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.
