The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

s, and 360 patents, and edited 12 books. He has also received over 80 major awards including the Gairdner Foundation International Award, Lemelson-MIT prize, ACS’s Applied Polymer Science and Polymer Chemistry Awards, AICHE’s Professional Progress, Bioengineering, Walker and Stine Materials Science and Engineering Awards. In 1989, Dr. Langer was elected to the Institute of Medicine of the National Academy of Sciences, and in 1992 he was elected to both the National Academy of Engineering and the National Academy of Sciences. He is the only active member of all three National Academies. Kevin Shakesheff was born in Ashington, Northumberland, U.K., in 1969. He received his Bacheclor of Pharmacy degree from the University of Nottingham in 1991 and a Ph.D. from the same institution in 1995. In 1996 he became a NATO Postdoctoral Fellow at MIT, Department of Chemical Engineering. He is currently an EPSRC Advanced Fellow at the School of Pharmaceutical Sciences, The University of Nottingham. His research group investigates new methods of engineering polymer surfaces and the application of these engineered materials in drug delivery and tissue engineering. 3182 Chemical Reviews, 1999, Vol. 99, No. 11 Uhrich et al.

Polymeric Systems for Controlled Drug Release

http://www.afinitica.com/arnews/sites/default/files/techdocs/Synthetic%20biodegradables.pdf

Synthetic biodegradable polymers as orthopedic devices.

23 Stereocontrol of Lactide ROP 6164 231 Isotactic Polylactides 6164 232 Syndiotactic Polylactides 6166 233 Heterotactic Polylactides 6166 3 Anionic Polymerization 6166 4 Nucleophilic Polymerization 6168 41 Mechanistic Considerations 6168 42 Catalysts 6169 421 Enzymes 6169 422 Organocatalysts 6169 43 Stereocontrol of Lactide ROP 6170 44 Depolymerization 6170 5 Cationic Polymerization 6170 6 Conclusion and Perspectives 6171 7 Acknowledgments 6173 8 References and Notes 6173

Controlled ring-opening polymerization of lactide and glycolide.

Sterilization, toxicity, biocompatibility and clinical applications of polylactic acid/polyglycolic acid copolymers

The mechanical properties of biodegradable polymers and composites proposed for use in internal fixation (in place of stainless steel) are crucial to the performance of devices made from them for support of healing bone. To assess the reported range of properties and degradation rates. we searched and reviewed papers and abstracts published in English from 1980 through 1988. Mechanical property data were found for poly(lactic acid), poly (glycolic acid), poly(ϵ-caprolactone), polydioxanone, poly(ortho ester), poly(ethylene oxide), and/or their copolymers. Reports of composites based on several of these materials, reinforced with nondegradable and degradable fibers, were also found. The largest group of studies involved poly(lactic acid). Mechanical test methods varied widely, and studies of the degradation of mechanical properties were performed under a variety of conditions, mostly in vitro rather than in vivo.

Compared to annealed stainless steel, unreinforced biodegradable polymers were initially up to 36% as strong in tension and 54% in bending, but only about 3% as stiff in either test mode. With fiber reinforcement, reported highest initial strengths exceeded that of stainless steel. Stiffness reached 62% of stainless steel wiht nondegradable carbon fibers, 15% with degradable inorganic fibers, but only 5% with degradable polymeric fibers.

The slowest-degrading unreinforced biodegradable polymers were poly(L-lactic acid) and poly(ortho ester). Biodegradable composites with carbon or inorganic fibers generally lost strength rapidly, with a slower loss of stiffness, suggesting the difficulty of fiber-matrix coupling in these system. The strength of composites reinforced wiht (lower modulus) degradable polymeric fibers decreased more slowly.

Low implant stiffness might be expected to allow too much bone motion for satisfactory healing. However, unreinforced or degradable polymeric fiber reinforced materials have been used successfully clinically. The key has been careful selection of applications, plus use of designs and fixation methods distinctly different from those appropriate for stainless steel devices.

Mechanical properties of biodegradable polymers and composites proposed for internal fixation of bone

Recent reports describe an unfavorable noninfective inflammatory response to acidic degradation products in clinical applications of bone fixation devices fabricated from bulk hydrolyzing polyglycolides and polylactides (PGA and PLA). The work described here suggests that poly(ortho esters) (POEs) offer an alternative. By comparison, hydrophobic POEs degrade predominately via surface hydrolysis, yielding first a combination of nonacidic degradation products, followed by alcoholic and acidic products gradually over time. POE specimens proved acutely nontoxic in United States Pharmacopeia tests of cellular, intracutaneous, systemic, and intramuscular implant toxicity. Hot-molded specimens degraded slowly in saline, retaining 92 % initial stiffness (1.6 GPa flexion) and retaining 80% initial strength (66 MPa flexion) in 12 weeks. Degradation was almost unaffected by decreasing saline pH from 7.4 to 5.0. This demonstrated the relative hydrophobicity of POEs, since incorporation of small amounts of acid within the polymer markedly increases the degradation rate. Degradation rates were increased substantially by dynamic mechanical loading in saline. This may be true for other degradable polymers also, but no data could be found in the literature. Presumably, tensile loading opens microcracks, allowing water to enter. Solvent cast POE films were strong in tension (30+ MPa tensile yield) and reasonably tough (12-15% elongation to yield). Higher molecular weight films (41-67 kDa) showed no degradation in mechanical properties after 31 days in physiological buffer at body temperature. A 27-kDa film offered similar initial strength and stiffness but began showing mechanical degradation at 31 days. The films showed a decrease in weight with exposure time but no change in either molecular weight or water absorption at 31 days, further supporting the observation that POE degrades by surface hydrolysis rather than by bulk hydrolysis. 0 1994 John Wiley & Sons, Inc.

Evaluation of absorbable poly(ortho esters) for use in surgical implants.

Bioabsorbable films show promise in preventing postoperative interfacial tissue adhesion. Absorbable polymers in film form are generally more sensitive to chemical environments, due to their large surface area to volume ratio. The in vivo environment contains lipids such as cholesterol, triglycerides, and phospholipids, which are known to affect the degradation of permanent and absorbable polymeric biomaterials. Preliminary investigations of in vitro lipid exposure of bioabsorbable poly(ortho ester) (POE) films for implant use are described. POE has been studied previously for use in controlled drug delivery and fracture fixation. Six-week in vitro exposure of 65:35 POE films to a cholesterol emulsion (1 g/L) showed no apparent difference in hydrolytic degradation rates of mechanical properties or mass loss compared to deionized water exposed films. Decreases of 28 and 6% in inherent viscosity were observed after 5 weeks for cholesterol and deionized water exposed films, respectively, suggesting cholesterol may have some effect. Further examination of the data, due to sample variation, revealed that clear, uniform films showed only minor changes in mass loss and mechanical properties after 6 weeks in either of the in vitro media. But slightly cloudy films possessing microscopic bubbles showed accelerated degradation in both media, indicating the effect of cholesterol was inconclusive due to sample variation. Control of the microbubble formation process could have utility in controlling hydrolytic degradation of POE films.

Melissa K. O. Chang

Papers

Mechanical properties of biodegradable polymers and composites proposed for internal fixation of bone

Evaluation of absorbable poly(ortho esters) for use in surgical implants.

Preliminary effects of in vitro lipid exposure on absorbable poly(ortho ester) films.