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Journal of Clinical and
Medical Images
ISSN: 2640-9615
Research Article
Nanomedicine Approach for the Rapid Healing of Diabetic Foot
Ulcers with Silver Nanoparticles
Almonaci-Hernández CA1&
, Luna-Vazquez-Gomez R2&
, Luna-Vazquez-Gomez RA3
, Valenciano-Vega JI4
, Carriquiry-Chequer NI2
,
Rembao-Hernández A2
, Gomez-Zendejas ML5
, Almanza-Reyes H6
, Garibo-Ruiz D7
, Pestryakov A8
and Bogdanchikova N9*
1
Integral and Advance Clinic, Ensenada, Baja California, Mexico
2
School of Medicine, Campus Ensenada, Autonomous University of Baja California, Mexico
3
Faculty of Medicine, Campus Mexicali. Autonomous University of Baja California, Mexico
4
Hospital El Mirador of ISSSTECALI Tijuana, Baja California, Mexico
5
Faculty of Science, Campus Ensenada. Autonomous University of Baja California, Mexico
6
Faculty of Medicine and Psychology, Campus Tijuana. Autonomous University of Baja California, Mexico
7
CONACYT - Center of Nanoscience and Nanotechnology, National Autonomous University of Mexico, Mexico
8
Research School of Chemistry & Applied Biomedical Science, Tomsk Polytechnic University, Russia
9
Department of Nanomaterial Physicochemistry Center of Nanoscience and Nanotechnology, National Autonomous
Volume 3 Issue 2- 2020
Received Date: 07 Jan 2020
Accepted Date: 22 Jan 2020
Published Date: 28 Jan 2020
2. Keywords
Diabetic foot ulcers; Diabetes
mellitus; Silver nanoparticles;
Nanomedicine; Chronic ul-
cers; Wound healing
1. Abstract
1.1. Objectives: We present the use of silver nanoparticles (AgNPs) for 3 the treatment of Diabetic Foot
Ulcers (DFU) of grade 2 and 3 of Wagner classification.
1.2. Methods: Ulcers were daily treated by topical administration of AgNPs (at 1.8mg/mL of metallic
silver) in addition to conventional antibiotics.
1.3. Results: In all three cases presented here, a significant improvement in the healing evolution of
ulcers was observed. The edges of the lesion reached the point of closure in 2 of the 3 clinical cases.
1.4. Conclusions: This work reports a nanomedicine approach for the successfully treatment of DFU
of Wagner classification degrees 2 and 3. Daily topical administration of AgNPs solution with metal-
lic silver concentration of 1.8mg/mL causes a healing improvement of DFU in less than 60 days in
average. The results constituted the basis for further studies on the use of AgNPs for the treatment of
diabetic and other ulcers from different origins.	
*Corresponding Author (s): Nina Bogdanchikova, Almonaci-Hernández CA, Lu-
na-Vazquez-Gomez R, Department of Centro of Nano Science and Nanotechnology National
Autonomous University of Mexico, UNAM, Km. 107 Carretera Tijuana-Ensenada, Ensenada,
Baja California, 22860 Mexico, E-mail: nina@cnyn.unam.mx
clinandmedimages.com
Citation: Bogdanchikova N, Department of Center of Nanoscience and Nanotechnology, National Autono-
mous University of Mexico. Journal of Clinical and Medical Images. 2020; V3(2): 1-7.
3. Introduction
Diabetes Mellitus (DM) is one of the most common chronic and
metabolic diseases. According with the World Health Organiza-
tion, in 2014 there were 422 million of diabetic people and 1.5 mil-
lion of people have died due to this illness in 2012 [1,2]. In Mex-
ico DM is the second major cause of death [3]. Impaired wound
healing is a common complication and the main cause of hospi-
talization and lower limbs amputation in patients with DM. This
causes what is known as Diabetic Foot Ulcers (DFU). The lifetime
risk of patients with DM to develop DFU is 25%. As a consequence
of DM, it is estimated that a lower limb is lost some where in the
world every 30 seconds [4,5].
Conventional treatments for DFU include debridement, adminis-
tration of antimicrobial agents, use of devices for off-loading, ap-
plication of silver impregnated dressings, topical administration
of cell growth factors, surgical techniques and amputation [6,8].
However, all of them have shown limited clinical success. Due to
polymicrobial infections, DFU are known to heal slowly [9,10].
Microbial infections found in DFU consist of 73% aerobic and 27%
anaerobic bacteria and also microorganisms with MultiDrug Re-
sistance (MDR) [11,12]. To overcome those infections, silver-im-
pregnated dressings have been used, but the need for constant
Author Contributions: Almonaci-Hernandez CA, Luna-Vazquez-Gomez R, These authors have contrib-
uted equally to this article.
reapplications and the deactivation of silver, constitute major lim-
itations [13]. Also, topical administration of cellular growth factors
has been demonstrated to be effective to heal DFU. However it is
extremely costly and only works for certain wagner stages of DFU
[6].
In this sense, nanotechnology has generated new applications for
biomedicine through nanomaterials [14].
One of the most used nanomaterials in medical products is silver
nanoparticles (AgNPs). These nanoparticles have shown broad mi-
crobicidal activity and also anti-inflammatory properties [15, 16].
Therefore, silver and AgNPs are commonly used in dressings for
conservative treatment of wounds and burns [16-19]. However, the
usage of AgNPs to heal DFU has been scarcely explored [20, 21].
Developed a potent antimicrobial sponge composed of chitosan,
hyaluronic acid and AgNPs as a wound dressing to treat DFU in-
fected with antibiotic resistant bacteria [21]. Also, [22] investigat-
ed wound healing in diabetic mice, where excised wounds treated
with AgNPs completely heal 2.5 days faster than untreated animals
[22]. However, although the role of AgNPs in wound healing is well
documented, the use of AgNPs to heal DFU in DM patients has
never been studied.
Taking this in consideration, the aim of this study was to investi-
gate the potential use of AgNPs to treat DFU in patients with DM.
Herein it is presented three cases of patients with DFU classified as
wagner ulcers 2 and 3. Patients were treated with a conventional
antibiotics schedule and additionally AgNPs solution was topically
administered. The evolution of the wound healing during treat-
ment was documented by photography, which clearly showed that
DFU disappeared or significantly reduce its area without develop-
ing infection after treatment with AgNPs.
4. Material and Methods
4.1. Study Design and Subjects
The series of clinical cases presented here belongs to a pilot study.
Data collection was performed at the Hospital of the Institute of
Security and Social Service of Government and Counties Workers
of Baja California State Hospital in Baja California, Mexico. Pa-
tients were included once the medical protocol was approved by
the ethics committee of the hospital. The objectives and methods
of the study were explained to the patients using documentation.
Also it was explained that no disadvantage would be incurred by
refusing to participate and that personal information would not be
disclosed.
Patient selection was independent of age and sex. However, the in-
clusion criterion was to be a DM type 2 patients under glycemic
control and the presence of a DFU of Wagner stages 1 to 3. Impor-
tantly was that patients must present a non responsive behavior
of necrotic ulcer tissue to conventional antibiotic treatment. The
treatment of DFUs with AgNPs started only after the patient signed
an informed consent letter giving their approval to be included in
the study.
4.2. Ethical Considerations
The medical protocol followed in this study was approved by the
Ethics Committee of the General Hospital, Tijuana, Baja Califor-
nia, Mexico. The method for the topical administration of AgNPs
for DFU treatment was developed.
4.3. Silver Nanoparticles
After comparison of different AgNPs formulations commercially
available, we concluded that only Argovit preparation resulted to
have multiple certificates for their usage in veterinary and human
applications [23]. Argovit AgNPs (Scientific and Production Cen-
ter Vector-Vita, Russia) is a preparation of highly dispersed silver
nanoparticles with an overall concentration of 200 mg/mL (20%)
of PVP-coated AgNPs in water. The content of metallic silver in Ar-
govit preparation is 12 mg/mL, stabilized with 188 mg/mL of Poly
Vinylpyrrolidone (PVP). AgNPs dilutions were calculated accord-
ing to the metallic silver content in Argovit preparation. Solutions
of AgNPs were prepared with distilled and sterile water and were
kept at 4°C in darkness.
5. Results
5.1. Silver Nanoparticles
Physicochemical characteristics of AgNPs have been recently re-
ported by our group [24]. A TEM micrograph showing the sphe-
roidal morphology and size of AgNPs used in this study is shown
in (Figure 1).
5.2. Patients
In the case of patient 1, besides inflammation, there was no evi-
dence of infection prior to debridement and treatment with Ag-
NPs. While in case of patients 2 and 3, due to previous infections,
a conventional antibiotic administration schedule continued on a
regular basis during treatment with AgNPs. Nevertheless necrosis,
inflammation and fetid odor were observed during debridement,
evidencing an active infection. Contrary to conventional treatment
of DFU, in this study the topical application of AgNPs solution
Copyright ©2020 Bogdanchikova N al This is an open access article distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and build upon your work non-commercially.
2
Volume 3 Issue 2 -2020 Research Article
(with a metallic silver concentration of 1.8 mg/mL) was performed
daily. To record the evolution of the wound healing process, photo-
graphs were taken before and after the treatment with AgNPs. Here
it is presented three clinical cases of diabetic patients with different
grades of DFU according with Wagner classification (Figure 2).
First patient (P1, Figure 2a) is a 77 years old female with controlled
type 2 diabetes, with a plantar Wagner-2 ulcer. The wound is lo-
cated at the metatarsal region of the first toe of the left foot. As
observed in Figure 2a the ulcer was restricted to an area of 4 cm
x 4 cm and exhibits hyperkeratosis in the affected and surround-
ing tissue, associated with desquamation at the metatarsal region
and fetid odor perception. Some grade of inflammation in forefoot
Figure 1: TEM image of AgNPs showing their spheroidal morphology and size.
Volume 3 Issue 2 -2020 Research Article
Clinandmedimages.com 3
Figure 2: Chronological evolution of different diabetic foot ulcers treated with topical administration
of AgNPs.
and toe was observed. Daily treatment of topical administration of
AgNPs solution started after the debridement of the lesion. After
20 days of AgNPs administration, the ulcer showed a decrease in
hyperkeratosis, noticeable on the lateral side of the first toe, while
the metatarsal region surrounding the injury regained its normal
appearance. It is shown a decrease of edema of the forefoot and
toes and a peripheral improved of the pigmentation indicating an
active edge of healing. No fetid odor was perceived. Forty days
after the beginning of treatment the hyperkeratosis was minimal,
the surrounding skin has regained its normal characteristics and
desquamation was only noticeable at the fold of the first toe. The
necrotic tissue disappeared and normal re-epithelialization process
and a normalization of the pigmentation were evident.
The second patient (P2, Figure 2b) is a 63 years old male with con-
trolled type 2-diabetes, who exhibited an ulcer grade 3 according
to Wagner classification. Ulcer exhibits a pitting morphology with
raised edges located on the lateral side of the third toe of the right
foot. As observed in Figure 2b changes in pigmentation are evident.
After 18 days of a daily topical administration of AgNPs, the DFU
showed reduction of the wound area in more than 50%, with evi-
dent re-epithelialization, active edges and presence of granulation
tissue in the center of the ulcer. At the 25th day of treatment, an
imminent closure of the ulcer is shown by secondary intention.
Finally, after 37 days post-AgNPs treatment, the ulcer edges have
been addressed, culminating in the closure of the injury where no
necrosis or inflammation was observed.
The third patient (P3, Figure 2c) is a 59 years old female patient
with controlled type 2 diabetes, exhibited a plantar ulcer in the
left hindfoot without vascular involvement. After 4 weeks under a
conventional antibiotics schedule no improvement in the evolution
of the ulcer was observed. Chronological evolution of DFU from
Features Heberprot-P (Cuba) Nagsil Dermo (Mexico-Russia)
On the market since 2007 2015
International distribution 15 countries 10 countries
Registration as Medicine Cosmetic
Origin Recombinant protein Silver nanoparticles
Number of treated patients More than 100,000 More than 420
Treatment duration 8 - 11 weeks 3 - 6 weeks (in average)
Treatment cost in Mexico
136,000 - 187,000 MEX pesos (7,555 – 10,390
USD)
1,000 MEX pesos (56 USD)
Necessary to administer along with
antibiotics
Yes No
Hospitalization for treatment and
product administration
Required No Only for initial debridement
Exclussion criteria of patients
This product is not recommended for patients
with: High blood pressure or hypertenssion
Risk of brain hemorrages
Risk of thrombosis
Blood glucose levels ≥ 160 Ulcers with necrotic
tissue
None
Stages of Wagner ulcer classification
for an effective treatment
1 and 2 1, 2 and 3
Route of administration Intra and perilesional zones Topically with spray
Shelf-life of the product 1 year 2-4 years
Experitation days beyond first use 3 days 1 year
Table 1. Comparison of Herberprot-P (Cuba) and Nagsil Dermo (Mexico-Russia) products available on the market for
the effective treatment of diabetic foot ulcers.
Volume 3 Issue 2 -2020 Research Article
Clinandmedimages.com 4
P3 before and after treatment with AgNPs was observed in Figure
2c. It is shown the initial appearance of a Wagner 2 ulcer after the
debridement process. The DFU was located at the hindfoot and
superimposed on the tarsal region of the left foot, with irregular
contours and edges with hyperkeratosis. After 30 days of treatment
with AgNPs solution, there was an improvement of the ulcer, clear-
ly observed as approximately 20% reduction of the wound surface
area. The evolution of the healing process after 42 and 45 days of
AgNPs administration showed a progressive diminishment of the
lesion extent. The outer contour of the ulcer showed a progressive
decrease of hyperkeratosis. An evident improvement of the coping
was observed along the edges of the DFU, while granulation tissue
is depicted at the center of the ulcer. The central zone of the ulcer
showed a diminishment of its diameter with an evident improve-
ment in pigmentation, re-epithelialization process and the pres-
ence of active edges that favoring closure of the injury.
6. Discussion
DFU has been recognized as a worldwide health problem, espe-
cially in developing countries and as the number of diabetic pa-
tients continues to rise, so will be the number of DFU [25]. These
types of ulcers are multifactorial, besides the presence of MDR mi-
croorganisms on it increases the risk for a chronic infection, limb
amputation and morbidity [26,27]. The microbicidal properties
of AgNPs are broader than ones of common antibiotics, which is
suitable to 1 treat wounds with polymicrobial infections includ-
ing MDR microorganisms also found in DFU [12]. The capability
of AgNPs to accomplish successful DFU healing, could be exerted
by several processes, indeed, the most important is their efficient
wide-spectra antimicrobial properties [15,27]. Because the precise
microbicidal mechanism of AgNPs has not been well established,
it is considered to be multifactorial [28,29]. For example, AgNPs
can interact with peptidoglycans present in both bacterial cell wall
and membrane, damaging their integrity and causing a leakage of
intracellular contents [16,30]. AgNPs also interact with intracellu-
lar proteins, interfering with microbial DNA duplication and in-
ducing the generation of reactive oxygen species that finally leads
to bacterial cell death by oxidative stress [27]. Once the infection
is eradicated, the anti-inflammatory properties of AgNPs promote
wound healing by decreasing the expression of pro-inflammato-
ry cytokines and by reducing the infiltration of lymphocytes and
mast cells. Causing with this a diminishment of local and systemic
inflammatory response [16,22]. Although AgNPs in wound heal-
ing has been studied, their role in curing diabetic foot ulcers has
been never addressed, thus limited information concerning this is
available. Moreover, AgNPs used in other studies have produced
genotoxic effects. Therefore, in attempts to compare the efficacy of
AgNPs treatment for DFU, we searched products on the market ca-
pable to cure DFU. In this sense, we found a Cuban product named
Heberprot-P [6]. To address the efficacy of both products to heal
DFU we present the following comparison (Table 1).
Heberprot-P is based on the recombinant human Epidermal
Growth Factor (rhEGF), a cytokine that stimulates cell growth and
differentiation. It has been associated the poor ability of DFU to
heal with the low levels of growth factors in the wound site [31].
Thus, the injection of Heberprot-P in the intra and perilesional
zones of DFU facilitates the healing process in the wound. It has
been reported that AgNPs promote wound healing due to several
processes, such as the expression of fibrogenic cytokines, migra-
tion of keratinocytes and induction of fibroblast differentiation to
myofibroblasts. These allowed to promote wound contraction and
epidermal re-epithelialization [19, 22, 32].
It is worth mention that we recently reported that Argovit AgNPs
have non genotoxic effects on cell lines at concentrations closer
to the IC50 (3.5μg/mL of metallic silver) [24]. Moreover, Argovit
AgNPs harbors many advantages over other silver formulations
available on the market, because it has been approved by interna-
tional instances as cosmetic and has been applied in medical devic-
es for human use [23]. Argovit AgNPs is available on the market
and distributed as cosmetic by the company Bionag S.A.P.I. de C.V.
According with the supplier, this product cures more than 90% of
patients with DFU with Wagner ulceration of stages 1 to 3 in ap-
proximately 2 months. The remaining patients are cured slower be-
cause they do not follow the directions given by the supplier.
Thus, to the best of our knowledge, this work represents the first
nanomedicine approach study performed for the successfully
treatment of DFU of Wagner classification degrees 2 and 3 by a
daily topical administration of AgNPs solution with metallic sil-
ver concentration of 1.8 mg/mL. AgNPs administered caused an
improvement of the wound healing in average in less than 60 days
of treatment.
The implementation of this nanotechnology for the rapid healing
of diabetic foot ulcers could help to drastically reduce the cost re-
lated to the care and treatment of DFU in the public health system.
Therefore, this study lays the 1st bases for further systematic clin-
ical and basic research on the usage of AgNPs for the treatment of
chronic ulcers such as DFU.
Volume 3 Issue 2 -2020 Research Article
Clinandmedimages.com 5
7. Conclusions
To the best of our knowledge, this work reports the first nanomed-
icine approach study performed for the successfully treatment of
DFU of Wagner classification degrees 2 and 3, where daily topical
administration of AgNPs solution with metallic silver concentra-
tion of 1.8 mg/mL causes an improvement of the wound healing in
average in less than 60 days of treatment. Therefore, this study lays
the bases for further systematic clinical and basic research on the
usage of AgNPs for the treatment of chronic ulcers such as DFU.
8. Acknowledgements
The authors thank the funding through CONACYT projects No.
279889, 269071, 1073, DGAPA PAPIIT-UNAM IT200114 and
RFBR project No 18-29-24037. Medical support was given by
Dr. Isis Cabrera, Carmen Enriques, Willfred Cardenas Acosta,
Michel Natay Peraza Perales, Alejandra Rembao Hernandez and
Nora Ines Carriquiry Chequer. We are grateful to Dr. Leonel Cota
(CNyN-UNAM) for the studentships given through the CONA-
CYT-SNI 3 researcher fund and to Dr. V. Burmistrov for the kindly
donation of Argovit AgNPs.
9. Declaration of Conflicting Interests
The authors declared no potential conflict of interest with respect
to the research, authorship, and/or publication of this article.
10. Author Contributions: Almonaci-Hernandez CA, Lu-
na-Vazquez-Gomez R
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Nanomedicine Approach for the Rapid Healing of Diabetic Foot Ulcers with Silver Nanoparticles

  • 1. Journal of Clinical and Medical Images ISSN: 2640-9615 Research Article Nanomedicine Approach for the Rapid Healing of Diabetic Foot Ulcers with Silver Nanoparticles Almonaci-Hernández CA1& , Luna-Vazquez-Gomez R2& , Luna-Vazquez-Gomez RA3 , Valenciano-Vega JI4 , Carriquiry-Chequer NI2 , Rembao-Hernández A2 , Gomez-Zendejas ML5 , Almanza-Reyes H6 , Garibo-Ruiz D7 , Pestryakov A8 and Bogdanchikova N9* 1 Integral and Advance Clinic, Ensenada, Baja California, Mexico 2 School of Medicine, Campus Ensenada, Autonomous University of Baja California, Mexico 3 Faculty of Medicine, Campus Mexicali. Autonomous University of Baja California, Mexico 4 Hospital El Mirador of ISSSTECALI Tijuana, Baja California, Mexico 5 Faculty of Science, Campus Ensenada. Autonomous University of Baja California, Mexico 6 Faculty of Medicine and Psychology, Campus Tijuana. Autonomous University of Baja California, Mexico 7 CONACYT - Center of Nanoscience and Nanotechnology, National Autonomous University of Mexico, Mexico 8 Research School of Chemistry & Applied Biomedical Science, Tomsk Polytechnic University, Russia 9 Department of Nanomaterial Physicochemistry Center of Nanoscience and Nanotechnology, National Autonomous Volume 3 Issue 2- 2020 Received Date: 07 Jan 2020 Accepted Date: 22 Jan 2020 Published Date: 28 Jan 2020 2. Keywords Diabetic foot ulcers; Diabetes mellitus; Silver nanoparticles; Nanomedicine; Chronic ul- cers; Wound healing 1. Abstract 1.1. Objectives: We present the use of silver nanoparticles (AgNPs) for 3 the treatment of Diabetic Foot Ulcers (DFU) of grade 2 and 3 of Wagner classification. 1.2. Methods: Ulcers were daily treated by topical administration of AgNPs (at 1.8mg/mL of metallic silver) in addition to conventional antibiotics. 1.3. Results: In all three cases presented here, a significant improvement in the healing evolution of ulcers was observed. The edges of the lesion reached the point of closure in 2 of the 3 clinical cases. 1.4. Conclusions: This work reports a nanomedicine approach for the successfully treatment of DFU of Wagner classification degrees 2 and 3. Daily topical administration of AgNPs solution with metal- lic silver concentration of 1.8mg/mL causes a healing improvement of DFU in less than 60 days in average. The results constituted the basis for further studies on the use of AgNPs for the treatment of diabetic and other ulcers from different origins. *Corresponding Author (s): Nina Bogdanchikova, Almonaci-Hernández CA, Lu- na-Vazquez-Gomez R, Department of Centro of Nano Science and Nanotechnology National Autonomous University of Mexico, UNAM, Km. 107 Carretera Tijuana-Ensenada, Ensenada, Baja California, 22860 Mexico, E-mail: nina@cnyn.unam.mx clinandmedimages.com Citation: Bogdanchikova N, Department of Center of Nanoscience and Nanotechnology, National Autono- mous University of Mexico. Journal of Clinical and Medical Images. 2020; V3(2): 1-7. 3. Introduction Diabetes Mellitus (DM) is one of the most common chronic and metabolic diseases. According with the World Health Organiza- tion, in 2014 there were 422 million of diabetic people and 1.5 mil- lion of people have died due to this illness in 2012 [1,2]. In Mex- ico DM is the second major cause of death [3]. Impaired wound healing is a common complication and the main cause of hospi- talization and lower limbs amputation in patients with DM. This causes what is known as Diabetic Foot Ulcers (DFU). The lifetime risk of patients with DM to develop DFU is 25%. As a consequence of DM, it is estimated that a lower limb is lost some where in the world every 30 seconds [4,5]. Conventional treatments for DFU include debridement, adminis- tration of antimicrobial agents, use of devices for off-loading, ap- plication of silver impregnated dressings, topical administration of cell growth factors, surgical techniques and amputation [6,8]. However, all of them have shown limited clinical success. Due to polymicrobial infections, DFU are known to heal slowly [9,10]. Microbial infections found in DFU consist of 73% aerobic and 27% anaerobic bacteria and also microorganisms with MultiDrug Re- sistance (MDR) [11,12]. To overcome those infections, silver-im- pregnated dressings have been used, but the need for constant Author Contributions: Almonaci-Hernandez CA, Luna-Vazquez-Gomez R, These authors have contrib- uted equally to this article.
  • 2. reapplications and the deactivation of silver, constitute major lim- itations [13]. Also, topical administration of cellular growth factors has been demonstrated to be effective to heal DFU. However it is extremely costly and only works for certain wagner stages of DFU [6]. In this sense, nanotechnology has generated new applications for biomedicine through nanomaterials [14]. One of the most used nanomaterials in medical products is silver nanoparticles (AgNPs). These nanoparticles have shown broad mi- crobicidal activity and also anti-inflammatory properties [15, 16]. Therefore, silver and AgNPs are commonly used in dressings for conservative treatment of wounds and burns [16-19]. However, the usage of AgNPs to heal DFU has been scarcely explored [20, 21]. Developed a potent antimicrobial sponge composed of chitosan, hyaluronic acid and AgNPs as a wound dressing to treat DFU in- fected with antibiotic resistant bacteria [21]. Also, [22] investigat- ed wound healing in diabetic mice, where excised wounds treated with AgNPs completely heal 2.5 days faster than untreated animals [22]. However, although the role of AgNPs in wound healing is well documented, the use of AgNPs to heal DFU in DM patients has never been studied. Taking this in consideration, the aim of this study was to investi- gate the potential use of AgNPs to treat DFU in patients with DM. Herein it is presented three cases of patients with DFU classified as wagner ulcers 2 and 3. Patients were treated with a conventional antibiotics schedule and additionally AgNPs solution was topically administered. The evolution of the wound healing during treat- ment was documented by photography, which clearly showed that DFU disappeared or significantly reduce its area without develop- ing infection after treatment with AgNPs. 4. Material and Methods 4.1. Study Design and Subjects The series of clinical cases presented here belongs to a pilot study. Data collection was performed at the Hospital of the Institute of Security and Social Service of Government and Counties Workers of Baja California State Hospital in Baja California, Mexico. Pa- tients were included once the medical protocol was approved by the ethics committee of the hospital. The objectives and methods of the study were explained to the patients using documentation. Also it was explained that no disadvantage would be incurred by refusing to participate and that personal information would not be disclosed. Patient selection was independent of age and sex. However, the in- clusion criterion was to be a DM type 2 patients under glycemic control and the presence of a DFU of Wagner stages 1 to 3. Impor- tantly was that patients must present a non responsive behavior of necrotic ulcer tissue to conventional antibiotic treatment. The treatment of DFUs with AgNPs started only after the patient signed an informed consent letter giving their approval to be included in the study. 4.2. Ethical Considerations The medical protocol followed in this study was approved by the Ethics Committee of the General Hospital, Tijuana, Baja Califor- nia, Mexico. The method for the topical administration of AgNPs for DFU treatment was developed. 4.3. Silver Nanoparticles After comparison of different AgNPs formulations commercially available, we concluded that only Argovit preparation resulted to have multiple certificates for their usage in veterinary and human applications [23]. Argovit AgNPs (Scientific and Production Cen- ter Vector-Vita, Russia) is a preparation of highly dispersed silver nanoparticles with an overall concentration of 200 mg/mL (20%) of PVP-coated AgNPs in water. The content of metallic silver in Ar- govit preparation is 12 mg/mL, stabilized with 188 mg/mL of Poly Vinylpyrrolidone (PVP). AgNPs dilutions were calculated accord- ing to the metallic silver content in Argovit preparation. Solutions of AgNPs were prepared with distilled and sterile water and were kept at 4°C in darkness. 5. Results 5.1. Silver Nanoparticles Physicochemical characteristics of AgNPs have been recently re- ported by our group [24]. A TEM micrograph showing the sphe- roidal morphology and size of AgNPs used in this study is shown in (Figure 1). 5.2. Patients In the case of patient 1, besides inflammation, there was no evi- dence of infection prior to debridement and treatment with Ag- NPs. While in case of patients 2 and 3, due to previous infections, a conventional antibiotic administration schedule continued on a regular basis during treatment with AgNPs. Nevertheless necrosis, inflammation and fetid odor were observed during debridement, evidencing an active infection. Contrary to conventional treatment of DFU, in this study the topical application of AgNPs solution Copyright ©2020 Bogdanchikova N al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially. 2 Volume 3 Issue 2 -2020 Research Article
  • 3. (with a metallic silver concentration of 1.8 mg/mL) was performed daily. To record the evolution of the wound healing process, photo- graphs were taken before and after the treatment with AgNPs. Here it is presented three clinical cases of diabetic patients with different grades of DFU according with Wagner classification (Figure 2). First patient (P1, Figure 2a) is a 77 years old female with controlled type 2 diabetes, with a plantar Wagner-2 ulcer. The wound is lo- cated at the metatarsal region of the first toe of the left foot. As observed in Figure 2a the ulcer was restricted to an area of 4 cm x 4 cm and exhibits hyperkeratosis in the affected and surround- ing tissue, associated with desquamation at the metatarsal region and fetid odor perception. Some grade of inflammation in forefoot Figure 1: TEM image of AgNPs showing their spheroidal morphology and size. Volume 3 Issue 2 -2020 Research Article Clinandmedimages.com 3 Figure 2: Chronological evolution of different diabetic foot ulcers treated with topical administration of AgNPs.
  • 4. and toe was observed. Daily treatment of topical administration of AgNPs solution started after the debridement of the lesion. After 20 days of AgNPs administration, the ulcer showed a decrease in hyperkeratosis, noticeable on the lateral side of the first toe, while the metatarsal region surrounding the injury regained its normal appearance. It is shown a decrease of edema of the forefoot and toes and a peripheral improved of the pigmentation indicating an active edge of healing. No fetid odor was perceived. Forty days after the beginning of treatment the hyperkeratosis was minimal, the surrounding skin has regained its normal characteristics and desquamation was only noticeable at the fold of the first toe. The necrotic tissue disappeared and normal re-epithelialization process and a normalization of the pigmentation were evident. The second patient (P2, Figure 2b) is a 63 years old male with con- trolled type 2-diabetes, who exhibited an ulcer grade 3 according to Wagner classification. Ulcer exhibits a pitting morphology with raised edges located on the lateral side of the third toe of the right foot. As observed in Figure 2b changes in pigmentation are evident. After 18 days of a daily topical administration of AgNPs, the DFU showed reduction of the wound area in more than 50%, with evi- dent re-epithelialization, active edges and presence of granulation tissue in the center of the ulcer. At the 25th day of treatment, an imminent closure of the ulcer is shown by secondary intention. Finally, after 37 days post-AgNPs treatment, the ulcer edges have been addressed, culminating in the closure of the injury where no necrosis or inflammation was observed. The third patient (P3, Figure 2c) is a 59 years old female patient with controlled type 2 diabetes, exhibited a plantar ulcer in the left hindfoot without vascular involvement. After 4 weeks under a conventional antibiotics schedule no improvement in the evolution of the ulcer was observed. Chronological evolution of DFU from Features Heberprot-P (Cuba) Nagsil Dermo (Mexico-Russia) On the market since 2007 2015 International distribution 15 countries 10 countries Registration as Medicine Cosmetic Origin Recombinant protein Silver nanoparticles Number of treated patients More than 100,000 More than 420 Treatment duration 8 - 11 weeks 3 - 6 weeks (in average) Treatment cost in Mexico 136,000 - 187,000 MEX pesos (7,555 – 10,390 USD) 1,000 MEX pesos (56 USD) Necessary to administer along with antibiotics Yes No Hospitalization for treatment and product administration Required No Only for initial debridement Exclussion criteria of patients This product is not recommended for patients with: High blood pressure or hypertenssion Risk of brain hemorrages Risk of thrombosis Blood glucose levels ≥ 160 Ulcers with necrotic tissue None Stages of Wagner ulcer classification for an effective treatment 1 and 2 1, 2 and 3 Route of administration Intra and perilesional zones Topically with spray Shelf-life of the product 1 year 2-4 years Experitation days beyond first use 3 days 1 year Table 1. Comparison of Herberprot-P (Cuba) and Nagsil Dermo (Mexico-Russia) products available on the market for the effective treatment of diabetic foot ulcers. Volume 3 Issue 2 -2020 Research Article Clinandmedimages.com 4
  • 5. P3 before and after treatment with AgNPs was observed in Figure 2c. It is shown the initial appearance of a Wagner 2 ulcer after the debridement process. The DFU was located at the hindfoot and superimposed on the tarsal region of the left foot, with irregular contours and edges with hyperkeratosis. After 30 days of treatment with AgNPs solution, there was an improvement of the ulcer, clear- ly observed as approximately 20% reduction of the wound surface area. The evolution of the healing process after 42 and 45 days of AgNPs administration showed a progressive diminishment of the lesion extent. The outer contour of the ulcer showed a progressive decrease of hyperkeratosis. An evident improvement of the coping was observed along the edges of the DFU, while granulation tissue is depicted at the center of the ulcer. The central zone of the ulcer showed a diminishment of its diameter with an evident improve- ment in pigmentation, re-epithelialization process and the pres- ence of active edges that favoring closure of the injury. 6. Discussion DFU has been recognized as a worldwide health problem, espe- cially in developing countries and as the number of diabetic pa- tients continues to rise, so will be the number of DFU [25]. These types of ulcers are multifactorial, besides the presence of MDR mi- croorganisms on it increases the risk for a chronic infection, limb amputation and morbidity [26,27]. The microbicidal properties of AgNPs are broader than ones of common antibiotics, which is suitable to 1 treat wounds with polymicrobial infections includ- ing MDR microorganisms also found in DFU [12]. The capability of AgNPs to accomplish successful DFU healing, could be exerted by several processes, indeed, the most important is their efficient wide-spectra antimicrobial properties [15,27]. Because the precise microbicidal mechanism of AgNPs has not been well established, it is considered to be multifactorial [28,29]. For example, AgNPs can interact with peptidoglycans present in both bacterial cell wall and membrane, damaging their integrity and causing a leakage of intracellular contents [16,30]. AgNPs also interact with intracellu- lar proteins, interfering with microbial DNA duplication and in- ducing the generation of reactive oxygen species that finally leads to bacterial cell death by oxidative stress [27]. Once the infection is eradicated, the anti-inflammatory properties of AgNPs promote wound healing by decreasing the expression of pro-inflammato- ry cytokines and by reducing the infiltration of lymphocytes and mast cells. Causing with this a diminishment of local and systemic inflammatory response [16,22]. Although AgNPs in wound heal- ing has been studied, their role in curing diabetic foot ulcers has been never addressed, thus limited information concerning this is available. Moreover, AgNPs used in other studies have produced genotoxic effects. Therefore, in attempts to compare the efficacy of AgNPs treatment for DFU, we searched products on the market ca- pable to cure DFU. In this sense, we found a Cuban product named Heberprot-P [6]. To address the efficacy of both products to heal DFU we present the following comparison (Table 1). Heberprot-P is based on the recombinant human Epidermal Growth Factor (rhEGF), a cytokine that stimulates cell growth and differentiation. It has been associated the poor ability of DFU to heal with the low levels of growth factors in the wound site [31]. Thus, the injection of Heberprot-P in the intra and perilesional zones of DFU facilitates the healing process in the wound. It has been reported that AgNPs promote wound healing due to several processes, such as the expression of fibrogenic cytokines, migra- tion of keratinocytes and induction of fibroblast differentiation to myofibroblasts. These allowed to promote wound contraction and epidermal re-epithelialization [19, 22, 32]. It is worth mention that we recently reported that Argovit AgNPs have non genotoxic effects on cell lines at concentrations closer to the IC50 (3.5μg/mL of metallic silver) [24]. Moreover, Argovit AgNPs harbors many advantages over other silver formulations available on the market, because it has been approved by interna- tional instances as cosmetic and has been applied in medical devic- es for human use [23]. Argovit AgNPs is available on the market and distributed as cosmetic by the company Bionag S.A.P.I. de C.V. According with the supplier, this product cures more than 90% of patients with DFU with Wagner ulceration of stages 1 to 3 in ap- proximately 2 months. The remaining patients are cured slower be- cause they do not follow the directions given by the supplier. Thus, to the best of our knowledge, this work represents the first nanomedicine approach study performed for the successfully treatment of DFU of Wagner classification degrees 2 and 3 by a daily topical administration of AgNPs solution with metallic sil- ver concentration of 1.8 mg/mL. AgNPs administered caused an improvement of the wound healing in average in less than 60 days of treatment. The implementation of this nanotechnology for the rapid healing of diabetic foot ulcers could help to drastically reduce the cost re- lated to the care and treatment of DFU in the public health system. Therefore, this study lays the 1st bases for further systematic clin- ical and basic research on the usage of AgNPs for the treatment of chronic ulcers such as DFU. Volume 3 Issue 2 -2020 Research Article Clinandmedimages.com 5
  • 6. 7. Conclusions To the best of our knowledge, this work reports the first nanomed- icine approach study performed for the successfully treatment of DFU of Wagner classification degrees 2 and 3, where daily topical administration of AgNPs solution with metallic silver concentra- tion of 1.8 mg/mL causes an improvement of the wound healing in average in less than 60 days of treatment. Therefore, this study lays the bases for further systematic clinical and basic research on the usage of AgNPs for the treatment of chronic ulcers such as DFU. 8. Acknowledgements The authors thank the funding through CONACYT projects No. 279889, 269071, 1073, DGAPA PAPIIT-UNAM IT200114 and RFBR project No 18-29-24037. Medical support was given by Dr. Isis Cabrera, Carmen Enriques, Willfred Cardenas Acosta, Michel Natay Peraza Perales, Alejandra Rembao Hernandez and Nora Ines Carriquiry Chequer. We are grateful to Dr. Leonel Cota (CNyN-UNAM) for the studentships given through the CONA- CYT-SNI 3 researcher fund and to Dr. V. Burmistrov for the kindly donation of Argovit AgNPs. 9. Declaration of Conflicting Interests The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. 10. Author Contributions: Almonaci-Hernandez CA, Lu- na-Vazquez-Gomez R References 1. World Health Organization. Global Report on Diabetes. Epub ahead of print 2016. DOI: ISBN 978 92 4 156525 7. 2. L’Heveder R, Nolan T. International Diabetes Federation. Diabetes Res Clin Pract. 2013; 101: 349-51. 3. Hernandez-Avila, Mauricio Gutierrez JP, Reynoso-Noveron N. Diabetes mellitus en México: El estado de la epidemia. Salud Pública de México. 2013; 55: 129-S136. 4. Bakker K, van Houtum WH, Riley PC. The International Diabetes Federation focuses on the diabetic foot. Curr Diab Rep. 2005; 5: 436-40. 5. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelvist J. The global burden of diabetic foot disease. Lancet. 2005; 366: 1719-24. 6. Berlanga J, Fernandez JI, Lopez E, Lopez PA, del Rio A, Valenzuela C et al. Heberprot-P: A Novel Product for Treating Advanced Diabetic Foot Ulcer. Medicc Rev. 2013; 15: 11-5. 7. Martí-Carvajal AJ, Gluud C, Nicola S, Simancas-Racines D, Reveis L, Oliva P et al. Growth factors for treating diabetic foot ulcers. Cochrane database Syst Rev. 2015; 10: CD008548. 8.Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet. 2003; 361: 1545- 51. 9. UcKay I, Gariani K, Pataky Z, Lipsky BA. Diabetic foot infections: State- of-the-art. Diabetes, Obes Metab. 2014; 16: 305-16. 10. Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG et al. Diabetic foot ulcers: Part I. Pathophysiology and prevention. Journal of the American Academy of Dermatology. 2014; 70: 1.e1-18. 11. Frykberg RG. Diabetic foot ulcers: Pathogenesis and management. Am Fam Physician. 2002; 66: 1655-62. 12. Ramani A, Ramani R, Shivananda PG, Kundaje GN. Bacteriology of diabetic foot ulcers. Indian J Pathol Microbiol. 1991; 34: 81-7. 13. Wright JB, Lam K, Hansen D, Burrell RE. Efficacy of topical silver against fungal burn wound pathogens. Am J Infect Control. 1999; 27: 344- 50. 14. Krol S, Ellis-Behnke R, Marchetti P. Nanomedicine for treatment of diabetes in an aging population: State-of-the-art and future developments. Maturitas. 2012; 73: 61-7. 15. Lara HH, Ayala-Nunez NV, Ixtepan Turrent L. del C, Rodriguez Padilla C. Bactericidal effect of silver nanoparticles against multidrug-resistant bacteria. World J Microbiol Biotechnol. 2009; 26: 615-21. 16. Gunasekaran T, Nigusse T, Dhanaraju MD. Silver nanoparticles as real topical bullets for wound healing. Journal of the American College of Clinical Wound Specialists. 2012; 3: 82-96. 17. Dunn K, Edwards-Jones V. The role of Acticoat??? with nanocrystalline silver in the management of burns. Burns. 2004; 30: S1-9. 18. Adibhesami M, Ahmadi M, Farshid AA, Sarrafzadeh-Rezaei F, Dalir- Naghadeh B. Effects of silver nanoparticles on Staphylococcus aureus contaminated open wounds healing in mice : An experimental study. Vet Res Forum. 2017; 8: 23-8. 19. Liu X, Lee P-Y, Ho C-M, Liu VC, Chen Y, Che CM et al. Silver nanoparticles mediate differential responses in keratinocytes and fibroblasts during skin wound healing. Chem Med Chem. 2010; 5: 468-75. Volume 3 Issue 2 -2020 Research Article Clinandmedimages.com 6
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