Engineered skin offers new hope

Like most scientific start-ups, the long and winding road to commercialisation started with a great idea followed by years of painstaking research and innovation. “At this stage we have a product that looks exciting but I can’t guarantee that it’s really going to work,” says Rod, referring to the importance of yet-to-be-conducted Phase I clinical trials.

Burns are recognised as a leading cause of childhood injury in New Zealand and the treatment for major injuries is slow and painful because it involves gruelling rounds of skin graft surgery. It was a conversation with plastic surgeon Michelle Locke about the limitations of existing skin replacement products that Rod says led to the ground-breaking engineered skin research at the Maurice Wilkins Centre, which is headquartered in the School of Biological Sciences.

The research has been a true collaboration with Vaughan Feisst, Rod’s former PhD student and post-doctoral research fellow, who carried out all the initial experimental work and is now also a co-founder and minority shareholder in the company. “Vaughan and I designed the product from the ground up around what the surgeons needed.”

Existing products consist of the thin upper layer of epidermal cells which are often too fragile to be useful, so the aim was to create multiple layers of the epidermis and lower dermis cells to better resemble full thickness human skin. Using skin donated for human cell research, single cells were placed into a liquid and nutrient filled culture chamber where they divided and grew on a frame covered with a dissolvable synthetic mesh.

“Our trick,” says Rod, “is to turn the whole thing upside down,” – hence the company name Upside Biotechnologies. As a result, the upper cell layer migrates toward a gas permeable interface in the chamber floor, while the lower layer moves away to form separate layers sandwiched over the dissolvable mesh.

The concept is simple and convenient which reduces the chances of things going wrong, but Rod says the seven-year long project has required a series of innovations to overcome a host of technical barriers. “At last count it was almost 20 different innovations that we’ve added on top of each other to get to a final system for growing skin that is substantially different from anything anywhere else in the world.”

One such innovation is the specially designed culture chamber made by the Auckland product development company, Adept, whose major challenge was to engineer a device capable of allowing gas in through the base of the container without any fluid leaking out.

Previous techniques were limited to growing seven-centimetre square sheets of skin, however Rod says they’ve already grown ten-centimetre square sheets and expect to achieve much larger sizes. Indeed, starting with a sample of just 10 by 20 centimetres, enough skin can theoretically be grown to cover an entire body within 16 days. 

As well as producing skin faster than any competitive pipeline product, the culture chamber also doubles as the shipping device. “The surgeons in the theatre can open the box, pull out the skin and put it on the patient – that’s the idea.” 

Auckland nanofibre production company, Revolution Fibres, was another external provider who supplied the dissolvable electrospun PLGA mesh for the skin to grow on. Producing mesh at just the right thickness and porosity for the cells to move into took a lot of experimentation, and Rod says the technical challenges included developing new ways of coating the material to make cells stick to it.

The project also drew on the skills of Rod’s materials colleagues in the School of Chemical Sciences, as well as the broader scientific ecosystem within the Maurice Wilkins Centre, which he leads. “This is one of the things that we’re focused on, getting people used to working in an interdisciplinary environment with people from other disciplines like the chemists and the engineers to build more complicated things and enable our research.”

Protecting the intellectual property around the project was also critical. “If you’re going to form a company and get investment then you have to be able to protect the inventions you’ve got,” says Rod. “If we’re serious about clinical translation then patenting has to be part of that, otherwise there’s no economic return evidence and no investment in technology. That’s the reality.”

In addition to arranging patents, the University of Auckland’s commercial arm (Auckland UniServices Limited) also incorporated Upside Biotechnologies and became a cornerstone investor along with Cure Kids Ventures and the Government-owned New Zealand Venture Investment Fund. Cure Kids funded some of the research following on from an initial grant from the Sir William and Lois Manchester Trust.

University funding was provided by the recently established University of Auckland Inventors Fund which has $10 million available to help transform good research into good businesses and exciting new products. That investment, says Rod, signals to people that all the University’s processes are behind it. “It’s putting skin in the game, and that gives other people confidence that the University is not just doing it at a distance but is directly involved.” 

Upside Biotechnologies was one of more than a dozen companies spun out of the University in 2016, something Rod says is a good thing because it brings in new sources of research funding. “It’s opening up University research to people outside who want to invest in new technologies.”

To that end, the company successfully raised $2.3 million in March 2017 through a Series A funding round for early stage venture capital which attracted high profile investors including Sir Stephen Tindall’s K One W One (No 3) Limited. “The shareholder register is fantastic,” says Rod, “It’s a dream list, really, in many senses."

The largest external investor is ICE Angels Nominees, New Zealand’s leading angel network that supports exceptional teams that are exploiting global opportunities. Pitching to high net worth investors for vital research funding is not part of his skill set, but Rod found himself doing just that at an ICE Angels fund raiser. “It was brilliant. It is gladiatorial, it’s like Dragons Den but with 100 dragons sitting there,” he says of the five-minute presentation and Q&A session, which raised a substantial amount of money on the spot.

One of the keys to successful capital raising has been the relatively simple business case, which investors get straight away because of the need for successful skin grafts in a global regenerative medicines market that’s projected to reach US$30 billion by 2022. 

The appointment of Dr Robert Feldman as chief executive officer was also strategic. As an experienced biotechnology executive with a background in start-ups, he has helped position the company for success by creating investment structures that build value for investors.

What’s really exciting, says Rod, is the fact that people want to put their money into things that are going to be good for New Zealand. “These are highly successful, highly motivated people. They don’t need to be doing this. They’ve all got this idea that it’s important to take their success and enable the next generation of successful people in New Zealand and I think that’s a fabulous thing.”

The outside world is also taking notice. The Miami-based Biofuels Digest – which claims to be the world’s most widely read biofuels daily with an online readership of 650,000 – has described Upside Biotechnologies as a ‘brilliant start-up’ and ‘an outstanding example of the use of cell-culturing technology to address a major medical challenge.

As an academic, Rod says that the University’s support for the venture has been incredibly enabling because “there are people who care about what I’ve got to offer in terms of translational ideas.” In addition to having a small shareholding in the company, Rod says he’s motivated by the potential to provide well paid jobs for graduates. 

“Through this kind of activity the people that I’m training now get to participate in these new businesses and see how their science can translate, and how they can generate their own ideas that can build businesses to employ their future students.”

The next critical step will be Phase I clinical trials at the National Burn Centre at Middlemore Hospital. As Rod puts it, the proof is in the clinical trial, so “the real heart-stopping moment” will be when the first skin product goes on the patient and then the bandages come off a couple of weeks later “and we see whether it’s worked or not.”

Phase II clinical trials are likely to be conducted overseas, however Rod says that the route to market is potentially quite quick because there is no product currently available that really fits the need. “So, it’s not many years away before we hope to see success.”