Tissue responses

Biomedical Applications. In the area of biomedical polymers and materials, two types of appHcations have been envisioned and explored. The first is the use of polyphosphazenes as bioinert materials for implantation in the body either as housing for medical devices or as stmctural materials for heart valves, artificial blood vessels, and catheters. A number of fluoroalkoxy-, aryloxy-, and arylamino-substituted polyphosphazenes have been tested by actual implantation ia rats and found to generate Httle tissue response (18). 

However, maximum leceptoi occupancy for fuU agonists was still requited for maximum tissue response. The efficacy, was introduced through the concept of a stimulus, 3", defined as... 

R. L. Whalen, "Connective Tissue Response to Movement at the Prosthesis /Tissue Interface," in Biocompatib/e Polymers, Metals and Composites, Technomic Publishing Co., Lancaster, Pa., 1983. 

Surface preparation of the dental implant prior to implantation wiH have an effect on corrosion behavior, initial metal ion release, and interface tissue response (316). The titanium and titanium aHoy dental implants in present use have many forms to assist bone ingrowth attachment including cylinders with holes, screw threaded surfaces, porous surfaces, and other types of roughened surfaces. Methods used to produce porous surfaces iaclude arc plasma... 

FIGURE 2.11 Receptor-occupancy curves for activation of human calcitonin type 2 receptors by the agonist human calcitonin. Ordinates (response as a fraction of the maximal response to human calcitonin). Abscissae (fractional receptor occupancy by human calcitonin). Curves shown for receptors transfected into three cell types human embryonic kidney cells (HEK), Chinese hamster ovary cells (CHO), and Xenopus laevis melanophores. It can be seen that the different cell types lead to differing amplification factors for the conversion from agonist receptor occupancy to tissue response. 

Kenakin, T. P., and Beek, D. (1984). The measurement of the relative efficacy of agonists by selective potentiation of tissue responses Studies with isoprenaline and prenalterol in cardiac tissue. J. Auton. Pharmacol. 4 153—159. 

The various components of classical theory relating receptor occupancy to tissue response are shown schematically in Figure 3.5. It will be seen that this formally is identical to the equation for response derived in the operational model (see material following), where x = [Rt]e/p. 

Black and Leff [11] presented a model, termed the operational model, that avoids the inclusion of ad hoc terms for efficacy. This model is based on the experimental observation that the relationship between agonist concentration and tissue response is most often hyperbolic. This allows for response to be expressed in terms of... 

FIGURE 3.5 Major components of classical receptor theory. Stimulus is the product of intrinsic efficacy (s), receptor number [R], and fractional occupancy as given by the Langmuir adsorption isotherm. A stimulus-response transduction function f translates this stimulus into tissue response. The curves defining receptor occupancy and response are translocated from each other by the stimulus-response function and intrinsic efficacy. 

FIGURE 3.7 Principal components of the operational model. The 3D array defines processes of receptor occupation (plane 1), the transduction of the agonist occupancy into response (plane 2) in defining the relationship between agonist concentration, and tissue response (plane 3). The term a refers to the intrinsic activity of the agonist. 

It can be seen that if KA< v then negative and/or infinite values for response are allowed. No physiological counterpart to such behavior exists. This leaves a linear relationship between agonist concentration and response (where Ka = v) or a hyperbolic one (KA>v). There are few if any cases of truly linear relationships between agonist concentration and tissue response. Therefore, the default for the relationship is a hyperbolic one. 

The operational model allows simulation of cellular response from receptor activation. In some cases, there may be cooperative effects in the stimulus-response cascades translating activation of receptor to tissue response. This can cause the resulting concentration-response curve to have a Hill coefficient different from unity. In general, there is a standard method for doing this namely, reexpressing the receptor occupancy and/or activation expression (defined by the particular molecular model of receptor function) in terms of the operational model with Hill coefficient not equal to unity. The operational model utilizes the concentration of response-producing receptor as the substrate for a Michaelis-Menten type of reaction, given as... 

Equation 6.8) into tissue response through the operational model ... 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism s ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 3.10 Populations That Are Unusually Susceptible. 

Andersen ME, Kirshnan K. 1994. Relating in vitro to in vivo exposures with physiologically based tissue dosimetry and tissue response models. In Salem H,ed. Animal test alternatives Refinement, reduction, replacement. New York, NY Marcel Dekker, Inc., 9-25. 

Pego AP, Luyn MJAV, Brouwer LA, et al. In vivo behaviour of poly (1,3-trimethylene carbonate) and copolymers of 1,3-trimethylene carbonate with D,L-lactide or e-caprolactone Degradation and tissue response. J Biomed Mater Res, 2003, 67A, 1044—1054. 

Testes from the males examined 43 days after the 8-D treatment appeared normal. However, the epididymis was involved in an inflammatory process with sperm granulomas formation. The granulomatous epididymal lesion resembled the lesion seen in auto-immune reaction following bacterial infections or tissue response to foreign bodies (16, 17,... 

Subcutaneous in vivo testing of these polymers (13,14) has shown minimal tissue response—similar, in fact, to the response to poly-(tetrafluoroethylene). These materials are candidates for use in heart valves, heart pumps, blood vessel prostheses, or as coating materials for pacemakers or other implantable devices. 

In summary, preliminary results from two animal models (rabbit and mouse) indicate that poly(N-palmitoylhydroxyproline ester) elicits a very mild, local tissue response that compares favorably with the responses observed for established biomaterials such as medical grade stainless steel or poly(lactic acid)/poly(glycolic acid) implants. At this point, additional assays need to be performed to evaluate possible allergic responses, as well as systemic toxic effects, carcinogenic, teratogenic, or mutagenic activity, and adaptive responses. 

After 7 days, the acute inflammatory response at the implantation site was evaluated. Bisphenol A resulted in a moderate level of irritation at the implantation site and was clearly the least biocompatible test substance. Tyrosine derivatives containing the benzyloxycar-bonyl group caused a slight inflammatory response, while all other tyrosine derivatives produced no abnormal tissue response at all. These observations indicate that tyrosine dipeptide derivatives, even if fully protected, are more biocompatible than BPA, a synthetic diphenol. ... 

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