Repair of rabbit segmental defects with the thrombin peptide, TP508

Abstract

The synthetic peptide, TP508 (Chrysalin@), was delivered to rabbit segmental bone defects in biodegradable controlled-release PLGA microspheres to determine its potential efficacy for enhancing healing of non-critically and critically sized segmental defects. Non-critically sized radial defects were created in the forelimbs of New Zealand White rabbits, which were randomized into three treatment groups receiving 10, 50 and 100 pg doses of TP508 in the right radius and control microspheres (without TP508) in the left radius. Torsional testing of the radii at six weeks showed a significant increase in ultimate torque, failure torque, ultimate energy, failure energy, and stiffness when treated with TP508 compared to controls (p < 0.01 for all measures). Thus, TP508 appeared to enhance or accelerate bone growth in these defects.In a second set of experiments, critically sized ulnar defects were created in the forelimbs of New Zealand White rabbits, which were randomized into two groups with each rabbit receiving microspheres with 100 or 200 pg of TP508 into the right ulnar defect and control microspheres (without TP508) alone into the left ulnar defect. Bone healing was evaluated with plain radiographs, synchrotron-based microtomography, and mechanical testing. Radiographs of the rabbit limbs scored by three blinded, independent reviewers demonstrated a significantly higher degree of healing when treated with TP508 than their untreated control limbs (p < 0.05). Three-dimensional synchrotron tomography of a limited number of samples showed that the new bone in TP508-treated samples had a less porous surface appearance and open marrow spaces, suggesting progression of bone remodeling. Torsional testing of the ulnae at nine weeks showed a significant increase in maximum torque and failure energy when treated with TP508 compared to controls (p < 0.01 for both measures). These results suggest that TP508 in a controlled release delivery vehicle has the potential to enhance healing of segmental defects in both critically and non-critically sized defects.

Custom-made composite scaffolds for segmental defect repair in long bones

“…Segmental defects still represent a considerable surgical, socioeconomic and research challenge, and greatly influence patients' quality of life [5,6]. Commonly, such defects are treated by transplantation of bone autografts to augment and accelerate bone regeneration [7,8]. The application of autografts, however, is associated with prolonged anaesthetic periods, limited availability, donor site morbidity (persistent pain and haemorrhage), risk of infection and predisposition to failure [9,10].…”

Accelerated Bone Regeneration by Chitosan/Nanometer Hydroxyapatite/Collagen Composite Incorporating BMP-7 Mimetic Peptide

“…Recently, some synthetic peptides with potential to treat bone defects have been reported, including TP508 15) , P-15 16) , 73-92 peptides 17) , B2A2 18) , F2A2-K-NS 19) . TP508 is a thrombin derived peptide with wide specificity that causes angiogenesis, cytokine release, and appears to act through activation of an inflammatory response 15) .…”

“…TP508 is a thrombin derived peptide with wide specificity that causes angiogenesis, cytokine release, and appears to act through activation of an inflammatory response 15) . P-15 is a collagen-derived high-affinity cell-binding peptide, which increases cell attachment and modulates a number of gene products 16) .…”

Materials in particulate form for tissue engineering. 2. Applications in bone

“…Regulates BMP-2 and -7 expression by human osteoblasts. Enhances bone formation (Bi et al, 2001;Wang et al, 2001Wang et al, , 2002Li et al, 2003;Sheller et al, 2004) Indomethacin Found to inhibit osteoclasts and to decrease the resorptive area (Adachi et al, 1991) Corticosteroids (glucocorticoids) Excess generally associated with net bone loss, due to decrease in bone formation and increase in bone resorption (Heersche and Aubin, 1990) Statins Generally used for inhibiting HMG Co-A reductase (rate-limiting step in cholesterol synthesis). (Mundy, 2000) Enhance transcription of BMP-2 in bone cells Oestrogen/testosterone Deficiency results in high turnover of bone remodelling in which the accelerated bone resorption and formation simultaneously occur, but with resorption exceeding formation.…”