Comparison between hierarchical and distributed caching architectures
\\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!
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His research in the fields of memory and conceptual knowledge are well known. He has held research positions at the MRC Cognition and Brain Sciences Unit in Cambridge (1994-1995), King’s College London (1998-2001), and the University of Cambridge (2001-2005). 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This, in turn, made the number of Internet users increase exponentially. Such increase in number of users, and the demand of information and services resulted in a variety of problems that affected the user\'s comfort in using and retrieving information from the Web. Despite all the advanced technologies used today, two main problems are still faced which are server overloading and network congestion. Network congestion can occur when a network link is carrying too much data that would affect its quality of service. Server overloading happens when the server receives more service requests than it can handle. Many researchers have tackled these issues since the early 90\'s and some helpful solutions have been implemented. One of the most effective solutions that alleviate server overload and reduce network congestion is web caching. Web caching is the process of saving copies of content (obtained from the Web) closer to the end user, in order to reduce bandwidth usage, prevent server overload, as well as reducing the user’s perceived latency. These studies have resulted in the development of a web caching notion which can be implemented at three levels. Level1 (L1) cache is known as the client caching which takes place at the browser level. Level2 (L2) takes place at the proxy level while Level3 (L3) is the cooperation of the proxies in sharing cached objects among the cooperation set (Dykes & Robbins, 2002). Researchers have agreed that caches on the client browser and proxy level can significantly improve performance (Abrahams et al., 1995). In addition, many studies encouraged the broad use of web caching within organizations that provide internet service to users (Korupolu & Dahlin, 1999, Gadde & Robinovich, 1999, Wolman & Voelker, 1999, Lee et al., 2001). Such studies helped in considering the possibility of constructing a large number of web caches from cooperative proxies and client caches (Zhu & Hu, 2003) to introduce a new cooperation level.
\n\t\t\tA range of studies agreed on the benefits of web caching and its major contribution to Internet services. Still the rapid growth of internet traffic and users has made us witness rapid improvements on the broadband services. Nowadays, Internet Service Providers (ISPs) are offering better broadband networking technologies, but still many residential and small-business users are using low-bandwidth connections. Any near promise of the availability of such broadband technologies for users in rural areas is still uncertain because of the associated high cost. However, even with the availability of high bandwidth, there are types of information such as multimedia that always demand more bandwidth. For example when YouTube became very popular, one of the Internet Service Providers (ISP) had huge increase in the amount of information entering the network and an increase in the user\'s perceived latency. When the problem was observed closely, the ISP discovered that 1Gb/s in the network was consumed by only one website, YouTube.com. In addition to the obvious benefits of web caching, some of the important properties desired in a web caching scheme are fast access, robustness, transparency, scalability, efficiency, adaptivity, stability, load balanced, ability to deal with heterogeneity, and simplicity (Wang, 1999).
\n\t\t\tOur area of interest in building a new hybrid web caching architecture is to reduce the client latency period in retrieving WWW information in rural areas as well as improving the performance of the broadband technology. This architecture explores and benefits from the free space offered by the client’s caches when they are connected to the internet, and reduces the load on the upper tier (proxies & web) servers.
\n\t\t\tWith the exponential growth of the internet, a single web cache is expected to become a hot spot. If the solution is to add more hardware, we can expect a point where no hardware is sufficient enough, and the managment of such number of extra harware is a burden in different aspects.
\n\t\tEver since web caching has been found as a solution for network congestion and server overloading, different caching architectures were proposed to ease the process of delivering the requested data through inter-cache cooperation. The next sections discuss some of the most common web caching architectures proposed in recent years. We classify these architectures into hierarchical architecture, distributed architecture, and hybrid architecture.
\n\t\t\tThe idea behind constructing a hierarchical cache is to arrange a group of caches in a tree-like structure and allow them to work together in a parent-child relationship to fulfil the requested objects by the client. If a hierarchical structure is arranged properly, the hit ratio can be increased significantly (Wang, 1999).
\n\t\t\t\tIn a hierarchical caching architecture, caches are placed at various levels of the network. As shown in Figure 1, there is a client’s cache, institutional cache, regional cache, national cache, and at the top is the original server. When a client requests a page, it first checks its browser cache. If the request is not fulfilled, then it is forwarded to the institutional cache. If the request is not satisfied by the institutional cache, then it is passed to the regional cache. If the request is not found at the regional cache, then it is redirected to the national cache. The national cache forwards the request to the original server if it cannot fulfill the request. When the object is found in a cache or the original server, it travels down the hierarchy and leaves a copy of the object in each caching level in its path to the client.
\n\t\t\tHierarchical Caching Architecture.
Researchers have proposed an alternative to the hierarchical caching architecture and eliminated the intermediate tiers except for the institutional tier. All caches in that tier contain meta-data about the content of every other cache. Another approach proposed in this architecture is to employ the hierarchical distribution mechanism for more efficient and scalable distribution of meta-data (Wang, 1999). Figure 2 illustrates this approach.
\n\t\t\t\tIn a distributed caching architecture that employs the hierarchical distribution mechanism, the layers that contain cached objects are only the client and institutional layers. Other layers contain information about the contents of the caches in the institutional layer.
\n\t\t\tA hybrid scheme is any scheme that combines the benefits of both hierarchical and distributed caching architectures. Caches at the same level can cooperate together as well as with higher-level caches using the concept of distributed caching (Wang, 1999). A rough comparison between hierarchical, distributed, and hybrid caching architectures is shown in Table 1.
\n\t\t\t\tA hybrid caching architecture may include cooperation between the architecture\'s components at some level. Some researchers explored the area of cooperative web caches (proxies). Others studied the possibility of exploiting client caches and allowing them to share their cached data. One study addressed the neglect of a certain class of clients in researches done to improve Peer-to-Peer storage infrastructure for clients with high-bandwidth and low latency connectivity. It also examines a client-side technique to reduce the required bandwidth needed to retrieve files by users with low-bandwidth. Simulations done by this research group has proved that this approach can reduce the read and write latency of files up to 80% compared to other techniques used by other systems. This technique has been implemented in the OceanStore prototype (Eaton et al., 2004).
\n\t\t\t\tDistributed Caching Architecture
Another study proposed an internet caching service called CRISP (Caching and Replication for Internet Service Performance). The problems that CRISP tried to solve are the performance, scalability, and organizational problems in large central proxy caches. The idea behind CRISP is to connect cooperative proxies through a mapping service which contains information about cached URLs in each proxy in the cooperative set. A drawback in this structure is the failure of the centralized mapping service. This drawback is solved by forcing the proxies to work individually without letting the user feel the impact of the failure except with the increase in the perceived latency. The study claims that this simple design and implementation of cooperative caching is effective and efficient for distributed web caches serving tens of thousands of users (Gadde & Robinovich, 1997).
\n\t\t\t\tAnother study was motivated by the studies that have shown that limited bandwidth is the main contributor to the latency perceived by users. And also the fact that the majority of the population was still using modems at that time. An approach to reduce user-perceived latency in limited bandwidth environments is investigated. It explores a technique based on prefetching between caching proxies and client browsers. The idea is that the proxy would predict what the user might request/access next, where it invests the user’s idle times while checking the result of the previous request and predicts what the user will request next. The proxy would push its prediction result to the client’s browser cache, noting that the proxy will only use the contents of its cache in this prediction. The result of this investigation showed that prefetching between low-bandwidth clients and caching proxies combined with data compression can reduce perceived user latency by over 23% (Fan et al., 1999).
\n\t\t\t\tOne analysis used a trace-based analysis and analytic modelling to put inter-proxy cooperation into the test and examine its performance in the large-scale WWW environment. It examines the improvement that such cooperation can provide in a 200 small organizations’ proxies environments, as well as with two large organizations handling 20,000 and 60,000 clients. However the modeling considered a much larger population containing millions of users. The overall studies and examination done in this paper concluded that cooperative caching has performance benefits only within limited populations (Wolman & Voelker, 1999).
\n\t\t\t\tAnother examination explored the benefits of the cooperation among proxies under different network configurations and user access patterns. This was achieved by classifying and analysing these cooperation schemes under a unified mathematical framework. These analytical results were validated using a trace-driven simulation. Using the results from the simulation and analysis, the following was concluded:
\n\t\t\t\tProxy cooperation is beneficial when the average object size is large and the working set does not fit in a single proxy. Such benefit also depends on the cluster configuration.
The cooperation between proxies, where each proxy serves missed requests from other proxies in its cooperation set, is mostly sufficient when the users’ interests are highly diverse.
The cooperation of the proxies in object replacement decisions would result in more benefits when the user accesses are dense and the requests are focused on a small number of objects.
Overall, the benefit of the cooperation among proxies is dependent on a number of factors including user access, user interest, and network configuration (Lee et al., 2001).
\n\t\t\t\tAnother study presented a decentralized, peer-to-peer web cache called Squirrel that uses a self-organizing routing substrate called Pastry (Rowstron & Peter Druschel, 2001) as its object location service. The key idea is to enable web browsers on desktop machines to share their local caches, to form an efficient and scalable web cache, without the need for dedicated hardware and the associated administrative cost. An evaluation of a decentralized web caching algorithm for Squirrel is also provided. Studies discovered that it exhibits performance comparable to a centralized web cache in terms of hit ratio, bandwidth usage and latency. It also achieves the benefits of decentralization, such as being scalable, self-organizing and resilient to node failures, while imposing low overhead on the participating nodes. Squirrel tested two different schemes called the home-store and directory schemes on a LAN organization. Performance studies have shown that the home-store scheme depicts less overhead on the serving nodes; this approach works for load balancing among the peer-to-peer nodes (Lyer et al., 2002).
\n\t\t\t\tAnother research proposes a more effective use of caching to cope with the continuing growth of the internet. This proposal is to exploit client browser caches in cooperative proxy caching by constructing the client caches within each organization as a large peer-to-peer client cache. The goal of this study is to investigate the possibility and benefit of constructing such large peer-to-peer client cache in improving the performance of the internet. In this architecture, clients can share objects cached not only at any proxy in the cooperative set but also at any neighbour\'s cache connected to the network. After doing some simulations with/without exploiting client caches, results have shown that exploiting client caches can improve performance significantly. It also introduces a hierarchical greedy dual replacement algorithm which provides cache coordination and utilizes client caches (Zhu & Hu, 2003).
\n\t\t\t\tAnother study presented the design and implementation of a previously proposed scheme based on a novel Peer-to-Peer cooperative caching scheme. It considers new means of communication between cooperative caches. It also proposes and examines different routing protocols for data search, data cache, and replication of data. The results of the performance studies show the impact of cache coherency on the system’s performance. It also shows that the proposed routing protocols significantly improve the performance of the cooperative caching system in terms of cache hit ratio, byte hit ratio, user request latency, as well as the number of exchanged messages between the caches in the cooperative set (Wang & Bhulawala, 2005).
\n\t\t\t\tYet another study presented a trustable peer-to-peer web caching system, in which peers in the network share their web cache contents. To increase the trust-level of the system, they have proposed to use sampling technique to minimize the chance of distributing fake web file copies among the peers. They further introduce the concept of opinion to represent the trustworthiness of individual peer. A prototype has been built and the experimental results demonstrated that it has fast response time with low overhead, and can effectively identify and block malicious peers. This paper proposed a reasonable solution in locating the cached object using a search history similar to a log file that is stored in each peer. Each peer might carry a different log of search history of the peers in the system. When a request is initiated by a client and a cache miss was returned from its local cache, the request is forwarded to the client’s nearest neighbour. If a cache miss occurred then this neighbour will look into the search history and find out which was the last peer that initiated a request to the same object and connect to that peer. This is an efficient solution but it would be rather faster if the client looks into the search history log it has before connecting to the neighbour in the first place. At the same time it can check if one of the peers that requested this object is any of its neighbours. Even though many papers have discussed the issue of trust between the peers, and some suggested “building trust” approach between peers, this issue is still largely unresolved and in need of further investigation (Liu et al., 2005).
\n\t\t\tThe proposed architecture is a cooperative client-client, client-proxy, proxy-proxy caching system that aims to achieve a broadband-like access to users with limited bandwidth. The proposed architecture is constructed from the caches of the connected clients as the base level, and a cooperative set of proxies on a higher level, as shown in Figure 3. The construction of the large client web cache is based upon some of the novel peer-to-peer (P2P) client web caching systems, where end-hosts in the network share their web cache contents.
\n\t\t\tThe proposed architecture is based upon the idea of a hybrid scheme. It consists of two tiers of cooperative caches: client caches and proxy caches. The properties that we wanted to achieve while designing the architecture are as follows:
\n\t\t\t\tSlight congestion in the parent caches.
Low latency and data transmission time.
Evenly distributed network traffic for faster transmission time and low latency achievement.
Long connection times.
Low bandwidth usage which is the priority in this architecture along with the low latency property.
A maximum of two hierarchical levels.
Low disk space usage therefore low duplication of objects.
Maintain an easy plan to keep the cached objects fresh.
Test different object retrieval approaches to achieve a high to a very high hit ratio and grant the user a fast response time.
Features | \n\t\t\t\t\t\t\tHierarchical | \n\t\t\t\t\t\t\tDistributed | \n\t\t\t\t\t\t\tHybrid | \n\t\t\t\t\t\t
Parent caches | \n\t\t\t\t\t\t\tCongested | \n\t\t\t\t\t\t\tslight congestion | \n\t\t\t\t\t\t\tslight congestion | \n\t\t\t\t\t\t
Latency | \n\t\t\t\t\t\t\thigh | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t
Connection times | \n\t\t\t\t\t\t\tshort | \n\t\t\t\t\t\t\tlong | \n\t\t\t\t\t\t\tlong | \n\t\t\t\t\t\t
Bandwidth required | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t\thigh | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t
No. of Hierarchies | \n\t\t\t\t\t\t\t<4 | \n\t\t\t\t\t\t\t1 | \n\t\t\t\t\t\t\tone - two | \n\t\t\t\t\t\t
Transmission time | \n\t\t\t\t\t\t\thigh | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t
Network traffic | \n\t\t\t\t\t\t\tUnevenly distributed | \n\t\t\t\t\t\t\tEvenly distributed | \n\t\t\t\t\t\t\tEvenly distributed | \n\t\t\t\t\t\t
Disk space usage | \n\t\t\t\t\t\t\tSignificant | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t
Placement of caches in strategic locations | \n\t\t\t\t\t\t\tvital | \n\t\t\t\t\t\t\tNot required | \n\t\t\t\t\t\t\tup to ISP | \n\t\t\t\t\t\t
Freshness of cached contents | \n\t\t\t\t\t\t\tdifficult | \n\t\t\t\t\t\t\teasy | \n\t\t\t\t\t\t\teasy | \n\t\t\t\t\t\t
Hit ratio | \n\t\t\t\t\t\t\tHigh | \n\t\t\t\t\t\t\tVery high | \n\t\t\t\t\t\t\thigh - very high | \n\t\t\t\t\t\t
Response time | \n\t\t\t\t\t\t\tmoderate | \n\t\t\t\t\t\t\tfast | \n\t\t\t\t\t\t\tfast | \n\t\t\t\t\t\t
Duplication of objects | \n\t\t\t\t\t\t\thigh | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t\tlow | \n\t\t\t\t\t\t
Comparison between hierarchical and distributed caching architectures
The new proposed hybrid architecture.
There are many challenges in the proposed approach since we are dealing with an unknown number of clients in an unstable environment. We have chosen to deal with the following issues:
\n\t\t\t\tThe main challenge in cooperative cache architecture is how to quickly locate the location of the requested cached object.
\n\t\t\t\t\tMelpani et al. (Malpani et al., 1995) proposed a scheme where a group of caches function as one. When the user requests a page, the request is sent to some random cache. If the page was found in that cache, then it is returned to the user. Otherwise, the request is forwarded to all the caches in the scheme via IP multicast. If the page is cached nowhere, the request is forwarded to the home site of the page.
\n\t\t\t\t\tHarvest cache system (Chankhunthod et. al, 1996) uses a scheme where caches are arranged in a hierarchy and uses the Internet Cache Protocol (ICP) for cache routing (Wessels & Claffy, 1998). When a user requests a page, the request travels up the hierarchy to locate the cached copy without overloading the root caches by allowing the caches to consult their siblings in each level before allowing the request to travel up the hierarchy.
\n\t\t\t\t\tAdaptive Web Caching (Michel et al., 2001) builds different distribution trees for different servers to avoid overloading any root. This scheme is robust and self-configuring. It is more efficient with popular objects. For less popular objects, queries need to visit more caches, and each check requires a query to and responses from a group of machines. It is suggested to limit the number of caches the query visits, to decrease the added delay.
\n\t\t\t\t\tProvey and Harrison (Povey & Harrison, 1997) proposed a distributed caching approach to address the problems faced in the previously proposed hierarchical caching. They constructed a manually configured hierarchy that must be traversed by all requests. Their scheme is promising in the way that it reduces load on top-level caches by only keeping location pointers in the hierarchy (Wang, 1999). A simulation study was done as well, where the results showed that this proposed approach performs well for most network topologies. Results have also shown that in topologies where the number of servers in the upper levels is low, the performance of the hierarchical caching is better than the proposed approach. The conclusion of this paper is that the overall results show that there is no significant performance difference between the old and the proposed approach.
\n\t\t\t\t\tWang (Wang, 1997) describes an initial plan in Cachemesh system to construct cache routing tables in caches. These tables guide each page or server to a secondary routing path if the local cache does not hold the document. A default route for some documents would help to keep table size reasonable (Wang, 1999).
\n\t\t\t\t\tLegedza and Guttag (Legedza & Guttag, 1998) offered to reduce the time needed to locate unpopular and uncached pages or documents by integrating the routing of queries with the network layer’s datagram routing services (Wang, 1999).
\n\t\t\t\tThe most outstanding benefit of web caching is that it offers the user lower access latency. It also defeats the side-effect of providing the user with stale pages (i.e. pages which are out of date with respect to their home site). The importance of keeping the cache\'s content coherent is to provide the user with fresh and up-to-date pages. Web caching reduces redundant data in the network which eases the process of keeping the pages updated. Some of the proposed mechanisms to keep cache coherency are strong cache consistency and weak cache consistency (Wang, 1999).
\n\t\t\t\t\tStrong cache consistency
Weak cache consistency
Proxy caches have been recognized as an effective and efficient solution to improve the web performance. A proxy serves in different roles: data cache, connection cache, and computation cache. A recent study has shown that caching Web pages at proxy level reduces the user access latency 3% - 5% as compared to the no-proxy scheme (Wang, 1999).
\n\t\t\t\t\tIt is very important to set the architecture and prepare it to deal with different types of resources. Most of the web resources are becoming dynamic with the invasion of web services. It is very helpful to use computation caching to retrieve dynamic data. It can be done by caching dynamic data at proxies and migrating a small piece of computation to proxies to generate or maintain the cached data. Also the architecture should be able to retrieve information about the requested resource before adding delay to the request by looking for it in the caches when it is an uncachable resource.
\n\t\t\t\tThe hot spot problem is one of the issues that triggered the web caching research area. It occurs any time a large number of clients access data or get some services from a single server. If the server is not set to deal with such situations, clients will perceive a lot of delay and errors and the quality of service will be degraded. Several approaches to overcome the hot spots have been proposed. Most use some kind of replication strategy to store copies of hot pages/services throughout the Internet; this spreads the work of serving a hot page/service across several servers (Wang, 1999). Another approach that can be used is to get the server to work in a cooperative set with other servers or caches to fulfil a request without overwhelming the home server with users\' requests.
\n\t\t\t\tThe flow of information in the architecture can have different scenarios and paths. The two scenarios chosen for this architecture are as follows.
Scenario1, each client keeps a search history log of the clients that contacted it. When a client initiates a request it first looks into its local cache. If the requested page is found, then it is fetched from the local cache of the client. Otherwise, it looks into its search history log and search for the last client who requested this page. If found, it fetches the requested page from the client otherwise it consults the proxy to fetch the requested page. If the proxy finds it in its cache, it forwards the requested page to the client. Otherwise, it consults the proxies in its cooperative set. If none has it, then the request is forwarded to the home server (see Figure 4).Scenario 1
Both of the mentioned scenarios are to be tested and analysed using a simulator. The simulation could result in the superiority of one of them or the need for a hybrid of both.
\n\t\t\t\tThe reason such scenarios are chosen is to explore and benefit from the free space offered by the client\'s caches when they are connected to the internet. This architecture aims to reduce the load on the upper tier, the proxy, by initiating direct communication between the clients in P2P-like atmosphere which are geographically close to each other. The communication between the clients better stay as simple as possible as not to produce more delay and load on the client and organize the flow of the network traffic.
\n\t\t\tScenario 2.
This chapter presented the basic web caching architectures that has been found in the literature as a solution for network congestion and server overloading problems. A rough comparison of common architectures has been presented to show the pros and cons of each. The chapter also proposed an architecture that is believed to offer a better performance in different aspects which is due to combining the benefits of many architectures and schemes into this new architecture. This architecture will look into some design issues such as the communication between the caches, the path to keep the caches\' contents coherent, cache contents, and load balancing at the client and proxy side. Current work is on the simulation of the architecture\'s flow of information scenarios, using OMNET++, to obtain results and fine tune the architecture.
\n\t\tA new type of biomedical devices was born when technologies and facilities for Micro and Nano Electro Mechanical Systems (MEMS and NEMS) fabrication have met medical and biological issues. These new kinds of biomedical devices are able to easily control physical and chemical parameters at a very small scale, down to nanomolar concentrations and nanometric sizes [1, 2, 3]. Moreover, the integration of such a device in wearable and/or mobile systems gave them popularity among commercial devices. In this technological frame, Microneedles based devices (MNDs) were born. Their height is sufficiently large to overcome the outer natural barrier of the human body, the stratum corneum of the skin, but not enough to reach the nerves, resulting in a lack of pain [4]. Usually, MN height is ranging from 10 to 1000 μm, depending on the application and how deep in the epidermis is the specific target analyte. Then, MNs based devices act as an interface between the body of the patient and a biomedical device, whose applications can range from fluid extraction for ex-situ analysis to drug and gene delivery, from in situ diagnostic tools to targeted cell therapy [1, 2, 3, 4]. Material, length, shape of the body and the tip of the MNs drastically vary depending on the application [2, 3] and the fabrication technology, according to new needs and challenges. Biosensing systems based on MNs have to overcome the stratum corneum without pain and to detect the target analytes directly in the interstitial fluid. In those cases, more than a strategy could be used: the functionalization of the surface of MNs with a specific probe, realizing a coated MND [5], the trapping of probe molecules into a swelling material [6] or the extraction of fluids and the analysis into a microfluidic system [7] are only some examples. In Figure 1A a sketch of different MNDs for sensing purposes is shown.
(A) Sketch of different MNDs for sensing purposes together with their working conditions into the human skin. Starting from the right, they are characterized by the locus of probe-analyte interaction: Swelling bulk MNs sensors (BMNDs), where probe-analyte interaction is inside the volume of MN; hollow MNs sensors (HMNDs), where a small material sampling of ISF is analyzed on or offline; coated MNs sensors (CMNDs), whose surface is the locus of the interaction between analytes and bioprobes; planar MNs sensors (PMNDs), where the probe–analyte interaction is on a specific zone of a flat MNs surface. (B) some configurations for MNs for drugs delivery: (from left) hollow MNs present a inner cavities to immediately administration of high dose and high MW drugs; soluble and hybrid MNs for fast administration with a high doses and medium MW; coated MNs for fast administration of low doses and any MW; swelling MNs for very slow administration of high doses of smaller molecules. Reproduced with permission of Ref. [8].
Moreover, microneedle-based devices (MNDs) can combine diagnostic sensing and therapeutic administration of drugs in one single tool. From this point of view, more than a painless door to the human body, a MND represents the a perfect example of theranostic instrument, since a single device could quantify the real value of a relevant biomolecule, such as glucose, and accurately deliver a drug, the insulin, if needed. MNDs are particularly interesting as simple drug administration tools, too. In fact, the transdermal route for drug administration is a very fascinating way, not only for the very low invasiveness and the easiness of self-administration, but also for the absence of first pass metabolism. However, the intercellular lipid matrix of the epidermis consists of ceramides, free fatty acids, and cholesterol, a complex mixture of neutral lipids arranged as bilayers with hydrophobic chains facing each other (lipophilic bimolecular leaflet) [9]. Transdermal delivery works only for lipophilic uncharged drugs with low MW (<500 Da), which need low dose and continuous delivery. Moreover, components, formulations and drugs must be non-irritating and non-sensitizing. MNs can be used with both lipophilic and hydrophilic formulations, both charged and uncharged drugs, both small and oversized molecules.
For all these cases, MN configurations are illustrated in Figure 1B, where the possibility to use solving or hybrid soluble/insoluble MNs are considered.
MNDs could be integrated on printed circuit boards, flexible electronics and microfluidic channels, thus allowing a continuous monitoring of the physiological parameters with very low invasiveness, together with sustained and localized administration of drugs. MNDs can be designed for very specific applications, from the detection of skin cancer to the monitoring of metabolic pathways.
Technologies, skills and facilities for Micro and Nano Electro Mechanical Systems (MEMS and NEMS) fabrication are the key elements for the development of new biomedical devices [1, 2, 3, 10]. Fabrication methods for Microneedles (MNs) strongly depend on the MNs shape, tip model, length, density of the MNs matrix, and the material of which they are made of.
Moreover, structural characteristics of the MNs matrix in turn depend on the specific application considered [11]. In fact, MNDs are exploited in fluid extraction [12] and in-situ diagnosis of diseases [13], in drug and gene delivery strategies [1, 11], in cell therapy [3] and so on.
At first, Silicon and silicon-based nanostructured materials, such as porous silicon, were largely employed in MNDs fabrication due to the well-established functionalization chemistry protocols and fabrication techniques, extenseively used in microelectronics, which simplified the integration into more complex systems [14]. However, silicon revealed to be a non-biocompatible material, due to its fragility and to the local inflammations (silicosis) it could provoke; for this reason its use has been limited in cell applications [15].
To overcome limitations on the use of silicon, polymers have been extensively proposed as alternative materials in many applications. Poly Dimethyl Siloxane (PDMS) is one of the most used materials in microfluidics to design biomedical devices, due to its well-known biological compatibility [16]. Usually, PDMS is employed as mold to fabricate MNDs by replica molding (see Figure 2). In case of PDMS molding, the fabrication involves the following steps: female PDMS mold fabrication by means of standard photolithography or laser drilling; patterned MNs in PDMS mold filling with liquid polymers in vacuum conditions; curing of the polymers by temperature and/or UV exposure; mold removal; eventually, an additional curing step [16]. Biodegradable polymers have been largely employed in MNDs for drugs delivery application [20, 21, 22, 23, 24], but the biodegradability is not required for biosensing.
Main fabrication strategies for MNs fabrication. Replica molding [16] centrifugal lithography [17] photolithography [18] drawing lithography [19].
A direct method for MNDs fabrication is the so-called drawing lithography [19]. Drawing lithography is a fabrication method, which does not need light irradiation and a mask, since it is based on the use of a thermosetting polymer directly drawn from a 2D solid surface (see Figure 2). In drawing lithography, commercial photoresist is usually spin coated or drop casted onto the substrate and cooled down. Drills are fixed in an array on a PDMS frame and used as pillars contacted with the photoresist. Conical-shaped bridges between the substrate and the pillars appear when their relative distance is increased by drawing (elongation). The bridges are cured to generate a rigid structure. Finally, the separation of the bridges produces the desired MND.
However, drawing method lacks in flexibility and the curing at high temperature of the polymers encapsulating biopharmaceutical molecules can cause their denaturation or inactivation. In fact, MNDs encapsulating drugs or bioprobes must be fabricated in a controlled environment to preserve the biological activity.
The increasing demand for simple methods that preserve the biological activity by utilizing the natural properties of polymers has conducted to the idea of centrifugal lithography [17]. In [17], centrifugal lithography was used for the fabrication of MNDs in a single centrifugation, by exploiting the self-shaping properties of hyaluronic acid (HA). Briefly, fabrication involves the following steps: HA drops encapsulating drugs molecules are casted onto the substrate; centrifugal force is applied under refrigerated conditions (4°C) to the droplets in order to shape in hourglass microstructures; finally, the mirroring shapes are separated to form MNs. Also in the case of HA, drug delivery is successfully obtained, but biosensing is unavailable due to its biodegradability.
On the other hand, hydrogel polymers are very attractive materials for MNDs and, generally, for biomedical devices, since a hydrated gel provides near physiological conditions. These gels are excellent encapsulation matrices for biological probes, such as enzymes and peptides [18, 20, 25, 26]. Moreover, the standard photolithographic processes can be employed to fabricate micrometric devices based on polymeric hydrogels [materials] (Figure 2). In [6, 18, 27, 28], authors proposed procedures of standard direct photolithography, where a mixture of Poly(ethylene glycol) diacrylate (PEGDA) and a commercial photoinitiator were used as an ordinary photoresist, without any etching step being required. In fact, PEGDA is a biocompatible polymer that solidifies at room temperature in presence of a photoinitiator after exposure to ultraviolet (UV) light for few seconds. In case of photolithographic process, the fabrication involves the following steps: the liquid photosensitive polymeric mixture is casted onto a UV-transparent substrate and exposed to ultraviolet radiation, in order to fabricate the MNDs base; a vessel is fulfilled with a second quantity of liquid mixture and the MNDs base is put on; a second exposure through a mask, whose pattern is an array of holes, is applied; finally the structure is developed by simply washing in deionized water. The PEGDA mixture can be customized to encapsulate a variety of drugs or sensing probes as biological molecules or inorganic nanoparticles [29, 30, 31].
Comparing the fabrication methods, all produced MNs have demonstrated high quality in indentation proof and a good grade of reproducibility, with some critical issues during the mold removal step in replica molding method.
Finally, we highlight that the photolithographic approach allows the fabrication of MNDs for a wide range of applications. In fact, this process allows the design of a wide range of MN types with different shape, length and tip, simply by adjusting the exposure parameters or shape photolithographic masks [18, 28]. In Figure 3, the whole range of possibilities enabled by photolithographic method are summarized: mask type 1 (simple circle) enables MNs with several heights depending on time exposure; mask type 2 (ring) enables hollow MNs with height and closure depending on time exposure; mask type 3 (mismatched concentric ring) enables in a single exposure the fabrication of hollow MNs with a lateral oblique aperture as in hypodermic syringes. Also in this case, lateral aperture is smaller as the exposure time increases.
The photolithographic methods offer a wide range of solutions for MNDs. Changing time exposure and/or photolithographic mask several configurations and arrays of MNs for both therapeutics and biosensing can be fabricated. From above: Mask type 1 (simple circle) enables MNs with several heights depending on time exposure; mask type 2 (ring) enables hollow MNs with height and closure depending on time exposure; mask type 3 (mismatched concentric ring) enables in one only exposure hollow MNs with a lateral oblique aperture, which is smaller as the exposure time increases.
MNs represent actually a flexible technological platform, which enables innovative diagnostic solutions and breakthrough therapeutic issues in biomedicine [1, 2, 3]. First, finding a painless alternative to hypodermic injections has driven researchers to the development of MNDs. In fact, belonephobia, which is the unreasonable fear of needles, affects up to 10% of the population and has implications for treatment and follow up, especially in the pediatric patients [32]. In reverse, the sensation caused by MNs has proved to be statistically indistinguishable from a smooth surface and the pain caused by a hypodermic needle has been perceived substantially more than MNs [4]. Moreover, as previously stated, the transdermal route for drug administration is a very fascinating way, not only for the very low invasiveness and the easiness of self-administration, but also for the absence of first pass metabolism. However, the intercellular lipid matrix of the epidermis consists of ceramides, free fatty acids, and cholesterol, a complex mixture of neutral lipids arranged as bilayers with hydrophobic chains facing each other (lipophilic bimolecular leaflet) [9]. Transdermal delivery works only for lipophilic uncharged drugs with low MW (<500 Da), which need low dose and continuous delivery. Moreover, components, formulations and drugs must be non-irritating and non-sensitizing. MNs can be used with both lipophilic and hydrophilic formulations, both charged and uncharged drugs, both small and oversized molecules. In fact, currently, interesting MNDs are involved in clinical trials both for some topical applications, as analgesic compounds, anti-inflammatory or anesthetic drugs, and for some traditional systemic drugs, such as anticancer drugs, vaccines, insulin or hormones [33].
Among the topical applications, MNDs can replace very invasive methods for warts therapy, such as electrocautery and cryotherapy. A MND developed by Ryu et al. for warts treatment resulted to be innovative and effective [34]. In this study, quite 40 patients with wart lesions were enrolled and referred less pain than cryotherapy, as well as more tolerability with respect to electrocautery. Other skin diseases have been treated by means of MNDs, as melasma in [35], where authors fabricated biocompatible polymeric MNs based on methacrylic acid and polyvinyl pyrrolidone (PVP) to locally administer tranexamic acid, an innovative molecule that inhibits excessive melanin production by acting on melanocytes.
Acne vulgaris is another common inflammatory skin disease, affecting both physiologically and psychologically on patients. Barrier properties of skin strongly limit the usual antibiotic drug creams used to cure acne, but the use of MNs can overcome this limits, by using a reactive oxygen species–responsive [36]. In some in-vivo studies, MNDs for anti-acne therapy demonstrated bioresponsivity and efficiency to prevent bacterial growth. Finally, among the local administration taking advantage of MNs, the treatment of cornea diseases must be quoted. In particular, using dissolving polymeric microneedles to deliver besifloxacin to the cornea, a significant improvement in besifloxacin deposition and permeation were proven after only 5 minutes of application [37].
On the other hand, also administration of systemic drugs by means of MNDs showed good results in effectiveness, safe and economic efficiency as disposal devices. A wide range of molecules has been proven to be compatible with MNDs and each category of drug showed specific advantages compared to the use of oral or hypodermic administration.
First of all, vaccine delivery is probably the most involved health issue in MN technology, due to the large number of people involved each year. Nguyen and Park recently reviewed MNDs enrolled in human studies and reported the progress of MNDs in the clinical trials [38]. Finally, the use of MNs in therapy for clinical vaccine was recognized as very important, but further tests are recommended.
When MNDs is used to deliver vaccines based on DNA, some studies show that the gene expression is improved with respect to the results of conventional hypodermic injection. Consequently, the use of MNs to administrate DNA based vaccine results in an improvement of the immune responses [38, 39]. In [39], Authors hypothesized that the improvement of the immune response by delivering DNA vaccine by means of MNs could be due to the enhancement of the protein expression of the encoded gene.
Another important issue of vaccine administration improved by MNDs is the stability of the active ingredients into dissolving or swellable MNs. Encapsulation of inactivated polio vaccine (IPV) into dissolving MNs gains a better thermal stability with respect to that of the conventional liquid formulation of IPV [40]. The greater thermostability of the MN patches can generally enable a mass distribution with less constrains on cold chain storage resulting in a great reduction of costs, since global vaccination strategies require large immunization coverage. Moreover, new MNDs have been proposed as an alternative solution to the standard needle injections, for the advantage of self-vaccination.
Further studies have been done to elucidate the interactions between polymers and vaccines, as in the case of hydrogel based MNs and dissolving MNs. In these cases, the antigen ovalbumin was used as a model protein interaction with polymers and the consequences on the immune response [40, 41].
Hollow MNs have the advantage of overcoming the skin barrier imposed by the stratum corneum and delivering bigger molecules, such as macromolecules or nanoparticle systems, in the fastest possible way. Polymeric nanoparticles encapsulating the model antigen ovalbumin have been intradermal delivered by means of hollow MNDs by Niu et al., reporting that this kind of delivery is a promising approach to improve the effectiveness of vaccine formulations [42]. Among the dissolving devices, MNs based on hyaluronic acid (HA) resulted a promising encapsulation method of high content of antigen molecules in intradermal vaccination [43].
Also anticancer drugs belong to an important field of application of MNDs: two research groups have investigated on DOX administration by means of MNs in [44] and in [45]. Nguyen et al. found in vitro studies that Polyvinyl Alcohol (PVA) MNs enhance the transdermal delivery of DOX. In an in vivo antitumor study of Hao et al., a near-infrared responsive PEGylated gold nanorod (GNR-PEG) and DOX-loaded dissolvable HA-based microneedle (GNR-PEG&DOX@HA MN) has been developed against cancer of epidermis. In the study, mice treated with GNR-PEG&DOX@HA MNs taken remarkable advantage in antitumor efficacy in only one treatment, such that all mice have been cured without recurrence.
Moreover, lipophilic drugs found a lot of benefits from the use of MNs: poorly soluble drugs were encapsulated and easily administrated by MNDs, as in the case of the widely used specific 5-HT3 receptor antagonist, namely granisetron, that prevents nausea and vomiting during emetogenic chemotherapy in cancer patients [46]. In vivo results in [46] proved the evidence of controlled release systemic delivery.
An innovative pharmaceutical solution involving a MND in the field of HIV treatment has been proposed by Yavuz et al. in [47]. Also in this case, the self-injection route of administration represents the key issue for care improvement, since it limited the risks of contamination of the personnel involved in therapy and guaranteed a painless delivery for the patients via patches of microneedles.
New drugs and innovative therapies have been put in place with the help of MNDs. In particular, polymeric MNs have been widely exploited for their porous nature, which is expressed both by soluble MNs and by simply biocompatible ones. In [48, 49], anti-obesity substances have been successfully administered. These substances modified the metabolic process by increasing the energy consumed and transforming the white fat that stores calories into brown fat that burns calories [48]. While in [49], gelatin MNDs were used to induce lipolysis and suppress adipocyte lipogenesis in fatty rats.
Particular attention has to be paid on insulin delivery, since diabetes is one of the most common diseases, not only in elder patients, but also in obesity-affected patients.
Avoiding use of enzymes, a polymeric MND has been developed for on-demand insulin delivery by Chen et al. [50]. Continuous and acute glycemic control was realized with a long-acting, safe, stable, economically efficient and on-demand insulin delivery by MND, without depending on patient compliance. Thus, this technology opens to next generation of diabetes therapies.
In the same field, the treatment of individuals with type II diabetes mellitus has been successfully obtained with metformin HCl, the most widely used drug for this disease, delivered by means of hydrogel MNs [51].
In [52], authors proposed a temperature-independent MND for glucose-responsive insulin release. The rapid and sustained regulation is enabled through a “skin layer” of Phenylboronic acid (PBA), formed on the surface of MNs. PBA is a synthetic hydrogel with reversible binding capability with glucose. Compared to other glucose-responsive MNDs based on nanoparticles or glucose oxidase, the proposed patch overcomes the safety concerns and provides a good sustainability for large-scale production. In Figure 4, a sketch of the proposed glucose-responsive insulin dispensing MND is presented together with main results in on-demand insulin release at physiological temperature.
Adapted with permission from ACS Appl. Polym. Mater. 2020, 2, 7, 2781–2790. Copyright (2020) American Chemical Society. Sketch of device and in vitro FITC-labeled insulin release at various temperatures, pH 7.4.
Finally, we cite the engage of MNDs in effective administration of small peptides, vitamin K and mRNA administered, both in vitro and in vivo studies [53, 54, 55, 56].
In Table 1, main studies on therapeutic delivery with MNDs are summarized. Another important issue is the integration of MNs in optical, microelectronic or microfluidic devices. In [6], authors present the proof-of-concept of an optical integrated MNDs based on polymeric MNs and porous silicon (PSi) for transdermal drug delivery (Figure 5). Since its surface can be chemically modified, PSi is one of the most popular porous material used in drug administration [57]. Moreover, PSi structures have a tunable refractive index that depends on their porosity [58]. The MND presented in [6] is based on PEGDA hydrogel MNs and includes a PSi free-standing membrane with a Bragg mirror optical structure, i.e. an optical structure that reflects a specific wavelength (color) in the visible spectrum. Furthermore, the Psi membrane not only acts as a drug/biomolecules reservoir, but also it can be used to optically monitor the released drug, since the reflected wavelength changes with the emptying of pores (Figure 5). In [6], the integrated-chip optical device guarantees the optimum disposable MND, which can be self-administrated and self-wasted, once the drug has been all delivered by only looking at the color variation at naked-eye.
MN type | Disease | Experiments | Refs. |
---|---|---|---|
Swelling | Acne vulgaris | In vivo (mouse) | [36] |
Swelling | Diabetes | In vitro | [50] |
Swelling | Diabetes | In vivo (mouse) | [51] |
Swelling | Immunity (vaccines) | In vitro | [40] |
Swelling | Nausea and vomiting | In vivo | [46] |
Swelling | Keloid scar | Ex vivo | [53] |
Swelling/hybrid | — | in vitro | [6] |
Hollow | Immunity (vaccines) | — | [42] |
Dissolving | Melasma | In vivo (mouse) | [35] |
Dissolving | Ocular infection | Ex vivo (cornea) | [37] |
Dissolving | Cancer | In vitro | [44] |
Dissolving | Cancer | In vivo (mouse) | [45, 54] |
Dissolving | Immunity (vaccines) | In vivo (mouse) | [41, 43] |
Dissolving | Obesity | In vivo (mouse) | [48, 49] |
Dissolving | Vitamin K deficiency | In vitro | [55] |
Coated | Warts | In vivo (human) | [34] |
Coated | Immunity (vaccines) | In vivo (mouse) | [39] |
hybrid | Diabetes | In vivo (mouse) | [52] |
Main studies on therapeutic delivery with MNDs. Adapted from [56].
The optical integrated MND presented in [6] have got a naked-eye monitor made up with a psi membrane to follow the release of a drug loaded in.
Human interstitial fluid (ISF) is on average between 9 and 13.5 L [59, 60]. Fluid moves from the lymphatic vasculature into the interstitium, among the endothelial walls of cells, then to the blood plasma, and finally returns to the lymphatic vasculature. Analytes enter into the ISF through three paths: first, by transcellular path, through the capillaries; secondly, by paracellular path, through the cell walls; finally, by vesicular path, from the cells to the ISF [61, 62]. ISF moves within a network of glycosaminoglycans, elastin, and collagen and transports electrolytes and metabolites to muscle cells, bone cells, cartilage, tissues, organs and so on [60, 63].
Dermal ISF is localized in the extracellular spaces between the vasculature, connective tissues and the cells. A lot of research efforts have been done to develop extraction methods of ISF in order to obtain an analytical composition and understand the relationship between plasma and ISF. Table 2 summarizes the main ISF constituents, measured concentrations, and typical concentration ranges for healthy people [63].
ISF constituent | Measured concentration | Typical concentration ranges |
---|---|---|
Glucose | 4–8 mM | 4.5–8 mM |
Cortisol | 24–40 nM | Morning: 1–50 nM Afternoon: 27–42 nM |
Lactate | 1.17 ± 0.23 mM | 1–2 mM |
Lipids | 1.5 ± 0.3 μM | Not reported |
Na+ | 141 mM | 135–150 mM |
K+ | 4.4 mM | 3.8–4.9 mM |
Cl− | 110 mM | 99–117 mM |
Main ISF constituents, measured concentrations and typical concentration ranges for healthy people [63].
Since its location just under human skin (the largest human organ) and its relationship with the vasculature system, analysis of ISF has received interest for the realization of new wearable devices.
On the other hand, new diagnostic methods can sensitively, rapidly and accurately detect, analyze and monitor relevant diseases of social interest, and can lead to an effective management of healthcare. Biomarkers and biosensors research receive, then, a constantly increasing thrust.
Despite the transduction method used, innovation in standard sensing technologies is continuously pursued. Although several optical techniques, such as fluorescence, surface plasmon resonance and surface enhanced Raman spectroscopy have been exploited, electrochemical methods, based either on voltammetry or impedance spectroscopy, have been demonstrated to quantify analytes in ISF with high sensitivity and easily integration into a MND [8].
Standard electrochemical sensors are realized confining bioprobes onto an electrode surface directly immersed in a solution, as the ISF. A key issue in the innovation of electrochemical devices is the design of the so-called working electrode, that can increase the performance of the whole biosensor. The development of electrochemical engineered biosensors has been recently the focus of many research groups, which provided several fabrication strategies [64].
Electrochemical sensors based on MNs can analytically monitor biomarkers, drug release, metabolites, electrolytes and other chemical species present in dermal ISF and involved in biological functions. Recently, in [65] authors gave a proteomic characterization of the dermal ISF, extracted by means of a hollow MND. In this work, 407 proteins have been found and quantified [65]. Moreover, less than 1% of these proteins have been identified only into the ISF, confirming that the ISF is strictly connected to both plasma and serum. Then, the MNDs can be minimally invasive alternative devices to blood-derived fluids sensors with potential for real-time monitoring applications. In addition, in [66] an extremely small quantity (<1 nL) of the ISF was extracted by means of a hollow MN to measure drug concentrations and the typically painful blood drawn was avoided. In [66], the inner cavity of a hollow MN was derivatized to bind vancomycin. Optical absorbance is used as off-line transducer method, after extracting ISF with an integrated optofluidic device. The optofluidic MND detected the vancomycin in a sample volume of 0.6 nL with a limit of detection (LoD) of less than 100 nM.
Before being widely adopted into clinical practice, MNDs used as biosensors have to pursuit some general issues: a low cost fabrication; continuous monitoring and/or long-lasting working time; the possibly of integration in MEMS; the protection of the bioprobe, critical in enzyme-based detection; a good electrical conductivity (EC) for electrochemical sensing [67]. Moreover, the biofouling at the tissue–device interface must be avoided to successfully realize a wearable MND sensor [68]. According to Da Silva et al., currently, wearable sensors are still not yet ready for commercial develop, but within a few years MNDs biosensors will conquer the market [69].
In the field of MNDs for diagnostics, as well as for therapy, the approach can drastically vary with shapes and materials; Figure 1A shows a sketch of different MNDs for sensing purposes together with their working conditions into the human skin. Starting from the right, Figure 6 reports: swelling bulk MNs sensors (BMNDs), whose diagnostic approach includes a volume effect in the probe-analyte interaction that will be considered separately; hollow MNs sensors (HMNDs), where a small material sampling of ISF is analyzed on or offline [70, 71, 72]; coated MNs sensors (CMNDs), whose surface is the locus of the interaction between analytes and bioprobes [73, 74, 75, 76, 77, 78, 79, 80, 81]; planar MNs sensors (PMNDs), where the probe–analyte interaction is on a specific zone of a flat MNs surface [82].
Design of the working electrode, optical images with and without metal coating and sketch of working of the MNDs. Experimental data for glucose and lactate acid dose–response. Reproduced with permission of Ref. [8]. PEGDA, polyethylene glycol diacrylate; FAD, flavin adenine dinucleotide.
The bulk volume of solid MNs (BMNDs) is often exploited in electrochemical biosensing. Usually, hydrogels and swelling polymers are employed in the fabrication of BMN. Examples are polyethylene glycol diacrylate (PEGDA), polyvinyl pyrrolidone (PVP), polyvinyl alcohol, poly(acrylic acid), poly-l-lactide, poly(lactide-coglycolide acid) and poly-N-isopropylacrylamide [83, 84]. These types of polymers can be processed by several fabrication techniques, such as replica molding, photolithography, drawing lithography and more [85]. Usually, probes and enhancers of transduction mechanisms are directly embedded in the porous polymer matrix during the fabrication. This environment protects probes without avoiding interaction between target analytes and bioprobes.
Caliò et al. trapped enzymes with vinyl-ferrocene mediator into a polymeric matrix of PEGDA in order to detect glucose and lactate exploiting the volume effect of the hydrogel matrix [27]. After being in contact with the ISF, the PEGDA matrix swells and the analytes solved into ISF enter the volume of the MNs, where a large number of probe molecules (enzymes) can be stored. The redox reaction takes place inside the volume and is transmitted to the electrode. The fabrication of the electrochemical MN biosensor only required a single further step (metal coating) in addition to the direct photolithographic process. The hybrid device traps GOx and LOX enzymes to enable the electrochemical detection of glucose and lactic acid, respectively, in physiological solution. The sensing MND showed a linear response from 0 to 4 mM for glucose, and from 0 to 1 mM for lactic acid (Figure 6) and a LoD of about 1 μM was found for both cases. Figure 6 shows design of the MN based working electrode, optical images with and without metal coating and a sketch of the working principle of the swelling MNDs. Moreover, experimental data for glucose and lactate acid dose–response are reported.
Appeared on scene as a painless alternative to syringes, MNDs have conquered the biomedicine. The flexibility of these innovative devices makes these technological platforms really attractive for even new fields of application. Almost all materials can be used in the fabrication of MNDs: noble metals (gold and silver), semiconductors (silicon), plastics (polymers and hydrogels), amorphous materials (ceramics) and artificial nanostructured materials (porous silicon). MNDs have been used for drug delivery, cosmetic industry or biosensing, where the MN microstructures have been used as electrodes for electrochemical transduction. For biosensing systems, pros and cons have been highlighted for each device type in terms of analytical performances such as LoD, detection time, sensitivity and so on. In all the application cases, considerations about the safety of MNDs is due, since MNDs are conceived for being in contact with the human body. Then, inert, biocompatible, or physiologically dissolvable materials have to be engaged for device fabrication, even if they show lower analytical or delivery performances. After the overcoming of the skin natural barrier, MNs are directly in contact with human ISF. Hollow, coated, and swelling MNDs are all used in two ways: sensing of analytes and delivery of drugs; biosensing and administration; therapy and diagnosis.
The authors declare no conflict of interest.
The Authors would like to thank all the Materias s.r.l. staff for supporting. In particular, Caterina Meglio, Aniello Cammarano, Maria Emilia Mercurio and Maria Grazia Ramaglia, those continuously help our research with their work.
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\n\nThe Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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\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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