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C H A P T E R 10

Biomaterial-based Controlled

Delivery of Bioactive Molecules

for Myocardial Regeneration

CHAPTER SUMMARY

As the therapeutic benefits of biomaterial treatments of MI and the paracrine effects of stem cells on cardiac regeneration are being established, a new strategy has emerged combining both bioactive molecules and biomaterials to achieve effective therapy. In this strategy, the biomaterials function both as supporting and ECM replacing platforms as well as local depots for controlled biomolecule delivery, in aim to achieve a long-term active form of myocardial regeneration. The present chapter presents the principles of this strategy, the type of growth factors and cytokines found to be inducers of myocardial regeneration, and the various strategies for their incorporation in different biomaterial systems to achieve protection and sustained presentation in the infarct zone. An emphasis is given in this chapter to the features of a novel affinity-binding alginate biomaterial, whose development by our group was bio-inspired by ECM interactions with heparin-binding proteins. This platform has shown its capability for prolonged presentation of multiple growth factors and was proven to elicit beneficial therapeutic effects in several ischemic disease models.

10.1 INTRODUCTION

The data collected from various preclinical and clinical trials clearly show that stem cell transplantation, although having some initial beneficial effects, have failed to provide long-term improvements in cardiac function. This has been mainly attributed to the low cell engraftment at the infarct and the lack of a true regeneration, i.e., differentiation of the transplanted cells into cardiomyocytes. The initial beneficial effects observed in some of these studies were mainly ascribed to the action of various soluble cell-secreted bioactive molecules, such as growth factors and cytokines. Indeed, studies that examined the effect of systemic delivery of exogenous bioactive molecules revealed positive effects on cardiac function, however, they also presented several drawbacks, such as the requirement for repeated and high doses, possible mutagenesis (when using viral vectors), and safety concerns in patients, originated from the pleiotropic actions of most of the growth factors/cytokines on various organism systems.

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The success of acellular biomaterials in providing in situ tissue support and their known property, at least of some of them, to act as depot for biological molecules, motivated the recent application of combinations of biomaterials and growth factors for cardiac repair. While the effects of sole biomaterial are mainly passive and mechanistic in nature, the combination with various bioactive molecules has the potential of adding an active component to this system, to achieve sustained and long-term effects. Both implantable constructs (scaffolds and sheets) and injectable forms (hydrogels and solutions) have been investigated as systems for bioactive molecule delivery, providing additional evidence to the versatility of biomaterial use for myocardial regeneration and repair.

10.2EVOLUTION OF BIOACTIVE MATERIAL APPROACH FOR MYOCARDIAL REGENERATION

To achieve a long-term cardiac function restoration and/or diminish adverse LV remodeling, the therapeutic strategy should be able to induce active myocardial regeneration, e.g., to introduce viable beating tissue (Fig. 10.1) [1].

This goal can be achieved by inducing resident myocyte proliferation, migration, and activation of resident stem/progenitor cells and/or effective salvaging of existing viable functional tissue after initial infarct. Various cytokines, growth factors, and other bioactive molecules could contribute significantly to these desired effects. Yet, to maximize the efficiency of this bioactive approach, the combination of bioactive molecules with biomaterials seems to be a very attractive option. In such a way, the biomaterial will provide structural temporary matrix support and direct the formation of functional tissue, by mainly passive mechanisms mentioned before. Simultaneously, it will provide a temporary depot for sustained delivery of bioactive molecules with spatial and controlled distribution of the desired agent to induce regenerative processes [2, 3].

146 10. BIOMATERIAL-BASED CONTROLLED DELIVERY OF BIOACTIVE MOLECULES

these molecules cover almost every target in the regeneration strategies, as discussed in Section 2.7 [4, 5, 6].

Table 10.1 lists the major bioactive molecules investigated for therapeutic myocardial regeneration and their respective activities. Many of these molecules have pleiotropic functions, emphasizing the need for careful, local, and time-adjusted interventions.

Table 10.1: Bioactive molecules to enhance self-repair, angiogenesis, and myocardial regeneration

The systemic delivery of some of the above growth factors was found to be beneficial for the restoration of cardiac function in animal models. However, data emerging from clinical studies has been less conclusive, as for example the case of using granulocyte colony-stimulating factor (G- CSF) [27, 28].The mixed results obtained with systemic cytokine or growth factor administration are also accompanied by numerous safety concerns and side effects.These include an increased incidence of restenosis, elevated blood pressure and viscosity, thrombolytic events, arrhythmogenesis, and other potential detrimental effects [4, 29, 30]. In addition, systemic administration requires higher doses of the drug due to unspecific delivery, fast elimination, and extremely low protein stability in the blood. Thus, significant efforts are being invested in the development of strategies for achieving effective local and temporary delivery of various bioactive molecules by employing biomaterialbased polymeric delivery systems.