Emerging Technologies

BST-CarGel

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. Box 16.2 summarizes the key findings of BST-CarGel–mediated cartilage repair.

Box 16.2

BST-CarGel Stabilized Blood Clots

Mechanisms of Action for Cartilage Repair

• Chitosan clearance via neutrophil phagocytosis after approximately 1 month

• Chemotaxis of marrow stromal cells toward the lesion

• Transient increase in vascularization in subchondral bone

• Greater porosity, remodeling, and vascularization of subchondral bone

• Induction of chondrogenic foci from repair tissue near 1 month

• Increased quality of hyaline cartilage repair arising from subchondral bone

• Improved integration of repair cartilage within the lesion

• All comparisons were made to drilled-only contralateral controls ( n = 49).

In another large study in adult (3–6 years) sheep, repair of surgically prepared 1-cm ² 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. Box 16.3 summarizes the efficacy of BST-CarGel treatment for cartilage repair. Fig. 16.1 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.

Box 16.3

BST-CarGel Stabilized Blood Clots

Six-Month Efficacy in Sheep

• Greater adhesion of CarGel blood clot to bone and cartilage

• Increased volume of repair tissue

• Improved hyaline character of repair tissue

• Increased GAG and collagen content of repair tissue

• Reduced incidence of subchondral cyst formation

• No treatment-specific safety issues

• All comparisons were made to microfracture-only control group. BST-CarGel ( n = 8), microfracture only ( n = 6).

Overall, the BST-CarGel device has been shown statistically to increase the volume and hyaline character of repair tissue compared with 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 16.2 and 16.3 ) were independent of species or bone marrow stimulation technique.

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 cm ² (mean 4.3 cm ² ). 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 ( Fig. 16.2 ). 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) 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.

In 2005, BioSyntech initiated a multicenter randomized level 1 clinical trial in Canada and Europe comparing BST-CarGel treatment with 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 (ICRS) Histological Scoring systems I and II provided statistically significant evidence that BST-CarGel improved the quality and quantity of repair tissue compared with microfracture. The 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, was also statistically significant. Full study analysis on all 80 patients after 12-month follow-up revealed statistically improved quantity and quality of repair tissue in the microfracture with BST-CarGel compared with microfracture treatment alone. Similar findings were observed 5 years postoperative with fewer overall failures in the BST-CarGel + microfracture group. BST-CarGel received regulatory approval in numerous countries, including Australia, Canada, and most European countries.

MaioRegen

Because the intrinsic ability of articular cartilage to self-repair is poor due to the lack of blood support and lymph and nervous systems, the development of effective therapies for articular cartilage and subchondral bone regeneration is an important goal in orthopedic surgery. After achondral damage, the repair tissue shows histologic and mechanical properties lower than the native tissue, which may lead to impaired functionality of the joint itself. Many treatment options have been proposed, but no optimal long-lasting solutions have been achieved, particularly for deep cartilaginous and osteochondral defects.

MaioRegen (Fin-Ceramica Faenza S.p.A., Faenza, Italy) is a novel composite osteochondral monolithic scaffold. It is a multilayered structure that reproduces the chemical gradient naturally found inside the osteocartilaginous compartment. MaioRegen is composed of equine tendon-derived type I collagen on the upper side, which mimics the cartilaginous layer, and a blending of type I collagen and magnesium-enriched nonstoichiometric hydroxyapatite (Mg-HA) on the bottom side, which mimics the subchondral bone ( Fig. 16.3 ). Due to its high similarity with the anatomic osteocartilaginous portion to be replaced, in terms of chemical, biologic, and structural composition, the scaffold is defined as a biomimetic device, able to be recognized as self by the recipient connective tissues. Toxicologic profile, performed in compliance to EN ISO 10993–1 European regulation on class III medical devices, showed high biocompatibility and tolerability.

An in vivo, randomized controlled study has been performed to assess the safety and efficacy of MaioRegen in an osteochondral reconstruction sheep model. An osteochondral lesion was induced in the right knee, either on the medial or lateral condyle, of each animal (n = 8). Animals were then randomly assigned to three treatment groups. The objective of the study was to demonstrate a substantial equivalence (in terms of effectiveness) between the acellular approach using MaioRegen alone (group A) and chondrocytes cultured on the scaffold (cell-engineered scaffold, group B). Comparisons were made with an untreated control group (group C). No adverse events were observed in all groups, and the device was completely tolerable and fully biocompatible. At 6 months postoperative, animals were euthanized, and macroscopic and histologic investigations showed complete absorption of MaioRegen. The newly formed tissues in the treated groups were well integrated, whereas a gap on the defect was still noticeable in the control group. Applying a Fortier score (0–15), no statistical differences in average score values were seen between scaffold alone (2.63 ± 0.71) and cell-engineered scaffold (4.00 ± 0.53), whereas both groups exhibited statistical difference ( P <.05) versus the control group (12.88 ± 0.95). Histologic evaluation showed newly formed tissue that was well organized and characterized by chondrocytes with tangential orientation in the upper part. In the two treated groups, tissues were differentiated at either the chondral or subchondral bone level, whereas fibrous tissue was evident in the control group ( Fig. 16.4 ).

The hypothesis of a scaffold-guided tissue regeneration process is that mesenchymal and progenitor cells from subchondral bone marrow blood after surgical curettage are able to migrate inside and wholly colonize the scaffold, then differentiate along either a chondrogenic or osteogenic lineage based on the peculiar physical–chemical gradient composition found. Therefore, MaioRegen itself promoted osteoblast differentiation and bone regeneration in the deepest portions while restoring the tidemark in the intermediate portion and hyaline cartilage formation in the upper surface (chondrogenic differentiation). After the preclinical and toxicologic studies, a pilot, uncontrolled, prospective clinical trial of 30 patients has been designed and approved by an institutional review board to investigate the performance and safety of MaioRegen. Inclusion criteria for study admission were patients ranging in age from 15 to 60 years who were affected by traumatic, posttraumatic, or degenerative osteochondral defects of the knee (grade III and IV Outerbridge classification) sizing 1–9 cm ² . After arthrotomy, a curettage of the defect was made and scaffold was implanted dry by simple press fit, without fixation with suture or surgical glue ( Fig. 16.5 ). Early stability of MaioRegen assessed 30 days postoperative by MRI revealed neither migration from the implant site nor delamination. With regard to the safety outcome, patients were monitored for the onset of any adverse events. Most of the episodes reported were considered related to surgery and not to the device itself and most occurred within the immediate postoperative period. In addition, clinical assessment by MRI performed 6 and 12 months postoperative evaluated the quality of regenerated osteochondral tissue and integration with recipient tissues applying the MRI MOCART Scoring System. Functional joint recovery, improvement of the patient’s quality of life, and return to normal sport activity were further evaluated by applying ICRS evaluation package questionnaires and Kujala and Tegner scores. Results of statistical data analysis highlighted positive results for each observed variable with respect to both surgeon and patient evaluations at each follow-up visit. Modifications of the result for each examined variable, comparing 6- and 12-month postsurgery scores to the preoperative score, were statistically significant ( P <.05). Upon study planning, the modification of study variables between preoperation and postoperation was identified as a success index. Because modifications in the study were reported as positive (i.e., sustained by statistical relevance), they were considered indexes of study success. Moreover, all of the parameters evaluated improved significantly after 12 months compared with 6 months, confirming good progression and enhancement of quality of life.

The preliminary results of the clinical trial at intermediate follow-up appear promising. MaioRegen may be considered a potential innovative surgical treatment of severe osteochondral lesions; however, longer follow-up would be essential to validate fully this one-step acellular approach.

Chondro-Gide

Chondro-Gide (Geistlich Pharma AG, Wolhusen, Switzerland) is a CE-marked product for covering articular cartilage defects that are treated with either ACI or bone marrow stimulation techniques (autologous matrix-induced chondrogenesis [AMIC]).

The proprietary manufacturing process of Chondro-Gide involves several steps before the unique bilayer design consisting of a compact side and a porous side is achieved ( Fig. 16.6 ). Standardized processes under clean room conditions and rigorous in-process and end controls guarantee a high-quality natural product. Chondro-Gide consists of porcine type I and III collagen, which is naturally resorbed. Collagenases, gelatinases, and proteinases are responsible for the breakdown of Chondro-Gide into oligopeptides and finally single amino acids.

The compact layer consists of a smooth, cell-occlusive surface that prevents cells, chondrocytes, and mesenchymal stem cells from diffusing into the joint space and protects them from mechanical stress. The porous layer of the matrix consists of loose collagen fibers that support cell invasion and attachment. The arrangement of the fibers provides high tensile strength and resistance to tearing.

Thorough biocompatibility safety testing according to international standards proves that all elements that could cause an undesirable local or systemic response are removed during the manufacturing process and that the immunogenic potential of the matrix is reduced to a minimum.

The Chondro-Gide matrix is available in sizes of 20 × 30 mm, 30 × 40 mm and now up to 60% thicker than the largest size 40 × 50 mm.

Kensey Nash Corporation Cartilage Repair Device

The Kensey Nash Corporation (Exton, PA) cartilage repair device (CRD) has been designed to address many of the concerns regarding current cartilage repair procedures. Significant preclinical research and development has yielded a bioresorbable, acellular, biphasic scaffold for cartilage repair. This technology uses an implant design that contains two phases, each specifically engineered to favor the growth of the histologically distinct tissues of articular cartilage and subchondral bone.