Background

BST-CarGel (BioSyntech Canada, Laval, Quebec, Canada), a new medical device for cartilage repair, was developed to improve outcomes of bone marrow stimulation procedures while preserving the intrinsic low cost and simple arthroscopic approach. With traditional marrow stimulating techniques, clot shrinkage and detachment from lesion surfaces occur. BST-CarGel was designed to stabilize the blood clot in the cartilage lesion by dispersing a soluble and adhesive chitosan scaffold throughout autologous, fresh whole blood. Chitosan, a cationic linear polysaccharide composed predominately of polyglucosamine, is derived from the deacetylation of chitin, the structural component of crustacean shells.^1,2 By dissolving chitosan in an aqueous glycerol phosphate buffer, BST-CarGel is uniquely obtained as a liquid chitosan solution having physiologic pH and osmolarity, intrinsic cytocompatibility, and biodegradability.^2,3 When mixed with blood (BST-CarGel-to-blood ratio of 1:3), the viscous mixture can easily be applied to cartilage lesions that have been prepared by bone marrow stimulation (microfracture, drilling), where it permits normal clot formation while simultaneously reinforcing the clot and impeding clot retraction. Furthermore, the cationic nature of the chitosan increases the adhesivity of the mixture to cartilage lesions, ensuring longer clot residency. This maintenance of critical blood components above the marrow access holes allows activation of the tissue repair process, while chitosan itself brings an intrinsic ability to stimulate wound repair.⁴ Box 14–1 summarizes the primary mode of action for BST-CarGel, an approach that has been termed scaffold-guided regenerative medicine, where BST-CarGel provides in situ chondroinduction for cartilage repair.⁵

Nonclinical Studies

The efficacy and underlying mechanisms of action of BST-CarGel were examined in several animal studies. A skeletally mature (8–15 months) rabbit model that used drilling of surgically prepared bilateral trochlear defects elucidated BST-CarGel early reparative events and compared them with drilled controls.^6,7 Box 14–2 summarizes the key findings of BST-CarGel–mediated cartilage repair.

In another large study in adult (3–6 years) sheep, repair of surgically prepared 1-cm² condylar and trochlear defects was investigated by measuring the quantity and quality of BST-CarGel repair tissue after 6 months compared with microfracture-only defects.⁸ Box 14–3 summarizes the efficacy of BST-CarGel treatment for cartilage repair. Figure 14–1 shows a best case repair from a sheep condylar lesion treated with BST-CarGel. After 6 months of repair, a relatively mature articular cartilage containing superficial, transitional, and radial zones with a reestablished tidemark was observed.

Figure 14–1 Best case cartilage repair of 1-cm² defects in adult sheep treated with BST-CarGel. At 6 months, uniform cartilage resurfacing was observed. Safranin O/fast green–stained section from this block reveals relatively mature articular cartilage containing superficial (SZ), transitional (TZ), and radial (RZ) zones with a reestablished tidemark (TM) above an actively remodeling bone bed.

Overall, the BST-CarGel device has been shown to statistically increase the volume and hyaline character of repair tissue compared to microfractured or microdrilled controls. The chondrogenic foci observed resemble endochondral processes and are believed to be responsible for the synthesis of cartilaginous repair tissue. Notably, the specific mechanisms underlying BST-CarGel–mediated repair (see Boxes 14–2 and 14–3) were independent of species or bone marrow stimulation technique.⁷

Clinical Experience

In 2003 and 2004, 33 human subjects were treated with BST-CarGel under Health Canada’s Special Access Program for medical devices (compassionate use on a case-by-case basis; not considered a clinical trial). Treated patients encompassed the spectrum of both traumatic and degenerative lesions, along with other pathologies. Lesions ranged in size from 0.5 to 12 cm² (mean 4.3 cm²). In 16 cases, opposing tibial lesions (kissing lesions) were debrided and treated with microfracture only. One case of osteochondritis dissecans and one exposed subchondral cyst were treated; two concomitant anterior cruciate ligament replacements were performed. BST-CarGel delivery by arthroscopic (22 patients) as well as mini-open approaches (11 patients) was confirmed (Figure 14–2). Physiotherapy follow-up was standardized and required 6 weeks of non–weight-bearing exercise and early passive range of motion by physiotherapists (i.e., no continuous passive motion). Western Ontario McMaster (WOMAC)⁹ osteoarthritis index questionnaires were administered preoperatively and again postoperatively after 3, 6, and 12 months. WOMAC scores for pain, stiffness, and function improved substantially over preoperative baseline scores, although the absence of a control group and the wide-ranging patient demographics and lesion types prevent overinterpretation of outcomes.⁵

Figure 14–2 A, BST-CarGel open surgical technique includes a mini-arthrotomy to facilitate visualization of the horizontal lesion and delivery of BST-CarGel. Using a syringe, the BST-CarGel/blood mixture is applied in a controlled dropwise manner over all of the bone marrow access holes and then into the entire lesion, taking care not to overfill. B, Arthroscopic delivery of BST-CarGel is performed when the entire lesion can be observed within the arthroscopic field of view. Prior to BST-CarGel application, the joint and lesion are fully suctioned of perfusion liquid and blood to create a “dry field” in the horizontal lesion. The delivery needle is positioned directly perpendicular and central to the lesion, and the BST-CarGel/blood mixture is delivered in dropwise fashion, being sure not to overfill. Both approaches A and B require a 15-minute solidification period, followed by incision closure.

In 2005, BioSyntech initiated a multicenter randomized level 1 clinical trial in Canada and Europe comparing treatment with BST-CarGel to microfracture in the repair of grade 3 or 4 articular cartilage lesions on the femoral condyles in the knee. The study was designed to measure repair tissue structure at 12 months as the primary endpoint through quantitative magnetic resonance imaging (MRI) of repair tissue volume and quality (T2, delayed gadolinium-enhanced magnetic resonance imaging of cartilage [dGEMRIC]) and microscopic analysis of biopsies (when available). The secondary endpoint assessed clinical benefit (Visual Analog Scale [VAS], WOMAC, Medical Outcomes Study 36-Item Short-Form Health Survey [SF-36]) and safety. The trial enrolled 80 patients, and an interim histologic analysis of 22 available biopsies (13 BST-CarGel and 9 microfracture patients) using International Cartilage Repair Society Histological Scoring systems I and II¹⁰ provided statistically significant evidence that BST-CarGel improved the quality and quantity of repair tissue compared to microfracture. The International Cartilage Repair Society (ICRS) II overall score, which assimilates all the parameters listed in the grading system and generates an overall assessment of tissue repair, was significant (P < .05), as were individual parameters of cell morphology, cell viability, and superficial zone morphology on the biopsies. Macroscopic grading of the cartilage repair by the surgeon at the time of biopsy, which included the extent of lesion filling, tissue surface characteristics, and integration with surrounding tissue, also was statistically significant. Full study analysis on all 80 patients after 12-month follow-up will be conducted in the spring of 2010, followed by Canadian and European submissions for device marketing approval. A similar pivotal study will be conducted in the United States for Food and Drug Administration (FDA) approval.

Autologous Chondrocyte Implantation

Autologous Matrix-Induced Chondrogenesis

AMIC as an enhanced microfracture technique combining microfracturing with the collagen I/III matrix Chondro-Gide has become a recognized cartilage repair technique. Studies evaluating the performance of this new treatment option are ongoing.

An initial study by Behrens et al³³ showed that costs were significantly reduced by AMIC compared to ACI, and immediate cartilage repair was possible in a single procedure. Improved tissue repair to ACI has not yet been studied.

Implant Description

The Kensey Nash CRD is a porous biphasic scaffold comprised of type I collagen, β-tricalcium phosphate (β-TCP), and polylactic acid (PLA), three well-known biomaterials with a long history of use in orthopedics. The implant (Figure 14–7) has 100% interconnected porosity that enables movement of cells and biologic fluids throughout the entire implant. The chondral phase of the implant consists of a type I collagen formulation. The collagen provides a malleable, biocompatible scaffold for repair of cartilage tissue that can be contoured to the surrounding joint surfaces. The implant’s subchondral bone phase contains 80% β-TCP and 20% PLA by mass. The ceramic provides an osteoconductive element to the subchondral phase of the CRD implant while supplying a source of calcium and phosphorous ions necessary for natural bone mineralization.^42,43 The PLA scaffold provides biomechanical support and three-dimensional structure for this region and ultimately breaks down into natural body metabolites via the Krebs cycle.^44,45 As a result of Kensey Nash’s proprietary process, the ceramic granules are suspended within, not coated by, the polymer scaffold so that the ceramic is immediately available to the host upon implantation. The implant is available in a range of diameters and is loaded in an insertion tool that facilitates implant hydration and arthroscopic placement.

Figure 14–7 The Kensey Nash cartilage repair device implant is a biphasic plug, designed as a resorbable scaffold for the repair of articular cartilage and subchondral bone. The chondral region is composed of type I collagen (top), with a subchondral bone region of β-tricalcium phosphate suspended within a polylactic acid lattice (bottom). Scanning electron micrograph (magnification ×100).

Preclinical Studies

Kensey Nash conducted a caprine study that evaluated the performance of the CRD in a 6-mm × 6-mm defect on the medial femoral condyle of 38 Nubian Cross goats at 6-, 12-, and 18-month time points (Figure 14–8). Histology, biomechanical testing, immunohistochemistry, MRI, gross evaluations, and radiographs were the evaluation methods used. The study concluded that, by 6 months, CRD-treated defects displayed a rapid repair that was sustained through the 12-month⁴⁶ and 18-month time points. Repair tissue at each time point appeared hyaline, stained positively for type II collagen, and was biomechanically similar to healthy articular cartilage. The repair tissue also displayed excellent integration not only with the host cartilage but with the host bone as well.

Figure 14–8 Caprine stifles treated with cartilage repair device at 12 months. A, Grossly, the defects were well filled with smooth resurfacing. B, Histologically, safranin O staining showed the presence of proteoglycan within the repair tissue. C, Repair tissue also stained strongly positive for type II collagen.

Kensey Nash is also studying the performance of the CRD in healing a 10-mm × 10-mm osteochondral defect on the lateral trochlear ridge of 12 horses (Figure 14–9). The repair of CRD-treated defects will be evaluated over a 2-year study, with interim arthroscopies at 4- and 12-month time points. Interim arthroscopies are scored using a modified ICRS system for safety and efficacy. At time of sacrifice, histology, biomechanical testing, immunohistochemistry, MRI, gross evaluations, and radiographs will be used to evaluate the repair compared to a microfracture control. Four-month interim arthroscopy showed equivalency to microfracture in terms of safety scores and a significant improvement over microfracture in efficacy scoring.⁴⁷

Figure 14–9 Four-month interim arthroscopy images for microfracture control (A) and Kensey Nash cartilage repair device (CRD)–treated defect (B) in equine lateral trochlear ridge. CRD treatment group scored significantly higher than microfracture in terms of efficacy and equivalent to microfracture in terms of safety using a modified International Cartilage Repair Society scoring system.

Together, these studies are being used to support an Investigational Device Exemption application to commence clinical investigation of the CRD in the United States. Kensey Nash is pursuing regulatory approvals for the CRD in both the United States and Europe.

Properties of TRUFIT CB

The TRUFIT CB scaffold (Smith & Nephew, Andover, MA) is a cartilage repair option for small chondral or osteochondral lesions. It comes in preformed cylindrical plugs with diameters ranging from 5 to 11 mm. This synthetic resorbable scaffold has two phases to mimic the critical portions of osteochondral healing. Each phase is designed to initially approximate the physical and mechanical properties of the adjacent cartilage and bone (Figure 14–10). TRUFIT CB is made of Polygraft, a porous material composed of 85:15 poly(d,l-lactide-co-glycolide) copolymer, polyglycolide (PGA) fibers, calcium sulfate, and a trace amount of surfactant. Slivka et al⁴⁸ showed that PGA reinforcement fibers improved the early structural integrity of the scaffold and provided a mechanically stable environment for cell migration and tissue repair. Calcium sulfate in the bone phase releases calcium ions, which are known to enhance osteoconductivity,^49,50 whereas the top phase is malleable to allow contouring with the adjacent articular surface after implantation. At the surgery, the original chondral/osteochondral defect is cored out with TRUKOR instrumentation to create a uniform circular defect. The implant is press fit into the defect site using the preloaded delivery device. Because the TRUFIT CB scaffold is hydrophilic, fluids such as blood and marrow containing nutrients, proteins, and cells can be easily wicked up into the pores. TRUFIT CB then acts as a scaffold for microfracture to hold the blood and marrow cells from subchondral bleeding. Its 70% porosity and interconnected pores promote cell infiltration across the scaffold and provide a mechanically stable environment for tissue repair. TRUFIT CB is currently sold in Europe, Canada, and Australia but is not available in the United States and its territories.

Figure 14–10 A, TRUFIT CB scaffolds. B, TRUFIT CB mimics cartilage, tidemark, and subchondral bone in osteochondral healing.

Preclinical Study Using an Ovine Osteochondral Model

In an ovine study assessing cartilage repair by TRUFIT CB implants in osteochondral defects at 18 months, a unilateral circular (5.1 mm diameter × 5 mm) osteochondral defect was created in the medial femoral condyle of skeletally mature sheep.⁵¹ The defects were repaired by TRUFIT CB (5.3 mm diameter × 5 mm; n = 6) press fit into the site or left empty in the empty defect control group (n = 3). Outcome of cartilage repair was assessed 18 months after surgery. None of the sheep showed any lameness and had regained a full range of motion. The medial condyle of all animals in the TRUFIT CB group had no abnormalities. By 18 months, the material of TRUFIT CB had predominantly resorbed, and the defect sites were filled with repair tissue. Cartilage restoration was evident in all TRUFIT CB specimens. The repaired cartilage was well integrated with the adjacent tissue and had a similar thickness and contour (Figure 14–11). Safranin O staining revealed a highly cellular tissue in the repair by TRUFIT CB with the same intensity of proteoglycan staining as the adjacent hyaline cartilage. The organized collagen patterns of the mid and deeper levels of TRUFIT CB repair were similar to those of normal cartilage (Figure 14–12). In contrast, repair cartilage in the empty defect control was thinner than normal cartilage tissue, and the adjacent cartilage showed signs of degeneration, including proteoglycan loss (see Figure 14–11). The subchondral bone portion of the defect repaired by TRUFIT CB was replaced by bone with a statistically similar bone volume as the untreated contralateral control (66.4% and 63.0%, respectively). Areas of new bone growth with active osteoblasts, increased cellularity, and nonlamellar structure were observed in the repair, indicating that subchondral bone remodeling was ongoing and expected to continue to completely remodel to mature bone over time.

Figure 14–11 Safranin O–stained sections of TRUFIT CB–treated defect and empty osteochondral defect.

Figure 14–12 Polarized light photomicrograph (hematoxylin–eosin stain, magnification ×100) of TRUFIT CB repair tissue at 18 months. The pattern of collagen is organized, similar to that of normal cartilage.

Clinical Case Series

A prospective series by the Spalding group reported the outcome of 24 patients (mean age 34 years, range 19–50 years) with 12- to 36-month follow-up for treatment of chondral or osteochondral lesions in the knee with TRUFIT CB implants.⁵² There were 13 primary procedures and 11 revision procedures (microfracture 7, osteochondral grafting 1, matrix-induced autologous chondrocyte implantation [MACI] 1, and failed fixation osteochondritis dissecans 2). Mean lesion size was 1.8 cm², 14 of which were on the medial femoral condyle, 4 on the lateral femoral condyle, and 6 on the lateral or central trochlea. Up to four implants were used in the repair. After surgery, patients who had undergone repair on the weight-bearing femoral condyle surface were allowed partial weight bearing at 2 weeks and full weight bearing at 4 weeks.

Lysholm score, International Knee Documentation Committee (IKDC) score, and Knee Injury and Osteoarthritis Outcome Score (KOOS) showed statistically significant improvement (P < .001) at 12 months compared to preoperatively (Figure 14–13). Activity levels and hence the mean Tegner activity score (P = .05, see Figure 14–4) improved after 12 months when return to sport was allowed. MRI showed maintenance of the thickness of the new articular surface, gradual differentiation of the implant, and remodeling of the bony component over time (Figure 14–14). Subchondral lamina formation also was evident. Five patients underwent second-look arthroscopy, which showed that although TRUFIT CB stayed soft up to 8 months or more, excellent defect fill and integration with surrounding cartilage were seen. In one patient with slow incorporation of the plugs, patience and perseverance with rehabilitation allowed full resolution of symptoms and return to semiprofessional soccer.⁵³

Figure 14–13 Knee Injury and Osteoarthritis Outcome Score (KOOS) (A), Lysholm score (B), International Knee Documentation Committee score (C), and Tegner activity level score (D). Mean KOOS pain, symptom, activities of daily living, sport, and quality-of-life scores increased 21, 16, 18, 42, and 28 points at 12 months from baseline, respectively (all P < .004)

Figure 14–14 A 37-year-old patient in the series undergoing repair of defect on medial femoral condyle. A, Initial operative view showed delamination. B, Repair with a 9-mm TRUFIT CB implant. C, Second-look arthroscopy at 8 months showed soft area of repair. D, Magnetic resonance imaging (MRI) at 8 months. E, Arthroscopy at 3 years postoperative showed a smooth articular surface. F, MRI showed reformation of the subchondral lamina and well-integrated articular cartilage.

Following the treatment of chondral or osteochondral lesions in the knee with TRUFIT CB, the most active patients in the series returned to semiprofessional sports; the remainder returned to their previous level of activity by 12 months, with no deterioration to date. This series of patients demonstrated outcome comparable to microfracture at 12 months. The improvement of KOOS (see Figure 14–13) was similar to Saris’ report on patients who received microfracture at 12 months (mean KOOS pain, symptom, activities of daily living [ADL], and quality-of-life [QOL] scores increased 13, 11, 12, and 16 points, respectively, from baseline).⁵⁴ TRUFIT CB provides a stable scaffold for early mobilization of the knee postoperatively, avoiding the prolonged period of limited weight bearing in microfracture. Other benefits of TRUFIT CB include its availability as an “off-the-shelf” product, the avoidance of donor site morbidity associated with osteochondral grafting, and the ease of the procedure. The results from this case series indicate that TRUFIT CB provides a one-step solution in managing small (<2-cm diameter) areas of chondral or osteochondral injury, particularly in patients who require rapid rehabilitation and a high level of activity.