Keratin Hydrogel Enhances In Vivo Skeletal Muscle Function in a Rat Model of Volumetric Muscle Loss.
Volumetric muscle loss (VML) injuries exceed the considerable intrinsic regenerative capacity of skeletal muscle, resulting in permanent functional and cosmetic deficits. VML and VML-like injuries occur in military and civilian populations, due to trauma and surgery as well as due to a host of congenital and acquired diseases/syndromes. Current therapeutic options are limited, and new approaches are needed for a more complete functional regeneration of muscle. A potential solution is human hair-derived keratin (KN) biomaterials that may have significant potential for regenerative therapy. The goal of these studies was to evaluate the utility of keratin hydrogel formulations as a cell and/or growth factor delivery vehicle for functional muscle regeneration in a surgically created VML injury in the rat tibialis anterior (TA) muscle. VML injuries were treated with KN hydrogels in the absence and presence of skeletal muscle progenitor cells (MPCs), and/or insulin-like growth factor 1 (IGF-1), and/or basic fibroblast growth factor (bFGF). Controls included VML injuries with no repair (NR), and implantation of bladder acellular matrix (BAM, without cells). Initial studies conducted 8 weeks post-VML injury indicated that application of keratin hydrogels with growth factors (KN, KN+IGF-1, KN+bFGF, and KN+IGF-1+bFGF, n = 8 each) enabled a significantly greater functional recovery than NR (n = 7), BAM (n = 8), or the addition of MPCs to the keratin hydrogel (KN+MPC, KN+MPC+IGF-1, KN+MPC+bFGF, and KN+MPC+IGF-1+bFGF, n = 8 each) (p < 0.05). A second series of studies examined functional recovery for as many as 12 weeks post-VML injury after application of keratin hydrogels in the absence of cells. A significant time-dependent increase in functional recovery of the KN, KN+bFGF, and KN+IGF+bFGF groups was observed, relative to NR and BAM implantation, achieving as much as 90% of the maximum possible functional recovery. Histological findings from harvested tissue at 12 weeks post-VML injury documented significant increases in neo-muscle tissue formation in all keratin treatment groups as well as diminished fibrosis, in comparison to both BAM and NR. In conclusion, keratin hydrogel implantation promoted statistically significant and physiologically relevant improvements in functional outcomes post-VML injury to the rodent TA muscle.
1 Biomedical Engineering Department, University of Virginia , Charlottesville, Virginia.|2 Wake Forest Institute for Regenerative Medicine, Wake Forest University , Winston-Salem, North Carolina.
J A
JA
Passipieri
2 Wake Forest Institute for Regenerative Medicine, Wake Forest University , Winston-Salem, North Carolina.|3 Fischell Department of Bioengineering, University of Maryland , College Park, Maryland.
H B
HB
Baker
2 Wake Forest Institute for Regenerative Medicine, Wake Forest University , Winston-Salem, North Carolina.
Mevan
M
Siriwardane
4 KeraNetics, LLC , Winston-Salem, North Carolina.
Mary D
MD
Ellenburg
2 Wake Forest Institute for Regenerative Medicine, Wake Forest University , Winston-Salem, North Carolina.
Manasi
M
Vadhavkar
5 Department of Chemical, Paper and Biomedical Engineering, Miami University , Oxford, Ohio.
Justin M
JM
Saul
4 KeraNetics, LLC , Winston-Salem, North Carolina.
Seth
S
Tomblyn
4 KeraNetics, LLC , Winston-Salem, North Carolina.
Luke
L
Burnett
1 Biomedical Engineering Department, University of Virginia , Charlottesville, Virginia.|2 Wake Forest Institute for Regenerative Medicine, Wake Forest University , Winston-Salem, North Carolina.|6 Orthopaedics Department, University of Virginia , Charlottesville, Virginia.
George J
GJ
Christ
D000818:Animals; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007633:Keratins / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000293:injuries / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D012038:Regeneration / Q000187:drug effects*
D020100:Hydrogels; C548904:insulin-like growth factor-1, rat; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D007633:Keratins
FGF; IGF; functional recovery; keratin; myogenesis; volumetric muscle loss