Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair
Introduction: Currently, there are no non-surgical FDA-approved biological approaches to accelerate fracture repair. Injectable therapies designed to stimulate bone healing represent an exciting alternative to surgically implanted biologics, however, the translation of effective osteoinductive thera...
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| Format: | Article |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Bioengineering and Biotechnology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fbioe.2023.1190371/full |
| _version_ | 1797822243924869120 |
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| author | Kevin O. Rivera Kevin O. Rivera Kevin O. Rivera Darnell L. Cuylear Darnell L. Cuylear Victoria R. Duke Kelsey M. O’Hara Justin X. Zhong Justin X. Zhong Nafisa A. Elghazali Nafisa A. Elghazali Joel A. Finbloom Bhushan N. Kharbikar Alex N. Kryger Theodore Miclau Ralph S. Marcucio Chelsea S. Bahney Chelsea S. Bahney Chelsea S. Bahney Chelsea S. Bahney Tejal A. Desai Tejal A. Desai Tejal A. Desai Tejal A. Desai |
| author_facet | Kevin O. Rivera Kevin O. Rivera Kevin O. Rivera Darnell L. Cuylear Darnell L. Cuylear Victoria R. Duke Kelsey M. O’Hara Justin X. Zhong Justin X. Zhong Nafisa A. Elghazali Nafisa A. Elghazali Joel A. Finbloom Bhushan N. Kharbikar Alex N. Kryger Theodore Miclau Ralph S. Marcucio Chelsea S. Bahney Chelsea S. Bahney Chelsea S. Bahney Chelsea S. Bahney Tejal A. Desai Tejal A. Desai Tejal A. Desai Tejal A. Desai |
| author_sort | Kevin O. Rivera |
| collection | DOAJ |
| description | Introduction: Currently, there are no non-surgical FDA-approved biological approaches to accelerate fracture repair. Injectable therapies designed to stimulate bone healing represent an exciting alternative to surgically implanted biologics, however, the translation of effective osteoinductive therapies remains challenging due to the need for safe and effective drug delivery. Hydrogel-based microparticle platforms may be a clinically relevant solution to create controlled and localized drug delivery to treat bone fractures. Here, we describe poly (ethylene glycol) dimethacrylate (PEGDMA)-based microparticles, in the shape of microrods, loaded with beta nerve growth factor (β-NGF) for the purpose of promoting fracture repair.Methods: Herein, PEGDMA microrods were fabricated through photolithography. PEGDMA microrods were loaded with β-NGF and in vitro release was examined. Subsequently, bioactivity assays were evaluated in vitro using the TF-1 tyrosine receptor kinase A (Trk-A) expressing cell line. Finally, in vivo studies using our well-established murine tibia fracture model were performed and a single injection of the β-NGF loaded PEGDMA microrods, non-loaded PEGDMA microrods, or soluble β-NGF was administered to assess the extent of fracture healing using Micro-computed tomography (µCT) and histomorphometry.Results:In vitro release studies showed there is significant retention of protein within the polymer matrix over 168 hours through physiochemical interactions. Bioactivity of protein post-loading was confirmed with the TF-1 cell line. In vivo studies using our murine tibia fracture model show that PEGDMA microrods injected at the site of fracture remained adjacent to the callus for over 7 days. Importantly, a single injection of β-NGF loaded PEGDMA microrods resulted in improved fracture healing as indicated by a significant increase in the percent bone in the fracture callus, trabecular connective density, and bone mineral density relative to soluble β-NGF control indicating improved drug retention within the tissue. The concomitant decrease in cartilage fraction supports our prior work showing that β-NGF promotes endochondral conversion of cartilage to bone to accelerate healing.Discussion: We demonstrate a novel and translational method wherein β-NGF can be encapsulated within PEGDMA microrods for local delivery and that β-NGF bioactivity is maintained resulting in improved bone fracture repair. |
| first_indexed | 2024-03-13T10:05:09Z |
| format | Article |
| id | doaj.art-2d67733dedb841e4b0796fa4acfa384e |
| institution | Directory Open Access Journal |
| issn | 2296-4185 |
| language | English |
| last_indexed | 2024-03-13T10:05:09Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-2d67733dedb841e4b0796fa4acfa384e2023-05-22T14:45:23ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852023-05-011110.3389/fbioe.2023.11903711190371Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repairKevin O. Rivera0Kevin O. Rivera1Kevin O. Rivera2Darnell L. Cuylear3Darnell L. Cuylear4Victoria R. Duke5Kelsey M. O’Hara6Justin X. Zhong7Justin X. Zhong8Nafisa A. Elghazali9Nafisa A. Elghazali10Joel A. Finbloom11Bhushan N. Kharbikar12Alex N. Kryger13Theodore Miclau14Ralph S. Marcucio15Chelsea S. Bahney16Chelsea S. Bahney17Chelsea S. Bahney18Chelsea S. Bahney19Tejal A. Desai20Tejal A. Desai21Tejal A. Desai22Tejal A. Desai23Graduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United StatesGraduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United StatesCenter for Regenerative and Personalized Medicine, The Steadman Philippon Research Institute (SPRI), Vail, CO, United StatesCenter for Regenerative and Personalized Medicine, The Steadman Philippon Research Institute (SPRI), Vail, CO, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United StatesUC Berkeley—UCSF Graduate Program in Bioengineering, San Francisco, CA, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United StatesUC Berkeley—UCSF Graduate Program in Bioengineering, San Francisco, CA, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United StatesSchool of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), San Francisco, CA, United StatesGraduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), San Francisco, CA, United StatesCenter for Regenerative and Personalized Medicine, The Steadman Philippon Research Institute (SPRI), Vail, CO, United StatesUC Berkeley—UCSF Graduate Program in Bioengineering, San Francisco, CA, United StatesGraduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United StatesDepartment of Bioengineering, University of California, Berkeley (UC Berkeley), Berkeley, CA, United StatesSchool of Engineering, Brown University, Providence, RI, United StatesIntroduction: Currently, there are no non-surgical FDA-approved biological approaches to accelerate fracture repair. Injectable therapies designed to stimulate bone healing represent an exciting alternative to surgically implanted biologics, however, the translation of effective osteoinductive therapies remains challenging due to the need for safe and effective drug delivery. Hydrogel-based microparticle platforms may be a clinically relevant solution to create controlled and localized drug delivery to treat bone fractures. Here, we describe poly (ethylene glycol) dimethacrylate (PEGDMA)-based microparticles, in the shape of microrods, loaded with beta nerve growth factor (β-NGF) for the purpose of promoting fracture repair.Methods: Herein, PEGDMA microrods were fabricated through photolithography. PEGDMA microrods were loaded with β-NGF and in vitro release was examined. Subsequently, bioactivity assays were evaluated in vitro using the TF-1 tyrosine receptor kinase A (Trk-A) expressing cell line. Finally, in vivo studies using our well-established murine tibia fracture model were performed and a single injection of the β-NGF loaded PEGDMA microrods, non-loaded PEGDMA microrods, or soluble β-NGF was administered to assess the extent of fracture healing using Micro-computed tomography (µCT) and histomorphometry.Results:In vitro release studies showed there is significant retention of protein within the polymer matrix over 168 hours through physiochemical interactions. Bioactivity of protein post-loading was confirmed with the TF-1 cell line. In vivo studies using our murine tibia fracture model show that PEGDMA microrods injected at the site of fracture remained adjacent to the callus for over 7 days. Importantly, a single injection of β-NGF loaded PEGDMA microrods resulted in improved fracture healing as indicated by a significant increase in the percent bone in the fracture callus, trabecular connective density, and bone mineral density relative to soluble β-NGF control indicating improved drug retention within the tissue. The concomitant decrease in cartilage fraction supports our prior work showing that β-NGF promotes endochondral conversion of cartilage to bone to accelerate healing.Discussion: We demonstrate a novel and translational method wherein β-NGF can be encapsulated within PEGDMA microrods for local delivery and that β-NGF bioactivity is maintained resulting in improved bone fracture repair.https://www.frontiersin.org/articles/10.3389/fbioe.2023.1190371/fullfracture repairendochondral ossificationbeta-nerve growth factordrug deliverysustained releasepoly (ethylene) glycol dimethacrylate |
| spellingShingle | Kevin O. Rivera Kevin O. Rivera Kevin O. Rivera Darnell L. Cuylear Darnell L. Cuylear Victoria R. Duke Kelsey M. O’Hara Justin X. Zhong Justin X. Zhong Nafisa A. Elghazali Nafisa A. Elghazali Joel A. Finbloom Bhushan N. Kharbikar Alex N. Kryger Theodore Miclau Ralph S. Marcucio Chelsea S. Bahney Chelsea S. Bahney Chelsea S. Bahney Chelsea S. Bahney Tejal A. Desai Tejal A. Desai Tejal A. Desai Tejal A. Desai Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair Frontiers in Bioengineering and Biotechnology fracture repair endochondral ossification beta-nerve growth factor drug delivery sustained release poly (ethylene) glycol dimethacrylate |
| title | Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair |
| title_full | Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair |
| title_fullStr | Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair |
| title_full_unstemmed | Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair |
| title_short | Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair |
| title_sort | encapsulation of β ngf in injectable microrods for localized delivery accelerates endochondral fracture repair |
| topic | fracture repair endochondral ossification beta-nerve growth factor drug delivery sustained release poly (ethylene) glycol dimethacrylate |
| url | https://www.frontiersin.org/articles/10.3389/fbioe.2023.1190371/full |
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