The role of biological research in vascular surgery · 2018-05-26 · ESCVS 2018 YOUNG SURGEON...
Transcript of The role of biological research in vascular surgery · 2018-05-26 · ESCVS 2018 YOUNG SURGEON...
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Role and importance of biological research in Vascular Surgery Centers. Personal experience:
the theoretical research and engineering application in vascular surgery
Prof. Domenico PalomboDirettore U. O. C. Chirurgia Vascolare ed Endovascolare
Ospedale Policlinico San MartinoUniversità degli Studi di Genova
Patras, 24th May 2018
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Introduction
The value of research in vascular surgery: from the Vascular Surgeon to the Vascular Specialist
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Introduction
School of Medical and Pharmaceutical Sciences –Genova (Italy)
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VASCULAR SURGERY TOPICS:
- Thoracic and Thoracoabdominal aortic diseases.
- Abdominal aortic diseases
- Carotid diseases
- Peripheral vascular disease
Introduction
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Introduction
Thoracic and Thoracoabdominalaortic diseases.
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Abdominal aortic diseases
Introduction
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Carotid diseases
Introduction
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Peripheral Arterial Obstructive Disease
Introduction
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Research Laboratory of Experimental and Clinical Vascular Biology
Department of Surgical and Integrated Diagnostic Sciences (DISC)University of Genoa
Introduction
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Research topics
Biological and biochemical research:
- vascular biology (polyphenols and inflammation and PPARγ agonist);- vascular bioprosthesis: functionalized electrospun scaffold;- nanoparticles as innovative targeted therapy in atherosclerosis.
In vivo medical image analysis and biomechanical simulations:
- endovascular implants: from medical images to patient specific structural simulations;- impact of peripheral endovascular repair on femoral popliteal artery kinematics;- assessment of FU geometry changes of TAAAs treated with MFM stent;- geometrical remodeling of the aortic arch after hybrid treatment.
Clinical research:- risk of rupture;- AAA screening.
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Civil, Chemical and Environmental Engineering Department
Surgical and Integrated Diagnostic Sciences
Vascular biology
Chemical engineering
Engineering for medicine and longevity
Several partnership:CardiologyAnatomyPathological AnatomyNuclear Medicine
Vascular surgery, vascular biology and…chemical engineering
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Research topics
- vascular biology (polyphenols and inflammation and PPARγ agonist);
- vascular bioprosthesis: functionalized electrospun scaffold;
- nanoparticles as innovative targeted therapy in atherosclerosis.
Biological and biochemical research1
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nucleus
TNF α receptor
TNF α
Akt
p38MAPK
Endothelial cell membrane
apigenin
apigenin
Vascular biology – Polyphenols and inflammation
TNF α receptor
TNF α
Akt
p38MAPK
Endothelial cell membrane
apigenin
apigenin
apigenin
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Mura M. et al «Simultaneous ultrasound-assisted water extraction and β-cyclodextrin encapsulation of polyphenols from Mangifera
indica stem bark in counteracting TNFα-induced endothelial dysfunction». Nat Prod Res. 2015;29(17):1657-63. doi:
10.1080/14786419.2014.996753. Epub 2015 Jan 15.
Palmieri D. et al «Effects of polyphenol extract from olive pomace on anoxia-induced endothelial dysfunction». Microvasc Res. 2012
May;83(3):281-9. doi: 10.1016/j.mvr.2012.02.010. Epub 2012 Feb 23.
Aliakbarian B. et al «Antioxidant activity and biological evaluation of olive pomace extract». Nat Prod Res. 2012;26(24):2280-90. doi:
10.1080/14786419.2012.660692. Epub 2012 Feb 15.
Palmieri D. et al «Apigenin inhibits the TNFα-induced expression of eNOS and MMP-9 via modulating Akt signalling through
oestrogen receptor engagement». Mol Cell Biochem 2012 Dec;371(1-2):129-36. doi: 10.1007/s11010-012-1429-1. Epub 2012 Aug 17.
Palmieri D. et al «Effects of polyphenol extract from olive pomace on anoxia-induced endothelial dysfunction». Microvasc Res. 2012
May;83(3):281-9. doi: 10.1016/j.mvr.2012.02.010. Epub 2012 Feb 23.
Vascular biology – Polyphenols and inflammation
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Monocyte activation, macrophage infiltration, vascular oxidative stress and matrix proteolysis are
inflammatory key steps contributing to abdominal aortic aneurysm (AAA) development. Resveratrol
counteracted the CD62L-monocyte subset expansion, CD143 monocyte expression, and circulating levels of MMP-9 activity and TNFa associated to AAA induction.
Vascular biology – Polyphenols and inflammation (in vivo)
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Vascular biology
30 Sprague Dawley male rats
15 treated with Resveratrol (10 mg / kg / day, in ethanol)15 placebo-treated (ethanol only)
Pancreatic elastase infusion
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Vascular biology
• MMP-9 levels are down-modulated by treatment with Resveratrol
• TNF levels are down-modulated by treatment with Resveratrol
Plasma levels of MMP-9 and TNF-α
Gelatin zymography ** P <0.01 vs Ct
ELISA assay * P <0.05 vs Ct
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Vascular biology
The number of macrophages infiltrated in aneurysmatic tissue is lower in Resveratrol treated sections than untreated rats
MACROPHAGOUS INFILTRATION
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Vascular biology
Expression of MMP-9 in aortic wall is lower in rats treated with Resveratrol than control group
Immunohistochemistry for MMP-9
MMP-9 TISSUE EXPRESSION
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Vascular biology
The expression of VEGF and TNF-α is lower in rats treated with Resveratrol than in the control group
VEGF
TNFα
TISSUE EXPRESSION OF VEGF AND TNF-α
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Pane B. et al “Inflammatory modulation through a PPARγ agonist during surgically
induced visceral ischemia in animal model”.
Several reports describe the anti-inflammatory effects of PPARγ agonists about their role as modulators of theperi-vascular inflammatory response. PPARγ agonists, such
as pioglitazone, are able to modulate the inflammatoryresponse and consequently the ischemia/reperfusion injuryespecially on the renal parenchyma
Annals of Vascular Surgery
2018
Vascular biology – PPARγ agonist
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Modulation of inflammatory response during surgical induction of visceral and renal ischemia in an animal model by pioglitazone vs placebo.
WHAT’S NEW? – OUR EXPERIENCE
Vascular biology – Thoracoabdominal aneurysm
Bianca Pane-Ospedale Policlinico San Martino Genova, Università degli Studi diGenova
1° prize“TOP ten Abstract” XV Congresso SICVE 2016
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Carbone F. et al “Serum Levels of Osteopontin predict major adverse cardiovascular
events in patients with severe carotid artery stenosis”.
Inflammatory mediators in the blood stream and within plaques are keydeterminants in atherogenesis.High circulating Osteopontin (OPN) levels were strongly correlated withvulnerability parameters within plaques and predict Major AdverseCardiovascular Events in patients with severe carotid artery stenosis. OPNcould be a promising clinical tool to assess atherosclerotic outcomes
International Journal of Cardiology
2018
Vascular biology – Inflammation and Atherosclerosis
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Research topics
- vascular biology (polyphenols and inflammation and PPARγ agonist);
- vascular bioprosthesis: functionalized electrospun scaffold;
- nanoparticles as innovative targeted therapy in atherosclerosis.
Biological and biochemical research1
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1. Fabrication of biodegradable electrospun
vascular prosthesis functionalized with
quercetin as anti-inflammatory agent;
2. external coating with gelatin to reduce
permeability;
3. scaffolds characterization in terms of
physico-chemical, mechanical and
biological properties;
4. in vivo suturability test.
Functionalized electrospun scaffold
5 mm of diameter
PCL:PGS + quercetin
PCL:PGS
Scanning Electron Microscopy analysisC
PCL:PGS + quercetinPCL:PGS
Ferrari PF, Aliakbarian B, Lagazzo A, Tamayol A, Palombo D, Perego P, 2017. Tailored electrospun small-diameter graft for vascular prosthesis, International Journal of Polymeric Materials and Polymeric Biomaterials 66, 635-643.Ferrari PF, Aliakbarian B, Palombo D, Perego P, 2017. Small diameter vascular grafts coated with gelatin. Chemical Engineering Transactions 57.Aliakbarian B, Ferrari PF, Bagnato P, Palombo D, Perego P. Engineered small diameter vascular grafts with anti-inflammatory properties. The Journal of Cardiovascular Surgery, abstract book, Vol. 58 –Suppl. 2 to n° 3, 14.
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Functionalized electrospun scaffold - Mechanical properties
0
50
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0 2 4 6 8 10 12 14 16 18 20 22 24
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%)
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PCL:PGS 1:1 + gelatina
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PCL:PGS 1:1+
gelatina
Degradation
Swelling
Gelatin release
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0.00
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1.00
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MTS assay zymography
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of
MM
P-9
(%
)
+ TNF-α + quercetin
+ TNF-α
Functionalized electrospun scaffold
Evaluation of cytotoxicity and anti-inflammatory activity in human vascular endothelial cell line EAhy 926
Q: scaffold with quercetinGQ: scaffold with quercetin and gelatin
Biocompatibility Anti-inflammatory activity
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Implantation of electrospun PCL:PGS prostheses
Feasibility study
• number of rats: 2
• technical success: 100 %
Functionalized electrospun scaffold
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Research topics
- vascular biology (polyphenols and inflammation and PPARγ agonist);
- vascular bioprosthesis: functionalized electrospun scaffold;
- nanoparticles as innovative targeted therapy in atherosclerosis.
Biological and biochemical research1
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Nanodelivery system to carryactive compounds directly on the plaque…
…in order to counteract the inflammation
A NEW TARGETED THERAPY IN ATHEROSCLEROSIS
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Nanoparticles, a new targeted therapy in atherosclerosis
Antibody-engineered nanoparticles allow us to introduce the concept of targeted therapy. CaCO3
nanoparticle containing therapeutic antibodies.
oxLDLLDL
Atherosclerotic plaque is enriched of oxidizedlow-density-lipoproteins (oxLDL). Site directed andibodyY
YY
Ferrari PF, Aliakbarian B, Zattera E, Pastorino L, Palombo D, Perego P, 2017. Engineered CaCO3 nanoparticles with targeting activity: a simple approach for a vascular intended drug delivery system. The Canadian Journal of Chemical Engineering 95: 1683-1689. Ferrari PF, Aliakbarian B, Bagnato P, Palombo D, Perego P. An innovative drug delivery system for atherosclerosis. The Journal of Cardiovascular Surgery, abstract book, Vol. 58 - Suppl. 2 to n° 3, 6.
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20 nm
Results – Morphology studies
TEM analysis SEM analysis Fluorescence
microscopy
analysis
ESCVS 2017 YOUNG SURGEON AWARD 2nd PLACE
P.F. Ferrari, B. Aliakbarian, P. Bagnato, D. Palombo, P. Perego. An innovative drug delivery system for atherosclerosis.
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Research topics
- endovascular implants: from medical images to patient specific structural simulations;
- impact of peripheral endovascular repair on femoral popliteal artery kinematics;
- assessment of FU geometry changes of TAAAs treated with MFM stent;
- geometrical remodeling of the aortic arch after hybrid treatment.
In vivo medical image analysis and biomechanical simulations2
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Computational Mechanics &
Advanced Materials Group
Vascular and Endovascular Surgery Unit
IRCCS San Martino IST
University of Pavia University of Genoa
Alice Finotello
PhD Fellow
Team:Ferdinando Auricchio, Michele Conti,
Simone Morganti, Elena Faggiano
Team:Domenico Palombo, Giovanni Spinella,
Bianca Pane
Engineering support to vascular surgery clinical practice
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Research topics
- endovascular implants: from medical images to patient specific structural simulations;
- impact of peripheral endovascular repair on femoral popliteal artery kinematics;
- assessment of FU geometry changes of TAAAs treated with MFM stent;
- geometrical remodeling of the aortic arch after hybrid treatment.
In vivo medical image analysis and biomechanical simulations2
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Computed Tomography
Angiography
Dicom images
Endovascular implants: from medical images to patient specific structural simulations
1 2
4
Endograft models
5
Post-processing
3
Abaqus
Simulation results
3D reconstruction
ZTA P 36 161
Label FE model
ZTA P 36 113Quantify apposition to the wall: less prone to
endoleak
6
ESCVS 2018 YOUNG SURGEON AWARD 1st PLACE
A. Finotello, G. Spinella, M. Conti, B. Pane, F. Auricchio, and D. Palombo. Toward the use of patient-specific structural simulations of
endovascular repair in the clinical practice.
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Endovascular implants: from medical images to patient specific structural simulations
AbaqusESCVS 2018 YOUNG SURGEON AWARD 1st PLACE
A. Finotello, G. Spinella, M. Conti, B. Pane, F. Auricchio, and D. Palombo. Toward the use of patient-specific structural simulations of
endovascular repair in the clinical practice.
Facing a real case: predictive value of simulations
Pre-operative Post-operative
6 months
Type IB endoleak
Could these complicationsbe predicted?
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Endovascular implants: from medical images to patient specific structural simulations
AbaqusESCVS 2018 YOUNG SURGEON AWARD 1st PLACE
A. Finotello, G. Spinella, M. Conti, B. Pane, F. Auricchio, and D. Palombo. Toward the use of patient-specific structural simulations of
endovascular repair in the clinical practice.
Facing a real case: predictive value of simulations
Pre-operative Post-operative
6 months
Type IB endoleak
Could these complicationsbe predicted?
Simulation results: good agreement with the reality…
Bad device apposition to the wall: Endoleak prediction
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Research topics
- endovascular implants: from medical images to patient specific structural simulations;
- impact of peripheral endovascular repair on femoral popliteal artery kinematics;
- assessment of FU geometry changes of TAAAs treated with MFM stent;
- geometrical remodeling of the aortic arch after hybrid treatment.
In vivo medical image analysis and biomechanical simulations2
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Complex arterial kinematics due to leg bending
Challenging structural stentsolicitation
Engineering point of view 3 levels of analysis
1. Understanding arterial kinematics loads acting on the stent
2. Structural analysis of stent solicitation under the loads
3. Fatigue analysis expected structural life of the devices
Impact of peripheral endovascular repair on femoral poplitealartery kinematics: from clinical experience to in vivo biomechanical modeling
Open issues
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• Preliminary results on a clinical case (Viabahn device)
STENT ZONE
SFA-PA
Vessel diameters in the stented zone (light blue)Nominal stent diameter (red)
Impact of peripheral endovascular repair on femoral popliteal artery kinematic: from clinical experience to in vivo biomechanical modeling
Dia
met
ers
[mm
]
Stent length [mm]
Vessel diameters in the stented region vs stent length
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Research topics
- endovascular implants: from medical images to patient specific structural simulations;
- impact of peripheral endovascular repair on femoral popliteal artery kinematics;
- assessment of FU geometry changes of TAAAs treated with MFM stent;
- geometrical remodeling of the aortic arch after hybrid treatment.
In vivo medical image analysis and biomechanical simulations2
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Medical image analysis to measure the FU geometry changes of TAAAs treatedwith Cardiatis Multilayed Flow Modulator stent
From CTs, verify, through geometrical analysis:
● perfusion of side branches;
● centerline changes induced by the Cardiatis MFM;
● presence/absence of blood flowing in the aneurysm sac;
● morphological changes of the aneurysm sac.
Segmentation of Lumen, MFM and
Aneurysm
Surface Registration
Principal Lumen Extraction
Geometrical Analysis
CTs selection
G. Spinella, A. Finotello, E. Faggiano, B. Pane, M. Conti, B. Pane, V. Gazzola, F. Auricchio, and D. Palombo. Mid-term follow-up geometrical analysis of thoraco-
abdominal aortic aneurysms treated with multilayer flow modulator. Annals of Vascular Surgery. IN PRESS
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Research topics
- endovascular implants: from medical images to patient specific structural simulations;
- impact of peripheral endovascular repair on femoral popliteal artery kinematics;
- assessment of FU geometry changes of TAAAs treated with MFM stent;
- geometrical remodeling of the aortic arch after hybrid treatment.
In vivo medical image analysis and biomechanical simulations2
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Image acquisition
• 22 patients
• Zones 0,1 and 2
• Pre-op and 1-month FU CTs
3D surface generation
• Lumen
• Endograft
Centerline distances
Outerline curvature at
endograft landing zones
Analysis Workflow: from CT scans to 3D geometric analysis
L
DAR-LSA
Assessment of geometrical remodeling of the aortic arch and descending thoracic
aorta after hybrid treatment
Aim: Analyze the geometric changes of the aortic arch after hybrid treatment, with a particular focus on the endograft landingzones, attempting to enhance the understanding on the possible reasons for the development of device-related complications
Our experience suggests that the physiological curvature of the aortic arch was altered after hibrid treatment,
probably due to spring-back force (SBF) exerted by the stent-graft at both ends of the stent-grafts.
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Research topics
- risk of rupture;
- AAA screening.
Clinical research3
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RISK OF RUPTURE
2014
2013
Vascular surgery – Abdominal Aortic Aneurysm
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2016
RISK OF RUPTURE
Vascular surgery – Abdominal Aortic Aneurysm
Biomechanical indices are a promising tool in the assessment of AAA rupture risk as they incorporate several factors, including geometry, tissue properties, and patient-specific risk factors. However, clinical implementation of biomechanical AAA assessment remains a challenge owing to a lack of standardization.
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2008
RISK OF RUPTURE
Vascular surgery – Abdominal Aortic Aneurysm
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Ann Vasc Surg 2011
Our Experience
RISK OF RUPTURE
Vascular surgery – Abdominal Aortic Aneurysm
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Our ExperienceRISK OF RUPTURE
Vascular surgery – Abdominal Aortic Aneurysm
Ann Vasc Surg 2011
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Research topics
- risk of rupture;
- AAA screening.
Clinical research3
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SCREENING
Vascular surgery – Abdominal Aortic Aneurysm
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Our Experience
SCREENING
Vascular surgery – Abdominal Aortic Aneurysm
J Vasc Surg 2011
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Our Experience
SCREENING
Vascular surgery – Abdominal Aortic Aneurysm
S.A.Ge
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S.A.GeScreening Aneurisma Aorta Addominale Genova
Aortic Abdominal Aneurysm Screening: male patients between 65 and 75 years in Genova: about 26000 examinations
U.O CHIRURGIA VASCOLARE ED ENDOVASCOLARE
SCREENING
Vascular surgery – Abdominal Aortic Aneurysm
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SCREENING
Vascular surgery – Abdominal Aortic Aneurysm
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Bonaventura A. et al »Intraplaque Expression of C-Reactive Protein PredictsCardiovascular Events in Patients with Severe Atherosclerotic Carotid ArteryStenosis». Mediators Inflamm. Epub 2016 Sep.
Carbone F. et al«Vitamin D receptor is expressed within human carotid plaques and correlates with pro-inflammatory M1 macrophages». Vascul Pharmacol.Epub 2016 Aug 20.
Pagano S. et al. «Anti-apolipoprotein A-1 auto-antibodies as active modulators ofAtherothrombosis». Thromb Haemost. 2016 Aug.
Lenglet S. et al «Statin treatment is associated with reduction in serum levels of receptoractivator of NF-κB ligand and neutrophil activation inpatients with severe carotid stenosis». Mediators Inflamm. Epub 2014 Feb.
Fraga-Silva RA. Et al «Treatment with Angiotensin-(1-7) reduces inflammation in carotidatherosclerotic plaques». Thromb Haemost. 2014 Apr.
Vuilleumier N. et al «Serum levels of anti-apolipoprotein A-1 auto-antibodies and myeloperoxidase as predictors of major adverse cardiovascular events after carotidendarterectomy». Thromb Haemost. 2013 Apr.
Montecucco F. et al «The activation of the cannabinoid receptor type 2 reducesneutrophilic protease-mediated vulnerability in atheroscleroticPlaques». Eur Heart J. 2012 Apr.
Montecucco F. et al «Anti-Apolipoprotein A-1 auto-antibodies are active mediators of atherosclerotic plaque vulnerability.» Eur Heart J. 2011Feb.
Montecucco F. «Systemic and intraplaque mediators of inflammation areincreased in patients symptomatic for ischemic stroke». Stroke. 2010 Jul.
Other studies and projects
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Conclusion
- Interdisciplinary experience has allowed to open new fields of inquiry.
- The engineers contribution to the team allows new therapeutic approaches.
- The goal for the future is a new professional figure able to blend the surgical skills and
the ability to conduct scientific projects for development of new therapeutic strategies:
the Vascular Specialist.
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Able to take care of the vascular disease
as a whole
In other words…
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Research Team
UNIVERSITY OF GENOVA - IRCCS SAN MARTINO HOSPITAL
COMPMECH GROUP UNIVERSITY OF PAVIA