Joshua J. Jacobs, Ph.D. - US grants

DESCRIPTION (provided by applicant): There is an increasing recognition that, in the long-term, total joint replacement (TJR) may be associated with adverse local and remote tissue responses that are mediated by the degradation products of prosthetic materials. There has been particular interest in the metallic degradation products of TJR because of the known toxicities of the metallic elements that comprise implant alloys. In this long-term study, metal release, transport, storage and excretion in patients with TJRs habs been investigated. In the current grant period, it has been demonstrated that (1) elevations in serum Ti, Co and Cr can be detected in individuals with well functioning total hip and knee replacements up to 84 months postoperative;(2) the highest Cr and Co levels have been observed in patients with metal-on-metal bearings;(3) passive dissolution from extensively porous coated Co-base alloy femoral stems is not a dominant mode of metal release;rather, fretting corrosion of femoral components at modular junctions is more closely associated with elevations in serum Cr;(4) in patients with TJR and elevated serum metal concentrations, two molecular weight ranges were found to bind Cr (at approximately 70 kD and approximately 180 kD) whereas a single molecular weight range (at approximately 70 kD) was found to bind Ti;(5) following revision surgery for a failed total hip replacement, circulating metal levels diminish, but remain chronically elevated up to 60 months post-revision;(6) Co- and Ti-alloy particulate degradation products, usually from sources other than the bearing surface, commonly disseminate to paraaortic lymph nodes, liver and spleen, particularly in individuals who have had a failed TJR;and (7) the bioreactivity of metal degradation products is governed by its'physiochemical nature and protein adducts: a Cr-containing 180 kD metal-protein complex was the most stimulatory in these studies. This proposal expands on these findings by addressing the following Specific Aims: (1) to quantify metal release in the prospective primary THR study groups which will be 10 to 15 years postoperative, an interval in which complications related to the implant are more prevalent;(2) to prospectively follow patients with Co-alloy metal-on-metal hip replacements to determine the prevalence of metal hypersensitivity in correlation with the serum and urine metal content;(3) to expand the autopsy retrieval program to characterize not: only the systemic distribution of particulate wear debris but also the tissue metal levels and the cellular localization;and (4) to conduct bioavailability and bioreactivity studies of circulating metal-protein complexes which result from corrosion and wear of joint replacement components.

DESCRIPTION (provided by applicant): Metal-on-metal (MoM) bearings for hip replacement have surged in popularity over the last several years due to lower volumetric wear (compared to conventional metal-on-ultrahigh molecular weight polyethylene) and the ability to use large femoral heads, reducing the risk of dislocation, a common complication of hip replacement necessitating revision surgery. Large femoral heads also provide the surgeon with the option of resurfacing the femoral head without breaching the femoral metaphysis or diaphysis (hip resurfacing arthroplasty) thereby preserving femoral bone stock. However, a cause for concern with MoM joint reconstruction, has recently emerged with increasing reports of early adverse local tissue responses compromising the functionality and survivorship of these reconstructions. These adverse responses, which include periprosthetic bone loss (osteolysis), delayed-type hypersensitivity and soft tissue masses (so-called pseudotumors) are governed by the local cellular reaction to particulate and ionic wear and corrosion debris. There is growing evidence that the local cell response is related to the amount of debris generated by these bearing couples. Thus, there is an urgent clinical need to delineate the mechanisms of debris generation in order to minimize these adverse local tissue responses. Unfortunately, the tribology of this bearing couple is little understood. Our laboratory has made the novel observation that metal-on-metal bearings undergo microstructural changes and tribochemical reactions with the joint environment during articulation. This behavior causes changes in the metallurgy of the upper surface and brings about the generation of a mechanically mixed zone of nanocrystalline metal (oxide) and organic constituents. Such a zone - also called tribomaterial - favorably influences the tribological properties as well as the tribocorrosive behavior, as has been shown for related boundary lubricated applications in mechanical and automotive engineering. In the present proposal, we will address the central hypothesis that the combination of metal particles and denatured proteins form a biotribological layer in metal on metal bearings that has synergistic effects in reducing wear and corrosion. We have assembled a multidisciplinary investigative team that will address the following specific aims that will likely have a significant impact of the performance of MoM bearings in hip replacement: 1) to determine the role of the biotribological layer constituents in the evolution of the near-surface region of the metal using wear simulations for accelerated testing and compare these to device retrievals obtained from patients undergoing MoM hip or surface replacement;2) to determine the relevant properties of the mechanically mixed zone of retrievals and in-vitro samples and demonstrate the effect of embedded organic constituents;and 3) to demonstrate that the presence of a mechanically mixed zone will beneficially effect the (tribo-)corrosion behavior of the cobalt-chromium alloy

The University of Chicago (UChicago) Institute for Translational Medicine (ITM) was created in 2007 to assemble, integrate, and create the intellectual, administrative, and physical resources required to catalyze research and research training in Clinical and Translational Science. We have trained university scientists and health care providers to work together with stakeholders in all concerned communities to determine the molecular, genetic, pathophysiologic, and social determinants of disease; to develop and test interventions directed toward those mechanisms; and to achieve these goals in a way that is rigorous, efficient, ethical, respectful of, and responsive to our community?s needs and values. In its first 9 years, the ITM has capitalized on outstanding intellectual and physical resources throughout UChicago and at ITM affiliate institutions ? Rush University Medical Center (Rush), NorthShore University HealthSystem (NorthShore), and Illinois Institute of Technology (IIT) ? to build the infrastructure for a transformative, energized, and self-improving home for clinical and translational research. Now, we pursue a bold guiding vision for ?ITM 2.0? ? that health outcomes will be improved throughout Chicagoland by mitigating disease risk, morbidity and mortality through collaborative, multidisciplinary team science. We will work toward this vision by assembling scientific, institutional, and community stakeholders, and together focusing on the highest value propositions to improve mutually defined health concerns, leveraging synergies that accelerate progress across the translational spectrum. Our core conviction is that participating in health research is a matter of shared self-interest and social justice, a ?new normal? prevailing viewpoint toward which we will strive together over the next 20 years. ITM 2.0 will work hand-in-hand with health stakeholders throughout Chicagoland and throughout the nation, conceptualizing, developing and deploying innovative processes and practices to achieve our common goal. Preparing for this ambitious challenge, we broadened the scope of institutional and community stakeholders. Rush now joins UChicago as an ITM lead institution, and Loyola University Medical Center and Advocate Health Care join as ITM affiliates. We partner with esteemed institutions ? the Chicago Community Trust, the Illinois Biotechnology Industry Organization, and the Chicago and Illinois Departments of Public Health ? and inclusively leverage strong collaborations with the other two Chicago CTSAs, with the Chicago-wide PCORnet CDRN CAPriCORN, and with the recently awarded Illinois Precision Medicine Consortium. In ITM 2.0, we will together develop innovative and sometimes disruptive approaches to advance the science and practice of clinical and translational research by rigorously determining which approaches work and then disseminating the results of both successes and failures. We expect that this approach will improve the conduct of and training for clinical and translational research for the benefit of Chicago, the CTSA Consortium, and the nation.

Project Summary/Abstract Osteoarthritis (OA) is the single most important cause of disability in mid and late life. About 27 million people in the United States suffer from this incurable process and 10 million have OA of the knee. Total knee arthroplasty (TKA) is a reliable treatment option for patients disabled by knee OA who have failed nonoperative treatment, with 58% of these surgeries being performed on patients 65 years or older. TKA surgeries were performed on more than 700,000 patients in the United States in 2012 and estimates expect this number to increase between 143% and 565% by 2050. Most patients experience pain relief within 6 to 12 weeks following TKA; however, 8 to 34% of patients experience chronic postsurgical pain, defined by the International Association for the Study of Pain as clinically important pain lasting more than 3 months after surgery, with limited improvement in functional outcomes often despite an uneventful surgical course and a satisfactory radiographic appearance. With one projected estimate of 3.48 million TKA surgeries per year in the USA by 2030, up to 500,000 patients annually could develop chronic pain following TKA. The objective of this project is to aid in the construction of a dataset that encompasses clinical, biological (omics), psychological, socioeconomical and imaging predictors for a diverse group of patients undergoing TKA. Rush University the largest provider of joint replacement surgery in Illinois, performing 2,100 TKA procedures in 2017. With our Institute for Translational Medicine (ITM) partners, the University of Chicago, and NorthShore University Health System our NCATS CTSA-funded program hub has extensive translational research expertise and serves a diverse patient population (>5 million) across many racial, ethnic and socioeconomic strata and collectively perform more than 4000 TKA procedures per year. The overall project goal of the proposed research study is to provide high fidelity clinical, biological and psychological data in conjunction with Clinical Coordination Center, the Data Integration and Resource Center, and the Omics Data Generation Center from patients undergoing TKA within our NCATS CTSA-funded program hub in line with NIH HEAL Initiative A2CPS. This information should enrich our understanding of how acute pain becomes chronic pain following surgery and enhance our ability to target effective preventive and treatment strategies for patients.