Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction

Abstract

Myocardial infarction (MI) induces a complex inflammatory immune response, followed by the remodelling of the heart muscle and scar formation. The rapid regeneration of the blood vessel network system by the attraction of hematopoietic stem cells is beneficial for heart function. Despite the important role of chemokines in these processes, their use in clinical practice has so far been limited by their limited availability over a long time-span in vivo. Here, a method is presented to increase physiological availability of chemokines at the site of injury over a defined time-span and simultaneously control their release using biodegradable hydrogels. Two different biodegradable hydrogels were implemented, a fast degradable hydrogel (FDH) for delivering Met-CCL5 over 24 hrs and a slow degradable hydrogel (SDH) for a gradual release of protease-resistant CXCL12 (S4V) over 4 weeks. We demonstrate that the time-controlled release using Met-CCL5-FDH and CXCL12 (S4V)-SDH suppressed initial neutrophil infiltration, promoted neovascularization and reduced apoptosis in the infarcted myocardium. Thus, we were able to significantly preserve the cardiac function after MI. This study demonstrates that time-controlled, biopolymer-mediated delivery of chemokines represents a novel and feasible strategy to support the endogenous reparatory mechanisms after MI and may compliment cell-based therapies.

Human cardiac tissue engineering: from pluripotent stem cells to heart repair

“…For example, a “pro-survival cocktail” containing anti-apoptotic peptides, immunosuppressant small molecules, and growth factors (IGF-1) has been co-delivered with hPSC-CMs to enhance their engraftment in the heart [41]. For longer-term effects following cell engraftment, controlled drug release from a degradable scaffold [42] combined with hPSC-CM therapy could provide further benefits to cell survival, blood vessel ingrowth, and functional integration with host tissue.…”

Controlled release strategies for modulating immune responses to promote tissue regeneration

“…Chemokines are a class of cytokines that recruit immune cells to an inflammatory site and have the potential to effectively target specific immune cell populations. Targeted blocking of C-X-C ligand (CXCL)12 and C-C ligand (CCL)5-CXCL4 through soluble release of these molecules, blocking antibodies, or antagonists reduced neutrophil infiltration with increased vascularization seen following simultaneous biomaterial-release of CXCL12 and CCL5 [48, 49]. T cell recruitment can be limited with CXCL3 blocking antibodies or IL-4 delivery, however, IL-4 can stimulate Th2 recruitment [42, 43, 50].…”

Distribution of Systemically Administered Nanoparticles Reveals a Size-Dependent Effect Immediately following Cardiac Ischaemia-Reperfusion Injury

“…Researchers have explored a broad range of therapeutic approaches, aiming to reduce cardiomyocyte death, lessen the degree of ventricular remodelling, and improve cardiac function following cardiac ischaemia. The most direct approaches typically involve the injection of cardioprotective growth factors, cytokines, antioxidants or bioactive small molecules directly into the infarcted area, or applying them in conjunction with a reparative or supportive biomaterial 13 14 15 16 17 18 19 20 . However, direct myocardial injection is highly invasive, volume-limited and has the potential to cause further injury to the already-weakened myocardium.…”