Injection Molding Composite Ansys

Abstract: Eliminating warpage in injection molded polymeric parts is one of the most important problems in the injection molding industry today. This situation is critical in geometries that are particularly susceptible to warping due to their geometric features, as occurs with topologies of great length and slenderness with high changes in thickness. These features are, in these special geometries, impossible to manufacture with traditional technologies meeting the dimensional and sustainable requirements of the industry. The paper presents an innovative green conformal cooling system that is specifically designed for parts with slender geometric shapes, highly susceptible to warping. Additionally, the work presented by the authors investigates the importance of using highly conductive inserts made of steel alloys in combination with the use of additively manufac- tured conformal channels in reducing influential parameters such as warpage, cooling time and residual stresses in the complex manufacturing of long and slender parts. The results for a real in- dustrial case study indicate that the use of conformal cooling layouts decreases cycle time by 175.1 s - 66% below the current cooling time, the temperature gradient by 78.5% specifically 18.16 ºC, the residual stress by 39.78 MPa or – 81.88 %, and the warpage by 6.9 mm or- 90.5%. In this way, it is possible to achieve a final warping in the complex geometry studied of 0.72 mm under the maxi- mum value required at the industrial level of 1 mm. The resulting values obtained by the researchers present a turning point from which the manufacturing and sustainability in injection molding of said plastic geometries is possible, taking into account that the geometric manufacturing features analyzed, will present a great demand in the coming years in the auto parts manufacturing industry Keywords: Conformal cooling; Green mold; Sustainability; Injection molding; Numerical simula-

Ntroduction

The plastic manufacturing process of injection molding is currently considered one of the most widely used plastic transformation technologies worldwide . It is estimated that 70% of consumer products incorporate components manufactured with this produc- tion process . The global scope of the plastic injection molded market was estimated at USD 265.1 billion in the year 2020, expected to grow annually by 4.6% between 2021 and 2028.

Although the demand for plastic components comes from various industrial fields such as packaging, electrical, electronic products, and medical devices, the automotive industry is one of the areas that produce the largest number of plastic parts, with a de- mand valued at 45,000 million in 2020 estimating the growth of up to 65 million USD in

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2027 mainly in Europe and China . The automobile requires the design of multiple plas- tic parts such as wheel covers, casings, interior parts, complex optical parts, etc. This fact causes manufacturers to increase the use of injection molded parts due to their recyclabil- ity, durability, vibration control, strength, etc .

The threat of climate change is high on international, European, and national political agendas . The commitments set out in the Paris Agreement set the baseline for cost- effective greenhouse gas emission reductions. To achieve climate neutrality in 2050, the EU raises the need to decarbonize the industry by increasing its competitiveness, demand- ing that technological products and processes be climate neutral . The injection mold- ing technology, processes around 117 million tons of thermoplastics worldwide every year, estimating the use of electricity in injection machines at approximately 105,109 Kw.h.

resulting in 80 million metric tons of CO2 emissions per year . Technologically, plastic injection molding is based on the process of melting and sub- sequent solidification of the plastic material that has been injected at high pressure and temperature into the mold cavity . Among the stages of the molding cycle, the cool- ing phase is the one with the highest energy and time consumption, being around 70% of the total cycle manufacturing time . In a conventional molding process, water, act- ing as a coolant, flows continuously through a set of channels in the mold, starting the solidification process of the injected melt when it comes into contact with the surface of the cavity at a lower temperature .

Decreasing the molding cycle time is a key factor in improving energy efficiency and the sustainability of the process . From the perspective of increasing productivity, an efficient cooling design is critical, since the cooling phase takes up a large part of the cycle time. Designing adaptative channel geometries capable of maintaining a constant distance between the part surface and the cooling channels, even in those difficult areas where material accumulation occurs, can dramatically decrease cooling time and increase the uniformity of temperatures at the surface of the molded part . In the same way, a uniform distribution of temperatures on the surface of the part helps not only to reduce the cooling time but also to improve the quality of the part in terms of metrology . An unbalanced temperature map can cause warpage in the plastic part and result in the re- jection of manufactured parts, which goes against the industrial sustainability criteria cur- rently required .

In industrial practice, the warpage of molded parts is an even bigger problem than shrinkage. Warpage is a consequence of unequal shrinkage values . The injection molding process significantly affects the warping phenomenon in the geometry obtained due to non-uniformities in the mold wall . Particularly of the parameters of manufac- turing by molding, the surface temperature of the mold is the most important in the phys- ical phenomenon of warping . The differential cooling of the part occurs when the surfaces are at different temperatures, specifically in the hot spots of the mold, such as core pins, corners, thick areas, gates, etc. Hot spots cause problems by adding extra crys- tallinity to the material and prolonging the part's cooling time so that the area that cools the longest, shrinks the most .

The cooling of the mold in the traditional way is achieved by making straight chan- nels in both cavities of the mold. Despite the economic manufacture of this type of chan- nels, they are not useful in the uniform cooling of parts with complex geometry. The dif- ficulty in establishing a uniform distance between the channel and the topology of the piece prevents this length from being kept constant, preventing the uniformity of temper- atures on the surface of the piece and increasing the number of rejections in production.

Additive manufacturing processes allow the manufacture of cooling channels following the contour of the part , giving design flexibility. Regarding the sustainability of the production process, additive manufacturing allows the use of shorter supply chains, as well as more efficient use of manufacturing materials. Likewise, conformal cooling chan- nels reduce cycle time and energy consumption, making them green channels. Compared

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to traditional cooling channels, the use of conformal cooling channels decreases the cool- ing time to a maximal range of 15 to 50%. Beard et al. decreased the cooling cycle time in a range of 20 to 40%. Torres et al. reduce cycle time by 13% in very complex optical parts with a high thickness ratio. Sayfullah and Masood reduced the total cycle time by 35% as well as the maximum temperature by 30%, improving the differential shrinkage and therefore its warpage. Mazur et al. obtained improvements of 5º C in the maxi- mum temperature, improving the shrinkage of the part as well as its warpage and Smidt et al. improved the cooling time by 32.7% reducing the warpage by 28.2%.

Given the high influence of conformal cooling channels in reducing cycle time and improving part uniformity, different applications and designs have been proposed. Con- cerning the geometry of the layout, the spiral layout is one of the most used . Unfor- tunately, these channels present sudden turns, increasing the pressure drop and slowing down the flow, weakening the effectiveness of the cooling process. To avoid these prob- lems, other authors use layouts whose axes follow a zigzag design. For highly complex geometries, it is possible to use cross-linked channel designs , porous , lattice or vascularized topologies. However, all these geometries have the problem of requiring a connection between channels, so in the event of an obstruction caused by foreign elements, it could not be easily removed from the layout. Another way to cool complex cores is the use of inserts made of high thermal conductive materials such as high conductive steel alloys. The high thermal conductivity of these materials helps in the process of reducing the cycle time while maintaining the corrosion and oxidation re- sistance of the mold .

Reducing the warpage of a plastic part to a minimum value is a highly significant factor, especially for complex optical parts where dimensional accuracy affects the func- tionality of the vehicle . The current designs demanded in the industry and espe- cially in the automotive sector, increasingly complicate the manufacturing process by molding. The trends place more and more emphasis on the development of the visual or aesthetic appearance of the vehicle, complicating the functional aspect of the molded parts. This fact increases if we take into account that, in addition to style, some of these pieces have to fulfill an optical function at the level of lighting or light signalling by the standards. The style implemented today in the automotive industry highlights futuristic concepts characterized by large-format stylized details that incorporate new technologies such as LEDs. These technologies require a marked precision in the dimensional aspect of the pieces, so it is necessary to look for designs that improve the current conception of the injection molding process. The procedures and tools used to date do not guarantee an optimal result in terms of the aesthetic or functional aspect of the piece, as well as of the manufacturing process that makes the activity competitive.

The use of long plastic parts with geometric slenderness including areas with large thickness ratios is becoming more and more common in the automotive field and more specifically in the area of optical plastic parts using LED technology. The upcoming lines of aesthetics and functionality that will come in the coming years for the car demand a type of lighting not only external but also internal to the vehicle. These optical plastic parts require high aesthetic and dimensional specifications, being also characterized by a great length and slenderness. These geometries cannot be manufactured with quality using the current means of production. To avoid these problems, the use of conformal cooling lay- outs together with high thermal conductivity materials can help to obtain a uniform and balanced temperature map in these complex parts. Unfortunately, currently, the applica- tion of green conformal cooling channels for the cooling of injection molds is a complex procedure from the initial design to the final manufacturing process of the mold. Despite previous literature and relevant review articles, unfortunately, there are still significant gaps in the research and application of conformal cooling layouts .

To avoid the problems raised so far, the paper proposes a new industrially sustaina- ble conformal cooling system that can reduce cycle times, longitudinal warpage, and re-

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sidual stresses in the manufacturing of highly complex injection molded parts, character- ized by their great length and slenderness as well as thick points. Research has not yet been conducted at a scientific or industrial level on the application of conformal layouts to the manufacture of this type of plastic geometry that is impossible to manufacture meet- ing the industry's requirements using traditional methods. The results obtained by the authors mark a turning point in the manufacture by molding of this type of topology, given that the geometric manufacturing features studied in the paper will present a very high demand in the coming years in the automotive industry . The research results obtained show that the use of conformal cooling layouts in the cooling of injection molds makes it possible to manufacture parts following the high dimensional requirements de- manded by current industries. Finally, the results presented by the authors are fully in line with the sustainability and energy-saving criteria demanded by the European Union and the rest of the world in terms of the manufacture of industrial plastic parts.

Aterials And Methods

2.1 Geometric analysis and functional description of the plastic part manufactured via injection

Molding

The analysis and determination of the geometric, technological, and functional re- quirements of the plastic part directly influence the process of geometric design and di- mensioning of the main elements that make up the mechanical systems of the injection mold. Likewise, geometric aspects such as the complexity of the surfaces, the distribution of the thickness map, general dimensions, and geometric tolerances, not only determine the final configuration of the injection mold but also establish the technological parame- ters that control its correct manufacturing process. That is why, in this section, the main geometric features and parameters of the plastic part under study are described in detail, as well as the definition of its main application and functional requirements.

The plastic part object of study is defined as a chimsel. As shown in Fig. 1, this real case study is an industrial part belonging to a LED - collimator lighting system, used in the automotive industry. The main function of this optical part is to collect the light com- ing from the LEDs using several collimating elements (see Fig. 1) and project it onto a light output surface, geometrically composed of a large number of small squares with closed angles "Pillows" in charge of distributing the light according to the desired purpose (see Fig. 1). In this way, the light generated by the LED lighting elements is directed along the plastic part according to the functionality and standards established by the automotive industry.

Fig. 1 Description of the plastic part for lighting application case study It should be noted that, as it is an optical part, the dimensional tolerances required to meet the requirements and standards of functionality and optical criteria are more de- manding, relevant, and significant than for any other plastic part. In general, the final or resulting dimensional tolerances in plastic geometries are closely related to the design of the main components of the injection mold. This is especially true for the elements that

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make up the cooling system. Similarly, it is equally pertinent to establish the technological parameters that define the cooling phase within the cycle of manufacturing the plastic part. After manufacturing, warping can be generated due to physical concepts related to the cooling phase, including distribution of the cooling temperature gradients on the sur- face of the plastic part, residual stresses caused by a nonuniform cooling temperature, and the associated unbalanced volumetric shrinkage of the thermoplastic material. Therefore, an optimal design and dimensioning would favor the reduction of the final warpage of the plastic part, and therefore, achieve its functional requirements.

During the cooling phase, the most relevant features and geometric parameters are the thickness map and the main part dimensions (width, length, height), see Fig. 2 and Fig. 3, being the resulting variables the time needed until reaching the ejection tempera- ture, the distribution of volumetric shrinkage, and the warpage after the cooling phase.

These parameters mainly determine the economic viability, the efficiency, and sustaina- bility of the manufacturing process as well as the compliance with the dimensional toler- ances and the functional requirements of the plastic part. Table 1 shows the magnitude of the main geometric parameters of the plastic part under study.

Fig. 2 Thickness map distribution of the plastic part

[Mm]

As can be seen in Table 1 and Fig. 3, the plastic part has a particular topology, fea- tures, and geometric parameters, which differ from the usual standards in the plastics industry. The nominal length of the plastic part is 630 mm. The difference between the average and maximum thickness is 5.5 mm. This thickness variation is given by the need to include an upper wing and several collimating elements, to project and direct the light beam coming from the LEDs towards the pillow elements (see Fig. 1). The part is made up of a set of reinforcing elements of variable dimensions that greatly increase the thick- ness of the part in its lower area, making it difficult to manufacture. These features and geometric parameters directly affect the design and manufacture of the main elements of the cooling system and its functionality.

Fig. 3 Plastic Part Main Dimensions

2.2.- Theoretical background and analytical study of the cooling phase The analytical study of the cooling phase of the plastic part under study focuses on the analysis of two technological parameters: time to reach the ejection temperature and longitudinal warpage. On the one hand, the evaluation of the current time that elapses until the plastic part reaches the ejection temperature facilitates the evaluation of the ther- mal performance associated with the design of the cooling system and the cooling phase of the plastic part. Meanwhile, the longitudinal warpage in a plastic part after cooling determines its compliance with dimensional tolerances and its functional requirements.

- Time To Reach The Ejection Temperature

The manufacturing cycle of the plastic part is determined by different technological phases: filling, packing, cooling, and ejection. Among all of them, the cooling phase is the most important in the thermoplastic injection molding process representing more than 70% of the total time invested in the manufacturing cycle and the one with the greatest influence on energy consumption. The cooling phase begins with the solidification of the gate. This is followed by the solidification of the molten plastic front, which has completed the mold cavity, cooling down until it reaches a sufficient and suitable temperature to go on to the ejection phase. The physical model used to determine the cooling time is estab- lished from the heat exchange by conduction that occurs between the thermoplastic ma- terial and the coolant flow. Consequently, the hypothesis is established that the thermal exchange by convection and radiation between the main elements of the injection mold and the external environment is neglected, as this represents less than 5% of the total heat exchange. The heat flow by conduction is defined, according to Eq. 1, using Fourier's dif- ferential equation, reduced to one dimension. Although this thermal analysis can be ap- plied to the three main directions of space, the heat exchange flow between the thermo- plastic material and the coolant flow is carried out in only one direction, the main direction of the thickness so the unidirectional approach of the analysis is valid . In this way, the one-dimensional heat flow or Fourier equation reduced to one dimension can be ex-

(1)

Being αp [m2/s] the coefficient for the thermal diffusivity of the mold material, taking into account that after the filling of the mold the temperature of the molten plastic is con- stant, while the temperature of the surface of the mold changes until it reaches a value stationary. For these conditions, a solution of a particular type can be found (see Eq. 2) for Eq. 1.

At a belonging point to the mold cavity it is possible to analyze the temperature of the molten plastic through the convergence of the Fourier series as indicated in equation 1.

(2)

Solving Eq. 2 concerning the cooling time variable, the expression that determines the cooling time tcooling is defined in Eq. 3.

(3)

Where Tp [m] represents the maximum thickness of the plastic part, Tmelt [ºC] repre- sents the temperature of the molten plastic front, Tmold [ºC] represents the surface temper- ature of the injection mold cavity and Teject [ºC] represents the recommended ejection tem- perature for the thermoplastic material (see Fig. 4).

Also, it should be noted that the boundary conditions established to define Eq.3 are that the thickness of the plastic part is much less than the rest of its dimensions and that the direction of the heat flow, which is exchanged between the plastic part and the coolant, is perpendicular to the melt plastic flow direction .

Secondly, the magnitude of the main thermal variables that define Eq. 3 are estab- lished and recommended by the manufacturer or supplier of the thermoplastic material. Also, Eq. 3, determined by a physical model, establishes an analytical and approximate cooling time. Well, in practice, the cooling time can be substantially longer if the mold maker considers that the plastic part requires more cooling time to achieve the required functional specifications and geometric tolerances. In addition, the definition of the mag- nitude of the surface temperature of the mold cavity Tmold [ºC] (see Eq. 3) depends directly on the design and dimensioning of the main elements that make up the injection mold cooling system. Therefore, an optimized design adjusted to the features and geometric properties of the plastic part can significantly reduce the result of the cooling time, im- proving the sustainability of the process.

Fig. 4 Thermal variables representation of the physical model

- Warpage Analysis Process

The warpage map generated on the plastic part is a result of its manufacturing pro- cess. This map defines the final quality of the part, according to its functional requirements and geometric tolerances. In general, the warpage map is related to the volumetric shrink- age that it undergoes during the different phases of the plastic injection cycle. In particu- lar, the main physical effect that generates volumetric shrinkage in the plastic part is the pressure and temperature gradients that develop along its surface, especially after the cooling phase.

According to the differential volumetric shrinkage, caused by temperature gra- dients and stresses along with the geometry of the plastic part, cause longitudinal warp- age outside its main plane (see Fig. 5) and can be expressed according to Eq. 4.

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Fig. 5 Warpage due to differential shrinkage of temperature gradient

(4)

Where W [m] represents the separation distance between the center of the plastic part and its outer contour, Sedge represents the percentage of linear shrinkage that is obtained along the outer contour of the plastic part, and Scenter represents the percentage of linear shrinkage obtained in the central region of the plastic piece. Likewise, the volumetric shrinkage parameter is defined from the linear shrinkage experienced by the thermo- plastic material in the three main directions of the space. In this way, if the hypothesis is established in which the thermoplastic material is considered to be isotropic, the linear shrinkage that it experiences in the three main directions of space is the same.

And, therefore, the linear shrinkage experienced by the thermoplastic material can be expressed as a function of the magnitude of volumetric shrinkage, according to Eq. 5.

(5)

Where S represents the percentage of linear shrinkage of the thermoplastic material and rv represents the percentage of volumetric shrinkage of the thermoplastic material. Finally, to complete the analytical study that determines the longitudinal warpages of the plastic part, Tait's double domain equations are used, which characterize the compressi- bility behavior of the thermoplastic material. From this analytical model, and as shown in Eq. 6, the specific volumes of the thermoplastic material can be defined from its tempera- ture and pressure.

(6)

Where υ0 [m3/kg] represents the reference specific volume of the thermoplastic mate- rial for the analyzed temperature, β [Pa] represents the compressibility of the thermo- plastic material for the analyzed temperature, and P [Pa] the analysis pressure of the ther- moplastic material. Furthermore, this set of variables can be expressed according to Eq. 7 and Eq. 8.

(8)

Where b1 [m3/kg], b2 [m3/kg], b3 [Pa], b4 [1/K] and b5 [K] are technological parameters specific to the thermoplastic material, provided by its manufacturer and supplier. Finally, to define the longitudinal shrinkage (see Eq. 4) suffered by the plastic part, both in its

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outer contour and in its central region, the percentage of volumetric shrinkage of the ther- moplastic material (see Eq. 5) is defined according to Eq. 9. All these requirements, for temperature and pressure conditions between the instant before the beginning of the cool- ing phase, and the end of the manufacturing process.

- Materials

In this item, we proceed to define the features and properties of the materials used during the research work both for the main elements that make up the injection mold and for the thermoplastic material of the part under study. In this case, the polymer family used to manufacture the plastic geometry is Polymethyl methacrylate (PMMA). This pol- ymer is a highly transparent thermoplastic that is established by the polymerization of the methylmethacrylate monomer. In this way, thanks to its optical and aesthetic features and its high surface strength, this thermoplastic material is used as a lightweight alternative to glass and polycarbonate (PC) when greater transparency, and strength to ultraviolet rays, and high mechanical performance against impacts are required. For this reason, the field of application of this thermoplastic material focuses on the automotive sector, espe- cially for the manufacture of lighting components included in vehicle headlights. In par- ticular, the trade name of the thermoplastic material used is Plexiglas 8N . According to the physical models analyzed in this manuscript, Table 2 shows the mechanical, ther- mal, and rheological properties of this thermoplastic material according to the infor- mation provided by the supplier and manufacturer.

Table. 2 Magnitude of the main properties of the material Plexiglas 8N

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Likewise, it should be noted that the manufacturing material can be subjected to a chemical recycling process. In other words, this material, in addition to encountering the requirements and specifications of the plastic part, is recyclable and maintains its original mechanical, thermal, and chemical properties without compromising the sustainability of the manufacturing process.

On the other hand, metallic materials have been defined as the main elements that called 1.2709 has been used. The selection of this metallic material is justified due to the need to use a 3D additive manufacturing process, based on laser sintering (SLS) technol- ogy, which allows the optical fabrication of green conformal cooling channels. In addition, to optimize the cooling of the plastic part under study, it is proposed to use a high con- ductive steel alloy – 50 at 44 HRC material for the auxiliary elements of the cooling system . The high thermal capacities and performance of this material, together with the loca- tion and design of the auxiliary cooling elements, optimize the exchange thermical be- tween part and mold. Especially, in those areas where the effectiveness of the cooling channels decreases and the temperature gradients are greater. Table 3 and Table 4 present several properties of the metallic materials used. The materials properties have been pro- vided by the plastic suppliers.

Table. 3 Thermal, physical and mechanical properties of Steel alloy 1.2709

W/M·K

Table. 4 Thermal, physical and mechanical properties of Fastcool – 50 at 44 HRC

- Cooling Channels Design

In this section, it is described the design of the devices and channels of the traditional cooling layout that is currently used for the industrial optical part under study. They have

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also presented the proposals for channels and elements of the cooling layout, based on the concept of green conformal cooling channels (GCCC) and Fastcool inserts, which allow the optimization of the cooling phase and the technological parameters and sustainability- related to the manufacture of the complex part.

In the first place, the geometry and topology of the part have a direct influence on the main parameters of the process using injection molds, such as cycle time, the temper- ature map of the plastic part, the map of longitudinal warpage and residual stresses of the plastic part after the cooling phase, the thermal performance of the cooling system and the uniformity in the thermal exchange between the plastic part and the coolant flow. So, these parameters have great relevance to the surface and dimensional quality of the plastic part and in the energy required for its manufacturing. As shown in Table 1 and Fig. 2, the plastic piece under study has a maximum thickness in the collimator area of 9.6 mm, while the average thickness in the rest of the geometry is equal to 4.1 mm. That is, the thickness ratio is equal to 2.34:1. Therefore, the manufacture of a plastic part with this thickness variation is a challenge since, as the dimensions and thickness gradients in the plastic part increase, the residual stresses, and longitudinal warpage increase similarly. In addition, the area of the part with greater thickness presents an increase in the accumulation of heat due to a slower cooling process. This variation in the temperature of the part generates an increase in the cooling time and, consequently, a non-uniform shrinkage process. Like- wise, the topology of the plastic piece makes it difficult for the cooling channels to access the pillow region (see Fig. 1) due to the reduced dimensions of the pillows. The use of traditional cooling channels in this area reduces the thermal exchange between the plastic material and the coolant flow, as well as their thermal performance.

On the other hand, the geometric design of the cooling system also determines the thermal and energy performance of the cooling phase of the plastic part. In particular, as shown in Fig. 6, the plastic part has a traditional injection mold design based on straight drilled channels. This traditional design must meet dimensional requirements that guar- antee the structural integrity of the different elements and systems that make up the in- jection mold. These requirements are the distance between cooling channels, the distance between cooling channels and elements of the ejection system, and the distance between cooling channels and the surface of the mold cavity. The diameter of the cooling channels is 8 mm. The separation distance between the cooling channels themselves and the surface of the injection mold cavity or any other element thereof is 16 mm, that is, twice the value of the diameter of the cooling channels. In this way, the sizing and structural integrity criteria established by the industry are met, with the minimum safety distance between elements of the injection mold always greater than 10 mm. Fig. 6 and Table 5 show the traditional design and magnitude of the geometric variables of the cooling system, for the two cavities of the injection mold, whose manufacture is carried out using computerized numerical control (CNC) techniques.

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Table. 5 Geometric variables of the traditional cooling system design

Mm

Starting from the design and configuration of the straight drilled channels defined for the current cooling system of the plastic part under study and, taking into account the thermal and rheological properties of the thermoplastic material associated with it, using Eq. 3 and Eq. 4, a predictive analytical calculation can be made of the maximum longitu- dinal warpage obtained after the cooling phase and the total time that elapses during the cooling phase. Table 6 shows the results obtained for said analytical calculation.

Table. 6 Results obtained from the cooling phase analytical model for the cooling system traditional

S

As can be seen, the analytical results (see Table 6) show that the plastic part under study warps longitudinally by 7.1 mm with a time of the cooling phase equal to 271.5 s, with a traditional cooling system. These analytical results do not meet the functional re- quirements and geometric and dimensional tolerances established in the industrial sector tor, the maximum longitudinal warpage should not exceed 1 mm. Likewise, the resulting cooling time is very long, which implies an increase in cost and energy expenditure asso- ciated with the manufacturing process and is contrary to sustainable manufacturing.

Therefore, the traditional tools, designs, and technologies for the manufacture and design of the injection mold cooling system are limited and sometimes do not allow the functional requirements and tolerances established by the industrial sector to be met. For this reason, in this manuscript, a new design of conformal cooling channels adapted to the geometry of the plastic part along with the use of auxiliary cooling elements such as Fastcool inserts and the application of new SLS 3D additive manufacturing techniques aim to optimize the cooling phase and the final quality of the plastic part, allowing the functional require- ments and tolerances established for the plastic part under study to be achieved.

- Green Conformal Cooling Channels Design

The design of the main elements that make up the cooling system of an injection mold focuses on optimizing the dissipation of the heat flow from the plastic part in a uniform manner and in the shortest possible time until it reaches the temperature of ejection. How- ever, this process presents great difficulties and inconveniences in plastic parts with com- plex surfaces, whose geometric and technological requirements, such as the case study, The conformal cooling channels allow these drawbacks to be solved since they are capable of optimizing the free volume between elements of the injection mold and, thanks to their SLS additive manufacturing process, reducing the distance between the cooling channels and the surface of the plastic part, mainly in geometric areas of difficult access.

Likewise, in this manuscript, to improve this problem, a novel design of conformal cooling channels is proposed (see Fig. 7), with a circular section, whose geometric arrangement

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allows traversing the upper and lower region of the plastic piece, as well as the area con- cave generated by the support to place the pillows in the correct position to project the light coming from the collimators. On the other hand, although the application of confor- mal channels for this geometric area is appropriate, sometimes the separation between the channels and the surface of the mold cavity is not enough to dissipate all the heat flow from this region uniformly. As a solution to this design problem, the use of Fastcool inserts in combination with the use of conformal channels is proposed (see Fig. 8 and Fig. 9).

Fastcool inserts are characterized by being associated with a metallic material with a high thermal transmission coefficient, which favors heat exchange in areas of the plastic part where high temperature gradients accumulate. However, during the cooling phase, the Fastcool insert exchanges a large amount of heat flow that it is not able to dissipate on its own. The use of conformal cooling channels, in these cases, can be very useful, not so much to directly cool the plastic part but to cool the Fastcool insert itself.

In this way, to evaluate the thermal performance of the application of conformal cool- ing channels and Fastcool inserts, three different cooling system designs are proposed. A design defined solely by conformal cooling channels, (see Fig. 7) and two hybrid designs that combine conformal cooling channels and Fastcool inserts of different lengths, see Fig.

8 and Fig. 9. Table 7 shows the geometric features of the cooling elements used in the proposed cooling system designs. It should be noted that the geometric parameters that define the proposed cooling systems, conformal and hybrid, have been optimized and adapted to the requirements presented by its own 3D SLS additive manufacturing pro- cess, the geometric features of the plastic part under study and the own complexity of the real injection mold with which the present case study is manufactured.

Fig. 7 Conformal Cooling Channels Design

Fig. 8 Hybrid cooling system design, Fastcool full bars

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).

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