Use of Biologics for Degenerative Joint Disease of the Knee

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CHAPTER 6 Use of Biologics for Degenerative Joint Disease of the Knee

William J. Long

Key Points

Current cartilage-based techniques provide improved clinical outcomes when addressing full-thickness cartilage lesions of the knee.

Newer techniques promise further refinements, with less invasive techniques, though only short-term outcome studies exist.

There is no current technique that reproduces the native hyaline surface of the knee joint.

Introduction

Significant advances have been achieved at the two ends of the spectrum in addressing knee pathology: at one end with the arthroscopic management of knee injuries and at the other, with arthroplasty options for end-stage arthritis. The management of articular defects sits at the crossroads between these two settings. The goals of treatment for articular defects are to achieve a stable, durable, hyaline-like scaffold while correcting any instability or alignment disorder that may have contributed to the creation of the lesion. Treatment allows patients to return to their desired level of function, though patient education regarding the repaired knee and some degree of activity modification are almost always helpful.

Classification

Options available for addressing cartilage lesions can be classified as palliative, enhanced intrinsic repair, whole-tissue (allo- or auto-) transplantation, scaffold-based repair, cell-based repair, and combined techniques. The individual strategy selected should take into consideration the specific risks, benefits, and objectives of each technique in a patient-specific manner.

Approximately 60% of knees undergoing surgical arthroscopy for knee pain have articular cartilage changes.¹ Many of these injuries are only partial thickness and are of indeterminate significance in terms of their association with symptoms and their long-term progression to full-thickness chondral defects. Those with full-thickness lesions undergo approximately 400,000 cartilage procedures per year in the United States.² It is these cases that form the basis for the treatment options reviewed in this chapter.

Treatment Options

Palliative: Débridement

Irrigation and débridement is designed to address patient symptoms over the short term. Inflammatory mediators and loose fragments of cartilage are removed by the irrigation process. Débridement of the chondral defect removes any flaps of cartilage that may have been creating a mechanical block or irritation during range of motion. This technique is primarily palliative, and does not provide any basis for cartilage repair or regrowth.

Enhanced Intrinsic Repair: Microfracture

Due to the avascular nature of cartilage beyond the tidemark, there is limited to no regenerative potential. By breaking through this barrier, blood and associated healing and inflammatory mediators are exposed to the lesion. This reparative process, similar to the process of healing an injury in a nonarticular location, proceeds through clot formation, metaplasia, and remodeling. An area of scar or nonhyaline cartilage is produced, providing some cushioning, structural support, and symptomatic relief.

Current microfracture techniques are based on this endogenous potential for regeneration, first proposed by Purdie,³ and first described by Steadman and colleagues.⁴

Indications

Symptomatic full-thickness chondral defects of the knee can be treated with microfracture techniques.

Technique

Appropriate visualization of the lesion must be achieved. Meticulous débridement of any thin overlying fibrous tissue and calcified cartilage exposes a healthy defect bed. A vertical stable shouldered border must be created to shield the healing area. A microfracture awl is then inserted and holes are made beginning in the periphery and moving centrally. Spacing of approximately 3 mm with lesions to a depth of 3 mm should be achieved. Arthroscopic inflow is occluded and holes can be visualized for bony bleeding, indicating an appropriate depth of penetration.

Postoperative Management

Classical training dictates a strict protocol of touch-down weight bearing and continuous passive motion (CPM) for 6 weeks.⁵ Animal models demonstrate an extended healing period up to 12 weeks, thus suggesting a potential benefit to a longer period of restricted load bearing. In contrast, a clinical study by Marder et al. compared this protocol to one of unrestricted weight bearing and no CPM for femoral chondral lesions less than 2 cm². At a mean 4.2-year follow-up (2–9 years) there was no difference in Lysholm and Tegner scores between groups.⁶

Outcomes

At early,⁷ midterm,⁸ and long-term⁹ follow-up, good results have been reported in clinical function and pain relief with microfracture. Good fill grades, low body mass index, younger age, lack of associated meniscal and ligamentous injuries, and shorter duration of preoperative symptoms are predictive of improved outcomes.

Traditional Cell-Based Technique: Autologous Chondrocyte Implantation

Indications

Lesions from 2 to 10 cm² in any area in the knee can be treated with this technique.

Technique

Originally described by Brittberg et al.¹⁰ in 1994, autologous chondrocyte implantation (ACI) is a two-stage technique that requires harvesting, culturing, and implantation of autologous chondrocytes. In the initial stage, surgical arthroscopy is used to assess whether or not the patient is a candidate for ACI; to address any associated meniscal pathology; to template the size, location, and dimensions of the defect; to locate any other cartilage lesions; and to obtain cartilage for culture. Typically the lateral edge of the notch, at the site of an anterior cruciate ligament notchplasty, is a good location for cartilage harvesting. A small curette or gouge can be used to harvest two to three small samples of cartilage, each about 3–5 mm in size. Samples are sent to a central lab. There these autologous cells are cultured to expand the cell count by up to 50 times. Chondrocytes are stored until appropriate time for implantation.

Using information gathered at the time of arthroscopy, an appropriately sized and positioned mini-arthrotomy is planned. The skin incision must be made while considering the need for a well-positioned arthrotomy, the periosteal patch harvest, and any future surgical management. Thus a midline incision is most often used. Following exposure of the lesion, it is débrided to stable borders and down to, but not through, the subchondral plate. The cross-sectional dimensions are measured and traced onto a sterile piece of paper. This is then used to harvest a periosteal flap approximately 2 mm larger than the defect. The outer layer should be marked so that the deep or cambium layer is placed facing the defect.

The periosteal patch is sutured into place with a 6-0 Vicryl stitch. An initial polar stitch in all four quadrants is helpful to appropriately position the graft, followed by interrupted simple sutures at 2- to 3-mm intervals. A small superior 5-mm opening is left to allow insertion of the cultured chondrocytes. The edges of the remainder of the patch are reinforced with fibrin glue, and the watertight nature is tested with saline. Appropriate reinforcements are made. The cultured chondrocytes are then inserted. Final sutures are tied and fibrin glue is applied. The knee is taken through a range of motion to ensure that the patch is stable and watertight.

Postoperative Management

Restricted weight bearing combined with early range of motion and CPM are begun immediately following surgery. Gradual progression of weight bearing and strengthening activities should be individually dictated by the size and location of the lesion. Impact activities are typically restricted for 6–9 months following ACI.

Outcomes

Long-term outcomes demonstrate durable results with ACI at 10–20 years postprocedure.¹¹ At a mean 12.8-year follow-up, 92% of patients were satisfied with results and would have the procedure again. Vasiliadis et al. examined the long-term magnetic resonance imaging appearance of lesions at 9–18 years. Though some degeneration was noted, the quality of the repair tissue was similar to that of surrounding normal cartilage.¹² In a double-blind trial, Knutsen et al. did not note any difference between short-term outcomes with ACI and microfracture, with both techniques demonstrating good results.¹³

Emerging and Developing Technologies

Despite clinical success with current conventional techniques, limitations exist. Inferior biomechanical properties of the reparative tissue,¹⁴ and progressive degeneration of the mixed reparative tissue created,¹⁵ limit success with a microfracture technique. Osteochondral autografts are limited by the availability of transplantable tissue. ACI is costly and time consuming and requires two surgeries, harvesting of a periosteal flap and an open arthrotomy. New technologies are currently in varied stages of development, and will seek to expand the options available for addressing cartilage lesions. These techniques are broadly categorized as cell based, and non–cell based. It is important to note that the Food and Drug Administration (FDA) has yet to approve any of these new techniques. Carticel (Genzyme, Cambridge, MA), approved by the FDA in 1995 for ACI, remains the only approved implant system in this field. As with any novel technology, long-term data do not exist to support their use. A few selected devices and techniques are reviewed.

Modifed ACI Techniques: Matrix-Associated Chondrocyte Implantation (MACI) and Hyalograft

These techniques involve placing the harvested cells in a porcine collagen membrane (MACI; Genzyme, Cambridge, MA) or a scaffold of hyaluronan derivatives (Hyalograft; Fidia Advanced Biopolymers, Abano Terme, Italy). The benefits to these modifications are a more uniform cell distribution; a smaller arthrotomy, as suturing is not required; and no need for periosteal harvest.

Postoperative Management

The rehabilitation protocol is similar to those of the traditional ACI technique. Midterm experience with a more intensive protocol in competitive athletes has demonstrated an earlier return to sport, and improved 5-year follow-up.¹⁶

Outcomes

In an early randomized trial comparing traditional ACI with a periosteal flap to MACI, Zeifang et al. found no difference in efficacy between the two groups.¹⁷ In a 2- to 7-year follow-up with Hyalograft, good results were achieved with isolated lesions. However, less successful outcomes were noted with complex and salvage cases, highlighting the limitations of these techniques.¹⁸

Scaffold-Based Techniques

TruFit Osteobiologic Plugs

TruFit bone graft substitute plugs (Smith and Nephew, Andover, MA) were designed to fill defects created during osteochondral autografting of lesions in the knee. The plugs consist of a synthetic polymer combining polylactide-co-glycolide, polyglycolide fibers, and calcium sulfate. A plug placed in a defect provides a scaffold for marrow elements and surrounding chondrocytes to migrate into. These plugs are not approved by the FDA for the treatment of primary cartilage lesions, though they have been used outside the United States, particularly in Europe, in this manner.

Indications

As noted, the approved indication for this device is to backfill autologous sites, though they have been used elsewhere to address cartilage lesions. This is not an FDA-approved technique.

Technique

When addressing a primary cartilage lesion of the femoral condyle during arthroscopy, the size and location of the lesion are defined (Fig. 6–1). A perpendicular approach must be obtained to seat the plug flush with surrounding cartilage. Tamps of increasing diameter are inserted to determine the appropriate-diameter plug (Fig. 6–2). An obturator is secured in the cutting tube and it is placed into the lesion. The obturator is removed, and the cutting tube is firmly held in place while it is malleted to a depth of 10–12 mm (Fig. 6–3). Care must be taken to ensure that the cutting tube remains perpendicular to the lesion. Failure to do so can damage surrounding cartilage, create a nontubular defect, and break the cutting tube. Hand reaming is performed until the reamer is flush with the cutting tube. The cutting tube is removed and the defect created is examined.

Figure 6–1 A large full-thickness cartilage lesion of the trochlea.

Figure 6–2 An appropriately sized tamp used as a template for sizing of the defect.

Figure 6–3 Final depth of the cutting tube perpendicular to the defect.

Measurements are taken from the base of the lesion to the chondral surface, in four quadrants (Fig. 6–4). A plug is cut to match this depth, attempting to achieve a flush position with surrounding cartilage. The plug is inserted and adjustments can be made with the appropriately sized tamp. Care must also be taken to ensure a perpendicular insertion of the plug, as it can be crushed or fractured if it is not in line with the hole. A similar open technique can be used to address patellar lesions. For larger or oblong-shaped lesions, more than one plug can be used. A narrow bony bridge (2–3 mm) should be maintained between plugs, to prevent collapse (Fig. 6–5).

Figure 6–4 Four-quadrant depth measurement of the defect.

Figure 6–5 Three plugs visible with a tamp completing the impaction of the third plug.

Postoperative Management

Management is modified based on the size and location of the lesion. Following treatment of femoral condylar lesions, patients are allowed to partially bear weight with crutches. A CPM machine is used for 3 weeks, and active range of motion is encouraged on a stationary bike, without resistance. For trochlear and patellar lesions, full weight bearing may be initiated immediately following surgery.

Outcomes

Limited successful early follow-up exists with TruFit plugs ¹⁹ (Fig. 6–6). Some caution must be used, as case reports have noted failure of the plugs to incorporate and giant cell reactions requiring revision surgery.²⁰ A prolonged course of physical therapy and rehabilitation may be necessary when addressing large lesions.²¹

Figure 6–6 Follow-up arthroscopy of a condylar lesion treated with a TruFit plug.

Cartilage Repair Device Plugs

The Cartilage Repair Device (CRD) (Kensey Nash, Exton, PA) is a biphasic scaffold comprised of type I collagen in the chondral region, and β-tricalium phosphate and polylactic acid, with interconnected pores, in the subchondral bone region (Fig. 6–7).

Figure 6–7 A CRD implant (A) with electron micrographs (B and C) demonstrating the biphasic nature of the plugs.

(Courtesy of Kensey Nash Corporation, Exton, PA.)

Indications

These plugs are intended for the treatment of primary full-thickness cartilage lesions of the knee.

Technique

The technique for the CRD is similar to that of the TruFit plugs. Technical modifications include a guide pin for the insertion of the cutting tube, and the application of marrow elements to the plug via a bone marrow aspiration. This provides an initial cell base for repair.

Outcomes

Good clinical results have been obtained in goat and horse models (Fig. 6–8). IDE approval was obtained in the United States in 2010, and clinical studies are underway comparing this CRD to microfracture for full-thickness cartilage lesions.

Figure 6–8 (A) A 12-month follow-up of a goat model with a cartilage plug. (B) Histologic examination with Safranin-O demonstrating proteoglycan. (C) Repair tissue staining strongly for type II collagen.

(Courtesy of Kensey Nash Corporation, Exton, PA.)

Cell-Based Techniques

DeNovo Natural Tissue (NT) Grafting

The DeNovo NT (Zimmer, Warsaw, IN; and ISTO Technologies, St. Louis, MO) graft is derived from juvenile allograft cartilage. Fragments are minced and then placed in suspension (Fig. 6–9). Its use is not subject to FDA approval as it is considered an allograft tissue product similar to osteochondral allografts and ligament allografts used in knee reconstructions.

Figure 6–9 DeNovo NT in suspension.

(Courtesy of Zimmer, Warsaw, IN; and ISTO Technologies, St. Louis, MO.)

Indications

DeNovo NT grafts are indicated for symptomatic full-thickness cartilage defects of the knee.

Technique

Surgical arthroscopy is used to identify the lesion, and to address any associated meniscal pathology. A mini-arthrotomy is then performed, exposing the lesion. Débridement of overlying fibrous and calcified tissue is performed to isolate a healthy bed with a stable shoulder of surrounding cartilage. The surgeon should avoid violating the subchondral bone layer. The defect is irrigated and a thin layer of fibrin glue is applied to stop bleeding. The cross-sectional area of the defect is measured with a ruler. One pack of graft is required per square inch (2.5 cm²) of defect. Simultaneously, the supplied suspension of cartilage fragments is opened and storage fluid is removed with a large angiocatheter. Foil is pressed into the lesion to create a matching mold (Fig. 6–10). This mold is then used to create a fibrin gel suspension of the cartilage fragments. Fragments are evenly spread in the foil defect. A layer of fibrin glue is then carefully applied to fill the defect to three fourths of the depth of the mold (Fig. 6–11). The construct is then left for up to 10 minutes to allow the fibrin to fully set. The defect is once again irrigated and dried. A further thin fresh layer of fibrin glue is then applied to the base of the defect, followed by the DeNovo construct (Fig. 6–12). It should be even to slightly countersunk. Time must be allowed for the fibrin to once again set. The knee is then cycled to ensure that the implant is stable.

Figure 6–10 A foil template in a trochlear defect.

(Coutesy of Zimmer, Warsaw, IN; and ISTO Technologies, St. Louis, MO.)

Figure 6–11 DeNovo NT graft following fibrin glue application.

(Coutesy of Zimmer, Warsaw, IN; and ISTO Technologies, St. Louis, MO.)

Figure 6–12 DeNovo NT graft inserted into the defect.

(Coutesy of Zimmer, Warsaw, IN; and ISTO Technologies, St. Louis, MO.)

DeNovo Engineered Tissue (ET) Grafting

DeNovo ET (Zimmer, Warsaw, IN; and ISTO Technologies, St. Louis, MO) also employs juvenile allograft cartilage. Chondrocytes are isolated from the allograft cartilage and expanded in a cell bank. A hyaline-like cartilage graft is created from these cells by placing them in a matrix that is both chondro-inductive and chondro-conductive (Fig. 6–13).

Figure 6–13 DeNovo ET graft.

(Coutesy of Zimmer, Warsaw, IN; and ISTO Technologies, St. Louis, MO.)

Indications

Indications for DeNovo ET grafts are as noted above for DeNovo NT grafts.

Technique

Outcomes

Preclinical trials demonstrated the ability of DeNovo ET to integrate into host defects, while retaining hyaline cartilage properties.²² Clinical trials with this product and with DeNovo NT are currently underway.

Combined Procedures

Osteochondral transplantation is reviewed in Chapter 7 in this text. A study by Lonner et al. demonstrated good early results with the use of autologous osteochondral allografts to the femoral condyles at the time of patellofemoral arthroplasty.²³ In a similar fashion, the option exists to combine partial knee arthroplasty with one of the cartilage procedures reviewed in this chapter, to address less advanced lesions in the remaining compartments. Long-term outcomes do not exist with these developing techniques.