Granular hydrogel product for wound healing in the middle ear, nasal cavity or sinus

Abstract

The invention relates to a granular hydrogel product for treatment of a surgical site of a human or animal, in particular a surgical site in the middle ear, nasal cavity or sinus. It is based on a cross-linked gelatin wherein particles of cross-linked hyaluronic acid are dispersed. The product has an adhesion surface energy of at least 4 J / m2 and therefore has a high adhesiveness. The main advantage of this is that the hydrogel product sticks well enough to the surgical site by itself, so that it is not necessary to fill the middle ear, the nasal cavity or the sinus completely with gel. In this way, normal physiological functions like drainage, mucociliary clearance, hearing, and breathing remain largely unaffected. Other advantageous properties are a high cohesiveness, a suitable injectability and a controlled degradability at the surgical site.

Description

[0001] GRANULAR HYDROGEL PRODUCT FOR WOUND HEALING IN THE MIDDLE EAR, NASAL CAVITY OR SINUS

[0002] FIELD OF THE INVENTION

[0003] The invention relates to a granular hydrogel product, to a method of preparing the granular hydrogel product and to a granular hydrogel product for use in the treatment of a surgical site, in particular a surgical site in the middle ear, sinus cavity or nasal cavity.

[0004] BACKGROUND

[0005] Adhesion as result of a wound or surgical intervention can nowadays effectively be prevented by biopolymer-based dressings. Besides this, they also prevent blood loss and induce the coagulation of blood - a natural process that often needs assistance in case of severe bleeding. Such dressings are usually hydrogels with properties that are tuned to the particular site of application.

[0006] Gelatine is a biopolymer that is often used to prepare the hydrogels.

[0007] One particularly advantageous application of granular hydrogels is in the prevention of adhesions in the middle ear, sinus or nasal cavity, especially following surgical procedures such as middle ear surgery or Functional Endoscopic Sinus Surgery (FESS). In this context, the hydrogel is administered to the inner surface of the middle ear, nasal or sinus cavity using a syringe or cannula, where it forms a protective, conformable coating over the wound site. This coating remains in place throughout the critical healing period, typically lasting 4 to 6 weeks.

[0008] In current treatments, the site of injection is completely filled. However, filling the middle ear, the nasal cavity or the sinus completely with gel during treatment can have several drawbacks. It may obstruct normal drainage pathways, leading to fluid retention and increased risk of infection. The gel can also interfere with mucociliary clearance, disrupting the natural cleaning mechanism of the respiratory tract. Pressure buildup may cause discomfort or even damage to delicate structures like the eardrum or sinus wall. Additionally, the presence of gel may affect hearing, breathing, or smell temporarily. Finally, removal of the gel canbe challenging and may require additional procedures, thereby increasing the complexity and duration of the medical treatment.

[0009] Ideally, the hydrogel fulfills a specific set of performance criteria. First, it should exhibit suitable injectability, allowing it to be easily delivered through narrow medical instruments without premature degradation or clogging. The underlying property here is viscosity. Second, once in place, the hydrogel must remain on the site of injection. To do so, it should have enough adhesiveness to a surface of the injection site as well as a sufficient cohesiveness to preserve the structural integrity of the gel matrix during the healing process. An additional important property is the hydrogel's degradation profile. The material must degrade gradually under physiological conditions, particularly in the humid environment of the middle ear, nasal or sinus cavity. A degradation rate that is too rapid would compromise wound healing, while a rate that is too slow could impede natural healing and clearance mechanisms.

[0010] Known hydrogels do not possess these properties to a sufficient extent. A property that in particular falls short is their adhesiveness. With values for the surface energy to aluminum that are typically lower than 1.0 J / m2, these hydrogels easily detach from the surface of the injection site to which they were initially applied.

[0011] A drawback of current preparation methods for granular hydrogels is their limited ability to systematically and predictably optimize key properties as prescribed for specific medical applications. Existing approaches largely rely on modifying the chemical composition or structure of the (bio)polymer to enhance mechanical performance. However, such chemical modifications often lack precision and reproducibility, and do not allow for fine-tuning of material behavior through controlled variation of particle-level parameters. As the current state of the art does not offer a robust, particle-based design strategy for tailoring granular hydrogel performance in a targeted manner, there is at present no satisfactory hydrogel product gel for wound healing in the middle ear, sinus cavity or nasal cavity that overcomes the abovementioned problems.

[0012] An example of a commercially available hydrogel is Chitogel™, which is based on chemically modified chitosan. This product consists of a three-component formulation that must be mixed just prior to administration in the sinusor nasal cavity. Upon mixing, a chemical reaction is initiated between the components, resulting in a time-dependent increase in viscosity. The hydrogel is injected once a suitable viscosity has been reached. After placement, the reaction continues in situ, leading to the development of the final material properties, viz. high viscosity, moderate cohesiveness and moderate adhesiveness, which are intended to support wound healing and mucosal protection.

[0013] While this approach can yield a hydrogel with desirable functional characteristics, it has several limitations. First, the system is not provided in a ready-to-use form, which complicates clinical handling. Secondly, the requirement for on-site mixing and precise timing introduces the risk of inconsistency in performance, especially in time-sensitive or high-throughput medical environments. Thirdly, chitosan, being a derivative of shellfish, may induce allergic reactions in sensitive patients, representing a potential safety concern. Finally, Chitogel™ has only a moderate adhesion characteristic. Therefore, during treatment for middle ear, nasal cavity or sinus, the cavity needs to be completely filled for an effective treatment. All these factors make Chitogel™ less favorable for applications where ease of use, reproducibility, patient safety and comfort are critical. Accordingly, there remains a need for alternative hydrogel systems that address these drawbacks.

[0014] Another drawback associated with conventional hydrogel preparation methods is that the production process, particularly the fragmentation of bulk hydrogel into microparticles, is typically performed in a batch-wise manner, which limits scalability and throughput. This renders commercial manufacturing labor-intensive, time-consuming, and difficult to standardize.

[0015] Additionally, many conventional methods require the use of auxiliary compounds or processing agents to achieve specific product characteristics. However, the presence of such substances, or their degradation products, is generally not permitted in the final hydrogel formulation, especially not when intended for medical use. Consequently, additional purification steps are required to remove these agents or remnants thereof, further complicating the production process and reducing overall efficiency and cost-effectiveness in large-scale manufacturing.SUMMARY OF THE INVENTION

[0016] It is therefore an object of the present invention to provide a hydrogel product that is suitable for application in the middle ear, nasal cavity or sinus, in particular for the healing of a wound in such cavity.

[0017] A particular object is that such hydrogel product has an adhesiveness that is higher than the adhesiveness of known hydrogel products, allowing the hydrogel product to stick well enough to the application site by itself.

[0018] Another particular object is that the adhesion surface energy is higher than the adhesion surface energy of known hydrogel products.

[0019] Another particular object is that such hydrogel has a cohesiveness that allows that it effectively coats the wall of the middle ear, nasal cavity or sinus such that the coating stays intact throughout the desired period for treatment.

[0020] Another particular object is that such hydrogel has a viscosity that allows injection into a cavity through an applicator, such as a needle.

[0021] Another particular object is that such hydrogel has a degradation profile that allows that a coating of the product does not prematurely degrade and ultimately degrades in such way that it becomes completely removed from the application site.

[0022] Another particular object is that such hydrogel product is provided in a ready-to-use form, e.g. that it is not a multi-component formulation wherein different components must be mixed just prior to administration of the hydrogel product at the application site.

[0023] It is also an object that such gel has both an adhesiveness and a cohesiveness that allow for the gel to remain effective at the application site during an extended period or time, for example of at least a week, in particular of at least four weeks.

[0024] It is also an object that the hydrogel has a better capability of delivering a drug to a site of application of the hydrogel.

[0025] It is also an object that the hydrogel causes less allergenic reactions than known hydrogels that are used in the middle ear, sinus and nasal cavity.

[0026] It is also an object that the preparation of the hydrogel on a large scale is easier and / or more efficient than the preparation of known hydrogels that are applied in the middle ear, sinus cavity or nasal cavity.It is a further object that the use of auxiliary compounds or substances is minimized in such preparation, when the presence of such auxiliary compounds or substances (or degradation products thereof) in the obtained hydrogel product is undesired and for example requires an additional purification step.

[0027] It has now been found that one or more of these objects can be reached by using a particular method of hydrogel particle granulation in the preparation of the hydrogel.

[0028] Accordingly, the present invention relates to a granular hydrogel product hydrogel product comprising

[0029] - cross-linked gelatin;

[0030] - particles of cross-linked hyaluronic acid, which particles are dispersed in the cross-linked gelatin;

[0031] - an interstitial aqueous fluid;

[0032] wherein the granular hydrogel product has an adhesion surface energy of at least 2 J / m2.

[0033] The present invention further relates to a process for preparing a granular hydrogel product as described above, the process comprising

[0034] - subjecting a hydrogel of cross-linked hyaluronic acid to high-pressure homogenization to obtain a granular hyaluronic acid hydrogel; then - mixing the granular hyaluronic acid hydrogel with a cross-linked gelatin to yield the granular hydrogel product.

[0035] BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 schematically displays a cross-section of a high-pressure homogenizer in a process of the present invention.

[0037] Figure 2 displays an application means (1) that is filled with a granular hydrogel product according to the invention.

[0038] Figure 3 displays micrographs of hydrogels that are produced using high-pressure homogenization under a range of different pressures.

[0039] Figure 4 displays in a graph the G’ behavior of not completely swollen granular HA hydrogels.

[0040] Figure 5 displays in a graph the G” behavior of not completely swollen granular HA hydrogels.Figure 6 displays in a graph the G’ behavior of maximally swollen granular HA hydrogels.

[0041] Figure 7 displays in a graph the G” behavior of maximally swollen granular HA hydrogels.

[0042] Figure 8 displays micrographs of hydrogels that are produced with a conventional process.

[0043] DETAILED DESCRIPTION OF THE INVENTION

[0044] Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in a figure may be exaggerated relative to other elements to help improve understanding of various exemplary embodiments of the present invention. For example, the relative dimensions of the different components of a high-pressure homogenizer and the chink that is defined for the passage of hydrogel cannot be derived from the figures.

[0045] Further, the terms “first”, “second”, and the like in the present description and claims, if any, are generally used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order.

[0046] In the context of the invention, by the term “surgical site” is meant the place of body where cuts or incisions are made to perform a surgery. Such site needs to heal after the surgery by repair of the tissue that has been damaged by the surgery.

[0047] In the context of the invention, by the term ‘hydrogel’ is meant a material that is a mixture of a porous solid and an interstitial aqueous liquid that makes up at least 10 wt.% of the hydrogel. In many cases, a hydrogel contains much higher amounts of the interstitial aqueous liquid, which may even reach 99.5 wt.%. The interstitial aqueous liquid is typically for the most part water, or even essentially completely water. It may comprise one or more salts that act as a buffer in the hydrogel, which may be the case in medical applications of the hydrogel.

[0048] The porous permeable solid of a hydrogel is a three-dimensional network of natural or synthetic polymers, typically obtained by cross-linking aprecursor polymer. In the context of the present invention, such precursor polymer is termed a ‘hydrogel-forming polymer’, as it converts into a hydrogel upon crosslinking it (and upon allowing the presence of water which in the end is absorbed in the cross-linked polymer). Depending on the degree of cross-linking, a hydrogel may behave as a fluid.

[0049] When, in the present patent document, a hydrogel is identified by the term ‘granular hydrogel’, then this means that the hydrogel is present as an assembly of hydrogel particles. This does not necessarily mean that such particles are obtained by a fragmentation step (such as granulation or grinding) as is the case in the method of the invention. For example, a conventional granular hydrogel may, as an alternative to fragmentation, also be obtained by preparing the hydrogel directly in the form of particles without a fragmentation step.

[0050] A granular hydrogel product of the invention comprises two different hydrogels; a first hydrogel comprising cross-linked gelatin and a second hydrogel comprising particles of cross-linked hyaluronic acid. The two hydrogels are present as a mixture wherein the particles of cross-linked hyaluronic acid are dispersed in the cross-linked gelatin. This mixture comprises water as an interstitial aqueous liquid.

[0051] Gelatin is a mixture of peptides and proteins that is obtained by partial hydrolysis of collagen extracted from animal tissues such as skin, bones, and connective tissues. Its chemical composition is in many aspects closely similar to that of its parent collagen. Gelatin readily dissolves in hot water and sets to a gel on cooling. However, it usually does not dissolve well when added to cold water.

[0052] The gelatin in a granular hydrogel product of the invention may in principle be any gelatin. For example, the gelatin is derived from a species selected from the group of pig, cow, horse, goat, sheep, fish and various poultry species. Preferably, however, it is selected from the group of pig, cow and horse. For application at body temperature, these gelatins are particularly suitable in view of their melting points. The gelatin in a product of the invention may be present in the form of particles such as microparticles.

[0053] The cross-linked gelatin in a product of the invention usually has crosslinks that are derived from an aldehyde, in particular from an aldehyde selected from the group of formaldehyde, paraformaldehyde, acetaldehyde,propionaldehyde, PEG propionaldehyde, butyraldehyde, isobutyraldehyde, valeraldehyde, heptaldehyde, decanal, terephthaldehyde, crotonaldehyde, glutaraldehyde, glyoxal, PEG-dialdehyde, dialdehyde carboxymethyl cellulose and dialdehyde starch.

[0054] The cross-linked hyaluronic acid in a product of the invention usually has cross-links that are derived from the group of diglycidyl ethers, diepoxyalkanes and divinyl sulfone, in particular from the group of 1 ,4-butanediol diglycidyl ether and divinyl sulfone.

[0055] The hyaluronic that is cross-linked has (before the crosslinking) a mass average molecular mass (Mw) at least 10 kDa, in particular at least 50 kDa.

[0056] Typically, it is in a range of 100-25,000 kDa, in particular it is in a range of 200-10,000 kDa and more in particular it is in a range of 400-4,000 kDa. Preferably it is in a range of 500-2,200 kDa or in a range of 1 ,000-2,000 kDa.

[0057] The particles of cross-linked hyaluronic acid are prepared by means of high-pressure homogenization, as will be further described below.

[0058] The content of cross-linked hyaluronic acid particles in a product of the invention is usually in a range 0.2-6.0 wt.%, in particular in a range of 0.3-3.0 wt.%, more in particular in a range of 1.0-2.0 wt.%.

[0059] The granular hydrogel product obtained with a process of the invention may comprise one or more active pharmaceutical ingredients, for example one or more active pharmaceutical ingredients selected from the group of antibiotics, steroids, analgesics, antifungals, vitamins and hemostatic drugs. This may be realized by allowing a not-completely water-saturated granular hydrogel to absorb an aqueous composition comprising the one or more active pharmaceutical ingredients. Therefore, the process of preparing the granular hydrogel product may comprise a step of allowing an obtained granular hydrogel to absorb an active pharmaceutical ingredient, in particular by absorbing an aqueous phase that contains the pharmaceutical ingredient.

[0060] The interstitial aqueous fluid is in principle designed to be a physiologically acceptable carrier fluid. The fluid is typically buffered at or around physiological pH, e.g. with a physiological saline solution such as phosphate buffered saline (PBS). The pH of a granular hydrogel product of the invention is usually in the range of 6.4 to 7.8, in particular in the range of 6.8 to 7.4.The content of interstitial aqueous fluid in a product of the invention is usually at least 90 wt.%, based on the total weight of the product as such. The content may also be at least 92 wt.%, at least 94 wt.%, at least 95 wt.%, at least 96 wt.%, at least 97 wt.%, at least 98 wt.%, at least 98.5 wt.%, or at least 99 wt.%. The content may also be 99 wt.% or less, 98 wt.% or less, 96 wt.% or less or 94 wt.% or less. Preferably, the content is in the range of 93-98 wt.%.

[0061] A granular hydrogel product according to the invention has a high adhesiveness to mucosal surfaces, ensuring that it firmly attaches to the moist tissue without being easily dislodged by gravity, mucus flow, or normal movements such as breathing or speaking. A granular hydrogel product according to the invention may therefore have a surface energy of at least 3 J / m2, at least 4 J / m2, at least 5 J / m2, at least 6 J / m2, at least 7 J / m2, at least 8 J / m2, at least 9 J / m2, at least 10 J / m2, at least 11 J / m2or at least 12 J / m2.

[0062] Herein, the adhesion surface energy is determined for adhesion to aluminum at 20 °C and measured with a rheometer configured in the following way: 40 mm parallel plate, Peltier plate aluminium, gap of 500 pm, trim gap offset of 50 pm, constant linear rate of 100 pm / s (see Example 1 for a more elaborate description).

[0063] A granular hydrogel product of the invention preferably has a favorable cohesiveness. This allows it to effectively coat the wall of the middle ear, nasal cavity or sinus without sagging and / or withdrawal of the hydrogel (no disintegration of the coating), so that the hydrogel coating stays intact throughout the treatment period of typically 1-6 weeks. Cohesiveness of a substance is herein expressed as the ‘drop size’ or ‘drop mass’ of the substance, which is the mass of a drop of the substance that forms when the substance is released from an outlet of a reservoir. When the drop size increases during the release, there comes a moment when it falls off under its own weight. The weight of the fallen drop is then measured (the drop mass), which value represents the cohesiveness. A granular hydrogel product of the invention preferably has a drop mass in a range of 40-400 mg, in particular in a range of 100-200 mg. The drop mass may also be in a range of 50-250 mg or in a range of 80-160 mg. It may be at least 35 mg, at least 45 mg, at least 65 mg, at least 95 mg, at least 125 mg, at least 150 mg, at least 180 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, or at least325 mg. It may also be 420 mg or less, 375 mg or less, 350 mg or less, 325 mg or less, 300 mg or less, 275 mg or less, 250 mg or less, 225 mg or less, 200 mg or less, 175 mg or less, 150 mg or less or 125 mg or less.

[0064] Herein, the drop mass of a hydrogel is preferably determined by the following measuring method, performed at a temperature of 20 °C:

[0065] allowing a drop of the hydrogel to form at an outlet of a syringe by pressing a piston into the syringe that contains the hydrogel, wherein the syringe is positioned vertically with the outlet facing the ground; and then

[0066] increasing the drop size by continuing the pressing of the piston into the syringe until the drop releases from the syringe under its own weight; and then catching the released drop of hydrogel and measuring its mass.

[0067] Besides the high adhesiveness and cohesiveness, the hydrogel is preferably at the same time viscoelastic, striking a balance between viscosity (G’) and elasticity (G”); it is then viscous enough to resist flow and deformation, yet elastic enough to conform to the irregular anatomy of application sites in body cavities such as the middle ear, the nasal cavity or the sinus.

[0068] The hydrogel product of the invention usually also possesses shearthinning behavior, allowing it to be easily applied (e.g., via injection) but also to rapidly solidify or become more viscous upon application, so that it maintains its position over time. This appears to be an inherent property of all the hydrogel products of the invention.

[0069] In the preparation of a granular hydrogel product according to the invention, the particles of cross-linked hyaluronic acid are prepared by subjecting a hydrogel of cross-linked hyaluronic acid to high-pressure homogenization. The particles then in essence form a granular hyaluronic acid hydrogel. In a next step, the obtained granular hyaluronic acid hydrogel is mixed with a cross-linked gelatin to yield the granular hydrogel product.

[0070] It was surprisingly found that subjecting a hyaluronic acid hydrogel to high pressure homogenization provides the obtained resulting granular hydrogel with beneficial properties that cannot be obtained by conventional methods, such as conventional grinding methods or conventional manufacturing methods wherein a hyaluronic acid hydrogel is prepared directly in the form of particles without a fragmentation step. A quite characteristic observation is that such granularhydrogel has a highly increased adhesiveness as compared to granular hydrogels obtained by conventional methods. In addition, it usually also has an increased cohesiveness. These properties together are particularly advantageous when the fragmented hyaluronic acid hydrogel is used to prepare a medical patch which has to stick by itself to a body part and which does not deform or sag over time.

[0071] The hyaluronic acid hydrogel that is subjected to the high-pressure homogenization is usually present as a plurality of particles of a size that allows an easy feeding to the high-pressure homogenizer, for example particles having at least one dimension, such as their largest dimension or their smallest dimension, in a range of 1-100 mm, in particular in a range of 5-50 mm. If present, these particles are usually obtained by fragmenting a hydrogel to smaller chunks prior to feeding the hyaluronic acid hydrogel to the high-pressure homogenizer. In principle, however, it is also possible that the hyaluronic acid hydrogel is fed to the high-pressure homogenizer as one single piece.

[0072] By high-pressure homogenization is meant a mechanical process which involves forcing a substance through a narrow nozzle at a high pressure, which may be as high as 4,000 bar. The substance is then subjected to very high shear stress, thereby altering one or more mechanical or physical properties of the substance, such as the size and morphology of its particles. For example, it is known in the art that when an oil-water emulsion is subjected to high-pressure homogenization, then droplet size is decreased to yield a stable submicron emulsion. For convenience, high-pressure homogenization may hereinafter also be abbreviated as HPH.

[0073] When, according to a process of the present invention, a hydrogel is subjected to high-pressure homogenization, then the porous solid that holds the water is fragmented upon passage through the nozzle. This then yields a plurality of hydrogel fragments. The smaller the nozzle aperture and / or the higher the pressure, the smaller is the mass of the particles that are produced.

[0074] In a process of the present invention, the nozzle is preferably a slit nozzle, more preferably a ring-shaped slit nozzle. Such nozzle may be formed when a blocking unit (impact head (5)) is moved closely to a corresponding opening (impact ring (6)) of a container. This is then performed without completely blocking the opening, so that a small annular gap (7) is formed. The width of thegap in a process of the invention, i.e. the smallest distance between the impact ring and the passage head, is usually in a range of 1 to 500 pm.

[0075] Figure 1 schematically displays a cross-section of a high-pressure homogenizer (4) in a process of the present invention. During the process, particles of the hyaluronic acid hydrogel are guided through a passage head (8), after which they pass through an annular gap (7) that is defined by an impact head (5) and an impact ring (6). In this area, fragmentation to smaller hydrogel particles occurs. The resulting granular hydrogel then travels away from the annular gap (7).

[0076] The pressure that is applied in a high-pressure homogenization refers to the pressure that is exerted on the substance to force it through the nozzle of the high-pressure homogenizer. In a process of the invention, the applied pressure is usually in a range of 20-2,000 bar. It may be 1 ,500 bar or less, 1 ,250 bar or less, 1 ,000 bar or less, 750 bar or less or 500 bar or less. It may be 25 bar or more, 40 bar or more, 75 bar or more, 150 bar or more, 250 bar or more, 500 bar or more, 750 bar or more or 1 ,000 bar or more.

[0077] In a process of the invention, the granular hyaluronic acid hydrogel that is obtained after the high-pressure homogenization usually has an elastic modulus G’ in a range of 900-1 ,300 Pa, in particular in a range of 1 ,000-1 ,200 Pa. Herein, the elastic modulus is determined at 25 °C with a rheometer configured in the following way: 40 mm parallel plate, Peltier plate aluminium, gap of 100 pm, trim gap offset of 50 pm, frequency of 0.7 Hz.

[0078] After mixing the granular hyaluronic acid hydrogel with the cross-linked gelatin, the elastic modulus G’ of the granular hydrogel product is in a range of 800-1 ,200 Pa. Thus, the elastic modulus G’ of a granular hydrogel product of the invention is not very much different from that of its granular hyaluronic acid hydrogel component (in other words, the granular hyaluronic acid hydrogel has a large influence on the elastic modulus G’ of the final product).

[0079] In a process of the invention, the granular hyaluronic acid hydrogel that is obtained after the high-pressure homogenization, and which is thereafter mixed with the cross-linked gelatin, usually has an viscous modulus G” in a range of 90-110 Pa, in particular in a range of 94-105 Pa. Herein, the viscous modulus is determined at 25 °C with a rheometer configured in the following way: 40 mmparallel plate, Peltier plate aluminium, gap of 100 pm, trim gap offset of 50 pm, frequency of 0.7 Hz.

[0080] After mixing with the cross-linked gelatin, the viscous modulus G” of the granular hydrogel product is in a range of 100-110 Pa. Thus, the viscous modulus G” of a granular hydrogel product of the invention is not very much different from that of its granular hyaluronic acid hydrogel component (in other words, the granular hyaluronic acid hydrogel has a large influence on the viscous modulus G” of the final product).

[0081] When applying high-pressure homogenization on a cross-linked hyaluronic acid, it unexpectedly appears possible to steer the properties of the granular hyaluronic acid hydrogel in a particular direction. This makes it possible to purposively prepare granular hyaluronic acid hydrogels with particular properties. Such control over the properties is possible by changing the pressure at which the high-pressure homogenization is carried out. It is for example found that a higher pressure yields granular hyaluronic acid hydrogels with a higher cohesiveness, a lower elasticity (G’ elastic modulus) and a lower viscosity (G” viscous modulus). This is demonstrated in Example 3 and visualized in Figures 4-7. Further, microscope pictures demonstrate that particle size (particle mass) decreases with an increasing pressure, and that more air is entrained in the hydrogel with an increasing pressure. Particle morphology is also influenced, as the hydrogel particles contain more and larger lobes with an increasing pressure. This is demonstrated in Example 3 and visualized in Figure 3. It is also found that the adhesiveness increases upon increasing the pressure in the HPH process. The lowest adhesivenesses are obtained when a conventional fragmentation step is applied, using a non-HPH technique such as granulation, grinding or pressing the hydrogel through a sieve.

[0082] It is contemplated that the high shears to which the hyaluronic acid hydrogel is subjected during high pressure homogenization cause that the hyaluronic acid hydrogel is torn apart into fragments that have several lobes, so that the fragments have a high surface-to-volume ratio. These lobes may then interlock with one another, and so become responsible for the high adhesiveness and the high cohesiveness. Microscope pictures of an obtained granular hydrogel also point into this direction (see Figure 3), although it is difficult to discriminate thedifferent particles from one another, likely because of the high cohesiveness as this results in agglomeration of the particles. The pictures of Figure 3 also demonstrate that particle morphology varies with the applied pressure, as the hydrogel particles contain more and larger lobes with an increasing HPH pressure.

[0083] A person skilled in the art knows how to operate a high-pressure homogenizer and how to perform a high-pressure homogenization on a hydrogel in accordance with the present invention. In particular, having taken account of the above teaching on how to steer hydrogel properties in a desired direction (such as the adhesiveness, the cohesiveness, the G’ elastic modulus and the G” viscous modulus), he will be able to arrive at the claimed granular hydrogel product by routine experimentation and without exerting an inventive effort.

[0084] The present invention provides a granular hydrogel product that has an unprecedented adhesiveness. This makes that it sticks very well to the surface of the injection site. It is within the capability of the skilled person to also provide such gel with a sufficient degree of one or more of the following properties: cohesiveness, injectability (e.g. viscosity), viscoelasticity and controlled degradability. With proper values for these four important properties the product is particularly well-suited for post-surgical wound management in the middle ear, sinus and nasal cavity applications.

[0085] An advantage of its adhesiveness is that the hydrogel product sticks very well to the application site by itself, so that it is not necessary to fill the middle ear, the nasal cavity or the sinus completely with gel. In this way, normal physiological functions like drainage, mucociliary clearance, hearing, and breathing remain largely unaffected. This localized approach also reduces patient discomfort and the need for complex removal procedures.

[0086] An advantage of its viscoelasticity is that the hydrogel product stays in the intended shape and does not deform due to sagging or natural body movement.

[0087] It is also advantageous that the hydrogel product degrades gradually under physiological conditions, particularly in the humid environment of the middle ear, nasal or sinus cavity.

[0088] It is also an advantage that the hydrogel product is prepared without the use of auxiliary compounds or processing agents to achieve its specific productcharacteristics. Therefore, no additional purification steps are required to remove these agents or remnants thereof, which would otherwise further complicate the production process and reduce overall efficiency and cost-effectiveness in large-scale manufacturing.

[0089] Another unexpected advantage is its high water absorption capability, measured as the mass increase of a sample of the hydrogel when allowed to absorb an excess of water. When present at the surface of the injection site, it is capable of absorbing high amounts of fluid, in particular body fluids such as mucus or blood. This is advantageous because it enhances the wound healing.

[0090] An important use of a granular hydrogel product of the invention is in the medical field. The invention therefore further relates to a granular hydrogel product as described hereabove for use in medical therapy, for use as a medicament and / or for use in medicine. This typically concerns treatment of a subject during or after ear, nose and throat surgery, in particular treatment of a surgical site of a subject, in particular a surgical site in the middle ear, nasal cavity or sinus.

[0091] The invention further relates to a method for treating a medical condition of a human or an animal, comprising administering to the human or animal, in particular at a surgical site, in particular a bleeding site, of the human or animal, an effective amount of a granular hydrogel as described hereabove.

[0092] The invention further relates to a method of treating a surgical site of a human or an animal, the method comprising administering to the surgical site an amount of a granular hydrogel product as described hereabove effective to prevent adhesions, to minimize scarring, to prevent undesired biological reactions and / or to stop bleeding at the surgical site. The surgical site is preferably is in the middle ear, nasal or sinus cavity of the human or animal.

[0093] By the phrase “administering the granular hydrogel product to the surgical site” is meant that the hydrogel product is applied to the surgical site so that the hydrogel is in touch with the surgical site. The effect of such treatment is one or more of the following; to prevent adhesions, to prevent undesired biological reactions, to minimize scarring and to stop bleeding. An effective amount for this is usually in a range of 0.1-15 mL. It is in particular in a range of 0.5-10 mL, more in particular in a range of 1-6 mL, depending on the size of the surgical site.As used herein, the term "effective amount" means that amount of a granular hydrogel product of the invention that will elicit the biological or medical response of an animal or human that is being sought, for instance, by a researcher or clinician.

[0094] The term medical condition as used herein is a broad term that includes all diseases, lesions, disorders, or nonpathological condition that normally receives medical treatment, such as pregnancy or childbirth.

[0095] The granular hydrogel may be provided in any suitable form, for example in a syringe for ease of application to e.g. the nasal cavity. Accordingly, the invention further relates to an application means comprising an effective amount of the granular hydrogel in order to stop bleeding at a bleeding site of a human or animal subject.

[0096] Figure 2 displays an application means (1) that is filled with a granular hydrogel product (2) of the invention. This syringe is suitable for applying a granular hydrogel product of the invention to a human or animal. It contains an elongate applicator (3) for access in body cavities such as the middle ear, the nasal cavity or the sinus. In a preferred embodiment, the hydrogel is sterilized after or before filling the application means (or other packaging means) with the hydrogel, in particular with the aim of increasing a shelf-life of the granular hydrogel product.

[0097] The invention further relates to the use of a granular hydrogel product as described hereabove for the manufacture of a medicament for treating a human or an animal, in particular for treating a surgical site of a human or an animal, more in particular a surgical site in the middle ear, nasal cavity or sinus.

[0098] EXAMPLES

[0099] 1. Preparation of a hydrogel of the invention

[0100] 1.1. General considerations

[0101] The chemicals and solvents were purchased from commercial sources and used without further purification. If necessary, residual water was removedfrom them prior to their use. When water itself was used in a procedure, it was demineralized prior to its use.

[0102] All prepared hydrogels contained a phosphate buffer to give the hydrogel a pH in the range 6.8-7.2.

[0103] The high-pressure homogenizer that was used in the preparation of the hydrogel particles was a laboratory homogenizer with a maximum operating pressure of 2,000 bar and a rated flow of 5 L / h. The hydrogel is to be introduced into the apparatus via a feeding hopper and a jacketed feed tank with pneumatic pusher.

[0104] The elastic modulus G’ and viscous modulus G” of each granular hydrogel sample were measured using a Discovery hybrid rheometer AR G2. For each measurement, an SS geometry with a 40 mm diameter was used wherein the gap was set at 500 pm and the trim gap offset at 50 pm. The temperature was set at 25°C and the frequency at 0.7 Hz.

[0105] The cohesiveness of the hydrogels was measured using a Hartech Multitest-i by slowly pressing the hydrogel out of a syringe that was positioned vertically with the outlet facing the ground. The drop shape was determined just before the moment that a drop fell off the syringe outlet. The fallen drop was caught and its drop mass was determined.

[0106] The adhesion surface energy of the hydrogels was measured using a Discovery hybrid rheometer AR G2, wherein the adhesion surface energy was determined for adhesion to aluminum at 20 °C. The rheometer was configured with the following geometry: 40 mm parallel plate, Peltier plate aluminium. The following procedure was applied. An amount of 1 mL of the hydrogel is placed on the bottom plate and then squeezed by the top plate (circular plate, 40 mm diameter). Excess hydrogel that is squeezed outside the plate perimeter is removed with a tissue. The gap is set at 500 pm and the trim gap offset at 50 pm. Next, the plates are pulled apart from one another at a constant linear rate of 100 pm / s. The adhesion surface energy is then determined taking into account the force required for this pulling apart.

[0107] The extrusion force of the hydrogels was measured using a Hartech Multitest-i by measuring the pressure that was needed to eject the hydrogel from a 10 mL syringe that had applicator mounted to its tip via a Luer-lock.1.2. Preparation of 2.5 wt.% cross-linked hyaluronic acid

[0108] An amount of 348 ± 1 g of sodium hyaluronate powder (Mw = 1 ,500-1 ,700 kDa) was weighed into a plastic bottle. A 0.25 M NaOH solution was prepared by dissolving 22 g of NaOH pellets in 2,200 g of demineralized water, using a 5 L glass beaker and under mechanical stirring. An amount of 2,103 ± 5 g of this solution was transferred to a planetary mixer with a mixing bowl of 5L. The sodium hyaluronate powder was added thereto in 10 portions at intervals of 2.5 minutes, under continuous stirring. When all of the powder had dissolved under the formation of a gel, 38 ± 0.5 g of BDDE was slowly added to the gel. The mixture was then stirred for 20 minutes. Thereafter, 240 ± 5 g of the gel mixture was transferred to a 1 ,000 mL plastic container. The container was closed and placed in an oven at 45 °C during 4 hours. The container was taken out of the oven and the cross-linked gel was cut into pieces of approximately 2.5 x 2.5 cm. The gel pieces were then poured into a mixture of 0.75 M acetic acid and PBS buffer solution for 16 hours to neutralize the pH. Thereafter, the resulting swollen gel fractions were transferred to a fresh solution of PBS-buffer and left to swell further until the HA content had fallen to 2.5 wt.%, which was monitored by intermediate weighing of the swollen pieces. The swollen gel fraction was then ground into mm-sized particles using a blender (fractionation), to produce the hyaluronic acid (HA) hydrogel for subjection to HPH.

[0109] 1.3. Granulation of cross-linked hyaluronic acid with HPH

[0110] A 2.5 wt.% hyaluronic acid hydrogel sample obtained from the preparation described in paragraph 1.2 was subjected to HPH at a pressure of 100 bar. The feed tank of the HPH was filled with the mm-sized particle gel and the pneumatic hopper was positioned. After the HPH apparatus was started, first, a frontrunning waste fraction was collected for 2 minutes. Then, product was collected until the tank became empty. The values for G’ and G” at 0.7 Hz were measured for the obtained granular hydrogel, G’ being 1 ,138 Pa and G” being 98 Pa.1.4. Preparation of the granular hydrogel product of the invention

[0111] The obtained HA gel (still buffered at a pH in the range 6.8-7.2) was mixed with a cross-linked gelatin powder that was also buffered at a pH in the range 6.8-7.2 (the gelatin cross-linking was performed by treatment with 1.1 wt.% formaldehyde). A syringe was filled with a homogeneous mixture of both gels. After sterilization and packaging, the syringe was ready for use. The granular hydrogel product of the invention that was prepared in this way was optimized to maximize its cohesion and adhesion characteristics. It has a viscous modulus G” of 105 Pa and an elastic modulus G’ of 1001 Pa.

[0112] 2. Comparison of a hydrogel of the invention with a conventional hydrogel

[0113] A number of mechanical properties of the granular hydrogel product of the invention were measured and then compared with those of the commercially available Chitogel™ endoscopic sinus surgery kit. This product comprises a hydrogel based on a combination of chitosan, dextran and glycerol that is chemically crosslinked to a network (once the individual components are mixed, the crosslinking starts). The results of this comparison are displayed in Table 1 , wherein the values for Chitogel™ are obtained by measuring the product after completion of the crosslinking.

[0114] Table 1. Comparison of the mechanical properties of the two hydrogels

[0115] Entry Test Invention Chitogel™ 1 cohesiveness by drop shape Yes Yes (elongated Y / N)

[0116] cohesiveness by drop mass 149 13

[0117] (mg)

[0118] 2 Adhesion surface energy to 13 0.21

[0119] aluminum (J / m2)

[0120] 3 Absorption by weight (wt.%) 226 62

[0121]

[0122] The results show that by subjecting the HA hydrogel to HPH, the adhesivity and cohesivity are significantly higher than those of the product known in the art. It further appeared that the absorption capability of the product of the invention is much higher than that of the product known in the art (the percentage given in Table 1 refers to the mass increase of a hydrogel sample when allowed to absorb an excess of water).

[0123] 3. Effect of HPH on mechanical properties of a hydrogel

[0124] For the development of a hydrogel product, both the elastic (G’) and viscous (G”) behavior are critical product variables. In this Example, the G’ and G” behavior of a granular hyaluronic acid (HA) hydrogel was investigated as a function of HPH pressure settings. Further, the obtained values for G’ and G” were compared with values for G’ and G” obtained with a manual granulation procedure. This was performed for non-maximally swollen HA hydrogels (paragraphs 3 and 4 of Example 3) and for maximally swollen HA hydrogels (paragraph 5 of Example 3).

[0125] 3.1. General considerations

[0126] The chemicals and solvents were purchased from commercial sources and used without further purification. If necessary, residual water was removed from them prior to their use. When water itself was used in a procedure, it was demineralized prior to its use. All prepared hydrogels contained a phosphate buffer to give the hydrogel a pH in the range 6.8-7.2.

[0127] The high-pressure homogenizer that was used in the preparation of the hydrogel particles was a laboratory homogenizer with a maximum operating pressure of 2,000 bar and a rated flow of 5 L / h. The hydrogel is to be introduced into the apparatus via a feeding hopper and a jacketed feed tank with pneumatic pusher.

[0128] The elastic modulus G’ and viscous modulus G” of the granular hydrogel sample were measured using a Discovery hybrid rheometer AR G2. For each measurement, an SS geometry with a 40 mm diameter was used wherein the gapwas set at 500 pm and the trim gap offset at 50 pm. The temperature was set at 25°C and the frequency at 0.7 Hz.

[0129] 3.2. Preparation of a 2.5 wt.% cross-linked HA hydrogel

[0130] An amount of 348 ± 1 g of sodium hyaluronate powder (Mw = 1 ,500-1 ,700 kDa) was weighed into a plastic bottle. A 0.25 M NaOH solution was prepared by dissolving 22 g of NaOH pellets in 2,200 g of demineralized water, using a 5 L glass beaker and under mechanical stirring. An amount of 2,103 ± 5 g of this solution was transferred to a planetary mixer with a mixing bowl of 5L. The sodium hyaluronate powder was added thereto in 10 portions at intervals of 2.5 minutes, under continuous stirring. When all the powder had dissolved under the formation of a gel, 38 ± 0.5 g of BDDE was slowly added to the gel. The mixture was then stirred for 20 minutes. Thereafter, 240 ± 5 g of the gel mixture was transferred to a 1 ,000 mL plastic container. The container was closed and placed in an oven at 45 °C during 4 hours. The container was taken out of the oven and the cross-linked gel was cut into pieces of approximately 2.5 x 2.5 cm. The gel pieces were then poured into a mixture of 0.75 M acetic acid and PBS buffer solution for 16 hours to neutralize the pH. Thereafter, the resulting swollen gel fractions were transferred to a fresh solution of PBS-buffer and left to swell further until the HA content had fallen to 2.0 wt.%, which was monitored by intermediate weighing of the swollen pieces. The swollen gel fraction was then ground into mm-sized particles using a blender (fractionation), to produce the HA hydrogel for subjection to HPH.

[0131] 3.3. Effect of HPH pressure on G’ and G” behavior of granular HA hydrogel

[0132] Six identical samples of the prepared fractioned cross-linked HA hydrogel (see paragraph 3.2.) were subjected to HPH at different pressures (each sample being subjected once to HPH by performing a run at a particular pressure), yielding samples #1-6. The HA content in these samples was 2.0 wt.% (the samples were not saturated with water, i.e. not completely swollen). In each run, the feed tank of the HPH was filled with the mm-sized particle gel and the pneumatic hopper was positioned. The pressure was set at the applicable valuefor the pressure and then the HPH apparatus was started. First, a frontrunning waste fraction was collected for 2 minutes. Then, product was collected until the tank became empty. The different pressures applied in the different runs were 30, 60, 100, 200, 300 and 400 bar. For each of the six runs, a separate sample was obtained. The values for G’ and G” were measured for each sample. The results are displayed in Table 2 and in Figures 4-5.

[0133] 3.4. Comparative: G’ and G” behavior of sieve-granulated HA hydrogel

[0134] Two additional samples of the prepared fractioned cross-linked HA hydrogel (not completely swollen) were subjected to a conventional granulation process. This concerns the manual pressing of a sample of fractioned HA through a sieve of a particular mesh to yield a sieve-granulated HA hydrogel (each sample being treated once by pressing the sample once through the sieve of a particular mesh). The different sieves applied were a 150 pm sieve and a 45 pm sieve. One run was performed for each sieve, yielding samples #7 and 8. The values for G’ and G” were measured for each sample. The results are displayed in Table 2 and in Figures 4-5.

[0135] Table 2. G’ and G” behavior of granular HA hydrogels (not completely swollen) Sample # HPH pressure HA content G’ at 0.7 Hz G” at 0.7 Hz (bar) (wt.%) (Pa) (Pa)

[0136] 1 30 2.0 672 66

[0137] 2 60 2.0 605 69

[0138] 3 100 2.0 494 53

[0139] 4 200 2.0 310 39

[0140] 5 300 2.0 217 35

[0141] 6 400 2.0 165 31

[0142] 7 manually ground 2.0 750 60 (comparative) (150 pm sieve)

[0143] 8 manually ground 2.0 799 85 (comparative) (45 pm sieve)

[0144]

[0145] 3.5. G’ and G” behavior at maximum swelling of granular HA hydrogel

[0146] The G’ and G” measurements as described in paragraphs 3.3 and 3.4 of Example 1 (see above) were now performed on a maximally swollen HA granular hydrogel. To this end, the same eight samples were used as those that were obtained from the HPH procedure (samples #1-6) and from the conventional sieving procedure (samples #7 and 8) as described in the above paragraphs 3.3 and 3.4, respectively.

[0147] Maximal swelling of a HA hydrogel sample was achieved in the following way. An amount of 1 gram of the granular hydrogel was weighed in a glass tube after which 8 gram of PBS buffer solution was added. The obtained gel mixture was then vortexed and left to stand for 6 hours, after which it was centrifuged for 10 minutes at 4,000 rpm (Eppendorf 5804). Excess water was discarded. The resulting gel was weighed to determine the HA content in wt.% by gravimetric ratio. Then, the values for G’ and G” were measured for each sample. The results are displayed in Table 3 and in Figures 6-7.

[0148] Table 3. G’ and G” behavior of granular HA hydrogels (completely swollen) Sample # HPH pressure HA content G’ at 0.7 Hz G” at 0.7 Hz (bar) (wt.%) (Pa) (Pa)

[0149] 1 30 1.05 265 75

[0150] 2 60 1.09 255 65

[0151] 3 100 1.14 200 55

[0152] 4 200 1.05 125 27

[0153] 5 300 1.25 102 20

[0154] 6 400 1.25 75 15

[0155] 7 manually ground 1.04 170 40 (comparative) (150 pm sieve)

[0156] 8 manually ground 1.05 180 66 (comparative) (45 pm sieve)

[0157]

[0158] 3.6. Particle characterization using confocal microscopy

[0159] The obtained hydrogels were further studied by characterizing the size and morphology of their HA particles using confocal microscopy. Microscope pictures of the hydrogels obtained at the different pressures are shown in Figure 3. This Figure also demonstrates how particle morphology varies with the applied pressure; the hydrogel particles contain more and larger lobes when the HPH is performed at a higher pressure.

[0160] For comparison, microscope pictures of hydrogels that are produced with the conventional sieving process are shown in Figure 8; the shape of these hydrogels most closely resembles that of a hydrogel obtained with a HPH pressure of 30 bar. So, the higher the HPH pressure, the more remote is the particle shape from the shape of conventional hydrogel particles.

[0161] 3.7. Conclusions

[0162] The measurements performed on granular hydrogels obtained by performing HPH at different pressures show that the elastic modulus G’ and the viscous modulus G” of the fractioned hydrogel both decrease with an increasing HPH pressure. This allows an estimation of the outcome of the HPH. When the fractioned hydrogel is swollen to its maximum capacity, the trend remains similar.

[0163] This is in contrast to the manually ground gels, where there is a limitation of the pressure that can be applied manually (no more than a few Newton).

[0164] Therefore, one cannot change the G’ or G” by manual granulation with a sieve. The same is true for sieve-granulation in a sieving machine, where applied pressures are also severely limited.

[0165] Visual inspection of the different images of Figure 3 reveals that the particles have a more complex morphology when their preparation involves a higher pressure in the HPH. They appear to have less regular contours and are possibly even composed of several lobes. From these pictures, it seems that the surface to volume ratio increases upon increasing the pressure of the HPH. This may be due to the high shear forces that are exerted onto the gel during the HPH, causing rupture to occur along long stretches of gel matter.

Claims

CLAIMS1. Granular hydrogel product comprising- cross-linked gelatin;- particles of cross-linked hyaluronic acid, which particles are dispersed in the cross-linked gelatin;- an interstitial aqueous fluid;wherein the granular hydrogel product has an adhesion surface energy of at least 4 J / m2, wherein the adhesion surface energy is measured for adhesion to aluminum and determined with a rheometer.

2. Granular hydrogel product according to claim 1 , wherein the granular hydrogel product has a drop mass in a range of 40-400 mg, in particular in a range of 100-200 mg, wherein the drop mass is obtained by the following measuring method, performed at a temperature of 20 °C:- allowing a drop to form at an outlet of a syringe by pressing a piston into the syringe, wherein the syringe is positioned vertically with the outlet facing the ground; and then- increasing the drop size by continuing the pressing of the piston into the syringe until the drop releases from the syringe under its own weight; and then- catching the released drop and measuring its mass.

3. Granular hydrogel product according to claim 1 or 2, wherein the granular hydrogel product has a surface energy of at least 5 J / m2, at least 6 J / m2, at least 7 J / m2, at least 8 J / m2, at least 9 J / m2, at least 10 J / m2or at least 12 J / m2.

4. Granular hydrogel product according to any one of claims 1-3, wherein the cross-linked gelatin is present as microparticles.

5. Granular hydrogel product according to any one of claims 1-4, wherein the content of cross-linked hyaluronic acid particles is in a range of 0.4-4.0 wt.%, in particular in a range of 1.0-2.0 wt.%.

6. Granular hydrogel product according to any one of claims 1-5, wherein the cross-linked gelatin has cross-links that are derived from an aldehyde, in particular from an aldehyde selected from the group of formaldehyde, paraformaldehyde, acetaldehyde, propionaldehyde, PEG propionaldehyde, butyraldehyde, isobutyraldehyde, valeraldehyde, heptaldehyde, decanal, terephthaldehyde, crotonaldehyde, glutaraldehyde, glyoxal, PEG-dialdehyde, dialdehyde carboxymethyl cellulose and dialdehyde starch.

7. Granular hydrogel product according to any one of claims 1-6, wherein, in the microparticles of cross-linked hyaluronic acid, the mass average molecular mass (Mw) of the hyaluronic acid is in a range of 500-2,200 kDa, in particular in a range of 1 ,000-2,000 kDa.

8. Granular hydrogel product according to any one of claims 1-7, comprising an active pharmaceutical ingredient, such as an active pharmaceutical ingredient selected from the group of antibiotics, steroids, analgesics, antifungals, vitamins and hemostatic drugs.

9. Process for preparing a granular hydrogel product according to any one of the preceding claims, the process comprising- subjecting a hydrogel of cross-linked hyaluronic acid to high-pressure homogenization to obtain a granular hyaluronic acid hydrogel; then - mixing the granular hyaluronic acid hydrogel with a cross-linked gelatin to yield the granular hydrogel product.

10. Process according to claim 9, wherein the high-pressure homogenization is performed by applying a pressure in a range of 30-1 ,000 bar, in particular in a range of 60-600 bar.

11. Process according to claim 9 or 10, wherein the process comprises allowing the obtained granular hydrogel and / or the obtained granular hydrogel product to absorb an active pharmaceutical ingredient, such as an active pharmaceutical ingredient selected from the group of antibiotics, steroids, analgesics, antifungals, vitamins and hemostatic drugs.

12. Process according to any one of claims 9-11 , wherein the granular hyaluronic acid hydrogel that is obtained after the high-pressure homogenization has an elastic modulus G’ in a range of 900-1 ,300 Pa, in particular in a range of 1 ,000-1 ,200 Pa, and / or wherein the obtained hydrogel product has an elastic modulus G’ in a range of 800-1 ,200 Pa.

13. Process according to any one of claims 9-12, wherein the granular hyaluronic acid hydrogel that is obtained after the high-pressure homogenization has a viscous modulus G” in a range of 90-110 Pa, in particular in a range of 94- 105 Pa, and / or wherein the obtained hydrogel product has a viscous modulus G” in a range of 100-110 Pa.

14. Granular hydrogel product according to any one of claims 1-8, for use in medical therapy.

15. Granular hydrogel product according to claim 14, for use in the treatment of a surgical site, in particular a surgical site in the middle ear, nasal cavity or sinus.

16. Method of treating a surgical site of a human or an animal, comprising administering to the surgical site an amount of the granular hydrogel product according to any one of claims 1-8, effective to prevent adhesions, to minimize scarring, to prevent undesired biological reactions and / or to stop bleeding at the surgical site.

17. Method according to claim 16, wherein the surgical site is in the middle ear, nasal or sinus cavity of the human or animal.

18. Method according to claim 16, wherein the amount effective to prevent adhesions, minimize scarring and stop bleeding is in the range of 0.1-15 mL, in particular in a range of 0.5-10 mL19. An application means (1) which includes an effective amount of a granular hydrogel product (2) according to any one of claims 1-8 in order to prevent adhesions, minimize scarring and stop bleeding at a bleeding site of a human or animal subject.

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