Semaphorin 3A delivered by a rapidly polymerizing click hydrogel overcomes impaired implant osseointegration in a rat type 2 diabetes model

Deng, Jingyao; Cohen, David J.; Sabalewski, Eleanor L.; Duyn, Christine Van; Wilson, David S.; Schwartz, Zvi; Boyan, Barbara D.

doi:10.1016/j.actbio.2022.11.030

Cited by 6 publications

(14 citation statements)

References 61 publications

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“…We used a copper-free click hydrogel as the sema3A delivery vehicle. We have successfully used click hydrogels to deliver biologics, drugs, and antibodies to bone defect sites, with no evidence of toxicity [ 41 , 43 , 44 ]. Swelling is minimal, and following an initial burst release, the payload is released at a steady rate, with degradation occurring over a 14-day period [ 41 , 43 , 44 ].…”

Section: Methodsmentioning

confidence: 99%

“…We have successfully used click hydrogels to deliver biologics, drugs, and antibodies to bone defect sites, with no evidence of toxicity [ 41 , 43 , 44 ]. Swelling is minimal, and following an initial burst release, the payload is released at a steady rate, with degradation occurring over a 14-day period [ 41 , 43 , 44 ]. The techniques used to prepare the hydrogel were adapted from previous work [ 41 , 43 , 44 ].…”

Section: Methodsmentioning

confidence: 99%

“…Swelling is minimal, and following an initial burst release, the payload is released at a steady rate, with degradation occurring over a 14-day period [ 41 , 43 , 44 ]. The techniques used to prepare the hydrogel were adapted from previous work [ 41 , 43 , 44 ]. Briefly, the copper-free click-based chemistry was used to combine two aqueous solutions that underwent in situ chemical crosslinking to create the quickly polymerizing hydrogel.…”

Section: Methodsmentioning

confidence: 99%

“…We knew that human sema3A could enhance surface-mediated osteoblast differentiation of human MSCs in vitro, as well as the production of factors associated with osteogenesis. Moreover, human sema3A restored the osseointegration of Ti implants in a type 2 diabetic rat model to normal levels, demonstrating that it was bioactive in vivo [ 28 , 41 ]. Therefore, the concentrations of the same human recombinant sema3A were adopted for this study.…”

Section: Methodsmentioning

confidence: 99%

“…We previously showed that the local delivery of human recombinant sema3A improved the osseointegration of Ti implants with a biomimetic surface topography placed transcortically in diabetic rat femurs, which have a similar bone phenotype to mechanically unloaded bone with respect to the loss of trabeculae in the metaphysis [ 40 , 41 ]. This suggested that sema3A might also improve implant integration in mechanically unloaded bone.…”

Section: Introductionmentioning

confidence: 99%

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Osseointegration of Titanium Implants in a Botox-Induced Muscle Paralysis Rat Model Is Sensitive to Surface Topography and Semaphorin 3A Treatment

et al. 2023

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Reduced skeletal loading associated with many conditions, such as neuromuscular injuries, can lead to bone fragility and may threaten the success of implant therapy. Our group has developed a botulinum toxin A (botox) injection model to imitate disease-reduced skeletal loading and reported that botox dramatically impaired the bone formation and osseointegration of titanium implants. Semaphorin 3A (sema3A) is an osteoprotective factor that increases bone formation and inhibits bone resorption, indicating its potential therapeutic role in improving osseointegration in vivo. We first evaluated the sema3A effect on whole bone morphology following botox injections by delivering sema3A via injection. We then evaluated the sema3A effect on the osseointegration of titanium implants with two different surface topographies by delivering sema3A to cortical bone defect sites prepared for implant insertion and above the implants after insertion using a copper-free click hydrogel that polymerizes rapidly in situ. Implants had hydrophobic smooth surfaces (PT) or multiscale biomimetic micro/nano topography (SLAnano). Sema3A rescued the botox-impaired bone formation. Furthermore, biomimetic Ti implants improved the bone-to-implant contact (BIC) and mechanical properties of the integrated bone in the botox-treated rats, which sema3A enhanced. This study demonstrated the value of biomimetic approaches combining multiscale topography and biologics in improving the clinical outcomes of implant therapy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Osseointegration of Titanium Implants in a Botox-Induced Muscle Paralysis Rat Model Is Sensitive to Surface Topography and Semaphorin 3A Treatment

et al. 2023

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Reduced osseointegration in disuse and denervation rat models results from impaired cellular responses to multiscale microstructured titanium surfaces

Deng,

Joshua Cohen,

Matias

et al. 2024

Journal Orthopaedic Research

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Immobilization‐induced skeletal unloading results in muscle atrophy and rapid bone loss, thereby increasing the risk of falling and the need for implant therapy in patients with extended bed rest or neuromuscular injuries. Skeletal unloading causes bone loss by altering bone growth and resorption, suggesting that implant performance might be affected. To test this, we focused on early events in implant osseointegration. We used the rat sciatic neurectomy‐induced disuse model under two different settings. In Study 1, 16 Sprague Dawley rats (SD) were separated into control, sham operated+cast immobilization, and sciatic neurectomy+casting groups; titanium implants with multiscale microtextured topography and hydrophilic chemistry (modSLA) were inserted in the distal femoral metaphysis. Neurectomy surgeries and casting were performed at the same surgical setting as implant placement; rats were euthanized 4 weeks post‐implantation. In Study 2, we established the unloaded condition before implantation. A total of 12 SD rats were divided into control and sciatic+femoral neurectomy groups. A total of 24 days after sciatic and femoral neurectomy surgery, rats received implants. Study 2 rats were euthanized at 4 weeks post‐implantation. MicroCT and histomorphometry showed that trabecular bone and osseointegration were reduced when disuse was established before implantation. Osteoblasts isolated from Study 1 sciatic neurectomy tibial bones exhibited impaired differentiation on modSLA culture disks, revealing a possible mechanism responsible for the decreased osseointegration observed in the Study 2 rats. This study addressed the importance of considering the mechanical unloading and muscle function history before implant insertion and suggests that implant performance was reduced due to poor cellular ability to regenerate.

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SiJunZi decoction ameliorates bone quality and redox homeostasis and regulates advanced glycation end products/receptor for advanced glycation end products and WNT/β-catenin signaling pathways in diabetic mice

Dai,

Liu,

Liu

et al. 2024

Journal of Ethnopharmacology

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Semaphorin 3A delivered by a rapidly polymerizing click hydrogel overcomes impaired implant osseointegration in a rat type 2 diabetes model

Cited by 6 publications

References 61 publications

Osseointegration of Titanium Implants in a Botox-Induced Muscle Paralysis Rat Model Is Sensitive to Surface Topography and Semaphorin 3A Treatment

Osseointegration of Titanium Implants in a Botox-Induced Muscle Paralysis Rat Model Is Sensitive to Surface Topography and Semaphorin 3A Treatment

Reduced osseointegration in disuse and denervation rat models results from impaired cellular responses to multiscale microstructured titanium surfaces

SiJunZi decoction ameliorates bone quality and redox homeostasis and regulates advanced glycation end products/receptor for advanced glycation end products and WNT/β-catenin signaling pathways in diabetic mice

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