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Drug Delivery Capabilities of Hyaluronic Acid: Comparison
Please note this is a comparison between Version 1 by Ciara Buckley and Version 3 by Ciara Buckley.

Hyaluronic acid (HA) is a naturally occurring mucopolysaccharide that belongs to a group of heteropolysaccharides referred to as glycosaminoglycans (GAGs). Mucopolysaccharides are long chain sugar molecules commonly found in mucous or joint fluid in the body. Endogenous HA is found throughout the human body in the vitreous humour, joints, umbilical cord, connective tissue, and skin. Native HA, extracted from animal sources such as rooster comb or from biotechnological processes such as Lactobacillus fermentation, has a major caveat in that it is readily degraded by the body. Through modification, however, HA displays resistance to degradation whilst also enabling conjugation or cross-linking with a variety of molecules. This freely accessible natural polysaccharide has a wide range of applications due to its unique physicochemical and bioactive properties, which will be explored in depth throughout this review. Furthermore, HA is biocompatible and biodegradable, making it a safe biomaterial for biomedical applications such as biomedical engineering, as well as finding applications in the cosmetics industry, wound healing, and drug delivery.

  • naturally-occurring polymers
  • polysaccharide
  • immunotherapies
  • heteropolysaccharides
  • hyaluronic acid
  • biomaterials
  • drug-delivery

1. Physicochemical Properties of Hyaluronic Acid (HA)

Structure

1.1. Structure

HA is an anionic polymer consisting of disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine, which are linked by β (1, 4) and β (1, 3) glycosidic bonds as shown in Figure 1 below.
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Figure 1.
Structure of a disaccharide of HA.
HA is renowned for its unusual viscoelastic properties, due to the interaction between chains of hydrogen bonds. The HA macromolecule is best represented as a hydrated spherical. In its most elongated conformation, HA exhibits its highest viscosity in an aqueous solution. As the concentration of HA in aqueous solution increases, so does the viscosity due to chain weaving and the formation of 3-dimensional matrices. This is the basis of gelation, however, salts can be added as viscosity modifiers to facilitate the use of high-concentration solutions, as demonstrated by Selyanin et al. [1].
HA is a polymer that is extremely hydrophilic. Each disaccharide contains a carboxylic acid component that dissociates at physiological pH, enhancing the polyanionic nature of the polysaccharide. Because of this polyanionic behavior, several metal ions can be coupled to the hydration shell, resulting in a 1000-fold increase in volume and the formation of 1000 weakly packed hydrated matrices [2]. This is the basis of HA’s physiological functions, such as its rheological characteristics, elasticity, wound healing capacity, and cell lubrication, and it also explains HA’s involvement as a structural component of the ECM [3].

Molecular Weight

1.2. Molecular Weight

The biological function of HA is mainly dependent on the polymer’s molecular weight (MW) [4][5][6][7][8]. Table 1 below summarises the average molecular weights of HA from different areas of the human body, however, this is not an exhaustive list as HA is ubiquitous throughout the body. While it typically exists as a high molecular weight polymer, of over 106 Daltons (Da) or 1000 Kilodaltons (kDa), it can be cleaved by an enzyme, hyaluronidase, in the body to obtain molecules of much lower MWs. The biological functions include control of tissue hydration, supramolecular assembly of proteoglycans in the extracellular matrix, and multiple roles in receptor-mediated cell detachment, mitosis, and migration [98][109].
Table 1.
Summary of the molecular weights of endogenous HA.
Tissue Concentration (µg/mL) Molecular Weight (kDa) References
Umbilical cord 4100 500 [1110]
Synovial fluid 1400–3600 6000–7000 [1211][1312]
Dermis 200–500 >1000 [1413][1514]
Epidermis 100 >1000 [1413][1514]
Thoracic lymph 0.2–50 1400 [1615][1716][1817]
Urine (excreted) 0.1–0.3 4–12 [1918]
For both commercial and endogenous HA, the applications are dependent on molecular weight as illustrated in Figure 2 below. HA of an MW larger than 1000 kDa is primarily useful in the surface hydration of cells and has applications in ophthalmology, wound healing, and cosmetics [2019]. Between 10 kDa and 1000 kDa, HA plays a vital role in wound healing. HA between 100–250 kDa has a role in embryonic development and ovulation and is necessary for successful ovulation and fertilisation in most mammals [2120]. Finally, oligosaccharides with an MW of ≤10 kDa are critical in promoting fibroblasts’ proliferation, and angiogenesis, and are also implicated in tumour growth [21][22][23][24]. As indicated in Figure 2, an MW of less than 10 kDa also finds application in the cosmetics industry as the smaller size allows for deeper penetration and subsequent hydration of the skin layers [2524]. It is in the cosmetics industry that the majority of the population has been introduced to the unique physicochemical properties of HA, such as viscosity and lubrication via the extraordinary ability of HA to bind water molecules, which has become a staple ingredient in products such as serums and creams. Additionally, the viscoelastic properties of HA have been utilised in cosmetic procedures such as dermal fillers as the viscoelasticity and biodegradability lend themselves perfectly to a flexible, comfortable, biocompatible, and biodegradable filler material for lips, cheeks, and jaws to name but a few [2625]. These fillers serve to replace lost volume and hydration from the skin and consist of cross-linked HA. The crosslinkers utilised depend on the desired physical or biological response sought. The water binding and viscoelastic properties of hyaluronic acid have also been exploited in the area of micro-needles. Micro-needles are medical devices, of approximately a micron in size, which penetrate the outermost layer of skin for the purpose of improving the transport of therapeutic through the epidermis [26][27][28][29]. Extensive research has been conducted over the past decade in micro-needle based drug delivery, and as a result, HA-based micro-needles are used extensively in both the pharmaceutical and cosmetics industries. In this way, HA is used as a dissolving microneedle, created through processes such as micro-molding which is an economic method suitable for mass production. These HA-based microneedles can facilitate the delivery of a variety of molecules such as adenosine and bioactive proteins for the catalysis of collagen and elastin [2726], and alendronate for osteoporosis [2827], or insulin for diabetes [2928].
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Figure 2.
Molecular weight-dependent applications of HA.

2. Endogenous Bioactive Properties

Receptor Interactions

HA interacts with various molecules and receptors and conducts numerous functions throughout the extracellular matrix (ECM) via specific and non-specific interactions. Some of the most commonly known receptors that HA interacts with are Neurocan, the receptor for hyaluronan-mediated motility (RHAMM), GHAP (glial HA binding protein), CD44, Aggrecan, and TSG6 (TNF-stimulated gene 6) [29][30][31]. The most biologically relevant receptor is CD44 due to its multifunctional cell surface conjugated protein that is present in an abundance of cell varieties. These cell surface binding proteins possess key residues which allow for wrapping around and securing the HA polymer chain to the CD44 receptor.
HA has many functions within tissues correlated to its interactions with the primary receptors CD44 and RHAMM. CD44 expression is a known activation marker that aids in classifying memory and effector T cells. It can also assist in early T cell signaling as it is bound to the lymphocyte-specific protein kinase [3130]. CD44 also contributes to cell adhesion interactions and proliferation as illustrated in Figure 3 below above [3231]. Despite the binding of HA to CD44, it has been evidenced that HA degradation can trigger inflammation through toll-like receptors such as TLR2 and TLR4 in macrophages and nerve fiber cells [3332]. Both TLR and HA are vital components of the innate immune system.
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Figure 3. The correspondence between RHAMM and CD44 following HA binding affects physiological and cellular functions. The track denoted in green highlights extracellular signaling involving CD44-HA mediated pathways. The blue track is for intracellular RHAMM signaling. Cell surface RHAMM interacts with CD44, HA, and growth factor receptors (GFR) to activate protein tyrosine kinase signaling cascades that activate the ERK1/2 MAP kinase cascade in a c-Src/FAK/ERK1/2 dependent manner (depicted in green track). In the absence of intracellular RHAMM, this signaling can stimulate the transcription of mitogenic effectors to regulate a mitogenic response (cell proliferation/random motility). In the presence of intracellular RHAMM (blue track), MEK-1/p-ERK1/2 also binds to a number of protein partners that allows activated RHAMM to enter the nucleus to regulate functions of microtubule dynamics via centrosome structure/function, and cell cycle progression. Activated RHAMM also controls the expression of genes involved in cell motility. Overall, the effect of HA is pro-proliferation and the development of cellular infrastructure whilst providing critical immune support.

3. Synthesis

HA is the only one of the mucopolysaccharides that are not synthesised by the Golgi apparatus. Despite the relatively simple structure of HA, it possesses a range of physiological roles in humans and animals. HA can be isolated from animal sources such as rooster comb, or certain bacteria such as Streptococcus. However, purification from sources such as these is difficult due to the inherent variability with animals and the presence of endotoxins in Streptococcus species. The main sources of commercial HA for the industry are either animal or microorganism derived.

Microbial Synthesis

3.1. Microbial Synthesis

For bacteria, such as the Streptococcus genus, three distinct genes are required to synthesise HA- HasA, HasB, and HasC. In the initial stage of HA biosynthesis, glucose is converted to glucose-6-phosphate via the enzyme hexokinase as illustrated in Figure 4 below. Glucose-6-phosphate is the most vital precursor in this biosynthesis pathway. Following this initial stage, there are two distinct routes in which two building blocks are produced: glucuronic acid and N-acetyl glucosamine [33][34][35][36][37]. However, Streptococcus are renowned for producing several endotoxins which would render the HA produced unsuitable for human use. Additionally, the expensive growth media necessary and difficulty in controlling the fermentation process make this genus less than ideal [3837].
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Figure 4.
Microbial synthesis of hyaluronic acid in
Streptococcus
.
To overcome the issues with Streptococcus production of HA, researchers have been investigating other strains which are generally regarded as safe (GRAS) and engineering them for HA production. One such strain is Lactococcus lactis, which was engineered by Sheng et al. using the HA biosynthesis operon and the lacF selectable marker [3938].

Animal Synthesis

3.2. Animal Synthesis

In vertebrates, there are three different has isozymes- has1, has2, and has3, which are involved in HA synthesis during embryonic development [4039], morphogenesis [4140], wound healing [4241], aging and cancer progression [4241]. The function of HA synthases is to lengthen the polysaccharide by repeated addition of glucuronic acid and N-acetyl-D-glucosamine groups as illustrated in Figure 5 below. These are then extruded into the cells through the cell wall via ABC-transporters [4342]. The different forms of has proteins possess other kinetic profiles, which ultimately affect the size of the HA produced. Has1 and has2 proteins are moderately active and implicated in the synthesis of high MW HA, whereas has3 proteins are highly active and produce low MW HA [3029].
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Figure 5.
Animal synthesis of HA.
HA extracted from animal tissues such as rooster comb still remains an important product due to the high molecular weights which can be recovered when isolating HA from animals. However, the harsh extraction process often results in poor yield and polydispersity of molecular weights [4443]. This is due to the grinding, acid treatments, and organic extractions which are necessary to extract the polysaccharide. Additionally, contaminant proteins are a significant issue in the isolation of HA from animals. Cellular proteins such as hyaluronidase, a HA-specific enzyme, may be bound to the polymer in animal tissues and could potentially elicit an immune response in humans if not completely removed from the end product. Similarly, there is the potential for nucleic acid contamination or the spread of animal prions which could result in infectious disease spread [4544]. Therefore, the molecular weight advantage of animal extraction is offset by the high cost and labour-intensive processes involved. Thus, biotechnological solutions are the preferred route of commercial HA synthesis where possible.

4. Degradation

Endogenous human HA is primarily degraded by an enzyme family known as hyaluronidases (HYAL, but may also be initiated by free radical degeneration. Free radical degradation is a process by which free radicals, or pro-oxidants, cause oxidative stress resulting in organic damage to molecules or cells. Free radical degradation, in particular, has been implicated in HA degradation in aging and arthritis. It initiates degradation via non-specific scission of the glycosidic bond [4645], and the concentration of free radicals is directly proportional to the degree of degradation of the HA molecule. The half-life of HA in human tissue ranges from three to five minutes in blood to approximately 70 days in the eye’s vitreous body [1514][4746]. This turnover rate is controlled by localised degradation or uptake and hydrolysis via the lymph system.
Extracellularly, there are various ways in which larger molecules of HA can be degraded into smaller fragments. This is important as fragmented HA can be used as an indicator of early disease in conditions such as arthritis, or a selection of molecular weights for specific applications may be needed as detailed earlier. For instance, smaller HA fragments are preferred for use in cancer treatments, as an antioxidant, or in cosmetics whereas medium chain HA can be useful in wound repair and regeneration [47][48][49]. External or extracellular methods include chemical degradation, physical force, free-radical cleavage, pH, temperature, ultrasonic stresses, and, of course, enzymatic degradation.

Enzymatic Degradation

Enzymatic degradation is performed by HYAL, of which six have been identified in humans- HYAL1, HYAL2, HYAL3, HYAL4, PH20, and HYALP1 [5049]. The function of the hyaluronidases is to cleave the large molecule into smaller oligosaccharides. In contrast, β-D-glucuronidase and β-N-acetyl hexosaminidase further degrade the fragments by removing non-reducing sugars from the terminal ends [5150]. The oligosaccharides and very low molecular weight fragments produced by this enzymatic degradation have exhibited angiogenic properties in numerous studies. They have also been identified in the disease process of degenerative diseases such as arthritis [51][52][53][54]. This is in stark contrast to the anti-angiogenic and anti-inflammatory properties displayed by high molecular weight (HMW) HA.
The small fragments of HA modulate gene expression in many cell types. They could invoke an inflammatory response through interaction with toll-like receptors (TLR) such as TLR-2, TLR-4, and CD44, which induce NF-kB activation that, in turn, is responsible for inflammatory mediator transcription such as TNF-α and Il-1β [5554]. Despite this, there is growing research into using these oligosaccharides of HA (<10 kDa) to modulate the inflammatory response. Wang et al. demonstrated how these oligos could be used as an agent for reconstructing cardiac function against myocardial infarction [5655].
This fragmentation of HA also interferes with HA signaling. There is a working hypothesis that HMW HA can cluster receptors on the cell membrane. In contrast, low molecular weight (LMW) cannot gather the cell membrane proteins the same way; therefore, signaling modulation differs from that induced by HMW in the same cells [5756]. Thus, the signaling capabilities of HA rely heavily upon fragmentation.

5. Modification

Native hyaluronic acid (HA) has found a broad range of applications in areas such as ophthalmology and cosmetics due to its unique physicochemical characteristics. However, this endogenous polymer is readily degraded in the body by the enzyme, hyaluronidase. The rate of degradation of native HA stifles its applicability to bioengineering applications or those which require a longer residence time in the body. To enable expansion of the applications of this polysaccharide, it can be modified to allow for cross-linking and engineering, to tailor the degradation profile in vivo, improve cell attachment, and enable conjugation. The relatively simple structure of HA allows for ease of modification of its two main functional groups- the hydroxyl and the carboxyl groups. Additionally, further synthetic modifications may be performed following the deacetylation of the acetamide group, which can allow for the recovery of amino functionalities. Regardless of the functional group to be modified, there are two options for modification; crosslinking or conjugation as outlined in Figure 1 below.

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Figure 1. Conjugation and crosslinking of HA.
Conjugation is modification via the grafting of a molecule onto the HA chain by a covalent bond, whereas crosslinking involves the formation of a matrix of polyfunctional compounds which link chains of native or conjugated HA via two or more covalent bonds [58][59]. Crosslinking can be performed on either native HA or conjugated HA. This is of particular interest in the area of bioconjugation. Bioconjugation is the act of conjugating peptides or proteins to a natural polymer to increase efficacy. Previously, this was performed using polyethene glycol (PEG). PEGylation was found to increase the effectiveness of drugs by reducing renal clearance, enzymatic degradation, and immunogenicity in vivo. However, repeated injection of PEGylated liposomes has been found to cause accelerated blood clearance and trigger hypersensitivity [60]. Thus, HA is now under investigation as a plausible alternative [61]. Conjugation allows for crosslinking with a variety of molecules to enable the improvement of drug carrier systems with optimised properties. The crosslinking of HA allows for fine-tuning of many characteristics, such as mechanical, rheological, and swelling properties, and protects the polymer from enzymatic degradation to allow for longer residence time at the required treatment site. The process of bioconjugation and crosslinking has found applications in medicine, aesthetics, and bioengineering to treat various ailments. The different approaches and applications of functionalisation have been discussed in great detail by Sanjay Tiwari and Pratap Bahadur (2019) [62], so only a brief overview of hydroxyl and carboxyl group chemical modifications will be discussed.

Modification of HA via the Hydroxyl Group

The standard recognition by degradative enzymes is preserved by retaining the carboxyl group and modifying the hydroxyl groups. Each disaccharide unit of HA consists of four hydroxyl groups, one amide group, and one carboxyl group. One of the most highly marketed HA derivatives, butanediol-diglycidyl ether (BDDE) HA, is produced in an alkaline aqueous solution through simple synthetic procedures [62]. Additionally, divinyl sulfone (DVS) or ethylene sulfide can be used to form other ether derivatives in water [63]. A novel HA drug delivery system targeting tumour cells was created when performing a dimethylaminopyridine (DMAP)-catalysed esterification reaction between butyric anhydride and LMW sodium hyaluronate in dimethylformamide (DMF). Butyric acid has been well reported as an inducer of cell differentiation and inhibitor of various human tumour cells [64]. Other modification methods involve isourea coupling and periodate oxidations. However, both of these methods are performed in harsh conditions and may compromise the integrity and biocompatibility of the HA.

Modification of HA via the Carboxyl Group

The main modifications of the carboxylic group of HA are esterification, carbodiimide mediated, 1-ethyl-3-N, N-dimethylaminopropyl]-carbodiimide (EDC)/N-hydroxy succinimide (NHS) modification, EDC/hydrazide modification and finally thiol modification [65]. HA modified via esterification is usually performed by preparing quaternary salt of HA followed by a reaction with an esterifying reagent. The higher the degree of esterification obtained, the more insoluble the resulting derivative becomes. Two of the best characterised esterified HA derivatives are ethyl and benzyl esters of HA, named HYAFF® 7 and HYAFF® 11, respectively [66][67]. These derivatives were created for tissue engineering applications. Another option is carbodiimide-mediated modifications whereby the carbodiimide activates the carboxyl group of the HA under acidic conditions. This activation allows for nucleophilic attack of the carboxylate anion to produce O-acylisourea, which the nucleophiles can capture. The most common nucleophilic agents are primary amines despite the low percentage in the nucleophilic amine state at equilibrium [67]. One of the biggest pitfalls of this method is forming the stable intermediate N-acyl urea from O-acylisourea, which can happen in seconds with viscous macromolecules, thus out-competing the exogenous amines [68]. To combat this, a two-step procedure utilising EDC and NHS was created, which was more efficient and increased the yield of modified products. However, the degree of substitution is poor, generally below 20%. This is preferable to most biological investigations so as not to interfere with CD44 interaction [69][70][71][72].

6. Immunomodulation

The principal function of the immune system is defence, either against foreign matter, including pathogens, or against disease, including cancer. The complexity of the immune system occurs when the immune response either fails to respond to a pathogen or is over-exasperated. Interventions such as vaccines can improve the immune response. Steroids or anti-inflammatory medications can reduce hyper-inflammation. Inflammation is a key, protective immunological function. If not appropriately controlled, it can cause harm to the host and lead to pathologies. Inflammation is linked to several chronic diseases. With increasing numbers of autoimmune conditions and infectious agents, molecules that interact positively with the immune system are always in demand. Hyaluronic acid (HA) is a natural polysaccharide that is abundant in the human body and can be obtained through animal extraction or bacterial fermentation. This unique biopolymer has been shown to have contrasting immune effects depending on the molecular weight of the molecule. Both low molecular weight and high molecular weight HA have found uses as moderators of inflammation and immune response which lends this molecule to a host of applications from wound repair to vaccine adjuvants. Herein, it seeks to evaluate the immunomodulatory uses and potentials of hyaluronic acid. 

The Role of Hyaluronic Acid in Inflammation

HA is a significant component of the extracellular matrix (ECM), which becomes fragmented during infection and tissue injury and is repaired when inflammation subsides. During inflammation, HA turnover is disrupted and HA fragments collect extracellularly. These fragments are linked to the proliferation of the inflammatory response, whereas the full-length, high molecular mass HA is linked to the resolution of inflammation. While all immune cells express the HA receptor CD44, under homeostatic circumstances only a few bind HA. This, however, is altered when immune cells are activated [73]. In response to changes in cell sensitivity and signaling pathway regulation, the expression levels of inflammatory genes are modulated by complex mechanisms. Most likely attributed to hyaluronidase activity, the chain length of high-molecular-weight HA reduces during inflammation [73]. HA absorption and fragmentation by macrophages may reduce inflammation [73]. Toll-like receptors are a family of pattern recognition receptors, which distinguish specific structures in pathogens. Plasma membranes express extracellular TLRs (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10). Through their extracellular/luminar leucine-rich repeats (LRRs) and cytosolic toll-like/interleukin-1 receptors, these molecules detect infection-derived ligands (TIR). TLRs are expressed on macrophages, neutrophils, dendritic cells (DCs), natural killer (NK) cells, mast cells, T and B lymphocytes, stromal cells, and tumour cells [4]. Both low and high molecular weight HA stimulates TLR-4. Conversely, LMW HA induces the activation of the NF-κB pathway which is associated with inflammation. HMW HA prevents lipopolysaccharide (LPS) a bacterial endotoxin, and activation of macrophages which is anti-inflammatory activity [74]. This contrasting activity demonstrates that the molecular weight of HA has a huge influence on the mode of action and ultimately response.

The Importance of Molecular Weight in HA Immunomodulation

Considering the importance of physicochemical properties in relation to bioactivity, it is surprising that there are currently very few investigations of the immunological responses induced by HA of varying molecular weights. Studies have demonstrated that antiangiogenic, immunosuppressive, and anti-inflammatory properties are seen in HA with a molecular weight larger than 1000 kDa. In contrast, pro-inflammatory, pro-angiogenic, and immunostimulatory characteristics are seen in medium- and low-molecular-weight HA [75]. An interesting study by Lee et al. (2021) tested HA at molecular weights of 10 to 1500 kDa and concentrations of 10 and 100 µg/mL on LPS-stimulated macrophages which are essentially inflamed [74]. They tested these parameters for the pro and anti-inflammatory effects of HA. Nitric Oxide (NO) generation from LPS-stimulated macrophages was used to measure HA-induced inflammation. They also evaluated the impact of different molecular weights of HA on M1 (Inflammatory) and M2 (anti-inflammatory) polarisation of macrophages. They also measured pro- and anti-inflammatory gene expression. Results demonstrated that various molecular weights of HA have distinct effects. LPS-unstimulated and LPS-stimulated macrophages exhibited differential regulation of inflammatory mediators, including cytokines and chemokines, based on the HA molecular weight. In the NO experiment with LPS-stimulated macrophages, HA demonstrated molecular weight-dependent effects on macrophages. Low molecular weight HA (50 kDa) increases iNOS levels significantly in LPS-stimulated chondrocytes. HA with a molecular weight of 1000 kDa had no noticeable effect on iNOS in LPS-stimulated chondrocytes. HA with a high molecular weight (5000 kDa) effectively decreases the iNOS increase generated by LPS. In addition, they evaluated the impact of various HA molecular weights on the expression levels of certain immune gene expression levels in LPS-unstimulated and LPS-stimulated macrophages. In response to LPS, macrophages will secrete inflammatory mediators, such as IL-6 and TNF-α. Macrophages treated concurrently with LPS and HA have the opposite effect, with TNF-α expression levels decreasing. Il-10 is a cytokine associated with anti-inflammatory pathways. In unstimulated macrophages, HMW HA significantly up-regulated IL-10 compared to other conditions tested again demonstrating that HMW HA influences an anti-inflammatory phenotype [4].

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