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Synthesis, material properties, and biocompatibility of a novel self-cross-linkable poly(caprolactone fumarate) as an injectable tissue engineering scaffold
Jabbari, E., S. Wang, et al. (2005), Biomacromolecules 6(5): 2503-11.
Abstract: A novel self-cross-linkable and biodegradable macromer, poly(caprolactone fumarate) (PCLF), has been developed for guided bone regeneration. This macromer is a copolymer of fumaryl chloride, which contains double bonds for in-situ cross-linking, and poly(epsilon-caprolactone), which has a flexible chain to facilitate self-cross-linkability. PCLF was characterized with Fourier transform infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopy, and gel permeation chromatography. Porous scaffolds were fabricated with sodium chloride particles as the porogen and a chemical initiation system. The PCLF scaffolds were characterized with scanning electron microscopy and micro-computed-tomography. The cytotoxicity and in vivo biocompatibility of PCLF were also assessed. Our results suggest that this novel copolymer, PCLF, is an injectable, self-cross-linkable, and biocompatible macromer that may be potentially used as a scaffold for tissue engineering applications.

Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering
Lutolf, M. P. and J. A. Hubbell (2005), Nat Biotechnol 23(1): 47-55.
Abstract: New generations of synthetic biomaterials are being developed at a rapid pace for use as three-dimensional extracellular microenvironments to mimic the regulatory characteristics of natural extracellular matrices (ECMs) and ECM-bound growth factors, both for therapeutic applications and basic biological studies. Recent advances include nanofibrillar networks formed by self-assembly of small building blocks, artificial ECM networks from protein polymers or peptide-conjugated synthetic polymers that present bioactive ligands and respond to cell-secreted signals to enable proteolytic remodeling. These materials have already found application in differentiating stem cells into neurons, repairing bone and inducing angiogenesis. Although modern synthetic biomaterials represent oversimplified mimics of natural ECMs lacking the essential natural temporal and spatial complexity, a growing symbiosis of materials engineering and cell biology may ultimately result in synthetic materials that contain the necessary signals to recapitulate developmental processes in tissue- and organ-specific differentiation and morphogenesis.

Synthetic biomaterials for pelvic floor reconstruction
Karlovsky, M. E., L. Kushner, et al. (2005), Curr Urol Rep 6(5): 376-84.
Abstract: Pelvic organ prolapse and stress urinary incontinence increase with age. The increasing proportion of the aging female population is likely to result in a demand for care of pelvic floor prolapse and incontinence. Experimental evidence of altered connective tissue metabolism may predispose to pelvic floor dysfunction, supporting the use of biomaterials, such as synthetic mesh, to correct pelvic fascial defects. Re-establishing pelvic support and continence calls for a biomaterial to be inert, flexible, and durable and to simultaneously minimize infection and erosion risk. Mesh as a biomaterial has evolved considerably throughout the past half century to the current line that combines ease of use, achieves good outcomes, and minimizes risk. This article explores the biochemical basis for pelvic floor attenuation and reviews various pelvic reconstructive mesh materials, their successes, failures, complications, and management.

Synthetic biomaterials for soft-tissue augmentation and replacement in the head and neck
Costantino, P. D. (1994), Otolaryngol Clin North Am 27(1): 223-62.
Abstract: Within the next 10 to 15 years, synthetic biomaterials will probably become available that may make many of the polymeric implants discussed in this article obsolete. These new, genetically engineered biomaterials will contain morphogenic proteins capable of directing new tissue growth. We may be able to engage in true "tissue engineering" that allows us to grow a number of tissue types at will, as opposed to implanting bioinert compounds that only mimic the shape of living tissue. Regardless of whether the promise of genetically engineered growth proteins is ever realized, there will be a steady move away from polymeric implant materials that show even the hint of being able to cause cancer or an immune reaction. This movement will result primarily from liability pressure rather than scientific or medical indications. Polymeric biomaterials that are generally regarded as safe now may not be considered safe in the future. The surgeon who implants a biomaterial now may have to deal with a malpractice situation many years after the implant was placed. This is exactly the situation now faced by general plastic surgeons who have used silicone gel breast implants. It is wise, then, to limit the use of these polymer implants in terms of the number implanted and types used. If autogenous tissue is available and will adequately solve the problem, it should be used preferentially. If this is not possible, the surgeon should select only those implants with the lowest potential for future immunologic problems, carcinogenicity, and polymeric degradation over time.

Synthetic biomaterials for spinal fusion
Nasca, R. J., J. E. Lemons, et al. (1989), Orthopedics 12(4): 543-8.
Abstract: Calcium hydroxylapatite (HAP), tricalcium phosphate (TCP), and Bioglass (BG) were implanted in the spines of dogs to determine their potential in augmenting and enhancing spinal fusion. HAP and TCP showed continuous bone to biomaterial interfaces of varying degrees. Trabecular bone surrounded and incorporated the particulate hydroxylapatite. Tricalcium phosphate ceramic showed little evidence of resorption. The glass particulate, BG, showed a thin, fibrous encapsulation with some adjacent bony trabeculae. Decortication and autogenous bone enhanced incorporation. This multivariant initial study showed that trends found for the biomaterials implanted independently were similar to those used in combination. No adverse tissue reactions were noted for the combination of materials.

Synthetic biomaterials in facial plastic and reconstructive surgery
Costantino, P. D., C. D. Friedman, et al. (1993), Facial Plast Surg 9(1): 1-15.

Synthetic MMP-13 degradable ECMs based on poly(N-isopropylacrylamide-co-acrylic acid) semi-interpenetrating polymer networks. I. Degradation and cell migration
Kim, S., E. H. Chung, et al. (2005), J Biomed Mater Res A 75(1): 73-88.
Abstract: Thermoresponsive and injectable semi-interpenetrating polymer networks (sIPNs) containing a biospecific cell-adhesive signal and proteolytically degradable domains were developed as a synthetic equivalent of the extracellular matrix (ECM). The sIPNs synthesized define a modular hydrogel ECM where different properties of the matrix can be manipulated independently, thus creating a system where parametric analysis of the effect of hydrogel properties on cell proliferation and differentiation is possible. sIPNs composed of poly(N-isopropylacrylamide-co-acrylic acid) [p(NIPAAm-co-AAc)] and RGD-grafted poly(acrylic acid) linear chains [p(AAc)-g-RGD] were synthesized with peptide crosslinkers containing a matrix metalloproteinase-13 (MMP-13, collagenase-3) degradable domain. The lower critical solution temperature (LCST) of peptide-crosslinked p(NIPAAm-co-AAc) sIPNs was not influenced by the addition of either linear p(AAc) or peptide-modified p(AAc) chains (approximately 34 degrees C) in PBS. Degradation of peptide-crosslinked hydrogels and sIPNs was enzyme specific and concentration dependent. Exposure of rat calvarial osteoblast (RCO) culture to the degradation products from the peptide-crosslinked hydrogels did not significantly affect cell viability. Migration of RCOs into the sIPNs was dependent upon the presence of both a cell-adhesive RGD peptide (Ac-CGGNGEPRGDTYRAY-NH2) and proteolytically-degradable crosslinks; however, there was greater dependence on the latter. The sIPNs synthesized are versatile materials for assessing cell fate in synthetic ECM constructs in vitro and tissue regeneration in vivo.

Synthetic scaffold morphology controls human dermal connective tissue formation
Wang, H., J. Pieper, et al. (2005), J Biomed Mater Res A 74(4): 523-32.
Abstract: Engineering tissues in bioreactors is often hampered by disproportionate tissue formation at the surface of scaffolds. This hinders nutrient flow and retards cell proliferation and tissue formation inside the scaffold. The objective of this study was to optimize scaffold morphology to prevent this from happening and to determine the optimal scaffold geometric values for connective tissue engineering. After comparing lyophilized crosslinked collagen, compression molded/salt leached PEGT/PBT copolymer and collagen-PEGT/PBT hybrid scaffolds, the PEGT/PBT scaffold was selected for optimization. Geometric parameters were determined using SEM, microcomputed tomography, and flow permeability measurements. Fibroblast were seeded and cultured under dynamic flow conditions for 2 weeks. Cell numbers were determined using CyQuant DNA assay, and tissue distribution was visualized in H&E- and Sirius Red-stained sections. Scaffolds 0.5 and 1.5 mm thick showed bridged connected tissue from top-to-bottom, whereas 4-mm-thick scaffolds only revealed tissue ingrowth until a maximum depth of 0.6-0.8 mm. Rapid prototyped scaffold were used to assess the maximal void space (pore size) that still could be filled with tissue. Tissue bridging between fibers was only found at fiber distances < or =401 +/- 60 microm, whereas filling of void spaces in 3D-deposited scaffolds only occurred at distances < or =273 +/- 55 microm. PEGT/PBT scaffolds having similar optimal porosities, but different average interconnected pore sizes of 142 +/- 50, 160 +/- 56 to 191 +/- 69 microm showed comparable seeding efficiencies at day 1, but after 2 weeks the total cell numbers were significantly higher in the scaffolds with intermediate and high interconnectivity. However, only scaffolds with an intermediate interconnectivity revealed homogenous tissue formation throughout the scaffold with complete filling of all pores. In conclusion, significant amount of connective tissue was formed within 14 days using a dynamic culture process that filled all void spaces of a PEGT/PBT scaffolds with the following geometric parameters: thickness 1.5-1.6 mm, pore size range 90-360 microm, and average interconnecting pore size of 160 +/- 56 microm.

Synthetic studies on nonthrombogenic biomaterials 14: synthesis and characterization of poly(ether-urethane) bearing a Zwitterionic structure of phosphorylcholine on the surface
Yang, Z. M., L. Wang, et al. (2003), J Biomater Sci Polym Ed 14(7): 707-18.
Abstract: A new Zwitterionic compound of the phosphorylcholine analogue, 4-hydroxylbutyl phosphorylcholine (HBPC), was synthesized and characterized. HBPC was chemically tethered onto the surface of poly(ether-urethane) (PEU) films with hexamethylene diisocyanate (HDI) as a coupling agent. The existence of a phosphorylcholine structure on the PEU surface was demomstrated by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FT-IR), X-ray photoelectron spectroscopy (XPS) and water contact angle measurements. The nonthrombogenicity of the modified films was evaluated by platelet-rich plasma (PRP) assay. The results showed that films grafted with HBPC have excellent platelet adhesion resistance.

Systemic effects of biomaterials
Black, J. (1984), Biomaterials 5(1): 11-8.
Abstract: Evaluation of the host response to implanted biomaterials usually focuses on the implant site tissue response. This may lead to erroneous conclusions in the same way that examination of battles outside of their historic context does. A broader view discloses a variety of possible and actual systemic effects of carcinogenic, metabolic, immunological and bacteriological nature. Recognition of these effects in patients is hampered by a lack of epidemiological studies.

Systemic inflammation after drug-eluting stent placement
Gogo, P. B., Jr., D. J. Schneider, et al. (2005), J Thromb Thrombolysis 19(2): 87-92.
Abstract: BACKGROUND: Systemic inflammation after coronary intervention identifies patients at increased risk of subsequent cardiac events. Cardiac events are less frequent after use of drug eluting stents (DES) compared with bare metal stents (BMS). Thus, we sought to determine whether attenuation of the systemic inflammatory response was contributing to the improved outcomes.METHODS: A prospective registry was initiated in late 2003. Peripheral venous blood samples from 75 patients undergoing percutaneous coronary intervention (PCI) were obtained before PCI, and both 1 hour and 24 hours after stenting. The concentrations of C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL1-Ra) were determined by ELISA. Eleven patients were excluded from the analysis because they had both DES and BMS.RESULTS: Patients treated with BMS (n=29) compared with DES (n=34) had a higher incidence of marker-positive acute coronary syndromes (40% vs. 17%, p=0.06), vein graft PCI (p=0.02) and a larger final balloon diameter (p=0.04). Consistent with the lower baseline clinical risk, pre-PCI concentrations of cytokines were lower in the DES group (p=0.04 for IL-6 and p=0.08 for CRP). Comparable and significant increases in CRP, IL-6 and IL1-Ra were evident 24 hours after PCI in patients treated with either DES or BMS. After controlling for baseline levels of CRP, there remained a similar and robust (300%) relative increase in CRP for both DES and BMS patients.CONCLUSIONS: The inflammatory response to PCI appears similar in those treated with DES and BMS. Accordingly, the reduction in restenosis after DES is likely not mediated by attenuation of the systemic markers CRP, IL-1Ra, or IL-6.

Systemic inflammatory response during cardiopulmonary bypass and strategies
Li, S., R. Price, et al. (2005), J Extra Corpor Technol 37(2): 180-8.
Abstract: Organ dysfunction after cardiopulmonary bypass (CPB) still is a major problem in patients undergoing cardiovascular surgery. Studies have demonstrated that systemic inflammatory response (SIR) remains one of the major causes of CPB-associated organ injury. The mechanism of SIR during CPB includes the interaction of blood and artificial surface and endotoxemia. The interaction of blood and artificial surface is initiated by protein adsorption. As a result of series of chain reactions, the numerous powerful inflammatory mediators, including hormones and autacoids, are formed and released. Subsequently, the contact system, coagulation system, complement system, fibrinolysis system, and leukocytes, platelets, and endothelial cells, are all activated to participate in the interaction of blood and artificial materials. These activations of different systems and blood cells can interact and magnify each other. CPB-associated endotoxemia has been demonstrated to intensify and deteriorate SIR during CPB. SIR leads to organ injury. In clinical setting, the most common SIR-related organ damage is pulmonary dysfunction, which often is manifested by decreasing of lung compliance, rise in shunt fraction, work of breathing, and likelihood of atelectasis and pneumonia. Strategies to control CPB-related SIR have been developed, such as improvement of biocompatibility of artificial surface (new biomaterials), temporary inhibition of blood cells activation ("blood anesthesia") during CPB, and blockage of the bioactivities and effects of inflammatory mediators.

Tailoring biomaterial compatibility: in vivo tissue response versus in vitro cell behavior
Mattioli-Belmonte, M., G. Giavaresi, et al. (2003), Int J Artif Organs 26(12): 1077-85.
Abstract: Biocompatibility relies essentially on surface phenomena, represented by cell-cell, cell-material and material (polymer)-protein interactions. An in vivo and in vitro experimental investigation was carried out on the biomaterials of two different classes with a good potential for in situ utilisation. Non-resorbable (Polypyrrole, Polyaniline, Polyimide) and resorbable (PLLA-PDXO-PLLA) materials for tissue engineering were studied for their overall tissue tolerance and cellular interactions. These non-resorbable polymers conceived for biosensor applications and implantable drug-delivery systems are intrinsically conductive. The PLLA-PDXO-PLLA triblock copolymer showed interesting tensile properties for bone and cartilage tissue engineering due to the presence of 1,5-dioxepan-2-one. In vitro and in vivo parallel studies showed an interesting correspondence: a) the cells in contact with the resorbable material that appeared to be capable of migratory-regenerative aspects in vitro exhibited good compatibility in vivo; whereas b) the non-resorbable materials, which are designed to remain in situ in vivo, were seen to have the potential to represent an adverse factor (inflammation, fibrotic reactions) that correlated with some aspects of cell behaviour in vitro.

Tailoring high-cut-off membranes and feasible application in sepsis-associated acute renal failure: in vitro studies
Mariano, F., V. Fonsato, et al. (2005), Nephrol Dial Transplant 20(6): 1116-26.
Abstract: BACKGROUND: As removal of pro-inflammatory cytokines is limited in conventional diffusive or convective extracorporeal therapies, we studied in two polysulphone membranes with an industrial albumin sieving coefficient of 0.05 (Type A) and 0.13 (Type B) cytokine (IL-6, IL-8, IL-1beta, IL-1ra, TNF-alpha) and plasma protein (albumin, cystatin C, total proteins) permeability profiles. Based on the convective membrane permeability, we evaluated in vitro the dialytic modality that could provide an acceptable balance between high cytokine and low albumin clearances. METHODS: Cytokine and plasma protein sieving coefficient (SC) and clearance were studied in (i) post-dilutional haemofiltration mode at 20% fixed ultrafiltration rate; (ii) haemodialysis mode (dialysate flow rate of 3 and 5 l/h); and (iii) haemodiafiltration mode (dialysate flow rate of 3 or 5 l/h with 0.5 l/h of ultrafiltrate). RESULTS: In haemofiltration mode both Type A and Type B haemodialysers at QB 150 ml/min exhibited similar median SC nearly up to 1 for IL-1beta and IL-1ra, at about 0.6 for IL-6, 0.4 for IL-8 and 0.7 for TNF-alpha, with clearance values ranging from 15 to 30 ml/min. SC were independent of blood flow and were stable throughout the whole experiment. Albumin SC was higher in Type B than in Type A and rapidly decreased from 0.2 to 0.02 and from 0.5 to 0.04 within 3 h for haemodialyser Types A and B, respectively. Cytokine SC was lower in haemodialysis than in haemodiafiltration and haemofiltration mode, and by increasing dialysate flow from 3 up to 5 l/h in both haemodialysis and haemodiafiltration mode, SC for all tested cytokines decreased. However, at 5 l/h clearances were not different or were higher, since increased amounts of dialysate outlet compensated for the decreased SC. Albumin clearances in haemodialysis and haemodiafiltration mode after 360 min at 5 l/h were 0.81 and 0.91 ml/min, respectively. CONCLUSIONS: Our studies show that a mixed convective and diffusive technique ensures high cytokine clearances with an acceptable loss of albumin.

Tailoring of new polymeric biomaterials for the repair of medium-sized corneal perforations
Bruining, M. J., H. G. Blaauwgeers, et al. (2000), Biomacromolecules 1(3): 418-23.
Abstract: The aim of this study was to investigate whether polymeric biomaterials can be designed such that they become suitable for surgical closure of medium-sized perforations in the cornea, the transparent tissue in the front of the eye. Such a biomaterial must meet stringent requirements in terms of hydrophilicity, strength, transparency, flexibility, and biocompatibility. Four different copolymers of n-butyl methacrylate (BMA) and hexa(ethylene glycol) methacrylate (HEGMA) were prepared and characterized. Poly(BMA) was made as a reference material. Physicochemical properties were measured (contact angles, glass-transition temperatures, thermal degradation, water uptake and swelling), and cytotoxicity in vitro was assessed with a MTT test. Moreover, the interaction between the materials and cultured human corneal epithelial cells was studied. The copolymers may be useful for temporary closure of corneal perforations.

Tailoring the porosity and morphology of gelatin-methacrylate polyHIPE scaffolds for tissue engineering applications
Barbetta, A., M. Dentini, et al. (2005), Langmuir 21(26): 12333-41.
Abstract: Gelatin is a natural protein with many desirable properties for application as a biomaterial, including scaffolding for tissue engineering. In this work gelatin A with a molecular weight in the range 50-100 kg mol-1 was modified with methacrylic anhydride and processed into a concentrated oil-in-water emulsion. Polymerization of the continuous phase gave rise to a polyHIPE, a porous material possessing a highly interconnected, trabecular morphology. In the paper, we focused on the goal of obtaining matrixes characterized by suitable sizes of both voids and interconnects, to allow an in depth colonization from transplanted cells. In this respect, we investigated the role of the volume percentage of the dispersed phase and the effect of additives. It was established that high pore volumes (>or=90%) are to be preferred, because they allow the production of solid foams characterized by average void and interconnect diameters of approximately 20 and 10 microm, respectively. These values are still inadequate for the intended application of these scaffolds but represent a good starting point for further improvements. These were achieved through the use of additives, namely sodium chloride and dimethyl sulfoxide, which partially destabilized the precursor emulsion and allowed a solid foam to be obtained with void and interconnect diameters in the range of 30-150 microm and 10-50 microm, respectively.

Tailor-made functional surfaces: potential elastomeric biomaterials I
Desai, S., D. Bodas, et al. (2003), J Biomater Sci Polym Ed 14(12): 1323-38.
Abstract: In the present investigation, different functional monomers, like hydroxyethyl methacrylate, acrylic acid, N-vinyl pyrrolidone and glycidyl methacrylate, have been grafted onto the surface of EPDM film (approx. 200 microm) using simultaneous photo-grafting (lambda > or = 290 nm) and cold plasma-grafting techniques, to alter the surface properties, such as hydrophilicity and, therefore, biocompatibility. Here, we have carried out simultaneous plasma-grafting, unlike the conventional post plasma-grafting. The effect of different surface grafting techniques on the degree of surface modification and resultant biocompatibility has been investigated. The chemical changes on the polymer backbone are followed from the results of attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectroscopy and X-ray photoelectron spectroscopy (XPS), which shows the peaks corresponding to the functional groups of the monomers grafted onto the film surface. The morphology of the modified surfaces was investigated using scanning electron microscopy (SEM) technique. The induced hydrophilicity and resultant cell compatibility were followed from the water contact angle measurements and in vitro human carcinoma cell adhesion/proliferation tests, respectively. All the grafted samples exhibited variable cell compatibilities depending upon the type of monomer and their degree of grafting; however, always better than the neat samples. Hydroxyethyl methacrylate and acrylic acid showed exceptionally high cell compatibility in terms of cell adhesion and proliferation.

Tape-casting technique can prepare beta-TCP sheets with uniform thickness and flexibility
Tanimoto, Y., T. Hayakawa, et al. (2005), J Biomed Mater Res B Appl Biomater 73(1): 157-63.
Abstract: The objective of this study is to propose a new fabrication technology for bone substitutes. In this study, a tape-casting method was used to prepare flexible beta-tricalcium phosphate (beta-TCP) sheets. A beta-TCP slurry containing a binder and plasticizer was used in a doctor blade system. The beta-TCP sheet obtained by this tape-casting method was highly flexible, enabling twisting and free-form shaping. The beta-TCP sheet was approximately 0.21 mm thick. X-ray diffraction and Fourier transform infrared spectrometry revealed that the structure of the beta-TCP component in the sheet is the same as that of the original beta-TCP powder. Observation by field-emission scanning electron microscopy showed that the beta-TCP sheet had a flat, microgranular surface. During the early stages, the tensile stress-strain curves of the beta-TCP sheet showed a nonlinear behavior until reaching the point of final fracture. This result was derived from the ductile property of the prepared beta-TCP sheet. In conclusion, a flexible beta-TCP sheet was easily prepared using a tape-casting technique. Fabrication using tape casting offers the advantages of enabling the preparation of ceramic sheets with precise thickness and not requiring expensive fabrication facilities.

Targeted delivery of arjunglucoside I using surface hydrophilic and hydrophobic nanocarriers to combat experimental leishmaniasis
Tyagi, R., S. Lala, et al. (2005), J Drug Target 13(3): 161-71.
Abstract: The purpose of the present study was to investigate the therapeutic efficacy of the indigenous drug arjunglucoside I (AG) against in vivo models of experimental leishmaniasis by incorporating it in surface hydrophilic co-polymeric nanogel particles of size less than 100 nm diameter and to compare its efficacy with that of the free drug as well as the drug encapsulated in hydrophobic poly-dl-lactide (PLA) nanoparticles. The drug AG, having glucose at the terminal end of the glycosidic chain, was isolated from an indigenous source. Drug-incorporated ultra-low-sized nanogels (approximately 90 nm in diameter) composed of cross-linked random co-polymer of N-isopropylacrylamide (NIPAAM) and N-vinyl pyrrolidone(VP) were prepared, characterized and used as delivery vehicles to combat experimental leishmaniasis in hamster models. For comparison, drug-encapsulated hydrophobic nanoparticles (approximately 250 nm in diameter) made from PLA were used as a control. The drug AG was incorporated in these nanocarriers and these drug-nanocarrier complexes were physically characterized. The efficacy of lowering spleen parasite load by the free drug, as well as that incorporated in nanogels and PLA nanoparticles were examined in vivo in equimolar concentration against hamsters undergoing experimental leishmaniasis. The reduction of drug toxicity by the nanogels and PLA nanoparticles was also assessed. The efficacy in the lowering of spleen parasite load with the free drug was found to be only 38% but was much higher when the drug was incorporated in co-polymeric nanogels (79%) or in polymeric nanoparticles (75%). Both the nanocarriers were found to be effective in reducing hepatotoxicity and nephrotoxicity nearly to the same extent. It was apparent that in addition to a smaller size and better drug release profile, the contribution of other parameters, e.g. overall surface hydrophilicity or hydrophobicity of the vehicles, also play an important role in the macrophage uptake of the drug. However, whatever be the exact mechanism, being highly efficient, non-hepatotoxic and non-nephrotoxic, AG in either of the two nanoparticulate forms may have useful application in humans

Targeting delivery of oligonucleotide and plasmid DNA to hepatocyte via galactosylated chitosan vector
Gao, S., J. Chen, et al. (2005), Eur J Pharm Biopharm 60(3): 327-34.
Abstract: Delivery of oligonucleotide to specific cells and maintenance of its biological function are important for nucleic acid therapy. The objective of this paper is to demonstrate that galactosylated low molecular weight chitosan (gal-LMWC) is a safe and effective vector of antisense oligonucleotide (ASO) and plasmid DNA for the hepatocyte targeting delivery. Gal-LMWC has been successfully prepared and MTT cytotoxic assay shows that cytotoxicity of gal-LMWC is lower than that of high molecular weight chitosan (HMWC) and low molecular weight chitosan (LMWC) in HepG2 cells. Using a complex coacervation process, gal-LMWC can form stable nano-complexes with plasmid DNA or with ASO by the electrostatic interaction. The morphometrics, particle size, and the zeta potential of gal-LMWC/ASO complexes and gal-LMWC/plasmid DNA complexes are very similar. The transfection efficiency by using gal-LMWC vector is significantly higher than that of naked DNA or naked ASO in HepG2 cells. Transfection efficiency of gal-LMWC/ASO complexes and gal-LMWC/plasmid DNA complexes depends on the molar ratio of the positive chitosan amino group and the negative DNA phosphate group (N/P ratio) strongly. Inhibition experiments confirm that the enhanced transfection efficiency is due to the ASGR mediated endocytosis of the gal-LMWC/ASO complexes or gal-LMWC/DNA complexes. These results suggest that gal-LMWC can be used in gene therapy to improve the transfection efficiency in vitro and in vivo.

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Last Modified: 8 February 2006