The Biologic Response to Orthopaedic Implants

Stuart B. Goodman, MD, PhD, FRCSC, FACS, FBSE, FICORS

Dr. Goodman or an immediate family member serves as a paid consultant to or is an employee of DePuy, A Johnson & Johnson Company, Integra, Pluristem, and Wishbone Medical; serves as an unpaid consultant to Accelalox and Biomimedica; has stock or stock options held in Accelalox, Arquos, and Biomimedica; and serves as a board member, owner, officer, or committee member of the Association of Residency Coordinators in Orthopaedic Surgery.

INTRODUCTION

Orthopaedic implants are commonly used as internal and external fixation devices for fracture repair, for stabilization/correction of spine fractures and deformities, for joint replacement procedures, and for other reconstructive purposes. Orthopaedic implants are usually made of materials and substances that normally do not reside in the body (eg, metallic, artificial polymeric, and ceramic devices) or are biologically based and manufactured or manipulated (such as hyaluronic acid for injection or musculoskeletal allografts). These materials may be permanent in nature, or biodegradable. This chapter will focus on the biological response to orthopaedic implants that are intended to remain permanently in the body or degrade slowly. Other chapters will review biologically based autograft and allograft implants and related materials.

Permanent orthopaedic biomaterials must demonstrate several fundamental properties to be successful for patient care. First, orthopaedic implants must accomplish their intended clinical function in exemplary fashion, that is to say they must be efficacious. Second, orthopaedic implants must be safe, and not lead to any major or minor local or systemic adverse effects in the majority of patients. Finally, for the benefit of society, these implants must be cost-effective.

A related topic is the concept of biocompatibility. Professor David Williams defines the term as follows: “Biocompatibility refers to the ability of a biomaterial to perform its desired function with respect to a medical therapy, without eliciting any undesirable local or systemic effects in the recipient or beneficiary of that therapy, but generating the most appropriate beneficial cellular or tissue response in that specific situation, and optimizing the clinically relevant performance of that therapy.”¹ These key concepts: safety, efficacy, and biocompatibility of orthopaedic implants must be considered on a backdrop of acute inflammation that accompanies all surgical procedures during which an implant is placed.

ORTHOPAEDIC IMPLANTS AND INFLAMMATION—GENERAL PRINCIPLES

Whenever a surgical procedure is performed (whether an implant is used or not), the inflammatory cascade of events is initiated.²^,³^,⁴ The surgical insult leads to local tissue destruction and the liberation of factors such as the pro-inflammatory cytokines (tumor necrosis factor [TNF], interleukin 1, and others), chemotactic cytokines or chemokines (interleukin-8, macrophage chemotactic protein, macrophage inflammatory protein, and others), nitric oxide and peroxide metabolites, and other substances that initiate local tissue necrosis and the migration of leukocytes both locally and systemically. This acute inflammatory response is universal and is orchestrated by polymorphonuclear leukocytes (PMNs) and macrophages. The local hematoma becomes rich in these inflammatory factors and cells, which continue the inflammatory cascade. Acute inflammation usually resolves to reconstitute relatively
normal tissue architectural and functional integrity; however, if this does not occur, either fibrosis or chronic inflammation follows.³ The latter condition occurs when active inflammation, continued tissue injury, and healing are ongoing simultaneously. Histologically, chronic inflammation is demonstrated by the persistence of inflammatory cells including PMNs, macrophages, foreign-body giant cells, lymphocytes, and plasma cells, in conjunction with continued fibrosis and angiogenesis. This scenario may persist or resolve. Granulomatous inflammation is a unique type of chronic inflammation, in which activated macrophages play a prominent role histologically, assuming a squamous or epithelioid appearance. This may result from microorganisms (some bacteria, parasites, fungi), organic and inorganic particulate material, etc. Granulomatous inflammation may be divided into two types: (1) the foreign body granuloma, which is nonantigen based and therefore nonspecific and contains few lymphocytes, and (2) the immune granuloma, which is antigen based and contains higher numbers of lymphocytes.⁴ These terms are extremely important when one considers the biological response to different materials and their byproducts. For example, sufficient numbers of polyethylene and poly methyl methacrylate (PMMA) particles elicit a foreign body granuloma, whereas in specific patients, byproducts of cobalt-chromium prostheses may induce an immune granuloma, often accompanied by more widespread tissue necrosis.

BIOLOGIC RESPONSE TO IMPLANTS USED IN AND AROUND BONE

BIOLOGIC RESPONSE TO IMPLANTS FOR JOINT REPLACEMENT

Joint replacement, particularly of the hip and knee, and to a lesser degree of the shoulder, elbow, finger joints, ankle, and feet, is a commonly performed surgical procedure worldwide. According to the July 2018 issue of Orthopedic Network News by Mendenhall and Associates, in the United States alone, there were 625,600 hip replacements and 966,900 knee replacements performed in 2017.⁵ These operations are among the most cost-effective surgeries, improving pain, function, and psychosocial well-being. Long-term survivorship of these operations has been over 90% or higher at 15 years of follow-up for good prosthetic designs.⁶^,⁷

The goal of joint replacement is to perform the surgical procedure meticulously in an appropriately selected patient to optimize long-term function and prosthetic fixation. Typically, there are two general methods for fixation of joint replacements to the skeleton. Joint replacements can be fixed to bone with poly methyl methacrylate (PMMA), which functions as a grout; alternatively, stable fixation to the surrounding bone can be accomplished using noncemented technique. When PMMA is used, state-of-the-art techniques are used including careful cleaning and drying of the bone, manipulation and containment of the bone cement to minimize voids and contaminating fluids that can weaken the cement, and delivery techniques to ensure proper filling of cavities and prosthetic positioning. When noncemented methods are chosen, the surrounding bone has to be prepared for an intimate fit with the prosthetic surface. Adjunctive techniques such as increasing the roughness of the prosthetic surface; porous or bioactive coatings; and screws, pegs, and other mechanical methods of fixation are also commonly used.

CEMENTED METAL-ON-POLYETHYLENE IMPLANTS

Sir John Charnley and others have documented the characteristics of the interface between well-fixed cemented implants and bone from postmortem human retrievals.⁸^,⁹^,¹⁰^,¹¹ Charnley reported that the interface displayed cellular damage (loss of the definition of fat and hematopoietic cells) in a 500 µm radius from the cement several weeks after the surgical procedure, due to chemical, thermal, and mechanical trauma. This interface developed into a fibrous or fibrocartilaginous zone containing circular PMMA bead impressions in some areas; elsewhere, PMMA beads directly abutted bony trabecula and cortical bone. In some localized areas, the original necrotic bone subsequently underwent regeneration, with or without an intervening layer of fibrous tissue or fibrocartilage; this layer then underwent metaplasia to mature cancellous or lamellar bone over many months to years. A foreign-body giant cell reaction was rarely seen at the interface of well-fixed cemented femoral hip components. Harris’ group found close bone-cement apposition and little evidence of fibrous tissue at the interface surrounding well-fixed femoral implants up to 17 years postoperatively.¹⁰ Similar to Charnley’s observations, they found that a secondary, circumferential, trabecular “neocortex” formed around the cement; this neocortex communicated with the internally expanded natural cortex via radial spicules of bone. However, Fornasier found evidence of an evolving foreign body response even when the cemented femoral implants at autopsy were not loose.¹¹ The presence of macrophages and foreign-body giant cells in the tissues correlated with the time after surgery, the thickness of the periprosthetic membrane, and the density of polyethylene particles. Cemented acetabular components demonstrated a progressive centripetally developing foreign body reaction to polyethylene and cement wear particles.¹² The linear osteolytic areas continued to grow with the generation of increasing amounts of wear particles and even ballooned into the bony supporting foundation until the prosthesis became mechanically loose.

NONCEMENTED METAL-ON-POLYETHYLENE IMPLANTS

When noncemented implants are used, the bone is prepared to achieve stable fixation to minimize micromotion and facilitate bone ongrowth or ingrowth without an intermediary grouting material (Figure 1). This goal is achieved by proper sizing of the implant and “machining” the bone for an intimate fit with
the prosthesis. Surface roughening, porous coating, and bioactive coating of the implant surface (eg, with hydroxyapatite) are adjunctive methods to achieve this goal. The aim is to induce prosthetic osseointegration, a stable physical and biofunctional incorporation of the implant within bone.¹³ Interfacial micromotion beyond approximately 50 µm will lead to fibrous tissue formation, rather than bone. More conventional porous coatings (such as metallic beads and wires) and newer highly porous roughened cancellous-like metallic surfaces (such as porous tantalum or titanium) have demonstrated great success in facilitating osseointegration.¹⁴^,¹⁵^,¹⁶ For porous coatings, a pore size of approximately 100 to 400 µm is optimal.¹⁵

FIGURE 1 AP radiograph of osseointegrated noncemented total hip replacement. A, 6 weeks post noncemented total hip replacement. B, 5 years post total hip replacement. Note the rounding off of the calcar femorale underneath the collar of the femoral implant. The pertrochanteric area is less radiodense than previously. There are also “spot welds” at the termination of the porous coating at the midlevel of the femoral implant.

The biological stages of bone ingrowth into stable porous coated implants parallel those of primary fracture healing. The initial hematoma that forms at the interface after noncemented prosthesis implantation is composed of localized areas of tissue necrosis, pro- and anti-inflammatory factors, and cells that consolidate into an amorphous gel. Mesenchymal stem cells migrate into the hematoma and, in the appropriate stable environment, begin to form immature woven bone via intramembranous ossification over several weeks to months. This bone undergoes remodeling to more mature cancellous and cortical bone over subsequent months to years. However, in an unstable environment with excessive micromotion, a large gap or poor vascularity, fibrous tissue, fibrocartilage, and a synovial lining layer form, and bone ingrowth is minimal. Infection will also produce a chronic inflammatory membranous interface that inhibits bone formation.

Much information concerning the interface between stable noncemented implants and bone can be learned from examining well-functioning implants retrieved at autopsy, rather than from specimens gathered at revision surgery. The latter implants are usually revised because of clinical failure due to chronic dislocation, unexplained pain, excessive wear or implant breakage, etc.¹⁷ Clinically successful noncemented implants that have been retrieved at autopsy minimize these confounding variables.¹⁸^,¹⁹ The amount of bone within pores or adjacent to the metal surface has varied widely.¹⁷^,¹⁸^,¹⁹ The location and orientation of fibrous tissue and bone around porous coated implants is determined by numerous factors including the material and design of the prosthesis, the location and extent of porous coating, the size of the pores, the addition of screws, the intimacy of the fit of the prosthesis with bone, and other variables.¹⁸ Bone ingrowth is greater in titanium alloy stems where the porous coating ends, adjacent to screws, and in locations of compressive load where there is an intimate prosthetic fit.¹⁸ Bone ingrowth is less around smooth as opposed to roughened surfaces, and in areas of localized infection or excessive motion. In such locations, fibrous tissue or an inflammatory membrane forms and may be associated with absorption of the adjacent bone. Unfilled screw holes containing fibrous tissue can provide a conduit for the migration of particles into the underlying cancellous bone. Bone ingrowth/ongrowth provides a more robust interface, preventing polyethylene particle migration compared with smooth implants.²⁰ Hydroxyapatite coatings can facilitate bone ongrowth, and preventing particle migration. However, at least one study reported a higher incidence of loosening when hydroxyapatite coatings are used to facilitate acetabular cup fixation.²¹

Recently, highly porous, corrosion-resistant metallic coatings and devices made out of tantalum, titanium, and other materials have been introduced to mimic the structure of cancellous bone.¹⁶^,²²^,²³ These new materials are manufactured with a higher coefficient of friction, encouraging the adhesion and proliferation of osteoprogenitor cells and other mesenchymal tissues. These materials are particularly useful in the reconstruction of areas of bone deficiency and act as a scaffold for bone formation. Porous metallic implants are often used as a substitute for the use of bulk allografts.

LOOSE METAL-ON-POLYETHYLENE IMPLANTS

Loose cemented implants demonstrate radiolucent lines at the bone-cement and/or cement-prosthesis interface, and the implants often migrate from their original positions (Figure 2). These implants are surrounded by a fibro-inflammatory membrane up to several millimeters in thickness and contain particulate debris (Figures 3 and 4). The cellular components of this chronic inflammatory and foreign body reaction include fibroblasts, macrophages, giant cells, and vascular structures, but only scant numbers of lymphocytes and PMNs (Figure 5). If interfacial motion
occurs, a synovial-like surface layer develops adjacent to the cement.²⁴^,²⁵ Large “cement lakes” in the retrieved tissue contain the remnants of PMMA (when used). Shards of polyethylene particles, which are birefringent under polarized light and stain positively with Oil Red O are seen in the interstitium and within mono- and multinucleated macrophages (Figure 5). These particles are often needle-like and may be up to a 1 mm or longer, but most the particulate debris are in the range of 0.3 to 5 µm in length. There is much heterogeneity throughout different locations of the tissue histologically, varying from highly oriented fibrous tissue to granulomatous inflammation, dependent on the concentration of polyethylene particles. High concentrations of osteoclasts line the membrane where bone resorption occurs; this coincides with the scalloped appearance seen around the cement mantle radiographically. Interestingly, evidence of active new bone formation is a predominant finding in the implant bone bed
histologically.²⁶ Loose noncemented implants display a similar histological finding, except that the fibrous tissue layer is usually thinner and contains macrophages and giant cells with phagocytosed polyethylene particles.

FIGURE 2 AP radiograph of a loose cemented total hip replacement with osteolysis. This failed hip replacement demonstrates loosening with osteolysis (arrows) of the acetabular and femoral components secondary to cement debris.

FIGURE 3 Histologic section of a granulomatous reaction to cement debris. Section from the bone-cement interface of a revised hip replacement demonstrates cement wear particles (larger and small round white cement “ghosts”), surrounded by a nonspecific granulomatous reaction composed of mono- and multinucleated macrophages and fibrous tissue. Hematoxylin and Eosin stain (magnification ×40). (Courtesy of Patricia Campbell, PhD, Los Angeles, CA.)

FIGURE 4 Histologic section from the bone-cement interface of a revised cemented hip arthroplasty. The large white circular cement “ghosts” are seen to the right of the figure, surrounded by fibrous tissue and scattered macrophages. To the left of the figure, macrophages have phagocytosed black metal debris. Hematoxylin and Eosin stain (magnification ×40). (Courtesy of Patricia Campbell, PhD, Los Angeles, CA.)

FIGURE 5 Histologic section showing the biological reaction to polyethylene wear debris. Large white shards of polyethylene are surrounded by macrophages and foreign-body giant cells. Hematoxylin and Eosin stain (magnification ×40). (Courtesy of Patricia Campbell, PhD, Los Angeles, CA.)

OSTEOLYSIS

Particle-associated periprosthetic bone loss is simply designated “osteolysis,” although this term is also used in other contexts when discussing more rapid bone loss associated with aggressive tumors, infections, sustained localized pressure, and other causes. In joint replacement, osteolysis refers to a radiographic phenomenon in which progressive linear, scalloped, or larger areas of bone loss are noted in conjunction with excessive wear debris (Figures 2 and 6). The wear debris and inflammatory fluid from chronic synovitis are pumped around the prosthesis, insinuating into the cancellous bone by waves of high pressure generated during episodic loading of the limb. Thus, the debris can be located at a great distance from where it was generated. Wear particles have been found in the local lymph nodes, in other reticuloendothelial organs such as the liver and spleen.

Osteolysis is a phenomenon in which bone degradation is accelerated and bone formation is depressed by the production of and biological reaction to excessive wear particles. In some cases, an aggressive granulomatous lesion develops; this consists of a rapidly progressive radiographic lucent area containing well-organized connective tissue, sheets of macrophages, and fibrocystic reactive zones in a highly vascularized stroma. Aggressive granulomatosis may be due to “uncoupling of the normal sequence of monocyte-macrophage-mediated clearance of foreign material and tissue debris that is normally followed by fibroblast-mediated synthesis and remodeling of the extracellular matrix.”²⁷

FIGURE 6 AP radiograph of a noncemented hip replacement with osteolysis due to polyethylene wear debris. This well-fixed noncemented total hip replacement demonstrates eccentric positioning of the femoral head in the acetabulum due to polyethylene wear. Note the severe polyethylene particle-associated periprosthetic osteolysis (arrows).

Only gold members can continue reading. Log In or Register to continue