Micro-engineered devices for assessing cellular responses to mechanical stimulation of ex vivo tissues

The soft tissue of lower-limb prosthetic users encounters unique biomechanical challenges. Although not intended to tolerate high loads and deformation, it becomes a weight-bearing structure within the residuum-prosthesis-complex. Consequently, deep soft tissue layers may be damaged, resulting in Deep Tissue Injury (DTI). Whilst considerable effort has gone into DTI research on immobilised individuals, only little is known about the aetiology and population-specific risk factors in amputees. There is a clear gap in understanding what mechanisms contribute to a biologically safe and biomechanically sound prosthetic fit. Therefore, new information is necessary to advance future body-device interface designs and management of symptoms. Considering this, it is fundamental to understand what is happening at the cellular and tissue-level in response to forces resulting from prosthetic use.



Research problem

To address this lack of understanding at the tissue and cellular level, new tools are required. Organ-on-a-chip (OOC) is an emerging area that builds upon technological advances in micro-engineering methods for biological applications (lab-on-a-chip, microfluidics, cell engineering) to develop in vitro systems that recapitulate the in vivo functions and physiochemical environment of tissues. However, whilst a diverse range of cell-culture based OOC models have been developed, they cannot fully replicate the complexity of tissues in vivo and there are few reports of on-chip tissue-based models (where intact tissue samples are maintained). Given the benefits of OOC technologies (precisely controlled fluid flows, ability to multiplex, control over the local cellular environment etc.), exciting opportunities exist to develop new microsystems for maintaining and analysing ex vivo tissue whose cellular and extracellular matrix architecture is preserved. Such systems would be well suited to novel investigations into monitoring tissue damage and remodelling in response to mechanical forces, both in the short-term (hours) and long-term (weeks).



The elastomer-based soft lithography approaches widely used to create OOC devices are well suited to the application of mechanical stimuli. Methods for applying stretch have been widely reported, though primarily for mono- and multi- layer cell culture systems (e.g. the seminal "lung-on-a-chip"). However, compression-based biomechanical stimuli have been little explored. Therefore, the aim of this project is to develop the first example of an ex vivo tissue-based OOC system optimised for maintaining skeletal muscle in vitro whilst applying controlled loading conditions. The system will be designed to enable live-cell microscopy of the tissue and to be adaptable for use other tissue types (e.g. skin, vascular).

The CDT students will help create solutions for amputees and people with debilitating conditions such as stroke and diabetes, reducing mortality and enabling them to live more satisfying, productive and fulfilling lives. These solutions, co-created with industry and people living with disabilities, will have direct economic and societal benefits. The principal beneficiaries are industry, P&O service delivery, people who need P&O devices, and society in general.
Industry
The novel methods, devices and processes co-created with users and industry will have a direct economic value to our industry partners (by the creation of IP, new products, and improved industry and academic links). Our CDT graduates will be the natural potential employees of our industry partners and for companies in the wider healthcare technology sector. This will help address the identified critical skills need and shortage leading to improvement in the UK's competitiveness in this rapidly developing and growing global market. The CDT outcomes will help UK businesses spread risk (because new developments are well founded) and more confidently enter new markets with highly skilled employees (CDT graduates).

P&O service delivery
Doctoral engineering graduates with clinical knowledge are needed to improve the deployment of advanced technologies in practice. Our main UK industry partner, Blatchford, stated: "As technology develops it will become easier for the end-user (the patient), but the providers (the clinicians) are going to need to have a higher level of engineering training, ideally to PhD level". The British Association of Prosthetists and Orthotists estimates that no more than ten practising P&O clinicians have a PhD in the UK. Long-term P&O clinical academic leadership will be substantially improved by the CDT supporting a select number of clinically qualified P&O professionals to gain doctorates.

Users
The innovation of devices, use of device and patient monitoring, and innovation approaches in LMIC should not only lead to improved care but also lower healthcare costs. Diabetes UK estimates that the total healthcare expenditure related to foot ulceration and amputation in diabetes was £1billion (2014-15), with 2/3 of this related to foot ulceration. Small innovations could lead to large cost savings if targeted at the right aspects of care (e.g. earlier adoption, and reducing device abandonment).
An ability to work is fundamental to a person's place in society and their sense of purpose and has a significant societal impact in all territories. This is perhaps greatest in LMIC where attitudes towards disability may still be maturing, and appropriate social care infrastructure is not always in place. In these cases, an ability to work is essential for survival.
Improved design approaches will impact on all users regardless of context, since the device solutions will better match local and individual user needs. Addressing issues related to prosthetic/orthotic device abandonment (e.g. cosmesis) and improved adherence should also lead to greater social participation. Improved device solutions will shift focus from what users "cannot do" to what they now "can do", and help progress attitudes towards acceptance of disability.
Societal
The majority of the global P&O users are of working age, and a key economic impact will be keeping users in work. The average age at amputation due to diabetes is just 52 in the USA but much younger in countries with less well-developed health care and trauma services (e.g. 38 in Iran). Diabetes UK reports that 35-50% of people are of working age at diagnosis and that there are around 70,000 foot ulcers in the UK, precursors to amputation. There is a similar concern for stroke survivors around a quarter of whom are of working age and are 2-3 times more likely to be out of work after eight years.