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Regulation of Tumor Cell Outcomes by The Extracellular Matrix

Degradation of the extracellular matrix (ECM) is a critical property of invasive cancer cells that allows movement through tissue barriers and is thought to be mediated, at least in part, through cellular invadopodial protrusions with associated proteolytic enzymes. In collaboration with Professor Alissa Weaver in Cancer Biology, we have shown that substrate rigidity can regulate invadopodia formation and function for tumor cells cultured on both tissue-derived model basement membrane (BM) and stromal matrices as well as synthetic materials.

We are also investigating the effects of the differential rigidity of the mineralized bone microenvironment on tumor cell gene expression. When breast and lung cancer cells metastasize to bone, they change their gene expression patterns to secrete osteolytic factors that stimulate osteoclasts to resorbed bone. TGF-beta released from the bone matrix further stimulates tumor growth, resulting in a positive feedback loop known as the vicious cycle of tumor-induced bone disease. In collaboration with Professor Julie Sterling in Cancer Biology, we have shown that expression of the osteolytic factor PTHrP by tumor cells increases 2 - 4-fold when cultured on rigid substrates with elastic moduli exceeding 1 MPa compared to soft hydrogels. Furthermore, the increase in osteolytic gene expression is mediated by both TGF-beta and ROCK.

In collaboration with Professor Joon Sung in Biomedical Engineering, we are investigating the effects of the biomechanical and surface properties of the matrix, as well as biochemical cues, on angiogenesis and inflammation. The objective of the project is to design novel biomaterials that promote angiogenesis.

Regeneration of Cutaneous Defects

Injectable scaffolds present compelling opportunities for wound repair and regeneration due to their ability to fill irregularly shaped defects and deliver biologics such as growth factors.  We are developing injectable polyurethane biocomposite scaffolds with a minimal reaction exotherm, clinically relevant working and setting times, and mechanical properties consistent with rubbery elastomers.  In a rat excisional wound model, injection of settable biocomposite scaffolds stents the wounds at early time points, resulting in a regenerative rather than a scarring phenotype at later time points. Analysis of cell proliferation and apoptosis shows that the scaffolds are biocompatible and support tissue ingrowth.  Furthermore, myofibroblast formation and collagen fiber organization provide evidence that the scaffolds have a positive effect on extracellular matrix remodeling by disrupting the formation of an aligned matrix under elevated tension.  The injectable scaffolds are also useful for local delivery of growth factors such as recombinant human platelet-derived growth factor (rhPDGF) to enhance wound healing.

Injectable weight-bearing bone/polymer biocomposites. There is a compelling clinical need for a resorbable biomaterial that has the appropriate biomechanical and biological properties for fracture reduction and fixation, eliminates the need for removal surgery, and integrates with host bone.  To address this  need, we are developing injectable allograft bone/polyurethane biocomposites for reconstruction of craniofacial and orthopedic defects. A key feature of these novel biocomposites is their ability to provide both mechanical strength and also actively remodel and participate in the healing process.

Injectable scaffolds and delivery systems for bone and skin tissue engineering.
Two-component reactive polymers are promising scaffolds because they can be formed in situ without the use of solvents. Porous PUR scaffolds prepared from lysine-derived and aliphatic polyisocyanates by reactive liquid molding have been reported to undergo controlled degradation to non-toxic decomposition products, while supporting the migration of cells and ingrowth of new tissue in vitro and in vivo. Additionally, these biomaterials have elastomeric mechanical properties, which enable them to maintain good contact with tissue. We are developing injectable polyurethane scaffolds that can be administered by minimally invasive surgical techniques and conform to the shape of the wounds being treated. Biologics, such as antibiotics and growth factors, can be added to the two-component polyurethane prior to mixing. The technology has been licensed to Osteotech, Inc. and is under commercial development as the Plexur biocomposites technology platform.

Polymer degradation and ingrowth of cells and new tissue into polyurethane scaffolds implanted in a rat tibia plug defect.

Bone Tissue Engineering

While autologous grafts stimulate healing of tissue defects, explantation both introduces additional surgery pain and also risks donor-site morbidity.  One promising alternative to autograft is polymeric biomaterials that are designed to enhance healing through the natural tissue remodeling process.  Polyurethanes comprise a class of synthetic polymers that are of fundamental interest to us because their mechanical and biological properties can be tuned to targeted values by controlling the structure.  New materials currently under development include:

Dual delivery of growth factors and antibiotics for healing of infected bone wounds. Infections often compromise the healing of open fractures. In the conflicts in Iraq and Afghanistan, approximately 80% of all extremity amputations are attributed to complications due to infection. Local delivery of antibiotics from PMMA beads followed by bone grafting is an established clinical treatment of infected fractures. However, the avascular graft can function as a nidus for infection leading to compromised healing. A more ideal implant would comprise a scaffold capable of delivery of both a growth factor and an antibiotic that can be administered in one procedure. We are developing biodegradable polyurethane scaffolds that release growth factors, such as rhBMP-2, and antibiotics to promote healing of infected fractures. By protecting the graft from infection, we anticipate that the dual-delivery approach will result in more predictable patient outcomes.

Research Interests

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