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Clearance of particles from the knee is an essential mechanism to maintain healthy joint homeostasis and critical to the delivery of drugs and therapeutics. One of the limitations in developing disease modifying drugs for joint diseases, such as osteoarthritis (OA), has been poor local retention of the drugs. Enhancing drug retention within the joint has been a target of biomaterial development, however, a fundamental understanding of joint clearance pathways has not been characterized. We applied near-infrared (NIR) imaging techniques to assess size-dependent in vivo clearance mechanisms of intra-articular injected, fluorescently-labelled polyethylene glycol (PEG-NIR) conjugates. The clearance of 2kDa PEG-NIR (τ = 171 ± 11 min) was faster than 40kDa PEG-NIR (τ = 243 ± 16 min). 40kDa PEG-NIR signal was found in lumbar lymph node while 2kDa PEG-NIR signal was not. Thus, these two conjugates may be cleared through different pathways, i.e. lymphatics for 40kDa PEG-NIR and venous for 2kDa PEG-NIR. Endothelin-1 (ET-1), a potent vasoconstrictor of vessels, is elevated in synovial fluid of OA patients but, its effects on joint clearance are unknown. Intra-articular injection of ET-1 dose-dependently inhibited the clearance of both 2kDa and 40kDa PEG-NIR. ET-1 caused a 1.63 ± 0.17-fold increase in peak fluorescence for 2kDa PEG-NIR and a 1.85 ± 0.15-fold increase for 40kDa PEG-NIR; and ET-1 doubled their clearance time constants. The effects of ET-1 were blocked by co-injection of ET receptor antagonists, bosentan or BQ-123. These findings provide fundamental insightful into retention and clearance mechanisms that should be considered in the development and delivery of drugs and biomaterial carriers for joint diseases. STATEMENT OF
This study demonstrates that in vivo knee clearance can be measured using NIR technology and that key factors, such as size of materials and biologics, can be investigated to define joint clearance mechanisms. Therapies targeting regulation of joint clearance may be an approach to treat joint diseases like osteoarthritis. Additionally, in vivo functional assessment of clearance may be used as diagnostics to monitor progression of joint diseases.
This article was published in the following journal.
Name: Acta biomaterialia
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A subtype of endothelin receptor found predominantly in the VASCULAR SMOOTH MUSCLE. It has a high affinity for ENDOTHELIN-1 and ENDOTHELIN-2.
Metalloendopeptidases which convert BIG ENDOTHELIN to ENDOTHELIN-1.
A subtype of endothelin receptor found predominantly in the KIDNEY. It may play a role in reducing systemic ENDOTHELIN levels.
Immunologic techniques based on the use of: (1) enzyme-antibody conjugates; (2) enzyme-antigen conjugates; (3) antienzyme antibody followed by its homologous enzyme; or (4) enzyme-antienzyme complexes. These are used histologically for visualizing or labeling tissue specimens.
A 21-amino acid peptide produced predominantly within the kidney and intestine, with smaller amounts produced in the myocardium, placenta, and uterus, but the cells of origin are not clear. Endothelin-2 has no unique physiologic functions, as compared with endothelin-1. (N Eng J Med 1995;333(6):356-63)
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