Nonunion fracture is a permanently broken bone that does not spontaneously heal and can occur in any bone tissue, causing severe pain and physical disability to patient. However, until now, there is no effective treatment for nonunion fracture and its pathological mechanism remains unidentified. To treat nonunion fracture, bone graft materials are often implanted into the damaged region to stimulate bone regeneration and to support bone structure. Among various bone implant materials, hydroxyapatite (HAP: Ca10(PO4)6(OH)2) and ?-tricalcium phosphate (?-TCP: Ca3(PO4)2) are the most widely used biomaterials due to excellent biocompatibility and bioresorbability, respectively. However, ?-TCP does not exist in our bone while it has microscale particle. In this respect, the current bone implant material, composed of HAP and ?-TCP, does not reflect composition and structure of bone at nanoscale and thus has a gap with natural bone tissue, that it is eventually purposed to be replaced by new bone. Therefore, to make a breakthrough in bone implant material, we propose to recreate an innovative bone implant material which can immediately harmonize with surrounding bone tissue after implantation, by utilizing the two major bone minerals, whitlockite (WH: Ca18Mg2(HPO4)2(PO4)12) and HAP. WH is the second most abundant crystal in bone and also known to exist with high ratio in younger aged and early stage of bone tissue formation. However, despite its significant distributions in bone, WH has been largely ignored from the research fields due to difficulty in its synthesis and analyses. Very recently, a facile synthetic method of WH nanoparticles has been reported and its beneficial effects on cellular proliferation and activities has been demonstrated. In this research, we aim to recreate bone-mimetic implant platform by controlling and optimizing the composition and the structure of the two major bone minerals in 3D hydrogel platform. We hypothesized that the two-phase WH/HAP composite will provide synergetic effects of material-, mechanical-, and biological properties on cellular proliferation and differentiation. This hypothesis will be verified by the following specific aims: 1) Assess the differentiation of MSCs into osteogenic cells in nanocomposite gels containing various ratios of WH and HAP nanoparticles; 2) Control the spatial architecture of MSC-laden WH/HAP nanocomposite gels by 3D printing; and 3) Assess the bone formation ability of WH/HAP nanocomposite gels in vivo. We expect that the new findings from the proposed research will provide better understandings of bone tissue and effective treatment for nonunion fractures.

Public Health Relevance

Nonunion fractures are permanent failing of healing in broken bone and occurs in one tenth of patients with bone fracture, causing chronic pains and physical disabilities. However, despite negative influences of nonunion fractures on public health and socioeconomic cost, until now, treatment and pathological mechanism of nonunion fracture remain unidentified. Since nonunion fractures cannot be spontaneously healed, they need a supporting bone implant material to stimulate new bone tissue formation. In this research, we will recreate a novel bone mimetic implant material at nanoscale by utilizing the two major bone minerals, whitlockite and hydroxyapatite, and optimizing their composition and structure in 3D hydrogel implant platform. Based on the assessment of cellular interactions depending on various arrangements of the two biological crystals, porous architecture of cell-laden hybrid gel implant platform will be developed by utilizing 3D printing. Also, biocompatibility and osteogenesis of a new 3D bone implant platform will be analyzed in vivo, to develop an effective treatment for nonunion fractures.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Guan, Xiaofei; Avci-Adali, Meltem; Alarçin, Emine et al. (2017) Development of hydrogels for regenerative engineering. Biotechnol J 12:
Cheng, Hao; Chawla, Aditya; Yang, Yafeng et al. (2017) Development of nanomaterials for bone-targeted drug delivery. Drug Discov Today 22:1336-1350
Alarçin, Emine; Guan, Xiaofei; Kashaf, Sara Saheb et al. (2016) Recreating composition, structure, functionalities of tissues at nanoscale for regenerative medicine. Regen Med 11:849-858
Jang, Hae Lin; Zhang, Yu Shrike; Khademhosseini, Ali (2016) Boosting clinical translation of nanomedicine. Nanomedicine (Lond) 11:1495-7