Efficacy of Particulate Amniotic Membrane and Umbilical Cord Tissues in Attenuating Cartilage Destruction in an Osteoarthritis Model.

Osteoarthritis (OA) is a progressive degenerative joint disease, and to date, no disease-modifying OA drug exists. Amniotic membrane and umbilical cord products have been used clinically in several diseases due to their anti-inflammatory and antiscarring properties. In the present study, we sought to evaluate whether a particulate amniotic membrane and umbilical cord (AM/UC) matrix could aid in attenuating disease progression. Lewis rats underwent medial meniscus transection (MMT) to induce OA. Two weeks after surgery, animals received intra-articular injections (50 µL) of either 50 or 100 µg/µL particulate AM/UC or saline control and were subsequently euthanized 1 or 4 weeks later. Cartilage degeneration was assessed using both histological scoring methods and equilibrium partitioning of an ionic contrast agent-microcomputed tomography (EPIC-µCT). EPIC-µCT analysis demonstrated that overall cartilage destruction was attenuated, with a significant increase in both cartilage thickness and volume as well as a significant decrease in total lesion area in animals injected with either dose of particulate AM/UC at 1 week, but only a high dose at 4 weeks postinjection. Osteoarthritis Research Society International (OARSI) histology scores of tibial sections corroborated EPIC-µCT results. Overall joint destruction was attenuated in animals injected with either dose of AM/UC tissue compared with saline-injected control animals at 1 week postinjection. Only high-dose AM/UC-injected animals continued to show less overall joint destruction by 4 weeks postinjection. Intra-articular injection of particulate AM/UC tissue attenuates cartilage degradation in a rat MMT model of OA, suggesting that it may be able to slow joint destruction in patients with OA.

Rictor/mTORC2 loss in osteoblasts impairs bone mass and strength.

Mammalian target of rapamycin (mTOR) is a Ser/Thr kinase conserved through evolution that coordinates extra cellular signals associated with cell growth. Main functions of mTOR present in the form of two complexes, namely mTORC1 and mTORC2, which are distinct in their unique components, raptor and rictor. In the current study, using a Cre/loxp system, we found an anabolic effect of mTORC2 signaling on skeleton. Osteoblast differentiation was reduced, with down-regulation of mTORC2 signaling activity in primary cultures of osteoblasts that did not contain rictor. Mice with a specific deletion of rictor in mature osteoblasts showed a significant reduction in lean mass and bone mineral density by dual energy x-ray absorptiometry analysis. Micro-computed tomography, histomorphometric, and molecular biological analyses revealed a marked impairment of the cortical bone mass and microarchitecture, as well as minor changes in trabecular bone, of the Rictorob(-/-) mice. Cortical bone mass and thickness of the femoral mid-shaft were dramatically reduced, with unusual increases in porosity and marrow area in Rictorob(-/-) mice. Thinner trabeculae were found in the L4 vertebrae with relatively normal structural indices of trabecular numbers and separation. A lower rate of bone turnover was observed, as the consequence of the decreased individual osteoblast activity and bone resorption. Furthermore, these changes were associated with significantly decreased bone biomechanical properties. In conclusion, expression of rictor in osteoblasts is essential for the maintenance of normal bone remodeling and microarchitecture, especially for the maintenance of the cortical bone.

Roles of contract research organizations in translational medicine.

Transitional medicine/science is shifting the medical research paradigm from compound-based to evidence-based drug/device discovery. It is increasing interdisciplinary collaborations, enhancing usage of advanced technologies, and facilitating therapeutics reaching patients faster. The fundamental theme of evidence-based discovery is to apply what is revealed in preclinical experimentation and to bring the resulting safety and efficacy to clinics. In the medical fields, a contract research organization (CRO) works like a hired agent who has corresponding knowledge and experience to conduct and complete tasks for a sponsor. The relationship is business, and the contract is for deliverables. The increasingly high volume of sponsored outsourcing work has made this for-profit business boom in the past decade. Location boundaries are being blurred under globalization in the sciences and cross-border regulatory reviews. Getting from bench to bedside is a winding road with many obstacles and high hurdles. Efficient teamwork becomes essential to materialize ideas and bring them to the market. The professionals within team communities include drug/device makers and CROs. It has become increasingly obvious that CROs play pivotal roles in the chain of discovery/design, developing product to market through in vitro, in vivo, and ex vivo testing during preclinical experimentations and clinical trials. Project management teams are responsible for nurturing the materialization in a collaborative manner and enhancing the productivity of the pipelines. CROs have many functional aspects and specialties, and no one organization is fully capable of serving, i.e., integrated services, with expertise in each step of the chain to the needs of a variety of sponsors. Instead of competition among the CROs themselves, the continuously expanding market demands can be shared by Expertise-Based Integrated Services among allied CROs, in contrast to the few large CROs. Empirically, the data generated from the chosen CROs should meet the regulatory requirements for approval. A quality assurance unit from the sponsor should be vigilant in performing audits and inspections of the candidate CROs prior to contracting. Subsequently, close monitoring and well-organized project management guard the path to the successful filing of the applications. A strategic alliance of translational medicine with CROs ensures proven therapeutics for disease treatment and prevention to be connected with patient populations in a timely and cost-effective manner. The unbiased data generated through CROs' services can be used for a patient-driven approach in drug discovery and device control design. Thereafter, findings from the merged efforts can promote and complete the feedback loop for refining existing medicines and exploring new medicines. A matchmaking business may emerge and evolve from the procurement department of the inventor in translational medicine and the business development sector of the CROs to generate a new landscape in translational medicine.

Inhibition of cathepsin K increases modeling-based bone formation, and improves cortical dimension and strength in adult ovariectomized monkeys.

Treatment with the cathepsin K (CatK) inhibitor odanacatib (ODN) protects against bone loss and maintains normal biomechanical properties in the spine and hip of ovariectomized (OVX) preclinical models. Here, we characterized the effects of ODN on the dynamics of cortical modeling and remodeling, and dimension and strength of the central femur in adult OVX-rhesus monkeys. Animals were treated with vehicle or ODN (6 or 30 mg/kg, once per day [q.d., p.o.]) in prevention mode for 21 months. Calcein and tetracycline double-labeling were given at 12 and 21 months, and the femoral cross-sections were subjected to dynamic histomorphometric and cement line analyses. ODN treatment significantly increased periosteal and endocortical bone formation (BFR/BS), accompanied with an increase in endocortical mineralizing surface (102%, p < 0.01) with the 6 mg/kg dose. ODN at both doses reduced remodeling hemiosteon numbers by 51% and 66% (p < 0.05), respectively, and ODN 30 mg/kg numerically reduced activation frequency without affecting wall thickness. On the same endocortical surface, ODN increased all modeling-based parameters, while reducing intracortical remodeling, consistent with the observed no treatment effects on cortical porosity. ODN 30 mg/kg markedly increased cortical thickness (CtTh, p < 0.001) and reduced marrow area (p < 0.01). Lastly, ODN treatment increased femoral structural strength (p < 0.001). Peak load was positively correlated with the increases in bone mineral content (BMC) (r(2) = 0.9057, p < 0.0001) and CtTh (r2 = 0.6866, p < 0.0001). Taken together, by reducing cortical remodeling-based and stimulating modeling-based bone formation, ODN significantly improved cortical dimension and strength in OVX monkeys. This novel mechanism of CatK inhibition in stimulating cortical formation suggests that ODN represents a novel therapeutic approach for the treatment of osteoporosis.

Effect of a ß-TCP collagen composite bone substitute on healing of drilled bone voids in the distal femoral condyle of rabbits.

In this study, we tested the performance and biocompatibility of a composite of ß-tricalcium phosphate (ß-TCP) to collagen as a bone void filler (Cerasorb(®) Ortho Foam) in a rabbit distal femoral condyle model. ß-TCP is a completely resorbable synthetic calcium phosphate and the addition of a collagen matrix couples the osteoconductive effects of the two components. Furthermore, the malleable properties of the implant material during surgical applications for shape control will be enhanced. A critical size defect of 6 mm in diameter and 10 mm in depth was drilled into each distal femur of the rabbits. One hole was filled with the test substance and the other was left empty for control. After 1, 3, and 6 months the animals were killed and the degree of bone healing analyzed. In total, 18 animals were investigated. When the ß-TCP composite was used, histological, histomorphometric, and biomechanical evaluations revealed significantly better bone healing in terms of quantity and quality of the newly formed bone. Moreover, no signs of inflammation were observed in the animals and no allergic or foreign body reaction was noted. This suggests high biocompatibility and osteoconductivity of the investigated material to a bone void in an immune responsive species.

Bone adaptation in osteoporosis.

Osteoporosis is a clinical manifestation of fracture from weakened bone tissues. Fracture is the result of incompatibility between biomechanical loading forces and material properties of bone tissues. Bone tissues constantly renew themselves and renovate microstructurally in responding to physiopathological changes. This kind of adaptation evolves as human lifestyles progress to modernization and as medicinal therapeutics advance to individualization. Realization of the bone tissues' adaptation broadens the choices for therapeutic approaches and the utilization of combinational treatments for the sake of not only prolonging life span but also improving life quality.

Comparison of Achilles tendon repair techniques in a sheep model using a cross-linked acellular porcine dermal patch and platelet-rich plasma fibrin matrix for augmentation.

The primary goal of this study was to evaluate a cross-linked acellular porcine dermal patch (APD), as well as platelet-rich plasma fibrin matrix (PRPFM), for repair of acute Achilles tendon rupture in a sheep model. The 2 surgically transected tendon ends were reapproximated in groups 1 and 2, whereas a gap was left between the tendon ends in group 3. APD was used to reinforce the repair in group 2, and autologous PRPFM was used to fill the gap, which was also reinforced with APD, in group 3. All sheep were humanely euthanized at 24 weeks after the repair, and biomechanical and histological testing were performed. Tensile strength testing showed a statistically significant difference in elongation between the operated limb and the unoperated contralateral limb in groups 1 and 3, but not in group 2. All operated tendons appeared healed with no apparent fibrosis under light and polarized microscopy. In group 1, all surgical separation sites were identifiable, and healing occurred via increasing tendon thickness. In group 2, healing occurred with new tendon fibers across the separation, without increasing tendon thickness in 2 out of 6 animals. Group 3 showed complete bridging of the gap, with no change in tendon thickness in 2 out of 6 animals. In groups 2 and 3, peripheral integration of the APD to tendon fibers was observed. These findings support the use of APD, alone or with PRPFM, to augment Achilles tendon repair in a sheep model.

Evaluation of DBM/AM composite as a graft substitute for posterolateral lumbar fusion.

Demineralized bone matrix (DBM) has been investigated as a bone graft substitute for spinal fusion with less morbidity. Various carriers have been added to DBM to enhance its handling characteristics. This study investigates the spinal fusion induced by a composite of DBM and acellular dermal matrix (AM) in comparison with autologous bone in an athymic rat spinal fusion model. Single-level intertransverse process fusions were performed in 60 athymic nude rats grafted with 2 mL/kg of DBM/AM composite, AM alone, or autologous bone. Fusion was assessed at 6 weeks by radiography, manual palpation, and histology. At 6 weeks, 70% of the animals from the DBM/AM composite group exhibited complete spine fusion, whereas 35% from the autologous bone group and 20% from AM group showed bridging with some gaps. The DBM/AM composite induced a significantly higher fusion rate than both the autologous bone and AM groups (p < 0.001) in all measured parameters. The current study demonstrated that using DBM/AM composite can have more robust fusion than autologous bone at 6 weeks in an athymic rat spinal fusion model.

Augmentation of intertransverse process lumbar fusion.

Spinal fusion surgery for alleviation of intractable lower back pain in humans is currently a primary therapeutic technique, with failure rates averaging between 5 to 35%. Implanted and external source-based electrical stimulation devices have been investigated in an attempt to increase osteogenesis at the fusion site in an attempt to reduce spinal fusion failure rates. The purpose of our study was to evaluate the efficacy of two co-processor systems and an additional system with an SIS generation field at 15.8 mA (rms) using biomechanical, dual-energy X-ray absorptiometry (DXA), and histomorphometric analyses, in rabbits following dorsolateral (= posteriolateral [in humans]) spinal fusion. Fifty-six male New Zealand White underwent bilateral lumbar spinal fusion by performing decortication of the transverse processes of lumbar vertebrae four and five with placement of autogenic cancellous bone graft harvested from the ilial wings. Four study groups were designated based on the type of IES device used for stimulation or as a control. Eight weeks after surgery all subjects were sacrificed and the quality and strength of the fusion masses were compared using radiographic, biomechanical, histomorphometry, and qualitative histological evaluation. While some variation existed within and between groups, Group 2 showed a significant improvement in all parameters measured as compared to the control group (P < 0.05). The use of adjunct non-invasive surface IES for improving bony fusion rates for patients undergoing lumbar spinal fusion is supported by this study.