Injectable Citrate-Based Hydrogel as an Angiogenic Biomaterial Improves Cardiac Repair after Myocardial Infarction

Abstract

Implanted medical biomaterials are closely in contact with host biological systems via biomaterial–cell/tissue interactions, and these interactions play pivotal roles in regulating cell functions and tissue regeneration. However, many biomaterials degrade over time, and these degradation products also have been shown to interact with host cells/tissue. Therefore, it may prove useful to specifically design implanted biomaterials with degradation products which greatly improve the performance of the implant. Herein, we report an injectable, citrate-containing polyester hydrogel which can release citrate as a cell regulator via hydrogel degradation and simultaneously show sustained release of an encapsulated growth factor Mydgf. By coupling the therapeutic effect of the hydrogel degradation product (citrate) with encapsulated Mydgf, we observed improved postmyocardial infarction (MI) heart repair in a rat MI model. Intramyocardial injection of our Mydgf-loaded citrate-containing hydrogel was shown to significantly reduce scar formation and infarct size, increase wall thickness and neovascularization, and improve heart function. This bioactive injectable hydrogel-mediated combinatorial approach offers myriad advantages including potential adjustment of delivery rate and duration, improved therapeutic effect, and minimally invasive administration. Our rational design combining beneficial degradation product and controlled release of therapeutics provides inspiration toward the next generation of biomaterials aiming to revolutionize regenerative medicine.

Solution structure of human myeloid-derived growth factor suggests a conserved function in the endoplasmic reticulum

“…Our goal in initiating these studies was to determine the solution structure of hMYDGF as a model for other members of the widespread MYDGF/UPF0556 family of proteins and to provide insights into the functions of MYDGF as a well-conserved resident ER protein 1 and as a paracrine/autocrine survival factor with therapeutic potential after myocardial infarction 7,32 . We found that hMYDGF consists of a β-sandwich occluded at one edge by an α-helical turn and small β-sheet (Fig.…”

“…Our structure is useful for thinking about MYDGF as a paracrine/autocrine survival factor with therapeutic potential after cardiac ischemia 7,32 . A number of ER proteins other than MYDGF have activities outside of the cell, including GRP78 (BiP) 34 , GRP94 35 , and mesencephalic astrocyte-derived neurotrophic factor (MANF) 36–38 .…”

Biomaterials for Sequestration of Growth Factors and Modulation of Cell Behavior

“…In bulk form, they have been applied, e.g., in the regeneration of vocal fold mucosa by gradually releasing hepatocyte growth factor (HGF) [41] and FGF-2, [51] or for cardiac repair after myocardial infarction, by releasing citrate and myeloid-derived growth factor. [70] In microspheres, hydrogels have been tested, for example, to steer the osteogenic commitment of mesenchymal stem/stromal cells (MSCs) by release of BMP-2. [52] A recent representative example of this type of systems is the combination of unmodified alginate with alginate sulfate, which presents an increased negative charge conferring higher affinity to multiple GFs, to develop an ovary mimetic microenvironment.…”

“…In bulk form, they have been applied, e.g., in the regeneration of vocal fold mucosa by gradually releasing hepatocyte growth factor (HGF) [ 41 ] and FGF‐2, [ 51 ] or for cardiac repair after myocardial infarction, by releasing citrate and myeloid‐derived growth factor. [ 70 ] In microspheres, hydrogels have been tested, for example, to steer the osteogenic commitment of mesenchymal stem/stromal cells (MSCs) by release of BMP‐2. [ 52 ]…”

Biomaterials Loaded with Growth Factors/Cytokines and Stem Cells for Cardiac Tissue Regeneration

“…Moreover, myeloid-derived growth factor (Mydgf) was incorporated into an injectable citrate-based polyester hydrogel to investigate its effects on improving cardiac tissue repair following MI. The combination of the released Mydgf and citrate, which is an important substrate in cellular energy metabolism, reduced cell apoptosis and scar formation as well as improved angiogenesis and cardiac function [ 65 ]. In the study by Waters and colleagues, therapeutic biomolecules, such as growth factors and cytokines, secreted by human adipose-derived stem cells (ADSCs), were loaded into laponite/gelatin hydrogel and injected into the peri-infarct region in an acute MI rat model, which resulted in increased angiogenesis and reduced fibrosis as well as a significant improvement in ejection fraction and cardiac output [ 66 ].…”