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Author Notes:

Nick J. Willett, nick.willett@emory.edu, Address: 1670 Clairmont Road, Room 5A-115, Decatur, GA 30033, Phone number: (01) 404-321-6111, ext. 3248

The authors would like to thank Joseph C. Shaver for his technical assistance towards synthesis of the PEG-NIR reagents.

No conflict of interest and thus, nothing to disclose.


Research Funding:

This work was supported by the National Center for Advancing Translation Science of the National Institutes of Health [grant number UL1TR000454]; the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health [grant number 5T32EB006343]; the Department of Defense PRMRP Grant [grant number PR171379].


  • Science & Technology
  • Technology
  • Engineering, Biomedical
  • Materials Science, Biomaterials
  • Engineering
  • Materials Science
  • Lymphatics
  • Intra-articular injection
  • Rat knees
  • NIR imaging

Endothelin-1 inhibits size dependent lymphatic clearance of PEG-based conjugates after intra-articular injection into the rat knee


Journal Title:



Volume 93


, Pages 270-281

Type of Work:

Article | Post-print: After Peer Review


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 2 kDa PEG-NIR (τ = 171 ± 11 min) was faster than 40 kDa PEG-NIR (τ = 243 ± 16 min). 40 kDa PEG-NIR signal was found in lumbar lymph node while 2 kDa PEG-NIR signal was not. Thus, these two conjugates may be cleared through different pathways, i.e. lymphatics for 40 kDa PEG-NIR and venous for 2 kDa 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 2 kDa and 40 kDa PEG-NIR. ET-1 caused a 1.63 ± 0.17-fold increase in peak fluorescence for 2 kDa PEG-NIR and a 1.85 ± 0.15-fold increase for 40 kDa 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 insight into retention and clearance mechanisms that should be considered in the development and delivery of drugs and biomaterial carriers for joint diseases. Statement of Significance: 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.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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