Andrew J. Holder

Professor of Chemistry

Links More Information Publications Brief Biography Interdisciplinary Collaborative Research Contact Office: 410H RHFH Phone: 816-235-2293 Fax: 816-235-6543 E-mail: holdera@umkc.edu

Computational Chemistry: Pathfinder for Rational Design

What is “rational design”? The properties and behaviors of molecules are a direct result of their molecular structure. Rational design is a process based on information and knowledge (not just data!) that enables the chemist to predict and propose the structures of molecules with specific properties. Our approach involves the use of semiempirical quantum mechanical methods coupled with quantitative structure activity relationships - QSAR - models. At its core is the idea that such a process will shorten the time and reduce the effort needed to bring new products to society for everyone's benefit.

Materials Science as History :  The technological achievement and quality of life of a civilization largely depend on the materials available to make various objects. Materials are so important that historians name historical eras after particular materials predominantly utilized at various points in time : the Stone Age, the Bronze Age, the Iron Age, etc.  An excellent book by Sass summarizes history from a materials' perspective.  The task that we have undertaken is to develop materials in the Biological Age.

Applied to Biomaterials: This observation holds true in the development of biomaterials and (in our case) dental restorative composites, where the necessary and primary emphasis has been on Edisonian or empirical techniques of discovery, where many experiments must be performed to discover and develop new materials. While these investigations are usually guided by an understanding of the basic physical and chemical phenomena that underlie materials science, the level of focus and precision applied to these investigations can be greatly increased by the application of modern computational chemistry methods. We have used successfully used a combination of computational chemistry informed by experimental evidence to propose and prove molecular design adeas.

Dental Restoratives The current focus of our work is on dental restorative materials for "filling" teeth damaged by decay. Repair of damage to tooth structure and replacement of lost tooth material has had a major positive impact on both the quality and longevity of the average person's life. However, the performance requirements for such materials are quite stringent.

Typically, mercury amalgam preparations are used to bulk-fill cavities in tooth structure. This material is used because of its superb wear and durability as well as its similarity in performance (thermal expansion, malleability, etc.) to tooth material. However, there are continuing concerns regarding the use of amalgam as a restorative material. First, there are likely long-term health implications of placing mercury (a known heavy metal toxin) in the body. Second, the restorations must be replaced after some period of time, an expensive (and often painful) process that results in mercury-rich waste. Third, there are negative cosmetic consequences to the silvery-metallic appearance of the amalgam fillings in tooth structure.

Polymeric composite systems have been used for over forty years as restoratives, but with some drawbacks. The most important problem is that most materials contract slightly in volume upon polymerization. This compromises restorative performance because of polymerization stress and shrinkage. Other deleterious effects include incomplete cure of the resin and water sorption of the cured matrix.

Three problems are commonly associated with the shrinkage and resulting stress of polymerizing materials, one of which can be traced to the interaction of the restorative with the adhesive. It involves failure of either the junction between the restorative (adhesive-restorative junction, ARJ) and the adhesive or the junction between the adhesive and the underlying dentin/enamel substrate (adhesive-dentin junction, ADJ), which leads to gap formation between the restoration and the tooth. This gap is an ideal environment for bacterial attack and subsequent decay of the dentin. The second and third effects both involve the polymerization stress and shrinkage; the stress develops from non-failure at the ARJ and ADJ. The tooth structure may be compromised by subsequent mechanical strain, such as chewing or change in volume due to thermal cycling. The third effect often leads to failure or reduced mechanical performance of the restorative material due to internal stresses. Such failure leads to the replacement of the restoration.

It is well-known that incomplete conversion of the double bonds occurs during methacrylate polymerizations. The final double bond conversion ranges from 55% to 75%, which leaves a significant amount of monomer trapped in the resin matrix. These molecules can serve as internal plasticizers, decreasing the strength of the polymer as well as increasing water sorption. A direct correlation between the degree of conversion (DC) of double bonds and bulk properties, such as hardness, wear, tensile and compressive strengths has been demonstrated. Also, monomers and small oligomers can leach out of the system and become potential biocompatibility hazards.

Commonly used methacrylate-based resins are hydrophilic, leading to water sorption after cure. The rate of absorption of water by the matrix proceeds by the laws of diffusion, and dental resins of this type lose tensile strength on aging in aqueous media. Three possible causes of this loss in wet strength have been postulated: water plasticizes the resin matrix; water degrades matrix/filler bonds; and/or water swells the polymer matrix.

Improved Dental Composites Through Molecular Design An interdisciplinary research team led by Professor J. David Eick in the UMKC School of Dentistry has been investigating new polymers for use in dental restoratives. The primary approach has been to blend a low-shrinkage polymer with good physical properties (an epoxide) with an expanding polymer (a spiroorthocarbonate - SOC) and polymerize these together with the objective of overall zero shrinkage/stress of the mixture.

In 1996, my research group began contributing to this effort in the area of screening and design of potential polymer candidates. The specific initial goal of that work was to computationally screen the SOC monomers proposed for polymerization with various epoxides for reactivity . To date, over 50 monomers have been examined for reactivity. This activity is still an important part of our contribution to the project.

In recent years, we have developed a number of QSAR models in support of this project. A summary of the models is included here. Some of our most recent work includes skin sensitization and polymer refractive index.

More than 30 presentations have been made to date at regional, national and international scientific meetings by Dr. Holder and members of the Group describing our findings. In addition, over 20 papers have been published.