Biologically-informed development of autologous platelet-based wound healing gels

RAPID生物动力Haematogel是一种正在进行2b期临床试验的研究性药物，以确定其治疗糖尿病足溃疡的疗效。这种富血小板血浆（PRP）凝胶是在护理点制造的，直接涂在伤口上，并封闭长达一周。虽然治疗效果背后的确切机制尚不完全清楚，但人们认为凝胶渗出液中含有生长因子（如血管内皮生长因子、胰岛素样生长因子1、血小板源性生长因子）和细胞因子，这些细胞因子储存在血小板分泌的a颗粒中。这些因子刺激成纤维细胞增殖、血管生成和胶原合成，从而加速伤口愈合过程。临床病例研究证实，这是一种改变生活的先进疗法，已经快速进入临床治疗对其他疗法无反应的糖尿病溃疡患者。然而，要实现血小板药物的全部潜力并使其更广泛地获得，还需要克服重大的工业和监管挑战。对疗法的合理科学理解是优化治疗效果、确保患者安全和通过实现循证指导的产品开发和监管来确保药品质量的关键。该项目的基本原理基于血小板的药物尚处于起步阶段，对其确切的作用机制知之甚少。尽管如此，PRP疗法已经俘获了临床医生和患者的想象力，以至于在支持该疗法的基础科学出现之前就将其应用于临床实践。PRP凝胶的活性成分和相应的代谢功能尚未明确确定，患者血液学的变化意味着PRP产品的化学和生物成分在凝胶之间会有很大差异。例如，来自老年人或急性创伤患者的血小板可能具有较低的愈合特性。在这方面，PRP凝胶不同于药物分子或常规药品，凝胶之间的很大程度的差异将违反正常的一致性监管要求。该项目将由两个假设驱动：(i)制备PRP凝胶的方法是可变的-这可能导致不一致或次优的临床结果，（ii）分泌组中的物理化学性质和生物标志物可以被确定为产品质量的指标。定义质量属性可以通过工艺和产品的规格设置来控制PRP凝胶的生产。目的和目标该项目旨在深入了解支撑PRP凝胶功效的作用机制，并将其与制造工艺和关键产品属性联系起来。这将使基于证据的规范设置和质量控制成为可能，以确保PRP产品在临床环境中使用时的质量。具体目标有：根据工艺参数优化prp -凝胶形成，并确定关键产品属性2。确定指示伤口愈合活性的生物学特征和化学特征3。在体内模型中研究伤口愈合效果

RAPID Biodynamic Haematogel is an investigational medicinal product in phase 2b clinical trials to establish its efficacy in treating diabetic foot ulcers. This platelet rich plasma (PRP) gel is manufactured at the point of care, applied directly onto the wound and occluded for a period of up to one week. Although the exact mechanism behind the therapeutic effect is not fully characterized, it is thought that the liquid exudate from the gel contains growth factors (e.g. vascular endothelial growth factor, insulin-like growth factor 1, platelet-derived growth factor) and cytokines which are stored in the secretory a-granules in platelets. These factors stimulate fibroblast proliferation, angiogenesis and collagen synthesis, thus accelerating the process of wound healing. Clinical case studies verify that this is a life-changing advanced therapy that has been fast-tracked to the clinic for patients with diabetic ulcers that are unresponsive to other therapies. However, there are significant industrial and regulatory challenges to overcome to realise the full potential of platelet-based medicines and make them more widely available. A sound scientific understanding of the therapy is key to optimising therapeutic efficacy, ensuring patient safety and assuring medicinal product quality by enabling evidence-guided product development and regulation.Rationale for the projectPlatelet-based medicines are in their infancy and little is known about their precise mechanism of action. Nonetheless, PRP therapy has captured the imagination of clinicians and patients such that adoption into clinical practice has preceded the basic science underpinning the therapy. The active ingredient(s) and corresponding metabolic functions of PRP gels are not definitively established and variation in patient haematology means that the chemical and biologic constituents of a PRP product will vary considerably from gel to gel. For example, platelets from elderly or acutely traumatised patients may have diminished healing properties. In this respect, PRP gels are unlike drug molecules or conventional medicinal products and the substantial degree of gel-to-gel variation would breach normal regulatory requirements for consistency.The project will be driven by two hypotheses: (i) the methodology for preparing PRP gels is variable - this may contribute to inconsistent or suboptimal clinical outcomes, (ii) physicochemical properties and biomarkers in the secretome can identified as indicators of product quality. Defining quality attributes will enable control of PRP gel manufacturing by specification-setting for the process and product.Aim and objectivesThe project aims to provide insights into the mechanism of action underpinning PRP gel efficacy and link this to the manufacturing process and critical product attributes. This will enable evidence-based specification-setting and quality control to assure PRP product quality when utilised in clinical settings. Specific objectives are:1. Optimise PRP-gel formation in terms of process parameters and identify critical product attributes2. Determine biological features and chemical signatures indicative of wound healing activity3. Investigate the wound healing effect in an in vivo model