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postgraduate thesis: Development of an rhBMP-2-binding PA carrier for spinal fusion : a porcine model

TitleDevelopment of an rhBMP-2-binding PA carrier for spinal fusion : a porcine model
Authors
Advisors
Issue Date2020
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Koh, H. Y. [許慧玉]. (2020). Development of an rhBMP-2-binding PA carrier for spinal fusion : a porcine model. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractLow back pain (LBP) is one of the most common musculoskeletal conditions and poses a huge health and socioeconomic burden worldwide. Spinal fusion surgery is often warranted for the treatment of LBP with neurological deficit or after treatment failure with nonsurgical methods. Despite well-established surgical procedures, postoperative pseudarthrosis still accounts for over 20% of revision spinal surgery. Since the discovery of bone morphogenetic proteins (BMPs), these osteogenetic growth factors, in particular, BMP-2 have been widely studied as a potential bone graft substitute to increase spinal fusion rates. Currently, only one BMP-2 bone graft substitute is approved for clinical use but its use was found to be associated with severe postoperative complications. This was attributed to the inefficacy of the collagen carrier which in turn requires supraphysiological doses of BMP-2 for successful bone fusion. Hence, the search for alternative carrier systems that reduces the amount of BMP-2 required ensues. We have developed a novel self-assembling peptide amphiphile (PA) carrier system that forms nanofiber scaffolds for bone regeneration. These scaffolds are biomimetic of the extracellular matrix and display a high density of BMP-2 binding sequence on its surface, thereby increasing the affinity for both endogenous and exogenous BMP-2. Previous in vitro and in vivo testing with small animals showed that this PA carrier is able to elicit bone fusion at a greatly reduced rhBMP-2 dosage. As the next step to evaluate the translational potential of the carrier before human clinical trials, we aim to validate the efficacy of this new PA carrier in a higher order animal (porcine) model and to determine the optimal dose of rhBMP-2 needed for inducing bone fusion. For this study, we conducted our experiments in three phases. Firstly, we sought to perform a proof-of-concept trial using miniature pigs but was met with postoperative wound complications and leakage of the PA carrier from the implant site. Hence, changes were proposed to increase the viscosity of the carrier, stabilize the spine with spinal instrumentation and to reduce the risk of surgical site infection (SSI). With these changes, our second phase of experiments showed successful spinal fusion in one out of four pigs using a 100-fold reduced dosage of rhBMP-2 in the absence of SSI. Still, subclinical SSI were observed in the other 3 pigs which prompted more aggressive prophylactic measures to eliminate risk of infection. Finally, in our last phase of experiments, no SSI was observed and solid bone fusion was formed in all spinal segments using a 200-fold reduction in rhBMP-2 concentration. In summary, our findings showed that the rhBMP-2-binding PA carrier was able to elicit solid bone fusion in the porcine spinal fusion model at a dosage 100-fold and 200-fold lower than the currently available rhBMP-2 product. These encouraging results demonstrate the potential of the carrier as a bone graft substitute that can greatly reduce the dosage of BMP-2 needed for successful spinal fusion. Further studies will be needed to increase sample size and to establish the dose-dependent curve of rhBMP-2 using the PA carrier. Abstract word count: 498 words
DegreeMaster of Philosophy
SubjectPeptide amphiphiles
Bone morphogenetic proteins
Dept/ProgramOrthopaedics and Traumatology
Persistent Identifierhttp://hdl.handle.net/10722/283126

 

DC FieldValueLanguage
dc.contributor.advisorKwan, KYH-
dc.contributor.advisorCheung, KMC-
dc.contributor.authorKoh, Hui Yu-
dc.contributor.author許慧玉-
dc.date.accessioned2020-06-10T01:02:15Z-
dc.date.available2020-06-10T01:02:15Z-
dc.date.issued2020-
dc.identifier.citationKoh, H. Y. [許慧玉]. (2020). Development of an rhBMP-2-binding PA carrier for spinal fusion : a porcine model. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/283126-
dc.description.abstractLow back pain (LBP) is one of the most common musculoskeletal conditions and poses a huge health and socioeconomic burden worldwide. Spinal fusion surgery is often warranted for the treatment of LBP with neurological deficit or after treatment failure with nonsurgical methods. Despite well-established surgical procedures, postoperative pseudarthrosis still accounts for over 20% of revision spinal surgery. Since the discovery of bone morphogenetic proteins (BMPs), these osteogenetic growth factors, in particular, BMP-2 have been widely studied as a potential bone graft substitute to increase spinal fusion rates. Currently, only one BMP-2 bone graft substitute is approved for clinical use but its use was found to be associated with severe postoperative complications. This was attributed to the inefficacy of the collagen carrier which in turn requires supraphysiological doses of BMP-2 for successful bone fusion. Hence, the search for alternative carrier systems that reduces the amount of BMP-2 required ensues. We have developed a novel self-assembling peptide amphiphile (PA) carrier system that forms nanofiber scaffolds for bone regeneration. These scaffolds are biomimetic of the extracellular matrix and display a high density of BMP-2 binding sequence on its surface, thereby increasing the affinity for both endogenous and exogenous BMP-2. Previous in vitro and in vivo testing with small animals showed that this PA carrier is able to elicit bone fusion at a greatly reduced rhBMP-2 dosage. As the next step to evaluate the translational potential of the carrier before human clinical trials, we aim to validate the efficacy of this new PA carrier in a higher order animal (porcine) model and to determine the optimal dose of rhBMP-2 needed for inducing bone fusion. For this study, we conducted our experiments in three phases. Firstly, we sought to perform a proof-of-concept trial using miniature pigs but was met with postoperative wound complications and leakage of the PA carrier from the implant site. Hence, changes were proposed to increase the viscosity of the carrier, stabilize the spine with spinal instrumentation and to reduce the risk of surgical site infection (SSI). With these changes, our second phase of experiments showed successful spinal fusion in one out of four pigs using a 100-fold reduced dosage of rhBMP-2 in the absence of SSI. Still, subclinical SSI were observed in the other 3 pigs which prompted more aggressive prophylactic measures to eliminate risk of infection. Finally, in our last phase of experiments, no SSI was observed and solid bone fusion was formed in all spinal segments using a 200-fold reduction in rhBMP-2 concentration. In summary, our findings showed that the rhBMP-2-binding PA carrier was able to elicit solid bone fusion in the porcine spinal fusion model at a dosage 100-fold and 200-fold lower than the currently available rhBMP-2 product. These encouraging results demonstrate the potential of the carrier as a bone graft substitute that can greatly reduce the dosage of BMP-2 needed for successful spinal fusion. Further studies will be needed to increase sample size and to establish the dose-dependent curve of rhBMP-2 using the PA carrier. Abstract word count: 498 words -
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshPeptide amphiphiles-
dc.subject.lcshBone morphogenetic proteins-
dc.titleDevelopment of an rhBMP-2-binding PA carrier for spinal fusion : a porcine model-
dc.typePG_Thesis-
dc.description.thesisnameMaster of Philosophy-
dc.description.thesislevelMaster-
dc.description.thesisdisciplineOrthopaedics and Traumatology-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2020-
dc.identifier.mmsid991044242095203414-

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