Optimizing the Porohyperelastic Response of a Layered Compliance Matched Vascular Graft to Promote Luminal Self-Cleaning.

Thrombosis and intimal hyperplasia have remained the major failure mechanisms of small-diameter vascular grafts used in bypass procedures. While most efforts to reduce thrombogenicity have used a biochemical surface modification approach, the use of local mechanical phenomena to aid in this goal has received somewhat less attention. In this work, the mechanical, fluid transport, and geometrical properties of a layered and porous vascular graft are optimized within a porohyperelastic finite element framework to maximize self-cleaning via luminal reversal fluid velocity (into the lumen). This is expected to repel platelets as well as inhibit the formation of and/or destabilize adsorbed protein layers thereby reducing thrombogenic potential. A particle swarm optimization algorithm was utilized to maximize luminal reversal fluid velocity while also compliance matching our graft to a target artery (rat aorta). The maximum achievable luminal reversal fluid velocity was approximately 246 µm/s without simultaneously optimizing for host compliance. Simultaneous optimization of reversal flow and compliance resulted in a luminal reversal fluid velocity of 59 µm/s. Results indicate that a thick highly permeable compressible inner layer and a thin low permeability incompressible outer layer promote intraluminal reversal fluid velocity. Future research is needed to determine the feasibility of fabricating such a layered and optimized graft and verify its ability to improve hemocompatibility.

Improving the hemocompatibility of a porohyperelastic layered vascular graft using luminal reversal microflows.

Vascular graft thrombosis is a long-standing clinical problem. A myriad of efforts have been devoted to reducing thrombus formation following bypass surgery. Researchers have primarily taken a chemical approach to engineer and modify surfaces, seeking to make them more suitable for blood contacting applications. Using mechanical forces and surface topology to prevent thrombus formation has recently gained more attention. In this study, we have designed a bilayered porous vascular graft capable of repelling platelets and destabilizing absorbed protein layers from the luminal surface. During systole, fluid penetrates through the graft wall and is subsequently ejected from the wall into the luminal space (Luminal Reversal Flow - LRF), pushing platelets away from the surface during diastole. In-vitro hemocompatibility tests were conducted to compare platelet deposition in high LRF grafts with low LRF grafts. Graft material properties were determined and utilized in a porohyperelastic (PHE) finite element model to computationally predict the LRF generation in each graft type. Hemocompatibility testing showed significantly lower platelet deposition values in high versus low LRF generating grafts (median±IQR = 5,708 ± 987 and 23,039 ± 3,310 platelets per mm2, respectively, p=0.032). SEM imaging of the luminal surface of both graft types confirmed the quantitative blood test results. The computational simulations of high and low LRF generating grafts resulted in LRF values of -10.06 µm/s and -2.87 µm/s, respectively. These analyses show that a 250% increase in LRF is associated with a 75.2% decrease in platelet deposition. PHE vascular grafts with high LRF have the potential to improve anti-thrombogenicity and reduce thrombus-related post-procedure complications. Additional research is required to overcome the limitations of current graft fabrication technologies that further enhance LRF generation.

Mechanical alterations of electrospun poly(ϵ-caprolactone) in response to convective thermobonding.

Vascular graft failure has persisted as a major clinical problem. Mechanical, structural, and transport properties of vascular grafts are critical factors that substantially affect their function and thus the outcome of implantation. The manufacturing method, post-processing technique, and material of choice have a significant impact on these properties. The goal of this work is to use thermal treatment to modulate the transport properties of PCL-based vascular engineered constructs. To this end, we electrospun PCL tubular constructs and thermally bonded the electrospun fibers in a convective oven at various temperatures (54, 57, and 60°C) and durations of treatment (15, 30, and 45 s). The effects of fiber thermal bonding (thermobonding) on the transport, mechanical, and structural properties of PCL tubular constructs were characterized. Increasing the temperature and treatment duration enhanced the degree of thermobonding by removing the interconnected void and fusing the fibers. Thermobonding at 57°C and 60°C for longer than 30 s increased the median tangential modulus (E = 126.1 MPa, [IQR = 20.7]), mean suture retention (F = 193.8 g, [SD = 18.5]), and degradation rate while it decreased the median permeability (kA  = 0 m/s), and median thickness (t = 60 µm, [IQR = 2.5]). In particular, the thermobonding at 57°C allowed a finer modulation of permeability via treatment duration. We believe that the thermobonding method can be utilized to modulate the properties of vascular engineered constructs which can be useful in designing functional vascular grafts.

In-vivo assessment of a tissue engineered vascular graft computationally optimized for target vessel compliance.

Tissue engineered vascular grafts (TEVGs) have the ability to be tuned to match a target vessel's compliance, diameter, wall thickness, and thereby prevent compliance mismatch. In this work, TEVG compliance was manipulated by computationally tuning its layered composition or by manipulating a crosslinking agent (genipin). In particular, these three acelluluar TEVGs were compared: a compliance matched graft (CMgel - high gelatin content); a hypocompliant PCL graft (HYPOpcl - high polycaprolactone content); and a hypocompliant genipin graft (HYPOgen - equivalent composition as CMgel but hypocompliant via increased genipin crosslinking). All constructs were implanted interpositionally into the abdominal aorta of 21 Sprague Dawley rats (n=7, males=11, females=10) for 28 days, imaged in-vivo using ultrasound, explanted, and assessed for remodeling using immunofluorescence and two photon excitation fluorescence imaging. Compliance matched grafts remained compliance-matched in-vivo compared to the hypocompliant grafts through 4 weeks (p<0.05). Construct degradation and cellular infiltration was increased in the CMgel and HYPOgen TEVGs. Contractile smooth muscle cell markers in the proximal anastomosis of the graft were increased in the CMgel group compared to the HYPOpcl (p=0.007) and HYPOgen grafts (p=0.04). Both hypocompliant grafts also had an increased pro-inflammatory response (increased ratio of CD163 to CD86 in the mid-axial location) compared to the CMgel group. Our results suggest that compliance matching using a computational optimization approach leads to the improved acute (28 day) remodeling of TEVGs. To the authors' knowledge, this is the first in-vivo rat study investigating TEVGs that have been computationally optimized for target vessel compliance.