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Natural Polymeric Carriers for Local Delivery of Therapeutic Agents to Promote Enhanced Bone Regeneration

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abstract
Bone has the innate ability to heal, but on occasion defects surpass a critical size capable of spontaneously healing. These critically-sized bone defects pose significant challenges for reforming bone continuity and often require surgical intervention to facilitate bone regeneration. Recently, products combining biomaterials with recombinant human bone morphogenetic protein 2 (rhBMP-2) have proven to be a successful clinical alternative to autografts in promoting bone regeneration. While collagen rhBMP-2 carriers have shown robust regenerative capabilities, adverse side effects such as ectopic bone growth are likely caused by a burst release of supraphysiological levels of rhBMP-2 from the carrier. We hypothesize that improved bone regeneration can be achieved through tailored rhBMP-2 release from keratin carriers or through fibrin surface-mediated delivery of siRNA targeting rhBMP-2 antagonists. For this reason, we developed an alternative natural polymer rhBMP-2 carrier from keratin. Keratin can be formed into a number of biomaterials which have advantages over collagen including controlled rates of degradation, flexible material properties, and tunable rates of rhBMP-2 delivery. In a critically-sized rat mandibular model the keratin biomaterials reduced ectopic bone growth, and achieved comparable levels of bone healing to existing collagen-based clinical alternative for craniofacial injuries. However, our keratin carriers still delivered a supraphysiological concentration of rhBMP-2. We have separately observed the ability of small interfering RNA (siRNA) delivered from fibrin carriers to knockdown myelin-associated glycoprotein (a molecular inhibitor to nerve regeneration). We therefore attempted to apply the same approach to bone regeneration. In order to lower the therapeutic rhBMP-2 dose, targeting rhBMP-2 antagonists such as noggin through substrate-mediated delivery of siRNA complexes can potentially increase local rhBMP-2 efficacy. Fibrin, a natural polymer involved in bone healing, is able to electrostatically bind siRNA complexed with polycationic transfection agents to its surface in order to locally control molecular inhibitors of bone regeneration. Sustained transfection of sequence specific siRNA targeting noggin was able to achieve dose-dependent reduction of noggin mRNA levels after administering a supraphysiological dose of rhBMP-2. In conclusion, regeneration of critically-sized bone defects can be enhanced through the delivery of therapeutic agents to control local molecular cues from natural polymers.
subject
Bone Morphogenetic Protein -2
fibrin
kerateine
myelin-associated glycoprotein
noggin
siRNA
contributor
Kowalczewski, Christine Jane (author)
Saul, Justin M (committee chair)
Andersson, Karl-Erik (committee member)
Goldstein, Aaron S (committee member)
Smith, Thomas L (committee member)
Van Dyke, Mark E (committee member)
Walker, Stephen J (committee member)
date
2015-01-21T09:35:17Z (accessioned)
2015-07-21T08:30:09Z (available)
2014 (issued)
degree
Biomedical Engineering (discipline)
embargo
2015-7-21 (terms)
identifier
http://hdl.handle.net/10339/47453 (uri)
language
en (iso)
publisher
Wake Forest University
title
Natural Polymeric Carriers for Local Delivery of Therapeutic Agents to Promote Enhanced Bone Regeneration
type
Dissertation

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