Learning from Successes of Tissue Engineering Strategies for Cartilaginous Disorders

10 Learning from Successes of Tissue Engineering Strategies for Cartilaginous Disorders

Stephen R. Sloan, Jr. and Lawrence J. Bonassar

Abstract

The design of biological and tissue engineered approaches for treating intervertebral disc (IVD) pathologies should not be an entirely novel progression; there are numerous examples of clinically successful treatments in medical fields bearing similarity to the spine. Tissue engineered implants have been US Food and Drug Administration (FDA) approved to treat a variety of musculoskeletal disorders in the clinic since the 1990s, providing ample time for long-term studies and design alterations.¹^,²^,³^,⁴^,⁵^,⁶ Autologous chondrocyte implantation (ACI) is one example of a clinically successful intervention in an orthopaedic field with great relevance to the spine that garnered success in thousands of patients.³^,⁶^,⁷^,⁸ Although treating the spine has its own complexities and unique challenges facing biological repair, important lessons can be learned from clinical triumphs in related fields.

Keywords: articular cartilage, auricular cartilage, autologous chondrocyte implantation, meniscus, nasal cartilage

10.1 Historical Perspective

Three types of biologics used clinically to treat pathological cartilage are biomolecule-, cell-, and scaffold-based approaches, which may be used independently or in combination with each other.²^,⁹^,¹⁰ The strategy of biomolecule therapies is to augment natural tissue healing processes through invigorating cells with signals to proliferate, migrate, or assemble proteins necessary for repair. There are a whole host of cytokines, growth factors, and enzymes used clinically to treat cartilaginous disorders including fibrin, transforming growth factor (TGF-β), bone morphogenetic proteins (BMP), platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF), to name a few. The strategy of cellular therapies with or without scaffold material is to induce cellular proliferation and the production of extracellular matrix (ECM) proteins as well as other signal biomolecules. Scaffold-based approaches comprise cytocompatible biomaterials that replace native tissue and/or function as carriers for cells producing native proteins and cytokines. This chapter primarily focuses on interventions involving tissue scaffolds, as there are already biomolecule- and cell-based biologics for intervertebral disc (IVD) in the clinical setting.¹¹^,¹²^,¹³

10.1.1 Relevant Cartilaginous Tissues

The IVD is by no means identical to other cartilaginous tissues; however, there are many anatomical, pathological, and macro-environmental similarities between the tissues. There are multiple types of cartilage found in the human body bearing semblances to the IVD that are worth discussing, such as meniscus, articular, ear, and nose cartilage. Just like the IVD, most types of cartilage, when healthy, are avascular and lack nerves.¹⁴^,¹⁵ Whereas chondrocytes, native cartilage cells, are at homeostasis under hypoxic conditions, avascular tissues do not receive the cocktail of growth factors and proteins necessary to proliferate and self-heal after injury. Degenerative disc disease (DDD) is a progressive disease that becomes more prevalent with increasing age and may be induced by traumatic injury, much akin to the degeneration of articular cartilage and meniscus.¹⁶^,¹⁷^,¹⁸^,¹⁹ Degenerated cartilage and IVD are chronic pathologies due to their inability to self-heal, and are difficult to treat without the introduction of biological material such as cells, biomolecules, and tissues.

Every cartilaginous tissue has a unique mechanical environment, but many mirror both the static and cyclic loading states experienced by the IVD during standing and walking/exercising.²⁰^,²¹ Articular cartilage and menisci are most similar to IVDs given they are sandwiched between bones and function to absorb shock, transmit loads, and stabilize joints.²² Articular cartilage in the knee is thoroughly discussed in this chapter because the cyclic compressive loading in the knee is the most analogous to the spine.²³ The ECM of cartilaginous tissues including IVDs are compositionally dense in collagen, proteoglycans, elastin, and water, with varying content in each tissue yielding excellent mechanical properties, flexibility, or structural integrity.¹⁷^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰ The cellular composition of IVDs is similar to other cartilage cell populations given that native annulus fibrosus (AF) cells are chondrocyte-like and native nucleus pulposus (NP) cells are fibroblast-like.³¹ Tissue engineered biologics used in the clinic to treat cartilage pathologies are composed of identical biomaterials and cells used in preclinical IVD studies, hence the necessity to look toward fields to promote translation of IVD biologics.¹^,¹³^,³²^,³³

10.2 Status of Successful Products

Orthopaedics and other surgical fields treating cartilage have seen a plethora of US Food and Drug Administration (FDA)-approved biologics enter clinical trials and the marketplace since the 1990s, and have much to offer IVD biologics in terms of strategy and design. The following sections discuss various FDA-approved products and those currently in clinical trials to offer guidance and motivation for IVD biologics.

10.2.1 Articular Cartilage

By the numbers, there are more commercially available and clinically tested products for treating and repairing articular cartilage than any other cartilaginous tissue (▶ Table 10.1). This could stem from the fact that focal chondral defects are present in up to 63% of patients undergoing arthroscopy of the knee; however, DDD has been shown to be present in up to 90% of older adults.³⁴^,³⁵ Articular cartilage lesions resulting from traumatic injury or degenerative diseases lead to chronic pain and decreased mobility, hindering patients from enjoying physical activities and a high quality of life.³⁶ Although translation of successful interventions from the laboratory to the clinic is notoriously difficult due to the FDA approval process, novel technologies for articular cartilage repair have had years of clinical success.

Autologous Chondrocyte Implantation—First Generation

Autologous chondrocyte implantation (ACI) and its stepwise iterations are great examples of clinically successful interventions to motivate the progression of IVD biologics (▶ Fig. 10.1, ▶ Table 10.2). Used to treat symptomatic cartilage defects of the femoral condyle, ACI treatments replaced interventions such as microfracture, abrasion chondroplasty, and osteochondral grafting. The aforementioned treatments are inadequate to restore native cartilage function and structure due to their lack of long-term stability and inability to treat large defect areas.³⁷, ³⁸ Carticel® (Vericel Corp.) is the shining star of the articular cartilage biologics, implanted in over 10,000 (and counting) patients since its introduction in 1995 and subsequent FDA approval in 1997.⁶ The two-step ACI procedure involves taking a cartilage biopsy upon first arthroscopy to harvest autologous chondrocytes from trivial knee cartilage, culturing cells in vitro to expand the population while maintaining correct phenotype, and then implanting the cells in a defect site under a periosteal membrane during the second arthroscopy.⁶ The strength of the procedures lies in the use of autologous chondrocytes, which decreases the risk of an immune response to the implanted cells and also ensures a phenotype similar to native cells. Carticel is considered the “first generation” of ACI, from which other procedures evolved with more complex treatment strategies involving scaffolds and biomolecules.³⁷

Fig. 10.1 Cartoon representation of the first three generations of autologous chondrocyte implantation.

Cases involving patients receiving Carticel ACI result in more successful outcomes over long periods of time than with contemporary nonbiological interventions. While there is debate whether ACI results in a greater percent of hyaline cartilage versus fibrocartilage, the failure rate for Carticel ACI at a 10-year follow-up was 17% versus 55% for mosaicplasty.⁷ Other studies have noted greater success rates in younger patients who presented sooner for surgery, demonstrating the value of prophylactic intervention before cartilage succumbs to degeneration.³⁹

Autologous Chondrocyte Implantation – Second and Third Generation

As Carticel ACI was performed in more patients, the “second generation” of ACI treatments substituted collagen membranes for the periosteal flap to avoid in situ patch hypertrophy and periosteal harvest morbidity.³⁷ Matrix-induced autologous chondrocyte implantation (MACI) employs a bovine type-I/III collagen patch on which to seed chondrocytes, reducing implant hypertrophy and the need for revision surgery.³⁶ The further classification of progressing generations of ACI are somewhat unclear; however, the “third generation” of products are characterized by the use of three-dimensional (3D) scaffold biomaterials to promote autologous chondrocyte expansion, such as NeoCart (Histogenics Inc.), BioCart II (ProChon Biotech Ltd.), and Novocart 3D (Aesculap Inc.).⁴⁰^,⁴¹^,⁴² The third generation also introduced new methods for culturing the autologous chondrocytes. NeoCart, for example, seeds chondrocytes onto a bovine type-I collagen matrix, which is mechanically stimulated in a hypoxic bioreactor to condition the matrix for optimal function in the body.⁴⁰ Second and third generation treatments show similar clinical outcomes to the first generation; however, there are surgical advantages such as reduced operative time, reduced tourniquet time, and ability to use minimally invasive techniques.³⁶

More recent advances in the ACI procedure aim to reduce ACI to a single operation and minimize the morbidity of autologous cartilage harvest.³⁷ Products such as RevaFlex (ISTO Technologies Inc.), Nose2Knee, and DeNovo NT (Zimmer Inc.) are still in the earlier stages of clinical trials; however, they offer novel technologies that may improve clinical outcomes compared with the earlier generations of ACI. DeNovo NT and RevaFlex substitute the autologous chondrocyte population for human juvenile chondrocytes, whereas DeNovo NT uses minced allograft cartilage as a scaffold biomaterial, and RevaFlex is scaffold-free.⁴³^,⁴⁴ Using allogenic chondrocytes enables cell implantation to be performed in a single operation; however, there are patient risks associated with histocompatibility and disease transmission. Nose2Knee attempts to reduce knee cartilage morbidity by harvesting autologous nasal septum cartilage for chondrocytes.⁴⁵^,⁴⁶ The Nose2Knee ACI procedure is similar to MACI due to the use of a collagen membrane; however, the use of nasal chondrocytes removes the necessity of additional knee cartilage damage during cell harvesting. IVD biologics can benefit from many ACI clinical trials; however, the need to refrain from multiple operations and progressing disc degeneration during cell harvest makes Nose2Knee a future-oriented product.

10.2.2 Meniscus—Autologous Concentrates

The menisci are fibrocartilaginous structures that transmit loads and reduce friction in many articulating joints, with the most prominent being the crescent-shaped lateral and medial menisci of the knee. Originally thought to be vestigial muscles of the knee, menisci were commonly completely removed when damaged, until biomechanical studies in the 1980s elucidated their role of reducing joint contact stresses.⁴⁷

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