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Principal Investigator: Dong Wang
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2024
Award: $427,763
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
ABSTRACT
Fracture is the leading musculoskeletal injury affecting over 9.4 million Americans annually. Approximately
~10% of fractures are complicated by delayed healing or non-union, resulting chronic pain, impaired mobility and
poor quality of life. Pathophysiological and habitual risk factors, including fracture site instability, concurrent
diseases (e.g., diabetes), chronic exposure to certain medications (e.g., glucocorticoids or GCs) and
tobacco/alcohol use are also major contributing causes, which may interfere with the fracture healing biology
and lead to delayed healing or non-union. GCs are widely used in treating hospitalized COVID patients. Given
the scale of the current pandemic and the significant COVID infection rate among the US population, a post
pandemic surge of fracture risk and delayed fracture healing cases may be anticipated. Currently, orthopaedic
surgery and autologous bone grafts are still the gold standard in clinical management of delayed fracture healing.
There are few FDA approved non-invasive therapeutic interventions for the treatment of GC-induced delayed
fracture healing. To address this significant unmet clinical need, we have developed a N-(2-
hydroxypropyl)methacrylamide (HPMA)-based water-soluble thermoresponsive polymeric prodrug (P-TAN) of
Tanshinone IIA (TAN, a potent bone anabolic agent). The aqueous solution of P-TAN is free-flowing at room
temperature and transitions into a hydrogel (ProGel-TAN) at ≥ 27°C, which provide a unique mechanism for
sustained local delivery of TAN. When tested in a prednisone-induced delayed fracture healing mouse model,
two consecutive monthly ProGel-TAN treatments were found to accelerate the fracture healing by 5 weeks
without any side effects observed. The biomechanical properties of the bone were also fully restored. While
two monthly ProGel-TAN treatment seems to be very promising, the current orthopaedic practice favors a single
dose treatment at the time of the fracture stabilization procedure for pragmatic reasons as well as less infection
risk. Therefore, we hypothesize that with further structural and formulation optimization, we will be able to identify
an optimized single dose ProGel-TAN formulation that is highly effective and safe in treating the GC-induced
delayed fracture union. To test this hypothesis, we propose three Specific Aims in this project: 1. To characterize
the impact of different structural and formulation parameters of ProGel-TAN; 2. To identify single dose ProGel-
TAN formulations that provide optimal fracture healing efficacy; 3. To understand ProGel-TAN’s unique
pharmacology and putative mechanisms of action. At the successful completion of the proposed research, we
anticipate the identification of at least one optimal ProGel-TAN formulation that would satisfy the demand for a
single dose treatment to accelerate the healing of the GC-induced delayed fracture union by ~ 5 weeks and
normalize biomechanical properties of the injured bone in mice. It will then be subjected to further pre-clinical
studies on large animal models in preparation for clinical translation.
Terms: <1, 2-Dehydrocortisone><Acceleration><Address><Affect><After Care><After-Treatment><Aftercare><Aging><Alcohol Drinking><Alcohol consumption><American><Anabolic Agents><Animal Model><Animal Models and Related Studies><Anticoagulant Agents><Anticoagulant Drugs><Anticoagulants><Antiinflammatory Effect><Autoimmune Diseases><Autologous><Biodistribution><Biology><Biomechanics><Blood Vessels><Blood flow><Body Tissues><Bone Formation><Bone Grafting><Bone Injury><Bone Transplantation><Bone callus><Bony Callus><COVID infected patient><COVID patient><COVID positive patient><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 virus infection><COVID19 infection><COVID19 patient><COVID19 positive patient><Callus><Cell Body><Cells><Characteristics><Chronic><Clinical><Clinical Management><Contrast Agent><Contrast Drugs><Contrast Media><Conventional X-Ray><Dan-Shen><Danshen><Decline in mobility><Decrease in mobility><Decreased mobility><Dehydrocortisone><Delta(1)-Cortisone><Deltacortisone><Deltadehydrocortisone><Development><Diabetes Mellitus><Diminished mobility><Disease><Disorder><Dose><Drug Kinetics><Drug Precursors><Drugs><Estrogen deficiency><EtOH drinking><EtOH use><Euthanasia><Event><Exhibits><Exposure to><FDA approved><Femoral Fractures><Femur><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Formulation><Fracture><Fracture Healing><Functional impairment><Glucocorticoids><Goals><Healing abnormal><Healing delayed><Hospital Admission><Hospitalization><Hydrogels><Hydrogen Oxide><Immunofluorescence><Immunofluorescence Immunologic><Impaired healing><In Vitro><Inflammatory><Investments><LC/MS><Label><Laser Electromagnetic><Laser Radiation><Lasers><Medication><Mercy Killing><Metacortandracin><Mice><Mice Mammals><Microfils><Mobility decline><Mobility impairment><Molecular><Molecular Weight><Monitor><Murine><Mus><Operative Procedures><Operative Surgical Procedures><Orthopedic><Orthopedic Surgery><Orthopedic Surgical Profession><Orthopedics><Osteogenesis><Osteoporosis><Pathologic><Perfusion><Pharmaceutical Preparations><Pharmacokinetics><Pharmacological Study><Pharmacology><Pharmacology Study><Phase Transition><Polymers><Population><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Prednisone><Prednisonum><Preparation><Pro-Drugs><Procedures><Process><Prodrugs><Property><QOL><Quality of life><Radiopaque Media><Reduced mobility><Reduction in mobility><Regimen><Research><Resolution><Risk Factors><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2 infection><Safety><Salvia miltiorrhiza><Sampling><Severe acute respiratory syndrome coronavirus 2 infection><Site><Skeleton><Surgical><Surgical Interventions><Surgical Procedure><Temperature><Testing><Therapeutic Agents><Therapeutic Intervention><Time><Tissues><Tobacco><Tobacco Consumption><Tobacco use><Transition Temperature><Treatment Efficacy><Viscosity><Water><Weight><X-Ray Imaging><X-Ray Medical Imaging><X-ray microtomography><Xray imaging><Xray medical imaging><Xray microtomography><after menopause><alcohol ingestion><alcohol intake><alcohol product use><alcohol use><alcoholic beverage consumption><alcoholic drink intake><angiogenesis><anti-inflammatory effect><aqueous><autoimmune condition><autoimmune disorder><autoimmunity disease><biomechanical><blood thinner><bone><bone fracture><bone fracture healing><bone fracture repair><bone quality><bone tissue formation><bone transplant><candidate selection><chronic pain><clinical efficacy><clinical translation><clinically translatable><conventional Xray><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 patient><coronavirus patient><current pandemic><deficiency in estrogen><delta-Cortisone><density><design><designing><developmental><diabetes><drug release kinetics><drug release rate><drug/agent><effective therapy><effective treatment><ethanol consumption><ethanol drinking><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><femur fracture><flow cytophotometry><following menopause><fracture repair><fracture risk><healing><improved><in vivo><in vivo optical imaging><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><infection rate><infection risk><injury of musculoskeletal system (disorder)><injury of musculoskeleted system><insight><intervention efficacy><intervention therapy><lipophilicity><liquid chromatography mass spectrometry><methacrylamide><micro CT><micro computed tomography><microCT><microtomography><model of animal><mouse model><murine model><musculoskeletal injury><musculoskeletal trauma><novel><osteogenic><past menopause><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><polymer><polymeric><post treatment><post-menopausal><post-pandemic><postmenopausal><postmenopausal status><pre-clinical study><preclinical study><preparations><present pandemic><rate of infection><resolutions><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><side effect><skeletons><standard care><standard treatment><surgery><therapeutic efficacy><therapy efficacy><thrombopoiesis inhibitor><tobacco product use><vascular><water solubility><weights>