Ana Rita C. Duarte

Management of degenerative spine pathologies frequently leads to the need for spinal fusion (SF), where bone growth is induced toward stabilization of the interventioned spine. Autologous bone graft (ABG) remains the gold-standard inducer, whereas new bone graft substitutes attempt to achieve effective de novo bone formation and solid fusion. Limited fusion outcomes have driven motivation for more sophisticated and multidisciplinary solutions, involving new biomaterials and/or biologics, through innovative delivery platforms. The present review will analyze the most recent body of literature that is focused on new approaches for consistent bone fusion of spinal vertebrae, including the development of new biomaterials that pursue physical and chemical aptitudes; the delivery of growth factors (GF) to accelerate new bone formation; and the use of cells to improve functional bone development. Bone graft substitutes currently in clinical practice, such as demineralized bone matrix and ceramics, are still used as a starting point for the study of new bioactive agents. Polyesters such as polycaprolactone and polylactic acid arise as platforms for the development of composites, where a mineral element and cell/GF constitute the delivery system. Exciting fusion outcomes were obtained in several small and large animal models with these. On what regards bioactive agents, mesenchymal stem cells, preferentially derived from the bone marrow or adipose tissue, were studied in this context. Autologous and allogeneic approaches, as well as osteogenically differentiated cells, have been tested. These cell sources have further been genetically engineered for specific GF expression. Nevertheless, results on fusion efficacy with cells have been inconsistent. On the other hand, the delivery of GF (most commonly bone morphogenetic protein-2 [BMP-2]) has provided favorable outcomes. Complications related to burst release and dosing are still the target of research through the development of controlled release systems or alternative GF such as Nel-like molecule-1 (NELL-1), Oxysterols, or COMP-Ang1. Promising solutions with new biomaterial and GF compositions are becoming closer to the human patient, as these evidence high-fusion performance, while offering cost and safety advantages. The use of cells has not yet proved solid benefits, whereas a further understanding of cell behavior remains a challenge.

The possibility of preparation of ophthalmic drug delivery systems using compressed anti-solvent technology was evaluated. Eudragit RS 100 and RL 100 were used as drug carriers, acetazolamide was the model drug processed. Compressed anti-solvent experiments were carried out as a semi-continuous or a batch operation from a liquid solution of polymer(s) + solute dissolved in acetone. Both techniques allowed the recovery of composite particles, but the semi-continuous operation yielded smaller and less aggregated populations than the batch operation. The release behaviour of acetazolamide from the prepared microparticles was studied and most products exhibited a slower release than the single drug. Moreover, the release could be controlled to some extent by varying the ratio of the two Eudragit used in the formulation and by selecting one or the other anti-solvent technique. Simple diffusion models satisfactorily described the release profiles. Composites specifically produced by semi-continuous technique have a drug release rate controlled by a diffusion mechanism, whereas for composites produced by the batch operation, the polymer swelling also contributes to the overall transport mechanism. © 2006 Elsevier B.V. All rights reserved.

The possibility of preparation of ophthalmic drug delivery systems using compressed anti-solvent technology was evaluated. Eudragit RS 100 and RL 100 were used as drug carriers, acetazolamide was the model drug processed. Compressed anti-solvent experiments were carried out as a semi-continuous or a batch operation from a liquid solution of polymer(s) + solute dissolved in acetone. Both techniques allowed the recovery of composite particles, but the semi-continuous operation yielded smaller and less aggregated populations than the batch operation. The release behaviour of acetazolamide from the prepared microparticles was studied and most products exhibited a slower release than the single drug. Moreover, the release could be controlled to some extent by varying the ratio of the two Eudragit used in the formulation and by selecting one or the other anti-solvent technique. Simple diffusion models satisfactorily described the release profiles. Composites specifically produced by semi-continuous technique have a drug release rate controlled by a diffusion mechanism, whereas for composites produced by the batch operation, the polymer swelling also contributes to the overall transport mechanism. © 2006 Elsevier B.V. All rights reserved.

Supercritical fluid impregnation was tested to prepare a new ophthalmic drug delivery device. Poly(methylmethacrylate-co-ethylhexylacrylate-co-ethyleneglycoldimethacr ylate), P(MMA-EHA-EGDMA) has been proposed by Mariz [M. Mariz, Preparação de uma lente intra-ocular dotada de um sistema de libertação controlada de fármaco, Master Thesis, Universidade de Coimbra, 1999] as a promising matrix to be used for intraocular delivery of anti-inflammatory drugs used in eye surgery. This matrix was successfully impregnated with flurbiprofen, a non-steroidal anti-inflammatory agent. The success of the impregnation was evaluated by scanning electron microscopy (SEM) analysis and also by in vitro drug release studies. The effect of some operating parameters was evaluated, namely, pressure and contact time. The operating pressure will influence both the solubility of the drug in the supercritical fluid but also the sorption degree of the polymeric matrix in the presence of carbon dioxide. The solubility of the drug in carbon dioxide and the sorption degree are reported in previous studies. A comparison between the batch and the semi-continuous impregnation process is also presented. The supercritical fluid impregnation proved to be feasible for the preparation of a new ophthalmic drug delivery system. The drug release profiles suggest that the drug can be released up to three months, which is a major advantage for the prevention of the inflammatory response after ophthalmic surgery. © 2007 Elsevier B.V. All rights reserved.