The faculty members of the program investigate aspects of tissue bioengineering, cellular and molecular mechanisms of human disease and regenerative processes. Brief descriptions of the faculty research interests appear below:
Tissue Engineering, Biologic Scaffolds, and Extracellular Matrix Biology:
Dr. Badylak’s laboratory is focused upon the translation of tissue engineering and regenerative medicine principles to the clinical setting. Dr. Badylak has successfully implemented the use of biologic scaffolds composed of naturally occurring mammalian extracellular matrix (ECM) into human clinical practice. The present efforts of the laboratory include studies to better understand the signals that control the host response to implanted scaffold materials; especially biologic scaffolds. There are major efforts and active projects in the areas of composition and ultrastructure of the ECM/cell signaling, environmental cues that regulate host response to injury and tissue reconstruction, musculotendinous tissue reconstruction, and CNS reconstruction. In addition, there are intense efforts to understand the relationship of the host innate immune response to the remodeling events that occur following the implantation of biologic scaffold and synthetic scaffold materials. Clinical translation efforts are focused upon esophageal replacement in patients with Barrett's Esophagus and the repair and reconstruction of musculotendinous structures. The lab is highly interdisciplinary and staffed by a rich mixture of biologists, engineers, chemists, physicians, and scientists.
Computational & Systems Biology:
Dr. Bahar will be advising on the use of computational models of different complexity for simulating dynamic processes at different levels. Her expertise is in the application of methods for reaction kinetics and machine learning to model and analyze the dynamics of cellular networks, and to develop computational tools for quantitative systems pharmacology. These approaches are becoming increasingly important with rapid accumulation of sequence, structure, & pathways data, and the growing need for personalized medicine tools.
Matrix Formation / Degradation in the Skeleton:
Dr. Blair’s group is interested in the balance of matrix formation and degradation, mainly in the skeleton, but also the regulation of macrophage degradation of cellular debris for recycling pathological damage. They study mesenchymal stem cells involved in matrix synthesis, including active transport to support extracellular mineralization. To study matrix degradation, they study CD14 monocytes purified from human blood, and monocytes from mice. They use these to differentiate macrophages and osteoclasts, and determine the interaction of these cells with extracellular matrix for matrix degradation and recycling. They are interested in applying modern techniques including mass spectroscopy of cell components and cell products and gene screening of mRNAs to determine how local and systemic signals interact with differentiating cells to regulate normal and pathological matrix turnover beyond the traditional cell-signaling pathways. Current projects include the roles of glycoprotein hormone receptors in modulation of skeletal cell formation and activity, particularly the roles of FSH and ACTH.
Cardiopulmonary Organ Replacements:
The Brown laboratory is broadly focused on the role of host response in regenerative medicine approaches to tissue reconstruction. More specifically, they seek to understand macrophage biology and its role in regenerative medicine strategies for tissue reconstruction. They have demonstrated that macrophage phenotype, and the ability of macrophages to switch polarization profiles in particular, plays a determinant role in outcomes following placement of biomaterials and tissue engineered constructs. Through development of a more in-depth understanding of immune interactions, they seek to engineer next generation solutions that control the temporal and spatial progression of the immune response and improve outcomes of regenerative medicine based therapies. The Brown Laboratory is increasingly focused upon the interplay between the host innate immune system and aging in the context of regenerative medicine, and the application of these concepts to women's health.
Mechanisms of Mitochondrial Stress and Autophagic Remodeling in Neurodegeneration:
A long-term goal of Dr. Chu’s research is to understand mechanisms of oxidative neuronal injury and neurodegeneration, which can be therapeutically targeted to promote regeneration of functional circuits. They hypothesize that protective/reparative responses are activated during injury, but prove inefficient or maladaptive in certain contexts. Since neurons retain the capacity for neuritic/synaptic plasticity throughout the lifetime, identifying cellular mechanisms that tip the balance to favor regenerative remodeling represents a promising approach for neurodegenerative diseases. Their work is focused on understanding injury & repair mechanisms relevant to Parkinson's disease, Lewy body dementia, environmental intoxications & hereditary parkinsonian syndromes, focusing on oxidative stress & autophagy.
Neural Tissue Engineering:
Dr Cui’s research interests lie in neural engineering with special emphasis on the neural electrode-tissue interface, neural tissue engineering, CNS drug delivery and biosensors. Specific projects include: 1) biomimetic surface coatings for neural microelectrode arrays to improve chronic neural recordings and stimulation stability, reliability and longevity; 2) micro-patterning of biochemical, surface chemical and electrical cues on electrode arrays for neural network study; 3) controlled drug delivery and biochemical sensing in the nervous system; and 4) control of neural stem cell growth and differentiation via surface and electrical cues.
Dr. Davidson’s research is focused on understanding the physical and chemical processes that shape embryonic tissues and organs. Cells and tissues are shaped by both mechanical forces and chemical signals during early development to produce the basic body plan and establish functional organs. His group takes a multi-level experimental approach to reverse-engineer these processes combining classical embryological and modern cell biological methods with advanced engineering tools. His group seeks to understand how the cytoskeleton, adhesion receptors and the extracellular matrix contribute to tissue mechanics & force generation during vertebrate morphogenesis. They use microscopy & image analysis techniques including fluorescent RNA in situ, FRET, photo-activation, & high-resolution time-lapse confocal imaging of live cells in tissues, computer simulations of developing embryos at the molecular, cellular and tissue scales.
Genetic Diversity in Liver Development and Regeneration:
Research in the Duncan lab focuses on liver development, homeostasis and regeneration. Polyploidy is a defining feature of the adult liver. Hepatocytes are either mononucleated or binucleated, and ploidy is determined by the number of nuclei per cell as well as the ploidy of each nucleus. Although hepatic polyploidy has been described for well over 100 years, the functional role of hepatic polyploidization is unclear. Dr. Duncan's lab recently showed that regenerating polyploid hepatocytes undergo specialized cell divisions to form aneuploid daughter cells, generating a high degree of genetic diversity within the liver. Moreover, in rodent models, chromosome-specific aneuploid hepatocytes were shown to play a specialized role in liver regeneration, promoting adaptation and resistance to different forms of chronic injury. Current studies explore mechanisms of hepatic polyploidy and aneuploidy, and effect on human health and disease.
Musculoskeletal Tissue Engineering:
Dr. Huard and the Stem Cell Research Center (SCRC) divides its attention and support among a variety of areas of specialization that utilize these Muscle-derived cells (MDCs) for the treatment of a myriad of conditions including: 1) Duchene muscular dystrophy, 2) Critical sized long bone and cranial defects, 3) Acutely injured and osteoarthritic articular cartilage, 4) ACL and meniscal tears, 5) Compartment syndrome injured limbs involving damage to the muscles, nerves, circulatory and lymphatic system vasculature, and 6) Infarct injured and cardiomyopathic hearts. The SCRC is also investigating the use of a variety of agents (Losartan, Suramin, Relaxin, Decorin) to prevent the formation of fibrosis and promote muscle fiber regeneration following muscle injuries caused by lacerations, strains, and contusions. Recently, the lab has begun to study the effects of Platelet-Rich Plasma on muscle, bone, and articular cartilage healing, an exciting new area of research. Members of the SCRC are also working with biomaterial engineers to further improve the sustained release of import growth factors to aid in tissue engineering protocols; for example, the use of a novel PEAD coacervate, which protects the bound growth factor BMP2 and releases it slowly and persistently, has been successfully used to repair bone injuries. Overall, the team is highly inter-disciplinary.
Stem Cells, Liver Tissue Engineering:
Dr. Lagasse’s research focuses on the development of novel cell-based therapies for patients suffering from degenerative diseases using stem/progenitor cells. In addition, they have established a Cancer Stem Cell Center, a collaborative effort between the McGowan and the University of Pittsburgh Cancer Institute. Their current research includes: Identification, isolation, and characterization of stem cells for liver diseases; development of assays for stem cells; in vitro & in vivo expansion of stem cells; and the development of cell-based therapies for liver diseases.
Smart Biotechnology for Immunotherapeutics and Tissue Engineering:
The Little lab explores new strategies to regenerate tissues by presenting biological stimuli in a way that mimics that of native cells. Researchers in his group have developed new ways to synthetically reproduce complex, temporo-spatial presentation of bioactive molecules by design. A wide array of nano and micro fabrication techniques are used to promote proper spatial context. Through key advances in the area of rational design, they have discovered ways to precisely tune a delivery vehicle to produce complex release behavior for the first time. The mission is to utilize "bio-mimetic" delivery systems to achieve: 1) enhanced therapeutic efficiency and create progressive new therapies that "imitate life" & 2) understand basic biological processes that would otherwise be obscured without engineering tools to replicate the presentation of spatially correct molecular information that occur in these processes.
Cardiac Development and Congenital Heart Diseases:
Dr. Lo’s research objectives are to elucidate genetic causes and developmental mechanisms of human congenital heart disease (CHD). Her group utilizes mouse models to examine the genetic etiology of CHD and validates these findings with human clinical studies. Their focus is also on the cellular and molecular basis of early cardiac development and on the developmental etiology of CHD. Eventual goals are to develop more effective diagnostic & therapeutic strategies to improve the lives of patients with structural heart diseases.
Stem Cell, Lung and Liver Biology and Cancer:
Dr. Locker investigates the role of Nkx2.8, a developmental homeobox transcription factor, in stem cell proliferation in the lung, ventral brain, and ventral spinal cord. Nkx2.8 null mice get progressive changes in their large airways that eventually lead to cancer. The similarity to human lung cancer has led to a pilot study of Nkx2.8 as a tumor suppressor of human cancer. Their group also studies (1) transcriptional regulators that control liver development and cell proliferation, (2) long-distance transcription controls that regulate a chromosomal locus, and (3) regulation of gene expression through a specific control language. Ongoing research includes analysis of the domains of Nkx2.8, molecular reconstruction of enhancer-promoter interactions, chromatin structure, and combined molecular-bioinformatics analysis of gene control regions. A related project studies drugs and hormones that induce an alternate pathway of hepatocyte cell proliferation via nuclear receptor transcription factors. This form of proliferation is of particular interest because the drugs that activate it are powerful cancer promoters. Bioinformatics analysis of microarrays is a major part of the project—they are using arrays to define genes that activate the hepatocyte cell cycle and cause it to progress. Dr. Locker has extensive expertise in high throughput analysis including GWAS studies, CHIP-Seq and others.
Tissue Engineering Using Adipose-Derived Stem Cells:
Dr. Marra’s laboratory pursues cellular therapies using adult stem cells derived from human adipose tissue. The potential of adult stem cells derived from discarded fat, or adipose tissue, in regenerative medicine is immense and significant. As 65% of Americans are overweight, adipose tissue represents a plentiful, attractive, and reliable source for somatic cells. In Dr. Marra’s laboratory, they routinely isolate adipose-derived stem cells (ASCs) from human and animal fat. They characterize the ASCs using flow cytometry, and by differentiation into multiple phenotypes, and utilize ASCs for soft tissue and nerve regeneration, as well as wound healing with the eventual goal of clinical translation.
Dr. Michalopoulos and his team are correlating liver regeneration to the development of therapies for liver failure and liver cancer. Simultaneous inhibition of the two mitogenic receptors for hepatocytes and stimulation of liver regeneration leads to liver failure. Genomic alterations highly prevalent in liver cancer are associated with growth suppressor pathways in normal hepatocyte growth. The evidence obtained from high-density genomic analysis of liver cancer cases has now implicated genes such as LSP1, PTPRD, MAML2 and RSU1 as essential growth suppressor pathways, which are involved in termination of liver regeneration and regulation of liver weight. Another protein, Glypican-3, highly over-expressed in liver cancer, regulates Hedgehog and Hippo pathway which controls YAP, an important protein in hepatocyte growth and liver size regulation. Liver regeneration has defined processes involved in organ growth with rich details not available in other organs and provides a framework to interpret cancer genomics in the context of normal tissue growth.
Liver Development, Stem Cells and Regeneration:
The major focus of Dr. Monga’s research is to develop novel therapies for liver insufficiency in acute or chronic liver failure. They investigate liver development to examine how cellular and molecular cues direct the expansion and differentiation of bipotential hepatic progenitors. Elucidating these mechanisms may be helpful in differentiating stem cell to hepatocytes. They study pathways like Wnt/b-catenin, FGF, Hippo and PDGFRa signaling in liver development. They also focus on the process of liver regeneration. Identification of molecular and cellular mechanisms that restore liver size will be of essence in treatment of liver insufficiency and form the basis of hepatic regenerative medicine. They are researching role of Wnt/b-catenin signaling pathway in liver regeneration process through use of multiple, sophisticated genetic mouse models and using chemical and hormonal modulators of this pathway to induce regeneration that is highly significant and translational.
Dr. Oertel’s research evaluates cell transplantation strategies and identifies essential cell characteristics that relate to the repopulation of the liver and tissue microenvironment conditions that foster this repopulation. They discovered that fetal liver stem/progenitor cells sufficiently replace hepatic mass in the near-normal rat liver. Recent studies are examining mechanisms of enhanced cellular engraftment. The lab is also investigating the therapeutic potential of progenitor cell transplantation in treating hepatic fibrosis/cirrhosis.
Liver Development and Regeneration:
Dr. Shin uses zebrafish as a model organism to understand liver development and regeneration at cellular and molecular levels. Using genetic tools that allow temporal manipulation of signaling pathways in zebrafish embryos, they investigate these processes. They have recently developed a regeneration model in zebrafish that allows for temporal ablation of hepatocytes during any developmental period. Using this model, they have been investigating the cellular and molecular mechanisms of liver regeneration. They will perform a chemical screen using zebrafish embryos to identify compounds that can augment or repress liver regeneration.
Cardiovascular Mechano-Energetics and Structure-Function Relationships
Our research interests are focused on three areas: (1) Relationships between left ventricular mechano-energetic function and underlying cellular processes, with a special emphasis on contractile and regulatory proteins and post-translational regulation of cardiac contraction (e.g., via phosphorylation or acetylation). Whole heart, isolated muscle, and single cell experiments are performed using various animal models, including transgenic mice. We are currently using this basic information regarding structure-function relationships to develop novel inotropic therapies that are based on altering cellular composition using genetic means and to optimize the fabrication protocol for engineered cardiac tissue such that it possesses the desired contractile and energetic properties. (2) The role of pulsatile arterial load (vascular stiffness in particular) in cardiovascular function and potential therapeutic applications of vascular stiffness-modifying drugs and/or hormones (e.g., relaxin). One of the hypotheses being investigated is that aberrant vascular stiffness changes are involved in the genesis of certain cardiovascular pathologies (e.g., preeclampsia, isolated systolic hypertension in elderly). Novel noninvasive measurement techniques are used to conduct longitudinal human studies, which are complimented by in vivo and in vitro vascular and cardiac studies with animal models. (3) The role of regional contraction dyssynchrony in global ventricular mechanics and energetics. In addition to basic research, we have developed and continue to develop novel, simulation-based material (i.e., mathematical models of biological systems and associated "virtual experiments") for education and engineering design.
Organ Replacement, Regenerative Medicine Approaches:
Dr. Soto-Gutierrez's research is focused on the development of new technologies for organ replacement using bioengineering, cell transplantation and organ engineering. His lab uses the structural connective tissue of discarded organs as a scaffold for growing new tissue/organs for transplantation. His laboratory works on liver cell differentiation and understanding liver cell maturation of embryonic or induced pluripotent stem cells using interactions with liver non-parenchymal cells, 3D-liver extracellular matrix and different molecules to produce transplantable tissue or modeling diseases (e.g. fatty liver). In addition his laboratory is interested in strategies for liver repopulation & regeneration in disease states (e.g. liver failure and liver steatosis) and hybrid organ engineering for transplantation to treat diabetes.
Biological Study of Development, Growth, Function and Health of Skeletal Tissue:
Dr. Tuan directs a multidisciplinary research program that focuses on orthopedic research as a study of the biological activities underlying the development, growth, function, and health of skeletal tissues, and the utilization of this knowledge to develop cell-based technologies that will regenerate and/or restore function to diseased and damaged skeletal tissues. Ongoing research projects are directed towards skeletal development, stem cells, growth factor signaling, bone-biomaterial interaction, extracellular matrix and cell-matrix interaction, nanotechnology, mechanobiology, regenerative medicine, & tissue engineering, utilizing integrated contemporary technologies of biochemistry, cell & molecular biology, embryology & development, cell imaging, & engineering.
Inflammation; Computational Modeling; Systems Biology
Dr. Vodovotz leads an interdisciplinary effort combining computational, experimental, and clinical studies aimed at a systems-based understanding of inflammation. He has created novel, translational applications of mathematical modeling, including in silico clinical trials and patient-specific predictive models, culminating in the design of a biohybrid device for patient-specific, self-adaptive control of inflammation. He is a co-founder and current President of the Society for Complexity in Acute Illness and a co-founder of Immunetrics, Inc., a company that commercializes mathematical work in the context of the pharmaceutical industry, applying computational models of inflammatory disease in the rational design of new therapies.
Biomechanics and Regeneration of Tubular Tissues:
The overall goals of Dr. Vorp’s work are 1) to use optical and biomechanical interrogation techniques to evaluate changes in the structure and biomechanical properties that occur with diseases of tubular tissues (e.g., blood vessels, urethra, esophagus), and 2) to use regenerative medicine techniques to develop strategies for the repair or replacement of these tissues. Their tissue-engineered blood vessels (TEBV) are fabricated by seeding stem cells into a biodegradable, elastomeric supporting scaffold. They investigate the ability of the TEBV to remodel into a functional blood vessel. This includes exploring the fate of the seeded cells & translational logistics, such as scale-up, effect of age, gender & disease states (e.g., diabetes) on TEBV remodeling. They also explore the effects of physiologic biomechanical forces on mesenchymal stem cell differentiation & proliferation.
Biomaterials for Cardiovascular Tissue Engineering:
Dr. Wagner and his team work in the area of cardiovascular tissue engineering. This focus grew from the observation that much of the early work in this field relied upon scaffold material such as poly(lactic-co-glycolic acid), which does not mechanically mimic the properties of soft tissues such as those of blood vessels and the heart wall. The group has focused on the molecular design of thermoplastic biodegradable elastomers that would be amenable to control at both the synthetic and processing stages to achieve scaffolds optimized for a given application. The team, linking polymer chemists, bioengineers and surgeons, has synthesized, processed and characterized a wide variety of polymers and polymer based scaffolds for the replacement and augmentation of various tissue types. These materials have been characterized in vivo as replacement scaffolds for blood vessels and abdominal wall in addition to being used as a mechanical support material for the failing ischemic ventricle and vein grafts. Furthermore, the group has pioneered novel assays that allow the evaluation of circulating platelet activation in both bovine and ovine models. This work allows for a much greater insight to be obtained during cardiovascular device implantation to quantify improvements in device design (e.g. surface coatings and flow path refinement). We have also conducted a variety of clinical studies regarding platelet activation with disease and device implantation.
Pediatric Cardiothoracic Diseases and Treatment:
Adult and Pediatric Cardiothoracic Surgeons face the limitations of existing mechanical circulatory support technology on a daily basis. Dr. Wearden’s expertise is in the management of patients with heart failure with ventricular assist devices. He has participated in and continues to lead several funded projects related to the development of heart pumps and other devices for children. He has experience in both the industrial & regulatory aspects of device development having served on Clinical Events Committees (CECs) for Berlin Heart, World Heart and ALung Technologies. He was an invited lecturer to FDA “in house” symposia and was part of Berlin Heart Pediatric EXCOR FDA panel team which was unanimously panel approved. Since 2003 he has directed all pre-clinical surgical cardiothoracic implants at MCGOWAN & has much experience with large animal models.
Tissue Micro-Environment in Regeneration and Cancer:
Dr. Wells’ lab aims to understand how tissue microenvironment alters cell behaviors and phenotypes and how this regulation dictates physiologic and pathologic situations. They examine soluble and matrix signals. His lab also examines wound repair, primarily of the skin and bone especially focusing on stem cells that undergo a biphasic phenotype change during limited repair. In the pathological situation of tumor dissemination, the phenotypically transitioned carcinoma cells are phenotypically shifted to accomplish ectopic seeding, metastatic establishment and dormancy. To derive the molecular bases of these situations so as to rationally effect better outcomes, they investigate how integrated cell responses are selected and the metabolic and phenotypic consequences of such. This integrative approach has enabled them to employ cell and tissue engineering principles to design surfaces that specifically promote repair over scarring. They also pursue novel studies in tumor metastasis in an innovative liver bioreactor and in skin organ cultures ex vivo.
Biomechanics of the Knee: Understanding Injury, Healing, and Repair:
Dr. Woo has shown that the healing ligament or tendon has a disorganized collagen matrix and inferior mechanical properties to normal tissue. Studies have shown that small intestine submucosa (SIS), when used as a combination of sheet and hydrogel form restores the histomorphological appearance, biomechanical content and mechanical properties of healing tissues. At this time, his group is developing a magnesium-based scaffold as a mechanical augmentation to bridge the gap between two ends of a torn anterior cruciate ligament (ACL) to provide initial joint stability. This is needed because the healing of an injured ACL is slow, and can lead to disuse atrophy. They have performed in vitro time-zero evaluation of the Mg-based scaffold and confirmed it restores joint stability better than suture repair alone, and is a faster process. Next they will combine the SIS material with the mechanical augmentation using the Mg-based scaffold to test their synergy in the healing of a torn ACL in a large animal study.
Wound healing, chemokine biology, matrix biology:
Studies in Dr. Yates’s laboratory are focused on dissecting the molecular and cellular mechanisms of skin remodeling and regeneration and its pathogenesis, by integrating basic science discoveries with clinical outcomes. Specifically, they are conducting animal and patient based research that incorporates multiple disciplines to accelerate discovery of novel treatment strategies for skin fibrosis in systemic sclerosis (SSc). The group is elucidating the biological mechanism that contributes to the coordination between inflammatory responses and extracellular matrix production that leads to development and progression of dermal fibrosis in SSc. In order to study fibrotic effects they use skin samples from patients with SSc, ex vivo organ cultures, and Y genetic animal models. Additional collaborative projects are in the areas of polymer based stem cell therapies for non-healing & scarring wounds and peptide therapies for pathological angiogenesis in eye diseases.