Developing generic scalable and standardised selection methods for human therapeutic cells

该提案旨在通过邻近大学（伯明翰大学、拉夫堡大学和牛津大学）之间的合作，为实际问题提供实用、科学和技术创新的解决方案。我们的目标是开发一种设备，可以直接从血液中选择血细胞。该装置将允许新的治疗方法来应对先进细胞疗法提出的生物选择挑战。有效的细胞疗法并不新鲜，可以追溯到1665年第一次成功输血的时候。今天，每年采血8100万单位，在全世界挽救了数十万人的生命。此外，全球每年至少有5万名患者接受干细胞移植（SCT，也称为骨髓移植）（为数不多的能够治愈癌症的疗法之一），每次花费约为10万英镑。造血干细胞只占血液中所有白细胞的0.2%。不幸的是，不可能只从血液中分离出干细胞，而是通过一种称为白细胞分离的过程从供者的血液中取出大量白细胞。捐赠者在接下来的几周内迅速补充白细胞。供体的副作用之一是他们的骨髓受到刺激生长，这经常导致骨痛。这些干细胞可能会给那些患有白血病或淋巴瘤的受者提供生命的礼物，这些细胞会迁移到骨髓，开始为病人产生血液。然而，来自供体的一些白细胞有可能造成伤害，这些免疫细胞将受体识别为外来物并试图攻击它们。为了防止这种情况，从白细胞中纯化干细胞并以更纯净的形式注入。科学家们对干细胞的了解比以往任何时候都多，现在可以在实验室中扩增这些罕见的细胞，甚至用它们创造新的器官（至少在老鼠身上）。现在的挑战是将这些新技术和知识带到临床医学的前沿。在此之前，需要新的技术来操作这些细胞，以一种不会引起感染的方式，并确保细胞的质量足够高，对患者有效。这项提议的目的是开发一种新的设备，可以使细胞富集。该设备将被设计成非常通用的，可以富集任何细胞类型，因此将引起许多寻求开发细胞疗法的公司的广泛兴趣。我们提出了两个步骤，首先是一个“捕获”装置，它甚至可以用来直接从供体/患者的循环血液中分离细胞。这可以通过只挑选出感兴趣的细胞来减少干细胞分离的副作用，如骨痛。下一步将是清洗这些捕获的细胞，并将它们通过较小的纯化柱，这将去除不需要的细胞类型并捕获感兴趣的细胞。这一点很重要，因为目前还没有办法选择细胞的亚群。最后，这些细胞将被释放并分析其特性。这项工作主要是由熟悉向临床采煤工作面提供新疗法的问题的临床医生开发的。我们有一个能够从全血中捕获和释放细胞的工作原型，正在寻求进一步发展的资金。我们在设计这款设备时考虑到了NHS的安全、有效，重要的是价格合理。

This proposal aims to deliver practical, scientific and technologically innovative solutions to a real problem through partnership between neighbouring Universities: the University of Birmingham, Loughborough University and the University of Oxford. We aim to develop a device to allow blood cells to be selected directly from the blood. This device would allow new treatments to meet the bioselection challenges presented by advanced cellular therapies. Effective cellular therapies are not new and date back to 1665 when the first successful blood transfusion took place. Today, 81 million units of blood are taken each year, saving hundreds of thousands of lives worldwide. In addition, at least 50,000 patients receive stem cell transplants (SCT; also known as Bone Marrow Transplants) globally every year (one of the few therapies able to cure individuals with cancer) with each costing around £100,000. The blood stem cells account for only 0.2% of all white blood cells in the blood. Unfortunately it is not possible to isolate just the stem cells from blood, but instead, a large number of white cells are removed from the donor's blood via a process termed leukapheresis. The donor quickly replenishes their white cells over the next few weeks. One side effect for the donor is that their bone marrow is stimulated to grow which frequently leads to bone pain. These stem cells potentially offer the gift of life to the recipient who typically will have leukaemia or lymphoma where these cells migrate to the bone marrow and start producing blood for the patient. However some of the white blood cells from the donor have to potential to cause harm, these immune cells recognise the recipient as foreign and try to attack them. To prevent this, the stem cells are purified from the white cells and infused in a purer form. Scientists are understanding more about stem cells then ever before and can now expand these rare cells in the laboratory and even create new organs from them (in mice at least). The challenge now is to bring these new techniques and knowledge to the forefront of clinical medicine. Before this can be done, new technologies are required to manipulate these cells in a manner that will not introduce infection and ensures the cells are of sufficiently high quality to be effective for the patient. The aim of this proposal is to develop a new device which would allow the enrichment of cells. The device will be engineered to be very versatile and would allow the enrichment of any cell type and thus will be of broad interest to many companies seeking to develop cellular therapies. We propose two steps, first a 'capture' device which could even be used to directly isolate cells from the circulating blood of a donor/patient. This could reduce side effects of stem cell isolation such as the bone pain by only picking out the cells of interest. The next step would be to wash these captured cells and pass them over smaller purification columns, which would remove unwanted cell types and capture the cells of interest. This is important as currently there are no ways to select subpopulations of cells. Finally the cells will be released and analysed for their properties. This work has been principally developed by a clinician familiar with the problems delivering new therapeutics to the clinical coalface. We have a working prototype able to capture and release cells from whole blood and are asking for funding to develop this further. We have designed the device with the NHS in mind, to be safe, effective and importantly affordable.