Project Areas

At the beginning of the twenty-first century, we are witnessing a remarkable convergence of our synthetic and physical technologies with the world of molecular biology, which will provide unprecedented opportunities for the creation of novel, functional biomolecules.  Biological systems display architectural complexity with hierarchical order at length scales greater than can be currently attained with synthetic systems.  The complex structures of biology are formed from the self-assembly of molecular components, which is mediated through specific supramolecular interactions that are programmed into their molecular structure.  The culmination of these events underlie the growth and differentiation of living cells, as well as those biological processes, which dictate morphogenesis and tissue repair.  Over the past five decades, basic research into the structure of biological macromolecules has begun to deconvolute the structural principles that underlie the unique functionality of biological systems.  While this course is far from complete, the information obtained from these studies has enabled the scientific community to gain an understanding of the relevant physical and engineering principles that guide self-assembly of biological systems on nano-, meso-, and macroscopic length scales, as well as the mechanistic features of these complex living systems that work in concert to generate distinctive functional responses in time and space. 

Our research group utilizes the same structural guidelines and biologically based engineering principles for the design and construction of non-native materials that display the structural specificity of native biomolecules, but with enhanced functionality.  The development of bio-inspired materials will provide component building blocks for enabling advances in cell-based therapies, artificial organs, and engineered living tissues, all of which will define the evolving field of Reparative Medicine.  While many investigations in the field of bio/molecular materials science and engineering will inevitably be classified as “basic” in nature and other efforts fundamentally deemed “applied”, the success of these endeavors will be dependant on multidisciplinary, collaborative interactions between investigators in diverse disciplines throughout the physical, biological, and clinical sciences.  Thus, despite the inevitably broad spectrum of studies, all of this research will remain motivated by the unique needs of patients that are defined within a specific clinical context.

Biologically Inspired Materials for Reparative Medicine and Organ Fabrication

Synthetic Elastin Analogues

In general terms, recombinant protein engineering can significantly increase protein yield over that which can be achieved by extraction of a native protein from animal tissues and offers the ability to use human amino acid sequences, so as to avoid adverse immunological responses.  However, the most important impact of this technology lies in the potential to introduce precise changes in the amino acid sequence and/or to construct new proteins based upon the assembly of de novo peptide sequences or through the use of non-natural amino acids.  One example is the generation of structural proteins, referred to as protein polymers that consist of sequentially repeated amino acid blocks.  Typically, the incorporation of repetitive oligopeptide sequences, derived from a consideration of the primary amino acid structure of a native protein, imparts critical structural properties from the parent protein to the recombinant polypeptide.  Moreover, opportunities to improve the biological, thermodynamic, and mechanical properties of the protein polymer exist through alteration of the peptide chain length, consensus repeat sequence, and the introduction of additional functional groups or oligopeptide units.  For example, we have demonstrated that substituting different amino acids for those ordinarily occurring in the sequence can affect the susceptibility of the protein to proteolytic degradation or facilitate the placement of crosslinks at well-defined intervals along the polypeptide chain. It is also significant that the uniformity of macromolecular structure achieved by recombinant strategies provides exquisite control over macroscopic polymer properties, including material processability.  In summary, the possibility now exists to generate synthetic polypeptides that mimic structural matrix proteins.  As a result, through a multidisciplinary effort involving a diverse group of chemists and engineers, our group is designing and investigating a number of novel photochemically and virtually crosslinked elastomeric recombinant protein polymers.

Synthetic Collagen Analogues

Collagen comprises the major structural protein component of the extracellular matrix of higher organisms; however it remains a major challenge to emulate the unique structural and biological properties of native collagenous biomaterials in synthetic analogues.  Collagens derived from animal sources are widely employed as biomedical materials although their practical utility is limited by the possible contamination of the material with pathogenic substances, such as viruses and prions, lack of sequence control, and potential immunogenicity in humans.  Consequently, numerous opportunities exist for synthetic collagens in biomedical applications as extracellular matrix analogues, if the appropriate materials could be constructed that retain and expand upon the desirable properties of native collagen fibrils. The exploration of chemical and molecular genetic techniques to design and synthesize collagen-mimetic polypeptides and fibers that are competent for self-assembly into structurally defined protein fibrils is an intriguing avenue for exploration.  We are not only involved in the synthesis of biopolymer analogues but have active programs in the application of novel fabrication strategies for the design of a variety of engineered tissues, including heart valves and blood vessel substitutes.

Synthetic Glycosaminoglycan and Proteoglycan Analogues

Heparan sulfate, a member of the glycosaminoglycan (GAG) polysaccharide family influences a variety of cell responses, including adhesive and motility behavior through direct interactions with specific receptors and, indirectly, as a reservoir for protein growth factors.  Heparan sulfate is currently derived from animal sources, but the lack of sequence control, potential immunogenicity in humans, and possible contamination with pathogenic substances remain major limitations.  This has led to efforts in our group to synthesize polymerizable building blocks that contain the disaccharide repeat units of heparan sulfate, as well as other glycosaminoglycan family members.  These and other analogues are under investigation for applications in controlled drug delivery and therapeutic angiogenesis.

Membrane-Mimetic Systems

Lipid-based membranes have attracted considerable attention due to their potential application as tools to probe cellular and molecular interactions and as bioactive coatings for biosensor or medical implant applications.  In particular, phospholipids differing in chemical composition, degree of saturation and size have provided primary building blocks for membrane-based structures of varying geometry because of their intrinsic biocompatibility, high packing density, and propensity to form lamellar systems.  Nonetheless, inherently limited stability continues to restrict the use non-covalently associated lipid membrane systems to transient or short-term applications.  Prior studies by our group have led to the fabrication of supported membrane-like films by photocrosslinking of polymerizable lipids.  Significantly, the ability to integrate bioactive membrane proteins has been demonstrated.  Recently, we have synthesized lipid bolaamphiphiles, which are comprised of two polar head groups separated by one or two hydrophobic spacer groups as an alternate approach for fabricating membrane-mimetic materials comprised of membrane-spanning constituents. In serving as mobile reservoirs for enzymatically active transmembrane proteins, we believe that properties can be incorporated into thin films that may be able to enhance the performance of a variety of artificial organs, cell transplants, and biosensor systems.

Atherosclerosis and Aneurysm Formation

Atherosclerosis, aneurysm formation, and diverse vascul ar wall injury responses, including postangioplasty restenosis and neointimal hyperplasia that follows arterial bypass grafting, are all initiated, orchestrated, or otherwise modulated by local inflammatory responses. For example, the recruitment of monocytes into the arterial wall is considered a critical step in the earliest stages of atherosclerosis and mature plaques are particularly rich in activated immune cells. Restenosis following angioplasty and vascular bypass can also be considered an inflammatory-relate d process and a significant body of evidence suggests that an inflammatory cascade, which leads to cytokine-mediated stimulation of metalloproteinase expression, is an important contributing factor in aneurysm expansion. Numerous clinical and epidemiological reports, as well as fundamental molecular and cellular studies, support the notion that both hypertension and increased levels of oxidized lipids are dominant and interactive factors that induce aneurysm formation by potentiating local inflammatory and proteolytic responses. However, the underlying molecular and cellular mechanisms that eventually lead to a pathologic endpoint as a consequence of these stimuli remain largely undefined. It has been recently recognized that cell surface heparan sulfates are important regulators of tissue repair and local inflammatory responses and their dysregulated expression may lead to a range of maladaptive responses that likely play a critical role in aneurysm formation and atherosclerosis. Opportunities at the interface of cell and molecular biology, as well as biomolecular and mechanical engineering, offer new strategies to decipher the etiology of these processes

Project Applications