Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity.

A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&S requirements must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&S should be actualized within a larger information technology framework--a dynamic knowledge repository--wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline

At the Biological Modeling and Simulation Frontier

We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods. Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena. An objective is to build better, working hypotheses of plausible mechanisms. A synthetic model is an extant hypothesis: execution produces an observable mechanism and phenomena. Mobile objects representing compounds carry information enabling components to distinguish between them and react accordingly when different compounds are studied simultaneously. We argue that the familiar inductive approaches contribute to the general inefficiencies being experienced by pharmaceutical R&D, and that use of synthetic approaches accelerates and improves R&D decision-making and thus the drug development process. A reason is that synthetic models encourage and facilitate abductive scientific reasoning, a primary means of knowledge creation and creative cognition. When synthetic models are executed, we observe different aspects of knowledge in action from different perspectives. These models can be tuned to reflect differences in experimental conditions and individuals, making translational research more concrete while moving us closer to personalized medicine

Computational methods for biofabrication in tissue engineering and regenerative medicine - a literature review

This literature review rigorously examines the growing scientific interest in computational methods for Tissue Engineering and Regenerative Medicine biofabrication, a leading-edge area in biomedical innovation, emphasizing the need for accurate, multi-stage, and multi-component biofabrication process models. The paper presents a comprehensive bibliometric and contextual analysis, followed by a literature review, to shed light on the vast potential of computational methods in this domain. It reveals that most existing methods focus on single biofabrication process stages and components, and there is a significant gap in approaches that utilize accurate models encompassing both biological and technological aspects. This analysis underscores the indispensable role of these methods in understanding and effectively manipulating complex biological systems and the necessity for developing computational methods that span multiple stages and components. The review concludes that such comprehensive computational methods are essential for developing innovative and efficient Tissue Engineering and Regenerative Medicine biofabrication solutions, driving forward advancements in this dynamic and evolving field

Towards 3D in vitro models for the study of cardiovascular tissues and disease

The field of tissue engineering is developing biomimetic biomaterial scaffolds which are showing increasing therapeutic potential for the repair of cardiovascular tissues. However, a major opportunity exists to use them as 3D in vitro models for the study of cardiovascular tissues and disease in addition to drug development and testing. These in vitro models can span the gap between 2D culture and in vivo testing thus reducing cost, time and the ethical burden of current approaches. This review outlines the progress to date and requirements for the development of ideal in vitro 3D models for blood vessels, heart valves and myocardial tissue

Mechanical Regulation of Angiogenesis in a Biomimetic Model

Collective cell migration is required for numerous developmental and pathological processes including angiogenesis, branching morphogenesis, and cancer progression. Dynamic regulation of cell-cell adhesions, transmission of long-range contractile forces across cells, and remodeling of the extracellular matrix (ECM) are all required for successful multicellular invasion. While actomyosin contractility is well studied in single cells on flat surfaces, less is understood about its regulation of collective cell migration, including during angiogenesis whereby endothelial cells from existing vessels invade as multicellular sprouts to form new vessels. Here, we have engineered a novel organotypic model of angiogenic sprouting and neovessel formation that originates from pre-formed artificial vessels fully encapsulated within a 3D ECM. Using this model, we screened the effects of angiogenic factors and identified two distinct cocktails that promoted robust multicellular endothelial sprouting. The angiogenic sprouts in our system exhibited hallmark structural features of in vivo angiogenesis, including directed invasion of leading cells that developed filopodia-like protrusions characteristic of tip cells and following polarized stalk cells that line lumens connecting back to parent vessels. Ultimately, sprouts bridged between pre-formed channels and formed perfusable neovessels. Using this model, we investigated the effects of angiogenic inhibitors on sprouting morphogenesis using quantitative evaluation metrics. Together, these results demonstrate an in vitro 3D biomimetic model that reconstitutes the morphogenetic steps of angiogenic sprouting. We used this biomimetic model to characterize the role of actomyosin contractility during multicellular sprout extension. We also described differences in tip cell-stalk cell and stalk cell-stalk cell adhesions by evaluating vascular endothelial (VE)-cadherin organization. Inhibition of actomyosin contractility through non-muscle myosin II caused a decrease in VE-cadherin organization at cell-cell adhesions, and a loss of cell-cell contact between leading tip cell and the following stalk during sprout extension. This effect is rescued when cells express a form of VE-cadherin that stabilizes its interactions with the actin cytoskeleton. Our findings reveal contractility is required for multicellular invasion during angiogenic sprout extension, and are validated using an in silico model developed by Bentley et al. 2014 to simulate cell dynamics during sprouting, and recapitulated in an in vivo model of mouse retinal angiogenesis

Magnetic nanoparticles as a versatile solid-support for fusion protein purification and antimicrobial assays

Magnetic nano-and microparticles are unique platforms for the development of bioseparation and antimicrobial devices. This work explored the application of magnetic particles for the purification of fusion proteins through the use of magnetic adsorbents coupled to novel affinity ligands towards peptidic and proteic tags. Furthermore, and in view of the novelty of these ligands, molecular modeling and simulation techniques were employed to explain the key structuralfeatures involved inthe binding of two affinity pairs: GFP/LA-A4C7 and RK-GFP/LR-A7C1.The results showed that the interaction between GFP and LA-A4C7 is mainly hydrophobicwhile the interaction between RK-GFP and LR-A7C1 is mostly driven byhydrogen bonds. Moreover, the same modeling techniques have been used to idealize a theoretical second generation library with view of maximizing the estimated free energy of binding and the correspondent affinity constant. When immobilizing the biomimetic ligands LA-A4C7 and LR-A7C1 onto magnetic nanoparticles, it was possibleto bind the protein of interest and recover pure elution fractions. The best elution condition for GFP elution was 0.1mM glycine-NaOH pH9 50% (v/v) ethylene glycoland the best elution condition for RK-GFP elution was PBS pH 7.4, 500mM arginine, which are in accordance with the theoretical results described previously. Final binding constants for the studied systems (Ka=0.83×105M-1and Qmax=4mg/g for GFP/LA-A4C7, Ka=3.21×105M-1and Qmax=2mg/g for RK-GFP/LR-A7C1) show promising results for an affinity-based protein purification system.Magnetic particleswere also functionalized with (RW)3, an peptidewith antimicrobial properties, by different routes. We were able to develop a novel antimicrobial nanodevice based on the EDC-coupling of (RW)3that has shown antimicrobial activity against Escherichiacoliand Bacillussubtilis

BIOLOGICALLY STRUCTURED MATERIALS

Biomimetics, biomechanics, and tissue engineering are three multidisciplinary fields that have been contemplated in this research to attain the objective of improving prosthetic implants reliability. Since testing and mathematical methods are closely interlaced, a promising approach seemed to be the combination of in vitro and in vivo experiments with computer simulations (in silico). An innovative biomimetics and biomechanics approach, and a new synthetic structure providing a microenvironment, which is mechanically coherent and nutrient conducive for tissue osteoblast cell cultures used in regenerative medicine, are presented. The novel hybrid ceramic-polymeric nanocomposites are mutually investigated by finite element analysis (FEA) biomimetic modeling, anatomic reconstruction, quantitative-computed-tomography characterization, computer design of tissue scaffold. The starting base materials are a class of innovative highly bioactive hybrid ceramic-polymeric materials set-up by the proponent research group that will be used as a bioactive matrix for the preparation of in situ bio-mineralized techno- structured porous nanocomposites. This study treats biomimetics, biomechanics and tissue engineering as strongly correlated multidisciplinary fields combined to design bone tissue scaffolds. The growth, maintenance, and ossification of bone are fundamental and are regulated by the mechanical cues that are imposed by physical activities: this biomimetic/biomechanical approach will be pursued in designing the experimental procedures for in vitro scaffold mineralization and ossification. Bio-tissue mathematical modeling serves as a central repository to interface design, simulation, and tissue fabrication. Finite element computer analyses will be used to study the role of local tissue mechanics on endochondral ossification patterns, skeletal morphology and mandible thickness distributions using single and multi-phase continuum material representations of clinical cases of patients implanted with the traditional protocols. New protocols will be hypothesized for the use of the new biologically techno-structured hybrid materials

Electroresponsive Silk-Based Biohybrid Composites for Electrochemically Controlled Growth Factor Delivery

Stimuli-responsive materials are very attractive candidates for on-demand drug delivery applications. Precise control over therapeutic agents in a local area is particularly enticing to regulate the biological repair process and promote tissue regeneration. Macromolecular therapeutics are difficult to embed for delivery, and achieving controlled release over long-term periods, which is required for tissue repair and regeneration, is challenging. Biohybrid composites incorporating natural biopolymers and electroconductive/active moieties are emerging as functional materials to be used as coatings, implants or scaffolds in regenerative medicine. Here, we report the development of electroresponsive biohybrid composites based on Bombyx mori silkworm fibroin and reduced graphene oxide that are electrostatically loaded with a high-molecular-weight therapeutic (i.e., 26 kDa nerve growth factor-β (NGF-β)). NGF-β-loaded composite films were shown to control the release of the drug over a 10-day period in a pulsatile fashion upon the on/off application of an electrical stimulus. The results shown here pave the way for personalized and biologically responsive scaffolds, coatings and implantable devices to be used in neural tissue engineering applications, and could be translated to other electrically sensitive tissues as well

In silico, experimental, mechanistic model for extended-release felodipine disposition exhibiting complex absorption and a highly variable food interaction

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog's plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability