Joshua G. Hunsberger

Manufacturing Road Map for Tissue Engineering and Regenerative Medicine Technologies

The Regenerative Medicine Foundation Annual Conference held on May 6 and 7, 2014, had a vision of assisting with translating tissue engineering and regenerative medicine (TERM)‐based technologies closer to the clinic. This vision was achieved by assembling leaders in the field to cover critical areas. Some of these critical areas included regulatory pathways for regenerative medicine therapies, strategic partnerships, coordination of resources, developing standards for the field, government support, priorities for industry, biobanking, and new technologies. The final day of this conference featured focused sessions on manufacturing, during which expert speakers were invited from industry, government, and academia. The speakers identified and accessed roadblocks plaguing the field where improvements in advanced manufacturing offered many solutions. The manufacturing sessions included (a) product development toward commercialization in regenerative medicine, (b) process challenges to scale up manufacturing in regenerative medicine, and (c) infrastructure needs for manufacturing in regenerative medicine. Subsequent to this, industry was invited to participate in a survey to further elucidate the challenges to translation and scale‐up. This perspective article will cover the lessons learned from these manufacturing sessions and early results from the survey. We also outline a road map for developing the manufacturing infrastructure, resources, standards, capabilities, education, training, and workforce development to realize the promise of TERM.

Accelerating stem cell trials for Alzheimer's disease

At present, no effective cure or prophylaxis exists for Alzheimers disease. Symptomatic treatments are modestly effective and offer only temporary benefit. Advances in induced pluripotent stem cell (iPSC) technology have the potential to enable development of so-called disease-in-a-dish personalised models to study disease mechanisms and reveal new therapeutic approaches, and large panels of iPSCs enable rapid screening of potential drug candidates. Different cell types can also be produced for therapeutic use. In 2015, the US Food and Drug Administration granted investigational new drug approval for the first phase 2A clinical trial of ischaemia-tolerant mesenchymal stem cells to treat Alzheimers disease in the USA. Similar trials are either underway or being planned in Europe and Asia. Although safety and ethical concerns remain, we call for the acceleration of human stem cell-based translational research into the causes and potential treatments of Alzheimers disease.

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

There is great need to develop more predictive drug discovery tools to identify new therapies to treat diseases of the central nervous system (CNS). Current nonpluripotent stem cell-based models often utilize non-CNS immortalized cell lines and do not enable the development of personalized models of disease. In this review, we discuss why in vitro models are necessary for translational research and outline the unique advantages of induced pluripotent stem cell (iPSC)-based models over those of current systems. We suggest that iPSC-based models can be patient specific and isogenic lines can be differentiated into many neural cell types for detailed comparisons. iPSC-derived cells can be combined to form small organoids, or large panels of lines can be developed that enable new forms of analysis. iPSC and embryonic stem cell-derived cells can be readily engineered to develop reporters for lineage studies or mechanism of action experiments further extending the utility of iPSC-based systems. We conclude by describing novel technologies that include strategies for the development of diversity panels, novel genomic engineering tools, new three-dimensional organoid systems, and modified high-content screens that may bring toxicology into the 21st century. The strategic integration of these technologies with the advantages of iPSC-derived cell technology, we believe, will be a paradigm shift for toxicology and drug discovery efforts.

Concise Review: Modeling Central Nervous System Diseases Using Induced Pluripotent Stem Cells

Induced pluripotent stem cells (iPSCs) offer an opportunity to delve into the mechanisms underlying development while also affording the potential to take advantage of a number of naturally occurring mutations that contribute to either disease susceptibility or resistance. Just as with any new field, several models of screening are being explored, and innovators are working on the most efficient methods to overcome the inherent limitations of primary cell screens using iPSCs. In the present review, we provide a background regarding why iPSCs represent a paradigm shift for central nervous system (CNS) disease modeling. We describe the efforts in the field to develop more biologically relevant CNS disease models, which should provide screening assays useful for the pharmaceutical industry. We also provide some examples of successful uses for iPSC‐based screens and suggest that additional development could revolutionize the field of drug discovery. The development and implementation of these advanced iPSC‐based screens will create a more efficient disease‐specific process underpinned by the biological mechanism in a patient‐ and disease‐specific manner rather than by trial‐and‐error. Moreover, with careful and strategic planning, shared resources can be developed that will enable exponential advances in the field. This will undoubtedly lead to more sensitive and accurate screens for early diagnosis and allow the identification of patient‐specific therapies, thus, paving the way to personalized medicine.

Bioengineering Priorities on a Path to Ending Organ Shortage

This perspective article covers current successes in and continuing challenges remaining in eliminating the growing organ shortage. We specifically cover data from a workshop entitled “Organ Bioengineering and Banking Roadmap Workshop” funded by the National Science Foundation (NSF) and the Methuselah Foundation in Washington, D.C. on May 27, 2015, and a subsequent Roundtable held at the White House Office of Science and Technology Policy (OSTP) on May 28, 2015. We address four parallel and potentially cooperative approaches for bioengineering tissues and organs. The first approach is bioprinting of tissues and organs. The second approach encompasses recellularization strategies, which can involve either developing tissue scaffolds from non-transplantable human (or xenogenic) organs or tissues and then reconstituting these templates with human cells to create a functional tissue/organ or seeding synthetic biodegradable scaffolds with human cells. The third approach is optimization of cellular repair and regeneration with strategies that include shifting the balance away from maladaptive processes that lead to chronic scarring. The fourth approach is xenotransplantation, which involves developing functional tissues for human use in transgenic animals whose cells are modified to prevent immune rejection. Current challenges and limitations are addressed, which include mapping, cell sourcing and manufacturing, immunosuppression, integration, and vascularization. We identify commercialization strategies that will make these approaches economically feasible. We present solutions toward a vision to one day ending the current organ and tissue shortage, and the impact this will have on treating disease and providing indirect economic benefit by decreasing the disease burden on society and improving quality of life.

Biofabrication: a secret weapon to advance manufacturing, economies, and healthcare.

Biofabrication is a revolutionary approach to healthcare that uses manufacturing processes to produce biomaterials, devices, cells, tissues, and organs. The core technology underlying biofabrication is 3D printing, or additive manufacturing—the same technology that has sparked advances in rapid prototyping through the additive manufacturing of polymer-based constructs. Biofabrication represents a variation on this theme, often described as 3D bioprinting, combining cells, biomaterials, and synthetic materials into biological constructs. Such constructs encompass a vast range of applications, including custom-made biomedical devices; microfluidic devices that incorporate 3D miniaturized organs called organoids for high-throughput drug and toxicity screening; tissue-engineered skin, cartilage, and bone; blood vessels and hollow organs such as the bladder; and even complex organs such as the kidney, liver, lung, and heart.This special issue of Trends in Biotechnology reviews many of these envisioned applications, or in cases where the translation of the technology remains hypothetical, gives opinions on their future potential. Some Opinion papers presented in this issue include those of Yeong and colleagues, who ask whether skin bioprinting is an impending reality or simply a fantasy; Visscher and colleagues, who foresee a biofabrication-based approach to craniofacial reconstruction using multiple tissue types; and Ozbolat and colleagues, who advocate the potential of bioprinting to overcome current limitations in 3D models for pharmaceutical testing. In addition, Rouwkema and Khademhosseini review the current applications of novel fabrication techniques to creating vasculature in engineered tissues.To realize the potential that biofabrication holds, manufacturing challenges need to be addressed. These manufacturing challenges are many, but there are central challenges that we believe the field can advance together, which will bring us one step closer to realizing the true benefits that biofabrication promises. Some of these central manufacturing challenges include (1) consistent, reliable, and multi-sourced starting materials for biofabrication (e.g., biomaterials, cells, and reagents); (2) coordinated standards and regulatory pathways for biomedical products; (3) advanced, modular, closed, and automated platform technologies for biofabication; and (4) quality-control systems integrated into the manufacturing process to ensure that biofabricated products are well defined, characterized, and aligned with regulatory standards.On the theme of manufacturing challenges, short articles by Knowlton and Tasoglu, and by Tamayol and colleagues, highlight some recent progress in biofabricated organs-on-chips and in biofabricated textile processing. In an Opinion, Wan poses the question of whether the advent of organoids has made a biomaterial-based approach to tissue engineering obsolete, while a Review by Picollet-D’hahan and colleagues discusses recent advances in fabricating flow-based organ models. Finally, Xu and colleagues describe how bioprinted constructs can evolve over time, in a process they term 4D bioprinting.Investments into realizing these diverse applications and overcoming the associated manufacturing challenges will yield tremendous returns in boosting economies across the world. We predict that countries that align funding efforts across private and government sectors to address and solve these manufacturing challenges will enjoy economic benefits of creating more jobs, as well as providing a new era of personalized medicine where off-the-shelf bioengineered products will become a reality. We hope this special issue inspires discussion and innovation throughout this exciting field and welcome your feedback at tibtech@cell.com.

Five Critical Areas that Combat High Costs and Prolonged Development Times for Regenerative Medicine Manufacturing

Purpose of ReviewThe purpose of this review is to examine five stages of process improvement in bioengineering of cellular products that could facilitate standardization and accelerate progress through the regulatory pathways and together make such treatments more widely available.Recent FindingsWe present solutions to reduce costs, promote standardization, and enable acceleration through the required regulatory pathways.SummaryRegenerative medicine-based technologies and products have the potential to revolutionize the practice of medicine and become the next standard of care. We identify current barriers that are limiting the widespread availability of these potential life-saving treatments and platform technologies. One central barrier is the cost of manufacturing these regenerative medicine-based technologies and products at commercial scale.

An Industry‐Driven Roadmap for Manufacturing in Regenerative Medicine

Regenerative medicine is poised to become a significant industry within the medical field. As such, the development of strategies and technologies for standardized and automated regenerative medicine clinical manufacturing has become a priority. An industry‐driven roadmap toward industrial scale clinical manufacturing was developed over a 3‐year period by a consortium of companies with significant investment in the field of regenerative medicine. Additionally, this same group identified critical roadblocks that stand in the way of advanced, large‐scale regenerative medicine clinical manufacturing. This perspective article details efforts to reach a consensus among industry stakeholders on the shortest pathway for providing access to regenerative medicine therapies for those in need, both within the United States and around the world. Stem Cells Translational Medicine 2018;7:564–568