Invented by Julio C. Palmaz, Vactronix Scientific LLC
The Vactronix Scientific LLC invention works as followsAn implantable medical device with enhanced endothelial mobility features generally consists of: A structural member comprising a leading edge, a trailing edges, and a third region interconnected by a third region. The leading edge includes a second region in a generally curvelinear cross section, while the trailing edge includes a fourth region in a generally curvilinear, where blood flow over the second region generates shear stress at that second region. There is no eddy area in the second region.
Background for Implantable medical devices with enhanced endothelial mobility features and methods for making them
The invention concerns implantable medical device and more specifically the control of surface properties of implantable biocompatible material suitable for fabrication of implantable devices.
Implantable medical device are made of sub-optimal materials in terms of the biological response that they elicit in vivo. Many conventional materials used to fabricate implantable devices, such as titanium, polytetrafluoroethylene, silicone, carbon fiber and polyester, are used because of their strength and physiologically inert characteristics. Tissue integration onto these materials can be slow and inefficient. Some materials, like silicone and polyester, can trigger an inflammatory foreign body response which drives fibrous encapsulation. Implants may be affected by fibrous encapsulation. Conventional biomaterials have not been able to produce the necessary healing response for device integration. Devices that touch blood such as stents or vascular grafts may be more thrombogenic if they are modified to encourage endothelial cell adhesion.
The implanted devices can be exposed to smooth muscle cell proliferation and thrombus formation. Metals have a superior biocompatibility when implanted in the body to polymers used to manufacture commercially available polymeric-grafts.
In examining cell interactions with prosthetic material surfaces, we found that cell adhesion is controlled by integrins on cell membranes that interact the prosthetic surface. Integrins make up the majority of an extracellular matrix (ECM), adhesion receptor class. Integrins, a large group of heterodimeric transmembrane protein with different?, are part of a large family. Integrins are a large family of heterodimeric transmembrane proteins with different???? and? subunits. There are many levels of regulation for integralins. Modulation of adhesion receptor affinity for ligand is known as affinity modulation. It is thought to be a mechanism that activates platelet aggregation. Adhesive strengthening by clustering of adhesion receptors or by cytoskeletal-dependent processes such as cell spreading has been shown to be crucial for strong cellular attachment, control of cell growth and cell motility. Leukocytes roll along the vessel’s surface under high shear forces due to flowing blood. The leukocytes will then move across the endothelium if a signal is sent to them, such as a cytokine or a cytokine. The activation of leukocyte Integrins is responsible for adhesion tightening, rolling, arrest, tethering and rolling.
Cell spreading and migration can be associated with adhesion junctions. Cell migration entails the coordination of cytoskeletal-mediated process extension, i.e., filopodia and lamellopodia, formation of adhesive contacts at the leading edge of a cell, breaking adhesive contacts, and cytoskeletal retraction at the trailing edge of the cell. Focal adhesions include integrins, which are the major adhesion receptors, and associated cytoplasmic plate proteins. Extracellular ligand binding events as well as intracellular signaling events control the assembly of focal adhesions. Ligand binding is responsible for the localization of integrins containing?1 and?3 into focal adhesions. The cytoplasmic domains are of the? The cytoplasmic domains of the???? subunits contain intrinsic signals for focal adhesion locationization. However, incorporation by focal adhesions of the integrins is prevented from the???? subunits. The heterodimers’ subunits. Ligand binding relieves this inhibition, and allows the subunits of the heterodimers to send signals from the cytoplasmic tail to recruit the integrin dimer into the focal adhesion.
It has been attempted to coat implanted metal devices such as stents with proteins that contain the Arg?Gly-Asp attachment site. RGD sequence is the cell attach site for a number of adhesive extracellular matrix, cell blood and cell surface proteins. Many of the known Integrins recognize this sequence in their adhesion ligands. Synthetic peptides that contain the RGD sequence may be able to reproduce the integrin-binding ability. However, implanted metal bare materials will not have native RGD attachment points. Metal implantable devices such as stents have been made with polymers that have RGD attachment sites attached to the polymer matrix.
It has been shown that prosthetic materials interact with integrin receptors when implanted. Cells react to contact with extracellular matrix such as prosthetic surfaces by extending filopodia. Integrins at the tips of filopodia bind to extracellular matrix to initiate formation of focal adhesions. As the cell spreads onto the extracellular matrix, lamellipodia rich in actin are often formed. Focal adhesions with actin stress fibers are fully developed. Cell migration is a time when cells form focal adhesions and associated actin stress fibers. Giancotti, F. G., et al. Science, 285:13 Aug. 1999, 1028-1032.
In vivo, the integrin receptors can only recognize certain ligands. Integrin-ligand docking may be used to determine if a particular protein is adsorbed onto a prosthetic surface. Also, it has been shown that proteins can bind to metals more permanently than polymers and provide a stable adhesive surface. Conformation of proteins to most medical metals or alloys surfaces appears to expose more ligands and attract endothelial cell with surface integrin clusters. This is preferentially than leukocytes.
Metals can be susceptible to platelet activity and/or blood clotting due to their higher adhesive surface profiles. You can offset these deleterious characteristics by routine administration of pharmacologically activated antithrombogenic drugs. The majority of surface thrombogenicity disappears within 1-3 weeks following initial exposure. For coronary stenting, this time period is used to provide antithrombotic coverage. Because of the same molecular considerations, metals are more compatible with tissue than polymers in non-vascular applications like musculoskeletal or dental. Van der Giessen, W. J. et. al. is the best article to show that polymers are inferior than metals. Inflammatory sequelae in porcine coronary arches following implantation of non-biodegradable and biodegradable polymers, Circulation 1996: 94(7), 1690-7.
Endothelial cells (EC), migrate and proliferate to cover the denuded area until confluence occurs. Exposure to blood flow can affect migration, which is more important than proliferation. EC can migrate at speeds of about 10 m/hr to 15 m/hr under static conditions. J. C. Palmaz, S. Bailey, D. Marton, and E. Sprague. Effect of stent design on procedure outcome J. Vasc. Surg. 2002; 36:1031-1039. Restenosis can also be caused by vessel injury due pressure from stent contraction and neointimal thickening (WSS) due to vessel wall shear stress decrease.
EC migrate through a rolling motion in the cell membrane coordinated by a complex system intracellular filaments attached clusters of cell membrane integrin receivers, specifically focal contacts points. Complex signaling mechanisms allow the expression of integrins at focal contact sites. These integrins eventually link to specific amino acids in substrate adhesion molecules. An EC’s cell surface is roughly 16-22% represented by integrin clusters. Davies, P. F. Robotewskyi A. Griem M.L. Endothelial cell adhesion is real-time. J. Clin. Invest. 1993; 91.2640-2652. Davies, P. F. and Robotewski A., Griem M. L. Qualitiative Studies of Endothelial Cell Adhesion, J. Clin. Invest. 1994; 93:2031-2038. This dynamic process involves more than half of the remodeling done in less than 30 minutes.
Although focal adhesion contacts can vary in size and distribution, 80% of them are less than 6?m2. The majority of them are about 1?m2 in area. They tend to be more elongated in the direction flow and concentrated at the cell’s leading edges. Although it is still not clear how attachment receptors recognize attachment sites and respond to them, attachment can be a positive factor in attachment and migration. Materials commonly used in medical grafts such as polymers don’t become covered with EC, so they do not heal once they are placed into the arteries. Vacuum deposited materials are ideal for controlling heterogeneities in materials that come into contact with blood flow.
There have been many attempts to increase the endothelialization implanted medical devices like stents. This includes covering them with a polymeric material (U.S. Patent. No. No. 5.897,911), which imparts a diamond-like carbon coating to the stent. (U.S. Patent. No. No. No. No. No. No. No. No. 5.387,247), covering the tissue-contacting surface a stent’s with a thin layer a Group V metal (U.S. Patent. No. No. No. 5,690,670), coating the stent, under ultrasonic conditions, with a synthetic or biological, active or inactive agent, such as heparin, endothelium derived growth factor, vascular growth factors, silicone, polyurethane, or polytetrafluoroethylene (U.S. Pat. No. No. No. No. No. 5,932,299). All these methods do not address the issue of polymer grafts failing to endothelialize.
The rate at which endothelial cells reach confluence on the blood contact surface of an implanted medical device is determined mainly by two factors: the rate of cell migration and the rate of proliferation. The latter being the most important. Three interrelated steps make up the rate of cell movement. Initialy, cells form lamellipodia and fibrodia that protrude from the outside. This involves the reassembly and reorganization of actins at the front of lambaepolia. The focal adhesion point is formed when the front end of the lamellipodia protrudes from the cell membrane at one or more points. This interaction between integrin on cell membrane and extracellular matrix binding sites will result in a tight attachment to the substratum. Myosin II is responsible for the contraction of myosin’s posterior end. This is the final step in cell movement. Because the protruding lamellipodia may otherwise collapse, it is crucial that a focal adhesion points be formed in order to facilitate cell movement. The cell stops moving if it lacks the tension force of the focal adhesion points.
The substratum must have attachment sites. This is important not only for focal adhesion point formation but also for propagation. Science 276:1425-1428 1997. It has been proven that cells that are forced to spread are more resilient and proliferate quicker than those that have the same surface area. This could explain why neighboring cells can stimulate a cell’s proliferation after it has been removed from the epithelium.
The cells that produce extracellular matrix (ECM), are responsible for much of its formation. Cells secrete molecules which make ECM. The structure and distribution of attachment sites on ECM for integrin binding determines the formation of focal adhesion points, which is the crucial step in cell movement. The speed of reendothelialization is greatly affected by the distribution of integrin binding site on an implanted medical device’s surface.
There is still a need to create a medical device that stimulates the endothelial movement and proliferation when implanted, in order for it to form an endothelial membrane over the medical device.” A method for fabricating such medical devices is also needed.
In one embodiment, an implantable device medical device with enhanced endothelial migrating features comprises: A structural member comprising a leading edge, a trailing edges, and a third region. The leading edge includes a second region in a generally curvilinear section, while the trailing edge includes a fourth region in a generally curvelinear section. Blood flow over the second region generates shear stress in the second region without creating an eddy area in the second region.
Another embodiment of the implantable biocompatible materials includes a number of functionally-oriented features. One embodiment of the implantable biocompatible materials includes a plurality grooves that are positioned on at least one edge of the structural member, including the leading edge and trailing edges.
A further embodiment of a method for forming an implantable medical devices with enhanced endothelial migrating features includes: Forming a structural member that includes a leading edge, a trailing edges, and a third area, the leading edge including an additional surface region in an generally curvilinear section, and the trailing Edge including a fourth region in an generally curvilinear section, where blood flow over the second region generates shear stress in the second region without creating an eddy zone in the second region.
The disclosure’s other advantages and features are evident in the detailed description of the exemplary embodiments. These drawings are accompanied by the accompanying drawings. Similar structural and functional elements are identified with like reference numbers.Click here to view the patent on Google Patents.