ReviewCell-based tissue engineering strategies used in the clinical repair of articular cartilage
Introduction
An adequate therapy for the long-term repair of cartilage lesions has yet to be developed. Being largely avascular and with low cellularity, articular cartilage has a limited ability to heal itself. Despite possessing remarkable mechanical properties, the tissue can develop defects following long-term wear or acute trauma. Defects in the highly organized matrix can progressively deteriorate through mechanisms of stress concentration and cell signaling cascades. Ultimately, the tissue loses mechanical integrity, breaks, thins, loses lubrication, and no longer functions in cushioning bone-to-bone contact – imparting great physical pain to the patient.
Focal lesions are the ideal indication for the repair of articular cartilage. The prevalence of focal lesions is difficult to estimate. In 2005, an estimated 27 million people in the U.S. had osteoarthritis [2]. In one study, 60% of all arthroscopies revealed the presence of articular lesions (36% being Outerbridge Grade III and IV lesions) and, of these, 67% were characterized as focal lesions [3]. From a surgical perspective, an estimated 250,000 articular cartilage repair procedures (involving chondroplasty, microfracture, mosaicplasty, and autologous chondrocyte implantation (ACI)) are performed annually in the U.S [4]. These cartilage repair therapies, however, do not consistently produce hyaline repair tissue, fill the entirety of the defect, and integrate repair tissue with adjacent native tissue.
To overcome these limitations, a number of cell-based, tissue engineered cartilage products have recently entered clinical trials in the U.S. and abroad. In this review, tissue engineered cartilage is defined as a construct formed by following the paradigm of integrating chondrocytes, signals, and scaffolds. The scaffolds can be exogenously provided or endogenously produced by the cells; the latter are usually referred to as scaffold-free or scaffold-less approaches if no exogenous scaffold is provided. Acellular scaffolds, considered an augmented form of microfracture, are not included in this definition. Tissue grafts including osteochondral autografts and allografts, as well as their particulated forms such as DeNovo® NT from Zimmer, are also not considered tissue engineered cartilage. Finally, using this definition, injection of passaged chondrocytes into a cartilage defect is also not considered tissue engineering. Through systematic design, tissue engineered cartilage can be manipulated in vitro to enhance its biochemical and biomechanical properties. Complete fill and good integration can be achieved by manipulating construct shape, the use of adhesives and other fixation methods, and other strategies. Tissue engineering offers a promising solution for the long-term treatment of cartilage lesions. Despite a plethora of research published on cartilage tissue engineering, it is known that 90% of new drugs that advance past animal studies fail clinical trials [1]. Therefore, reviewing the scientific details of tissue engineered cartilage products that have demonstrated efficacy in clinical trials would provide both foundational knowledge and insight in how to move the field forward.
The first section of this review aims to provide a description of current repair therapies and the tissue engineered cartilage products – BioCart™II, Bioseed®-C, CaReS®, Cartipatch®, Chondrosphere®, Hyalograft® C, INSTRUCT, NeoCart®, NOVOCART® 3D, MACI, and RevaFlex™. Table 1 lists the construct specifications, and Table 2 lists the products' clinical indications, current status, and clinical trials. The second section aims to discuss the tissue engineering strategies used in product fabrication, identify current challenges, and suggest future directions. The authors note that the information in this review was gathered from published literature, company websites, and relevant patents. Owing to this and the fact that there may be a plethora of proprietary details not publicly available, the current status of the products may not be adequately reflected. In reviewing the details on the science behind each product, one quickly realizes that improvements can be made on five areas. These include 1) defining and optimizing the chondrocyte cell source, 2) understanding tissue-scaffold interaction and scaffold degradation, 3) identifying and applying novel stimuli, 4) understanding construct maturation, biomechanics, and functionality, and 5) improving implantation, fixation, and rehabilitation methods. The current challenges and future directions in these five areas, along with challenges in commercialization, are discussed in Perspectives. By understanding the general details of how these clinically used tissue engineered products are fabricated, one can gain insight as to how to best use them and how to design the next generation of tissue engineered cartilage.
Section snippets
Current cartilage repair therapies
Chondroplasty (76.6%) and microfracture (22.0%) account for the majority of the procedures performed on articular cartilage in the knee [4], [5]. However, these cartilage repair options may have several shortcomings [6], [7], [8], [9], [10], [11]. Chondroplasty, used only when wear is minor, has acceptable short-term but potentially poor long-term results [6], [7]. In microfracture, the defect is cleaned and the bone punctured to induce bleeding, resulting in a fibrocartilaginous repair tissue
BioCart™II (Histogenics, Waltham, MA)
Biocart™II was first developed by Prochon Biotech, Ltd. until the company's acquisition by Histogenics in 2011. The product is a fibrinogen/hyaluronic acid scaffold seeded with expanded autologous chondrocytes. Cells were expanded in the presence of autologous serum and 10 ng/mL fibroblast growth factor 2 variant (FGF2v) [26]. FGF2v has been shown to increase cell proliferation rates and maintain the chondrocytic phenotype during expansion [27]. The scaffold was described to be composed of
Tissue engineering strategies used in current clinical products
This section of the review compares the different tissue engineering strategies used during each stage of the tissue engineering paradigm. The paradigm consists of 1) identifying a cell source (i.e., primary or passaged articular chondrocytes), 2) forming the construct either using scaffold or scaffold-free approaches, and 3) culturing the construct in vitro, where biomimetic stimuli can be further applied, before implantation (Fig. 1). Construct maturation, implantation, fixation, and
Perspectives
The recent wave of cell-based articular cartilage products in clinical trials in the U.S. and abroad indicates a growing recognition that current repair techniques can be improved by using a tissue engineering approach. Through a detailed account of how these products are fabricated, one can gain insight to the key strategies, current challenges, and future directions in five areas: 1) defining and optimizing the chondrocyte cell source, 2) understanding tissue-scaffold interaction and scaffold
Disclaimer
Kyriacos A. Athanasiou is on the scientific advisory board for Histogenics Corporation (2011-present). He was on the scientific advisory board for Prochon Biotech Ltd. (2009–2011). He has served as a consultant for multiple companies including DePuy and Arthrex. In 1993, he was a co-founder of Osteobiologics Inc., which was acquired by Smith and Nephew in 2006.
Conflict of interest
The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgements
The authors would like to acknowledge support from the following grants: the National Institutes of Health (NIH) grant R01AR067821 and California Institute for Regenerative Medicine (CIRM) grant TR3-05709.
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