Decellularized Extracellular Matrix Hydrogels as a Delivery Platform for MicroRNA and Extracellular Vesicle Therapeutics

Abstract

In the last decade, the use of microRNA (miRNA) and extracellular vesicle (EV) therapies has emerged as an alternative approach to mitigate the negative effects of several disease pathologies ranging from cancer to tissue and organ regeneration; however, delivery approaches towards target tissues have not been optimized. To alleviate these challenges, including rapid diffusion upon injection and susceptibility to degradation, porcine-derived decellularized extracellular matrix (ECM) hydrogels are examined as a potential delivery platform for miRNA and EV therapeutics. The incorporation of EVs and miRNA antagonists, including anti-miR and antago-miR, in ECM hydrogels results in a prolonged release as compared to the biologic agents alone. In addition, individual in vitro assessments confirm the bioactivity of the therapeutics upon release from the ECM hydrogels. This work demonstrates the feasibility of encapsulating miRNA and EV therapeutics in ECM hydrogels to enhance delivery and potentially efficacy in later in vivo applications.

Bioengineering strategies for the treatment of peripheral arterial disease

“…Various EVs derived from different cell sources, including MSCs [ 36 ], cardiac progenitor cells [ 37 ], glioblastoma cells [ 38 ], and CD34 + stem cells [ 39 ], have been explored for the purposes of therapeutic angiogenesis in PAD. Like growth factors, EVs diffuse rapidly and require large doses, thus treating with EVs alone is insufficient.…”

“…2 ) [ 40 ]. In similar work, the incorporation of EVs and miRNA antagonists, including anti-miR and antago-miR, in porcine-derived decellularized ECM hydrogels lead to a prolonged release as compared to the use of these biologic agents alone [ 37 ].…”

“… Biomaterial Cell Type Factor Comment Animal Model Delivery Method Ref. Glycosylated chitosan hydrogel MSCs derived from human placenta VEGF and miR-126 Augmented the angiogenic effects of HUVECs in vitro Superior angiogenic effects and ameliorated limb function BALB/c nude mice; 8–12 weeks old; Transgenic Vegfr2-luc mice The femoral artery ligated and excised between the proximal location near the groin and the distal location close to the knee Adductor muscle; 100 μg exosomes in100 μL PBS; 3 injection sites [ 36 ] Porcine-derived decellularized ECM hydrogel Human cardiac progenitor cells None An advantageous platform for the delivery of miRNAs and EVs None None None [ 37 ] Alginate beads Glioblastoma cells (A-172) miR-221, glypican-1, syndecan-4 Enhanced endothelial cell proliferation tubule formation in vitro Promoted revascularization in comparison to alginate gels and FGF-2 alone C57BL/6 mice The femoral artery ligated Ischemic hindlimb; Delivery volume: 200 μL; ~13 billion exosomes/mouse; 1.5 μg/mouse [ 38 ] None Human CD34 + stem cells miR-126–3p Induced therapeutic angiogenesis mediated by exosomal miR-126–3p Internalized by endothelial cells in the ischemic tissue to induce cell cycle induction, angiogenesis and proliferation Balb C mice; 8–10 weeks old A ligation was made around the femoral artery and all arterial branches were removed Ischemic hindlimb; Delivery volume: 20 μL; 4 injection sites; 5 × 10 6 cells/kg [ 39 ] <...>…”

Toward Cardiac Regeneration: Combination of Pluripotent Stem Cell-Based Therapies and Bioengineering Strategies

“…The use of a decellularized extracellular matrix (dECM) directly isolated from tissues represents another option to build scaffolds for cardiac tissue engineering and has been applied in several conditions, from myocardial infarction to orthopedic injures (Shen et al, 2011;Perea-Gil et al, 2016;Hernandez et al, 2018;Hussey et al, 2018). dECM contains adhesion proteins, such as laminin or fibronectin, able to promote cell attachment, and retains biochemical cues and mechanical properties of the native tissue; these characteristics are critical for the subsequent recellularization of the scaffold.…”

Targeted Drug Delivery via the Use of ECM-Mimetic Materials

“…Owing to the preservation of biochemical cues from the native tissue microenvironment, dECM matrices trigger cellular response that have been exploited clinically in tissue engineering and regenerative medicine [Tissue Mend R (Stryker Orthopaedics, United States), AlloDerm R (LifeCell Corp. United States), CutffPatch TM (Organogenesis, United States)]. In addition, the delivery of growth factors (Seif-Naraghi et al, 2012) and microRNA (Hernandez et al, 2018) using dECM has recently been explored.…”