Header Image

Advanced Regenerative Medicine ARM Phase III

Projects

Go to Regenerative Medicine Approach for the Treatment of Peripheral Compartment Syndrome
Go to Control of the Microenvironmental Niche to Promote Epimorphic Regeneration in Amputated Digits
Go to Long-term Immunosuppressionfree Survival of a Combined Composite Tissue Allograft (CTA) and Autologous Skin in a Swine Model
Go to Profiling, Computational Simulation and Bioreactor Regulation of Cytokine Networks Mediating Acute Rejection After Composite Tissue Allotransplantation
Go to Temporal Delivery of Growth Factors for Wound Healing Using Porous Hollow Fibers
Go to The USAISR-Pittsburgh ARM III Undergraduate and Postdoctoral Fellowship Training Program



Badylak, Stephen

“Regenerative Medicine Approach for the Treatment of Peripheral Compartment Syndrome”

Background:
Peripheral compartment syndrome represents a serious complication of traumatic extremity injury; especially the type of trauma sustained by soldiers in combat. The swelling and associated increased intracompartmental pressure, seen in this syndrome, severely compromise blood flow resulting in ischemic necrosis of all tissues within the compartment (e.g., muscle, nerves, and associated structures). The loss of functional tissue is frequently severe enough to require amputation of the affected limb. The standard of care for peripheral compartment syndrome is fasciotomy with an attempt to salvage the viability of as much functional tissue as possible. Morbidity is high and includes severe aesthetic abnormalities (because of lost compartmental space).

Our work investigates a method for utilizing the inductive properties of extracellular matrix (ECM) as a scaffold for the recruitment of endogenous stem cells, and the attachment, proliferation, and spatial organization of these cells into functional tissue. Previous work has shown that manufactured forms of extracellular matrix (e.g., porcine small intestinal submucosa, porcine urinary bladder, porcine and bovine dermis, pericardium, among others) have the potential to promote constructive remodeling of damaged or missing body parts in place of inflammation and scarring.

Previous work (ARM 2) extended this concept by investigating methods for use of ECM scaffolds (with and without the presence of stem cells) in conjunction with traditional treatment methods to better facilitate regeneration of affected skeletal muscle compartments. In addition, we developed methods of in-situ decellularization of the necrotic tissue while retaining the native extracellular matrix (autologous ECM). Stated differently, the extracellular matrix within the compartment would be isolated from its original cell population (which has now become necrotic) and this matrix would then be used as a template for tissue reconstruction.

The ARM 3 project follows on from the findings of this previous work to investigate strategies for binding the decellularization compounds within the compartment of interest and combining bioactive or inductive molecules with the remaining ECM scaffolds to facilitate functional tissue replacement.

“Control of the Microenvironmental Niche to Promote Epimorphic Regeneration in Amputated Digits”

Background:
Preliminary work conducted in our laboratory suggests that regeneration of complex tissues, such as limb and digit tissues, is possible in adult humans. The fundamental concepts of this preliminary work are built around the principle of recruitment of endogenous multipotential stem cells to the site of injury, followed by provision of an appropriate microenvironment in which these stem cells are directed to form functional tissue. The recruitment of endogenous stem cells has been shown to be possible through the use of chemotactic matricryptic peptides derived from extracellular matrix (ECM). We have called this recruited cell mass a “multipotential cell cluster” (MCC). The present study involves two primary tasks: 1. identification of the genetic signature and transcriptome of the multipotential cell cluster (MCC), and 2. creation of the appropriate microenvironmental niche which should contribute to the inductive signals required to simulate functional tissue formation from the MCC.

CONTACT INFORMATION:

Bio: Dr. Stephen Badylak
Phone: 412-624-5253
Email: Dr. Stephen Badylak
Lab Website




Lee, W.P. Andrew, Gerlach, Jörg, and Patzer, Jack

“Long-term Immunosuppressionfree Survival of a Combined Composite Tissue Allograft (CTA) and Autologous Skin in a Swine Model”

Background:
Composite tissue allografts (e.g., hand transplants) are now a clinical reality and have been performed in multiple centers worldwide. To date, approximately 57 hand/forearm transplants and 8 face transplants have been performed globally with highly encouraging functional, immunological and graft survival outcomes. However, widespread use of composite tissue allotransplantation (CTA) is currently limited by the high dose and long-term immunosuppressive treatment required to overcome the high immunogenicity of the skin and prevent graft rejection.

In this study we aim to achieve long-term immunosuppression-free survival in a swine model of CTA. The first step is to induce “split tolerance” towards the musculoskeletal component of a CTA followed by subsequent replacement of the immunologically stringent epidermis and reconstitution of the skin component achieved by either autologous skin or cultured keratinocytes.

CONTACT INFORMATION:

Bio: Dr. Andrew W.P. Lee
Phone: 443-287-2001
Mailing Address:
Johns Hopkins Outpatient Center
Main Office: Department of Plastic and Reconstructive Surgery
601 N. Caroline Street
8th Floor
Baltimore, MD 21287

Bio: Dr. Jörg Gerlach
Phone: 412-383-7150
Email: Dr. Jörg Gerlach

Bio: Dr. Jack Patzer
Phone: 412-624-9819
Email: Dr. Jack Patzer




Lee, W.P. Andrew and Vodovotz, Yoram

“Profiling, Computational Simulation and Bioreactor Regulation of Cytokine Networks Mediating Acute Rejection After Composite Tissue Allotransplantation”

Background:
Composite tissue allotransplantation (CTA) has become a clinical reality over the past decade with excellent short to intermediate functional outcomes. Despite these encouraging results, wider clinical application of this procedure has been limited by the need for long‐term and high dose immunosuppression to prevent acute rejection and sustain graft survival, bearing the risks of various drug‐related side effects. The skin component is still considered the main target of an immune response towards CTA due to its highly antigeneic nature. Therefore a thorough understanding of the unique immunological aspects of composite tissue grafts is warranted to overcome such immunological hurdles and to be able to minimize drug‐related side effects for this type of non life‐saving transplants. The objective of this project is to determine the specific cytokine profiles during the initiation, evolution, progression and culmination of rejection in CTA and to characterize, simulate, and modulate the cytokine networks mediating rejection after CTA.

CONTACT INFORMATION:

Bio: Dr. Andrew W.P. Lee
Phone: 443-287-2001
Mailing Address:
Johns Hopkins Outpatient Center
Main Office: Department of Plastic and Reconstructive Surgery
601 N. Caroline Street
8th Floor
Baltimore, MD 21287

Bio: Dr. Yoram Vodovotz
Phone: 412-647-5609
Email: Dr. Yoram Vodovotz





Little, Steven

“Temporal Delivery of Growth Factors for Wound Healing Using Porous Hollow Fibers”

Background:
Our objective is to optimize angiogenesis through temporal delivery of growth factors using porous hollow fibers extending into an acellular site. Because angiogenesis is, in many cases, one of the first steps towards wound healing, we propose to demonstrate enablement of this technology by mimicking the natural sequence of stimuli that directs angiogenesis. Our hypothesis is that sequential delivery of appropriate angiogenesis-promoting factors from our externally-regulated delivery system, as opposed to simultaneous delivery of multiple factors, will result in more mature and integrated neo-vasculature.

CONTACT INFORMATION:

Bio: Dr. Steven R. Little
Phone: 412-624-9614
Email: Dr. Steven Little
Lab Website




Schanck, Joan

“The USAISR-Pittsburgh ARM III Undergraduate and Postdoctoral Fellowship Training Program”

Background:
The US Army Institute of Surgical Research (ISR) has ongoing interest and research programs in the application of biomedical science to the treatment of traumatic injury, especially injuries suffered by soldiers in combat. The Pittsburgh Tissue Engineering Initiative (PTEI) shares this interest and focuses on bringing the promise of regenerative medicine to the treatment of our injured warriors with the goal to more fully restore function after traumatic injury. With ARM as the host organization, the ISR and PTEI have jointly developed training opportunities for undergraduate and post-doctoral researchers who train at the ISR and participate in mission driven research in the application of regenerative medicine to combat casualty care. The ISR-based ARM training program reveals a formal, inter-disciplinary, inter-agency structure with the purpose to contribute to the development of a long-term pipeline of trained RM research professionals with emphasis on participation in research that will transition rapidly into relevant therapies and technologies to address battlefield trauma issues and, ultimately, which will result in improved functional outcomes in soldiers.

The 2009 ARM training program provided some support for the participation of seven undergraduate researchers and two postdoctoral fellows who worked in collaboration with military and civilian researchers and clinicians to restore function to damaged tissues and organs and to replace tissue lost from severe trauma wounds by:

• Designing surgical adhesives, sealants and hemostatus the will revolutionize wound closure
• Investigating and understanding the molecular determinants of scarless wound healing
• Engineering a bone regeneration therapy for the craniofacial complex
• Verifying that a bioresorbable scaffold bulk-seeded with stem cells and cultured in-vitro will yield a vascular graft suitable for implantation.

CONTACT INFORMATION:

Joan Schanck
Phone: 412-624-5576
Email: Joan Schanck