What is Tissue Engineering? Summary

• Building Body Parts: Tissue engineering is a field that aims to create functional tissues and organs in the lab, for use in repairing or replacing damaged tissues in the body.
• Beyond Transplants: It’s an alternative to organ transplantation, which faces challenges like donor shortages and immune rejection.
• Cells, Scaffolds, and Signals: The three key ingredients are:
  • Cells: The building blocks of the tissue.
  • Scaffolds: A 3D structure that supports the cells and guides their growth.
  • Signals: Chemical, mechanical, or electrical cues that tell the cells what to do (grow, differentiate, organize).
• A multidisciplinary field: requires deep understadning of biology, and materials as well as mechanical engineering.
• Many Applications: Tissue engineering has potential applications in treating a wide range of conditions, including burns, heart disease, diabetes, and spinal cord injuries.
• From Lab to Clinic: Some tissue-engineered products, like skin grafts, are already in clinical use. Others, like bioartificial organs, are still in development.
• Bioelectricity’s Role: Bioelectric signals can act as powerful “signals” in tissue engineering, guiding cell behavior and promoting tissue organization. The anatomical complier takes those beyond incremental steps.
• Limitations with today’s technology Most tissue engineering method require micromanaging of specific cell locations/structure; where with bioelectricty guided tissue re-generation, cells exhibit decision to perform to *outcome* and the correct errors (often on its own). This can create structures/organization/repair beyond current lab capabilities.

Beyond Organ Transplants: Building Tissues from Scratch

When a tissue or organ in the body is damaged beyond repair, the traditional solution has often been transplantation – replacing the damaged tissue with a healthy one from a donor. But transplantation has significant limitations:

• Donor Shortages: There are far more people who need organ transplants than there are available organs.
• Immune Rejection: The recipient’s immune system may attack the transplanted tissue, leading to rejection.
• Lifelong Medication: Transplant recipients need to take immunosuppressant drugs for the rest of their lives, which can have serious side effects.

Tissue engineering offers a different approach: What if, instead of *transplanting* tissues, we could *build* them from scratch in the lab?

The Three Pillars of Tissue Engineering: Cells, Scaffolds, and Signals

Tissue engineering is about creating functional, three-dimensional tissues *in vitro* (in the lab, outside of a living organism) that can then be implanted into the body to repair or replace damaged tissues. The process typically involves three key components, considered “classic” approach:

1. Cells: These are the “building blocks” of the tissue. They can be:
   • Autologous: Taken from the patient’s own body (reducing the risk of immune rejection).
   • Allogeneic: Taken from a different person (a donor).
   • Xenogeneic: Taken from a different species (this is less common due to immune compatibility issues).
   • Stem Cells: Cells that have the potential to differentiate into different cell types (embryonic stem cells or adult stem cells).
   The “best” source depends on many different needs and situations: the patient, target tissues, and possible donor availability.
2. Scaffolds: This is a three-dimensional structure that provides support for the cells and guides their growth. It’s like the framework of a building. Scaffolds can be made from:
   • Natural Materials: Collagen, fibrin, hyaluronic acid (components of the body’s own extracellular matrix).
   • Synthetic Materials: Polymers like PLA, PGA, and PLGA (these can be designed to degrade over time).
   • Decellularized Tissues: Tissues from which the original cells have been removed, leaving behind the extracellular matrix scaffold.
   The scaffold should be, usually: Biocompatible, not triggering/reduced changes for immune response; support cell function (e.g. enabling, or not blocking cell to cell interactions); biodegrade over-time.
3. Signals: These are the cues that tell the cells what to do. They can be:
   • Chemical Signals: Growth factors, hormones, or other signaling molecules that promote cell growth, differentiation, or matrix production.
   • Mechanical Signals: Forces applied to the tissue (stretching, compression) that can influence cell behavior.
   • Electrical Signals: *Bioelectric signals* (voltage gradients, electric fields) that can guide cell migration, alignment, and differentiation. This often represents newer/active research.

It’s like baking a cake. The *cells* are the ingredients, the *scaffold* is the cake pan, and the *signals* are the recipe (and the oven’s heat). You need all three to create a functional tissue.

From Skin Grafts to Bioartificial Organs: A Range of Applications

Tissue engineering has already led to some clinical successes, and it holds immense promise for the future. Applications include:

• Skin Grafts: For treating burns and other skin wounds. This is one of the most established tissue-engineered products.
• Cartilage Repair: For treating joint injuries.
• Bone Grafts: For repairing bone fractures or defects.
• Bladder Repair: Tissue-engineered bladders have been successfully used in patients.
• Blood Vessels: Creating artificial blood vessels for bypass surgery or for treating vascular diseases.
• Heart Valves: Engineering heart valves to replace damaged ones.
• Bioartificial Pancreas: Encapsulating insulin-producing cells to treat diabetes.
• Bioartificial Liver: Developing liver assist devices to support patients with liver failure.
• Whole organ A very important target!  This can save, improve and fundamentally extend our human health capacity.

• Note that despite impressive science advances over decades; many engineering (blood vessel network across entire large-size organ); physical structure(the scaffolding design with full cell placement/embedding for cells/signals/control), tissue “connection”, or, the simple capacity/difficulty over *building large enough construct at once*… Many issues persist. Tissue engineering continues its research with major science organizations/corporations over numerous programs/investments.

The “holy grail” of tissue engineering is to create fully functional, complex organs like hearts, lungs, and kidneys, but this is still a very challenging goal. Many, if successful, may take generations.

Bioelectricity: A Powerful Signal for Tissue Engineers

Bioelectric signals are increasingly recognized as a crucial factor in tissue development and regeneration. They can act as powerful “signals” in tissue engineering, providing cues that:

• Guide Cell Migration: Cells can sense and follow voltage gradients, allowing researchers to direct them to specific locations within a scaffold.
• Promote Cell Alignment: Electric fields can align cells along specific axes, which is important for tissues like muscle and nerve.
• Enhance Cell Differentiation: Bioelectric signals can influence what type of cell a stem cell becomes.
• Stimulate Matrix Production: Cells can be stimulated to produce more of the extracellular matrix, the structural “glue” that holds tissues together.
• Beyond traditional model: With bioelectrcity involved, tissue can and will demonstrate error correction, and re-creation for goal – even with the host damage or defects that had, very strong, very crucial disruption/blockage during re-construction/development of parts.
• It is a tool and also signal. It represents a critical link between “engineering” and “self assembly/error correcting collective behaviour for achieving correct morphology” — crucial when compare with all conventional Tissue Engineering (more in later explainations!)

Researchers are exploring various ways to incorporate bioelectric signals into tissue engineering strategies, including:

• Conductive Scaffolds: Using scaffolds made from materials that conduct electricity.
• External Electrical Stimulation: Applying electrical fields directly to the tissue-engineered construct.
• Genetic Manipulation: Altering the expression of ion channels in cells to control their bioelectric behavior.
• Bioelectric “Cocktails”: Delivering drugs that target ion channels or gap junctions to modulate bioelectric patterns.
• Top-down methods: Where goal matters (to trigger appropriate responses) and the individual cellular path becomes less critical when compare to large structure-target of bioelectric maps.

The Anatomical Compiler: The Future of Tissue Engineering?

The Anatomical Compiler, with its potential to “program” biological form using bioelectricity, could revolutionize tissue engineering. Imagine:

• Designing a Tissue “Blueprint”: Specifying the desired shape, size, and composition of the tissue.
• Translating the Blueprint into Bioelectric Signals: Using the Anatomical Compiler to generate the precise electrical patterns needed to guide cell behavior.
• Building the Tissue *in Situ*: Instead of building the tissue in the lab and then implanting it, we could potentially trigger the body to build the tissue *directly* at the site of injury.
• Beyond direct construction. Instead of “cell placement” and other direct micromanaging, with goal-driven, collective, tissue behaviour in morphogenesis, those become uncessary, possibly providing robust self-assembling methods for organ/tissues growth.

This is still a highly speculative vision, but it highlights the potential power of combining tissue engineering with a deep understanding of bioelectric control.

Major limitations, new concepts and thinking on control

• The major difficulties:
• Complex large organs cannot be replicated in detail (with conventional approach): such as specific cells needing the correct, proper signal that, over very complex structure/arrangements remain almost completely unresolved today.
• Micromanagement: for tissues/organ bioengineering (like bio printing) has enormous overhead – cells needed and have proper structure to get them to act, cooperate; while cells and groups demonstrate capabilites, such as, at times – toward correct structures/endpoints on their own. Bioelectric control represent better solutions in numerous occasions!
• Bioelectricity and tissue-engineering has connections (electrical fields; scaffolding materials with conductance – even the silk scaffolding itself in some of the bioreactor, acting/enabling certain bioelectric signals); but unlike cell-construction, Bioelectrity enables cells themselves (such as error correction, or to “know” shape endpoints when rebuilding); whereas existing tech cannot offer “program cells to build this structure/organ”, and bioelectricity has good supporting demonstrations of these kind of information and behaviours at work.

Conclusion

Tissue Engineering continues with many limitations; Bioelectricity offer new model of research with the potential (someday!) to realize very challenging problems within tissue engineering (not merely replacement but design, re-construct and customized organs etc.) It has fundamental paradigm and discoveries for better control, more informed method that uses biological, intrinsic morphogensis capacity (as seen in basal cognition for non-neural tissues/systems.) This describes core concept and future – by integrating two field and highlighting core connection, differences of conventional method and Dr. Levin group and others.

什么是组织工程 (Tissue Engineering)？摘要

• 构建身体部件： 组织工程是一个旨在在实验室中创建功能性组织和器官的领域，用于修复或替换体内受损的组织。
• 超越移植： 它是器官移植的替代方案，器官移植面临着供体短缺和免疫排斥等挑战。
• 细胞、支架和信号： 三个关键要素是：
  • 细胞： 组织的构建块。
  • 支架： 支持细胞并指导其生长的 3D 结构。
  • 信号： 告诉细胞做什么（生长、分化、组织）的化学、机械或电信号。
• 一个多学科领域： 需要对生物学、材料以及机械工程有深入的了解。
• 许多应用： 组织工程在治疗各种疾病方面具有潜在的应用，包括烧伤、心脏病、糖尿病和脊髓损伤。
• 从实验室到临床： 一些组织工程产品，如皮肤移植物，已经在临床使用。其他的，如生物人工器官，仍在开发中。
• 生物电的作用： 生物电信号可以在组织工程中充当强大的“信号”，指导细胞行为并促进组织组织。解剖编译器将这些超越了渐进的步骤。
• 当今技术的局限性： 大多数组织工程方法需要对特定细胞位置/结构进行微观管理；而通过生物电引导的组织再生，细胞表现出对*结果*的决策并纠正错误（通常是自行）。这可以创建超出当前实验室能力的结构/组织/修复。

超越器官移植：从头开始构建组织

当体内的组织或器官受损到无法修复时，传统的解决方案通常是移植 —— 用来自供体的健康组织替换受损组织。但移植有很大的局限性：

• 供体短缺： 需要器官移植的人远远多于可用的器官。
• 免疫排斥： 受者的免疫系统可能会攻击移植的组织，导致排斥。
• 终身用药： 移植受者需要终生服用免疫抑制药物，这可能会产生严重的副作用。

组织工程提供了一种不同的方法：如果，不是*移植*组织，我们可以在实验室中从头*构建*它们呢？

组织工程的三大支柱：细胞、支架和信号

组织工程是关于在*体外*（在实验室中，在活的有机体之外）创建功能性的三维组织，然后可以将这些组织植入体内以修复或替换受损的组织。该过程通常涉及三个关键组成部分，被认为是“经典”方法：

1. 细胞： 这些是组织的“构建块”。它们可以是：
   • 自体： 来自患者自身身体（降低免疫排斥的风险）。
   • 同种异体： 来自另一个人（供体）。
   • 异种： 来自不同的物种（由于免疫相容性问题，这种情况不太常见）。
   • 干细胞： 有可能分化成不同细胞类型的细胞（胚胎干细胞或成体干细胞）。
   “最佳”来源取决于许多不同的需求和情况：患者、目标组织和可能的供体可用性。
2. 支架： 这是一种三维结构，为细胞提供支持并指导它们的生长。这就像建筑物的框架。支架可以由以下材料制成：
   • 天然材料： 胶原蛋白、纤维蛋白、透明质酸（身体自身细胞外基质的成分）。
   • 合成材料： 聚合物，如 PLA、PGA 和 PLGA（这些可以被设计成随着时间的推移而降解）。
   • 脱细胞组织： 已去除原始细胞的组织，留下细胞外基质支架。
   支架通常应该是：生物相容性，不触发/减少免疫反应的变化；支持细胞功能（例如，启用或不阻止细胞间的相互作用）；随着时间的推移生物降解。
3. 信号： 这些是告诉细胞该做什么的线索。它们可以是：
   • 化学信号： 生长因子、激素或其他促进细胞生长、分化或基质产生的信号分子。
   • 机械信号： 施加在组织上的力（拉伸、压缩），可以影响细胞行为。
   • 电信号： *生物电信号*（电压梯度、电场），可以指导细胞迁移、排列和分化。这通常代表更新/更活跃的研究。

这就像烤蛋糕。*细胞*是配料，*支架*是蛋糕盘，*信号*是食谱（和烤箱的热量）。你需要这三者才能创造出一个功能性的组织。

从皮肤移植物到生物人工器官：一系列应用

组织工程已经取得了一些临床成功，并且它为未来带来了巨大的希望。应用包括：

• 皮肤移植物： 用于治疗烧伤和其他皮肤伤口。这是最成熟的组织工程产品之一。
• 软骨修复： 用于治疗关节损伤。
• 骨移植： 用于修复骨折或缺损。
• 膀胱修复： 组织工程膀胱已成功用于患者。
• 血管： 创建人造血管用于搭桥手术或治疗血管疾病。
• 心脏瓣膜： 工程心脏瓣膜以替换受损的瓣膜。
• 生物人工胰腺： 包裹产生胰岛素的细胞来治疗糖尿病。
• 生物人工肝脏： 开发肝脏辅助设备来支持肝功能衰竭患者。
• 整个器官：一个非常重要的目标！这可以拯救、改善并从根本上扩展我们的人类健康能力。

• 请注意，尽管几十年来科学取得了令人瞩目的进步；许多工程（整个大型器官的血管网络）；物理结构（具有完整细胞放置/嵌入以用于细胞/信号/控制的支架设计），组织“连接”，或者，在*一次构建足够大的结构*方面的简单能力/难度……许多问题仍然存在。组织工程继续与主要的科学组织/公司就众多项目/投资进行研究。

组织工程的“圣杯”是创造完全功能的复杂器官，如心脏、肺和肾脏，但这仍然是一个非常具有挑战性的目标。许多，如果成功，可能需要几代人的时间。

生物电：组织工程师的强大信号

生物电信号越来越被认为是组织发育和再生的关键因素。它们可以在组织工程中充当强大的“信号”，提供以下线索：

• 指导细胞迁移： 细胞可以感知并跟随电压梯度，使研究人员能够将它们引导到支架内的特定位置。
• 促进细胞排列： 电场可以使细胞沿着特定轴排列，这对于肌肉和神经等组织非常重要。
• 增强细胞分化： 生物电信号可以影响干细胞变成哪种类型的细胞。
• 刺激基质产生： 可以刺激细胞产生更多的细胞外基质，即结合组织的结构“胶水”。
• 超越传统模式： 涉及生物电，组织可以并且将表现出纠错和重新创建目标 —— 即使在宿主损伤或缺陷时，这些损伤或缺陷在部分重建/发育过程中具有非常强、非常关键的破坏/阻碍。
• 它既是工具又是信号。它代表了“工程”和“自组装/纠错集体行为以实现正确形态”之间的关键联系 —— 与所有传统组织工程相比至关重要（稍后会详细解释！）

研究人员正在探索将生物电信号纳入组织工程策略的各种方法，包括：

• 导电支架： 使用由导电材料制成的支架。
• 外部电刺激： 将电场直接施加到组织工程结构上。
• 基因操纵： 改变细胞中离子通道的表达以控制其生物电行为。
• 生物电“鸡尾酒”： 提供靶向离子通道或间隙连接的药物来调节生物电模式。
• 自上而下的方法： 目标很重要（触发适当的反应），当与生物电图的大型结构目标相比时，单个细胞路径变得不那么关键。

解剖编译器：组织工程的未来？

解剖编译器具有利用生物电“编程”生物形态的潜力，可以彻底改变组织工程。想象一下：

• 设计组织“蓝图”： 指定组织的所需形状、大小和组成。
• 将蓝图转换为生物电信号： 使用解剖编译器生成指导细胞行为所需的精确电模式。
• *原位*构建组织： 与其在实验室中构建组织然后植入，我们可以潜在地触发身体*直接*在损伤部位构建组织。
• 超越直接构建。 代替“细胞放置”和其他直接微观管理，通过形态发生中的目标驱动、集体、组织行为，这些变得不必要，可能为器官/组织生长提供强大的自组装方法。

这仍然是一个高度推测性的愿景，但它突出了将组织工程与对生物电控制的深刻理解相结合的潜在力量。

主要局限性、新概念和控制思想

• 主要困难：
• 复杂的 大器官无法详细复制（使用传统方法）：例如需要正确、适当信号的特定细胞，在非常复杂的结构/排列中，这些信号在今天几乎完全没有解决。
• 微观管理：组织/器官生物工程（如生物打印）具有巨大的开销 —— 需要细胞并具有适当的结构才能使其发挥作用、合作；虽然细胞和群体表现出能力，例如，有时 —— 朝着正确的结构/终点前进。生物电控制在许多情况下代表了更好的解决方案！
• 生物电和组织工程有联系（电场；具有电导率的支架材料 —— 甚至某些生物反应器中的丝绸支架本身，起作用/启用某些生物电信号）；但与细胞构建不同，生物电使细胞本身（例如纠错，或在重建时“知道”形状终点）；而现有技术无法提供“编程细胞以构建这种结构/器官”，并且生物电很好地证明了这些类型的信息和行为在起作用。

结论

组织工程仍然存在许多局限性；生物电提供了一种新的研究模式，有可能（有一天！）实现组织工程中非常具有挑战性的问题（不仅仅是替换，还有设计、重建和定制器官等）。它具有基本的范式和发现，可以更好地控制，更明智的方法，利用生物固有的形态发生能力（如非神经组织/系统的基础认知中所见）。 这是描述核心概念和未来 —— 通过整合两个领域并突出传统方法与 Levin 博士小组和其他人的核心联系、差异。