Tissue Engineering a Suture Replacement for Children with Craniosynostosis

组织工程作为颅缝早闭儿童的缝线替代品

• 批准号: 8074367
• 负责人: Gregory M. Cooper
• 金额: $ 35.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074367
• 关键词: Accounting; Address; Adipose tissue; Age; Alkaline Phosphatase; Area; BMP2 gene; Biopsy; Birth; Bone Marrow; Bone Tissue; Brain; Calvaria; Cell Differentiation process; Cell Fraction; Cell Therapy; Cells; Child; Clinical; Coculture Techniques; Congenital abnormal Synostosis; Craniosynostosis; Cues; Data; Databases; Development; Diagnosis; Dose; Dura Mater; Early treatment; Effectiveness; Engineering; Etiology; Extracellular Matrix; FGF2 gene; Failure; Fatty acid glycerol esters; Fibrin; Funding; Genetic; Genetic Predisposition to Disease; Goals; Growth; Growth Factor; Human; In Vitro; Individual; Intervention; Intracranial Pressure; Joint structure of suture of skull; Liquid substance; Measures; Modeling; Molecular; Morbidity - disease rate; Muscle; Muscle Cells; Natural regeneration; Operative Surgical Procedures; Oryctolagus cuniculus; Osteogenesis; Outcome; Patients; Pattern; Pattern Formation; Phase; Population; Positioning Attribute; Postoperative Period; Printing; Proteins; Regimen; Regulation; Relative (related person); Reproducibility; Research Personnel; Screening procedure; Side; Skeletal Muscle; Source; Staining method; Stains; Stem cells; Stimulus; Surgeon; Surgical Management; Surgical sutures; System; Techniques; Technology; Testing; Thick; Time; Tissue Engineering; Tissues; Work; base; bone; cell type; clinically relevant; coronal suture; craniofacial; design; dosage; effective therapy; experience; improved; in vivo; insight; mortality; multipotent cell; novel; osteogenic; osteoprogenitor cell; premature; prevent; public health relevance; response; scaffold; stem cell biology; stem cell differentiation; suture fusion; technology development; therapy design; vector

DESCRIPTION (provided by applicant): Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures. Current therapy involves extensive surgical intervention including fronto-orbital advancement and radical calvarial bone repositioning. Although the current techniques often successfully restore normal brain growth vectors, increase intracranial volume, and decrease intracranial pressure, the surgical intervention is extensive and the outcomes are variable. Furthermore, the calvarial bone regenerates quickly and can refuse shortly after surgery. When refusion occurs, secondary surgeries are required which increases patient morbidity and mortality. Our group has set out to radically improve the treatment of craniosynostosis by minimizing the extent of surgical intervention, improving outcomes, and inhibiting the occurrence of refusion. We are in a unique position to design a novel therapy that could be tailored to improve the treatment of children who present with craniosynostosis, regardless of the molecular or genetic etiology. To determine the proper growth factor cues, doses, and cell fraction, we will employ stem cell characterization using a novel inkjet printing technology to assess the osteogenic potential of skeletal muscle-derived and adipose-derived cells isolated from a rabbit model of human nonsyndromic coronal suture synostosis (Aim #1A). Based on our findings from Aim #1A, we will create a suture replacement scaffold using our inkjet printing to create spatially-defined patterns of immobilized growth factors that will reproducibly form two regions of bone separated by an interdigitating non- bone region in vitro (Aim #1B). We will then test the effectiveness of our suture replacement scaffolds to improve the surgical treatment of rabbits with craniosynostosis in vivo (Aim #2). To demonstrate the clinical relevance of this approach in humans, we will employ similar progenitor cell characterization as in Aim #1 on cells derived from skeletal muscle and adipose of children with craniosynostosis and assess these cells' responsiveness to our suture replacement scaffolds in vitro (Aim #3). By completing these Aims, we will make significant progress in improving the surgical treatment of craniosynostosis. Furthermore, the development of technologies that can be used to both characterize stem cell differentiation potential and to spatially control the differentiation of multipotent cells will have broad impact in the field of tissue engineering. Public Health Relevance Statement (Provided by Applicant): Project Narrative Craniosynostosis is the term given to the premature fusion of one or more of the calvarial sutures. Fusion of a suture results from a failure of correct pattern formation between bone and non-bone tissues. We have set out to improve the surgical management of children with craniosynostosis through tissue engineering. We will develop emergent inkjet printing technology to characterize progenitor cells and to reproducibly pattern tissue formation in vivo. By patterning cell differentiation, it may be possible to create tissues that function similarly to normal, unfused sutures. The technology that will be developed in performing the proposed work will have broad impact on the field of stem cell biology, the application of tissue engineering, and on the treatment of children with craniosynostosis.

描述（由申请人提供）： 颅骨突变的定义为一个或多个颅骨缝合线的过早融合。当前的疗法涉及广泛的手术干预，包括额轨道的进步和根治性的颅骨重新定位。尽管当前的技术通常成功地恢复了正常的脑生长载体，增加颅内体积并降低颅内压，但手术干预却是广泛的，结果是可变的。此外，颅骨会迅速再生，并且可以在手术后不久拒绝。当发生拒绝时，需要进行继发手术，以增加患者的发病率和死亡率。我们的小组已经着手通过最大程度地降低手术干预的程度，改善预后并抑制拒绝的发生来从根本上改善颅突的治疗。我们处于设计一种新型疗法的独特位置，该疗法可以量身定制，以改善出现颅内突变病的儿童的治疗，无论分子或遗传病因如何。为了确定适当的生长因子提示，剂量和细胞分数，我们将使用新型的喷墨印刷技术采用干细胞表征来评估骨骼肌衍生的和脂肪衍生的细胞的成骨潜力，从人类非杂质的冠状动脉刺激性刺激性的兔模型中分离出来（AIM＃1A）。根据AIM＃1A的发现，我们将使用喷墨打印创建一个缝合式替换支架，以创建固定生长因子的空间定义模式，这些模式将可重复地形成两个骨骼的两个区域，这些区域由互联面的非骨区域分离（AIM＃1B）。然后，我们将测试缝合替换支架的有效性，以改善体内颅突的外科手术治疗（AIM＃2）。为了证明这种方法在人类中的临床相关性，我们将采用类似的祖细胞特征，与骨骼肌骨骼肌和患有颅突变儿童脂肪的细胞相似，并评估这些细胞对我们的缝合替换支架的反应性（AIM＃3）。通过完成这些目的，我们将在改善颅突式症的手术治疗方面取得重大进展。此外，可以用来既表征干细胞分化潜力的技术的发展又可以在空间控制多能细胞的分化中对组织工程领域产生广泛的影响。 公共卫生相关声明（由申请人提供）：项目叙事颅骨突变是一种或多种钙质缝线的过早融合的术语。缝合线的融合是由于骨骼和非骨组织之间正确模式形成的失败而导致的。我们已经着手通过组织工程改善患有颅突的儿童的手术管理。我们将开发出紧急的喷墨印刷技术，以表征祖细胞并在体内重现组织形成。通过对细胞分化的模式，可以创建与正常的，未连接的缝合线相似的组织。在执行拟议工作的过程中将开发的技术将对干细胞生物学，组织工程的应用以及对颅内突变病儿童的治疗产生广泛的影响。