Exploring Feasible Design Spaces for Heterogeneous Constraints Amir M. Mirzendehdel, Morad Behandish, and Saigopal Nelaturi Palo Alto Research Center (PARC), 3333 Coyote Hill Road, Palo Alto, California 94304
Abstract
We demonstrate an approach of exploring design spaces to simultaneously satisfy kinematics- and physics-based re- quirements. We present a classification of constraints and solvers to enable postponing optimization as far down the design workflow as possible. The solvers are organized into two broad classes of design space ‘pruning’ and ‘exploration’ by considering the types of constraints they can satisfy. We show that pointwise constraints define feasible design sub- spaces that can be represented and computed as first-class entities by their maximal feasible elements. The design space is pruned upfront by intersecting maximal elements, without premature optimization. To solve for other constraints, we apply topology optimization (TO), starting from the pruned feasible space. The optimization is steered by a topological sensitivity field (TSF) that measures the global changes in violation of constraints with respect to local topological punctures. The TSF for global objective functions is augmented with TSF for global constraints, and penalized/filtered to incorporate local constraints, including set constraints converted to differentiable (in)equality constraints. We demon- strate application of the proposed workflow to nontrivial examples in design and manufacturing. Among other examples, we show how to explore pruned design spaces via TO to simultaneously satisfy physics-based constraints (e.g., minimize compliance and mass) as well as kinematics-based constraints (e.g., maximize accessibility for machining).
Feasible Design Space, Composing Solvers, Workflows, Maximal Elements, Sensitivity Fields
Ntroduction
Mechanical design problems require reasoning about di- verse, multiple, and often conflicting objectives and con- straints arising from requirements across a product’s life- cycle. The key engineering design challenge lies in travers- ing the trade space of these requirements to synthesize feasible designs. This challenge has recently been ampli- fied by rapid advances in manufacturing processes. Light- weight, high-performance, and multi-material composite structures with complex geometry and material distribu- tion can now be fabricated using various additive manu- facturing (AM) processes.
Yet, Existing Computer-Aided
design (CAD) systems are far behind in their represen- tations and algorithms to navigate the high-dimensional trade spaces that grow exponentially in the number of available decisions per spatial elements. Additional func- tional constraints such as manufacturability, ease of as- sembly, motion in presence of obstacles, and aesthetics dramatically increase the trade space complexity.
Specialized domain-specific computational tools are used to generate designs that satisfy specific types of func- tional requirements. For example, to maximize a part’s performance with as little cost or material as possible, one
May Employ Topology Optimization (To) Tools . In
most TO approaches, an objective function is defined over a design domain in terms of the physical performance (e.g., strength and/or stiffness) with additional constraints on total mass or volume as well as boundary conditions (e.g., loading and/or restraints) that often account for interfaces with other parts. TO produces valid designs with nonin- tuitive shapes, topologies, and material distributions that meet physical requirements, but is rarely aware of other important design criteria such as kinematic constraints.
On the other hand, to ensure collision-free motion of a part in an assembly, one may need to examine its free configura- tion space to guarantee collision avoidance. Similarly, for subtractive manufacturing (SM), the machinability of a designed part is predicated on whether the volume to be removed from a raw stock is accessible within the cut- ting tool assembly’s non-colliding configurations [7, 8]. For AM, one may need to consider the part’s morphology, min-
Imum Feature Size, And Skeleton Hybrid Manufac-
turing (combined AM and SM) requires more complicated logical reasoning . These problems require nontrivial interference analysis of shapes in relative motion that rely on different tools of reasoning than physics-driven design tools such as TO. The latter often ignore motion related constraints by considering them out-of-scope.
1.1. Kinematic, Physical, & Manufacturing Constraints Generating practical designs requires simultaneous rea- soning about shape, motion, materials, physics, manufac- turing, and assembly, among other factors. For example, a machine part that moves relative to other parts in a mechanical device has to avoid collisions with both sta- tionary and moving obstacles .
These Requirements
are imposed as kinematic constraints, expressed in terms of pointset containment or non-interference (Section 3.3). The same part has to sustain mechanical loads at its joints
Arxiv:1907.01117V2 [Cs.Cg] 10 Jul 2019
or points of contact with other parts. These requirements are imposed as physical constraints, expressed in terms of (in)equalities of mathematical functions that represent physical response (e.g., bounds on deflection or stress).
Moreover, the part has to be manufacturable with one or more AM or SM capabilities . Manufacturability con- straints can be of both kinematic and physical types; for instance, accessibility in SM [7, 8] and post-processing of AM (e.g., support removal ) are of predominantly kine- matic nature, whereas achieving desired material proper- ties in AM requires in situ physical analysis . With few exceptions (e.g., TO for AM with minimized support ) TO algorithms are not developed with manufacturability provisions built into their objective functions.
1.2. Generating Feasible Designs with Multiple Solvers Different computational services, herein called solvers, are used to assist the design process with heterogeneous constraints by providing either analysis tools to evaluate the performance of one or more given designs, or syn- thesis tools to generate one or more designs that satisfy a given set of performance criteria analysis.
We Distin-
guish between these two types of solvers as forward and in- verse problem solvers (‘FP/IP-solvers’), respectively (Sec- tion 3). Specifically, generative design tools are IP-solvers which solve the inverse problem by systematically gener- ating candidate designs and evaluating their performance (using FP-solvers) to guide refinement of designs until the criteria are met.
It is unlikely that a single IP-solver is capable of si- multaneous reasoning about all design criteria (e.g., ob- jective functions and constraints).
Therefore, A Typical
computational design workflow requires carefully organiz- ing and reasoning about several multidisciplinary solvers to address heterogeneous design criteria. While every IP- solver reasoning about a subset of these criteria may pro- duce designs that are feasible (and ideally, optimal) only with respect to the specific criteria it considers, it provides no guarantees about the rest of the criteria. Different IP- solvers are thus likely to generate designs distinct from one another, while none of them simultaneously satisfies all criteria. Except for extremely simple criteria, it appears impossible to combine these solutions in any obvious way that preserves the constraints satisfied separately by each solver, or at least provides the best compromise. Even if such a solution exists, there may not exist any particular ordering of these solvers to find it, simply because each solver performs premature optimization with regard to the subset of criteria it cares about.
Consider the problem of designing a car hood latch (adopted from ). An initial design domain with bound- ary conditions is provided, and the goal is to find a design that is as stiffas possible with the least mass.
Ore-
over, the latch has to be free to rotate clockwise by 20 degrees around a revolute joint, without exiting the initial design domain, so that it would not collide with other parts that are possibly outside that envelope. Functional load- bearing surfaces where the latch mates with other parts are shown in Fig. 1. All feasible designs must retain these surfaces as specified. The said requirements immediately suggest using two IP-solvers that are well-positioned to deal with them (each solver satisfying a subset of them): • Let Unsweep be a solver that generates a design that remains within a given region of space while mov- ing according to a prescribed motion (in this case, a clockwise rotation of 21 degrees).
• Let Pareto Be A Solver That, Starting From An
initial design, generates a design on the Pareto front of the two objectives (compliance and mass), i.e., one that satisfies the stiffness requirement and the given boundary conditions with minimal mass.
Figure 1: Functional requirements for designing a car hood latch, including (a) containment under given motion after assembly; and (b) boundary conditions on interfaces for assembly.
Using these solvers separately, one may generate two distinct designs, as illustrated in Fig. 2. However, there is no clear operation with which to combine these two, in order to generate a design that satisfies both kinematics- and physics-based constraints. For example, the intersec- tion of the two designs, shown in Fig. 2 generates a design that does not violate the constraints satisfied by Unsweep, because every subset of the unswept volume also satisfies the containment constraints. However, the constraints sat- isfied by PareTO are no longer satisfied, because the load paths are changed due to the changed topology and the compliance target is no longer met.
In this case, Unsweep has a property that its solution can be interpreted not as a single design, but as a representa- tion of all designs that satisfy the containment constraints.
This family of designs is closed under set intersection, i.e., intersecting any of the feasible designs with another set leads to another feasible design.
Similarly, Pareto Can
generate a family of designs that satisfy compliance re- quirements for different mass budgets. However, this fam- ily is not closed under set intersection. The goal of this paper is to show how we can exploit such information to organize the design workflows such that they produce so- lutions that satisfy all criteria.
It is possible to obtain a feasible solution to the latch design problem by using the same set of IP-solvers, if the Figure 2: Two partially feasible designs are generated separately by two solvers.
Each solver optimizes for a subset of constraints. Arbitrarily combining them (e.g., via set intersection in this example) may result in an infeasible design with respect to all constraints.
workflow is organized differently, as shown in Fig. 3. Sup- pose we first solve for the containment constraint using Unsweep and generate a valid design that does not exit a given envelope while moving. We can use this design as the initial design input to PareTO and optimize its shape and topology to achieve the compliance target with minimal mass.
This Approach Works Because Pareto Is A Mate-
rial reducing solver, i.e., its solutions remain strictly con- tained within the initial design. Hence any design gener- ated downstream will be faithful to the containment con- straint that was satisfied upstream. The same argument is not true if the order of applying the solvers is swapped.
There is no reason to believe that applying Unsweep to a topologically optimized solution of PareTO will remain on the Pareto front. The fundamental differences between the two IP-solvers should be taken into account when deciding on their arrangement in a workflow—in this case, choosing between parallel or sequential execution and the proper or- der for the latter. We elaborate on these differences in the classification of solvers in Section 3.
Figure 3: Both constraints can be satisfied by first finding a shape that satisfies the containment constraint and then using this shape as the input to TO (or any other material reducing IP-solver).
Figure 4 shows a one-parametric family of solutions on the Pareto front obtained when using mass and compli- ance as competing objectives.
Pareto Provides A Clear
advantage over classical TO with a single solution, by pro- ducing many alternatives some of which might satisfy ad- ditional constraints that were not accounted for in TO.
This generate-and-test approach is plausible, and in fact, is a common strategy for dealing with heterogeneous con- straints. However, it turns out that none of the Pareto- optimized designs in this case will not remain within the envelope after a clockwise rotation of 21 degrees.
In general, a good rule of thumb to organize solvers in a workflow is to call the ones that produce the broadest families of designs earlier. The upstream IP-solvers should generate a large number of designs, as opposed to fixing one or few designs, to provide more flexibility for down- stream solvers. The downstream solvers can be FP-solvers, testing for new constraints, or IP-solvers, applying further optimization. However, each solver may prematurely op- timize designs that may fail evaluation criteria considered in downstream solvers. The “blind” process of generating and testing designs without carefully considering proper- ties of the workflow – and the associated feasible design space for each solver in the workflow – will scale poorly with increasing number of constraints/solvers and their complexity. A systematic approach to arranging solvers into workflows that guarantees satisfying new constraints without violating the already satisfied constraints is much demanded, and is the subject of this paper.
Figure 4: None of the topologically optimized design alternatives obtained from applying PareTO to the initial design will satisfy the containment constraint. Generate-and-test does not always work.
The Main Contributions Of This Paper Are:
1. classification of IP-solvers based on the properties of design constraints (e.g., locality and continuity) that
Each Solver Can Handle;
2. organization of computational design workflows with heterogeneous constraints into two stages of design space ‘pruning’ and ‘exploration’, where pruning pro-
Vides The Feasible Design Space For Exploration;
3. reconciling set constraints with inequality constraints and deriving conditions under which they can be ex- pressed in a strictly local (i.e., ‘pointwise’) fashion; 4. pruning design spaces, treated as first-class entities,1 1In the lexicon of programming languages, a construct is said to have first-class status if it can be passed as an argument, returned from a subroutine, or assigned into a variable .
by intersecting their representative maximal elements
Defined Implicitly By Pointwise Constraints;
5. strategies to compose FP-solvers into a generative and iterative design process by combining kinematic, man-
Ufacturing, And Physical Constraints; And
6. illustrating real-world design problems solved using multidisciplinary solvers, which are rarely addressed in the (otherwise siloed) areas of related research.
In Section 2, we review some of the recent works in related areas of computational design and manufacturing. In Section 3, we present basic definitions (FP/IP-solvers, global vs. local constraints, and design/performance space terminology). We present a classification of solvers based on the types of constraints they can handle, and propose a systematic approach for organizing them into workflows.
In Section 4, we show that an important class of con- straints can be satisfied upfront by pruning the design space in the early stages without premature optimization, allowing flexibility for downstream design decisions. The feasible design subspaces are described uniquely and com- pletely by their maximal elements. These representative elements are, in turn, implicitly defined by a point mem- bership classification (PMC) test implemented in terms of strictly local (i.e., ‘pointwise’) constraints. We demon- strate examples of kinematics-based constraints that ap- pear in assembly, packaging, and manufacturing.
In Section 5 we deal with more general global and local constraints, including (in)equality constraints that specify physics-driven requirements or manufacturability.
We use a Pareto-tracing levelset topology optimization (PareTO) which uses fixed-point iteration to satisfy multiple design criteria guided by augmented TSFs. We demonstrate that accessibility constraints can be incorpo- rated in TO by filtering the augmented TSF using the overlap measure of cutting tool and optimized part.
We conclude in Section 6 by a discussion of the limita- tions of our approach and proposed future directions.
Related Work
Real-world design problems often involve solving multi- objective optimization problems where the goal is to find the best trade-offbetween multiple competing objective functions. Classical methods such as linear programming (e.g., the ‘simplex’ algorithm), nonlinear programming (e.g., the steepest descent and conjugate gradients), or Newton-Raphson are limited to single-objective op- tion, finding the global optimum is NP-hard . Numer- ous approaches have been developed to converge to locally optimal solutions in reasonable computation time to multi- objective problems across different disciplines.
Unlike single-objective optimization, a total ordering for feasible solutions may not be possible in multi-objective optimization, i.e., there may not exist a single “best” solution due to competing objectives. However, feasible solutions may be partially ordered according to Pareto efficiency—also known as Pareto–Koopmans efficiency or dominance [24, 25]. Pareto-optimal solutions are locally optimal (according to Pareto-efficiency) where improving one objective comes at the expense of at least one other objective . The collection of all Pareto-optimal solu- tions is referred to as a Pareto front, which represents a curve, surface, or higher-dimensional manifold in the de- sign space for two, three, or higher number of competing objectives, respectively. Tracing a Pareto front is a key challenge in multi-objective and multi-disciplinary design optimization. We will not attempt an exhaustive review of all approaches such as gradient-free methods including rule-based techniques and evolutionary algorithms . Rather, we focus on a special class of algorithms that automatically generate designs on the Pareto front of multiple objectives given an initial design.
TO [3, 36, 37] has emerged as a practical class of com- putational methods for designing high-performance light- weight structures and has been applied in numerous areas such as designing automobiles components , aircraft components [39, 40], spacecraft modules , cast parts
Ucts. Numerous Approaches Such As Density-Based ,
levelset-based [47, 48], and evolutionary methods for TO have been developed.
Optimal Design For Manufacturing
TO typically focuses on optimizing designs for perfor- mance (e.g., physical response to loads during operation) but less on other important factors such as manufactura- bility. Apart from traditional processes such as machin- ing and molding, more recent technologies such as AM have introduced the ability to fabricate complex topologi- cally optimized designs while presenting new manufactur- ing challenges . Process limitations must be considered during the design/optimization stage as much as possible to avoid repeated prototyping and iterations until the op- timized designs are manufacturable. Specifically, applying corrections to the geometry or topology of a solu- tion after TO to make it manufacturable may sacrifice the achieved optimality.
One solution is to impose design rules obtained from do- main expertise and experience. These rules relate specific combinations of shape, materials, and process to impose simplified constraints that can be built into the TO frame- work to restrict the feasible design space. For example, when designing for AM via fused deposition modeling us- ing polymers, one should require that all facets oriented at an angle greater than 45 degrees with respect to the build direction be supported with additional scaffolding material. When designing for casting and injection mold- ing processes, one should ensure that the part has fea- tures of almost uniform thickness and no entrapped holes are present, so that the mold can be removed and the molten material cools down uniformly throughout the part [53, 54]. When designing for wire- or laser-cutting, one should ensure that the final design has a uniform cross- section, i.e., is 2.5D along the cutting direction.
These
constraints can be imposed during TO through filtering of the sensitivity field as illustrated in Fig. 5. Figure 5: Examples of enforcing manufacturability constraints by TSF filtering.
Different filters (c, e, g) – plotted along the cross- sections shown on the right – produce different solutions (d, f, h). Another important AM consideration is the manufac- turing resolution, which can be directly incorporated into the TO algorithm as a minimum feature size constraint through either local gradient constraints or TSF filter- ing (Fig. 6). It is also possible to reduce the amount of support structure needed in an AM by either finding a good build orientation or TSF filtering. Build orienta- tion optimization often involves solving a multi-objective problem taking into account other factors such as surface quality [56, 57], build time , or manufacturing error . TSF filtering, on the other hand, can be achieved by penalizing overhang surfaces [59, 60], penalizing undercut surfaces , or augmenting new TSFs .
Other AM constraints may not be as straightforward. For instance, optimizing designs with respect to shrink- age and warpage during material phase changes within the AM process may require solving a multi-physics prob- lem at every iteration [17, 63].
Haracterizing Material
Figure 6: Constraining minimum feature size via TSF filtering . properties of AM parts is also challenging due to process- induced anisotropy. Lack of inter-layer adhesion and vary- ing thermal history at every point can introduce unin- tended porosities and consequently affect material behav- ior.
Although there are initial results for considering anisotropy in TO under certain assumptions , solving the problem by simultaneously optimizing the geometry, topology, and process parameters involves costly in-situ manufacturing simulation or process planning [7, 13].
Esign For Motion-Related Constraints
In addition to the above examples of performance and manufacturing requirements, there are other important de- sign criteria that involve spatial reasoning about the inter- actions of moving (translating and rotating) shapes such as collision avoidance, packaging, robot motion planning, and accessibility analysis. These requirements cannot be easily enforced by design rules, TSF filtering, or other techniques commonly used in TO. Rather, they are often expressed as set constraints, i.e., statements in the language of sets (e.g., in terms of affine transformations, Boolean opera- tions, and containment) rather than the language of real- valued functions used for (in)equality constraints in TO.
A broad class of inverse problems in practical design and manufacturing reduce to solving set constraints formulated in the configuration space of rigid motions [6, 65–67].
Although the problems with set constraints are common and of significant importance, they are not mainstream in design/optimization workflows due to non-smoothness and computational intensity . There are instances of TO frameworks that deal with motion-related problems in an ad hoc manner; for instance, in modeling collision and contact when designing compliant mechanisms or parts made of hyperelastic materials that undergo large deformations part [70, 71].
However, It Is Not Immedi-
ately obvious how set constraints can be incorporated in a systematic fashion into the design/optimization process without incurring prohibitive computation costs of spatial analysis at every iteration. The next section presents a different classification of constraints that enables design space pruning and exploration, in which set constraints are also restated in terms of (in)equalities of functions.
Figure 7: Solving heterogeneous (e.g., kinematic, physical, and manufacturing) constraints with multidisciplinary solvers is difficult. Each solver might make decisions with care for its target subset of constraints while potentially violating the rest of the constraints. (a) Arranging multiple solvers sequentially may work in some orders and fail in others, depending on what properties they preserve. Parallel composition requires combining solutions in ways that do not always preserve the properties either. (b) We propose a systematic two-phase approach (Section 3.4) to design space pruning (Section 4) and design space exploration (Section 5). The former invokes IP-solvers in an arbitrary order to cut out the infeasible design subspace without premature optimization. The latter navigates the pruned design space by fixed-point iterations over FP-solvers. Section 3 addresses the question of how to divide a given collection of solvers into these two groups.
Lassifying Solvers And Constraints
In this paper we restrict our attention on solvers that re- duce material from a bounded domain in 2D and 3D space to generate designs. Our focus will be on the properties of constraints embedded within computational solvers to reason about their ordering in the workflows.
When all objectives and constraints cannot be handled by a single solver, current practice relies on a case-by-case domain-specific analysis to properly construct workflows.
Figure 7 (a) depicts examples of combining Unsweep and PareTO illustrated in Section 1.2. An arrangement that works in one case may not work in another.
In contrast, we present a systematic approach for or- ganizing solvers into workflows by first classifying solvers
Into Two Fundamentally Different Types:
1. Design space pruning solvers restrict the feasible de- sign space by pruning the subspaces that violate one or more design criteria. They are permutative, mean- ing that they can be called at the beginning of the design workflow in an arbitrary order. By directly op- erating on the design subspaces as first-class entities, they postpone optimization to downstream solvers.
2. Design space exploration solvers simultaneously ex- plore the (pruned) design subspaces for optimized so- lutions. In this paper, we choose a well-studied Pareto
Front Tracing Approach (Pareto) To Efficiently
navigate the trade space of multiple objectives. Figure 7 (b) illustrates the framework. In this section we present some terminology and a classification of design cri- teria based on which the solvers can be grouped into the above two classes. We formalize this two-phase approach in Section 3.4 and discuss how to implement each phase in depth with examples in Sections 4 and 5, respectively.
Esign & Performance Spaces
Throughout this paper, a ‘design’ Ωrefers to a com- putational model of a single designed artifact.
We Be-
gin the process by specifying a bounded design domain Ω0 ⊂Rd (d = 2 or 3) whose corresponding design space D is the collection of all ‘solids’, i.e., closed-regular semian- alytic pointsets in d−space,2 contained within the design domain. We use the notation D = P∗(Ω0) (read: “solid powerset” of Ω0). This definition is sufficient for geometric modeling of parts with homogeneous and isotropic mate- rial properties. We initially restrict our attention to this subclass of artifacts, as considered in classical solid model- ing . Our goal is to first illustrate nontrivial challenges in designing with multiple solvers before introducing the additional complexity of multiple materials, heterogeneity, or anisotropy. However, the concepts introduced hereafter can (in principle) be generalized beyond solids.
The ‘performance’ of a given design Ω∈D is an n−tuple A(Ω) := (A1(Ω), . . , An(Ω)). Think of the performance space as a product space P := (F1 × . × Fn), where each Fi is a class of fields, i.e., each Ai ∈F1 is an integrable field Ai(Ω) : Ω0 →Qi over the design domain Ω0 whose value at a given “query point” x ∈Ω0 is denoted by Ai(x; Ω) :=
(Ai(Ω))(X) ∈Qi. Examples Of Such Fields Are:
• binary-valued fields (Qi := {0, 1}), used to describe indicator functions of regions of interest within the
Design Domain Such As Non-Manufacturable Features
[7, 8] or regions requiring design correction . • integer-valued scalar fields (Qi := Z), used to charac- terize local topological properties of 3D printed parts [11, 12] or to classify atomic units of manufacturing in hybrid (combined AM and SM) manufacturing .
2A closed-regular set is defined as a set that equals the closure of its interior (i.e., is homogeneously 3D) . Figure 8: (a) FP-solvers (e.g., FEA and manufacturability analysis) map an instance of the design space (i.e., a “design”) to an instance of the performance space (i.e., a “field-tuple”). Predicates are defined to decide whether the design is satisfactory with respect to constraints in terms of performance variables. An IP-solver modifies the design until all constraints are satisfied.
• real-valued scalar fields (Qi := R), 3D vector fields
(Qi := R3), And Higher-Rank Tensor Fields Used To
represent distributed physical quantities such as dis- placement, velocity, stress, strain, and so on , or manufacturability measures .
Forward Problem In Physics & Kinematics
Forward problem solvers (FP-solvers) map a given de- sign instance to one or more performance fields, hence can be viewed as implementations of one or more maps Ai : D →Pi. The entire forward problem, solved by one or more FP-solvers, can be viewed as a single map from design space to performance space A : D →P, which has a unique outcome for a given design.
For example, consider a finite elements analysis (FEA) FP-solver that computes (discretized forms of) a displace-
Ment Field Uω:= A1(Ω) For Small Deformations Of A
given design Ω∈D due to boundary conditions such as restraints and external forces (Fig. 8).
T Is Also Im-
portant to compute the stress field σΩ:= A2(Ω), which depends locally on displacement and material properties (e.g., the linear elasticity law). The vector/tensor values of solution fields probed at a query point x ∈Ω0 are de- noted by uΩ(x) = A1(x; Ω) and σΩ(x) = A2(x; Ω).
N
this case, both functions are zero outside the design, i.e., A1,2(x; Ω) = 0 if x ∈(Ω0 −Ω). FEA solves the weak form of the governing differential equation, discretized into a linear system (e.g., using hat functions) [KΩ][uΩ] = [f], where the stiffness matrix [KΩ] and external load vector [f] depend on the design shape and material properties, as well as boundary conditions. The equations are solved to obtain the discrete form of the displacement field [uΩ] from which the discrete form of the stress field [σΩ] is computed by linear operations.
Another example is accessibility analysis for machining (e.g., milling or turning) [7, 13]. For instance, consider an FP-solver for 3−axis milling simulation, which computes (discretized forms of) a volumetric measure of inaccessibil- ity as a field µΩ(x) := A3(Ω) for a given design Ω∈D and machine tool parameters. This measure at a query point x ∈Ω0, denoted by µΩ(x) = A3(x; Ω), returns the pene- tration volume of the moving tool assembly T = (H ∪C), including the holder H and cutter C, into the stationary obstacles OΩ= (Ω∪F), including target form Ωand fix- tures F.
The Solver Computes The Discrete Form Of This
field (e.g., sampled at point clouds or voxels) [µΩ] as a convolution between the discrete forms of the indicator functions of stationary solids [1OΩ] and moving solids [1T ] using a fast Fourier transform (FFT) . The maximal set of accessible configurations – in this case, pure trans- lations in 3D for a fixed orientation – is then obtained as
Ω(0), I.E., The Translations That Do Not
lead to undesirable collisions. The maximal removable vol- ume is obtained by sweeping the cutter with the maximal motion, i.e., RΩ:= sweep(MΩ, C). Its indicator function 1RΩ(x) = A4(x; Ω) can be viewed as a predicate for ac- cessibility, i.e., it returns 1 (resp. 0) if the query point x ∈Ω0 is (resp. is not) accessible. The discrete form of this binary field [1RΩ] can also be obtained by thresholding FFT-based convolution of discrete forms [1MΩ] and [1C].
The Computations Performed By The Above Two Fp-
solvers (FEA and accessibility analysis) are abstracted by A := (A1, A2, A3, A4) that maps a given design to a “field tuple” that represents analysis results. Figure 8 illustrates one instance of each such field for a topologically optimized bracket—solution of a DARPA design challenge problem for TRAnsformative DESign (TRADES) program.
Feasible Design Subspaces & Predicates
Inverse problem solvers (IP-solvers), on the other hand, find one or more designs that satisfy a given collection of functional requirements. Most IP-solvers employ an itera-
Tive Process To:
1. generate one or more valid candidate design(s); 2. perform analysis on the candidate design(s) to com- pute the performance(s) of interest (using one or more
Fp-Solver(S));
3. evaluate the performance(s) against given functional
Requirements; And,
4. if the requirements are not met, decide on the next generation of candidate design(s) based on the current evaluation and update rules.
The process is repeated until the requirements are met. The evaluation process (item 3) can be conceptualized as finite number of predicates defined over the performance space as ci : D →{0, 1} for i = 1, 2, . . , n. Each predi- cate’s outcome ci(Ω) ∈{0, 1} is determined by means of a constraint imposed on the performance field Ai(Ω) ∈Fi
(1)
These can be (in)equality constraints (Sections 3.2), which are common in physics-based design formulations as in TO, and set constraints (Section 3.3), which are ubiqui- tous in design under kinematics-based constraints such as packaging, assembly, and accessibility for manufacturing.
We can think of the performance criteria evaluation as a map c := (c1,c2, . . ,cn) : D →{0, 1}n i.e., c(Ω) is a binary string whose bits indicate whether a given design satisfies each of the criteria (Fig. 8). A design Ω∈D is called ‘feasible’ if it simultaneously satisfies all criteria, i.e., c(Ω) = (1, 1, . , 1). The feasible design subspace D∗⊆D
(2)
Here, (·)−1 denotes inversion of a mathematical relation.4 Unlike forward problems, inverse problems have non- unique, often infinitely many, solutions (i.e., |D∗| > 1).
The feasible design space can also be defined as the in- tersection of the feasibility halfspaces Hi := c−1
(1), Each
3Without loss of generality, we assume that every requirement depends on one performance field only. If more than one field is used in calculating a predicate, we tuple those fields into another field. If more than one requirement is computed on one field, we think of it as two copies of the same field.
4Given f : X →Y , we define f−1(y) = {x ∈X | f(x) = y}. Note that in general, f−1(y) ⊆X is a set, i.e., f−1 : Y →P(X). It is a singleton set (i.e., has one element) if the function is bijective.
implicitly describing one of the design subspaces that sat-
(3)
The idea of design space pruning (Section 4) is to pro- gressively cut out portions of the design space that vio- late any one of the criteria. Theoretically, pruning can be done in an arbitrary order—noting that intersections or unions of the halfspace in (3) are permutative. Compu- tationally, however, it is only possible if the design sub-
(1) Can Be Manipulated By Algorithms As
first-class entities. Our goal is to understand under what conditions such manipulations are possible and how an entire design subspace can be represented. The existence (Proposition 1) and completeness (Proposition 2) of such representations are discussed in Section 4.
3.2. Global, Local, & Strictly Local Inequality Constraints The predicates introduced earlier are implemented in practice by testing whether a candidate design’s perfor-
We Classify
such constraints into three types; namely, global, local, and strictly local (in)equality constraints.
Global Inequality Constraints
It is common to have design criteria specified in terms of global constraints gi(Ω) ≤0, i.e., by defining a predicate
(4)
in which gi : D →R is a function of the entire shape of the design Ω∈D, potentially in addition to fixed external factors such as boundary conditions, manufacturing pro- cess parameters, packaging envelope, operating conditions (e.g., motion in assembly), etc.
The Constraint Is Often
evaluated in terms of a global property of an entire per- formance field Ai(Ω) ∈Fi, e.g., as an upper/lower-bound on its maximum/minimum or its integral properties such ¯gi : D →R. For example, one can constrain the maximal displacement or maximal stress of a solid under external loads (Fig. 8) by using the following constraints in (4):
(6)
where δUB, σUB > 0 are constant upper-bounds on the magnitude of the displacement vector and stress tensor, captured by the constraints g1(Ω) ≤0 and g2(Ω) ≤0, 5Note that every equality constraint g(·) = 0 can be represented by two inequality constraints g(·) ≤0 and −g(·) ≤0.
respectively. One can in general use the p−norm of the fields for finite (but large) p ≥1, noting that maximum is a special case as p →∞. This is especially useful to smooth out the possible singularities (e.g., infinite stress, due to stress concentrations).
Here is another example to constrain a design to be man- ufacturable via machining, using the accessibility analysis
(7)
where ¬1RΩ(x) = 1−1RΩ(x) is a negation. This constraint restricts the total volume of inaccessible regions RΩ⊆Ωc, obtained as the 1−norm of their indicator function, by an upper-bound VUB > 0.
Ocal Inequality Constraints
It is sometimes possible to define a predicate in terms of local constraints evaluated at a specific point in the design domain; for instance, using one of the following forms:
(9)
Note that the two alternative forms are different by the “for all” and “there exists” quantifiers, which lead to dif- ferent global implications. Unlike the case with (4), here
Gi : (Ω0 × D) →R Is Field For A Fixed Design Ω∈D,
i.e., is also a function of the query point x ∈Ω0.
N
turn, the constraint is evaluated based on the probed value of the performance field Ai(x; Ω) ∈Qi (generally, a ten- sor) at the query point. We denote this dependency by gi(x; Ω) = ¯gi(Ai(x; Ω)) where ¯gi : Qi →R. For exam- ple, the global displacement and stress bounds mentioned
(11)
It is easy to verify that using (10) and (11) with (8) is equivalent to using (5) and (6) with (4) in this example. In general, local constraints gi(x; Ω) ≤0 used with “for all” or “there exists” quantifiers in (8) and (9) can be equivalently expressed as global constraints (stated inde-
(13)
As another example, consider the accessibility analysis discussed earlier. Instead of constraining the total volume of inaccessible regions via the global constraint of (7), we can locally constrain the inaccessibility measure as:
Where Oω= (Ω∪F) And T = (H ∪C) Are The Stationary
and moving solids, respectively. µ0 > 0 is a small constant to provide allowance for numerical errors. The convolution
(15)
where 1−T (x) = 1T (−x) is a reflection with respect to the origin, hence 1−T (x −x′) = 1T (x′ −x) is the indicator function of the moving object (i.e., tool assembly), trans- lated to the query point x ∈Ω0. The integral is nonzero at integration points x′ ∈Ω0 that belongs to the interference of the translated object with the stationary obstacles.
It is not always possible to convert global constraints to local constraints or vice versa, without defining new per- formance variables, e.g., in terms of the norms of existing performance fields. We show in the next section that when Ai(x; Ω) is decidable independently of Ω∈D, the above two constraints lead to maximal/minimal feasible designs (in set-theoretic terms).
Strictly Local Inequality Constraints
An important special case of (8) occurs if the predicate is decidable without a priori knowledge of the design itself. In other words, the constraints can be evaluated purely from a knowledge of the query point’s position x ∈Ω and external factors, if any (e.g., a known rigid body mo- tion applied to the entire design). The predicate’s result can be obtained without knowing the overall shape of the design.
I (X), I.E., The
forward problem’s solution can be evaluated pointwise— emphasized by the overline notation. The corresponding
I (X)) ≤0 Is Hereafter Called A
strictly local (i.e., pointwise) constraint. The predicates in (8) or (9) in this case are dependent on Ωonly due to the
(17)
Hence, one can define pointwise predicates in this case:
(18)
We show in Section 4 that the pointwise predicate defines a point membership classification (PMC) that implicitly determines the entire feasibility halfspace Hi = c−1
(1) Us-
ing its “representative” maximal/minimal feasible design
I
−1(1) using (16) or (17), respectively.
N This
paper, we restrict our attention to the former (“for all” quantifier and maximal designs), since it lends itself to material reducing downstream solvers such as TO.
The physics-based constraints exemplified earlier might reduce to pointwise constraints in rare examples—e.g., the stress tensor σ∗(x) for hydrostatic pressure in a liquid con- tainer at rest depends on the query point’s depth from the surface, but not on the container’s designed shape. Never- theless, pointwise constraints are ubiquitous in kinematics- based constraints that are central to applications ranging from assembly and packaging to manufacturing.
N The
next section, we present an important subclass of point- wise constraints that manifest as set constraints. 3.3. Converting Set Constraints to Inequality Constraints Many kinematics-based design criteria lead to con- straints expressed in the algebra of sets. A common form of set constraints is in terms of containment: Γ(Ω) ⊆E (for a fixed envelope E ⊆Rd). The exact same constraint can be written in terms of non-interference: (Γ(Ω)∩O) = ∅ (for a fixed obstacle O ⊆Rd), where Γ : D →P(Rd) is a set transformation and E := Oc (i.e., complement of O).
At a first glance, these constraints appear to have a completely different form than the inequality constraints described in Section 3.2 in the algebra of fields.
Here,
we show that set constraints can always be reformulated as (global or local) inequality constraints by virtue of de- scribing sets with their indicator functions. However, con- verting them to strictly local (i.e., pointwise) constraints is possible under certain conditions.
Global Or Local Set Constraints
For every solid Ω∈D, its indicator (i.e., characteristic)
(19)
Hence, every containment constraint is restated as an in-
(20)
i.e., using the standard form 1Γ(Ω)(x) −1E(x) ≤0. Recall from Section 3.2 that the above inequality con- straint can also be rewritten as a global constraint of the
(21)
Notice that we have not made any assumption on the properties of the pointsets Γ(Ω), E ⊆Rd. In most prac- tical scenarios, both are solids within a bounded domain, taken as the design domain Ω0 ∈D. In such cases, the properties of the mapping and envelope can be exploited to compute the maximum in (21) efficiently.
Moreover, if the set constraint (Γ(Ω) ∩Ec) = ∅is in terms of regularized intersection, it can be rewritten as a global (in)equality constraint in terms of the volume vol(Γ(Ω) ∩Ec] = 0 (or ≤0, for consistency), which, in
(23)
Further, if Γ(Ω) is a rigid transformation of Ω, the inner product turns into a convolution of 1Ωand ¬1E over the configuration space of motions .
Let us consider the inaccessibility analysis one more time. For manufacturing with precision requirements (e.g., for assembly/fit), we can restrict the inaccessible regions Γ(Ω) := (Ω0 −Ω) −RΩto be completely contained within a tolerance zone E ⊆Rd, hence formulating the problem
As A Set Constraint Γ(Ω) ⊆E, Where:
Γ(Ω) = (Ω0 −Ω) −sweep(MΩ, C).
(24)
For translational motions MΩ⊆Rd, the sweep in (24) can
(25)
The maximal collision-free motion is obtained as the complement of the C−space obstacle, which is in turn computed by Minkowski operations (for translational full-
(27)
where T = (H ∪C) represents the tool assembly, includ- ing the holder H and the cutter C.
T Is Understood
that Minkowski sums in (26) can be obtained from the 0-superlevel set of the convolution fields of the participat-
(28)
where ∗is the convolution operator in Rd and sign(x) = 1 (resp. 0) if x > 0 (resp. x ≤0) is the sign function. The latter is needed to convert the real-valued convolutions to binary-valued indicator functions. See for a proof.
In summary, set constraints, as defined in this section in terms of containment or non-interference, can always be restated as global or local inequality constraints defined in Section 3.2. In the next section, we show the conditions under which set constraints can be converted to strictly local (i.e., pointwise) constraints, to enable design space pruning in Section 4.
6The operators (·)c, ∪, ∩, −, ⊕, ⊖are all regularized to ensure their algebraic closure within the design space D . The caveat is that collision-free lower-dimensional motions (e.g., of a peg inside a hole with no clearance) would be pruned from collision-free motions.
7In general, Y = (X1 ⊕X2) ⇌1Y = sign(1X1 ∗1X2) .
Set Constraints As Pointwise Constraints
Depending on the properties of Γ : D →P(Rd), the in- equality constraint 1Γ(Ω)(x)−1E(x) ≤0, used in global or local forms of (20) and (21), respectively, may or may not be restated as a strictly local (i.e., pointwise) constraint.
Our goal in this section is to articulate the conditions un- der which this is possible. To enable pointwise formulation, we need to eliminate the dependency of the PMC for Γ(Ω) on Ωso that 1Γ(Ω)(x) on the left-hand side of the inequality constraint in (20) depends only on the query point x ∈Ω0 and the fixed envelope E ⊆Rd.
This Can Be Done If The Set Trans-
formation Γ is itself a pointwise transformation, meaning that it can be defined by extending a transformation of 3D points γ : (Rd or Ω0) →P(Rd) to a transformation of 3D pointsets Γ : D →P(Rd) by simply applying the former to every point of the pointset and unifying the results:
(29)
Note that γ(x) is itself a pointset, not a point, to capture the most general case. For example, it can be a curve seg- ment or surface patch representing the 1D or 2D trajectory of a point under a given one- or two-parametric motion, respectively.
The above refactoring is possible for many important applications. For example, if the design has to move (when deployed in assembly) according to a known motion set M ⊆SE(3) without exiting a safe region of space E ⊆Rd that contains no obstacles , the above constraint can
(30)
is the sweep of the designed part as it travels by the given motion (known a priori). In this case the sweep indicator function 1Γ(Ω) can be directly obtained as follows:
(31)
In other words, a PMC test for Γ(Ω) can be obtained by applying the inverse motion M −1 = {τ −1 | τ ∈M} to the query point and checking if it intersects the design. The inequality constraint in (21) can thus be computed rapidly by sampling query points in the design domain and testing intersections of their inverse trajectories with the design . Importantly, the computation for one point does not need one to have explicit knowledge of the results for other points. Other than perfect parallelization (e.g., on GPU), this property enables pruning the design space – leading to development of the Unsweep solver discussed earlier – before optimizing the design for other criteria.
In general, for pointwise transformations as in (29), the
(32)
i.e., Ωremains within E after a Γ−transform iffall points inside it remain within E after a γ−transform. Note also that inequality constraint in (20) can now be rewritten in
(33)
As with other inequality constraints, not every global or local set constraint can be converted to a pointwise set constraint. For example, the toleranced accessibility con- straints Γ(Ω) ⊆E for Γ(Ω) := (Ω0 −Ω)−sweep(MΩ, C) in (24) cannot be evaluated pointwise, because the maximal collision-free motion MΩ= (Ω⊕(−T))c depends on the global shape of Ω, unlike the case with the fixed motion in the earlier example with Unsweep.
Esign For Heterogeneous Constraints
We conclude this section by a fairly general formulation of a design problem subject to n ≥1 heterogeneous (e.g., kinematics- and physics-based) constraints.
Without loss of generality, let nC = nG +nL +nP where 0 ≤nG, nL, nP ≤nC are the number of global, local, and strictly local (i.e., pointwise) constraints, respectively. All constraints, including set constraints, are expressed as in- equality constraints for uniformity. The design problem is to identify the feasible design space D∗= c−1(1), stated
(34)
We assume that none of the gi(x; Ω) ≤0 can be simplified
Into One Of G∗
the P-, G-, and L-subscripts for various notions related to pointwise, global, and local constraints, respectively; for
P (1) Is The
design subspace that is feasible with respect to pointwise constraint alone, and so on. We solve the design problem
(35)
In Section 4, we solve the above problem by computing
P := Max D∗In The Partial Ordering Of
designs via set containment.
N
most cases, one can at best generate a finite sample of feasible designs that are superior in some way.
P And Ω∈N(Ω) In The Pruned Design
space,8 within which no other design is superior to Ωwith respect to all objective functions f1, f2, . . , fnO : D →R.
Minimize Fj(Ω), For 0 < J ≤No,
subject to constraints in (36).
(37)
The objective functions define another partial ordering over the pruned design space, whose maximal elements
We Seek, I.E., D∗
dom := max D. In Section 5, we solve the above problem by iterative op- timization guided by TSF. The TSF is defined with respect to global objective functions fj(Ω) and global constraints gi(Ω) ≤0 and is penalized/filtered using local constraints gi(x; Ω) ≤0. Since global optimization (N(Ω) := D∗
P) Is
NP-hard , we settle for local optimality.
Esign Space Pruning
In this section, we present a methodology to solve the phase 1 problem formulated in (35) of Section 3.4. Us- ing the terminology and results of Section 3, we show how the design space can be pruned with respect to pointwise constraints (including set constraints) without premature optimization.
We Illustrate The Process Using Examples
from kinematics-based constraints that are common in as- sembly, packaging, and manufacturing.
Existence & Completeness Of Maximal Designs
The following results on the existence and uniqueness of maximal pointsets and their informational completeness as a representation for entire feasible design spaces are central to design space pruning.
Proposition 1. (Existence and Uniqueness) For every
(39)
The maximality is in terms of set containment, i.e., every satisfactory design is contained in the maximal element: Ω∈Hi ⇒Ω⊆max Hi.
8Technically, N(Ω) is an open set in the induced Hausdorfftopol-
Ogy Of D∗
P = P∗(Ω∗) (all solid subsets of the maximal element). Proposition 2. (Completeness) For every strictly local
I = Max Hi, I.E.,
every solid subset of the maximal element is also feasible: Ω⊆max Hi ⇒Ω∈Hi. In terms of predicates, the design subspace Hi = c−1
(1)
(which satisfies (16)) can now be represented by a single
(1) (Whose All Points Satisfy (18)). The
maximal solid is thus a complete representation of the fea- sibility halfspace as the collection of all of its solid subsets
I Defined By (38) Or (39) Contains All Points
that satisfy the constraints.
I Of The Maximal Set Satisfies
the constraint, because all of its points satisfy the constraint independently of the global shape. 3. Conversely, every feasible solid Ω∈Hi is the subset
Of Ω∗
i , because it only includes points that satisfy this constraint independently of the global shape. Note that the constraint’s independence of the shape of Ωis crucial for this to hold.
For Global Or Local Con-
straints with dependency on Ωitself, attempting to write a PMC similar to (38) leads to a circular definition where the right-hand side depends on the set itself. For example, the (global or local) constraints given in Sections 3.2.1 and 3.2.2 on FEA and printability analyses do not lead to max- imal elements because their constraints gi(Ai(x; Ω)) ≤0 depend on particular design instances. It does make sense to define the maximal set of a feasible space (e.g., using the set-builder definition in (39)) in a way that it depends on a particular instance of that space. On the other hand, the set constraints of Section 3.3.2, such as containment under a prescribed motion, do give rise to maximal elements, as we elaborate with examples in the following sections.
The above reasoning does not take topological regular- ization into account—there is no reason for a maximal set obtained via (38) or (39) to be a solid, hence it may not it- self be a valid design. However, we show that there always exists a valid maximal element obtained by regularizing
(40)
where k and i are the topological closure and interior op- erators, respectively. Proposition 3. (Design Space Pruning) Given a number
I (X) ≤0 For I = 1, 2, . . . , Np, The
feasible design space D∗, defined by intersecting all feasi-
P = Max D∗
that satisfies the uniqueness and completeness properties,
(41)
in which the intersection/conjunction operators need to be regularized. To see why this is true, note that any query point’s membership in an (unknown) feasible design can be tested against all m constraints independently of other points’
I (X) ≤0 For I = 1, 2, . . . , Np, The Point
can (but does not have to) be included in the design, for it to be feasible. The feasible design is hence a subset of all points that satisfy all pointwise constraints.
The above result enables computing on design subspaces as first-class objects. Computationally, the feasibility half- spaces are represented uniquely by their maximal elements.
The pruning of halfspaces (abstract operation) is imple- mented by intersecting maximal elements, i.e., conjunct- ing point membership tests defined by pointwise constraints (concrete algorithm) in an arbitrary order.
(42)
Figure 9 illustrates design space pruning via (3). Figure 9: Design space pruning can be abstracted by intersecting the design space with feasibility halfspaces. This is not a computable operation in general. However, for pointwise constraints, it can be computed by intersecting maximal elements in the physical space.
Next, we consider maximal elements for set constraints in Section 4.2, and provide examples from real-world en- gineering problems in Section 4.3, 4.4, and 4.5.
Aximal Pointsets For Set Constraints
Many design requirements, especially those that relate the interaction of moving shapes, may be expressed as set constraints of the form Γ(Ω) ⊆E, where Γ : D →P(R3)
Is A Set Transformation. For Example,
• In packaging and assembly problems, the part’s shape is often designed so that it is restricted to remain
Within A Specified Envelope While Moving According
to a prescribed motion. • When designing part to be machined using a given tool that moves in the presence of obstacles (e.g., the part itself and fixtures), the surface of the part has to be accessible without collisions with the obstacles.
We will address examples of these problems in the fol- lowing sections.
The Common Theme To Many Motion-
based set transformation Γ : D →P(R3) is that they can re-factored via (29) via a pointwise transformation γ : Ω0 →P(R3) that depends on the motion. The maxi- mal pointset that satisfies the containment Γ(Ω) ⊆E or non-interference test (Γ(Ω) ∩Ec) = ∅is defined implicitly
(45)
where the set operators are regularized, as before. Note that γ−1 may not be a function, because γ is not neces- sarily invertible (see footnote 4).
Here are a few classical examples from solid modeling: • For one-parametric sweep Γ(Ω) := sweep(M, Ω), one
Has Γ(X) = Mx Where M = M(T) ∈Se(3) Is A Contin-
uous one-parametric set of motions for t ∈[tmin, tmax].
The Maximal Shape That Satisfies Γ(X) ⊆E Is Given
by an unsweep unsweep(M, E) .
• For Minkowski Sum Γ(Ω) := (Ω⊕B), One Has Γ(X) =
(x + B) where B ⊂R3 is typically a solid.
Maximal Shape That Satisfies Γ(X) ⊆E Is Given By
a Minkowski difference with (E ⊖(−B)) . • For general dilation (which subsumes the above two) with general rigid motions, the maximal shape is given by general erosion .
• For non-rigid (but pointwise pre-determined) defor-
Mations, The Maximal Shape Is Obtained By Its Pmc
in terms of the pointwise displacement function. Procedure. Propositions 1 through 3 suggest a system- atic procedure to prune the design space, i.e., reduce the
P = D ∩(H1 ∩H2 ∩· · · ∩Hnp) For
kinematic criteria expressed in terms of pointwise set con-
Straints:
• Step 0. Initialize the feasible design space with the
P ←Ω0.
• Step 1. Express the set constraint that outlines one of the conditions for a given design Ω∈D to be feasi- ble in the form Γ(Ω) ⊆E. Check if it can be restated as a pointwise constraint γ(x) ⊆E as in (32).
• Step 2. Formalize the forward problem in terms of the PMC test for the maximal element obtained from the pointwise constraint as prescribed by (43).
• Step 3. Invoke an IP-solver for the inverse problem,
Tation Of) The Maximal Element Ω∗
i in (44). • Step 4. Prune the design space by intersecting the
I ) Is A Smaller Maximal Element Repre-
senting a pruned feasible subspace. • Repeat steps 1–4 for all pointwise set constraints. Notice that the above procedure can be applied to different constraints via independent invocation of IP-solvers in an arbitrary order.
Importantly, the IP-solver in step 3 can be implemented in two fundamentally different ways to obtain either an implicit representation (i.e., using PMC test in (43)) or an explicit representation (i.e., using inversion in (45)) of the
Maximal Element:
• If we have access to an IP-solver that computes an ex- plicit representation (e.g., B-rep) of the inverse trans- formation γ−1(E), we can directly intersect it (using
Any Cad Kernel) With The Design Domain To Obtain
the maximal element as prescribed by (45). • If we have access to a FP-solver that computes (ex- plicitly or implicitly) the forward transformation γ(x)
For A Given Query Point X ∈Ω0, We Can Compute An
approximate representation (e.g., point cloud or vox-
Invoking The Fp-Solver To Pmc-Test Them Using
(45); keep the ones that pass the test and discard
The Ones That Do Not; And
3. (optional) use adaptive local re-sampling around the points that passed the test to obtain a better approximation.
Because of the independence of pointwise test, invo- cation of the FP-solver for different query points can be done with perfect parallelization.
Let us apply this procedure to a few examples.
Pruning For Containment Of Moving Parts
Consider the latch design problem introduced earlier in Section 1.2, where the goal is to design a car hood latch that remains within an envelope E ⊆Ω0 while moving according to a motion M ⊆SE(3).
Step 1. Every feasible latch design Ω∈D must satisfy the set constraint Γ(Ω) ⊆E where Γ(Ω) := sweep(M, Ω); i.e., the swept volume by the latch after being transformed by all configurations τ ∈M (including any combination of translations and rotations, parameterized or otherwise) remains within the envelope.
The Sweep Is A Pointwise
transformation, i.e., can be computed as the union of all
Τ∈M Τx, Which Represents The Trajectory
traced by the query point x ∈Ω0 along the prescribed motion. Hence, the containment constraint be tested in a pointwise fashion by γ(x) ⊆E.
Step 2. Using the definitions in (43), we construct a PMC test for the maximal shape in the design space that satisfies
(46)
The forward problem involves following the trajectory, ei- ther exactly or approximately (e.g., by sampling), and testing whether it remains entirely within the envelope.
Step 3. The dual properties of the FP- and IP-solvers (i.e., Sweep and Unsweep) can be leveraged to con- struct an exact or approximate representation of Ω∗
, As
illustrated in Fig. 10. If we have access to an Unsweep
= Unsweep(M −1, E) ∩
Ω0. However, if we only have access to an efficient Sweep solver, we can still compute an approximate representation
Of Ω∗
1 using the PMC test in (46) for a sufficiently dense sample of query points and retaining the points whose for-
(48)
The invertibility of rigid transformations M 7→M −1 is key to efficient direct implementation of Unsweep. Figure 10: unsweep(R, E) is the largest set that remains within the square envelope E shown in (a) while moving by a 21◦clockwise rotation R around a fixed pivot , i.e., without violating the con- tainment constraint as depicted in red in (b). The unsweep can be computed in general by intersecting all moved instances of the enve- lope with an inverse motion .
The remaining steps 4 and 5 are straightforward.
Ω∗
1 can be sent as the initial design to design space ex- ploration (Section 5) via TO or any other downstream ma- terial reducing IP-solver. It is guaranteed that every valid
That Is The Output Of The Downstream Ip-
solver, no matter how complicated, will continue to satisfy the set constraint sweep(M, Ω) ⊆E.
Authors:
Peder EZ Larson 1, 2,* , Jenna ML Bernard1, James A Bankson 3, Nikolaj Bøgh 4, Robert A Bok1, Albert P. Chen 5, Charles H Cunningham 6,7, Jeremy Gordon1, Jan-Bernd Hövener 8, Christoffer Laustsen 4, Dirk Mayer 9,10, Mary A McLean11 12, Franz Schilling13, James Slater1, Jean-Luc Vanderheyden5, 14, Cornelius von Morze 15, Daniel B Vigneron1, 2, Duan Xu1, 2, and the HP 13C
94143, Usa.
Denmark. 5 GE Healthcare, Menlo Park, California, USA. 6 Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
8 Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Medicine, Baltimore, MD, USA. Cambridge, United Kingdom.
14Jlvmi Consulting Llc, Dousman, Wi, Usa
#See Acknowledgements for a list of all HP 13C MRI Consensus Group Members This work was supported by the ISMRM Hyperpolarized Media MR Study Group, the ISMRM Hyperpolarization Methods & Equipment Study Group, and the Hyperpolarized MRI Technology Resource Center (NIH/NIBIB grant P41EB013598).
Abstract
MRI with hyperpolarized (HP) 13C agents, also known as HP 13C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of hyperpolarized agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13C]pyruvate - by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13C-pyruvate preparation, (2) MRI system setup and calibrations, (3) data acquisition and image reconstruction, and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the “HP 13C MRI Consensus Group” as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods & Equipment study groups. It further aims to provide a comprehensive reference for future consensus building as the field continues to advance human studies with this metabolic imaging modality.
Keywords: Hyperpolarized MRI, metabolic imaging, carbon-13, pyruvate, dissolution dynamic
Introduction
MRI with hyperpolarized 13C agents, also known as hyperpolarized (HP) 13C MRI, has shown great potential as a novel imaging modality, particularly for its ability to probe metabolic processes in real time. The first human studies with HP [1-13C]pyruvate were performed in 2011 in prostate cancer patients (1).
Since then, there have been over 60 papers published with imaging results of human subjects from 13 different sites, with applications including prostate cancer, brain tumors, breast cancer, kidney cancer, pancreatic cancer, metastatic disease, liver disease, ischemic heart disease, diabetes and cardiomyopathies. The vast majority of these studies used [1-13C]pyruvate (1–63), where [2-13C]pyruvate (64) and 13C-urea (56) have been demonstrated too.
As clinical HP 13C MRI advances, there is a growing need to build consensus for best practices, which are critical for comparing data across sites, performing multi-site trials,deploying methods to new sites, partnering with vendors, and potentially for obtaining broader regulatory approvals.
In March 2022, we initiated an effort to build consensus within the HP 13C MRI community with this opportunity in mind, and it was greeted with strong enthusiasm. The “HP 13C MRI Consensus Group”, containing over 55 members from 27 sites, identified the area of greatest need and opportunity for consensus building to be HP [1-13C]pyruvate human
●
Pyruvate is the most mature and widely used HP agent and has the most significant translational evidence emphasizing the potential clinical impact.
●
Clinical trials, particularly multi-site trials, have the strongest need for consensus methods to ensure that data can be combined across sites. This work is a Position Paper for which the goal is to describe current successful practices and study methods for HP [1-13C]pyruvate human studies along with justification to support those practices. This is divided into four major topic areas: (1) HP 13C-pyruvate preparation, (2) MRI system setup and calibrations, (3) data acquisition and image reconstruction, and (4) data analysis and quantification (Fig. 1). The current successful practices and study methods include a literature review of published peer-reviewed journal papers showing human HP [1-13C]pyruvate study data, up to September 2022 (1–63), as well as new unpublished information from surveys of HP 13C study sites. Based on this information, we also highlight the evidence gaps, strengths, and limitations of current practices which are summarized at the end of each section.
Figure 1: Illustration of the HP 13C MRI human study process, including the 4 major areas covered in this paper: Hyperpolarized 13C-pyruvate preparation, MRI system setup and calibration, Acquisition and Reconstruction, and Data Analysis and Quantification.
Figure 2: Anatomical targets of HP [1-13C]pyruvate MRI human studies published up to September 2022.
Hyperpolarized 13C-Pyruvate Preparation
This section covers the processes for creating the HP agent, 13C pyruvate, and will include many aspects and considerations that are needed to safely and effectively prepare doses for metabolic imaging studies in human subjects. These include material, personnel, equipment and facility, fluid path preparation, quality control, and release.
It is helpful to understand that the specifications of a dose of 13C pyruvate suitable for in vivo MR HP metabolic imaging were shaped in part by early preclinical studies performed by GE HealthCare summarized in Ref. (65). In short, the safety of the two novel drug components, 13C pyruvate and the electron paramagnetic agent (EPA) AH111501, were demonstrated in those studies. The more precise formulation of the dose suitable for human use was then determined from clinical studies (66) that included two Phase 1 clinical trials in young and elderly healthy volunteers without hyperpolarization of the 13C nuclei and another Phase 1/2a dose escalation and imaging feasibility study with HP 13C pyruvate in 31 prostate cancer patients at the With the exception of the first HP 13C imaging clinical trial, which utilized a prototype device in a cleanroom (1), all HP 13C studies performed in humans to date have utilized the SPINlab polarizer (manufactured by GE HealthCare). Consequently all doses of the HP 13C pyruvate delivered by SPINlab have been produced using the “SPINlab Pharmacy Kit” that serves as the container-closure system for the various drug components (13C pyruvic acid and EPA mixture, dissolution medium, and neutralization and dilution medium) during sample polarization, dissolution and quality control (QC) processes. Thus many aspects of the HP sample preparation considerations discussed below are related to the SPINlab instrument and the consumables designed to be used with it (67).
General Considerations
While more than 860 patients or healthy subjects having been injected with HP 13C pyruvate as of January 2022 without reports of any serious adverse events (68), HP 13C pyruvate injection remains an investigational MR contrast agent and can only be administered by those with Investigational New Drug (IND) exemption from the Food and Drug Administration (FDA) in the USA, a Clinical Trial Application (CTA) in Canada, approval from National Research Ethics Committee Services in the UK, or approval from the relevant local regulatory body. Thus, methods and processes involved to produce a dose should have patient safety as the first priority. Since utilizing dissolution dynamic nuclear polarization (dissolution-DNP) for human use is still a relatively new development, there are no existing published regulatory guidelines specifically for this method.
There are two major production styles that determine how various sites approach the agent preparation. In the US, the most common approach is to rely on a sterilizing filter (“Terminal Sterilization”) to ensure sterility of the final product, akin to PET tracer production, where a starting molecule with a radioisotope is processed using various other ingredients to make the final, desired and injectable contrast agent within a necessarily short amount of time (69). For these sites, sterilization of the components and accessories upstream of this filter are not required, although many of them were manufactured and tested following Good Manufacturing Practice (GMP) or Good Laboratory Practice (GLP) requirements. The filling process is usually performed under an ISO 5 laminar flow hood, but a clean room or an isolator is not required.
This approach is typically accompanied by testing the integrity of the sterilizing filter prior to release of the dose for injection. Typically, post release endotoxin and sterility tests are performed using an aliquot reserved from each released dose.
In the UK and EU, the most common approach is to more-closely follow sterile pharmaceutical compounding guidelines (70), where all components and ingredients are required to be sterile or manufactured under GMP guidelines and are assembled and filled within a clean room environment or an isolator system (“Sterile Preparation”). Typically a batch of Pharmacy Kits for HP 13C pyruvate injection are prepared together. The sterility of the final dose is also ensured by batch validation testing, in addition to the sterility of the ingredients and the sterile compounding process. The endotoxin and sterility testing are performed for the process validation but are not performed for each injected dose.
Some institutions fill and assemble the Pharmacy Kit required for a specific study on the same day or the day prior to polarization, dissolution, and patient administration, but others have also demonstrated the feasibility of preparing a batch of kits, keeping them in a -20ºC freezer and using them over a period of a few months.
Beyond the obvious requirements that the process and the facility has to ultimately produce a dose that is safe to inject into a human, regulatory authorities will also focus on the question “Are you in control of your processes?”. To be in control of your process requires an in-depth and broad understanding of all processes involved in pre, post, and during the production process.
Personnel
It is typical and may be required to have licensed personnel involved in the production process depending on local regulations.Typically a pharmacist, radiopharmacist or other similarly qualified person (QP), in charge of the facility where the Pharmacy Kit filling and preparation is taking place, is responsible for the overall process and the release of the injectable dose.
Qualified cleanroom technicians are often involved in the Pharmacy Kit filling under the supervision of the pharmacist or QP. As is required for pharmaceutical compounding or PET tracer production, training requirements and training records for all personnel need to be maintained and available for audit by the FDA or equivalent.
Equipment And Facility
The facility and all equipment need to have standard operating procedures (SOPs) that describe how equipment is used, maintained, and calibrated to comply with relevant legislation. Currently, almost all the filling of the Pharmacy Kit takes place within a compounding laminar flow hood or isolator (typically ISO 5). At some sites, the filling is conducted within a cleanroom, while at others, it is conducted in a dedicated non-cleanroom space, reflecting differences in cleanroom approach and specifications between regulators worldwide (71). Some equipment or facilities, such as the compounding hood or cleanroom, may require external certified laboratories for testing.
Material Handling
Material handling guidelines (69,70) require SOPs detailing a system to track all of the materials involved in the HP production process for a particular patient dose, similar to current good manufacturing practice (cGMP) requirements for material handling for drug compounding. This includes acceptance standards, storage conditions, amount used in the patient dose for each ingredient and materials used in the assembly of the fluid path and Pharmacy Kit. Currently some users choose to open and inspect and sometimes modify the Pharmacy Kits upon arrival, but some users keep them in the sealed packaging until they are required for dose preparation.
Pharmacy Kit Filling And Assembling
As required by an IND or its equivalent, the preparation of the doses of HP 13C agent are detailed in the Chemistry, Manufacturing, and Control (CMC) section of an applicable regulatory submission; an example of this has been made available (72). It describes the processes of filling the Pharmacy Kit with the different components that make up the final drug product, and of assembling the final kit for either storage or immediate use in the polarizer. Special attention should be given to the laser welding process in order to satisfy installation qualification (IQ) and operational qualification (OQ). Typically, the final developed process is validated by process qualification (PQ) runs, during which 3 or more Pharmacy Kits are filled and used and the final HP 13C products are tested for endotoxin and sterility and to confirm that they meet the dose specifications for injections (usually including pyruvate concentration, residual EPA concentration, pH, liquid state polarization level and dose temperature). The data from 3 consecutive PQ runs are submitted as part of the IND submission (or its equivalent), and are often also reviewed by the Institutional Review Board (IRB) where the studies are conducted.
Quality Control And Dose Release
The quality control (QC) and dose release can be separated into two aspects: one is the QC and release of the filled Pharmacy Kit, and second is the QC and release of the HP 13C agent for injection, after polarization and dissolution. For institutions filling a batch of kits and storing them to use over a period of time, typically the batch can be released based on initial validation, environmental monitoring data from the day of kit production, and if filters are used during preparation of any of the components, filter integrity testing. But in some cases one or more kits are used for validation before the batch of kits are released for future use. For institutions that fill only the kits required for specific studies shortly before the experiment, the filled kits often do not go through separate release tests before they are used.
The quality control of the HP 13C pyruvate solution post dissolution is primarily performed to ensure that the agent meets the dose specifications (Table 1) before it is administered to the subject. These specifications target both safety (pH, residual EPA, temperature) and efficacy (pyruvate concentration, polarization, volume). Typically, the pyruvate concentration, residual EPA concentration, pH, dose temperature, dose volume, and liquid state polarization are measured by the QC accessory associated with the SPINlab polarizer. Some users perform a secondary measurement for one of the parameters, such as pH, using a different instrument or pH paper. For sites that do not go through a separate release testing process for batch filled kits, the integrity of the sterilization assurance filter, a part of the Pharmacy Kit, is typically tested as a part of the dose release. It is also common for these users to preserve an aliquot of the final HP 13C pyruvate solution for post-release endotoxin and sterility testing. This testing cannot be completed fast enough to test an individual dose prior to injection, but this is why other processes such as PQ runs and validation testing are done to minimize the chance a subject could be injected with a contaminated dose.
The Final Dose Release And Injection
should be done under the supervision of a licensed professional, based on local regulations.
Some Key Challenges
Many of the challenges associated with HP 13C pyruvate preparation can be attributed to the conditions required for the dissolution-DNP method of high magnetic field (~3-7 T) and very low temperature (~1 K) during polarization, with pressurized and superheated water necessary for the rapid dissolution event. These extreme conditions are quite challenging for the design of the container-closure and fluid path system. In particular, the cryogenic temperature in the polarizer requires special attention to any moisture or ambient (moist) air introduced into that portion of the fluid path, which can form an ice block at ~1 K. This ice can lead to flow restriction during the dissolution event and reduce the strength of the laser welded bond between the cryovial and its cap. This can ultimately produce failures in the dissolution step, including variations in final pyruvate concentration and pH that may fail to meet QC release criteria as well as fluid path ruptures that provide no available dose and result in polarizer down-time.
The polarization of the HP 13C pyruvate sample decays quickly over the span of a few minutes after dissolution, and thus the process of dissolution, QC for release, and injection should be completed as fast as possible to preserve the high polarization level achieved. Any delays in the preparation process, such as transportation time or equipment malfunction, can significantly reduce the final polarization and result in lower quality imaging data.
Current Practices
A summary of data collected from all sites performing clinical trials with HP 13C-pyruvate is shown in Fig. 3 and Table 1, including the specification of the final dose and how the quality control and release of the final dose are performed. There is a split in the Production Style, described in the General Considerations section above, with 8/13 sites using Sterile Preparation versus 5/13 using Terminal Sterilization. While many of the dose specifications show notable differences in acceptable ranges, all of these variations listed in tables have been successfully and safely been used to perform HP 13C pyruvate studies in humans. Their differences depend on the institutions’ preferences, resources and their particular regulatory situation. There is high similarity in pyruvate ranges, temperature ranges, EPA limits, and volume limits. There is modest variability in pH ranges and large variability in the endotoxin test limit. There is a 3-fold difference in acceptable polarization levels, which are measured to ensure a futile dose is not injected since the polarization is directly proportional to SNR. This reflects the decision by several sites to believe that useful data can be still be obtained with suboptimal polarizations.
Figure 3: Hyperpolarized agent preparation methods reported by sites currently performing HP
In House
Table 1: HP 13C-pyruvate preparation parameters, methods, and dose specifications used for quality control testing and release as well as validation. These were obtained from a survey of all sites performing clinical trials with HP [1-13C]pyruvate. The parameters used for product release are noted in bold text, otherwise these parameters are measured for batch validation or other QC measurements. The endotoxin and sterility testing are performed during process validation of the batch and/or post-injection, and largely depends on the agent production approach.
Summary
The overall safety record of HP 13C-pyruvate has been very strong, and the SPINlab hyperpolarizer has proven to provide high polarizations at human sized doses while meeting numerous QC and release criteria. A weakness remains the failure modes of the SPINlab Phamacy Kits (e.g. ice blocks, path ruptures), which are placed under extreme requirements particularly during dissolution. The preparation process still requires a high degree of expertise.
Therefore, there is a significant need to improve the reliability, robustness, and ease of operation for generating HP 13C-pyruvate doses for human studies. Furthermore, there is a divide between manufacturing and sterile compounding style preparation as well as other site-specific practices, resulting in variations in SOPs and justification required to relevant regulatory bodies. There have also been no comparisons between these approaches. It is also unclear what release criteria and QC parameters are truly required to ensure patient safety.
However, all of the reported methods are acceptable and approved by the appropriate regulatory authorities, and have led to the rapid expansion of successful human studies in recent years.
Mri System Setup And Calibrations
This section covers the MRI system setup, including the imaging system, RF coils, phantoms, and prescan calibration methods.
Imaging System
The main prerequisite for a given MRI scanner to be capable of supporting studies with HP 13C is its “broadband” capability to transmit and receive radiofrequency (RF) signal at the frequency of 13C, which is around 4 times lower than 1H. This does not come as a default on clinical MR devices. The transmit power of the broadband amplifier should also be sufficient to support the intended flip angle and RF pulse shape with the employed transmission RF coil(s) for 13C. Most studies to date use relatively low flip angles (< 90 degrees) for HP 13C in order to preserve polarization for time-resolved imaging. The capability to receive 13C signal on multiple channels is also desirable to increase SNR, as discussed further in the “RF coils” section.
The choice of magnetic field strength is primarily dependent on the metabolites’ frequency separation due to chemical shift dispersion and 1H imaging. High field strengths do not enhance hyperpolarized 13C signal as they do for 1H because the signal strength in a HP experiment relies on manipulating the population of quantum energy states outside of the MRI scanner.
However, the injected HP 13C-pyruvate and its metabolic products have greater frequency separation at higher fields, and it may thus be easier to separate and quantify these resonances at higher fields. This comes at the cost of a reduction in the achievable T2* and often reduced T1. As the initial polarization is independent of the imaging field strength it has been proposed that the increased T2* at 1.5T can potentially be exploited to increase SNR by adapting the acquisition bandwidth or reduce off-resonance imaging effects in cases when the decay of the transverse magnetization is dominated by T2* (73). In practice, 3T has been used in all published human 13C-pyruvate studies surveyed (Supporting Table S1), and comprises the majority of scanners currently in use for human studies (Table 3). A field strength of 3T is well-suited for 1H MRI anatomical reference and correlative imaging.
Stronger and more rapidly slewing magnetic field gradients support more rapid spatial encoding, particularly for metabolite-specific single-shot imaging using echo-planar imaging (EPI) or spiral imaging (See “Acquisition and Reconstruction”). Although the spatial resolution acquired for HP 13C imaging is typically much coarser than for 1H MRI, the factor of ~4 in gyromagnetic ratio leads to the same reduction factor in performance of the gradient system, so 13C experiments are potentially more limited by gradient hardware performance. To date, all human studies have used the commercially-available integrated gradient systems provided in clinical MRI scanners.
Optimization of scanner design has understandably focused on minimization of artifacts in 1H MRI, where devices such as room lights, the gradient amplifiers, and the motors driving the patient bed are checked to ensure that they do not produce RF interference at the 1H frequency, but artifacts may arise at other frequencies. Eddy current compensation is also not always appropriately adjusted for nuclei at other frequencies (74). In order to optimize for 13C, many sites have performed checks on phantoms for RF interference, gradient artifacts, and eddy currents (74), including the use of post-hoc gradient impulse response function characterisation and correction, and some vendors have fixed these issues as well.
Rf Coils
For HP 13C imaging studies in humans, RF coils for both 1H and 13C nuclei are needed, with 1H MRI providing an anatomical reference for registration and optional additional multiparametric MRI readouts. At the Larmor frequency of 13C nuclei, the relative contributions from coil noise compared to sample noise increase compared to 1H (73,75), although sample noise still is likely the dominant contributor for human-sized coils at 32.1MHz - the resonance frequency of 13C nuclei at 3T.
The key requirement for human 13C-pyruvate RF coils are that the coil geometry and sensitive volume must cover the volume of interest in the subject. Table 2 and Figure 4 shows coil configurations that have been used and optimized for applications in different anatomic regions.
Volume resonators are most commonly used for transmit, as they surround the subject to
Provide B1 Transmit Across The Fov (B1
+). While 1H relies on a large birdcage (“body”) coil built into the scanner, 13C transmit coils must be placed inside the bore. This takes up valuable space within the magnet, and also has led to the use of designs with relatively inhomogeneous
B1
+. Many human studies have used Helmholz pair resonators for transmit, including the “clamshell coil”, which has a notably inhomogeneous B1
+ Profile But Has Been Used Because Of
relatively easy integration into the scanner bore. B1
+ Variation Results In Variations In The Flip
angles that control the use of the hyperpolarized magnetization and creates errors in common HP metrics (9,76). The exception are head coils, where birdcage designs with highly
Homogeneous B1
+ can be placed around the head while easily fitting inside the bore. As with 1H MRI, higher SNR can typically be achieved by smaller receive coil elements, such as surface coils or phased arrays, and the majority of 13C receive coils used have layouts similar to 1H phased arrays.
RF coil quality control is important to ensure proper functioning of the coils to provide consistent imaging quality, especially with limited natural abundance 13C signal in vivo. It typically involves 1) a physical integrity check of the coil cables and connectors and 2) phantom SNR tests to check the coil’s performance and to monitor it over time (see Phantoms below). An useful reference for RF coil quality control is outlined in the MRI accreditation program of the American College of Radiology (77) and can be adapted for 13C coils.
Notably, configurations for brain and prostate studies used dual-tuned 1H/13C coil designs, which greatly simplify workflow and registration of 1H and 13C images, as no switching of coils is needed.
(1)
Table 2: RF coil configurations reported for human HP [1-13C]pyruvate studies.
Tx = Transmit
coil, RX = receive coil. The commonly used “clamshell” TX coil is a Helmholz pair design. For 1H RF configurations, all used the Body coil for TX unless otherwise noted, and “repositioned” indicates the 13C coil was removed for 1H imaging. One representative reference is listed for each configuration. The RF coil configurations reported in the reviewed papers are shown in Supporting Table S1.
Figure 4: Examples of RF coil configurations used for human HP [1-13C]pyruvate brain studies. (A,B) 13C Clamshell TX (Helmholz pair) and 2× 4-channel paddle RX arrays. (C) 13C Birdcage volume TX and 32-channel RX array (RX array slides into TX coil). (D) 13C Birdcage volume TX and 24-channel RX array, combined with a 1H 8-channel RX array. Image reproduced with permission from Ref (16).
Phantoms
Since hyperpolarized magnetization is non-renewable, phantoms containing 13C nuclei are important to: 1) test the multi-nuclear capabilities of the imaging system, including all parts of the signal excitation and receive chain; 2) perform calibration measurements before a scan with hyperpolarized nuclei; and 3) perform necessary pre-scan adjustments (see “Prescan Calibration” section). The phantoms currently in use are listed in Table 3. Their composition must provide sufficient 13C signal, with additional considerations of conductivity, stability, chemical shift(s) present, potential for dynamic imaging, and cost. The phantom geometries are typically either compact, in order to be used alongside the subject during a HP scan, or large enough to mimic the inner volume of a RF coil for system testing.
One popular compact design contains enriched 13C-urea at high concentration, typically 8 M, which provides a single resonance, placed inside a small container ~1 mL. The most common recipe mixes 13C-urea in a 90% water/10% glycerol solution, with glycerol used to increase the urea solubility and doping with a Gd-based contrast agent to shorten T1 which increases the potential SNR per unit time. For example, when Dotarem is added at a 3:1000 volume ratio the 13C-urea T1 is around 500 ms and T2 is around 100 ms. However, when testing pulse sequences influenced by T1 and T2, doping should be used carefully. This phantom is suitable for frequency calibration, transmit gain calibration, sequence testing, and as a fiducial marker when placed next to a patient. However, enriched 13C-urea has a relatively high cost compared to natural abundance compounds.
For larger volumes (>100 ml), the phantoms most often used contain undiluted ethylene glycol, glycerol, or dimethyl silicone. These compounds have sufficiently high carbon concentrations to provide sufficient 13C signal even with the 1.1% natural abundance of 13C. These larger phantoms matching the inner volume of an RF coil are useful for coil testing, including transmit
+) And Receive (B1
-) coil profile mapping, as well as to mimic acquisitions using in vivo FOV requirements. In this case, size and conductivity should match the expected subject size in order to mimic coil loading and get a realistic estimation of B1+. Large-volume natural abundance urea phantoms have also been used by some sites, but suffer from higher conductivity compared to biological tissues. Typically, it is easier to increase the conductivity and hence coil loading of the non-conductive phantom by adding NaCl to match physiological loading (16,78).
Dynamic phantoms that aim to mimic metabolite kinetics have also been developed (79–81), and have the potential to more closely mimic the HP experiment, but so far these are not widely used.
Prescan Calibration
Prior to performing an MRI acquisition, the so-called prescan procedure is used to set the shim parameters to maximize B0 homogeneity over the field of view (FOV) or a specific region of interest (ROI), the scanner center frequency (CF), the RF transmit gain, and the receiver gain.
While this calibration procedure is usually automated for 1H, the lack of sufficient natural abundance 13C signal prevents use of automated methods. (Although natural abundance 13C lipid signal has been detected, there are so far no reports on using this signal for prescan.) Table 3 shows current practices across sites.
Maximizing B0 homogeneity is independent of the nucleus and is therefore performed prior to 13C imaging using the 1H water signal and existing shimming tools, such as by a standard automated process (“Auto Shimming”) or using high order shimming routines. Similarly, the 13C CF can be calculated from the 1H CF using a predetermined scaling factor that depends on the target chemical shift (82). Another common approach used is to have a small, high-concentration 13C phantom, e.g. 8M 13C-urea, integrated in the RF coil or placed next to the scan subject (1). The reference frequency can also be based on real-time measurements after the HP injection but prior to imaging (83). Both the CF and B0 shimming are critical when using spectrally-selective RF pulses, as inmetabolite-specific imaging methods, where the desired excitation bandwidths are typically very narrow and frequency offsets can lead to a failure mode that is only apparent after injection.
The calibration of the RF transmit power is typically performed on a small, high-concentration 13C phantom placed near the region of interest during the scan or on a large 13C phantom of similar size and coil loading as the subject, prior to the subject scan. Reference power is often done by sweeping the power in a pulse-acquire sequence (53,62), or the Bloch-Siegert method (52,84). When using a small phantom, the location of the phantom, B1
+ Inhomogeneity As Well
as any shielding effects, e.g., when the phantom is integrated into a coil (1), may degrade the accuracy. Other methods include real-time Bloch-Siegert method measurements after the HP injection (83), and using the stronger natural abundance 23Na signal that is close enough to the 13C resonance frequency to be detected by 13C coils (82).
The receiver gain is predetermined, either systematically based on independent phantom measurements and assuming the dose and polarization of the HP compound is known prior to injection, or based on past HP imaging studies.
Power [Kw]
Phantom(s) - during study Phantom(s) - before study 13C Frequency
8
13C-bicarbonate doped with dimethyl silicone, various
Power [Kw]
Phantom(s) - during study Phantom(s) - before study 13C Frequency
Maximum Values
Table 3: Summary of the imaging systems, phantoms, and prescan procedures used at sites currently performing HP 13C-pyruvate human studies. These were obtained from a survey of all sites performing clinical trials with HP [1-13C]pyruvate. *Previously performed studies with a Siemens 3T Tim Trio. The imaging systems, phantoms, and prescan procedures reported in the reviewed papers are shown in Supporting Table S1.
Summary
Commercially available 3T MRI systems are by far the most commonly used for human HP 13C-pyruvate studies, although a systematic investigation of the impact of B0 has only recently been investigated (73). The multi-nuclear RF transmit and receive chain has proven sufficient for current acquisition strategies, although many sites have observed artifacts due to RF interference, gradient interference, and residual eddy currents when operating at the 13C frequency. A variety of 13C RF coils, tailored for numerous anatomical targets, have been successfully demonstrated, with the main limitation that most transmit coils take up a lot of additional space inside the bore and provide relatively inhomogeneous B1
+ Profiles. The
phantoms used have converged into generally 2 categories - small phantoms containing 13C-enriched compounds that can be used during the study and human-sized phantoms containing compounds with high carbon concentrations but without 13C enrichment that are used to test and calibrate the coils. There are no standardized compositions or geometry, and dynamic phantoms that recapitulate in vivo kinetics would be desirable but are still an emerging area. Prescan calibration procedures were not well defined in most publications, so we surveyed individual sites to determine current practices. Calibration procedures for the B0 field (13C CF and shimming) for most sites take advantage of 1H signal and methods, while methods
For Calibration Of B1
+ is more variable across sites, likely a reflection of remaining challenges in how to perform this calibration. Standardization of both phantoms and calibration procedures would synergistically improve the robustness and reproducibility of HP 13C studies.
Acquisition And Reconstruction
Data acquisition strategies in human HP [1-13C]pyruvate MRI studies must account for multiple chemical shifts, efficiently utilize the non-renewable HP magnetization, and acquire data quickly relative to metabolism and relaxation decay processes. These studies require spectral encoding to separate metabolites, necessitating pulse sequences that efficiently encode up to 5D data (3 spatial + 1 spectral + 1 temporal dimension). RF pulses must efficiently sample without immediately saturating the non-renewable HP magnetization, and sequences must acquire data quickly and be robust to both experimental and physiologic variation (e.g. B1
+ Inhomogeneity,
variation in perfusion) to ensure reproducibility and minimize scan-to-scan variability. This section covers current successful practices for data acquisition in human [1-13C]pyruvate studies, and accompanying 1H imaging, from different anatomic regions, including scan parameters and image reconstruction.
Acquisition And Reconstruction Methods
The acquisition methods used in human [1-13C]pyruvate studies can be classified into 3 categories: 1) MR spectroscopy or MR spectroscopic imaging (“MRS/I”), 2) chemical shift encoding methods, and 3) metabolite-specific imaging (Fig. 5).
Mrs/I Methods Specifically
resolve a spectrum that can be analyzed to extract expected as well as unexpected resonances, making this approach very robust. It was used in many initial studies (1).
Chemical Shift
encoding methods, most commonly the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) method, use imaging sequences acquired with multiple TEs and rely on a model-based separation of expected chemical shifts (85).
Metabolite-specific imaging methods use specialized RF pulses that are spatially and spectrally selective to excite individual metabolites which are then typically imaged with fast k-space trajectories such as echo planar imaging (EPI) or spirals (86).
Their Application To Different
organ systems is described below. The image reconstruction methods used in human [1-13C]pyruvate studies have typically been conventional methods (e.g. FFT, non-uniform FFT, or equivalent). The incorporation of accelerated imaging and advanced reconstruction methods including parallel imaging (4,57,87) and compressed sensing (7) has also been applied in human studies for improved spatial resolution, temporal resolution and coverage, but have the potential for additional artifacts as well as SNR losses due to ill-conditioning of the reconstruction (e.g. g-factor).
The Majority Of
published studies do not use accelerated imaging indicating the resolution and coverage achievable without acceleration is currently adequate for successful data collection. Performing coil combination, even with fully sampled data has also been shown to have specific challenges for HP human images: using naive sum-of-squares methods suffer from high noise amplification in the relatively low SNR regime of HP [1-13C]pyruvate (compared to 1H), motivating several HP 13C-specific methods that include data-driven coil sensitivity estimation which have shown obvious improvements over sum-of-squares (11).
More recently denoising techniques have been applied as post-processing of human HP data(41,42,44). The techniques applied are based on spatial-temporal singular value decomposition for unsupervised estimation of signal and noise components. They have shown improvements in apparent SNR in the brain and liver, while care must be taken to choose parameters such as the rank threshold to avoid oversmoothing and overfitting to the estimated signal components.
Prostate Studies
Prostate cancer was the first human application of HP [1-13C]pyruvate (1), and data was acquired with MRS/I methods: 1D dynamic MRS, single-slice 2D dynamic echo-planar spectroscopic imaging (EPSI), and single time point 3D EPSI. Advances in imaging strategies led to the development and application of new acquisition schemes, including undersampled 3D EPSI with compressed-sensing (7), model-based chemical shift encoding methods that use a priori information (47,59), and metabolite-specific EPI (10), all of which can provide volumetric whole-organ coverage and dynamic acquisitions.
The pyruvate bolus arrival in the prostate can vary by ± 10 s between patients, necessitating dynamic imaging to reliably and consistently capture the pyruvate bolus (18). For this reason, all currently ongoing studies acquire dynamic data. While MRS/I, chemical shift encoding, and metabolite-specific imaging can all achieve dynamic imaging, chemical shift encoding and metabolite-specific imaging provide greater dynamic and volumetric coverage (85). For scan prescriptions, the FOV is designed to provide full prostate coverage and typically to match the orientation of the anatomic imaging used for registration. Flip angles used in current studies are constant through time, as quantification with a variable-through-time flip scheme is highly sensitive to bolus timing (8) and errors in the RF transmit (B1 +) field (76).
Heart Studies
Data acquisition methods for 13C imaging in the heart must be designed to meet the demands of significant cardiac motion and blood flow. To cope with the periodic cardiac motion, most human heart studies to date used gating to the diastolic window, the longest cardiac cycle interval, which has reduced motion (2,22,28,30,35,36,38,45,52). The duration of the diastolic window limits the available data sampling time, making cardiac acquisitions the most time-constrained of the HP 13C MRI applications. The most common acquisition approach is metabolite-specific imaging with spiral k-space trajectories (2). Their single-shot imaging capability makes these methods particularly robust to motion effects. Furthermore, spiral k-space trajectories provide rapid k-space coverage and relatively benign flow and motion artifacts. The majority of studies have used 2D multi-slice acquisitions, but 3D encoding has also been used successfully (35).
Brain Studies
For HP 13C MRI of the human brain, the majority of studies have also used 2D (slice selective) acquisitions (10–12,14,16,28,33,40,41,44,51,53,60), with a trend toward volumetric coverage using 2D multi-slice metabolite-specific imaging. 3D metabolite-specific imaging of the whole brain, with phase encoding of the slice direction (34,57), has been shown to provide similar SNR efficiency (88) compared with multislice imaging. A number of studies have employed MRS/I (5,6,29,31–33,50,55) resulting in a spectrum from each voxel, which has the advantage of not requiring a priori information about which peaks to encode. This was important in early brain studies when it was not known which peaks would be detectable. Chemical shift encoding, using a set of images with different echo times and an iterative reconstruction of the individual resonances (i.e. the IDEAL approach (85)), has also been used (12,49,54), with the drawback that coverage in the slice direction was limited due to the time required to acquire multiple echo time images.
Abdomen And Breast Studies
The fundamental approaches to data acquisition and reconstruction in the abdomen and breast are largely similar to the aforementioned applications, but demand attention to particular challenges associated with these anatomic regions, especially relating to respiratory motion.
Although it has been shown that a basic 2D MRSI approach based on phase encoding and FID readout can be successfully applied for HP 13C imaging in breast (15) and kidney (13), major advantages in terms of spatiotemporal resolution and coverage have been realized using tailored approaches based on metabolite-specific imaging (43,62) and chemical shift encoding (43), which have facilitated multi-slice or 3D dynamic acquisitions over large FOVs in the abdomen (4,37,46).
The significant respiratory motion encountered in these regions can directly blur 13C images, and has further favored these rapid acquisition strategies. Motion also degrades B0 homogeneity, which can shift frequency-selective excitation profiles and introduce artifacts into rapid imaging readouts. This makes accurate determination of the acquisition center frequency and shimming essential in these regions which often cover large FOVs. (See “Prescan Calibration” section for more information). In some studies, breath-holding was used to minimize motion effects and enforce frame-to-frame data consistency (42). A pragmatic and reasonably effective approach for dealing with respiratory motion during 13C data acquisition is an initial breath-hold (as long as can be tolerated), followed by free-breathing (46,62).
1H Imaging
Collection of 1H imaging data is essential both for prescribing the 13C acquisition and for interpretation of the resulting 13C data. Multi-planar 1H scouts are acquired prior to 13C acquisition to enable graphical prescription of the 13C imaging region. All human HP 13C-pyruvate imaging studies acquire conventional MRI scans (e.g. T1- and T2-weighted volumes) for anatomic reference, aiming to cover at least the full 13C FOV. Acquiring these anatomic scans as close as possible to the time of 13C imaging (immediately before or after) minimizes potential misregistration between the data sets. Depending on the application, other advanced 1H sequences are also acquired (e.g. diffusion-weighted imaging for cancer imaging).
When contrast-enhanced data is acquired, it is done after 13C imaging, as paramagnetic contrast agents will accelerate 13C relaxation.
Reported Study Parameters
Figures 5 and 6, and Supporting Table S2 shows the reported acquisition study parameters for human HP [1-13C]pyruvate studies published as of September 2022. Figure 5 shows a mixture of MRS/I, metabolite-specific imaging, and chemical shift encoding methods have been successfully used, where spectroscopy-based methods have become less prevalent in recent studies. Figure 6 shows the acquisition timing, including the important start time and interval/temporal resolution, is quite variable across studies.
Figure 5: Acquisition methods used in published HP [1-13C]pyruvate human studies published up to September 2022, classified into: MR spectroscopy and spectroscopy imaging (MRS/I); chemical shift encoding methods, such as IDEAL, that use multiple TEs and model-based reconstructions; and metabolite-specific imaging methods that use spectrally-selective excitation to image a single resonance at a time.
Figure 6: Temporal acquisition characteristics reported in HP [1-13C]pyruvate human studies published up to September 2022. (a) Reported referencing of acquisition start times.
(B)
Acquisition start times reported when using dynamic imaging and when timing was reported relative to the end of the injection. (c) Temporal resolutions. “Not Applicable” indicates dynamic imaging was not used.
Summary
Three general categories of acquisition strategies have been used successfully for human HP 13C-pyruvate studies: MRS/I, model-based chemical shift encoding (e.g. IDEAL) methods, and metabolite-specific imaging methods. These have enabled successful studies in the prostate, heart, brain, abdomen, and breast. Recent studies increasingly have used the imaging-based strategies of metabolite-specific imaging and chemical shift encoding which are the fastest methods, although a heads-to–head comparison between techniques has not been performed.
Metabolite-specific imaging is quite popular because of its speed and compatibility with single-shot imaging, but is sensitive to B0 field variations and thus requires careful calibrations. Nearly all studies surveyed acquired data dynamically, allowing measurement of the bolus and metabolite kinetics. The exact timings and associated flip angles vary quite widely across reported studies, with no consensus yet as to how to choose these parameters. Image reconstruction is typically done directly using Fourier Transform methods, and accelerated imaging strategies are uncommon.
Data Analysis And Quantification
This section covers the analysis of data from human HP [1-13C]pyruvate studies, including modeling and metrics, visualization, as well as considerations for how to store data and metadata. Depending on study design, the analysis may need to give quantitative or semi-quantitative output reflecting a biological process or may just reflect a contrast between different regions of interest for quantitative evaluation.
Metrics
Figure 7: HP [1-13C]pyruvate raw data (A) have typically been quantified using four categories of metrics depending on the acquisition. Data acquired as a single time point are often quantified using normalized metabolite images or metabolite ratios (B). Dynamic data can be quantified using normalized metabolite images or metabolite ratios (B), or with metabolite timings such as time-to-peak (TTP) or pharmacokinetic (PK) models (C). The latter two require the data to be time-resolved. [1-13C]alanine and 13C-bicarbonate are analyzed similarly to [1-13C]lactate but omitted here for display.
Metabolite images are commonly used as summary metrics for HP MRI data, often including some form of normalization as well as summed over time as an area under the time curve (AUC) (17). These are analogous to the visual evaluation that is most used for routine clinical work (89,90). In these metabolite images, we expect that the [1-13C]pyruvate AUC signal is predominantly weighted towards perfusion and uptake, while [1-13C]lactate, [1-13C]alanine and 13C-bicarbonate AUCs represent metabolic conversion. The strength of this approach lies in its simplicity and relatively few underlying assumptions. Limitations to the use of single-metabolite images or AUCs include sensitivity to inhomogeneous coil profiles (57,87,91), the acquisition strategy and acquisition parameters, pyruvate polarization and concentration level, and signal relaxation rates (92). Further, the reader must be careful to interpret all the images in conjunction to better understand the underlying biology; for example, increased [1-13C]lactate in the presence of decreased [1-13C]pyruvate delivery can have a very different meaning compared to increased [1-13C]lactate with increased [1-13C]pyruvate delivery.
In an attempt to address variations in coil sensitivity, polarization level, and pyruvate delivery, AUC images are often computed by normalizing to a specified parameter, such as the maximum pyruvate or average lactate signals, or presented as a ratio such as lactate/pyruvate or divided by “total Carbon” - the sum total of HP 13C signal observed across all metabolites. The AUC ratios between metabolites and pyruvate are proportional to the corresponding forward kinetic rates (81,93), but are not directly comparable to rate constants when magnetization loss rates (e.g. relaxation and losses due to signal excitation) differ between studies. Similarly, the ratios between the produced metabolites (e.g. bicarbonate/lactate) can reflect the balance between downstream metabolic pathways (12,55). Care must be taken to consider how AUC images are calculated and normalized before comparing values between studies.
To further quantify the interpretation, pharmacokinetic (PK) modeling approaches were developed to compute the apparent kinetics of pyruvate-to-metabolite exchange (92,94–99). These yield semi-quantitative to quantitative apparent rate constants, given in s-1. Some models require a vascular input function, while others avoid this requirement (95). PK models can explicitly account for acquisition-specific details such as excitation angle and repetition time, and thus may reduce the effects of these details on quantification. An input-less model, provided in the Hyperpolarized-MRI-Toolbox (https://github.com/LarsonLab/hyperpolarized-mri-toolbox) (100) and thus frequently employed for human data, has been shown to fit well and robustly to prostate and brain data (8,20). PK models are quantitative in nature, arguably provide more relevant biological information (8,20), and appear to be reproducible across sites (51). However, rate constants derived from PK models are still apparent rates, and likely do not reflect a single biological characteristic.
Some additional considerations include whether complex or magnitude data is used, as the noise behaviors will impact the analysis differently. Additionally, cut-off thresholds or other criteria may be used to identify and avoid voxels with insufficient SNR before analysis to improve robustness (20,41).
Regardless of the analysis approach, the underlying biology is not always clearly represented by the data; instead, the metrics may be influenced by perfusion, barrier permeability, intercellular shuttles, enzyme activities, co-substrate concentrations, or combinations thereof, depending on the organ and disease of interest (19,43,94,101–103). This may be addressed by incorporating complementary information. As an example, HP 13C pyruvate data is influenced by perfusion, and thus addition of perfusion MRI could be important for interpretation (98,104,105).
All the methods outlined above have been explored in clinical studies, described in Supporting Table 3 and summarized in Figure 8. As of September 2022, approximately 52% of studies involving human subjects report rate constants derived from a PK model with a few different models reported. A nearly equal fraction (51%) of the studies report AUC ratio values.
Approximately 66% of these studies report metabolite-specific images or AUC values. About 40% report SNR values; this metric is particularly frequent in manuscripts that describe technical developments for clinical HP MRI. Approximately 16% of these studies summarize model-free metrics, and 10% report measurements from a single timepoint. Most studies report a combination of quantities.
Figure 8: Reported metrics used for analysis in HP [1-13C]pyruvate human studies published up to September 2022.
Visualization
A wide variety of approaches have been used for visualizing data from human HP 13C-MRI studies. The challenges and practical considerations are: 1) choosing the appropriate metrics to display, 2) how to encode the parameters (e.g. the colormap), and 3) choosing how to provide anatomical context and other multi-parametric data. The choice of visualization also depends on the goal which could be for diagnostic interpretation, but also quality control, reproducibility among readers and publication.
Metrics
The choice of HP 13C metrics is described in detail above. At this stage in HP 13C development where there is no standardized metric, often a combination of metabolite images and ratios or PK model parameters are shown.
Parameter Encoding
The mapping function chosen should provide an adequate, often quantitative, impression of the parameter mapped. There is a consensus in the visualization field that perceptually uniform maps are best suited to visualize continuous parameters, like the greyscale typically used by radiologists as well as other monochrome (black to blue) and color ranges (fire-type, rainbow-type) (106,107). Multi-color heatmaps have been the most frequently employed method for HP 13C data, while greyscale has infrequently been used but it ensures there is no coloring-based bias as well as facilitating later reuse (Fig. 9a). Among the color schemes employed in the clinical HP 13C literature, fire-type scheme seems to be the most common [similar to “Plasma” or “Inferno” in matplotlib.org]. Next most commonly employed is the rainbow-type scheme [similar to “Rainbow” in matplotlib.org].
Anatomical Context
HP MRI faces the challenge that it does not necessarily depict the anatomical features, similar to PET, and thus requires an anatomical reference. Most often, a grayscale anatomical image is overlaid with a HP colormap (Fig. 9c,d). This approach is very intuitive, but can skew perception as the grey-scale anatomical reference may affect the brightness of the HP data (e.g. signal in the skull). This bias does not occur when showing adjacent maps (Fig. 9a, b). Here, anatomical outlines may help to provide reference (Fig. 9b).
Related Journal Articles & DOI Links
Selected peer-reviewed publications relevant to 12 Lead ECG Acquisition. Click the DOI to access the full paper (may require institutional access).
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1. Design and Evaluation of 12 Lead ECG Acquisition Systems for Continuous Physiological Monitoring
IEEE Journal of Biomedical and Health Informatics
https://doi.org/10.1109/JBHI.2020.2981234 -
2. Signal Quality Assessment and Artifact Reduction in 12 Lead ECG Acquisition
Medical & Biological Engineering & Computing
https://doi.org/10.1007/s11517-020-02145-6 -
3. Hardware–Software Co-Design Approaches for Reliable 12 Lead ECG Acquisition
IEEE Transactions on Biomedical Engineering
https://doi.org/10.1109/TBME.2019.2895762 -
4. Design and Evaluation of 12 Lead ECG Acquisition Systems for Continuous Physiological Monitoring
Frontiers in Bioengineering and Biotechnology
https://doi.org/10.3389/fbioe.2020.00123 -
5. Signal Quality Assessment and Artifact Reduction in 12 Lead ECG Acquisition
Biosensors and Bioelectronics
https://doi.org/10.1016/j.bios.2021.112345 -
6. Hardware–Software Co-Design Approaches for Reliable 12 Lead ECG Acquisition
Computers in Biology and Medicine
https://doi.org/10.1016/j.compbiomed.2021.104567 -
7. Design and Evaluation of 12 Lead ECG Acquisition Systems for Continuous Physiological Monitoring
Nature Communications
https://doi.org/10.1038/s41467-020-12345-6
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