Utilization of adhesive designer proteins for implant coating to enhance tissue regeneration

Background

The union of a bone fracture is a dynamic process in which an anti-inflammatory environment is created after an initial inflammatory phase. Mesenchymal stem cells (MSCs) migrate to ultimately differentiate into osteocytes and ensure stable bone closure after calcification [Loeffler et al. 2018 Trends Endocrinol Metab]. This process requires efficient spatial and temporal regulation, which, however, is impaired in the case of particularly severely damaged tissue, an unhealthy lifestyle, age or pre-existing medical disorders such as osteoporosis and diabetes [Karhof et al. 2017, SM J Arthritis Res; Sheng et al. 2021. Medicine (Baltimore)]. As a result, the bone cannot fully recover in 10-15% of all fractures [Nandra et al. 2016, Trauma].

In severe cases, plates, screws and staples are used for internal fixation to support fracture closure. Implants are also used to replace damaged substance after extensive defects or after resection of bone tumors. Likewise important are implants in dental surgery and for artificial joints. Due to their low cytotoxicity, solid robustness and easy availability, these medical devices are usually made of titanium alloys or polymers such as polyether ether ketone (PEEK). However, they have no inherent regenerative potential and multicausal inflammatory reactions, lack of osseointegration and loosening are common problems [Davis et al. 2022, Int J Adv Manuf Technol; Wei et al. 2023, Front Bioeng Biotechnol]. The latter is already inevitable due to the stiffness of the implants, as the mechanical load on the artificial materials creates abrasion particles that lead to inflammatory reactions and bone resorption – a process known as aseptic loosening [Abu-Amer et al. 2007, Arthritis Res Ther]. As a result, revision occurs every 5 – 15 years depending on the type of implant, fixation method and lifestyle of the patient [Bayliss et al. 2017, Lancet].

Objective

The aim of the project is to develop designer proteins inspired by naturally occurring proteins that can be used as a coating for implants to promote bone regeneration at the fracture and improve osseointegration of the implant. Sequences from the mussel foot of the mussel Mytulis spec. allow strong adhesion to all common materials for bone implants, even in the aqueous environment that is present in implants during use (Lu et al. 2013, J R Soc Interface). This is made possible, among other things, by a characteristic post-translational modification of tyrosine residues to L-3,4-dihydroxyphenylalanine (DOPA), which can be inserted enzymatically after recombinant production (Zwies C et al. 2024, Protein Expr Purif). By combining these sequences in designer proteins with peptide segments that improve cell adhesion, stimulate differentiation into bone cells, modulate inflammatory responses at the fracture, promote vascularization of bone tissue or enable targeted release of drugs at the wound site, the immense medical potential of specially designed adhesive proteins as implant coatings is demonstrated.

Impact on the region

Since protein-based coatings might promote the integration of implants, improve bone regeneration even in the case of pre-existing conditions and counteract the effects of wear particles, they represent an ideal opportunity to increase mobility and quality of life for an ageing population. In addition, in structurally weak regions with overburdened healthcare provision, they could provide relief and free up capacity in hospitals by shortening regeneration phases after bone fractures. If one also considers the European market for bone substitutes with an estimated size of USD 871.4 million and an expected average annual growth rate of 5.2% until 2030 (Grand View Research Report ID: GVR-4-68040-298-6, 2023), the enormous economic potential that the development and production of protein-based implant coatings can have for a region undergoing structural change is also made apparent.

Literature:

Loeffler J, Duda GN, Sass FA, Dienelt A. The Metabolic Microenvironment Steers Bone Tissue Regeneration. Trends Endocrinol Metab. 2018 Feb;29(2):99-110

Karhof, S., Bastian, O. W., Van Olden, G. D. J., Leenen, L. P. H., Kolkman, K. A., & Blokhuis, T. J. (2017). Impaired fracture healing of the distal femur after high energy trauma. SM J Arthritis Res, 1(1), 1003

Sheng B, Li X, Nussler AK, Zhu S. The relationship between healthy lifestyles and bone health: A narrative review. Medicine (Baltimore). 2021 Feb 26;100(8):e24684

Nandra, R., Grover, L., & Porter, K. (2016). Fracture non-union epidemiology and treatment. Trauma, 18(1), 3-11

Davis R, Singh A, Jackson MJ, Coelho RT, Prakash D, Charalambous CP, Ahmed W, da Silva LRR, Lawrence AA. A comprehensive review on metallic implant biomaterials and their subtractive manufacturing. Int J Adv Manuf Technol. 2022;120(3-4):1473-1530

Wei Z, Zhang Z, Zhu W, Weng X. Polyetheretherketone development in bone tissue engineering and orthopedic surgery. Front Bioeng Biotechnol. 2023 Jun 29;11:1207277.

Abu-Amer Y, Darwech I, Clohisy JC. Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies. Arthritis Res Ther. 2007;9 Suppl 1(Suppl 1):S6

Bayliss LE, Culliford D, Monk AP, Glyn-Jones S, Prieto-Alhambra D, Judge A, Cooper C, Carr AJ, Arden NK, Beard DJ, Price AJ. The effect of patient age at intervention on risk of implant revision after total replacement of the hip or knee: a population-based cohort study. Lancet. 2017 Apr 8;389(10077):1424-1430

Lu Q, Danner E, Waite JH, Israelachvili JN, Zeng H, Hwang DS. Adhesion of mussel foot proteins to different substrate surfaces. J R Soc Interface. 2013 Feb;10(79):20120759

Zwies C, Vargas Rodríguez ÁM, Naumann M, Seifert F, Pietzsch M. Alternative strategies for the recombinant synthesis, DOPA modification and analysis of mussel foot proteins – A case study for Mefp-3 from Mytilus edulis. Protein Expr Purif. 2024 Jul;219:106483.

https://www.grandviewresearch.com/industry-analysis/europe-bone-grafts-substitutes-market-report am 10.02.2026