Stimuli Responsive Delivery Vehicles for Cardiac Microtissue Transplantation

Abstract

Cell transplantation has emerged as the most promising therapy for restoring the scarred myocardium in the treatment of heart failure. However, clinical effi cacy of (stem) cell therapies is still limited by poor retention rate and survival of injected cells in the ischemic tissue. Here we present a new strategy to deliver microtissues in the treatment of heart dysfunction in order to improve the retention, survival, and integration of the delivered cells. For this purpose, we developed stimuli responsive biodegradable polymer constructs consisting of a thin fi lm of thermosensitive hydrogel coupled to a thin fi lm of non-responsive polymer. Due to the temperature responsive swelling behavior of the hydrogel layer, the bilayer polymer constructs can roll or unroll at will. Therefore they can potentially be used for effi cient encapsulation and protection of cell clusters during delivery, while under physiological conditions, the constructs, named cell wraps, can unroll and expose the delivered microtissue to the ischemic tissue.

Hydrogels for cardiac tissue engineering

“…2,4,9,12,13 Although tissue engineering platforms have been successfully used for engineering of avascular organs, generating artificial substitutes for highly vascularized cardiac tissues remains remarkably challenging. 14 Because of their highly tunable features, engineered hydrogels have been used to address these limitations.…”

“…MI evokes obstruction of blood flow to the heart, leading to oxygen deficiency in the heart muscles and ultimately cell death. 2 As a result, the remaining muscle tissue undergoes structural and functional remodeling indicated by ventricular wall thinning and chamber dilatation. 3 The limited regeneration capability of the adult cardiomyocytes in the heart prevents the tissue to regenerate fully on its own.…”

“…5 Therefore cardiac transplantation remains a viable option to treat end-stage heart failure patients. 2 However, due to the limited number of organ donors and potential rejection problems, innovative alternative approaches are needed. 6,7 Direct injection of cells into the cardiac muscle has been used as a method of delivering cells into the infarcted tissue.…”

“…10,11 However, B90% of the injected cells die after implantation, demonstrating the importance of vasculature and appropriate tissue microarchitecture for cardiac tissue regeneration. 2,8 In particular, environmental stress associated with the lack of a three dimensional (3D) flexible biomimetic microenvironment and direct exposure of single cells to oxygen tension, free radicals and inflammatory cytokines induce cell death. 10 Therefore, there is a significant need for engineered biomaterials that can be used as 3D matrices to efficiently deliver cells to the damaged cardiac muscle and facilitate myocardial regeneration.…”

Quantifying the bending of bilayer temperature-sensitive hydrogels

“…[6][7][8][9][10][11][12], with dramatic changes in their properties, which can therefore be potentially harvested for diverse applications. For example, stimuli-responsive hydrogels with homogeneous swelling/shrinkage are desirable for applications such as artificial muscles [13] and soft machines, while those with inhomogeneous swelling/shrinkage can be employed as chemical valves [14][15][16][17], manipulators [18][19][20][21], crawlers [9,22], etc.…”