Current Projects

We train and assess machine learning models using clinical, biomechanical, and morphological indices from patients to develop an aneurysm prognosis classifier to predict one of three outcomes for a given AAA patient: their AAA will remain stable, their AAA will require repair based as currently indicated from the maximum diameter criterion, or their AAA will rupture. This study represents the largest cohort of AAA patients that utilizes the first available medical image and clinical data to classify patient outcomes. The APC model therefore represents a potential clinical tool to striate specific patient outcomes using machine learning models and patient-specific image-based (biomechanical and morphological) and clinical data as input. Such a tool could greatly assist clinicians in their management decisions for patients with AAA.

Related publications  

1. Chung TK, Gueldner PH, Aloziem OU, Liang NL, Vorp DA. An artificial intelligence based abdominal aortic aneurysm prognosis classifier to predict patient outcomes. Sci Rep. 2024 Feb 9;14(1):3390. doi: 10.1038/s41598-024-53459-5. PMID: 38336915; PMCID: PMC10858046.

Our lab, in collaboration with vascular surgeon Mohammad Eslami, has begun developing a novel endovascular orifice detector (EOrD) designed for antegrade in-situ fenestration of off-the-shelf endografts for complex abdominal aortic aneurysm (AAA) repair. Complex AAAs, which extend into key branching arteries, are challenging to treat due to limited room for graft sealing and anchoring. The EOrD uses fiber optic strands arranged around a steerable catheter to transmit infrared and white light, which can penetrate endograft material and blood, thereby enabling the accurate detection of target visceral artery orifices. 

We are currently focused on testing the initial prototype device in vitro. The device was evaluated in a human cadaveric torso, where successful fenestration was achieved under fluoroscopic guidance and using an in-house custom MATLAB graphical interface. After cadaveric testing, we developed an in-vitro pulsatile flow loop for further surgical simulation. The flow loop includes an ideal geometry-compliant AAA phantom manufactured with silicone molding in-house.  The next step is to develop patient-specific AAA phantom models for testing. 

Related publications  

1. Darvish CJ, Lagerman NP, Virag O, Parks H, Pandya YK, Eslami MH, Vorp DA, Chung TK. Development of a method to achieve antegrade in situ fenestration of endovascular stent grafts in abdominal aortic aneurysms. J Vasc Surg Cases Innov Tech. 2024 Oct 28;11(1):101661. doi: 10.1016/j.jvscit.2024.101661. PMID: 39697799; PMCID: PMC11653130.

This project focuses on the design, construction, and validation of a bubble inflation testing (BIT) device to accurately assess the mechanical strength of aortic aneurysms (AA). BIT simulates in-vivo loading conditions by applying biaxial stress through inflation, providing a physiologically realistic alternative to traditional uniaxial and planar biaxial testing methods. The system incorporates a tissue clamping module, pressurization apparatus, and optical strain measurement capabilities, utilizing stereo digital image correlation to generate 3D strain maps. These advanced capabilities enable the characterization of elastic and failure properties from a single inflation test. By replicating multiaxial loading conditions, this project seeks to improve our understanding of AA tissue mechanics and provide data for developing material models that better predict AA wall strength under physiological conditions.

Our lab has interest in investigating sex-based differences in abdominal aortic aneurysm, with specific areas of interest in biomechanical differences and outcome prediction. Although men experience a higher prevalence of abdominal aortic aneurysm, it has been demonstrated that well women experience higher rupture rates as well as worse surgical outcomes relative to their male counterparts. Our lab has developed computational methods to incorporate sex-based differences into machine learning models that predict patient outcome in abdominal aortic aneurysm.

This project explores the relationship between bulk tissue density and the mechanical strength of aortic aneurysms, aiming to establish density as a predictive marker for aortic aneurysm tensile strength. Using porcine thoracic aorta as a model, enzymatic degradation with collagenase and elastase was used to reduce tissue density, which was then quantified by measuring mass and volume. Mechanical strength was evaluated using uniaxial tensile testing. Our results supported our hypothesis that tissue density correlates with aortic tensile strength. Ongoing work is utilizing diffusion tensor imaging and localized density reductions to explore a potential non-invasive technique for predicting aortic tensile strength distribution. By linking density measurements to mechanical properties, this project could pave the way for improved diagnostics and patient-specific risk assessment for aortic aneurysm management. 

Related publications

1. Gueldner, P.H., Darvish. C.J., Chickanosky, I.K.M., Ahlgren, E.E.$, Fortunato, R.N., Chung, T.K., Rajagopal, K., Benjamin, C., Maiti, S., Rajagopal, K.R., Vorp, D.A, Aortic Tissue Stiffness and Tensile Strength are Correlated with Density Changes Following Proteolytic Treatment, Journal of Biomechanics, 2024. https://doi.org/10.1016/j.jbiomech.2024.112226.

Our laboratory has had a long-standing interest in the biomechanical evolution of the aorta from the native to the aneurysmal state. Our initial computational work focused on the abdominal aortic aneurysm, which allowed for easy conversion of clinical images to a three-dimensional tubular model. Notably, we include the intraluminal thrombus (ILT) in our model, which is unique to abdominal aneurysms and modifies the response to the biomechanical environment. We have also begun generating three dimensional models of the more geometrically complex thoracic aorta, including the ascending portion and the aortic arch.

To provide important parameters to enter into our computational model, we have performed biomechanical testing of aneurysmal human thoracic and abdominal aortas from open repair surgeries, as well as samples of ILT. With our experimental data, we have developed a biomechanics-based rupture potential index, which can be calculated directly from patient-specific aortic geometries. For the case of abdominal aneurysm, we employ our well-cited constitutive models to noninvasively estimate wall strength based on patient age, gender, and local variables such as ILT thickness, diameter, etc. We are now beginning to translate these same techniques to the case of thoracic aneurysms.                
                
Related publications  

1. Pasta S, Phillippi JA, Gleason TG, Vorp DA, “ Effect of Aneurysm on the Mechanical Dissection Properties of the Human Ascending Aorta”, Journal of Thoracic and Cardiovascular Surgery, 2012 Feb;143(2):460-7, PMID 21868041
2. Pasta S, Cho JS, Dur O, Pekkan K, Vorp DA, “Computer modeling for the prediction of thoracic aortic stent graft collapse”, Journal of Vascular Surgery, 2013 May; 57(5):1353-61, PMID 23313184,
3. Pasta S, Rinaudo A, Luca A, Pilato M, Scardulla C, Gleason TG, Vorp DA, “Difference in hemodynamic and wall stress of ascending thoracic aortic aneurysms with bicuspid and tricuspid aortic valve”, J Biomech., 2013 Jun; 46(10):1729-38, PMID: 23664314, PMCID: PMC4016719
4. Pichamuthu JE, Phillippi JA, Cleary DA, Chew DW, Hempel J, Vorp DA, Gleason TG, “Differential Tensile Strength and Collagen Composition in Ascending Aortic Aneurysms by Aortic Valve Phenotype”, Annals of Thoracic Surgery, 2013 Dec; 96(6):2147-54, PMID 24021768, PMCID: PMC4016718

Our lab has developed a series of technologies, including a rotational seeding device and a bilayered silk scaffold, which serve as the basis of our small-diameter tissue-engineered vascular graft (TEVG). We have previously explored the use of mesenchymal stem cells (MSCs) from a variety of cell sources for our TEVG. We have also shown that MSCs sourced from patients in demographics typically associated with cardiovascular risk such as diabetic and elderly individuals may be deficient in TEVG applications.

Our current work is therefore focused on utilizing extracellular vesicles (EVs) secreted from MSC-EVs instead of the MSCs themselves and on advancing our TEVG towards clinical translation. EVs are nano-sized lipid membrane vesicles that contain protein and RNA similar to the parent cell and has reduced immunogenicity. In vitro, we have shown that MSC-EVs significantly increase proliferation and migration of endothelial cells and smooth muscle cells. In vivo, we have shown that bilayer silk grafts with MSC-EVs implanted as a rat abdominal aortic interposition graft result in improved patency and remodeling compared to control grafts. We are currently rescaling our bilayer silk + EVs TEVGs to clinically sized grafts. 

Related publications

1. Soletti L, Nieponice A, Guan J, Stankus JJ, Wagner WR, Vorp DA. A seeding device for tissue engineered tubular structures. Biomaterials. 2006 Oct;27(28):4863-70. doi: 10.1016/j.biomaterials.2006.04.042. Epub 2006 Jun 12. PMID: 16765436.
2. Nieponice A, Soletti L, Guan J, Deasy BM, Huard J, Wagner WR, Vorp DA. Development of a tissue-engineered vascular graft combining a biodegradable scaffold, muscle-derived stem cells and a rotational vacuum seeding technique. Biomaterials. 2008 Mar;29(7):825-33. doi: 10.1016/j.biomaterials.2007.10.044. Epub 2007 Nov 26. PMID: 18035412; PMCID: PMC2354918.
3. Soletti L, Hong Y, Guan J, Stankus JJ, El-Kurdi MS, Wagner WR, Vorp DA. A bilayered elastomeric scaffold for tissue engineering of small diameter vascular grafts. Acta Biomater. 2010 Jan;6(1):110-22. doi: 10.1016/j.actbio.2009.06.026. Epub 2009 Jun 18. PMID: 19540370; PMCID: PMC3200232.
4. Nieponice A, Soletti L, Guan J, Hong Y, Gharaibeh B, Maul TM, Huard J, Wagner WR, Vorp DA. In vivo assessment of a tissue-engineered vascular graft combining a biodegradable elastomeric scaffold and muscle-derived stem cells in a rat model. Tissue Eng Part A. 2010 Apr;16(4):1215-23. doi: 10.1089/ten.TEA.2009.0427. PMID: 19895206; PMCID: PMC2862609.
5. He W, Nieponice A, Soletti L, Hong Y, Gharaibeh B, Crisan M, Usas A, Peault B, Huard J, Wagner WR, Vorp DA. Pericyte-based human tissue engineered vascular grafts. Biomaterials. 2010 Nov;31(32):8235-44. doi: 10.1016/j.biomaterials.2010.07.034. Epub 2010 Aug 3. PMID: 20684982; PMCID: PMC3178347.
6. Krawiec JT, Weinbaum JS, Liao HT, Ramaswamy AK, Pezzone DJ, Josowitz AD, D'Amore A, Rubin JP, Wagner WR, Vorp DA. In Vivo Functional Evaluation of Tissue-Engineered Vascular Grafts Fabricated Using Human Adipose-Derived Stem Cells from High Cardiovascular Risk Populations. Tissue Eng Part A. 2016 May;22(9-10):765-75. doi: 10.1089/ten.TEA.2015.0379. PMID: 27079751; PMCID: PMC4876541.
7. Haskett DG, Saleh KS, Lorentz KL, Josowitz AD, Luketich SK, Weinbaum JS, Kokai LE, D'Amore A, Marra KG, Rubin JP, Wagner WR, Vorp DA. An exploratory study on the preparation and evaluation of a "same-day" adipose stem cell-based tissue-engineered vascular graft. J Thorac Cardiovasc Surg. 2018 Nov;156(5):1814-1822.e3. doi: 10.1016/j.jtcvs.2018.05.120. Epub 2018 Jul 2. PMID: 30057192; PMCID: PMC6200342.
8. Ramaswamy AK, Sides RE, Cunnane EM, Lorentz KL, Reines LM, Vorp DA, Weinbaum JS. Adipose-derived stromal cell secreted factors induce the elastogenesis cascade within 3D aortic smooth muscle cell constructs. Matrix Biol Plus. 2019 Sep 4;4:100014. doi: 10.1016/j.mbplus.2019.100014. PMID: 33543011; PMCID: PMC7852215.
9. Gupta P, Lorentz KL, Haskett DG, Cunnane EM, Ramaswamy AK, Weinbaum JS, Vorp DA, Mandal BB. Bioresorbable silk grafts for small diameter vascular tissue engineering applications: In vitro and in vivo functional analysis. Acta Biomater. 2020 Mar 15;105:146-158. doi: 10.1016/j.actbio.2020.01.020. Epub 2020 Jan 17. PMID: 31958596; PMCID: PMC7050402.
10. Cunnane EM, Lorentz KL, Ramaswamy AK, Gupta P, Mandal BB, O'Brien FJ, Weinbaum JS, Vorp DA. Extracellular Vesicles Enhance the Remodeling of Cell-Free Silk Vascular Scaffolds in Rat Aortae. ACS Appl Mater Interfaces. 2020 Jun 17;12(24):26955-26965. doi: 10.1021/acsami.0c06609. Epub 2020 Jun 5. PMID: 32441910; PMCID: PMC12039313.
11. Cunnane EM, Lorentz KL, Soletti L, Ramaswamy AK, Chung TK, Haskett DG, Luketich SK, Tzeng E, D'Amore A, Wagner WR, Weinbaum JS, Vorp DA. Development of a Semi-Automated, Bulk Seeding Device for Large Animal Model Implantation of Tissue Engineered Vascular Grafts. Front Bioeng Biotechnol. 2020 Oct 23;8:597847. doi: 10.3389/fbioe.2020.597847. PMID: 33195168; PMCID: PMC7644804.
12. Lorentz KL, Marini AX, Bruk LA, Gupta P, Mandal BB, DiLeo MV, Weinbaum JS, Little SR, Vorp DA. Mesenchymal Stem Cell-Conditioned Media-Loaded Microparticles Enhance Acute Patency in Silk-Based Vascular Grafts. Bioengineering (Basel). 2024 Sep 21;11(9):947. doi: 10.3390/bioengineering11090947. PMID: 39329689; PMCID: PMC11428691.

A main interest in our lab is to develop a tissue engineered vascular graft (TEVG) that promotes remodeling and native tissue formation. A main barrier to TEVG success is the lack of an endothelial monolayer after implantation, which would provide vascular homeostasis and prevent thrombosis. Our lab has developed a bilayer silk graft with extracellular vesicles that is able to remodel in a rat abdominal aortic interposition model. Rat models, however, do not represent clinical in situ endothelialization, the formation of the endothelial monolayer. On the other hand, sheep models, which more closely mimic clinical endothelialization, can be an expensive alternative.

Our lab is currently developing in vitro models to assess and improve endothelialization on TEVGs before moving to preclinical sheep models. The models include a 2D microfluidic device to study endothelialization on our silk biomaterial (in collaboration with Ioannis Zervantonakis) and a 3D bioreactor system to evaluate endothelialization and thrombotic response within our TEVGs (in collaboration with Susan Shea).

One of the main interests of our lab is to describe the connective fiber microstructure of vascular tissue using multi-photon microscopy. Quantification of microstructural parameters could provide insight into the biomechanical response of the aortic wall to different loading conditions. Our image analysis algorithms have characterized the two main ECM proteins responsible for vascular biomechanics, elastin and collagen, with respect to fiber architecture in the aortic wall. Our custom image analysis tool can be used to analyze various parameters of the connective fiber architecture of the aortic wall in numerous conditions and diseases, such as different aortic phenotypes, aging effects, etc., with the potential to describe fibrous or tube-like structures with components of varying tortuosity. In the future, the tool could be extended to other imaging modalities, such as confocal microscopy, accounting for different levels of noise and fluorescent signal.

Related Publications

1. Tsamis A, Krawiec JT, Vorp DA,  “Elastin and collagen fibre microstructure of the human aorta in ageing and disease: a review”, J R Soc Interface, 2013 Jun 6, 10(83):20121004, PMID 23536538 PMCID: PMC3645409
2. Koch RG, Tsamis A, D’Amore A, Wagner WR, Watkins SC, Gleason TG, Vorp DA, “A Custom Image-Based Analysis Tool for Quantifying Elastin and Collagen Micro-Architecture in the Wall of the Human Aorta from Multi-Photon Microscopy”, J Biomech, 2014 Mar 21;47(5):935-43, PMID 24524988, PMCID: PMC4036225

Our lab has used our image-based analysis of aortic microarchitecture to look at fiber variation in several different “coordinate systems” of the thoracic aorta. One area of inhomogeneity we have investigated is the transmural transition from the vascular intima to the media, then to the adventitia. From this work, we have identified the presence of radially-oriented fibers which could reduce the likelihood of dissection between layers. The amount of these fibers differs between two clinically distinct aortic valve morphologies - the natural tricuspid valve and the bicuspid valve (BAV) seen in 1-2% of the population. From our work, we hypothesize that the reduced undulation of collagen fibers in the aorta of BAV patients could predispose them to the formation of an intimal tissue tear, and ensuing dissection. The second area of inhomogeneity we are investigating is the variation that occurs around the circumference of the aorta, with respect to landmarks such as the left and right coronary arteries. Our initial data suggests that additional radially-oriented fibers in the region coincident with the left coronary artery, solely in the case of BAV, could provide extra strength and explain the circumferentially asymmetric geometry of aneurysms in BAV patients.

Related Publications

1. Tsamis A, Krawiec JT, Vorp DA, "Elastin and collagen fibre microstructure of the human aorta in ageing and disease: a review”, J R Soc Interface, 2013 Jun 6, 10(83):20121004, PMID 23536538, PMCID: PMC3645409
2. Tsamis A, Phillippi JA, Koch RG, Pasta S, D’Amore A, Watkins SC, Wagner WR, Gleason TG, Vorp DA, “Fiber Micro-Architecture in the Longitudinal-Radial and Circumferential-Radial Planes of Ascending Thoracic Aortic Aneurysm Media”, J Biomech, 2013 Nov 15; 46(16):2787-94 PMID 24075403, PMCID: PMC3898198
3. Pal S, Tsamis A, Pasta S, D’Amore A, Gleason T, Vorp DA, Maiti S, "A mechanistic model on the role of “radially-running” collagen fibers on dissection properties of human ascending thoracic aorta", J Biomech, 2014 Mar 21; 47(5):981-8 PMID 24484644
4. Tsamis A, Pal S, Phillippi JA, Gleason TG, Vorp DA, “Effect of aneurysm on biomechanical properties of “radially-oriented” collagen fibers in human ascending thoracic aortic media collagen fibers in human ascending thoracic aortic media”, Journal of Biomechanics, 2014 Dec 18;47(16):3820-4, PMID:25468299, PMCID: PMC4278426

Our lab, in collaboration with Dr. John Curci at Vanderbilt University, has developed a small animal model for treating an established and expanding abdominal aortic aneurysm with periadventitial delivery of adipose-derived mesenchymal stem cells. Unlike many other groups, we deliver therapeutic cells not coincident with injury but five days later, using an implantable port. Our published data show an effective halt in aneurysmal dilation following stem cell delivery, in the short term. Currently we are looking into methods to actively deliver cells into the thicker aortic wall seen in aneurysm patients.

Related Publications

1. Blose KJ, Ennis TL, Arif B, Weinbaum JS, Curci JA, Vorp DA, “Periadventitial adipose-derived mesenchymal stem cell treatment halts elastase-induced abdominal aortic aneurysm progression”, Regenerative Medicine, 2014. Nov;9(6):733-741, PMID:25431910, PMCID: PMC4283481

Endometriosis is a chronic gynecologic disease that presents with debilitating symptoms (80% rate of chronic pelvic pain, 50% rate of infertility), complex comorbidities, and persistent inflammation. On top of this, endometriosis takes on average 7-10 years to diagnose from the onset of symptoms and can only be diagnosed using surgical visualization and histological confirmation. It has been found that nearly 40% of patients who undergo surgical diagnosis do not have this disease. Therefore, it is critical to find a way to spare these 40% of patients from an unnecessary surgery and to minimize the time to diagnosis for endometriotic patients. EndoDx is a collaboration with Dr. Timothy Chung, geneticist Dr. Dave Peters, statistician Dr. Chris McKennan, and gynecologists Dr. Nicole Donnellan and Dr. John Harris. We are developing this minimally invasive diagnostic tool to screen for endometriosis presence and stage among symptomatic endometriosis and symptomatic non-endometriosis patients using patient symptom data, clinical data, and biomarkers. EndoDx has also involved the establishment of a university-wide biobank and database that began in 2010 and in the past three years has gone from 150 patients to over 600 patients enrolled. 

Endometriosis is thought to form through both eutopic endometrial pro-invasion capabilities and ectopic peritoneal immune dysregulation. This disease is challenging to diagnose as it requires surgical and histological intervention, indicating an increased need to identify at-risk patients. EndoChip models the pro-invasive behavior of eutopic endometrial cells and tissue-remodeling behavior or ectopic immune cells in 3-dimensional microfluidic culture to identify differences between symptomatic endometriosis, symptomatic non-endometriosis patients, and control patients. EndoChip is a collaboration with Dr. Ioannis Zervantonakis and minimally invasive gynecologic surgeon Dr. Nicole Donnellan to develop a minimally invasive, patient-specific model for endometriosis screening and diagnosis.