Injectable Anabolic Biomaterials for Bone Regeneration

细胞移植作为一种有前景的加速组织再生的临床策略正在兴起。然而，这项技术的成功临床转化面临着一些工程和生物学方面的挑战。主要的挑战在于我们无法在愈合部位运送和保留移植细胞，以及在受伤组织的不友好环境中防止不受控制的细胞死亡。我们实验室的长期目标是利用再生工程的原理，利用先进的生物材料和独特的细胞来源再生复杂的组织、器官和器官系统。我们的直接目标之一是设计细胞递送载体，它将在移植时在愈合部位短暂地作为一个有利的微环境来调节细胞的性能。本研究的目的是评估基于乳铁蛋白的可注射生物材料作为人工微环境对包封大鼠间充质干细胞（rBMSC）存活率和成骨活性的影响。本研究基于我们对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的初步研究。实验假设可注射重组人乳铁蛋白凝胶（rhLfG）通过抑制细胞凋亡、促进细胞增殖和成骨分化提供良好的促骨微环境。实验计划将探讨

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.