Investigators at Brigham and Women’s Hospital (BWH) are performing innovative research into the use of stem cells and nanomedicine to improve fracture-healing after trauma. This research is funded by the Gillian Reny Stepping Strong Foundation.
“Fracture-healing remains a poorly understood yet vital process for all procedures in orthopedics. From the perspective of a trauma surgeon, a clearer understanding of this essential process and specific areas in which we can impact the consistency of the result would optimize clinical outcomes,” explained Mitchel Harris, MD, FACS, Chief, Orthopedic Trauma Service. “We are currently investigating mechanisms whereby we can reinvigorate the vitality of osteoblasts, particularly in the elderly, after fractures. If we can identify factors that improve this process in the geriatric population, we may be able to apply this to the younger population as well. In addition to our cellular work, we are also investigating the nanodelivery of chemicals that work locally but can be administered without surgical intervention.”
Shuanhu Zhou, PhD, lead investigator in the Department of Orthopedic Surgery, recently discovered that there are paracrine (local) effects of blood-forming hematopoietic cells on human mesenchymal stem cells (hMSCs), which are bone-forming precursors found in bone marrow (Sci. Rep. 5, 10573; doi: 10.1038/srep10573 [2015]). According to Dr. Zhou, this discovery may help to identify interventions to prevent age-related changes such as the decline in stem cell function and an increased risk for osteoporosis, bone fractures, and skeletal tissue degradation.
Dr. Zhou found that certain soluble factors that are secreted by hematopoietic cells may contribute to osteoblast differentiation and inhibit the senescence of bone-forming cells. Dr. Zhou reported that these factors may allow hematopoietic cells to interact with hMSCs. Of particular note, he found that the secreted factor TNF-α (tumor necrosis factor α), a multifunctional protein that increases with age, inhibits the proliferation and differentiation of osteoblasts.
“Our bench studies with human skeletal cells could identify potential interventions for senile osteoporosis and bone fracture and may lead to novel therapeutic strategies to prevent skeletal tissue degeneration and loss in the aging population,” noted Dr. Zhou. In addition, future therapeutic strategies could target the interaction between hematopoietic cells and mesenchymal stem cells in order to potentially restore skeletal tissue.
“This study identifies the ways in which marrow hematopoietic cells influence osteoblast differentiation and identifies new targets for optimizing skeletal health,” said Julie Glowacki, PhD, Director of the Skeletal Biology Laboratory.
Another area of groundbreaking research at BWH pertains to the role of activated vitamin D in osteoblast differentiation. Dr. Glowacki explained, “One of the reasons that vitamin-D sufficiency is important for skeletal health is that osteoblast differentiation is directly stimulated by activated vitamin D. Several years ago, we discovered that MSCs have the biochemical machinery to synthesize and activate vitamin D, thus making these cells both a source of and a target of active vitamin D.”
In a recent study, Dr. Glowacki and colleagues observed an unexpected difference in vitamin D metabolism in MSCs from boys and girls, a difference that is not found in cells from adults (J Steroid Biochem Mol Biol. 2015 Sep 15. pii: S0960-070[15]30085-6). The MSCs were obtained as excess bone graft discarded during the course of surgical repair of the orofacial cleft in children between eight and 12 years of age. Significantly higher levels of the enzymes and receptors involved in vitamin-D synthesis and activation were found in MSCs from boys than in those from girls. The differences ranged from 2.6 to 3.5-fold. It was possible to dramatically increase the levels in cells from girls by treating them with a vitamin-D precursor molecule or with an estrogen as an in vitro mimic of puberty.
These discoveries indicate how puberty may trigger systems in the body to support the pubertal growth spurt differently in boys and girls. They also may indicate a relative vitamin D-deficiency in prepubescent girls as compared with boys. Current research is focused on determining the significance of these findings and to finding ways to translate them to ensure skeletal health in children.
(For more information on this research, contact Dr. Glowacki at jglowacki@bwh.harvard.edu)
Omid Farokhzad, MD, Director of the Laboratory of Nanomedicine and Biomaterials within the Department of Anesthesiology, Perioperative and Pain Medicine, and colleagues are conducting groundbreaking research involving the use of “nano drones” to address the problem of bacterial infections and lack of new bone growth in patients who undergo orthopedic trauma surgery.
Injuries resulting from severe trauma are often challenging because they are associated with large open bone fractures that are prone to high rates of infection. In such cases, orthopedic trauma surgeons are faced with the challenge of simultaneously stabilizing the bone injury, preventing infection, and promoting bone-healing.
The current standard of care is rudimentary: a cement paste containing antibiotics is molded into the open fracture, and the wound is closed. The disadvantages of this method are that only a fraction of the antibiotic is released from the cement spacer, the patient requires an additional operation for cement removal, and the cement can cause bacterial biofilms to grow, leading to further infection.
Dr. Farokhzad and colleagues are addressing these challenges by developing very small biodegradable robots called nanomedicines that can deliver antibiotics to target bacteria and other drugs to promote bone growth and wound-healing. The advantages of this approach are that bacterial infections are minimized or eradicated, natural bone growth is accelerated, and the patient will not need follow-up surgery as the moldable matrix can biodegrade in the body, leaving new bone in its place.
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