H. Gautier

Isostatic compression, a new process for incorporating vancomycin into biphasic calcium phosphate: comparison with a classical method.

Isostatic compression has rarely been used to load calcium-phosphate biomaterials with therapeutic agents. This report, concerning four processes associating vancomycin, compares isostatic compression with wet granulation, a classical method. In the wet granulation study, vancomycin was associated with biphasic calcium-phosphate (BCP) granules either by adsorption or incorporation with a new granulation. In the isostatic compression study, BCP powder was compressed at 100, 140 and 200 MPa. The blocks obtained were crushed and 200-500 microm, sieved; thus, the vancomycin solution was absorbed on these granules. Compaction of BCP and vancomycin powders gave, after crushing and sieving, granules loaded with vancomycin. In each study, 5% vancomycin was associated with BCP. Vancomycin release profiles were assessed by an in vitro culture chamber dissolution test. Physicochemical studies of BCP and vancomycin showed their structural integrity after isostatic compression. Isostatic compression prolonged vancomycin release time from 3 to 7 days and the release time became greater as isostatic pressure increased, probably because of the porosity decrease of the granules during compression.

Association of vancomycin and calcium phosphate by dynamic compaction: in vitro characterization and microbiological activity

Dynamic compaction has rarely been used to produce drug-delivery devices in granule form. This report considered four processes associating vancomycin and compared dynamic compaction with wet granulation, a classical method. In the wet granulation study, vancomycin was associated with biphasic calcium-phosphate (BCP) granules either by adsorption or incorporation with a new granulation. In the dynamic compaction study, BCP powder was compacted at 1.1, 1.5 and 1.9 MPa. The compacts obtained were crushed and sieved (200-500 microm), and the vancomycin solution was adsorbed on the resulting granules. After crushing and sieving, the compaction of BCP and vancomycin powders produced vancomycin-loaded granules. In each study, 4.76% of vancomycin was associated with BCP. Granules were characterized in terms of porosity, vancomycin release and vancomycin biological activity. Physicochemical studies of BCP and vancomycin showed their structural integrity after dynamic compaction, which prolonged vancomycin release time from 1 to 6 days. However, a microbiological assay indicated that vancomycin had been altered since only 27.7% was found to be active.

Influence of isostatic compression on the stability of vancomycin loaded with a calcium phosphate-implantable drug delivery device.

It is essential to prevent microbial infections after osteoarticular trauma or prosthesis implantation. As an alternative to antibiotic parenteral administration, antibiotic-loaded biomaterials allow high concentrations to be obtained in situ without systemic toxicity. Although the formulation of biphasic calcium-phosphate (BCP)-vancomycin granules by isostatic compression has recently been used to produce drug-delivery devices, the stability of vancomycin needs to be proven. In this study, vancomycin was associated with BCP powders by isostatic compression at 100, 140, or 200 MPa and then extracted or released by a rotating paddle system for 24 h. Vancomycin assays were performed by spectrophotometric and microbiological methods. The results show that all vancomycin associated with the material was recovered after extraction without degradation. Thus, vancomycin was not denaturated after application of 100, 140, or 200 MPa of isostatic compression. The results for vancomycin released from granules compressed at the three pressures were not significantly different (p =.01) whether assays were performed microbiologically or spectrophotometrically, indicating a good correlation between the two methods. This process involving high pressure appears to be a good means of developing drug delivery devices loaded with therapeutic agents without denaturating the components.

In vitro influence of apatite-granule-specific area on human growth hormone loading and release

Although calcium phosphate biomaterials often are used as drug delivery systems (DDS) at bone sites, the conditions affecting the loading of the therapeutic agent (TA) have not been well documented. A human growth hormone (hGH) adsorption method was used in this study to investigate the influence of the formulated apatite (AP)-specific area on loading and release. AP powders were formulated with a 200-500 microm granulometry and various specific areas. Two milligrams of hGH in solution were deposited for 24 h at 37 degrees C on 100 mg of AP with different specific areas. The amount of hGH loaded was determined by immunoradiometric assay (IRMA) and eluted stain bioassay (ESTA) using Nb2 lymphoma rat cells. Although loading was not greatly influenced by a specific area between 3 and 25 m2/g, dependency was noted for higher specific areas. Human GH release was measured by IRMA and ESTA over a 33-day period, with half-time release between 25 and 79 h. Comparison of IRMA and ESTA measurements for the hGH amounts loaded showed that hGH biologic activity was conserved. Results indicate that it is feasible to control the quantity of TA loading on AP by modifying specific areas for in vivo applications.

In Vitro and In Vivo Bactericidal Activities of Vancomycin Dispersed in Porous Biodegradable Poly(ε-Caprolactone) Microparticles

ABSTRACT Treatment of methicillin-resistant Staphylococcus aureus osteomyelitis requires a prolonged antibiotic therapy with vancomycin. Because of its weak diffusion, the in situ implantation of vancomycin could be interesting. The activity of vancomycin encapsulated in microparticles was evaluated in vitro and in vivo on rabbit osteomyelitis and showed a good activity compared to intravenous administration.

Compactibility study of calcium phosphate biomaterials.

This study investigated the micromechanism responsible for the densification and consolidation of powders during dynamic compaction, an experimental process in which ceramic is formed without heating. Three calcium-deficient apatites (CDA: two powders and a fibrous compound) and a biphasic calcium phosphate (BCP) were studied to determine their aptitude (rheological and physical properties) for compactibility under various dynamic compaction pressures. Powders were investigated for their physicochemistry, particle size, and flow time, and compacts for their compaction rate, density, specific area, mechanical characteristics, and disintegration time. Powder particles showed different morphological features depending on the synthesis protocol used, specific area and rheological behaviour. Compacts were not obtained with BCP, regardless of the gas pressure used, whereas CDA produced compacts with good mechanical properties (high hardness and compression stress), particularly for the fibrous compound. The poor compressibility and compactibility of BCP powders were confirmed, whereas fibrous CDA powders showed good compactibility conducive to high-quality filling of biomaterials.

Inactivation of Staphylococcus aureus in Calcium Phosphate Biomaterials via Isostatic Compression

High hydrostatic pressure is currently used as a sterilization technique in agroalimentary field. This study explores the potential use of high pressure for bacterial inactivation of bone substitute calcium phosphate materials. Staphylococcus aureus strain incorporated in calcium phosphate powder was subjected to isostatic compression. Several parameters of compression were tested: application of pressure, time of plateau, number of compressions, and waiting time between two compressions. The results showed that the efficacy of compression increased with applied pressure and that time of plateau did not play an important role. The number of compressions influenced the efficiency of the technique and it was necessary to allow ample time between two compressions for bacteria to sufficiently multiply. The most effective protocol for preventing the growth of S. aureus in calcium phosphate involved two compressions of 5 minutes each at 140 MPa spaced at a 24-hour interval.

Toward the development of biomimetic injectable and macroporous biohydrogels for regenerative medicine

Repairing or replacing damaged human tissues has been the ambitious goal of regenerative medicine for over 25years. One promising approach is the use of hydrated three-dimensional scaffolds, known as hydrogels, which have had good results repairing tissues in pre-clinical trials. Benefiting from breakthrough advances in the field of biology, and more particularly regarding cell/matrix interactions, these hydrogels are now designed to recapitulate some of the fundamental cues of native environments to drive the local tissue regeneration. We highlight the key parameters that are required for the development of smart and biomimetic hydrogels. We also review the wide variety of polymers, crosslinking methods, and manufacturing processes that have been developed over the years. Of particular interest is the emergence of supramolecular chemistries, allowing for the development of highly functional and reversible biohydrogels. Moreover, advances in computer assisted design and three-dimensional printing have revolutionized the production of macroporous hydrogels and allowed for more complex designs than ever before with the opportunity to develop fully reconstituted organs. Today, the field of biohydrogels for regenerative medicine is a prolific area of research with applications for most bodily tissues. On top of these applications, injectable hydrogels and macroporous hydrogels (foams) were found to be the most successful. While commonly associated with cells or biologics as drug delivery systems to increase therapeutic outcomes, they are steadily being used in the emerging fields of organs-on-chip and hydrogel-assisted cell therapy. To highlight these advances, we review some of the recent developments that have been achieved for the regeneration of tissues, focusing on the articular cartilage, bone, cardiac, and neural tissues. These biohydrogels are associated with improved cartilage and bone defects regeneration, reduced left ventricular dilation upon myocardial infarction and display promising results repairing neural lesions. Combining the benefits from each of these areas reviewed above, we envision that an injectable biohydrogel foam loaded with either stem cells or their secretome is the most promising hydrogel solution to trigger tissue regeneration. A paradigm shift is occurring where the combined efforts of fundamental and applied sciences head toward the development of hydrogels restoring tissue functions, serving as drug screening platforms or recreating complex organs.

Les substituts osseux à bioactivité contrôlée : un vecteur pour la libération de principes actifs. Place des antibiotiques

Resume Les substituts osseux sont largement utilises depuis une dizaine d’annees en odontologie, orthopedie et chirurgie maxillo-faciale. A l’origine, ils ont ete crees pour combler les defects osseux survenus a la suite de traumatismes ou de maladies. Les ceramiques phosphocalciques se revelent etre les meilleurs candidats pour cette substitution de par leur composition tres voisine de celle de l’os humain, leur pouvoir osteoconducteur, leur biocompatibilite et leur biodegradabilite. Suite au developpement de ces biomateriaux, l’incorporation d’un principe actif au substitut osseux est devenue un nouveau challenge. Les formes pharmaceutiques obtenues appartiennent a la classe des Drug Delivery System dans laquelle la matrice joue a la fois le role de substitut osseux et de matrice liberant l’agent therapeutique. De nombreux principes actifs tels que les antibiotiques, facteurs de croissance, anticancereux, antiosteoporotiques trouvent une application interessante en orthopedie, chirurgie maxillo-faciale ou en traumatologie. L’agent therapeutique peut ainsi etre libere par diffusion in situ au niveau du site d’implantation, ceci dans un but prophylactique ou therapeutique. Ainsi, la place des substituts osseux associes a des antibiotiques est appelee a augmenter avec les progres de la chirurgie orthopedique.