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NOVATO, CA, United States

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 214.91K | Year: 2010

DESCRIPTION (provided by applicant): Abdominal aorta aneurysms (AAA) are diagnosed in more than 100,000 patients in the U.S. each year. About 70% of these patients require surgical intervention to prevent aneurysm progression. Nearly 20 years ago, Parodi revolutionized AAA treatment and repair by using an ePTFE stent graft that could be delivered via an endovascular approach. Today, more than 35,000 AAA stent grafts are placed annually, making AAA repair devices a 700 million industry in the U.S. alone. Despite the rapid adoption of endovascular repair, the devices are associated with a significant failure rate (more than 20% at one year). The majority of these failures are caused by leakage around or through the device. This type of endoleakage is caused by relative motion between the stent graft device and the native aorta. This relative motion is aggravated by the fact that the stent grafts are static devices that cannot remodel as the native aorta moves and remodels dynamically. Moreover, most stent grafts are wrapped in ePTFE (Teflon), which works well as a blood contacting surface, but does not adhere well to the surrounding tissue. We hypothesized that by replacing the ePTFE covering on a stent graft with a biological sheet, we might improve upon the fixation of the device into the native aorta. That is, by providing a natural collagen substrate which would support cell ingrowth and tissue adhesion, we would increase the bonding strength between the device and the native aorta. We termed this approach biological neck fixation. The objective of this Phase I grant is to demonstrate the initial feasibility of biological neck fixation such that we can more appropriately justify expanded efficacy studies in Phase II. Specifically, in Phase I, we will: develop a sheet built from canine cells that closely matches the mechanical properties of human sheets that we have developed previously (Specific Aim 1); implant the biological stent graft via a 10 French catheter in a canine model to evaluate durability, morphology, and histological properties (Specific Aim 2.1); and compare the adhesion and anchoring properties of biological stent grafts relative to the standard of care in a canine model (Specific Aim 2.2). Exclusion of the AAA without signs of migration or endoleakage at 3 months post-implant, and equal or greater anchoring strength relative to ePTFE stent grafts will be the key milestones to justify advancing to Phase II. The long-term objective of this project will be to commercialize a completely biological stent graft that can remodel with the host aorta, thereby reducing the overall failure rate relative to the current standard of care. PUBLIC HEALTH RELEVANCE: Abdominal aorta aneurysms (AAA) are diagnosed in more than 100,000 patients in the U.S. each year, and are the 13th leading cause of death. Today, more than 35,000 AAA endovascular stent grafts are placed annually, making AAA repair devices a 700 million industry in the U.S. alone. This Research Proposal describes a new repair device which may significantly reduce the relatively high failure rates associated with the standard of care in AAA repair.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.47M | Year: 2011

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in industrialized nations. While interventional techniques such as angioplasty and/or stenting can often delay the need for coronary arterial bypass surgery (CABG),long-term efficacy still favors revascularization. Still today, 450,000 coronary bypasses are performed annually in the U.S. alone. Moreover, the number of revascularization procedures for peripheral arterial disease or hemodialysis access is increasingdramatically. Today, 400,000 hemodialysis patients in the U.S. need a patent vascular graft to survive. Creation and maintenance of hemodialysis access grafts takes up nearly 2% of Medicare's entire budget. In addition, population aging and increasing incidence of diabetes and obesity indicate that this is a major public health concern. A patient's own blood vessels clearly remain the best conduits for both coronary and peripheral bypass, as well as for hemodialysis access. Unfortunately, native veinor artery may not be available due to previous harvest or systemic disease progression. Indeed, the primary limitation to arterial revascularization is the availability of suitable native graft material. While synthetic blood vessels made from materialssuch as Dacron or expanded polytetraflouroethylene (ePTFE) perform well in large diameter applications, these synthetic conduits show unacceptably high failure rates in small diameter applications. We have recently reported excellent clinical trials results with a completely biological human vascular graft built in vitro using a self-assembly approach termed Sheet-Based Tissue Engineering (SBTE). However, a significant drawback of this self-assembly approach is the long production time. Here, we propose the development of a novel assembly strategy, called Thread-Based Tissue Engineering (TBTE). This novel approach offers the same advantages of a completely biological human product but will dramatically reduce the production time and cost. Combined with an allogeneic and/or devitalization approach, TBTE could finally make completely biological human vascular grafts available off-the-shelf and commercially much more competitive. In Phase I of this project, we demonstrated our ability to createthreads of various strengths and sizes from both clinically relevant human cells and from canine cells. These threads were then woven into tubes on a custom circular loom to create human and canine vascular grafts. These grafts displayed promising mechanical properties in vitro. Phase I culminated in a short-term in vivo study that demonstrated the very promising clinical potential of human and canine grafts. These results met and exceeded all milestones set forth in the Phase I proposal. In SpecificAim 1 of Phase II, we will finalize the graft design based on promising data obtained in Phase I. These efforts will lead to six designs that will be tested in vivo in Specific Aim 2. Groups of four canines will receive H7 cm x 4.2 mm unendothelialized,devitalized grafts as arteriovenous shunts (femoral-to-femoral). The six designs will be: 1) Autologous, 2) Allogeneic, 3) Allogeneic decellularized, 4) Allogeneic gamma- sterilized, 5) Allogeneic seeded with autologous bone marrow in the operating room,6) Allogeneic, punctured 3 times weekly with a 16Ga hemodialysis needle after a 3 month post-implantation maturation period. These groups cover the following cost-effectiveness range: 1lt lt 5lt lt 3lt 2lt 4. By comparing the performance of these groups, we can determine which design offers the best combination of efficacy and cost. Group 6 will give a first glimpse at the potential of this new type of graft to serve as a hemodialysis access graft. Finally, In Specific Aim 3, we will explore importantparameters for the long-term commercialization of these grafts. We will study the use of serum-free medium to produce threads, which would improve reproducibility, reduce cost and simplify regulatory acceptance of the grafts (compared to bovine serum-containing medium). We will also study the use of molecular crowding additives to the culture medium. These large molecules have the potential to double or triple collagen assembly and hence, reduce production time and cost. Finally, we will determine if we can seed an endothelium on the woven grafts. While endothelium is not critical in high-flow applications like hemodialysis access grafts, it will be for other important markets/indications like coronary or lower limb bypass. However, establishing anautologous endothelium (allogeneic endothelium are highly immunogenic) introduces significant additional costs. As a cost-effective alternative, we will explore the possibility of replacing it by a new type of heparin coating. This Phase II project will provide: 1) the most cost-effective yet efficacious graft design; 2) initial in vivo efficacy data to justify a more extensive in vivo study to support and IND-submission; 3) additional data to further improve the grafts commercial and regulatory prospects. PUBLIC HEALTH RELEVANCE: Over the last 10 years we have developed a completely biological tissue engineered vascular graft comprised exclusively of human cells, without the need for exogenous biomaterials or synthetic scaffolds. While initialclinical use of this engineered graft represented a landmark achievement in the field, the manufacturing process is time consuming and expensive and thus, we have developed and performed initial optimization work on a much faster manufacturing process,termed Thread-based Tissue Engineering (TBTE), in which cell- synthesized, biological threads are woven into robust tissues. In this grant, we propose to expand our initial work into developing a clinically relevant graft, investigate the in vivo performance of the grafts in a canine model, and research key parameters to facilitate the transition to commercialization.

Cytograft Tissue Engineering, Inc. | Date: 2010-03-17

The invention includes methods and apparatus to deploy a blood vessel conduit via a catheter-based, percutaneous approach. In particular, a prosthetic blood conduit can be introduced around or through an arterial obstruction without requiring open bypass surgery. The technology includes coupling devices for docking the tips of two catheters, one situated inside a blood vessel, the other situated outside the blood vessel wall.

Cytograft Tissue Engineering, Inc. | Date: 2013-03-25

A single-layer tissue sheet having a puncture strength of 2 kgf to 6 kgf. A valve, such as a heart valve, made of one or more leaflets formed from a single-layer tissue sheet. A method of making a tissue sheet having a puncture strength of 2 kgf to 5 kgf. The ultra-strong tissue sheets described herein have very long culture times, such as in excess of 20 weeks. Valves that comprise one or more leaflets made from the ultra-strong tissue sheets described herein may be delivered via trans-cathete aortic valve implantation.

Cytograft Tissue Engineering, Inc. | Date: 2012-04-23

The present technology provides for a cell-synthesized biological particle, the processes for making a cell-synthesized particle, and a process for assembling such cell-synthesized particles into tissues and organs. The particles are synthesized in culture in vitro by living cells that produce natural extracellular matrix. Multiple particles can be assembled into tissues that have significant void space. The particles or tissues can act as a substrate for additional cell types. The particles or tissues can be further cultured in vitro to achieve favorable cell or extracellular matrix growth, organization or other desired characteristics. The particles or tissues can be devitalized or decellularized. The particles or tissues can be injected or implanted in a human to repair, enhance, or create a secretory, mechanical, or aesthetic function.

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