Hydrogels in the clinic

Injectable hydrogels are one of the most widely investigated and versatile technologies for drug delivery and tissue engineering applications. Hydrogels ’ versatility arises from their tunable structure, which has been enabled by considerable advances in fields such as materials engineering, polymer science, and chemistry. Advances in these fields continue to lead to invention of new polymers, new approaches to crosslink polymers, new strategies to fabricate hydrogels, and new applications aris-ing from hydrogels for improving healthcare. Various hydrogel technologies have received regulatory approval for healthcare applications ranging from cancer treatment to aesthetic corrections to spinal fusion. Beyond these applications, hydrogels are being studied in clinical settings for tissue regeneration, incontinence, and other applications. Here, we analyze the current clinical landscape of injectable hydrogel technologies, including hydrogels that have been clinically approved or are currently being investigated in clinical settings. We summarize our analysis to highlight key clinical areas that hydrogels have found sustained success in and further discuss challenges that may limit their future clinical translation.


| INTRODUCTION
Hydrogels are crosslinked hydrophilic polymer networks of high-water content. Due to this high water content, hydrogels exhibit favorable biocompatibility and as such have been developed for and used in a variety of medical applications. [1][2][3] Since hydrogel properties can be tuned through a variety of chemical approaches, their rational design and engineering has enabled new modalities for delivery of small molecules, 4-7 proteins, [8][9][10][11][12] and cells 13,14 and as tissue engineering scaffolds for directing cell fate/lineage, 15,16 stem cell expansion, [17][18][19][20] and tissue regeneration. [21][22][23][24][25] Research efforts to develop hydrogels for biomedical applications represents one of the most studied areas at the interface of engineering and medicine. 26 The translation of hydrogels into the clinic, especially for advanced hydrogel systems, remains a challenge despite many products and current clinical investigations.
This article summarizes the present state of hydrogel materials in clinical medicine. Of all the hydrogels currently in preclinical development, studied in clinical trials, and used in the clinic as approved products, injectable hydrogels represent a subset that are capable of providing the most versatile deployment as delivery/regeneration platforms.
Injectable hydrogels can be directly applied to sites of interest, independent of, and in many cases conforming to, local geometric/physiological constraints. For detail on the various scientific aspects of hydrogels, please refer to the following recent reviews. [26][27][28][29][30][31] In this review, we provide a general overview of the clinical landscape of injectable hydrogels, highlighting both approved hydrogel systems and current clinical trials.
We conclude with a discussion of current challenges to bolster translation of hydrogel materials.
As shown in Figure 1, the most abundant medical application of hydrogels is for soft contact lenses. As compared to glass lenses, hydrogels permit gas diffusion and retain water at the eye surface. 32 Clinical trials on new hydrogel lens products have focused on a variety of outcomes, including extending the time of continuous wear, adding pigments, and optimizing the lens geometry. To better delineate the various applications and types of hydrogels in the clinic, we separated them based on their structure in terms of hydrogel patches, coils, or bulk materials. Within each structural grouping, hydrogels that partition and deliver a therapeutic agent were separated from hydrogels that exert their therapeutic function without delivering a drug. For the purpose of our analysis, we defined a hydrogel patch as any material which is topically applied. Hydrogel patches are mostly used to provide an engineered barrier between compromised tissue and the external environment. For example, in the treatment of burn wounds, a hydrogel patch can achieve any combination of (a) preventing bacterial growth within the wound, (b) delivering therapeutics which accelerate healing, and (c) maintaining a moist tissue environment thereby reducing pain.
Specific hydrogel patches are currently being explored for facilitating healing processes in diabetic ulcers, treating skin conditions such as eczema and psoriasis, and more. While accounting for only eight of the hydrogel clinical trials, hydrogel coils are useful as a replacement for platinum coils in the treatment of aneurism. For these applications, hydrogels of natural (i.e., gelatin) or synthetic (i.e., acrylamide, acrylic acid, glycolic acid) materials have been utilized, as well as composite structures (i.e., hydrogel-coated metal coils). The third and most abundant class of hydrogels in the clinic, bulk hydrogels, is typically used for tissue augmentation or regeneration. Bulk hydrogels can act as a filler or replacement for soft tissue (e.g., to treat osteoarthritis, lipoatrophy), or provide mechanical support for compromised tissue (e.g., urinary incontinence, myocardial infarction).
Current efforts include fabricating cell-laden bulk hydrogels for tissue regeneration (e.g., kidney augmentation, myocardial regeneration). Similar to hydrogel patches, bulk hydrogels can themselves exert a therapeutic action or act as a depot for delivering a bioactive agent.

| Facial correction/aesthetic products
The improved biocompatibility especially of hyaluronic acid (HA)based hydrogels have found a wide application as temporary dermal fillers in soft tissue augmentation. Juvéderm ® , one of the leading HAbased products currently in the market is widely used for the correc-

| Spinal fusion products
As scaffolding materials, hydrogels have garnered remarkable attention due to their ability to provide mechanical support to the existing

| Other indications
Other than aesthetics, cancer and spinal fusion products, hydrogels have been approved in many other indications. LoneStar's Algisyl-LVR ® is the only hydrogel product derived from alginate that has been approved for advanced heart failure. While both Bulkamid ® and

| CURRENT HYDROGEL CLINICAL TRIALS
Considerable efforts in the clinic are focused on evaluating new injectable hydrogel-based systems as therapeutic, diagnostic, and aesthetic agents. In this section, we will briefly review (a) the current landscape of hydrogel-based systems currently being investigated in the clinic ( joint pain and joint effusion that limit the clinical translation of these synthetic matrixes. 34 Additionally, apart from alginate, gelatin-based hydrogels are widely investigated with cellular components for heart and kidney diseases due to improved interaction with natural biological matrices.

| Hydrogel scaffolds in cancer care
It is not surprising that hydrogels are also being investigated for improved cancer care. In particular, synthetic hydrogels including

| Hydrogels for other indications
Injectable hydrogels for ocular applications have remained one of the most investigated areas in the preclinical space, 35

| DESIGN CHALLENGES
A hydrogel must meet application-specific design criteria to suitably treat a medical condition. Broadly, these design criteria can be defined as either physical, chemical, or biological. Here, we will discuss the current status of hydrogel design and fabrication, as it pertains to each design challenge.

| Mechanical robustness
Injectable hydrogels must have a sufficiently low viscosity to be introduced via a needle and syringe and a sufficient elasticity in situ to maintain their injected volume and sustain repetitive load. Overcoming this paradox is a major design challenge. One approach is to use a shear thinning polymer, such as HA. 36,37 As described in the previous section HA is used currently as a dermal filler, and is being investigated as an injectable replacement for cartilage. These materials gel by physical mechanisms (i.e., intermolecular interactions between polymer chains) which are disrupted by the shear of injection. 27 Other clinically approved hydrogels that form via a physical mechanism are hydroxyapatite-carboxymethylcellulose and collagen.
Another approach is to use in situ crosslinking to inject a hydrogel precursor which gels via a chemical reaction either within a mixing tip or within the physiological environment. [38][39][40] Depending upon the application of interest, these chemical crosslinking reagents can be biodegradable or nonbiodegradable. For example, the Bulkamid (polyacrylamide) hydrogel employs a nondegradable crosslinking agent, while the SpaceOAR and TraceIT (polyethylene glycol) hydrogels each employ a hydrolytically degradable crosslinker.
As illustrated in Figure 2, there are a number of hydrogel parameters that can be optimized to achieve specific mechanical properties.
In particular, the molecular weight of polymer chains, extent of crosslinking, and crosslinking mechanism. In general, the viscosity of a polymer solution scales linearly with the molecular weight. 41,42 The hydrogel elastic modulus scales inversely with the molecular weight between crosslinks. 43,44 The crosslinking mechanism is determined by the chemical functionality of the polymer and any crosslinking agents.

| Loading and release of therapeutic agents
Therapeutic agents, which can be delivered to the surrounding environment by an injectable hydrogel carrier, can include small molecules, macromolecules (i.e., peptides, proteins, nucleic acids), or engineered cells. Cargo release from injected hydrogels is determined by the (a) size of the cargo, relative to the mesh size of the hydrogel and (b) affinity of the cargo-gel interaction.
Injectable hydrogels currently used in the clinic that include a therapeutic agent deliver a small molecule drug or a biologic (microparticle depot systems). The most common therapeutic agent is lidocaine, an anesthetic drug that reduces the pain associated with the subcutaneous hydrogel injection. Lidocaine is included as a therapeutic agent within a number of hyaluronic acid hydrogels approved for facial correction applications. As a small molecule, lidocaine's release from the injected hydrogel is minimally perturbed by the hydrogel mesh. Lidocaine's release is likely quite rapid from these gels, similar to what has been seen in the published literature. 45 For other drugeluting hydrogel applications, such as active wound dressings, a sustained release of protein drugs is needed. In these cases, one must either reduce the hydrogel mesh size via crosslinking, to perturb solute elution, or increase the hydrogel-drug affinity with tailored gel compositions to increase retention.

| Hydrogel bioactivity
For advanced tissue regeneration purposes, host cells must infiltrate, modify, and degrade bulk hydrogel materials. To achieve this aim, cells must adhere to the material. Some natural polymers, such as fibrin, 46 collagen, gelatin, 47 and HA, 40 are naturally adhesive. 48 For example, current clinical trials (NCT04115345, NCT04115345, and NCT00981006) uses a gelatin hydrogel with cells and/or growth factors. The hydrogels facilitate tissue healing following an injury (to the kidney or myocardium) by generating a suitable microenvironment, within which cell adhesion is paramount. Other common hydrogel F I G U R E 2 Design of hydrogels to overcome biophysical and biochemical challenges. When designing a new hydrogel, one determines the chemical functionality and chain rigidity by either selecting or synthesizing a proper backbone material (e.g., hyaluronic acid, polyethylene glycol, polyacrylate). The molecular weight of that linear backbone, the mechanism of crosslinking/gelation, as well as the molecular weight between crosslinks (i.e., extent of crosslinking) will determine the physical properties of the system. The combination of these chemical and physical identities will determine the gels' mechanical integrity, solute transport properties, and interactions with host cells. Shown above are the clinical applications of (top) intra-articular or subcutaneous injection, (middle) drug elution from an injected hydrogel depot, and (bottom) cell infiltration of an injected hydrogel scaffold materials, such as polyethylene glycol and polyacrylamide, are nonadhesive and must be modified chemically with adhesive ligands to facilitate cell infiltration. 49 However, for other applications discussed in this paper, such as marking tumor margins (e.g., TraceIT), rapid biodegradability is a design limitation, and therefore it is advantageous to use a hydrogel that degrades slowly over weeks to months.
Immune responses to injected biomaterials have been an active area of research for many years. 50,51 In seemingly all applied cases, it is important to minimize any immune response to the hydrogel injection. Immunological responses are responsible for adverse outcomes of biomaterial injection or implantation, including inflammation and fibrosis. 52 While these responses are deleterious in their own right, their associated physicochemical shifts (i.e., changes in the local pH or temperature) can also alter the hydrogel material, impairing function further. Therefore, minimizing the host immune response to hydrogel injection is a critical biological design parameter.

| Technological challenges
Despite the success of hydrogel-based delivery systems, key technological challenges including chemistry, manufacturing and controls, defined regulatory guidelines, and practical adaptability remain as major roadblocks in their successful clinical translation. Since hydrogel fabrication is complex and varies between hydrogel systems, the development costs through clinical translation range in estimation from $50 million up to $800 million. 30 In this section, we discuss the major translational barriers that must be addressed in order to improve healthcare with an inflating arsenal of injectable hydrogelbased scaffolds and delivery systems.

| Scale-up strategies and GMP processes
A major hurdle in the clinical translation and integration of biomaterials-based hydrogels is their compatibility with current good manufacturing practices (cGMPs). Since most hydrogel systems are synthesized in small batches at preclinical stage, efforts to translate fabrication/synthesis strategies to scaled systems are required. Batch variations, robustness, safety and efficiency issues are inevitable when performed at a larger scale. Natural polymer hydrogels may face additional difficulties, since natural polymers are heterogeneous and can exhibit different properties or characteristics at the molecular scale and potentially after synthesis into hydrogels. Additionally, the highwater content of hydrogels makes the sterilization, storage and fabrication processes even more demanding.

| Regulatory approvals
The diversity of crosslinking agents and biomaterials employed to develop hydrogel scaffolds, renders their regulatory classification and approval challenging. Unlike drugs which are broadly classified, hydrogels are classified under the "devices" category which according to the Section 201(g) of the FD&C Act covers "any product which does not achieve its primary intended purposes through chemical action within or on the body". Furthermore, other than few exceptions, majority of the hydrogel-based products are required to undergo additional FDA review of a 510(k) Pre-Market Notification submission for obtaining legal marketing rights in the United States. In case of hydrogel scaffolds encompassing a drug or drug-secreting cells, they are considered as a combination product, and thus their regulatory approval takes up to 7-10 years, which further limits their commercial viability. 30

| CONCLUSIONS
Injectable hydrogel systems provide a tunable platform to enable sustained release of small molecules or biologics and can also serve as a bulk material to interface between biological surface for application in tissue engineering or regeneration. Many examples of clinically and commercially successful injectable hydrogels exist ( Table 1) and the newer injectable hydrogel systems that are being investigated in the clinic ( Table 2)