The authors searched through the literature using the terms “blockchain” and “healthcare” based on Medical Subject Headings to identify related existing work. The inclusion criteria were focused on studies related to health care and clinical research; a working framework was proposed as well as implementation and testing with data. Exclusion criteria are presented in Figure 1.

The literature sources for this systematic review were PubMed, Medline, and the Cochrane library in addition to a preliminary search of IEEE Xplore, which had works with a technical focus rather than a health care outcome focus.

Reviewers created a data extraction sheet and identified the required data, and 31 full-text studies were critically evaluated; among these, 9 studies were finally selected, and they are summarized in Table 1.

First, we provide an overview of the essential elements of blockchains for readers and then explain the specific methodology in detail.

The 3 pillars of blockchain technology that make it a revolutionary technology are decentralization, transparency, and immutability. A block is a virtual data storage unit that holds records, transactions, or other means of data. Each block is chronologically linked to the previous blocks using cryptography; once a block is created, it is permanently stored on the blockchain and cannot be modified or removed, thus becoming immutable. If one wishes to update a network node, make another transaction, or add new data, a new block must be added to the chain; all the previous blocks will still be unchanged and visible. Another aspect of a blockchain is that it is a decentralized database using the distributed ledger technology, which simultaneously stores a full replica of the data on multiple nodes, unlike most other data management technologies where data storage is centralized, meaning that it is stored at a single location, mostly on a single server or mainframe computer [2].

The immutability of a blockchain is attributed to different factors; each block has an autogenerated header, which has a unique identification and a timestamp. The block also has a hash key, which is the header of the previous block. Therefore, all blocks are interlocked within their respective blockchains.

Once a verified permissioned node (node C) wants to add new data or make a transaction, a request is sent to all associated blockchain nodes to verify that the content of node C’s blockchain matches the content of all the other nodes (nodes A, B, etc). In addition to ensuring a complete match of all the block headers, a unique signature header will be generated for the new block. The new block is added to the blockchain only after the approval of the node.

Blockchains may be permissionless (public), permissioned (private), or sometimes hybrid, as described below. Public blockchains allow any user to join, view, and add data to the ledger, which offers maximal transparency. However, private blockchains allow only those with access to interact with the network and are usually controlled and maintained by a single organization offering superior privacy and scalability compared to public blockchains. Finally, in consortium-based blockchains, which are hybrids of the other 2 types, the configuration for viewing and writing access is determined by a group of organizations or entities.

Based on this general overview of blockchain technology, we present the salient features of blockchains, which include cybersecurity, applications, and various domains associated with them.

EHRs play a vital role in providing smooth, safe, and efficient health care delivery. As many countries do not currently possess a unified health care system, data sharing and interoperability (in a secure manner) become essential for providing patients with the best care. However, this has been a major issue in current health care management systems. Data are one of the most valuable commodities; since the increased reliance on digital systems, cybercriminals have adjusted their methods owing to huge financial incentives, especially through selling the identifying data of people. Thus, medical records are currently worth more than social security numbers on the black market, as they include the date of birth, home addresses, contact data, health data, and other sensitive data. EHR data can be employed for various criminal activities like identity frauds, insurance frauds, phishing, and ransomware, leaving the patients compromised and susceptible to harm [13]. Cyberattacks on hospital systems have increased worldwide in the past decade; such attacks not only impede health care delivery and cause financial losses but also affect patients' trust in medical providers [13,14].

In 2018, a cyberattack on SingHealth (Singapore Health Services) compromised the records of 1.5 million patients [15]; it is considered one of the biggest data breaches in Singapore and worldwide. It has stirred considerable controversy about the security of patients’ data and the reasons behind not implementing any significant measures for changing the EHR data systems. Compared to the conventional methods of EHR storage, a blockchain is a potentially secure and an immutable method for data storage and management owing to its decentralized nature. This means that the latest version of the chain is replicated, sent, and widely distributed in a huge network of nodes; there are no weak links for hackers to breach. Each block has a key of its own, in addition to having the hash key of the previous block. Once a transaction request has been made by a user, the blockchain protocol requests the network nodes to verify the validity of the entire blockchain content. This in turn means that unless the networks nodes verify that the current version of the chain is identical to theirs and approve the transaction, it cannot be added to the chain [16,17].

Furthermore, the transaction validation uses cryptominers, which are nodes that possess specialized hardware and software capable of solving energy-intensive cryptographic puzzles. It would be extremely difficult for someone to gather enough computing power to hack the blockchain database by altering the ledgers. The larger the blockchain, the more distributed it is, the more enormous is the computing power required for hacking, and the more secure it becomes [16,17].

Finally, digital signatures are employed to verify the identity of those who wish to access or add data to the blockchain. Additional features such as hardware security modules (HSMs) can be added as an additional layer to further enhance the protection of the patients’ data. HSMs are specialized hardware devices that are used to guard highly sensitive data. An HSM acts as a trusted network node that performs several cryptographic processes such as key generation and management, as well as encryption and decryption of digital signatures. HSMs are usually placed in a secure physical location and cannot be accessed, thereby making them highly tamper-resistant systems [18].

Blockchain technology has thrived in many industries ranging from banking to supply chain management. It is predicted to have a major impact on the health care industry. According to the forecast report for 2018 to 2023 provided by Market Research Future, the global blockchain market is predicted to expand exponentially.

Fundamentally, from a patient’s perspective, the potential role of a blockchain in developing a patient’s personal health record could be significant. The patient-facing applications of this technology would benefit from one window and one operating system for the personal health records, out-of-pocket costs, covered versus uncovered services, clinical trial searches, consenting for clinical trials, and “omics” data interpretation.

The review focuses on 5 main areas in which most health care–related implementations fall under remote patient monitoring (including IoT devices), EHRs, patient-centered interoperability, clinical trial data management, and monetization, as shown in Table 2 and Figure 2. The potential application areas of blockchain technology in health care are depicted in Figure 3.

The integration of blockchains with other technologies such as artificial intelligence (AI), IoT, and big data management can be highly effective and act as a catalyst for innovation and increased efficiency, which is invaluable for the interpretation and management of data.

IoT refers to a world where people, things, and devices are all connected through the internet, allowing them to collect and exchange data seamlessly over the network. From coffee machines, wearable devices, and sensors to home security systems, IoT will likely change the way people live because 5G wireless technology (with high bandwidth and low latency) is becoming readily available. All the data streamed over the network can interlock without the need for human interactions. Future smart cities are based on IoT devices and applications. Additionally, it has been gaining considerable attention from stakeholders, investors, and various organizations owing to its unlimited application possibilities [19-21].

Data from sensors and wearable devices can revolutionize the way health care is viewed and delivered, especially in an era of patient-centered care, precision medicine, and individualized health care delivery. IoT can transform the approach to health care and take patient-centered care to a new level, where people can take charge of their health, providing patients and physicians with invaluable continuous real-time data about the physiological state and well-being of patients, ranging from data such as the heart rate, temperature, or sleeping habits to biochemical marker measurements in biofluids through various biosensor technologies, as well as sending alerts when certain thresholds are crossed or abnormal patterns are detected [22-27].

Using IoT technology in conjunction with blockchain technology can maximize its efficacy and potential uses. The massive amounts of various data streamed through different IoT devices can be used to collect large amounts of invaluable data for researchers to analyze and interpret. It could also be useful for data-hungry AI technology companies, public health surveillance, monitoring of disease outbreaks (eg, for monitoring COVID-19), epidemiology, and patient-oriented outcomes [28-33].

AI has been one of the key catalysts in health care innovation; for instance, researchers at the Massachusetts Institute of Technology made a ground-breaking discovery of a new antibiotic using AI technology through a trained deep learning model that was able to produce a powerful wide-spectrum antibiotic called Halicin [34]. However, one of the most critical shortcomings of AI and a crucial component for achieving revolutionary benefits is the requirement of tons of data for training its models to produce accurate and useful outputs. The combination of AI, IoT, and blockchain technologies can be powerful, where IoT devices provide the data (input), blockchains facilitate their transmission to various machine learning, and deep learning models can translate these data into extremely useful outputs. Some of the newer developments in machine learning are significantly driving blockchains to be better integrated with AI in the health care field. This enables improvements in the security, privacy, functionality, and operational aspects of blockchain technology for health care applications [12,35,36].

If Chenoa had IoT devices that could monitor her vital signs (particularly temperature) 24/7 and the information was transmitted live via a blockchain to live monitors powered by machine learning algorithms, then her temperature fluctuations and trends would have prompted a return to the transplant center much sooner. Although research on nanotechnology and IoT-based sensors for detecting cancers (or relapses) is in its infancy, IoT devices for monitoring vital signs have already proved their effectiveness in monitoring patient physiology. Moreover, if Chenoa’s EHR was available to all the treating clinicians across the country via a blockchain, it may have triggered a sense of urgency in the local physician treating her.

For Khaled, having his EHR not readily available to a treating emergency room physician is perhaps a classic example of a disjointed medical ecosystem. If there are IoT devices detecting potassium, oxygen, and vital signs in a heart failure patient, they could be instrumental in saving the lives of many patients with heart and kidney diseases. Moreover, having a living will and information on the power of attorney on a blockchain could be very helpful in certain end-of-life cases as well. Finally, for the hundreds of thousands of patients participating in clinical trials, informed consent on a blockchain could be very beneficial for the trial sponsors, ethics boards (eg, institutional review boards), and patient care providers.

Thus, the potential benefits of blockchains are limitless; however, concrete data on long-term clinical outcomes based on blockchains powered and supplemented by AI and IoT are yet to be achieved. Nonetheless, the implementation of blockchains as a novel way to integrate EHRs nationwide and manage common clinical problems in an algorithmic fashion has the potential of saving thousands of lives like those of Chenoa and Khaled.