BIOMIMETIC, MUSSEL-INSPIRED, BIOACTIVE BONE GRAFT SUBSTITUTE MATERIALS COMPRISING EXTRACELLULAR MATRICES: NOVEL COMPOSITIONS AND METHODS FOR BONE GRAFTS AND FUSIONS

Bone grafting is a surgical procedure used to create new bone. New bone is often needed in a broad range of healthcare applications, from spinal fusion to dental surgery. The gold standard bone graft is autologous bone, which is bone that is taken from and used in the same individual. However, autologous bone is limited in supply and is not always effective – and using it often requires an additional surgery for obtaining the donor bone and may cause morbidity (e.g., pain) at the site of obtainment. Bone graft substitutes are alternatives to autologous bone and aim to reduce or replace the need for autologous bone in bone grafting procedures. Current bone graft substitutes (e.g., Infuse™ Bone Graft, Medtronic; Memphis, TN) offer no better grafting outcomes to autologous bone, and in some cases carry significant complication profiles. The present dissertation pertains to the creation and evaluation of novel bone graft substitute materials. These materials were designed to overcome the limitations of current bone graft substitutes, like bio-disparate designs and non-controlled growth factor delivery. At their core, the materials are porous, homogenously dispersed solid mixtures of pro-regenerative extracellular matrices (e.g., small intestinal submucosa) and inorganic components (e.g., calcium phosphates, bioactive glasses) in a compositional makeup that is biomimetic to bone. The materials are created from a “one-pot” liquid hydrogel solution at room temperature and physiologic pH, which allows virtually any additive (e.g., pharmaceuticals, minerals, cells) to be added during the synthesis and homogenously incorporated into the final material. In some embodiments, the materials are infused with polydopamine, conferring controlled growth factor delivery. The materials underwent preclinical evaluation of bone forming efficacy and safety using a clinically translatable rat model of spinal fusion. In this model, use of one embodiment (termed “BioMim-PDA”) achieved superior bone volume and quality at a 10-fold lower dose of recombinant human bone morphogenetic protein-2 relative to use of the Infuse™ Bone Graft; the overall fusion rate using BioMim-PDA was 97% (29/30 animals). In a separate study, a small molecule-loaded embodiment of the materials yielded a spinal fusion rate of 100% (16/16 animals). These results compare favorably to previous work, in which a recent meta-analysis of the rat model of spinal fusion reported an overall fusion rate of 42.5% using autologous (iliac crest) bone graft. The ability to create a virtually infinite array of efficacious and scalable bone graft substitutes, as described herein, is unique and offers significant research and clinical value. Future work will focus on identifying graft compositions with the greatest therapeutic potential for bone grafting. The ultimate goal of this work is to create bone graft substitute materials that deliver reliable, safe, and effective grafting outcomes for patients requiring a bone graft

BIOMIMETIC, MUSSEL-INSPIRED, BIOACTIVE BONE GRAFT SUBSTITUTE MATERIALS COMPRISING EXTRACELLULAR MATRICES: NOVEL COMPOSITIONS AND METHODS FOR BONE GRAFTS AND FUSIONS

Bone grafting is a surgical procedure used to create new bone. New bone is often needed in a broad range of healthcare applications, from spinal fusion to dental surgery. The gold standard bone graft is autologous bone, which is bone that is taken from and used in the same individual. However, autologous bone is limited in supply and is not always effective – and using it often requires an additional surgery for obtaining the donor bone and may cause morbidity (e.g., pain) at the site of obtainment. Bone graft substitutes are alternatives to autologous bone and aim to reduce or replace the need for autologous bone in bone grafting procedures. Current bone graft substitutes (e.g., Infuse™ Bone Graft, Medtronic; Memphis, TN) offer no better grafting outcomes to autologous bone, and in some cases carry significant complication profiles. The present dissertation pertains to the creation and evaluation of novel bone graft substitute materials. These materials were designed to overcome the limitations of current bone graft substitutes, like bio-disparate designs and non-controlled growth factor delivery. At their core, the materials are porous, homogenously dispersed solid mixtures of pro-regenerative extracellular matrices (e.g., small intestinal submucosa) and inorganic components (e.g., calcium phosphates, bioactive glasses) in a compositional makeup that is biomimetic to bone. The materials are created from a “one-pot” liquid hydrogel solution at room temperature and physiologic pH, which allows virtually any additive (e.g., pharmaceuticals, minerals, cells) to be added during the synthesis and homogenously incorporated into the final material. In some embodiments, the materials are infused with polydopamine, conferring controlled growth factor delivery. The materials underwent preclinical evaluation of bone forming efficacy and safety using a clinically translatable rat model of spinal fusion. In this model, use of one embodiment (termed “BioMim-PDA”) achieved superior bone volume and quality at a 10-fold lower dose of recombinant human bone morphogenetic protein-2 relative to use of the Infuse™ Bone Graft; the overall fusion rate using BioMim-PDA was 97% (29/30 animals). In a separate study, a small molecule-loaded embodiment of the materials yielded a spinal fusion rate of 100% (16/16 animals). These results compare favorably to previous work, in which a recent meta-analysis of the rat model of spinal fusion reported an overall fusion rate of 42.5% using autologous (iliac crest) bone graft. The ability to create a virtually infinite array of efficacious and scalable bone graft substitutes, as described herein, is unique and offers significant research and clinical value. Future work will focus on identifying graft compositions with the greatest therapeutic potential for bone grafting. The ultimate goal of this work is to create bone graft substitute materials that deliver reliable, safe, and effective grafting outcomes for patients requiring a bone graft

Synthesis, crystal structure, and magnetism of the binuclear radical complex [N-hydrogenpyridinium]₂[Ni(tdas)₂]₂

<div><p>The binuclear radical complex [N-hydrogenpyridinium]₂[Ni(tdas)₂]₂ (tdas = 1,2,5-thiazole-3,4-dithiolate) has been prepared and its crystal structure determined by X-ray crystallography. In the binuclear radical complex, the two nickel ions assume a distorted pyramidal geometry and are bridged by two sulfurs of different tdas anionic ligands. ESR spectra and the theoretical calculations reveal a very strong antiferromagnetic interaction in the binuclear radical complex, leading to diamagnetic crystals. The theoretical calculations also reveal a very weak antiferromagnetic interaction between adjacent radical complexes. This study is the first to report the magnetism of a binuclear radical nickel complex with tdas as ligand.</p></div