys. Pearson correlation coefficients assessed relationships between side-to-side differences in kinematics and kinetics at baseline and changes in Lysholm and KOOS Pain/QOL scores from 2 to 8 years post-ACL reconstruction. Significant associations were seen between greater average varus rotation (Lysholm: R = -0.654, p = 0.006) and less anterior femoral displacement (Lysholm: R = 0.578, p = 0.019) during stance of the ACL reconstructed knee versus the contralateral knee at baseline and worse follow-up outcome scores. Significant associations were seen between greater peak knee flexion moment (KOOS Pain: R = -0.572, p = 0.026; KOOS QOL: R = -0.636, p = 0.011), peak knee adduction moment (Lysholm: R = -0.582, p = 0.018; KOOS Pain: R = -0.742, p = 0.002; KOOS QOL: R = -0.551, p = 0.033), and peak internal rotation moment (Lysholm: R = 0.525, p = 0.037; KOOS Pain: R = 0.815, p < 0.001; KOOS QOL: R = 0.777, p = 0.001) in the ACL reconstructed knee at baseline with worse follow-up outcomes. The results of this study support the hypotheses that early changes in gait mechanics following ACL reconstruction are associated with longer-term clinical changes in patient-reported outcomes, suggesting that biomechanical markers obtained as early as 2 years after ACL reconstruction may be useful to understand clinical outcomes in this population. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:634-640, 2017.

    View details for DOI 10.1002/jor.23317

    View details for PubMedID 27238273

  • Addition of Mesenchymal Stem Cells to Autologous Platelet-Enhanced Fibrin Scaffolds in Chondral Defects Does It Enhance Repair? JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME Goodrich, L. R., Chen, A. C., Werpy, N. M., Williams, A. A., Kisiday, J. D., Su, A. W., Cory, E., Morley, P. S., McIlwraith, C. W., Sah, R. L., Chu, C. R. 2016; 98A (1): 23-34
  • Addition of Mesenchymal Stem Cells to Autologous Platelet-Enhanced Fibrin Scaffolds in Chondral Defects: Does It Enhance Repair? journal of bone and joint surgery. American volume Goodrich, L. R., Chen, A. C., Werpy, N. M., Williams, A. A., Kisiday, J. D., Su, A. W., Cory, E., Morley, P. S., McIlwraith, C. W., Sah, R. L., Chu, C. R. 2016; 98 (1): 23-34


    The chondrogenic potential of culture-expanded bone-marrow-derived mesenchymal stem cells (BMDMSCs) is well described. Numerous studies have also shown enhanced repair when BMDMSCs, scaffolds, and growth factors are placed into chondral defects. Platelets provide a rich milieu of growth factors and, along with fibrin, are readily available for clinical use. The objective of this study was to determine if the addition of BMDMSCs to an autologous platelet-enriched fibrin (APEF) scaffold enhances chondral repair compared with APEF alone.A 15-mm-diameter full-thickness chondral defect was created on the lateral trochlear ridge of both stifle joints of twelve adult horses. In each animal, one defect was randomly assigned to receive APEF+BMDMSCs and the contralateral defect received APEF alone. Repair tissues were evaluated one year later with arthroscopy, histological examination, magnetic resonance imaging (MRI), micro-computed tomography (micro-CT), and biomechanical testing.The arthroscopic findings, MRI T2 map, histological scores, structural stiffness, and material stiffness were similar (p > 0.05) between the APEF and APEF+BMDMSC-treated repairs at one year. Ectopic bone was observed within the repair tissue in four of twelve APEF+BMDMSC-treated defects. Defects repaired with APEF alone had less trabecular bone edema (as seen on MRI) compared with defects repaired with APEF+BMDMSCs. Micro-CT analysis showed thinner repair tissue in defects repaired with APEF+BMDMSCs than in those treated with APEF alone (p < 0.05).APEF alone resulted in thicker repair tissue than was seen with APEF+BMDMSCs. The addition of BMDMSCs to APEF did not enhance cartilage repair and stimulated bone formation in some cartilage defects.APEF supported repair of critical-size full-thickness chondral defects in horses, which was not improved by the addition of BMDMSCs. This work supports further investigation to determine whether APEF enhances cartilage repair in humans.

    View details for DOI 10.2106/JBJS.O.00407

    View details for PubMedID 26738900

  • A Systems View of Risk Factors for Knee Osteoarthritis Reveals Insights into the Pathogenesis of the Disease ANNALS OF BIOMEDICAL ENGINEERING Andriacchi, T. P., Favre, J., Erhart-Hledik, J. C., Chu, C. R. 2015; 43 (2): 376-387


    Early detection of osteoarthritis (OA) remains a critical yet unsolved multifaceted problem. To address the multifaceted nature of OA a systems model was developed to consolidate a number of observations on the biological, mechanical and structural components of OA and identify features common to the primary risk factors for OA (aging, obesity and joint trauma) that are present prior to the development of clinical OA. This analysis supports a unified view of the pathogenesis of OA such that the risk for developing OA emerges when one of the components of the disease (e.g., mechanical) becomes abnormal, and it is the interaction with the other components (e.g., biological and/or structural) that influences the ultimate convergence to cartilage breakdown and progression to clinical OA. The model, applied in a stimulus-response format, demonstrated that a mechanical stimulus at baseline can enhance the sensitivity of a biomarker to predict cartilage thinning in a 5 year follow-up in patients with knee OA. The systems approach provides new insight into the pathogenesis of the disease and offers the basis for developing multidisciplinary studies to address early detection and treatment at a stage in the disease where disease modification has the greatest potential for a successful outcome.

    View details for DOI 10.1007/s10439-014-1117-2

    View details for Web of Science ID 000350234500012

    View details for PubMedID 25224078

    View details for PubMedCentralID PMC4340713

  • Osteoarthritis: From Palliation to Prevention AOA Critical Issues JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME Chu, C. R., Millis, M. B., Olson, S. A. 2014; 96A (15)
  • The Effect of Platelet-Rich Plasma Formulations and Blood Products on Human Synoviocytes Implications for Intra-articular Injury and Therapy AMERICAN JOURNAL OF SPORTS MEDICINE Braun, H. J., Kim, H. J., Chu, C. R., Dragoo, J. L. 2014; 42 (5): 1204-1210


    The effect of platelet-rich plasma (PRP) on chondrocytes has been studied in cell and tissue culture, but considerably less attention has been given to the effect of PRP on synoviocytes. Fibroblast-like synoviocytes (FLS) compose 80% of the normal human synovium and produce cytokines and matrix metalloproteinases that can mediate cartilage catabolism.To compare the effects of leukocyte-rich PRP (LR-PRP), leukocyte-poor PRP (LP-PRP), red blood cell (RBC) concentrate, and platelet-poor plasma (PPP) on human FLS to determine whether leukocyte and erythrocyte concentrations of PRP formulations differentially affect the production of inflammatory mediators.Controlled laboratory study.Peripheral blood was obtained from 4 donors and processed to create LR-PRP, LP-PRP, RBCs, and PPP. Human synoviocytes were cultured for 96 hours with the respective experimental conditions using standard laboratory conditions. Cell viability and inflammatory mediator production were then evaluated.Treatment with LR-PRP resulted in significantly greater synoviocyte death (4.9% ± 3.1%) compared with LP-PRP (0.72% ± 0.70%; P = .035), phosphate-buffered saline (PBS) (0.39% ± 0.27%; P = .018), and PPP (0.26% ± 0.30%; P = .013). Synoviocytes treated with RBC concentrate demonstrated significantly greater cell death (12.5% ± 6.9%) compared with PBS (P < .001), PPP (P < .001), LP-PRP (P < .001), and LR-PRP (4.9% ± 3.1%; P < .001). Interleukin (IL)-1β content was significantly higher in cultures treated with LR-PRP (1.53 ± 0.86 pg/mL) compared with those treated with PBS (0.22 ± 0.295 pg/mL; P < .001), PPP (0.11 ± 0.179 pg/mL; P < .001), and RBCs (0.64 ± 0.58 pg/mL; P = .001). IL-6 content was also higher with LR-PRP (32,097.82 ± 22,844.300 pg/mL) treatment in all other groups (P < .001). Tumor necrosis factor-α levels were greatest in LP-PRP (9.97 ± 3.110 pg/mL), and this was significantly greater compared with all other culture conditions (P < .001). Interferon-γ levels were greatest in RBCs (64.34 ± 22.987 pg/mL) and significantly greater than all other culture conditions (P < .001).Treatment of synovial cells with LR-PRP and RBCs resulted in significant cell death and proinflammatory mediator production.Clinicians should consider using leukocyte-poor, RBC-free formulations of PRP when administering intra-articularly.

    View details for DOI 10.1177/0363546514525593

    View details for Web of Science ID 000335567700024

    View details for PubMedID 24634448

  • Articular cartilage changes in maturing athletes: new targets for joint rejuvenation. Sports health Luria, A., Chu, C. R. 2014; 6 (1): 18-30


    Articular cartilage has a unique functional architecture capable of providing a lifetime of pain-free joint motion. This tissue, however, undergoes substantial age-related physiologic, mechanical, biochemical, and functional changes that reduce its ability to overcome the effects of mechanical stress and injury. Many factors affect joint function in the maturing athlete-from chondrocyte survival and metabolism to structural composition and genetic/epigenetic factors governing cartilage and synovium. An evaluation of age-related changes for joint homeostasis and risk for osteoarthritis is important to the development of new strategies to rejuvenate aging joints.This review summarizes the current literature on the biochemical, cellular, and physiologic changes occurring in aging articular cartilage.PubMed (1969-2013) and published books in sports health, cartilage biology, and aging.Keywords included aging, athlete, articular cartilage, epigenetics, and functional performance with age.Systematic review.Level 3.To be included, research questions addressed the effect of age-related changes on performance, articular cartilage biology, molecular mechanism, and morphology.The mature athlete faces challenges in maintaining cartilage health and joint function due to age-related changes to articular cartilage biology, morphology, and physiology. These changes include chondrocyte loss and a decline in metabolic response, alterations to matrix and synovial tissue composition, and dysregulation of reparative responses.Although physical decline has been regarded as a normal part of aging, many individuals maintain overall fitness and enjoy targeted improvement to their athletic capacity throughout life. Healthy articular cartilage and joints are needed to maintain athletic performance and general activities. Genetic and potentially reversible epigenetic factors influence cartilage physiology and its response to mechanical and injurious stimuli. Improved understandings of the physical and molecular changes to articular cartilage with aging are important to develop successful strategies for joint rejuvenation.

    View details for DOI 10.1177/1941738113514369

    View details for PubMedID 24427438

  • Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis. Arthritis & rheumatology (Hoboken, N.J.) Lepus, C. M., Song, J. J., Wang, Q., Wagner, C. A., Lindstrom, T. M., Chu, C. R., Sokolove, J., Leung, L. L., Robinson, W. H. 2014; 66 (1): 101-106


    We previously demonstrated that carboxypeptidase B (CPB) protects against joint erosion in rheumatoid arthritis by inactivating complement component C5a. We also found that levels of CPB are abnormally high in the synovial fluid of individuals with another joint disease, osteoarthritis (OA). We undertook this study to investigate whether CPB plays a role in the pathogenesis of OA.We compared the development of OA in CPB-deficient (Cpb2(-/-) ) mice and wild-type mice by subjecting them to medial meniscectomy and histologically assessing cartilage damage, osteophyte formation, and synovitis in the stifle joints 4 months later. We measured levels of proCPB, proinflammatory cytokines, and complement components in synovial fluid samples from patients with symptomatic and radiographic knee OA. Finally, we used enzyme-linked immunosorbent assay, flow cytometry, and hemolytic assays to assess the effect of CPB on formation of membrane attack complex (MAC)-a complement effector critical to OA pathogenesis.Cpb2(-/-) mice developed dramatically greater cartilage damage than did wild-type mice (P < 0.01) and had a greater number of osteophytes (P < 0.05) and a greater degree of synovitis (P < 0.05). In synovial fluid samples from OA patients, high levels of proCPB were associated with high levels of proinflammatory cytokines and complement components, and levels of proCPB correlated positively with those of MAC. In in vitro complement activation assays, activated CPB suppressed the formation of MAC as well as MAC-induced hemolysis.Our data suggest that CPB protects against inflammatory destruction of the joints in OA, at least in part by inhibiting complement activation.

    View details for DOI 10.1002/art.38213

    View details for PubMedID 24449579

  • Carboxypeptidase B Serves as a Protective Mediator in Osteoarthritis ARTHRITIS & RHEUMATOLOGY Lepus, C. M., Song, J. J., Wang, Q., Wagner, C. A., Lindstrom, T. M., Chu, C. R., Sokolove, J., Leung, L. L., Robinson, W. H. 2014; 66 (1): 101-106

    View details for DOI 10.1002/art.38213

    View details for Web of Science ID 000337356300014

  • T2 texture index of cartilage can predict early symptomatic OA progression: data from the osteoarthritis initiative OSTEOARTHRITIS AND CARTILAGE Urish, K. L., Keffalas, M. G., Durkin, J. R., Miller, D. J., Chu, C. R., Mosher, T. J. 2013; 21 (10): 1550-1557


    There is an interest in using Magnetic Resonance Imaging (MRI) to identify pre-radiographic changes in osteoarthritis (OA) and features that indicate risk for disease progression. The purpose of this study is to identify image features derived from MRI T2 maps that can accurately predict onset of OA symptoms in subjects at risk for incident knee OA.Patients were selected from the Osteoarthritis Initiative (OAI) control cohort and incidence cohort and stratified based on the change in total Western Ontario and McMaster Universities Arthritis (WOMAC) score from baseline to 3-year follow-up (80 non-OA progression and 88 symptomatic OA progression patients). For each patient, a series of image texture features were measured from the baseline cartilage T2 map. A linear discriminant function and feature reduction method was then trained to quantify a texture metric, the T2 texture index of cartilage (TIC), based on 22 image features, to identify a composite marker of T2 heterogeneity.Statistically significant differences were seen in the baseline T2 TIC between the non-progression and symptomatic OA progression populations. The baseline T2 TIC differentiates subjects that develop worsening of their WOMAC score OA with an accuracy between 71% and 76%. The T2 TIC differences were predominantly localized to a dominant knee compartment that correlated with the mechanical axis of the knee.Baseline heterogeneity in cartilage T2 as measured with the T2 TIC index is able to differentiate and predict individuals that will develop worsening of their WOMAC score at 3-year follow-up.

    View details for DOI 10.1016/j.joca.2013.06.007

    View details for Web of Science ID 000326430000017

    View details for PubMedID 23774471

  • Repeatability of ultrashort echo time-based two-component T2*measurements on cartilages in human knee at 3 T MAGNETIC RESONANCE IN MEDICINE Qian, Y., Williams, A. A., Chu, C. R., Boada, F. E. 2013; 69 (6): 1564-1571


    Repeatability of in vivo measurement of multicomponent T2* relaxation in articular cartialges in human knee is important to clinical use. This study evaluated the repeatability of two-component T2* relaxation on seven healthy human subjects. The left knee was scanned once a day in three consecutive days, on a clinical 3T MRI scanner with eight-channel knee coil and ultrashort echo time pulse sequence at 11 echo times=0.6-40 ms. The intrasubject and intersubject repeatability was evaluated via coefficient of variation (CV=standard deviation/mean) in four typical cartilage regions: patellar, anterior articular, femoral, and tibial regions. It was found that the intrasubject repeatability was good, with CV<10% for the short- and long-T2* relaxation time in the layered regions in the four cartilages (with one exception) and CV<13% for the component intensity fraction (with two exceptions). The intersubject repeatability was also good, with CV∼8% (range 1-15%) for the short- and long-T2* relaxation time and CV∼10% (range 2-20%) for the component intensity fraction. The long-T2* component showed significantly better repeatability (CV∼8%) than the short-T2* component (CV∼12%) (P<0.005). These CV values suggest that in vivo measurement of two-component T2* relaxation in the knee cartilages is repeatable on clinical scanner at 3 T, with a signal-to-noise ratio of 90.

    View details for DOI 10.1002/mrm.24392

    View details for Web of Science ID 000319074100007

    View details for PubMedID 23034822

  • Effects of doxycycline on mesenchymal stem cell chondrogenesis and cartilage repair OSTEOARTHRITIS AND CARTILAGE Lee, H. H., O'Malley, M. J., Friel, N. A., Chu, C. R. 2013; 21 (2): 385-393


    Strategies to improve cartilage repair tissue quality after bone marrow cell-based procedures may reduce later development of osteoarthritis. Doxycycline is inexpensive, well-tolerated, and has been shown to reduce matrix-metalloproteinases (MMPs) and osteoarthritis progression. This study tests the hypotheses that doxycycline reduces MMP, enhances chondrogenesis of human bone marrow-derived mesenchymal stem cells (hMSC), and improves in vivo cartilage repair.Ninety hMSC pellets were cultured in chondrogenic media with either 0-, 1- or 2-μg/mL doxycycline. Pellets were evaluated with stereomicroscopy, proteoglycan assay, qRT-PCR, and histology. Osteochondral defects (OCDs) were created in the trochlear grooves of 24-Sprague-Dawley rats treated with/without oral doxycycline. Rats were sacrificed at 12-weeks and repair tissues were examined grossly and histologically.hMSC pellets with 1-μg/mL (P = 0.014) and 2-μg/mL (P = 0.002) doxycycline had larger areas than pellets without doxycycline. hMSC pellets with 2-μg/mL doxycycline showed reduced mmp-13 mRNA (P = 0.010) and protein at 21-days. Proteoglycan, DNA contents, and mRNA expressions of chondrogenic genes were similar (P > 0.05). For the in vivo study, while the histological scores were similar between the two groups (P = 0.116), the gross scores of the OCD repair tissues in doxycycline-treated rats were higher at 12-weeks (P = 0.017), reflective of improved repair quality. The doxycycline-treated repairs also showed lower MMP-13 protein (P = 0.029).This study shows that doxycycline improves hMSC chondrogenesis and decreases MMP-13 in pellet cultures and within rat OCDs. Doxycycline exerted no negative effect on multiple measures of chondrogenesis and cartilage repair. These data support potential use of doxycycline to improve cartilage repair to delay the onset of osteoarthritis.

    View details for DOI 10.1016/j.joca.2012.11.010

    View details for Web of Science ID 000314668800016

    View details for PubMedID 23186943

  • Registration of Magnetic Resonance Image Series for Knee Articular Cartilage Analysis: Data from the Osteoarthritis Initiative CARTILAGE Urish, K. L., Williams, A. A., Durkin, J. R., Chu, C. R. 2013; 4 (1): 20-27


    Although conventional radiography is used to assess osteoarthritis in a clinical setting, it has limitations, including an inability to stage early cartilage degeneration. There is a growing interest in using quantitative magnetic resonance imaging to identify degenerative changes in articular cartilage, including the large multicentered study, the Osteoarthritis Initiative (OAI). There is a demand for suitable image registration and segmentation software to complete this analysis. The objective of this study was to develop and validate the open source software, ImageK, that registers 3 T MRI T2 mapping and double echo steady state (DESS) knee MRI sequences acquired in the OAI protocol.A C++ library, the insight toolkit, was used to develop open source software to register DESS and T2 mapping image MRI sequences using Mattes's Multimodality Mutual information metric.Registration was assessed using three separate methods. A checkerboard layout demonstrated acceptable visual alignment. Fiducial markers placed in cadaveric knees measured a registration error of 0.85 voxels. Measuring the local variation in Mattes's Mutual Information metric in the local area of the registered solution showed precision within 1 pixel. In this group, the registered solution required a transform of 56 voxels in translation and 1 degree of rotation.The software we have developed, ImageK, provides free, open source image analysis software that registers DESS and T2 mapping sequences of knee articular cartilage within 1 voxel accuracy. This image registration software facilitates quantitative MRI analyses of knee articular cartilage.

    View details for DOI 10.1177/1947603512451745

    View details for Web of Science ID 000209218200003

  • The Role of ACL Injury in the Development of Posttraumatic Knee Osteoarthritis CLINICS IN SPORTS MEDICINE Friel, N. A., Chu, C. R. 2013; 32 (1): 1-?


    Acute anterior cruciate ligament (ACL) tears are most frequently sustained by young, physically active individuals. ACL injuries are seen at high incidence in adolescents and young adults performing sports and occupational activities that involve pivoting. Young women participating in pivoting sports have a 3 to 5 times higher risk of ACL injury than men. Studies show that ACL injury increases osteoarthritis (OA) risk with symptomatic OA appearing in roughly half of individuals 10-15 years later. Because the majority of patients sustaining acute ACL tears are younger than 30, this leads to early onset OA with associated pain and disability during premium work and life growth years between ages 30 and 50. Effective strategies to prevent ACL injury and to reduce subsequent OA risk in those sustaining acute ACL tears are needed.

    View details for DOI 10.1016/j.csm.2012.08.017

    View details for Web of Science ID 000312624300003

    View details for PubMedID 23177457

  • Serum CTXii Correlates With Articular Cartilage Degeneration After Anterior Cruciate Ligament Transection or Arthrotomy Followed by Standardized Exercise. Sports health Coyle, C. H., Henry, S. E., Haleem, A. M., O'Malley, M. J., Chu, C. R. 2012; 4 (6): 510-517


    Anterior cruciate ligament injury increases risk for accelerated development of osteoarthritis. The effect of exercise on articular cartilage following joint injury is not well understood. Biochemical biomarkers of collagen degradation and proteoglycan turnover are potential indicators for early articular cartilage degeneration.This study tests the hypothesis that serum concentrations of CS846 and CTXii correlate with structural changes to articular cartilage following joint injury in exercised animals.Controlled laboratory study.Twenty-four Sprague-Dawley rats underwent either arthrotomy alone (sham surgery) or anterior cruciate ligament transection (ACLT). Animals were recovered for 3 weeks and then exercised on a treadmill at 18 m per minute, 1 hour per day, 5 days per week, until sacrifice either 6 or 12 weeks later. Articular cartilage was assessed grossly, and histology was graded using modified Mankin, toluidine blue, and modified David-Vaudey scales. Serum collected preoperatively and at sacrifice was assayed by ELISA for CTXii and CS846.At 6 weeks, gross grades (P < 0.01), modified Mankin scores (P < 0.03), and toluidine blue scores (P < 0.04) were higher, reflecting increased degeneration in ACLT animals compared with sham surgery animals. Serum CS846 increased after 6 weeks in ACLT animals (P < 0.05). Serum CTXii levels strongly correlated with Mankin degenerative scores (coefficient = 0.81, P < 0.01) and David-Vaudey histology grades (coefficient = 0.73, P < 0.01) at 6 weeks. While gross grades remained higher at 12 weeks in ACLT animals (P < 0.04), no differences were seen in serum CS846 and CTXii. Histology scores also showed no differences between ACLT and sham due to increasing degeneration in the sham surgery group.The strong correlation between serum CTXii and microstructural changes to articular cartilage following joint injury demonstrates potential use of serum biomarkers for early detection of cartilage degeneration. Increasing cartilage degeneration in exercised sham-surgery animals suggests that early loading may have negative effects on articular cartilage due to either mechanical injury or hemarthrosis after arthrotomy.Patients with anterior cruciate ligament injury are at increased risk for development of posttraumatic osteoarthritis. CTXii may be useful for early detection of joint degeneration. Further study on the effects of exercise after injury is important to postinjury and postoperative rehabilitation.

    View details for DOI 10.1177/1941738112451425

    View details for PubMedID 24179591

  • The feasibility of randomized controlled trials for early arthritis therapies (Earth) involving acute anterior cruciate ligament tear cohorts. American journal of sports medicine Chu, C. R., Beynnon, B. D., Dragoo, J. L., Fleisig, G. S., Hart, J. M., Khazzam, M., Marberry, K. M., Nelson, B. J. 2012; 40 (11): 2648-2652


    Osteoarthritis (OA) is a leading cause of disability for which disease-modifying treatments are lacking. Anterior cruciate ligament (ACL) tear provides opportunities to study potential interventions from the initiation of heightened OA risk at the time of injury. This institutional review board (IRB)-approved prospective cross-sectional study (level of evidence: 2) was performed to test the hypothesis that adequate sample sizes of ACL-injured subjects to support randomized controlled trials (RCT) of early intervention strategies can be achieved. A total of 307 ACL-injured patients were entered into the database from 3-month collection periods at 7 clinical sites, with 65 subjects aged 18 to 30 years passing the inclusion/exclusion criteria. From sites that were IRB approved to ask, 89 of 96 (93%) subjects were willing to participate in an RCT. Extrapolating the 3-month data to a 1-year recruitment period would potentially yield 242 subjects aged 18 to 30 years willing to undergo randomization. This study shows that adequate sample sizes to perform RCT of early intervention strategies in ACL-injured cohorts comprising healthy young adults ages 18 to and 30 without prior joint injuries can be achieved within 1 to 2 years through recruitment at 5 to 7 orthopaedic sports medicine practices. Continued development of ACL-tear cohorts will provide the clinical base to critically evaluate new diagnostic and therapeutic strategies that can help transform clinical care of OA from palliation to prevention.

    View details for DOI 10.1177/0363546512465409

    View details for PubMedID 23115253

  • UTE-T2* mapping detects sub-clinical meniscus injury after anterior cruciate ligament tear OSTEOARTHRITIS AND CARTILAGE Williams, A., Qian, Y., Golla, S., Chu, C. R. 2012; 20 (6): 486-494


    Meniscus tear is a known risk factor for osteoarthritis (OA). Quantitative assessment of meniscus degeneration, prior to surface break-down, is important to identification of early disease potentially amenable to therapeutic interventions. This work examines the diagnostic potential of ultrashort echo time-enhanced T2∗ (UTE-T2∗) mapping to detect human meniscus degeneration in vitro and in vivo in subjects at risk of developing OA.UTE-T2∗ maps of 16 human cadaver menisci were compared to histological evaluations of meniscal structural integrity and clinical magnetic resonance imaging (MRI) assessment by a musculoskeletal radiologist. In vivo UTE-T2∗ maps were compared in 10 asymptomatic subjects and 25 ACL-injured patients with and without concomitant meniscal tear.In vitro, UTE-T2∗ values tended to be lower in histologically and clinically normal meniscus tissue and higher in torn or degenerate tissue. UTE-T2∗ map heterogeneity reflected collagen disorganization. In vivo, asymptomatic meniscus UTE-T2∗ values were repeatable within 9% (root-mean-square average coefficient of variation). Posteromedial meniscus UTE-T2∗ values in ACL-injured subjects with clinically diagnosed medial meniscus tear (n=10) were 87% higher than asymptomatics (n=10, P<0.001). Posteromedial menisci UTE-T2∗ values of ACL-injured subjects without concomitant medial meniscal tear (n=15) were 33% higher than asymptomatics (P=0.001). Posterolateral menisci UTE-T2∗ values also varied significantly with degree of joint pathology (P=0.001).Significant elevations of UTE-T2∗ values in the menisci of ACL-injured subjects without clinical evidence of subsurface meniscal abnormality suggest that UTE-T2∗ mapping is sensitive to sub-clinical meniscus degeneration. Further study is needed to determine whether elevated subsurface meniscus UTE-T2∗ values predict progression of meniscal degeneration and development of OA.

    View details for DOI 10.1016/j.joca.2012.01.009

    View details for Web of Science ID 000304733900005

    View details for PubMedID 22306000

  • Novel quantitative imaging for early detection of joint tissue injury to support early treatment strategies. HSS journal : the musculoskeletal journal of Hospital for Special Surgery Stepp, P. C., Williams, A. A., Chu, C. 2012; 8 (1): 54-56

    View details for DOI 10.1007/s11420-011-9242-z

    View details for PubMedID 23372532

  • High-resolution ultrashort echo time (UTE) imaging on human knee with AWSOS sequence at 3.0 T JOURNAL OF MAGNETIC RESONANCE IMAGING Qian, Y., Williams, A. A., Chu, C. R., Boada, F. E. 2012; 35 (1): 204-210


    To demonstrate the technical feasibility of high-resolution (0.28-0.14 mm) ultrashort echo time (UTE) imaging on human knee at 3T with the acquisition-weighted stack of spirals (AWSOS) sequence.Nine human subjects were scanned on a 3T MRI scanner with an 8-channel knee coil using the AWSOS sequence and isocenter positioning plus manual shimming.High-resolution UTE images were obtained on the subject knees at TE = 0.6 msec with total acquisition time of 5.12 minutes for 60 slices at an in-plane resolution of 0.28 mm and 10.24 minutes for 40 slices at an in-plane resolution of 0.14 mm. Isocenter positioning, manual shimming, and the 8-channel array coil helped minimize image distortion and achieve high signal-to-noise ratio (SNR).It is technically feasible on a clinical 3T MRI scanner to perform UTE imaging on human knee at very high spatial resolutions (0.28-0.14 mm) within reasonable scan time (5-10 min) using the AWSOS sequence.

    View details for DOI 10.1002/jmri.22639

    View details for Web of Science ID 000298093200024

    View details for PubMedID 22002811

  • Clinical and Basic Science of Cartilage Injury and Arthritis in the Football (Soccer) Athlete CARTILAGE Lee, H. H., Chu, C. R. 2012; 3 (1): 63S-68S
  • Single intra-articular injection of adeno-associated virus results in stable and controllable in vivo transgene expression in normal rat knees OSTEOARTHRITIS AND CARTILAGE Payne, K. A., Lee, H. H., Haleem, A. M., Martins, C., Yuan, Z., Qiao, C., Xiao, X., Chu, C. R. 2011; 19 (8): 1058-1065


    To test the hypothesis that in vivo transgene expression mediated by single intra-articular injection of adeno-associated virus serotype 2 (AAV2) persists within intra-articular tissues 1 year post-injection and can be externally controlled using an AAV2-based tetracycline-inducible gene regulation system containing the tetracycline response element (TRE) promoter.Sprague Dawley rats received intra-articular injections of AAV2-cytomegalovirus (CMV)-enhanced green fluorescent protein (GFP) and AAV2-CMV-luciferase (Luc) into their right and left knees, respectively. Luciferase expression was evaluated over 1 year using bioluminescence imaging. After sacrifice, tissues were analyzed for GFP+ cells by fluorescent microscopy. To study external control of intra-articular AAV-transgene expression, another set of rats was co-injected with AAV2-TRE-Luc and AAV2-CMV-reverse-tetracycline-controlled transactivator (rtTA) into the right knees, and AAV2-CMV-Luc and AAV2-CMV-rtTA into the left knees. Rats received oral doxycycline (Dox), an analog of tetracycline, for 7 days. Luciferase expression was assessed by bioluminescence imaging.Luciferase expression was localized to the injected joint and persisted throughout the 1-year study period. Abundant GFP+ cells were observed within intra-articular soft tissues. Transgene expression in AAV2-TRE-Luc injected joints was upregulated by oral administration of Dox, and downregulated following its removal, at 14 days and 13 months post-AAV injection.This longitudinal in vivo study shows that sustained and stable AAV-mediated intra-articular transgene expression can be achieved through a single intra-articular injection and can be controlled using a tetracycline-controlled inducible AAV system in a normal rat knee model. Highly regulatable long-term intra-articular transgene expression is of potential clinical utility for development of treatment strategies for chronic intra-articular disease processes such as inflammatory and degenerative arthritis.

    View details for DOI 10.1016/j.joca.2011.04.009

    View details for Web of Science ID 000294240400016

    View details for PubMedID 21571082

  • Release of Bioactive Adeno-Associated Virus from Fibrin Scaffolds: Effects of Fibrin Glue Concentrations TISSUE ENGINEERING PART A Lee, H. H., Haleem, A. M., Yao, V., Li, J., Xiao, X., Chu, C. R. 2011; 17 (15-16): 1969-1978


    Fibrin glue (FG) is used in a variety of clinical applications and in the laboratory for localized and sustained release of factors potentially important for tissue engineering. However, the effect of different fibrinogen concentrations on FG scaffold delivery of bioactive adeno-associated viruses (AAVs) has not been established. This study was performed to test the hypothesis that FG concentration alters AAV release profiles, which affect AAV bioavailability. Gene transfer efficiency of AAV-GFP released from FG was measured using HEK-293 cells. Bioactivity of AAV transforming growth factor-beta1 (TGF-β(1)) released from FG was assessed using the mink lung cell assay, and by measuring induction of cartilage-specific gene expression in human mesenchymal stem cells (hMSCs). Nondiluted FG had longer clotting times, smaller pore sizes, thicker fibers, and slower dissolution rate, resulting in reduced release of AAV. AAV release and gene transfer efficiency was higher with 25% and 50% FG than with the 75% and 100% FG. AAV-TGF-β(1) released from dilute-FG transduced hMSCs, resulting in higher concentrations of bioactive TGF-β(1) and greater upregulation of cartilage-specific gene expression compared with hMSC from undiluted FG. This study, showing improved release, transduction efficiency, and chondrogenic effect on hMSC of bioactive AAV-TGF-β(1) released from diluted FG, provides information important to optimization of this clinically available scaffold for therapeutic gene delivery, both in cartilage regeneration and for other tissue engineering applications.

    View details for DOI 10.1089/ten.tea.2010.0586

    View details for Web of Science ID 000293217700007

    View details for PubMedID 21449684

  • Closing the Gap Between Bench and Bedside Research for Early Arthritis Therapies (EARTH) Report From the AOSSM/NIH U-13 Post-Joint Injury Osteoarthritis Conference II AMERICAN JOURNAL OF SPORTS MEDICINE Chu, C. R., Beynnon, B. D., Buckwalter, J. A., Garrett, W. E., Katz, J. N., Rodeo, S. A., Spindler, K. P., Stanton, R. A. 2011; 39 (7): 1569-1578


    This report summarizes the 2010 AOSSM/NIH (American Orthopaedic Society for Sports Medicine/National Institutes of Health) U13 Post-Joint Injury Osteoarthritis II Conference to include the discussion concerning potential study cohorts, assessment considerations, and research priorities. There was strong consensus and enthusiasm for approaching the development of disease-modifying treatments for osteoarthritis through study of "pre-osteoarthritic" cohorts, particularly human subjects under 30 years of age following acute anterior cruciate ligament injuries. Clinical study of acute treatment strategies initiated within a few days after injury will need development of recruitment pathways and short-term proof-of-concept outcome measures that are specific to the intervention being studied. For example, measures of joint inflammation can be used in short-term prospective randomized controlled trials to determine whether an anti-inflammatory intervention was effective in decreasing early inflammation. These short-term clinical trials will need to be followed by longer-term evaluation of the clinical cohorts for joint and cartilage degeneration to determine if the acute intervention affected later development of osteoarthritis. Research priorities were identified in several disciplines, particularly regarding development and validation of quantitative imaging, biomechanics, and biomarker measures of joint structure, composition, and function that predict the accelerated development of osteoarthritis. Systematic study of posttraumatic osteoarthritis is anticipated to advance understanding and treatment of all forms of osteoarthritis.

    View details for DOI 10.1177/0363546511411654

    View details for Web of Science ID 000292375300028

    View details for PubMedID 21730208

  • Arthroscopic optical coherence tomography in diagnosis of early arthritis. Minimally invasive surgery O'Malley, M. J., Chu, C. R. 2011; 2011: 671308-?


    Osteoarthritis (OA) is a progressive, debilitating disease that is increasing in prevalence. The pathogenesis of OA is likely multifactorial but ultimately leads to progressive breakdown of collagen matrix and loss of chondrocytes. Current clinical modalities employed to evaluate cartilage health and diagnose osteoarthritis in orthopaedic surgery include, radiography, MRI, and arthroscopy. While these assessment methods can show cartilage fissuring and loss, they are limited in ability to diagnose cartilage injury and degeneration prior breakdown of the articular surface. An improved clinical ability to detect subsurface cartilage pathology is important for development and testing of chondroprotective and chondrorestorative treatments because the pathological changes following surface breakdown are generally considered to be irreversible. Optical Coherence Tomography (OCT), is a novel, non-destructive imaging technology capable of near-real time cross-sectional images of articular cartilage at high resolutions comparable to low power histology. This review discusses a series of bench to bedside studies supporting the potential use of OCT for enhanced clinical diagnosis and staging of early cartilage injury and degeneration. OCT was also found to be useful as a translations research tool to assist in clinical evaluation of novel quantitative MRI technologies for non-invasive evaluation of articular cartilage.

    View details for DOI 10.1155/2011/671308

    View details for PubMedID 22091362

  • UTE-T2* mapping of human articular cartilage in vivo: a repeatability assessment OSTEOARTHRITIS AND CARTILAGE Williams, A., Qian, Y., Chu, C. R. 2011; 19 (1): 84-88


    Ultrashort echo-time enhanced T2∗ (UTE-T2∗) mapping of articular cartilage is a novel quantitative MRI technique with the potential to visualize deep cartilage characteristics better than standard T2 mapping. The feasibility and intersession repeatability of UTE-T2∗ mapping of cartilage in vivo has not previously been evaluated.Eleven asymptomatic subjects underwent repeat UTE-T2∗ imaging on a whole-body 3T MRI scanner on three consecutive days. Full-thickness, superficial and deep regions of interest (ROIs) were evaluated in the central weight-bearing zones of the medial femoral condyle (cMFC) and tibial plateau (cMTP). Intersession precision error across subjects was evaluated by the root-mean-square average coefficients of variation (RMSA-CV) and by the median of intra-subject standard deviations (SDs) of UTE-T2∗ values in each ROI.UTE-T2∗ values in vivo were found to be repeatable with relative (RMSA-CV) intersession precision errors of 8%, 6%, 16% for full-thickness, superficial and deep cMFC ROIs, corresponding to absolute errors (SD) of 1.2, 1.5, 1.5 ms, respectively. In cMTP tissue, UTE-T2∗ relative repeatability was 8%, 8%, 13%, corresponding to absolute repeatability of 1.0, 1.5, 2.1 ms (full-thickness, superficial, deep). UTE-T2∗ values were higher in superficial cartilage compared to deep in both cMFC (P≪0.001) and cMTP (P=0.0004) regions.In vivo 3D UTE-T2∗ mapping at 3T is feasible and can be implemented using a standard clinical MRI scanner and knee coil. Intersession precision error of UTE-T2∗ values in full-thickness ROIs in the weight-bearing regions of asymptomatic subjects is under 1.2 ms or 8% (RMSA-CV). Significant zonal and regional variations of UTE-T2∗ were seen.

    View details for DOI 10.1016/j.joca.2010.10.018

    View details for Web of Science ID 000286542300010

    View details for PubMedID 21035556

  • Multicomponent T2* mapping of knee cartilage: technical feasibility ex vivo. Magnetic resonance in medicine Qian, Y., Williams, A. A., Chu, C. R., Boada, F. E. 2010; 64 (5): 1426-1431


    Disorganization of collagen fibers is a sign of early-stage cartilage degeneration in osteoarthritic knees. Water molecules trapped within well-organized collagen fibrils would be sensitive to collagen alterations. Multicomponent effective transverse relaxation (T2*) mapping with ultrashort echo time acquisitions is here proposed to probe short T(2) relaxations in those trapped water molecules. Six human tibial plateau explants were scanned on a 3T MRI scanner using a home-developed ultrashort echo time sequence with echo times optimized via Monte Carlo simulations. Time constants and component intensities of T2* decays were calculated at individual pixels, using the nonnegative least squares algorithm. Four T2*-decay types were found: 99% of cartilage pixels having mono-, bi-, or nonexponential decay, and 1% showing triexponential decay. Short T2* was mainly in 1-6 ms, while long T2* was ∼ 22 ms. A map of decay types presented spatial distribution of these T2* decays. These results showed the technical feasibility of multicomponent T2* mapping on human knee cartilage explants.

    View details for DOI 10.1002/mrm.22450

    View details for PubMedID 20865752

  • Multicomponent T-2(star) Mapping of Knee Cartilage: Technical Feasibility Ex Vivo MAGNETIC RESONANCE IN MEDICINE Qian, Y., Williams, A. A., Chu, C. R., Boada, F. E. 2010; 64 (5): 1427-1432

    View details for DOI 10.1002/mrm.22450

    View details for Web of Science ID 000283616900022

  • The association of osteoarthritis risk factors with localized, regional and diffuse knee pain OSTEOARTHRITIS AND CARTILAGE Thompson, L. R., Boudreau, R., Newman, A. B., Hannon, M. J., Chu, C. R., Nevitt, M. C., Kwoh, C. K. 2010; 18 (10): 1244-1249


    To identify determinants of different patterns of knee pain with a focus on risk factors for knee osteoarthritis (OA).The Knee Pain Map is an interviewer-administered assessment that asks subjects to characterize their knee pain as localized, regional, or diffuse. A total of 2677 participants from the Osteoarthritis Initiative were studied. We used multinomial logistic regression to examine the relationship between risk factors for OA and knee pain patterns. We examined the bivariate and multivariate relationships of knee pain pattern with age, body mass index (BMI), sex, race, family history of total joint replacement, knee injury, knee surgery, and hand OA.We compared 2462 knees with pain to 1805 knees without pain. In the bivariate analysis, age, sex, BMI, injury, surgery, and hand OA were associated with at least one pain pattern. In the multivariate model, all of these variables remained significantly associated with at least one pattern. When compared to knees without pain, higher BMI, injury, and surgery were associated with all patterns. BMI had its strongest association with diffuse pain. Older age was less likely to be associated with localized pain while female sex was associated with regional pain.We have shown that specific OA risk factors are associated with different knee pain patterns. Better understanding of the relationship between OA risk factors and knee pain patterns may help to characterize the heterogeneous subsets of knee OA.

    View details for DOI 10.1016/j.joca.2010.05.014

    View details for Web of Science ID 000283452600002

    View details for PubMedID 20633678

  • The Clinical Use of Human Culture-Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects: A Pilot Study and Preliminary Results CARTILAGE Haleem, A. M., El Singergy, A. A., Sabry, D., Atta, H. M., Rashed, L. A., Chu, C. R., El Shewy, M. T., Azzam, A., Aziz, M. T. 2010; 1 (4): 253-261


    OBJECTIVE: To test the hypothesis that platelet-rich fibrin glue (PR-FG) can be used clinically as a scaffold to deliver autologous culture-expanded bone marrow mesenchymal stem cells (BM-MSCs) for cartilage repair and to report clinical results 1 y after implantation of MSCs PR-FG. PATIENTS AND METHODS: Autologous BM-MSCs were culture expanded, placed on PR-FG intraoperatively, and then transplanted into 5 full-thickness cartilage defects of femoral condyles of 5 patients and covered with an autologous periosteal flap. Patients were evaluated clinically at 6 and 12 mo by the Lysholm and Revised Hospital for Special Surgery Knee (RHSSK) scores and radiographically by x-rays and magnetic resonance imaging (MRI) at the same time points. Repair tissue in 2 patients was rated arthroscopically after 12 mo using the International Cartilage Repair Society (ICRS) Arthroscopic Score. STUDY DESIGN: Case series; level of evidence 4. RESULTS: All patients' symptoms improved over the follow-up period of 12 mo. Average Lysholm and RHSSK scores for all patients showed statistically significant improvement at 6 and 12 mo postoperatively (P < 0.05). There was no statistically significant difference between the 6 and 12 mo postoperative clinical scores (P = 0.18). ICRS arthroscopic scores were 8/12 and 11/12 (nearly normal) for the 2 patients who consented to arthroscopy. MRI of 3 patients at 12 mo postoperatively revealed complete defect fill and complete surface congruity with native cartilage, whereas that of 2 patients showed incomplete congruity. CONCLUSION: Autologous BM-MSC transplantation on PR-FG as a cell scaffold may be an effective approach to promote the repair of articular cartilage defects of the knee in human patients.

    View details for DOI 10.1177/1947603510366027

    View details for Web of Science ID 000209217100001

  • Optical Coherence Tomography Detection of Subclinical Traumatic Cartilage Injury JOURNAL OF ORTHOPAEDIC TRAUMA Bear, D. M., Szczodry, M., Kramer, S., Coyle, C. H., Smolinski, P., Chu, C. R. 2010; 24 (9): 577-582


    Posttraumatic arthritis is a major cause of disability. Current clinical imaging modalities are unable to reliably evaluate articular cartilage damage before surface breakdown, when potentially reversible changes are occurring. Optical coherence tomography (OCT) is a nondestructive imaging technology that can detect degenerative changes in articular cartilage with an intact surface. This study tests the hypothesis that OCT detects acute articular cartilage injury after impact at energy levels resulting in chondrocyte death and microstructural changes, but insufficient to produce macroscopic surface damage.Bovine osteochondral cores underwent OCT imaging and were divided into a control with no impact or were subjected to low (0.175 J) or moderate (0.35 J) energy impact. Cores were reimaged with OCT after impact and the OCT signal intensity quantified. A ratio of the superficial to deep layer intensities was calculated and compared before and after impact. Chondrocyte viability was determined 1 day after impact followed by histology and polarized microscopy.Macroscopic changes to the articular surface were not observed after low and moderate impact. The OCT signal intensity ratio demonstrated a 27% increase (P = 0.006) after low impact and a 38% increase (P = 0.001) after moderate impact. Cell death increased by 150% (P < 0.001) and 200% (P < 0.001) after low and moderate energy impacts, respectively. When compared with unimpacted controls, both Mankin histology and David-Vaudey polarized microscopy scores increased (P = 0.036 and P = 0.002, respectively) after moderate energy impact.This study shows that OCT detects acute cartilage changes after impact injury at levels insufficient to cause visible damage to the articular surface but sufficient to cause chondrocyte death and microscopic matrix damage. This finding supports the use of OCT to detect microstructural subsurface cartilage damage that is poorly visualized with conventional imaging.

    View details for Web of Science ID 000281603100014

    View details for PubMedID 20736798

  • Clinical Optical Coherence Tomography of Early Articular Cartilage Degeneration in Patients With Degenerative Meniscal Tears ARTHRITIS AND RHEUMATISM Chu, C. R., Williams, A., Tolliver, D., Kwoh, C. K., Bruno, S., Irrgang, J. J. 2010; 62 (5): 1412-1420


    Quantitative and nondestructive methods for clinical diagnosis and staging of articular cartilage degeneration are important to the evaluation of potential disease-modifying treatments in osteoarthritis (OA). Optical coherence tomography (OCT) is a novel imaging technology that can generate microscopic-resolution cross-sectional images of articular cartilage in near real-time. This study tested the hypotheses that OCT can be used clinically to identify early cartilage degeneration and that OCT findings correlate with magnetic resonance imaging (MRI) T2 values and arthroscopy results.Patients undergoing arthroscopy for degenerative meniscal tears were recruited under Institutional Review Board-approved protocols. Thirty consecutive subjects completing preoperative 3.0T MRI, arthroscopy, and intraoperative OCT comprised the study group. Qualitative and quantitative OCT results and MRI T2 values were compared with modified Outerbridge cartilage degeneration scores (0-4 scale) assigned at arthroscopy.Arthroscopic grades showed cartilage abnormality in 23 of the 30 patients. OCT grades were abnormal in 28 of the 30 patients. Both qualitative and quantitative OCT strongly correlated with the arthroscopy results (P = 0.004 and P = 0.0002, respectively, by Kruskal-Wallis test). Neither the superficial nor the deep cartilage T2 values correlated with the arthroscopy results. The quantitative OCT results correlated with the T2 values in the superficial cartilage (Pearson's r = 0.39, P = 0.03).These data show that OCT can be used clinically to provide qualitative and quantitative assessments of early articular cartilage degeneration that strongly correlate with arthroscopy results. The correlation between the quantitative OCT values and T2 values for the superficial cartilage further supports the utility of OCT as a clinical research tool, providing quantifiable microscopic resolution data on the articular cartilage structure. New technologies for nondestructive quantitative assessment of human articular cartilage degeneration may facilitate the development of strategies to delay or prevent the onset of OA.

    View details for DOI 10.1002/art.27378

    View details for Web of Science ID 000279432400024

    View details for PubMedID 20213801

  • Assessing degeneration of human articular cartilage with ultra-short echo time (UTE) T-2* mapping OSTEOARTHRITIS AND CARTILAGE Williams, A., Qian, Y., Bear, D., Chu, C. R. 2010; 18 (4): 539-546


    To examine the sensitivity of ultra-short echo time (UTE) T(2)* mapping to collagen matrix degeneration in human articular cartilage.Magnetic resonance imaging (MRI) UTE-T(2)* maps and standard T(2) maps were acquired on four human tibial plateau explants. Thirty-three osteochondral cores were harvested for polarized light microscopy (PLM), and composition analyses. Collagen matrix integrity was evaluated from PLM and histological images. Matrix integrity and composition was compared to standard T(2) values and UTE-T(2)* values on a spatially registered basis.UTE-T(2)* values varied with matrix degeneration (P=0.008) and were lower in severely degraded cartilage compared to healthy tissue (P=0.012). A trend for higher UTE-T(2)* values in healthy tissue compared to mildly degenerate tissue (P=0.051) was detected. Standard T(2) values were not found to vary with matrix degeneration (P=0.13) but tended to be higher in severely degraded cartilage compared to healthy tissue. UTE-T(2)* value variations were independent of type-II collagen and glycosaminoglycan contents. UTE-T(2)* mapping of deep cartilage, adjacent to subchondral bone, was more robust than standard T(2) mapping in this zone.UTE-T(2)* mapping of articular cartilage is sensitive to matrix degeneration and detects short-T(2) signal, particularly in deep tissue, that is not well captured by standard T(2) mapping. Correlation of UTE-T(2)* values and PLM indices supports the hypothesis that both may be sensitive to collagen microstructure. Further exploration of UTE-T(2)* mapping as a non-invasive tool to detect early articular cartilage degeneration is warranted.

    View details for DOI 10.1016/j.joca.2010.02.001

    View details for Web of Science ID 000276867900008

    View details for PubMedID 20170769

  • Optical Coherence Tomography Grading Correlates with MRI T2 Mapping and Extracellular Matrix Content JOURNAL OF ORTHOPAEDIC RESEARCH Bear, D. M., Williams, A., Chu, C. T., Coyle, C. H., Chu, C. R. 2010; 28 (4): 546-552


    Optical coherence tomography (OCT) and T2 mapping are emerging clinical imaging technologies with potential to detect subsurface changes in cartilage retaining a macroscopically intact articular surface. This study tests the hypothesis that OCT correlates with magnetic resonance imaging (MRI) T2 values, and that OCT signal is sensitive to cartilage matrix degeneration. Forty-five osteochondral cores were harvested from five human tibial plateau explants after MRI T2 mapping. Cores underwent OCT imaging and were graded as follows: A, obvious birefringence; B, no birefringence; C, subsurface voids and/or irregular surface. Extracellular matrix content was determined and cores underwent histologic and polarized light microscopy (PLM) evaluation. Grade B and C cores had 25% higher superficial T2 values (p = 0.047) and 50% higher deep T2 values (p = 0.012) than grade A cores. Grade B and C cores had 36% higher glycosaminoglycan (GAG) content compared to grade A cores (p = 0.009). Histology and PLM demonstrated increased surface irregularity and structural disorganization with increasing OCT grade. OCT grade and T2 value increased with increasing collagen disorganization, suggesting that MRI T2 mapping and OCT are sensitive to changes in collagen structure. Our results demonstrate the ability of OCT and T2 mapping to detect early cartilage degeneration in clinically normal appearing cartilage.

    View details for DOI 10.1002/jor.20998

    View details for Web of Science ID 000275958900020

    View details for PubMedID 19834953

  • In vivo effects of single intra-articular injection of 0.5% bupivacaine on articular cartilage. journal of bone and joint surgery. American volume Chu, C. R., Coyle, C. H., Chu, C. T., Szczodry, M., Seshadri, V., Karpie, J. C., Cieslak, K. M., Pringle, E. K. 2010; 92 (3): 599-608


    Single intra-articular injections of local anesthetics are commonly used clinically. Recent in vitro studies have demonstrated chondrotoxic effects of local anesthetics, with the greatest emphasis on bupivacaine toxicity. This in vivo study was conducted to determine whether a single intra-articular injection of 0.5% bupivacaine results in chondrocyte morbidity and rapid chondrolysis.Forty-eight Sprague-Dawley rats received a 100-microL injection of sterile 0.9% saline solution (negative control) into one stifle joint and 100 microL of either preservative-free 0.5% bupivacaine (experimental group) or 0.6 mg/mL monoiodoacetate (positive control) into the contralateral joint. The rats were killed at one week, four weeks, twelve weeks, or six months. Live and dead cells were quantified with use of three-dimensional confocal reconstructions of fluorescent-stained tissues at standardized locations on the distal part of the femur. Histological findings were graded with use of a modified Mankin score, and cell density was quantified with use of custom image-analysis software.In the specimens injected with bupivacaine, the chondral surfaces remained intact as seen with gross and histological examination. No differences in superficial chondrocyte viability or modified Mankin scores were observed between the saline-solution and bupivacaine groups at any location or time point (p > 0.05). Quantitative histological analysis of the bupivacaine-treated knees at six months revealed an up to 50% reduction in chondrocyte density compared with that of the saline-solution-treated knees (p < or = 0.01). Monoiodoacetate injection resulted in death of up to 87% of the superficial chondrocyte cells at one week and chondrolysis at six months. Despite severe histological abnormalities by four weeks after monoiodoacetate injection, cartilage injury was not evident on gross inspection until six months.This in vivo study showing reduced chondrocyte density without cartilage tissue loss six months after a single intra-articular injection of 0.5% bupivacaine suggests bupivacaine toxicity. The effects of bupivacaine were milder than those of an injection of 0.6% monoiodoacetate, which resulted in chondrolysis over the same time period.

    View details for DOI 10.2106/JBJS.I.00425

    View details for PubMedID 20194318

  • Novel multiarm PEG-based hydrogels for tissue engineering JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Tan, H., DeFail, A. J., Rubin, J. P., Chu, C. R., Marra, K. G. 2010; 92A (3): 979-987
  • In Vivo Effects of Single Intra-Articular Injection of 0.5% Bupivacaine on Articular Cartilage JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME Chu, C. R., Coyle, C. H., Chu, C. T., Szczodry, M., Seshadri, V., Karpie, J. C., Cieslak, K. M., Pringle, E. K. 2010; 92A (3): 599-608
  • Novel multiarm PEG-based hydrogels for tissue engineering. Journal of biomedical materials research. Part A Tan, H., DeFail, A. J., Rubin, J. P., Chu, C. R., Marra, K. G. 2010; 92 (3): 979-987


    Injectable scaffolds are promising substrates for regenerative medicine applications. In this study, multiarm amino-terminated poly(ethylene glycol) (PEG) hydrogels were crosslinked with genipin, a compound naturally derived from the gardenia fruit. Four- and eight-arm amino-terminated PEG hydrogels crosslinked with varying concentrations of genipin were characterized. Both surface and cross-sectional structures of PEG-based hydrogels were observed by scanning electron microscopy. In vitro gelation time, water uptake, swelling, and weight loss of PEG hydrogels in phosphate buffered saline at 37 degrees C were studied. The results showed that the eight-arm PEG demonstrated a much slower gelation time compared with the four-arm PEG, which may be due to the differing structures of the multiarm PEG hydrogels, which in turn affects the ability of genipin to react with the amine groups. Human adipose-derived stem cells were seeded onto the four- and eight-arm PEG hydrogels in vitro to assess the biological performance and applicability of the gels as cell carriers. The four-arm PEG hydrogel resulted in enhanced cell adhesion when compared with the eight-arm PEG hydrogel. Overall, these characteristics provide a potential opportunity for multiarm PEG hydrogels as injectable scaffolds in a variety of tissue engineering applications.

    View details for DOI 10.1002/jbm.a.32438

    View details for PubMedID 19291691

  • Animal Models for Cartilage Regeneration and Repair TISSUE ENGINEERING PART B-REVIEWS Chu, C. R., Szczodry, M., Bruno, S. 2010; 16 (1): 105-115


    Articular cartilage injury and degeneration are leading causes of disability. Animal studies are critically important to developing effective treatments for cartilage injuries. This review focuses on the use of animal models for the study of the repair and regeneration of focal cartilage defects. Animals commonly used in cartilage repair studies include murine, lapine, canine, caprine, porcine, and equine models. There are advantages and disadvantages to each model. Small animal rodent and lapine models are cost effective, easy to house, and useful for pilot and proof-of-concept studies. The availability of transgenic and knockout mice provide opportunities for mechanistic in vivo study. Athymic mice and rats are additionally useful for evaluating the cartilage repair potential of human cells and tissues. Their small joint size, thin cartilage, and greater potential for intrinsic healing than humans, however, limit the translational value of small animal models. Large animal models with thicker articular cartilage permit study of both partial thickness and full thickness chondral repair, as well as osteochondral repair. Joint size and cartilage thickness for canine, caprine, and mini-pig models remain significantly smaller than that of humans. The repair and regeneration of chondral and osteochondral defects of size and volume comparable to that of clinically significant human lesions can be reliably studied primarily in equine models. While larger animals may more closely approximate the human clinical situation, they carry greater logistical, financial, and ethical considerations. A multifactorial analysis of each animal model should be carried out when planning in vivo studies. Ultimately, the scientific goals of the study will be critical in determining the appropriate animal model.

    View details for DOI 10.1089/ten.teb.2009.0452

    View details for Web of Science ID 000274423200011

    View details for PubMedID 19831641

  • Progressive Chondrocyte Death After Impact Injury Indicates a Need for Chondroprotective Therapy AMERICAN JOURNAL OF SPORTS MEDICINE Szczodry, M., Coyle, C. H., Kramer, S. J., Smolinski, P., Chu, C. R. 2009; 37 (12): 2318-2322


    Impact injury to articular cartilage can lead to posttraumatic osteoarthritis.This study tests the hypotheses that (1) chondrocyte injury occurs after impact at energies insufficient to fracture the cartilage surface, and that (2) cartilage injury patterns vary with impact energy, time after injury, and cartilage thickness.Controlled laboratory study.Fresh bovine osteochondral cores were randomly divided into 5 groups: (1) control, (2) 0.35 J, (3) 0.71 J, (4) 1.07 J, and (5) 1.43 J impact energies. Cores were subjected to computer-controlled impact loading and full-thickness sections were then prepared and incubated in Dulbecco's Modified Eagle's Medium/F12 at 37 degrees C. Adjacent sections were harvested 1 and 4 days after impact for viability staining and fluorescent imaging. The area of dead and living chondrocytes was quantified using custom image analysis software and reported as a percentage of total cartilage area.The highest impact energy fractured the cartilage in all cores (1.43 J, n = 17). Seventy-three percent and 64% of the osteochondral cores remained intact after lower energy impacts of 0.71 J and 1.07 J, respectively. At lower energy levels, fractured cores were thinner (P <.01) than those remaining intact. In cores remaining intact after impact injury, chondrocyte death increased with increasing impact energy (P <.05) and with greater time after impact (P <.05). A progressive increase in dead cells near the bone/cartilage interface and at the articular surface was observed.These data showing progressive chondrocyte death after impact injury at energies insufficient to fracture the cartilage surface demonstrate a potential need for early chondroprotective therapy.These data show that efforts to reduce chondrocyte morbidity after joint injury may be a useful strategy to delay or prevent the onset of posttraumatic osteoarthritis.

    View details for DOI 10.1177/0363546509348840

    View details for Web of Science ID 000272180500003

    View details for PubMedID 19864505

  • The Knee Pain Map: Reliability of a Method to Identify Knee Pain Location and Pattern ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH Thompson, L. R., Boudreau, R., Hannon, M. J., Newman, A. B., Chu, C. R., Jansen, M., Nevitt, M. C., Kwoh, C. K. 2009; 61 (6): 725-731


    To describe the location and pattern of knee pain in patients with chronic, frequent knee pain using the Knee Pain Map, and to evaluate the inter- and intrarater reliability of the map.A cohort of 799 participants from the University of Pittsburgh Osteoarthritis Initiative Clinical Center who had knee pain in the last 12 months were studied. Trained interviewers assessed and recorded participant-reported knee pain patterns into 8 local areas, 4 regional areas, or as diffuse. Inter- and intrarater reliability were assessed using Fleiss' kappa.Participants most often reported localized (69%) followed by regional (14%) or diffuse (10%) knee pain. In those with localized pain, the most commonly reported locations were the medial (56%) and lateral (43%) joint lines. In those with regional pain, the most commonly reported regions were the patella (44%) and medial region (38%). There was excellent interrater reliability for the identification of localized and regional pain patterns (kappa = 0.7-0.9 and 0.7-0.8, respectively). The interrater reliability for specific locations was also excellent (kappa = 0.7-1.0) when the number of participants with pain in a location was >4. For regional pain, the kappa for specific regions varied from 0.7-1.0.The majority of participants could identify the location of their knee pain, and trained interviewers could reliably record those locations. The variation in locations suggests that there are multiple sources of pain in knee OA. Additional studies are needed to determine whether specific knee pain patterns correlate with discrete pathologic findings on radiographs or magnetic resonance images.

    View details for DOI 10.1002/art.24543

    View details for Web of Science ID 000267115300003

    View details for PubMedID 19479703

  • Sustained Hypoxia Enhances Chondrocyte Matrix Synthesis JOURNAL OF ORTHOPAEDIC RESEARCH Coyle, C. H., Izzo, N. J., Chu, C. R. 2009; 27 (6): 793-799


    Articular cartilage is an avascular tissue with chondrocytes in the deeper zones existing under conditions of sustained hypoxia. Using a hypoxic chamber to provide controlled hypoxia, this study was performed to determine whether sustained hypoxia enhances the production of cartilage matrix proteins. Freshly isolated primary bovine articular chondrocytes were encapsulated in three-dimensional alginate beads and maintained at 2% oxygen with media changes using media pre-equilibrated to 2% oxygen. Immunolocalization of HIF-1alpha was performed to verify hypoxic conditions. Sustained hypoxia resulted in an increase in proteoglycan synthesis after only 1 day, as measured by 35S-sulfate incorporation. This increase was maintained for the duration of the 17 day study. After 17 days of hypoxic culture, increases in total type II collagen and COL2A1 gene expression were probed by indirect immunofluorescence, type II collagen ELISA, and real-time qPCR; in addition, increased glycosaminoglycan deposition was observed as determined by chemical analysis. These studies show that sustained hypoxia enhances articular chondrocyte matrix synthesis and viability in three-dimensional alginate culture.

    View details for DOI 10.1002/jor.20816

    View details for Web of Science ID 000266123100015

    View details for PubMedID 19051248

  • Injectable in situ forming biodegradable chitosan-hyaluronic acid based hydrogels for cartilage tissue engineering BIOMATERIALS Tan, H., Chu, C. R., Payne, K. A., Marra, K. G. 2009; 30 (13): 2499-2506


    Injectable, biodegradable scaffolds are important biomaterials for tissue engineering and drug delivery. Hydrogels derived from natural polysaccharides are ideal scaffolds as they resemble the extracellular matrices of tissues comprised of various glycosaminoglycans (GAGs). Here, we report a new class of biocompatible and biodegradable composite hydrogels derived from water-soluble chitosan and oxidized hyaluronic acid upon mixing, without the addition of a chemical crosslinking agent. The gelation is attributed to the Schiff base reaction between amino and aldehyde groups of polysaccharide derivatives. In the current work, N-succinyl-chitosan (S-CS) and aldehyde hyaluronic acid (A-HA) were synthesized for preparation of the composite hydrogels. The polysaccharide derivatives and composite hydrogels were characterized by FTIR spectroscopy. The effect of the ratio of S-CS and A-HA on the gelation time, microstructure, surface morphology, equilibrium swelling, compressive modulus, and in vitro degradation of composite hydrogels was examined. The potential of the composite hydrogel as an injectable scaffold was demonstrated by the encapsulation of bovine articular chondrocytes within the composite hydrogel matrix in vitro. The results demonstrated that the composite hydrogel supported cell survival and the cells retained chondrocytic morphology. These characteristics provide a potential opportunity to use the injectable, composite hydrogels in tissue engineering applications.

    View details for DOI 10.1016/j.biomaterials.2008.12.080

    View details for Web of Science ID 000264691200009

    View details for PubMedID 19167750

  • Lidocaine Potentiates the Chondrotoxicity of Methylprednisolone ARTHROSCOPY-THE JOURNAL OF ARTHROSCOPIC AND RELATED SURGERY Seshadri, V., Coyle, C. H., Chu, C. R. 2009; 25 (4): 337-347


    This study examined the viability of bovine articular chondrocytes after exposure to methylprednisolone, methylprednisolone with lidocaine, and methylprednisolone in a simulated inflammatory environment.Bovine articular chondrocytes were suspended in alginate beads and cultured in Dulbecco's modified Eagle's medium/F-12 for 1 week before experimentation. Suspended chondrocytes were exposed to 0.9% saline solution (negative control), methylprednisolone (4, 8, and 16 mg/mL), methylprednisolone (8 mg/mL) with 1% lidocaine, or methylprednisolone (8 mg/mL) and saline solution in a simulated inflammatory environment (interleukin [IL] 1beta exposure, 10 ng/mL) for 15, 30, and 60 minutes. Flow cytometry was performed 1 day, 4 days, and 7 days after exposure by use of annexin V and propidium iodide to assess chondrocyte viability.Chondrocyte viability decreased from 84% in saline solution to 62%, 38%, and 2.4% 1 day after 60 minutes of exposure to 4, 8, and 16 mg/mL of methylprednisolone, respectively (n = 7, P < .05). Chondrotoxicity increased with increasing time of exposure to methylprednisolone and with increasing time after exposure. In IL-1beta-activated chondrocytes, viability decreased from 76% in saline solution to 2.9% after 60 minutes of methylprednisolone exposure (8 mg/mL) (n = 4, P < .05). The combination of 8 mg/mL of methylprednisolone and 1% lidocaine further reduced viability to 1.0% after 60 minutes (n = 4, P < .05).These results show a dose- and time-dependent decrease in chondrocyte viability after exposure to clinically relevant doses of methylprednisolone. The combination of methylprednisolone and lidocaine was toxic, with virtually no cells surviving after treatment. In addition, methylprednisolone did not mitigate the inflammatory effects of IL-1beta; rather, it further potentiated the chondrotoxicity.Intra-articular injections of corticosteroids and local anesthetics are widely used in clinical practice. This in vitro study provides information on the potential effects of these drugs on articular cartilage.

    View details for DOI 10.1016/j.arthro.2009.01.003

    View details for Web of Science ID 000264980500002

    View details for PubMedID 19341919

  • The Role of the Biochemical and Biophysical Environment in Chondrogenic Stem Cell Differentiation Assays and Cartilage Tissue Engineering CELL BIOCHEMISTRY AND BIOPHYSICS Wescoe, K. E., Schugar, R. C., Chu, C. R., Deasy, B. M. 2008; 52 (2): 85-102


    The field of regenerative medicine offers hope for the development of a cell-based therapy for the repair of articular cartilage (AC). Yet, the greatest challenge in the use of stem cells for tissue repair, is understanding how the cells respond to stimuli and using that knowledge to direct cell fate. Novel methods that utilize stem cells in cartilage regeneration will require specific spatio-temporal controls of the biochemical and biophysical signaling environments. Current chondrogenic differentiation research focuses on the roles of biochemical stimuli like growth factors, hormones, and small molecules, and the role of the physical environment and mechanical stimuli, such as compression and shear stress, which likely act through mechanical receptors. Numerous signals are associated with chondrogenic-like activity of cells in different systems, however many variables for a controlled method still need to be optimized; e.g., spatial and temporal application of the stimuli, and time of transplantation of an engineered construct. Understanding the necessary microenvironmental signals for cell differentiation will advance cell therapy for cartilage repair.

    View details for DOI 10.1007/s12013-008-9029-0

    View details for Web of Science ID 000260064500002

    View details for PubMedID 18841496

  • The in vitro effects of bupivacaine on articular chondrocytes. journal of bone and joint surgery. British volume Chu, C. R., Izzo, N. J., Coyle, C. H., Papas, N. E., Logar, A. 2008; 90 (6): 814-820


    We have studied the effects of bupivacaine on human and bovine articular chondrocytes in vitro. Time-lapse confocal microscopy of human articular chondrocytes showed > 95% cellular death after exposure to 0.5% bupivacaine for 30 minutes. Human and bovine chondrocytes exposed to 0.25% bupivacaine had a time-dependent reduction in viability, with longer exposure times resulting in higher cytotoxicity. Cellular death continued even after removal of 0.25% bupivacaine. After exposure to 0.25% bupivacaine for 15 minutes, flow cytometry showed bovine chondrocyte viability to be 41% of saline control after seven days. After exposure to 0.125% bupivacaine for up to 60 minutes, the viability of both bovine and human chondrocytes was similar to that of control groups. These data show that prolonged exposure 0.5% and 0.25% bupivacaine solutions are potentially chondrotoxic.

    View details for DOI 10.1302/0301-620X.90B6.20079

    View details for PubMedID 18539679

  • The in vitro effects of bupivacaine on articular chondrocytes JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME Chu, C. R., Izzo, N. J., Coyle, C. H., Papas, N. E., Logar, A. 2008; 90B (6): 814-820
  • Optimizing CO2 normalizes pH and enhances chondrocyte viability during cold storage JOURNAL OF ORTHOPAEDIC RESEARCH Dontchos, B. N., Coyle, C. H., Izzo, N. J., Didiano, D. M., Karpie, J. C., Logar, A., Chu, C. R. 2008; 26 (5): 643-650


    Fresh osteochondral allografts are an important treatment option for the repair of full-thickness articular cartilage defects. Viable chondrocytes within the transplanted tissue are considered important to maintaining matrix integrity. The purpose of this study is to determine whether an increase in pH decreases chondrocyte viability during cold storage and whether equilibration of Dulbecco's modified Eagle's medium (DMEM) in 5% CO(2) normalizes pH and increases chondrocyte survival during storage at 4 degrees C. Freshly isolated bovine articular chondrocytes cultured in alginate beads were stored for up to 5 days at 4 degrees C or 37 degrees C in DMEM exposed to ambient air or in DMEM equilibrated with 5% CO(2). Chondrocyte viability was determined by flow cytometry. Physiologic pH was maintained when DMEM was equilibrated with 5% CO(2), while pH increased in ambient air. After 5 days of storage at 4 degrees C, chondrocyte necrosis was higher when stored in ambient air than if equilibrated with 5% CO(2). No decrease in chondrocyte viability was observed with storage at 37 degrees C. In addition, chondrocyte viability in bovine cartilage osteochondral cores was examined after storage for 14 days at 4 degrees C in DMEM with and without HEPES, and with and without 5% CO(2). Under these conditions, the superficial layer of chondrocytes was more viable when stored in DMEM with HEPES or DMEM equilibrated with 5% CO(2) than when stored in DMEM in ambient air. This data shows that an increase in pH decreased bovine chondrocyte viability when refrigerated at 4 degrees C in DMEM, and that optimization of CO(2) normalized pH and improved chondrocyte viability during cold storage in DMEM.

    View details for Web of Science ID 000254960700008

    View details for PubMedID 18050310

  • The 2007 ABC Traveling Fellowship: building international orthopaedic bridges. journal of bone and joint surgery. American volume Chu, C. R., Antoniou, J., Donley, B. G., Frick, S. L., Hilibrand, A. S., Ricci, W. M., Younger, A. S. 2008; 90 (3): 672-674

    View details for DOI 10.2106/JBJS.G.01127

    View details for PubMedID 18310717

  • Lidocaine exhibits dose- and time-dependent cytotoxic effects on bovine articular chondrocytes in vitro AMERICAN JOURNAL OF SPORTS MEDICINE Karpie, J. C., Chu, C. R. 2007; 35 (10): 1621-1627


    Intra-articular lidocaine is commonly used.This study was conducted to determine whether short-term exposures to 1% and 2% lidocaine are toxic to articular chondrocytes, whether this is due to pH, and whether an intact articular surface is protective.Controlled laboratory study.Fresh bovine articular chondrocytes in alginate bead cultures were treated with 1% or 2% lidocaine or buffered saline (pH 7.4, 7.0, and 5.0) for 15, 30, or 60 minutes. Chondrocytes were then analyzed for viability by flow cytometry 1 hour, 1 day, and 1 week later. Bovine osteochondral cores with and without the superficial 1 mm of cartilage removed were submerged in either 0.9% saline (pH 7.4) or in 1% or 2% lidocaine for 30 minutes and assessed for viability using fluorescent microscopy.Chondrocyte viability decreased after just 15-minute exposures to 1% lidocaine. Longer exposures to 1% and 2% lidocaine further reduced chondrocyte viability. Chondrotoxicity of 2% lidocaine was greater than 1% lidocaine. There was no difference in chondrocyte viability after exposures to saline solutions of pH 7.4, 7.0, or 5.0. An intact articular surface did not affect lidocaine's chondrotoxic effects.Results show dose- and time-dependent cytotoxic effects of lidocaine on bovine articular chondrocytes. Reduction of pH alone did not decrease chondrocyte viability, and the intact articular surface was not protective.Although lidocaine chondrotoxicity was less than previously reported with bupivacaine, these observations suggest that local anesthetics as a class of drugs may negatively affect articular cartilage.

    View details for DOI 10.1177/0363546507304719

    View details for Web of Science ID 000250049800002

    View details for PubMedID 17664340

  • Clinical diagnosis of potentially treatable early articular cartilage degeneration using optical coherence tomography Conference on Water Environment-Membrane Technology Chu, C. R., Izzo, N. J., Irrgang, J. J., Ferretti, M., Studer, R. K. SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS. 2007


    A series of bench to operating room studies was conducted to determine whether it is feasible to use optical coherence tomography (OCT) clinically to diagnose potentially reversible early cartilage degeneration. A human cadaver study was performed to confirm the reproducibility of OCT imaging and grading based on identification of changes to cartilage OCT form birefringence using a polarized OCT system approved for clinical use. Segregation of grossly normal appearing human articular cartilage into two groups based on the presence or absence of OCT form birefringence showed that cartilage without OCT form birefringence had reduced ability to increase proteoglycan synthetic activity in response to the anabolic growth factor IGF-1. The bench data further show that IGF-1 insensitivity in cartilage without OCT form birefringence was reversible. To show clinical feasibility, OCT was then used arthroscopically in 19 human subjects. Clinical results confirmed that differences to OCT form birefringence observed in ex vivo study were detectable during arthroscopic surgery. More prevalent loss of cartilage OCT form birefringence was observed in cartilage of human subjects in groups more likely to have cartilage degeneration. This series of integrated bench to bedside studies demonstrates translational feasibility to use OCT for clinical studies on whether human cartilage degeneration can be diagnosed early enough for intervention that may delay or prevent the onset of osteoarthritis.

    View details for DOI 10.1117/1.2789674

    View details for Web of Science ID 000251549600019

    View details for PubMedID 17994876

  • Adeno-associated viral gene transfer of transforming growth factor-beta 1 to human mesenchymal stem cells improves cartilage repair GENE THERAPY Pagnotto, M. R., Wang, Z., Karpie, J. C., Ferretti, M., Xiao, X., Chu, C. R. 2007; 14 (10): 804-813


    Bone marrow cells are routinely accessed clinically for cartilage repair. This study was performed to determine whether adeno-associated virus (AAV) effectively transduces human bone marrow-derived mesenchymal stem cells (hMSC) in vitro, whether AAV infection interferes with hMSC chondrogenesis and whether AAV-transforming growth factor-beta-1 (TGF-beta1)-transduced hMSC can improve cartilage repair in vivo. Adult hMSC were transduced with AAV-green fluorescent protein (GFP) or AAV-transforming growth factor beta1 (TGF beta1) and studied in pellet cultures. For in vivo studies, AAV-GFP and AAV-TGF-beta1-transduced hMSCs were implanted into osteochondral defects of 21 athymic rats. GFP was detected using fluorescent microscopy. Cartilage repair was assessed using gross and histological analysis at 4, 8 and 12 weeks. In pellet culture, GFP expression was visualized in situ through 21 days in vitro. In vivo GFP transgene expression was observed by in situ fluorescent surface imaging in 100% of GFP implanted defects at 2 , 67% at 8 and 17% at 12 weeks. Improved cartilage repair was observed in osteochondral defects implanted with AAV-TGF-beta1-transduced hMSC at 12 weeks (P=0.0047). These results show that AAV is a suitable vector for gene delivery to improve the cartilage repair potential of human mesenchymal stem cells.

    View details for DOI 10.1038/

    View details for Web of Science ID 000246210900003

    View details for PubMedID 17344902

  • Controlled in vivo degradation of genipin crosslinked polyethylene glycol hydrogels within osteochondral defects TISSUE ENGINEERING Ferretti, M., Marra, K. G., Kobayashi, K., DeFail, A. J., Chu, C. R. 2006; 12 (9): 2657-2663


    Polyethylene glycol (PEG) hydrogels show promise as scaffolds for growth factor delivery to enhance cartilage repair. However, methods to control growth factor release in vivo are needed. We have recently shown that in vitro polymer degradation and in vitro growth factor release kinetics can be altered using PEG crosslinked with different concentrations of genipin. However, the degradation and behavior of PEG-genipin in vivo within the cartilage repair site are unknown. This study was conducted to test the hypotheses that the degradation of PEG-genipin can be altered in vivo within osteochondral defects by changing the concentration of genipin, and that PEG-genipin is biocompatible within the mammalian diarthrodial environment. PEG-genipin cylindrical polymers crosslinked using 8mM, 17.6 mM, or 35.2 mM of genipin were implanted into osteochondral defects made in the trochlea of 24 male Sprague- Dawley rats (48 knees). Rats were sacrificed at 5 weeks and gross, cross-sectional, and histologic assessments were performed. Altering the genipin concentration changed the in vivo degradation properties of the hydrogel ( p < 0.01). Consistent with in vitro findings, polymer degradation was inversely related to the concentration of genipin. Near-complete degradation was seen at 8 mM, intermediate degradation at 17.6 mM, and minimal degradation at 35.2 mM. The results of this study show the degradation of PEGgenipin can be altered in vivo within osteochondral defects by changing the concentration of genipin and that PEG-genipin is biocompatible within osteochondral defects. This new in vivo data support potential use of PEG-genipin polymer as an innovative delivery system to control in vivo release of growth factors for improving articular cartilage repair.

    View details for Web of Science ID 000240780900026

    View details for PubMedID 16995799

  • In vitro exposure to 0.5% bupivacaine is cytotoxic to bovine articular chondrocytes ARTHROSCOPY-THE JOURNAL OF ARTHROSCOPIC AND RELATED SURGERY Chu, C. R., Izzo, N. J., Papas, N. E., Fu, F. H. 2006; 22 (7): 693-699


    Intra-articular use of 0.5% bupivacaine is common in arthroscopic surgery. This study was conducted to test the hypotheses that (1) 0.5% bupivacaine is toxic to articular chondrocytes, and (2) the intact articular surface protects chondrocytes from the effects of short-term exposure to 0.5% bupivacaine.Freshly isolated bovine articular chondrocytes were prepared into alginate bead cultures and were treated with 0.5% bupivacaine solution or 0.9% saline for 15, 30 or 60 minutes, washed, and returned to growth media. Chondrocytes were recovered from alginate 1 hour, 1 day, and 1 week after bupivacaine exposure; they were fluorescently labeled to identify apoptotic and dead cells and were analyzed by flow cytometry. Twelve osteochondral cores were harvested from bovine knees. The superficial 1 mm of cartilage was removed from 6 cores (top-off). Intact and top-off cores were submerged in 0.9% saline or 0.5% bupivacaine solution for 30 minutes and then maintained in chondrocyte growth media for 24 hours. Live-cell/dead-cell fluorescent imaging was assessed using confocal microscopy.Greater than 99% chondrocyte death/apoptosis was observed in all bupivacaine-exposed alginate bead cultures compared with 20% cell death in saline-treated controls (P < .05). Osteochondral cores with intact surfaces treated with 0.5% bupivacaine showed 42% dead chondrocytes. When the articular surface was removed, 0.5% bupivacaine resulted in increased cell death, with 75% dead chondrocytes (P < .05).Results show that 0.5% bupivacaine solution is cytotoxic to bovine articular chondrocytes and articular cartilage in vitro after only 15 to 30 minutes' exposure. The intact bovine articular surface has some chondroprotective effects.Because healthy chondrocytes are important for maintenance of the cartilage matrix, chondrocyte loss may contribute to cartilage degeneration. This study shows a cytotoxic effect of 0.5% bupivacaine solution on bovine articular chondrocytes in vitro. Although these results cannot be directly extrapolated to the clinical setting, the data suggest that caution should be exercised in the intra-articular use of 0.5% bupivacaine.

    View details for DOI 10.1016/j.arthro.2006.05.006

    View details for Web of Science ID 000239630100001

    View details for PubMedID 16843803

  • Controlled release of bioactive TGF-beta(1) from microspheres embedded within biodegradable hydrogels BIOMATERIALS DeFail, A. J., Chu, C. R., Izzo, N., Marra, K. G. 2006; 27 (8): 1579-1585


    Transforming growth factor-beta1 (TGF-beta1) is of great relevance to cartilage development and regeneration. A delivery system for controlled release of growth factors such as TGF-beta1 may be therapeutic for cartilage repair. We have encapsulated TGF-beta1 into poly(DL-lactide-co-glycolide) (PLGA) microspheres, and subsequently incorporated the microspheres into biodegradable hydrogels. The hydrogels are poly(ethylene glycol) based, and the degradation rate of the hydrogels is controlled by the non-toxic cross-linking reagent, genipin. Release kinetics of TGF-beta1 were assessed using ELISA and the bioactivity of the released TGF-beta1 was evaluated using a mink lung cell growth inhibition assay. The controlled release of TGF-beta1 encapsulated within microspheres embedded in scaffolds is better controlled when compared to delivery from microspheres alone. ELISA results indicated that TGF-beta1 was released over 21 days from the delivery system, and the burst release was decreased when the microspheres were embedded in the hydrogels. The concentration of TGF-beta1 released from the gels can be controlled by both the mass of microspheres embedded in the gel, and by the concentration of genipin. Additionally, the scaffold permits containment and conformation of the spheres to the defect shape. Based on these in vitro observations, we predict that we can develop a microsphere-loaded hydrogel for controlled release of TGF-beta1 to a cartilage wound site.

    View details for DOI 10.1016/j.biomaterials.2005.08.013

    View details for Web of Science ID 000234731900045

    View details for PubMedID 16140372

  • Adenoviral-mediated transfer of TGF-beta 1 but not IGF-1 induces chondrogenic differentiation of human mesenchymal stem cells in pellet cultures EXPERIMENTAL HEMATOLOGY Kawamura, K., Chu, C. R., Sobajima, S., Robbins, P. D., Fu, F. H., Izzo, N. J., Niyibizi, C. 2005; 33 (8): 865-872


    The objective of the present study was to investigate the potential of application of growth factor genes to induce chondrogenic differentiation of human-derived mesenchymal stem cells (MSCs). The growth factor genes evaluated in the present study were transforming growth factor 1 (TGF-beta1) and insulin-like growth factor 1 (IGF-1).Human MSCs were transduced with the adenoviral vectors carrying either TGF-beta1 or IGF-1 (AdTGF-beta1 and AdIGF-1 respectively) or a combination of both growth factor genes at different multiplicities of infection (MOI) and were then made into pellets. Pellets were also made from nontransduced cells and maintained in culture medium supplemented with 10 ng/mL of TGF-beta1. At specified time points, histological analysis, cartilage matrix gene expression, and immunofluorescence were performed to determine the extent of chondrogenic differentiation.MSCs transduced with the AdTGF-beta1 demonstrated robust chondrogenic differentiation, while those made from AdIGF-1 did not. AdTGF-beta1 pellets demonstrated aggrecan gene expression as early as day 3 of pellet culture, while type II collagen gene expression was detected by day 10 of culture. The AdIGF-1, alone or in combination with TGF-beta1 pellets, did not show any type II collagen gene expression at any time point. By immunofluoresecence, type X collagen was distributed throughout the matrix in TGF-beta1 protein pellets while the growth factor gene pellets displayed scant staining.The results suggest that sustained administration of TGF-beta1 may be more effective in suppressing terminal differentiation than intermittent dosing and thus effective for cartilage repair.

    View details for DOI 10.1016/j.exphem.2005.05.010

    View details for Web of Science ID 000231238400003

    View details for PubMedID 16038778

  • p38 MAPK and COX2 inhibition modulate human chondrocyte response to TGF-beta JOURNAL OF ORTHOPAEDIC RESEARCH Studer, R. K., Chu, C. R. 2005; 23 (2): 454-461


    These studies compare actions of p38 MAPK inhibition and COX2 inhibition to modulate human arthritic chondrocyte responses to TGF-beta and FCS under basal and IL-1 activated conditions. Chondrocytes isolated from arthritic human femoral condyle cartilage obtained at total knee replacement were grown to 80% confluence. Proteoglycan synthesis and proliferation were measured with and without IL-1 activation in the presence and absence of growth factors and with and without inhibition of p38 MAPK or COX2 activity. Experiments to evaluate TIMP-1 production under these conditions were done using cartilage organ cultures. Neither p38 MAPK inhibitors nor COX2 inhibition affected basal proliferation. However both inhibitors enhanced the proliferative response to TGF-beta and FCS in IL-1 activated chondrocytes. TGF-beta stimulated proteoglycan synthesis was decreased by p38 MAPK inhibition, however COX2 inhibition restored the response to TGF-beta in IL-1 activated cells. In contrast, COX2 inhibition did not modulate TIMP-1 production while p38 MAPK inhibitors potentiated TGF-beta stimulated production of TIMP-1 in IL-1 activated cartilage. p38 MAPK inhibition and COX2 inhibition have unique and similar abilities to counteract some of the effects of IL-1 on human chondrocyte/cartilage metabolism. Both will partially restore the proliferative response to growth factors. p38 MAPK inhibition blunts TGF-beta stimulation of proteoglycan synthesis, but increases TIMP-1 synthesis. COX2 inhibition can restore the proteoglycan synthetic response to TGF-beta, but has no effect on cartilage TIMP-1 production. Use of these inhibitors to minimize cartilage damage in arthritic and mechanically stressed joints should reflect these characteristics.

    View details for DOI 10.1016/j.orthres.2004.08.012

    View details for Web of Science ID 000227567100032

    View details for PubMedID 15734262

  • Mini-pig fresh osteochondral allografts deteriorate after 1 week of cold storage CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Rohde, R. S., Studer, R. K., Chu, C. R. 2004: 226-233


    As a well-defined animal transplantation model, the mini-pig potentially is well-suited for large animal studies of fresh osteochondral allograft transplantation. This study was done to determine the histologic characteristics and function of proteoglycan synthesis of mini-pig articular cartilage after refrigeration in basal media for as much as 6 weeks. Osteochondral sections of 10 mini-pig knees were refrigerated in various media at 4 degrees C for 1 to 42 days after slaughter. Four hundred twenty samples were evaluated by 35S uptake and 260 samples by histologic evaluations. Proteoglycan synthesis declined by 7 days to 21% of the level measured on Day 1 and was undetectable at 42 days. Histologic evaluation revealed progressive degeneration. Mankin scores rose from 3.69 +/- 0.27 on Day 1 to 6.40 +/- 0.18 on Day 7, and logarithmically increased to 10.83 +/- 0.07 on Day 42. These results indicate that the metabolic characteristics of porcine articular cartilage were not retained after refrigeration in basal media for 7 days. Optimum cold storage of porcine osteochondral allografts for cartilage transplantation research may be less than 7 days. Because osteochondral grafts for clinical use currently are stored for greater than 7 days, similar studies of the viability of human articular cartilage are needed.

    View details for DOI 10.1097/01.blo.0000138955.27186.8e

    View details for Web of Science ID 000224422500036

    View details for PubMedID 15552162

  • Recovery of articular cartilage metabolism following thermal stress is facilitated by IGF-1 and JNK inhibitor AMERICAN JOURNAL OF SPORTS MEDICINE Chu, C. R., Kaplan, L. D., Fu, F. H., Crossett, L. S., Studer, R. K. 2004; 32 (1): 191-196


    The safety of intra-articular use of thermal probes is related to whether chondrocytes can tolerate exposure to high temperatures and whether cytoprotective agents may improve chondrocyte survival after thermal injury.This study was conducted to characterize the metabolic responses of articular cartilage after short-term exposure to temperatures between 50 degrees C and 60 degrees C with and without addition of insulin-like growth factor 1 (IGF-1) and c-Jun N-terminal kinase (JNK) inhibitor.Human articular cartilage from osteoarthritic knees was subjected to defined thermal stress.Although significant reduction of proteoglycan synthesis was observed after 5 seconds of exposure to 55 degrees C and 60 degrees C and after 10- to 30-second exposures to 53 degrees C, recovery of metabolic activity levels was observed after 7 days.Addition of IGF-1 and JNK inhibitor Sp600125 enabled the cartilage to maintain significantly higher levels of proteoglycan synthesis immediately after thermal stress. IGF-1 also enhanced recovery of metabolic activity after 7 days.Results from this study indicate that there may be time and temperature parameters within which thermal chondroplasty can be safely performed. The data additionally suggest that inadvertent chondrocyte injury may be minimized through potential addition of substances like IGF-1 or JNK inhibitor.

    View details for Web of Science ID 000220711300025

    View details for PubMedID 14754743

  • Hand-held arthroscopic optical coherence tomography for in vivo high-resolution imaging of articular cartilage JOURNAL OF BIOMEDICAL OPTICS Pan, Y. T., Li, Z. G., Xie, T. Q., Chu, C. R. 2003; 8 (4): 648-654


    We describe a novel hand-held polarization optical coherence tomographic (OCT) probe that can be inserted into mammalian joints to permit real-time cross-sectional imaging of articular cartilage. The transverse and axial resolutions of the arthroscopic OCT device are roughly 17 and 10 microm, respectively. Two-dimensional cross-sectional images of cartilage tissue with 500 x 1000 pixels covering an area 6 mm in length and 2.8 mm in depth can be acquired at nearly five frames/s and with over 100 dB of dynamic range. Design of an OCT as a hand-held device capable of providing such an optical biopsy of articular cartilage allows eventual in vivo detection of microstructural changes in articular cartilage that are not apparent using conventional arthroscopic cameras. The OCT probe can be easily incorporated in a conventional arthroscope for cartilage site guidance. The optical arrangement in the OCT scope minimizes specular back-reflection of the probe end face and absorption of body fluid in the path and ensures in-focus OCT imaging when it is in contact with the cartilage specimen to be examined. Successful application of in vivo arthroscopy to porcine articular cartilage demonstrates sufficient resolution and practicality for use in human joints.

    View details for DOI 10.1117/1.1609201

    View details for Web of Science ID 000186348800010

    View details for PubMedID 14563203

  • Recovery of chondrocyte metabolic activity after thermal exposure AMERICAN JOURNAL OF SPORTS MEDICINE Kaplan, L. D., Chu, C. R., Bradley, J. P., Fu, F. H., Studer, R. K. 2003; 31 (3): 392-398


    The relationship between temperature elevation and thermal exposure time during thermal chondroplasty has implications for cell viability and subsequent articular cartilage function.To characterize cartilage metabolic changes after exposure to thermal stress and to determine whether changes seen acutely are reversible.Controlled laboratory study.Human cartilage was exposed to a 45 degrees, 50 degrees, or 55 degrees C bath for up to 3 minutes. Untreated control specimens were analyzed with each group. Viability and metabolic capability of treated and untreated specimens were evaluated immediately or 1 week after thermal stress by using methylthiotetrazole conversion, (3)H-serine incorporation into protein, and (35)S-sulfate incorporation into newly synthesized proteoglycan.Nonarthritic and arthritic articular cartilage metabolic activity declined with increasing thermal exposure. Articular cartilage displayed a recovery from thermal stress after exposure to the 50 degrees C but not the 55 degrees C bath. Arthritic cartilage displayed increased sensitivity with higher temperatures.Understanding of the increased sensitivity to thermal stress of arthritic articular cartilage may be helpful in thermally based treatments.Further correlation with the temperatures attained during thermal chondroplasty will be necessary to confirm the clinical relevance of these in vitro observations to the use of radiofrequency energy devices to treat partial-thickness chondral lesions.

    View details for Web of Science ID 000183187400011

    View details for PubMedID 12750132

  • Analysis of rabbit articular cartilage repair after chondrocyte implantation using optical coherence tomography OSTEOARTHRITIS AND CARTILAGE Han, C. W., Chu, C. R., Adachi, N., Usas, A., Fu, F. H., Huard, J., Pan, Y. 2003; 11 (2): 111-121


    To evaluate the utility and limitations of optical coherence tomography (OCT) for immediate, high-resolution structural analysis of rabbit articular repair tissue following chondrocyte implantation without excising or sectioning the specimen.Full thickness articular cartilage defects were created in the patellar grooves of 30 adult rabbit knee joints. Allogenic cultured chondrocytes embedded in collagen gels were implanted into the surgical defects. A periosteal patch was then sutured over the chondrocyte-collagen composites. Six animals per time point were sacrificed at 2, 4, 8, 12 and 24 weeks after surgery. The repair tissues were sequentially analysed by arthroscopic surface imaging, OCT, and histology. The resulting images were compared to determine qualitative and quantitative features of surface roughness, repair tissue integration, and micro-architecture. Statistical analysis was performed using Student's t -testing and linear regression.OCT was able to identify the bone and cartilage interface in normal rabbit articular cartilage and regenerated cartilage at 24 weeks post chondrocyte implantation. OCT was able to identify hypertrophy at 4 and 8 weeks, and subtle surface fibrillations at 24 weeks, comparable with histological analysis at low magnification (20x). More importantly, OCT was able to detect embedded gaps between the repair tissue and surrounding host cartilage.Close correlation was observed between OCT and histological analysis of morphological features important to the assessment of articular cartilage repair. These results demonstrate that OCT is capable of providing immediate 'optical biopsy' of the rabbit articular cartilage repair tissue without damaging the specimen, and suggest that this new technique, if integrated with an arthroscope, can potentially be used in longitudinal studies of articular cartilage repair in vivo.

    View details for DOI 10.1053/joca.2002.0862

    View details for Web of Science ID 000181040600004

    View details for PubMedID 12554127

  • Articular cartilage transplantation - Clinical results in the knee CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Chu, C. R., Convery, F. R., Akeson, W. H., Meyers, M., Amiel, D. 1999: 159-168


    Between December 1983 and August 1991, 55 consecutive patients (55 knees) who underwent articular cartilage transplantation to their damaged knees were enrolled in the study. Average followup was 75 months (range, 11-147 months). Eight-two percent were younger than 45 years of age. Patients were evaluated through an 18-point scale, with 6 points each allocated to pain, range of motion, and function. An excellent knee was pain free, had full range of motion, and permitted unlimited activity. A good knee allowed full time employment and moderate activity. Eleven of 15 (73%) allografts transplanted 10 or more years ago were still good or excellent at the time of last followup. Overall, 45 of 55 (76%) knees that received the transplants were rated good or excellent. Specifically, 36 of 43 (84%) patients with unipolar transplants regained normal use of their resurfaced knee. The results after bipolar resurfacing were less encouraging, with only six of 12 (50%) knees rated good or excellent. The described technique of osteochondral shell allograft resurfacing of the knee capitalize on the different healing potentials of bone and cartilage by transplanting the viable articular cartilage organ in its entirety along with just enough of the underlying bone to allow for graft incorporation through creeping substitution. The results support the use of fresh osteochondral shell allograft transplantation for the treatment of large, full thickness articular cartilage defects to the medial or lateral femoral condyles and to the patella.

    View details for Web of Science ID 000079252100019

    View details for PubMedID 10101321

  • The Marshall R. Urist Young Investigator Award. Autogenous flexor tendon grafts. Biologic mechanisms for incorporation. Clinical orthopaedics and related research Seiler, J. G., Chu, C. R., Amiel, D., Woo, S. L., Gelberman, R. H. 1997: 239-247


    To examine the hypothesis that different types of dense regular connective tissue may have different repair mechanisms within the synovial space, intrasynovial and extrasynovial autogenous donor flexor tendon grafts were placed within the synovial sheaths of the medial and lateral forepaw digits of dogs. Histologic, ultrastructural, biochemical, and biomechanical analyses were done between 10 days and 6 weeks after tendon grafting. Intrasynovial tendon grafts remained viable when transferred to the synovial space and appeared to heal through an intrinsic process with preservation of the gliding surface and improved functional characteristics. Extrasynovial tendon grafts functioned as a scaffolding for the early ingrowth of new vessels and cells. Early cellular necrosis consistently was followed by the ingrowth of fibrovascular adhesions from the periphery. The formation of dense peripheral adhesions, obliterating the gliding surface of the tendon, led to diminished tendon excursion and proximal interphalangeal joint rotation.

    View details for PubMedID 9418646

  • Autogenous flexor tendon grafts - Biologic mechanisms for incorporation CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Seiler, J. G., Chu, C. R., Amiel, D., Woo, S. L., Gelberman, R. H. 1997: 239-247
  • Osteochondral repair using perichondrial cells - A 1-year study in rabbits CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Chu, C. R., Dounchis, J. S., Yoshioka, M., Sah, R. L., Coutts, R. D., Amiel, D. 1997: 220-229


    Articular cartilage repair remains a clinical and scientific challenge with increasing interest focused on the transplantation of chondrogenic cells. This study evaluated the repair response during a 1-year period after implantation of allogenic perichondrium cell polylactic acid composite grafts into 3.7 x 5 mm osteochondral defects drilled into the medial femoral condyles of 82 adult New Zealand White rabbits. The repair tissue was evaluated grossly, histologically, histomorphometrically, biochemically, and biomechanically at 6 weeks, 12 weeks, 6 months, and 1 year after implantation. After gross evaluation, cartilaginous material appeared to fill the defect in 70 experimental knees, for an overall repair frequency of 85%. The histomorphometric results and the histologic appearances were variable. None of the specimens were completely normal at 1 year. Only specimens with subchondral bone reformation displayed a definable cartilage appearing surface with chondrocytes surrounded by dense matrix. Subchondral bone reformation was inconsistent, reaching 50% at 1 year. Biochemically, the repair tissue matured during a 1-year period into a hyaline Type II collagen dominant tissue, whereas glycosaminoglycan content remained low at all time periods. The measured compressive properties of the repair tissue at 1 year were not significantly different from those of the contralateral knee that was not surgically treated. The treatment of osteochondral defects in the rabbit knee with allogenic perichondrium cell polylactic acid composite grafts yielded a high percentage of grossly successful repairs that showed inconsistent subchondral bone reformation. These results suggest that healthy subchondral bone is important to articular cartilage repair. They also highlight that a cartilaginous appearing tissue at gross inspection may not represent structurally normal articular cartilage. Continued multidisciplinary studies on the arthroplastic potential of rib perichondrial cells are needed before human studies, which rarely can extend beyond gross assessment of repair tissue appearance can be undertaken.

    View details for Web of Science ID A1997XJ87300029

    View details for PubMedID 9224260



    Efforts to expand treatment options for articular cartilage repair have increasingly focussed on the implantation of cell polymer constructs. Primary cells cultured from perichondrium, a chondrogenic tissue, were found to survive in vitro within a biodegradable porous polylactic acid matrix. The novel application of an in situ fluorescent double-stain protocol to cell polymer constructs was supported by increased 3H-thymidine uptake and the ability of cell seeded polylactic acid to form first passage explant cultures. This in situ viability staining technique allowed for rapid determination of cell viability and, in conjunction with confocal microscopy, assessment of cellular distribution within a biodegradable scaffold. Advantages of using this method over histological and electron microscopic analysis include in situ observation, absence of distortion in scaffold architecture due to polymer dissolution and disruption during processing, and obtaining a viability assessment within 30 min. Potential applications of this protocol as a screening tool for laboratory engineered tissues and in the evaluation of cellular injury in natural tissues are discussed.

    View details for Web of Science ID A1995TF73400003

    View details for PubMedID 8590764



    Efforts to expand treatment options for articular cartilage repair have increasingly focused on the implantation of cell-polymer constructs. The purpose of this study is to determine the suitability of porous D,D-L,L-polylactic acid as a carrier for delivering repair cells obtained from rib perichondrium into full-thickness articular cartilage defects. In vitro characterization of perichondrocyte-polylactic acid composite grafts was combined with in vivo assessment of the early articular cartilage repair in a clinically relevant model. Using a fluorescent double-stain protocol to visualize live and dead cells in situ, primary cells cultured from perichondrium were found to be capable of attaching to and surviving within a porous D,D-L,L-polylactic acid matrix. These perichondrocyte-polylactic acid composite grafts were then implanted within osteochondral defects drilled into the left medial femoral condyles of 16 adult New Zealand white rabbits. Experimental animals were sacrificed 6 weeks after implantation and the repair tissue was evaluated grossly, histologically, and biochemically. Grossly, 96% (15/16) of the experimental animals demonstrated repairs consisting of a smooth, firm neocartilage which appeared similar in color and texture to the surrounding articular surface. Matrix staining for cartilaginous protein was seen surrounding chondrocyte-like cells in the cartilage regions of the repair. Cellular alignment was found to be related to scaffold architecture. These results suggest that scaffolds composed of porous D,D-L,L-polylactic acid support the growth of cartilaginous repair tissue and are compatible with both in vitro and in vivo survival of chondrogenic cells.

    View details for Web of Science ID A1995RR47700014

    View details for PubMedID 8567713



    On the basis of recent evidence that the healing processes of tendon grafts are donor-tissue specific, in situ hybridization, using a 372 bp cDNA fragment complementary to a portion of pro alpha 1(I) collagen mRNA, was utilized to compare the cellular responses to transplantation exhibited by autogenous intrasynovial and extrasynovial flexor tendon grafts. Intrasynovial and extrasynovial tendons from the hindpaw were transferred to synovial sheaths in the forepaw of 12 mongrel dogs (24 tendons) and treated with immediate controlled passive motion. The tendon grafts were harvested at 2, 4, and 6 weeks, and each was divided into a proximal, central (8 mm), and distal portion. Sections from the central portion were embedded in paraffin and subjected to in situ hybridization, autoradiography, and staining; levels of procollagen mRNA then were assessed by microscopic examination. The two types of tendon grafts exhibited different levels of pro alpha 1(I) collagen mRNA expression at all three time points. Intrasynovial tendon grafts displayed no areas of increased type-I procollagen mRNA at 2, 4, and 6 weeks. The extrasynovial tendon grafts displayed increased surface levels of type-I procollagen mRNA at 2 and 4 weeks; the levels decreased to background levels by 6 weeks. The high levels of procollagen mRNA exhibited by the extrasynovial grafts suggest increased collagen synthetic activity, indicative of a cellular response to injury, whereas the preservation of low levels of expression in the intrasynovial grafts may signify a less inflammatory cellular response.

    View details for Web of Science ID A1995RG92000020

    View details for PubMedID 7602408



    Intrasynovial and extrasynovial donor autogenous flexor-tendon grafts were placed in the synovial sheaths of the medial and lateral digits of the forepaw in twenty dogs (forty tendons). Postoperatively, the dogs were managed with early, controlled, passive mobilization. Histological and ultrastructural evaluations were carried out at ten days, three weeks, and six weeks, and biomechanical analyses were performed at three and six weeks. The intrasynovial and extrasynovial tendon grafts showed different healing processes histologically. The extrasynovial tendon grafts healed with early ingrowth of peripheral adhesions, which appeared to become larger and more dense over time. These grafts exhibited decreased cellularity and early neovascularization at ten days, and there was evidence of progressive revascularization and cellular repopulation at three and six weeks. In contrast, the intrasynovial tendon grafts demonstrated minimum adhesions, and both cellularity and collagen organization were normal at each time-interval. The intrasynovial grafts had significantly more angular rotation at the proximal interphalangeal joint at three and six weeks than did the extrasynovial grafts (p < 0.05).

    View details for Web of Science ID A1993LP57400006

  • The fate of autogenous tendon grafts. The Iowa orthopaedic journal Seiler, J. G., Chu, C., ABRAHAMSSON, S. O., Gelberman, R. H. 1993; 13: 56-62

    View details for PubMedID 7820753



    On the basis of recent evidence that flexor tendon grafts may heal without the ingrowth of vascular adhesions, eighteen autogenous donor tendons of intrasynovial and extrasynovial origin were transferred to the synovial sheaths in the forepaws of nine dogs, and controlled passive mobilization was instituted early in the postoperative period. The angiogenic responses of the tendon grafts were determined with perfusion studies with India ink followed by cleaing of the tissues with the Spalteholz technique at two, four, and six weeks. A consistent pattern of neovascularization was noted in the donor tendons of extrasynovial origin. Vascular adhesions arising from the flexor digitorum superficialis and the tendon sheath enveloped the tendon grafts by two weeks. By six weeks, the vascularity of the tendon grafts of extrasynovial origin appeared completely integrated with that of the surrounding tissues. Examination of cross sections revealed that the segments of tendon had been completely vascularized by obliquely oriented intratendinous vessels. In contrast, the flexor tendon grafts of intrasynovial origin healed without ingrowth of vascular adhesions. Primary intrinsic neovascularization took place from the proximal and, to a lesser extent, distal sites of the sutures. Examination of cross sections revealed vessels extending through the surface layer of the tendon graft, with small vessels penetrating the interior of the tendons at regular intervals.

    View details for Web of Science ID A1992JV59500011