Stem cell metabolomics for bone therapies and tissue engineering

就像印第安纳·琼斯电影中的一个场景，想象一下这样一个场景：一位人类学家在探索失落的玛雅文明时，偶然发现了似乎有几乎全套假牙的头骨。这些牙齿是死后植入的，还是它们在地球上的时候植入的？更仔细的检查表明，它们确实是贝壳的碎片，被塑造成单独的牙齿，被插入颌骨中，以取代因自然原因而失去的牙齿。值得注意的是，详细的分析表明，这些贝壳假牙已经完全整合到颌骨中。换句话说，颌骨已经愉快地接受了贝壳植入--这一特征被称为骨整合。进一步的研究表明，贝壳不仅整合到骨骼中，它还具有骨诱导作用，即促进骨形成。它也做到了这一点，没有明显的植入物排斥反应。更耐人寻味的是，我们这里有一个无脊椎动物系统(软体动物壳)，可以在脊椎动物(人类)中形成骨。它们之间的联系在哪里？解开这种联系是这个项目的一个重要方面。不仅是为了确定它是如何发生的，也是为了解锁和利用骨诱导机制，并用它来提供骨移植的材料。玛雅人使用的贝壳，就像大多数无脊椎动物一样，是由碳酸钙或白垩石组成的。通常情况下，碳酸钙以两种形式之一存在，称为多晶型：方解石和文石。文石也被称为珍珠岩或珍珠之母。虽然这些多态具有相同的化学成分，但它们具有不同的结构。我们的初步数据证实，其中一种无脊椎动物的多态，珍珠层，确实可以诱导骨形成。另一种晶型方解石似乎具有不同的功能，因为它鼓励细胞避免特化成特定类型的细胞，如脂肪或骨骼产生细胞。我们的目标是了解这些反应，以便我们能够设计和构建能够用来引发所需的和可预测的细胞反应的材料。这一点很重要，原因如下：到2031年，英国将有超过50%的人超过65岁。这种人口结构的情况将给骨科医生带来极大的压力，所需的髋关节和膝关节置换手术数量将会增加。与此同时，人口寿命延长，因此，可能需要在以后的生活中进行进一步的干预。目前，更多运动活跃的年轻人群现在出现了运动损伤，很有可能导致随后的骨关节炎。问题是，在更年轻、更活跃的人中，植入物往往失败得更快，翻修手术比最初的替代手术更不成功。在创伤诊所，面部重建手术需要大片完整的骨骼；通常是痛苦地隔离在方便的部位。这些例子给临床医生带来了重大挑战，也给科学家和工程师带来了重大挑战，他们需要迅速推动新技术的适当规模，以便通过为关节植入提供新材料来满足这些需求。在另一个单独的临床问题上，向临床提供高质量的非专门化细胞将促进直接再生治疗，并有助于组织工程。目前的问题是，在培养中生长的细胞几乎立即就会特化。方解石鼓励细胞保持非特化状态的事实提供了为组织治疗提供足够数量细胞的可能性，时机再好不过了。我们现在才能理解和利用骨形成和细胞供应，随着人口的迅速老龄化，迫切需要这种变革性的方法。

Like a scene from an Indiana Jones movie, imagine the scenario where an anthropologist, exploring the lost civilisation of the Mayans, comes across skulls that appear to have an almost full set of false teeth. Were these teeth inserted post mortem to embellish their way to the after-life, or, had they been inserted during their time on Earth? Closer inspection showed that they were indeed pieces of shell, fashioned into individual teeth that had been inserted into the jaw bone to replace teeth that had been lost through natural causes. Remarkably, detailed analysis showed that these shell dentures had totally integrated into the jaw bone. In other words, the jaw bone had happily accepted the shell implants - this feature is called osteo-integration. Further work showed that, not only was the shell integrated into the bone - it was also osteo-inductive, i.e. encouraged bone formation. It also did this without apparent rejection of the implant. What is even more intriguing is that here we have an invertebrate system (mollusc shell) enabling bone formation in a vertebrate (human). Where does the connection lie? Unravelling this connection is an important aspect of this project. Not just the quest to determine how and why it happens, but to unlock and exploit the mechanism of osteo-induction and use this to provide material for bone implants.The shell used by the Mayans, as in most invertebrates, is composed of calcium carbonate, or chalk. Normally, calcium carbonate exists in one of two forms, called polymorphs: calcite and aragonite. Aragonite is also called nacre or Mother of Pearl. Although these polymorphs have the same chemical composition they have different structures.Our preliminary data confirm that one of these invertebrate polymorphs, nacre, does indeed induce bone formation. The other polymorph, calcite, appears to hold a different function in that it encourages cells to avoid specialisation into specific cell types such as fat- or bone-producing cells. We aim to understand these responses so that we can design and construct materials that can be used to elicit desirable and predictable cellular responses. This is important for the following reasons:By 2031 more than 50% of people in the UK will be over 65. This demographic scenario will place extreme pressure on orthopaedic surgeons with a rise in the required number of hip and knee replacements. Simultaneously, the population is living longer and thus, further intervention may be required later in life. Currently, a more sports active younger population are now presenting with sport injuries with a high potential for subsequent osteoarthritis. The problem is that in younger and more active people, implants tend to fail more rapidly and revision operations are less successful than the original replacement surgery. In trauma clinics, facial reconstructive surgery demands large areas of intact bone; usually painfully sequestered from convenient sites. These examples present major challenges for clinicians, and also for scientists and engineers who need to rapidly drive new technologies on a suitably large scale in order to meet these demands by supplying novel materials for joint implantation. In a separate clinical issue, the supply of high-quality non-specialised cells to clinic would advance direct regenerative therapy and aid tissue engineering. The current problem is that cells grown in culture tend to become specialised almost immediately. The fact that calcite encourages cells to remain non-specialised offers the possibility of providing sufficient quantities of cells for tissue therapies.The timing could not be better. We are only now in a position to understand and exploit bone formation and supply of cells, with such a rapidly ageing population, there is urgent need for such transformative approaches.