Control of the post-infarct immune microenvironment through biotherapeutic and biomaterial-based approaches

Abstract

Ischemic heart failure (IHF) is a leading cause of morbidity and mortality worldwide, for which heart transplantation remains the only definitive treatment. IHF manifests from myocardial infarction (MI) that initiates tissue remodeling processes, mediated by mechanical changes in the tissue (loss of contractility, softening of the myocardium) that are interdependent with cellular mechanisms (cardiomyocyte death, inflammatory response). The early remodeling phase is characterized by robust inflammation that is necessary for tissue debridement and the initiation of repair processes. While later transition toward an immunoregenerative function is desirable, functional reorientation from an inflammatory to reparatory environment is often lacking, trapping the heart in a chronically inflamed state that perpetuates cardiomyocyte death, ventricular dilatation, excess fibrosis, and progressive IHF. Therapies can redirect the immune microenvironment, including biotherapeutic and biomaterial-based approaches. In this review, we outline these existing approaches, with a particular focus on the immunomodulatory effects of therapeutics (small molecule drugs, biomolecules, and cell or cell-derived products). Cardioprotective strategies, often focusing on immunosuppression, have shown promise in pre-clinical and clinical trials. However, immunoregenerative therapies are emerging that often benefit from exacerbating early inflammation. Biomaterials can be used to enhance these therapies as a result of their intrinsic immunomodulatory properties, parallel mechanisms of action (e.g., mechanical restraint), or by enabling cell or tissue-targeted delivery. We further discuss translatability and the continued progress of technologies and procedures that contribute to the bench-to-bedside development of these critically needed treatments.

Keywords: Biomaterials; Biotherapeutics; Heart failure; Immune modulation; Inflammatory disease.

Fig. 1

Left ventricular (LV) remodeling and progression of the post-MI inflammatory response. a The heart undergoes LV remodeling after MI. Initial ischemia (left) results in cardiomyocyte apoptosis and loss of muscle contraction. Within the following days and weeks, softening of the myocardium by ECM degradation and apoptosis in the border zone result in geometric changes to the heart that include infarct thinning and expansion (middle). Over time, global remodeling is characterized by ventricular dilation, cardiac hypertrophy, and valve dysfunction which result in a loss of heart function that manifest clinically as ischemic heart failure (IHF). Figure adapted from [5]. b Following MI, the inflammatory response is incited and can be described in three phases—an early, intermediate, and late response that temporally correlate to the stages of LV remodeling. Innate immune cells (neutrophils, Mo) initially dominate the immune microenvironment, giving way to a wave of inflammatory (M1-like) and later pro-healing (M2-like) MF that exist in a heterogeneous and diverse pool of phenotypes. The inflammatory milieu guides later B and T cell response

Fig. 2

Toolbox of models and methods of image-based assessment. Developing an understanding of IHF etiology and developing therapeutics to treat newly revealed targets requires appropriate selection and pairing of animal models with methods of assessment. Imaging-based assessments are frequently aided by imaging probes or nanotracers, designed to label specific immune cell subsets

Fig. 3

Nanomaterials and probes for imaging. a Confocal fluorescence images of ⁶⁸Ga-NOTA-anti-MMR Nb, a nanotracer with specificity toward M2-like MF via mannose receptor (MR), uptaken in MF in the infarct zone 7 days post-MI. Figure reproduced from [138]. b PET/MRI of a non-human primate after administration of ¹⁸F-Macroflor over 90 min. The MF-targeted agent is rapidly cleared from circulation by renal excretion (half-life of 21.7 min) to enable subsequent whole-body imaging of MF abundance. Figure reproduced from [141]. c MRI (left) and corresponding histology (right) of infarcted rat hearts before and after injection of the theranostic iron oxide polymer nanocarriers (PP/PS@MIONs), showing MF-targeted accumulation that is further enhanced by application of an external magnetic field (+ M). Image reproduced from [143]

Fig. 4

Diversity of immunotherapeutic nanomaterials. a Composition, properties, and therapeutic cargo dictate how nanoparticles interact with immune cells. These aspects enable cell-targeted delivery, receptor-mediated control of cell programs, and influence over downstream effector or suppressor signaling programs. b Lipid nanoparticles, synthesized with varying surface charges, were incubated with human MF in vitro; surface charge positively correlated with cell uptake. Figure reproduced from [283]. c siRNA loaded particle treatment (siCCR2) silences CCR2 to reduce inflammatory Mo infiltration and MF populations compared to the control (siCON) following IR injury. Figure reproduced from [164]

Fig. 5

Epicardial affixed devices such as patches and wraps allow for mechanical stabilization of the infarct and can simultaneously deliver therapeutics or incorporate bioactive materials. a The evolution of epicardial affixed devices initiated with mechanical restraints to prevent LV dilation and has moved to incorporate living tissue constructs and bioactive materials for immunomodulation. b Schematic of the Therapi system, which incorporates a semipermeable membrane in contact with the heart surface and a delivery reservoir, replenishable via an externally accessible refill port. Luciferase-expressing MSCs were loaded before implantation (control) and optionally re-filled (day 4). Figure reproduced from [147]. c Synthesis of PTFU (an ROS scavenger) combined with PTK and PPF is clicked with pro-angiogenic REDV peptides to create a multifunctional macroporous cardiac patch. The cardiac patch is further loaded with rosuvastatin and surgically implanted onto the LV ischemic areas of rat hearts in an acute MI model. In vivo, the patch acts as a ROS scavenger and regulates MF phenotype. Figure reproduced from [321]

Fig. 6

Injectable materials, such as hydrogels, potentiate minimally invasive and local delivery of therapeutic cargo to the heart via intramyocardial or pericardial injection. a Hydrogels loaded with cells and biologics can be delivered to aid in immunomodulation, while the hydrogels themselves provide needed mechanical restraint of the infarct. b Shear-thinning Ad-HA and CD-HA hydrogels including IL-10-loaded NorHA microgels were injected into the border zone of the infarct in a rat MI model. Local delivery of IL-10 decreased CD68⁺ MF after 1 week. Figure reproduced from [167]. c The pericardial space acts as a natural mold for hydrogels to form a cardiac patch in situ and release loaded therapeutics. Pericardial injection of methacrylated HA hydrogels with MSC-derived exosomes in pigs increases exosome retention in the heart and offers a local and minimally invasive delivery approach. Figure reproduced from [151]