Hydrogel-Based Matrix-Associated Autologous Chondrocyte Implantation Shows Greater Substantial Clinical Benefit at 24 Months Follow-Up than Microfracture: A Propensity Score Matched-Pair Analysis.

OBJECTIVE: To compare substantial clinical benefit (SCB) of a hydrogel-based, matrix-associated autologous chondrocyte implantation (M-ACI) method versus microfracture (MFx) in the treatment of knee cartilage defects. DESIGN: Propensity score matched-pair analysis, using the MFx control group of a phase III study as comparator for M-ACI treatment in a single-arm phase III study, resulting in 144 patients in the matched-pair set. RESULTS: Groups were comparable regarding baseline Knee Injury and Osteoarthritis Outcome Score (KOOS), sex, age, body mass index, symptom duration, smoking status, and previous knee surgeries. Defect sizes in the M-ACI group were significantly larger than in the MFx group (6.4 cm2 vs. 3.7 cm2). Other differences concerned location, number, and etiology of defects that were not considered to influence the interpretation of results. At 24 months, significantly more patients in the M-ACI group achieved SCB in KOOS pain (72.2% vs. 48.6%; P = 0.0108), symptoms (84.7% vs. 61.1%, P = 0.0039), sports/recreation (84.7% vs. 56.9%, P = 0.0008), and quality of life (QoL; 72.2% vs. 44.4%, P = 0.0014). The SCBs for KOOS activities in daily living and International Knee Documentation Committee score were higher for M-ACI but not significantly different from MFx. The SCB rates consistently favored M-ACI from 3 months onward. The highest improvements from baseline at 24 months in patients with SCB were observed for KOOS sports/rec. (M-ACI: 60.8 points, MFx: 55.9 points) and QoL (M-ACI: 58.1, MFx: 57.4). CONCLUSION: Hydrogel-based M-ACI demonstrated superior SCB in KOOS pain, symptoms, sports/rec., and QoL compared with MFx in patients with knee cartilage defects through 2 years follow-up.

Comparison of Hydrogel-Based Autologous Chondrocyte Implantation Versus Microfracture: A Propensity Score Matched-Pair Analysis.

Background: Few studies exist for large defects comparing matrix-associated autologous chondrocyte implantation (M-ACI) with other cartilage repair methods due to the limited availability of suitable comparator treatments. Purpose: To compare the clinical efficacy of a novel hydrogel-based M-ACI method (NOVOCART Inject plus) versus microfracture (MFx) in patients with knee cartilage defects. Study Design: Cohort study; Level of evidence, 3. Methods: Propensity score matched-pair analysis was used to compare the 24-month outcomes between the M-ACI treatment group from a previous single-arm phase 3 study and the MFx control group from another phase 3 study. Patients were matched based on preoperative Knee injury and Osteoarthritis Outcomes Score (KOOS), symptom duration, previous knee surgeries, age, and sex, resulting in 144 patients in the matched-pair set (72 patients per group). The primary endpoint was the change in least-squares means (ΔLSmeans) for the KOOS from baseline to the 24-month assessment. Results: Defect sizes in the M-ACI group were significantly larger than in the MFx group (6.4 versus 3.7 cm2). Other differences included defect location (no patellar or tibial defects in the MFx group), number of defects (33.3% with 2 defects in the M-ACI group versus 9.7% in the MFx group), and defect cause (more patients with degenerative lesions in the M-ACI group). The M-ACI group had higher posttreatment KOOS (M-ACI versus MFX: 81.8 ± 16.8 versus 73.0 ± 20.6 points) and KOOS ΔLSmeans from baseline to 24 months posttreatment (M-ACI versus MFX: 36.9 versus 26.9 points). Treatment contrasts in KOOS ΔLSmeans from baseline indicated statistical significance in favor of M-ACI from 3 to 24 months posttreatment (P = .0026). Significant and clinically meaningful differences in favor of M-ACI at 24 months were also found regarding International Knee Documentation Committee (IKDC) score ΔLSmeans from baseline (37.8 versus 30.4 points; P = .0334), KOOS responder rates at 24 months (≥10-point improvement from baseline; 94.4% versus 65.3%; P < .0001), IKDC responder rates at 24 months (>20.5-point improvement from baseline; 83.3% versus 61.1%, P = .0126) and MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score in a subgroup of patients (LS means, 86.9 versus 69.1; P = .0096). Conclusion: In this exploratory analysis, M-ACI using an in situ crosslinked hydrogel demonstrated superior clinical and structural (MOCART) 24-month outcomes compared with MFx in patients with knee cartilage defects.

Effects of Titanium Implant Surface Topology on Bone Cell Attachment and Proliferation in vitro.

Purpose: Titanium is commonly used for implants because of its corrosion resistance and osseointegration capability. It is well known that surface topology affects the response of bone tissue towards implants. In vivo studies have shown that in weeks or months, bone tissue bonds more efficiently to titanium implants with rough surfaces compared to smooth surfaces. In addition, stimulating early endosseous integration increases the long-term stability of bone-implants and hence their clinical outcome. Here, we evaluated the response of human MG-63 osteoblast-like cells to flat and solid, compared to rough and porous surface topologies in vitro 1-6 days post seeding. We compared the morphology, proliferation, and attachment of cells onto three smooth surfaces: tissue culture (TC) plastic or microscope cover glasses, machined polyether-ether-ketone (PEEK), and machined solid titanium, to cells on a highly porous (average Ra 22.94 µm) plasma-sprayed titanium surface (composite Ti-PEEK spine implants). Methods: We used immuno-fluorescence (IF) and scanning electron microscopy (SEM), as well as Live/Dead and WST-1 cell proliferation assays. Results: SEM analyses confirmed the rough topology of the titanium implant surface, compared to the smooth surface of PEEK, solid titanium, TC plastic and cover glasses. In addition, SEM analyses revealed that MG-63 cells seeded onto smooth surfaces (solid titanium, PEEK) adopted a flat, planar morphology, while cells on the rough titanium surface adopted an elongated morphology with numerous filopodial and lamellipodial extensions interacting with the substrate. Finally, IF analyses of focal adhesions (vinculin, focal adhesion kinase), as well as proliferation assays indicate that MG-63 cells adhere less and proliferate at a slower rate on the rough than on a smooth titanium surface. Conclusion: These observations suggest that bone-forming osteoblasts adhere less strongly and proliferate slower on rough compared to smooth titanium surfaces, likely promoting cell differentiation, which is in agreement with other porous implant materials.

Porous titanium-coated polyetheretherketone implants exhibit an improved bone-implant interface: an in vitro and in vivo biochemical, biomechanical, and histological study.

PURPOSE: Spinal interbody fusion cages are designed to provide immediate stabilization for adjoining vertebrae and ideally enable bony ingrowth to achieve successful integration. For such an implant, cells must be able to attach, move, grow, and differentiate on its surface. These cellular interactions are dependent on how the implant surface enables the coating and binding of blood and tissue fluid proteins that support cell adhesion. The purpose of this study was to evaluate the in vitro and in vivo osteoblast cell-implant surface interactions that result in osseointegration onto a surface composed of plasma-sprayed titanium on a polyetheretherketone (PEEK) substrate or titanium-coated PEEK (Ti-PEEK) (PlasmaporeXP®) as compared to uncoated PEEK implants. MATERIALS AND METHODS: The influence of the Ti-PEEK surface modification on the biochemical, biomechanical, and histological properties at the bone-implant interface is demonstrated both in vitro using simulated bone-forming cell culture experiments and in vivo using a 12- and 24-week ovine implant model. RESULTS: Osteoblast-like cells attached to the Ti-PEEK surface upregulated early bone-forming activity as measured by an increase in transcription and translation of ALP and BMP-2 when compared to cells on PEEK. Similarly, a significant increase in new bone formation, bony apposition, and pullout strength was demonstrated on Ti-PEEK implants when compared to PEEK implants at 12 and 24 weeks in an ovine implant in vivo model. CONCLUSION: The study shows that the Ti-PEEK surface demonstrated enhanced osseointegrative properties compared to PEEK both in vitro and in vivo.

The potential and limitations of a cell-seeded collagen/hyaluronan scaffold to engineer an intervertebral disc-like matrix.

STUDY DESIGN: The use of a cell-seeded biomatrix for tissue engineering of the intervertebral disc. OBJECTIVE: To evaluate the ability of a biomatrix to support the viability of intervertebral disc cells and to accumulate the extracellular matrix that they produce. SUMMARY OF BACKGROUND DATA: Intervertebral disc degeneration is a common occurrence during adult life that has adverse economic consequences on the health care system. Current surgical treatments are aimed at removing or replacing the degenerate tissue, which can alter the biomechanics of the spine and result in degeneration at adjacent disc levels. The ideal treatment of the degenerate disc would involve biologic repair, and tissue-engineering techniques offer a means to achieve this goal. METHODS: Scaffolds of type I collagen and hyaluronan were seeded with bovine nucleus pulposus or anulus fibrosus cells and maintained in culture for up to 60 days in the presence of fetal calf serum or a variety of growth factors to try to generate a tissue whose properties could mimic those of the nucleus pulposus with respect to proteoglycan content. RESULTS: During the culture period, various proteoglycans (aggrecan, decorin, biglycan, fibromodulin, and lumican) and collagens (types I and II) accumulated in the scaffold. Proteoglycan accumulation in the scaffold was greatest under conditions in which transforming growth factor-beta1 was present, but under all conditions, more proteoglycan was lost into the culture medium than retained in the scaffold. Both the nucleus and anulus cells behaved in a similar manner with respect to their ability to synthesize matrix macromolecules and have them retained in the scaffold. By day 60 of culture, the proteoglycan content of the scaffolds never exceeded 10% of that present in the mature nucleus pulposus, although this figure could have been considerably increased if most of the proteoglycan being synthesized could have been retained. Furthermore, proteoglycan retention was not uniform within the scaffold, but increased near its periphery. CONCLUSIONS: This work demonstrates that although it is possible to maintain functional disc cells in a biomatrix, it will be necessary to optimize proteoglycan synthesis and retention if any resulting tissue is to be of value in the biologic repair of the degenerate disc. The ability of the anulus cells to replicate the matrix production of the nucleus cells, at least in the collagen/hyaluronan scaffold, suggests that repair may not be limited to the availability of authentic nucleus cells.

Hyaluronate-heparin conjugate gels for the delivery of basic fibroblast growth factor (FGF-2).

The stability and activity of recombinant growth factors administered locally for the repair of damaged tissue can be directly influenced by the physical structure and chemical composition of the delivery matrix. This study describes a novel basic fibroblast growth factor-2 (FGF-2) delivery system synthesized by the conjugation of a structure-stabilizing polymer, hyaluronate (HA), with a sulfated glycosaminoglycan, heparin (HP), that has inherent specific binding sites for members of the FGF family. The biopolymers were formed via stable amine or labile imine bonds by coupling amine-modified HA with oxidized heparin. The addition of recombinant human FGF-2 resulted in the rapid binding of FGF-2 to the heparin segment of the hyaluronate-heparin (HAHP) conjugate. The FGF-2 was released in vitro from the imine-bonded (HAHPi) gels in the form of FGF-2-heparin complexes through the hydrolysis of the imine bonds. In contrast, the release of growth factor from the more stable amine-bonded (HAHPa) gels required treatment with free heparin or enzymatic digestion of the hyaluronate segment. Functional analysis of the released FGF-2 showed that the HAHP conjugate gels increased both the stability and activity of the growth factor.