An ideal biomaterial for medical devices: Recombinant Human Albumin

Surface engineering is key for medical devices, particularly the ones that interact with the human body like tubing, catheters, and stents which need to be implanted. It is essential to have strong control on the performance of the coatings, so that everyone is assured that they are uniformly present on the surfaces, that the coatings allow an effective flow of body fluids (such as blood), and that they promote a long lifespan not diminishing or reducing the effectiveness of the medical device in use1 - all of the above, according to the regulation standards, are required to be met by oversight groups.

As such, medical device manufacturers are always looking for new biocompatible surface coating solutions that make validation processes quicker, safer and more reliable in getting their products to market faster.

Thromboresistance: an essential feature of implantable devices

Even though most of the biomedical polymers currently employed are relatively inert, unreactive, and non-toxic, most implant materials when in contact with the blood will cause the activation of blood cells, as well as the plasma proteolytic enzyme systems². For example, surfaces of implantable and blood contact devices accumulate adsorbed and denatured proteins; and, this anomalous layer of proteins may help trigger unwanted events, such as activation of coagulation systems or even chronic inflammation³. In order to overcome these problems, researchers have tried to modify the surface chemistry of the blood-contacting biomaterials so that they become thromboresistant. One potential strategy to address the problem of the chaotic adsorption of proteins to medical devices and surfaces, is to create a layer of albumin as a functional "barrier-protein cover". As such, a thin layer of albumin has been reported to minimize adhesion and aggregation of platelets to medical device surfaces^2,4.

But serum albumin also has the ability to bind to a wide variety of compounds, including drugs, while neither cells nor proteins adsorb to an albumin-coated surface. As such, these properties of albumin are useful for improving the blood compatibility of biomaterial surfaces. For example, researchers Yamazoe and Tanabe⁵ from the Institute of Advanced Industrial Science and Technology in Japan, created a water-insoluble film by cross-linking pharmaceutical-grade recombinant human albumin (rHA) aimed to clinical applications, and loaded the film with a synthetic antiplatelet drug, cilostazol. The resultant film had native albumin characteristics, such as drug binding ability; and also, resistance to cell adhesion. Their results show that fibroblasts did not adhere on the rHA film, just as they did not adhere on native albumin-coated surfaces⁵. Furthermore, when the rHA film carrying cilostazol was placed in solution, the release of cilostazol was sustained over a long period of time. These results indicate that the surface coating with a rHA-prepared film can give biomaterials an anti-thrombogenic surface, by virtue of its non-adhesiveness to cells, and also by releasing antithrombotic drugs⁵. This is an important feature, since implantable devices and particularly coronary stents, are of increasing importance in today’s medical practice with an unprecedent growth in the number of Coronary Artery Disease (CAD) patients. The global implantable medical device market is expected to reach a value of US$160.3 billion by 2026⁶, as thousands of people aim to enhance the quality of their lives by going through surgical procedures that involve these devices.

Next-generation hydrogels

Albumin has the dual predisposition to cover hydrophobic and hydrophilic surfaces depending on the arrangement of the adsorbed albumin^7,8. This makes albumin a prime candidate to be used as an hydrophobic antithrombotic medium in medical implant coatings, as discussed above; but also as an hydrophilic medium in hydrogels⁹.

Hydrogels were introduced in medicine over 50 years ago and have evolved from static, bioinert materials to dynamic, bioactive microenvironments, which can be used to direct specific biological responses such as cellular ingrowth in wound-healing or on-demand delivery of therapeutics¹⁰. A hydrogel is a multicomponent system, consisting of a 3D network of polymeric chains, where water occupies the spaces between those chains¹¹. Hydrogels have the capability to absorb large amounts of water or biological fluids into their three-dimensional hydrophilic polymer networks, making them attractive materials to be used in different medical specialities, like biomedical implants and tissue engineering.

By manipulating pH and temperature, albumin in solution polymerizes and forms a well-defined hydrogel¹². Protein-based hydrogels, like albumin-based ones, have substantial advantages in comparison with synthetic materials (e.g., Polyvinyl Alcohol, PVA). Biocompatibility, biodegradability, tuneable mechanical properties, molecular binding abilities, and intelligent responses to external stimuli such as pH, ionic strength, and temperature are all known features of protein-based hydrogels¹³. As such, research in albumin-based hydrogels has recently gained a new interest due to its versatility and affordability.

Cross-linking albumin hydrogels

Most commonly, chemical crosslinking is the reported method of choice to derive albumin hydrogels. Synthetic polymers such as polyethylene glycol (PEG) are activated to form PEG-albumin complexes, or alternatively, functional groups may be added to the ends of the PEG molecule to target specific chemical compositions or binding sites of other target proteins for conjugation⁹. For example, Kim and colleagues¹⁴ from the Hanyang University in South Korea developed an easy-forming PEG-albumin hydrogel loaded with an apoptotic TRAIL protein that can be locally injected and support the release of anti-cancer agents.

Although it is well established that albumin itself is non-immunogenic, there is growing evidence that PEG is not bioinert, with clinical trials involving PEGylated drugs demonstrating that the occurrence of PEG-specific immunoglobulin M (IgM) and IgG antibodies in patients is not infrequent, and it can result in adverse outcomes¹⁵. As such, other less commonly used agents have been explored to crosslink albumin. For example, Ma and colleagues¹⁶ from the department of Biomedical Engineering of the University of Connecticut, developed a Glutaraldehyde cross-linked albumin hydrogel that exhibits green and red autofluorescence in vivo without the use of any additional fluorescent labels. This biocompatible fluorescent hydrogel can be a practical application as a tracer in biomedical engineering, being a promising non-invasive approach to monitor physiological parameter changes and to track the in vivo degradation of biomaterials. These are essential features for biosensing devices, for example, because fluorescence can increase their sensitivity limits and allow for wider potential applications¹⁶.

Cold-gelation albumin scaffolds

Researchers have also demonstrated that albumin hydrogels can be formed by salt-induced cold gelation, with the addition of calcium chloride and DL-dithiothreitol, plus a protocol of heating followed by cooling and freezing¹⁷. The resulting hydrogel can be freeze-dried to create a porous scaffold which is biocompatible, and can be used for the in vivo regeneration of human tissues¹⁷. Furthermore, recently Ong and colleagues¹⁸ from the Department of Engineering of the University of Cambridge developed a method for stable and translucent albumin hydrogels by controlling thermal gelation in the presence of sodium chloride. The resulting bio-inert hydrogel was then subjected to air plasma treatment, which functionalised its surface with basement membrane proteins, enabling the attachment of human osteoblasts. Even though this is still a proof-of-concept study, it shows how albumin hydrogels can be the perfect platform for the development of personalized regenerative medicine devices. The beneficial effects of albumin hydrogels in related applications were also demonstrated by the upregulation of osteogenic and angiogenic gene expression; where mineralisation, extracellular matrix production, and formation of vessel-like structures were enhanced in albumin-enriched hydrogels compared to fibrin hydrogels alone¹⁹. Collectively, the results indicate that albumin-enriched hydrogels are a promising bio-matrix for bone tissue engineering and future orthopaedic applications.

Conclusions

The inertness, reduced immunogenicity, biodegradability, and affordability make albumin a prime choice for different medical device applications. Because human serum albumin isolated by fractioning human plasma can carry contamination risks, Albumedix' recombinant human albumin is the wisest and safest preparation to achieve all the potentials of this protein in the medical device field.

rHA can ensure the proper cover of large surface areas of tubing’s (e.g., Rheopack surface coating from Chalice Medical⁴), where 1-2mg of rHA can cover 1 m² of surface; and, thereby limit the exposure of body-fluids to incompatible surfaces, increasing product safety. Furthermore, the consistency and purity of rHA ensures it can reliably produce the same surface coverage, diminishing the need for product performance monitoring and extra release procedures. When all of these are controlled and the process is not merely validated in the research laboratory but includes production-level verification, medical device risks are minimized and manufacturers can move forward with certainty that each device is coated properly.

Additionally, albumin hydrogels hold great potential as customizable transplantable constructs for tissue engineering and regenerative medicine, making them a strong asset for potential patient-specific therapies of the future. With its clinically demonstrated safety profile and huge potential for functionalization, rHA is an ideal biomaterial.

References:

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4          ChaliceMedical. Rheopak Surface Coating, 2021).

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