The Problem: Cardiovascular disease is the leading cause of death in the Western world. In the US, nearly 500,000 coronary artery bypass surgeries are performed annually with an estimated 89% of these using the technique of cardiopulmonary bypass (CPB). CPB patients experience complications, many of which are considered to be due to the activation of leukocytes (LE) which can result in systemic inflammatory response syndrome (SIRS). The Product: The Leukocyte Modulator (L-MOD) is based on biomimetic membrane device (BMD) platform technology that has been shown to alter the state of systemic LE. When the BMD is placed in a citrated extracorporeal blood circuit, LE are transiently sequestered in the low ionized calcium environment within the BMD and released in an altered state back to the circulation. The L- MOD will be developed specifically to modulate the LE activation associated with CPB, thereby mitigating the associated inflammatory response. Innovation: Previous approaches to block SIRS associated with cardiac surgery including: use of pharmacologic agents, operative techniques, improved biocompatibility and LE depleting filters; have failed to meet clinical endpoints. The L-MOD is the application of BMD technology to CPB associated SIRS and represents an innovative therapy option. The goal of this proposal is to demonstrate efficacy of the L-MOD in ameliorating the inflammatory response and the leukocyte mediated tissue damage that is associated with use of CPB during cardiac procedures. Long Term Goal: This proposal details the initial steps to assess the L-MOD as an effective adjunct therapeutic device to be used in conjunction with current CPB clinical protocol. Phase I Hypothesis: L-MOD therapy will effectively reduce LE activation, minimizing SIRS and accompanying tissue damage resulting from CPB.
Specific Aim 1 : Confirm a study protocol that results in a robust CPB associated SIRS using a pig model of cardiac surgery with CPB.
Specific Aim 2 : Compare the SIRS and LE-induced tissue damage resulting from cardiac surgery and CPB with and without including L-MOD therapy using the developed model. Phase II Objective: Phase II will include survival studies in which the ability of LMOD to protect agains organ damage will be evaluated in recovered animals at 24h, with an emphasis on evaluating the safety and efficacy of L-MOD therapy for limiting activated innate immune system-mediated tissue damage occurring in response to on-pump CPB in patients undergoing cardiac surgery. Commercial Opportunity: The LMOD is inexpensive and easy to distribute. Value will be realized in reduced health care cost from CPB complications.

Public Health Relevance

The use of cardiopulmonary bypass (CPB) during corrective heart surgeries elicits a systemic inflammatory response syndrome (SIRS) that is associated with bleeding disorders and multiple organ dysfunctions in the post-operative period. Leukocyte activation, a major component of this immune reaction, contributes to the vascular dysfunction, oxidative stress and organ injury resulting from leukocyte infiltration into tissues. The leukocyte modulator (L-MOD) is a biomimetic membrane device designed for use within the extracorporeal blood circuit during CPB and was developed to modulate leukocyte activation thereby mitigating this inflammatory response. Clinical trials using this technology have demonstrated as much as a 50% reduction in mortality and a faster return of lung and kidney function in patients with SIRS and multiple organ failure resulting from sepsis. In this proposal, pre-clinical animal model of cardiac surgery with CPB will be used to assess the ability of L-MOD therapy to ameliorate the inflammatory response and reduce leukocyte mediated organ injury arising from CPB surgery.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Mitchell, Phyllis
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Innovative Biotherapies, Inc.
Ann Arbor
United States
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Johnston, Kimberly A; Westover, Angela J; Rojas-Pena, Alvaro et al. (2018) Novel Leukocyte Modulator Device Reduces the Inflammatory Response to Cardiopulmonary Bypass. ASAIO J :