Protease-sensitive atelocollagen hydrogels promote healing in a diabetic wound model

📝 Abstract

The design of exudate-managing wound dressings is an established route to accelerated healing, although such design remains a challenge from material and manufacturing standpoints. Aiming towards the clinical translation of knowledge gained in vitro with highly swollen rat tail collagen hydrogels, this study investigated the healing capability in a diabetic mouse wound model of telopeptide-free, protease-inhibiting collagen networks. 4 vinylbenzylation and UV irradiation of type I atelocollagen (AC) led to hydrogel networks with chemical and macroscopic properties comparable to previous collagen analogues, attributable to similar lysine content and dichroic properties. After 4 days in vitro, hydrogels induced nearly 50 RFU% reduction in matrix metalloproteinase (MMP)-9 activity, whilst showing less than 20 wt.-% weight loss. After 20 days in vivo, dry networks promoted 99% closure of 10x10 mm full thickness wounds and accelerated neodermal tissue formation compared to Mepilex. This collagen system can be equipped with multiple, customisable properties and functions key to personalised chronic wound care.

💡 Analysis

The design of exudate-managing wound dressings is an established route to accelerated healing, although such design remains a challenge from material and manufacturing standpoints. Aiming towards the clinical translation of knowledge gained in vitro with highly swollen rat tail collagen hydrogels, this study investigated the healing capability in a diabetic mouse wound model of telopeptide-free, protease-inhibiting collagen networks. 4 vinylbenzylation and UV irradiation of type I atelocollagen (AC) led to hydrogel networks with chemical and macroscopic properties comparable to previous collagen analogues, attributable to similar lysine content and dichroic properties. After 4 days in vitro, hydrogels induced nearly 50 RFU% reduction in matrix metalloproteinase (MMP)-9 activity, whilst showing less than 20 wt.-% weight loss. After 20 days in vivo, dry networks promoted 99% closure of 10x10 mm full thickness wounds and accelerated neodermal tissue formation compared to Mepilex. This collagen system can be equipped with multiple, customisable properties and functions key to personalised chronic wound care.

📄 Content

Protease-sensitive atelocollagen hydrogels promote healing in a diabetic wound model Giuseppe Tronci,1,2* Jie Yin,1,2 Roisin A. Holmes,2 He Liang,1,2 Stephen J. Russell,1 David J. Wood2
1 Nonwovens Research Group, School of Design, University of Leeds, Leeds, United Kingdom 2 Biomaterials and Tissue Engineering Research Group, School of Dentistry, University of Leeds, Leeds, United Kingdom

Table of contents entry

Protease-sensitive atelocollagen hydrogels were chemically designed to promote accelerated wound healing in vivo compared to a dressing gold standard.

• Corresponding author: Level 7 Wellcome Trust Brenner Building, St. James’s University Hospital, University of Leeds, Leeds LS9 7TF, UK. E-mail address: g.tronci@leeds.ac.uk (G. Tronci)

Abstract The design of exudate-managing wound dressings is an established route to accelerated healing, although such design remains a challenge from material and manufacturing standpoints. Aiming towards the clinical translation of knowledge gained in vitro with highly-swollen rat tail collagen hydrogels, this study investigated the healing capability in a diabetic mouse wound model of telopeptide-free, protease-inhibiting collagen networks. 4-vinylbenzylation and UV irradiation of type I atelocollagen (AC) led to hydrogel networks with chemical and macroscopic properties comparable to previous collagen analogues, attributable to similar lysine content and dichroic properties. After 4 days in vitro, hydrogels induced nearly 50 RFU% reduction in matrix metalloproteinase (MMP)-9 activity, whilst showing less than 20 wt.-% weight loss. After 20 days in vivo, dry networks promoted 99% closure of 10×10 mm full thickness wounds and accelerated neo-dermal tissue formation compared to Mepilex®. This collagen system can be equipped with multiple, customisable properties and functions key to personalised chronic wound care.
Keywords: atelocollagen, hydrogel wound dressings, chronic wounds, MMPs

1. Introduction
   Chronic wounds in the form of venous leg ulcers (VLUs), diabetic foot ulcers (DFUs) and pressure ulcers (PUs) fail to repair in an orderly and timely self-healing process.1,2 With increasing life expectancy and the associated occurrence of vascular diseases and type II diabetes, costs associated with chronic wound care represent a significant burden to healthcare systems worldwide and are expected to continue to rise. In the UK alone, ~ 650,000 patients are affected by such pathological conditions, resulting in a £3 billion annual cost to the National Health Service (NHS).3 Additionally, chronic wounds are responsible for prolonged pain and morbidity in patients.
   Dressing materials have been widely employed in the clinic for the treatment of chronic wounds.4,5 In contrast to skin substitutes,6 wound dressings are temporarily applied to the wound bed, in order to ensure a defined environment in terms of moisture (to minimise the risk of tissue maceration) and exudate management (to retain growth factors, MMPs and specific cells key to healing).7,8 Furthermore, an ideal wound dressing should (i) provide thermal insulation and oxygen exchange; (ii) protect damaged tissue from secondary infections and bacterial contamination; (iii) display low adherence in situ to enable complete dressing removal without debris formation and integration with the host tissue; (iv) control activity of up-regulated MMPs, such as MMP-9,9,10,11,12,13,14,15,16,17 in order to promote wound healing; (v) not induce any toxic response to tissue microenvironment. Although these requirements can be individually provided by many existing commercial dressings, such controlled multi-functionality is still challenging to accomplish in a single, soluble factor-free material system. Here, we report a synthetically processed, triple helix preserved collagen system that fulfils the above requirements and successfully leads to complete wound closure in diabetic mice. Moreover, the system can be customised to provide bespoke material architectures, i.e. hydrogels, fibres and fabrics. As they are based on hydrophilic building blocks, hydrogels have been widely employed for the design of wound dressings;18 their water content can be tuned in order to ensure defined levels of exudate in situ,19,20,21 whilst the moist interface with the skin prevents dressing adherence and allows for easy removal. Additionally, hydrogels can be customised into fibres and fabrics, whereby the creation of both internal pores and fabric architecture offers advantages with regard to wound exudate management and material dressability.22,23 Polyurethane24 and methylcellulose25 have been successfully employed for the development of wound dressing products, i.e. Mepilex® and Aquacel®, respectively. Particularly the methylcellulose-based materials can become significantly weaker in the wet-state, highlighting the

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