Hydrogen sulfide exhibits significant potential in vascular therapy due to its anti-inflammatory, antioxidant, and cytoprotective properties. However, clinical translation is hindered by the absence of biomaterial systems capable of sustained, physiologically relevant sulfide release. To address this, we have developed two coaxial electrospun systems as vascular grafts, which are impregnated with diallyl trisulfide, a stable sulfide donor, enabling controlled sulfide release through a core-shell fiber structure that enhances mechanical properties and cellular interactions. Results show that both polysulfide-impregnated graft systems significantly mitigated inflammation while promoting endothelial cell proliferation and migration in vitro. Over seven days, these grafts released over an order of magnitude more sulfide than controls (non-polysulfide grafts), leading to higher endothelial proliferation and reduced TNF-α-induced inflammation. When implanted as abdominal aorta interposition grafts in rats, grafts maintained full patency at both 1 and 12 weeks. In vivo, compared to controls, polysulfide-impregnated grafts exhibited rapid cell penetration and reduced inflammation at one week. Histological and immunofluorescence analyses confirmed robust endothelialization and a predominantly M2-type macrophage response, indicative of a pro-healing environment. By 12 weeks, polysulfide-impregnated grafts demonstrated reduced capsule formation, uniform extracellular matrix remodeling, and superior integration with neighboring arteries. These findings highlight the potential of polysulfide-impregnated coaxial fibers for sustained sulfide delivery, mitigating anti-inflammation, enhancing early vascular cell function, and long-term graft stability. This strategy represents a promising approach to improving small-diameter vascular graft outcomes by leveraging sulfide-based signaling to prevent thrombosis and inflammation, addressing key limitations of current synthetic grafts. STATEMENT OF SIGNIFICANCE: Current small-diameter vascular grafts often suffer from poor integration and chronic inflammation. This study introduces new designs of coaxial electrospun fiber graft systems that release hydrogen sulfide (H₂S), an endogenous gasotransmitter that supports vascular regeneration and modulates inflammation. By incorporating a polysulfide emulsion into the fiber core, we mimic physiological H₂S delivery. Two crosslinked graft systems were developed, featuring either a protein-based sheath for native adhesion or a functional sheath enabling 'click chemistry' for peptide tethering. In vitro, H₂S release enhanced endothelial cell proliferation and migration while suppressing proinflammatory signaling. In vivo implantation in rat abdominal aortas demonstrated improved endothelialization, reduced inflammation with increased M2 macrophage polarization, and balanced vascular remodeling. This platform offers a bioinspired strategy for improving graft integration and long-term patency.

Phenotypic plasticity, or adaptability, of a cell determines its ability to survive and function within changing cellular environments. Changes in the mechanical environment, ranging from stiffness of the extracellular matrix (ECM) to physical stress such as tension, compression, and shear, are critical environmental cues that influence phenotypic plasticity and stability. Furthermore, an exposure to a prior mechanical signal has been demonstrated to play a fundamental role in modulating phenotypic changes that persist even after the mechanical stimulus is removed, creating stable mechanical memories. In this mini review, our objective is to highlight how the mechanical environment alters both phenotypic plasticity and stable memories through changes in chromatin architecture, mainly focusing on examples in cardiac tissue. We first explore how cell phenotypic plasticity is modulated in response to changes in the mechanical environment, and then connect the changes in phenotypic plasticity to changes in chromatin architecture that reflect short-term and long-term memories. Finally, we discuss how elucidating the mechanisms behind mechanically induced chromatin architecture that lead to cell adaptations and retention of stable mechanical memories could uncover treatment methods to prevent mal-adaptive permanent disease states.

Stents are a widely-used device to treat a variety of cardiovascular diseases. The purpose of this review is to explore the application of regenerative medicine principles into current and future stent designs. This review will cover regeneration-relevant approaches emerging in the current research landscape of stent technology. Regenerative stent technologies include surface engineering of stents with cell secretomes, cell-capture coatings, mimics of endothelial products, surface topography, endothelial growth factors or cell-adhesive peptides, as well as design of bioresorable materials for temporary stent support. These technologies are comparatively analyzed in terms of their regenerative effects, therapeutic effects and challenges faced; their benefits and risks are weighed up for suggestions about future stent developments. This review highlights two unique regenerative features of stent technologies: selective regeneration, which is to selectively grow endothelial cells on a stent but inhibit the proliferation and migration of smooth muscle cells, and stent-assisted regeneration of ischemic tissue injury.

The bypass graft is the mainstream of surgical intervention to treat vascular diseases. Ideal bypass materials, yet to be developed, require mechanical properties, availability, clinically feasible manufacturing logistics, and bioactivities with precise physicochemical cues defined to guide cell activities for arterial regeneration. Such needs instigated our fabrication of vascular grafts, which consist of coaxial, nanostructured fibers exhibiting a polycaprolactone (PCL) core and a photoclickable, 4-arm thiolated polyethylene glycol-norbornene (PEG-NB) sheath. The graft strength and bioactivity were modulated by the PCL concentration and the peptides (RGD, transforming growth factor β-1 or TGF-β1) conjugated to thiol-ene of PEG-NB, respectively. Structural, physical, and mechanical characterizations demonstrated that the fibrous grafts mimicked the key features of the native extracellular matrix, including a crosslinked fiber network for structural stability, viscoelasticity emulating arteries, hydration property, and high porosity for cell infiltration. Meanwhile, these grafts displayed strength and toughness exceeding or meeting surgical criteria. Furthermore, the grafts with higher PCL concentration (3 vs 1.8%) showed thicker fibers, lower porosity and pore size, and increased elastic and storage moduli. Graft bioactivity was determined by the mesenchymal stem cell (MSC) behaviors on the grafts and arterial regeneration in vivo using interposition grafting. Results showed that the cell adhesion and proliferation increased with the RGD density (25 vs 5 mM). After 1 week implantation, all peptide-functionalized PCL/PEG-NB grafts with or without MSC preseeding, as opposed to PCL grafts, showed expeditious endothelial lining, abundant vascular cell infiltration, and matrix production. Compared to RGD grafts, RGD/TGF-β1 grafts enhanced MSC differentiation into smooth muscle cells in vitro and developed thicker smooth muscle cell layers in vivo. Overall, the versatile porous vascular grafts offer superior properties and tunability for future translation.

Small-caliber vascular grafts are used in a wide range of clinical conditions. However, there remains a substantial unfulfilled need for readily-available, synthetic vascular grafts with high long-term patency rate. To fulfill the translational goal for bioengineered vascular grafts, important considerations for the pre-clinical evaluation include the graft design, cell incorporation and selection of an animal model. To assess the three factors, we used vascular grafts consisting of core/shell-structured microfibers of polycaprolactone/gelatin with a thin polycaprolactone overlay. The respective influences of the heparin release mode, animal age, and allogeneic bone marrow-derived stromal cells (MSCs) seeded in the lumen on the graft remodeling were assessed after four-and-half-month implantation on an interposition graft of abdominal aorta model. Except two rats dying from graft-unrelated issues, all other rats (18 out of 20) showed good graft patency upon explantation. The cell phenotype, matrix content and structure in the neotissues around the graft, as well as the flow perfusion through the graft were examined. More grafts in the aged rats showed local narrowing and flow incongruence than the other grafts in young adult rats. Compared to acellular grafts, cellular grafts showed efficient recruitment of vascular cells to form more organized structures with elastin in the vascular wall. Endothelialization and α-smooth muscle actin-positive cells were shown in all four types of vascular grafts. This study revealed the significant effects of MSC and recipient age but not heparin release pattern on graft remodeling. STATEMENT OF SIGNIFICANCE: The vascular graft is a mainstream of surgical intervention to treat vascular diseases. Currently, vascular grafts, particularly small-diameter ones, still show high failure rates. This study has evaluated the respective impacts of heparin release pattern, allogeneic bone marrow-derived stromal cell seeding, and recipient age on the long-term remodeling of vascular grafts. There is a dearth of literature which considers the recipient age as an influencing factor for vascular grafting. However, adults particularly elderly constitute the majority of vascular graft recipients in the "real" clinical environment. While juvenile animals were widely used for graft evaluations, this study involved adult animals. The study outcomes provided important implications regarding graft designs and evaluation approaches.

Tissue regeneration requires scaffolds that exhibit mechanical properties similar to the tissues to be replaced while allowing cell infiltration and extracellular matrix production. Ideally, the scaffolds' porous architecture and physico-chemical properties can be precisely defined to address regenerative needs. We thus developed techniques to produce hybrid fibers coaxially structured with a polycaprolactone core and a 4-arm, polyethylene glycol thiol-norbornene sheath. We assessed the respective effects of crosslink density and sheath polymer size on the scaffold architecture, physical and mechanical properties, as well as cell-scaffold interactions in vitro and in vivo. All scaffolds displayed high elasticity, swelling and strength, mimicking soft tissue properties. Importantly, the thiol-ene hydrogel sheath enabled tunable softness and peptide tethering for cellular activities. With increased photopolymerization, stiffening and reduced swelling of scaffolds were found due to intra- and inter-fiber crosslinking. More polymerized scaffolds also enhanced the cell-scaffold interaction in vitro and induced spontaneous, deep cell infiltration to produce collagen and elastin for tissue regeneration in vivo. The molecular weight of sheath polymer provides an additional mechanism to alter the physical properties and biological activities of scaffolds. Overall, these robust scaffolds with tunable elasticity and regenerative cues offered a versatile and effective platform for tissue regeneration.

The importance of matrix micromechanics is increasingly recognized in cardiovascular research due to the intimate role they play in local vascular cell physiology. However, variations in micromechanics among arterial layers (i.e. intima, media, adventitia), as well as dependency on local matrix composition and/or structure, anatomical location or developmental stage remain largely unknown. This study determined layer-specific stiffness in elastic arteries, including the main pulmonary artery, ascending aorta, and carotid artery using atomic force indentation. To compare stiffness with age and frozen processing techniques, neonatal and adult pulmonary arteries were tested, while fresh (vibratomed) and frozen (cryotomed) tissues were tested from the adult aorta. Results revealed that the mean compressive modulus varied among the intima, sub-luminal media, inner-middle media, and adventitia layers in the range of 1-10 kPa for adult arteries. Adult samples, when compared to neonatal pulmonary arteries, exhibited increased stiffness in all layers except adventitia. Compared to freshly isolated samples, frozen preparation yielded small stiffness increases in each layer to varied degrees, thus inaccurately representing physiological stiffness. To interpret micromechanics measurements, composition and structure analyses of structural matrix proteins were conducted with histology and multiphoton imaging modalities including second harmonic generation and two-photon fluorescence. Composition analysis of matrix protein area density demonstrated that decrease in the elastin-to-collagen and/or glycosaminoglycan-to-collagen ratios corresponded to stiffness increases in identical layers among different types of arteries. However, composition analysis was insufficient to interpret stiffness variations between layers which had dissimilar microstructure. Detailed microstructure analyses may contribute to more complete understanding of arterial micromechanics. (C) 2019 Elsevier Ltd. All rights reserved.