ON101 Cream Increases the Wound Healing Rate in Diabetic Patients with Uremia—Cases Report ()
1. Introduction
Diabetes is one of the most common diseases worldwide, estimated to affect 693 million adults by 2045, according to the report of the International Diabetes Federation (IDF) [1] . Vascular complications, including cardiovascular disease (CVD), chronic kidney disease (CKD), diabetic retinopathy, and neuropathy, are the leading cause of morbidity and mortality in diabetic patients [2] . CKD as well as the leading cause of end-stage renal disease (ESRD), suggested diabetic patients wereat a higher risk to lose renal functions and need undergo lifelong dialysis or even renal transplantation [3] [4] .
Diabetic foot ulcer (DFU) affects up to 34% of diabetes patients, causing enormous economic burden and reducing life quality [5] . The International Working Group on the Diabetic Foot (IWGDF) has proposed that diabetic patients with ESRD should be classified as category 3 in podiatric risk [6] , suggesting that impaired renal function is tightly associated with ulcer management strategies. Studies revealed that dialysis is a critical risk factor for the prevalence of ulceration in diabetes patients [7] [8] [9] . In addition, diabetic patients who undergo dialysis treatment have disproportionately higher rates of amputation caused by poor healing rate [10] [11] [12] . Furthermore, a retrospective study demonstrated that reduced eGFR level, which means regression of kidney function, in patients with DFU was associated with poor prognoses of both the limbs and mortality [13] . These observations indicate that impaired renal function and dialysis treatment would prolong diabetic foot ulcer healing. Hence, the improvement of the healing rate of DFU patients whose renal function was impaired and who underwent dialysis was an emergent medical need.
ON101 topical cream has effectively promoted wound healing in diabetic patients by modulating the activity of M1 and M2 macrophages [14] [15] . Current research revealed long-term peritoneal dialysis results in acute and chronic inflammation, with elevated relative inflammatory cytokines [16] . A hypothesis was made that ON101 may overcome the chronic inflammation caused by dialysis and efficious promote wound healing. Here, we report five dialysis patients who receive ON101 as a therapeutic option to manage their DUFs in Taiwan region. The results indicate that ON101 maintained good healing efficacy in dialysis DFUs.
2. Case Series
2.1. Case 1
A 64-year-old male patient with hypertension, type 2 DM, and uremia under regular hemodialysis for more than 6 years. He has a high BMI of 34.9 and has smoked a pack of cigarettes every day for more than 50 years. He visited the plastic surgery outpatient department (OPD) of Cathay General Hospital (CGH) due to a chronic unhealed wound with pus discharge at the right lateral malleolar area for 2 weeks. He suffered from a right ankle fracture post ORIF for 10 years, and multiple implanted nails were found in the X-ray. The duplex scan showed 50% stenosis of the right anterior tibia artery. After multiple debridements, negative pressure wound therapy and parenteral antibiotics treatment, the wound is getting better, and the patient is discharged from the hospital, followed by OPD management. However, 2 months after he was discharged, the wound size didn’t decrease due to persistent inflammation with over-granulation tissue, even though we used other kinds of artificial dressings to treat the wound. We used a new macrophage-modulating drug, ON101 (Oneness Biotech Co, Ltd., Taiwan region), for wound treatment. The wound size was 8.96 cm2 when he started to use the ON101 (Figure 1(a)). We applied topically with gauze twice daily, the wound quickly down-grade from 2A to 1A after 2 weeks of treatment (Figure 1(b)) and completely healed 8 weeks after ON101 application (Figure 1(c), Table 1).
2.2. Case 2
A 60-year-old male patient is a victim of parkinsonism and uremia under regular hemodialysis for more than 10 years. He also suffered from hyperlipidemia, CAD and congestive heart disease. He came to plastic surgery OPD of CGH due to right foot pain, and right 5th toe gangrene noted for several weeks. Right 5th toe amputation was performed, but he encountered poor wound healing after surgery. He was admitted for further wound management. Surgical debridement was performed, and an artificial dermis was applied to the wound. But the
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Table 1. Demography information of five subjects.
BMI, Body Mass Index; DM, Diabetes Mellitus; UT, University of Texas; eGFR, estimated Glomerular filtration rate.
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Figure 1. Patient No. 1 with target ulcer on right ankle. (a) Before treatment; (b) 2 weeks of ON101 treatment; (c) 8 weeks afterON101 treatment.
wound didn’t show improvement. The duplex scan showed a right posterior tibia artery occlusion. The patient refused further surgical reconstruction, including percutaneous transluminal angioplasty. So, we suggested the patient receive ON101treatment, which was applied topically with gauze twice daily. The wound size was 7.27 cm2 when he started to use ON101 (Figure 2(a)) and down-grade from 2A to 1A within 2 weeks with 48% wound size reduction (Figure 2(b)). The wound got 87% size reduction 6 weeks after ON101application (Figure 2(c)) and healed completely at 10thweeks of ON101 usage (Figure 2(d)). The target ulcer didn’t show recurrence for 16 months (Table 1).
2.3. Case 3
A 55-year-old female patient has been a victim of CVA(Cardiovascular accident) and hemiparalysis for several years. She can only ambulate by wheelchair and lay in bed most of the time. She was also diagnosed with type 2 DM and uremia under regular hemodialysis for 8 years. This time, she suffered from a plantar ulcer on her left heel for about six months. The wound is located in a pressure region with some necrotic tissue. The Duplex scan showed no remarkable change in the left lower leg arteries. We debrided the necrotic tissue at clinics and used sulfadiazine silver cream to treat the wound for 3 weeks, but the wound didn’t improve. Then, we used AquaCel Ag to treat the wound for another 3 weeks, and the wound didn’t show any improvement. The wound looked persistent inflammation stage and showed unhealthy granulation tissue, and the size was 5.74 cm2 (Figure 3(a)). So, ON101was instead applied topically with gauze twice daily, and the wound size reduced to 2.01 cm2 at 6 weeks of ON101 application (Figure 3(b)) and healed completely after 10 weeks (Figure 3(c)) and didn’t show recurrence for 6 months (Table 1).
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Figure 2. Patient No. 2 with target ulcer on right 5th toe. (a) Before treatment; (b) 2 weeks of ON101 treatment; (c) 6 weeks after ON101 treatment; (d) 10 weeks after ON101 treatment.
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Figure 3. Patient No. 3 with target ulcer on left heel. (a) Before treatment; (b) 6 weeks of ON101 treatment; (c) 10 weeks after ON101 treatment.
2.4. Case 4
A 40-year-old male patient diagnosed with type 2 DM, uremia, and under regular hemodialysis for more than 10 years. He has a high BMI of 34.3 and has smokedless than a pack of cigarettes every day for more than 20 years. The wound on the side of his left foot had been present for about four months. The Duplex scan showed the suspected hematoma near left SFA proximal portion. We debrided the necrotic tissue at clinics and used AquaCel Ag to treat the wound, but the wound didn’t improve. So, we suggested that the patient receive ON101 treatment, which is applied topically with gauze twice daily. The wound size was 7.47 cm2 when he started to use the ON101. The wound was reduced by 99% and almost completely healed in 20 weeks after using ON101 (Table 1).
2.5. Case 5
A 53-year-old male patient diagnosed with type 2 DM, uremia, and under regular peritoneal dialysis (PD) for more than 4.5 years. He also suffered from hyperlipidemia, chronic ischemic heart disease, and peripheral vascular disease. The wound on the right heel, which is located in a pressure region, had been present for about two years. The Duplex scan showed diffuse atherosclerosis involving bilateral lower limb arteries. Surgical debridement and split-thickness graft were applied to the wound to promote wound healing. After the surgery, the wound was treated with Aquacel Extra hydrofiber for 4 weeks, but the wound didn’t improve. So, we suggested that the patient receive ON101 treatment, which was applied topically with gauze twice daily. The wound size was 8.80 cm2 when he started to use theON101. The wound has not improved after using ON101for 20 weeks (Table 1).
3. Discussion
DM patients encountered multiple complications and impaired wound healing due to systemic inflammation. The vascular access-related infectious complications and dialysis solutions during dialysis exaggerate local and systemic inflammation, which even increases the mortality rate [17] [18] . In such circumstances, wounds in diabetic patients are more challenging to heal, leading to an increased likelihood of amputation and a heavier burden on daily life. We report five DFU patients who have been on dialysis for at least 4.5 years, and the average ulcer sizes were 7.65 cm2 before applying ON101. Three ulcers healed within 10 weeks when daily ON101 applications and one ulcer was reduced for 99% at 20 weeks of the treatment period. The complete healing rate is 60% within 10 weeks in these five patients, suggesting ON101 displayed consistent healing efficacy in dialysis cohorts compared to those without [15] . Such a result further confirmed the macrophage regulative ability of ON101 could target DFU patients who are undergoing dialysis.
Among the five cases, patient No. 5 is the only one who performed PD and the ulcerdid not improve after ON101 was used. Although patient No. 5 didn’t displayed nutritional insufficiency, peritoneal dialysis was known to more loss more protein and nutrition than hemodialysis [19] . Previous studies demonstrated excessively high dialysate glucose load caused by long-term PD may exacerbate the glycemia conditions in DM patients [20] . Indeed, theHbA1c level of patient No. 5 was elevated during the treatment period (HbA1c from 5.5% to 9.3%). In addition to poor glycemic control, this patient has plantar ulcers at both heels, which could not be off-loading properly, and the target ulcer has been existed for 24 months, suggesting that there may other extrinsic factors affect the wound healing of patient 5.
Except patient No. 5, the remaining four subjects demonstrated significant reduction in ulcer size under ON101 treatment regardless of the low eGFR and long-term dialysis history (Table 1). Conclusively, ON101 exhibits a unique mechanism by rebalancing the population of M1 and M2 macrophages and, in turn, reshaping the wound microenvironments to facilitate hard-to-heal ulcers to healing. Therefore, it suggests that ON101 would be an ideal treatment option for patients who have DFUs and are undergoing dialysis.
Acknowledgements
We would like to thank study nurse Jia-Ying Lin for their care of the patients. We would like to thank Onenessbio Co., Ltd. for kindly provide ON101. We would like to thank Dr. Hsiung-Fei Chien for providing medical support. We would like to thank Dr. Ching-Wen Lin, Dr. Min-Liang Kuo, Hui-Ju Ho, and Yu-Ting Kuofor their editing service on the English version of the manuscript.
Statement of Ethics
The research was conducted in ethical accordance with the World Medical Association Declaration of Helsinki. Written informed consent was obtained from the caregivers for the publication of this case report and any accompanying images. A copy of the written consent is available for review from the Editor of this journal.
Author Contributions
YHY data collection, data analysis, and data interpretation; CMP data collection and wrote the manuscript.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.