Tissue engineering encompasses the study of the life sciences and engineering to discover fundamental differences between healthy and diseased tissue and develop new methods and materials to treat diseased and deficient tissues/organ systems (1). Tissue engineers aim to induce fully functional skin, bone, cartilage, capillary, and periodontal tissues in patients with clinical needs due to trauma, cancer, disease, or congenital defects (2). In bone tissue engineering, researchers use novel biomaterials, often in combination with cells or signaling growth factors, to restore, maintain, or enhance natural bone (3).
It is estimated that more than 1.5 million bone grafting procedures are performed in the United States each year (4). Bone grafting can be used to treat patients suffering from injuries, tumors, infection, and degenerative disease (5). The applications for bone grafts are expansive, with the majority of procedures related to spinal fusions (6, 7), orthopaedic defects (8, 9), and craniomaxillofacial defects (10). According to the World Health Organization, direct and indirect costs associated with musculoskeletal conditions in the United States reached $215 billion in 1995 (11). As the population ages the number of bone graft operations is anticipated to rise, with an expected doubling of patients over 50 experiencing bone disease by 2020 (12, 13). There is considerable interest in using tissue engineering approaches to develop new, more economical biomaterials for bone grafting and to help standardize the success of such procedures.
A number of treatment options are available in bone grafting with autograft bone, taken from a separate site in the same patient, considered the clinical gold standard. However, autograft use is constrained by limited availability in the iliac crest and the potential for chronic pain and donor site morbidity (14). There are a variety of biodegradable, synthetic alternatives to autograft that include polymers, ceramics, bioactive glasses, and composites (15). The aim of this dissertation is to develop and characterize low viscosity (LV) polyurethane (PUR) biocomposites for bone regeneration and to test growth factor release and remodeling characteristics of the LV grafts in vitro and in vivo.
Chapter II examines the previous literature in the field of tissue engineering and bone regeneration. The work discussed herein applies materials science and biological fundamentals to help solve clinically relevant medical conditions. A thorough review of the currently accepted practices and understanding in the field of biomaterials and tissue regeneration is necessary prior to discussion of specific research topics.
Researchers in the field of tissue engineering are currently developing new bone grafts that match the chemical, mechanical, and physical properties of natural bone (13). Ceramics are often used in bone regeneration due to their osteogenic nature, however they can be brittle and fail quickly under tension limiting their direct use (16). Composites of polymers and ceramics are frequently studied as these combine the ductile nature but poor strength of polymers with the osteogenic but low fracture toughness of ceramics (17). Chapter III discusses the testing of a LV/ceramic biocomposite in a sheep femoral plug model against a clinically available ceramic control.
RhBMP-2 is an osteoinductive growth factor widely used in clinical bone repair (18). RhBMP-2 is FDA approved for some craniomaxillofacial and spinal bone treatments when delivered via an acellular collagen sponge (ACS). RhBMP-2 must be locally delivered at the desired site, and the specific release kinetics affect cellular ingrowth and bone healing (19). To ascertain the effect of growth factor delivery from delivery systems of interest, it is necessary to thoroughly characterize the rhBMP-2 release kinetics from biocomposite delivery systems of interest (20). Chapter IV describes the release kinetics of rhBMP-2 delivered from an LV graft tested both in vivo and in vitro.
There are a variety of animal models used to test bone grafts. The canine saddle defect model is commonly used to test bone grafts intended for craniomaxillofacial applications, as the anatomy of the canine mandible is similar to that of humans and healing progression is comparable (21). Defect space maintenance poses a problem in the mandible due to the forces applied by soft tissue. To maintain the space through healing, most grafts require the use of guided bone regeneration (GBR).These techniques use a polymer or metal external fixation device to preserve the defect volume (22). However, GBR has been associated with complications including seroma, infection, or wound failure (23, 24). Chapter V investigates the use of a compression resistant LV graft, which eliminates the need for external fixation, augmented with rhBMP-2 in a canine saddle defect model.
While autograft and allograft remodel in a similar manner to natural bone, the degradation properties of many ceramics and bioactive glasses is not fully understood. A number of intrinsic and extrinsic factors contribute to remodeling making it more difficult to study in vitro, including graft porosity, chemical composition, implantation site, and biological signaling molecules (25, 26). A number of groups have studied osteoclast resorption using growth factors to drive differentiation since the 1990s when the Suda research group determined that receptor activator of nuclear factor κβ ligand (RANKL) is responsible for producing active osteoclasts (27). These methods, however, rely on expensive growth factors and the harvest of primary cells. Additionally, there is no accepted method for the quantification of osteoclast pitting on surfaces. Chapter VI describes the development of an in vitro assay based on established cell lines to quantify osteoclast resorption of synthetic matrices using optical profilometry.
Spinal fusion procedures are widely performed in the United States to treat patients suffering from degenerative conditions. Previous research has suggested that hospital stays and muscle destruction associated with posteolateral fusions could potentially be decreased with the use of minimally invasive surgical (MIS) techniques; however, no clinical studies have compared the outcomes of conventional and MIS approaches (28). Additionally, posterolateral spinal fusions are challenged by limited bony surfaces and compressive forces of the posterior musculature (29). Chapter VII describes an injectable, compression-resistant LV graft that promotes union in a single level posterolateral rabbit spinal fusion model. The LV graft is a potential candidate for use with MIS techniques for posterolateral fusion.
In conclusion, Chapter VIII summarizes the findings presented in this work and lists recommendations for future studies. Broadly, the work presented here informs the reader about the current treatment options in bone grafting and presents studies demonstrating the potential of polyurethane biocomposites in a clinical setting.
|Advisor:||Guelcher, Scott A.|
|Commitee:||Lang, Matthew J., LeVan, M. Douglas, Sterling, Julie A.|
|School Location:||United States -- Tennessee|
|Source:||DAI-B 79/07(E), Dissertation Abstracts International|
|Subjects:||Biomedical engineering, Chemical engineering|
|Keywords:||Bone grafts, Bone regeneration, Compression resistant, Growth factor, Osteoclast resorption, Polyurethane|
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