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Micellized protein transduction domain-bone morphogenetic protein-2 accelerates bone healing in a rat tibial distraction osteogenesis model

 Cheol Hee Jeong  ;  Song-Yi Lim  ;  Jo Eun Um  ;  Hyo Won Lim  ;  Kyu Ho Hwang  ;  Kyeong-Mee Park  ;  Jun Seop Yun  ;  Dohun Kim  ;  Jong-Ki Huh  ;  Hyun Sil Kim  ;  Jong In Yook  ;  Nam Hee Kim  ;  Yoon Hae Kwak 
 ACTA BIOMATERIALIA, Vol.170 : 360-375, 2023-10 
Journal Title
Issue Date
Animals ; Bone Morphogenetic Protein 2 / pharmacology ; Bone Morphogenetic Protein 7 / pharmacology ; Bone Morphogenetic Proteins ; Humans ; Osteogenesis ; Osteogenesis, Distraction* / methods ; Prodrugs* / pharmacology ; Rats ; Tibia / metabolism ; X-Ray Microtomography
Distraction osteogenesis ; Lipid nanoparticle ; Micellized protein transduction domain-bone morphogenetic protein-2 ; Osteogenic supplement ; Prodrug type bone morphogenetic protein-2
The clinical application of growth factors such as recombinant human bone morphogenetic protein-2 (rh-BMP-2), for functional bone regeneration remains challenging due to limited in vivo efficacy and adverse effects of previous modalities. To overcome the instability and short half-life of rh-BMP-2 in vivo, we developed a novel osteogenic supplement by fusing a protein transduction domain (PTD) with BMP-2, effectively creating a prodrug of BMP-2. In this study, we first created an improved PTD-BMP-2 formulation using lipid nanoparticle (LNP) micellization, resulting in downsizing from micrometer to nanometer scale and achieving a more even distribution. The micellized PTD-BMP-2 (mPTD-BMP-2) demonstrated improved distribution and aggregation profiles. As a prodrug of BMP-2, mPTD-BMP-2 successfully activated Smad1/5/8 and induced mineralization with osteogenic gene induction in vitro. In vivo pharmacokinetic analysis revealed that mPTD-BMP-2 had a much more stable pharmacokinetic profile than rh-BMP-2, with a 7.5-fold longer half-life. The in vivo BMP-responsive element (BRE) reporter system was also successfully activated by mPTD-BMP-2. In the in vivo rat tibia distraction osteogenesis (DO) model, micro-computed tomography (micro-CT) scan findings indicated that mPTD-BMP-2 significantly increased bone volume, bone surface, axis moment of inertia (MOI), and polar MOI. Furthermore, it increased the expression of osteogenesis-related genes, and induced bone maturation histologically. Based on these findings, mPTD-BMP-2 could be a promising candidate for the next-generation osteogenesis drug to promote new bone formation in DO surgery. STATEMENT OF SIGNIFICANCE: This study introduces micellized bone morphogenetic protein-2 (mPTD-BMP-2), a next-generation osteogenic supplement that combines protein transduction domain (PTD) and nano-sized micelle formulation technique to improve transduction efficiency and stability. The use of PTD represents a novel approach, and our results demonstrate the superiority of mPTD-BMP-2 over rh-BMP-2 in terms of in vivo pharmacokinetic profile and osteogenic potential, particularly in a rat tibial model of distraction osteogenesis. These findings have significant scientific impact and potential clinical applications in the treatment of bone defects that require distraction osteogenesis. By advancing the field of osteogenic supplements, our study has the potential to contribute to the development of more effective treatments for musculoskeletal disorders.
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2. College of Dentistry (치과대학) > Research Institute (부설연구소) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral and Maxillofacial Surgery (구강악안면외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Nam Hee(김남희) ORCID logo https://orcid.org/0000-0002-3087-5276
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Park, Kyeong-Mee(박경미)
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Jeong, Cheol-Hee(정철희) ORCID logo https://orcid.org/0000-0003-1260-076X
Huh, Jong Ki(허종기) ORCID logo https://orcid.org/0000-0002-7381-3972
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