Parameters for re-engineering stump skin to alleviate pressure ulcers

压力性溃疡，也被称为褥疮或褥疮，是一种严重的使人衰弱的疾病，在英国每年有50万人受到影响。当皮肤和肌肉在骨骼突出和坚硬表面之间受到挤压时，例如臀部的坐骨和轮椅，或截肢肢的胫骨和假体装置，就会产生压疮。由于压迫，软组织变形，毛细血管被切断，组织缺氧和缺乏营养，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，溃疡通常从内部肌肉开始。目前缓解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。在这项研究计划中，我们的目标是描述是否，以及通过多少，修改皮肤本身会减轻压疮的形成。如果皮肤更厚、更结实，它能驱散压缩和剪切力，使它们不会到达肌肉，造成变形、细胞死亡和溃疡吗？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，更柔顺，摩擦系数更低。我们相信这些特性将有助于压缩和剪切力的消散。整个方案利用从腿部和足部皮肤活检中分离出来的人类细胞，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。在本提案的工作计划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构建物进行测序，以确定不同皮肤类型的分子特性。在工作计划2中，我们将评估不同身体部位的皮肤对机械压迫的适应是否不同。我们假设足底皮肤和重新设计的腿部皮肤将具有一种分子特征，能够适应并增加皮肤厚度以响应压缩。相比之下，我们认为腿部皮肤结构会在压力下分解，表明水疱形成。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，以响应机械压缩。在工作计划3中，我们将确定代表不同身体部位的皮肤结构的材料特性。然后，我们将把它整合到工作计划4的数学模型中，以评估改变截肢肢上皮肤的材料特性是否会消散压缩和剪切力，降低肌肉内部的压力和应力。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。总之，除了评估皮肤再造对适应性和耗散等特性的影响外，我们还将描述来自不同身体部位的人体皮肤的分子和材料特性。我们的总体目标是确定再造残肢皮肤成为类似足底皮肤是一个可行的治疗策略，以减轻压力性溃疡。

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.