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Exploring the Role of a Novel AMPK Activator in Diabetic Wound Repair: Development of a Controlled-Release Dermal Gel
Secondary Supervisor(s): Dr Lissette Sanchez-Aranguren
University of Registration: Aston University
BBSRC Research Themes: Integrated Understanding of Health (Ageing, Pharmaceuticals)
Project Outline
This interdisciplinary project aims to develop a dermal gel loaded with MHY908 for treatment of diabetic wounds. Diabetic wounds, particularly foot ulcers, represent a significant global health concern. In the UK, approximately 450,000 diabetic patients develop foot ulcers annually, costing the NHS around £900million. These wounds are notoriously difficult to heal due to increased inflammation, oxidative stress, and impaired angiogenesis, often leading to severe complications such as infection, sepsis, and amputation. This project focuses on developing an MHY908-loaded gel to improve wound healing targeting these underlying issues.
MHY908, an AMP-activated protein kinase (AMPK) activator, plays a crucial role in modulating inflammation and energy metabolism, key contributors to poor wound healing in diabetic patients. By activating AMPK, MHY908 can enhance mitochondrial function, promote angiogenesis, and reduce chronic inflammation, all essential for effective wound healing. These properties suggest MHY908 could address metabolic dysfunctions that hinder healing in diabetic wounds. Our preliminary data indicate MHY908 is safe on dermal cell cultures and effectively reduces inflammation, highlighting its potential as a therapeutic agent.
The use of gel formulations for the dressing provides multiple advantages, including enhanced MHY908 stabilisation and sustained drug release over several days. This controlled release is crucial for maintaining therapeutic levels of MHY908 at the wound, promoting continuous healing without needing frequent reapplication. By incorporating MHY908 into a controlled-release gel formulation, this project seeks to directly target the mechanisms that impede wound healing in diabetic patients.
Objectives
1. Development and characterisation of gel formulations loaded with MHY908. The gels will be characterised by testing their mechanical properties, stability, and release profiles.
2. Development of a diabetic 3D skin model using human umbilical vein endothelial cells (HUVECs), human dermal fibroblasts (HDFs), and keratinocytes.
3. The therapeutic efficacy of MHY908-loaded gels will be evaluated in a 3D skin model by assessing wound healing indicators, including cell migration, angiogenesis, and wound closure rates, mitochondrial function as well as measuring inflammatory markers and oxidative stress levels.
Methods
Gel formulations will be developed using biocompatible polymers such as hydroxypropyl methylcellulose or sodium alginate, ideal for sustained drug-release. These gels have already been established in our lab with the aid of 3D printing. MHY908-loaded gels will be characterised for viscosity, spreadability, and stability. MHY908 release profiles will be assessed using high-performance liquid chromatography.
The 3D diabetic skin model will be established using a co-culture of HUVECs, HDFs, and keratinocytes. The model will be cultured and characterised in a high-glucose medium and TNF-α will be added to induce inflammation, mirroring conditions of a diabetic wound.
Gel therapeutic efficacy will be evaluated by applying to 3D skin model. Scratch assays will assess wound closure. Tube formation assays will evaluate angiogenesis. Levels of inflammatory markers (IL-6, IL-8, and TNF-α) and oxidative stress will be measured using ELISA and oxidative stress assays, respectively. Additionally, mitochondrial function will be assessed by measuring key indicators such as, mitochondrial membrane potential, and oxygen consumption rate using assays like Seahorse XF analysis. This will help evaluate MHY908’s impact on restoring cellular energy balance, crucial for effective wound healing in diabetic conditions.
This approach offers an advanced treatment option for diabetic wounds. Developing a 3D diabetic skin model introduces a valuable preclinical tool that offers a more precise representation of diabetic wound conditions compared to traditional 2D models. This could accelerate translation into clinical applications.