Articular Cartilage Repair: Augmentation, Regeneration, Replacement, and Substitution

Erica G. Gacasan, MS

Robert L. Sah, MD, ScD

Dr. Sah or an immediate family member has stock or stock options held in GlaxoSmithKline, Johnson & Johnson, and Medtronic. Neither Ms. Gacasan nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

INTRODUCTION

Throughout adult life, the articular cartilage normally functions as a key component of diarthrodial joints, withstanding years of repetitive loading and facilitating pain-free motion. However, with injury and aging, this cartilage is often damaged. Unfortunately, damaged adult articular cartilage exhibits a limited intrinsic repair response and often deteriorates.¹ Thus, damaged articular cartilage is an attractive candidate for reparative interventions.² In general, cartilage repair strategies aim to augment, regenerate, replace, or substitute the damaged or missing tissue. Augmentation strategies seek to generate a tissue, often fibrous and not identical to the articular cartilage, but one that reduces pain and restores some function. In contrast, regenerative strategies aim to elicit a biological response that reforms normal adult articular cartilage. Both strategies use cells, scaffolds, and signals as components which induce or facilitate biological responses, including those that recapitulate development and growth. Repair by tissue replacement entails placement of a tissue graft containing articular cartilage (eg, autograft or allograft). Finally, repair by substitution involves placement of a nonliving prosthetic structure (eg, total joint replacement).

This chapter begins with a brief overview of normal articular cartilage and its poor intrinsic healing response, and then addresses restorative components for damaged cartilage, how they are delivered, the focal defect and osteoarthritic cartilage that are targeted for repair, and strategies for assessing repair. It then summarizes the established surgical procedures for cartilage repair, beginning with the bone marrow stimulation by standard and enhanced microfracture, then covering autologous chondrocyte implantation as it has evolved over multiple generations, and concluding with osteochondral grafts, both autogenic and allogeneic. It then reviews current and emerging strategies for cartilage augmentation, regeneration, or replacement. Emphasized throughout are the biological and biomechanical processes involved in repair within a synovial joint, and how resultant changes lead to measurable structural and functional outcomes.

KEY POINTS

Damaged adult articular cartilage does not typically mount an effective repair response.
The type of cartilage damage targeted for repair is of two main types: focal defects and osteoarthritis.
The types of cartilage repair that target regeneration and replacement aim to restore the damaged region to normal articular cartilage, mimicking native structural, biochemical, and biomechanical properties; in contrast, cartilage repair by augmentation does not aim to necessarily restore normal tissue, and cartilage repair by substitution inserts a classic inert biomaterial.
Cartilage repair via augmentation, regeneration, or replacement all use one or more of the following components: cells, chemical and physical signals, and scaffolds.
Cartilage repair strategies can be classified by their primary therapeutic modality as biomechanical or biological.
Cartilage repair strategies can also be classified according to their mode of delivery, systemic, local, or surgical.
Treatments for cartilage damage are used when symptoms persist despite pharmacologic and nonpharmacologic physical interventions.
Treatment of focal defects by either microfracture, autologous chondrocyte implantation, or osteochondral autograft or allograft is based on the size and location of the defect, quality of the surrounding cartilage, as well as patient age, lifestyle, and presence of comorbidities such as obesity, joint malalignment, and ligamentous instability.
Experimental studies are underway to develop more effective or readily available treatments for focal cartilage defects, and also to create effective treatments for damaged or eroded cartilage in OA.

ARTICULAR CARTILAGE FUNCTION, STRUCTURE, AND LIMITATIONS OF INTRINSIC REPAIR

Articular cartilage is a hyaline cartilage covering the subchondral bone in diarthrodial joints. This cartilage provides a load-bearing, low-permeability, low-friction, and wear-resistant surface for pain-free joint movement. Regional, site, and depth-dependent variation in tissue organization is critical to normal function under complex loading.³^,⁴ Healthy adult articular cartilage is composed of resident chondrocytes (˜2% v/v), extracellular matrix (˜20% to 40% w/w), and water (˜60% to 80% w/w).⁵ The extracellular matrix is largely comprised of collagen type II (˜200 mg/g wet weight) and proteoglycan (˜25 mg/g wet weight).⁵ The chondrocytes produce and maintain the cartilage matrix, balancing its synthesis and degradation. The collagen network contributes to overall tissue integrity and the resistance of cartilage to tension. Negatively charged proteoglycans, mainly aggrecan, are entrapped within the collagen network and contribute to compressive resistance, providing a high osmotic pressure within the tissue. The relatively high density, charged nature, and binding sites within the extracellular matrix affects storage, partitioning, and transport of solutes, including regulatory factors, nutrients, and waste products through and within the tissue.⁶^,⁷ Different types of mechanical stimuli, static and dynamic, compressive and shear, distinctly regulate indwelling cells and matrix turnover. Additionally, the synovial joint, including the articular cartilage, subchondral bone, synovium, and synovial fluid, acts as an interactive organ system. Each joint organ can change with time and interact with the more traditional organ systems. Just as abnormalities of system components cause joint degeneration, repair of components may restore the homeostatic function of joint systems.

Unfortunately, adult articular cartilage exhibits limited intrinsic repair as demonstrated by experimental studies in animal models and supported by clinical observations. Mature articular cartilage is mostly avascular and receives nutrients primarily by diffusion from the synovial fluid. Thus, when lacerated, articular cartilage does not bleed or undergo the classic wound-healing response. The resultant wound repair response is ineffective, with only proliferation of some nearby cells, possibly driven by release of matrix-bound FGF-2.⁸ In addition, resident chondrocytes are largely immobilized within the dense extracellular matrix and exhibit limited migration to injured sites. Finally, damaged tissue does not normally secrete sufficient chemotactic factors to attract reparative cells.

Thus, long-standing approaches to stimulating a biologic response to repair cartilage defects involve surgical penetration of the subchondral plate to initiate a cascade of events occurring in particular locations with characteristic times⁹ (Figure 1). Initially, there is an influx of blood and marrow elements including stem cells and growth factors from the subchondral marrow and vasculature. During and following clot formation, the repair cells undergo the regulated fate processes of differentiation, proliferation, and apoptosis. Subsequently, the repair cells gradually form and maintain the extracellular matrix, ideally to create bulk cartilage tissue with appropriate site-specific and depth-dependent biological and biomechanical properties. Additionally, such cartilaginous tissue should form the appropriate interfaces with the surrounding tissues for the various types of defect repair (Figure 2), integrating with adjacent cartilage, transitioning to subchondral bone, and maintaining a lubricated articular surface. Unfortunately, although such stimulated repair exhibits many regenerative features, it does not result in reliable formation of
stable hyaline articular cartilage, but rather a fibrocartilage or inadequate articular-like cartilage that does not fully fill the defect and/or deteriorates in the ensuing months.

FIGURE 1 Characteristic time frames of focal defect repair by bone marrow stimulation. In microfracture, (A) penetration of the subchondral bone plate leads to (B) formation of a clot containing cells, growth factors, and matrix molecules. Over time, (C) cells remain at the defect site, differentiate, and (D) form and maintain the repair tissue.

COMPONENTS FOR, AND APPROACHES TO, CARTILAGE AUGMENTATION, REGENERATION, AND REPLACEMENT

The goal of many cartilage treatment strategies is to deliver or attract cells, effective in repair and regeneration, within and adjacent to the defect site, to ultimately regenerate normal articular cartilage. Interventions which aim to augment, replace, or regenerate injured tissues often use a variety of components which can be classified as cells, signals, or scaffolds, which enable a biological response (Figure 3). Cartilage repair strategies can be classified according to (1) their primary mode of therapeutic action, biomechanical or biological, and (2) their mode of delivery, systemic, local, or surgical (Table 1).

FIGURE 2 Normal osteochondral unit and spatial aspects of repair of cartilage defects. A, Normal osteochondral unit. Defects that are (B) partial-thickness, (C) full-thickness, and (D) osteochondral and spatial aspects of repair strategies. Specialized surfaces, tissues, and interfaces include the (a) articular surface, (b) bulk cartilage, (c) interface of repair with host cartilage, (d) interface of repair cartilage with subchondral plate, (e) formation of a bone-cartilage interface, (f) repair of trabecular bone, and (g) interface of repair with host bone.

Mechanically directed treatment strategies aim to correct abnormal joint loading and joint malalignment or provide mechanically functional (ie, load bearing) tissues or tissue substitutes. Changes in normal loading due to injury, joint laxity, neuromuscular changes, obesity, and varus-valgus malalignment may initiate degenerative pathways leading to cartilage deterioration and osteoarthritis.¹⁰ If identified early, abnormal joint mechanics leading to cartilage deterioration may be ameliorated by improving joint alignment.¹¹ Surgical interventions such as osteotomy and joint distraction aim to enable intrinsic cartilage repair by either restoring normal joint alignment or decreasing mechanical loading on compromised portions of the joint. Other nonsurgical interventions include orthotics and unloader braces. Conversely, implantation of fully functional tissue, or tissue substitutes, may use autologous or allogeneic grafts, or synthetic implants such as metal and plastic protheses, to resurface joints with widespread deterioration.

Many cartilage regenerative therapies enable a biological response which aim to regenerate the tissue, restore normal structure and function, and may involve cells, scaffolds, and
small molecules, individually and in combination. Perforation of the subchondral bone to release a milieu of mesenchymal stem cells and growth factors via bone marrow stimulation techniques is commonly used to incite formation of fibrocartilage repair tissue at the defect site. Similarly, use of platelet-rich plasma (PRP), containing a mixture of platelets, leukocytes, growth factors, and cytokines depending on the formulation, alone or to augment repair, has shown promise, although more clinical studies are necessary.¹² Autologous chondrocyte implantation (ACI), in which autologous chondrocytes are harvested, expanded, and implanted to the defect site, initially developed in the 1990s, has since undergone several generations of development and is a promising cell-based treatment for cartilage lesions.

FIGURE 3 Engineered tissue components. Signals, cells, and scaffolds are the major elements of pharmacologic and tissue engineering approaches to cartilage repair. These elements may be used separately, or in combination, to treat symptomology or affect regeneration or restoration of tissue function.

TABLE 1 Repair Strategies to Treat (osteo)chondral Lesions

		Therapy
		Mechanical	Biological
Mode of delivery	Systemic	Exercise/PT, weight loss, orthotics	NSAIDs, analgesics, nutritional supplements
	Local	Viscosupplements, CPM, braces	Corticosteroids, stem cells, PRP
	Surgical	Osteotomy, allografts, autografts, total/partial joint replacement	Bone marrow stimulation, ACI, minced cartilage, joint distraction
Repair strategies can be classified according to their primary therapeutic mode of action, biomechanical or biological, and also by mode of delivery (systemic, local, or surgical). ACI = autologous chondrocyte implantation, CPM = continuous passive motion, PRP = platelet-rich plasma , PT = physical therapy

Combination strategies, which attempt to acutely, mechanically restore function to the tissue as well as enable a long-term functional biological repair, have also been developed. For instance, cell-free osteochondral scaffolds have robust mechanical properties which rapidly restore mechanical function but also contain osteoconductive scaffolding, which allows for bone growth and integration of the implant with host tissue.

Depending on the biological components used, human cells, tissues, and cellular-based products (HCT/Ps) may be designated as “minimally manipulated” by the United States FDA. Minimally manipulated products are those that have not altered the original relevant characteristics of the tissue or cell-type relating to its utilization for homologous reconstruction,
repair, or replacement and do not require premarket approval by the FDA.¹³ If a HCT/P does not qualify as minimally manipulated, it may be classified as a drug, device, or biologic material and are subjected to the requisite regulations. Many acellular (Table 2) and cellular (Table 3) products targeting cartilage repair have been developed, are currently marketed, or are in development.

TABLE 2 Acellular Scaffold-based Therapies to Treat (osteo)chondral Lesions

Product	Company	Material	Procedure	Market Status
Agili-C	Cartiheal (Kfar Saba, Israel)	Hyaluronan, aragonite	Cell-free osteochondral scaffold	[check mark](Europe), clinical trials (USA)
BioCartilage	Arthrex (Naples, FL, USA)	Allogeneic cartilage matrix	Augmented microfracture	[check mark]
BioPoly RS	BioPoly (Fort Wayne, IN, USA)	Ultra-high-molecular-weight polyethylene	Focal defect repair	[check mark] (Europe), clinical trials (USA)
BST-CarGel	Smith & Nephew (London, UK)	Chitosan	Augmented microfracture	[check mark] (Canada, Europe)
Cartifill	Sewon Cellontech (Seoul, South Korea)	Collagen	Augmented microfracture	Withdrawn
Cartilage allograft matrix	MTF Biologics (Edison, NJ, USA)	Allogeneic cartilage matrix	Augmented microfracture	[check mark]
Cartiva	Cartiva (Alpharetta, GA, USA)	Polyvinyl alcohol	Metatarsophalangeal joint replacement	[check mark]
Chondrofix	Zimmer Biomet (Warsaw, IN, USA)	Devitalized osteochondral allograft	Osteochondral allograft	[check mark]
GelrinC	Regentis Biomaterials (Haifa, Israel)	Poly(ethylene glycol)-modified fibrinogen	Augmented microfracture	[check mark] (Europe), clinical trials (USA)
HemiCap Classic	Arthrosurface (Franklin, MA, USA)	Metal	Focal defect repair	[check mark]
Hyalofast	Anika Therapeutics (Bedford, MA, USA)	Hyaluronan	Augmented microfracture	[check mark] (Europe), clinical trials (USA)
Maioregen	Fin-ceramica (Faenza, Italy)	Collagen I, hydroxyapatite	Cell-free osteochondral scaffold	[check mark] (Europe)
Trufit CB	Smith& Nephew (London, UK)	Poly(glycolic acid), poly(lactic-co-glycolic acid), calcium sulfate	Cell-free osteochondral scaffold	Withdrawn

FOCAL DEFECTS AND OSTEOARTHRITIC DEGENERATION AS TARGETS FOR ARTICULAR CARTILAGE REPAIR

FOCAL DEFECTS

The current articular cartilage repair strategies address focal defects, some of which are large. Of the six types of synovial joints, hinge (eg, knee, ankle, finger) and spherical joints (eg, hip, shoulder) are currently targets for biological intervention.¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸ Other synovial joints include pivot, saddle, plane, and condyloid joints. Joint motion, either translation or rotation, is constrained by joint geometry and surrounding tissue structures. The incidence of joint pathologies is in part dependent on joint type and motion, age, anatomic location, as well as other risk factors including genetics, joint malalignment, and ligamentous instability. Joint pathologies including articular cartilage encompass osteoarthritis, focal chondral defects, chondromalacia patellae, osteochondritis dissecans, acetabular impingement, joint malalignment, and other types.¹⁹

Focal chondral and osteochondral defects are injuries or areas of degeneration which are limited to a defined focal area. Focal defects may occur because of acute traumatic injury causing compression, shear, or both, disorders of the bone or cartilage, including subchondral osteonecrosis, or may be idiopathic. Defects can present as (1) partial-thickness chondral defects where damage is restricted to the chondral layer and where resurfacing of the articular cartilage may be helpful, (2) full-thickness chondral defects extending completely to the calcified cartilage or subchondral bone, and (3) osteochondral defects which affect both the cartilage and underlying bone where repair may

involve interaction with, or penetration of, the subchondral plate (Figure 2). Defects may present as softened or partially eroded tissue and are classified according to size and geometry.¹⁹

TABLE 3 Cell-based Therapies to Treat (osteo)chondral Lesions

Product	Company	Cells	Material	3D Culture Conditions	Procedure	Market Status
CAIS	DePuy Mitek (Raynham, MA, USA)	Autologous chondrocytes	Minced autologous cartilage product	–	–	Withdrawn
CaReS	Arthrokinetics (Esslingen, Germany)	Autologous chondrocytes	Collagen I scaffold	10-13 d in autologous serum	Autologous chondrocyte implantation (third generation)	Withdrawn
Carticel	Genzyme Biosurgery (Cambridge, MA, USA)	Autologous chondrocytes	–	–	Autologous chondrocyte implantation (first generation)	Withdrawn
Cartiform	Arthrex (Naples, FL, USA)	Allogeneic chondrocytes	Osteochondral allograft	–	–	[check mark]
CartiLife	Biosolution (Seoul, South Korea)	Autologous chondrocytes	Autologous ECM	–	Autologous chondrocyte implantation (fourth generation)	Phase 2 clinical trials (USA)
CartiMax	MTF Biologics (Edison, NJ, USA)	Allogeneic chondrocytes	Cartilage allograft matrix	–	–	[check mark]
Cartistem	Medipost (Seoul, South Korea)	Allogeneic umbilical cord MSCs	–	–	Subchondral drilling	Phase 2 clinical trials (USA), approved in Korea
ChondroCelect	Tigenix (Haasrode, Belgium)	Autologous chondrocytes	–	–	Autologous chondrocyte implantation (first generation)	Withdrawn
Chondrosphere/Spherox	Co.Don AG (Teltow, Germany)	Autologous chondrocytes (2 × 10⁵ cells/spheroid; 10-70 spheroids/cm²)	Autologous ECM	14 d as cell spheroids	Autologous chondrocyte implantation (fourth generation)	[check mark] (Europe)
DeNovo NT	Zimmer Biomet (Warsaw, IN, USA)	Allogeneic chondrocytes	Minced allogeneic cartilage product	–	–	[check mark]
Hyalograft-C	Anika Therapeutics (Bedford, MA, USA)	Autologous chondrocytes (1 × 10⁶ cells/cm²)	Hyaluronic acid ester scaffold (HYAFF-11S)	14 d	Autologous chondrocyte implantation (third generation)	Withdrawn
MACI	Genzyme Biosurgery (Cambridge, MA, USA)	Autologous chondrocytes (0.5-1.0 × 10⁶ cells/cm²)	Collagen I/III scaffold	3 d in autologous serum	Autologous chondrocyte implantation (third generation)	[check mark]
NeoCart	Histogenics (Waltham, MA, USA)	Autologous chondrocytes	Honeycomb collagen I scaffold	7 d in bioreactor culture (high pressure, oxygen concentration, perfusion), 3D static culture for 2-4 wk	Autologous chondrocyte implantation (fourth generation)	Phase 3 clinical trials (USA)
Novocart	TETEC GmbH (Reutlingen, Germany)	Autologous chondrocytes	–	–	Autologous chondrocyte implantation (first generation)	Withdrawn
Novocart 3D	TETEC GmbH (Reutlingen, Germany)	Autologous chondrocytes (0.5-3.0 × 10⁶ cells/cm²)	Biphasic collagen scaffold with chondroitin sulfate	2 d in autologous serum	Autologous chondrocyte implantation (third generation)	Phase 3 clinical trials (USA)
ProChondrix	Allosource (Centennial, CO, USA)	Allogeneic chondrocytes	Osteochondral allograft	–	–	[check mark]
Tissue Gene-C/Invossa	Kolon TissueGene (Rockville, MD, USA)	Allogeneic chondrocytes (18 × 10⁶ cells/3.5 mL, virally transduced to express TGF-β)	–	–	IA injection	Phase 3 clinical trials (USA)
ECM = extracellular matrix, MSC = mesenchymal stem cell

Decision-making algorithms to treat cartilage injury include size of the defect and quality of the surrounding cartilage as well as patient age, lifestyle, and presence of comorbidities such as obesity, joint malalignment, and ligamentous instability. In conjunction with specific patient characteristics, treatment options for cartilage defects are generally categorized according to “small” (<2 to 4 cm²) and “large” (>2 to 4 cm²) lesions¹⁷ (Figure 4). In addition to defect size, interventional algorithms may consider patient age and lifestyle or may require correction of comorbidities.

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