Research Description

Biomimetic Microenvironments for Tissue Repair

Benjamin Wu, D.D.S., Ph.D., is a practicing clinician and biomaterial scientist.   His research brings to bear bioengineering approaches to regenerate lost tissues based on the following biomimetic strategy:  (i) learn from natural developmental biology, wound healing, and tissue remodeling; (ii) copy nature and engineer biomimetic microenvironments to promote tissue repair; and (iii) investigate the mechanisms by which progenitor cells and biomolecules interact with engineered microenvironments, which can be formed with a combination of surface bound and/or diffusible biochemical signals and/or biomechanical signals.  The projects summarized below demonstrate the application of this general strategy to solve significant clinical problems.   

1)  Bone Repair with Biomimetic Apatites
This project mimics the natural formation of a thin layer of biological apatites around certain foreign implant materials during bone healing.  These apatites are distinct from commercially available, synthetic hydroxyapatites with regard to composition and properties.  Prof. Wu’s team has developed a rapid materials processing strategy to confer uniform, biocompatible apatite coatings throughout the pores of complex three dimensional scaffolds. By controlling microstructure, his group has extended the classic structure-processing-property-performance paradigm by demonstrating that the distinct apatite microenvironments derived from various processing routes can yield significantly different cellular expression of mature osteoblastic genes.  His team recently reported in Nature Biotechnology that this microenvironment alone, without the addition of expensive and specific biochemicals, is sufficient to stimulate adipose-derived and marrow-derived progenitor cells to differentiate into bone-forming cells and restore large, critical-size bony defects.  This novel finding has motivated intense efforts to establish the molecular understanding of the effects of changes in microenvironment on cell fate.  Specifically, Prof. Wu is currently focused on the identification of the dominant signaling pathways by which these biomimetic apatites affect progenitor cells in order to establish molecular-based design criteria for creating even better materials in the future. 

2)  Bone Repair with Bioinspired Growth Factors
This project mimics the expression of a human growth factor, UCB, that is naturally expressed at the osteogenic front of a premature cranial suture fusion associated with craniosynostosis.  Unlike bone morphogenetic proteins (BMP’s) which signal non-specifically upstream of core-binding factor Cbfa1/Runx2 and are responsible for numerous clinical complications in human cervical spinal fusion, UCB appears to signal downstream of Cbfa1/Runx2 and may therefore potentially yield fewer complications.  Prof. Wu’s team has identified this growth factor, and has effectively delivered this protein.  Specifically, complete healing of large, critical sized defects in various animal models have been achieved by selecting the proper carrier-protein combination while simultaneously providing the mechanical and chemical requirements for the carrier to meet the needs of the given biological environment.  Prof. Wu’s team is currently investigating the electrostatic, hydrophobic, hydrogen bonding, and van der Waals interactions that operate between UCB and the microenvironment.  In addition, his team is also developing osteogenic microenvironments that work synergistically with UCB to reduce the dosage of UCB by at least four orders of magnitude.

3)  Intracranial Aneurysm Management with Bioactive Microfilaments
This project mimics and accelerates the simultaneous formation of a natural blood clot, initiation of a foreign body reaction, and formation of granulation tissues around non-degradable platinum coils within un-ruptured intracranial aneurysms.  Prof. Wu’s team hypothesized that such tissue formation can be greatly accelerated by creating a local microenvironment that is initially, and only transiently, pro-inflammatory.  Prof. Wu’s team demonstrated that delivery of a biodegradable coil comprised of a transiently pro-inflammatory polymer can indeed accelerate tissue formation, and subsequently, tissue shrinkage after coil degradation.  Observing that dense granulation tissues tend to form around the coils, Prof. Wu has developed a novel processing technique to incorporate chemically immiscible components to produce oriented microfilaments, and therefore, maximize the surface area available for dense granulation tissue formation.  Moreover, the cell-surface interactions within the aneurysm will also be enhanced by incorporating additional pro-inflammatory agents in the material.  The ultimate application of this approach is to expand the clinical indication and overall success rate of intracranial aneurysm management using degradable coils. 

4)  Engineering of Intestinal Tissues
This project mimics the intestinal microenvironment by engineering (i) an epithelial intestinal villae layer with high surface area for efficient mass transfer and (ii) a functional smooth muscle layer that provides intestinal contractility.   Prof. Wu’s team has developed a novel computer-driven fabrication approach to produce high resolution, microporous villae-like structures that are adhesive for epithelial cells, and patented the conditions to differentiate human adipose derived stem cells into the smooth muscle lineage.  The overall goal of the project is to establish the design rules to control the three dimensional spatial positioning of the appropriate biochemical cues to simultaneously manage the adhesion, differentiation, and function of multiple cell types for the purpose of engineering intestinal tissues.

5)  Biomechanical Stimulation of Ligaments
This project mimics the non-static microenvironment during biomechanical stimulation of natural tissues and the resultant effects on cellular adaptation and extracellular matrix synthesis.  Although the precise signaling mechanism underlying mechanotransduction is not completely understood, there is little doubt that mechanical stimulation plays a significant role in ligament formation.  The literature clearly shows that exercise results in ligament hypertrophy, increased ligament strength and stiffness, and increased attachment strength at the ligament-bone junction, while immobilization results in atrophy.  Prof. Wu’s team has constructed a computer-driven, customized bioreactor that controls strain amplitude, frequency, strain rate, and duty cycle, and has reported that early adaptation of cells to the 3D microenvironment is significantly enhanced by the addition of biomechanical stimulation.  Prof. Wu’s laboratory is currently identifying the optimal combination of biochemical components (i.e. surface modification and growth factor delivery) that will work synergistically to significantly enhance the cell response to biomechanical stimulation.  In this manner, we hope to better understand the effects of biochemical stimulation on ligament formation.

6)  Biomineralization with Biomimetic Peptides
This project mimics the natural biomineralization process in which selected amino acids of proteins induce nucleation and growth of biominerals.  The objective of this project is to promote tooth remineralization by creating a surface microenvironment that is favorable to nucleation, growth, and stability of natural biominerals.  Simultaneously, Prof. Wu’s team is also developing peptide libraries with controlled electrostatic, hydrophobic, hydrogen bonding, and van der Waals interactions to investigate biomaterial-protein/peptide interactions, which can be used in the future to modify surfaces.  Note that this peptide-based strategy is also being investigated for the biomimetic apatite project described earlier.