Early Diagnosis of Orthopedic Implant Failure Using Macromolecular Imaging Agents

Ren, Ke; Dusad, Anand; Zhang, Yijia; Purdue, P. Edward; Fehringer, Edward V.; Garvin, Kevin L.; Goldring, Steven R.; Wang, Dong

doi:10.1007/s11095-014-1310-x

Cited by 9 publications

(7 citation statements)

References 39 publications

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“…Recently, a polymeric nanocarrier system targeting inflammatory cells was revealed by a series of experiments performed by a group of researchers at the University of Nebraska, to be enriched at inflamed sites with a few animal models. 8 , 77–80 The system makes use of water-soluble copolymers of N -(2-hydrocpropyl)methacrylamide (HPMA), that were originally designed for cancer chemotherapy due to the meritorious properties of the nanoparticles. These include an enhanced permeability and retention effect, water-solubility, low immunogenicity, and high stability.…”

Section: Detection and Diagnosismentioning

confidence: 99%

“…These include an enhanced permeability and retention effect, water-solubility, low immunogenicity, and high stability. 81 , 82 While HPMA copolymers have been labeled with near-infrared dye 800CW and radioisotope 125 I for imaging purposes 78 , 80 and loaded with a drug dexamethasone for therapeutic intention, 77 , 78 it is anticipated that conjugates of these copolymers with other radioisotopes such as 111 In, 99m Tc, 18 F, and 64 Cu, and other drugs, will be explored in the future in order to achieve the clinical use of nanocarriers for early diagnosis and effective treatment of periprosthetic osteolysis. These nanocarriers are in contrast to FDG-labeled probes, which are not feasible for drug conjugation as they are too nonspecific and lack durability.…”

Section: Detection and Diagnosismentioning

confidence: 99%

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A review of UHMWPE wear-induced osteolysis: the role for early detection of the immune response

et al. 2016

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In a world where increasing joint arthroplasties are being performed on increasingly younger patients, osteolysis as the leading cause of failure after total joint arthroplasty (TJA) has gained considerable attention. Ultra-high molecular weight polyethylene wear-induced osteolysis is the process by which prosthetic debris mechanically released from the surface of prosthetic joints induces an immune response that favors bone catabolism, resulting in loosening of prostheses with eventual failure or fracture. The immune response initiated is innate in that it is nonspecific and self-propagating, with monocytic cells and osteoclasts being the main effectors. To date, detecting disease early enough to implement effective intervention without unwanted systemic side effects has been a major barrier. These barriers can be overcome using newer in vivo imaging techniques and modules linked with fluorescence and/or chemotherapies. We discuss the pathogenesis of osteolysis, and provide discussion of the challenges with imaging and therapeutics. We describe a positron emission tomography imaging cinnamoyl-Phe-(D)-Leu-Phe-(D)-Leu-Phe-Lys module, specific to macrophages, which holds promise in early detection of disease and localization of treatment. Further research and increased collaboration among therapeutic and three-dimensional imaging researchers are essential in realizing a solution to clinical osteolysis in TJA.

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Section: Detection and Diagnosismentioning

confidence: 99%

Section: Detection and Diagnosismentioning

confidence: 99%

A review of UHMWPE wear-induced osteolysis: the role for early detection of the immune response

et al. 2016

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“…There was only one paper that measured behavior, as a surrogate for pain assessment . Six papers examined biomarkers with four focusing on blood, urine or synovial fluid and two using imaging biomarkers …”

Section: Resultsmentioning

confidence: 99%

“…LPS contamination of particles, either by incubating the particles in LPS‐containing solution or by administering LPS via intraperitoneal injection, was shown to exacerbate peri‐implant osteolysis . Early diagnosis was assessed in two studies; one used a macromolecular bioimaging approach and one used a bone turnover biomarker . Both studies showed that early detection of osteolysis is feasible in highly controlled preclinical animal models.…”

Section: Resultsmentioning

confidence: 99%

Arthrotomy‐based preclinical models of particle‐induced osteolysis: A systematic review

Moran

Wilson

Ross

et al. 2017

Journal Orthopaedic Research

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We completed a systematic literature review of in vivo animal models that use arthrotomy-based methods to study particle-induced peri-implant osteolysis. The purpose of the review was to characterize the models developed to date, to determine the questions addressed, to assess scientific rigor and transparency and to identify gaps in knowledge. We probed three literature databases (Medline, Embase and Scopus) and found 77 manuscripts that fit the search parameters. In the most recent 10 years, researchers mainly used rat and mouse models, whereas in the previous 20 years large animal, canine and rabbit models were more common. The studies have demonstrated several pathophysiology pathways, including macrophage migration, particle phagocytosis, increased local production of cytokines and lysosomal enzymes, elevated bone resorption and suppressed bone formation. The effect of variation in particle characteristics and concentration received limited attention with somewhat mixed findings. Particle contamination by endotoxin was shown to exacerbate peri-implant osteolysis. The possibility of early diagnosis was demonstrated through imaging and biomarker approaches. Several studies showed that both local and systemic delivery of bisphosphonates inhibits the development of particle-induced osteolysis. Other methods of inhibiting osteolysis include the use of anabolic agents and altering the implant design. Few studies examined non-surgical rescue of loosened implants, with conflicting results with alendronate. We found that the manuscripts often lacked the methodological detail now advocated by the ARRIVE guidelines, suggesting that improvement in reporting would be useful to maximize rigor and transparency.

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“…In this analysis, we also found the 125 I activity (representing the amount of P-Dex) between the particle-injected left femur and non-particle-injected right femur was not significantly different, which was not consistent with our previous findings. 17, 28 The systemic exposure of the conjugate increased when the MW was raised. The AUC 0-∞ (blood) of the conjugates positively correlated with the MW of the conjugates and Cl of the polymers was negatively correlated to the MW of the polymers.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model

Wei

Zhao

et al. 2017

Mol. Pharmaceutics

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N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers were previously found to represent a versatile delivery platform for the early detection and intervention of orthopedic implant loosening. In this manuscript, we evaluated the impact of different structural parameters of the HPMA copolymeric system (e.g. molecular weight (MW), drug content) to its pharmacokinetics and biodistribution (PK/BD) profile. Using 125I, Alexa Fluor® 488 and IRDye® 800 CW-labeled HPMA copolymer-dexamethasone (P-Dex) conjugates with different MW and dexamethasone (Dex) contents, we found the MW to be the predominant impact factor on the PK/BD profiles of P-Dex, with Dex content as a secondary impact factor. In gamma counter-based PK/BD studies, increased MW of P-Dex reduced elimination, leading to lower clearance, longer half-life, and higher systemic exposure (AUC and MRT). In the semi-quantitative live animal optical imaging evaluation, the distribution of P-Dex to the peri-implant inflammatory lesion increased when MW was increased. This result was further confirmed by FACS analyses of cells isolated from peri-implant regions after systemic administration of Alexa Fluor® 488-labeled P-Dex. Since the in vitro cell culture study suggested that the internalization of P-Dex by macrophages is generally independent of P-Dex’ MW and Dex content, the impact of the MW and Dex content on its PK/BD profile was most likely exerted at physiological and pathophysiological levels rather than at the cellular level. In both gamma counter-based PK/BD analyses and semi-quantitative optical imaging analyses, P-Dex with 6 wt% Dex content showed fast clearance. Dynamic light scattering analyses unexpectedly revealed significant molecular aggregation of P-Dex at this Dex content level. The underlining mechanisms of the aggregation and fast in vivo clearance of the P-Dex warrant further investigation.

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Early Diagnosis of Orthopedic Implant Failure Using Macromolecular Imaging Agents

Cited by 9 publications

References 39 publications

A review of UHMWPE wear-induced osteolysis: the role for early detection of the immune response

A review of UHMWPE wear-induced osteolysis: the role for early detection of the immune response

Arthrotomy‐based preclinical models of particle‐induced osteolysis: A systematic review

Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model

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