Biomaterlals in Drug Dellvery and Tissue Enginering Langor or pulmo In another example.an electrically conducting polyme to get the desired cel density Techniques such as polypyrrole(PP)was synthesized as a substrate for nerve pohTmealap wth.I use first in in vitro studies in which P proaches were developed to create fibrous structures in specific anatomic shapes. d Ti We h acid (PL of tis One Current approaches involve transplants which have dono e ush the limitation problems as well as difficulties in shaping the tissue (b compati at the host-device interface.Our objective was to enginee cartilage from polymers and chondrocytes. oach has we prop procedures and grow the cells on the polymer scaffold cers. and grown into she s to creat cre a placed. Conclusion To examine a plastic urgery application,we extracted w of some cartilage cells and i such rosearch man laboratories are conducting studies problem.By making a mold of a polymer in the specific in these areas.With chemists and materials scientists shape desired and then placing cartilage cells on the work ing togethe wit mportant ob engi d grafted onto be found Recently.clinical trials began.The first patient was a 1-ear-boy.Hehaa defo References c prote t if he e to were implanted on a polymer scaffold that was created sue Enginee in the shape of a ribca This created new cartilage and d p ection of t Lang with urothelial cells and a ement for Mikos.AG.Growing neworgans Sci Am.1999 incomplete urethra. Urinary valves have also been dellvery and targeting,Nature 1998,392(Suppl) damaged valve that all ontinence which affects 1-3 millio people%women.can be similarly treated by augment 193. ing the v logic tissue engin nr with t of coll muscle and endothelial cells.by necting the tubes to a pump.nutrient med ough them in vit pulsatile radial str s in the hioreactor n (10) ontr ns for ns has a beating heart.This enabled the cells to produce more collagen anc (11)lyce ce b tronger nal blo :50%collas high B.:Karel,M.:L and ability to be sutured.When transplanted into pigs e od flow VOL.33.NO.2,2000 ACCOUNTS OF CHEMICAL RESEARCH 99(RGD) could be attached.59 Such sequences can help guide cell behavior.60 The polymers must then be manufactured into scaf￾folds that have a very large surface area per unit volume to get the desired cell density. Techniques such as incorporating water-soluble salts into polymer matrices followed by leaching can lead to foams.61 Several ap￾proaches were developed to create fibrous structures in specific anatomic shapes.62,63 Examples of Engineered Tissues. We have attempted to engineer a variety of tissues. One example is cartilage. Current approaches involve transplants which have donor limitation problems as well as difficulties in shaping the tissue (because of cartilage’s mechanical properties), or prostheses which suffer from inflammation or loosening at the host-device interface. Our objective was to engineer cartilage from polymers and chondrocytes. In theory, we proposed to remove a small sample of cartilage cells from a patient by minimally invasive procedures and grow the cells on the polymer scaffold, creating “explants”. The explants are then placed in an animal, where they occupy the precise dimensions of the polymer scaffold onto which the cells were originally placed. To examine a plastic surgery application, we extracted cartilage cells from an animal and multiplied them in a bioreactor.63 This helped address the donor shortage problem. By making a mold of a polymer in the specific shape desired and then placing cartilage cells on the polymer matrix, the polymer cell scaffold was grafted onto mice and rabbits in that specific anatomic shape.64 Recently, clinical trials began. The first patient was a 12-year-old boy. He had a deformed chest, with no ribcage and hence no protection to his heart if he were to be struck in the chest. Right over the heart, cartilage cells were implanted on a polymer scaffold that was created in the shape of a ribcage. This created new cartilage and offered protection of the heart. In another case, modified polymer tubes were seeded with urothelial cells and generated a replacement for an incomplete urethra.66 Urinary valves have also been bioengineered to replace damaged valves that allow urine backflow, by local injection of a cell-polymer matrix. The reverse problem, incontinence, which affects 1-3 million people, 85% women, can be similarly treated by augment￾ing the weakened urologic tissue.67 To engineer blood vessels, 3-mm-diameter polymer tubes were cultured with two types of cellsssmooth muscle and endothelial cells. By connecting the tubes to a pump, nutrient medium flowed through them in vitro in a bioreactor. To do this successfully, it was important to use pulsatile radial stress in the bioreactor, mimicking a beating heart. This enabled the cells to produce more collagen and hence be stronger than vessels grown in static culture. The synthesized vessels were similar to normal blood vessels: 50% collagen, high rupture strength, and ability to be sutured. When transplanted into pigs, the vessels retained the ability to allow blood flow for 1 monthsthe study duration.68 To make replacement heart or pulmonary valves, two cell types, endothelial cells and fibroblasts, were also employed. After 6 months, the synthetic valves were functional in lambs.69 In another example, an electrically conducting polymer￾polypyrrole (PP) was synthesized as a substrate for nerve regrowth. It was used first in in vitro studies in which PC- 12 (a nerve-like cell) or Schwann cells were grown. Interestingly, while minimal growth or attachment of such cells was observed on polylactic acid or polylactic-glycolic acid (PLGA) films, neurite extension was observed on PP films, and neurite outgrowth doubled when an electric stimulus (100 mV for 2 h) was passed through the film. Initial in vivo studies showed these polymers were bio￾compatible.70 When used as a nerve guide, in a sciatic nerve regeneration rat model, they display a density and topology of nerve fibers similar to those of native nerve. In a final example, this same general approach has been used to create skin for patients with burns or skin ulcers.71 In this case, neonatal dermal fibroblasts are placed on PLGA scaffolds and grown into sheets to create skin. Conclusion The above examples review of some of our research efforts in biomaterials. There are numerous challenges ahead in such research. Many laboratories are conducting studies in these areas. With chemists and materials scientists working together with clinicians and engineers, new solutions to important medical problems will hopefully be found. References (1) Ratner, B. D.; Hoffman, A. S.; Schoen, F. J.; Lemons, J. An introduction to materials in medicine. Biomaterials Science; Academic Press: San Diego, CA, 1996; pp 1-469. (2) Lanza, R. P.; Langer, R.; Chick, W. L. Principles of Tissue Engineer￾ing; Academic Press: Austin, TX, 1997; pp 405-427. (3) Ron, E.; Langer, R. Erodible Sytems. In Treatise on Controlled Drug Delivery; Kydonieus, A., Ed.; Marcel Dekker: New York, 1992; pp 199-221. (4) Mooney, D. J.; Mikos, A. G. Growing new organs. Sci. Am. 1999, 240 (4), 60-65. (5) Langer, R. Drug delivery and targeting, Nature 1998, 392 (Suppl.), 5-10. (6) Langer, R.; Brem, H.; Falterman, K.; Klein, M.; Folkman, J. Isolation of a cartilage factor that inhibits tumor neovascularization. Science 1976, 193, 70-72. (7) Langer, R. Bioavailability of macromolecular drugs and its control in controlled drug bioavailability. In Bioavailability Control by Drug Delivery System Design; Smolen, V., Ed.; J. Wiley and Sons: New York, 1985; Vol. 3, pp 307-362. (8) Ball, P. Spare parts: biomedical materials. Made to Measure: New Materials for the 21st Century; Princeton University Press: Princeton, NJ, 1997; p 240. 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