Heparin Conjugated to Collagen-Binding Peptides for Targeting to Biological and Synthetic Tissues

NU 2017-175

INVENTORS

Guillermo Ameer*
Jason Wertheim*
Bin Jiang
Kyle Koss

SHORT DESCRIPTION

A synthetic form of heparin optimized to reduce blood coagulation by collagen stabilization.

BACKGROUND

Thrombosis, the local formation of blot clots, presents a major challenge to regenerative medicine procedures that utilize matrix scaffolds. Patients undergoing procedures such as coronary angioplasty and balloon angioplasty of renal, femoral or lower extremity arteries typically require daily doses of systemic anticoagulants in order to prevent intravascular thrombosis at the site of injury. Anti-thrombotic drugs have historically been limited to traditional products such as heparin, warfarin and oral Vitamin K antagonists. Unfortunately, the side effects of these agents can be severe and difficult to control in patients and are often associated with bleeding, cerebral stroke and gastric ulcers. There is, therefore, a recognized need for improved anti-coagulants that offer more specificity in blocking the coagulation cascade and greater predictable pharmacodynamic and pharmacokinetic properties to increase patient safety. Furthermore, the elimination of the current dosing regimen and complicated requirements of laboratory monitoring would offer overall healthcare cost savings.

ABSTRACT

Thrombogenesis within small blood vessels is one of the major challenges in using decellularized tissues as a scaffold for tissue or regenerative engineering. Northwestern researchers have developed a novel easy to implement approach to reduce thrombogenicity without deleterious effects on the mechanical properties and ultrastructure of the extracellular matrix (ECM). This approach is implemented through the targeted delivery of a modified heparin molecule to exposed collagen at the site of vessel injury. The heparin is immobilized onto the ECM scaffold via collagen binding peptide (CBP), an intermediate linker. Preliminary results show that vascular ECM modified with CBP-heparin exhibits reduced thrombogenicity, improved long-term adhesion of endothelial cells, and increased binding of the growth factor VEGF. Initial in vivo proof-of-concept data also shows that CBP-heparin remains bound to endogenous collagen up to one week following delivery, enhancing heparin function. This technology may ultimately substitute the need for repetitive, daily doses of anti-thrombotic therapy, commonly associated with serious bleeding side effects. Moreover, the heparin can be immobilized onto a variety of other decellularized and acellular scaffolds as well, which leads to potential applications of the agents to vascularized grafts or the vasculature or organs. Taken together, this approach helps overcome challenges associated with some regenerative medical procedures and presents new opportunities to further engineer patient-specific vascular grafts and networks.

APPLICATIONS

Anticoagulation in decellularized organs, e.g. vascular grafts, hearts, livers, and kidneys
Anticoagulation in re-cellularized organs that are not 100% covered with cells before implantation
Heparin binding growth factors (e.g. Fibroblast growth factor, epidermal growth factor) delivery and presentation in ECM based biomaterials for tissue engineering applications
Anticoagulant during vascular surgical procedures such as percutaneous or balloon angioplasties

ADVANTAGES