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Controlled delivery of heparin-binding (HB) proteins represents a challenge in regenerative medicine strategies. Here, we describe the features of novel nanoparticles (NPs), spontaneously coassembled due to affinity interactions between HB proteins and the semisynthetic anionic polysaccharide, alginate-sulfate. The NPs efficiently encapsulated and protected the proteins from proteolysis. Injection of a combination of NPs encapsulating multiple therapeutic growth factors promoted effective and long-term tissue repair in animal models of severe ischemia (murine model of hindlimb ischemia and acute myocardial infarction in rats). This simple yet efficient NP fabrication method is amenable for clinical use.

Alginate biomaterial is widely utilized for tissue engineering and regeneration due to its biocompatibility, non-thrombogenic nature, mild and physical gelation process, and the resemblance of its hydrogel matrix texture and stiffness to that of the extracellular matrix. In this review, we describe the versatile biomedical applications of alginate, from its use as a supporting cardiac implant in patients after acute myocardial infarction (MI) to its employment as a vehicle for stem cell delivery and for the controlled delivery and presentation of multiple combinations of bioactive molecules and regenerative factors into the heart. Preclinical and first-in-man clinical trials are described in details, showing the therapeutic potential of injectable acellular alginate implants to inhibit the damaging processes after MI, leading to myocardial repair and tissue reconstruction.

Proper spatio-temporal delivery of multiple therapeutic proteins represents a major challenge in therapy strategies aimed at inducing myocardial regeneration after myocardial infarction (MI). We hypothesized that the dual delivery of insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) by injectable affinity-binding alginate biomaterial would maximize their therapeutic effects, leading to a more favorable course of tissue restoration after acute MI. A sequential release of IGF-1 followed by HGF was attained from affinity-binding alginate biomaterial, which also protected the proteins from proteolysis (shown by mass spectroscopy). The released factors retained bioactivity, as judged by their capability to activate their respective signaling pathways and to prevent cardiomyocyte apoptosis in vitro. In a rat model of acute MI, an intramyocardial injection of the dual IGF-1/HGF affinity-bound alginate biomaterial preserved scar thickness, attenuated infarct expansion and reduced scar fibrosis after 4 weeks, concomitantly with increased angiogenesis and mature blood vessel formation at the infarct. Furthermore, this treatment prevented cell apoptosis, induced cardiomyocyte cell cycle re-entry and increased the incidence of GATA-4-positive cell clusters. The dual delivery of IGF-1 and HGF from affinity-binding alginate biomaterial represents a useful strategy to treat MI. It showed a marked therapeutic efficacy at various tissue levels, as well as potential to induce endogenous regeneration of cardiac muscle.

Induction of cardiac muscle regeneration following myocardial infarction (MI) represents a major challenge in cardiovascular therapy, as the current clinical approaches are limited in their ability to regenerate a new muscle tissue and to replace infarcted myocardium. Here, we describe the conception of two strategies based on bio-inspired materials, aimed at myocardial repair after MI. In the first strategy, alginate biomaterial was designed with affinity-binding moieties, enabling the binding of heparin-binding proteins and their controlled presentation and release. The combined features of this unique alginate hydrogel, as a temporary extracellular matrix replacement and a depot for bio-molecules such as insulin-like growth factor-1 and hepatocyte growth factor, led to improvements in cardiac structure and function, as demonstrated by the biomaterial's abilities to thicken the scar and prevent left-ventricular remodeling and dilatation. Endogenous regeneration occurring at the infarct as manifested by the enhanced angiogenesis, cardiomyocyte proliferation, and appearance of cardiac-related stem cells is likely to have contributed to this. In the second strategy, phosphatidylserine (PS)-presenting liposomes were developed to mimic apoptotic cells bodies, specifically their capability of immunomodulating activated macrophages into anti-inflammatory state. In a rat model of acute MI, targeting of PS-presenting liposomes to infarct macrophages after injection via the femoral vein was demonstrated by magnetic resonance imaging. The treatment promoted angiogenesis, the preservation of small scars, and prevention of ventricular dilatation and remodeling. Collectively, the two bio-inspired material-based strategies presented herein represent unique and clinical accessible approaches for myocardial infarct repair.

Cardiac tissue reconstruction following myocardial infarction represents a major challenge in cardiovascular therapy, as current clinical approaches are limited in their ability to regenerate or replace damaged myocardium. Thus, different novel treatments have been introduced aimed at myocardial salvage and repair. Here, we present a review of recent advancements in cardiac cell, gene-based and tissue engineering therapies. Selected strategies in cell therapy and new tools for myocardial gene transfer are summarized. Finally, we consider novel approaches to myocardial tissue engineering as a platform for the integration of various modalities in an attempt to rejuvenate infarcted tissue in vivo.

Alginate biomaterial is widely utilized for tissue engineering and regeneration due to its biocompatibility, non-thrombogenic nature, mild and physical gelation process, and the resemblance of its hydrogel matrix texture and stiffness to that of the extracellular matrix. In this review, we describe the versatile biomedical applications of alginate, from its use as a supporting cardiac implant in patients after acute myocardial infarction (MI) to its employment as a vehicle for stem cell delivery and for the controlled delivery and presentation of multiple combinations of bioactive molecules and regenerative factors into the heart. Preclinical and first-in-man clinical trials are described in details, showing the therapeutic potential of injectable acellular alginate implants to inhibit the damaging processes after MI, leading to myocardial repair and tissue reconstruction.

Tissue regeneration after myocardial infarction (MI) represents a major challenge in cardiovascular therapy, as current clinical approaches are limited in their ability to regenerate damaged myocardium. This chapter presents an overview of two emerging strategies based on the use of biomaterials, as stand-alone therapy or in combination with regeneration signals and cells, for regenerating the infarcted heart. One strategy is cardiac tissue engineering, which creates cardiac patches from functional cells seeded in a biomaterial scaffold, bio-inspired to provide the appropriate interface for cellular interactions. Implementation of perfusion bioreactors and pre-vascularization strategies can nowadays produce thicker cardiac patches that are better integrated into the host, thus advancing the realization of this strategy in the clinics. The second strategy, injection of biomaterials, has shown great promise as a stand-alone therapy. The intracoronary delivery of alginate solution that undergoes gelation only at the infarct in the presence of elevated calcium ions, was shown to increase scar thickness and LV dimensions in acute MI models in rats and pigs and was proven safe in phase I/II clinical studies. To enable the spatio-temporal presentation of regeneration factors, the alginate was modified with sulfate groups to mimic the binding of heparin-binding proteins to heparin/heparan-sulfate. When combining alginate-sulfate with the in-situ formed alginate hydrogel, multiple factor delivery was prolonged in ischemic tissues and enabled regeneration and cardiac repair after MI. The chapter emphasizes the increasing important role of biomaterials in various therapeutic strategies aimed at cardiac regeneration.

Augmentation of myocardial tissue regeneration processes in injured hearts represents a major challenge in cardiology as current therapeutic approaches do not regenerate the myocardial tissue. Herein, we describe three emerging biomaterial-based strategies to treat heart injuries, as stand-alone therapies or in combination with regeneration-inducing signals and/or cells. One strategy relies on the injection of acellular biomaterials, at an early stage after myocardial infarction (MI); these materials replace the damaged extracellular matrix, maintain left ventricular (LV) thickness, and prevent the negative LV remodeling and progression to heart failure. This strategy is currently being investigated in advanced clinical trials using a novel alginate-based biomaterial. The second strategy employs engineered biomaterials, spatially presenting multiple regeneration-inducing factors, to promote myocardial tissue regeneration in chronic infarcted hearts. The recent attempts to understand the “natural capacity” of the myocardium to heal and the factors involved in these processes are promising to advance this therapy. The third strategy applies biomaterials to promote cardiac tissue engineering and create a pre-vascularized cardiac patch to replace damaged or missing myocardial tissue. Collectively, this review emphasizes the increasing importance of biomaterials in cardiology, describes the engineering schemes used in their fabrication, and their implementation in various therapeutic strategies aimed at cardiac tissue regeneration and repair. It mainly highlights the contribution of our group in developing these strategies.

Tissue regeneration following myocardial infarction (MI) represents a major challenge in cardiovascular therapy, as current clinical approaches are limited in their ability to regenerate or replace damaged myocardium. The lack of clinically-relevant cell sources, and the growing importance of paracrine effects of cell therapy, mediated by soluble growth factors and cytokines, favors the use of acellular biomaterials for myocardial tissue engineering. While the efficacy of acellular scaffold-based approaches have already been shown, applying the biomaterial in an injectable form represents a more clinically-appealing strategy, where only minimally invasive interventions are required to deliver the biopolymer solution. However, in order to enhance the passive effects mediated by the injected biomaterial on infarct stabilization and mechanical support, and achieve long-term functional improvement and regeneration of the cardiac muscle, the combination with controlled spatio-temporal delivery of bioactive molecules is required. Biomaterial-based growth factor delivery has already been shown to improve therapeutic outcome after MI. Affinity-binding alginate represents an example of such a system. This strategy has promising potential for myocardial repair and regeneration, as it provides mechanical support conferred by in situ hydrogel formation, and can affect multiple processes of myocardial regeneration by controlled delivery of multiple proteins. In conclusion, as the development of novel polymer schemes and approaches continues, the application of biomaterials that can instruct a favorable tissue reconstruction, facilitate self-repair, tissue salvage and regeneration, represents a platform for future modifications and combinations (for instance, with cell therapy). Hopefully, such efforts will have major clinical consequences on the treatment of MI and improve long-term outcome in heart failure patients.

The recent progress made in the bioengineering of cardiac patches offers a new therapeutic modality for regenerating the myocardium after myocardial infarction (MI). We present here a strategy for the engineering of a cardiac patch with mature vasculature by heterotopic transplantation onto the omentum. The patch was constructed by seeding neonatal cardiac cells with a mixture of prosurvival and angiogenic factors into an alginate scaffold capable of factor binding and sustained release. After 48 h in culture, the patch was vascularized for 7 days on the omentum, then explanted and transplanted onto infarcted rat hearts, 7 days after MI induction. When evaluated 28 days later, the vascularized cardiac patch showed structural and electrical integration into host myocardium. Moreover, the vascularized patch induced thicker scars, prevented further dilatation of the chamber and ventricular dysfunction. Thus, our study provides evidence that grafting prevascularized cardiac patch into infarct can improve cardiac function after MI.

Adverse cardiac remodeling and dysfunction after myocardial infarction (MI) is associated with excessive damage to the extracellular matrix. Biomaterials, such as the in situ-forming alginate hydrogel (BioLineRx, BL-1040 myocardial implant), provide temporary support and attenuate these processes. Here, we tested the effects of decorating alginate biomaterial with cell adhesion peptides, containing the sequences RGD and YIGSR, or a non-specific peptide (RGE), in terms of therapeutic outcome soon after MI. The biomaterial (i.e., both unmodified and peptide-modified alginate) solutions retained the ability to flow after cross-linking with calcium ions, and could be injected into 7-day infarcts, where they underwent phase transition into hydrogels. Serial echocardiography studies performed before and 60 days after treatment showed that alginate modification with the peptides reduced the therapeutical effects of the hydrogel, as revealed by the extent of scar thickness, left ventricle dilatation and function. Histology and immunohistochemistry revealed no significant differences in blood vessel density, scar thickness, myofibroblast or macrophage infiltration or cell proliferation between the experimental groups BioLineRx BL-1040 myocardial implant. Our studies thus reveal that the chemical and physical traits of the biomaterial can affect its therapeutical efficacy in attenuating left ventricle remodeling and function, post-MI.