In silico multiscale computational modelling of botulinum toxin a diffusion for glabellar wrinkle treatment: Optimizing injection volumes across formulations
Eqram Rahman , Jean D.A. Carruthers , Parinitha Rao , Munim Ahmed , Greg J. Goodman , William Richard Webb
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引用次数: 0
Abstract
While botulinum neurotoxin A (BoNT/A) is a cornerstone in glabellar wrinkle treatment, inconsistencies in clinical outcomes often stem from formulation-dependent diffusion behaviour. Currently volumes recommendation per site lacks mechanistic justification, especially in anatomically confined regions like the glabella, where millimetric diffusion differences can produce significant adverse effects. A high-fidelity, multiscale in silico platform was developed, integrating quantum mechanical (TD-DFT) modelling of SV2-binding (ΔG_bind range: −9.2 to −11.7 kcal/mol), molecular dynamics-derived hydrodynamic radius (R_H: 9.4–11.2 nm), anisotropic finite element modelling of poroelastic muscle tissue, and agent-based receptor and immune kinetics. Simulations encompassed five formulations— AbobotulinumtoxinA (ABO), DaxibotulinumtoxinA (DAXI), IncobotulinumtoxinA (INCO), OnabotulinumtoxinA (ONA), and PrabotulinumtoxinA (PRABO)—across injection volumes from 0.025 to 0.1 mL, at fixed toxin unit dosing, within anatomically realistic glabellar meshes (n = 10,000 synthetic patient variants). Diffusion profiles varied significantly by formulation. ABO showed the largest Reff (1.64 ± 0.14 cm) and E_off, while PRABO and ONA remained spatially constrained (Reff = 0.96 ± 0.07 cm and 1.13 ± 0.08 cm, respectively). Increasing injection volume from 0.025 to 0.1 mL caused a 2.2-fold rise in E_off and a 36–49 % increase in off-target V_IC50 across formulations. Optimal containment was formulation-specific: PRABO and ONA achieved ≥95 % V_IC90 coverage with <10 % V_IC50 spillover at 0.025–0.035 mL; INCO and DAXI required 0.035–0.05 mL; ABO balanced broader coverage with acceptable diffusion at 0.04–0.045 mL. Agent-based models revealed 78 % receptor saturation at 0.025 mL versus 56 % at 0.1 mL, with immune clearance rates up to 42 % higher at high volumes due to increased perivascular redistribution. Volume emerged as the dominant spread driver (Sobol S1 = 0.48), followed by hydrodynamic radius (S1 = 0.35) and macrophage density (S1 = 0.28); interaction terms were negligible (S_T − S1 < 0.05). This study provides the first in-silico quantitative, multiscale evidence that reducing BoNT/A reconstitution volume to ≤0.045 mL/site significantly enhances target localization while minimizing off-target effects. Contrary to prevailing clinical heuristics, dilution amplifies mechanical spread and immune clearance risk.
期刊介绍:
Toxicon has an open access mirror Toxicon: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. An introductory offer Toxicon: X - full waiver of the Open Access fee.
Toxicon''s "aims and scope" are to publish:
-articles containing the results of original research on problems related to toxins derived from animals, plants and microorganisms
-papers on novel findings related to the chemical, pharmacological, toxicological, and immunological properties of natural toxins
-molecular biological studies of toxins and other genes from poisonous and venomous organisms that advance understanding of the role or function of toxins
-clinical observations on poisoning and envenoming where a new therapeutic principle has been proposed or a decidedly superior clinical result has been obtained.
-material on the use of toxins as tools in studying biological processes and material on subjects related to venom and antivenom problems.
-articles on the translational application of toxins, for example as drugs and insecticides
-epidemiological studies on envenoming or poisoning, so long as they highlight a previously unrecognised medical problem or provide insight into the prevention or medical treatment of envenoming or poisoning. Retrospective surveys of hospital records, especially those lacking species identification, will not be considered for publication. Properly designed prospective community-based surveys are strongly encouraged.
-articles describing well-known activities of venoms, such as antibacterial, anticancer, and analgesic activities of arachnid venoms, without any attempt to define the mechanism of action or purify the active component, will not be considered for publication in Toxicon.
-review articles on problems related to toxinology.
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