*7.1. TEVGs That Have Reached Clinical Trials*

After analyzing the current trends in TEVGs, five clinical trials were identified regarding TEGVs for human use in different contexts. The main mechanical properties of each vascular graft compared to GSV and IMA grafts are summarized in Table S1. The mean values of the mechanical properties of the TEVGs on clinical trial are summarized and compared in Table 4 and Figure 6.

The most recent TEVG that has entered to clinical trial phase is a Polyhedral oligomeric silsesquioxane poly (carbonate-urea) urethane (POSS-PCU) small-diameter vascular graft, fabricated through extrusion and phase inversion method using sodium bicarbonate as a porogen. This TEVG is currently being tested as arteriovenous fistulas for hemodialysis; the study began in 2021 and is expected to reach completion in April of 2025. This TEVG has a small diameter (<5 mm) with a mean wall thickness of 0.94 mm that is placed in adult female patients undergoing hemodialysis and in need of new arteriovenous access but without any viable access for dialysis. This study has an inclusion criteria of patients on oral contraceptives or with an intrauterine device, aiming to demonstrate patency in patients with increased risk of thrombosis. It is expected to measure patency rates at 18 months by Doppler ultrasonography (d-US) and compare it to the patency of the PTFE grafts. They also will measure the occurrence of any Serious Adverse Event (SAE) related to the implantation of the POSS-PCU TEVG. For the initial characterization of the POSS-PCU vascular graft, they used Delfino's strain energy potential to capture the viscoelastic properties of the materials. Later, they conducted different experimental and computational experiments to show shear stress within the graft wall in the context of increased uniaxial strength. They concluded that besides the overall resistance of the graft, the stiffness and long-term viscoelastic properties could be improved with better manufacturing techniques; detailed mechanical properties of this TEVG can be found in the Supplementary Data [60]. The POSS-PCU TEVG offers similar longitudinal tensile strength compared to GSV and IMA grafts (3210 vs. 2405 and 4300 KPa), however, its suture resistance strength is markedly higher (4460 vs. 3200 and 1350 KPa, respectively). Furthermore, it presents reduced dynamic compliance compared to the allografts (1.59 vs. 4.4 and 5.22%/100 mmHg respectively) may explain its increased stiffness and poor vascular physiology resemblance (Figure 6).

A Human Acellular Vessel (HAV) from Humacyte is a graft also developed for patients with need of hemodialysis access but who are not candidates for a fistula. This TEVG is created in vitro through the culture of human smooth muscle cells and fibroblast cultured over a biodegradable polymer. Further decellularization process creates a structure that retains the extracellular matrix protein and provides corresponding mechanical properties. Animal models were performed in baboons as arteriovenous grafts with 80% patency at six months. This vascular graft has been included in different clinical trials. One of the most relevant, made in 2016 as a phase 2 trial in 40 elected patients, demonstrated primary patency rates of 63% (95% CI 47–72) at six months and 28% (95% CI 17–40) at 12 months. Conversely, secondary assisted patency rates at six and 12 months were 97% (95% CI 85–98) and 89% (95% CI 74–93), respectively. Secondary patency rates in extensive multicenter cohort studies with PTFE were 55–66% at one year, making HAV a suitable option. In the group of patients, they also measured serious adverse events (SAEs) that occurred 155 times in 33 patients, leading to increased reintervention rates. SAEs mainly included patency loss, infection, and one case of steal syndrome. HAV provides an exciting conclusion, as they have better secondary patency rates than PTFE-based VGs, leading to a well-tolerated TEVG with no signs of aneurysm formation or degradation with low immunogenicity. For which it has been included in different clinical trials from 2015 to 2020. Researchers found that Artegraft®has primary, primary-assisted, and secondary patency rates of immunogenicity. However, HAV has the lower reported tensile strengths (circumferential and longitudinal) along all TEVGs in clinical trial phases (1400 and 1200 KPa) and low dynamic compliance compared to human allografts (1.5 vs. 4.4 and 5.22%/100 mmHg), leading to increased stiffness and a poor vascular physiology resemblance; complete data can be found in the Supplementary Material.

Likewise, the TRUE vascular graft is also a decellularized arteriovenous TEVG designed by neonatal human dermal fibroblasts seeded in a bovine fibrin gel. A baboon pre-clinical model was performed on 10 subjects to determine its safety in terms of occurrence of adverse events and to find patency rates. They found patency rates at 3 and 6 months of 83% (5 of 6) and 60% (3 of 5), respectively, with evidence of recellularization of smooth muscle cells and endothelium formation. This TEVG is currently being tested as an arteriovenous graft for hemodialysis access on 10 participants beginning in May of 2021 and it is expected to finish in June of 2022. The mechanical properties of this kind of graft can be seen in the Supplementary Data. However, circumferential tensile strength and suture resistance strength were like the IMA (3800 and 1950 vs. 4100 and 1350 KPa, respectively), making it a newly suitable option for further study.

Another kind of TEVG for hemodialysis accesses is Artegraft®, a decellularized bovine carotid artery used for arteriovenous fistula generation. These TEVG have been included in different clinical trials from 2015 to 2020. Researchers found that Artegraft® has primary, primary-assisted, and secondary patency rates of 73.3%, 67%, and 89%, respectively. SAE was present in one immunocompromised patient that presented a resistant infection, leading to the early removal of Artegaft® at two months. A relevant finding is that anastomotic venous stenosis occurred in some grafts and was the most common indication of graft removal. Artegraft® demonstrated similar tensile strength properties compared to PTFE VGs. However, its low dynamic compliance [1,5] can explain the occurrence of stenotic venous anastomosis in most grafts (Figure 6).

BioIntegral Surgical No-React ® are bovine pericardial xenografts used as a strategy for vascular graft infections due to their regenerative properties; these series of clinical trials began in 2019. A prospective study of six patients with infected aortoiliac segments treated with BioIntegral Surgical No-React ® demonstrated that four out of the six patients are still alive with complete patency demonstrated by d-US. Unfortunately, two died from acute myocardial infarction, and the other due to sepsis secondary to the vascular infection. Although this graft has a remarkably increased longitudinal tensile strength compared to GSVs and IMA (10,000 vs. 2405 and 4300 KPa), it conferred to most patients (4 out of 6) a proper control of the infection with reasonable long-term patency rates.

According to the reported data, a mean value was extracted from the mechanical properties of the current vascular grafts undergoing on clinical trials and were compared to the mechanical properties of the GSV, as shown in Table 4 and Figure 6; individual data are shown on a bar graph in Figure 6. out of 6) a proper control of the infection with reasonable long-term patency rates. According to the reported data, a mean value was extracted from the mechanical properties of the current vascular grafts undergoing on clinical trials and were compared to the mechanical properties of the GSV, as shown in Table 4 and Figure 6; individual data are shown on a bar graph in Figure 6.

treated with BioIntegral Surgical No-React ® demonstrated that four out of the six patients are still alive with complete patency demonstrated by d-US. Unfortunately, two died from acute myocardial infarction, and the other due to sepsis secondary to the vascular infection. Although this graft has a remarkably increased longitudinal tensile strength compared to GSVs and IMA (10,000 vs. 2405 and 4300 KPa), it conferred to most patients (4

**Table 4.** Mechanical properties in blood vessels: grafts in clinical trials (CT grafts) and great saphenous vein (GSV). **Table 4.** Mechanical properties in blood vessels: grafts in clinical trials (CT grafts) and great saphenous vein (GSV).


*Polymers* **2022**, *14*, x FOR PEER REVIEW 16 of 34
