Extracellular Matrix Hydrogel Promotes Tissue Remodeling, Arteriogenesis, and Perfusion in a Rat Hindlimb Ischemia Model.
OBJECTIVE
This study aimed to examine acellular extracellular matrix based hydrogels as potential therapies for treating peripheral artery disease (PAD). We tested the efficacy of using a tissue specific injectable hydrogel, derived from decellularized porcine skeletal muscle (SKM), compared to a new human umbilical cord derived matrix (hUC) hydrogel, which could have greater potential for tissue regeneration because of its young tissue source age.


BACKGROUND
The prevalence of PAD is increasing and can lead to critical limb ischemia (CLI) with potential limb amputation. Currently there are no therapies for PAD that effectively treat all of the underlying pathologies, including reduced tissue perfusion and muscle atrophy.


METHODS
In a rodent hindlimb ischemia model both hydrogels were injected 1-week post-surgery and perfusion was regularly monitored with laser speckle contrast analysis (LASCA) to 35 days post-injection. Histology and immunohistochemistry were used to assess neovascularization and muscle health. Whole transcriptome analysis was further conducted on SKM injected animals on 3 and 10 days post-injection.


RESULTS
Significant improvements in hindlimb tissue perfusion and perfusion kinetics were observed with both biomaterials. End point histology indicated this was a result of arteriogenesis, rather than angiogenesis, and that the materials were biocompatible. Skeletal muscle fiber morphology analysis indicated that the muscle treated with the tissue specific, SKM hydrogel more closely matched healthy tissue morphology. Short term histology also indicated arteriogenesis rather than angiogenesis, as well as improved recruitment of skeletal muscle progenitors. Whole transcriptome analysis indicated that the SKM hydrogel caused a shift in the inflammatory response, decreased cell death, and increased blood vessel and muscle development.


CONCLUSIONS
These results show the efficacy of an injectable ECM hydrogel alone as a potential therapy for treating patients with PAD. Our results indicate that the SKM hydrogel improved functional outcomes through stimulation of arteriogenesis and muscle progenitor cell recruitment.
Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA.
Jessica L
JL
Ungerleider
Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA.
Todd D
TD
Johnson
Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA.
Melissa J
MJ
Hernandez
Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA.
Dean I
DI
Elhag
Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA.
Rebecca L
RL
Braden
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado, Aurora, CA, USA.
Monika
M
Dzieciatkowska
Animal Care Program, University of California San Diego, La Jolla, CA, USA.
Kent G
KG
Osborn
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado, Aurora, CA, USA.
Kirk C
KC
Hansen
Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA, USA.
Ehtisham
E
Mahmud
Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA.
Karen L
KL
Christman
Biomaterial; Critical Limb Ischemia; Decellularization; Hydrogel; Injectable; Peripheral Artery Disease