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Monthly Spin-Off #7 [A Graft that Could Revolutionize Hemodialysis Access]

Targeted Drug Delivery to Prevent Outflow Complications From Hemodialysis Access Grafts


Background

End-stage renal disease (ESRD) is a serious and chronic medical condition characterized by the permanent loss of kidney function, and may sometimes go undetected until it has progressed into advances stages. ESRD affects more than 4 million patients worldwide and nearly 0.8 million people in the US need life-sustaining dialysis or kidney transplant (1) and is a significant public health concern.


ESRD is associated with significant morbidity and mortality, with patients requiring ongoing dialysis or kidney transplantation to maintain their health and quality of life. Over 2 million patients worldwide (and 554,000 in US alone) have received hemodialysis treatment, about 15-30% of which require early access (1). The current gold standard for permanent hemodialysis access are autogenous vein fistulas (AVF) which have significant issues like they require several weeks to months to mature before they can be used for hemodialysis and often exhibit low primary patency rates after 2 years of implantation (3). Additionally, most patients do not have available vasculature due to co-morbidity, obesity, prior harvesting for a surgery, or the need to save the vessel for a different surgical procedure. When patients do not have a healthy vasculature, a synthetic (polymers not made in nature) arteriovenous graft (AVG) is considered for access.

A majority of current synthetic AVGs are made from either expanded polytetrafluoroethylene (ePTFE) (Gore-Tex

Stretch® and Acuseal®), or layers of polyurethane (PU) and silicone (Vectra® by Bard Inc.). While AVGs are effective in providing reliable access for hemodialysis, there are some potential problems associated with their use including a higher risk of infection, thrombosis, and stenosis (narrowing) at the at the distal anastomosis, which can lead to decreased blood flow and is the primary cause of AVG failure (4, 5).


Localized drug delivery directly from the AVG is an ideal strategy for addressing complications such as infection, thrombosis, and outflow stenosis (the target of this application). However, there are no current AVG products in the market where a biologically active agent is spatially incorporated with nanofibers for targeted drug delivery that have been approved for use in patients.


NuSpun™ Vascular Graft – A Synthetic Access Graft Designed to Resemble Natural Tissue Scaffold

BioSurfaces has successfully applied electrospinning technology for the development of a synthetic nanofibrous vascular graft that can be used for hemodialysis access as well as for bypassing blood vessels in the leg (peripheral bypass), which is referred to as the NuSpun™ Vascular Graft. The NuSpun™ Vascular Graft has an internal diameter

of 6 mm and is made of a blend of polymers through electrospinning technology (Figure 1). The NuSpun™ Vascular Graft provides a suitable microarchitecture for cell attachment and eventual cell migration into the matrix, and the adequate initial stiffness and structural stability required for tissue growth and remodeling (Figure 2).


NuSpun™ Vascular Grafts were implanted in a preclinical vascular model for 90 and 180 days. These studies showed that the NuSpun™ Vascular Grafts had 100% patency at 90 and 180 days. In contrast, ePTFE grafts had a patency rate of 100% at 90 days and 83% at 180 days. Histologic assessment of the distal anastomosis of ePTFE and NuSpun™ grafts after implantation for 180 days revealed that the NuSpun™ graft had slightly less hyperplasia than the ePTFE graft while possessing excellent tissue ingrowth throughout the wall of the graft with minimal capsule formation (Figure 3). However, outflow narrowing due to SMC proliferation was not completely prevented.


Ability to Provide Targeted Drug Delivery to Prevent Potential Outflow Complications

One hypothesis is to deliver a target drug to improve graft patency is to accelerate early reendothelialization while simultaneously suppressing the excessive proliferation of SMCs. The company is developing a drug-eluting AVG (NuSpun™-DE) for hemodialysis access to target narrowing of the graft due to overgrowth of smooth muscle cells (SMCs). Incorporating drugs such as Sirolimus, a drug being used in FDA-approved devices and is known to prevent SMC proliferation and migration without being cytotoxic (6), into the NuSpun™ graft results in an elastomeric and kink-resistant graft that is soft and has handling properties similar to knitted PET grafts.


In Figure 4, the in vitro release profiles of the NuSpun™ grafts with various Sirolimus concentrations show a slow sustained release of Sirolimus from all concentrations was observed for 15 days for all drug-loaded NuSpun™ samples. Figure 5 shows the presence of Sirolimus in the graft was found to inhibit the SMC growth. These findings suggested the long-term effectiveness of localized Sirolimus release for inhibiting SMC proliferation.


Future Development for NuSpun™-DE Vascular Graft


The NuSpun™-DE Vascular Graft is being developed to provide earlier access for hemodialysis than other AVG options with excellent long-term patency. Inclusion of anti-proliferative agents at the outflow anastomosis and antimicrobial agents in combination with the self-sealing properties of the electrospun polymers will work together in a synergistic manner, resulting in a hemodialysis access graft that will be accessible early, have greater patency rates than current vascular grafts, and prevent graft infection caused by repeated access. By providing immediate access, reducing hyperplasia, decreasing infection rates, and increasing primary patency rates, the NuSpun™-DE vascular graft could become the new standard of care for hemodialysis access, surpassing the current clinical standard grafts.


Written By:

Jayashree Chakravarty, Ph.D.

Senior Research Associate


References:

1. U.S. Renal Data System 2022 Annual Data Report, https://usrds-adr.niddk.nih.gov/2022

2. Lok CE, Huber TS, Lee T, Shenoy S, Yevzlin AS, Abreo K, Allon M, Asif A, Astor BC, Glickman MH, Graham J, Moist LM, Rajan DK, Roberts C, Vachharajani TJ, Valentini RP; National Kidney Foundation. KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update. Am J Kidney Dis. 2021. 77 (4):551. doi: 10.1053/j.ajkd.2019.12.001.

3. Arasu R, Jegatheesan D, Sivakumaran Y. Overview of hemodialysis access and assessment. Can Fam Physician. 2022. 68 (8):577-582. doi: 10.46747/cfp.6808577.

4. Akoh JA. Prosthetic arteriovenous grafts for hemodialysis. J Vasc Access. 2009. 10 (3):137-47. doi: 10.1177/112972980901000301.

5. MacRae JM, Dipchand C, Oliver M, Moist L, Lok C, Clark E, Hiremath S, Kappel J, Kiaii M, Luscombe R, Miller LM; Canadian Society of Nephrology Vascular Access Work Group. Arteriovenous Access Failure, Stenosis, and Thrombosis. Can J Kidney Health Dis. 2016. 27(3):2054358116669126. doi:10.1177/2054358116669126.

6. Marx SO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP Inhibits Cell Cycle Regulators of Proliferation in Vascular Smooth Muscle Cells. Circ Res. 1995. 76: 412–417. doi.org/10.1161/01.RES.76.3.412

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