Angiogenesis Implants

The controlled release from PTA-SA 50 50 of several drugs known to inhibit the formation of new blood vessels in vivo, cortisone and heparin, is shown in Fig. 9 (15). The inhibitors of angiogenesis delivered in vivo using this polyanhydride were shown to prevent new blood vessel growth for over 3 weeks, following the implantation of the VX2 carcinoma into rabbit cornea (15). 

FIGURE 9 Influence of angiogenesis inhibitors on blood vessel growth. Several inhibitors of angiogenesis were released from PTA-SA 50 50 in vivo. The effect of these agents on the growth of blood vessels around the VX2 carcinoma implanted into rabbit corneas was then determined as described in the text. 

Erdmann et al. (2000) report the fabrication of devices for the localized delivery of salicylic acid from the poly(anhydride-co-ester)s mentioned in Section II.C. A unique feature of this drug delivery system is that the drug compound is part of the polymer backbone. Devices were implanted intraorally and histopathology was reported (Erdmann et al., 2000). Chasin et al. (1990) review fabrication and testing of implantable formulations for other drugs including angiogenesis inhibitors for treatment of carcinomas and bethanechol for the treatment of Alzheimer s disease. 

Tomita K, Izumi K, Okabe S Roxatidine- and cimetidine-induced angiogenesis inhibition suppresses growth of colon cancer implants in syngeneic mice. J Pharmacol Sci 2003 93 321-330. 

Additionally, we could neither find any evidence that MSCs are able to differentiate into vascular endothelial cells nor did we find more vessels within the transplantation areas as compared to the control group. But, in contrast to normal myocardium the amount of vessels was twice as high in the injection areas. This might indicate that the injury (puncture) of the myocardium caused by the syringe needle alone can be an adequate stimulus for the induction of angiogenesis. Therefore, rather the paracrine effects of implanted MSCs than the incorporation of these cells into the vessel walls may be required for vascular growth in the adult (Kinnaird et al., 2004). 

It should be noted, however, that mechanisms of action of most anti-angiogenic compounds are not well understood at present. For example, trombospondrn-1 (TSP-1) is able to inhibit tumour-associated angiogenesis, but when TSP-1 pellets were implanted into the ankles of AIA rats, it enhanced joint swelling and body weight loss in a dose- and time-dependent manner. These, possibly indirect, effects may be due to the involvement of TSP-1 in cell adhesion, as well as to its interactions with other adhesion molecules and inflammatory mediators [125]. 

It is well recognized that in vitro angiogenesis assays can have clear advantages. However, the major drawback of all of these assays is that they require the endothelial cells to be removed from their natural microenvironment, which alters their physiological properties. To study angiogenesis in vivo, the most frequently used assay systems exploit chicken chorio-allanto-ic membrane (CAM) [28,60], the corneal pocket [61], transparent chamber preparations such as the dorsal skin fold chamber [62,63], the cheek pouch window [64] and polymer matrix implants [65,66]. 

In vivo assays however, also have a munber of disadvantages. For example, the pharmacokinetics, necessary for correct interpretation of results, are often unknown, and in addition the host might respond nonspecifically to the implantation. For a review on in vivo angiogenesis models and their potentials and problems, the reader is referred to reference [67]. 

Demit R, Yaba A, Huppertz B (2010) Vasculogenesis and angiogenesis in the endometrium during menstrual cycle and implantation. Acta Histochem 112 203-214... 

Hamano K, Nishida M, Hirata K, Mikamo A, Li TS, Harada M, Miura T, Matsuzaki M, Esato K. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease clinical trial and preliminary results. Jpn Circ / 2001 65 845-847. 

Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003 361 47-A9. 

Kellar RS, Kleinert LB, Williams SK. Characterization of angiogenesis and inflammation surrounding ePTFE implanted on the epicardium. Journal of Biomedical Materials Research 2002, 61, 226-233. 

The influence of NO in thrombogenesis, bacterial infection, angiogenesis, and the immune response suggest that its active release into the tissue surrounding a sensor may minimize the FBR. Sensor coatings that release NO could reduce the occurrence and severity of bacterial infection, minimize inflammation and collagen capsule formation, and promote the formation of new blood vessels, all of which would create a more favorable implant environment. Since NO is reactive (i.e., has a short half-life), the effects of NO would remain localized to the area from which it is released. 

The results by Hetrick et al.32 support the use of NO-release coatings for developing more tissue-compatible sensors. However, the impact of NO on the biocompatibility at a NO-releasing implant is a multifaceted question that is still not fully understood. Further study into the mechanisms by which NO decreases tissue encapsulation and chronic immune response while increasing angiogenesis will aid in optimization of the NO release properties (e.g., flux, concentration, and duration) of an implant coating for sensor applications. 

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