Cardiac extracellular matrix hydrogel enriched with polyethylene glycol presents improved gelation time and increased on-target site retention of extracellular vesicles Articles uri icon

authors

  • GOMEZ CID, LIDIA
  • LOPEZ DONAIRE, MARIA LUISA
  • VELASCO BAYON, DIEGO
  • MARÍN, VÍCTOR
  • GONZALEZ, MARIA ISABEL
  • SALINAS RODRIGUEZ, BEATRIZ
  • CUSSO MULA, LORENA
  • GARCÍA, ÁNGEL
  • BRAVO, SUSANA BELÉN
  • FERNÁNDEZ-SANTOS, MARÍA EUGENIA
  • ELVIRA, CARLOS
  • SIERRA, JOHANNA
  • ARROBA, ESTER
  • BAÑARES, RAFAEL
  • GRIGORIAN-SHAMAGIAN, LILIAN
  • FERNÁNDEZ-AVILÉS, FRANCISCO

publication date

  • September 2021

start page

  • 9226

issue

  • 17

volume

  • 22

International Standard Serial Number (ISSN)

  • 1422-0067

abstract

  • Stem-cell-derived extracellular vesicles (EVs) have demonstrated multiple beneficial effects in preclinical models of cardiac diseases. However, poor retention at the target site may limit their therapeutic efficacy. Cardiac extracellular matrix hydrogels (cECMH) seem promising as drug-delivery materials and could improve the retention of EVs, but may be limited by their long gelation time and soft mechanical properties. Our objective was to develop and characterize an optimized product combining cECMH, polyethylene glycol (PEG), and EVs (EVs–PEG–cECMH) in an attempt to overcome their individual limitations: long gelation time of the cECMH and poor retention of the EVs. The new combined product presented improved physicochemical properties (60% reduction in half gelation time, p < 0.001, and threefold increase in storage modulus, p < 0.01, vs. cECMH alone), while preserving injectability and biodegradability. It also maintained in vitro bioactivity of its individual components (55% reduction in cellular senescence vs. serum-free medium, p < 0.001, similar to EVs and cECMH alone) and increased on-site retention in vivo (fourfold increase vs. EVs alone, p < 0.05). In conclusion, the combination of EVs–PEG–cECMH is a potential multipronged product with improved gelation time and mechanical properties, increased on-site retention, and maintained bioactivity that, all together, may translate into boosted therapeutic efficacy.

keywords

  • extracellular vesicles; hydrogel; extracellular matrix; drug delivery; polyethylene glycol; cardiac regenerative therapy