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Polyester/Polypeptide hybrid biomaterials for biomedical scaffolds

Periodic Reporting for period 1 - EsterPep (Polyester/Polypeptide hybrid biomaterials for biomedical scaffolds)

Reporting period: 2017-04-01 to 2019-03-31

An annual growth rate for biomaterials of 16% is forecast to reach $149.17 billion by 2021 from $70.90 billion in 2016. The next generation of biomaterials, i.e. materials that interact with biological systems, are key for the development of new medical devices and advanced approaches in healthcare with significant impact on applicable and affordable treatments for EU citizens. EsterPep has brought together expertise in polymer synthesis, biomaterial design and medical applications with the objective to design a new class of polymeric biomaterials fully based on natural raw materials. These 'hybrid' materials are designed to be novel functional, processible biomaterials with adaptable properties not available from the current technologies on the market.

The overall research aim of this project is to:
• Develop and optimise new route to produce synthetic biomaterials employing natural raw materials.
• Investigate the tunability of their mechanical properties, biodegradability and biocompatibility as a function of their chemical make-up to match the requirements for biomedical applications.
• Demonstrate applicability of biomaterials as a scaffold for tissue regeneration or implantable devices.

Owing to their tunable properties (i.e. mechanical strength, processing temperatures etc.) synthetic polyesters have been at the forefront of degradable implantable materials. However, issues such as inflammation at the site of implantation and mechanical failure has allowed for commercialisation of only a limited number of polyester biomaterials. As an alternative, synthetic polypeptides have received a lot of attention in the past decade. As polypeptides are naturally derived, they offer better biocompatibility, however, polypeptide materials often display poor mechanical strength. It is proposed that the amalgam of these families of materials offer the ability to combine the mechanical strength and processability of polyesters and biocompatibility of polypeptides.

Using a range of well-known polymerisation techniques, we were able to generate a range of polyesters and synthetic polypeptides which could be combined in an affordable way to produce biomaterials. These materials were tested during the course of the action and it was found that by changing the quantities of polyester to polypeptide, the mechanical strength could be tuned from rigid to flexible materials. This potentially allows for these materials to be used in the regeneration of a range of tissue types (i.e. skin, cartilage, bone etc.). Additionally, the rate of degradation could also be tuned depending the required lifetime of an implant. This potentially allows for these materials to be used in the development of degradable implantable devices with varying lifetimes in the patent (i.e. sutures, meshes, stents etc.).Currently, preliminary applicability of the materials for biomedical applications are still under investigation. Biocompatibility studies are ongoing in collaboration with the Tissue Engineering Research Group at Royal College of Surgeons in Ireland (RCSI).
1. Demonstration of the feasibility of the synthesis of polyester and poly(ester-peptide) hybrids and create a new family of biomaterials;

Polyester, polypeptides and poly(ester-peptide) materials were successfully generated through a series of known polymerisation techniques. This allowed for a family of materials to be synthesised with a wide range of properties, such as mechanical strength, thermal stability and degradation rate. Furthermore, modulation of the starting monomeric materials may allow access to an even broader range of advanced properties such as bioadhesion, targeted delivery of therapeutics etc. The general synthetic methodologies are described below;

i. Synthesis of unsaturated polyesters:
This utilisation of the metal free ‘organocatalysts’, outlined in the proposed project, was found to yield polyesters with low molecular weights and mutli-modal molecular weight distributions. As such, a series of unsaturated polyesters were synthesised through the polycondensation of dimethyl esters and diols using a commercially applicable the tin-based catalyst.

ii. Synthesis polypeptide macromers:
Telechelic polypeptides were generated through the diamine initiated ring-opening polymerisation (ROP) of N-carboxyanhydride analogues of a protected natural amino acids. The polypeptide was modified to yield a ‘crosslinker’ with polymerisable chain ends.

iii. Synthesis of crosslinked materials
Polyesters were UV crosslinked in the presence of a photoinitiator and varying quantities of telechelic polypeptide macromer. This yielded a family of crosslinked poly(ester-peptide) hybrid materials.

iv. Polymer characterisation
Polymers were characterised by nuclear magnetic resonance (NMR) and Fourier-transform infrared (FT-IR) spectroscopy to determine their chemical composition and gel permeation chromatography (GPC) to determine their molecular weights.

2. Demonstration of how composition influences the material properties;

Hybrid materials were subjected to thermal, mechanical and degradation/stability analysis in order to produce a composition-property relationship. It was found that the composition greatly dictated the properties of the materials (Figure 1-3). The general analytical methodologies are described below;

i. Differential Scanning Calorimetry (DSC) analysis
Differential scanning calorimetry (DSC) of samples was conducted under nitrogen atmosphere between -70 and 120 °C.

ii. Mechanical analysis
Compression data was obtained at ambient temperature by axially loading ‘pucks’ in a tensiometer.

iii. Degradation studies
All materials were formed into “degradation disks” and subjected to accelerated degradation studies. The disks were placed in individual vials containing a sodium hydroxide solution and incubated with constant agitation. The mass was measured periodically using an analytical balance.

3. Produce a prototype sample for application in tissue regeneration and demonstrate preliminary applicability of poly(ester-peptide) scaffolds;
Preliminary applicability of poly(ester-peptide) as scaffolds are still under investigation. Biocompatibility studies are ongoing in collaboration with the Tissue Engineering Research Group (TERG) at Royal College of Surgeons in Ireland.
This project represent a significant advancement in the current state-of-the-art polymer-peptide hybrid systems. We generated a range of polyesters and synthetic polypeptides which could be combined in an affordable way to yield novel biomaterials with a wide range of mechanical and degradation properties. This potentially allows for these materials to be used in the regeneration of a range of tissues (i.e. cartilage, bone etc.) or in the development of tailored degradable implantable devices (i.e. sutures, stents etc.). Additionally, the development of the synthetic strategy utilised to generate the hybrid materials offers a unique platform to access a range of materials dependent on the chemical composition of component polymers (i.e. amino acids, co-monomers, polymer architecture etc.). The results of the project offer progression toward the development of biomaterials which fulfill current unmet clinical needs.
Mechanical analysis of poly(ester-peptide) hybrid materials
Poly(ester-peptide) hybrid materials
Degradation rates of poly(ester-peptide) hybrid materials