A Novel Scaffold to Promote Skin Regeneration

项目总结： 皮肤疤痕每年影响全球8000多万人-超过440万人 在机动车事故中受伤，超过240万名患者严重烧伤，数千名勇士 在军事爆炸中受伤。在严重烧伤中，超过40%的患者会出现增生性瘢痕收缩， 这会导致增生性瘢痕紧缩(HSC)。HSC是僵硬、缩小的伤疤，限制了流动性、冲击力 生活质量高，每年在外科治疗和物理治疗上花费数百万美元。HSC是由 通过增加机械张力，并发生在受伤后6-12个月。目前的组织工程支架，如 作为IntegraTM，具有类似于未受损伤的皮肤的机械性能，但胶原基支架很快就会形成 退化超过2个月，寿命太短，不能预防HSC。预防HSC的关键是有一个 生物相容性支架，可降解12个月以上。为了实现这一目标，脚手架的发展 提出了由粘弹性共聚物组成的聚(ι-丙交酯-co-ε-己内酯)(PLCL)。出版的作品有 证明了电纺~100微米厚的PLCL支架具有合适的力学性能 皮下移植及对小鼠肝星状细胞的抑制。然而，电纺不能用来 由于需要很大的电压梯度，所以生成大型动物研究所需的厚度的支架 用于脚手架生产。为了克服这一障碍，将使用溶剂浇注/颗粒浸出(SCPL)来 创建三维多孔PlcL支架。这种方法包括将聚合物与有机颗粒混合在一起 溶剂，然后浇注到模具中。然后，水穿过模具，将颗粒滤出， 从而形成相互连接的多孔3D支架。此SPCL方法已成功用于创建 2 mm厚的PlcL支架，具有合适的机械性能和可调的植入孔隙率 在皮肤移植下面。我们假设优化的SCPL PlcL支架将促进移植物的生物结合 并抑制体内的纤维化。检验我们假设的三个目标是： 目的1.确定SCPL制备工艺参数，以制备孔径可控的均匀PlcL支架， 孔隙率和机械性能。 目的2.确定胶原包覆的SCPL-PlcL支架组织植入的最佳孔隙率。 目的3.评价最佳孔隙率PlcL支架在促进皮片存活方面的安全性和有效性。 这些目标的完成将验证一种可扩展的方法来创建PlcL支架并在 啮齿动物和猪创伤模型的安全性和有效性。这一结果将使我们更接近于开发 预防HSC的优化技术，有可能改善全球数百万人的生活。

PROJECT SUMMARY: Dermal scarring affects more than 80 million people worldwide annually - over 4.4 million people are injured in motor vehicle accidents, over 2.4 million patients are severely burned, and thousands of warriors are wounded in military blasts. In severe burns, more than 40% of patients develop hypertrophic scar contraction, which leads to hypertrophic scar contractures (HSc). HSc are stiff, shrunken scars that limit mobility, impact quality of life and cost millions of dollars per year in surgical treatment and physical therapy. HSc are caused by increased mechanical tension and occur 6-12 months after injury. Current tissue engineered scaffolds, such as IntegraTM, have mechanical properties akin to unwounded skin, but the collagen based scaffolds rapidly degrade over 2 months, being too short-lived to prevent HSc. The key to preventing HSc is having a biocompatible scaffold which degrades over 12 months. To achieve this goal, the development of scaffolds composed of viscoelastic copolymer, poly(ι-lactide-co-ε-caprolactone) (PLCL) is proposed. Published work has demonstrated that electrospun ~100 µm thick PLCL scaffolds possess appropriate mechanical properties for implantation beneath skin grafts and inhibition of HSc in mice. However, electrospinning cannot be used to generate scaffolds at thickness necessary for large animal studies due to the great voltage gradient required for scaffold production. To overcome this hurdle solvent casting/particulate leaching (SCPL) will be used to create 3D porous PLCL scaffolds. This method involves the mixing of polymers with particles within an organic solvent followed by casting into a mold. Water is then passed through the mold to leach out the particles, resulting in an interconnected porous 3D scaffold. This SPCL method has successfully been used to create 2mm thick PLCL scaffolds, which have appropriate mechanical properties and tunable porosity for implantation beneath skin grafts. We hypothesize that optimized SCPL PLCL scaffolds will promote graft bioincorporation and dampen fibrosis in vivo. The three Aims to test our hypothesis are: Aim 1. Determine SCPL manufacturing parameters to create uniform PLCL scaffolds with controlled pore size, porosity, and mechanical properties. Aim 2. Determine the optimal porosity of collagen coated SCPL PLCL scaffolds for tissue ingrowth. Aim 3. Evaluate the safety and efficacy of optimal porosity PLCL scaffolds at promoting skin graft survival. The completion of these aims will validate a scalable method to create PLCL scaffolds and test them in rodent and swine wound models for safety and efficacy. The results will bring us closer toward developing an optimized technology that prevents HSc with the potential to improve millions of lives worldwide.