Tissue engineered vascular grafts transform into autologous neovessels with biomimetic function

Tissue engineered vascular grafts transform into autologous neovessels with biomimetic function
Natural history of tissue engineered vascular graft development. (A) TEVG scaffold was fabricated from PGA fibers that were knitted into a tube (left) and coated on the inner and outer surface with a PCLA (right). B) Magnified SEM images of the scaffold demonstrated sponge layers of PCLA surrounding the PGA fibers outlined with a white dotted line. Scale bars 1 mm left, 100 µm right. C) Representative 3D reconstructions of a TEVG (outlined in yellow) over its 2-year implantation as an IVC interposition graft in a sheep model. D) Representative histologic H&E images demonstrated characteristic changes in TEVG over the 1-year time course. Scale bar 4 mm. TEVG: tissue engineered vascular graft, PGA: polyglycolic acid, PCLA: polycaprolactone-lactide, SEM: scanning electron microscope, IVC: inferior vena cava. Communications Medicine, doi.org/10.1038/s43856-021-00063-7

Tissue engineered vascular grafts (TEVGs) can advance surgical management of infants and children who require congenital heart surgery, by creating functional vascular conduits with growth capacity. In a new report now published in Communication Medicine, Kevin G. Blum, Jacob C. Zbinden, Abhay B. Ramachandra and a large team of multidisciplinary and multi-institutional researchers used an integrative computational-experimental approach to understand the natural history of neovessel formation in a large preclinical animal model. During the experiments they combined large animal implantation studies with in vivo imaging and histology alongside computational growth and remodeling methods. The outcomes can provide insights to TEVG (tissue-engineered vascular graft) remodeling, with important implications for clinical translation for children with congenital heart disease.

Correcting birth defects—from the lab to clinic

Congenital heart surgery is aimed at correcting birth defects and require the development of artificial blood vessels known as vascular grafts. The potential to develop a vascular conduit with capacity to grow as the patient develops holds great promise in the field of advancing congenital heart surgery. Currently, patients typically outgrow a synthetic graft and require additional surgery. By using tissue engineering, bioengineers can form a promising solution to this problem by creating a vascular conduit that grows with the patient to mitigate somatic overgrowth. Results of ongoing clinical and preclinical studies in the field have confirmed the possibility of forming living vascular conduits with TEVGs to explore biological growth potential. While multiple groups have advanced the clinical translation of TEVGs, they remain to be approved in the United States. In this work, the team of researchers, conducted a series of laboratory and computational experiments to understand how TEVGs (tissue-engineered ) developed into fully functional blood vessels. During the experiments, they showed the presence of two phases of changes to the TEVG after implantation, including an early phase of inflammation and latter phase of mechano-mediated scaffold neotissue (new tissue) remodeling. The resulting blood vessels showed the ability to grow and respond to blood flow, much like the body's own blood vessels. The outcomes provide insight to the process of TEVG transformation to functional blood vessels, with implications of technical transfer to clinical practice.

Tissue engineered vascular grafts transform into autologous neovessels with biomimetic function
Morphometric changes during neotissue formation and development. A) Representative intravascular ultrasound (IVUS) imaging of TEVG, with lumen outlined in green and original TEVG size overlayed for reference in yellow. Scale bar 5 mm. B) Remodeling in TEVGs occurred through two main processes, inward remodeling (blue) with a decrease of outer diameter, and intramural growth (red) with a thickening of the vessel wall. C) Quantification of changes in inner and outer diameter of TEVGs in the sheep model measured by IVUS. D) High magnification representative trichrome staining demonstrated intramural growth via inflammatory tissue formation and vascular neotissue formation, followed by subsequent mural thinning as the scaffold degraded and the inflammatory neotissue subsided resulting in the creation of a neovessel. Scale bar 500 µm. Data shown as mean+/-SD. IVUS: intravascular ultrasound, TEVG: tissue-engineered vascular graft. Communications Medicine, doi.org/10.1038/s43856-021-00063-7
The computational model

The research team built the on more than a decade of experience in modeling growth and remodeling of native vessels, in response to changing mechanobiological and immunobiological stimuli. Since the TEVG model is based on an existing model originally developed to describe and predict native behavior, modifications to the model relative to scaffold biodegradation, led to the hypothesis that TEVGs can transform into a neovessel that mimics native blood vessels upon scaffold degradation. During the simulations, Blum et al. tracked the mass density of each structurally significant wall constituent, including polymer, smooth muscle cells, and collagen fibers across time through several quasi-equilibrium steps and identified mass densities of these constituents into those produced via mechanobiological processes, and immunobiological processes. They simulated four case studies, and classified the behavior of TEVGs into two periods, the first referred to the period of neotissue formation influenced by the immune response of the scaffold material, followed by neovessel remodeling that occurred after scaffold degradation. A key result of the model highlighted how neovessel growth and remodeling mimicked purely mechano-mediated dynamics in native vessels.

Characterizing neovessel formation

Tissue engineered vascular grafts transform into autologous neovessels with biomimetic function
Hemodynamic changes throughout neovessel formation. A) 3D anatomical models of TEVGs at 1-week, 6 weeks and 52 weeks post-TEVG implantation with representative velocity magnitude (peak flow), pressure, and wall shear stress maps (averaged over the cardiac cycle), as measured by FSI simulations. A corresponding cross-section shows flow through a slice of the TEVG volume (dotted line) and its corresponding luminal thickness. Note the increase in velocity magnitude across time points, the decrease in diameter and length from 1-week to 6 weeks and the flow patterns that were a result of geometric changes. Average ± standard deviation of lumen cross-sectional area (B), vessel wall thickness (C), time averaged wall shear stress (D), and Cauchy Stress (averaged over the cardiac cycle) (E) shown along the normalized length of the graft for each time point. Proximal to distal arrow indicates direction of flow. TEVG: tissue-engineered vascular grafts, FSI: fluid–structure interaction. Communications Medicine, doi.org/10.1038/s43856-021-00063-7

The scientists developed the scaffolds using polyglycolic acid (PGA) fibers knitted into a tube and coated with a 50:50 copolymer of polycaprolactone and poly-L-lactide to form a porous sponge. The designed scaffold could be dissolved via hydrolysis. Upon implantation in a sheep model, the team noted morphological changes in the initial 26-week period, followed by complete scaffold degradation by 52 weeks to result in a neovessel, which grossly resembled a native blood vessel. Based on serial intravascular ultrasound imaging across 52 weeks post-implantation, the team observed additional information on the morphology of evolving TEVGs, alongside histological assessments of explants at specific timeframes of interest. The team next conducted in vitro and in vivo biodegradation studies of the neovessels during growth and remodeling to examine the diminishing mass of the material, which originally provided stress shielding and inflammatory stimuli. They noted the rates of biodegradation in phosphate buffered solution up to 70 degrees Celsius and the dynamic timeframe of biodegradation in vitro and in vivo, respectively. The in-lab studies showed progressive compliance of the scaffold during polymer degradation. The scientists also examined scaffold-induced inflammation in vivo by observing the presence of markers of inflammation and credited the biomechanical properties of TEVG to material behavior and neotissue constituents.

Tissue engineered vascular grafts transform into autologous neovessels with biomimetic function
Computational model predicts TEVG neovessel formation. A) Computational G&R modeling of TEVG neotissue formation demonstrating the combinatory effects of inflammation and mechano-mediated neotissue formation and remodeling predicted for the experimentally tested graft (left). Additional computational modeling results for theoretical cases with the absence of an immune response (mid left), only an immune response (mid right), and a lack of mechano-mediation for neotissue production (right). B) Plot of inward remodeling vs intramural growth, with changes over time demonstrated by arrows from the origin. C) Comparison of computational modeling prediction of inflammatory and mechanical neotissue to histological findings. D) Stress-mediated thickness prediction and (E) stress-mediated luminal area prediction based on hemodynamic and morphology measurements taken from a computational hemodynamics study and the assumption that perturbations in flow and pressure are proportional to their homeostatic values. Perturbed shear and circumferential stress calculated using the proportionality constants and resulting thickness and radius changes inferred. 52-week native IVC values were taken to be the homeostatic values. Measured values +/- standard deviation are shown through circular markers. All values were calculated at 77% of the distance from the proximal to distal anastomosis, where stenosis routinely occurs in 6-week sheep. TEVG: tissue-engineered vascular graft, G&R: growth and remodeling, IVC: inferior vena cava. Communications Medicine, doi.org/10.1038/s43856-021-00063-7

Hemodynamics and the analysis of neotissue

Blum et al. then assessed the effects of evolving neovessel scaffolds and their morphological changes on hemodynamics by performing subject-specific computational simulations and calculated 3D maps of major hemodynamic indices to create 3D anatomical models of TEVGs after implantation. The simulations highlighted the natural history of scaffold development in vivo from stenosis development evidenced by marked narrowing of lumen cross-sectional area, which reversed by 52 weeks. Further analyses showed the importance of extent and timing of immune- and mechano-mediated neotissue formation during scaffold evolution. Based on the simulations, Blum et al. suggested that growth and remodeling after scaffold degradation would progressively yield a neovessel that mimics native vessels. By 52 weeks after implantation, using surface scanning electron microscopy they noted continuous luminal covering of endothelial cells, and using immunofluorescent staining they envisioned the confluence of endothelial cells. The neovessels also exhibited contractile responses similar to native vessels in response to biochemical stimulation, to suggest native-like biomimetic structures with bioinspired function.

Tissue engineered vascular grafts transform into autologous neovessels with biomimetic function
TEVG neovessels demonstrate biological growth. A) Representative images of growth of sheep over implantation time. B) Quantification of weight for TEVG-implanted and non-implanted control animals over long-term implantation. C) Representative 3D angiography imaging of a sheep over the implantation time. Native IVC colored yellow, TEVG colored dark blue, and surrounding anatomic structures colored light blue. Measurements taken from each representative image shown below. D) Quantification of TEVG volume over time. E) Representative images of mid-graft TEVG at minimum and maximum area over a cardiac cycle as measured by MRI, at 1-week (Left) and 52-week (Right). F) Quantification of area deformation of TEVG and adjacent IVC at 1-week and 52-week post-implantation. G) Length of TEVG and vertebral body as measured from angiography. Red boxes denote the time until complete TEVG degradation. Data shown as mean+/-SD. Statistical significance in area deformation data determined using Mann-Whitney test for unequal variances test. *<0.05, **<0.01, ***<0.001, ****<0.0001. TEVG: tissue engineered vascular grafts, IVC: inferior vena cava, MRI: magnetic resonance imaging. Communications Medicine, doi.org/10.1038/s43856-021-00063-7
Outlook from the lab to the clinic—pediatric population

The scientists further examined the biological growth of neovessels based on progressive changes in size, shape and function during the development and maturation of an organism by using juvenile (four-month-old) lambs to show that, as the lambs matured to sheep, the age-matched constructs did not show any growth restriction of the animal. They also revealed limitations of the method relative to the computational modeling process. In this way, Kevin G. Blum and colleagues comprehensively studied the transformation of TEVG (tissue engineered vascular graft) into a neovessel, which eventually behaved like a native vessel with adverse growth/remodeling during the first six months of implantation. After this critical period, the neovessel evolved to possess biological growth potential including a fully functional endothelium for bioinspired hemodynamics and hemocompatibility with a highly compliant and vasoactive wall to match the vessel into which it was implanted. The outcome has significant impact on the pediatric population. The team envision continued optimization of the computational-experimental approach to hold great promise for improved time- and cost-effective technology transfer from the lab to the clinic.


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More information: Kevin M. Blum et al, Tissue engineered vascular grafts transform into autologous neovessels capable of native function and growth, Communications Medicine (2022). DOI: 10.1038/s43856-021-00063-7

Nicolas L'Heureux et al, Human tissue-engineered blood vessels for adult arterial revascularization, Nature Medicine (2006). DOI: 10.1038/nm1364

Journal information: Nature Medicine

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Citation: Tissue engineered vascular grafts transform into autologous neovessels with biomimetic function (2022, January 20) retrieved 18 May 2022 from https://medicalxpress.com/news/2022-01-tissue-vascular-grafts-autologous-neovessels.html
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