The Development of MaxSi™ Graft Technology

Interview conducted by Alessandro PiroliniJul 23 2014

In this interview, Professor Iain Gibson, Chief Scientific Officer (CSO) at SIRAKOSS, talks to AZoM about the development of their MaxSi™ Graft technology.

To begin with, can you please give an explanation of how the concept of the MaxSi™ Graft technology began?

Most of my research to date has been on ceramics of different forms. This has typically focused on the classic production of an inorganic powder and then sintering this into a dense form. We started to notice that most products available as synthetic bone graft materials are all ultimately ceramics.

They might be made to have large macro-pores within them, but the inorganic materials within them are still produced as a ceramic. All of these products tend to have the problem that they allow bone to grow into them but the body is very slow at resorbing them.

This is something that surgeons and studies have shown after 10-20 years of implantation, where the hydroxyapatite implants are still in the body and have not been resorbed or replaced.

This led us to ask the question - do we actually need to sinter these materials?

A range of prototype graft materials utilising the MaxSi™ Graft technology - Courtesy of SIRAKOSS.

Sintering is used to generally make materials stronger, but these bone graft materials are never allowed to be used in load-bearing applications without metal instrumentation to take the load.

So, there is always a cage or plate/pins in place, which are bearing the mechanical load. The bone graft material is just filling that defect. It doesn’t necessarily need to be strong in the classic case of dense ceramics. We just asked the question, “What if we removed the classic sintering step?”.

The advantage of this is that you end up with a size-scale of your material that is much closer to the size-scale of the calcium phosphate that is in our bone mineral. The calcium phosphate apatite in our bone mineral is around 50-100 nanometers size scale, so without having to do that sintering step you can actually make your synthetic material of that size scale. Our hypothesis was that the body would see that as something closer to bone mineral and be able to resorb that easily as opposed to ceramics, which are at the micron scale.

What form is the material produced in and what materials are used to synthesise the calcium phosphate-based bone graft?

It is a granular material in a dry form. It can be combined with an organic component to produce a paste or putty. It is based on a hydroxyapatite, generic composition but the way that we make it allows us to substitute a much higher level of silicate ions into the hydroxyapatite lattice than previously achieved. This is both through the design of the composition but also the method of making the material. That is really the novelty of the IP of the material.

Does this approach lead to benefits in the manufacturing process of the material?

Essentially yes it does. Our rationale is two-fold - the first is that the method that we use to make the material produces a granular calcium phosphate material that is no longer sub-classed as a ceramic in the classic sense (where the material is sintered and then you achieve densification of the material). We use a lower temperature method so it never actually undergoes the sintering process. This means that the material retains the nanoscale that the primary precipitate has.

Most ceramics used for bioceramic applications are usually produced by similar methods of precipitation or a sol-gel method, and this is to try and achieve a very fine, high surface area powder primarily for improved sintering to form a ceramic. So we removed this step. We still use a precipitation method, but we thought that there is not the need to form a ceramic material.

Ultimately we want the material to be resorbed by the body with time and that has been the issue with most synthetic calcium phosphates; they are actually made as a ceramic meaning it is very slow for the body to resorb and replace.

In 2012 there were over 1.7 million clinical procedures globally which used bone graft substitutes. When MaxSi™ Graft becomes commercially available, do you believe it could be used in a lot of these types of operations?

We do because all of the alternatives that a surgeon has are problematic in some form. The favoured type of bone graft that surgeons use is the autograft, bone from the patient themselves. This, however, is problematic as there is limited availability (limited stock of bone) that the surgeon can harvest.

There are also serious problems associated with secondary surgery to remove the grafts. This also has costs in terms of treating the donor site where the graft is harvested, particularly in cases associated with significant pain at this donor site. Surgeons have been moving away from this, however it is still considered to be the "gold standard" bone graft.

A prototype putty formulation of the MaxSi™ Graft technology that could be shaped by a surgeon in the operating theatre to fill a specific defect - Courtesy of SIRAKOSS

The other option a surgeon has is using Allograft; bone from a cadaver. This has problems such as the potential for disease transmission and sterilization processes can lose some of the properties that the graft would naturally have. These both make up large percentages of the total bone graft procedures but they are not optimum.

Another option a surgeon has is to use a pharmacological approach. There are a number of growth factor options available for surgeons, these are essentially proteins which stimulate or enhance bone formation and the most commonly used is one based on Bone Morphogenetic Protein BMP-2.

However, there have been a number of well documented situations where this appears to work too well and problems arise where a patient has too much bone formation at the graft site. This does still have a large portion of the market in terms of total procedures but due to the problems being experienced, surgeon usage is declining.

Our technique is to use a non-pharmacological approach. We don't use animal or human material within the graft materials. It is purely materials science, that is to say an inorganic, synthetic approach.

The problems you highlighted; disease and reduction of properties through sterilization, can these all be avoided by the use of your fully synthetic material?

Yes absolutely. Also if a synthetic material can match the performance of some of these more biological growth factors, then a huge advantage which they have is that they can be produced in a virtually limitless supply.

Autografts are fairly limited and this is a problem especially in younger or elderly patients where their bone stock that you can graft from is not very good. Allografts require donors to be available to provide tissue, whereas synthetic material production is just scaling up to meet demands.

How long do you believe it will be before MaxSi™ Graft technology is available at the kind of scale required for use in medical applications by surgeons?

Subject to us (SIRAKOSS) getting the financial resources to go through the stages required, it is likely to be roughly 2 years. It could be a little less depending on both the level of investment that we get to push that forward but also the regulatory process and how long that takes. Between 2-3 years is certainly a realistic answer.

On the note of investment, you recently received the Venture prize which awarded you with some funding and have been endorsed by the Worshipful Company of Armourers & Brasiers. How significant is this achievement for you in terms of attracting further funding and investment?

We believe it will lead to further investment. It is a big endorsement of the material science aspect of the technology that we have developed and that is critical to us. This highlights the strength and the novelty of our technology and to have that validated by a major material science supporting body is quite important to us.

It is easier for us to have our business plan validated, be it by investors or corporate bodies and to get instant feedback on that. But to have the validation of the technology by a body like this is important to us as it is very specialized. For them to not only review our technology, but to award it with a prize, we hope will have a very big impact in terms of investment.

With regards to SIRAKOSS as a company, did you originally work in conjunction with universities?

We did yes. As a company, we spun out from the University of Aberdeen. We did this in the early stages of the development of the company. This was a strategic plan to do this because it would allow us to apply for funding which wouldn't be available to us if the technology remained within the university. We do realize that we are an early stage company and a lot of what we have built the company around is developing new products and understanding how existing products work.

We do work closely with the university and in fact we have just had our first industry-supported PhD student finish. That was the first PhD that SIRAKOSS as a company has been involved in.

Additionally, one of our employees recently applied for and was awarded an Industrial Fellowship from the Royal Commission of 1851 to allow them to still be employed within the company, so they're still a SIRAKOSS employee, but they can now study for a PhD. This is being done at Aberdeen.

That has been very important to us because it allows us to have access to university research facilities, but also it increases that level of collaboration between universities and companies, which we believe is a two-way process.

Does SIRAKOSS have plans to expand operations in the near future and how do you see the company expanding over the next 5-10 years?

Over the next 5-10 years, we plan to have our initial product well established in the market as well as defined product range extensions. We have also been looking to expand out to see where we can use the technology in other medical devices.

At the moment, our technology would be used as a stand-alone bone graft filler. But there is also potential to incorporate it into, for example, composite materials. This could be with a resorbable polymer, which could give us applications in sports medicine.

Applications such as fixation/interference screws which are used to hold cruciate ligaments in place when they are carrying out ACL replacement. These typically use metallic screws that are there for the lifetime of the patient or they are now available as resorbable polymer screws. Our material could be incorporated into the resorbable polymer to produce a composite which would be very attractive as a device for fixation screws or fixation plate/pins.

There is also the potential for our material's use as a coating. Hydroxyapatite coatings have been established for a long time, but there is a drive now to apply these coatings to materials like polymers.

The polymer PEEK is being used extensively now in structural applications, one of which being a spinal cage. But like many implant materials, it is classed as bioinert so it will fix in place but it won't actually form a direct bond with the bone. We strongly believe our material has the potential to provide a very good coating in terms of being able to accelerate the rate that the polymer would form a bond to the surrounding bone.

Do you believe that MaxSi™ Graft has the potential to be used as a coating on implants such as those used in total hip/knee replacements where a significantly strong bond to the bone is absolutely essential?

It does have the potential to, however not using existing coating technology. The way our material is designed, it avoids the high temperature sintering process in terms of forming the granular material.

For techniques such as plasma spraying it would not be suitable for the application of it as a coating because of the very high temperatures used. It would probably change the composition of the material. As people are now moving to alternative coating methods which don't use high temperatures, it is very feasible that we could use our MaxSi™ Graft material as a coating.

So if MaxSi™ Graft was to be used as a coating, what kind of techniques could you adopt to coat a surface?

I think in the short term we would be focussing on coating polymers in the first instance. The need to avoid high temperatures when applying the coating to the polymers is critical. So there is a potential of essentially incorporating the material onto the surface of the polymer and we have some clear thoughts on how this could be achieved.

As a company we have deliberately focussed on developing the bone graft material itself and avoided the issue many early stage companies encounter by trying to cover all possible applications early on in the development of a material, ending up being stretched too far and failing to achieve their primary goals. We have however kept aware of the way advancements are developing in coating technologies and also the use of composite materials.

I think as procedures change, the materials that people are coating will transition from metals to more polymer materials. We are in a position now where it is easier to use our material than, for example, 10 years ago when plasma spraying was pretty much the only method used to coat implant materials.

In terms of large-scale manufacturing of the product, what is involved in the synthesis of MaxSi™ Graft and is it an easily scalable process?

This has gone from a university-based basic study, right through to proven concepts within the university, to early commercial development. We have gone from a traditional laboratory-scale where a reaction would be producing roughly 10 grams of material through to now where we can make a kilogram of material. This allows us to create close to commercial-scale batches. We have identified that it will be easy to scale up even further.

Typically, surgeons use roughly 10cc of graft material which equates to around 3 grams of our material. So producing a kilogram of material is enough for 300 procedures per batch. Going from a very small scale, academic-based development, to a 1 kilogram batch is quite a large scale up that we have achieved already.

One of our next steps would be to move to a certified GMP manufacturing facility, which is a requirement for a medical device. By that stage we would be getting close to a 3-5 kilogram-type scale.

How long do you believe it will be before SIRAKOSS is in a position to expand to that level of industrial production?

We think it will be quite soon. We are raising funds at the moment to allow us to move to that stage. We hope to complete that within the next 6 months and manufacture to that level under certified GMP conditions.

With this cGMP product, we can then go on and test in the required studies that are needed for regulatory approval using ISO13485 compliant materials and processes. So, by moving into that stage, it will enable us to take the next big steps to do the required testing needed by regulating bodies to then get approval for clinical use of the product.

Once the product is able to be produced in a large-scale, certified and approved, how big is the next step to this being used in medical devices?

It is a relatively clear series of tests required. There is some biological evaluation of the product that we need to do. We have de-risked that in terms of an investment point by doing similar studies on our lab-based product, which will not be that much different from cGMP product. But we are still required to do these tests on the final product.

About Prof. Iain Gibson

Iain is the principal investigator behind the MaxSi™ Graft technology and has been researching bone graft materials since 1996. He heads up his own Biomaterials Research Group at the University of Aberdeen where his research is driven by the transfer of lab-based research to real clinical applications.

Iain is a co-founder and director of SIRAKOSS and he is committed to the transfer of the MaxSi™ Graft technology to successful clinical application and the development of the technology platform.

Prior to joining the University of Aberdeen in 2002, Iain previously worked as a post-doc at the IRC in Biomedical Materials at Queen Mary, University of London, where he contributed to the spin-out of ApaTech Ltd.

He completed his first degree in Chemistry at Aberdeen, and then completed a PhD in 1995, also from the University of Aberdeen, studying yttria-stabilised zirconia ceramics for use in solid oxide fuel cells.

His research at Aberdeen has received funding from various bodies including the EPSRC, BBSRC, Technology Strategy Board, European Commission, Royal Society, British Council and Scottish Enterprise.