Research

Overview

The efforts within the Bioengineering Research Center at the University of Kansas are focused on performing innovative research to address issues relating to the integration of engineered materials into human physiology and to the development of novel technologies for early-stage diagnosis and management of disease.  The theme that connects all of the projects in the Bioengineering Research Center is the translation of research to the public sector.  The active participation of scientists, engineers, clinicians and industrial partners on the project teams drive the basic science to product development.  This structure stimulates the free flow of ideas, outcomes and needs between the investigators, end-users and industrial partners.

The development of novel synthetic or tissue-engineered materials that could serve as durable replacements for biologic tissue destroyed by disease, injury or the aging process is one of the most exciting areas of investigation in both medicine and dentistry.  One challenge is to develop biomaterials that possess lightweight hierarchical structures with self-healing capabilities and fatigue-resistant design while also recognizing the need for technological approaches that will reduce cost, improve productivity and assure the delivery of high quality products in a timely manner. The ACE approach, presented below, represents an integration of structure/property data collected from the biologic tissue and captured in computational tools.  This approach offers an effective mechanism for developing lightweight, self-healing and fatigue resistant biomaterials while addressing the need to improve productivity and decrease time spent on synthesis and testing of materials that do not meet the requirements.

 [Adapted from Kohn J, et al. Biomaterials 28:4171-4177, 2007].

 The combination of multi-scale experimental measurements with computational/ mathematical modeling provides insights beyond what could be accomplished if either of the approaches were applied independently.  This combination will alleviate the typical disadvantage of mathematical models that stems from the less-than-perfect empirical information available to make the models realistic. Needless to say, the proposed multi-scale modeling approach will afford the advantage that parameters that cannot be easily modified in the laboratory may be easily varied in the models, and the models may be exercised for a variety of conditions.

 Material/Tissue Interface Characterization

In the exploration of new biomaterials, one area that has been largely overlooked is chemical and mechanical characterization of the material/tissue interface.  This is a particularly challenging area of investigation since many of the current analytical techniques do not offer the required spatial resolution to study reactions occurring at the interface of the conditions, i.e. temperature, vacuum, etc. under which the sample must be analyzed destroy or significantly damage/alter the biologic tissue.  To address these problems, we have developed nondestructive techniques to characterize and quantify reactions at the material/tissue interface.

 Research Highlights

The instrumentation in the KU Bioengineering Research Center provides structure/property imaging capabilities at the cellular and tissue levels.  These resources offer investigators the opportunity to explore the new frontiers where imaging interfaces with bioengineering. Activities are focused in the following areas:

1. understanding the micro- and nano-structure/property relationships of natural tissues and using this knowledge to design new biomaterials;
2. development of new biomimetic materials and devices;
3. defining the fundamental phenomena that control reactions occurring at the interface of biological tissues with synthetic and tissue-engineered materials;
4. development of materials to deliver therapeutic agents to specific cells, tissues or organs;
5. development of methodology and devices for the examination of biological structure and function; the ultimate goal of this work is early diagnosis and effective treatment of disease.

Spectroscopic imaging of biointerfaces
Work from Dr. Spencer’s laboratories provided the first molecular structural analysis of acid-etched smear layers (Spencer et al. 2001; Wang and Spencer 2002).  This work represented the first study to quantify dentin demineralization under conditions that permit hydration of the specimen throughout the analysis.  Hydration is critical to these efforts since it is widely accepted that the collagen within the demineralized dentin will collapse if it is allowed to dry; such collapse would lead to inaccurate characterization of the extent of degree of dentin demineralization.  The micro-Raman spectral data indicate that 15 sec of acid-etching with 35% phosphoric acid gel demineralized dentin to a depth of ~ 10 micrometers.  The spectral results presented in this study indicated that collagen within the smear layer is disorganized but not denatured.  This disorganized collagen is denatured by the 15-second acid-treatment used in this study.

Development of non-destructive techniques for analyzing material/tissue interfaces
Because of the non-destructive nature of the analytical characterization techniques, the same specimen and the same small region of the specimen was analyzed using both scanning acoustic microscopy (SAM) and micro-Raman spectroscopy (µRS). Thus, the structure as determined by measurement of the molecular features can be related directly to the acoustic impedance (modulus of elasticity) within the same small region of the sample.  These complementary techniques allow us to relate differences in the micro-mechanical properties -specifically the modulus of elasticity- to the molecular structure within the region analyzed.

 Multi-scale characterization and modeling of tissues, materials and tissue/material interfaces
In the exploration of new biomaterials, one area that has been largely overlooked is chemical and mechanical characterization of the material/tissue interface.  This is a particularly challenging area of investigation since many of the current analytical techniques do not offer the required spatial resolution to study reactions occurring at the interface of the conditions, i.e. temperature, vacuum, etc. under which the sample must be analyzed destroy or significantly damage/alter the biologic tissue.  To address these problems, we have developed nondestructive techniques to characterize and quantify reactions at the material/tissue interface.

Multi-scale computational modeling of hierarchical biologic tissues
While there may be as many as five or six distinct length scales in the hierarchical structural architectures of native tissues and material/tissue interfaces, the influence of small features in the hierarchy on the overall mechanical properties is not well understood.  The generation of mechanistic models that relate global mechanical response to initial degradation requires the development of experimental techniques that allow the measurement of mechanical properties of small substructures, e.g. in the range of 10-1000nm.  In addition, mathematical models that meaningfully use the measurements at small scales to predict behavior at larger scales are also not widely available.  The combination of experimental measurements with the modeling is expected to provide insights beyond what could be accomplished if either of the approaches were applied independently.  Moreover, the combination of experimental and modeling techniques will help alleviate the typical disadvantage of mathematical models that stems from the less-than-perfect empirical information available to make the models realistic.  The multi-scale modeling approach offers the advantage that the parameters that cannot be easily modified in the laboratory may be easily varied in the models and the models may be exercised for a variety of conditions.

Finite Element Modeling of Dentin/Adhesive Interface

Synthesis of monomers and evaluation of dentin adhesives
The lifetime of methacrylate adhesives in the mouth has fallen far short of expectations. Though many factors may contribute to the premature breakdown of these adhesives, their chemical “Achilles heel” may prove to be the ester linkages in the methacrylate matrix since these are susceptible to attack by water and esterases. Our group has designed and synthesized new monomers, and characterized and evaluated the interface and the enzymatic degradation of dentin adhesives containing new monomer.

Net cumulative MAA release from control and experimental adhesives [A0:HEMA/BisGMA; A0T: HEMA/BisGMA/new monomer; A8: A0 + 8% water; A8T: A0T + 8% water; A16: A0 + 16% water; A16T: A0 + 16% water]; N = 3 +/- S.D.

Photoacoustic imaging of biological tissue
Photoacoustic imaging (PAI) is a novel, hybrid, and nonionizing imaging modality that combines the merits of both optical and ultrasonic imaging methods.  It is highly sensitive to the optical absorption of biological tissue.  PAI provides greater spatial resolution than purely optical imaging in deep regions while simultaneously overcoming the disadvantages of ultrasonic imaging regarding both biochemical contrast and speckle artifact.  PAI can provide high spatial resolution images with optical contrast in a region up to 5 cm deep in biological tissue, whereas purely optical imaging techniques cannot provide high spatial resolution in regions beyond the quasiballistic regime (1 mm deep) because of the strong scattering in biological tissues.  With PAI, we can image the structure of biological tissue with optical contrast, detect functional changes (through measuring blood oxygenation, blood volume) in brains, and interrogate tissue molecular information (molecular imaging).

The structural image of the cerebral cortex of a rat (left) and the corresponding oxygenation map (right).  The image was acquired by a PAI system noninvasively