Inductive Materials for Regenerative Engineering.

Regenerative engineering has pioneered several novel biomaterials to treat critical-sized bone injuries. However, despite significant improvement in synthetic materials research, some limitations still exist. The constraints correlated with the current grafting methods signify a treatment paradigm shift to osteoinductive regenerative engineering approaches. Because of their intrinsic potential, inductive biomaterials may represent alternative approaches to treating critical bone injuries. Osteoinductive scaffolds stimulate stem cell differentiation into the osteoblastic lineage, enhancing bone regeneration. Inductive biomaterials comprise polymers, calcium phosphate ceramics, metals, and graphene family materials. This review will assess the cellular behavior toward properties of inductive materials.

Identification of Heparan-Sulfate Rich Cells in the Loose Connective Tissues of the Axolotl (Ambystoma mexicanum) with the Potential to Mediate Growth Factor Signaling during Regeneration.

Limb regeneration is the outcome of a complex sequence of events that are mediated by interactions between cells derived from the tissues of the amputated stump. Early in regeneration, these interactions are mediated by growth factor/morphogen signaling associated with nerves and the wound epithelium. One shared property of these proregenerative signaling molecules is that their activity is dependent on interactions with sulfated glycosaminoglycans (GAGs), heparan sulfate proteoglycan (HSPG) in particular, in the extracellular matrix (ECM). We hypothesized that there are cells in the axolotl that synthesize specific HSPGs that control growth factor signaling in time and space. In this study we have identified a subpopulation of cells within the ECM of axolotl skin that express high levels of sulfated GAGs on their cell surface. These cells are dispersed in a grid-like pattern throughout the dermis as well as the loose connective tissues that surround the tissues of the limb. These cells alter their morphology during regeneration, and are candidates for being a subpopulation of connective tissue cells that function as the cells required for pattern-formation during regeneration. Given their high level of HSPG expression, their stellate morphology, and their distribution throughout the loose connective tissues, we refer to these as the positional information GRID (Groups that are Regenerative, Interspersed and Dendritic) cells. In addition, we have identified cells that stain for high levels of expression of sulfated GAGs in mouse limb connective tissue that could have an equivalent function to GRID cells in the axolotl. The identification of GRID cells may have important implications for work in the area of Regenerative Engineering.

Novel tubular composite matrix for bone repair.

Tissue engineering develops organ replacements to overcome the limitations associated with autografts and allografts. The work presented here details the development of biodegradable, porous, three-dimensional polymer-ceramic-sintered microsphere matrices to support bone regeneration. Poly(lactide-co-glycolide)/hydroxyapatite microspheres were formed using solvent evaporation technique. Individual microspheres were placed in a cylindrical mold and sintered at various temperatures. Scaffolds were characterized using scanning electron microscopy, mercury porosimetry, and mechanical testing in compression. After varying the temperature of sintering, a single temperature was selected and the time of sintering was varied. Mechanical testing indicated that as the sintering temperature or time was increased, the elastic modulus, compressive strength, maximum compressive load, and energy at failure significantly increased. Furthermore, increasing the sintering temperature or time resulted in a decreased porosity and the spherical morphology of the microspheres was lost as the microspheres blended together. To more closely mimic the bone marrow cavity observed in native bone tissue, tubular composite-sintered microsphere matrices were formed. These scaffolds demonstrated no statistically significant difference in compressive mechanical properties when compared with cylindrical composite-sintered microsphere matrices of the same dimension. One potential application for these scaffolds is bone regeneration.

Formation of hydroxyapatite-polyphosphazene polymer composites at physiologic temperature.

Aspects of the formation of bone analog composites at 37 degrees C are described. The composites are composed of hydroxyapatite (HAp) and the calcium salt of a biocompatible polymer and are capable of forming under in vivo conditions. Composite formation involves the formation of monolithic HAp from particulate calcium phosphate precursors while Ca ions liberated to the aqueous medium in which this reaction is occurring form crosslinks with the acidic polymer. The reactants are poly[bis(carboxylatophenoxy)phosphazene] (acid-PCPP), tetracalcium phosphate [Ca4(PO4)2O, TetCP], and anhydrous dicalcium phosphate (CaHPO4, DCPA). The effects of the proportion of polymer (5, 10, or 15 wt %) on the kinetics of HAp formation were studied. Compositional evolution of the solid calcium phosphates present was followed by X-ray diffraction and infrared spectroscopy analyses. HAp formation through a dissolution-precipitation process provided a mildly alkaline medium suitable for deprotonation of the acid-PCPP and for the formation of the calcium crosslinks, as monitored by infrared spectroscopy. Concurrence of crosslinking of the polymer and HAp formation was established, indicating true composite formation can be realized at physiologic temperature.

Orthopaedic applications of gene therapy.

Current treatment modalities for musculoskeletal injuries due to disease or trauma often implement the use of tissue grafts, cell transplantations, and artificial scaffolding. These approaches may be augmented with the use of specific biological factors, which accelerate healthy tissue regeneration. Unfortunately, the short half-life and inherent instability of proteins requires the delivery of high doses or multiple doses of these molecules, neither of which is ideal for the patient or clinician. Gene therapy, as an alternative approach, has the potential to circumvent the existing limitations associated with protein delivery by producing a sustained release of the biologic agent at therapeutic levels. This is achieved by the direct transfer of the gene encoding the therapeutic agent to the cells of the afflicted tissue or by implanting cells that have been previously genetically modified in vitro. Using these methods, several laboratories have demonstrated the ability to deliver genes in vitro and in vivo resulting in accelerated and enhanced musculoskeletal tissue regeneration or inhibited disease progression. Many of these investigations, which involved bone, ligament, tendon, and cartilage, are covered in this review. Specifically, musculoskeletal tissue anatomy, factors relevant to musculoskeletal tissue regeneration, target cells, and in vivo and ex vivo gene therapy approaches for musculoskeletal regeneration are discussed. The experience and knowledge gained from these studies have affirmed gene therapy is a promising therapeutic strategy to combat musculoskeletal tissue repair and regeneration following disease or injury.

Low temperature formation of hydroxyapatite-poly(alkyl oxybenzoate)phosphazene composites for biomedical applications.

The formation of biodegradable composites which may be suitable as bone analogs is described. Polyphosphazene-hydroxyapatite (HAp) composites were produced via an acid-base reaction of tetracalcium phosphate and anhydrous dicalcium phosphate in the presence of polyphosphazenes bearing alkyl ester containing side-groups. The polyphosphazenes used were poly(ethyl oxybenzoate)phosphazene (PN-EOB) and poly(propyl oxybenzoate) phosphazene (PN-POB). The effects of temperature and the proportions of polymers, PN-EOB and PN-POB on the kinetics, reaction chemistry and phase evolution during the formation of stoichiometric HAp were studied. Kinetics, phase evolution and microstructural development were evaluated using isothermal calorimetry, X-ray diffraction and scanning electron microscopy, respectively. Analysis of solution chemistry revealed that the increases in the pH during the formation of SHAp, resulted in partial hydrolysis of the polymer surfaces, which led in turn to the formation of a calcium cross-linked polymer surface. The calcium cross-linked polymer surface appeared to facilitate the nucleation and growth of apatite deposits on the polymer. The current study illustrates the in situ formation of HAp in the presence of polyphosphazenes, where HAp is chemically bonded to the polymer.

Biodegradable polyphosphazenes for drug delivery applications.

Biodegradable polymers such as poly(alpha-hydroxy acids), poly(anhydrides), poly(ortho esters), poly(amino acids) and polyphosphazenes have raised considerable interest as short-term medical implants due to their transient nature. Among these, polyphosphazenes are a relatively new class of polymers, quite distinct from all the biodegradable polymers synthesized so far, due to their synthetic flexibility and versatile adaptability for applications. These are high molecular weight, essentially linear polymers with an inorganic backbone of alternating phosphorous and nitrogen atoms bearing two side groups attached to each phosphorous atom. Controlled tuning of physico-chemical properties, including biodegradability, can be achieved in this class of polymers via macromolecular substitutions. Biodegradable polyphosphazenes, due to their hydrolytic instability, nontoxic degradation products, ease of fabrication and matrix permeability, are an excellent platform for controlled drug delivery applications. This review discusses the mode of degradation and drug delivery applications of biodegradable polyphosphazenes.

Toxicity, biodegradation and elimination of polyanhydrides.

Although originally developed for the textile industry, polyanhydrides have found extensive use in biomedical applications due to their biodegradability and excellent biocompatibility. Polyanhydrides are most commonly synthesized from diacid monomers by polycondensation. Efficient control over various physicochemical properties, such as biodegradability and biocompatibility, can be achieved for this class of polymers, due to the availability of a wide variety of diacid monomers as well as by copolymerization of these monomers. Biodegradation of these polymers takes place by the hydrolysis of the anhydride bonds and the polymer undergoes predominantly surface erosion, a desired property to attain near zero-order drug release profile. This review examines the mode of degradation and elimination of these polyanhydrides in vivo as well as the biocompatibility and toxicological aspects of various polyanhydrides.

Tissue engineered bone-regeneration using degradable polymers: the formation of mineralized matrices.

In the development of 3-dimensional cell-polymer matrices for tissue engineering, the ability of osteoblast cells to maintain their phenotypic properties and form a mineralized matrix while seeded on the polymer surface is very important. Osteoblast cell differentiation and bone formation using rat calvaria cells were studied on the surface of a porous poly(lactide/glycolide)/hydroxyapatite (PLAGA/HA) 3-dimensional polymer matrix. Cell adhesion and proliferation were determined at 24 hr, 3, 7, 14, and 21 days. Cell attachment and proliferation were observed to increase throughout the first two weeks of the study, followed by a period of gradual plateauing of cell numbers. Environmental scanning electron microscopy demonstrated that cells grown on the surface of the 3-dimensional porous PLAGA/HA matrix retained their characteristic morphology and grew in a multi-layer fashion. Light microscopy observations of experiment cultures revealed active osteoblastic cells forming a characteristic mineralized matrix in the presence of beta-glycerophosphate as a phosphate donor. Mineralization did not occur in media either not supplemented with beta-glycerophosphate or when the matrix without cells was incubated with the reagents, indicating that the mineralization was due to the cells and not the HA in the matrix. These results suggest that the 3-dimensional PLAGA/HA matrix could provide a matrix for bone cell differentiation and mineralization in vitro and, therefore, may be a candidate as a synthetic implant for bone regeneration.

Structural and human cellular assessment of a novel microsphere-based tissue engineered scaffold for bone repair.

The limitations of current grafting materials have driven the search for synthetic alternatives for the regeneration of trabecular bone. A variety of biodegradable polymer foams composed of 85/15 poly(lactide-co-glycolide) (PLAGA) have been evaluated for such uses. However, structural limitations may restrict the clinical use of these scaffolds. We have developed a novel sintered microsphere scaffold with a biomimetic pore system equivalent to the structure of trabecular bone. By modifying processing parameters, several different sintered microsphere structures were fabricated. Optimization of the structure dealt with modifications to sphere diameter and heating time. Compressive testing illustrated a trend between microsphere diameter and modulus, where increased microsphere diameter resulted in decreased modulus. In addition, evaluation of the pore system showed a positive correlation between sphere diameter and pore diameter. Mercury porosimetry showed increased median pore size with an increased microsphere diameter. Heating time modifications showed that compressive modulus was dependent on the period of heating with longer heating times resulting in higher moduli. It was also shown that heating time did not affect the pore structure. Analysis of the structural data indicated that the microsphere matrix sintered for 4h at a temperature of 160 degrees C with a microsphere diameter of 600-710 microm resulted in an optimal, biomimetic structure with range in pore diameter of 83-300 microm, a median pore size of 210 microm, 35% porosity, and a compressive modulus of 232 MPa. An in vitro evaluation of human osteoblasts seeded onto the sintered matrix indicated that the structure was capable of supporting the attachment and proliferation of cells throughout its pore system. Immunofluorescent staining of actin showed that the cells were proliferating three-dimensionally through the pore system. The stain for osteocalcin was used and showed that cells maintained phenotypic expression for this bone specific protein. Through this work, it was shown that an osteoconductive PLAGA scaffold with a pore system used as a reverse template to the structure of trabecular bone could be fabricated through the sintered microsphere method.

Chemical changes during in vivo degradation of poly(anhydride-imide) matrices.

The in vivo degradation characteristics of a novel class of biodegradable polymers, poly(anhydride-imides), were investigated. The poly(anhydride-imides) examined were poly[trimellitylimidoglycine-co-1,6-bis(p-carboxyphenoxy)hex ane] (TMA-gly:CPH) in 10:90, 30:70 and 50:50 molar ratios and poly[pyromellitylimidoalanine-co-1,6-bis(p-carboxyphenoxy)he xane] (PMA-ala:CPH) in 10:90 and 30:70 molar ratios. The polymer matrices were compression-molded into circular discs, then implanted in rat subcutaneous tissues for nearly two months. At defined time intervals, the animals were sacrificed and explants analyzed. Proton NMR spectroscopic analysis revealed a complete absence of imide monomer units in PMA-ala: CPH compositions after 28 d and complete removal of imide units at 56 d from TMA-gly matrices. Gross observation of the implants closely correlated to the imide content: with decreasing imide content, the explants darkened and fragmented at a faster rate. The chemical compositions of the poly(anhydride imide) explants were also monitored using IR spectroscopy. The residual amount of anhydride bonds in the polymer backbone following implantation were calculated from peaks specific to the anhydride bonds relative to the total amount of carbonyl bonds present. Initially, the imide (TMA-gly or PMA-ala) anhydride bonds were rapidly hydrolyzed then solubilized, followed by the slower hydrolysis of the CPH monomer anhydride bonds.

Osteoblast-like cell (MC3T3-E1) proliferation on bioerodible polymers: an approach towards the development of a bone-bioerodible polymer composite material.

An osteogenic cell line (MC3T3-E1) was used to study the potential of bioerodible polymers and ceramics to support osteoblast growth for a proposed bone-polymer composite for skeletal tissue repair. MC3T3-E1 cells were seeded on to 50:50 poly(lactide-co-glycolide), hydroxyapatite, 50:50 hydroxyapatite/poly(lactide-co-glycolide), and the poly(anhydride), poly(bis(p-carboxyphenoxy) propane surfaces. Cell attachment and growth on these surfaces was found to be highest on poly(lactide-co-glycolide), the least on hydroxyapatite and hydroxyapatite/poly(lactide-co-glycolide) combinations gave intermediate values. The order of adhesion and growth of MC3T3-E1 cells on the polymer and ceramic systems was poly(lactide-co-glycolide) is greater than hydroxyapatite/poly(lactide-co-glycolide) which is greater than hydroxyapatite. Negligible growth was found on poly(bis(p-carboxyphenoxy) propane. High alkaline phosphatase activity for the cells grown on poly(lactide-co-glycolide) and hydroxyapatite/poly(lactide-co-glycolide) confirmed retention of the osteoblast phenotype. This in vitro evaluation suggests that poly(lactide-co-glycolide) and hydroxyapatite/poly(lactide-co-glycolide) combinations may be candidate biomaterials for the construction of a cell-polymer matrix for skeletal tissue regeneration.

Novel polyphosphazene/poly(lactide-co-glycolide) blends: miscibility and degradation studies.

A novel biodegradable polymer blend was developed for potential biomedical applications. A 50:50 poly(lactide-co-glycolide) (PLAGA) was blended in a 50:50 ratio with the followiing polyphosphazenes (PPHOS): poly[(25% ethyl glycinato)(75% p-methylphenoxy)phosphazene[, poly[(50% ethyl glycinato)(50% p-methylphenoxy)phosphazene], and poly[(75% ethyl glycinato)(25% p-methylphenoxy)phosphazene] to obtain Blends A, B, and C, respectively, using a mutual solvent technique. The miscibility of these blends was determined by measuring their glass transition temperature (Tg) using differential scanning calorimetry. After fabrication using a casting technique, the degradation of the matrices was examined. Differential scanning calorimetry showed one glass transition temperature for each blend which was between the Tg's of their respective parent polymers indicating miscibility of the blends. Surface analysis by scanning electron microscopy showed the matrices to have smooth uniform surfaces. Degradation studies showed near-zero order degradation kinetics for the blends with Blends A and B losing 10% of their mass after two weeks and Blend C degrading more rapidly (30% mass loss during the same period). These findings suggest that these novel biodegradable PLAGA/PPHOS blends may be useful for biomedical purposes.

Extracellular matrix production by human osteoblasts cultured on biodegradable polymers applicable for tissue engineering.

The nature of the extracellular matrix (ECM) is crucial in regulating cell functions via cell-matrix interactions, cytoskeletal organization, and integrin-mediated signaling. In bone, the ECM is composed of proteins such as collagen (CO), fibronectin (FN), laminin (LM), vitronectin (VN), osteopontin (OP) and osteonectin (ON). For bone tissue engineering, the ECM should also be considered in terms of its function in mediating cell adhesion to biomaterials. This study examined ECM production, cytoskeletal organization, and adhesion of primary human osteoblastic cells on biodegradable matrices applicable for tissue engineering, namely polylactic-co-glycolic acid 50:50 (PLAGA) and polylactic acid (PLA). We hypothesized that the osteocompatible, biodegradable polymer surfaces promote the production of bone-specific ECM proteins in a manner dependent on polymer composition. We first examined whether the PLAGA and PLA matrices could support human osteoblastic cell growth by measuring cell adhesion at 3, 6 and 12h post-plating. Adhesion on PLAGA was consistently higher than on PLA throughout the duration of the experiment, and comparable to tissue culture polystyrene (TCPS). ECM components, including CO, FN, LM, ON, OP and VN, produced on the surface of the polymers were quantified by ELISA and localized by immunofluorescence staining. All of these proteins were present at significantly higher levels on PLAGA compared to PLA or TCPS surfaces. On PLAGA, OP and ON were the most abundant ECM components, followed by CO, FN, VN and LN. Immunofluorescence revealed an extracellular distribution for CO and FN, whereas OP and ON were found both intracellularly as well as extracellularly on the polymer. In addition, the actin cytoskeletal network was more extensive in osteoblasts cultured on PLAGA than on PLA or TCPS. In summary, we found that osteoblasts plated on PLAGA adhered better to the substrate, produced higher levels of ECM molecules, and showed greater cytoskeletal organization than on PLA and TCPS. We propose that this difference in ECM composition is functionally related to the enhanced cell adhesion observed on PLAGA. There is initial evidence that specific composition of the PLAGA polymer favors the ECM. Future studies will seek to optimize ECM production on these matrices for bone tissue engineering applications.

Poly(anhydride-co-imides): in vivo biocompatibility in a rat model.

The degradation and tissue compatibility characteristics of a novel class of biodegradable poly(anhydride-co-imide) polymers: poly[trimellitylimidoglycine-co-1,6-bis(carboxyphenoxy)hexan e] (TMA-gly: CPH) (in 10:90; 30:70 and 50: 50 molar ratios) and poly[pyromellitylimidoalanine-co-1,6-bis(carboxyphenoxy)hexa ne] (PMA-ala:CPH) (in 10:90 and 30:70 molar ratios) were investigated and compared with control poly(lactic acid/glycolic acid) (PLAGA in 50:50 molar ratio) matrices, a well-characterized biocompatible polymer, in rat subcutaneous tissues for 60 days. Polymers were compression-molded into circular discs of 14 mm x 1 mm in diameter. On post-operative days 7, 14, 28 and 60, histological tissue samples were removed, prepared by fixation and staining, and analyzed by light microscopy. PLAGA matrices produced mild inflammatory reactions and were completely degraded at the end of 60 days, leaving implant tissues that were similar to surgical wounds without implants. TMA-gly:CPH (10:90 and 30:70) matrices produced mild inflammatory reactions by the end of 60 days, similar to those seen with PLAGA. TMA-gly: CPH (50: 50) produced moderate inflammatory reactions characterized by macrophages and edema. PMA-ala:CPH matrices elicited minimal inflammatory reactions that were characterized by fibrous encapsulation by the end of 60 days. In vivo degradation rates of poly(anhydride-co-imides) were similar to PLAGA. Both PMA-ala:CPH and TMA-gly: CPH matrices maintained their shapes and degraded at a constant rate over the period of two months. These polymers, possessing good mechanical properties and tissue compatibility, may be useful in weight-bearing applications in bone.

Poly(lactide-co-glycolide)/hydroxyapatite delivery of BMP-2-producing cells: a regional gene therapy approach to bone regeneration.

Currently, functional treatment of fracture non-unions and bone loss remains a significant challenge in the field of orthopaedic surgery. Tissue engineering of bone has emerged as a new treatment alternative in bone repair and regeneration. Our approach is to combine a polymeric matrix with a cellular vehicle for delivery of bone morphogenetic protein-2 (BMP-2), constructed through retroviral gene transfer. The objective of this study is to develop an osteoinductive, tissue-engineered bone replacement system by culturing BMP-2-producing cells on an osteoconductive, biodegradable, polymeric-ceramic matrix. The hypothesis is that retroviral gene transfer can be used effectively in combination with a biodegradable matrix to promote bone formation. First, we examined the in vitro attachment and growth of transfected BMP-producing cells on a PLAGA-HA scaffold. Second, the bioactivity of the produced BMP in vitro was evaluated using a mouse model. It was found that the polymer-ceramic scaffold supported BMP-2 production, allowing the attachment and growth of retroviral transfected, BMP-2-producing cells. In vivo, the scaffold successfully functioned as a delivery vehicle for bioactive BMP-2, as it induced heterotopic bone formation in a SCID mouse model.

Regional drug delivery with radiation for the treatment of Ewing's sarcoma. In vitro development of a taxol release system.

Recently, several studies have suggested the radiosensitizing effect of taxol, a microtubular inhibitor. Our overall hypothesis is that a combination of radiation and taxol may demonstrate therapeutic efficacy over doses of either individually. Studies examining taxol use have mostly focused on systemic administration, which can lead to undesired effects. To circumvent these side effects, we propose a locally administered polymeric microsphere delivery system combined with radiation therapy for the treatment of Ewing's sarcoma. The present study focuses on the in vitro ability of taxol when present as a microencapsulated drug delivery system, and delivered locally at the site of the sarcoma/tumor, to block cells in the G2/M phase of the cell cycle and potentially enhance the radiation sensitivity of cells. Using the bioresorbable poly(anhydride-co-imide), poly[pyromellityl-imidoalanine-1,6-bis(carboxy-phenoxy)hexane] (PMA-CPH), and the radiosensitizing agent taxol, a microsphere based delivery system was fabricated. A solvent evaporation technique was used to encapsulate taxol at doses of 1%, 5%, and 10% in PMA-CPH microspheres. Release kinetics studies demonstrated that the total amount of taxol released and the release rate were directly dependent on loading percentage. Taxol's bioactivity and radiosensitizing ability were measured using flow cytometry. Co-culture of Ewing's sarcoma cells with and without taxol-loaded microspheres demonstrated that released taxol retained its bioactivity and effectively blocked cells in the radiosensitive G2/M phase of mitosis. The taxol-radiation delivery system studied achieved an 83% decrease in tumor cell count compared to control. Taxol effectively sensitized Ewing's sarcoma cells to radiation with radiosensitivity shown to be independent of radiation dose at levels of dosages studied. This work has demonstrated that taxol can be effectively released from a biodegradable PMA-CPH microsphere delivery system while maintaining potent combined cytotoxic and radiosensitizing abilities.

In vitro bone biocompatibility of poly (anhydride-co-imides) containing pyromellitylimidoalanine.

Poly(anhydride-co-imides) are currently under study for applications involving bone. The cytotoxicity of a series of poly(anhydride-co-imides) with osteoblast-like cells (MC3T3-E1) was evaluated. The imide component of the copolymers was based on pyromellitylimidoalanine and the anhydride component was based on either sebacic acid or 1,6-bis(carboxyphenoxy)hexane. Cell adhesion and proliferation on the surfaces of the polymer discs were observed by environmental scanning electron microscopy. During the first 24 hours of attachment, the cells showed normal morphology when cultured on copolymers containing 1,6-bis(carboxyphenoxy)hexane. The cells did not adhere to the polymers containing sebacic acid, probably due to the rapid degradation of the polymer surfaces. Concurrently, the effects of polymer breakdown products on osteoblast-like cells were evaluated by studying their proliferation (cell numbers), viability (dye exclusion), morphology (light microscopy), and phenotypic expression. The morphology of osteoblast-like cells cultured in the presence of the polymer breakdown products pyromellitylimidoalanine and pyromellitic acid was found to be similar to that of the same cells grown on tissue culture polystyrene and consisted of a characteristic polygonal shape. With use of a monoclonal antibody to osteocalcin, these cells were shown to demonstrate preserved osteoblast phenotype with growth over a 21-day period. In addition, the cells reached confluency after 3-4 days, similar to cells grown on tissue culture polystyrene. This in vitro evaluation showed that the poly(anhydride-co-imides) evaluated are non-cytotoxic and may be viable biomaterials for orthopaedic applications.

Bioerodible polyanhydrides for antibiotic drug delivery: in vivo osteomyelitis treatment in a rat model system.

Acute and chronic osteomyelitis can be difficult to treat by conventional means. Current methods of treatment involve the use of systemic antibiotics, the local implantation of non-degradable drug carriers, and surgical débridement. Each method has specific drawbacks. We report on the use of a new controlled release system utilizing gentamicin and bioerodible, biocompatible polymers (polyanhydrides) designed for drug delivery applications for the treatment of clinical osteomyelitis. We compared this system's ability to reduce bacterial levels in infected bone with that of conventional non-degradable delivery systems based on polymethylmethacrylate (PMMA) and gentamicin. Polyanhydride copolymers of bis-carboxyphenoxypropane and sebacic acid P loaded with gentamicin sulfate and PMMA/gentamicin matrices were implanted in the long bones of Sprague-Dawley rats infected with a strain of Staphylococcus aureus. After 3 weeks of implantation, the polymeric delivery devices were removed and quantitative cultures were used to determine bacterial levels in bone. The polyanhydride/gentamicin matrices demonstrated significant degradation over the 3 week implantation period. Levels of bacteria, measured in colony forming units, were significantly lower in bone implanted with the polyanhydride/gentamicin release system than in long bones of control animals without an implant (p < 0.01), of animals with a polyanhydride polymer implant alone (p < 0.01), and of animals with a PMMA/gentamicin implant (p = 0.03). Bioerodible polyanhydrides show promise as a new treatment modality for infections in bone.

Polymeric controlled release systems: new methods for drug delivery.

Controlled release delivery systems are playing an ever-increasing role in drug therapy. By means of polymeric devices, drugs with a variety of physicochemical properties can be released predictably in therapeutic dosages.