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Computationally Optimizing the Compliance of a Biopolymer Based Tissue Engineered Vascular Graft.

ABSTRACT: Coronary heart disease is a leading cause of death among Americans for which coronary artery bypass graft (CABG) surgery is a standard surgical treatment. The success of CABG surgery is impaired by a compliance mismatch between vascular grafts and native vessels. Tissue engineered vascular grafts (TEVGs) have the potential to be compliance matched and thereby reduce the risk of graft failure. Glutaraldehyde (GLUT) vapor-crosslinked gelatin/fibrinogen constructs were fabricated and mechanically tested in a previous study by our research group at 2, 8, and 24?hrs of GLUT vapor exposure. The current study details a computational method that was developed to predict the material properties of our constructs for crosslinking times between 2 and 24?hrs by interpolating the 2, 8, and 24?hrs crosslinking time data. matlab and abaqus were used to determine the optimal combination of fabrication parameters to produce a compliance matched construct. The validity of the method was tested by creating a 16-hr crosslinked construct of 130??m thickness and comparing its compliance to that predicted by the optimization algorithm. The predicted compliance of the 16-hr construct was 0.00059?mm Hg-1 while the experimentally determined compliance was 0.00065?mm Hg-1, a relative difference of 9.2%. Prior data in our laboratory has shown the compliance of the left anterior descending porcine coronary (LADC) artery to be 0.00071 ± 0.0003?mm Hg-1. Our optimization algorithm predicts that a 258-?m-thick construct that is GLUT vapor crosslinked for 8.1?hrs would match LADC compliance. This result is consistent with our previous work demonstrating that an 8-hr GLUT vapor crosslinked construct produces a compliance that is not significantly different from a porcine coronary LADC.

SUBMITTER: Harrison S

PROVIDER: S-EPMC4845160 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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Computationally Optimizing the Compliance of a Biopolymer Based Tissue Engineered Vascular Graft.

Harrison Scott S Tamimi Ehab E Uhlorn Josh J Leach Tim T Vande Geest Jonathan P JP

Journal of biomechanical engineering 20160101 1

Coronary heart disease is a leading cause of death among Americans for which coronary artery bypass graft (CABG) surgery is a standard surgical treatment. The success of CABG surgery is impaired by a compliance mismatch between vascular grafts and native vessels. Tissue engineered vascular grafts (TEVGs) have the potential to be compliance matched and thereby reduce the risk of graft failure. Glutaraldehyde (GLUT) vapor-crosslinked gelatin/fibrinogen constructs were fabricated and mechanically t ...[more]

PMID: 26593773

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Project description:ObjectiveOne of the rate-limiting barriers within the field of vascular tissue engineering is the lengthy fabrication time associated with expanding appropriate cell types in culture. One particularly attractive cell type for this purpose is the adipose-derived mesenchymal stem cell (AD-MSC), which is abundant and easily harvested from liposuction procedures. Even this cell type has its drawbacks, however, including the required culture period for expansion, which could pose risks of cellular transformation or contamination. Eliminating culture entirely would be ideal to avoid these concerns. In this study, we used the raw population of cells obtained after digestion of human liposuction aspirates, known as the stromal vascular fraction (SVF), as an abundant, culture-free cell source for tissue-engineered vascular grafts (TEVGs).MethodsSVF cells and donor-paired cultured AD-MSCs were first assessed for their abilities to differentiate into vascular smooth muscle cells (SMCs) after angiotensin II stimulation and to secrete factors (eg, conditioned media) that promote SMC migration. Next, both cell types were incorporated into TEVG scaffolds, implanted as an aortic graft in a Lewis rat model, and assessed for their patency and composition.ResultsIn general, the human SVF cells were able to perform the same functions as AD-MSCs isolated from the same donor by culture expansion. Specifically, cells within the SVF performed two important functions; namely, they were able to differentiate into SMCs (SVF calponin expression: 16.4% ± 7.7% vs AD-MSC: 19.9%% ± 1.7%) and could secrete promigratory factors (SVF migration rate relative to control: 3.1 ± 0.3 vs AD-MSC: 2.5 ± 0.5). The SVF cells were also capable of being seeded within biodegradable, elastomeric, porous scaffolds that, when implanted in vivo for 8 weeks, generated patent TEVGs (SVF: 83% patency vs AD-MSC: 100% patency) populated with primary vascular components (eg, SMCs, endothelial cells, collagen, and elastin).ConclusionsHuman adipose tissue can be used as a culture-free cell source to create TEVGs, laying the groundwork for the rapid production of cell-seeded grafts.

Project description:The advent of single-cell RNA sequencing (scRNA-Seq) has brought with it the ability to gain greater insights into the cellular composition of tissues and heterogeneity in gene expression within specific cell types. For tissue-engineered blood vessels, this is particularly impactful to better understand how neotissue forms and remodels into tissue resembling a native vessel. A notable challenge, however, is the ability to separate cells from synthetic biomaterials to generate high-quality single-cell suspensions to interrogate the cellular composition of our tissue-engineered vascular grafts (TEVGs) during active remodeling in situ. We present here a simple, commercially available approach to separate cells within our TEVG from the residual scaffold for downstream use in a scRNA-Seq workflow. Utilizing this method, we identified the cell populations comprising explanted TEVGs and compared these with results from immunohistochemical analysis. The process began with explanted TEVGs undergoing traditional mechanical and enzymatic dissociation to separate cells from scaffold and extracellular matrix proteins. Magnetically labeled antibodies targeting murine origin cells were incubated with enzymatic digests of TEVGs containing cells and scaffold debris in suspension allowing for separation by utilizing a magnetic separator column. Single-cell suspensions were processed through 10 × Genomics and data were analyzed utilizing R to generate cell clusters. Expression data provided new insights into a diverse composition of phenotypically unique subclusters within the fibroblast, macrophage, smooth muscle cell, and endothelial cell populations contributing to the early neotissue remodeling stages of TEVGs. These populations were correlated qualitatively and quantitatively with immunohistochemistry highlighting for the first time the potential of scRNA-Seq to provide exquisite detail into the host cellular response to an implanted TEVG. These results additionally demonstrate magnetic cell isolation is an effective method for generating high-quality cell suspensions for scRNA-Seq. While this method was utilized for our group's TEVGs, it has broader applications to other implantable materials that use biodegradable synthetic materials as part of scaffold composition. Impact statement Single-cell RNA sequencing is an evolving technology with the ability to provide detailed information on the cellular composition of remodeling biomaterials in vivo. This present work details an effective approach for separating nondegraded biomaterials from cells for downstream RNA-sequencing analysis. We applied this method to implanted tissue-engineered vascular grafts and for the first time describe the cellular composition of the remodeling graft at a single-cell gene expression level. While this method was effective in our scaffold, it has broad applicability to other implanted biomaterials that necessitate separation of cell from residual scaffold materials for single-cell RNA sequencing.

Project description:A reliable and cost-effective scaffold for tissue-engineered vascular graft that would not only support cell proliferation and growth but also maintain cell phenotype has been a long-term challenge. In this study, we propose a biodegradable and biomimetic copolymer of gelatin with vinyl acetate synthesized via a graft copolymerization technique to generate tubular scaffolds for vascular tissue engineering. Two fabrication techniques, freeze drying and electrospinning, were used to generate the differing architectures for the scaffolds and characterized. The electrospun scaffolds were found to have a faster rate of mass loss in physiological saline of 81.72% within 4 months compared with 60% mass loss for the freeze-dried samples, though the materials were more crystalline. Vascular (v) smooth muscle cells (SMCs) were seeded on these tubes, which were then subjected to dynamic pulsatile stimulation on a vascular bioreactor for a week. Gross examination of the tissue-engineered constructs revealed that the cells secreted extensive extracellular matrix, with the dynamically conditioned samples exhibiting well-orientated SMCs and collagenous fibers in comparison with growth in static conditions. In addition, the alignment of cells in the direction of strain was greater in the electrospun constructs. The electrospun scaffolds maintained the characteristic contractile phenotype of SMCs, which was confirmed by higher gene expression rates of contractile protein markers like SM22? and calponin. A significant increase in the total matrix components (collagen and elastin) in the electrospun constructs compared with the freeze-dried samples was confirmed by biochemical analysis. The results of this study indicate that a combination approach involving a biomimetic scaffold with the nanofibrillar architecture and good mechanical strength conducive to the growth of SMCs and the use of the pulsatile forces to modulate the cell morphology and phenotypic plasticity of vSMCs helps in the successful engineering of a medial layer of blood vessel.

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Computationally Optimizing the Compliance of a Biopolymer Based Tissue Engineered Vascular Graft.

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Computationally Optimizing the Compliance of a Biopolymer Based Tissue Engineered Vascular Graft.

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