Restoring Prohealing/Remodeling-Associated M2a/c Macrophages Using ON101 Accelerates Diabetic Wound Healing

Lin, Ching-Wen; Chen, Chih‐Chiang; Huang, Wen‐Yen; Chen, Yen‐Yu; Chen, Shiou-Ting; Chou, Hung‐Wen; Hung, Chien-Ming; Chen, Wan-Jiun; Lu, Chia-Sing; Nian, Shi-Xin; Chen, Shyi-Gen; Chang, Hsuen-Wen; Chang, Vincent H.S.; Liu, Liying; Kuo, Ming-Liang; Chang, Stephen S.

doi:10.1016/j.xjidi.2022.100138

Cited by 23 publications

(23 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…M2 macrophages promote angiogenesis and participate in tissue remodeling and repair. 43 As a typical M2 macrophage marker, the CD206 level was found to increase in the Shik-Fe group, four times higher than that in the control group (Figure 6E,F).…”

Section: ■ Results and Discussionmentioning

confidence: 83%

Nanosized Shikonin-Fe(III) Coordination Material for Synergistic Wound Treatment: An Initial Explorative Study

Feng

Cong

et al. 2022

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

Shikonin (Shik), a natural pigment, has received growing interest in various biomedical fields due to its anti-inflammatory, antitumor, antimicrobial, and antioxidant ability. However, some inherent characteristics of Shik, such as its virulence, low bioavailability, and poor solubility, have limited its biomedical applicability. Here, we reported a facile synthetic method to produce the Shik-iron (III) nanoparticles (Shik-Fe NPs), which could overcome these limitations of Shik. The synthesized Shik-Fe NPs possessed a uniform size range of 110 ± 10 nm, negative surface charges, good water dispersity, and high safety. Iron distributed uniformly inside Shik-Fe NPs, and iron constituted 20% of total mass in PEGylated Shik-Fe NPs. When interacting with activated macrophages, Shik-Fe NPs significantly reduced the level of cellular inflammatory factors, for example, iNOS, IL-1β, and TNF-α. Furthermore, the Shik-Fe NPs demonstrated synergistic anti-inflammation and anti-bacterial properties in vivo, since they could release Fe3+ and Shik to eradicate bacteria (Staphylococcus aureus and P. aeruginosa were used as model microbes here) during wound infections and provide full recovery for scald wounds. Collectively, the study established a dual-functional Shik-derived nanoplatform, which could be useful for the treatment of various inflammation-involved diseases.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 83%

Nanosized Shikonin-Fe(III) Coordination Material for Synergistic Wound Treatment: An Initial Explorative Study

Feng

Cong

et al. 2022

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

show abstract

“…ON101 is the first macrophage-regulating agent to be approved for the treatment of diabetic foot ulcers topically in Taiwan. ON101 was formulated using identified, defined fractions of Plectranthus amboinicus (PA-F4) and Centella asiatica (S1) in a proprietary ratio [ 97 ]. The mechanism via which ON101 promotes diabetic wound healing occurs dually through the attenuation of M1 macrophage polarization and the enrichment of M2 macrophages.…”

Section: Innovative Therapies For Diabetic Foot Ulcersmentioning

confidence: 99%

“…PA-F4, which is the major active pharmaceutical ingredient (API) of ON101, exerts its anti-inflammation action by suppressing LPS-induced macrophage activation via the down-regulation of NF-κB-mediated NLRP3 inflammasome activation, thus inhibiting the release of IL-1β, IL-18, and IL-6 from macrophages [ 98 ]. In addition, administration of ON101 during the polarizing progression of M1 macrophages from either a THP-1 monocyte cell line or monocytes isolated from peripheral blood mononuclear cells (PBMCs) results in the suppression of the expression of genes encoding the M1 markers CD80 and CD86 [ 97 ]. The expression of M1-associated cytokines (IL-6, IL-1β, and TNF-α) and chemokines (CXCL1, CXCL9-12, and CCL12) was also suppressed by ON101.…”

Section: Innovative Therapies For Diabetic Foot Ulcersmentioning

confidence: 99%

“…The expression of M1-associated cytokines (IL-6, IL-1β, and TNF-α) and chemokines (CXCL1, CXCL9-12, and CCL12) was also suppressed by ON101. Conversely, chemokines including CCL2, IL-4, and CCL3, which have been shown to display M2 macrophage-recruiting abilities [ 25 , 53 , 54 , 99 ], were up-regulated upon ON101 treatment, suggesting that M1 macrophage suppression leads to the alleviation of the chronic inflammatory cytokine profile and alters the microenvironment to favour M2 macrophage recruitment [ 97 ]. Furthermore, ON101 stimulated the expression of GCSF and CXCL3 from adipocyte progenitor cells (ADPCs), which are a type of skin-resident mesenchymal stem cell.…”

Section: Innovative Therapies For Diabetic Foot Ulcersmentioning

confidence: 99%

“…Furthermore, ON101 stimulated the expression of GCSF and CXCL3 from adipocyte progenitor cells (ADPCs), which are a type of skin-resident mesenchymal stem cell. In vitro treatment with GCSF or CXCL3 recombinant proteins demonstrated that GCSF enhanced CD206 and CD163 expression, whereas CXCL3 enhanced CD163 expression in M1 macrophages, suggesting that these two proteins promote the M1-to-M2 transition [ 97 ]. A genome-wide screening would be critical to explore the manner in which ON101 deeply alters the behaviour of ADPCs.…”

Section: Innovative Therapies For Diabetic Foot Ulcersmentioning

confidence: 99%

See 2 more Smart Citations

New Horizons of Macrophage Immunomodulation in the Healing of Diabetic Foot Ulcers

Lin

Hung²,

Chen³

et al. 2022

Pharmaceutics

View full text Add to dashboard Cite

Diabetic foot ulcers (DFUs) are one of the most costly and troublesome complications of diabetes mellitus. The wound chronicity of DFUs remains the main challenge in the current and future treatment of this condition. Persistent inflammation results in chronic wounds characterized by dysregulation of immune cells, such as M1 macrophages, and impairs the polarization of M2 macrophages and the subsequent healing process of DFUs. The interactive regulation of M1 and M2 macrophages during DFU healing is critical and seems manageable. This review details how cytokines and signalling pathways are co-ordinately regulated to control the functions of M1 and M2 macrophages in normal wound repair. DFUs are defective in the M1-to-M2 transition, which halts the whole wound-healing machinery. Many pre-clinical and clinical innovative approaches, including the application of topical insulin, CCL chemokines, micro RNAs, stem cells, stem-cell-derived exosomes, skin substitutes, antioxidants, and the most recent Phase III-approved ON101 topical cream, have been shown to modulate the activity of M1 and M2 macrophages in DFUs. ON101, the newest clinically approved product in this setting, is designed specifically to down-regulate M1 macrophages and further modulate the wound microenvironment to favour M2 emergence and expansion. Finally, the recent evolution of macrophage modulation therapies and techniques will improve the effectiveness of the treatment of diverse DFUs.

show abstract

Cost-effectiveness of Novel Macrophage-Regulating Treatment for Wound Healing in Patients With Diabetic Foot Ulcers From the Taiwan Health Care Sector Perspective

Yang

et al. 2023

JAMA Netw Open

Self Cite

View full text Add to dashboard Cite

ImportanceDiabetic foot ulcers (DFUs) and subsequent amputation incur enormous health and economic burdens to patients, health care systems, and societies. As a novel macrophage-regulating drug, ON101 is a breakthrough treatment for DFUs, which demonstrated significant complete wound healing effects in a phase 3 randomized clinical trial, but its economic value remains unknown.ObjectiveTo assess the cost-effectiveness of an ON101 cream added on to general wound care (GWC; ie, conventional treatments for DFUs, which comprised initial and regular foot examinations, ulcer management, comorbidity control, patient education, and multidisciplinary care) vs GWC alone for DFUs from the Taiwan health care sector perspective.Design, Setting, and ParticipantsThis economic evaluation used a hypothetical cohort of patients with diabetes, with characteristics mirroring those of the participants in the ON101 trial. A Markov state-transition simulation model was constructed to estimate costs and health outcomes associated with the ON101 with GWC and GWC alone strategies over a 5-year time horizon, discounting costs and effectiveness at 3% annually. Costs were in 2021 US dollars. Data were sourced from the ON101 trial and supplemented from published literature. Deterministic and probabilistic sensitivity analyses were performed to assess the uncertainty of input parameters and study generalizability. The analysis was designed and conducted from September 1, 2020, to January 31, 2022.ExposuresON101 with GWC vs GWC alone.Main Outcomes and MeasuresDFU-related complications, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio.ResultsPatients in the hypothetical cohort had a mean age of 57 years and an uninfected DFU of 1 to 25 cm2 that was present for 4 or more weeks with a Wagner grade of 1 or 2. Over 5 years, the ON101 with GWC group vs the GWC alone group experienced more healing events, stayed for a longer time in the healing state, and had fewer infected DFUs, gangrene, and amputations (eg, 2787 additional healing events and 2766 fewer infected DFU, 72 fewer amputation, and 7 fewer gangrene events in the ON101 with GWC group vs GWC alone group). The ON101 with GWC strategy vs GWC alone yielded an additional 0.038 QALYs at an incremental cost of $571, resulting in $14 922/QALY gained. Economic results were most sensitive to healing efficacy, drug cost, and health utility of the healing state. Cost-saving results were observed in patient subgroups with poor glycemic control, larger ulcer sizes, longer ulcer durations, and current smoking. The ON101 with GWC strategy was considered cost-effective in 60% to 82% of model iterations against willingness-to-pay thresholds of $32 787/QALY gained to $98 361/QALY gained.Conclusions and RelevanceIn this economic evaluation study using a simulated patient cohort, the ON101 with GWC strategy represented good value compared with GWC alone for patients with DFUs from the Taiwan health care sector perspective and may be prioritized for those with high risks for disease progression of DFUs.

show abstract

Restoring Prohealing/Remodeling-Associated M2a/c Macrophages Using ON101 Accelerates Diabetic Wound Healing

Cited by 23 publications

References 42 publications

Nanosized Shikonin-Fe(III) Coordination Material for Synergistic Wound Treatment: An Initial Explorative Study

Nanosized Shikonin-Fe(III) Coordination Material for Synergistic Wound Treatment: An Initial Explorative Study

New Horizons of Macrophage Immunomodulation in the Healing of Diabetic Foot Ulcers

Cost-effectiveness of Novel Macrophage-Regulating Treatment for Wound Healing in Patients With Diabetic Foot Ulcers From the Taiwan Health Care Sector Perspective

Contact Info

Product

Resources

About