Early patellofemoral cartilage and bone pathology in a rat model of noninvasive anterior cruciate ligament rupture.

OBJECTIVE: Anterior cruciate ligament rupture (ACLR) is a risk factor for the development of post-traumatic osteoarthritis (PTOA). While PTOA in the tibiofemoral joint compartment is well-characterized, very little is known about pathology in the patellofemoral compartment after ACL injury. Here, we evaluated the extent to which ACLR induces early patellofemoral joint damage in a rat model. METHODS: Adult female Lewis rats were randomized to noninvasive ACLR or Sham. Two weeks post-injury, contrast-enhanced micro-computed tomography (µCT) of femoral and patellar cartilage was performed using 20% v/v ioxaglate. Morphometric parameters of femoral trochlear and patellar cartilage, subchondral bone, and trabecular bone were derived from µCT. Sagittal Safranin-O/Fast-Green-stained histologic sections were graded using the OARSI score in a blinded fashion. RESULTS: Cartilage and bone remodelling consistent with an early PTOA phenotype were observed in both femoral trochleas and patellae. ACLR caused osteophyte formation of the patella and pathology in the superficial zone of articular cartilage, including surface fibrillation, fissures, increased cellularity, and abnormal chondrocyte clustering. There were significant increases in thickness of patellar and trochlear cartilage. Loss of subchondral bone thickness, bone volume fraction, and tissue mineral density, as well as changes to patellar and trochlear trabecular microarchitecture, were indicative of catabolic bone remodelling. Several injury-induced changes, including increased cartilage thickness and trabecular spacing and decreased trabecular number were more severe in the patella compared to the trochlea. CONCLUSION: The patellofemoral joint develops mild but evident pathology in the early period following ACL rupture, extending the utility of this model to the study of patellofemoral PTOA.

Local and Systemic In Vivo Responses to Osseointegrative Titanium Nanotube Surfaces.

Orthopedic implants requiring osseointegration are often surface modified; however, implants may shed these coatings and generate wear debris leading to complications. Titanium nanotubes (TiNT), a new surface treatment, may promote osseointegration. In this study, in vitro (rat marrow-derived bone marrow cell attachment and morphology) and in vivo (rat model of intramedullary fixation) experiments characterized local and systemic responses of two TiNT surface morphologies, aligned and trabecular, via animal and remote organ weight, metal ion, hematologic, and nondecalcified histologic analyses. In vitro experiments showed total adherent cells on trabecular and aligned TiNT surfaces were greater than control at 30 min and 4 h, and cells were smaller in diameter and more eccentric. Control animals gained more weight, on average; however, no animals met the institutional trigger for weight loss. No hematologic parameters (complete blood count with differential) were significantly different for TiNT groups vs. control. Inductively coupled plasma mass spectrometry (ICP-MS) showed greater aluminum levels in the lungs of the trabecular TiNT group than in those of the controls. Histologic analysis demonstrated no inflammatory infiltrate, cytotoxic, or necrotic conditions in proximity of K-wires. There were significantly fewer eosinophils/basophils and neutrophils in the distal region of trabecular TiNT-implanted femora; and, in the midshaft of aligned TiNT-implanted femora, there were significantly fewer foreign body giant/multinucleated cells and neutrophils, indicating a decreased immune response in aligned TiNT-implanted femora compared to controls.

Pharmacological tools to mobilise mesenchymal stromal cells into the blood promote bone formation after surgery.

Therapeutic approaches requiring the intravenous injection of autologous or allogeneic mesenchymal stromal cells (MSCs) are currently being evaluated for treatment of a range of diseases, including orthopaedic injuries. An alternative approach would be to mobilise endogenous MSCs into the blood, thereby reducing costs and obviating regulatory and technical hurdles associated with development of cell therapies. However, pharmacological tools for MSC mobilisation are currently lacking. Here we show that ß3 adrenergic agonists (ß3AR) in combination with a CXCR4 antagonist, AMD3100/Plerixafor, can mobilise MSCs into the blood in mice and rats. Mechanistically we show that reversal of the CXCL12 gradient across the bone marrow endothelium and local generation of endocannabinoids may both play a role in this process. Using a spine fusion model we provide evidence that this pharmacological strategy for MSC mobilisation enhances bone formation.

Titania nanotube morphologies for osseointegration via models of in vitro osseointegrative potential and in vivo intramedullary fixation.

As total joint replacements increase annually, new strategies to attain solid bone-implant fixation are needed to increase implant survivorship. This study evaluated two morphologies of titania nanotubes (TiNT) in in vitro experiments and an in vivo rodent model of intramedullary fixation, to simulate joint arthroplasty conditions. TiNT surfaces were prepared via an electrochemical etching process, resulting in two different TiNT morphologies, an aligned structure with nanotubes in parallel and a trabecular bone-like structure. in vitro data showed bone marrow cell differentiation into osteoblasts as well as osteoblastic phenotypic behavior through 21 days. In vivo, both TiNT morphologies generated greater bone formation and bone-implant contact than control at 12 weeks, as indicated by µCT analyses and histology, respectively. TiNT groups also exhibited greater strength of fixation compared to controls, when subjected to wire pull-out testing. TiNT may be a promising surface modification for promoting osseointegration.

Effect of Bisphosphonate Pretreatment on Fresh Osteochondral Allografts: Analysis of In Vitro Graft Structure and In Vivo Osseous Incorporation.

Fresh allograft transplantation of osteochondral defects restores functional articular cartilage and subchondral bone; however, rapid loss of chondrocyte viability during storage and osteoclast-mediated bone resorption at the graft-host interface after transplantation negatively impact outcomes. The authors present a pilot study evaluating the in vitro and in vivo impact of augmenting storage media with bisphosphonates. Forty cylindrical osteochondral cores were harvested from femoral condyles of human cadaveric specimens and immersed in either standard storage media or storage media supplemented with nitrogenated or non-nitrogenated bisphosphonates. Maintenance of graft structure and chondrocyte viability were assessed at 3 time points. A miniature swine trochlear defect model was used to evaluate the influence of bisphosphonate-augmented storage media on in vivo incorporation of fresh osteochondral tissue, which was quantified via µCT and decalcified histology. In the in vitro study, Safranin-O/Fast Green staining showed that both low- and high-dose nitrogenated-treated grafts retained chondrocyte viability and cartilage matrix for up to 43 days of storage. Allografts stored in nitrogenated-augmented storage media showed both µCT and histologic evidence of enhanced in vivo bony and cartilaginous incorporation in the miniature swine trochlear defect model. Several preclinical studies have shown the potential for enhanced storage of fresh osteochondral allografts via additions of relatively common drugs and biomolecules. This study showed that supplementing standard storage media with nitrogenated bisphosphonates may improve maintenance of chondrocyte viability and graft structure during cold storage as well as enhance in vivo osseous and cartilaginous incorporation of the graft. [Orthopedics: 2018; 41(3):e376-e382.].