Conventional treatment for intervertebral disc herniation alleviates pain but does not repair the... more Conventional treatment for intervertebral disc herniation alleviates pain but does not repair the annulus fibrosus (AF), resulting in a high incidence of recurrent herniation and persistent disfunction. The lack of repair and the acute inflammation that arise after injury further compromises the disc and can result in disc-wide degeneration in the long term. To address this clinical need, we developed tension-activated repair patches (TARPs) for annular repair and the local delivery of bioactive anti-inflammatory factors. TARPs transmit physiologic strains to mechanically-activated microcapsules (MAMCs) embedded within, which activate and release encapsulated biomolecules in response to physiologic loading. Here, we demonstrate that the TARP design modulates implant biomechanical properties and regulates MAMC mechano-activation. Next, the FDA-approved anti-inflammatory molecule, interleukin 1 receptor antagonist, Anakinra, was loaded in TARPs and the effects of TARP-mediated annular...
Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability o... more Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopaedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs towards the annulus fibrosus fate remain unknown. Here, we screened a number of candidate factors (and their combinations) and assessed the transcriptomic signatures of key signaling factors involved in embryoni...
Tissue-engineered intervertebral discs demonstrate long-term functional integration in rat and go... more Tissue-engineered intervertebral discs demonstrate long-term functional integration in rat and goat disc replacement models.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, Jan 24, 2018
Low back pain due to disc degeneration is a major cause of morbidity and health care expenditures... more Low back pain due to disc degeneration is a major cause of morbidity and health care expenditures worldwide. While stem cell-based therapies hold promise for disc regeneration, there is an urgent need to develop improved in vivo animal models to further develop and validate these potential treatments. The objectives of this study were to characterize a percutaneous needle injury model of intervertebral disc degeneration in the mouse caudal spine, and compare two non-invasive quantitative imaging techniques, microcomputed tomography and magnetic resonance imaging (MRI), as effective measures of disc degeneration in this model. Percutaneous needle injury of mouse caudal discs was undertaken using different needle sizes and injury types (unilateral or bilateral annulus fibrosus (AF) puncture). Mice were euthanized 4 weeks post-injury, and MRI and microcomputed tomography were used to determine T2 relaxation time of the NP and disc height index, respectively. Disc condition was then fur...
The development of engineered tissues has progressed over the past 20 years from in vitro charact... more The development of engineered tissues has progressed over the past 20 years from in vitro characterization to in vivo implementation. For musculoskeletal tissue engineering in particular, the emphasis of many of these studies was to select conditions that maximized functional and compositional gains in vitro. However, the transition from the favorable in vitro culture environment to a less favorable in vivo environment has proven difficult, and, in many cases, engineered tissues do not retain their preimplantation phenotype after even short periods in vivo. Our laboratory recently developed disc-like angle-ply structures (DAPS), an engineered intervertebral disc for total disc replacement. In this study, we tested six different preculture media formulations (three serum-containing and three chemically defined, with varying doses of transforming growth factor β3 [TGF-β3] and varying strategies to introduce serum) for their ability to preserve DAPS composition and metabolic activity d...
Translational research : the journal of laboratory and clinical medicine, Mar 28, 2016
Spinal conditions related to intervertebral disc (IVD) degeneration cost billions of dollars in t... more Spinal conditions related to intervertebral disc (IVD) degeneration cost billions of dollars in the US annually. Despite the prevalence and soaring cost, there is no specific treatment that restores the physiological function of the diseased IVD. Thus, it is vital to develop new treatment strategies to repair the degenerating IVD. Persons with IVD degeneration without back pain or radicular leg pain often do not require any intervention. Only patients with severe back pain related to the IVD degeneration or biomechanical instability are likely candidates for cell therapy. The IVD progressively degenerates with age in humans, and strategies to repair the IVD depend on the stage of degeneration. Cell therapy and cell-based gene therapy aim to address moderate disc degeneration; advanced stage disease may require surgery. Studies involving autologous, allogeneic, and xenogeneic cells have all shown good survival of these cells in the IVD, confirming that the disc niche is an immunologi...
Odontoid fractures are the most common cervical spine fracture in the elderly, and their incidenc... more Odontoid fractures are the most common cervical spine fracture in the elderly, and their incidence is increasing. The majority of these fractures are Type II and are associated with significant morbidity in the elderly population, irrespective of treatment options (surgical vs. nonsurgical). There is no clear consensus regarding the long-term morbidity of nonunion, with some authors advocating stable fibrous nonunion as an acceptable endpoint versus bony union. Surgical management is advocated by some due to the significantly greater union rate, and some studies report improved outcomes with surgery. Prospective studies are needed to better delineate optimal treatment.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2015
Magnetic resonance imaging (MRI) with T2-weighting is routinely performed to assess intervertebra... more Magnetic resonance imaging (MRI) with T2-weighting is routinely performed to assess intervertebral disc degeneration. Standard clinical evaluations of MR images are qualitative, however, and do not focus on region-specific alterations in the disc. Utilizing a rabbit needle puncture model, T2 mapping was performed on injured discs to develop a quantitative description of the degenerative process following puncture. To do so, an 18G needle was inserted into four discs per rabbit (L3/L4 to L6/L7) and T2 maps were generated pre- and 4 weeks post-injury. Individual T2 maps were normalized to a disc-specific coordinate system and then averaged for pre- and post-injury population composite T2 maps. We also developed a method to automatically segment the nucleus pulposus by fitting the NP region of the T2 maps with modified 2-D and 3-D Gaussian distribution functions. Puncture injury produced alterations in MR signal intensity in a region-specific manner mirroring human degeneration. Popula...
Discectomy, decompression, and fusion are traditionally used to manage cervical disc disease acco... more Discectomy, decompression, and fusion are traditionally used to manage cervical disc disease accompanied by neural element compression that is refractory to conservative management. Concerns regarding stress at levels adjacent to fusion and possible adjacent-level degeneration as well as a desire to maintain a more normal biomechanical environment have led to investigation of cervical disc replacement as an alternative to fusion procedures. Cervical disc prostheses currently under investigation are constructed of predominantly metal-on-polyethylene or metal-on-metal bearing surfaces, and use roughened titanium surfaces and osteoconductive coatings to facilitate fixation. The unique anatomy and biomechanics of the cervical spine must be considered when extrapolating from the experience of appendicular arthroplasty and lumbar disc replacement.
ObjectMagnetic resonance imaging has been proposed as a powerful technique for assessing the inte... more ObjectMagnetic resonance imaging has been proposed as a powerful technique for assessing the integrity of the posterior ligamentous complex (PLC) in spinal trauma. Because MR imaging is often used to determine appropriate treatment, it is important to determine the accuracy and reliability of MR imaging in diagnosing PLC disruption. The purpose of this study is to compare the ability of the radiologist and surgeon to assess disruption of the PLC in the setting of acute cervical and thoracolumbar trauma using MR imaging.MethodsThe components of the PLC in 89 consecutive patients with cervical or thoracolumbar fractures following acute spinal trauma were evaluated using MR imaging by both a musculoskeletal radiologist and an independent spine surgeon and assessed intraoperatively under direct visualization by the treating surgeon. The MR imaging interpretations of the musculoskeletal radiologist and surgeon were compared with the intraoperative report for accuracy, sensitivity, specif...
Conventional treatment for intervertebral disc herniation alleviates pain but does not repair the... more Conventional treatment for intervertebral disc herniation alleviates pain but does not repair the annulus fibrosus (AF), resulting in a high incidence of recurrent herniation and persistent disfunction. The lack of repair and the acute inflammation that arise after injury further compromises the disc and can result in disc-wide degeneration in the long term. To address this clinical need, we developed tension-activated repair patches (TARPs) for annular repair and the local delivery of bioactive anti-inflammatory factors. TARPs transmit physiologic strains to mechanically-activated microcapsules (MAMCs) embedded within, which activate and release encapsulated biomolecules in response to physiologic loading. Here, we demonstrate that the TARP design modulates implant biomechanical properties and regulates MAMC mechano-activation. Next, the FDA-approved anti-inflammatory molecule, interleukin 1 receptor antagonist, Anakinra, was loaded in TARPs and the effects of TARP-mediated annular...
Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability o... more Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopaedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs towards the annulus fibrosus fate remain unknown. Here, we screened a number of candidate factors (and their combinations) and assessed the transcriptomic signatures of key signaling factors involved in embryoni...
Tissue-engineered intervertebral discs demonstrate long-term functional integration in rat and go... more Tissue-engineered intervertebral discs demonstrate long-term functional integration in rat and goat disc replacement models.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, Jan 24, 2018
Low back pain due to disc degeneration is a major cause of morbidity and health care expenditures... more Low back pain due to disc degeneration is a major cause of morbidity and health care expenditures worldwide. While stem cell-based therapies hold promise for disc regeneration, there is an urgent need to develop improved in vivo animal models to further develop and validate these potential treatments. The objectives of this study were to characterize a percutaneous needle injury model of intervertebral disc degeneration in the mouse caudal spine, and compare two non-invasive quantitative imaging techniques, microcomputed tomography and magnetic resonance imaging (MRI), as effective measures of disc degeneration in this model. Percutaneous needle injury of mouse caudal discs was undertaken using different needle sizes and injury types (unilateral or bilateral annulus fibrosus (AF) puncture). Mice were euthanized 4 weeks post-injury, and MRI and microcomputed tomography were used to determine T2 relaxation time of the NP and disc height index, respectively. Disc condition was then fur...
The development of engineered tissues has progressed over the past 20 years from in vitro charact... more The development of engineered tissues has progressed over the past 20 years from in vitro characterization to in vivo implementation. For musculoskeletal tissue engineering in particular, the emphasis of many of these studies was to select conditions that maximized functional and compositional gains in vitro. However, the transition from the favorable in vitro culture environment to a less favorable in vivo environment has proven difficult, and, in many cases, engineered tissues do not retain their preimplantation phenotype after even short periods in vivo. Our laboratory recently developed disc-like angle-ply structures (DAPS), an engineered intervertebral disc for total disc replacement. In this study, we tested six different preculture media formulations (three serum-containing and three chemically defined, with varying doses of transforming growth factor β3 [TGF-β3] and varying strategies to introduce serum) for their ability to preserve DAPS composition and metabolic activity d...
Translational research : the journal of laboratory and clinical medicine, Mar 28, 2016
Spinal conditions related to intervertebral disc (IVD) degeneration cost billions of dollars in t... more Spinal conditions related to intervertebral disc (IVD) degeneration cost billions of dollars in the US annually. Despite the prevalence and soaring cost, there is no specific treatment that restores the physiological function of the diseased IVD. Thus, it is vital to develop new treatment strategies to repair the degenerating IVD. Persons with IVD degeneration without back pain or radicular leg pain often do not require any intervention. Only patients with severe back pain related to the IVD degeneration or biomechanical instability are likely candidates for cell therapy. The IVD progressively degenerates with age in humans, and strategies to repair the IVD depend on the stage of degeneration. Cell therapy and cell-based gene therapy aim to address moderate disc degeneration; advanced stage disease may require surgery. Studies involving autologous, allogeneic, and xenogeneic cells have all shown good survival of these cells in the IVD, confirming that the disc niche is an immunologi...
Odontoid fractures are the most common cervical spine fracture in the elderly, and their incidenc... more Odontoid fractures are the most common cervical spine fracture in the elderly, and their incidence is increasing. The majority of these fractures are Type II and are associated with significant morbidity in the elderly population, irrespective of treatment options (surgical vs. nonsurgical). There is no clear consensus regarding the long-term morbidity of nonunion, with some authors advocating stable fibrous nonunion as an acceptable endpoint versus bony union. Surgical management is advocated by some due to the significantly greater union rate, and some studies report improved outcomes with surgery. Prospective studies are needed to better delineate optimal treatment.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2015
Magnetic resonance imaging (MRI) with T2-weighting is routinely performed to assess intervertebra... more Magnetic resonance imaging (MRI) with T2-weighting is routinely performed to assess intervertebral disc degeneration. Standard clinical evaluations of MR images are qualitative, however, and do not focus on region-specific alterations in the disc. Utilizing a rabbit needle puncture model, T2 mapping was performed on injured discs to develop a quantitative description of the degenerative process following puncture. To do so, an 18G needle was inserted into four discs per rabbit (L3/L4 to L6/L7) and T2 maps were generated pre- and 4 weeks post-injury. Individual T2 maps were normalized to a disc-specific coordinate system and then averaged for pre- and post-injury population composite T2 maps. We also developed a method to automatically segment the nucleus pulposus by fitting the NP region of the T2 maps with modified 2-D and 3-D Gaussian distribution functions. Puncture injury produced alterations in MR signal intensity in a region-specific manner mirroring human degeneration. Popula...
Discectomy, decompression, and fusion are traditionally used to manage cervical disc disease acco... more Discectomy, decompression, and fusion are traditionally used to manage cervical disc disease accompanied by neural element compression that is refractory to conservative management. Concerns regarding stress at levels adjacent to fusion and possible adjacent-level degeneration as well as a desire to maintain a more normal biomechanical environment have led to investigation of cervical disc replacement as an alternative to fusion procedures. Cervical disc prostheses currently under investigation are constructed of predominantly metal-on-polyethylene or metal-on-metal bearing surfaces, and use roughened titanium surfaces and osteoconductive coatings to facilitate fixation. The unique anatomy and biomechanics of the cervical spine must be considered when extrapolating from the experience of appendicular arthroplasty and lumbar disc replacement.
ObjectMagnetic resonance imaging has been proposed as a powerful technique for assessing the inte... more ObjectMagnetic resonance imaging has been proposed as a powerful technique for assessing the integrity of the posterior ligamentous complex (PLC) in spinal trauma. Because MR imaging is often used to determine appropriate treatment, it is important to determine the accuracy and reliability of MR imaging in diagnosing PLC disruption. The purpose of this study is to compare the ability of the radiologist and surgeon to assess disruption of the PLC in the setting of acute cervical and thoracolumbar trauma using MR imaging.MethodsThe components of the PLC in 89 consecutive patients with cervical or thoracolumbar fractures following acute spinal trauma were evaluated using MR imaging by both a musculoskeletal radiologist and an independent spine surgeon and assessed intraoperatively under direct visualization by the treating surgeon. The MR imaging interpretations of the musculoskeletal radiologist and surgeon were compared with the intraoperative report for accuracy, sensitivity, specif...
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Papers by Harvey Smith