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Original research
In situ decellularization of a large animal saccular aneurysm model: sustained inflammation and active aneurysm wall remodeling
  1. Robert M King1,2,
  2. Jildaz Caroff1,3,
  3. Erin T Langan1,
  4. Anita Leporati1,4,
  5. Aurora Rodriguez-Rodriguez5,
  6. Christopher M Raskett1,
  7. Suresh Gupta4,
  8. Ajit S Puri1,
  9. Peter Caravan5,
  10. Matthew J Gounis1,
  11. Alexei A Bogdanov, Jr.1,4
  1. 1Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, Massachusetts, United States
  2. 2Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, United States
  3. 3Department of Interventional Neuroradiology, NEURI Center, Bicêtre Hospital, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France
  4. 4Department of Radiology, Laboratory of Molecular Imaging Probes, University of Massachusetts Medical School, Worcester, MA, United States
  5. 5The Athinoula A. Martinos Center for Biomedical Imaging, The Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
  1. Correspondence to Dr Matthew J Gounis, Radiology, University of Massachusetts Medical School, Worcester, MA 1655, USA; matthew.gounis{at}umassmed.edu

Abstract

Objective To investigate in situ decellularization of a large animal model of saccular aneurysm as a strategy for achieving aneurysmal growth and lasting inflammation.

Methods 18 New Zealand White rabbits were randomized 2:1 to receive endoluminal sodium dodecyl sulfate infusion (SDS, 1% solution, 45 min) following elastase or elastase-only treatment (control). All aneurysms were measured by digital subtraction angiography every 2 weeks. Every 2 weeks, three of the rabbits (two elastase + SDS, one control) underwent MRI, followed by contrast injection with myeloperoxidase (MPO)-sensing contrast agent. MRI was repeated 3 hours after contrast injection and the enhancement ratio (ER) was calculated. Following MRI, aneurysms were explanted and subjected to immunohistopathology.

Results During follow-up MRI, the average ER for SDS-treated animals was 1.63±0.20, compared with 1.01±0.06 for controls (p<0.001). The width of SDS-treated aneurysms increased significantly in comparison with the elastase aneurysms (47% vs 20%, p<0.001). Image analysis of thin sections showed infiltration of MPO-positive cells in decellularized aneurysms and surroundings through the 12-week observation period while control tissue had 5–6 times fewer cells present 2 weeks after aneurysm creation. Immunohistochemistry demonstrated the presence of MPO-positive cells surrounding decellularized lesions at early time points. MPO-positive cells were found in the adventitia and in the thrombi adherent to the aneurysm wall at later time points.

Conclusions In situ decellularization of a large animal model of saccular aneurysms reproduces features of unstable aneurysms, such as chronic inflammation (up to 12 weeks) and active aneurysm wall remodeling, leading to continued growth over 8 weeks.

  • aneurysm
  • inflammation
  • MRI
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Footnotes

  • Twitter @jildazz

  • RMK and JC contributed equally.

  • Contributors All authors: designed and performed the experiments, analyzed the data, drafted the manuscript, approved the final manuscript.

  • Funding This research was funded by NINDS 5R01NS091552-04 (principal investigators: AAB and MJG) and the NIH Shared Instrument grant program (S10OD010650, S10OD025234) for analytical instrumentation. JC was supported by research grants from the Fulbright Program, the Philippe Foundation, and the French society of Radiology (SFR-CERF). The content is solely the responsibility of the authors and does not reflect the opinions of the sponsors.

  • Competing interests RMK, AL, AR-R, CMR, SG, and AAB declare no competing interest. JC has received educational scholarships from Medtronic Neurovascular and Microvention/Terumo. ETL has served as a consultant on a fee-per-hour basis for InNeuroCo, Imperative Care, Mivi Neurosciences, Route 92 Medical, Stryker Neurovascular, and Neurovasc. PC has equity in and is a consultant to Collagen Medical LLC, has equity in Reveal Pharmaceuticals Inc, and has research support from Pliant Therapeutics, Celgene, Takeda, and Indalo Therapeutics. MJG Has been a consultant on a fee-per-hour basis for Astrocyte Pharmaceuticals, Cerenovous, Imperative Care, Medtronic Neurovascular, Mivi Neurosciences, Phenox, Q’Apel, Route 92 Medical, Stryker Neurovascular; holds stock in Imperative Care, InNeuroCo, and Neurogami; and has received research support from the National Institutes of Health (NIH), the United States – Israel Binational Science Foundation, Anaconda, ApicBio, Arsenal Medical, Axovant, Cerenovus, Ceretrieve, Cook Medical, Galaxy Therapeutics, Gentuity, Imperative Care, InNeuroCo, Insera, Magneto, Microvention, Medtronic Neurovascular, MIVI Neurosciences, Naglreiter MDDO, Neurogami, Omniox, Philips Healthcare, Pulse Medical, Rapid Medical, Route 92 Medical, Stryker Neurovascular, Syntheon, ThrombX Medical, the Wyss Institute, and Xtract Medical. ASP: consultant for Medtronic Neurovascular and Stryker Neurovascular; research grants from Medtronic Neurovascular, and Stryker Neurovascular.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available by contacting the corresponding author.

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