Ease of Application and Removal of Common Total-Contact Cast Systems Used in the Podiatric Medical Community

Ludwig, Kathryn; Homer, Von; Jensen, Jeffrey L.

doi:10.7547/17-222

Cited by 2 publications

(2 citation statements)

References 9 publications

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“…In addition, total-contact casting is not widely practiced, as less than 6% of eligible patients receive this treatment. 13 In a study of 194 patients (67.5% with WG1 and 31.4% with WG2−3), 65% of the DFUs treated with standard of care healed completely with a median time of 5 weeks, 16% did not heal in 6 months, 15% underwent amputation, and 4% died. 14 Patients with infected or ischemic DFUs had increased risk of undergoing a lowerlimb amputation (11-or 3-fold, respectively) and took a longer time for wound healing.…”

Section: Challenges In Treatment Of Dfusmentioning

confidence: 99%

“…However, the total-contact cast cannot be removed, making daily wound care impossible. In addition, total-contact casting is not widely practiced, as less than 6% of eligible patients receive this treatment . In a study of 194 patients (67.5% with WG1 and 31.4% with WG2–3), 65% of the DFUs treated with standard of care healed completely with a median time of 5 weeks, 16% did not heal in 6 months, 15% underwent amputation, and 4% died .…”

Section: Introductionmentioning

confidence: 99%

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Strategy for Treatment of Infected Diabetic Foot Ulcers

2021

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Conspectus Diabetic foot ulcers (DFUs) are chronic wounds that develop in 30% of diabetic patients. In DFUs, the normal wound healing process consisting of inflammation, angiogenesis, and extracellular matrix (ECM) remodeling is dysregulated and stalled. Upon injury, neutrophils and monocytes arrive at the wound and secrete matrix metalloproteinase (MMP)-8 and reactive oxygen species (ROS). ROS activates nuclear factor kappa beta (NF-κB), which upregulates MMP-9. Monocytes become macrophages, secreting tumor growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) for angiogenesis, resulting in remodeling of the ECM. MMP-9 cleaves laminin for keratinocyte migration. MMP-8 is beneficial for remodeling the ECM and healing the wound. In DFUs, the excess unregulated MMP-9 is detrimental, destroying the ECM and preventing the wound from healing. DFUs are typically infected, many with biofilm-producing bacteria that are resistant to antibiotics. Infection increases the time for wound healing and the likelihood for a lower-limb amputation. Despite the use of antibiotics, amputations occur in 24.5% of patients with DFUs. Clearly, new strategies for treatment of DFUs are needed. With the use of an affinity resin that binds exclusively to the active forms of MMPs and proteomics, we identified two proteinases, MMP-8 and MMP-9, in wounds of diabetic mice and diabetic humans. With the use of selective inhibitors, gene ablation of MMP-9, and exogenous application of MMP-8, we demonstrated that MMP-8 is beneficial to wound repair and that MMP-9 prevents the diabetic wound from healing. Our research has shown that infection increases active MMP-9, increasing inflammation and decreasing angiogenesis. As a result, infected diabetic wounds take a longer time to heal than uninfected ones. We found that active MMP-9 and NF-κB increased in human DFUs with wound severity and infection. The best strategy for treatment of DFUs is to selectively inhibit the detrimental proteinase MMP-9 without affecting the beneficial MMP-8 so that the body can repair the wound. Lead optimization of the thiirane class of inhibitors led to the discovery of (R)-ND-336, a potent (19 nM) and selective (450-fold) MMP-9 inhibitor. (R)-ND-336 accelerated wound healing in diabetic mice by decreasing ROS and NF-κB, lowering inflammation, and increasing angiogenesis. (R)-ND-336 in combination with the antibiotic linezolid improved wound healing in infected diabetic mice by inhibiting MMP-9, which mitigated macrophage infiltration and increased angiogenesis, thereby restoring the normal wound healing process.

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Section: Challenges In Treatment Of Dfusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%