Tissue engineered vascular grafts transform into autologous neovessels capable of native function and growth

Abstract

Background Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity. Methods Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models. Results Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid–structure interaction simulations providing detailed hemodynamic and wall stress information. Conclusions These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.

Controlled and Synchronised Vascular Regeneration upon the Implantation of Iloprost- and Cationic Amphiphilic Drugs-Conjugated Tissue-Engineered Vascular Grafts into the Ovine Carotid Artery: A Proteomics-Empowered Study

“…The progress in the development of TEVGs largely depends on the molecular understanding of their in situ remodeling and decoding of molecular signatures associated with physiological and pathological vascular regeneration during and upon the polymer replacement. This corresponds to the recent trends in the field [ 29 ], although vascular tissue engineers primarily focus their efforts on harnessing novel visualisation modalities (such as intravascular ultrasound, 3D fast spin-echo T1 black-blood imaging, contrast-enhanced 3D magnetic resonance angiography, time-resolved magnetic resonance 2D and 3D flow velocity mapping, and delayed enhancement magnetic resonance imaging) as well as on employing computational modeling of fluid–structure interactions in context of subject-specific 3D TEVG geometries. Yet, we believe that the following studies should extensively employ transcriptomic and proteomic approaches to characterise the gene and protein expression in TEVGs at ascending time points, identify the molecular signatures of various vascular regeneration patterns, pinpoint the molecular events behind the polymer degradation and replacement in the anastomotic sites and in the midgraft, and evaluate the distance between in situ regenerated blood vessels and contralateral arteries.…”

“…Another obstacle in the field is the dearth of unbiased mass spectrometry profiling in studies investigating vascular regeneration during TEVG degradation and synchronisation of these processes [ 29 ], as proteomic analysis has been limited to decellularised human umbilical [ 30 , 31 ] or placental [ 32 ] arteries. As compared to the proteomics, an RNA sequencing approach is inferior for TEVG analysis, as differentially expressed transcripts are often not translated correspondingly and it does not reflect the molecules which emerge from the systemic circulation rather than being produced in situ.…”

Engineering Smooth Muscle to Understand Extracellular Matrix Remodeling and Vascular Disease

“…Further exploration of these materials in vascular grafts could facilitate more clinically relevant models and more insight into CVD mechanisms than is currently possible [ 11 , 72 ]. In addition, computational modeling before designing 3D vascular systems allows researchers to implement better design principles and forego much of the costly empirical experimentation usually needed to optimize these vascular systems [ 92 , 93 , 94 ]. Ultimately, combining all of these techniques can move the field forward in analyzing cardiovascular disease mechanisms in more depth and further testing potential future therapeutics or mitigation strategies that could help patients.…”

Tissue Engineering of Vascular Grafts: A Case Report From Bench to Bedside and Back

“…C , After the scaffold has degraded (52 weeks), the change in graft size occurs more gradually at a rate similar to the native IVC. 18 Adapted from Blum et al 56 Copyright ©2022, Springer Nature.…”