Is angiogenesis an organizing principle in biology and medicine? Judah Folkman  Journal of Pediatric Surgery  Volume 42, Issue 1, Pages 1-11 (January 2007) DOI: 10.1016/j.jpedsurg.2006.09.048 Copyright © 2007 Elsevier Inc. Terms and Conditions

Fig. 1 Publications with angiogenesis in the title from 1971 to May 1, 2006. Journal of Pediatric Surgery 2007 42, 1-11DOI: (10.1016/j.jpedsurg.2006.09.048) Copyright © 2007 Elsevier Inc. Terms and Conditions

Fig. 2 A, Canine thyroid gland perfused through the carotid artery with hemoglobin solutions. Thick-walled silicone rubber tubing is used in the circuit and thin-walled silicone rubber is used in the oxygenator. B, Canine thyroid gland containing a murine melanoma that stopped growing at approximately 1 mm3. The gland is transilluminated to visualize the melanotic tumor. C, Histologic section of thyroid gland showing viable tumor embedded among thyroid follicles. D, When the nonexpanding tumor mass in the thyroid gland was transplanted to the syngeneic mouse from which the tumor originated, the tumor grew more than 1000 times the volume in the isolated perfused thyroid gland and became highly neovascularized. Journal of Pediatric Surgery 2007 42, 1-11DOI: (10.1016/j.jpedsurg.2006.09.048) Copyright © 2007 Elsevier Inc. Terms and Conditions

Fig. 3 A, The idea for controlled release of drugs came from the observation that although most water-soluble dyes such as chlorazol black did not diffuse through silicone rubber (right), certain oil-soluble dyes such as Sudan IV did (left), suggesting that some drugs might do the same. B, Subsequently the 5-year implantable contraceptive, Norplant, used the same principle and in fact the same design of silicone rubber tubing to release a steroid hormone (progesterone derivative) when implanted subcutaneously. C, Silicone rubber tubing containing estrogen derivatives in the form of a ring are used today as a vaginal insert for postmenopausal women. Journal of Pediatric Surgery 2007 42, 1-11DOI: (10.1016/j.jpedsurg.2006.09.048) Copyright © 2007 Elsevier Inc. Terms and Conditions

Fig. 4 A, A pellet made of the polymer ethylene vinyl acetate copolymer (ELVAX) containing a purified angiogenic protein isolated from a tumor and implanted into an intracorneal pocket between the layers of rabbit cornea. The protein was subsequently demonstrated to be bFGF. At day 2 after the implant, there is no inflammation and there are no new blood vessels. The pellet is approximately 0.5 mm. B, By 10 to 12 days, new capillary blood vessels have grown from the limbal edge of the cornea to reach the polymer pellet that is slowly releasing the angiogenic protein. The vessels grow between lamellar layers of cornea, not on its surface. There is no inflammation, the cornea remains clear and transparent, and the rabbits do not notice any irritation. The distance covered by the new blood vessels is approximately 2.0 mm. C, After a small incision is made over the pellet, it pops out easily and the cornea heals (all procedures are carried out under general anesthesia). After this, the vessels undergo gradual but complete regression. Journal of Pediatric Surgery 2007 42, 1-11DOI: (10.1016/j.jpedsurg.2006.09.048) Copyright © 2007 Elsevier Inc. Terms and Conditions

Fig. 5 The first report of the sequential morphological events that occur during regression of neovascularization after removal of the angiogenic stimulus. This experiment in 1978 was an important milestone because it gave me the confidence that in the future, angiogenesis inhibitor drugs (if they could be discovered), might have a similar effect. Journal of Pediatric Surgery 2007 42, 1-11DOI: (10.1016/j.jpedsurg.2006.09.048) Copyright © 2007 Elsevier Inc. Terms and Conditions

Fig. 6 Bioassays for angiogenesis developed in my laboratory during the 1970s. These included A, the chick chorioallantoic membrane, B, corneal neovascularization stimulated by implanted proteins, C, capillary endothelial cells in vitro, and D, angiogenesis in vitro. Journal of Pediatric Surgery 2007 42, 1-11DOI: (10.1016/j.jpedsurg.2006.09.048) Copyright © 2007 Elsevier Inc. Terms and Conditions

Fig. 7 Molecules with antiangiogenic activity discovered in my laboratory from 1980 to 2005. Some of these are specific angiogenesis inhibitors and have no other known activities at this writing (ie, angiostatin, endostatin, TNP-470, and Caplostatin). Endostatin inhibits tumor-induced vessels, but has no effect on pregnancy or wound healing. Journal of Pediatric Surgery 2007 42, 1-11DOI: (10.1016/j.jpedsurg.2006.09.048) Copyright © 2007 Elsevier Inc. Terms and Conditions

Fig. 8 Drugs with antiangiogenic activity that have been approved by the FDA in the United States for the treatment of cancer and macular degeneration and have also been approved by similar agencies in 30 other countries. Journal of Pediatric Surgery 2007 42, 1-11DOI: (10.1016/j.jpedsurg.2006.09.048) Copyright © 2007 Elsevier Inc. Terms and Conditions