骨软骨损伤：新的（修复骨软骨损伤的）生物支架和细胞

新的（修复骨软骨损伤的）生物支架和细胞

New Scaffolds ＆ Cells

Classic technique for autologous chondrocyte implantation (ACI). A, Arthroscopic evaluation of the knee joint and identification of a full-thickness medial femoral condyle injury. A cartilage biopsy is taken from the superior intercondylar notch, digested, and cultured. Autologous chondrocyte transplantation will occur when the cells have reached a volume that can fill the articular cartilage defect. B, A two-incision approach is made to the knee. The first is a medial arthrotomy to expose the full-thickness medial femoral condyle defect. The second is an incision distal to the pes anserinus tendon insertion to harvest periosteum templated exactly to the defect after it is debrided. C, The technique of ACI. A periosteal patch is harvested distal to the pes anserinus tendons. It is microsutured with interrupted 6.0 Vicryl sutures flush to the articular surface and tested for water integrity tightness. It is then sealed with fibrin glue to maintain water tightness. The autologous chondrocyte suspension is injected deep to the periosteal cover to fill the defect, and the opening is sutured over and sealed with fibrin glue. The knee joint is closed. The patient undergoes careful rehabilitation to restore motion and allow the graft to mature uneventfully.

图1：2步支架移植法修复软骨缺损：自体软骨细胞移植（ACI）的经典技术。A，膝关节的关节镜评估和鉴定全层厚度的股骨髁骨软骨损伤。软骨块是股骨髁窝上部取得的（非负重关键区），被消化和培养。当细胞达到可以填补关节软骨缺陷的体积时，将准备自体软骨细胞移植。B，膝关节采取了两种切口方法。首先是髌旁内侧关节切开术，可暴露全层厚度股骨内侧髁缺损。第二个是髂胫束肌腱附着处的远端切口，以收获骨膜，这些骨膜被清理后，精确地插入了骨软骨缺损处（与骨软骨缺损处形态一致）。C，自体软骨细胞移植ACI技术。从髂胫束肌腱附着处的远端切口收集骨膜块。用6.0 vicryl微创可吸收线缝合至关节表面并测试完整性、水紧密性。然后用纤维蛋白胶将其密封以保持密封性。自体软骨细胞悬浮液植入骨膜下以填补缺损，并用纤维蛋白胶将开口缝合并密封。膝关节关闭。患者进行了认真的术后康复，以恢复运动，并使移植物与自体软骨相融合为一体。

数十年来，已经提出并尝试了许多手术方式，以治疗关节软骨（称为软骨病变）或软骨以及基础（骨软骨病变）的损害，目的是尽可能紧密地恢复（移植修复）组织到原始软骨。但是，迄今为止，没有任何方法能够完全修复正常、健康软骨的特性。

软骨生物支架是临时的3D生物降解结构，由于患病或受损的软骨而被放置在软骨缺损处。软骨生物支架通常分为四种主要类型：基于蛋白质的支架，基于碳水化合物的支架，合成或基于人造聚合物的支架，以及这些类型材料的复合支架。软骨生物支架也可以以几种形式：膜状，多孔状或水凝胶状。

软骨生物支架应该是：

•生物相容性，体内几乎没有炎症反应；

•能被身体分解时无害物质；

•多孔，足以允许新的软骨细胞生长和最终的软骨生物支架降解，同时形成“网状”以维持最合适的软骨修复微环境；

•易于生产和多种功能，具体取决于所需的尺寸和形状；

•能够承受关节内的压应力和剪切应力（例如，膝关节）。

软骨生物支架可以作为两步软骨修复手术的一部分植入，其中软骨生物支架与先前在实验室中扩增的软骨细胞相结合。这是一个类似于自体软骨细胞植入（ACI）的过程，称为基质辅助自体软骨细胞移植（MACT）或基质辅助自体软骨细胞植入（MACI）。

或者，将支架植入一步过程中，其中软骨生物支架刺激后的软骨生物支架被放置在有缺损的软骨中，或者是移植柱，或作为促进新软骨生长（称为“智能”软骨生物支架）。

尽管有长期的随访表明先前使用的软骨生物支架和软骨细胞会产生良好的结果，但正在等待新的“智能”软骨生物支架的长期研究数据。

下面讨论了软骨修复中软骨生物支架的用途，优势和缺点以及临床证据。

目标受众（阅读者）

本文适用于任何关节软骨受损的人及其家人，他们想了解新的支架，以及任何对软骨问题感兴趣的人。

什么是新的软骨修复支架？

用于软骨再生的支架在1990年代后期被引入临床。这些是先进的生物聚合物，用作从患者身上提取的软骨细胞或“自体软骨细胞”的支持物。

与自体软骨细胞移植ACI的手术相似，外科医生首先进行（关节镜检查）以从关节的非负重部分采集含有软骨细胞（软骨细胞）的小块软骨。软骨片被送到实验室，在那里分离和培养（增殖）细胞3-5周以获得足够数量的细胞（通常在5到1200万个细胞之间）。然后将软骨细胞放置在支架上，以便它们可以繁殖和成熟1到几天。随后将与软骨细胞结合的支架移植到关节的受损或患病区域。

与此同时，一步技术也变得可用。对于这些程序，一种改进的“智能”生物材料被放置在软骨缺损内，该材料能够帮助身体自身的“构建细胞”形成软骨组织。骨髓刺激技术通常与这些支架结合使用，以允许身体自身的细胞离开骨髓并参与填充支架。

这些骨髓细胞迁移到支架中，支架的目标是引导软骨单独或骨和软骨细胞生长、成熟并构建相应的组织。今天，有设计用于仅重建软骨（软骨缺损）或骨和软骨（骨软骨缺损）的支架。

基质辅助自体软骨细胞移植MACT或具有自体软骨细胞的支架与“智能”支架之间的区别在于是否存在软骨细胞，以及是否需要进行一次或两次手术。

软骨生物支架和细胞的优缺点是什么？

新软骨生物支架和细胞的优点是什么？

与其他手术治疗相比，使用不含软骨细胞的支架具有优势。例如，自体骨软骨移植需要两次手术，并且确实去除了一小块“正常软骨”。从尸体（供体）中采集的同种异体移植物的使用在欧盟存在问题，因为它们难以获得。此外，使用同种异体材料（即来自其他人）具有与潜在疾病传播相关的风险（尽管极低）。

结合软骨细胞的支架已经上市大约15年，研究人员报告了良好的结果。使用没有软骨细胞的智能支架的优点是：它们是现成的，并且作为一步手术操作，也就是说，外科医生可以决定是否在他们在手术室时使用它，当他们对软骨损伤有更清晰的术中判断。

新软骨生物支架和细胞的缺点是什么？

就缺点而言，这完全取决于您放入的生物材料。换句话说，你有钻石、红宝石、蓝宝石和祖母绿。都是宝石，但都不同。软骨生物支架也是如此——你不能直接比较它们，因为每个软骨生物支架都是不同的。

使用基质辅助自体软骨细胞移植MACT，它是一种相当统一的技术：软骨被收获，软骨细胞增殖并放置在支架上/支架内。然后将支架放置在软骨缺损处。对于“智能”支架技术，只需将支架放置在患病或受损的关节中，无论是否进行骨髓刺激（例如钻孔或微骨折）。最终结果与所使用的生物材料有关。

“智能”支架已经很久没有使用了，因此缺乏长期甚至中期的成果。一些支架的短期结果令人鼓舞，但我们需要一些时间来了解这些支架是否表现良好。

常见问题(FAQ)

新的软骨需要多长时间才能在支架内生长？

这因患者而异（骨软骨损伤面积大小、程度、部位以及是否合并有其他临近部位组织的损伤及程度）。请与您的医生在术前进行详细的讨论。

Numerous surgical procedures have been suggested and tried over many decades to treat damage to joint (‘articular’) cartilage (known as chondral lesions) or cartilage and the underlying bone (osteochondral lesions), with the aim of restoring the tissue as closely as possible to the original cartilage. However, no methods to date have been able to completely match the properties of normal, healthy cartilage.

Scaffolds are temporary 3D biodegradable structures that are placed inside cartilage defects as a result of diseased or damaged cartilage. The scaffolds typically fall into four main types: protein-based scaffolds, carbohydrate-based scaffolds, synthetic or artificial polymer-based scaffolds, and a combination of any of these types. Scaffolds can also be in several forms: membranes, meshes or hydrogels.

Scaffolds should be:

· Biocompatible, and cause little or no inflammatory response in the body

· Harmless when broken down by the body

· Porous enough to allow new cartilage growth and the eventual breakdown of the scaffold, while forming a ‘net’ to maintain the most suitable environment for cartilage repair

· Easy to produce and versatile, depending on the size and shape required

· Able to withstand the stresses and forces within the joint (e.g., the knee)

Scaffolds can be implanted as part of a two-step procedure, in which the scaffolds are combined with cartilage cells (chondrocytes) multiplied previously in the laboratory. This is a process similar to that used in autologous chondrocyte implantation (ACI) and is called matrix-assisted autologous chondrocyte transplantation (MACT) or matrix-assisted autologous chondrocyte implantation (MACI).

Alternatively, the scaffolds are implanted in a one-step procedure, in which the scaffold is placed in the defective cartilage either after marrow stimulation (drilling or microfracture) or as a plug that encourages new cartilage growth (known as ‘smart’ scaffolds).

While there is long-term follow-up showing that the previously used scaffolds plus chondrocytes produce good results, longer-term data for the newer ‘smart’ scaffolds is awaited.

The uses, advantages and disadvantages, and clinical evidence for scaffolds in cartilage repair are discussed below.

Intended audience

This article is intended for anyone suffering from damage to their articular cartilage and their families who would like to find out about new scaffolds, as well as anyone interested in cartilage problems.

Figure 2: New Scaffolds 2 Steps.

图2：2步支架移植法修复软骨缺损：自体软骨细胞移植（ACI）的经典技术（与图1中的描述一致）。

What are new scaffolds for cartilage repair?

Scaffolds for cartilage regeneration were introduced the late 1990s. These were advanced biopolymers used as a support for cartilage cells taken from the patient, or ‘autologous chondrocytes’.

Similarly to the procedure for ACI, the surgeon first performs (arthroscopy) to harvest small pieces of cartilage containing cartilage cells (chondrocytes), from a non-weight-bearing part of the joint. The cartilage pieces are sent to a laboratory, where the cells are isolated and cultured (multiplied) for 3–5 weeks to obtain sufficient number of cells (usually between 5 and 12 million cells). The chondrocytes are then placed on the scaffold so that they can multiply and mature for one to several days. The scaffold combined with chondrocytes is subsequently transplanted into the damaged or diseased area of the joint.

In parallel, one-step techniques have also become available. For these procedures, an improved, ‘smart’ biomaterial, which is capable of assisting the body’s own “building cells” to form cartilage tissue, is placed inside the cartilage defect. Bone marrow stimulation techniques are often used in conjunction with these scaffolds to allow the body’s own cells to leave the bone marrow and participate in populating the scaffold.

These bone marrow cells migrate into the scaffold, and the scaffold’s goal is to direct cartilage alone or bone and cartilage cells to grow, mature, and build the corresponding tissues. Today, there are scaffold designed for the reconstruction of cartilage only (chondral defects), or of both bone and cartilage (osteochrondral defects).

The differences between MACT, or scaffolds with autologous chondrocytes, and ‘smart’ scaffolds are the presence of cartilage cells, or chondrocytes, and whether one or two surgeries are required.

What are the advantages and disadvantages of New Scaffolds ＆ Cells?

What are the advantages of New Scaffolds ＆ Cells?

The use of scaffolds without chondrocytes has advantages compared to other procedures. For example,autologous osteochondral transplantation requires two surgeries and does remove a small piece of “normal cartilage”. The use of allografts, which are harvested from cadavers (donors), is problematic in the European Union as they are difficult to obtain. Moreover, the use of allogenic materials (i.e., from other people) has risks (though extremely low) associated with potential disease transmission.

Scaffolds combined with chondrocytes have been on the market for around 15 years, and researchers have reported good results. The advantages of using a smart scaffold without chondrocytes are: they are available off-the-shelf and are performed as a one-step procedure, that is, the surgeon can decide whether to use it while they are in the operating room, when they have a clearer idea of the cartilage damage.

What are the disadvantages of New Scaffolds ＆ Cells?

In terms of disadvantages, it depends completely on the biomaterial you are putting inside. To put it another way, you have diamonds, rubies, sapphires and emeralds. All are precious stones, but they are all different. It’s the same with scaffolds – you cannot compare them directly, because each scaffold is different.

With MACT, it is a rather uniform technique: the cartilage is harvested, the chondrocytes are multiplied and the placed on/in the scaffold. The scaffold is then placed in the cartilage defect. For the ‘smart’ scaffold techniques, the scaffold is simply placed in the diseased or damaged joint, with or without marrow stimulation (e.g., drilling or microfracture. The final result is related to the biomaterial used

The ‘smart’ scaffolds have not been in use for a long time, so there is a lack of long- or even medium-term results. The short-term results for some scaffolds are encouraging, but we will need some time to understand whether these scaffolds are performing well or not.

Frequently Asked Questions (FAQs)

How long will the new cartilage take to grow inside the scaffold?

This varies from patient to patient. Please discuss with your doctor.

Further reading

There have been numerous studies on the outcomes of scaffolds for cartilage repair. Some papers that give a good overview of the evidence so far include:

进一步阅读

已经有许多关于支架用于软骨修复的结果的研究。迄今为止，一些对证据进行了很好的概述的论文包括：

· Filardo G, Kon E, Roffi A, Di Martino A, Marcacci M. Scaffold-based repair for cartilage healing: a systematic review and technical note. Arthroscopy. 2013;29(1):174-186.

· Goyal D, Goyal A, Keyhani S, Lee EH, Hui JH. Evidence-Based Status of Second- and Third-Generation Autologous Chondrocyte Implantation Over First Generation: A Systematic Review of Level I and II Studies. Arthroscopy. 2013

· Irion VH, Flanigan DC. New and Emerging Techniques in Cartilage Repair: Other Scaffold-Based Cartilage Treatment Options. Operative Techniques in Sports Medicine. 2013;21:125-137.

· Kon E, Verdonk P, Condello V et al. Matrix-assisted autologous chondrocyte transplantation for the repair of cartilage defects of the knee: systematic clinical data review and study quality analysis. Am J Sports Med. 2009;37 Suppl 1:156S-166S.

· Kon E, Vannini F, Buda R et al. How to treat osteochondritis dissecans of the knee: surgical techniques and new trends: AAOS exhibit selection. J Bone Joint Surg Am. 2012;94(1):e1(1-e18).

· Kon E, Filardo G, Di Martino A et al. Clinical Results and MRI Evolution of a Nano-Composite Multilayered Biomaterial for Osteochondral Regeneration at 5 Years. Am J Sports Med. 2013

· Kon E, Filardo G, Di Matteo B, Perdisa F, Marcacci M. Matrix assisted autologous chondrocyte transplantation for cartilage treatment: A systematic review. Bone Joint Res. 2013;2(2):18-25.

· Marcacci M, Filardo G, Kon E. Treatment of cartilage lesions: what works and why? Injury. 2013;44 Suppl 1:S11-S15.

· Olson A, Graver A, Grande D. Scaffolds for articular cartilage repair. J Long Term Eff Med Implants. 2012;22(3):219-227.

Keywords

autologous, biomaterial, chondrocytes, regeneration, Scaffolds