Research

Research 2018-08-14T12:45:13+00:00

Research Summary

The Plastic Surgery Research Laboratory at the University of Pittsburgh is directed by Kacey G. Marra, PhD, Associate Professor of Plastic Surgery (primary) and Bioengineering (secondary) and focuses on tissue reconstruction. As such, we have three separately housed laboratories focused on tissue engineering, transplant immunology, and pediatric craniofacial biology. Each of the laboratories is co-directed by a surgeon and a scientist. Total, we have 10 Faculty involved in our Research Laboratories.


Adipose Stem Cell Center

The Adipose Stem Cell Research Laboratory
Co-Directors: Peter Rubin, MD, FACS, Lauren E. Kokai, PhD

In 2002, founders J. Peter Rubin, MD, FACS and Kacey G. Marra, PhD formed the Tissue Engineering Research Laboratory, with a focus on soft tissue and nerve regeneration. To build upon the significant research successes and growth in both fields, a new Adipose Stem Cell Center was created in 2005 to expand the tissue engineering research laboratory to focus on efforts on Adipose Stem Cell Biology. Now co-directed by J. Peter Rubin, MD, FACS and Lauren Kokai, PhD, the ASCC focuses on research regarding the use of adipose-derived stem cells for tissue engineering and regenerative medicine. In addition to stem cells, the ASCC conducts scientific investigation in multiple interdisciplinary areas, including development of novel biomaterials for soft tissue, skin and nerve regeneration, with a strong focus on polymeric materials, both native and synthetic.

There are currently 20 members in the ASCC, including high school students, undergraduate students, medical students, graduate students, post-doctoral fellows, laboratory technicians, trained surgeons, general surgery residents, plastic surgery residents, and research faculty.


Research within the ASCC

Engineered Soft Tissue Substitutes
Clinical Significance: While the implications of selectively manipulating fat tissue growth certainly include the treatment for obesity, there is a tremendous clinical utility for making fat grow. An ideal soft tissue substitute for reconstructive and aesthetic surgery is yet to be identified.

Innovation: Adipose-derived stem cells (ASCs), the mesenchymal precursors to fat cells, are abundant within adipose tissue and can be harvested with low risk by minimally invasive procedures. We have been examining novel biodegradable scaffolds and adipose-derived stem cells as potential soft tissue engineering implants.

Translation: Recent initiatives have identified a tissue engineering model that can maintain fat graft retention for 6 months. With this discovery, Dr. Rubin launched clinical trials in this area.

Neuronal Tissue Engineering
Clinical Significance: There is a need for an off-the-shelf nerve guide to repair large peripheral nerve gaps, with over 200,000 patients per year requiring surgical intervention.

Innovation: This project, led by Dr. Marra, involves the fabrication of a nerve guide composed of biodegradable, FDA-approved polymers, cells and bioactive factors that will stimulate axon growth. Our novel approach permits a slow, controlled delivery of relevant factors or cells that will guide axons to bridge a nerve gap.

Translation: Our research focuses on sciatic nerve as well as the recently established median nerve defect. We are moving forward via several industry collaborations to pursue a clinical trial for long gap extremity nerve injuries. (Industry relationships are discussed in the following sections.)

Wound Healing
Clinical Significance: Non-healing wounds afflict over two million people per year. These wounds include burns, diabetic and venous ulcers, and other chronic wounds. In addition to their morbidity, these wounds place a significant burden on healthcare costs.

Innovation: With leadership by Drs. Marra and Rubin, and support from the Armed Forces Institute of Regenerative Medicine (AFIRM), we have expanded our wound healing efforts to include preclinical models of full thickness excisional defects, burn wounds, diabetic wounds, and infected wounds.

Translation: We have established a Wound Care Center in Cranberry Township, Pennsylvania and a wound care service line within UPMC.

Inflammation of Adipose Tissue
Clinical Significance: It is now known that adipose tissue is a complex and multi-faceted tissue with mechanical and endocrine functions. As a result of hypoxia following grafting or metabolic imbalances, significant inflammation occurs within adipose tissue resulting in a variety of significant and systemic co-morbidities.

Innovation: With leadership by Dr. Kokai and support from the Plastic Surgery Foundation, we are exploring novel adipocyte signaling mechanisms that control immune cell phenotype and promote regenerative instead of inflammatory cell phenotypes.

Translation: We have optimized small animal models to investigate new pharmaceuticals with anti-inflammatory and tissue healing functions in adipose tissue.


Vascularized Composite Allotransplantation (VCA)

Director: Mario G. Solari, MD

Research Summary
Conventional surgical techniques such as skin grafting or free tissue transfer (microvascular transfer of a combination of skin, muscle, and bone based on an artery and vein) are used to reconstruct tissue damaged by trauma or infection/sepsis. Certain structures such as the nose, lips, ears, and the hand are very challenging to reconstruct with established techniques. Vascularized Composite Allotransplantation (VCA) can be a superior method of restoring the aesthetics and function of these complex structures in select patients. However, major hindrances for widespread application of VCA are the need for chronic immunosuppression for graft survival (which places the recipient at risk for infection, neoplasia, and metabolic dysfunction) and nerve regeneration for functional success.

The VCA Laboratory engages in basic and translational research to advance the broader understanding of VCA immunobiology and to develop strategies that facilitate reduction of systemic immunosuppression, prevent acute and chronic rejection, promote allograft survival, and maximize functional outcome.

Our lab focuses on studies in small and large animal (mechanistic and pre-clinical) models of limb, face and abdominal wall allotransplantation related to basic immunologic mechanisms, drug and cell-based therapy, tolerance induction, nerve regeneration, and functional outcomes. The ultimate goal is translating new research findings into novel strategies that will improve the care and quality of life after clinical VCA such as hand and facial tissue allotransplantation. Our laboratory is located within the Thomas E. Starzl Transplantation Institute. Our research faculty has diverse backgrounds and expertise that facilitate the execution of high-level multidisciplinary science in collaboration with leading institutional, national and international centers of research, academia and industry partners with the support of funding from federal (NIH, DOD), private, industry or intramural entities


Pediatric Craniobiology Laboratory

Laboratory Director: Gregory M. Cooper, PhD

Research Summary
The Pediatric Craniofacial Biology Laboratory has been led by Dr. Gregory M. Cooper since 2006. The labs research is focused on the control of bone formation and healing. There are two cases when this research is applicable: 1) when there is too much bone, as in patients with certain congenital bone malformations, and 2) when there is not enough bone, usually after trauma or surgical complications.


Research within the Crainiobiology Laboratory

Craniosynostosis
The initial focus of the laboratory fits into the “too much bone” category. Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures, the cracks between the bones of the skull. This means that the body makes bone where it is not supposed to be. When craniosynostosis occurs, it stops the skull from growing in certain directions, leading to secondary deformations of the brain. In order to allow the brain to grow normally, surgery is performed. Although surgical techniques are often able to improve the growth and development of children with craniosynostosis, more work needs to be done to expand our understanding of the biology that underlies craniofacial malformation and to further improve the treatment of these patients.

The Pediatric Craniobiology laboratory is pursuing the genetics causes of craniosynostosis and the developmental processes that lead to this pathology. Further, the lab seeks to combine tissue engineering techniques with developmental biology to create tissues that can mimic normal suture function. By understanding the molecular mechanisms used by the body to exert control over bone formation, the lab intends to control the differentiation of tissues within the surgical site.


Bone Tissue Engineering

The pediatric craniofacial surgeon encounters many scenarios where osseous deficiencies must be restored, in the absence of a readily available supply of bone. Children between 2 and 10 years of age are especially problematic. Autologous bone grafts from distant sites such as the iliac crest or rib offer sources of bone, but such procedures are limited by low tissue yield and significant donor site morbidity (such as infection, pain, hemorrhage, and nerve injury) in up to 8% of patients. Many studies have been conducted to evaluate various bone substitutes such as cadaveric bone grafts, demineralized bone matrix, bioactive glass, hydroxyapatite, and methylmethacrylate. While some of these alternatives are promising, none are as reliable as autogenous bone, and all are fraught with disadvantages ranging from lack of bioactivity (and subsequent incompatibility with the growing pediatric craniofacial skeleton) to weakness and susceptibility to infection.

Recent advances in molecular biology have improved the understanding of craniofacial biology and made possible what some have termed “generative” craniofacial surgery. Instead of using exogenous materials, it is becoming increasingly realistic to repair craniofacial defects by inducing the generation of autogenous bone. Bone morphogenetic protein-2 (BMP2) therapy has been found to induce osteogenesis by chemical signaling. As with any powerful technology, a thorough evaluation of BMP2’s potential efficacy and associated morbidities must be conducted to allow for a properly informed risk / benefit analysis. The Pediatric Craniobiology laboratory is currently investigating the safety and efficacy of BMP2-based therapies for several different craniofacial applications.