Current Projects

Adipose Stem Cell TEVG's


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

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

5.    Tsamis A, Phillippi JA, Koch R, Chan PG, Krawiec JT, D’Amore A, Watkins SC, Wagner WR, Vorp DA, Gleason TG, “Extracellular Matrix Fiber Microarchitecture is Region-Specific in Bicuspid Aortic Valve-Associated Ascending Aortopathy”, Journal of Thoracic and Cardiovascular Surgery, 2016 Feb 13 (Epub ahead of print), PMID: 26979916

Coil embolization involves treating cerebral aneurysm from the inside out, whereby metallic coils are placed into the aneurysm to induce thrombosis of the lumen and eliminate the risk of rupture and hemorrhage. However a significant number of aneurysms remain incompletely occluded and recurrences are expected in the range of 11-36% after coil embolization depending on the degree of filling achieved. Our laboratory has developed computational tools to study how the coil thrombus mass (CTM) also known as coil packing density (CPD) after coil embolization influences the intracranial aneurysm wall stress at different degrees of coil filling.

Our lab has developed a series of technologies, including a rotational seeding device and a bilayered elastomeric scaffold, which serve as the basis of our small-diameter tissue-engineered vascular graft (TEVG). We have explored the use of a variety of mesenchymal stem cells for our TEVG, including cells from bone marrow, muscle, and most recently fat. The latter cells, termed adipose-derived stem cells (ADSC), can be obtained from the waste product of patients undergoing elective liposuction.

Our current work is focused on advancing our TEVG towards clinical translation utilizing an autologous (i.e. “self-into-self”) and addressing practical barriers. As a first step we have utilized ADSC sourced from patients in demographics typically associated with cardiovascular risk such as diabetic and elderly individuals. In vitro we have shown that ADSC from healthy and diabetic (but not elderly) patients produce factors essential for TEVG regeneration including stimulation of smooth muscle cell migration. Implantation testing of ADSC-derived TEVG is currently underway to see if cells from different donor groups have different remodeling potential in vivo.

Related publications

1.    Soletti L, Nieponice A, Hong Y, Ye SH, Stankus JJ, Wagner WR, Vorp DA, “In Vivo Performance of a Phospholipid-Coated Bioerodable Elastomeric Graft for Small-Diameter Vascular Applications”,  J Biomed Mat Res: Part A, 2011 Feb;96(2):436-48, PMID: 21171163, PMCID: PMC3178339

2.    He W, Nieponice A, Hong Y, Wagner W, Vorp DA, “Rapid Engineered Small Diameter Vascular Grafts from Smooth Muscle Cells”, Cardiovascular Engineering and Technology, 2011 Sept; 2(3)149-159, DOI: 10.1007/s13239-011-0044-8

3.    Udelsman BHibino NVillalona GAMcGillicuddy EANieponice ASakamoto YMatsuda SVorp DA, Shinoka TBreuer CJul;17(7):731-6, PMID 21410308, PMCID: PMC3124112.

4.    Krawiec JT, Vorp DA, “Adult Stem Cell-Based Tissue Engineered Blood Vessels: A Review”, Biomaterials, 2012 Apr; 33(12): 3388-400, PMID 22306022

5.    Krawiec JT, Weinbaum JS, St. Croix CM, Phillippi JA, Watkins SC, Rubin JP, Vorp DA, “A Cautionary Tale for Autologous Vascular Tissue Engineering: Impact of Human Demographics on the Ability of Adipose-Derived Mesenchymal Stem Cells to Recruit and Differentiate Into Smooth Muscle Cells”, Tissue Eng: Part A, 2015 Feb;21(3-4):426-37, PMID: 25119584

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 Medicine2014. Nov;9(6):733-741, PMID:25431910, PMCID: PMC4283481