Effect of thrombin peptide 508 (TP508) on bone healing during distraction osteogenesis in rabbit tibia

Thrombin-related peptide 508 (TP508) accelerates bone regeneration during distraction osteogenesis (DO). We have examined the effect of TP508 on bone regeneration during DO by immunolocalization of Runx2 protein, a marker of osteoblast differentiation, and of osteopontin (OPN) and bone sialoprotein (BSP), two late markers of the osteoblast lineage. Distraction was performed in tibiae of rabbits over a period of 6 days. TP508 (30 or 300 μg) or vehicle was injected into the distraction gap at the beginning and end of the distraction period. Two weeks after active distraction, tissue samples were harvested and processed for immunohistochemical analysis. We also tested the in vitro effect of TP508 on Runx2 mRNA expression in osteoblast-like (MC3T3-E1) cells by polymerase chain reaction analysis. Runx2 and OPN protein were observed in preosteoblasts, osteoblasts, osteocytes of newly formed bone, blood vessel cells and many fibroblast-like cells of the soft connective tissue. Immunostaining for BSP was more restricted to osteoblasts and osteocytes. Significantly more Runx2- and OPN-expressing cells were seen in the group treated with 300 μg TP508 than in the control group injected with saline or with 30 μg TP508. However, TP508 failed to increase Runx2 mRNA levels significantly in MC3T3-E1 cells after 2–3 days of exposure. Our data suggest that TP508 enhances bone regeneration during DO by increasing the proportion of cells of the osteoblastic lineage. Clinically, TP508 may shorten the healing time during DO; this might be of benefit when bone regeneration is slow

The role of peptides in bone healing and regeneration: A systematic review

Background: Bone tissue engineering and the research surrounding peptides has expanded significantly over the last few decades. Several peptides have been shown to support and stimulate the bone healing response and have been proposed as therapeutic vehicles for clinical use. The aim of this comprehensive review is to present the clinical and experimental studies analysing the potential role of peptides for bone healing and bone regeneration. Methods: A systematic review according to PRISMA guidelines was conducted. Articles presenting peptides capable of exerting an upregulatory effect on osteoprogenitor cells and bone healing were included in the study. Results: Based on the available literature, a significant amount of experimental in vitro and in vivo evidence exists. Several peptides were found to upregulate the bone healing response in experimental models and could act as potential candidates for future clinical applications. However, from the available peptides that reached the level of clinical trials, the presented results are limited. Conclusion: Further research is desirable to shed more light into the processes governing the osteoprogenitor cellular responses. With further advances in the field of biomimetic materials and scaffolds, new treatment modalities for bone repair will emerge

The effect of low-intensity pulsed ultrasound on autologous osteochondral plugs in a canine model

Background: Low-intensity pulsed ultrasound promotes the enchondral portion of fracture healing, which has a direct stimulatory effect on cartilage formation and maturation. Hypothesis: Daily ultrasound treatment positively affects the repair and incorporation of modified autologous osteochondral plugs in a canine model. Study Design: Controlled laboratory study. Methods: In 18 dogs, 2 autologous plugs separated from host cartilage by a 1.5-mm gap were created on the medial femoral condyle in both knees of each dog. One knee was treated daily with a clinically available ultrasound bone stimulator. Animals were sacrificed after 6 and 12 weeks of therapy and the articular surfaces evaluated grossly and histologically. Results: Ultrasound-treated sites had significantly improved gross appearance at 6 weeks and histologic appearance at 6 and 12 weeks. The interface repair tissue of ultrasound-treated sites had a more normal translucent appearance than control sites. Ultrasound treatment improved the cell morphologic characteristics of the interface repair tissue and increased subchondral bone regeneration. Bonding of the interface repair tissue between plug and adjacent cartilage was significantly improved compared with control sites. Conclusion: Low-intensity pulsed ultrasound improved interface cartilage repair of autologous osteochondral plugs compared with controls in a canine model. Clinical Relevance: Improvements in the quality and rate of repair of autologous osteochondral plugs may reduce postoperative recovery time and improve functional outcome

Early Osteogenic Marker Expression in hMSCs Cultured onto Acid Etching-Derived Micro- and Nanotopography 3D-Printed Titanium Surfaces

Polyetheretherketone (PEEK) titanium composite (PTC) is a novel interbody fusion device that combines a PEEK core with titanium alloy (Ti6Al4V) endplates. The present study aimed to investigate the in vitro biological reactivity of human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) to micro- and nanotopographies produced by an acid-etching process on the surface of 3D-printed PTC endplates. Optical profilometer and scanning electron microscopy were used to assess the surface roughness and identify the nano-features of etched or unetched PTC endplates, respectively. The viability, morphology and the expression of specific osteogenic markers were examined after 7 days of culture in the seeded cells. Haralick texture analysis was carried out on the unseeded endplates to correlate surface texture features to the biological data. The acid-etching process modified the surface roughness of the 3D-printed PTC endplates, creating micro- and nano-scale structures that significantly contributed to sustaining the viability of hBM-MSCs and triggering the expression of early osteogenic markers, such as alkaline phosphatase activity and bone-ECM protein production. Finally, the topography of 3D-printed PTC endplates influenced Haralick’s features, which in turn correlated with the expression of two osteogenic markers, osteopontin and osteocalcin. Overall, these data demonstrate that the acid-etching process of PTC endplates created a favourable environment for osteogenic differentiation of hBM-MSCs and may potentially have clinical benefit

The effect of ultrasound on the healing of muscle-pediculated bone graft in scaphoid non-union

The use of pedicled vascularised bone grafts from the distal radius makes it possible to transfer bone with a preserved circulation and viable osteoclasts and osteoblasts. Experiments performed at the basic science level has provided substantial evidence that low-intensity ultrasound can accelerate and augment the fracture healing process. Only an adequate double-blind trial comparing treatment by ultrasound stimulation in patients treated by similar surgical techniques can provide evidence of the true effect of ultrasound. This paper describes the results of such a trial. From 1999 to 2004, 21 fractures of the scaphoid with established non-union treated with vascularised pedicle bone graft were selected for inclusion in a double-blind trial. All patients were males, with an average age of 26.7 years (range 17–42 years) and an average interval between injury and surgery of 38.4 months (range 3 months–10 years). Low-intensity ultrasound was delivered using a TheraMed 101-B bone-growth stimulator (30 mW/cm2, 20 min/day), which was modified to accomplish double-blinding. These modifications did not affect the designated active units. The placebo units were adjusted to give no ultrasound signal output across the transducer. Externally, all units appeared identical but were marked with individual code numbers. Patients were randomly allocated to either an active or placebo stimulation. Follow-up averaged 2.3 years (range 1–4 years). All patients achieved fracture union (active and placebo groups), but compared with the placebo device (11 patients), the active device (ten patients) accelerated healing by 38 days (56±3.2 days compared with 94±4.8 days, p<0.0001, analysis of variance)

Vascular Endothelial Growth Factor: An Essential Component of Angiogenesis and Fracture Healing

Fractures require adequate stability and blood supply to heal. The vascular supply to long bones is compromised in a fracture, and the ability to heal hinges on the ability of new blood vessels to proliferate from surrounding vessels in a process known as angiogenesis. This process is largely driven by the growth factor, vascular endothelial growth factor (VEGF), whose levels are increased locally and systemically during fracture healing. VEGF is involved in many steps throughout the fracture healing cascade, from initially being concentrated in fracture hematoma, to the promotion of bone turnover during the final remodeling phase. This article reviews the current literature surrounding the role of VEGF and other growth factors in reestablishing vascular supply to fractured bone, as well as medications and surgical techniques that may inhibit this process