原始干细胞治疗顽固性骨折

2020/8/25 16:12:55 本站原创 佚名 【字体:

廖联明    编译

 

 

每年,美国约有60万人经历延迟或不完全的骨愈合。对于其中一些病例,医生只能指望外科手术,包括将骨组织移植到修复部位。这些骨移植通常来自两个来源:病人自己的骨,称为自体骨,或深度加工的人体尸体骨。

 

  然而,这两种类型的骨移植都有各自的缺点。例如,自体骨移植需要额外的手术来取骨,增加患者的康复时间,有时还产生慢性疼痛。尸体骨虽然排除了两次手术的需要,但这些移植物往往缺乏许多促进骨修复的生物分子。

 

   德克萨斯州A&M健康科学中心的副教授Carl Gregory博士同时也是这项研究的通讯作者,他说:“从尸体骨上移植的骨具有骨的一些物理特性,甚至有一点生物本质,但就其功能而言,已经非常差了。”

 

先前的研究表明,干细胞,特别是间充质干细胞,可以用来生产具有生物活性的骨移植。特别是,这些细胞转化为骨细胞,产生骨生长和存活所需的支架材料或细胞外基质。

 

然而,这些干细胞通常是从成人骨髓中提取出来的,因此,它们的年龄较大。考纳斯说,它们的年龄影响细胞分裂和产生细胞外基质的能力。

 

为了避免这个问题,研究人员求助于间充质干细胞的祖先,称为多能干细胞。他们指出,与寿命相对较短的成人间充质细胞不同,这些原始细胞可以继续增殖,从而创造出制造骨移植细胞外基质所需的无限的间充质干细胞。他们补充说,多能干细胞可以通过对捐赠的成体细胞进行基因重编程而获得。

 

当研究人员通过实验诱导多能干细胞产生全新的间充质干细胞时,他们能够产生一种细胞外基质,这种基质的生物学活性远远高于从成人骨获得的间充质细胞的基质的生物学活性。

       格雷戈里说:“我们的材料不仅富含制造骨组织所需的生物分子,还富含促进血管形成的生长因子。”。

 

为了测试支架材料作为骨移植的效果,他们仔细地提取和提纯了丰富的细胞外基质,然后将其植入骨缺损部位。在几周内检查骨修复状况后,他们发现他们的多能干细胞衍生基质比FDA批准的最好的移植物刺激剂有效56倍。

  

格雷戈里说:“使用骨移植的金标准进行骨修复试验,就像骨形态发生蛋白-2的强力骨生长刺激剂一样,可能需要8周的时间,但我们可在4周内就完全实现愈合。”因此,在这些条件下,我们的材料比骨形态发生蛋白-2的功效高出一大截,是对现有骨修复技术的巨大改进。”

 

研究人员还说,从临床的角度来看,移植骨可以融入到许多工程植入物中,比如3D打印的植入物或金属螺钉,这样这些部分就能更好地与周围的骨骼结合。他们还指出,骨移植也将更容易生产。

 

考纳斯说:“我们的材料非常有前景,因为多能干细胞可以理想地从一个供体中产生多批细胞外基质,这将大大简化这些骨移植的大规模生产。”。

 

“骨移植后可能会出现一些问题,比如炎症和疼痛。此外,会出现松散,导致二次手术。二次手术有时候比第一次骨移植手术还更复杂”罗兰考纳斯博士,生物医学工程系副教授和通讯作者说。“因此,通过加快骨愈合过程,我们的材料可能会减少这些二次手术的数量。”

 

研究人员在6月份出版的《自然通讯》杂志上发表了他们的发现。

 

 

Characterization of a pluripotent stem cell-derived matrix with powerful osteoregenerative capabilities.

 

Each year, around 600,000 people in the United States experience delayed or incomplete bone healing. For some of these cases, physicians turn to surgical procedures that involve transplanting bone tissue to the repair site. These bone grafts have generally come from two sources: the patient's own bone from another location on the body called autografts, or cadaver bones.

 

However, both types of bone grafts have their share of drawbacks. For example, autografts require additional surgery for bone tissue extraction, increasing the recovery time for patients and sometimes, chronic pain. On the other hand, grafts derived from cadaver bone preclude the need for two surgeries, but these transplants tend to be devoid of many of the biomolecules that promote bone repair.

  

"Grafts from cadaver bone have some of the physical properties of bone, and even a little bit of the biological essence but they are very depleted in terms of their functionality," said Dr. Carl Gregory, associate professor at the Texas A&M Health Science Center, also a corresponding author on the study.

 

Previous studies have shown that stem cells, particularly a type called mesenchymal stem cells, can be used to produce bone grafts that are biologically active. In particular, these cells convert to bone cells that produce the materials required to make a scaffolding, or the extracellular matrix, that bones need for their growth and survival.

 

However, these stem cells are usually extracted from the marrow of an adult bone and are, as a result, older. Their age affects the cells' ability to divide and produce more of the precious extracellular matrix, Kaunas said.

 

To circumvent this problem, the researchers turned to the cellular ancestors of mesenchymal stem cells, called pluripotent stem cells. Unlike adult mesenchymal cells that have a relatively short lifetime, they noted that these primitive cells can keep proliferating, thereby creating an unlimited supply of mesenchymal stem cells needed to make the extracellular matrix for bone grafts. They added that pluripotent cells can be made by genetically reprogramming donated adult cells.

 

When the researchers experimentally induced the pluripotent stem cells to make brand new mesenchymal stem cells, they were able to generate an extracellular matrix that was far more biologically active compared to that generated by mesenchymal cells obtained from adult bone.

 

"Our materials were not just enriched in the biological molecules that are required to make the chunky part of bone tissue but also growth factors that drive blood vessel formation," said Gregory.

 

To test the efficacy of their scaffolding material as a bone graft, they then carefully extracted and purified the enriched extracellular matrix and then implanted it at a site of bone defects. Upon examining the status of bone repair in a few weeks, they found that their pluripotent stem-cell-derived matrix was five to sixfold more effective than the best FDA-approved graft stimulator.

 

"Bone repair assays using the gold standard of grafts, like those administered with the powerful bone growth stimulator called bone morphogenic protein-2, can take about eight weeks, but we were getting complete healing in four weeks," said Gregory. "So, under these conditions, our material surpassed the efficacy of bone morphogenic protein-2 by a longshot, indicating that it is a vast improvement of current bone repair technologies."

 

The researchers also said that from a clinical standpoint, the grafts can be incorporated into numerous engineered implants, such as 3D-printed implants or metal screws, so that these parts integrate better with the surrounding bone. They also noted that the bone grafts will also be easier to produce.

 

"Our material is very promising because the pluripotent stem cells can ideally generate many batches of the extracellular matrix from just a single donor which will greatly simplify the large-scale manufacturing of these bone grafts," said Kaunas.

 

"There are several problems that can occur with orthopedic implants, like inflammation and pain. Also, they can loosen, requiring revision surgeries that are often more complicated than the original surgery to put in the implant," Dr. Roland Kaunas, associate professor in the Department of Biomedical Engineering and a corresponding author on the study. "So, by speeding up the bone healing process, our material can potentially reduce the number of these revision surgeries."

 

 

The researchers have published their findings in the June issue of the journal Nature Communications.

 

Journal Reference:

 

Eoin P. McNeill, Suzanne Zeitouni, Simin Pan, Andrew Haskell, Michael Cesarek, Daniel Tahan, Bret H. Clough, Ulf Krause, Lauren K. Dobson, Mayra Garcia, Christopher Kung, Qingguo Zhao, W. Brian Saunders, Fei Liu, Roland Kaunas, Carl A. Gregory. Characterization of a pluripotent stem cell-derived matrix with powerful osteoregenerative capabilities. Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-16646-2

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