计算机模拟骨折愈合的研究进展

[摘要]骨折愈合是一个复杂的生物学过程。在不同的时间段内骨折的愈合过程受到多种因素的干预,主要分为机械刺激因素和生物刺激因素。为了更好地研究骨折愈合这一过程,人们开发出了多种计算机模型对骨折愈合进行模拟,包括力学刺激模型、生物刺激模型、力学生物刺激模型,而后逐步完善为多尺度模型。但是无论哪种计算机模型在临床应用中均存在一定缺陷。为此,本文对骨折愈合过程中受到的刺激因素和已开发的计算机模型进行系统的整理,归纳了目前仍存在的问题,以期为计算机模拟骨折愈合的临床使用提出有益的启示。     

可溶性B7-H3在人脑创伤合并骨折愈合中的表达及意义

目的检测外周血中可溶性B7-H3在脑创伤合并骨折,单纯骨折和单纯脑损伤患者中的表达,并研究其对间充质干细胞分化为成骨细胞的作用。方法 ELISA检测可溶性B7-H3及骨折愈合的标志物Cbfa1在脑创伤合并骨折、单纯骨折,单纯脑创伤和正常志愿者外周血中的表达,茜素红、real-time PCR检测不同浓度重组B7-H3蛋白对间充质干细胞向成骨细胞分化的作用。结果可溶性B7-H3在脑创伤合并骨折及单纯脑创伤患者中的表达明显高于单纯骨折和正常人中的表达;可溶性B7-H3在外周血中的含量与脑创伤严重程度相关;重组B7-H3蛋白可促进间充质干细胞向成骨细胞的分化,并随着质量浓度的升高其促分化能力增强。结论脑创伤导致的外周血中升高的可溶性B7-H3促进了骨折愈合。     

Drosophila as a model of wound healing and tissue regeneration in vertebrates

Understanding the molecular basis of wound healing and regeneration in vertebrates is one of the main challenges in biology and medicine. This understanding will lead to medical advances allowing accelerated tissue repair after wounding, rebuilding new tissues/organs and restoring homeostasis. Drosophila has emerged as a valuable model for studying these processes because the genetic networks and cytoskeletal machinery involved in epithelial movements occurring during embryonic dorsal closure, larval imaginal disc fusion/regeneration, and epithelial repair are similar to those acting during wound healing and regeneration in vertebrates. Recent studies have also focused on the use of Drosophila adult stem cells to maintain tissue homeostasis. Here, we review how Drosophila has contributed to our understanding of these processes, primarily through live-imaging and genetic tools that are impractical in mammals. Furthermore, we highlight future research areas where this insect may provide novel insights and potential therapeutic strategies for wound healing and regeneration.     

Synthesis and characterization of a fluvastatin-releasing hydrogel delivery system to modulate hMSC differentiation and function for bone regeneration

Increases in bone formation have been demonstrated in mice and rats treated with statins, a group of molecules that increase the production of bone morphogenetic proteins-2 (BMP2) by stimulating its promoter. However, clinical use of statins (e.g., fluvastatin) is limited by the lack of a suitable delivery system to localize and sustain release. To harness the therapeutic effect of statins in orthopedic applications, a fluvastatin-releasing macromer was synthesized. When copolymerized with a dimethacrylated poly(ethylene glycol) solution, this fluvastatin-containing molecule was covalently incorporated into hydrogel networks, and hydrolysis of lactic acid ester bonds resulted in the release of the pendantly tethered fluvastatin from the hydrogel into the surrounding solution. The rate of fluvastatin release was controlled by the length of lactic acid spacer (2–6 repeats), and the dose was controlled by the initial comonomer composition (5–500 μg fluvastatin/gel). Released fluvastatin increased human mesenchymal stem cell (hMSC) gene expression of CBFA1, ALP, and COL I by 34-fold, 2.6-fold, and 1.8-fold, respectively, after 14 days of in vitro culture. In addition, treating hMSCs with the released fluvastatin resulted in an average of 2.0- and 1.5-fold greater BMP2 production whereas mineralization increased an average of 3.0-fold and 2.5-fold for 0.01 and 0.1 μM fluvastatin, respectively, over the 2 week culture period. Therefore, fluvastatin-releasing hydrogels may be useful in bone tissue engineering applications, not only for triggering osteogenic differentiation of hMSCs, but also by modulating their function.     

预处理间充质干细胞促进创面愈合的研究进展

各种急、慢性创面发生率较高,给患者及医疗资源带来极大负担,干细胞疗法目前被广泛应用于临床研究,移植后能够有效修复损伤组织。但由于受到感染、缺氧、炎性因子等多种因素的影响,移植后干细胞存活率低下,无法有效归巢至损伤组织。因此,增加干细胞在体效率对促进创面修复有至关重要的作用。预处理干细胞能够改变细胞生物学活性,是提高干细胞在微环境的耐受力以及归巢能力的最佳策略。本文就预处理间充质干细胞促进创面愈合的研究进展作一综述。     

异位骨化预防性放疗对骨折愈合影响的实验研究

目的探索骨折后48h给予单次放疗预防异位骨化的同时对骨折愈合造成的影响,并将其用于创伤骨折初期预防异位骨化的可能性。方法取成年SD大鼠50只,随机分成5组,制成双侧股骨骨折模型,实验侧骨折后48h予放疗,对侧为对照侧。分别于骨折后2周、4周、8周、12周、16周取双侧股骨,进行放射学,组织学和生物力学评估骨折愈合情况。实验还采取实验侧伤口旁皮毛和部分股四头肌组织作组织学观察。结果骨折后4周时实验侧骨痂厚度明显小于对照侧(0.05),其余各组双侧无显著性差异;骨组织切片观察发现骨折2周组中实验侧的股骨愈合的组织学评分显著低于对照侧(0.05),其余各组双侧无显著性差异;生物力学测试,4周组大鼠的实验侧股骨最大弯曲载荷显著低于对照侧(0.05),其余各组双侧无显著性差异。结论用于预防异位骨化的单次小剂量放疗的确在早期抑制了骨折修复,骨折都是会逐步愈合,只是愈合的时间相对延长。这种放疗对皮肤伤口愈合,毛发生长,骨周围软组织无明显损害。临床应用尚需进一步论证。     

Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells

Both mesenchymal stem cells (MSCs) and dendritic cells (DCs) are engaged in the regulation of the immune response parallel to their numerous functions.The main objective of this study was to compare the effects of mesenchymal stem cells isolated from human adipose tissue or human bone marrow on the expression of specific cell surface markers as well as the secretion of some cytokines by monocyte-derived dendritic cells. The set of methods used includes cell cultures, magnetic beads isolation of cells, flow cytometry, ELISA and proteome profiler kit assays. The results obtained show that MSCs isolated from human adipose tissue are more potent immunomodulators of differentiation of human DCs in comparison to the bone marrow-derived MSCs. In both cases the percentages of CD14+ cells were increased in co-cultures of MSCs and DCs and at the same time down-regulated the expression of CD80, CD86 and CD83 as in all experiments the effect of adipose tissue MSCs was stronger. Similarly, the secretion of IL-10 by dendritic cells was up-regulated in co-cultures of MSCs and dendritic cells and the effect was stronger when adipose tissue-derived MSCs were used.Taken together all results presented reveal the higher potential of the adipose tissue-derived MSCs to inhibit the differentiation and expression of functionally important co-stimulatory molecules on the surface of monocyte-derived dendritic cells than the bone marrow-derived MSCs.     

The osteogenic response of mesenchymal stem cells to an injectable PLGA bone regeneration system

The enrichment of substrates/surfaces with selected functional groups, methyl (–CH₃), allyl amine (–NH₂), allyl alcohol (–OH) and acrylic acid (–COOH), can be used to trigger mesenchymal stem (MSC) cell differentiation into specified lineages, minimising the need for exogenous biological supplementation. We present the successful translation of this research phenomenon to an injectable two phase injectable PLGA system, utilising plasma techniques, for the repair of bone defects. Modified microspheres were characterised using water contact angel (WCA), X-ray Photon Spectroscopy (XPS) and scanning electron microscopy (SEM). When cultured in contact with MSCs in vitro, the ability of the modified particles, within the 2 phase system, to induce differentiation was characterised using quantitative assays for cell viability and histological analysis for key markers of differentiation throughout the entirety of the three dimensional scaffold. Biological analysis proved that selected modified microspheres have the ability to induce MSC osteogenic (-NH₂ modified scaffolds) and chondrogenic (–OH modified scaffolds) differentiation throughout the entirety of the formed scaffold. Therefore optimised plasma modification of microspheres is an effective tool for the production of injectable systems for the repair of bone and cartilage defects.     

Mathematical modeling of fracture healing in mice: comparison between experimental data and numerical simulation results

The combined use of experimental and mathematical models can lead to a better understanding of fracture healing. In this study, a mathematical model, which was originally established by Bailón-Plaza and van der Meulen (J Theor Biol 212:191–209, 2001), was applied to an experimental model of a semi-stabilized murine tibial fracture. The mathematical model was implemented in a custom finite volumes code, specialized in dealing with the model’s requirements of mass conservation and non-negativity of the variables. A qualitative agreement between the experimentally measured and numerically simulated evolution in the cartilage and bone content was observed. Additionally, an extensive parametric study was conducted to assess the influence of the model parameters on the simulation outcome. Finally, a case of pathological fracture healing and its treatment by administration of growth factors was modeled to demonstrate the potential therapeutic value of this mathematical model.     

力学因素在间充质干细胞构建功能性组织工程化软骨中的作用

间充质干细胞具有多向分化潜能,可定向分化为软骨组织,并且取材广泛、体外扩增能力强,是广泛应用于软骨组织工程的理想细胞之一。由于关节软骨具有重要的生物力学功能,需要强调和评估间充质干细胞构建组织工程化软骨组织的力学生物学性能。为更好地了解和认识修复软骨的诱导因素、信号通路与力学特性之间的关系,本文回顾了间充质干细胞在功能性软骨组织工程研究中的力学生物学研究进展,并论述了该领域内目前存在的问题及若干可供探索的途径和新方向。