Injectable Anabolic Biomaterials for Bone Regeneration

描述(由申请人提供)：项目摘要：细胞移植是一种很有前途的加速组织再生的临床策略。然而，这项技术的成功临床翻译面临着几个工程和生物学挑战。主要的挑战在于我们无法将移植的细胞运送和保留在愈合部位，并防止在受伤组织的不友好环境中不受控制的细胞死亡。我们实验室的长期目标是利用先进的生物材料和独特的细胞来源，利用再生工程的原理再生复杂的组织、器官和器官系统。我们的近期目标之一是设计细胞输送载体，这种载体将在愈合部位瞬时发挥有利的微环境，以调节移植后的细胞性能。本研究的目的是评价一种基于乳铁蛋白的可注射生物材料作为人工微环境提高包裹的大鼠骨髓间充质干细胞(RBMSC)存活和成骨活性的效果。这项拟议的研究是基于我们的初步研究，展示了可溶性重组人乳铁蛋白(RhLf)的抗凋亡、促有丝分裂和成骨作用。正在测试的假设是，可注射的重组人乳铁蛋白凝胶(RhLfG)将通过抑制细胞凋亡、促进细胞增殖和成骨分化而呈现出良好的骨刺激微环境。该实验计划将探索其生物活性。 可注射重组人乳铁蛋白凝胶细胞载体通过两个特定的目的。第一个目的是评价重组人乳铁蛋白凝胶(RhLfG)对大鼠骨髓间充质干细胞的体外抗凋亡、促有丝分裂和成骨作用。将使用已知的诱导细胞凋亡的细胞培养条件。一种可注射明胶凝胶将作为对照基质来评价乳铁蛋白凝胶的疗效。 微环境在改善细胞存活、促进细胞增殖分化中的作用。第二个目的是利用大鼠颅骨骨缺损模型，在体内评价可注射的重组人LfG在促进rBMSC存活、增殖和成骨方面的效果。我们推测，与注射明胶载体相比，重组人LfG提供的生物活性微环境将促进rBMSC的骨再生和更好的宿主组织整合。拟议的初步研究将有助于了解开发一种基于重组人Lf的细胞指导性可注射再生生物材料作为骨再生的细胞输送载体的可行性。如果成功，这种基于乳铁蛋白的注射载体将通过以下方式在基于细胞的治疗策略的临床翻译中产生重大影响 解决了它目前的一些限制。

DESCRIPTION (provided by applicant): PROJECT SUMMARY Cell transplantation is emerging as a promising clinical strategy to accelerate tissue regeneration. However, the successful clinical translation of this technology faces several engineering and biological challenges. Major challenges lies in our inability to deliver and retain the transplanted cells at the healing site and prevent the uncontrolled cell death in the unfriendly milieu of the injured tissue. The long-range goal of our laboratory is to regenerate complex tissues, organs and organ systems using the principles of regenerative engineering with advanced biomaterials and unique cell sources. One of our immediate objectives is to design cell delivery vehicles that will transiently act as a favorable microenvironment at the healing site to modulate cell performance upon transplantation. The aim of the proposed study is to evaluate the efficacy of an injectable biomaterial based on lactoferrin as an artificial microenvironment to increase the survival and osteogenic activity of encapsulated rat mesenchymal stem cells (rBMSC). The proposed research is designed based on our preliminary studies demonstrating the anti-apoptotic, mitogenic and osteogenic effect of soluble recombinant human lactoferrin (rhLf). The hypothesis being tested is that the injectable recombinant human lactoferrin gel (rhLfG) will present a favorable osteostimulative microenvironment by inhibiting cellular apoptosis and promoting cell proliferation and osteogenic differentiation. The experimental plan will explore the bioactivity of the injectable recombinant human lactoferrin gel based cell delivery vehicle through two specific aims. The first aim is designed to evaluate in vitro the anti apoptotic, mitogenic and osteogenic effect of recombinant human lactoferrin gels (rhLfG) to rat bone marrow derived mesenchymal stem cells. Cell culture conditions that are known to induce cellular apoptosis will be used. An injectable gelatin gel will be used as a control matrix to evaluate the efficacy of lactoferrin gel microenvironment in improving cell survival and promoting cell proliferation and differentiation. The second aim is designed to evaluate in vivo the efficacy of the injectable rhLfG in enhancing rBMSC survival, proliferation and osteogenesis, using a rat calvarial bone defect model. We hypothesize that the biologically active microenvironment provided by rhLfG will promote bone regeneration and better host tissue integration upon rBMSC delivery compared to injectable gelatin delivery vehicle. The proposed pilot study will help to understand the feasibility of developing a cell instructive injectable regenerative biomaterial based on rhLf as a cell delivery vehicle for bone regeneration. If successful, the injectable lactoferrin based delivery vehicle could have a significant impact in the clinical translation of cell based therapeutic strategies by addressing some of its current limitations.