3D bioprinted scaffolds for diabetic wound-healing applications

AbstractThe treatment strategy required for the effective healing of diabetic foot ulcer (DFU) is a complex process that is requiring several combined therapeutic approaches. As a result, there is a significant clinical and economic burden associated in treating DFU. Furthermore, these treatments are often unsuccessful, commonly resulting in lower-limb amputation. The use of drug-loaded scaffolds to treat DFU has previously been investigated using electrospinning and fused deposition modelling (FDM) 3D printing techniques; however, the rapidly evolving field of bioprinting is creating new opportunities for innovation within this research area. In this study, 3D-bioprinted scaffolds with different designs have been fabricated for the delivery of an antibiotic (levoflocixin) to DFU. The scaffolds were fully characterised by a variety of techniques (e.g. SEM, DSC/TGA, FTIR, and mechanical characterisation), demonstrating excellent mechanical properties and providing sustained drug release for 4 weeks. This proof of concept study demonstrates the innovative potential of bioprinting technologies in fabrication of antibiotic scaffolds for the treatment of DFU. Graphical abstract

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Treatment Strategies Against Diabetic Foot Ulcer: Success so far and Road Ahead

Current Diabetes Reviews ◽

10.2174/1573399816999201102125537 ◽

2020 ◽

Vol 16 ◽

Author(s):

Ankit Awasthi ◽

Sachin Kumar Singh ◽

Bimlesh Kumar ◽

Monica Gulati ◽

Rajesh Kumar ◽

...

Keyword(s):

Lower Limb ◽

Diabetic Foot ◽

Treatment Strategies ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Arterial Disease ◽

Current Status ◽

Limb Amputation ◽

Bibliographic Databases ◽

Inflammatory Phase

Background: Diabetic foot ulcer (DFU) is one of the leading complications of type-2 diabetes mellitus. It isassociated with neuropathy and peripheral arterial disease of the lower limb in patients with diabetes. Basically, there are four stages of wound healing namely hemostasis phase, inflammatory phase, proliferative phase and maturation phase. In case of DFU, all these stages are disturbed which lead to delay in healing and consequently to lower limb amputation. Traditionally the dosage forms like tablets, creams, ointments, gels and capsules have been used for the treatment of diabetic foot ulcer from many years. Introduction: In this review the global prevalence as well as etiopathogenesis related to diabetic foot ulcer has been discussed. Potential role of various synthetic and herbal drugs as well as their conventional dosage form for the effective management of diabetes foot ulcer has been highlighted. Methods: Structured search of bibliographic databases for previously published peer-reviewed research papers was explored and data was culminated in terms of various approaches that are used for the treatment of diabetic foot ulcer. Results: About 142 papers including both, research and review articles, were included in this review in order to produce a comprehensive as well as readily understandable article. A series of herbal and synthetic drugs have been discussed along with their current status of treatment in terms of dose and mechanism of action. Conclusion: DFU has become one of the most common complications in patients having more than ten years of diabetes. Hence, understanding the root cause and its successful treatment is a big challenge because it depends upon multiple factors such as judicious selection of drug as well as proper control of blood sugar level. Most of the drugs that have been used so far either belong to the category of antibiotics, antihyperglycaemics or, they have been repositioned. Moreover, in clinical practice, much focus has been given towards dressings that have been used to cover the ulcer. The complete treatment of DFU is still a farfetched dream to be achieved and it is expected that a combination therapy of herbal and synthetic drug with multiple treatment pathway could be able to overcome the disease.

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Antihyperglycemic and diabetic wound healing activity of smallanthus sonchifolius leaves extract

MATEC Web of Conferences ◽

10.1051/matecconf/201819707001 ◽

2018 ◽

Vol 197 ◽

pp. 07001

Author(s):

Rina Herowati ◽

Alip D.S. Saputri ◽

Tri Wijayanti ◽

Gunawan P. Widodo

Keyword(s):

Wound Healing ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Topical Administration ◽

Serum Glucose ◽

Diabetic Wound ◽

Smallanthus Sonchifolius ◽

Biopsy Punch ◽

Diabetic Wound Healing ◽

Wound Healing Activity

Diabetic patient tend to suffer from lower extremity complication that contribute to the occurence of diabetic foot ulcer. Smallanthus sonchifolius or yacon leaves extract has been used as an alternative medicine for diabetes and also showed antibacterial activity. This research aims to obtain the antihyperglycemic and diabetic wound healing activity of yacon leaves extract. Diabetic condition of rat was induced by streptozotocin (45 mg/kg bw) and nicotinamide (110 mg/kg bw). Rats were then allowed to develop diabetes for 21 days. A biopsy punch then was used to create a wound. Yacon leaves extract were administered by oral and topical for 14 day. The serum glucose level and diameter of the wound were measured every week, and histopatology study of the skin was conducted at the end of the study. Oral administration of yacon leaves extract (150 mg/kg bw) together with topical administration showed antihyperglycemic as well as diabetic wound healing activities comparable to the reference drugs (glibenclamide oral and nebacetin cream).

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Epidermal Vascular Endothelial Growth Factor Improved Wound Healing of Patients with Diabetic Foot Ulcer

Advanced Science Letters ◽

10.1166/asl.2018.12653 ◽

2018 ◽

Vol 24 (8) ◽

pp. 6136-6139

Author(s):

Maria Francisca Ham ◽

Pradana Soewondo ◽

Saphora Dien ◽

Kusmardi Kusmardi ◽

Mpu Kanoko

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Diabetic Foot ◽

Standard Procedure ◽

Vascular Complications ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Complex Process ◽

Proximal Site ◽

Endothelial Growth Factor

Diabetic foot ulcer (DFU) is a kind of chronic vascular complications in diabetes. Wound healing in DFU is a complex process where reduced proangiogenic growth factor is an important factor. We studied angiogenesis factors which may contribute to the healing of DFU. Twenty five type 2 diabetes patients with acute DFU were treated with hospital standard procedure and closely observed for 1 month. Biopsies from wound edges were subjected to histopathology assessment and immunohistochemical staining of CD34, bFGF and VEGF. All examination was performed two times consecutively. We observed that granulation tissues developed faster at proximal site of the foot. Weak tissue VEGF was expressed before treatment. Interestingly, VEGF expression in epidermis increased significantly after patients received treatment. Increased VEGF is consistent with increased number of CD34 positive endothelial cells. These data suggest that epidermal VEGF is an important angiogenesis factor and may improve healing in acute DFU receiving standard treatment.

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Pathogenesis and management of diabetic foot ulcers

International Journal of Community Medicine and Public Health ◽

10.18203/2394-6040.ijcmph20184249 ◽

2018 ◽

Vol 5 (11) ◽

pp. 4953 ◽

Cited By ~ 1

Author(s):

Yousif Alsanawi ◽

Hassan Alismail ◽

Mustafa AlabdRabalnabi ◽

Hattan Alturki ◽

Abdullah Alsuhaibani ◽

...

Keyword(s):

Diabetes Mellitus ◽

Diabetic Foot ◽

Management Strategies ◽

Blood Glucose Control ◽

Disease Process ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Limb Amputation ◽

Wound Debridement ◽

Significant Impairment

Diabetes mellitus is a major healthcare issue worldwide, and the trends keep rising. Diabetic foot ulcer is a morbidity associated with the disease process and causes significant impairment in quality of life due to its severe complications including infection, gangrene, and amputation. In this study, we aim to understand the pathogenesis of diabetic foot ulcer, its complications, and management strategies. We conducted this review using a comprehensive search of MEDLINE, PubMed and EMBASE from January 1970 to March 2017. The following search terms were used: diabetic foot ulcer, complications of diabetes mellitus, foot gangrene, surgical debridement of foot ulcer, osteomyelitis. Diabetic foot ulcer is a common morbidity in patients with diabetes mellitus, which can lead to lower limb amputation unless a prompt, rational, multidisciplinary approach to therapy is taken. Proper management can ensure successful and fast healing which includes patient education, blood glucose control, wound debridement, advanced dressing, offloading, and surgery.

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Rationale of Orthosiphon aristatus for Healing Diabetic Foot Ulcer

Natural Product Communications ◽

10.1177/1934578x20953308 ◽

2020 ◽

Vol 15 (9) ◽

pp. 1934578X2095330

Author(s):

Farah Izana Abdullah ◽

Lee Suan Chua ◽

Siti Pauliena Mohd Bohari ◽

Eka Sari

Keyword(s):

Wound Healing ◽

Plant Extract ◽

Diabetic Foot ◽

Healing Process ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

South East Asia ◽

Diabetic Wound Healing ◽

Preclinical And Clinical Studies ◽

Significant Concentration

Orthosiphon aristatus (Blume) Miq. is traditionally used for wound healing in South East Asia and scientifically proven for its antidiabetic potential. Wounds due to diabetes, especially diabetic foot ulcer (DFU), always involve a complicated healing process. The present work aims to review the information on the rationale of the phytochemicals from O. aristatus in promoting DFU healing. The findings showed that the DFU healing potential of O. aristatus was characterized by a reduction in the blood glucose level, mainly attributed to the significant concentration of constituents such as caffeic acid, rosmarinic acid, and sinensetin in the plant extract. These phytochemicals possibly induce insulin secretion and sensitivity, improve the lipid profile, and stimulate glucose uptake. Furthermore, the healing effect may also be contributed to the antioxidant, anti-inflammatory, and antihyperglycemic properties of the plant. The roles of phytochemicals have been systematically postulated in the 4 phases of the healing process. Moreover, no adverse toxic sign or abnormality has been reported upon oral administration of the plant extract. This suggests that O. aristatus extract could be a potential diabetic wound healing phytomedicine for further preclinical and clinical studies.

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Prevalence of Peripheral Arterial Disease in Diabetic Foot Ulcer Patients and its Impact in Limb Salvage

The International Journal of Lower Extremity Wounds ◽

10.1177/15347346211027063 ◽

2021 ◽

pp. 153473462110270

Author(s):

Ahmed Azhar ◽

Magdy Basheer ◽

Mohamed S. Abdelgawad ◽

Hossam Roshdi ◽

Mohamed F. Kamel

Keyword(s):

Peripheral Arterial Disease ◽

Limb Salvage ◽

Diabetic Foot ◽

Negative Impact ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Arterial Disease ◽

Limb Amputation ◽

Cross Sectional ◽

Peripheral Arterial

Diabetic foot ulcer syndrome is a common complication of diabetes mellitus. Three main factors contribute to it: neuropathy, vasculopathy, and infection. This study was conducted to evaluate the prevalence of peripheral arterial disease (PAD) in diabetic foot ulcer patients and its impact on limb salvage as an outcome. This prospective cross-sectional study included 392 cases, who were divided according to the presence of PAD into 2 groups; patients with PAD were labeled as PAD +ve (172 cases) and those without PAD were labeled as PAD −ve (22 cases). All cases were clinically assessed, and routine laboratory examinations were ordered. Moreover, duplex ultrasound was done for suspected cases of having PAD by examination. Computed tomography angiography was ordered for patients who are in need of a revascularization procedure. Cases were managed by debridement and/or revascularization. After that, these cases were assessed clinically and radiologically for vascularity and infection and the possibility for amputation was evaluated. Infection was classified using Wagner Classification System, and revascularization was decided according to the TASC II system. The incidence of PAD in cases with diabetic foot ulcer syndrome was 43.87%. No difference was detected between the 2 groups regarding age and gender ( P > .05). The prevalence of smoking, hemodialysis, ischemic heart disease (IHD), and hypertension was more significantly higher in cases with PAD ( P < .05). Revascularization procedures were only performed in cases that had documented severe PAD or chronic limb-threatening ischemia in addition to foot ulcer and/or infection. With regard to limb salvage, it was more significantly performed in cases without PAD (82.3% vs 48.3% in PAD cases; P < .001). Male gender, smoking, ankle-brachial pressure index, hemodialysis, IHD, neuropathy, HbA1C, PAD, and high Wagner classification were predictors of limb amputation ( P < .05). PAD is associated with worse outcomes in diabetic foot ulcer patients. Not only does it constitute a great number among diabetic foot ulcer patients, but it also has a negative impact on limb salvage.

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Use of Sodium-Glucose Co-Transporter-2-Inhibitors (SGLT2-Is) and Risk of Lower Limb Amputation.

Current Drug Safety ◽

10.2174/1574886315666200805103053 ◽

2020 ◽

Vol 15 ◽

Cited By ~ 1

Author(s):

Nikki C.C. Werkman ◽

Johannes T.H. Nielen ◽

Joop P.W. van den Bergh ◽

Niels Ejskjaer ◽

Johan Røikjer ◽

...

Keyword(s):

Lower Limb ◽

Foot Ulcer ◽

Specific Effect ◽

Diabetic Foot Ulcer ◽

Underlying Mechanism ◽

Limb Amputation ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

Increased Risk ◽

Using Data

Background: Treatment with sodium-glucose co-transporter-2-inhibitors (SGLT2-Is), such as canagliflozin, has been associated with an increased risk of lower limb amputations (LLAs) in type 2 diabetes mellitus (T2DM). However, conflicting results have been reported for different SGLT2-Is and the underlying mechanism is unclear. Objective: To investigate the risk of LLA and diabetic foot ulcer with SGLT2-I use compared to other anti-diabetic drugs and to explore hypovolemia as a potential underlying mechanism. Methods: A cohort study was conducted using data from the Clinical Practice Research Datalink GOLD (2013-2019). The study population (N=51,847) consisted of T2DM patients over 18 years of age with at least one prescription of a noninsulin anti-diabetic drug. Concomitant diuretic use and the presence of signs of hypovolemia were determined to assess the potential underlying mechanism. Cox proportional hazard models were used to estimate the hazard ratio (HR) for LLA in current SGLT2-I use versus current sulphonylurea (SU) use. Analyses were adjusted for life-style variables, comorbidities and concomitant drug use. Results: Current SGLT2-I use was not associated with an increased risk of LLA compared to current SU use (fully adjusted HR 0.70; 95% confidence interval 0.38-1.29). Concomitant use of diuretics and the presence of signs of hypovolemia were not associated with an increased risk of LLA. Conclusion: Use of SGLT2-Is, with or without signs of hypovolemia, was not associated with an increased risk of LLA or DFU versus current SU use. Future studies powered to detect potential differences between individual SGLT2-Is are required to rule out a canagliflozin-specific effect.

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Evaluation of Incisional Diabetic Wound Healing Activity of Ethanolic Leave Extract of Mimosa pudica L. in Rats

International Journal of Pharmacognosy and Phytochemical Research ◽

10.25258/phyto.v9i08.9623 ◽

2017 ◽

Vol 9 (08) ◽

Author(s):

R. Santosh Kumar ◽

K. Rajkiran ◽

Sunil Kumar Patnaik

Keyword(s):

Wound Healing ◽

Breaking Strength ◽

Foot Ulcer ◽

Limb Amputation ◽

Control Group ◽

Diabetic Wound ◽

Mimosa Pudica ◽

Herbal Products ◽

Diabetic Wound Healing ◽

Wound Healing Activity

Diabetes mellitus (DM) is a fast growing epidemic throughout the world. India is going to become the capital of DM. DM patients are at greater risk of serious infective foot ulcer or wound. The diabetic wound may be associated with late healing and septic manifestation and finally reach to limb amputation which is an overpriced incident. The herbal products are more precious in both prophylaxis as well as curative in delayed diabetic wound healing activity when compare to synthetic drugs. The present study was carried out to evaluate the diabetic incisional wound healing activity of ethanolic leave extract of Mimosa pudica L. (EMP) in Streptozotocin (55 mg/kg, i.p.) induced diabetic rats. A wound of 1cm incision was made on ventral side of diabetic male albino wistar rats. The two different doses (2.5% and 5%) of EMP are applied on wound b.i.d for 11 days. The initial and final fasting serum glucose levels were estimated to confirm the disease state. The breaking strength and histopathological studies of incisional healed skin was estimated. The EMP 2.5 % and EMP 5% have shown significant (p>0.01) increase in wound breaking strength as well as well epithelialization compared to diabetic control group.

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Diabetic foot ulcer and its surgical management

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20195644 ◽

2019 ◽

Vol 8 (1) ◽

pp. 25

Author(s):

Darshan J. Lakhani ◽

Jignesh P. Dave ◽

Jignesh K. Ramani ◽

Kartik K. Agrawal ◽

Chirag R. Makadiya ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Surgical Management ◽

Diabetic Foot ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Lower Class ◽

Arterial Disease ◽

Limb Amputation ◽

Surgical Approaches ◽

Female Ratio

Background: Almost 80% population of diabetic foot are from low to middle income countries like India, a country with second largest number of diabetic populations. Prevalence of diabetes mellitus in India is 9.3%. Lower extremity diseases, including peripheral neuropathy, peripheral arterial disease, and foot ulceration, is twice common in diabetic subjects. the most feared consequence of diabetic foot ulcer is limb amputation, which is seen 10 to 30 times more often in person with diabetes. The objective of this study concentrates on surgical management of diabetic foot ulcer.Methods: This is an observational prospective study of 100 cases for evaluation of diabetic foot ulcer and its surgical management at P.D.U. Hospital, Rajkot from January 2017 to November 2018.Results: The average age of presentation is 55.70 year. The male to female ratio was 1.27:1. Most of the patients are from lower middle class and upper lower class according to modified kuppuswamy socioeconomic classification. Most of the patients have duration of diabetes more than 5 years. Most common microorganism grown from culture was Staphylococcus aureus. This study has higher rate of amputations of 74% due to late presentation and neglected disease due to peripheral neuropathy causes decreased pain sensation. There was no mortality in this study.Conclusions: Management of diabetic foot ulcer is by multimodal approach with conservative and surgical approaches. Preventive measures, early diagnosis and timely surgical intervention prevents limb amputations in diabetic foot ulcer.

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Direct Cyclodextrin Based Powder Extrusion 3D Printing for One-step Production of the BCS Class II Model Drug Niclosamide

10.21203/rs.3.rs-965993/v1 ◽

2021 ◽

Author(s):

Monica Pistone ◽

Giuseppe Francesco Racaniello ◽

Ilaria Arduino ◽

Valentino Laquintana ◽

Antonio Lopalco ◽

...

Keyword(s):

3D Printing ◽

Hydroxypropyl Methylcellulose ◽

Class Ii ◽

Active Principle ◽

Fused Deposition Modelling ◽

Sustained Drug Release ◽

Pharmaceutical Dosage Forms ◽

Fused Deposition ◽

Bcs Class Ii

Abstract Niclosamide (NCS) is a drug that has been used as an anthelmintic and anti-parasitic active principle for about 40 years. Recently, some studies have highlighted its potential in treating various tumors, allowing a repositioning of this drug. Despite its potential, NCS is a Biopharmaceutical Classification System (BCS) Class II drug, and is consequently characterised by low aqueous solubility, poor dissolution rate and reduced bioavailability, which limits its applicability. In this work, we utilize a very novel technique, Direct Powder Extrusion (DPE) 3D printing, which overcomes the limitations of previously used techniques (Fused Deposition Modelling, FDM) to achieve direct extrusion of pharmaceutical grade powder mixtures consisting of NCS, hydroxypropyl methylcellulose (HPMC, Affinisol 15 LV), hydroxypropyl-b-cyclodextrin (HP-β-CD) and polyethylene glycol (PEG) 6000. For the first time, direct printing of powder blends containing HP-β-CD was explored. For all tablets, in vitro dissolution studies showed sustained drug release over 48 hours, but for tablets containing HP-β-CD, the release was faster. Solid-state characterisation studies showed that during extrusion, the drug lost its crystal structure and was evenly distributed within the polymer matrix. All printed tablets exhibited good mechanical and physical features and guarantee stability of the drug content for up to 3 months. This innovative printing technique has demonstrated the possibility to produce personalised pharmaceutical dosage forms starting directly from powders, avoiding the use of filament used by FDM.

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