Ciqi Shen ,Wuhn Wei ,Aijun Zhng ,Chngbo To ,Xueyng Li ,Ynping Guo ,Hnxio Wei,Qing Li,＊,Peisheng Jin,＊

aDepartment of Plastic Surgery,Affiliated Hospital of Xuzhou Medical University,Xuzhou 221002,Jiangsu,China

bGraduate School,Xuzhou Medical University,Xuzhou 221004,Jiangsu,China

Keywords:Diabetic foot ulcer Nocardia rubra cell wall skeleton External application Wound healing

ABSTRACT Diabetic foot ulcers are one of the most severe complications of diabetes that have imposed great financial and psychological burdens on diabetic patients.A Nocardia rubra cell wall skeleton(Nr-CWS)can be externally applied to accelerate wound healing.However,its clinical application has not yet been reported.Herein,we report two patients with diabetic foot ulcers treated with Nr-CWS.After wound debridement,the wound was covered with a sterile cotton ball infiltrated with an Nr-CWS that was diluted with 2.0 mL of saline.The covers were changed every two days until complete wound healing occurred.The two wounds healed after 3 and 12 weeks,respectively.This article aims to provide a new treatment for diabetic foot ulcers,with the hope that physicians may consider an Nr-CWS as a complementary method for the treatment of chronic wounds.

1.Introduction

A diabetic foot ulcer is a severe complication that may lead to prolonged hospitalization and limb amputation.Impaired neovascularization and continuous inflammatory reactions are the main causes of chronically poor woud healing.1An experiment in mice revealed that theNocardia rubracell wall skeleton (Nr-CWS) increased the recruitment of macrophages and promoted revascularization,resulting in accelerated healing.2Herein,we report two diabetic foot ulcers that were cured by external application of Nr-CWS.The optimal medication treatment outcome is largely dependent on patient compliance.Compared to the traditional therapies,the Nr-CWS has many advantages such as simplicity,easily operable,having high efficiency,and ability to be used as a complementary and alternative therapy.

2.Case presentation

2.1.Case 1

A 55-year-old woman had a history of diabetes for more than five years,which was controlled with insulin for two years.She was admitted to our outpatient clinic for a 1.5 cm × 1 cm,partially healed wound on the dorsum of the right foot(Fig.1A).Previously,she was treated with a Chinese medicine dressing in a private clinic.However,the result was not very favorable.She had progressive blackening of the wound for six months.After disinfecting the wound with iodophor,a sterile cotton ball,infiltrated with 0.02% Nr-CWS 2.0 mL was applied to it after cleaning and debridement.Vaseline oil and sterile gauzes were applied to cover the wound.The wound dressing was changed every two days.The patient underwent wound treatment and dressing changes at the outpatient clinic.The wound healed gradually in three weeks and healed satisfactorily(Fig.1B–1E).

2.2.Case 2

A 98-year-old woman had a history of diabetes for more than 20 years.The full-thickness skin of the right foot heel was necrotic,and the necrotic crust was approximately 1.5 cm in diameter (Fig.2A).The patient reported evident swelling and pressing pain in the right foot.Upon admission,surgical debridement was performed to remove the necrotic crust,and wound granulation tissue was observed after debridement (Fig.2B).An Nr-CWS was applied to the wound,which was covered with Vaseline oil and sterile gauzes.The dressing was changed once to twice daily,depending on the amount of wound secretion.Her blood glucose levels were controlled with insulin and maintained at approximately 7 mmol/L before each meal.Systemic antibiotic therapy was administered for one week.The patient continued to attend our outpatient clinic for three months to receive treatment for the wound until it completely healed (Fig.2C–2G).

Fig.1.Photos of case 1.(A)Before treatment.(B)One week after treatment.(C)Two weeks after treatment.(D)Three weeks after treatment.(E)Twenty four weeks after treatment.

3.Discussion

A diabetic foot ulcer is one of the most severe complications of diabetes.Overproduction of reactive oxygen species,resulting from elevated blood glucose levels,causes local ischemia and vascular dysfunction,inducing or aggravating infection and leading to delayed wound healing.1Diabetic foot ulcers exhibit delayed wound closure,prolonged inflammation,and poor vascularization.3Moreover,the wounds are difficult to heal due to persistent infection and severe inflammation.

An Nr-CWS is the cell wall skeleton obtained fromN.rubra,a grampositive bacterium,and mainly contains arabinogalactan,muramic acid,and mucopeptide.4The Nr-CWS has been approved as a class 2 new drug in China,and it has already been used as an immunomodulator for cervical erosion,mucosal ulcers,and various human papilloma virus infections.5It can activate the immune response without showing an immunotoxic capacity.Many studies have found that the Nr-CWS releases cytokines,such as tumor necrosis factor and interferon,to promote the microbicidal function of macrophages and the activity of killer T cells.4,6,7In addition,experiments in mice have shown that the Nr-CWS can effectively accelerate wound healing by activating macrophages and increasing angiogenesis.2Therefore,the Nr-CWS acts as an anti-inflammatory agent that promotes wound healing.

These two patients,who met the diagnostic criteria of the World Health Organization for a diabetic foot (1999) had non-healing ulcers despite the use of multiple treatments.After topical application of the Nr-CWS,the two wounds healed after 3 and 12 weeks,respectively.Compared to that in case 1,the wound condition in case 2 was worse.Therefore,the treatment time was prolonged,as the wound in case 2 was larger and deeper,extending to the epidermis and subcutaneous tissue.In addition,it is certain that the drug response might be different in individual patients,indicating the need to devise treatment strategies in different populations.During the 6-month followup,no wound recurrence was observed.The topical application of the Nr-CWS was well tolerated,and no adverse side effects were observed.However,it is necessary to conduct large-scale clinical trials with long-term follow-up to validate the efficacy and safety of Nr-CWS treatment.

4.Conclusion

To our knowledge,this is the first case report of the use of the Nr-CWS for the treatment of diabetic foot ulcers.The present cases indicate that the Nr-CWS can be used to accelerate cutaneous diabetic wound healing.

Fig.2.Photos of case 2.(A) Before treatment.(B) After surgical debridement.(C) Two weeks after treatment.(D) Four weeks after treatment.(E) Eight weeks after treatment.(F) Twelve weeks after treatment.

Ethics approval and consent to participate

The need for ethical approval and consent to participate was waived as this is a case report.

Consent for publication

All patients provided written informed consent to publish the data contained within this study.

Competing interests

The authors declare that they have no competing interests.

Authors’contributions

Shen C:Writing-Original Draft,Conceptualization,Methodology.Wei W:Writing-Original Draft,Validation,Resources.Zhang A:Resources,Data Curation,Investigation.Tao C:Data Curation,Resources,Investigation.Li X:Validation,Resources,Investigation.Guo Y:Resources,Data Curation.Wei H:Resources,Data Curation.Li Q:Writing-Review and Editing,Supervision,Project administration.Jin P:Writing-Review and Editing,Supervision,Project administration,Funding acquisition.

Acknowledgments

This study was sponsored by the National Natural Science Foundation of China(grant no.82172224).