Biomaterials with enhanced properties and devices made therefrom

Abstract

Biomaterials with enhanced properties such as improved strength, flexibility, durability and reduced thickness are useful in the fabrication of biomedical devices, particularly those subjected to continuous or non-continuous loads where repeated flexibility and long-term durability are required. These enhanced properties can be attributed to elevated levels of elastin, altered collagen types, and other biochemical changes which contribute to these enhanced properties. Examples of devices which would be improved by use of such tissue include heart valves, including percutaneous heart valves, and vascular grafts, patches and the like. Such enhanced materials can be sourced from specific populations of animals, such as neonatal calves, or in range-fed adult cattle, or can be fabricated or created from cell populations exhibiting such properties. In one embodiment, glutaraldehyde-fixed neonatal pericardial tissue is used to create leaflets in a percutaneous heart valve, and may be used without chemical fixation, with or without processes to remove residual cellular membranes, and utilized as a scaffold material for tissue engineering.

Description

[0001]This application claims the benefit of PCT application No. PCT / US2011 / 049027 filed Aug. 24, 2011, which claims the benefit of U.S. Provisional Application No. 61 / 376,627 filed Aug. 24, 2010, which applications are incorporated herein by reference.FIELD[0002]The subject matter described herein relates generally to new biomaterials with enhanced properties, such as improved strength, flexibility, durability and reduced thickness, where these enhanced properties enable the creation of new and improved medical devices, such as small-profile percutaneous heart valves, thin, flexible patches for repair, and tissue engineering scaffolds with enhanced elasticity and durability. These enhanced properties are due to compositional differences between the embodiments described herein and the prior art, including elevated elastin levels, altered collagen types, and other biochemical differences which contribute to enhanced strength, flexibility, durability and reduced thickness.BACKGROUND[...

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Benefits of technology

[0007]Embodiments provided herein are directed to new biomaterials with enhanced properties which will enable the development of new and improved medical devices. These properties of enhanced strength, durability, flexibility and reduced thickness are due, in part, to identification and selection of materials having an elevated elastin content. The biomaterials can be selected from natural sources of tissues, or can be constructed in the laboratory or in an animal model. The new biomaterials can be processed in a variety of ways to target selective needs of a particular device. In one embodiment, the biomaterial can be crosslinked with glutaraldehyde so that the tissue can be used as a leaflet material in a percutaneous bioprosthetic heart valve. Because of the tissue is ultrathin, it can enable the packing of the valve to be reduced compared to existing technologies, for example, to 16 French (16F), or 5.3 mm in diameter, or less to enable low profile insertion of prosthetic valves. In another embodiment it could be crosslinked with a carbodiimide and sterilized for use in soft tissue reconstruction, as a patch, strip, or wrap. In another embodiment, the tissue is isolated from the donar animal, decellularized and disinfected to be used as a tissue, graft, transplant, or engineering scaffold, where the greater strength and elasticity of the material enables tissue engineered devices to be made which experience a high degree of flexure or working stress, such as in a heart valve leaflet or as a vascular graft.

[0008]Embodiments provided herein are also directed to a method of fabricating the new biomaterials, including sourcing from animals of a particular age or species, such as, e.g., New Zealand calves. As these tissues are composed primarily of collagen, the degradation of collagen with time is the primary mode of failure. If tissue could be selectively enriched, or identified as naturally enriched, in components that enhance the mechanical performance of the device and thus delay structural deterioration, improved devices could be produced which exhibit enhanced durability. Elastin is one such component—tissues with higher elastin content would exhibit improved flexibility, greater elasticity, and longer durability. Devices fabricated from such tissues would be more resistant to fatigue-related failure by reducing the mechanical stress on the tissues during use, thereby reducing the degradation rate of the collagen in the tissues. Elastin is a very hydrophobic molecule and contains about 30% glycine, arranged randomly along its chain. This is in marked contrast to fibrillar collagens, which also contain 30% glycine, but have a very ordered repeat structure to the glycine placement—every third amino acid is glycine, which allows the collagen molecule to curl into a helix shape. Because the glycines in elastin are arranged randomly, elastin does not form helices, but is rather amorphous. It acts like a spring, stretching out when stress is applied to it, and recoiling to its original shape when the stress is released. Elastin molecules slide over each other in a way that reduces shear stress, a critical type of stress that greatly fatigues tissues which are subject to repeated flexure and loading. Therefore tissues with higher elastin content can better withstand shear stress.

[0010]Tissues high in elastin exhibit great dimensional stability and have the ability to store mechanical energy. This feature is believed to be very important in the cardiovascular system, for example, where the elastic arteries serve as elastic reservoirs, enabling the arterial system to undergo large volume changes with little change in pressure. The large elastic arteries are capable of storing a portion of the stroke volume with each systole and discharging that volume with diastole. This phenomenon, known as the windkessel effect, helps to decrease the load on the heart and to optimize blood flow in the smaller arteries. In a review of the development of the vascular system J E Wagenseil et al, Vascular extracellular matrix and arterial mechanics, Physiology Reviews, volume 89, pp 957-89, 2009, report that elastin synthesis is maximum by Day 14 in mice, declining sharply by Day 30, and maintaining almost no synthesis thereafter. Therefore, these selected tissues are procured from an identified source having the desirable parameters disclosed herein. The parameters can be verified either in individual animals, tissue portions, or animal population or species. The tissues are removed surgically, treated with processes designed to enhance their use in transplants, and typically cut into sizes to fascilitate their use as grafts or other structures e.g. heart valve leaflets. Tissues harvested shortly after birth should contain maximal amounts of elastin.

[0011]Altered collagen types would also result in tissues with enhanced durability and fatigue resistance. Reduced collagen crosslinking and other proteins are other components of tissue which would be desirable to use in creating bioprosthetic devices with improved properties. Because of the juvenile or fetal nature of the tissues used to create these devices, the devices themselves not only perform better, but also exhibit enhanced healing, reduced scar formation, and reduced fibrosis, compared to current devices. This is partially due to the reduced immunogenicity of the juvenile and fetal tissues, thereby resulting in improved healing after implantation of the device.

[0012]Because juvenile and fetal tissues are less crosslinked compared to adult tissues, processing of these juvenile and fetal tissues can allow enhanced stabilization of the resulting constructs, as more crosslinking sites will be available for the stabilization chemistry in juvenile and fetal tissues compared to adult tissues. Processing conditions can also be more mild and gentle when preparing juvenile and fetal tissue compared to adult tissues, because of this reduced crosslinking.

[0013]For example, harsh chemical conditions and mechanical and sometimes enzymatic degradation are required to process adult cow skin or tendons into a collagen slurry, which can then be processed into a variety of coatings, sheets, devices and so forth. Processing juvenile or fetal skin or tendon, which is less crosslinked compared to adult skin or tendon, and has a less mature composition of collagens, can be done using less stringent conditions. Processing under less stringent conditions can create materials with reduced degradation, higher molecular weight, and in general enhanced properties compared to adult tissues. In some cases, more mild processing conditions may enable certain compounds to be generated that could not be created or isolated from adult tissues. Enzymes, growth factors, very high molecular weight proteoglycans, and other biomolecules are some of the compounds which would be degraded, inactivated, or completely destroyed by the more aggressive conditions required to process adult tissues. In one embodiment of the invention, the animals may be juvenile bovines, under 12 months of age. Even fetal tissues may be used, provided the tissues meet the criteria of strength, flexibility and are ultrathin. In another embodiment, adult animals may be used as the source of the tissue, but in order to provide the desired characteristics of strength and flexibility, these animals are free-range fed, rather than fed in a stationary hold pen such as a feed lot. Feed lot bovines are typically used as a source material for bovine pericardium today. In another embodiment, animals may be specifically bred or genetically controlled to provide tissues with greater flexibility and reduced thickness compared to current source animals. Even cells from such animals which are capable of producing these new materials may be utilized to create materials with enhanced properties through the application of cell and organ culturing techniques.

Problems solved by technology

As these tissues are composed primarily of collagen, the degradation of collagen with time is the primary mode of failure.

The authors summarize that mechanical stresses initiate calcification by damaging the structural integrity of the leaflet tissue.

While the industry has focused on modification of designs as a means to reduce stresses on the tissue, and chemical treatments to inhibit calcification, no one has examined the possibility of reducing functional stresses through special selection of tissue properties and combinations throughout.

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