Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 1 of 6
1 Driving the Bumpy Road to Commercialization Nancy L. Parenteau 1,2
1
Ingenium BioTherapy Corporation, 2 Parenteau BioConsultants, LLC
1,2Ingenium
BioTherapy Corporations, Parenteau BioConsultants, LLC
354 Money Hole Rd. Fair Haven, VT 05743 P; (617) 275-8845 F: (617) 275-8845 E-mail for Parenteau: [email protected]
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 2 of 6
2
Abstract Tissue engineering has always had an applied focus and there is hardly an academic publication that does not mention the applicability of its findings to the future development of a medical product. I have been involved in the industry side of tissue engineering from the start, pursuing a variety of applications, some making it to the marketplace. There have been many lessons that I have learned from direct experience (mistakes and successes), observation, through advising others, and now, in developing innovative ways to identify and eliminate the regenerative cell populations within a tumor. This brief overview of some of these lessons is written with the next generation of pioneering product developers in mind: the biologists, biochemists and engineers who will dedicate their careers to driving medical and commercial progress in tissue engineering.
Tissue Engineering to an Applied Standard A common perception is that the kind of academic research needed to publish in a high impact journal equates to the kind of information needed for effective translation.
Rarely does academic research alone provide enough enabling
information or innovation needed for translation. There will be many details to fill in – some of them in surprisingly pivotal science and engineering. This does not mean that quality academic research does not have an impact on medical progress. Today in particular, companies will not have the resources to bridge gaps in information and knowledge without academic research making substantial
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 3 of 6
3 contributions. But one of my biggest concerns as a head of R&D has been that our work will fail to develop an effective product when we could have succeeded with the right knowledge, decisions and execution. How can we better enable productive R&D of complex biological products? What kind of information do we need to create a successful tissue engineered product?
Productive insight is the definition of a breakthrough suggesting that not all information has the same value. An important part of the most productive applied science is acquiring actionable knowledge. Applied science is not simply about making things and testing them. However, even today, many regenerative medicine efforts still follow a classic iterative approach of “make it, put it in (an animal or human being) and see what it does – an approach used in medical device development in the past. That may be sufficient for a Dacron tube but not a tissue engineered one. An advanced biological product expected to interact with the body in some way does not yield it secrets easily using a simple iterative approach, although some might argue that the complexity of the biology necessitates this approach. Biology need not be a mystery and having it remain one is both risky and costly. Tissue engineered products, in my experience, benefit by deliberate design that incorporates pivotal multi-disciplinary information. We can’t expect to know everything, nor is this needed to develop an effective product, but we do need the right information. So how do we identify this pivotal information?
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 4 of 6
4 A good place to start is to be sure that the objectives of the product or therapy are as clear as possible given current medical and scientific information. There should be a rational connection between what needs to happen for the patient, both mechanistically and practically, with what a technology or approach will have to reasonably do to accomplish it.
There will undoubtedly be questions and
technology gaps. The goal will be to resolve enough of them to establish that connection. Answering these questions and identifying important gaps make it easier to then identify the most important features in your product, e.g., the character of the matrix or scaffold, or whether cells are needed, and if they are, how they should function. This knowledge is important to optimize effectiveness as well.
Aim high. The “good enough” approach usually won’t turn out to be good enough to make it through pivotal clinical trials, dominate the competition in the marketplace, or be reimbursed at a reasonable level by payers. Aim for the best that can be achieved in the simplest way, but make design decisions based on knowledge that allows you to discern when simpler won’t be better.
One way to obtain this
knowledge is to test components of your technology to failure. We can appreciate that a single form of extracellular matrix is not likely to be the answer to all structural tissue repair and that different populations of mesenchymal stem cells are unlikely to be equally potent contributors to a therapy. Failure can illuminate where even relatively minor refinements could yield significant positive differences in product effectiveness.
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 5 of 6
5 Anyone that works with the clinical application of a tissue engineered product knows that biology can be humbling. Biological response does not conform to what is easier, faster or more convenient for the developer so both academic and industry scientists must be willing to take on the tough questions. Confidence is key. Applied scientists and engineers must be confident that they can discover innovative solutions to technology limitations. Biology will drive the robustness, durability and quality of the result, and effectiveness will drive what is or is not a reasonable product in the marketplace – even with regulatory approval. Not all applications of a technology will be justified based on cost/benefit. We can also expect today’s healthcare environment to make it increasingly important to demonstrate value to the patient and the medical system.
Tissue engineering is still full of possibilities and progress on the tough problems is being made. For example, a way to engineer a microvascular supply(1), the design of a cell-enabling scaffold with the biomechanics of cartilage(2), and the design and use of human collagen biomaterials for corneal regeneration that can restore sight and maintain it while remodeling over time(3), are all evidence that pioneering work in tissue continues suggesting that, despite the challenges, industry scientists and engineers will indeed be able to produce new and better regenerative products enabled by tissue engineering, with the help of lessons learned so far.
References 1. Baranski JD, Chaturvedi RR, Stevens KR, Eyckmans J, Carvalho B, Solorzano RD, et al. Geometric control of vascular networks to enhance engineered tissue
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 6 of 6
6 integration and function. Proceedings of the National Academy of Sciences of the United States of America. 110, 7586, 2013. 2. Garrigues NW, Little D, Sanchez-Adams J, Ruch DS, Guilak F. Electrospun cartilage-derived matrix scaffolds for cartilage tissue engineering. Journal of biomedical materials research Part A. 2013. 3. Fagerholm P, Lagali NS, Ong JA, Merrett K, Jackson WB, Polarek JW, et al. Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold. Biomaterials. 2013.
Page 1 of 6
1 Driving the Bumpy Road to Commercialization Nancy L. Parenteau 1,2
1
Ingenium BioTherapy Corporation, 2 Parenteau BioConsultants, LLC
1,2Ingenium
BioTherapy Corporations, Parenteau BioConsultants, LLC
354 Money Hole Rd. Fair Haven, VT 05743 P; (617) 275-8845 F: (617) 275-8845 E-mail for Parenteau: [email protected]
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 2 of 6
2
Abstract Tissue engineering has always had an applied focus and there is hardly an academic publication that does not mention the applicability of its findings to the future development of a medical product. I have been involved in the industry side of tissue engineering from the start, pursuing a variety of applications, some making it to the marketplace. There have been many lessons that I have learned from direct experience (mistakes and successes), observation, through advising others, and now, in developing innovative ways to identify and eliminate the regenerative cell populations within a tumor. This brief overview of some of these lessons is written with the next generation of pioneering product developers in mind: the biologists, biochemists and engineers who will dedicate their careers to driving medical and commercial progress in tissue engineering.
Tissue Engineering to an Applied Standard A common perception is that the kind of academic research needed to publish in a high impact journal equates to the kind of information needed for effective translation.
Rarely does academic research alone provide enough enabling
information or innovation needed for translation. There will be many details to fill in – some of them in surprisingly pivotal science and engineering. This does not mean that quality academic research does not have an impact on medical progress. Today in particular, companies will not have the resources to bridge gaps in information and knowledge without academic research making substantial
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 3 of 6
3 contributions. But one of my biggest concerns as a head of R&D has been that our work will fail to develop an effective product when we could have succeeded with the right knowledge, decisions and execution. How can we better enable productive R&D of complex biological products? What kind of information do we need to create a successful tissue engineered product?
Productive insight is the definition of a breakthrough suggesting that not all information has the same value. An important part of the most productive applied science is acquiring actionable knowledge. Applied science is not simply about making things and testing them. However, even today, many regenerative medicine efforts still follow a classic iterative approach of “make it, put it in (an animal or human being) and see what it does – an approach used in medical device development in the past. That may be sufficient for a Dacron tube but not a tissue engineered one. An advanced biological product expected to interact with the body in some way does not yield it secrets easily using a simple iterative approach, although some might argue that the complexity of the biology necessitates this approach. Biology need not be a mystery and having it remain one is both risky and costly. Tissue engineered products, in my experience, benefit by deliberate design that incorporates pivotal multi-disciplinary information. We can’t expect to know everything, nor is this needed to develop an effective product, but we do need the right information. So how do we identify this pivotal information?
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 4 of 6
4 A good place to start is to be sure that the objectives of the product or therapy are as clear as possible given current medical and scientific information. There should be a rational connection between what needs to happen for the patient, both mechanistically and practically, with what a technology or approach will have to reasonably do to accomplish it.
There will undoubtedly be questions and
technology gaps. The goal will be to resolve enough of them to establish that connection. Answering these questions and identifying important gaps make it easier to then identify the most important features in your product, e.g., the character of the matrix or scaffold, or whether cells are needed, and if they are, how they should function. This knowledge is important to optimize effectiveness as well.
Aim high. The “good enough” approach usually won’t turn out to be good enough to make it through pivotal clinical trials, dominate the competition in the marketplace, or be reimbursed at a reasonable level by payers. Aim for the best that can be achieved in the simplest way, but make design decisions based on knowledge that allows you to discern when simpler won’t be better.
One way to obtain this
knowledge is to test components of your technology to failure. We can appreciate that a single form of extracellular matrix is not likely to be the answer to all structural tissue repair and that different populations of mesenchymal stem cells are unlikely to be equally potent contributors to a therapy. Failure can illuminate where even relatively minor refinements could yield significant positive differences in product effectiveness.
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 5 of 6
5 Anyone that works with the clinical application of a tissue engineered product knows that biology can be humbling. Biological response does not conform to what is easier, faster or more convenient for the developer so both academic and industry scientists must be willing to take on the tough questions. Confidence is key. Applied scientists and engineers must be confident that they can discover innovative solutions to technology limitations. Biology will drive the robustness, durability and quality of the result, and effectiveness will drive what is or is not a reasonable product in the marketplace – even with regulatory approval. Not all applications of a technology will be justified based on cost/benefit. We can also expect today’s healthcare environment to make it increasingly important to demonstrate value to the patient and the medical system.
Tissue engineering is still full of possibilities and progress on the tough problems is being made. For example, a way to engineer a microvascular supply(1), the design of a cell-enabling scaffold with the biomechanics of cartilage(2), and the design and use of human collagen biomaterials for corneal regeneration that can restore sight and maintain it while remodeling over time(3), are all evidence that pioneering work in tissue continues suggesting that, despite the challenges, industry scientists and engineers will indeed be able to produce new and better regenerative products enabled by tissue engineering, with the help of lessons learned so far.
References 1. Baranski JD, Chaturvedi RR, Stevens KR, Eyckmans J, Carvalho B, Solorzano RD, et al. Geometric control of vascular networks to enhance engineered tissue
Tissue Engineering Part A Driving the Bumpy Road to Commercialization (doi: 10.1089/ten.tea.2014.2012) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 6 of 6
6 integration and function. Proceedings of the National Academy of Sciences of the United States of America. 110, 7586, 2013. 2. Garrigues NW, Little D, Sanchez-Adams J, Ruch DS, Guilak F. Electrospun cartilage-derived matrix scaffolds for cartilage tissue engineering. Journal of biomedical materials research Part A. 2013. 3. Fagerholm P, Lagali NS, Ong JA, Merrett K, Jackson WB, Polarek JW, et al. Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold. Biomaterials. 2013.
