Skin-nerve interaction plays an important role in promoting wound healing.However,in diabetic ulcers(DUs),the diabetic periphery neuropathy and excessive levels of reactive oxygen species(ROS)block skin-nerve interact...Skin-nerve interaction plays an important role in promoting wound healing.However,in diabetic ulcers(DUs),the diabetic periphery neuropathy and excessive levels of reactive oxygen species(ROS)block skin-nerve interaction and further impede the DUs healing.Herein,we developed a nanoscale metal-organic framework loaded with nerve growth factor(NGF/Ce-UiO-66,denoted NGF/CU)for the treatment of DUs.The Ce-UiO-66(CU)was applied as an antioxidant to scavenge ROS and reduce the inflammatory response while the NGF aided in the recovery of cutaneous nerves to further promote DUs healing.Both in vitro and in vivo experiments revealed the effective ability of NGF/CU for DUs healing.Subsequent RNA sequencing analysis revealed the mechanism that NGF/CU can improve wound healing by inhibiting the NF-κB signaling pathway and recovering the neuroendocrine system of the skin.This strategy of nerve regulation will provide more ideas for the treatment of DUs and other organ injuries.展开更多
Reactive oxygen and nitrogen species (RONS) are essential for normal physiological processes and play important roles in cell signaling, immunity, and tissue homeostasis. However, excess radical species are implicat...Reactive oxygen and nitrogen species (RONS) are essential for normal physiological processes and play important roles in cell signaling, immunity, and tissue homeostasis. However, excess radical species are implicated in the development and augmented pathogenesis of various diseases. Several antioxidants may restore the chemical balance, but their use is limited by disappointing results of clinical trials. Nanoparticles are an attractive therapeutic alternative because they can change the biodistribution profile of antioxidants, and possess intrinsic ability to scavenge RONS. Herein, we review the types of RONS, how they are implicated in several diseases, and the types of nanoparticles with inherent antioxidant capability, their mechanisms of action, and their biological applications.展开更多
Disruption of mitochondrial reactive oxygen species (mitoROS) plays a major role in cancer cell apoptosis. Here, we designed a core/shell-structured mitochondriatargeting upconversion-based nano-photosensitizer (TP...Disruption of mitochondrial reactive oxygen species (mitoROS) plays a major role in cancer cell apoptosis. Here, we designed a core/shell-structured mitochondriatargeting upconversion-based nano-photosensitizer (TPP-UC(PS)) with a lanthanidedoped upconversion nanoparticle (UCNP) core coated by a photosensitizer (PS)-incorporated dense silica shell. Following irradiation with external nearinfrared laser (NIR), TPP-UC(PS) in mitochondria caused serious mitochondrial matrix swelling for the activated upconversion-based photodynamic therapy (UC-PDT), and the mobilization of cytochrome c (cyt c) was amplified in response to the increased mitoROS. Specifically, this heme-containing cyt c could be monitored by varying TPP-UC(PS)'s upconversion luminescence signal (UCL), which may facilitate the in situ detection of cyt c for apoptosis research. As a proof of concept, our designed TPP-UC(PS) may provide significant opportunities for controlling cancer cell apoptosis under NIR stimulation and for studying apoptosis using the dynamic UCL, which is influenced by local cyt c.展开更多
Wound delayed healing or non-healing has seriously affected patients’quality of life and has been a significant economic burden for public health systems worldwide.Excess reactive oxygen species(ROS)play important ro...Wound delayed healing or non-healing has seriously affected patients’quality of life and has been a significant economic burden for public health systems worldwide.Excess reactive oxygen species(ROS)play important roles for impeding the process of wound healing.Herein,we report a hydrogel system containing low-valence-state molybdenum nanomaterials(Mo hydrogel)for wound healing by scavenging the detrimental ROS.Both in vitro and in vivo results demonstrate that the synthesized Mo hydrogel can accelerate wound healing,promote angiogenesis,and stimulate the expression of growth factors.Since the molybdenum is an essential element for the survival of all organisms,such novel Mo-hydrogel has the great potential to be clinically translated for wound healing.展开更多
Sonodynamic therapy(SDT)has been more attractive to carry out oncology treatments in recent years.However,imagingguided sonodynamic therapeutic nanomedicine is still a shortage in SDT development.In this work,we desig...Sonodynamic therapy(SDT)has been more attractive to carry out oncology treatments in recent years.However,imagingguided sonodynamic therapeutic nanomedicine is still a shortage in SDT development.In this work,we designed and fabricated an organic SDT system based on combination of 1,2,4,5-tetrakis(4-carboxyphenyl)-porphyrin(TCPP)and gadolinium(III)(Gd^(3+))creatively(Gd-PPNs).Gd^(3+)was traditionally used to be T_(1)-weighted magnetic resonance imaging(MRI)contrast agent and TCPP was initiatively a fluorescence imaging organic media.Therefore,these new designed nanoparticles have immense potential to integrate MRI and FLI to visualize the Gd-PPNs accumulating and keeping in tumor for a long time,which could be applied for guidance of SDT on tumors in clinical practice.Importantly,excellent SDT efficiency under imaging guidance was verified both in vitro and in vivo in this work.Our findings suggested that Gd-PPNs,as innovative imaging and therapy combinational nanomedicines,were successfully synthesized and were proved to possess excellent imaging-guided sonodynamic therapeutic efficacy.Moreover,this new designed sonosensitizer had great biocompatibility to avoid unnecessary biotoxicity.Overall,this strategy shed light on the MRI/FLI-guidance and successfully induced pancreatic tumor growth inhibition by sonodynamic therapy.展开更多
Combination therapy is a promising cancer treatment strategy that is usually based on the utilization of complicated nanostructures with multiple components functioning as photo-thermal energy transducers, photo-sensi...Combination therapy is a promising cancer treatment strategy that is usually based on the utilization of complicated nanostructures with multiple components functioning as photo-thermal energy transducers, photo-sensitizers, or dose intensifiers for phototherma! therapy (PTT), photodynamic therapy (PDT), or radiation therapy (RT). In this study, ultrathin tungsten oxide nanowires (W18O49) were synthesized using a solvothermal approach and examined as a multifunctional theranostic nanoplatform. In vitro and in vivo analyses demonstrated that these nanowires could induce extensive heat- and singlet oxygen-mediated damage to cancer cells under 980 nm near infrared (NIR)-laser excitation. They were also shown to function as radiation dose intensifying agents that enhance irradiative energy deposition locally and selectively during radiation therapy. Compared to NIR-induced PTT/PDT and RT alone, W18O49 - based synergistic tri-modal therapy eradicated xenograft tumors and no recurrence was observed within a 9-month follow up. Moreover, the strong X-ray attenuation ability of the tungsten element (Z = 74, 4.438 cm^2·g^-1, 100 KeV) qualified these nanowires as excellent contrast agents in X-ray-based imaging, such as diagnostic computed tomography (CT) and cone-beam CT for image-guided radiation therapy. Toxicity studies demonstrated minimal adverse effects on the hematologic system and major organs of mice within one month. In conclusion, these nanowires have shown significant potential for cancer therapy with inherent image guidance and synergistic effects from phototherapy and radiation therapy, which warrants further investigation.展开更多
DNA tetrahedro n nano structure (DTN) is one of the simplest DNA nano structures and has bee n successfully applied for biose nsin g, imagi ng, and treatment of can cer. To facilitate its biomedical applications and p...DNA tetrahedro n nano structure (DTN) is one of the simplest DNA nano structures and has bee n successfully applied for biose nsin g, imagi ng, and treatment of can cer. To facilitate its biomedical applications and pote ntial clinical tran slation, fun dame ntal un derstandi ng of DTN's transportation among major organs in living organisms becomes increasingly important. Here, we describe the efficient renal clearanee of DTN in healthy mice by using positron emission tomography (PET) imaging. The kidney elimination of DTN was later applied for renal function evaluation in murine models of unilateral ureteral obstruction (UUO). We further established a mathematical program of DTN to validate its changes of transportation pattern in healthy and UUO mice. We believe the establishment of pharmacokinetic profiles and mathematical model of DTN may provide in sight for future optimization of DNA nano structures for biomedical applications.展开更多
Photodynamic therapy(PDT)by near-infrared(NIR)irradiation is a promising technique for treating various cancers.Here,we reported the development of free-standing wafer-scale Au nanosheets(NSs)that exhibited an impress...Photodynamic therapy(PDT)by near-infrared(NIR)irradiation is a promising technique for treating various cancers.Here,we reported the development of free-standing wafer-scale Au nanosheets(NSs)that exhibited an impressive PDT effect.The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm.These Au NSs were found very effective in generating singlet oxygen under NIR irradiation.In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology.Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation.This performance is comparable to using 10 times mass loading of Au nanoparticles(NPs).This work suggests that two-dimensional(2D)Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency.展开更多
Acute kidney injury(AKI)leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs.Here,a series of polyvinylpyrrolidone(PVP)-curcumin nanopa...Acute kidney injury(AKI)leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs.Here,a series of polyvinylpyrrolidone(PVP)-curcumin nanoparticles(PCurNP)are designed to meet the renal excretion threshold(~45 kDa),presenting a controllable delivery nanosystem for kidney targeting.Renal accumulation of the relatively small nanoparticles,^(89)Zr-PCurNP M10 with the diameter between 5 and 8 nm,is found to be 1.7 times and 1.8 times higher than the accumulation of^(89)Zr-PCurNP M29(20-50 nm)and M40(20-50 nm)as revealed by PET imaging.Furthermore,serum creatinine analysis,kidney tissues histology,and tubular injury scores revealed that PCurNP M10 efficiently treated cisplatin-induced AKI.Herein,PCurNP offers a novel and simple strategy for precise PET image-guided drug delivery of renal protective materials.展开更多
Osteosarcoma(OS)is the most normally primary malignant bone cancer in adolescents.Due to their analogous X-ray attenuation properties,healthy bones and malignancies with iodine enhancement cannot be distinguished by c...Osteosarcoma(OS)is the most normally primary malignant bone cancer in adolescents.Due to their analogous X-ray attenuation properties,healthy bones and malignancies with iodine enhancement cannot be distinguished by conventional computed tomography(CT).As one kind of spectral CT,dual-energy CT(DECT)offers multiple functions for material separation and cancer treatments.Herein,bismuth sulfide(Bi_(2)S_(3))nanorods(NRs)were synthesized as special contrast agents(CAs)for DECT,which have superior imaging properties than clinical iodine CAs.At the same time,the high photothermal conversion rates of Bi_(2)S_(3)NRs can be used for DECT-guided photothermal therapy(PTT)to destroy OS and inhibit tumor growth under the guidance of DECT imaging.Importantly,DECT imaging real-timely monitored that PTT could accelerate the diffusion of Bi2S3 NRs in the tumor,obtaining detailed information on the internal distribution of nanomaterials in tumors around the bone to avoid injury to normal tissues by PTT.Overall,the proposed strategy of DECT imaging-guided PTT appears enormous promise for bone disease treatment.展开更多
基金the financial support from National Natural Science Foundation of China(Grant No.82372098 and 82104073)Opening Project of State Key Laboratory of High Performance Ceramics and Superfine Microstructure(SKL202212SIC)Shanghai Science and Technology Commission/General Project of Natural Science Foundation of Shanghai in 2021(21ZR1440600).
文摘Skin-nerve interaction plays an important role in promoting wound healing.However,in diabetic ulcers(DUs),the diabetic periphery neuropathy and excessive levels of reactive oxygen species(ROS)block skin-nerve interaction and further impede the DUs healing.Herein,we developed a nanoscale metal-organic framework loaded with nerve growth factor(NGF/Ce-UiO-66,denoted NGF/CU)for the treatment of DUs.The Ce-UiO-66(CU)was applied as an antioxidant to scavenge ROS and reduce the inflammatory response while the NGF aided in the recovery of cutaneous nerves to further promote DUs healing.Both in vitro and in vivo experiments revealed the effective ability of NGF/CU for DUs healing.Subsequent RNA sequencing analysis revealed the mechanism that NGF/CU can improve wound healing by inhibiting the NF-κB signaling pathway and recovering the neuroendocrine system of the skin.This strategy of nerve regulation will provide more ideas for the treatment of DUs and other organ injuries.
文摘Reactive oxygen and nitrogen species (RONS) are essential for normal physiological processes and play important roles in cell signaling, immunity, and tissue homeostasis. However, excess radical species are implicated in the development and augmented pathogenesis of various diseases. Several antioxidants may restore the chemical balance, but their use is limited by disappointing results of clinical trials. Nanoparticles are an attractive therapeutic alternative because they can change the biodistribution profile of antioxidants, and possess intrinsic ability to scavenge RONS. Herein, we review the types of RONS, how they are implicated in several diseases, and the types of nanoparticles with inherent antioxidant capability, their mechanisms of action, and their biological applications.
基金This work has been financially supported by the National Natural Science Foundation of China (Nos. 51372260, 51132009, and 81471714), and the Shanghai Excellent Academic Leaders Program (No. 16XD1404000). Thanks to Linlin Zhang, Heliang Yao, Qingfeng Xiao,Huaiyong Xing, Wenpei Fan, Zhaowen Cui, Li Jiang, and Jianan Liu from Shanghai Institute of Ceramics, Chinese Academy of Sciences for useful discussions.
文摘Disruption of mitochondrial reactive oxygen species (mitoROS) plays a major role in cancer cell apoptosis. Here, we designed a core/shell-structured mitochondriatargeting upconversion-based nano-photosensitizer (TPP-UC(PS)) with a lanthanidedoped upconversion nanoparticle (UCNP) core coated by a photosensitizer (PS)-incorporated dense silica shell. Following irradiation with external nearinfrared laser (NIR), TPP-UC(PS) in mitochondria caused serious mitochondrial matrix swelling for the activated upconversion-based photodynamic therapy (UC-PDT), and the mobilization of cytochrome c (cyt c) was amplified in response to the increased mitoROS. Specifically, this heme-containing cyt c could be monitored by varying TPP-UC(PS)'s upconversion luminescence signal (UCL), which may facilitate the in situ detection of cyt c for apoptosis research. As a proof of concept, our designed TPP-UC(PS) may provide significant opportunities for controlling cancer cell apoptosis under NIR stimulation and for studying apoptosis using the dynamic UCL, which is influenced by local cyt c.
基金the financial support from the National Natural Science Foundation of China(Nos.82102190 and 81773347)Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(No.20191805)the Foundation of National Facility for Translational Medicine(Shanghai)(No.TMSK-2021-122).
文摘Wound delayed healing or non-healing has seriously affected patients’quality of life and has been a significant economic burden for public health systems worldwide.Excess reactive oxygen species(ROS)play important roles for impeding the process of wound healing.Herein,we report a hydrogel system containing low-valence-state molybdenum nanomaterials(Mo hydrogel)for wound healing by scavenging the detrimental ROS.Both in vitro and in vivo results demonstrate that the synthesized Mo hydrogel can accelerate wound healing,promote angiogenesis,and stimulate the expression of growth factors.Since the molybdenum is an essential element for the survival of all organisms,such novel Mo-hydrogel has the great potential to be clinically translated for wound healing.
基金We greatly acknowledge the financial support from the National Natural Science Foundation of China(No.82102190)Shanghai Municipal Education Commission--Gaofeng Clinical Medicine Grant Support(No.20191805)+4 种基金the Foundation of National Facility for Translational Medicine(Shanghai)(No.TMSK-2021-122)this work was also supported,in part,by China Postdoctoral Science Foundation(No.2020M681326)Shanghai Sailing Program(No.19YF1410100)Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)ZJ Lab,Shanghai Center for Brain-Inspired Technology.
文摘Sonodynamic therapy(SDT)has been more attractive to carry out oncology treatments in recent years.However,imagingguided sonodynamic therapeutic nanomedicine is still a shortage in SDT development.In this work,we designed and fabricated an organic SDT system based on combination of 1,2,4,5-tetrakis(4-carboxyphenyl)-porphyrin(TCPP)and gadolinium(III)(Gd^(3+))creatively(Gd-PPNs).Gd^(3+)was traditionally used to be T_(1)-weighted magnetic resonance imaging(MRI)contrast agent and TCPP was initiatively a fluorescence imaging organic media.Therefore,these new designed nanoparticles have immense potential to integrate MRI and FLI to visualize the Gd-PPNs accumulating and keeping in tumor for a long time,which could be applied for guidance of SDT on tumors in clinical practice.Importantly,excellent SDT efficiency under imaging guidance was verified both in vitro and in vivo in this work.Our findings suggested that Gd-PPNs,as innovative imaging and therapy combinational nanomedicines,were successfully synthesized and were proved to possess excellent imaging-guided sonodynamic therapeutic efficacy.Moreover,this new designed sonosensitizer had great biocompatibility to avoid unnecessary biotoxicity.Overall,this strategy shed light on the MRI/FLI-guidance and successfully induced pancreatic tumor growth inhibition by sonodynamic therapy.
基金Acknowledgements This work has been financially supported by the National Natural Science Foundation of China (Nos. 51372260, 51132009, and 21172043), the Shanghai Rising-Star Program (No. 12QH1402500), the Science and Technology Commission of Shanghai (No. 11nm0505000 and 124119a0400), the Shanghai Municipal Commission of Health (No. 20134360), the Development Foundation for Talents of Shanghai (No. 2012035).
文摘Combination therapy is a promising cancer treatment strategy that is usually based on the utilization of complicated nanostructures with multiple components functioning as photo-thermal energy transducers, photo-sensitizers, or dose intensifiers for phototherma! therapy (PTT), photodynamic therapy (PDT), or radiation therapy (RT). In this study, ultrathin tungsten oxide nanowires (W18O49) were synthesized using a solvothermal approach and examined as a multifunctional theranostic nanoplatform. In vitro and in vivo analyses demonstrated that these nanowires could induce extensive heat- and singlet oxygen-mediated damage to cancer cells under 980 nm near infrared (NIR)-laser excitation. They were also shown to function as radiation dose intensifying agents that enhance irradiative energy deposition locally and selectively during radiation therapy. Compared to NIR-induced PTT/PDT and RT alone, W18O49 - based synergistic tri-modal therapy eradicated xenograft tumors and no recurrence was observed within a 9-month follow up. Moreover, the strong X-ray attenuation ability of the tungsten element (Z = 74, 4.438 cm^2·g^-1, 100 KeV) qualified these nanowires as excellent contrast agents in X-ray-based imaging, such as diagnostic computed tomography (CT) and cone-beam CT for image-guided radiation therapy. Toxicity studies demonstrated minimal adverse effects on the hematologic system and major organs of mice within one month. In conclusion, these nanowires have shown significant potential for cancer therapy with inherent image guidance and synergistic effects from phototherapy and radiation therapy, which warrants further investigation.
基金University of Wisconsin-Madison, the National Institutes of Health (NIBIB/NCI P30CA014520, T32CA009206)the American Cancer Society (125246-RSG-13- 099-01-CCE), the National Natural Science Foundation of China (Nos. 51573096, 51703132, 31771036, and 81630049)+2 种基金the Basic Research Program of Shenzhen (Nos. JCYJ20170412111100742 and JCYJ20160422091238319)the Guangdong Province Natural Science Foundation of Major Basic Research and Cultivation Project (No. 2018B030308003)Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China (No. 161032).
文摘DNA tetrahedro n nano structure (DTN) is one of the simplest DNA nano structures and has bee n successfully applied for biose nsin g, imagi ng, and treatment of can cer. To facilitate its biomedical applications and pote ntial clinical tran slation, fun dame ntal un derstandi ng of DTN's transportation among major organs in living organisms becomes increasingly important. Here, we describe the efficient renal clearanee of DTN in healthy mice by using positron emission tomography (PET) imaging. The kidney elimination of DTN was later applied for renal function evaluation in murine models of unilateral ureteral obstruction (UUO). We further established a mathematical program of DTN to validate its changes of transportation pattern in healthy and UUO mice. We believe the establishment of pharmacokinetic profiles and mathematical model of DTN may provide in sight for future optimization of DNA nano structures for biomedical applications.
基金This work was supported by the Army Research Office(No.W911NF-16-1-0198)the National Science Foundation(No.DMR-1709025)+2 种基金National Institutes of Health(Nos.R01EB0213360,1R21EB027857,and P30CA014520)Diffraction data was collected at ChemMatCARS Sector 15,which is principally supported by the Divisions of Chemistry and Materials Research,National Science Foundation,under grant number NSF/CHE-1834750Use of the Advanced Photon Source,an Office of Science User Facility operated for the U.S.Department of Energy(DOE)Office of Science by Argonne National Laboratory,was supported by the U.S.DOE(No.DEAC02-06CH11357).
文摘Photodynamic therapy(PDT)by near-infrared(NIR)irradiation is a promising technique for treating various cancers.Here,we reported the development of free-standing wafer-scale Au nanosheets(NSs)that exhibited an impressive PDT effect.The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm.These Au NSs were found very effective in generating singlet oxygen under NIR irradiation.In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology.Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation.This performance is comparable to using 10 times mass loading of Au nanoparticles(NPs).This work suggests that two-dimensional(2D)Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency.
基金supported by the National Natural Science Foundation of China(81601605,21571147,82102121)the Postdoctoral Science Foundation of China(2016M600670)+2 种基金supported by the University of Wisconsin–Madison,the National Institutes of Health(NIBIB/NCI P30CA014520)the Natural Science Foundation of SZU(Grant No.827-000143)the Shenzhen Peacock Plan(KQTD2016053112051497).
文摘Acute kidney injury(AKI)leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs.Here,a series of polyvinylpyrrolidone(PVP)-curcumin nanoparticles(PCurNP)are designed to meet the renal excretion threshold(~45 kDa),presenting a controllable delivery nanosystem for kidney targeting.Renal accumulation of the relatively small nanoparticles,^(89)Zr-PCurNP M10 with the diameter between 5 and 8 nm,is found to be 1.7 times and 1.8 times higher than the accumulation of^(89)Zr-PCurNP M29(20-50 nm)and M40(20-50 nm)as revealed by PET imaging.Furthermore,serum creatinine analysis,kidney tissues histology,and tubular injury scores revealed that PCurNP M10 efficiently treated cisplatin-induced AKI.Herein,PCurNP offers a novel and simple strategy for precise PET image-guided drug delivery of renal protective materials.
基金This work was supported by the National Natural Science Foundation of China(No.82102190)the Foundation of National Facility for Translational Medicine(Shanghai)(No.TMSK-2021-122)+1 种基金Shanghai Municipal Health Commission Research Project(No.201840082)The animal study protocol was approved by the Institutional Animal Care and Use Committee at Shanghai JiaoTong University。
文摘Osteosarcoma(OS)is the most normally primary malignant bone cancer in adolescents.Due to their analogous X-ray attenuation properties,healthy bones and malignancies with iodine enhancement cannot be distinguished by conventional computed tomography(CT).As one kind of spectral CT,dual-energy CT(DECT)offers multiple functions for material separation and cancer treatments.Herein,bismuth sulfide(Bi_(2)S_(3))nanorods(NRs)were synthesized as special contrast agents(CAs)for DECT,which have superior imaging properties than clinical iodine CAs.At the same time,the high photothermal conversion rates of Bi_(2)S_(3)NRs can be used for DECT-guided photothermal therapy(PTT)to destroy OS and inhibit tumor growth under the guidance of DECT imaging.Importantly,DECT imaging real-timely monitored that PTT could accelerate the diffusion of Bi2S3 NRs in the tumor,obtaining detailed information on the internal distribution of nanomaterials in tumors around the bone to avoid injury to normal tissues by PTT.Overall,the proposed strategy of DECT imaging-guided PTT appears enormous promise for bone disease treatment.