TEVG Stenosis Control via Prasugrel-Losartan Modulation
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Solution Overview
Problem
Existing methods to prevent thrombosis and stenosis in tissue engineered vascular grafts (TEVGs) are not effective, leading to high rates of graft failure due to neointimal hyperplasia and mural thrombosis, with current treatments like heparin, warfarin, and aspirin being ineffective.
Innovation Solution
Administering Prasugrel, a thienopyridine ADP receptor inhibitor, in combination with Losartan, an angiotensin II receptor blocker, to inhibit ADP-mediated signaling and platelet aggregation, thereby reducing thrombosis and stenosis in TEVGs by blocking the P2Y12 receptor and angiotensin II type 1 receptors, respectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If prosthetic materials are used in vascular repair, then surgical repair or replacement can be performed, but thromboembolic events and neointimalhyperplasia occur increasing the risk of graft failure
Solution Approach 1:
The patent changes the chemical parameters of the graft surface by incorporating negatively charged polymers (heparin, sulfated polysaccharides) and basic amino acids (lysine, arginine) to create a surface that resists thrombosis and modulates the foreign body response, thereby improving graft durability while maintaining surgical repair capability
Solution Approach 2:
The patent creates composite material surfaces by combining prosthetic materials with bioactive molecules including heparin, sulfated polysaccharides, basic amino acids, and growth factors. This composite approach provides both the structural integrity needed for surgical repair and the biochemical properties that prevent thrombosis and reduce neointimalhyperplasia, thus improving graft reliability
2Reliability
If drug eluting stents are used to reduce restenosis, then tissue growth is inhibited, but restenosis can still occur later especially in patients with diabetes or chronic kidney disease
Solution Approach 1:
The patent designs graft surfaces with multi-functional bioactive coatings that simultaneously provide antithrombotic protection, anti-inflammatory effects, and anti-proliferative properties. This universal approach addresses multiple pathological processes (thrombosis, inflammation, neointimalhyperplasia) that contribute to graft failure across different patient populations including those with diabetes and chronic kidney disease, thereby improving adaptability while maintaining restenosis prevention
3Reliability
If the foreign body reaction is activated for implant integration, then the implant integrates with tissue, but sustained immune activation leads to thromboembolic events and poor long-term durability
Solution Approach 1:
The patent modifies the biochemical parameters of the graft surface by incorporating specific molecules (heparin, sulfated polysaccharides, basic amino acids) that change the nature of the foreign body response from a harmful sustained immune activation to a beneficial acute phase response that promotes integration while minimizing thromboembolic events and neointimalhyperplasia
Solution Approach 2:
The patent converts the potentially harmful foreign body reaction into a beneficial process by using bioactive surface modifications that direct the immune response toward constructive outcomes. The acute foreign body reaction is harnessed to promote tissue integration and endothelialization, while the surface chemistry prevents sustained immune activation and thrombosis, thus transforming a harmful mechanism into a beneficial one for long-term graft durability
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The combination of Prasugrel and Losartan significantly reduces the incidence and severity of TEVG stenosis without adverse effects, maintaining vascular patency and preventing excessive platelet aggregation and macrophage infiltration.
Implementation Method 1
inhibit ADP-mediated signaling and platelet aggregation, thereby reducing thrombosis and stenosis in TEVGs by blocking the P2Y12 receptor
Implementation Method 2
blocking the P2Y12 receptor and angiotensin II type 1 receptors, respectively
Data Source
AI summary
Therapeutic agents such as Prasugrel, a thienopyridine ADP receptor inhibitor, which inhibit ADP mediated signaling through the P2Y12 receptor, alone or in combination with an angiotensin II receptor blocker (ARB) such as Losartan that specifically blocks the angiotensin II type 1 (AT1) receptors, have been shown to be effective in reducing thrombosis and stenosis of grafts, including vascular grafts and tissue engineered vascular grafts (“TEVGs”) in multiple in vivo, and that the combination of a inhibitor of the purinergic receptors P2Y12 such as Prasugrel, with losartan, an angiotensin II type 1 receptor inhibitor, more than additively reduced the incidence of TEVG stenosis. In a preferred embodiment, a multi-dosing unit for treatment to reduce stenosis delivers a 2-week course of losartan and Prasugrel.