Particulated Articular Cartilage: CAIS and DeNovo NT


Particulated Articular Cartilage: CAIS and DeNovo NT

Jack Farr, Brian J. Cole, Seth Sherman, and Vasili Karas

Articular cartilage lesions are a common cause of knee symptoms.1,2 The ultimate goal of surgical intervention is to restore the patient′s comfort and function while the secondary goal is to prevent or delay osteo-arthritis.35 As with other tissues, articular cartilage form follows function, and recent studies suggest that improved clinical results correlate with better cartilage restoration constructs.6 Current surgical treatment options for symptomatic cartilage lesions include debridement/lavage, marrow stimulation, osteochondral autograft implantation, fresh osteochondral allograft implantation, and autologous chondrocyte implantation (ACI).712 More recently, minced cartilage autograft (Cartilage Autograft Implantation System [CAIS]; DePuy/Mitek, Raynham, MA) and particulated juvenile cartilage allograft (DeNovo Natural Tissue [NT]; ISTO, St. Louis, MO) options have been reported.3,13

One repair strategy is to use a bioactive component (i.e., cells or growth factors) that drives the biological process and a matrix (biomaterial that serves as a carrier or scaffold) that provides architectural support and facilitates the integration of the repaired tissue with the contiguous tissue.3 Current treatment options have unique advantages and disadvantages. Autograft osteochondral plugs provide a living osteochondral unit but are limited to smaller lesions ranging from 1 to 2.5 cm2.14,15 Marrow stimulation is easy to perform but may also be limited with regard to the extent of durable hyaline-like cartilage formation, lesion size, and long-term sustained clinical gains.15,16 ACI was the first cultured chondrocyte-based therapy, but it has variable long-term benefits when compared with microfracture and is technically tedious. Today, it is indicated for second-line treatment, especially for those patients with larger chondral defects.8,17,18 Similar to ACI, other cultured chondrocyte techniques (e.g., ChondroCelect; DePuy/Mitek, Raynham, MA) have promising mid-term results.6,16 Second- and third-generation cultured chondrocyte techniques culture the chondrocytes on a matrix, which improves the technical aspects, yet the results are similar to first generation and still require two-staged surgical procedures for harvest and implantation. Until recently, allograft treatment options have been limited to osteochondral grafts, as graft incorporation to host tissue was possible only at the bone level. The biologic requirement of transplant bone remodeling/incorporation to host bone at the basilar bone layer remains a challenge, and availability is limited.1,2 In light of these limitations, ongoing research continues to search for cartilage restoration techniques that form durable tissue, are technically easier for the surgeon to perform, and are less disruptive to patients’ lives during the recovery phase.

The concept that cartilage could be transplanted without its underlying bony component and heal would have been considered heretical even a few years ago by most cartilage surgeons. However, the potential safety and efficacy of both CAIS and DeNovo NT are challenging this paradigm. As in many aspects of science, the key to advances is “seeing” what has been there all along. While the phenomenon of hyaline cartilage repair using particulated articular cartilage is relatively new to the English language literature, a thorough literature review reveals a published report by Albrecht et al in the German literature dating back to 1983.19 Their work showed that cartilage autograft implantation without bone can lead to cartilage defect healing if the cartilage is cut into small pieces. Most scientists in the English-speaking world were unaware of this article until recently, after US-based scientists noted the production of new chondrocyte and matrix formation adjacent to minced cartilage fragments. Researchers Lu and Binette began a series of experiments to investigate these findings. What followed was a rapid progression from in vitro experiments to the mouse, goat, and finally the horse model.20,21 All these studies together demonstrated that autograft cartilage, when mechanically minced into cubes of 1 to 2 mm, could affect cartilage repair.19,21 In essence, chondrocytes in the cartilage pieces could “escape” from the extracellular matrix, migrate, multiply, and form a new hyaline-like cartilage tissue matrix that would integrate with the surrounding host tissue. In addition, unlike cultured chondrocytes that take on a spindle-shaped morphology during culture, the chondrocytes from the minced cartilage retained the standard chondrocyte spheroid shape.21

These preclinical data were compelling enough for the Food and Drug Administration (FDA) to approve a proof of concept and safety pilot study of what the sponsor referred to as CAIS.3 The clinical outcomes are now published at 2 years, and an extension follow-up study is complete to 4 years postoperative with publication to follow. Based on a parallel European study, the technique received a CE (Conformité Européenne) mark and is available through a limited release in Europe. In the United States, the FDA has approved a pivotal study of the technique, which began recruiting patients in 2010 and will enroll over 300 patients for a randomized prospective comparison of CAIS to MFX (microfracture) (i.e., CAIS is not available for general use in the United States; use is limited to study patients).

In another laboratory, Yao noted these early preclinical reports and decided to evaluate similar studies using particulated juvenile cartilage allograft (DeNovo NT; distributed by Zimmer, Warsaw, IN) in place of autograft.1,2 This alternative approach was based on two factors: (1) allograft allows conceptually no limit to the amount of harvested tissue and (2) juvenile cartilage has the potential of more robust cellular activity than older cartilage tissue.13,2225 Yao demonstrated that new extracellular matrix can be formed from juvenile cartilage cubes in an explant culture study.1 In addition, he demonstrated that particulated juvenile articular cartilage xenografts healed chondral defects on the trochlea of the horse knee joint.1 Given the momentum from these positive results, the FDA now considers DeNovo NT as a minimally manipulated human tissue allograft, regulated as a 361 HCT/P product similar to fresh osteochondral allograft and bone-tendon-bone allograft. It is available for use in clinical applications without an investigational device exemption (IDE) study and, to date, over 2,200 patients have received this product.2 During this same market release, the sponsor supported a prospective study of 25 patients in a multicenter study with preliminary results reported that complement a case report in the literature.2,26


The indications for CAIS (DePuy/Mitek) and DeNovo NT (ISTO) are evolving. In general, they mirror the selection criteria for other cell-based cartilage procedures. On the basis of limited clinical trials, these products are indicated for treatment of symptomatic articular cartilage defects in patients from age 18 to 55. Prior to treatment, same-day arthroscopic evaluation should confirm a cartilage lesion that is at least International Cartilage Repair Society (ICRS) grade 3 or higher. After peripheral cartilage debridement, lesion size should range from 1 to 5 cm2. As with the treatment of all cartilage defects, careful attention must be paid to meniscal status and to restoring or maintaining knee alignment and stability. Potential contraindications to CAIS (DePuy/Mitek) or DeNovo NT (ISTO) include bipolar lesion > ICRS grade 2, significant underlying subchondral bony edema, or osteochondritis dissecans lesion with > 6 mm subchondral bone loss, as the two last scenarios may require an osteochondral allograft or alternative techniques.

Surgical Technique


Standard arthroscopic portals are established and the lesion(s) are evaluated to confirm size, location, and appropriateness for treatment. If CAIS (DePuy/Mitek) is indicated, hyaline cartilage is then harvested arthroscopically from a low load-bearing surface (i.e., lateral wall of the intercondylar notch or trochlear margin with an amount similar to that harvested for ACI, roughly 200 mg) using a unique device that minces the cartilage into 1- to 2-mm pieces. After harvest, the device (DePuy/Mitek, Raynham, MA) uniformly disperses the minced cartilage onto a biodegradable scaffold. (The CAIS scaffold implant consists of an absorbable copolymer foam of 35% polycaprolactone and 65% polyglycolic acid, reinforced with a polydioxanone [PDO mesh] [Advanced Technologies and Regenerative Medicine, Raynham, MA].) The polymer foam is designed to keep the tissue fragments in place and serves as a three-dimensional scaffold for cartilage matrix generation. The reinforcing PDO mesh enables the foam to have adequate mechanical strength during implant handling. The fragments are then secured to this scaffold using a commercially available fibrin sealant (Tisseel, Baxter, IL). A mini-arthrotomy is performed, and the defect is identified and prepared similar to the technique used for ACI, whereby vertical lesion walls are created and the damaged cartilage is removed to the level of the subchondral bone using a ring curet. If bleeding is noted, hemostasis is achieved using epinephrine-soaked sponges and/or punctuated amounts of fibrin glue. An arthroscopic ruler is used to measure width, length, and depth of the prepared lesion. Subsequently, a template sizes the area of the lesion. Sterile paper or foil is used to make a template of the cartilage defect and used to cut the minced cartilage/scaffold construct to the appropriate size. The trimmed CAIS scaffold (DePuy/Mitek) implant is transferred to the defect with the cartilage fragments facing the subchondral bone and affixed with two or more biodegradable staple anchors (prototype, Advanced Technologies and Regenerative Medicine), which consist of PDO straps and tip (Advanced Technologies and Regenerative Medicine).

DeNovo NT

After confirmatory arthroscopy, a limited medial or lateral arthrotomy is performed to fully visualize the lesion(s) as shown in Fig. 9.1a The defect is outlined with a scalpel to create a shoulder (vertical peripheral wall) of normal or nearly normal host articular cartilage. The cartilage within the outlined area is removed carefully with a curet to the vertical wall of the host cartilage shoulder and the base of the defect ( Fig. 9.1b ). The base is cleared of all cartilage tissue, including the calcified layer, without entering into the subchondral bone. No marrow stimulation procedure is performed. Hemostasis, without a tourniquet, is achieved with epinephrine-soaked cottonoids and fibrin glue. After measuring the defect dimensions and recording the visual findings with photographs, a thin aluminum sterile foil is pressed into the defect to create a three-dimensional mold, as a complete replica of the defect ( Fig. 9.1c ). Once formed, the foil mold is removed from the defect and placed on the back table of the operating room. Using the measured defect dimensions, the defect surface area was calculated. One package of DeNovo NT graft (ISTO) is used for each 2.5-cm2 defect. Larger defects require proportionally more packages of DeNovo NT graft (ISTO).

The DeNovo NT graft (ISTO), in a specially formulated nutrient preservation medium, is shipped in an aseptic temperature- controlled packaging ( Fig. 9.1d ). The medium is aspirated ( Fig. 9.1e ) and the particulated cartilage pieces are transferred to the foil mold and distributed ∼ 1 to 2 mm apart (potentially less separation depending upon the ratio between the implanted tissue volume and the surface area of the defect) ( Fig. 9.1f ). Fibrin glue is then added to the cartilage pieces until the foil mold is filled to within ∼ 1 mm of its full depth ( Fig. 9.1g ). The glue is allowed to cure (typically 3 to 10 minutes). At that point, the fibrin glue/cartilage tissue construct is gently separated and then lifted from the foil in one piece ( Fig. 9.1h ). Fresh fibrin glue is applied at the base of the patient′s cartilage lesion and the fibrin glue/particulated cartilage construct is pressed into the defect and the glue allowed to cure ( Fig. 9.1i ). As an alternative to the Zimmer/ISTO technique, some surgeons are directly applying the particulated cartilage into the defect and gluing it in situ.26 It is imperative that the fibrin glue–cartilage tissue construct is thinner (average 1 mm) than the surrounding cartilage shoulders (average 2 to 3 mm), to minimize the potential for shear or direct compressive load.

Surgical technique for DeNovo NT. (a) The defect is identified, and a curet is used to clear the base of the defect (b). (c) A thin aluminum sterile foil is pressed into the defect to create a three-dimensional mold. The DeNovo NT is shipped in a temperature-controlled package (d). The nutrient-preserving medium (e, f) is aspirated. The cells are then transferred to the foil mold approximately 1 mm apart (g). Fibrin glue is then added and the cells are allowed to cure (g). At this time the construct is lifted in one piece (h). Fibrin glue is added to the base of the defect and the cartilage construct is then placed in the defect and sealed with fibrin glue and allowed to cure for 10 minutes. The cartilage construct is recessed relative to the surrounding cartilage (i). (Reprinted with permission from Farr J, Yao JQ. Chondral defect repair with particulated juvenile cartilage allograft. Cartilage 2011;2(4):346–353.)

Rehabilitation Protocol

In general, the rehabilitation program focuses initially on protection of the cartilage repair process and then progresses toward controlled loading, increased range of motion, and progressive muscle strengthening.3 protocol depending on whether they had a lesion in the patellofemoral compartment or the tibiofemoral compartment. Immediately after surgery, all patients receive a hinged knee brace locked in extension. Patients with a lesion on the femoral condyle are made non–weightbearing for the first 2 weeks and are advanced to partial weight bearing with an unlocked brace from weeks 2 through 6. Patients with a trochlear lesion are allowed to bear weight as tolerated immediately with the brace locked in extension. Regardless of lesion location, the brace is removed each day for continuous passive motion during the first 4 weeks, which is progressively increased (as tolerated) during the subsequent 3 weeks. Muscle strength is maintained using isometric quadriceps sets, straight-leg raises, and isometric contraction of the hamstrings, hip abductors, and hip adductors. When tolerated, patients use a stationary bike without resistance to maintain passive range of motion. Patients return to low-load activity levels at week 6 to 8 and progress in activity as strength and comfort permitted.

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Jun 26, 2020 | Posted by in RHEUMATOLOGY | Comments Off on Particulated Articular Cartilage: CAIS and DeNovo NT
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