Regenerative Medicine Initiative in Cardiac Restoration Therapy

Collaborator: Technion University (Israel)

Organ failure is a major health problem, accounting for about half of total annual medical expenditures worldwide. The best treatment option currently available is a transplant from a donor; however, the waiting list is long, and possible complications involving organ rejection overshadow any procedure. In recent decades tissue engineering (TE), also termed regenerative medicine (RM), has emerged as an exciting alternative therapeutic option that can potentially replace transplants and improve patient life quality and health.

In this programme, we focus our multidisciplinary knowledge and research to develop tissue regenerative solutions for one of the most vital and complex organs: the heart. The heart is the most vital and complex organ in the human body. Unlike other organs, the heart has only limited regenerative capacity; therefore, following damage such as after myocardial infarction (MI), scar tissue (ST) is formed. This ST is non-active, less resilient than native tissue, and eventually deteriorates resulting in heart failure and death. Unfortunately, current clinical treatments are limited and do not regenerate the ST once formed.

Statistical evidence of the current challenges facing this field is that cardiovascular diseases (CVD) remain the leading cause of death worldwide, more than all cancers combined. It is estimated that by 2030, there will be 23.6 million deaths annually, with the largest increase expected in Southeast Asia (source: World Health Organization). In Singapore, nearly 15 people die daily from cardiovascular disease (CVD) – accounting for 32.4% of all deaths (source: Singapore MOH Burden of Disease Study, 2008).

For the engineering of cardiac mimetic tissue with physiological and clinically-relevant thicknesses, novel composite biomaterials should be isolated or developed with supportive vascularization that occurs in a time frame that prevents cell death within the core following implantation. This issue is particularly crucial when constructs exceed 100 – 150µm in thickness, under static culture conditions, and much more so when engineering ventricular wall mimetic tissue where in humans, the thicknesses required are in the vicinity of 10 – 15mm. Furthermore, the lack of a connectable vascular tree within most of the currently reported pre-vascularized constructs limits the ability to ensure instant blood supply to reseeded cells upon transplantation into the infarcted heart rigorous environment. Thus, the development of core dynamic culture and supportive technologies, enabling the production of tissue-engineered constructs with a functional connectable vascular network is imperative.

Our primarily focus is the development of a functional tissue-engineered bio-active cardiac patch. The use of a fully functional cardiac patch that can be surgically attached and integrated onto the MI region of the injured heart is seen as having the greatest potential to restore cardiac function effectively.

Our approach is comprehensive; ensuring the use of a stable reparative cell source, adequate in vitro culture conditions to precondition the cells, an appropriate scaffold material with 3D architecture to promote vascularization and support cell organization and integration, and a precise surgical placement for subsequent integration with the host myocardium. Various stem and progenitor cells are being utilized; several scaffold types, of synthetic and natural origin, are being developed in parallel with emphasis on controllable and reproducible processing methodologies such as decellularization, electrospinning, meltspinning, robotic printing etc. The cell-seeded scaffolds are further cultivated in vitro using custom-designed bioreactor systems for cardiac preconditioning, and the tissue patches are surgically implanted into the ischemic heart using MI models in small and large animals.

Funding agency: National Research Foundation

Publications:

(1) Ang HY, Irvine SA, Avrahami R, Sarig U, Bronshtein T, Zussman E, Boey FY, Machluf M, Venkatraman SS. Entrapment of cells within core-shell electrospun scaffold fibers. European Cells and Materials, In-press (2014).

(2) Ang HY, Irvine SA, Avrahami R, Sarig U, Bronshtein T, Zussman E, Boey FY, Machluf M, Venkatraman SS. Characterization of a bioactive fiber scaffold with entrapped HUVECs in coaxial electrospun core-shell fiber. Biomaterials, 4, (2014).

(3) Lee BH, Tin SPH, Chaw SY, Cao Y, Xia Y, Steele TW, Seliktar D, Bianco-Peled H, Venkatraman SS. Influence of soluble PEG-OH incorporation in a 3D cell-laden PEG-fibrinogen (PF) hydrogel on smooth muscle cell morphology and growth. Journal of Biomaterials Science, Polymer Edition. 1–16 (2013).

(4) Terry W.J. Steele, Charlotte L. Huang, Evelyne B.V. Nguyen, Udi Sarig, Seranya Kumar, Effendi Widjaja, Joachim L.S. Chye, Marcelle Machluf, Freddy Y.C. Boey, Zlata Vukadinovic, Andreas Hilfiker, Subbu S. Venkatraman. Collagen-cellulose composite thin films that mimic soft-tissue and allow stem-cell orientation. Journal of Materials Science, Materials in Medicine, 24 (8), (2013).

(5) Tomer Bronshtein, Gigi A.Y.C. Ting, Udi Sarig, Evelyne B.V. Nguyen, Freddy Y.C. Boey, Subbu S. Venkatraman, Marcelle Machluf. A mathematical model for analyzing the elasticity, viscosity and failure of soft tissue: comparison of native and decellularized porcine cardiac extracellular matrix for tissue engineering. Tissue Engineering, Part C, Methods, 19 (8), 620–630 (2013).

(6) Wang Yao, Tomer Bronshtein, Udi Sarig, Evelyne B.V. Nguyen, Freddy Y.C. Boey, Subbu S. Venkatraman, Marcelle Machluf. A mathematical model predicting the co-culture dynamics of endothelial and mesenchymal stem cells for tissue regeneration. Tissue Engineering, Part A, 19 (9–10), 1155–1164 (2013).

(7) Udi Sarig, Gigi A.Y.C. Ting, Wang Yao, Tomer Bronshtein, Nitsan Dahan Freddy Y.C. Boey, Subbu S. Venkatraman, Marcelle Machluf. Thick acellular heart extracellular matrix with inherent vasculature: a potential platform for myocardial tissue regeneration. Tissue Engineering, Part A, 18 (19 – 20), 2125–2137 (2012).

(8) Terry W.J. Steele, Charlotte L. Huang, Seranya Kumar, Scott A. Irvine, Freddy Y.C. Boey, Joachim L.S. Chye, Subbu S. Venkatraman. Novel gradient casting method provides high-throughput assessment of blended polyester poly(lactic-co-glycolic acid) thin films for parameter optimization. Acta Biomaterialia, 8 (6), 2263–2270 (2012).

(9) Scott A. Irvine, Xia Yun, Subbu S. Venkatraman. Anti-platelet and tissue engineering approaches to biomaterial blood compatibilization: how well have these been translated into the clinic?. Drug Delivery and Translational Research, 2 (5), 384–397 (2012).

(10) Chor Y. Tay, Scott A. Irvine, Freddy Y. C. Boey, Lay P. Tan, Subbu S. Venkatraman. Micro-/nano-engineered cellular responses for soft tissue engineering and biomedical applications. Small, 7 (10), 1361–1378 (2011).