TY - JOUR
T1 - Drug-Free ROS Sponge Polymeric Microspheres Reduce Tissue Damage from Ischemic and Mechanical Injury
AU - O'Grady, Kristin P.
AU - Kavanaugh, Taylor E.
AU - Cho, Hongsik
AU - Ye, Hanrong
AU - Gupta, Mukesh K.
AU - Madonna, Megan C.
AU - Lee, Jinjoo
AU - O'Brien, Christine M.
AU - Skala, Melissa C.
AU - Hasty, Karen A.
AU - Duvall, Craig L.
N1 - Funding Information:
*E-mail: [email protected]. Address: Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, PMB 351631, 2301 Vanderbilt Place, Nashville, TN 37235-1631, USA. ORCID Taylor E. Kavanaugh: 0000-0002-8798-2670 Present Address ⊥M.C.S. is currently at Morgridge Institute for Research and Department of Biomedical Engineering, University of Wisconsin−Madison Author Contributions †K.P.O., T.E.K., and H.C. contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding This work was supported by a Vanderbilt Discovery Grant, NIH R21 HL109748; American Heart Association Grant-in-Aid 12GRNT 12060235; and DOD PRORP OR130302. K.P.O. was supported by a P.E.O. Scholar Award and an NSF Graduate Research Fellowship DGE-0909667. T.E.K was supported by the NSF Graduate Research Fellowship Program under Grant 1445197. K.A.H and H.C. were supported by funds from a VA Merit Award. Notes The authors declare no competing financial interest.
Funding Information:
This work was supported by a Vanderbilt Discovery Grant, NIH R21 HL109748; American Heart Association Grant-in-Aid 12GRNT 12060235; and DOD PRORP OR130302. K.P.O. was supported by a P.E.O. Scholar Award and an NSF Graduate Research Fellowship DGE-0909667. T.E.K was supported by the NSF Graduate Research Fellowship Program under Grant 1445197. K.A.H and H.C. were supported by funds from a VA Merit Award.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2018/4/9
Y1 - 2018/4/9
N2 - The inherent antioxidant function of poly(propylene sulfide) (PPS) microspheres (MS) was dissected for different reactive oxygen species (ROS), and therapeutic benefits of PPS-MS were explored in models of diabetic peripheral arterial disease (PAD) and mechanically induced post-traumatic osteoarthritis (PTOA). PPS-MS (∼1 μm diameter) significantly scavenged hydrogen peroxide (H2O2), hypochlorite, and peroxynitrite but not superoxide in vitro in cell-free and cell-based assays. Elevated ROS levels (specifically H2O2) were confirmed in both a mouse model of diabetic PAD and in a mouse model of PTOA, with greater than 5- and 2-fold increases in H2O2, respectively. PPS-MS treatment functionally improved recovery from hind limb ischemia based on ∼15-25% increases in hemoglobin saturation and perfusion in the footpads as well as earlier remodeling of vessels in the proximal limb. In the PTOA model, PPS-MS reduced matrix metalloproteinase (MMP) activity by 30% and mitigated the resultant articular cartilage damage. These results suggest that local delivery of PPS-MS at sites of injury-induced inflammation improves the vascular response to ischemic injury in the setting of chronic hyperglycemia and reduces articular cartilage destruction following joint trauma. These results motivate further exploration of PPS as a stand-alone, locally sustained antioxidant therapy and as a material for microsphere-based, sustained local drug delivery to inflamed tissues at risk of ROS damage.
AB - The inherent antioxidant function of poly(propylene sulfide) (PPS) microspheres (MS) was dissected for different reactive oxygen species (ROS), and therapeutic benefits of PPS-MS were explored in models of diabetic peripheral arterial disease (PAD) and mechanically induced post-traumatic osteoarthritis (PTOA). PPS-MS (∼1 μm diameter) significantly scavenged hydrogen peroxide (H2O2), hypochlorite, and peroxynitrite but not superoxide in vitro in cell-free and cell-based assays. Elevated ROS levels (specifically H2O2) were confirmed in both a mouse model of diabetic PAD and in a mouse model of PTOA, with greater than 5- and 2-fold increases in H2O2, respectively. PPS-MS treatment functionally improved recovery from hind limb ischemia based on ∼15-25% increases in hemoglobin saturation and perfusion in the footpads as well as earlier remodeling of vessels in the proximal limb. In the PTOA model, PPS-MS reduced matrix metalloproteinase (MMP) activity by 30% and mitigated the resultant articular cartilage damage. These results suggest that local delivery of PPS-MS at sites of injury-induced inflammation improves the vascular response to ischemic injury in the setting of chronic hyperglycemia and reduces articular cartilage destruction following joint trauma. These results motivate further exploration of PPS as a stand-alone, locally sustained antioxidant therapy and as a material for microsphere-based, sustained local drug delivery to inflamed tissues at risk of ROS damage.
KW - diabetes
KW - inflammation
KW - microspheres
KW - osteoarthritis
KW - peripheral arterial disease
KW - reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85045213276&partnerID=8YFLogxK
U2 - 10.1021/acsbiomaterials.6b00804
DO - 10.1021/acsbiomaterials.6b00804
M3 - Article
AN - SCOPUS:85045213276
SN - 2373-9878
VL - 4
SP - 1251
EP - 1264
JO - ACS Biomaterials Science and Engineering
JF - ACS Biomaterials Science and Engineering
IS - 4
ER -