quantifying-inferior-vena-cava-compliance-distensibility-an-vivo

Quantifying Inferior Vena Cava Compliance and Distensibility in an <i>In Vivo</i> Ovine Model Using 3D Angiography

Synthetic vascular grafts overcome some challenges of allografts, autografts, and xenografts but are often more rigid and less compliant than the native ...

Nationwide Children's Hospital

To date, there has been little investigation of biodegradable tissue engineered arterial grafts (TEAG) using clinically relevant large animal models. The purpose of this study is to explore how pore size of electrospun scaffolds can be used to balance neoarterial tissue formation with graft structural integrity under arterial environmental conditions throughout the remodeling process. TEAGs were created with an outer poly-ε-caprolactone (PCL) electrospun layer and an inner sponge layer composed of heparin conjugated 50:50 poly (l-lactide-co-ε-caprolactone) copolymer (PLCL). Outer electrospun layers were created with four different pore diameters (4, 7, 10, and 15 µm). Fourteen adult female sheep underwent bilateral carotid artery interposition grafting (n = 3-4 /group). Our heparin-eluting TEAG was implanted on one side (n = 14) and ePTFE graft (n = 3) or non-heparin-eluting TEAG (n = 5) on the other side. Twelve of the fourteen animals survived to the designated endpoint at 8 weeks, and one animal with 4 µm pore diameter graft was followed to 1 year. All heparin-eluting TEAGs were patent, but those with pore diameters larger than 4 µm began to dilate at week 4. Only scaffolds with a pore diameter of 4 µm resisted dilation and could do so for up to 1 year. At 8 weeks, the 10 µm pore graft had the highest density of cells in the electrospun layer and macrophages were the primary cell type present. This study highlights challenges in designing bioabsorbable TEAGs for the arterial environment in a large animal model. While larger pore diameter TEAGs promoted cell infiltration, neotissue could not regenerate rapidly enough to provide sufficient mechanical strength required to resist dilation. Future studies will be focused on evaluating a smaller pore design to better understand long-term remodeling and determine feasibility for clinical use. STATEMENT OF SIGNIFICANCE: In situ vascular tissue engineering relies on a biodegradable scaffold that encourages tissue regeneration and maintains mechanical integrity until the neotissue can bear the load. Species-specific differences in tissue regeneration and larger mechanical forces often result in graft failure when scaling up from small to large animal models. This study utilizes a slow-degrading electrospun PCL sheath to reinforce a tissue engineered arterials graft. Pore size, a property critical to tissue regeneration, was controlled by changing PCL fiber diameter and the resulting effects of these properties on neotissue formation and graft durability was evaluated. This study is among few to report the effect of pore size on vascular neotissue formation in a large animal arterial model and also demonstrate robust neotissue formation.

The effect of pore diameter on neo-tissue formation in electrospun biodegradable tissue-engineered arterial grafts in a large animal model.

Cardiovascular disease (CVD) is the leading cause of death in western countries. Although surgical outcomes for CVD are dramatically improving with the development of surgical techniques, medications, and perioperative management strategies, adverse postoperative events related to the use of artificial prosthetic materials are still problematic. Moreover, in pediatric patients, using these artificial materials make future re-intervention inevitable due to their lack of growth potential.

Current status of developing tissue engineering vascular technologies.

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.

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

Cardiovascular-related medical conditions remain a significant cause of death worldwide despite the advent of tissue engineering research more than half a century ago. Although autologous tissue is still the preferred treatment, donor tissue is limited, and there remains a need for tissue-engineered vascular grafts (TEVGs). The production of extensive vascular tissue (>1 cm3) in vitro meets the clinical needs of tissue grafts and biological research applications. The use of TEVGs in human patients remains limited due to issues related to thrombogenesis and stenosis. In addition to the advancement of simple manufacturing methods, the shift of attention to the combination of synthetic polymers and bio-derived materials and cell sources has enabled synergistic combinations of vascular tissue development. This review details the selection of biomaterials, cell sources and relevant clinical trials related to large diameter vascular grafts. Finally, we will discuss the remaining challenges in the tissue engineering field resulting from complex requirements by covering both basic and clinical research from the perspective of material design.

Clinical Application for Tissue Engineering Focused on Materials.

Patients with single ventricle heart defects requires a series of staged open-heart procedures, termed Fontan palliation. However, while lifesaving, these operations are associated with significant morbidity and early mortality. The attendant complications are thought to arise in response to the abnormal hemodynamics induced by Fontan palliation, although the pathophysiology underlying these physicochemical changes in cardiovascular and other organs remain unknown. Here, we investigated the microRNA (miRNA) content in serum and serum-derived extracellular vesicles (EVs) by sequencing small RNAs from a physiologically relevant sheep model of the Fontan operation. The differential expression analysis identified the enriched miRNA clusters in (1) serum vs. serum-derived EVs and (2) pre-Fontan EVs vs. post-Fontan EVs. Metascape analysis showed that the overexpressed subset of EV miRNAs by Fontan procedure target liver-specific cells, underscoring a potentially important pathway involved in the liver dysfunction that occurs as a consequence of Fontan palliation. We also found that post-Fontan EV miRNAs were associated with senescence and cell death, whereas pre-Fontan EV miRNAs were associated with stem cell maintenance and epithelial-to-mesenchymal transition. This study shows great potential to identify novel circulating EV biomarkers from Fontan sheep serum that may be used for the diagnosis, prognosis, and therapeutics for patients that have undergone Fontan palliation.

Computational analysis of serum-derived extracellular vesicle miRNAs in juvenile sheep model of single stage Fontan procedure.

Tissue engineering has paved the way for the development of artificial human cardiac muscle patches (hCMPs) and cardiac tissue analogs, especially for treating Myocardial infarction (MI), often by increasing its regenerative abilities. Low engraftment rates, insufficient clinical application scalability, and the creation of a functional vascular system remain obstacles to hCMP implementation in clinical settings. This paper will address some of these challenges, present a broad variety of heart cell types and sources that can be applied to hCMP biomanufacturing, and describe some new innovative methods for engineering such treatments. It is also important to note the injection/transplantation of cells in cardiac tissue engineering.

Advances in Cardiac Tissue Engineering.

As the number of arteriosclerotic diseases continues to increase, much improvement is still needed with treatments for cardiovascular diseases. This is mainly due to the limitations of currently existing treatment options, including the limited number of donor organs available or the long-term durability of the artificial organs. Therefore, tissue engineering has attracted significant attention as a tissue regeneration therapy in this area. Porous scaffolds are one of the effective methods for tissue engineering. However, it could be better, and its effectiveness varies depending on the tissue application. This paper will address the challenges presented by various materials and their combinations. We will also describe some of the latest methods for tissue engineering.

The Application of Porous Scaffolds for Cardiovascular Tissues.

Hydrogels are being investigated for their application in inducing the regeneration of various tissues, and suitable conditions for each tissue are becoming more apparent. Conditions such as the mechanical properties, degradation period, degradation mechanism, and cell affinity can be tailored by changing the molecular structure, especially in the case of polymers. Furthermore, many high-functional hydrogels with drug delivery systems (DDSs), in which drugs or bioactive substances are contained in controlled hydrogels, have been reported. This review focuses on the molecular design and function of biopolymer-based hydrogels and introduces recent developments in functional hydrogels for clinical applications.

Recent Developments in Biopolymer-Based Hydrogels for Tissue Engineering Applications.

Inducing tissue regeneration in many skin defects, such as large traumatic wounds, burns, other physicochemical wounds, bedsores, and chronic diabetic ulcers, has become an important clinical issue in recent years. Cultured cell sheets and scaffolds containing growth factors are already in use but have yet to restore normal skin tissue structure and function. Many tissue engineering materials that focus on the regeneration process of living tissues have been developed for the more versatile and rapid initiation of treatment. Since the discovery that cells recognize the chemical-physical properties of their surrounding environment, there has been a great deal of work on mimicking the composition of the extracellular matrix (ECM) and its three-dimensional network structure. Approaches have used ECM constituent proteins as well as morphological processing methods, such as fiber sheets, sponges, and meshes. This review summarizes material design strategies in tissue engineering fields, ranging from the morphology of existing dressings and ECM structures to cellular-level microstructure mimicry, and explores directions for future approaches to precision skin tissue regeneration.

Anudari Ulziibayar

Center for Regenerative Medicine

Nationwide Children's Hospital

Quantifying Inferior Vena Cava Compliance and Distensibility in an In Vivo Ovine Model Using 3D Angiography