Using Acellular Bioactive Extracellular Matrix Scaffolds to Enhance Endogenous Cardiac Repair

Review published: 11 April 2018 doi: 10.3389/fcvm.2018.00035 Using Acellular Bioactive Extracellular Matrix Scaffolds to Enhance Endogenous Cardiac Repair Daniyil A. Svystonyuk, Holly E. M. Mewhort and Paul W. M. Fedak* Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada Edited by: Joshua D. Hutcheson, Florida International University, United States Reviewed by: Glenn Gaudette, Worcester Polytechnic Institute, United States Willi Jahnen-Dechent, RWTH Aachen Universität, Germany *Correspondence: Paul W. M. Fedak Specialty section: This article was submitted to Atherosclerosis and Vascular Medicine, a section of the journal Frontiers in Cardiovascular Medicine Received: 04 January 2018 Accepted: 22 March 2018 Published: 11 April 2018 Citation: Svystonyuk DA., Mewhort HEM. and Fedak PWM. (2018) Using Acellular Bioactive Extracellular Matrix Scaffolds to Enhance Endogenous Cardiac Repair. Front. Cardiovasc. Med. 5:35. doi: 10.3389/fcvm.2018.00035 An inability to recover lost cardiac muscle following acute ischemic injury remains the biggest shortcoming of current therapies to prevent heart failure. As compared to standard medical and surgical treatments, tissue engineering strategies offer the promise of improved heart function by inducing regeneration of functional heart muscle. Tissue engineering approaches that use stem cells and genetic manipulation have shown promise in preclinical studies but have also been challenged by numerous critical barriers preventing effective clinical translational. We believe that surgical intervention using acellular bioactive ECM scaffolds may yield similar therapeutic benefits with minimal translational hurdles. In this review, we outline the limitations of cellular-based tissue engineering strategies and the advantages of using acellular biomaterials with bioinductive properties. We highlight key anatomic targets enriched with cellular niches that can be uniquely activated using bioactive scaffold therapy. Finally, we review the evolving cardiovascular tissue engineering landscape and provide critical insights into the potential therapeutic benefits of acellular scaffold therapy. Keywords: extracellular matrix, biomaterials science, cardiovascular diseases, regeneration mechanisms, cardiovascular surgery Introduction Heart failure is a growing epidemic that is predicted to disable 1 in 5 Americans in their life time (1). Despite the prevalence of heart failure, effective treatment options remain limited. Pharmacological interventions can improve symptoms and prolong survival, but are unable to promote functional recovery of cardiomyocytes lost to injury (2). Organ transplantation remains the only curative option but a disparity between donor heart supply and patient demand coupled with the need for immunosuppressive therapy makes this an ineffective solution to address the growing needs of the heart failure population (3). Durable mechanical support therapies continue to evolve and improve but complications for destination therapy patients are a concern. As our understanding of the factors and mechanisms that regulate heart structure and function have improved, the concept of engineering cardiovascular tissues to restore heart function has rapidly advanced (4, 5). Whole organ regeneration is the ultimate goal of tissue engineering but at present exists only as a futuristic possibility. Early tissue engineering approaches using stem cell and gene therapy have shown promise, but remain fraught with translational hurdles. As such, there has been an increasing shift in focus towards utilizing tissue engineering strategies that can stimulate repair by modulating the host-substrate microenvironment and enhancing endogenous tissue repair processes (6). Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 April 2018 | Volume 5 | Article 35 Svystonyuk et al. Cardiac Repair with Acellular Scaffolds In this review, we focus on the translational limitations of contemporary cardiac regenerative approaches and describe how acellular bioactive ECM scaffolds may provide an effective solution. Specifically, we outline important anatomical and cellular targets that may benefit from bioactive scaffold therapy and provide insights into the future of cardiovascular tissue engineering and its translation into viable clinical applications. The lessons learned from attempts at gene therapy for heart failure are important: enhancing targeted molecular pathways and signalling mechanisms in failing myocardium can have substantial therapeutic benefits (18). This challenged the notion that tissue engineering must necessarily be an “outside-in” approach and instead, argued that tissue engineering can occur from within by rescuing and/or stimulating endogenous repair pathways. Early Tissue Engineering Strategies Towards Cardiac Regeneration Leveraging Acellular Bioactive Scaffolds Towards Cardiac Regeneration The field of cardiovascular tissue engineering was born out of a need to design functional substitutes for tissue that was presumed irreversibly damaged. Leveraging the plasticity of stem cells and direct genetic manipulation became popular options to achieve this goal. The ability to effectively isolate and expand endogenous stem cells offered the exciting promise of leveraging the cells’ inherent regenerative capacity to treat cardiovascular disease (7). Over the past decades there has been significant enthusiasm within the scientific community for cell-therapies based on a foundation of encouraging preclinical evidence. Why is it that cell-mediated regeneration remains absent from conventional treatment modalities? Part of the problem lies in the biology surrounding exogenous cell delivery to the microenvironment of a failing heart. Damaged myocardium lacks the necessary structural and biological microenvironment to support proper cell health and function. Accordingly, it is no surprise that stem cell survival and engraftment is poor and this remains a dominant issue preventing effective clinical translation (8). Interestingly, the benefits of cell therapy are well documented in preclinical animal models despite the fact that cells are delivered to similar hostile microenvironments in the heart. Long term donor cell engraftment and survival is poor yet functional myocardial recovery is readily observed. These findings represent a paradigm shift in our understanding of the cell-mediated therapeutic effect, indicating that the benefits of cell therapy may lie in their ability to act as source of regenerative and reparative paracrine factors (9, 10). Gene therapy allows targeted control of specific molecular pathways, typically through adenoviral vectors, that can restore lost functionality or enhance endogenous cardiac repair processes (11). Contemporary gene therapy approaches have targeted a number of cardiovascul (...truncated)