Parameters for re-engineering stump skin to alleviate pressure ulcers

压力性溃疡，也被称为压疮或压疮，是一种严重虚弱的疾病，每年在英国影响50万人。当皮肤和肌肉被压在骨性隆起和坚硬的表面之间时，如臀部的坐骨和轮椅，或截肢残肢的胫骨和假肢装置，就会出现压疮。由于受压，软组织变形，毛细血管被切断，组织缺乏氧气和营养物质，导致细胞死亡。肌肉对内部压力的耐受性比皮肤低，因此在皮肤表面观察到影响之前，溃疡通常在肌肉内部开始。目前减轻压疮形成的策略包括改变外部环境以减少皮肤上的压缩和剪切力。在这项研究方案中，我们的目标是表征皮肤本身的修饰是否会减轻压疮的形成，以及修饰程度有多大。如果皮肤更厚更坚固，它是否可以驱散压力和剪切力，这样它们就不会到达肌肉，导致变形、细胞死亡和溃疡？我们计划重新设计残肢皮肤，使其获得足底皮肤的材料和行为特性。足底皮肤比身体其他部位的皮肤更厚，更顺从，摩擦系数更低。我们相信这些特性将有助于消散压力和剪切力。整个方案利用从腿部和足部皮肤活检中分离出来的人体细胞，在实验室中设计出代表身体不同部位(腿部和足底)的皮肤结构。在这项提案的工作计划1中，我们将对代表腿部皮肤、足底皮肤和重新设计的腿部皮肤的结构进行排序，以确定不同皮肤类型的分子特性。在工作计划2中，我们将评估来自不同身体部位的皮肤是否对机械挤压有不同的适应。我们假设，足底皮肤和重新设计的腿部皮肤将具有一个分子签名，使适应和皮肤厚度增加，以响应压缩。相比之下，我们认为腿部皮肤结构会因压力而分解，这表明水泡的形成。我们将把皮肤的分子特性与适应和增加厚度的能力联系起来，以应对机械压缩。在工作计划3中，我们将确定代表不同身体部位的皮肤构造的材料特性。然后，我们将把这一点整合到工作计划4的数学模型中，以评估改变截肢残肢上皮肤的材料属性是否会分散压缩和剪切力，从而降低肌肉内的内部压力和应力。我们将把肌肉内的应力和应变的大小与压疮的发生率联系起来。总而言之，除了评估皮肤重组对适应和消散等性能的影响外，我们还将表征来自不同身体部位的人类皮肤的分子和材料属性。我们的总体目标是确定重新设计残肢皮肤，使其变得像足底皮肤一样，是否是缓解压疮的可行治疗策略。

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.