SOT-MTJ device parameters.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"5768",leadTitle:null,fullTitle:"Desalination",title:"Desalination",subtitle:null,reviewType:"peer-reviewed",abstract:"Increasing population and environmental pollution are the main stress on freshwater sources. 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",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"ff43b37dcacf578f87ca22d5a292e7af",bookSignature:"Dr. Hazem Orabi",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/6773.jpg",keywords:"Urethroplasty, Wound healing in urology, Intestine replacement, Grafts in urology, Tissue engineering, Scaffolds, Growth factors, Peyronie disease, Urethral stricture, Ureteral replacement, Cystoplasty, Stem cells induced-wound remodeling, Urethral injuries, Pyeloplasty",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 23rd 2017",dateEndSecondStepPublish:"December 14th 2017",dateEndThirdStepPublish:"February 12th 2018",dateEndFourthStepPublish:"May 3rd 2018",dateEndFifthStepPublish:"July 2nd 2018",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"173149",title:"Dr.",name:"Hazem",middleName:null,surname:"Orabi",slug:"hazem-orabi",fullName:"Hazem Orabi",profilePictureURL:"https://mts.intechopen.com/storage/users/173149/images/6420_n.jpg",biography:"Dr. Hazem Orabi is the Associate Professor of Urology at Assiut University, Egypt and a postdoctoral researcher at the University of Laval, Canada. He received his MD degree and after a urology residency training was appointed as tenured track urologist at Assiut University Hospital in 2001. In 2005, he was awarded a research scholarship with Prof. Dr. Anthony Atala at Wake Forest University, Urology Department and Institute for Regenerative Medicine, North Carolina, USA, which is also where he earned his Ph.D. degree in 2008. In 2010, he received the UCSF-SIU Fellowship with Prof. Tom F. Lue and Prof. Emil Tanagho at the University of California, San Francisco, USA. In Canada, he has worked as a postdoctoral researcher in LOEX, Quebec followed by a reconstructive urology training program which lasted for 6 months at the University of Alberta, Canada with Dr. Keith Rourke. Lastly, was also a GURS fellow with Prof. Dr. Sanjay Kulkarni in Reconstructive Urology in India.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"192910",firstName:"Romina",lastName:"Skomersic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/192910/images/4743_n.jpg",email:"romina.s@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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The expected large number of the IoT nodes forces the limitation of their power budget [1]. In particular, for the majority of the IoT nodes that are powered by energy harvesters, their anticipated power budget can be as small as sub μWatt [1]. Thus, employing nonvolatile (NV) memory in these nodes would aid in reducing their power consumption. This is because leakage power constitutes a significant percentage of the total power consumed due to the long idle durations. Hence, the memory can be power gated, thanks to its nonvolatility, and consequently eliminates its leakage contribution. In addition, IoT nodes powered by energy harvesters may suffer from multiple durations of power discontinuities as a result of using the unreliable power source. Therefore, having NV memory aids to continue the computation from where it’s stopped without restarting every single operation once the power goes down [2], which aids in increasing the overall performance as well. Furthermore, the different modules on these nodes need to be area efficient. Area efficiency aids in decreasing the overall parasitic contribution, which enhances the performance and energy efficiency. More importantly, the smaller the silicon area consumed by the IoT node, the lower the overall cost. The cost is an important metric for the success of a specific IoT design as it is targeted to have these IoT chips with prices as low as 50 cents. Thus, a combination of improved technologies and circuits is needed to achieve energy- and area-efficient designs.
\nEmerging devices such as a magnetic tunnel junction (MTJ) may be used to implement a nonvolatile memory, which would be called magnetic random-access memory (MRAM). An MTJ, highlighted in Figure 1, comprises two ferromagnetic (FM) layers separated by a tunneling oxide barrier. One FM layer has a pinned magnetization (i.e. pinned layer (PL)), while the other has a free magnetization (M\nF) (i.e. free layer (FL)). Manipulating the direction of the FL to be either parallel (P) or anti-parallel (AP) to the PL magnetization direction determines the electrical resistance state of the MTJ to be either low resistance (R\nP) or high resistance (R\nAP), respectively. An MTJ offers different benefits like nonvolatility, programmability, high endurance, long state retention time and compatibility with CMOS fabrication flow. Consequently, the MRAM inherits the MTJ advantages, which makes MRAM a standout solution to implement a nonvolatile memory that is suitable to replace or co-exist with these leaky charge-based memories in both on-chip and off-chip memory.
\n(a) Two-terminal MTJ with two magnetization configurations reflects two resistance states depending on the write current direction if STT technology is used. (b) Three terminal SOT-MTJ.
The MRAM can be classified based on the writing technique employed to switch the MTJ resistance state. These techniques, such as field-induced magnetization reversal (FIM) [3], spin-transfer torque (STT) [4, 5], voltage-controlled magnetic anisotropy (VCMA) [6] and spin-orbit torque (SOT) [7, 8, 9, 10, 11], result in the different corresponding MRAM types like FIM MRAM, STT MRAM, VCMA MRAM, and SOT MRAM, respectively. FIM requires applying an external magnetic field to program the MTJ, which hinders its scalability and increases its energy consumption, while STT, VCMA, and SOT are known to be highly scalable [9]. STT programming has a common current path for both writing and reading the MTJ, whereby the write current (I\nwrite) must flow through the MTJ directly. This results in higher writing voltage requirements, due to the MTJ high resistance, and device reliability degradation. Similarly, VCMA demands voltage application across the MTJ, which subjects it to reliability issues such as tunnel barrier breakdown. The FIM, STT, and VCMA technologies use the MTJ device independently in its two-terminal form, shown in Figure 1(a). On the other hand, the SOT technology requires placing the MTJ over a heavy metal (HM) electrode from the FL side, which results in a three-terminal device as depicted in Figure 1(b). In SOT technology, a charge current passes through the HM electrode that in return results in spin accumulation in the FL of the MTJ due to the spin-orbit interaction, which assists in the reversal of the FL magnetization to either P or AP state depending on the current direction relative to the FL easy axis. Thus, SOT programming solves the aforementioned issues [9]. Firstly, it features high energy efficiency due to its low critical current requirements and fast switching speed. In particular, due to the SOT-MRAM high switching speed (i.e. high performance) that can be down to 100 s of ps [12, 13], in addition to its nonvolatility and smaller cell area, it becomes more appealing to replace SRAM in cache memory applications. Secondly, the I\nwrite flows through the low resistance heavy metal (HM) rather than the MTJ. This improves the device reliability, permits the usage of smaller write voltages, and increases the voltage headroom margin for the write transistor, which relaxes the current source design. Finally, the write and read paths are separated, which leads to a more optimized design as it permits satisfying the contradictory requirements for the access transistors sizing in both read and write modes. In the write mode, larger access transistor is required to supply higher I\nwrite (at least larger than SOT-MTJ critical switching current), whereas in the read mode, smaller access transistor is required to reduce the read current to avoid read disturbances. Consequently, SOT-MRAM is considered as the most promising MRAM to realize reliable, high speed, and energy-efficient on-chip memory [14, 15].
\nHowever, the separation of the read and write paths comes with a penalty of requiring two access transistors per cell to fully isolate both paths of the nonselected cells in the conventional approach of implementing the SOT-MRAM, presented in Figure 2(a). This increases the 1-bit effective area of the conventional SOT-MRAM, which limits its use in high-density memories. Thus, various SOT-MRAM cell designs in the literature have been proposed to improve the area efficiency of the SOT-MRAM. In this chapter, these proposals in the literature are going to be presented, highlighting the advantages and disadvantages of each design. The various proposals are divided into two main categories, which are diode-based and non-diode-based SOT-MRAM. Moreover, the technology requirements to realize these proposals are discussed. Finally, the proposals are evaluated from both cell and system level perspectives.
\nVarious SOT-MRAM proposals in the literature. (a) Conventional SOT-MRAM [15], (b) Schottky diode-based SLC SOT-MRAM [14], (c) P-MLC [15], and (d) S-MLC [15].
The chapter is organized as follows: Section 2 presented the nondiode-based SOT-MRAM proposals discussing their operation, pros, and cons. Similarly, the operation, pros, and cons of the various diode-based SOT-MRAMs are illustrated in Section 3. Section 4 evaluates the various diode and non-diode-based SOT-MRAM proposals from both cell and system-level perspectives. Finally, Section 5 provides the concluding remarks.
\nIn this section, the various SOT-MRAM proposals in the literature that do not require employing a diode (or selector) in the cell are presented. Nondiode based SOT-MRAM cells only rely on access transistors for current flow control. Avoiding using diodes offer an advantage of a simpler fabrication process and may achieve higher energy efficiency as lower read voltages may be applied. The nondiode-based SOT-MRAMs in the literature include the conventional single-level cell (SLC) SOT-MRAM, as shown in Figure 2(a), and two multi-level cell (MLC) proposals depicted in Figure 2(c) and (d).
\nThe conventional SOT-MRAM, depicted in Figure 2(a), as discussed in various works [14, 15] requires two transistors to access one bit per cell. One of the transistors is used to control the write current flow (i.e. write Tx shown in Figure 2(a)) and the second transistor is required to control the read current flow (i.e. read transistor). The two transistors are essential to fully isolate the nonselected bits to avoid nonintentional read and write of these bits when not selected. Furthermore, the existence of a single MTJ per heavy metal (HM) electrode to be programmed for each cell write operation maintains the high energy efficiency of SOT technology. In addition, the single-level cell sensing scheme for this cell enhances the distinguishability, bit error rate (BER), and read energy consumption. Consequently, the conventional SLC SOT-MRAM design, shown in Figure 2(a), represents the baseline of the energy consumption for the SOT-MRAM. However, the usage of two transistors to access a single bit increases the 1-bit effective area significantly, which is estimated to be 69F\n2 using the design rules in [16] that is used in the area estimation throughout this chapter. This limits the application of the conventional SOT-MRAM as it will not be suitable for high-density memory applications. Thus, further SOT-MRAM cells are proposed in the literature to reduce the 1-bit effective area with an expected penalty in the various performance and energy metrics of the SOT-MRAM as discussed in the following sections.
\nKim et al. [15] proposed to employ a multi-level cell (MLC) SOT-MRAM instead of the single-level cell (SLC) SOT-MRAM to reduce the 1-bit effective area. In the MLC memory, each cell comprises two bits (i.e. two MTJs exists per cell) instead of only 1-bit (1 MTJ) in the SLC. This means that the two MTJ resistance combinations should represent four different resistance states instead of only two resistance states in the SLC. In this MLC design, the two bits are accessed by two transistors (i.e. effectively one transistor per bit), which results in an approximately 50% smaller 1-bit effective area compared to conventional SLC SOT-MRAM. However, there is still a margin to improve the 1-bit effective area than their estimated value of 34.5F\n2, using the design rules in [16], as illustrated later in Section 3. Moreover, their two proposed MLC designs, which are known as parallel MLC (P-MLC), shown in Figure 2(c), and series MLC (S-MLC), depicted in Figure 2(d), do suffer from various drawbacks that result in higher energy consumption and reliability issues as discussed below.
\nP-MLC, depicted in Figure 2(c), encloses two MTJs in-parallel and both placed side-by-side over a common HM electrode. The main advantage of this cell structure is that the two bits are accessed by two transistors, which results in approximately 50% reduction in the 1-bit effective area. As the two MTJs are placed on the HM, both of the MTJs may be programmed by SOT effect. Writing the two MTJs with identical bits (‘00’ or ‘11’) can be done using only one write pulse with duration following the slower MTJ. However, to write independent bits on the two MTJs (‘01’ or ‘10’), the two MTJs must have different critical currents (I\nc) (i.e. the MTJs with smaller I\nc switches faster for the same supplied current amplitude). Thereafter, either time-dependent or current-dependent writing [17] can be adopted. In time-dependent writing, a constant write current flows through the HM electrode, where both MTJs are firstly programmed within pulse duration t1, followed by the programming of faster MTJ2 with time t2 (t1 > t2 and t2 is not long enough for MTJ1 to switch), whereas in current-dependent writing, both MTJs are firstly written with larger write current (I\nwrite1). Subsequently, the faster MTJ2 is programmed with smaller write current (I\nwrite2) (I\nwrite1 > I\nwrite2 and I\nwrite2 is not large enough for MTJ1 to switch).
\nReleasing the two MTJs with different I\nc can be achieved by having different MTJ free layer thickness, dimensions [17], and/or width of underlying electrodes [15]. Therefore, P-MLC manufacturing might be challenging due to this imposed nonuniformity in cell architecture. The imposed different current requirements may result in lower energy efficiency (i.e. additional energy penalty) as one of the MTJs should switch with larger current amplitude compared to the other MTJ (under equivalent switching time assumption), whereas in conventional SLC SOT-MRAM, all the SOT-MTJs consume the same energy (i.e. no enforced rule of using two SOT-MTJs with different I\nc). However, this energy penalty can be reduced by having a smaller ΔI\nc between the two SOT-MTJs, as depicted in Figure 3. The minimum ΔI\nc (minimum energy penalty) depends on the tolerable switching probability (PSW) of MTJ2 (slower SOT-MTJ) while writing MTJ1, as the smaller the ΔI\nc, the higher the PSW of MTJ2. It is important to note that in real MRAM chip, the ΔI\nc should be large enough to accommodate for the different distributions of switching time, switching current, and error rates. This should be chosen carefully by considering the potential variability of critical current (σI\nc/μI\nc), which can be as large as 10% [13].
\nPercentage of increase in the energy resulting from having two MTJs of different IC versus ΔI\nc = I\nc2 − I\nc1 and the corresponding probability of switching (PSW) of slower MTJ2 while writing faster MTJ1 [17].
The reading operation is done similarly to the conventional SOT-MRAM, where the sense current or voltage is used to identify the equivalent resistance state. However, it is required to differentiate between four different resistances states unlike the only two states that exist in the conventional SLC. In addition, the in-parallel configuration of the two MTJs during reading results in a reduced minimum difference between the various resistance states (and consequently reduced read margin compared to in-series configuration and SLC), as the equivalent resistance for two parallel resistances is always smaller than the smallest resistance. For instance, if the parallel configuration resistance (R\np) of MTJ1 (R\np1) =7 kΩ, R\np of MTJ2 (R\np2) = 12 kΩ, anti-parallel configuration resistance (R\nap) of MTJ2 (R\nap2) = 22 kΩ, the equivalent resistance for in-parallel MTJs connecting for case1 (R\np1, R\np2) is R\ntot1 = 4.4 kΩ and for case2 (R\np1, R\nap2) is R\ntot2 = 5.3 kΩ. That results in a minimum resistance difference (ΔR\nmin) of 0.9 kΩ only, while for SLC or even in-series MTJ connection, a larger ΔR\nmin can be achieved. For instance, if the MTJ connected in-series instead of in parallel using the same MTJ resistance values, the R\ntot1 becomes equal to 19 kΩ and R\ntot2 = 29 kΩ, which results in ΔR\nmin of 10 kΩ. Consequently, the combination of both MLC scheme and in-parallel connectivity increases the expected BER.
\nS-MLC, shown in Figure 2(d), consists of two in-series MTJs placed over an electrode made of heavy metal. The first MTJ (MTJ1) in contact with the heavy metal electrode can be programmed by SOT effect, whilst the second MTJ (MTJ2) (stacked over MTJ1) must be programmed by conventional spin-transfer torque (STT). Similarly, the main advantage of this proposal is that each cell comprises two bits that are accessed by two transistors. This results in a nearly 50% reduction of the 1-bit effective area compared to conventional SOT-MRAM. In the write operation of S-MLC, MTJ2 must be programmed before MTJ1 to avoid a final state of write disturb failures for MTJ1, which means that the programming for the two MTJs should be serial and cannot be simultaneous. The need for STT in programming MTJ2 results in low energy efficiency as STT programming requires passing current by the high resistance MTJ stack, which demands high writing voltage in addition to the large critical current of STT switching compared to SOT switching. In addition, passing a large current through the MTJ stack reduces the tunnel barrier reliability, which jeopardizes one of the main advantages of using SOT-MRAM. The reading operation of the S-MLC is similar to P-MLC. Being an MLC requires the stack to represent four different resistance states. Thus, S-MLC uses MTJs with different cross-sectional dimensions to achieve the four different resistance states, which may result in a complex fabrication process. Furthermore, there is a need to employ low resistance MTJs in the stack to be able to supply enough current to achieve the STT switching. This results in a smaller minimum difference between the four distinct resistance states (i.e. smaller ΔR\nmin between the four possible resistances (R11, R10, R01 and R00)). The reduced ΔR\nmin minimizes the read margin for the S-MLC memory and thus longer reading delay.
\nThis section presents the various diode-based or selector-based SOT-MRAM proposals in the literature. These proposals mainly rely on replacing the read transistor (Tx), highlighted in Figure 2(a), by a diode or selector. As the read operation in SOT-MRAM requires mainly a relatively small and unidirectional current, a diode or a selector can successfully satisfy these requirements. The employed diodes are targeted to be nonsilicon-based, and thus, the cell silicon area would have one less transistor, as further explained below. However, employing a diode or selector may come with an energy penalty as larger read voltage may be required to overcome the diode’s on-voltage.
\nSeo et al. [14] proposed a diode-based single-level cell (SLC) SOT-MRAM, shown in Figure 2(b). In that design, the SOT-MRAM cell area is reduced by replacing the read transistor, depicted in Figure 2(a), with a Schottky diode. Thus, the cell requires only one transistor to access a single bit. This design’s main advantage is the reduction of the 1-bit effective area by approximately 50% compared to conventional SLC SOT-MRAM that requires two transistors to access a single bit. In this design, the 1-bit effective area is estimated to be 34.5F\n2 using the design rules in [16]. The write and read operations in this proposal are similar to that of the conventional SLC SOT-MRAM. The write operation would consume similar write energy, as each cell comprises only 1-bit (MTJ). Moreover, the read operation follows the same biasing as in the conventional SLC SOT-MRAM, where the RWL of the required row is activated and the WWL is deactivated. However, the diode usage increases the read energy as the read voltage needs to account for the additional voltage drop across the diode. In addition, there is still a margin to achieve smaller 1-bit effective area by using the diode as it is shown in the following sections.
\nAli et al. [18] extended the SLC diode-based SOT-MRAM proposal to be a multi-bit per cell (MBC). Their proposed design, shown in Figure 4, relies on a metal-oxide-metal (MOM) diode (or also known as selector) stacked over an MTJ (forming a D-MTJ) to replace the task of the read Tx in controlling the read current flow. The cell comprises two D-MTJs with similar tunnel oxide barrier thicknesses and their free-layers are placed in contact with a common HM electrode. The two D-MTJs can be programmed with two different bits through a common electrode. The sharing of common electrode allows the use of only single transistors to access the two bits (2 D-MTJs). This result is the main advantage of this proposal, which is a reduced 1-bit effective area that is 4× smaller than the conventional SOT-MRAM and offers at least double the density compared to any MRAM proposal in the literature. Given the design rules in [16], the 1-bit effective area is estimated to be 18F\n2. The cell also employs separate read word line (RWL) for each D-MTJ, as in Figure 5. On the other hand, similar to [14], employing a dedicated diode per MTJ may increase the read energy and limit the maximum acceptable diode area.
\n3D structure of the proposed dedicated diode multi-bit per cell (MBC) DD SOT-MRAM with (a) uniform HM electrode and MTJs with different t\nfl [18], (b) different HM width and MTJs with similar t\nfl [18].
Proposed MBC-DD SOT-MRAM cell in the (a) write and (b) read operations [18].
The MOM diode MTJ stack employed in this design is similar to the experimentally validated device used in the 1S1R 3D cross-point STT-MRAM developed by avalanche [19, 20, 21]. However, employing the D-MTJ device in the SOT technology would be more efficient than in the STT technology as the energy and performance degradation effects of the diode would only exist in the read operation and is avoided in the write operation. This is because the diode only exists in the read path, while in the STT technology, the write operation is dependent on the employed diode as the write current has to flow through both the MTJ and diode to achieve the STT switching.
\nThe writing operation of this cell is similar to that in the P-MLC, where either time-dependent or current-dependent writing can be adopted as elaborated before. During the write operation, the WWL of the row comprising the required cell is asserted high. A ‘0’/‘1’ is written on the MTJ if the BL is set high/low, and SL is pulled low/high for the column including the targeted cell, allowing the charge current to flow through the HM electrode in the essential direction, as shown in Figure 5(a). Furthermore, the RWLs of the row comprising the targeted cell are set low to ensure that the diodes are reverse-biased and no leakage current flows through the MTJs. It is worth mentioning that the low voltage while using the MOM diode may not be exactly zero volts, as a hold voltage (V\nhold ∼ 0.02 V) might be needed.
\nThe separate RWLs for each of the two D-MTJs permit selective reading of the two bits. During the read operation, the WWL is deactivated, and the SL of the column comprising the targeted D-MTJs is pulled to GND. The RWL of the targeted D-MTJ is then connected to the sense amplifier to forward bias the diode and read out the data stored in the MTJ, as shown in Figure 5(b). Although switches are still needed to select different RWL, it has a negligible impact on the area per unit cell as these switches are shared by all the cells in the row. Furthermore, as both MTJs are sensed independently and the RMTJ is an order of magnitude larger than RHM, hence, the RHM impact on the effective TMR is minimized (average sensed resistance = RHM + RMTJ).
\nThe realization of the MBC-DD SOT-MRAM has two main essential requirements. Firstly, employing two SOT-MTJs with different I\nc to be able to write the two bits independently as discussed before. This is achieved by using either different widths of the HM below each MTJ (W\nHM), as illustrated in Figure 4(b), or using different free layer (FL) thicknesses (t\nfl) within each MTJ, as shown in Figure 4(a). Uniform HM would be preferred in high-density memories, as W\nHM for both SOT-MTJs are limited to the technology minimum feature size (F), and any increase in the W\nHM than F increases the overall cell area. However, it may require two MTJ stack deposition with additional lithography steps, which may increase the manufacturing cost, whereas SOT-MTJs with uniform t\nfl is preferred from reading perspective as both MTJs would have similar TMR [22], which simplifies the read operation. It also offers lower fabrication cost due to simple processing. Nevertheless, due to the higher density, at least double other designs, it is expected that both structures would lead to lower overall cost per bit cell. Secondly, a 3D diode MTJ stack is required to have the diode replacing the read transistor without consuming silicon area. Incorporating the diode in the reading process requires applying a relatively higher read voltage (V\nRead) that is enough to overcome the diode on-voltage (i.e. forward bias the diode) and supply the required read current. The required magnitude of the V\nRead at a targeted read current (I\nRead) depends mainly on two factors, which are the diode’s cross-sectional area and the load resistance (R\nload). Firstly, the smaller the diode’s area, the smaller the diode supplied current at given bias voltage, as shown in Figure 6(a). Thus, the needed V\nRead increases with diode scaling down to supply the targeted I\nRead, as depicted in Figure 6(b). Secondly, the load resistance (R\nload) affecting the diode, which is the in-parallel SOT-MTJs equivalent resistances and the existing transistors in the I\nRead path. The smaller the R\nload, the smaller the required V\nRead to supply certain I\nRead for a given diode area, as illustrated in Figure 6(c) and modeled in Eq. (1). Thus, smaller R\nload aids to achieve lower read energy at a given I\nRead.
\n(a) The diode current versus diode area @ bias voltage = 1 V and no-load resistance. The data are from the implemented diode Verilog-A model verified against experimental data in [23]. (b) The required read voltage to supply I\nRead = 40 μA with diode area scaling for various R\nload. (c) The required read voltage for the diode to supply I\nRead = 40 μA versus different R\nload using both Verilog-A model simulation and Eq. (1) [18].
where V\non_noload is the diode’s required bias voltage to supply certain I\nRead with no load condition.
\nAli et al. [17] also proposed another diode-based SOT-MRAM cell in which a shared diode (selector) between the two MTJs in the cell is employed, as illustrated in Figure 7, instead of a dedicated diode (selector) per each MTJ. Similar to MBD-DD SOT-MRAM, each cell comprises 2-bits (MTJs) accessed with a single transistor. This result is a similar 1-bit effective area that is 4× smaller than conventional SOT-MRAM and at least double the density compared to any of the MRAM design in the literature. The 1-bit effective area is estimated to be 17.5F\n2 using the design rules in [16]. On the other hand, employing a shared diode permits increasing the diode area as it is no longer limited by one MTJ area. However, the needed memory sensing will be MLC (i.e. the cell has four different resistance states) instead of a SLC (i.e. the cell has only two resistance states), which complicates the sensing operation and reduces the read margin.
\n3D structure of the proposed shared diode multi-level cell (MLC) SOT-MRAM with (a) uniform HM electrode and MTJs with different t\nfl [17], (b) different HM width and MTJs with similar t\nfl [17].
The two MTJs in the MLC-SD cell also share a common HM electrode to be able to program the two MTJs with the energy-efficient SOT technology. This enforces using two SOT-MTJs with different I\nc as well, which can be written following the same approach of P-MLC using either time or current-dependent writing. Consequently, similar to MBC-DD in the write operation, the WWL of the row comprising the required cell is asserted high. A ‘0’/‘1’ is written to the MTJ if the BL is set to high/low and SL is pulled to low/high for the column including the targeted cell, allowing the charge current to flow through the HM electrode in the essential direction, as depicted in Figure 8(a). In addition, the RWL of the row comprising the targeted cell are set low to ensure that the diodes are reverse biased and no leakage current flows through the non-selected cells.
\nProposed 1D1T2R MLC-SD SOT-MRAM configuration and current flow direction in (a) write mode and (b) read mode [17].
Employing a shared diode requires connecting the two MTJs in-parallel, which enforces the cell to be MLC. Consequently, the two MTJs in the cell should have different RP and RAP such that their equivalent resistance has four distinct values, which represents two-bit logic values of ‘00’, ‘01’, ‘10’ and ‘11’. To read the bits in the cell, the WWL and the SL signals are pulled low to deactivate all the write transistors and allow the read current to flow through the targeted MTJs. The row RWL is connected to the sense amplifier and consequently is pulled up to the required read voltage (V\nRead), as shown in Figure 8(b). Thereafter, the equivalent 2 bits for the targeted MLC cell are identified sequentially by comparing the currents flowing through the sensed combined MTJs and the appropriate reference MTJs using a binary search algorithm [7]. In this algorithm, the sensed MTJs are first compared with the first reference resistance to determine the first-bit state. Based on the first-bit state, one of the two other reference resistances are then chosen to compare with the sensed MTJs to determine the second-bit state. The same technique can be used to sense the state of any of the MLC proposals illustrated above.
\nAs can be inferred from above, the realization of MLC-SD SOT-MRAM has three main essential requirements. Similar to the MBC-DD SOT-MRAM design, it requires employing two SOT-MTJs with different I\nc and a 3D diode MTJ stack. In the MLC-SD cell, as the diode is shared, the employed diode can be large, and its size can be approximately up to the whole cell area instead of just one MTJ area. A larger diode requires a smaller read voltage to supply the required I\nRead, as depicted in Figure 6(a). Moreover, the in-parallel combination of the two MTJs results in smaller overall resistance compared to a single MTJ resistance. This reduces the diode’s R\nload, which further decreases the required V\nRead, as shown in Figure 6(b). Hence, the two factors that affect the required V\nRead (i.e. diode area and R\nload) are improved in this design compared to the MBC-DD and SLC diode-based SOT-MRAM designs. Hence, the smaller required V\nRead may permit the MLC-SD design to achieve smaller read energy consumption. Furthermore, MLC-SD cell requires employing two MTJs with different R\nP and R\nAP values as it is an MLC. Assuming that both the MTJs use the same materials, different MTJ resistances are achieved by varying either the MTJ dimensions (i.e. W\nMTJ and L\nMTJ), the dielectric thickness (tox\n), or combination of both [24]. It is essential to have a large minimum resistance difference (ΔR\nmin) between the distinct in-parallel equivalent resistance states to increase the distinguishability and read speed. However, the MLC would mainly have smaller ΔR\nmin compared to the SLC, which in-return may result in reduced reading speed and would be a competing factor with the reduced V\nRead to decide the read energy efficiency of this cell compared to the SLC proposals.
\nIn this section, the various proposals in the literature are evaluated using the same SOT-MTJ technology in [13] on both cell and system level perspectives. The cell level analyses are done based on a 2 × 2 memory array. The simulations run over Cadence Virtuoso and using the SOT-MTJ Verilog-A model demonstrated in [25] and the parameters in Table 1. The system-level analyses are done using the non-volatile memory simulator, known as NVSim [26]. NVSim estimates the overall memory performance, power consumption, energy, and area based on the given memory cell parameters.
\n\nTable 2 presents a comparison between the different MRAM designs. In terms of area, MBC-DD and MLC-SD SOT-MRAM do offer the smallest 2-bit cell area among the various designs, which are estimated to be 36F\n2 and 34.5F\n2, respectively, based on the rules in [16]. This is at least double the density compared to other MRAMs and achieves 75% smaller 1-bit effective area compared to conventional SOT-MRAM. From energy perspective, these designs consume at least 36% less energy compared with designs utilizing STT writing (S-MLC), due to the high energy efficiency of SOT writing. Unlike P-MLC and MLC-SD SOT-MRAM, MBC-DD has no write current leakage through the MTJ from the HM during write mode as the diodes are reverse-biased, which also leads to better energy efficiency. However, the significant area reduction for both MBC-DD and MLC-SD SOT-MRAMs comes with additional energy penalty in both worst-case write operation (i.e. writing non-identical bits) and read operation. The additional energy consumption in the worst-case write operation of non-identical bits is because of the enforced rule of using two MTJs per cell with different I\nc. For instance, writing two different bits (‘10’ or ‘01’) in MBC-DD and MLC-SD consume higher energy (0.88 pJ with 10.5 ns delay) compared to writing two SLC SOT-MRAM (0.76 pJ). However, to write identical bits (‘00’ or ‘11’) on the MBC-DD and MLC-SD cells require only a single write pulse, which leads to better energy efficiency than SLC SOT-MRAM. This is because programming two identical bits in the SLC SOT-MRAM always requires two write pulses. Thus, if equal probability of programming ‘00’, ‘01’, ‘10’, and ‘11’ is assumed, MBC-DD and MLC-SD designs may result in similar average energy efficiency to two bits of SLC SOT-MRAM, as shown in Table 2. Moreover, the energy penalty for non-identical bits writing can be also minimized as discussed before. In terms of reading, MBC-DD maintains similar distinguishability to conventional SLC, as indicated by the ΔR\nmin values in Table 2, because each of the two MTJs is sensed separately. This is unlike the P-MLC, S-MLC, and MLC-SD structures that have a reduced ΔR\nmin as a result of relying on an MLC approach. However, to ensure sufficient diode drive current within the D-MTJs, a larger read voltage is needed compared to cells with read transistors, which does increase the read energy consumption compared to conventional SLC SOT-MRAM.
\n\nSymbol | \nParameter | \nValue | \n
---|---|---|
\nW\nMTJ × L\nMTJ\n | \nMTJ dimensions (W × L) (nm2) | \n50 × 100 | \n
\nt\nFL\n | \nFree layer thickness (nm) | \n1.5 | \n
\nK\nu\nV/KT | \nThermal stability | \n46 | \n
\nt\nox\n | \nTunnel barrier thickness (nm) | \n1.8 | \n
\nM\ns\n | \nMagnetization saturation (emu/cm3) | \n1114 | \n
\nR\nAP\n | \nMTJ high resistance value (kΩ) | \n15 | \n
TMR | \nTunnel magneto-resistance ratio (%) | \n114 | \n
\nα\n | \nGilbert damping | \n0.012 | \n
\nρ\nHM\n | \nHeavy metal (W) resistivity (μΩ·cm) | \n200 | \n
\nW\nHM × L\nHM\n | \nHM dimensions (W × L) (nm2) | \n115 × 150 | \n
\nt\nHM\n | \nHeavy metal thickness (nm) | \n3 | \n
\nJ\nco\n | \nCritical current density (×1010 A/m2) | \n7 | \n
\nθ\nSHE\n | \nSpin hall angle | \n0.3 | \n
\nP\n | \nSpin polarization | \n0.6 | \n
\nγ\n | \nGyromagnetic ratio (rad s−1 T−1) | \n1.76 × 1011\n | \n
\nЂ\n | \nReduced Planck constant (J s) | \n1.054 × 1034\n | \n
\n | SLC SOT (2-bit) | \n1D1T SLC-SOT (2-bit) [14] | \nS-MLC [15] | \nP-MLC [15] | \nMLC-SD SOT-MRAM [17] | \nMBC-DD SOT-MRAM [18] | \n|
---|---|---|---|---|---|---|---|
Energy per 2-bit (pJ) | \nWrite (EW)\na\n\n (w. case) | \n0.76 | \n0.76 | \n1.13 | \n0.72 (0.88) | \n0.72 (0.88) | \n0.72 (0.88) | \n
Write leakage | \n0.0002 | \n0.0001 | \n0.0001 | \n0.19 | \n0.2 | \n0.0001 | \n|
Read (Er) | \n0.024 | \n0.036 | \n0.034 | \n0.039 | \n0.041 | \n0.036 | \n|
Total energy/2-bit | \n0.78 | \n0.8 | \n1.17 | \n1.11 | \n1.11 | \n0.9 | \n|
Delay per 2-bit (ns) | \nWrite a (w. case) | \n9 | \n9 | \n10.5 | \n8.1 (10.5) | \n8.1 (10.5) | \n8.1 (10.5) | \n
Read | \n1 | \n1 | \n1.4 | \n1.6 | \n1.6 | \n1 | \n|
Read voltage (V) | \n1.2 | \n1.8 | \n1.2 | \n1.2 | \n1.3 | \n1.8 | \n|
ΔR\nmin (kΩ)\nb\n\n | \n5 | \n5 | \n3 | \n1.4 | \n1.4 | \n5 | \n|
Diode area (F\n2)\nd\n\n | \n— | \n24 | \n— | \n— | \n24 | \n10 | \n|
Area (A)/1bit (F\n2)\nc\n\n | \n69 | \n34.5 | \n50 | \n34.5 | \n17.25 | \n18 | \n|
FOM (Er*Ew*A) | \n2.19× | \n1.65× | \n5.7× | \n2.5× | \n1.34× | \n1 | \n
Comparison of various MRAM technologies.
Energy and delay are the average of writing the data ‘00’, ‘01’, ‘10’, ‘11’.
ΔR\nmin is R\nAP − R\nP for SLC, while it is the minimum resistance difference among the four different states in MLC.
Area estimated based on standard design rules reported in [16].
\nF is the minimum feature size of the employed technology (i.e. In 32 nm technology, F = 32 nm).
The diode-based SLC SOT-MRAM design [14] does offer the advantage of maintaining a similar write energy efficiency compared to the conventional SOT-MRAM (i.e. baseline from write energy perspective). Moreover, it offers 50% 1-bit effective area savings compared to conventional SOT-MRAM, which is on level with P-MLC and S-MLC designs with the advantage of maintaining an SLC sensing approach. However, diode-based SLC SOT-MRAM still consumes double the area compared to the MBC-DD and MLC-SD designs, while it still also suffers from the energy and fabrication complexity penalty of employing a diode.
\nSimilar to diode-based SLC SOT-MRAM, P-MLC design offers 50% 1-bit effective area savings compared to conventional SOT-MRAM, whereas S-MLC does offer only 28% savings as the transistor size needs to increase to supply the required STT current through the high resistance MTJ stack. On the other hand, both P-MLC and S-MLC do not employ a diode, which may aid in reducing the read energy and avoiding the fabrication process issues related to incorporating a diode. However, they suffer from other drawbacks that increase both energy consumption and fabrication complexity. In particular from energy perspective, S-MLC consumes high energy due to using STT technology in writing one of the two MTJs per cell, whereas P-MLC shares the additional write energy penalty issue in writing nonidentical bits per cell with MBC-DD and MLC-SD designs. In addition, both of the designs rely on the MLC sensing approach, which harms the sensing speed and distinguishability as reflected by the reduced ΔR\nmin values.
\nOverall, if a figure-of-merit (FOM) is defined as the product of the area, read and write energy products [27], MBC-DD SOT-MRAM may outperform other designs by at least 34%, thanks to its significant area reduction and maintaining the SLC sensing approach.
\nAs aforementioned, NVSim [26] is used to evaluate the various SOT-MRAM cells from a system-level perspective. NVSim does consider the different write/read peripherals, array organization, and routing network required in the overall memory architecture. NVSim supports various nonvolatile memories such as STT-MRAM, PCRAM, and ReRam in addition to the well-known volatile memories such as SRAM and DRAM. NVSim can be tuned to support SOT-MRAM as well. In this study, the comparison is based on the utilization of the various nonvolatile MRAM cells as cache memory and they are mainly compared to the current widely used technology as cache memory, which is the SRAM. SRAM does offer high performance; however, currently, it suffers from a significant increase in the 1-bit area and the leakage power consumption [28]. Thus, the utilization of an area-efficient, high-speed and nonvolatile SOT-MRAM would be a promising solution to replace the existing SRAM technology, especially in higher-level caches. The considered cache has 4-way set associativity and 64 Byte line size and is optimized to achieve the smallest overall silicon area. The 32 nm technology node is assumed for the various designs, in which the SRAM cell area is 170F2 [28], and the same cell parameters for the various MRAM technologies are maintained as stated above.
\nTo clarify the pros and cons of the various memory technologies, three different memory capacities are considered, which are 256 KB, 1 MB, and 8 MB. Figure 9 depicts the total leakage power consumption for the various designs with three different capacities. The volatile SRAM technology does consume significant leakage power, which increases by order of magnitudes for larger memory capacities. On the other hand, the nonvolatility of the MRAM designs results in relatively negligible leakage among the various capacities. This demonstrates the advantage of significant power consumption reduction by employing the nonvolatile MRAM designs as a replacement of the volatile SRAM, especially in battery-powered mobile devices that demand long idle durations.
\nTotal leakage power consumption of SRAM, STT-MRAM, conventional, SLC DSOT-MRAM, S-MLC, P-MLC, MLC-SD, and MBC-DD SOT-MRAMs for various memory capacities.
From area perspective, Figure 10 shows the comparison between the various memory technologies, estimated by NVSim, while being used as cache memory. Figure 10(a) reports the different MRAM designs relative to the overall SRAM memory area for the three different capacities. The figure indicates the significant reduction in the overall area by employing the various MRAM technologies in comparison to SRAM, which consumes at least 50% smaller silicon area. Furthermore, the area saving percentage increases noticeably for larger memory capacities. This is because for larger memory capacity, the impact of the cell area overtakes the impact of the periphery. The periphery area for MRAM consumes larger area than the periphery area of the SRAM due to the need for relatively larger write currents, whereas the cell area of the MRAM is much smaller than the SRAM cell area [29]. Hence, at larger capacities, the MRAMs that have significantly smaller cell area compared to SRAM would consume much lower overall silicon area. For instance, the area saving for the MBC-DD and MLC-SD cells, which are the cells with smallest footprints, can reach up to 90% smaller area compared to SRAM for large cache memory size, such as 8 MB size.
\nArea comparison of the STT-MRAM, conventional, SLC diode-based, S-MLC, P-MLC, MLC-SD, and MBC-DD SOT-MRAMs for different capacity relative to (a) SRAM and (b) conventional SOT-MRAM.
The impact of the smaller cell area is also clear while comparing the various MRAM technologies, as presented in Figure 10(b). The smaller 1-bit effective area of S-MLC, SLC diode-based, P-MLC, MLC-SD, and MBC-DD SOT-MRAMs by 28, 50, 50, 75, and 74% compared to the conventional SOT-MRAM results in similar overall memory silicon area reduction. In particular, for larger memory capacity (e.g. 8 MB), where the impact of the cell area is more significant, the overall memory silicon area of the various designs in the literature relative to conventional SOT-MRAM design shows approximately equal area reduction as the 1-bit effective area reduction. Moreover, the smaller silicon area consumption of the various proposed designs in the literature compared to SRAM and conventional SOT-MRAM with equivalent capacity permits realizing the cache memory using these cells with higher capacity under the iso-area assumption. For instance, 2 MB capacity of conventional SOT-MRAM consumes similar silicon area to an 8 MB capacity of MBC-DD SOT-MRAM. Higher memory capacity results in higher performance metrics, such as instruction per cycle (IPC) and energy efficiency due to reduced access counts for the off-chip memory [30].
\nFrom energy and performance perspective, SRAM can have higher hit/miss performance and energy efficiency compared to the various SOT-MRAM proposals at small memory capacity (e.g. 256 KB), as depicted by Figure 11(a). This is because the impact of the large load capacitance of the SRAM cell would be minimal at these capacities [29]. However, for large memory capacity, the much higher load capacitance, parasitic, and routing complexity of the six transistors SRAM cell (as SRAM consume significantly larger silicon area compared to SOT-MRAM) causes the MRAM proposals to achieve better hit/miss performance and energy efficiency. On the contrary, the write energy for the various MRAM proposals is larger than that of the SRAM for the various memories capacity, as shown in Figure 11(b). This is attributed to the larger write current requirement for the MRAM-based technologies relative to the SRAM technology. However, with improved SOT-MRAM technology such as the type-x SOT-MTJ [13] (achieves sub ns switching with write current of 100 μA), or the presented high-performance SOT-MRAM by IMEC [12] that achieves successful switching in 100’s of ps range, the write energy can be reduced significantly, as illustrated in Figure 12. This makes the various SOT-MRAM proposals a viable and realistic solution to replace the SRAM technology in certain applications.
\nComparison of the SRAM, STT-MRAM, conventional, SLC diode-based, S-MLC, P-MLC, MLC-SD, and MBC-DD SOT-MRAMs for different capacities relative to SRAM from (a) cache hit/miss energy per access perspective and (b) cache write dynamic energy per access perspective.
Cache write dynamic energy per access comparison of the SRAM, conventional, P-MLC, MLC-SD, and MBC-DD SOT-MRAMs for different capacity relative to SRAM assuming improved high-speed SOT-MTJ technology (e.g. type-x reported in [13]).
In conclusion, the previous discussion shows that the various proposed SOT-MRAM cells do offer nonvolatility (i.e. nearly zero leakage), smaller silicon area, and high performance. It also indicates that these designs can compete with the current CMOS volatile technologies such as SRAM and DRAM. However, further development to reduce the write energy for the existing SOT-MTJ technology may be required to widen the application window for such SOT-MRAM technologies.
\nThis chapter presents the various SOT-MRAM proposals in the literature highlighting the pros, cons, and operation of each design. SOT-MRAM relies on SOT technology, which offers various advantages such as high energy efficiency, fast switching speed, and high device reliability. However, conventional SLC SOT-MRAM requires two transistors to access a single bit. This in return results in a relatively large 1-bit effective area, which limits its application for large memory capacities. Hence, the various proposals in the literature targets reducing the 1-bit effective area compared to both conventional SOT-MRAM while maintaining the main advantages of SOT technology.
\nThe various SOT-MRAM proposals have been divided into two main categories, which are diode-based and nondiode-based SOT-MRAM cells. These various SOT-MRAM cells have been evaluated from both cell and system level perspectives. The system-level evaluation is performed based on the utilization of the various cells as cache memory, and they are mainly compared to the current widely used technology as cache, which is the SRAM. In particular, five different proposals have been investigated. These proposals are S-MLC, P-MLC, diode-based SLC, MBC-DD, and MLC-SD SOT-MRAMs that are shown to offer 70, 79, 79, 89, and 89% reduced 1-bit effective area compared to SRAM and 28, 50, 50, 74, and 75% compared to conventional SOT-MRAM, respectively.
\nFrom energy perspective, S-MLC, P-MLC, MBC-DD, and MLC-SD consume higher write energy compared to conventional SOT-MRAM. P-MLC, MBC-DD, and MLC-SD consume higher worst-case write energy while writing nonidentical bits on the cell due to the enforced rule of employing two SOT-MTJs with different I\nc. However, if an equal probability of programming the various bits options is assumed, average energy efficiency similar to conventional SOT-MRAM may be achieved, whereas S-MLC involves writing one of the two MTJs in the cell using the energy-inefficient STT technology, which also degrades the device reliability as a result of supplying large current through the MTJ stack. On the other hand, diode-based SLC SOT-MRAM may achieve similar write energy to the conventional SLC SOT-MRAM. However, similar to other diode-based designs (MBC-DD and MLC-SD), it still incorporates a diode in the read operation, which may add additional energy penalty as the read voltage needs to be large enough to overcome the diode’s on-voltage.
\nIt is noteworthy that the SLC proposals such as diode-based SLC and MBC-DD would be preferred solutions, thanks to their offered significant area reduction in addition to maintaining the advantages of the SLC sensing such as improved BER. However, that requires further improvement in the diode-MTJ stack technology such that the diode transient response would match the required read performance and the diode’s on voltage would be small, and thus, the read energy will be reasonable. On the other hand, the MLC proposals such as P-MLC, S-MLC, and MLC-SD require improvements in the MLC sensing techniques to enhance its sensing distinguishability and BER such that it will meet the industry standards.
\n“It is a truism that each solution brings its own problems. Diabetic retinopathy in survivors of longstanding diabetes…represents the price paid for conquests that are not quite complete. The prolongation of life without corresponding prolongation of health, is loaded with intractable problems.” commented Arnold Sorsby on the “striking increase” of blindness from diabetes for both men and women between 1948 and 1962. [1]
\nThe next six decades saw intensive research in the pathogenesis and epidemiology of diabetic eye disease and the introduction of laser photocoagulation in the early treatment of diabetic retinopathy, pars plana vitrectomy for traction, and rhegmatogenous retinal detachment and intravitreal pharmacotherapy in the management of diabetic macular edema (DME), all addressing prevention of vision loss in these patients.
\nReports on the vision loss attributable to diabetes in the 1980s and 1990s vary greatly in their methodology—some have derived clinical information from hospital series, and others have reviewed the registry forms of certified disabled persons from the records of societies of the blind; there are reviews on patients referred to low vision rehabilitation centers and finally some present data from population-based observational studies. Each source has its shortcomings. Definitions in registry databases depend on the national disability legislation and often differ from the categories for blindness and low vision in the International Classification of Diseases (ICD)—Ninth and Tenth Revisions—that were in use at that time. Many authors stress on the difficult task of identifying the onset and the main cause of vision loss in diabetic patients with multiple ophthalmic comorbidities, especially in their final stages. For a long period, well into the 1980s, non-ophthalmic professionals were allowed to certify blind persons for registration that raises reservations regarding the accuracy of the cause. A common concern is the inability to determine the number of underreported and unregistered diabetic persons with vision loss as registration is voluntary, and it depends on clinical, social, and cultural factors; many authors have noted a rise in the incidence rates of DR with the arrival of more consultants in the area, after upgrade in the financial benefits and social support for legally blind or following campaigns to improve public awareness and reduce stigmatization.
\nHospital series analyze clinical data collected in specialized diabetic units over long periods in a consistent manner and provide reliable estimate on the severity and progression of vision loss; however, extrapolations of their findings for the population beyond their urban region are seldom possible.
\nPublications from the UK, Denmark, and Sweden demonstrate a decrease in the incidence of new blindness from DR in the 1980s and 1990s [2, 3, 4, 5]; however it remained unchanged between 1967 and 1991 in Italy and Avon, UK [6, 7]. In their review on the trends in blindness in Singapore, See et al. [8] present a sharp increase in the prevalence of diabetes in the age between 15 and 69 from 1.99% in 1975 to 8.6% in 1992 and a rise in the proportion of blindness from diabetic complications from 5% in the 1950s to 47.3% in the 1980s.
\nGlobal data on blindness [9, 10], a review report of the WHO programme for prevention of blindness, summarized available information from population-based assessment of visual loss and its causes. DR was not among the four major causes for blindness and low vision globally and ranked between the first and fourth only in Western Europe, the former socialist economies of Europe, North America, Latin America, and Oceania. The authors note the lack of relevant epidemiological data for some specific causes of blindness; however they emphasize that this disease is “generally recognized to be the leading cause of blindness among those in working age in developed countries and rapidly emerging in urban areas of the developing world.”
\nAn update on the estimates of global and regional blindness and low vision was published in 2004 presenting results of new population-based studies and other sources of information. The proportion of DR rose to 4.8% globally, and it was ranked fifth as a cause of blindness, with significant regional variations reaching 17% for North America and Australia, 17–15% in Europe, and 3–7% in the rest of the world where the majority of vision loss was due to cataract, glaucoma, and corneal opacities as complications of trachoma [11].
\nA meta-analysis of all available population-based studies performed worldwide from 1990 to 2010 [12] estimated that 833,690 people were blind and 3.7 million were visually impaired globally in 2010 due to DR. The highest number of blind diabetic patients was in South Asia, 295,000; North Africa/Middle East, 108,000; Eastern sub-Saharan Africa, 50,000; and Western sub-Saharan Africa, 66,000. The age-standardized prevalence of blindness from diabetic retinopathy in people over the age of 50 years was 0.05% globally, reaching 0.19% in Western sub-Saharan Africa, 0.16% in North Africa/Middle East, 0.14% in Eastern sub-Saharan Africa, and 0.12% in Southeast and East Asia. Moderate and severe vision impairment due to DR affected 3174 million, and the largest number of them were in South Asia, 1450 million, followed by North Africa/Middle East, 336,000; Eastern Asia, 279,000; Western Europe, 225,000; Western sub-Saharan Africa, 193,000; Eastern Europe, 166,000; Eastern sub-Saharan Africa, 128,000; and Central Latin America, 109,000. The age-standardized prevalence of moderate and severe vision impairment due to DR in people over the age of 50 years was 1.9% globally and was highest—0.51%—in South Asia, 0.50% in Western sub-Saharan Africa, 0.44% in North Africa/Middle East, 0.36% in Southern Latin America, 0.33% in Central sub-Saharan Africa, 0.32% in Andean Latin America, 0.31% in Eastern sub-Saharan Africa, and 0.26% in Oceania [13]. From 1990 to 2010, the number of blind diabetics had increased by 27% and those with visual impairment by 64% globally. Globally, age-standardized prevalence of blindness and vision impairment of diabetics over the age of 50 years was relatively unchanged in the course of these 20 years. It reduced by half in high-income Pacific Asia, Europe, Australasia, and North America; however it remained high in large, densely populated regions of Africa and Asia with rapidly increasing prevalence of diabetes.
\nA continuation of this systematic review and meta-analysis of data from 261 population-based studies published till 2014 [14] observed that while blindness to all causes reduced between 1990 and 2015, DR was the only one with prevalence that increased by 7.7% for blindness and by 28.6% for impairment. The proportion of vision loss attributable to diabetes ranked seventh in 2015 at 1.06% (0.15–2.38) globally and was highest in Eastern Europe, 4.91%, followed by Australasia, high-income North America, high-income Pacific Asia, and Central Asia. The contribution of DR to moderate and severe vision impairment was 1.30% (0.20–2.93) and reached 5.06% in Eastern Europe, followed by Australasia, high-income North America, high-income Pacific Asia, and Central Asia. The same regions were leading in the percentage of blindness and low vision due to DR for people over the age of 50 years. The age-standardized prevalence of blindness from DR across all ages was relatively low, in the range of 0.00–0.01 (0.00–0.02), and was considerably higher for vision impairment, 0.03% (0.00–0.13), with Eastern Europe ranking first at 0.11%, Central Asia, 0.09%; Southern Latin America, 0.08%; and North Africa/Middle East and Australasia, 0.07%. The age-standardized prevalence of blindness of diabetics over the age of 50 was 0.02% (0.00–0.07) and was highest in North Africa/Middle East, Eastern Europe, and Central Asia. The age-standardized prevalence of low vision in the same age group was 0.13% (0.01–0.48), and the same regions were most affected. For the first time, this report presented data on the gender differences in the cause and magnitude of vision loss and demonstrated that the relative risk of blindness and vision impairment in diabetic women as compared to men was 2.52. The number of people with blindness due to diabetic retinopathy was estimated at 400,000 (0–1.5 million) and low vision 2.6 million (0.2 million—9.9 million), both almost doubled since 1990. The projections for diabetic complications for 2020 are for further increase, and the largest number of people are expected to reside in North Africa/Middle East, 73,000 blind and 4,480,000 with low vision; Eastern Europe, 47,000 blind and 362,000 with low vision; Western Europe, 46,000 blind and 422,000 with low vision; East Asia, 41,000 blind and 400,000 with low vision; and Southeast Asia, 30,000 blind and 216,000 with low vision. The authors point out that the prevalence of any DR and sight-threatening DR was similar in men and women, whereas their analysis suggested female preponderance for vision-impairing DR. They attribute this discrepancy to the use of aggregated data for both genders combined in some of the studies and highlight the need for further research into the gender differences. There are considerable regional variations in the blindness and low vision due to DR, and they are related to the prevalence of diabetes in the population and the life expectancy of the diabetic patients. In the Middle East, Kuwait, for example, the prevalence of diabetes has reached 20–25% of the whole population and over 50% after the age of 60 years. In some regions, in particular in South Asia, the life expectancy of diabetic individuals is reduced, they do not have the chance to develop retinopathy as sequela of the disease, and the prevalence of debilitating retinopathy is low despite the high proportion of diabetes.
\nA detailed meta-analysis of the trends in vision loss in high-income countries in Pacific Asia, Australasia, North and Latin America and Western Europe, as well as Central and Eastern Europe from 1990 to 2015 [15] presented a relatively low and stable prevalence of blindness due to DR for all ages in the range of 0.01–0.02% in the whole super-region; however the rates for moderate and severe visual impairment varied in the range from 0.6–0.7% in most of the high-income countries to 1.6% in Eastern Europe and Australasia. The crude prevalence of blindness among diabetics over 50 years was in the range of 0.02–0.03% in the high-income countries, 0.04% in Central Europe, and 0.06–0.07% in Eastern Europe, and visual impairment was lowest in Western and Central Europe and Pacific Asia, followed by North America and Australasia and highest in Eastern Europe. The projections for 2020 were for stable or slightly reduced prevalence of blindness and gradual increase of patients with visual impairment in the super-region.
\nVision loss in the multiethnic population of Singapore over the age of 40 years was investigated in a series of population-based studies that demonstrated relatively high prevalence of diabetes in the sample—29.5%; DR was the second leading cause of vision impairment and blindness, and Indians and Malays were more affected than the Chinese. The authors point out that DR-related blindness in these three ethnicities in Singapore was less than the mainland Southern Indians, mainland Han Chinese, and peninsula Malays, and they attribute this to better access to qualified eye screening and care in Singapore. Diabetes was a significant contributing factor for visual impairment generally and increased the risk by 2.96 for people below the age of 60 years and 12.70 times for those over 60, particularly for females and patients with cognitive impairment and deafness, a tendency that was consistently observed across Malays, Indians, and Chinese. Diabetes in combination with other comorbidities, hypertension, hyperlipidemia, cardiovascular, or renal disease, was associated with higher risk of vision loss, up to 9.51 for people younger than 60 years and 26.56 for those older than 60, particularly for Indians, and an interaction effect for concomitant diabetes and renal diseases [16].
\nVision-threatening DR (VTDR) is a compound term used in the literature for the presence of proliferative disease grading over level 60 by EDTRS scale and its modification and/or macular edema in its various stages [17, 18], and its magnitude is essential for planning the life-long management of these patients and prevention of blindness. The prevalence and risk factors of VTDR were estimated in a large meta-analysis of 38 population-based studies from Australia, the USA, Europe, and Asia involving 42,091 participants from 20 to 79 years with diabetes. There was no discernible sex difference in the age-standardized prevalence of VTDR, 11.7%; it was highest among African Americans, 16.89%; followed by Caucasians, 15.45%; and Hispanics, 10.35, and was lowest in South Asians—5.2%. Duration of diabetes (DM) was associated with rapidly increasing prevalence from 3.53% for DM less than 10 years to 17.78% for 10–20 years and up to 87% for more than 20 years. Metabolic control, estimated by the levels of HbA1c, directly affected the extent of VTDR—the disease doubled in patients with levels between 7.1 and 8.0% and tripled among those with more than 9.0%. Elevated blood pressure over 140/90 and hypercholesterolemia over 4.0 mMol/L elevated the risk of VTDR twice, particularly for macular edema. Individuals with type 1 diabetes for more than 20 years were 15 times more likely to have proliferative diabetic retinopathy (PDR) (15.3 [11.3–20.8]), 5 times more likely to have DME (4.83 [3.71–6.30]), and 8.7 times more likely to have VTDR (8.69 [7.10–10.63]) than those with type 2 diabetes for less than 10 years. On a positive note, the prevalence of VTDR reduced from 15.62% in studies where the fundus photographs were taken before the year 2000 to 7.86% in the studies with assessment of the patients after 2000.
\nThis pivotal work highlighted the importance and cutoff levels of the systemic factors associated with progression of DR to sight-threatening stage and the need for close collaboration with the treating diabetology team. It outlined the profile of the patients at risk of vision loss with their features—type and duration of diabetes, levels of metabolic control, hypertension, and hypercholesterolemia. The role of ethnicity was limited to the populations studied, and the authors note the absence of studies from Middle East, Africa, and South America that could affect the accuracy of their global estimates. The differences in the rates of VTDR in the various populations could be due to both genetic factors and access to health care. Ethnicity itself is multidimensional, and it may not be possible to differentiate its effect from the risk associated with remoteness, urbanization, lifestyle, education, health awareness, and individual income.
\nSocial and economic factors have a fundamental impact on the visual prognosis of diabetic eye disease. A number of studies have investigated the negative influence of deprivation on the prevalence of diabetes, access to evaluation and care, level of metabolic control, and rate of complications and were reported in systematic reviews for type 1 [19] and type 2 diabetes [20]. Remoteness [odds ratio (OR) 2.02] and diabetes in combination with never having had an eye examination (OR 14.47) were among the main risk factors for vision loss in indigenous Australians, and blindness prevalence was 2.8 times higher among them than in non-indigenous Australians after age and gender adjustment [21]. The presence of PDR was associated with low income (OR = 3.6 for developing PDR if income was less than $20000) in the Proyecto VER Study in the USA involving 4774 Hispanics over the age of 40, after controlling for other factors [22]. Deprivation, as a comprehensive measure of income, employment, health and disability, education, crime, barriers to housing, services, and living environment at the level of small geographic areas, was developed in the UK as a numerical index per residential code and used in a large national database study of 79,775 diabetic patients to highlight its effect on visual acuity and need for early treatment at first hospital presentation [23]. The OR of presenting with “sight impairment” at first visit to the hospital eye service was gradually decreasing from 1.29 in the most deprived group to 0.77 in the least deprived one, and OR for “severely sight impaired” was 1.17 in the most deprived decile versus 0.88 in the least deprived one. The risk of sight-threatening maculopathy and vitreous hemorrhages showed little variations across the deprivation range, and tractional retinal detachment was less likely in the two least deprived deciles. The large scale of the study and use of “real-world” multicenter in-hospital dataset provided statistical strength to the conclusion that the impact of deprivation extends to late presentation of retinopathy, significant loss of vision at presentation, and a pattern of advanced retinal complications that affect the treatment these patients receive. Financial factors are often self-reported by diabetic patients who are missing screening appointments and treatment sessions. However a study in Tanzania revealed that the reasons for poor compliance are more complicated. The clarity of referral process and ease of navigation through the unfamiliar hospital environment are essential, particularly for the elderly and less educated patients from remote areas [24]. Another formidable obstacle is the widespread complacency and fatalistic resignation with the notion that retinopathy will inevitably end up with blindness. Constant assurance and encouragement that diabetic eye disease is a treatable condition with good prognosis is a practical strategy to prevent delays in diagnosis of sight-threatening complications. Lack of education greatly affects the health awareness and adherence with retinopathy management. In Kuwait, 16% of the men and 46% of the women over 65 years are illiterate, and 20% of the men and 24% of the women in the same age group can only read and write [25]. This is a significant barrier to in-depth understanding and compliance with recommended treatment and lifestyle and eventually compromises the visual outcome despite the high economic standard of the Kuwaiti nationals and availability of services in the country. Family support greatly improves the continuum of care and is essential for the regular attendance of the patients, especially females from a more conservative background.
\nProgression of nonproliferative to proliferative disease was investigated in several large cohort studies [26, 27]. Disease severity was estimated by the EDTRS classification and taken separately for each eye or concatenated as the bilateral grade, and progression was defined as the increase of two or more steps in severity. The rate of progression to PDR varied greatly—it was from 4 to 9.9% in the first 4–5 years and 8–12% in the next 5 years and reached a cumulative level of 31% after 16 years and 42% after 25 years in type 1 and type 2 diabetics. There are differences between the populations and methodology applied in the hospital-based and community-based studies as more patients with severe disease that required active management were probably referred to tertiary care centers [28, 29, 30, 31, 32].
\nThe diagnosis of diabetic macular edema has evolved with the introduction of stereoscopic photography of the posterior pole and optical coherence tomography (OCT). The presence of any edema and clinically significant edema (CSME) by the modified EDTRS classification has been investigated in multiple hospital series and population-based studies. Detection of DME in non-stereoscopic fundus photographs is less sensitive to milder forms with recent onset, and probably the reported prevalence covers the more severe chronic stage. The prevalence of CSME in type 1 patients was from 5.73% in Spain to 9.4% in Brazil [33, 34]. Among patients with type 2 diabetes, it was in the range from 1.4% in Portugal to 12.8% in Denmark [35, 36]. There are reports indicating that the prevalence of DME in Central and Eastern Europe [37], North Africa, and Middle East [38] is considerably higher, and further research on the magnitude of CSME and risk factors for its progression will contribute to the estimates of sight-threatening retinopathy globally.
\nDiabetic nephropathy (DN), the primary cause of chronic kidney disease, is significantly associated with incidence and progression of diabetic retinopathy as demonstrated in Brazilian [39], Spanish [40], Korean [41], Taiwanese Chinese [42], and Australian [43] patients. The presence of chronic kidney impairment had adjusted a hazard ratio of 5.01 for nonproliferative and 9.7 for proliferative disease as compared to patients without nephropathy. At 5-year follow-up, the hazard ratio of progression to PDR was 2.26 in patients with DN, and it was related to the levels of microalbuminuria and estimated glomerular filtration rate with cutoff below 60 mL/min/1.73 m2 [44]. Hypertension and DN in patients with chronic kidney disease increased the risk of progression to proliferative disease; however diabetic nephropathy did not significantly affect the development or progression of DME. Among the Taiwanese Chinese patients, diabetic macular edema had high crude hazard ratio association with cerebrovascular accidents and lesser one for hypertension and use of statins; however the significance was lost after controlling for age, sex, comorbidities, and medications.
\nDiabetes affects 17% of pregnancies worldwide and can be pre-existing type 1, gestational, or type 2, in some of the patients—previously undiagnosed. The highest rate of diabetes in pregnancy is recorded in Southeast Asia, 25%, and the prevalence of pre-existing diabetes is highest among women from the Middle East and North Africa—3.1%. Australian mothers who were born in high diabetes risk areas such as Polynesia, Asia, and the Middle East are 1.4 times more likely to have type 2 diabetes during pregnancy [45]. Similarly, in the USA and UK, patients belonging to Black, Asian, Hispanic, and Pacific Island ethnic minorities had higher proportion of pre-existing diabetes and pre-existing type 2 DM. Progression of retinopathy during pregnancy is related to the level of diabetic retinopathy prior to conception and was noted in 58% of the patients with moderate or more severe DR at baseline. Duration of diabetes type 1 greater than 15 years and type 2 more than 6 years was significantly associated with higher rate of progression of retinopathy in patients with pre-existing proliferative disease. Poor glycemic control prior and during pregnancy was an independent risk factor for retinopathy progression; however tight control and rapid optimization of metabolic control in such patients were associated with worsening of retinopathy. As the long-term benefits of proper glycemic management outweigh the short-term risk of deteriorating retinopathy, optimal control is currently recommended prior to and as soon as possible after conception for the health of the mother and fetus. Progression of retinopathy during pregnancy was significantly higher in diabetic patients with preeclampsia, with sight-threatening complications in 50% of the diabetic women with preeclampsia compared to 8% without it [46]. Other risk factors for deteriorated retinopathy during pregnancy include young age of type 1 onset, insulin treatment in type 2 prior to pregnancy, low vision at baseline, and pre-existing macular edema at baseline [47].
\nDiabetic foot syndrome is one of the important consequences of long-term uncontrolled diabetes, which occurs due to a combination of peripheral neuropathy and microvasculopathy in the lower extremities. It may vary from a minor ulceration to necrosis of tissues, sometimes warranting amputation [48]. Several hospital series demonstrated the presence of retinopathy in 90–95% and proliferative disease and severe nonproliferative changes in 39–55% in such patients independent of the ulcer severity [49]. Diabetic foot syndrome in type 1 and type 2 diabetic patients with retinopathy was associated with higher levels of HbA1c, serum creatinine, older age, and lower hematocrit, particularly elevated in the subgroup with proliferative disease—all characteristics of concomitant chronic kidney disease and neuropathy in poorly controlled, long-lasting diabetes. Despite the lack of data on macular edema, the presence of any stage of diabetic foot ulcer is emerging as a predictor for retinopathy deterioration [50, 51].
\nThe overall prevalence of depressive symptoms in diabetic patients with retinopathy is estimated in the range of 35% in China to 50% in African Americans and is more prevalent in type 2 [52, 53]. The association between depressive symptoms, diabetes, and diabetic retinopathy is likely to be bidirectional: the impairment and burden of diabetes and its complications can precipitate depression and vice versa, and depression can impair diabetes control through various biological and behavioral pathways [54, 55]. Depression aggregates negative attitudes toward treatment and often leads to poorer glycemic control, less adherence to treatment, higher risk for PDR, greater morbidity and mortality, and higher costs [56]. Low income has been implicated in some research from the USA; however it was not found significant in a large cross-sectional study from Australia. Patients with longer duration of diabetes, worse glycemic control, lower educational level, and severe vision impairment below 20/63 were associated with greater depression symptoms. Symptoms of anxiety were associated with type 1 diabetes, presence of myocardial infarction/angina, arrhythmia, stroke, asthma, anemia, arthritis or osteoporosis, younger age, and female gender [57]. Severe NPDR and PDR, but not macular edema, were independently associated with depressive symptoms, and the authors suggest that severity of retinopathy could be an indicator to prompt monitoring of depression in at-risk diabetic individuals. Antidepressant medications have been associated with slowing the progression of retinopathy in diabetic patients. However the outcome was limited to subjects with elevated C-reactive protein over 0.3 mg/dL. Selective serotonin reuptake inhibitor users had significantly lower risk of developing severe retinopathy than non-SSRI users [58]. The results of longitudinal studies show that the speed of cognitive decline in type 2 diabetic patients is up to twice as fast as that of normal aging individuals and diabetic patients have an increased risk of mild cognitive impairment (MCI). In addition, type 2 diabetic patients had an almost twofold higher risk of developing Alzheimer’s disease than age-matched nondiabetic subjects. This increased risk was maintained even after adjusting for vascular risk factors. The annual conversion rate from MCI to dementia ranges between 10 and 30% in the general population, but this is much higher in the type 2 diabetic population. The impact of cognitive impairment on the compliance with lifelong retinopathy treatment and its outcome needs further evaluation; however clinical practice indicates the need for personalized multidisciplinary approach.
\nThe variability in the rate of progression to vision-threatening retinopathy and particularly in the response to treatment was noted from the onset of clinical and epidemiological studies in diabetic patients and has been attributed to the effect of genetic predisposition together with systemic and socioeconomic factors. Single-nucleotide polymorphisms [58, 59, 60] and genome-wide associations [61, 62, 63] have been investigated in patients with proliferative disease and macular edema, and the results so far are inconclusive mainly due to the size of the samples and the inclusion of cases with coexisting proliferations and edema in the cohorts. Detailed assessment in the polymorphisms of the VEGF gene revealed that some of them are related to higher susceptibility to severe retinopathy, but not to the outcome of ranibizumab intravitreal injections [64] in contrast to an earlier report on the response to bevacizumab [65]. In order to confirm the association of several novel genetic loci with severe retinopathy, replication studies and extension in additional cohorts and ethnic groups have been recommended [66]. Research of systemic and retinal inflammation as risk factors for DR and DME [67, 68], upregulated leptin [69, 70] and adiponectin [71], oxidative stress [72], and vitamin D deficiency [73] has provided significant associations. Reliable and accessible markers of these factors can be important predictors of the disease severity and progression and thus provide early guidance in personalizing the monitoring and treatment of the patients at risk of vision loss.
\nThe introduction of intravitreal anti-VEGF drugs and corticosteroid implants revolutionized the management of DME. Prospective randomized clinical trials have addressed the efficacy and safety of different types of agents and administration regimens and have shown wide variations in terms of visual acuity gain. In the DRCR.net trial, after 2 years of treatment, approximately 98% of the patients maintained their visual acuity and attained visual gain in 37% of the patients on ranibizumab, 35% of those on bevacizumab, and 39% of those on aflibercept [74]. Stratified analysis of RESTORE in DME, RETAIN, and Protocol I demonstrated that the most significant gain in number of EDTRS letters after 12–36 months was in patients with baseline BCVA 60 and less letters in the range of 8.6–10.36 letters, versus the gain for patients with baseline BCVA 61–71 letters who achieved 7.96–4.36 letters, and the least gain of 5.42–4.2 letters was in the group with baseline BCVA better that 73 letters [75]. Thus, the patients with most severe vision deterioration and baseline BCVA in the range of 20/320–20/63 who responded favorably to 2 years of intensive therapy improved to BCVA from 20/160 to 20/40. High visual acuity in the range of 20/40–20/32 was achieved only in patients with baseline BCVA over 20/30 despite the small number of gained EDTRS letters. The range and stability of this visual improvement depended on increasing age, level of glycemic control, and previous panretinal photocoagulation [76]. OCT markers of better functional outcome after anti-VEGF treatment were the presence of intact ellipsoid zone and lack of hyperreflective spots or disruption of the inner retinal layers, which are seen in patients with more recent onset of the edema and no previous macular grid laser [77]. Patients with chronic macular edema had considerably better functional and structural results after treatment with steroid implants. Visual gain of more than 15 letters was achieved in 22% after 3 years on intravitreal dexamethasone [78] and in 34% after 3 years on fluocinolone acetonide [79]. Eyes with submacular fluid, no hyperreflective foci, and a continuous IS-OS layer responded better to dexamethasone implants with gain of 10 or more letters after 2 and 4 months [80]. The adverse effects of both implants included the formation of cataract, 13–50% after 1 year on dexamethasone and 82% after 3 years on fluocinolone acetonide, and intraocular pressure rise over 25 mmHg in 42% of the eyes with dexamethasone and 38% with fluocinolone acetonide; however a small percentage required glaucoma surgery—0.5% of the eyes with dexamethasone and 4.8% with fluocinolone acetonide. Patients with poorly controlled diabetes and DME, severe nonproliferative or proliferative disease, epimacular membranes, myopia, glaucoma, and various degrees of cataract are excluded from the randomized clinical trials; however such cases are predominant in real-world practice and add new dimensions to the challenge of visual rehabilitation. Analysis of large electronic medical record databases from the USA [81] and Korea [82] demonstrated visual outcomes that are meaningfully inferior to those in the clinical trials and were attributed to undertreatment and lack of close monitoring. A sizable group of DME patients were lost to follow-up in the initial stages of anti-VEGF treatment—25% were reported from a single retina practice in the USA and the main risk factors were being Hispanic, Black, or a Pacific islander; low income, AGI less than $50,000; and decreasing baseline visual acuity [83]. In a study of European DME patients, 46% had at least one break-off in their anti-VEGF treatment for more than 100 days, and the most common reason for poor compliance was comorbidity. In 60% of these cases, the visual acuity deteriorated significantly after the break [84]. Prevention of vision loss from diabetic macular edema is achievable with the current therapeutic modalities; however it requires very early identification at stages with relatively high visual acuity and needs the introduction of best-corrected visual acuity and OCT in the screening protocol. As shown in the Protocol G—Subclinical DME study of the DRCR.net that involved a longitudinal assessment of eyes that had retinal thickening on OCT without thickening on clinical exam, a progression to clinically apparent DME was seen in 23–58% of eyes within 2 years.
\nVision loss in approximately 25% of patient with diabetic retinopathy is associated with complications of proliferative disease. An estimated 17 million diabetic people worldwide have PDR [17], and without treatment more than half of the patients with high-risk PDR will be blind within 5 years. Panretinal photocoagulation was established as an effective treatment to reduce by 50% the incidence of severe vision loss, if performed prior to the development of vitreous hemorrhages and tractional retinal detachment [85]. Still, the EDTRS has shown that 5% of patients with PDR will require vitreous surgery despite having received adequate PRP [86]. The Diabetic Retinopathy Vitrectomy Study validated the superiority of vitrectomy over observation; however despite the fact that the trial did not include patients with macula, involving traction, the visual outcome was low. Subsequent studies on vitrectomy for PDR reported that between 10 and 20% of the patients did not improve their visual acuity above hand motion or less [87]. Favorable factors for visual rehabilitation after vitrectomy for macula-involving tractional retinal detachment included short duration of detachment, previous panretinal photocoagulation, and lack of severe neovascularization and vitreous hemorrhage. Predictors of poor visual results were iris neovascularization and neovascular glaucoma, papillo-vitreal traction, baseline visual acuity below 20/200, initial macular detachment, intraoperative iatrogenic break, or use of heavy silicone oil [88, 89, 90]. Functional outcome was significantly affected in patients with postoperative macular ischemia, recurrent vitreous hemorrhage, optic atrophy, epiretinal membranes, and recurrent retinal detachment [91, 92]. The introduction of small-gauge vitrectomy instruments and trans-scleral cannulas enabled the fast and effective removal of most fibrovascular membranes with the vitrectomy probe applying the lift and shave technique [93]. Visual outcomes were poorer in older age group, tractional retinal detachments involving macula and eyes with extensive membranes and with silicone oil as tamponade; however both 23-gauge and 25-gauge groups were comparable in relation to visual improvement, anatomical success, and intraoperative and postoperative complications [94]. The integration of swept-source optical coherence tomography and digital displays can provide important guidance during surgery for PDR complications and facilitate decision-making [95]; however further research will show whether these technological advances will translate into better postoperative visual outcome.
\nMedical treatment for PDR has had minimal advancement over the past 40 years since the wide acceptance of panretinal photocoagulation in the early management of the disease. Regression of proliferative activity was noted in eyes treated with anti-VEGF for concomitant macular edema [96] and that lead to a series of trials on aflibercept and ranibizumab versus panretinal photocoagulation in the management of PDR. Both drugs were superior to PRP in 1 [97] and 2 years [98] in terms of visual acuity and visual field sensitivity. Assessment of the peripapillary retinal nerve fiver layer thickness in patients treated with ranibizumab revealed reduction that was due to decreased edema rather than loss of axons [99]. Patients with mild and moderate vitreous hemorrhages treated with ranibizumab had significantly less need for vitrectomy, less recurrences of hemorrhage, and better visual acuity on all follow-up visits than the patient under observation or operated for non-resolving or aggravated hemorrhages [100]. However, despite the improvement in retinopathy severity on color photographs, the retinal perfusion did not improve on wide-field fluorescein angiography that revealed no reperfusion of small vessels in areas of previous capillary non-perfusion [101]. Diabetic patients are prone to significant loss to follow up due to illness, financial hardship, and lack of compliance. The rate of complications and loss of vision after unintentional interruptions for more than 6 months in PDR patients treated only on anti-VEGF was considerably higher than the eyes that received PRP, with a significantly higher number of eyes with tractional retinal detachment and neovascularization of the iris [102]. In a retrospective review of 13 eyes treated exclusively with anti-VEGF for PDR with or without macular edema or severe NPDR with macular edema, with hiatus of 12 months, 9 presented with vitreous hemorrhage, 5 with neovascular glaucoma, and 4 with tractional retinal detachment. Despite the aggressive treatment of the complications, 10 eyes lost more than 3 lines of vision, and 2 had final vision hand motions [103]. So, while anti-VEGF proved to be effective for PDR in the clinical trials, in real-world the unclear long-term advantages of pharmacological monotherapy over PRP, the increased cost, and treatment burden are not optimal for many diabetic patients.
\nNeovascular glaucoma is a late complication of proliferative disease with chronic ischemia in the posterior segment and development of a fibrovascular membrane on the anterior surface of the iris and iridocorneal angle of anterior chamber, and usually its onset correlates with poor glycemic control. In the early stages, iris neovascularization can be found without elevated IOP. Panretinal photocoagulation remains the mainstay in controlling the neovascular drive and should be considered in all cases of neovascularization of the anterior segment when retinal ischemia is present. After panretinal photocoagulation, complete regression of retinal neovascularization can be reached in 67–77% of cases, visual loss can be prevented in 59–73%, and IOP reduction can be achieved in 42% [104]. Anti-VEGF injections can lead to regression of both iris and angle neovascularization and improve intraocular pressure control when the angle remains open. However, the effects of anti-VEGF agents seemed to induce only a temporary regression of new vessels in the anterior chamber angle and IOP reduction, generally lasting between 4 and 6 weeks [105]. Glaucoma drainage devices are usually considered the first treatment option for refractory glaucoma. Neovascular glaucoma patients are at greater risk for surgical failure after glaucoma valve surgery compared with non-neovascular glaucoma controls. A recent retrospective, comparative, case series of 163 eyes of 151 patients with neovascular glaucoma included 99 treated without and 64 treated with intravitreal bevacizumab. IOP decreased to 18.3 ± 13.8 mmHg in the non-bevacizumab group and 15.3 ± 8.0 mmHg in the bevacizumab group. Panretinal photocoagulation substantially reduced the need for glaucoma surgery (P < 0.001) in bevacizumab-treated eyes. Therefore, although bevacizumab delayed the need for glaucoma surgery, panretinal photocoagulation was the most important factor that reduced the need for surgery. Vision and IOP in eyes with neovascular glaucoma treated with bevacizumab showed no long-term differences when compared with eyes that were not treated with bevacizumab. Thus, intravitreal anti-VEGF drugs serve as an effective temporizing treatment but are not a replacement for close monitoring and definitive treatment of neovascular glaucoma [106, 107].
\nImpairment of vision in diabetic patients is not limited to retinopathy—the leading causes of deteriorated vision and progression of vision loss in a cohort from South India were cataracts and uncorrected refractive errors [108]. The introduction of phacoemulsification significantly reduced the surgical trauma and leads to a growing tendency toward earlier cataract surgery in diabetic patients [109]. This approach facilitates panretinal photocoagulation and allows for the identification and adequate treatment of diabetic macular edema before and after cataract surgery. Preexisting macular edema can increase the risk of edema progression by 20–50%, and intravitreal anti-VEGF agents are recommended perioperatively [110]. Steroids, on the other hand, have been shown to be effective for persistent or refractory diabetic macular edema prior to and after cataract procedures. Dexamethasone implants and fluocinolone implants resulted in significant improvement in clinically significant macular edema and visual outcomes [111]. Despite the advancement in phacoemulsification technology, poor visual acuity following cataract extraction is still common in patients with diabetes. Posterior capsule opacification, postoperative cystoid macular edema, diabetic macular edema [112], and worsening of the DR are the main complications seen in diabetic patients. According to the Early Treatment of Diabetic Retinopathy Study, the presence of clinically significant diabetic macular edema at the time of cataract surgery was significantly associated with poor visual acuity and was a predictor of final visual acuity worse than 20/200 following uncomplicated phacoemulsification [113]. The severity of DR at the time of cataract surgery is also a significant determinant of postoperative VA; more severe retinopathy seems to be associated with an increased prevalence of macular ischemia or edema and a reduced tendency for spontaneous resolution of postoperative macular edema with associated poor postoperative VA. Treatment-naïve PDR before cataract surgery may progress to vitreous hemorrhage and tractional retinal detachment following phacoemulsification, thus threatening good visual outcome [114].
\nIn conclusion, vision loss due to diabetic complications in the eye is growing worldwide despite availability of screening programs, advanced diagnostic tools, pharmacotherapy, and rapidly evolving surgical technology. Prevention requires:
Identification of the social groups and individuals at high risk of vision-threatening diabetic complications
Coverage with diabetic retinopathy screening with introduction of AI tools, wide-field retinal assessment, telemedicine, and OCT of the posterior segment
Outreach of qualified management closer to the diabetic patients’ communities
Early, intensive management before significant vision loss
Lifetime, highly qualified monitoring and early management of complications
Close, continuous collaboration with the treating diabetology team
Involvement of the family, community, diabetic patients’ organizations, and social media in patient care, adherence to treatment, prevention of physical and mental disability, and improvement of quality of life
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\\n\\nAs a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 118,000 international scientists and researchers.
\n\nThe Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
\n\nOAPF Publishing Options
\n\n*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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\n\nYour Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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