Van Varkensaorta tot Digitale Tweeling: De Geheimen van onze Slagaders Ontrafeld met Artificiële Intelligentie
Ongeveer elke seconde pompt ons hart bloed door een complex netwerk van (slag)aders. Dat vitale systeem functioneert geruisloos op de achtergrond, tot er iets misgaat. Hart- en vaatziekten zijn wereldwijd doodsoorzaak nummer één. Om die stille moordenaars te begrijpen, zijn computermodellen cruciaal. In mijn masterproef aan de KU Leuven heb ik zo een model getoetst aan de realiteit, en met behulp van een supercomputer een artificiële intelligentie (AI)-model getraind dat de belangrijkste factoren voor de stevigheid van een slagader kan identificeren.
Stel je onze slagaders voor als een hoogtechnologisch bouwwerk. Ze moeten flexibel genoeg zijn om bij elke hartslag uit te zetten, maar ook sterk genoeg om niet te scheuren onder hoge druk. Dat delicate evenwicht wordt bepaald door de microstructuur (mikrós/μικρός is klein in het Grieks) van de slagaderwand: een samenspel van onder andere elastine en collageen. Elastine is een elastische vezel die fungeert als een soort rubber; collageen is een vezel die dient als stevige wapening. Wanneer dat evenwicht verstoord wordt door bijvoorbeeld veroudering of een ongezonde levensstijl liggen ziektes als aneurysma’s (lokale verwijdingen van de slagader) op de loer.
Er zijn apparaten die de microstructuur van onze slagaders tot op een nanometer visualiseren aangezien deze bijna niet te zien is met het blote oog!
Om deze processen te bestuderen gebruiken wetenschappers geavanceerde computermodellen — ‘digitale tweelingen’ van een slagader. Deze digitale tweelingen kunnen simuleren hoe een slagader reageert op druk en vervorming. De meeste modellen zijn echter gebouwd op simplistische, theoretische formules. Ze missen de biologische realiteit van de microstructuur, waardoor ze onnauwkeurig zijn bij het voorspellen van het kantelpunt naar falen. Mijn missie: de digitale tweeling funderen in de biologische realiteit.
Van het slachthuis naar het lab
Om de digitale tweeling te voeden met data uit de echte wereld begon mijn onderzoek met varkensaorta’s uit het slachthuis, die qua samenstelling sterk lijken op die van de mens. Geen overbodig dierenleed veroorzaakt dus. Om de unieke rol van elke bouwsteen te isoleren heb ik de stalen in drie groepen verdeeld. De eerste groep was het natuurlijke, onbehandelde weefsel. Bij de tweede groep heb ik met behulp van een chemische reactie collageen laten oplossen. Bij de derde groep werd juist elastine weggehaald. Aangezien elastine de rubberachtige component is, kan je in de figuur zien dat het verwijderen hiervan leidt tot weefsel met weinig elasticiteit.
Vervolgens werden al deze stukjes weefsel onderworpen aan mechanische trekproeven. Zo bracht ik in kaart hoeveel kracht er nodig is om deze uit te rekken. De trekproeven toonden aan dat elastine zorgt voor de soepelheid van onze slagaders, terwijl collageen als een beveiliging dient bij hoge uitrekking om scheuren te voorkomen. In de figuur is de trekproefopstelling met onbehandeld weefsel te zien.
Een digitale tweeling die de waarheid spreekt
Met deze unieke experimentele data kon ik de digitale tweeling kalibreren en valideren. Ik kalibreerde het model door de parameters aan te passen tot de modelsimulaties overeenkwamen met de trekproeven van de varkensaorta’s. Vervolgens heb ik gecontroleerd of het model ook echt klopt door de modelsimulaties te vergelijken met de experimenten, dat wordt valideren genoemd. De digitale tweeling was nu niet langer gebaseerd op aannames, maar geworteld in de biologische realiteit.
De supercomputer als turbo
De digitale tweeling was wel accuraat, maar vreselijk traag. Hier stuitte ik op de grootste uitdaging van mijn onderzoek. Om dat trage model te versnellen, wilde ik een AI-model trainen dat de modelsimulaties kon nabootsen. Maar zo een AI-model trainen is geen sinecure: het vereist honderden voorbeelden en een immense rekenkracht die een gewone computer overstijgt. De oplossing lag bij het Vlaams Supercomputer Centrum.
Ik liet de supercomputer dagenlang rekenen en voerde honderden voorbeelden van de digitale tweeling aan mijn AI-model. Net zoals een kind leert fietsen door te oefenen leerde het systeem zo de complexe wiskundige patronen herkennen. De beloning was enorm: een modelsimulatie die eerst een uur duurde voltooide het AI-model nu in minder dan een seconde!
Weten wat er echt toe doet in onze slagaders
Met dat razendsnelle en betrouwbare AI-model kon ik eindelijk de ultieme vraag beantwoorden: welke microscopische eigenschappen zijn cruciaal voor de gezondheid van een slagader? Ik voerde een grootschalige gevoeligheidsanalyse uit. Dat is een wetenschappelijke term voor een experiment waarbij je aan alle mogelijke digitale knoppen draait om te zien welke de grootste invloed heeft.
De analyse gaf een haarscherp beeld. Bij lage uitrekking wordt de stevigheid van de slagaderwand bijna volledig bepaald door de eigenschappen van elastine. Bij hoge uitrekking, wanneer het risico op scheuren toeneemt, nemen drie collageen-gerelateerde factoren het roer over: de hoeveelheid collageen, de stijfheid ervan, en het punt waarop de collageenvezels op spanning komen. Deze digitale resultaten bevestigden dus wat ik experimenteel had waargenomen.
Dit was geen louter academische vaststelling. Bij het ouder worden verliezen we van nature elastine. Onze slagaders worden stijver, de bloeddruk stijgt, en de collageenvezels komen onder hogere spanning te staan. Dit verhoogt de slijtage en het risico op scheuren. Mijn analyse toonde welke factoren in dit proces de zwakste schakels zijn.
De toekomst: een virtuele patiënt
Dit onderzoek leverde een concreet stappenplan op: van experimenteel werk tot een waarheidsgetrouw en versneld computermodel van de slagader. Het ware potentieel ligt echter in de toekomst. We evolueren naar een geneeskunde waarin we voor elke patiënt een persoonlijke digitale tweeling willen maken. Stel je voor dat we de eigenschappen van jouw slagaderwand kunnen meten via een ziekenhuisscan en invoeren in dit AI-model. We zouden dan virtueel kunnen testen hoe een medicijn de gezondheid van jouw slagader beïnvloedt, of het risico op een slagaderwandscheur kunnen voorspellen.
Honderdduizend keer per dag ondergaan onze slagaders een mini-stresstest, bij elke hartslag opnieuw. Het is een wonder waar we zelden bij stilstaan, tot het faalt. Dankzij dit onderzoek, dat tot stand kwam door Belgische samenwerkingen in de biomechanica tussen ingenieurs en chirurgen, komen we steeds dichter bij een digitale blauwdruk van dat wonder. Sta daar dus eens bij stil de volgende keer dat je jouw hart in jouw borstkas voelt kloppen.
Bibliografie
[1] B. B. Aaron and J. M. Gosline. Elastin as a random-network elastomer: A
mechanical and optical analysis of single elastin fibers. Biopolymers, 20(6):1247–
1260, June 1981.
[2] V. A. Acosta Santamaría, M. Flechas García, J. Molimard, and S. Avril. Three-
Dimensional Full-Field Strain Measurements across a Whole Porcine Aorta
Subjected to Tensile Loading Using Optical Coherence Tomography–Digital
Volume Correlation. Frontiers in Mechanical Engineering, 4:3, Mar. 2018.
[3] V. Agrawal, S. A. Kollimada, A. G. Byju, and N. Gundiah. Regional variations
in the nonlinearity and anisotropy of bovine aortic elastin. Biomechanics and
Modeling in Mechanobiology, 12(6):1181–1194, Nov. 2013.
[4] P. W. Alford, A. W. Feinberg, S. P. Sheehy, and K. K. Parker. Biohybrid
thin films for measuring contractility in engineered cardiovascular muscle.
Biomaterials, 31(13):3613–3621, May 2010.
[5] A. Ali Kadhem, N. I. Abdul Wahab, I. Aris, J. Jasni, and A. N. Abdalla.
Computational techniques for assessing the reliability and sustainability of
electrical power systems: A review. Renewable and Sustainable Energy Reviews,
80:1175–1186, Dec. 2017.
[6] E. Altay, H. Kıztanır, P. Kösger, N. Cetin, A. Sulu, A. K. Tufan, H. Ozen, and
B. Ucar. Evaluation of Arterial Stiffness and Carotid Intima-Media Thickness
in Children with Primary and Renal Hypertension. Pediatric Cardiology,
44(1):54–66, Jan. 2023.
[7] M. Amabili, M. Asgari, I. D. Breslavsky, G. Franchini, F. Giovanniello, and
G. A. Holzapfel. Microstructural and mechanical characterization of the layers
of human descending thoracic aortas. Acta Biomaterialia, 134:401–421, Oct.
2021.
[8] M. Amabili, P. Balasubramanian, and I. Breslavsky. Anisotropic fractional
viscoelastic constitutive models for human descending thoracic aortas. Journal
of the Mechanical Behavior of Biomedical Materials, 99:186–197, Nov. 2019.
[9] J. A. Ambrose and R. S. Barua. The pathophysiology of cigarette smoking
and cardiovascular disease. Journal of the American College of Cardiology,
43(10):1731–1737, May 2004.
[10] H. Åstrand, J. Stålhand, J. Karlsson, M. Karlsson, B. Sonesson, and T. Länne.
In vivo estimation of the contribution of elastin and collagen to the mechanical
properties in the human abdominal aorta: Effect of age and sex. Journal of
Applied Physiology, 110(1):176–187, Jan. 2011.
[11] V. Ayyalasomayajula, B. Pierrat, and P. Badel. A computational model for
understanding the micro-mechanics of collagen fiber network in the tunica
adventitia. Biomechanics and Modeling in Mechanobiology, 18(5):1507–1528,
Oct. 2019.
[12] V. Ayyalasomayajula, B. Pierrat, and P. Badel. An evaluation of fiber-based
damage for assessing the failure of aortic tissue: Comparison between healthy
and aneurysmal aortas. Mechanics of Soft Materials, 4(1):4, June 2022.
[13] V. Ayyalasomayajula, B. Pierrat, and P. Badel. Evaluation of a multi-scale
discrete fiber model for analyzing arterial failure. Journal of Biomechanics,
157:111700, Aug. 2023.
[14] P. O. Bayguinov, D. M. Oakley, C.-C. Shih, D. J. Geanon, M. S. Joens, and
J. A. J. Fitzpatrick. Modern Laser Scanning Confocal Microscopy. Current
Protocols in Cytometry, 85(1):e39, July 2018.
[15] J. S. Bell, A. O. Adio, A. Pitt, L. Hayman, C. E. Thorn, A. C. Shore, J. L.
Whatmore, and C. P. Winlove. Microstructure and mechanics of human
resistance arteries. American Journal of Physiology. Heart and Circulatory
Physiology, 311(6):H1560–H1568, Dec. 2016.
[16] M. Ben-Or Frank, J. A. Niestrawska, G. A. Holzapfel, and G. deBotton.
Micromechanically-motivated analysis of fibrous tissue. Journal of the Mechanical
Behavior of Biomedical Materials, 96:69–78, Aug. 2019.
[17] M. R. Bennett, S. Sinha, and G. K. Owens. Vascular Smooth Muscle Cells in
Atherosclerosis. Circulation Research, 118(4):692–702, Feb. 2016.
[18] J. Bergstra and Y. Bengio. Random Search for Hyper-Parameter Optimization.
Journal of Machine Learning Research, 13:281–305, 2012.
[19] S. Bose, S. Li, E. Mele, and V. V. Silberschmidt. Exploring the Mechanical
Properties and Performance of Type-I Collagen at Various Length Scales: A
Progress Report. Materials, 15(8):2753, Apr. 2022.
[20] E. C. Boyle, D. G. Sedding, and A. Haverich. Targeting vasa vasorum dysfunction
to prevent atherosclerosis. Vascular Pharmacology, 96–98:5–10, Sept.
2017.
[21] J. H. Bracamonte, S. K. Saunders, J. S. Wilson, U. T. Truong, and J. S. Soares.
Patient-Specific Inverse Modeling of In Vivo Cardiovascular Mechanics with
Medical Image-Derived Kinematics as Input Data: Concepts, Methods, and
Applications. Applied sciences (Basel, Switzerland), 12(8):3954, Apr. 2022.
[22] G. Brahmachari. Biotechnology of Microbial Enzymes. Elsevier, 2023.
[23] J. L. Brisman, J. K. Song, and D. W. Newell. Cerebral Aneurysms. New
England Journal of Medicine, 355(9):928–939, Aug. 2006.
[24] V. J. Brookes, D. Jordan, S. Davis, M. P. Ward, and J. Heller. Saltelli
Global Sensitivity Analysis and Simulation Modelling to Identify Intervention
Strategies to Reduce the Prevalence of Escherichia coli O157 Contaminated
Beef Carcasses. PLOS ONE, 10(12):e0146016, Dec. 2015.
[25] B. A. Brown, H. Williams, and S. J. George. Evidence for the Involvement of
Matrix-Degrading Metalloproteinases (MMPs) in Atherosclerosis. In Progress
in Molecular Biology and Translational Science, volume 147, pages 197–237.
Elsevier, 2017.
[26] N. E. Buglak, J. Lucitti, P. Ariel, S. Maiocchi, F. J. Miller, and E. S. M. Bahnson.
Light sheet fluorescence microscopy as a new method for unbiased threedimensional
analysis of vascular injury. Cardiovascular Research, 117(2):520–
532, Jan. 2021.
[27] A. E. Cartaya, S. Maiocchi, N. E. Buglak, S. Torzone, G. Messinger, and
E. S. M. Bahnson. Application of Machine Learning and Virtual Reality for
Volumetric Analysis of Arterial Lesions, Dec. 2022.
[28] N. Chalouhi, B. L. Hoh, and D. Hasan. Review of Cerebral Aneurysm Formation,
Growth, and Rupture. Stroke, 44(12):3613–3622, Dec. 2013.
[29] H. Chen and G. S. Kassab. Microstructure-based biomechanics of coronary
arteries in health and disease. Journal of Biomechanics, 49(12):2548–2559, Aug.
2016. Table 1 contains data of the percentual content of elastin and collagen
within media and adventitia.
[30] W. Cheng, R. Pu, and B. Wang. AMC: Adaptive Learning Rate Adjustment
Based on Model Complexity. Mathematics, 13(4):650, Feb. 2025.
[31] Y. Cheng, D. Wang, P. Zhou, and T. Zhang. A Survey of Model Compression
and Acceleration for Deep Neural Networks, 2017.
[32] M. J. Cho, M.-R. Lee, and J.-G. Park. Aortic aneurysms: Current pathogenesis
and therapeutic targets. Experimental & Molecular Medicine, 55(12):2519–2530,
Dec. 2023.
[33] O. P. Choudhary and P. Ka. Scanning Electron Microscope: Advantages
and Disadvantages in Imaging Components. International Journal of Current
Microbiology and Applied Sciences, 6(5):1877–1882, May 2017.
[34] M.-J. Chow, R. Turcotte, C. P. Lin, and Y. Zhang. Arterial Extracellular
Matrix: A Mechanobiological Study of the Contributions and Interactions of
Elastin and Collagen. Biophysical Journal, 106(12):2684–2692, June 2014.
[35] T. E. Clark, M. A. Lillie, A. W. Vogl, J. M. Gosline, and R. E. Shadwick.
Mechanical contribution of lamellar and interlamellar elastin along the mouse
aorta. Journal of Biomechanics, 48(13):3599–3605, Oct. 2015.
[36] W. Clarke and M. A. Marzinke. Contemporary Practice in Clinical Chemistry.
Elsevier, 2020.
[37] A. J. Cocciolone, J. Z. Hawes, M. C. Staiculescu, E. O. Johnson, M. Murshed,
and J. E. Wagenseil. Elastin, arterial mechanics, and cardiovascular
disease. American Journal of Physiology - Heart and Circulatory Physiology,
315(2):H189–H205, Aug. 2018.
[38] C. Costopoulos, Y. Huang, A. J. Brown, P. A. Calvert, S. P. Hoole, N. E.
West, J. H. Gillard, Z. Teng, and M. R. Bennett. Plaque Rupture in Coronary
Atherosclerosis Is Associated With Increased Plaque Structural Stress. JACC:
Cardiovascular Imaging, 10(12):1472–1483, Dec. 2017.
[39] M. Dalbosco, T. A. Carniel, E. A. Fancello, and G. A. Holzapfel. Multiscale
numerical analyses of arterial tissue with embedded elements in the finite strain
regime. Computer Methods in Applied Mechanics and Engineering, 381:113844,
Aug. 2021.
[40] M. Dalbosco, E. A. Fancello, and G. A. Holzapfel. Multiscale computational
modeling of arterial micromechanics: A review. Computer Methods in Applied
Mechanics and Engineering, 425:116916, May 2024.
[41] E. Dall’Ara and G. Tozzi. Digital volume correlation for the characterization of
musculoskeletal tissues: Current challenges and future developments. Frontiers
in Bioengineering and Biotechnology, 10:1010056, Oct. 2022.
[42] S. De Bournonville, S. Vangrunderbeeck, H. G. T. Ly, C. Geeroms, W. M.
De Borggraeve, T. N. Parac-Vogt, and G. Kerckhofs. Exploring polyoxometalates
as non-destructive staining agents for contrast-enhanced microfocus
computed tomography of biological tissues. Acta Biomaterialia, 105:253–262,
Mar. 2020.
[43] J. F. Debongnie. On the approximation of incompressible materials in the
displacement method. International Journal for Numerical Methods in Engineering,
14(7):1095–1099, Jan. 1979.
[44] G. deBotton and T. Oren. Analytical and numerical analyses of the micromechanics
of soft fibrous connective tissues. Biomechanics and Modeling in
Mechanobiology, 12(1):151–166, Jan. 2013.
[45] M. A. Depuydt, K. H. Prange, L. Slenders, T. Örd, D. Elbersen, A. Boltjes,
S. C. De Jager, F. W. Asselbergs, G. J. De Borst, E. Aavik, T. Lönnberg,
E. Lutgens, C. K. Glass, H. M. Den Ruijter, M. U. Kaikkonen, I. Bot, B. Slütter,
S. W. Van Der Laan, S. Yla-Herttuala, M. Mokry, J. Kuiper, M. P. De Winther, and G. Pasterkamp. Microanatomy of the Human Atherosclerotic Plaque by
Single-Cell Transcriptomics. Circulation Research, 127(11):1437–1455, Nov.
2020.
[46] V. K. Dixit and C. Rackauckas. GlobalSensitivity. jl: Performant and parallel
global sensitivity analysis with julia. Journal of Open Source Software,
7(76):4561, 2022.
[47] P. Dobrin, W. Baker, and W. Gley. Elastolytic and Collagenolytic Studies of
Arteries: Implications for the Mechanical Properties of Aneurysms. Archives
of Surgery, 119(4):405, Apr. 1984.
[48] P. B. Dobrin and T. R. Canfield. Elastase, collagenase, and the biaxial elastic
properties of dog carotid artery. American Journal of Physiology-Heart and
Circulatory Physiology, 247(1):H124–H131, July 1984.
[49] R. Doll, R. Peto, J. Boreham, and I. Sutherland. Mortality in relation to
smoking: 50 years’ observations on male British doctors. BMJ, 328(7455):1519,
June 2004.
[50] D. Enea, F. Henson, S. Kew, J. Wardale, A. Getgood, R. Brooks, and N. Rushton.
Extruded collagen fibres for tissue engineering applications: Effect of
crosslinking method on mechanical and biological properties. Journal of Materials
Science: Materials in Medicine, 22(6):1569–1578, June 2011.
[51] P. Erhart, C. Grond-Ginsbach, M. Hakimi, F. Lasitschka, S. Dihlmann,
D. Böckler, and A. Hyhlik-Dürr. Finite Element Analysis of Abdominal Aortic
Aneurysms: Predicted Rupture Risk Correlates With Aortic Wall Histology
in Individual Patients. Journal of Endovascular Therapy, 21(4):556–564, Aug.
2014.
[52] A. Faggiotto, R. Ross, and L. Harker. Studies of hypercholesterolemia in
the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis:
An Official Journal of the American Heart Association, Inc.,
4(4):323–340, July 1984.
[53] D. Fairweather. Sex Differences in Inflammation during Atherosclerosis. Clinical
Medicine Insights: Cardiology, 8s3:CMC.S17068, Jan. 2014.
[54] N. Famaey, L. Geris, and H. Fehervary. Community Challenge towards Consensus
on Characterization of Biological tissue. Unpublished, 2025.
[55] J. Fan and T. Watanabe. Atherosclerosis: Known and unknown. Pathology
International, 72(3):151–160, Mar. 2022.
[56] H. Fehervary, J. Vander Sloten, and N. Famaey. Development of an improved
parameter fitting method for planar biaxial testing using rakes. International
Journal for Numerical Methods in Biomedical Engineering, 35(4):e3174, Apr.
2019.
[57] D. M. Fernandez, A. H. Rahman, N. F. Fernandez, A. Chudnovskiy, E.-a. D.
Amir, L. Amadori, N. S. Khan, C. K. Wong, R. Shamailova, C. A. Hill,
Z. Wang, R. Remark, J. R. Li, C. Pina, C. Faries, A. J. Awad, N. Moss,
J. L. M. Bjorkegren, S. Kim-Schulze, S. Gnjatic, A. Ma’ayan, J. Mocco,
P. Faries, M. Merad, and C. Giannarelli. Single-cell immune landscape of
human atherosclerotic plaques. Nature Medicine, 25(10):1576–1588, Oct. 2019.
[58] T. Y. Foong, Y. Hua, R. Amini, and I. A. Sigal. Who bears the load? IOPinduced
collagen fiber recruitment over the corneoscleral shell. Experimental
Eye Research, 230:109446, May 2023.
[59] G. Franchini, I. D. Breslavsky, G. A. Holzapfel, and M. Amabili. Viscoelastic
characterization of human descending thoracic aortas under cyclic load. Acta
Biomaterialia, 130:291–307, Aug. 2021.
[60] S. G. Frangos. Localization of Atherosclerosis: Role of Hemodynamics. Archives
of Surgery, 134(10):1142, Oct. 1999.
[61] O. Fritze, M. Schleicher, K. König, K. Schenke-Layland, U. Stock, and C. Harasztosi.
Facilitated Noninvasive Visualization of Collagen and Elastin in Blood
Vessels. Tissue Engineering Part C: Methods, 16(4):705–710, Aug. 2010.
[62] Y.-C. Fung. Biomechanics: Mechanical Properties of Living Tissues. Springer
New York, New York, NY, 1993.
[63] E. Gacek, R. R. Mahutga, and V. H. Barocas. Hybrid discrete-continuum
multiscale model of tissue growth and remodeling. Acta Biomaterialia, 163:7–24,
June 2023.
[64] C. M. García-Herrera, J. M. Atienza, F. J. Rojo, E. Claes, G. V. Guinea, D. J.
Celentano, C. García-Montero, and R. L. Burgos. Mechanical behaviour and
rupture of normal and pathological human ascending aortic wall. Medical &
Biological Engineering & Computing, 50(6):559–566, June 2012.
[65] T. C. Gasser, R. W. Ogden, and G. A. Holzapfel. Hyperelastic modelling
of arterial layers with distributed collagen fibre orientations. Journal of The
Royal Society Interface, 3(6):15–35, Feb. 2006.
[66] E. Gentleman, A. N. Lay, D. A. Dickerson, E. A. Nauman, G. A. Livesay, and
K. C. Dee. Mechanical characterization of collagen fibers and scaffolds for
tissue engineering. Biomaterials, 24(21):3805–3813, Sept. 2003.
[67] R. G. Gerrity. The role of the monocyte in atherogenesis: II. Migration of
foam cells from atherosclerotic lesions. The American Journal of Pathology,
103(2):191–200, May 1981.
[68] N. M. Ghadie, J.-P. St-Pierre, and M. R. Labrosse. The Contribution of
Glycosaminoglycans/Proteoglycans to Aortic Mechanics in Health and Disease:A Critical Review. IEEE transactions on bio-medical engineering, 68(12):3491–
3500, Dec. 2021.
[69] X. J. Girerd, C. Acar, J. J. Mourad, P. Boutouyrie, M. E. Safar, and S. Laurent.
Incompressibility of the human arterial wall: An in vitro ultrasound study.
Journal of Hypertension. Supplement: Official Journal of the International
Society of Hypertension, 10(6):S111–114, Aug. 1992.
[70] A. Giudici, I. B. Wilkinson, and A. W. Khir. Review of the Techniques Used for
Investigating the Role Elastin and Collagen Play in Arterial Wall Mechanics.
IEEE Reviews in Biomedical Engineering, 14:256–269, 2021.
[71] M. S. Godinho, C. T. Thorpe, S. E. Greenwald, and H. R. Screen. Elastase
treatment of tendon specifically impacts the mechanical properties of the
interfascicular matrix. Acta Biomaterialia, 123:187–196, Mar. 2021.
[72] A. R. Godwin, M. Singh, M. P. Lockhart-Cairns, Y. F. Alanazi, S. A. Cain,
and C. Baldock. The role of fibrillin and microfibril binding proteins in elastin
and elastic fibre assembly. Matrix Biology, 84:17–30, Nov. 2019.
[73] J. Golledge. Abdominal aortic aneurysm: Update on pathogenesis and medical
treatments. Nature Reviews Cardiology, 16(4):225–242, Apr. 2019.
[74] Google DeepMind. Gemini. https://gemini.google.com, 2025.
[75] Google for Developers. Overfitting: L2 regularization | Machine
Learning. https://developers.google.com/machine-learning/crashcourse/
overfitting/regularization, Oct. 2024. Accessed: 10 May 2025.
[76] E. M. Green, J. C. Mansfield, J. S. Bell, and C. P. Winlove. The structure and
micromechanics of elastic tissue. Interface Focus, 4(2):20130058, Apr. 2014.
[77] N. Gundiah, M. B Ratcliffe, and L. A Pruitt. Determination of strain energy
function for arterial elastin: Experiments using histology and mechanical tests.
Journal of Biomechanics, 40(3):586–594, Jan. 2007.
[78] N. Gundiah, A. R. Babu, and L. A. Pruitt. Effects of elastase and collagenase
on the nonlinearity and anisotropy of porcine aorta. Physiological Measurement,
34(12):1657–1673, Dec. 2013.
[79] D. Haskett, G. Johnson, A. Zhou, U. Utzinger, and J. Vande Geest. Microstructural
and biomechanical alterations of the human aorta as a function of age
and location. Biomechanics and Modeling in Mechanobiology, 9(6):725–736,
Dec. 2010.
[80] H. W. Haslach. Nonlinear viscoelastic, thermodynamically consistent, models
for biological soft tissue. Biomechanics and Modeling in Mechanobiology,
3(3):172–189, Mar. 2005.
[81] S. Hatefi Ardakani, P. Fatemi Dehaghani, H. Moslemzadeh, and S. Mohammadi.
3D large strain hierarchical multiscale analysis of soft fiber-reinforced tissues:
Application to a degraded arterial wall. Engineering Computations, 39(6):2108–
2143, June 2022.
[82] H. B. Henninger, C. J. Underwood, S. J. Romney, G. L. Davis, and J. A.
Weiss. Effect of elastin digestion on the quasi-static tensile response of medial
collateral ligament: ELASTIN MECHANICS IN LIGAMENT. Journal of
Orthopaedic Research, 31(8):1226–1233, Aug. 2013.
[83] A. Hey. Hyperband Hyperparameter Optimization.
https://medium.com/@heyamit10/hyperband-hyperparameter-optimizationd7bd…,
Dec. 2024. Accessed: 21 May 2025.
[84] M. R. Hill, X. Duan, G. A. Gibson, S. Watkins, and A. M. Robertson. A
theoretical and non-destructive experimental approach for direct inclusion of
measured collagen orientation and recruitment into mechanical models of the
artery wall. Journal of Biomechanics, 45(5):762–771, Mar. 2012.
[85] H. Hinkley, D. A. Counts, E. VonCanon, and M. Lacy. T Cells in Atherosclerosis:
Key Players in the Pathogenesis of Vascular Disease. Cells, 12(17):2152, Aug.
2023.
[86] G. E. Hinton, N. Srivastava, A. Krizhevsky, I. Sutskever, and R. R. Salakhutdinov.
Improving neural networks by preventing co-adaptation of feature
detectors, 2012.
[87] A. H. Hoffman, Z. Teng, J. Zheng, Z.Wu, P. K.Woodard, K. L. Billiar, L.Wang,
and D. Tang. Stiffness Properties of Adventitia, Media, and Full Thickness
Human Atherosclerotic Carotid Arteries in the Axial and Circumferential
Directions. Journal of Biomechanical Engineering, 139(12):124501, Dec. 2017.
[88] W. Hollander. Role of hypertension in atherosclerosis and cardiovascular
disease. The American Journal of Cardiology, 38(6):786–800, Nov. 1976.
[89] G. Holzapfel. Collagen in Arterial Walls: Biomechanical Aspects. In P. Fratzl,
editor, Collagen, pages 285–324. Springer US, Boston, MA, 2008.
[90] G. A. Holzapfel. Determination of material models for arterial walls from
uniaxial extension tests and histological structure. Journal of Theoretical
Biology, 238(2):290–302, Jan. 2006.
[91] G. A. Holzapfel and T. C. Gasser. A viscoelastic model for fiber-reinforced composites
at finite strains: Continuum basis, computational aspects and applications.
Computer Methods in Applied Mechanics and Engineering, 190(34):4379–
4403, May 2001.
[92] G. A. Holzapfel, T. C. Gasser, and R. W. Ogden. A New Constitutive Framework
for Arterial Wall Mechanics and a Comparative Study of Material Models.
Journal of Elasticity, 61(1/3):1–48, 2000.
[93] G. A. Holzapfel, K. Linka, S. Sherifova, and C. J. Cyron. Predictive constitutive
modelling of arteries by deep learning. Journal of The Royal Society Interface,
18(182):20210411, Sept. 2021.
[94] G. A. Holzapfel, J. A. Niestrawska, R. W. Ogden, A. J. Reinisch, and A. J.
Schriefl. Modelling non-symmetric collagen fibre dispersion in arterial walls.
Journal of The Royal Society Interface, 12(106):20150188, May 2015.
[95] G. A. Holzapfel and R. W. Ogden. A damage model for collagen fibres with
an application to collagenous soft tissues. Proceedings. Mathematical, Physical,
and Engineering Sciences, 476(2236):20190821, Apr. 2020.
[96] Y. M. Hong. Atherosclerotic Cardiovascular Disease Beginning in Childhood.
Korean Circulation Journal, 40(1):1, 2010.
[97] P. J. Huber. Robust Estimation of a Location Parameter. The Annals of
Mathematical Statistics, 35(1):73–101, Mar. 1964.
[98] J. Humphrey. Possible Mechanical Roles of Glycosaminoglycans in Thoracic
Aortic Dissection and Associations with Dysregulated Transforming Growth
Factor-β. Journal of Vascular Research, 50(1):1–10, 2013.
[99] J. D. Humphrey. Cardiovascular Solid Mechanics: Cells, Tissues, and Organs.
Springer Science \& Business Media, 2013.
[100] J. D. Humphrey, E. R. Dufresne, and M. A. Schwartz. Mechanotransduction
and extracellular matrix homeostasis. Nature Reviews Molecular Cell Biology,
15(12):802–812, Dec. 2014.
[101] S. Ioffe and C. Szegedy. Batch Normalization: Accelerating Deep Network
Training by Reducing Internal Covariate Shift, 2015.
[102] T. Iwanaga, W. Usher, and J. Herman. Toward SALib 2.0: Advancing the accessibility
and interpretability of global sensitivity analyses. Socio-Environmental
Systems Modelling, 4:18155, May 2022.
[103] M. Jadidi, M. Habibnezhad, E. Anttila, K. Maleckis, A. Desyatova, J. MacTaggart,
and A. Kamenskiy. Mechanical and structural changes in human thoracic
aortas with age. Acta Biomaterialia, 103:172–188, Feb. 2020.
[104] A. Jadon, A. Patil, and S. Jadon. A Comprehensive Survey of Regression
Based Loss Functions for Time Series Forecasting, 2022.
[105] B. I. Jugdutt, M. J. Joljart, and M. I. Khan. Rate of Collagen Deposition
During Healing and Ventricular Remodeling After Myocardial Infarction in
Rat and Dog Models. Circulation, 94(1):94–101, July 1996.
[106] K. Karimian. What Is a Neural Network? A Simple Explanation.
https://www.alation.com/blog/what-is-a-neural-network/, Sept. 2024. Accessed:
25 May 2025.
[107] M. A. Kemler, W. F. Kolkman, P. J. Slootweg, and M. Kon. Adventitial
stripping does not strip the adventitia. Plastic and Reconstructive Surgery,
99(6):1626–1631, May 1997.
[108] D. P. Kingma and J. Ba. Adam: A Method for Stochastic Optimization, 2014.
[109] J. C. Kohn, M. C. Lampi, and C. A. Reinhart-King. Age-related vascular
stiffening: Causes and consequences. Frontiers in Genetics, 6, Mar. 2015.
[110] C. E. Korenczuk, R. Y. Dhume, K. K. Liao, and V. H. Barocas. Ex Vivo
Mechanical Tests and Multiscale Computational Modeling Highlight the Importance
of Intramural Shear Stress in Ascending Thoracic Aortic Aneurysms.
Journal of Biomechanical Engineering, 141(121010), Nov. 2019.
[111] T. Kotsiopoulos, P. Sarigiannidis, D. Ioannidis, and D. Tzovaras. Machine Learning
and Deep Learning in smart manufacturing: The Smart Grid paradigm.
Computer Science Review, 40:100341, May 2021.
[112] S. Kovacic and M. Bakran. Genetic Susceptibility to Atherosclerosis. Stroke
Research and Treatment, 2012:1–5, 2012.
[113] B. M. Krafcik, D. H. Stone, M. Cai, I. A. Jarmel, M. Eid, P. P. Goodney, J. A.
Columbo, and M. F. Mayo Smith. Changes in global mortality from aortic
aneurysm. Journal of Vascular Surgery, 80(1):81–88.e1, July 2024.
[114] P. L. Kronick and M. S. Sacks. Matrix Macromolecules That Affect the
Viscoelasticity of Calfskin. Journal of Biomechanical Engineering, 116(2):140–
145, May 1994.
[115] J. Kukačka, V. Golkov, and D. Cremers. Regularization for Deep Learning: A
Taxonomy, 2017.
[116] M. H. Kural, M. Cai, D. Tang, T. Gwyther, J. Zheng, and K. L. Billiar. Planar
biaxial characterization of diseased human coronary and carotid arteries for
computational modeling. Journal of Biomechanics, 45(5):790–798, Mar. 2012.
[117] P. Lacolley, V. Regnault, P. Segers, and S. Laurent. Vascular Smooth Muscle
Cells and Arterial Stiffening: Relevance in Development, Aging, and Disease.
Physiological Reviews, 97(4):1555–1617, Oct. 2017.
[118] A. R. Lawrence and K. J. Gooch. Transmural pressure and axial loading interactively
regulate arterial remodeling ex vivo. American Journal of Physiology-
Heart and Circulatory Physiology, 297(1):H475–H484, July 2009.
[119] B. T. Ledford, A. W. Akerman, K. Sun, D. C. Gillis, J. M. Weiss, J. Vang,
S. Willcox, T. D. Clemons, H. Sai, R. Qiu, M. R. Karver, J. D. Griffith, N. D.
Tsihlis, S. I. Stupp, J. S. Ikonomidis, and M. R. Kibbe. Peptide Amphiphile
Supramolecular Nanofibers Designed to Target Abdominal Aortic Aneurysms.
ACS Nano, 16(5):7309–7322, May 2022.
[120] L. Leyssens, T. Balcaen, M. Pétré, N. Béjar Ayllón, W. El Aazmani, A. De Pierpont,
G. Pyka, V. Lacroix, and G. Kerckhofs. Non-destructive 3D characterization
of the blood vessel wall microstructure in different species and blood
vessel types using contrast-enhanced microCT and comparison with synthetic
vascular grafts. Acta Biomaterialia, 164:303–316, July 2023.
[121] D. Li, P. Jiang, C. Hu, and T. Yan. Comparison of local and global sensitivity
analysis methods and application to thermal hydraulic phenomena. Progress
in Nuclear Energy, 158:104612, Apr. 2023.
[122] J. Li, X. Cao, L. Xu, and L. Qi. Finite Element Analysis for the Effects of the
Descending Aorta Tortuosity on Aortic Hemodynamics. Procedia Computer
Science, 209:148–156, 2022.
[123] L. Li, K. Jamieson, G. DeSalvo, A. Rostamizadeh, and A. Talwalkar. Hyperband:
A novel bandit-based approach to hyperparameter optimization. Journal
of Machine Learning Research, 18:1–52, Jan. 2017.
[124] P. Libby. The changing landscape of atherosclerosis. Nature, 592(7855):524–533,
Apr. 2021.
[125] M. Lillie and J. Gosline. Tensile Residual Strains on the Elastic Lamellae along
the Porcine Thoracic Aorta. Journal of Vascular Research, 43(6):587–601,
2006.
[126] M. Lillie and J. Gosline. Mechanical properties of elastin along the thoracic
aorta in the pig. Journal of Biomechanics, 40(10):2214–2221, Jan. 2007.
[127] M. Lillie, R. Shadwick, and J. Gosline. Mechanical anisotropy of inflated elastic
tissue from the pig aorta. Journal of Biomechanics, 43(11):2070–2078, Aug.
2010.
[128] K. Linka and E. Kuhl. A new family of Constitutive Artificial Neural Networks
towards automated model discovery. Computer Methods in Applied Mechanics
and Engineering, 403:115731, Jan. 2023.
[129] A. C. Liu and A. I. Gotlieb. Molecular Basis of Cardiovascular Disease. In
Essential Concepts in Molecular Pathology, pages 161–173. Elsevier, 2010.
[130] H. Liu, J. S. Soares, J. Walmsley, D. S. Li, S. Raut, R. Avazmohammadi,
P. Iaizzo, M. Palmer, J. H. Gorman, R. C. Gorman, and M. S. Sacks. The
impact of myocardial compressibility on organ-level simulations of the normal
and infarcted heart. Scientific Reports, 11(1):13466, June 2021.
[131] I. Livshin. Neural network prediction outside the training range. In Artificial
Neural Networks with Java: Tools for Building Neural Network Applications,
pages 109–163. Apress, Berkeley, CA, 2019.
[132] L. Liyanage, L. Musto, C. Budgeon, G. Rutty, M. Biggs, A. Saratzis, D. A.
Vorp, V. Vavourakis, M. Bown, and A. Tsamis. Multimodal Structural Analysis
of the Human Aorta: From Valve to Bifurcation. European Journal of Vascular
and Endovascular Surgery, 63(5):721–730, May 2022.
[133] I. Loshchilov and F. Hutter. Decoupled Weight Decay Regularization, 2017.
[134] A. C. Luca, S. G. David, A. G. David, V.T,
arcă, I.-A. Păduret,
, D. E. Mîndru,
S. T. Ros,
u, E. V. Ros,
u, H. Adumitrăchioaiei, J. Bernic, E. Cojocaru, and
E.T,
arcă. Atherosclerosis from Newborn to Adult—Epidemiology, Pathological
Aspects, and Risk Factors. Life, 13(10):2056, Oct. 2023.
[135] A. J. Lusis. Atherosclerosis. Nature, 407(6801):233–241, Sept. 2000.
[136] R. A. Macrae, K. Miller, and B. J. Doyle. Methods in Mechanical Testing of
Arterial Tissue: A Review. Strain, 52(5):380–399, Oct. 2016.
[137] M. Madani and E. Golts. Cardiovascular Anatomy. In Reference Module in
Biomedical Sciences, page B9780128012383001963. Elsevier, 2014.
[138] A. Maes, C. Pestiaux, A. Marino, T. Balcaen, L. Leyssens, S. Vangrunderbeeck,
G. Pyka, W. M. De Borggraeve, L. Bertrand, C. Beauloye, S. Horman,
M. Wevers, and G. Kerckhofs. Cryogenic contrast-enhanced microCT enables
nondestructive 3D quantitative histopathology of soft biological tissues. Nature
Communications, 13(1):6207, Oct. 2022.
[139] L. Maes, H. Fehervary, J. Vastmans, S. J. Mousavi, S. Avril, and N. Famaey.
Constrained mixture modeling affects material parameter identification from
planar biaxial tests. Journal of the Mechanical Behavior of Biomedical Materials,
95:124–135, July 2019.
[140] R. R. Mahutga and V. H. Barocas. Investigation of Pathophysiological Aspects
of Aortic Growth, Remodeling, and Failure Using a Discrete-Fiber Microstructural
Model. Journal of Biomechanical Engineering, 142(11):111007, Nov.
2020.
[141] S. Maiti, J. R. Thunes, R. N. Fortunato, T. G. Gleason, and D. A. Vorp.
Computational modeling of the strength of the ascending thoracic aortic media
tissue under physiologic biaxial loading conditions. Journal of Biomechanics,
108:109884, July 2020.
[142] L. A. Martinez-Lemus. The Dynamic Structure of Arterioles. Basic & Clinical
Pharmacology & Toxicology, 110(1):5–11, Jan. 2012.
[143] J. M. Mattson, R. Turcotte, and Y. Zhang. Glycosaminoglycans contribute to
extracellular matrix fiber recruitment and arterial wall mechanics. Biomechanics
and Modeling in Mechanobiology, 16(1):213–225, Feb. 2017.
[144] P. Maurice, S. Blaise, S. Gayral, L. Debelle, M. Laffargue, W. Hornebeck, and
L. Duca. Elastin fragmentation and atherosclerosis progression: The elastokine
concept. Trends in Cardiovascular Medicine, 23(6):211–221, Aug. 2013.
[145] A. Mauriello, A. Orlandi, G. Palmieri, L. Spagnoli, M. Oberholzer, and H. Christen.
Age-related modification of average volume and anisotropy of vascular
smooth muscle cells. Pathology - Research and Practice, 188(4-5):630–636,
June 1992.
[146] R. L. Maynard and N. Downes. Histology of the Vascular System. In Anatomy
and Histology of the Laboratory Rat in Toxicology and Biomedical Research,
pages 91–95. Elsevier, 2019.
[147] D. Minion, V. Davis, Nejezchleb, Y.Wang, B. McManus, and B. Baxter. Elastin
Is Increased in Abdominal Aortic Aneurysms. Journal of Surgical Research,
57(4):443–446, Oct. 1994.
[148] M. Mishra. The Learning Rate: A Hyperparameter That Matters.
https://mohitmishra786687.medium.com/the-learning-rate-ahyperparameter-
that-matters-b2f3b68324ab, May 2023. Accessed: 21
May 2025.
[149] Y. F. Missirlis. Use of enzymolysis techniques in studying the mechanical
properties of connective tissue components. Journal of Bioengineering, 1(3):215–
222, Aug. 1977.
[150] H. Miyazaki and K. Hayashi. Tensile tests of collagen fibers obtained from the
rabbit patellar tendon. Biomedical Microdevices, 2(2):151–157, 1999.
[151] M. Mooney. A Theory of Large Elastic Deformation. Journal of Applied
Physics, 11(9):582–592, Sept. 1940.
[152] H. Mozafari, L. Wang, Y. Lei, and L. Gu. Multi-scale modeling of the lamellar
unit of arterial media. Nanotechnology Reviews, 8(1):539–547, Jan. 2019.
[153] A. V. Mures,
an, E.-M. Arbănas,
i, E. Russu, R. Kaller, C. C. Ciucanu, A. P. Ion,
A. B. Cordos,
, M. Harpa, and E.-M. Arbănas,
i. The Role of the Mechanical
Characteristics and Microstructure of the Porcine Aortic Wall: Implications
for Abdominal Aortic Aneurysm Rupture Risk. Journal of Cardiovascular
Emergencies, 10(1):13–19, Mar. 2024.
[154] M. Myneni and K. Rajagopal. Constitutive modeling of the mechanical response
of arterial tissues. Applications in Engineering Science, 11:100111, Sept. 2022.
[155] S. K. Nadkarni, B. E. Bouma, J. De Boer, and G. J. Tearney. Evaluation
of collagen in atherosclerotic plaques: The use of two coherent laser-based
imaging methods. Lasers in Medical Science, 24(3):439–445, May 2009.
[156] A. Newby. Fibrous cap formation or destruction — the critical importance
of vascular smooth muscle cell proliferation, migration and matrix formation.
Cardiovascular Research, 41(2):345–360, Feb. 1999.
[157] J. A. Niestrawska, A. Pukaluk, A. R. Babu, and G. A. Holzapfel. Differences
in Collagen Fiber Diameter and Waviness between Healthy and Aneurysmal
Abdominal Aortas. Microscopy and Microanalysis, 28(5):1649–1663, Oct. 2022.
[158] J. A. Niestrawska, C. Viertler, P. Regitnig, T. U. Cohnert, G. Sommer, and
G. A. Holzapfel. Microstructure and mechanics of healthy and aneurysmatic
abdominal aortas: Experimental analysis and modelling. Journal of The Royal
Society Interface, 13(124):20160620, Nov. 2016.
[159] P. Nigro, J.-i. Abe, and B. C. Berk. Flow Shear Stress and Atherosclerosis: A
Matter of Site Specificity. Antioxidants & Redox Signaling, 15(5):1405–1414,
Sept. 2011.
[160] B. Ning, Y. Chen, A. B. Waqar, H. Yan, M. Shiomi, J. Zhang, Y. E. Chen,
Y. Wang, H. Itabe, J. Liang, and J. Fan. Hypertension Enhances Advanced
Atherosclerosis and Induces Cardiac Death in Watanabe Heritable Hyperlipidemic
Rabbits. The American Journal of Pathology, 188(12):2936–2947, Dec.
2018.
[161] M. Oconnell, S. Murthy, S. Phan, C. Xu, J. Buchanan, R. Spilker, R. Dalman,
C. Zarins, W. Denk, and C. Taylor. The three-dimensional micro- and nanostructure
of the aortic medial lamellar unit measured using 3D confocal and
electron microscopy imaging. Matrix Biology, 27(3):171–181, Apr. 2008.
[162] R. W. Ogden. Non-Linear Elastic Deformations. Courier Corporation, 1997.
[163] B. R. Olsen. Matrix Molecules and Their Ligands. In Principles of Tissue
Engineering, pages 189–208. Elsevier, 2014.
[164] T. O’Malley, E. Bursztein, J. Long, F. Chollet, H. Jin, L. Invernizzi, et al.
KerasTuner, 2019.
[165] OpenAI. ChatGPT. https://chat.openai.com, 2025.
[166] H. Oxlund, J. Manschot, and A. Viidik. The role of elastin in the mechanical
properties of skin. Journal of Biomechanics, 21(3):213–218, Jan. 1988.
[167] J. Park, Y. Kim, J. W. Yoon, H. So, J. Lee, and S. Ko. Finite element modeling
and durability evaluation for rubber pad forming process. IOP Conference
Series: Materials Science and Engineering, 651(1):012096, Nov. 2019.
[168] J. A. Peña, M. A. Martínez, and E. Peña. Failure damage mechanical properties
of thoracic and abdominal porcine aorta layers and related constitutive
modeling: Phenomenological and microstructural approach. Biomechanics and
Modeling in Mechanobiology, 18(6):1709–1730, Dec. 2019.
[169] J. Pérez Zerpa, A. Canelas, B. Sensale, D. Bia Santana, and R. Armentano.
Modeling the arterial wall mechanics using a novel high-order viscoelastic
fractional element. Applied Mathematical Modelling, 39(16):4767–4780, Aug.
2015.
[170] M. Pétré, H. Wolfs, L. Maes, G. Kerckhofs, and N. Famaey. From Microstructure
to Mechanics: A Multi-constituent Micro-scale Computational Model of
Arterial Tissue. Unpublished, 2025.
[171] G. Philipp. The Nonlinearity Coefficient - A Practical Guide to Neural Architecture
Design, 2021.
[172] L. A. Pittman, P. Whittaker, M. L. Milne, and C. S. Chung. Collagenase
treatment reduces the anisotropy of ultrasonic backscatter in rat myocardium
by reducing collagen crosslinks. Physiological Reports, 11(21):e15849, Nov.
2023.
[173] S. Polzer, T. Gasser, K. Novak, V. Man, M. Tichy, P. Skacel, and J. Bursa.
Structure-based constitutive model can accurately predict planar biaxial properties
of aortic wall tissue. Acta Biomaterialia, 14:133–145, Mar. 2015.
[174] N. V. K. Pothineni, S. Subramany, K. Kuriakose, L. F. Shirazi, F. Romeo,
P. K. Shah, and J. L. Mehta. Infections, atherosclerosis, and coronary heart
disease. European Heart Journal, 38(43):3195–3201, Nov. 2017.
[175] M. Rahman and A. B. Siddik. Anatomy, Arterioles. In StatPearls. StatPearls
Publishing, Treasure Island (FL), 2024.
[176] C. A. Reardon, A. Lingaraju, K. Q. Schoenfelt, G. Zhou, C. Cui, H. Jacobs-El,
I. Babenko, A. Hoofnagle, D. Czyz, H. Shuman, T. Vaisar, and L. Becker. Obesity
and Insulin Resistance Promote Atherosclerosis through an IFN$\gamma$-
Regulated Macrophage Protein Network. Cell Reports, 23(10):3021–3030, June
2018.
[177] K. D. Reesink and B. Spronck. Constitutive interpretation of arterial stiffness
in clinical studies: A methodological review. American Journal of Physiology.
Heart and Circulatory Physiology, 316(3):H693–H709, Mar. 2019.
[178] J. Resendez and D. Rehagen. Infusion Toxicology and Techniques. In A
Comprehensive Guide to Toxicology in Nonclinical Drug Development, pages
555–583. Elsevier, 2017.
[179] R. Rezakhaniha, E. Fonck, C. Genoud, and N. Stergiopulos. Role of elastin
anisotropy in structural strain energy functions of arterial tissue. Biomechanics
and Modeling in Mechanobiology, 10(4):599–611, July 2011.
[180] J. A. Rhodin. The ultrastructure of mammalian arterioles and precapillary
sphincters. Journal of Ultrastructure Research, 18(1):181–223, Apr. 1967.
[181] S. Ricard-Blum. The collagen family. Cold Spring Harbor Perspectives in
Biology, 3(1):a004978, Jan. 2011.
[182] R. Rivlin. Large elastic deformations of isotropic materials IV. further developments
of the general theory. Philosophical Transactions of the Royal Society
of London. Series A, Mathematical and Physical Sciences, 241(835):379–397,
Oct. 1948.
[183] M. R. Roach and A. C. Burton. The reason for the shape of the distensibility
curves of arteries. Canadian Journal of Biochemistry and Physiology, 35(8):681–
690, Aug. 1957.
[184] F. F. Rocha, P. J. Blanco, P. J. Sánchez, and R. A. Feijóo. Multi-scale modelling
of arterial tissue: Linking networks of fibres to continua. Computer Methods
in Applied Mechanics and Engineering, 341:740–787, Nov. 2018.
[185] A. Saltelli. Making best use of model evaluations to compute sensitivity indices.
Computer Physics Communications, 145(2):280–297, May 2002.
[186] A. Sarkar, S. V. Pawar, K. Chopra, and M. Jain. Gamut of glycolytic enzymes in
vascular smooth muscle cell proliferation: Implications for vascular proliferative
diseases. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease,
1870(3):167021, Mar. 2024.
[187] A. J. Schriefl, T. Schmidt, D. Balzani, G. Sommer, and G. A. Holzapfel. Selective
enzymatic removal of elastin and collagen from human abdominal aortas:
Uniaxial mechanical response and constitutive modeling. Acta Biomaterialia,
17:125–136, Apr. 2015.
[188] A. J. Schriefl, G. Zeindlinger, D. M. Pierce, P. Regitnig, and G. A. Holzapfel.
Determination of the layer-specific distributed collagen fibre orientations in
human thoracic and abdominal aortas and common iliac arteries. Journal of
The Royal Society Interface, 9(71):1275–1286, June 2012.
[189] W. Schroeder, K. Martin, and B. Lorensen. The Visualization Toolkit (4th
Ed.). Kitware, 2006.
[190] J. Schultz and D. Bader. Structure and Function of the Adult Vertebrate Cardiovascular
System. In Encyclopedia of Cardiovascular Research and Medicine,
pages 499–510. Elsevier, 2018.
[191] P. Segers and J. A. Chirinos. Chapter 7 - Arterial wall stiffness: Basic principles
and methods of measurement in vivo. In J. A. Chirinos, editor, Textbook of
Arterial Stiffness and Pulsatile Hemodynamics in Health and Disease, pages
111–124. Academic Press, Jan. 2022.
[192] R. Shahbad, M. Kazim, S. A. Razian, A. Desyatova, and M. Jadidi. Variations
in stiffness and structure of the human aorta along its length. Scientific Reports,
15(1):11120, Apr. 2025.
[193] M. S. Shajib, K. Futrega, T. Jacob Klein, R. W. Crawford, and M. R. Doran.
Collagenase treatment appears to improve cartilage tissue integration but
damage to collagen networks is likely permanent. Journal of Tissue Engineering,
13:20417314221074207, Jan. 2022.
[194] S. Sherifova, G. Sommer, C. Viertler, P. Regitnig, T. Caranasos, M. A. Smith,
B. E. Griffith, R. W. Ogden, and G. A. Holzapfel. Failure properties and
microstructure of healthy and aneurysmatic human thoracic aortas subjected to
uniaxial extension with a focus on the media. Acta Biomaterialia, 99:443–456,
Nov. 2019.
[195] M. D. Shields, K. Teferra, A. Hapij, and R. P. Daddazio. Refined Stratified
Sampling for efficient Monte Carlo based uncertainty quantification. Reliability
Engineering & System Safety, 142:310–325, Oct. 2015.
[196] S. J. Shin and H. Yanagisawa. Recent updates on the molecular network of
elastic fiber formation. Essays in Biochemistry, 63(3):365–376, Sept. 2019.
[197] P. Skacel and J. Bursa. Poisson’s ratio and compressibility of arterial wall –
Improved experimental data reject auxetic behaviour. Journal of the Mechanical
Behavior of Biomedical Materials, 131:105229, July 2022.
[198] I. Sobol. Sensitivity Estimates for Nonlinear Mathematical Models. Mathematical
Modeling and Computational Experiment, 1(4):407–414, 1993.
[199] I. Sobol′. Global sensitivity indices for nonlinear mathematical models and
their Monte Carlo estimates. Mathematics and Computers in Simulation,
55(1-3):271–280, Feb. 2001.
[200] D. P. Sokolis. Passive mechanical properties and structure of the aorta: Segmental
analysis. Acta Physiologica, 190(4):277–289, Aug. 2007.
[201] D. P. Sokolis and S. A. Papadodima. Regional delamination strength in the
human aorta underlies the anatomical localization of the dissection channel.
Journal of Biomechanics, 141:111174, Aug. 2022.
[202] C. Song and R. Kawai. Monte Carlo and variance reduction methods for structural
reliability analysis: A comprehensive review. Probabilistic Engineering
Mechanics, 73:103479, July 2023.
[203] S. R. Srinivasan, B. Radhakrishnamurthy, E. R. Dalferes, and G. S. Berenson.
Collagenase-solubilized lipoprotein-glycosaminoglycan complexes of human
aortic fibrous plaque lesions. Atherosclerosis, 34(2):105–118, Oct. 1979.
[204] V. Strbac, D. Pierce, B. Rodriguez-Vila, J. Vander Sloten, and N. Famaey.
Rupture risk in abdominal aortic aneurysms: A realistic assessment of the
explicit GPU approach. Journal of Biomechanics, 56:1–9, May 2017.
[205] B. Sullivan and A. Kaszynski. PyVista: 3D plotting and mesh analysis through
a streamlined interface for the Visualization Toolkit (VTK). Journal of Open
Source Software, 4(37):1450, May 2019.
[206] B. Sun. The mechanics of fibrillar collagen extracellular matrix. Cell Reports
Physical Science, 2(8):100515, Aug. 2021.
[207] W. Sun, M. S. Sacks, and M. J. Scott. Effects of Boundary Conditions on
the Estimation of the Planar Biaxial Mechanical Properties of Soft Tissues.
Journal of Biomechanical Engineering, 127(4):709–715, Aug. 2005.
[208] X. Sun, B. Croke, S. Roberts, and A. Jakeman. Investigation of determinismrelated
issues in the Sobol′ low-discrepancy sequence for producing sound global
sensitivity analysis indices. ANZIAM Journal, 62:C84–C97, Dec. 2021.
[209] J. A. K. Suykens, J. P. L. Vandewalle, and B. L. R. De Moor. Artificial Neural
Networks for Modelling and Control of Non-Linear Systems. Springer US,
Boston, MA, 1996.
[210] A. M. Taylor and B. Bordoni. Histology, Blood Vascular System. In StatPearls.
StatPearls Publishing, Treasure Island (FL), 2024.
[211] A. M. Taylor and B. Bordoni. Histology, Blood Vascular System. In StatPearls.
StatPearls Publishing, Treasure Island (FL), 2025.
[212] Z. Teng, J. Feng, Y. Zhang, Y. Huang, M. P. F. Sutcliffe, A. J. Brown, Z. Jing,
J. H. Gillard, and Q. Lu. Layer- and Direction-Specific Material Properties,
Extreme Extensibility and Ultimate Material Strength of Human Abdominal
Aorta and Aneurysm: A Uniaxial Extension Study. Annals of Biomedical
Engineering, 43(11):2745–2759, Nov. 2015.
[213] TensorFlow Developers. TensorFlow. Zenodo, Mar. 2025.
[214] J. R. Thunes, J. A. Phillippi, T. G. Gleason, D. A. Vorp, and S. Maiti.
Structural modeling reveals microstructure-strength relationship for human
ascending thoracic aorta. Journal of Biomechanics, 71:84–93, Apr. 2018.
[215] Z. Tonar, T. Kubíková, C. Prior, E. Demjén, V. Liška, M. Králíčková, and
K. Witter. Segmental and age differences in the elastin network, collagen, and
smooth muscle phenotype in the tunica media of the porcine aorta. Annals of
Anatomy - Anatomischer Anzeiger, 201:79–90, Sept. 2015.
[216] W. D. Tucker, Y. Arora, and K. Mahajan. Anatomy, Blood Vessels. In
StatPearls. StatPearls Publishing, Treasure Island (FL), 2024.
[217] T. Ushiki and M. Murakumo. Scanning electron microscopic studies of tissue
elastin components exposed by a KOH-collagenase or simple KOH digestion
method. Archives of Histology and Cytology, 54(4):427–436, Oct. 1991.
[218] C. J. Van Andel, P. V. Pistecky, and C. Borst. Mechanical properties of porcine
and human arteries: Implications for coronary anastomotic connectors. The
Annals of Thoracic Surgery, 76(1):58–64, July 2003.
[219] C. Van De Lest, E. Versteeg, J. Veerkamp, and T. Van Kuppevelt. Digestion
of proteoglycans in porcine pancreatic elastase-induced emphysema in rats.
European Respiratory Journal, 8(2):238–245, Feb. 1995.
[220] K. Vander Linden, H. Fehervary, L. Maes, and N. Famaey. An improved
parameter fitting approach of a planar biaxial test including the experimental
prestretch. Journal of the Mechanical Behavior of Biomedical Materials,
134:105389, Oct. 2022.
[221] P. A. VanderLaan, C. A. Reardon, and G. S. Getz. Site Specificity of Atherosclerosis:
Site-Selective Responses to Atherosclerotic Modulators. Arteriosclerosis,
Thrombosis, and Vascular Biology, 24(1):12–22, Jan. 2004.
[222] A. Venkatasubramaniam, M. Fagan, T. Mehta, K. Mylankal, B. Ray, G. Kuhan,
I. Chetter, and P. McCollum. A Comparative Study of Aortic Wall Stress
Using Finite Element Analysis for Ruptured and Non-ruptured Abdominal
Aortic Aneurysms. European Journal of Vascular and Endovascular Surgery,
28(2):168–176, Aug. 2004.
[223] T. Vervenne, M. Peirlinck, N. Famaey, and E. Kuhl. Constitutive neural networks
for main pulmonary arteries: Discovering the undiscovered. Biomechanics
and Modeling in Mechanobiology, Feb. 2025.
[224] P. Virtanen, R. Gommers, T. E. Oliphant, M. Haberland, T. Reddy, D. Cournapeau,
E. Burovski, P. Peterson, W. Weckesser, J. Bright, S. J. van der Walt,
M. Brett, J. Wilson, K. J. Millman, N. Mayorov, A. R. J. Nelson, E. Jones,
R. Kern, E. Larson, C. J. Carey, İ. Polat, Y. Feng, E. W. Moore, J. VanderPlas,
D. Laxalde, J. Perktold, R. Cimrman, I. Henriksen, E. A. Quintero, C. R. Harris,
A. M. Archibald, A. H. Ribeiro, F. Pedregosa, P. van Mulbregt, and SciPy
1.0 Contributors. SciPy 1.0: Fundamental algorithms for scientific computing
in python. Nature Methods, 17:261–272, 2020.
[225] A. G. Vouyouka, B. J. Pfeiffer, T. K. Liem, T. A. Taylor, J. Mudaliar, and C. L.
Phillips. The role of type I collagen in aortic wall strength with a homotrimeric
[A1(I)]3 collagen mouse model. Journal of Vascular Surgery, 33(6):1263–1270,
June 2001.
[226] VRT NWS. Cardiologen vragen verplichte screening voor 50-plussers
op slagaderverkalking: "Symptomen zijn onzichtbaar" | VRT NWS:
nieuws. https://www.vrt.be/vrtnws/nl/2024/06/03/cardiologen-vragenverplichte-
screening-voor-50-plussers-op-slag/, June 2024. Accessed: 23 May
2025.
[227] J. E. Wagenseil and R. P. Mecham. Elastin in Large Artery Stiffness and
Hypertension. Journal of Cardiovascular Translational Research, 5(3):264–273,
June 2012.
[228] K. R. Waitkus-Edwards, L. A. Martinez-Lemus, X. Wu, J. P. Trzeciakowski,
M. J. Davis, G. E. Davis, and G. A. Meininger. Alpha(4)beta(1) Integrin
activation of L-type calcium channels in vascular smooth muscle causes arteriole
vasoconstriction. Circulation Research, 90(4):473–480, Mar. 2002.
[229] S. D. Waldman and J. Michael Lee. Boundary conditions during biaxial testing
of planar connective tissues. Part 1: Dynamic Behavior. Journal of Materials
Science: Materials in Medicine, 13(10):933–938, 2002.
[230] K. Wang, X. Meng, and Z. Guo. Elastin Structure, Synthesis, Regulatory
Mechanism and Relationship With Cardiovascular Diseases. Frontiers in Cell
and Developmental Biology, 9:596702, Nov. 2021.
[231] M. Wang, K. R. McGraw, R. E. Monticone, and G. Pintus. Unraveling
Elastic Fiber-Derived Signaling in Arterial Aging and Related Arterial Diseases.
Biomolecules, 15(2):153, Jan. 2025.
[232] T. Watanabe, M. Hirata, Y. Yoshikawa, Y. Nagafuchi, H. Toyoshima, and
T. Watanabe. Role of macrophages in atherosclerosis. Sequential observations
of cholesterol-induced rabbit aortic lesion by the immunoperoxidase technique
using monoclonal antimacrophage antibody. Laboratory Investigation; a Journal
of Technical Methods and Pathology, 53(1):80–90, July 1985.
[233] T. Watanabe, O. Tokunaga, J. Fan, and T. Shimokama. Atherosclerosis and
Macrophages. Acta Pathologica Japonica, 39(8):473–486, Aug. 1989.
[234] R. C. Webb. Smooth muscle contraction and relaxation. Advances in Physiology
Education, 27(1-4):201–206, Dec. 2003.
[235] H. Weisbecker, D. M. Pierce, P. Regitnig, and G. A. Holzapfel. Layer-specific
damage experiments and modeling of human thoracic and abdominal aortas
with non-atherosclerotic intimal thickening. Journal of the Mechanical Behavior
of Biomedical Materials, 12:93–106, Aug. 2012.
[236] H. Weisbecker, M. J. Unterberger, and G. A. Holzapfel. Constitutive modelling
of arteries considering fibre recruitment and three-dimensional fibre distribution.
Journal of The Royal Society Interface, 12(105):20150111, Apr. 2015.
[237] H. Weisbecker, C. Viertler, D. M. Pierce, and G. A. Holzapfel. The role of
elastin and collagen in the softening behavior of the human thoracic aortic
media. Journal of Biomechanics, 46(11):1859–1865, July 2013.
[238] J. Wheeler, J. Jones, and J. Ikonomidis. Aortic extra cellular matrix (ECM)
remodeling. In Cardiac Regeneration and Repair, pages 315–349. Elsevier,
2014.
[239] S. Wiesner, K. R. Legate, and R. Fässler. Integrin-actin interactions. CMLS
Cellular and Molecular Life Sciences, 62(10):1081–1099, May 2005.
[240] Wikipedia contributors. Variance-based sensitivity analysis. Wikipedia, June
2024.
[241] Z. Win, J. M. Buksa, K. E. Steucke, G. W. Gant Luxton, V. H. Barocas, and
P. W. Alford. Cellular Microbiaxial Stretching to Measure a Single-Cell Strain
Energy Density Function. Journal of Biomechanical Engineering, 139(071006),
June 2017.
[242] H. Winkels, E. Ehinger, M. Vassallo, K. Buscher, H. Q. Dinh, K. Kobiyama,
A. A. Hamers, C. Cochain, E. Vafadarnejad, A.-E. Saliba, A. Zernecke, A. B.
Pramod, A. K. Ghosh, N. Anto Michel, N. Hoppe, I. Hilgendorf, A. Zirlik, C. C.
Hedrick, K. Ley, and D. Wolf. Atlas of the Immune Cell Repertoire in Mouse
Atherosclerosis Defined by Single-Cell RNA-Sequencing and Mass Cytometry.
Circulation Research, 122(12):1675–1688, June 2018.
[243] P. Withers. Physical Properties of Composites. In Reference Module in
Materials Science and Materials Engineering, page B9780128035818028320.
Elsevier, 2016.
[244] H. Yamada. Inelastic Constitutive Models of Blood Vessels in Physiological
Conditions. In T. Yamaguchi, editor, Clinical Application of Computational
Mechanics to the Cardiovascular System, pages 19–28. Springer Japan, Tokyo,
2000.
[245] G. J. Ye, A. P. Nesmith, and K. K. Parker. The Role of Mechanotransduction
on Vascular Smooth Muscle Myocytes Cytoskeleton and Contractile Function.
The Anatomical Record, 297(9):1758–1769, Sept. 2014.
[246] G. C. Yeo, F. W. Keeley, and A. S. Weiss. Coacervation of tropoelastin.
Advances in Colloid and Interface Science, 167(1-2):94–103, Sept. 2011.
[247] O. H. Yeoh. Some Forms of the Strain Energy Function for Rubber. Rubber
Chemistry and Technology, 66(5):754–771, Nov. 1993.
[248] Z. Yosibash, I. Manor, I. Gilad, and U. Willentz. Experimental evidence of the
compressibility of arteries. Journal of the Mechanical Behavior of Biomedical
Materials, 39:339–354, Nov. 2014.
[249] O. E. Yossef, M. Farajian, I. Gilad, U. Willenz, N. Gutman, and Z. Yosibash.
Further experimental evidence of the compressibility of arteries. Journal of the
Mechanical Behavior of Biomedical Materials, 65:177–189, Jan. 2017.
[250] T. Yu and H. Zhu. Hyper-Parameter Optimization: A Review of Algorithms
and Applications, 2020.
[251] S. Zeinali-Davarani, Y. Wang, M.-J. Chow, R. Turcotte, and Y. Zhang. Contribution
of Collagen Fiber Undulation to Regional Biomechanical Properties
Along Porcine Thoracic Aorta. Journal of Biomechanical Engineering,
137(5):051001, May 2015.
[252] G. Zhang, C. Wang, B. Xu, and R. Grosse. Three Mechanisms of Weight Decay
Regularization, 2018.
[253] X.-Y. Zhang, M. N. Trame, L. J. Lesko, and S. Schmidt. Sobol Sensitivity
Analysis: A Tool to Guide the Development and Evaluation of Systems Pharmacology
Models. CPT: pharmacometrics & systems pharmacology, 4(2):69–79,
Feb. 2015.
[254] Y. Zou and Y. Zhang. An Experimental and Theoretical Study on the
Anisotropy of Elastin Network. Annals of Biomedical Engineering, 37(8):1572–
1583, Aug. 2009.
[255] Y. Zou and Y. Zhang. The orthotropic viscoelastic behavior of aortic elastin.
Biomechanics and Modeling in Mechanobiology, 10(5):613–625, Oct. 2011.
