Exogenous miR-29B Delivery Through a Hyaluronan-Based Injectable System Yields Functional Maintenance of the Infarcted Myocardium

Abstract

Myocardial infarction (MI) results in debilitating remodeling of the myocardial extracellular matrix (ECM). In this proof-of-principle study it was sought to modulate this aggressive remodeling by injecting a hyaluronic acid-based reservoir delivering exogenous microRNA-29B (miR-29B). This proof-of-principal study was executed whereby myocardial ischemia/reperfusion was performed on C57BL/6 mice for 45 min after which five 10 μL boluses of a hydrogel composed of thiolated hyaluronic acid cross-linked with poly (ethylene glycol) diacrylate, containing exogenous miR-29B as an active therapy, were injected into the border zone of the infarcted myocardium. Following surgery, the myocardial function of the animals was monitored up to 5 weeks. Delivering miR-29B locally using an injectable hyaluronan-based hydrogel resulted in the maintenance of myocardial function at 2 and 5 weeks following MI in this proof-of-principle study. In addition, while animals treated with the control of a nontargeting miR delivered using the hyaluronan-based hydrogel had a significant deterioration of myocardial function, those treated with miR-29B did not. Histological analysis revealed a significantly decreased presence of elastin and significantly less immature/newly deposited collagen fibers at the border zone of the infarct. Increased vascularity of the myocardial scar was also detected and Raman microspectroscopy discovered significantly altered ECM-specific biochemical signals at the border zone of the infarct. This preclinical proof-of-principle study demonstrates that an injectable hyaluronic acid hydrogel system could be capable of delivering miR-29B toward maintaining cardiac function following MI. In addition, Raman microspectroscopy revealed subtle, yet significant changes in ECM organization and maturity. These findings have great potential with regard to using injectable biomaterials as a local treatment for ischemic tissue and exogenous miRs to modulate tissue remodeling.

Injectable Hydrogel-Based Nanocomposites for Cardiovascular Diseases

“…According to the pathway of MMP2 related to the cardiac harmful remodeling process, an injectable hydrogel complexed with siRNA up-regulate the hydrolytic activity of MMP2 protein to inhibit the harmful remodeling process of the heart and promote heart repair . In addition, an injectable Hyaluronan-Based hydrogel modulate remodeling of the myocardial extracellular matrix (ECM) by injecting a hyaluronic acid-based reservoir delivering exogenous microRNA-29B (miR-29B) (Monaghan et al, 2018). Noteworthily, protocols for injection-based delivery of Cre-CPP by ultrasound-guided injection to cardiac muscle in mice is mature owing to widely used technique of Cre-mediated DNA recombination at loxP sites (Chien et al, 2017), which provides a feasible mean for genetic material composite hydrogel.…”

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

“…[102,106] Whether one of the routes may be better suited for clinical translation remains to be elucidated, although in situ transfecting scaffolds hold greater potential to exist as "off-the-shelf" products. [107] Many distinct scaffold types have been tuned to serve the purpose of miRNA delivery, including several hydrogels, [58,92,106,[108][109][110][111][112][113][114] electrospun fibers, [63,[115][116][117][118] and more prolifically porous or spongy scaffolds. [46,47,50,54,55,96,112,[119][120][121][122][123][124][125][126][127][128][129][130] Before reviewing the details of their applications, summarized in Table 2 and described further in the next section, we will discuss the key characteristics making these materials amenable to miRNA delivery.…”

“…Other natural polymers included in miRNA eluting hydrogels are alginate, [112] silk fibrin, [111] fibrinogen, thrombin, and Matrigel. [92,110] Of note, hydrogels are the first biomaterials used successfully for the delivery of naked miRNA therapeutics, [106,108,109] that is, without the addition of a delivery vector. While this strategy simplifies the fabrication of the final miRNA-activated scaffolds, it may also accelerate the release of the cargo, leading to undesired bolus effects.…”

“…[108,109] Firstly it was shown to ameliorate ECM remodeling when delivered from a collagen-based scaffold. Primary fibroblasts seeded on scaffolds loaded with naked miR-29b demonstrated reduced collagen type I and collagen type III mRNA expression of ≈40% and ≈15% respectively following 2 weeks of in vitro culture.…”

“…The scaffolds were used to treat full thickness rat skin excisional wounds in vivo and showed reduced wound contraction, a 25% increase in granulation tissue, increased collagen type III/I ratios and improved MMP-8: tissue inhibitor of metalloproteinase (TIMP)-1 ratio when the scaffolds were functionalized with miR-29b in a dose-dependent manner (0.5 or 5 µg miR-29b). As myocardial infarction (MI) results in debilitating remodeling of the myocardial ECM, Monaghan et al [109] performed a proof-of-principle study to modify aggressive myocardial remodeling by injecting a HyA-based hydrogel delivering exogenous miR-29b. Myocardial ischemia/reperfusion was performed on C57BL/6 mice for 45 min after the miRNA-activated hydrogel, composed of thiolated-HyA cross-linked with PEG-diacrylate (Glycosan HyStem) and naked exogenous miR29b, was injected into the border zone of the infarcted myocardium.…”