PLASTIC SURGERY RESEARCH LABORATORY
The Plastic Surgery Research Laboratory at the University of Pittsburgh conducts scientific investigation in multiple interdisciplinary areas. The scope of our projects revolves around tissue reconstruction. As such, we have three separately housed laboratories focused on tissue engineering, transplant immunology, and pediatric craniofacial biology (Figure 1). Each of the laboratories is co-directed by a surgeon and a scientist. Total, we have 15 Faculty involved in our Research Laboratory.
Our laboratory has identified itself as an integral part of the University of Pittsburgh Research community. We have strong collaborations with the McGowan Institute for Regenerative Medicine (MIRM), the Starzl Transplantation Institute, the Drug Delivery Institute, the Center for Biologic Imaging, and the newly formed Center for Military Medicine. Our dedication to developing new therapies for our wounded warriors is evident by our strong history of Department of Defense (DOD) funding. All four labs have DOD funding, and indeed, 70% of the laboratory’s funding is from the DOD. Our PI’s are leaders in the Armed Forces Institute for Regenerative Medicine, (AFIRM) an 85 million dollar project funded by the DOD.
A particular effort in our laboratory is the training of our residents. Our program requires the residents to spend one dedicated year in one of our laboratories. During this year, the residents are able to interact with a multitude of experienced researchers, and are encouraged to explore their own research ideas. They are also mentored by their PI’s and asked to submit grant applications, primarily submitted to the Plastic Surgery Foundation. Indeed, our Department has been awarded the majority of the PSF awards over the past 5 years. The residents have published in numerous top-tier journals and have won numerous awards throughout the past decade.
Adipose Stem Cell Center
In 2002, J. Peter Rubin, MD and Kacey G. Marra, PhD formed the Tissue Engineering Research Laboratory, and shortly thereafter, they developed the Adipose Stem Cell Center (ASCC). As such, a major focus in the laboratory is the use of adipose-derived stem cells for tissue engineering and regenerative medicine. There are currently 30 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.
Engineered Soft Tissue Substitutes
- Clinical Significance: While the implications of selectively manipulating fat tissue growth certain 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 has still not been 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: Excitingly, we have recently identified a tissue engineering model that can maintain fat graft retention for 6 months. We have initiated two clinical trials in this area, both directed by Dr. Rubin.
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 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 animal models include a sciatic nerve gap in the rat, as well as the recently established median nerve defect in the non-human primate. 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 Laboratory
- 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 the recent recruitment of Sandeep Kathju, MD, PhD, Spencer Brown, PhD, and Patricia Hebda, PhD, we have been able to expand our wound healing efforts to include preclinical models of full thickness excisional defects, burn wounds, diabetic wounds, and infected wounds. The animal models established in our laboratory include mice, rabbits and pigs.
- Translation: We are in the process of establishing a Wound Care Center in Cranberry and plan to translate our research efforts in that center.
Transplant Immunology (Vascularized Composite Allotransplantation, VCA) Laboratory
- Clinical Significance: Major soft tissue and skeletal defects, including limb amputation, represent a deficit of form and function, as well as diminution of life quality for the affected individuals.
- Innovation: Our laboratory investigates novel techniques in inducing tolerance to composite tissue allografts without the need for long-term immunosuppression as well as strategies to improve functional outcome of these transplants. This includes stem cell-based immunomodulation and topical skin immunotherapy.
- Translation: With the recruitment of Mario Solari, MD, who is the new Director of the Vascularized Composite Allotransplantation Research Laboratory, we will explore innovative modalities for VCA. All research projects will have the benefit of review and guidance from core team investigators including Giorgio Raimondi, PhD, for basic Immunology studies and Kia Washington, MD for nerve and functional studies. Additionally, faculty members Alexander Spiess, MD, and Vijay Gorantla, MD, PhD, are actively involved
Pediatric Craniofacial Biology Laboratory
- Clinical Significance: One aspect of this Laboratory’s research (housed in the Children’s Hospital) is the treatment of craniosynostosis, or the premature fusion of one or more of the cranial sutures, which occurs in 1 out of every 2200 births.
- Innovation: A unique rabbit model of human, nonsyndromic craniosynostosis that is housed here at the University of Pittsburgh allows us to test biologically-based therapies to improve the surgical treatment of craniosynostosis.
- Translation: Under the direction of Joseph Losee, MD and Greg Cooper, PhD, we have been able to test the effects of several different protein-based therapies on the inhibition of synostosis, the inhibition of postoperative resynostosis, and the improvement of postoperative outcomes. The recruitment of Sandeep Kathju, MD, PhD from AGH has enhanced our efforts in understanding the biology of craniosynostosis. Although Dr. Kathju’s laboratory space is located in the Starzl Biomedical Science Tower, he has been collaborating with Dr. Cooper for several years. Together, they are identifying the genetic variations present in craniosynostosis.
- Clinical Significance:
- Innovation: With the addition of new faculty member Anand Kumar, MD, we have been able to expand our research interests to include heterotopic ossification (HO). It is estimated that 50-60% of all extremity injuries in the U.S. military are complicated by delayed HO. Systemic inflammation caused by traumatic injury is thought to influence HO. We are currently evaluating the effect of inflammatory cytokines on osteogenic differentiation of stem cells as a model of HO. Further study of HO in our translational model will 1) facilitate treatment of this pathologic condition and 2) harness the potential of stem cells to regenerate bone in extremity trauma.
An essential component of our laboratory’s long-term success is our relationship with industry. We have (or had) active collaborations with over 15 companies, including LifeCell, Medtronic, AxoGen, Pfizer, TechShot, Kensey Nash, Synedgen, and MedGenesis. These relationships involve sponsored research contracts allowing for in vitro, in vivo and clinical studies. As we are focused on clinical translation, it is essential that we continue to maintain these relationships.
We have been fortunate throughout the past decade to have maintained a continuous funding stream from federal sources, industry and foundations. Figure 2 depicts the funds acquired by our faculty and residents since 2003. While the majority of our research is obtained from federal sources, we have acquired both foundation and industry funding. Figure 2a is indicative of our strong and steady growth. Our lines of research have matured (an excellent example is our nerve regeneration project which began in vitro, moved into a small rodent model, and now into a large animal (non-human primate model). Future clinical trials will be planned with assistance of our Center for Innovation in Restorative Medicine.
In conclusion, we anticipate our Department to continue to expand in these cutting-edge research areas. Our plastic surgery research efforts have had a positive impact on the University of Pittsburgh and UPMC landscape. For example:
- Three laboratories of 50+ personnel encompassing trained surgeons to undergraduates
- Laboratory directors with leadership positions throughout the globe
- Training of future surgeon-scientists as evidenced by our dedication to resident research
- Continuous funding levels > $10 million annually (total portfolio)
- Outreach programs established to disseminate our efforts to K-12 population
- Enhanced industry collaborations
- Strong and steady growth in cutting edge areas
- The utilization of CIRM within our Department to translate our basic science into clinical trials