Saphenous Vein Extracellular Matrix Scaffolds for Use in Coronary Artery Bypass

Minnesota Department of Health statistics indicate that almost 100,000 Minnesotan’s are currently affected by ischemic heart disease (IHD), resulting from blockage of a coronary artery. Coronary artery bypass graft (CABG) surgery, to address the underlying cause of IHD, currently relies on harvesting a remotely located vessel (e.g., leg, arm or chest) from the patient to serve as a conduit to allow bypass of obstructed coronary vessels and restore normal heart muscle blood flow. However, vessel harvest procedures increase surgical time, and are associated with increased pain and potential complications for patients undergoing CABG procedures. This proposal aims to develop a safe and effective off-the-shelf vessel replacement material for use in CABG procedures to overcome limitations associated with current approaches.

Research Focus: Coronary bypass - artery graft

Year 1 Progress Report:

This grant aims to develop off-the-shelf small diameter vascular grafts from animal derived tissues (i.e., bovine vessels), for use in patients undergoing coronary artery bypass grafting and other vascular replacement procedures. The grant seeks to overcome patient immune response towards bovine vessels by eliminating those components of the graft (i.e., antigens) which stimulate immune-mediated destruction when implanted into humans (Aim 1.1). During the current reporting period, antigens which stimulate immune destruction in humans have been identified and eliminated from bovine tissue. Critically, by assessing the content and response toward individual antigens that we have shown to stimulate immune response in humans, we are able to confirm the safety of the resultant grafts before ever implanting the material in human patients.

Elimination of antigens from bovine vascular tissues must be achieved in such a way as to avoid damaging the remaining components (i.e., extracellular matrix (ECM)) of the graft. This grant further seeks to determine the extent to which different methods of graft production preserve or disrupt the remaining ECM components. In the current reporting period, we have shown that disruption of structural ECM components results in the recipient’s body recognizing the biomaterial as a foreign body, which prevents integration of the material with the recipient’s tissues (Aim 1.2). Conversely, preservation of native ECM structural components using methods developed by our team results in the recipient’s body recognizing the biomaterial as being part of their own body, which then allows integration and replacement of the biomaterial with the recipients own tissue.

Finally, this grant seeks to determine the effect of maintaining the normal ECM proteins which form the lining of vessels on recipient cellular repopulation and resultant patency (i.e., absence of clotting) of vascular grafts (Aim 2). In the current reporting period, we have completed studies which show that specific components of the ECM which line the inside of normal vessels have a dramatic effect on the rate at which vessel grafts repopulate with recipient cells and the associated patency of such vessels. Specifically, presence of such vessel lining components was shown to result in 100% vessel patency, whereas absence of these lining components in otherwise identical vessel grafts resulted in 0% vessel patency. This work has the potential to overcome the final previously insurmountable problem in off-the-shelf vessel engineering, which is that vessels smaller than 3-4 mm have invariably clotted following implantation.

Consequently, this grant has made outstanding progress during year 1, demonstrating ground-breaking results under all Aims of the project. Importantly, the results indicate the potential for this work to result in off-the-shelf animal-derived vessel grafts which are immune-compatible with humans (Aim 1.1), turn into the patient’s own tissue following implantation (Aim 1.2) and remain patent throughout the patient’s lifetime (Aim 2).

Final Progress Report: 

This grant sought to address the critical clinical need for development of off-the-shelf small diameter vascular grafts for use in coronary artery bypass and other vascular replacement procedures. Each year, almost 400,000 Americans undergo coronary artery bypass procedures, which currently require harvesting of the patients own vessels at the time of surgery to serve as the bypass conduit. Vessel harvest results in increased surgical time and post-operative complications, making it far from ideal. Worse still due to widespread systemic vascular disease, in many patients no suitable donor vessel can be found which further increases the duration, risk and complications of surgery. However, currently no suitable off-the-shelf small diameter vascular graft exists to overcome the complications associated with current coronary artery bypass procedures.

This grant aimed to develop off-the-shelf small diameter vascular grafts from animal derived tissues (i.e., bovine vessels), for use in patients undergoing coronary artery bypass grafting and other vascular replacement procedures. The grant sought to overcome patient immune response towards bovine vessels by eliminating those components of the graft (i.e., antigens) which stimulate immune-mediated destruction when implanted into humans (Aim 1.1). Through successful completion of this grant, antigens which stimulate immune destruction in humans have been identified and eliminated from bovine vascular tissue. Critically, by assessing the content and response toward individual antigens that stimulate immune responses in humans, we are able to confirm the safety of the resultant grafts before ever implanting the material in human patients.

Elimination of antigens from bovine vascular tissues must be achieved in such a way as to avoid damaging the remaining components (i.e., extracellular matrix (ECM)) of the graft. This grant sought to determine the extent to which different methods of graft production preserve or disrupt the remaining ECM components. Through successful completion of the grant, we have shown that disruption of structural ECM components results in the recipient’s body recognizing the biomaterial as a foreign body, which prevents integration of the material with the recipient’s tissues (Aim 1.2). Conversely, preservation of native ECM structural components using methods developed by our team results in the recipient’s body recognizing the biomaterial as being part of their own body, which then allows integration and replacement of the biomaterial with the recipients own tissue.

Finally, this grant sought to determine the effect of maintaining the normal ECM proteins which form the lining of vessels on recipient cellular repopulation and resultant patency (i.e., absence of clotting) of vascular grafts (Aim 2). The successful completion of these studies showed that specific components of the ECM which line the inside of normal vessels have a dramatic effect on the rate at which vessel grafts repopulate with recipient cells and the associated patency of such vessels. Specifically, presence of such vessel lining components was shown to result in 100% vessel patency, whereas absence of these lining components in otherwise identical vessel grafts resulted in 0% vessel patency. This work is the first to show a method which successfully overcomes the final previously insurmountable problem in off-the-shelf vessel engineering, which is that vessels smaller than 3-4 mm have invariably clotted following implantation.

Consequently, this grant has made outstanding progress in the field of small diameter vascular tissue engineering, demonstrating ground-breaking results under all Aims of the project. Importantly, the results indicate the potential for this work to result in off-the-shelf animal-derived vessel grafts which are immunecompatible with humans (Aim 1.1), turn into the patient’s own tissue following implantation (Aim 1.2) and remain patent throughout the patient’s lifetime (Aim 2).