RESUMEN
In this paper, we propose a novel biomechanics-aware robot-assisted steerable drilling framework with the goal of addressing common complications of spinal fixation procedures occurring due to the rigidity of drilling instruments and implants. This framework is composed of two main unique modules to design a robotic system including (i) a Patient-Specific Biomechanics-aware Trajectory Selection Module used to analyze the stress and strain distribution along an implanted pedicle screw in a generic drilling trajectory (linear and/or curved) and obtain an optimal trajectory; and (ii) a complementary semi-autonomous robotic drilling module that consists of a novel Concentric Tube Steerable Drilling Robot (CT-SDR) integrated with a seven degree-of-freedom robotic manipulator. This semi-autonomous robot-assisted steerable drilling system follows a multi-step drilling procedure to accurately and reliably execute the optimal hybrid drilling trajectory (HDT) obtained by the Trajectory Selection Module. Performance of the proposed framework has been thoroughly analyzed on simulated bone materials by drilling various trajectories obtained from the finite element-based Selection Module using Quantitative Computed Tomography (QCT) scans of a real patient's vertebra.
Asunto(s)
Procedimientos Quirúrgicos Mínimamente Invasivos , Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Procedimientos Quirúrgicos Robotizados/instrumentación , Procedimientos Quirúrgicos Mínimamente Invasivos/instrumentación , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Fenómenos Biomecánicos/fisiología , Fusión Vertebral/instrumentación , Fusión Vertebral/métodos , Columna Vertebral/cirugía , Columna Vertebral/diagnóstico por imagen , Diseño de Equipo , Tornillos PedicularesRESUMEN
Spinal fixation with rigid pedicle screws have shown to be an effective treatment for many patients. However, this surgical option has been proved to be insufficient and will eventually fail for patients experiencing osteoporosis. This failure is mainly attributed to the lack of dexterity in the existing rigid drilling instruments and the complex anatomy of vertebrae, forcing surgeons to implant rigid pedicle screws within the osteoporotic regions of anatomy. To address this problem, in this article, we present the design, fabrication, and evaluation of a unique flexible yet structurally strong concentric tube steerable drilling robot (CT-SDR). The CT-SDR is capable of drilling smooth and accurate curved trajectories through hard tissues without experiencing buckling and failure; thus enabling the use of novel flexible pedicle screws for the next generation of spinal fixation procedures. Particularly, by decoupling the control of bending and insertion degrees of freedom (DoF) of the CT-SDR, we present a robotic system that (i) is intuitive to steer as it does not require an on-the-fly control algorithm for the bending DoF, and (ii) is able to address the contradictory requirements of structural stiffness and dexterity of a flexible robot interacting with the hard tissue. The robust and repeatable performance of the proposed CT-SDR have been experimentally evaluated by conducting various drilling procedures on simulated bone materials and animal bone samples. Experimental results indicate drilling times as low as 35 seconds for curved trajectories with 41 mm length and remarkable steering accuracy with a maximum 2% deviation error.
Asunto(s)
Tornillos Pediculares , Procedimientos Quirúrgicos Robotizados , Robótica , Fusión Vertebral , Cirugía Asistida por Computador , Animales , Humanos , Vértebras Lumbares/cirugía , Cirugía Asistida por Computador/métodos , Fusión Vertebral/efectos adversos , Fusión Vertebral/métodosRESUMEN
A quantitative structure-activity relationship (QSAR) study has been carried out on growth hormone secretagogue receptor antagonistic activity of the derivatives of 2,4-diaminopyrimidine. To obtain significant QSARs, the approaches involving the non-parametric such as Fujita-Ban, and the parametric based on physicochemical and DRAGON descriptors in Hansch type of analysis have been employed. The Fujita-Ban approach, however, was constrained to 18 compounds only due to a limited number of substituents appeared at varying positions. The derived contributions of different substituents and the parent moiety were used to identify the potential congeners. The physicochemical model of Hansch was subsequently used to interpret the type of interactions involved between the receptor sites and varying positions of these compounds. The study, employing DRAGON descriptors in Hansch approach was also carried out on this data set to discuss the prevailing interactions in terms of topological descriptors. The derived highest significant model was discussed to delineate the type of interactions involved and suggestions have been made for different alterations to lead to further potential compounds of the series.
Asunto(s)
Modelos Moleculares , Pirimidinas/síntesis química , Receptores de Ghrelina/antagonistas & inhibidores , Animales , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad CuantitativaRESUMEN
The structure-activity models of the VEGFR2 kinase inhibitory activity of the derivatives of 2-anilino-5-aryloxazole have been investigated using Combinatorial Protocol in Multiple Linear Regression (CP-MLR) with nearly 500 topological descriptors which were calculated from DRAGON software. Among the descriptor classes considered collectively in the study, the inhibitory activity was, however, correlated with simple functional (FUN), topological (TOPO), atom centered fragments (ACF), molecular walk counts (MWC) and 2D-autocorrelation (2D-AUTO) descriptors. The developed models and participating descriptors in them have suggested that the substitutional modifications in the 2-anilino-5-aryloxazole moiety may have sufficient scope in optimization of prevailing inhibitory activity of these analogues.
Asunto(s)
Modelos Moleculares , Oxazoles/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Modelos Lineales , Programas InformáticosRESUMEN
The human A(3) adenosine receptor agonistic activity of 2-chloro-N(6)-substituted-4'-thioadenosine-5'-uronamides has been analyzed through Combinatorial Protocol in Multiple Linear Regression (CP-MLR) using 488 topological descriptors obtained from DRAGON software for the energy minimized 3D-structures of these molecules. Among the various descriptor classes considered in the study, the human A(3) adenosine receptor agonistic activity is correlated with simple topological descriptors (TOPO), Modified Burden eigenvalues (BCUT) and functional group (FUNC) classes of descriptors. The average valence connectivity index of order zero, X0Av, the sum of topological distances between O and Cl, T (O...Cl) from the TOPO class, the lowest eigenvalue n.2 of Burden matrix/weighted by atomic masses, BELm2, from the BCUT class and the number of secondary aliphatic amides, nCONHR, from FUNC class have contributed significantly in the development of a statistical sound models. The models developed and the participating descriptors suggest that the substituent groups at N(6)-position and/or 5'-uronamide of 2-chloro-N(6)-substituted-4'-thioadenosine-5'-uronamide derivatives hold scope for structural modification in the optimization of activity.
Asunto(s)
Agonistas del Receptor de Adenosina A3 , Modelos Moleculares , Tionucleósidos/química , Tionucleósidos/farmacología , Diseño de Fármacos , Humanos , Ligandos , Modelos Lineales , Conformación Molecular , Relación Estructura-Actividad Cuantitativa , Receptor de Adenosina A3/metabolismo , Tionucleósidos/metabolismoRESUMEN
The affinity profiles for the bovine adenosine receptors, A(1) and A(2A), of a series of 1,8-naphthyridine derivatives were quantitatively analyzed using physicochemical and structural parameters of the substituents, present at varying positions of the molecules. The derived significant correlation, for bovine A(1) receptor, suggested that a R(1) substituent having a higher van der Waals volume, a R(2) substituent being a hydrogen-bond donor and a R(3) substituent able to transmit a higher field effect are helpful in augmenting the pK(i) of a compound. Similarly the study, pertaining to bovine A(2A) receptor, revealed that a less bulky substituent at R(2) and a strong electron-withdrawing substituent at R(3) are desirable in improving the binding affinity of a compound while substituents at R(1) remain insignificant to any interaction.
Asunto(s)
Naftiridinas/farmacología , Antagonistas de Receptores Purinérgicos P1 , Relación Estructura-Actividad Cuantitativa , Antagonistas del Receptor de Adenosina A1 , Antagonistas del Receptor de Adenosina A2 , Animales , Bovinos , Naftiridinas/química , Relación Estructura-ActividadRESUMEN
The structure-activity models of the myorelaxant activity of the cromakalim analogues have been investigated with nearly 470 topological descriptors from DRAGON software using Combinatorial Protocol in Multiple Linear Regression (CP-MLR). Among the descriptor classes considered in the study, the binding affinity is correlated with simple functional (FUN), topological (TOPO), atom centered fragments (ACF), empirical (EMP), modified Burden eigenvalues (BCUT), Galvez topological charge indices (GVZ), 2D-autocorrelation (2D-AUTO) and constitutional (CONS) descriptors. The models developed, and the participating descriptors suggest that the substituent groups of 4,6-disubstituted-2,2-dimethylchromans hold scope for further modification in the optimization of activity. The higher path lengths rich in polarizability and lower path length rich in atomic mass in addition to the lower charge indices of the molecule are beneficiary to the activity. The participating descriptors also suggested that certain structural features such as carbon atoms attached to the heteroatom by single or multiple bonding, and lesser or 'no' branching in a molecule are helpful to augment the activity.
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Cromakalim/análogos & derivados , Cromakalim/farmacología , Canales KATP/agonistas , Relación Estructura-Actividad Cuantitativa , Animales , Cromakalim/química , Canales KATP/metabolismo , Estructura Molecular , RatasRESUMEN
The tyrosine kinase inhibitory action of the derivatives of N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}urea is quantitatively analyzed using multiple regression analysis. The analysis has helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds for two receptors, namely vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor alpha (PDGFRalpha). From a derived significant correlation equation for inhibition of VEGFR-2, it was concluded that a less hydrophobic molecule with ortho-substituent(s), exerting less steric hindrance and para-substituent devoid of hydrogen-bond acceptor property augment the inhibition action. Besides, a 3-substituent transmitting a higher negative field effect is advantageous to improve the pIC(50) value of a compound. The correlation equation, derived for the inhibition of PDGFRalpha, has revealed that a less hydrophobic molecule, having a 3-substituent which transmits a more negative resonance effect, is helpful in raising its activity. Likewise, in the middle phenyl ring, absence of a fluoro substituent augments the inhibitory activity. Based on derived QSAR equations pertaining to VEGF-2 and PDGFalpha receptors, the drawn guidelines for selection of substituents, may be used to synthesize potent compounds in future.
Asunto(s)
Antineoplásicos/química , Compuestos de Fenilurea/química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad Cuantitativa , Quinolinas/química , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Estructura Molecular , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The inhibitory activity of glucose-induced insulin secretion on isolated rat pancreatic islets and the contractile activity of KCl-depolarized rat aorta rings of the derivatives of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide are quantitatively analyzed using multiple regression analysis. The study has helped to ascertain the role of different substituents in explaining these observed inhibitory activities. From a derived most significant correlation equation, it was concluded that a less hydrophobic 3-substituent and a less bulky 7-substituent in addition to a 3-aminoisopropyl and a 6-chloro substituent are advantageous to enhance the inhibitory action of a compound towards rat pancreatic islets. On the other hand, the more hydrophobic 6- and 7-substituents augment the contractile activity. The analysis, in this way, provided the grounds for rationalizing the substituent selection in designing the improved potency compounds in the series.
Asunto(s)
Adenosina Trifosfato/farmacología , Benzotiadiazinas/farmacología , Canales de Potasio/fisiología , Animales , Canales de Potasio/efectos de los fármacos , Cloruro de Potasio/farmacología , Relación Estructura-Actividad CuantitativaRESUMEN
The anticancer activity of rhinacanthins and related naphthoquinone esters is quantitatively analyzed through Fujita-Ban and Hansch approaches. The analyses have helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds. From both approaches it appeared that naphthalene ring instead of benzene ring, dimethyl substitution at R(1) and R(2), and hydrogen-bond acceptor substituents at R(3) (Figure 1) are advantageous to improve the activity of a compound against KB cell lines. This in turn leads to the suggestion that the rhinacanthin-N scaffold is the structural entity that needs exploration for new potential compounds. Further, in the Fujita-Ban analysis, it is observed that the compounds bearing a OMe substitution, relative to H, at R(4) have a slight positive contribution to pIC(50) (KB) whereas the substituents H or OMe at R(5), relative to OH, have negative contributions. In conformity with these findings, the Hansch approach revealed that a more hydrophobic group at R(4) and a more hydrophilic group at R(5) positions are beneficial in raising the activity. The two quantitative structure-activity relationship (QSAR) analyses, differing in parametric approach, therefore, provided the grounds for rationalizing the substituent selection to design more potent compounds of the series.
Asunto(s)
Antineoplásicos/farmacología , Lignanos/farmacología , Naftoquinonas/farmacología , Ésteres , Humanos , Células KB/efectos de los fármacos , Relación Estructura-Actividad CuantitativaRESUMEN
The antagonistic activities of derivatives of spiroethyl phenyl(substituted)piperazine at the 5-HT(1A) and adrenergic alpha(1d) receptors is quantitatively analyzed employing physicochemical and structural parameters. The derived correlation equation revealed that a substituent, other than 2-CH3 in the phenyl ring, having higher molar refraction, MR, and a substituent producing higher positive field effect at the 3-position are beneficial in increasing the binding affinity at the 5-HT(1A) receptor. In addition, a less hydrophobic substituent at the 4-position is also helpful in augmenting the binding affinity. The 5-R substituents which have higher MR values, however, elicit a detrimental effect. Two disubstituted compounds which are not present in the original data-set and have higher theoretical binding affinities are designed from the correlation equation. These compounds consisting of 2-OCH(CH3)2, 3-Cl and 2-C3H7, 3-Cl in the phenyl ring, have theoretical pK(i) values 10.57 and 10.12 respectively. For the adrenergic alpha(1d) receptor, a less bulky group at the 3-position with 5-Cl (or simply a 3-Cl) is advantageous in increasing the binding affinity. Likewise, a substituent exhibiting a less negative resonance effect at the 4-position and the substituent with low polarizability and showing more a negative resonance effect at the 5-position are suitable for enhancement of the binding affinity. The analysis provides the grounds for rationalizing substituent selection in designing better potency antagonists in the series.