Patrick Orth

Effect of Subchondral Drilling on the Microarchitecture of Subchondral Bone Analysis in a Large Animal Model at 6 Months

Background: Marrow stimulation techniques such as subchondral drilling are clinically important treatment options for symptomatic small cartilage defects. Little is known about whether they induce deleterious changes in the subchondral bone. Hypothesis: Subchondral drilling induces substantial alterations of the microarchitecture of the subchondral bone that persist for a clinically relevant postoperative period in a preclinical large animal model. Study Design: Controlled laboratory study. Methods: Standardized full-thickness chondral defects in the medial femoral condyles of 19 sheep were treated by subchondral drilling. Six months postoperatively, the formation of cysts and intralesional osteophytes was evaluated. A standardized methodology was developed to segment the ovine subchondral unit into reproducible volumes of interest (VOIs). Indices of bone structure were determined by micro–computed tomography (micro-CT). Results: Analysis of the microarchitecture revealed the absence of zonal stratification in the ovine subarticular spongiosa, permitting an unimpeded and simultaneous analysis of the entire subchondral trabecular network. Subchondral drilling led to the formation of subchondral bone cysts (63%) and intralesional osteophytes (26%). Compared with the adjacent unaffected subchondral bone, drilling induced significant alterations in nearly all parameters for the microarchitecture of the subchondral bone plate and the subarticular spongiosa, most importantly in bone volume, bone surface/volume ratio, trabecular thickness, separation, pattern factor, and bone mineral density (BMD) (all P ≤ .01). Conclusion: The data show that the ovine subchondral bone can be reliably evaluated using micro-CT with standardized VOIs. We report that subchondral drilling deteriorates the microarchitecture both of the subchondral bone plate and subarticular spongiosa and decreases BMD. These results suggest that the entire osteochondral unit is altered after drilling for an extended postoperative period. Clinical Relevance: The subchondral bone remains fragile after subchondral drilling for longer durations than previously expected. Further evaluations of structural subchondral bone parameters of patients undergoing marrow stimulation are warranted.

Current perspectives in stem cell research for knee cartilage repair

Protocols based on the delivery of stem cells are currently applied in patients, showing encouraging results for the treatment of articular cartilage lesions (focal defects, osteoarthritis). Yet, restoration of a fully functional cartilage surface (native structural organization and mechanical functions) especially in the knee joint has not been reported to date, showing the need for improved designs of clinical trials. Various sources of progenitor cells are now available, originating from adult tissues but also from embryonic or reprogrammed tissues, most of which have already been evaluated for their chondrogenic potential in culture and for their reparative properties in vivo upon implantation in relevant animal models of cartilage lesions. Nevertheless, particular attention will be needed regarding their safe clinical use and their potential to form a cartilaginous repair tissue of proper quality and functionality in the patient. Possible improvements may reside in the use of biological supplements in accordance with regulations, while some challenges remain in establishing standardized, effective procedures in the clinics.

Small Subchondral Drill Holes Improve Marrow Stimulation of Articular Cartilage Defects

Background: Subchondral drilling is an established marrow stimulation technique. Hypothesis: Osteochondral repair is improved when the subchondral bone is perforated with small drill holes, reflecting the physiological subchondral trabecular distance. Study Design: Controlled laboratory study. Methods: A rectangular full-thickness chondral defect was created in the trochlea of adult sheep (n = 13) and treated with 6 subchondral drillings of either 1.0 mm (reflective of the trabecular distance) or 1.8 mm in diameter. Osteochondral repair was assessed after 6 months in vivo by macroscopic, histological, and immunohistochemical analyses and by micro–computed tomography. Results: The application of 1.0-mm subchondral drill holes led to significantly improved histological matrix staining, cellular morphological characteristics, subchondral bone reconstitution, and average total histological score as well as significantly higher immunoreactivity to type II collagen and reduced immunoreactivity to type I collagen in the repair tissue compared with 1.8-mm drill holes. Analysis of osteoarthritic changes in the cartilage adjacent to the defects revealed no significant differences between treatment groups. Restoration of the microstructure of the subchondral bone plate below the chondral defects was significantly improved after 1.0-mm compared to 1.8-mm drilling, as shown by higher bone volume and reduced thickening of the subchondral bone plate. Likewise, the microarchitecture of the drilled subarticular spongiosa was better restored after 1.0-mm drilling, indicated by significantly higher bone volume and more and thinner trabeculae. Moreover, the bone mineral density of the subchondral bone in 1.0-mm drill holes was similar to the adjacent subchondral bone, whereas it was significantly reduced in 1.8-mm drill holes. No significant correlations existed between cartilage and subchondral bone repair. Conclusion: Small subchondral drill holes that reflect the physiological trabecular distance improve osteochondral repair in a translational model more effectively than larger drill holes. Clinical Relevance: These results have important implications for the use of subchondral drilling for marrow stimulation, as they support the use of small-diameter bone-cutting devices.

Gene Therapy for Cartilage Repair

The concept of using gene transfer strategies for cartilage repair originates from the idea of transferring genes encoding therapeutic factors into the repair tissue, resulting in a temporarily and spatially defined delivery of therapeutic molecules to sites of cartilage damage. This review focuses on the potential benefits of using gene therapy approaches for the repair of articular cartilage and meniscal fibrocartilage, including articular cartilage defects resulting from acute trauma, osteochondritis dissecans, osteonecrosis, and osteoarthritis. Possible applications for meniscal repair comprise meniscal lesions, meniscal sutures, and meniscal transplantation. Recent studies in both small and large animal models have demonstrated the applicability of gene-based approaches for cartilage repair. Chondrogenic pathways were stimulated in the repair tissue and in osteoarthritic cartilage using genes for polypeptide growth factors and transcription factors. Although encouraging data have been generated, a successful translation of gene therapy for cartilage repair will require an ongoing combined effort of orthopedic surgeons and of basic scientists.

Improved repair of chondral and osteochondral defects in the ovine trochlea compared with the medial condyle

Associations between topographic location and articular cartilage repair in preclinical animal models are unknown. Based on clinical investigations, we hypothesized that lesions in the ovine femoral condyle repair better than in the trochlea. Full‐thickness chondral and osteochondral defects were simultaneously established in the weightbearing area of the medial femoral condyle and the lateral trochlear facet in sheep, with chondral defects subjected to subchondral drilling. After 6 months in vivo, cartilage repair and osteoarthritis development was evaluated by macroscopic, histological, immunohistochemical, and biochemical analyses. Macroscopic and histological articular cartilage repair and type‐II collagen immunoreactivity were better in the femoral trochlea, regardless of the defect type. Location‐independently, osteochondral defects induced more osteoarthritic degeneration of the adjacent cartilage than drilled chondral lesions. DNA and proteoglycan contents of chondral defects were higher in the condyle, reflecting physiological topographical differences. The results indicate that topographic location dictates the structural patterns and biochemical composition of the repair tissue in sheep. These findings suggest that repair of cartilage defects at different anatomical sites of the ovine stifle joint needs to be assessed independently and that the sheep trochlea exhibits cartilage repair patterns reflective of the human medial femoral condyle.

Small-Diameter Awls Improve Articular Cartilage Repair After Microfracture Treatment in a Translational Animal Model

Background: Microfracture is the most commonly applied arthroscopic marrow stimulation procedure. Hypothesis: Articular cartilage repair is improved when the subchondral bone is perforated by small-diameter microfracture awls compared with larger awls. Study Design: Controlled laboratory study. Methods: Standardized rectangular (4 × 8 mm) full-thickness chondral defects (N = 24) were created in the medial femoral condyle of 16 adult sheep and debrided down to the subchondral bone plate. Three treatment groups (n = 8 defects each) were tested: 6 microfracture perforations using small-diameter awls (1.0 mm; group 1), large-diameter awls (1.2 mm; group 2), or without perforations (debridement control; group 3). Osteochondral repair was assessed at 6 months in vivo using established macroscopic, histological, immunohistochemical, biochemical, and micro–computed tomography analyses. Results: Compared with control defects, histological cartilage repair was always improved after both microfracture techniques (P < .023). Application of 1.0-mm microfracture awls led to a significantly improved histological overall repair tissue quality (7.02 ± 0.70 vs 9.03 ± 0.69; P = .008) and surface grading (1.05 ± 0.28 vs 2.10 ± 0.19; P = .001) compared with larger awls. The small-diameter awl decreased relative bone volume of the subarticular spongiosa (bone volume/tissue volume ratio: 23.81% ± 3.37% vs 30.58% ± 2.46%; P = .011). Subchondral bone cysts and intralesional osteophytes were frequently observed after either microfracture treatment. Macroscopic grading, DNA, proteoglycan, and type I and type II collagen contents as well as degenerative changes within the adjacent cartilage remained unaffected by the awl diameter. Conclusion: Small-diameter microfracture awls improve articular cartilage repair in the translational sheep model more effectively than do larger awls. Clinical Relevance: These data support the use of small microfracture instruments for the surgical treatment of cartilage defects and warrant prolonged clinical investigations.

A low morbidity surgical approach to the sheep femoral trochlea

BackgroundThe ovine stifle joint is an important location for investigations on the repair of articular cartilage defects in preclinical large animals. The classical medial parapatellar approach to the femoral trochlea is hazardous because of the high risk of postoperative patellar luxation. Here, we describe a low morbidity surgical exposure of the ovine trochlea without the necessity for intraoperative patellar luxation.MethodsBilateral surgical exposure of the femoral trochlea of the sheep stifle joint was performed using the classical medial parapatellar approach with intraoperative lateral patellar luxation and transection of the medial patellar retinaculum in 28 ovine stifle joints. A low morbidity approach was performed bilaterally in 116 joints through a mini-arthrotomy without the need to transect the medial patellar retinaculum or the oblique medial vastus muscle nor surgical patellar luxation. Postoperatively, all 72 animals were monitored to exclude patellar luxations and deep wound infections.ResultsThe novel approach could be performed easily in all joints and safely exposed the distal two-thirds of the medial and lateral trochlear facet. No postoperative patellar luxations were observed compared to a postoperative patellar luxation rate of 25% experienced with the classical medial parapatellar approach and a re-luxation rate of 80% following revision surgery. No signs of lameness, wound infections, or empyema were observed for both approaches.ConclusionsThe mini-arthrotomy presented here yields good exposure of the distal ovine femoral trochlea with a lower postoperative morbidity than the classical medial parapatellar approach. It is therefore suitable to create articular cartilage defects on the femoral trochlea without the risk of postoperative patellar luxation.

Comprehensive analysis of translational osteochondral repair: Focus on the histological assessment.

Articular cartilage guarantees for an optimal functioning of diarthrodial joints by providing a gliding surface for smooth articulation, weight distribution, and shock absorbing while the subchondral bone plays a crucial role in its biomechanical and nutritive support. Both tissues together form the osteochondral unit. The structural assessment of the osteochondral unit is now considered the key standard procedure for evaluating articular cartilage repair in translational animal models. The aim of this review is to give a detailed overview of the different methods for a comprehensive evaluation of osteochondral repair. The main focus is on the histological assessment as the gold standard, together with immunohistochemistry, and polarized light microscopy. Additionally, standards of macroscopic, non-destructive imaging such as high resolution MRI and micro-CT, biochemical, and molecular biological evaluations are addressed. Potential pitfalls of analysis are outlined. A second focus is to suggest recommendations for osteochondral evaluation.

Bone Marrow Aspirate Concentrate-Enhanced Marrow Stimulation of Chondral Defects

Mesenchymal stem cells (MSCs) from bone marrow play a critical role in osteochondral repair. A bone marrow clot forms within the cartilage defect either as a result of marrow stimulation or during the course of the spontaneous repair of osteochondral defects. Mobilized pluripotent MSCs from the subchondral bone migrate into the defect filled with the clot, differentiate into chondrocytes and osteoblasts, and form a repair tissue over time. The additional application of a bone marrow aspirate (BMA) to the procedure of marrow stimulation is thought to enhance cartilage repair as it may provide both an additional cell population capable of chondrogenesis and a source of growth factors stimulating cartilage repair. Moreover, the BMA clot provides a three-dimensional environment, possibly further supporting chondrogenesis and protecting the subchondral bone from structural alterations. The purpose of this review is to bridge the gap in our understanding between the basic science knowledge on MSCs and BMA and the clinical and technical aspects of marrow stimulation-based cartilage repair by examining available data on the role and mechanisms of MSCs and BMA in osteochondral repair. Implications of findings from both translational and clinical studies using BMA concentrate-enhanced marrow stimulation are discussed.

Basic science of osteoarthritis.

Osteoarthritis (OA) is a prevalent, disabling disorder of the joints that affects a large population worldwide and for which there is no definitive cure. This review provides critical insights into the basic knowledge on OA that may lead to innovative end efficient new therapeutic regimens. While degradation of the articular cartilage is the hallmark of OA, with altered interactions between chondrocytes and compounds of the extracellular matrix, the subchondral bone has been also described as a key component of the disease, involving specific pathomechanisms controlling its initiation and progression. The identification of such events (and thus of possible targets for therapy) has been made possible by the availability of a number of animal models that aim at reproducing the human pathology, in particular large models of high tibial osteotomy (HTO). From a therapeutic point of view, mesenchymal stem cells (MSCs) represent a promising option for the treatment of OA and may be used concomitantly with functional substitutes integrating scaffolds and drugs/growth factors in tissue engineering setups. Altogether, these advances in the fundamental and experimental knowledge on OA may allow for the generation of improved, adapted therapeutic regimens to treat human OA.