Parameters for re-engineering stump skin to alleviate pressure ulcers

Pressures ulcers, also known as bedsores or decubitus ulcers, are a severely debilitating condition that affect half a million people per year in the UK. Pressure ulcers arise when the skin and muscle is compressed between a bony prominence and a hard surface, eg the sitz bone on the buttocks and a wheel chair, or the tibia of an amputated stump and a prosthetic device. In response to compression the soft tissue is deformed, blood capillaries are cut-off and the tissue becomes starved of oxygen and nutrients resulting in cell death. Muscle has a lower tolerance to internal pressures than skin, and ulceration therefore often starts within the interior muscle before effects are observed on the skin surface.

Current strategies to alleviate pressure ulcer formation involve modification of the external environment to reduce compression and shear forces on the skin. In this research proposal, we aim to characterise whether, and by how much, modification of the skin itself would alleviate pressure ulcer formation. If skin was thicker and stronger could it dissipate compressive and shear forces, so they do not reach the muscle and cause deformation, cell death and ulceration? We plan to re-engineer stump skin so it acquires the material and behavioural properties of plantar skin. Plantar skin is thicker, more compliant, and has a lower frictional coefficient than skin on other body sites. We believe these properties will help in dissipation of compressive and shear forces.

This entire proposal utilises human cells isolated from leg and foot skin biopsies to engineer skin constructs in a lab that represent different sites on the body (leg and plantar). In work plan 1 of this proposal we will sequence constructs representing leg skin, plantar skin, and re-engineered leg skin to determine the molecular properties of the different skin types. In work plan 2 we will assess whether skin from different body sites adapts differently to mechanical compression. We hypothesise that plantar skin, and re-engineered leg skin will have a molecular signature that enables adaptation and an increase in skin thickness in response to compression. Comparatively, we believe that leg skin constructs will break down in response to pressure, indicative of blister formation. We will link the molecular properties of skin with the ability to adapt and increase in thickness in response to mechanical compression. In work plan 3 we will determine the material properties of skin constructs representing different body sites. We will then integrate this into mathematical models in work plan 4 to evaluate if changing the material properties of skin on an amputated stump will dissipate compressive and shear forces, lowering internal pressure and stress within the muscle. We will correlate the magnitude of stresses and strains within the muscle with the incidence of pressure ulcers.

In summary, we will characterise the molecular and material properties of human skin from different body sites, in addition to assessing the effect of skin re-engineering on properties like adaptation and dissipation. Our overall goal is to determine whether re-engineering stump skin to become like plantar skin is a feasible therapeutic strategy for alleviating pressure ulcers.

Who will benefit?

Several groups will benefit from this research. Academics, including PI's, postdocs and students will all benefit, as will Academic clinicians and clinical students. Other beneficiaries include the commercial private sector, military personnel, patients and the NHS, the wider public, and the staff working on this project.

How will they benefit?

-Academics (PI's, postdocs, students)
Several academics will benefit (as indicated in the beneficiaries section) through an increased understanding of cell reprogramming, cell adaptation, material properties of skin, positional information in skin, and the role of skin in dissipation of shear and compressive forces.

-Academics (Clinicians and clinical students)
Medical clinicians and clinical students regularly see patients with pressure ulcers. Currently, methods to alleviate ulcers aim to reduce the pressure and shear stress at the contact interface. For example, padding is incorporated into prosthetics to reduce compression, while bed liners are being developed that reduce shear on the skin surface. This proposal aims to determine whether a new treatment, fibroblast therapy) would be a suitable therapeutic to reduce the incidence of pressure ulcers. This will benefit clinical academics.

-Commercial private sector
There are several companies, for example Blatchford, who specialise in developing prosthetics, orthotics, special seating and wheelchairs for amputees. They decide on treatment plans on a patient specific basis. We hope that our research will demonstrate that fibroblast therapy is a suitable therapeutic strategy to alleviate pressure ulcers, and that one day companies such as Blatchford will integrate this into their treatment options for patients.

-Military personnel
Up to 70% of military personnel injured in explosive blasts have lower limb injuries. Of these, 7.4% require limb amputation, and 55% of these individuals will develop a pressure ulcer. Understanding whether fibroblast therapy is a viable therapeutic strategy to alleviate pressure ulcers will impact the treatment and rehabilitation of these personnel, enhancing the quality of life for affected individuals.

-Patients and the NHS
The NHS spends over £2.1 billion every year, treating the half a million patients that are admitted to hospitals with pressure ulcers. Over 20% of hospitalised patients will also develop a pressure ulcer, meaning many of the burdens on the NHS come from within the system. At the end of this research proposal, we aim to make a recommendation on whether fibroblast therapy could be used to prevent pressure ulcers. This will impact both patients within the NHS, and the NHS itself.

-The general public
Pressure ulcers are more commonly known as bedsores. They impact people with low mobility, from disabled individuals through to premature babies. Pressure ulcers can occur after just a few hours of sustained pressure, but take weeks to heal. As such, the general public is relatively well informed on pressure ulcers and the detrimental effects they have on quality of life.
Cellular reprogramming is also a very 'hot' topic at the moment, and mechanisms that enable fibroblasts to re-engineer a leg keratinocyte to a plantar fate will be of public interest.

-Staff working on this project
The postdoctoral researcher who is employed to work on this project will gain an in-depth experience of a broad variety of techniques, including sequencing and bioinformatics analysis, mechanical engineering, tribology, and finite element analysis. All these skills are highly transferable, and it is unique to have an individual with such a range of expertise.
The research technician who is employed to work on this project will become an expert in cell culture techniques, including skin construct formation.