Spatiotemporally Controlled Release of Etamsylate from Bioinspired Peptide-Functionalized Nanoparticles Arrests Bleeding Rapidly and Improves Clot Stability in a Rabbit Internal Hemorrhage Model.

Achieving rapid clotting and clot stability are important unmet goals of clinical management of noncompressible hemorrhage. This study reports the development of a spatiotemporally controlled release system of an antihemorrhagic drug, etamsylate, in the management of internal hemorrhage. Gly-Arg-Gly-Asp-Ser (GRGDS) peptide-functionalized chitosan nanoparticles, with high affinity to bind with the GPIIa/IIIb receptor of activated platelets, were loaded with the drug etamsylate (etamsylate-loaded GRGDS peptide-functionalized chitosan nanoparticles; EGCSNP). Peptide conjugation was confirmed by LCMS, and the delivery system was characterized by DLS, SEM, XRD, and FTIR. In vitro study exhibited 90% drug release till 48 h fitting into the Weibull model. Plasma recalcification time and prothrombin time tests of GRGDS-functionalized nanoparticles proved that clot formation was 1.5 times faster than nonfunctionalized chitosan nanoparticles. The whole blood clotting time was increased by 2.5 times over clot formed under nonfunctionalized chitosan nanoparticles. Furthermore, the application of rheometric analysis revealed a 1.2 times stiffer clot over chitosan nanoparticles. In an in vivo liver laceration rabbit model, EGCSNP spatially localized at the internal injury site within 5 min of intravenous administration, and no rebleeding was recorded up to 3 h. The animals survived for 3 weeks after the injury, indicating the strong potential of the system for the management of noncompressible hemorrhage.

Biological analysis of an innovative biodegradable antibiotic eluting bioactive glass/gypsum composite bone cement for treating experimental chronic MRSA osteomyelitis.

A multi-barrier antibiotics loaded biodegradable composite bone cement for resolving chronic osteomyelitis has been studied to understand the physico-mechanical properties, drug loading/eluting efficiency, and different merits and demerits prior to clinical application. After successful induction of bone infection in 28 rabbits using methicillin-resistant Staphylococcus aureus (MRSA) strains, calcium sulfate/bioactive glass based composite cement was implanted in 12 defects to assess its performance over parenteral therapy with microscopic and radiological examination for 90 days. The composite cement revealed acceptable physico-mechanical properties and controlled drug elution kinetics. Furthermore, the antibiotics concentrations in bone up to 42 days were sufficient to kill MRSA without eliciting adverse drug reactions. The striking feature of platelets aggregation by composite cement could assist bone healing. The controlled degradation with simultaneous entrapment of composite cement within the osteoid tissues and complete repair of infected cortical defects (holes) in rabbit tibia at 6 weeks indicated the excellent anti-infective and osteoconductive properties of composite cement. Thus, the animal study demonstrated the superiority of composite over injectable antibiotic therapy based on infection resolution and bone regeneration. We thereby conclude that the composite cement can be effectively applied in the treatment of resistant cases of chronic osteomyelitis.

Biological analysis of an innovative biodegradable antibiotic eluting bioactive glass/gypsum composite bone cement for treating experimental chronic MRSA osteomyelitis / 药物分析学报

A multi-barrier antibiotics loaded biodegradable composite bone cement for resolving chronic osteo-myelitis has been studied to understand the physico-mechanical properties,drug loading/eluting effi-ciency,and different merits and demerits prior to clinical application.After successful induction of bone infection in 28 rabbits using methicillin-resistant Staphylococcus aureus(MRSA)strains,calcium sulfate/bioactive glass based composite cement was implanted in 12 defects to assess its performance over parenteral therapy with microscopic and radiological examination for 90 days.The composite cement revealed acceptable physico-mechanical properties and controlled drug elution kinetics.Furthermore,the antibiotics concentrations in bone up to 42 days were sufficient to kill MRSA without eliciting adverse drug reactions.The striking feature of platelets aggregation by composite cement could assist bone healing.The controlled degradation with simultaneous entrapment of composite cement within the osteoid tissues and complete repair of infected cortical defects(holes)in rabbit tibia at 6 weeks indicated the excellent anti-infective and osteoconductive properties of composite cement.Thus,the animal study demonstrated the superiority of composite over injectable antibiotic therapy based on infection reso-lution and bone regeneration.We thereby conclude that the composite cement can be effectively applied in the treatment of resistant cases of chronic osteomyelitis.

Surface characteristics of titanium dental implants with improved microdesigns: An in vivo study of their osseointegration performance in goat mandible.

Current trends in endosseous implant research are focused on the modification of microdesign of implants to achieve early and strong osseointegration. This study compares the influence of zinc doped hydroxyapatite (ZnHAp) coated, hydrothermally treated (HT) and machined Ti6Al4V (control) implants on osseointegration. The surface characterisation and microbial affinity test for implants were performed. Twenty seven (27) cylinders (3 types in each animal) were placed in the mandible of 9 black Bengal goats. Bone-implant interface was examined with histological, radiological parameters and scanning electron microscopy at 6, 12, and 24 weeks post-implantation. Surface roughness alterations of bone-separated implants were analysed by non-contact profilometer with time. The ZnHAp coated implants revealed direct and early bone-implant contact but high bacterial adherence and coating cracks. Low bacterial affinity and early strong bony integration was observed with HT implants. Poor bacterial affinity and delayed but strong fixation was evident with control implants. Based on the results of laboratory and animal experiments, we conclude that the hydrothermal modification of titanium implant is the more suitable way to achieve safe and effective osseointegration than the other two implant types for endosseous application.

Metallic ion doped tri-calcium phosphate ceramics: Effect of dynamic loading on in vivo bone regeneration.

The present study was carried out to evaluate the effect of dynamic loading on bone regeneration performance of different doped ß-tri-calcium phosphate ceramics. We have developed porous beta tri-calcium phosphate (ß-TCP), 5%zinc doped, 5% magnesium doped and 5% titanium doped ß-TCP by aqueous solution combustion technique. All the synthesized ß-TCP powders showed pore size of 21-146 µm (pure ß-TCP), 16-142 µm (Zn-ß-TCP), 28-156 µm (Mg- ß-TCP) and 14-173 µm (Ti-ß-TCP) while their apparent porosity 17.89%, 28.09%, 26.54% and 25.87% respectively. The pure and doped samples were implanted in femoral bone defect model (rabbit) to assess bone regeneration under dynamic loading. Bone regeneration was assessed after 1 and 2 month post-implantation on the basis of clinical radiological, histological, fluorochrome labelling, micro computed tomography (µ-CT) and scanning electron microscopy (SEM). Radiological and fluorochrome labelling study showed reduced size of 5%Ti-ß-TCPimplant vis-à-vis more new bone formation as compared to other groups. Micro-CT of the implanted bone sample showed a significant amount of newly formed bony tissue surrounding the Ti-ß-TCP implant as compared to other samples. Similar findings of less interfacial gap between the implant and bone were also observed in SEM study. However, all the doped materials are suitable as bone grafting material and have potential for application in bone tissue engineering.

Effect of bone morphogenetic protein on Zn-HAp and Zn-HAp/collagen composite: A systematic in vivo study.

Due to good biocompatibility and osteoconductivity, hydroxyapatite (HAp) and its composite with different polymers have been widely investigated for the application in the field of bone tissue engineering. The present study reports the, in vivo performance of zinc doped HAp and HAp/collagen composite (HAC) using bone morphogenetic protein-2. It was done for a span of two months on New Zealand rabbit model. After two months postoperatively, there was no marked inflammatory reaction in experimental groups and control groups. The histological images showed well-formed bony matrix with well differentiated haversian system. From the fluorochrome labeling study, it was observed that higher amount of new bone formed in case of bone morphogenetic protein-2 (BMP-2) loaded Zn-HAp (50%) and HAC (27%) specimens than control. The percentage of new bone formation was significantly higher in case of BMP loaded Zn-HAp group than BMP loaded HAC group. From the SEM images similar trend was observed. As the HAC specimen consists of amorphous phase, it had a negative impact on new bone formation.

Strategies for delivering bone morphogenetic protein for bone healing.

Bone morphogenetic proteins (BMPs) are the most significant growth factors that belong to the Transforming Growth Factor Beta (TGF-ß) super-family. Though more than twenty members of this family have been identified so far in humans, Food and Drug Administration (FDA) approved two growth factors: BMP-2 and BMP-7 for treatments of spinal fusion and long-bone fractures with collagen carriers. Currently BMPs are clinically used in spinal fusion, oral and maxillofacial surgery and also in the repair of long bone defects. The efficiency of BMPs depends a lot on the selection of suitable carriers. At present, different types of carrier materials are used: natural and synthetic polymers, calcium phosphate and ceramic-polymer composite materials. Number of research articles has been published on the minute intricacies of the loading process and release kinetics of BMPs. Despite the significant evidence of its potential for bone healing demonstrated in animal models, future clinical investigations are needed to define dose, scaffold and route of administration. The efficacy and application of BMPs in various levels with a proper carrier and dose is yet to be established. The present article collates various aspects of success and limitation and identifies the prospects and challenges associated with the use of BMPs in orthopaedic surgery.

A novel, multi-barrier, drug eluting calcium sulfate/biphasic calcium phosphate biodegradable composite bone cement for treatment of experimental MRSA osteomyelitis in rabbit model.

This article discloses the development of an effective and versatile technology to prepare a novel antibiotics-loaded biodegradable composite bone cement to treat methicillin-resistant Staphylococcal (MRSA) osteomyelitis and reports its detail in vitro characterization, drug loading efficiency, physico-mechanical properties, drug elution in simulated body fluid (SBF) and human plasma, merits and demerits over poly-methyl methacrylate (PMMA) cement. Chronic osteomyelitis in rabbit tibia (42) was induced by MRSA and composite cement was implanted to evaluate its safety and efficacy over PMMA cement and parenteral treated animals with histopathology, radiographs, bone/plasma drugs concentration, and SEM for 90days. The composite cement showed higher setting time, degradability, pH rise, injectability, in vitro drug elution but lesser mechanical strength than PMMA cement. Antibiotics release from cement beads was faster in SBF than plasma. Further, in vivo antibiotics elution from composite (42days) showed effective concentration against MRSA without eliciting drug-toxicity. Platelets activation by composite was an extraordinary feature. The in vivo studies also proved the superiority of composite cement than other treatment methods in terms of faster infection control and osteosynthesis. Based particularly on drug elution and in vivo results, this newly developed cement can successfully be used in clinical cases of chronic osteomyelitis.

Enhanced bone regeneration with carbon nanotube reinforced hydroxyapatite in animal model.

In order to improve the inherently poor mechanical properties of hydroxyapatite (HAp) and to increase its feasibility as load bearing implant material, in the present investigation, functionalised (HFC1 and HFC2) and non-functionalized (HC1 and HC2) multi-walled carbon nanotubes were used as reinforcing material with HAp. Significant improvement with respect to fracture toughness, flexural strength and impact strength of the composites was noticed. In vitro biological properties of HAp-carbon nanotube (CNT) biocomposites have also favored uniform and systematic apatite growth on their surface. Subsequently, in vivo osseous ingrowth at bone defect of rabbit femur was evaluated and compared using radiology, push out test, fluorochrome labeling, histology and scanning electron microscopy after 2 and 4 months respectively. The results demonstrated growth of web like soft callus from the host bone towards the implant, ensuring strong host bone interaction. Toxicological studies of the liver and kidney cells exhibited no abnormality, thereby confirming non-toxicity of the CNT in the animal body. Host-implant biomechanical strength showed high interfacial strength of the composites, indicating their high potentials to be used for bone remodeling applications.

Clinical Outcome of Hydroxyapatite Coated, Bioactive Glass Coated, and Machined Ti6Al4V Threaded Dental Implant in Human Jaws: A Short-Term Comparative Study.

INTRODUCTION: Growing aspect of endosseous implant research is focused on surface modification of dental implants for the purpose of improving osseointegration. The aim of this study was to evaluate and compare the clinical outcome (ie, osseointegration) of hydroxyapatite coated, bioactive glass coated and machined titanium alloy threaded dental implants in human jaw bone after implantation. MATERIALS AND METHODS: One hundred twenty-six implants (45 hydroxyapatite coated, 41 bioactive glass coated, and 40 machined titanium implants) have been placed in incisor areas of 62 adult patients. Outcome was assessed up to 12 months after prosthetic rehabilitation using different clinical and radiological parameters. Surface roughness of failed implants was analyzed by laser profilometer. DISCUSSION: Hydroxyapatite and bioactive glass coating materials were nontoxic and biocompatible. Least marginal bone loss in radiograph, significantly higher (P < 0.05) interface radiodensity, and less interfacial gaps were observed in computed tomography with bioactive glass coated implants at anterior maxilla compared to other 2 types. CONCLUSION: Bioactive glass coated implants are equally safe and effective as hydroxyapatite coated and machined titanium implants in achieving osseointegration; therefore, can be effectively used as an alternative coating material for dental implants.

Safety and efficacy of additive and subtractive surface modification of Ti6Al4V endosseous implant in goat bone.

Growing interest of endosseous implant research is focused on surface modification to achieve early and strong osseointegration. The present study compared the behaviour of hydroxyapatite coated, zinc doped hydroxyapatite coated and hydrothermally treated titanium (Ti6Al4V) with machined Ti6Al4V implants (control) on osseointegration. The surface characterization and bacterial affinity test for implants were performed. Forty eight (48) cylinders (4 types in each animal) were placed in the humerus bone of 12 black Bengal goats. Bone-implant interface was examined with histological, radiological parameters and scanning electron microscopy on 42nd, 90th, and 180th day post-implantation. Surface roughness alterations of bone-detached implants with time were analyzed by non-contact profilometer. Push-out test (90th day) was performed to assess the strength of bony integration of implants. The coated implants revealed direct and early bone-implant contact but high bacterial affinity and coating resorption/cracks. Low bacterial affinity and strongest osseointegration was observed with hydrothermally treated implants. Poor bacterial affinity and delayed but strong fixation were evident with control implant. Based on the results of laboratory and animal experiments, we conclude that the hydrothermal modification of titanium implant is the more suitable way to achieve safe and effective osseointegration than the other three implant types for endosseous application.