An engineered heart patch from embryonic stem cells

心脏没有自我修复的能力，因此心脏病发作后肌肉组织的损失会使心脏永久衰弱。许多研究人员的目标是用细胞来修复这种损伤，但确切的细胞类型和将它们引入心脏的方式是一个有很大争议的问题。在本研究中，我们将使用胚胎干细胞培养的心肌细胞（肌细胞）。这样做的优点是有稳定的供应，因为胚胎干细胞在培养成不同的细胞类型之前会持续分裂。我们能够培养人类和小鼠胚胎干细胞，并将它们转化为跳动的肌细胞：在这两种情况下，我们都使用现有的细胞系。大多数研究都是通过将新细胞注入液体悬浮液来将其引入心脏。然而，许多细胞在注射后的第一周内丢失。如果心脏病发作不是最近发生的，疤痕组织就会形成，注入其中的细胞得不到血液供应，也无法与心脏的其他部分电连接。因此，我们想在一块材料上培养细胞，并将其移植到心脏上。这将克服与细胞注射相关的问题，并将具有额外的优势，即贴片可以防止疤痕拉伸。将心脏置于支架内以防止其扩张已经被尝试作为一种治疗方法。我们打算开发一种合适的材料，它可以作为胚胎干细胞生长的支撑，然后缝合到心脏上。它需要具有诸如生物相容性、强度和承受反复拉伸的能力等特性。它将被设计成在体内缓慢降解，这样当移植细胞融入心脏时，贴片材料就会消失。我们将首先测试胚胎干细胞在贴片上培养时的生长和成为肌细胞的能力。可以根据形状和大小、收缩和松弛特征、对激素和药物的反应以及电耦合来建立肌细胞的详细轮廓。这些可以与我们的正常培养物，以及我们也研究的成人和小鼠细胞进行比较。拉伸和电刺激将应用于贴片的细胞，试图发展心脏肌肉和刺激血管的生长。贴片本身的效果将在动物模型上进行测试，在大鼠身上产生心肌梗塞（心脏病发作）。这个模型在许多方面模仿人类疾病。我们将确定移植贴片是否能够减缓心力衰竭的发展并防止心脏扩张。当贴片被优化为细胞生长和移植时，将研究贴片加细胞的联合效应。我们将寻找的关键是移植细胞与心脏的整合，电连接的发展，血管的生长以及心脏功能的改善。该项目将需要国家心肺研究所的生物学家和生物材料工程、胚胎干细胞培养、肌细胞生成、肌细胞表征和动物外科材料部工程师的专业知识。

The heart does not have the capacity to self-repair, so loss of muscle tissue following a heart attack leaves it permanently weakened. Many researchers are aiming to use cells to repair this damage, but the exact type of cell and the way to introduce them into the heart is a matter of great debate. In the present study we will use cardiac muscle cells (myocytes) grown from embryonic stem cells. These have the advantage that there is a steady supply, since the ES cells will divide continuously in culture before being directed into different cell types. We are able to grow human and mouse ES cells and convert them to beating myocytes: in both cases we use existing cell lines. Most studies have introduced new cells into the heart by injecting them in a fluid suspension. However, many cells are lost within the first week after injection. If the heart attack was not recent, scar tissue develops, and cells injected into this do not receive a blood supply or connect electrically to the rest of the heart. We therefore want to grow the cells on a patch of material and graft it to the heart. This will overcome the problems associated with cell injection and will have the added advantage that the patch can prevent the scar from stretching. Containing the heart within a scaffold to prevent it from expanding is already being tried as a therapy by itself. We intend to develop a suitable material which can be used as a support for the growth of ES cells and then sewn into place on the heart. It will need to have properties such as biocompatibility, strength and the ability to withstand repeated stretch. It will be designed to degrade slowly when in the body, so that the patch material will disappear as the grafted cells integrate into the heart. We will first test the ability of ES cells to grow and become myocytes when cultured on the patch. A detailed profile of the myocytes can be built up in terms of shape and size, contraction and relaxation characteristics, responses to hormones and drugs, and electrical coupling. These can be compared with our normal cultures, and with adult human and mouse cells which we also study. Stretching and electrical stimulation will be applied to the patch with cells, to try to develop the heart muscle and stimulate the growth of blood vessels. The effect of the patch itself will be tested on an animal model, where a myocardial infarction (heart attack) is produced in rat. This model mimics the human disease in many aspects. We will determine whether grafting of the patch is able to slow the development of heart failure and prevent the heart from expanding. When the patch is optimised for both cell growth and grafting, the combined effect of the patch plus cells will be studied. The key things we will be looking for are the integration of the grafted cells into the heart, the development of electrical connections, the growth of blood vessels and an improvement in the function of the heart. The project will require the combined expertise of the biologists of the National Heart and Lung Institute and the engineers of the Department of Materials for biomaterial engineering, ES cell culture, myocyte generation, myocyte characterisation and animal surgery.