From Promise to Practice: Recent Growth in 30 Years of Tissue Engineering Commercialization

Introduction: A Historical Perspective

In the mid-20th century surgical advances made organ allotransplantation possible for kidneys, liver, lungs, hearts, and other major organs.^1–4 These strides represented a considerable bound in modern medicine, one where collaborative effort between physicians, surgeons, and scientists partially mitigated challenges with transplant rejection that plagued progress. In the present day, the success of allotransplantations has continued to prevent deaths and prolong lives globally.

Unfortunately, allotransplantation is an imperfect solution. Donor matching can prove challenging or impossible, and transplant recipients who avoid rejection still require lifelong reliance on immunosuppressants.^5,6 Furthermore, allotransplantation remains entirely dependent on qualifying recently deceased or charitable living donors, the deficit of which expands annually.^7,8 By the early 1990s, the recognition of this new class of challenges had set the stage for the birth of a new field, aiming to pioneer the development of autologously sourced and manufactured tissues. Autologous cell sources would resolve the need for immunosuppression, and manufacturing organs could alleviate organ supply shortages. In this era, clinical trials of autologous chondrocyte implantation had just generated positive results on follow-up, ⁹ and a patient with Poland’s syndrome received the first engineered implant—a cell-laden synthetic polymer sternum. ¹⁰

Fittingly, researchers began to pursue ‘tissue engineering’; ¹¹ many early investigations are attributable to the research partnership of Robert Langer, an engineer at Massachusetts Institute of Technology, and Joseph P. Vacanti, a surgical physician at Boston Children’s Hospital. The two, alongside a global cohort of prominent researchers, were among the first to investigate the methods required to realize engineered tissue constructs. ¹² Their early and guiding definitions of the field defined it as an “interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue or whole organ function” (Fig. 1).

OPEN IN VIEWER

FIG. 1.

Three perspectives on the 30-year evolution of tissue engineering (A) Timeline of historical milestones in tissue engineering. (B) Tissue engineering paradigm incorporating the process of cell isolation from patient source; cell, material, or signal selection for the fabrication of tissue engineered construct; and maturation of the construct in vitro prior to implantation. (C) Volume of tissue engineering, biomaterials, and stem cell publications from 1994 to 2022 demonstrating parallel growth in the field. [data from pubmed.gov, PubMed database keyword search: tissue engineering, biomaterials, and stem cell, filtering for years 1994 to 2022].

However, despite the great promise of the field, progress to clinical translation has been slow, hindered by gaps in knowledge related to autologous stem cell harvest and directed differentiation to somatic cell phenotypes, difficulties in precise manufacturing of tissue constructs, and challenges with maintaining cellular viability and function in large tissue constructs. ¹³ –16 Irrespective of these fundamental biology and biomedical engineering gaps, the field has maintained a record of clinical advances alongside major preclinical achievements (Fig. 1a).^{1–4,9,10,17–27} For example, in 2001, a 4-year-old girl received an engineered pulmonary artery that demonstrated impressive postoperative performance at a 7-month follow-up²². Only 5 years later came the discovery of stem cells with inducible pluripotency (iPSCs),^23,24,28 which were used less than a decade later to fabricate a retinal sheet implanted in a woman with macular degeneration. ²⁷

Now, 30 years from its inception, the field of tissue engineering has several therapeutic products on the market for applications in the regeneration of articular cartilage, bone, and burn wounds.^29,30 Furthermore, the field has evolved from its original definition and purpose, now encompassing ex-vivo tissue constructs that aim to recapitulate native tissue structure and function (Fig. 1b). These constructions are becoming increasingly popular as performance assessment platforms, so much so that they now play a role in regulatory approval of therapeutics beyond tissue engineering and regenerative medicine. These changes have arisen since the latest review on the tissue engineering industry. ³¹ In this study, we plan to discuss in detail the expansion of tissue engineering as an industry within the last five years of growth.

In this review, we discuss the following three key elements of the field of tissue engineering: 1) commercialized technology and approved therapeutics that have reached patients’ bedside, 2) ongoing clinical trials to investigate the safety and efficacy of therapies, and 3) preclinical directions at the industry and academic level. While discussing these topics, we aim to highlight key historical events in the last 30 years of tissue engineering and regenerative medicine, provide the reader with detailed discussions of the most contemporary trends in the field, and finally, predict the discipline’s overall future.

Methods

Herein we pursue an evolution of methodologies, choosing best practices from previous iterations of reviewing the tissue engineering discipline, including the first set of reviews by Lysaght.^31–34

Identification of potential tissue engineering companies

Potential tissue engineering companies were identified (Fig. 2) through the following: 1) abstraction from prior reviews,^32,34,35 2) a PubMed search of peer-reviewed literature for abstracting companies listed in affiliation and conflict of interest statements, 3) the most current list of FDA-approved cellular & gene therapies, and 4) a ClinicalTrials.gov search for trials listing companies as sponsors or collaborators. We limited all database searches to results from 2019 to September 2023, such that we only include data since the last review. Specific documentation of search terms and data scope are described in the next section of the methods. We defined search terms based on previous reviews, in-laboratory discussions, and consultation with our university’s specialist librarian in bioengineering. The consolidated dataset consisted of 6,259 companies and was deduplicated and cleaned to remove names of individuals, hospitals, government agencies, universities, foundations, and trusts. The finalized list of potential TERM companies included 3,324 entries.

OPEN IN VIEWER

FIG. 2.

Methods for Identifying Active Tissue Engineering Companies. Tissue engineering companies were identified from author affiliations and conflict of interest statements in the last 5 years of PubMed searchable literature, listings of sponsors and collaborators of trials indexed by ClinicalTrials.gov, and FDA approved cell and gene therapies. An inclusion/exclusion criterion narrowed the list to currently active tissue engineering and regenerative medicine companies.

Companies were further classified by stage based on the stage of their leading product as commercial, clinical, or preclinical stage. Commercial products were defined as products that were commercially available to customers, clinical products were defined as potential products currently undergoing clinical trial investigation, and preclinical products were defined as products that are still in the in vitro or in vivo experimental testing phase. Furthermore, companies were categorized by their product sector as stem cell companies, biomaterial companies, or cells and biomaterial companies. Stem cell companies were defined as companies whose leading product used a cell therapeutic as its primary mode of action, biomaterial companies were defined as those whose leading product used a biomaterial or hydrogel technology as its primary mode of action, and cell and biomaterial companies were defined as companies whose leading product used a combination of a cell and biomaterial or hydrogel technology for therapeutic purposes. The authors acknowledge that these categorizations comprise company views at a snapshot in time which can evolve quickly as products change and are based on the author’s interpretation of openly available company information.

International Tissue Engineering Commercialization

Our investigations have identified 347 tissue engineering companies internationally, 87% being private companies (Table 1). Notably, our selection criteria are more conservative by exclusion of blood and tissue banks, which made up a substantial portion of all companies in past iterations of this review.^34,35 Despite this, 347 companies represent a 71% growth in the number of companies since the figure was last reported by Jaklenec et al. in 2012 (Fig. 3b). ³⁵ Furthermore, an estimated quarter of these companies originated in the last five years, indicating healthy expansion of the field.

OPEN IN VIEWER

FIG. 3.

(A) Heatmap of tissue engineering companies included in our review. Each point represents a single company, while the intensity is determined by their reported sales in USD. (B) Trend in number of tissue engineering companies identified over the last 3 decades of reviews. (C) Estimated sales volume from the tissue engineering industry. (D) Breakdown of identified tissue engineering company stages, product sectors, and attributed sales estimates.

The largest volume of companies, employees, and sales resides most heavily in the northeastern United States, continuing with historical trends (Fig. 3a). Nevertheless, there is a great deal of activity internationally as the industry has expanded to form large hubs worldwide. Of these, additional hotspots exist on the United States’ west coast, in the Asian Pacific (particularly in Japan and the Republic of Korea), and in Western Europe (specifically the United Kingdom, Germany, and Italy).

These 347 international companies made an estimated 53.7 billion USD in cumulative sales, 15 times the amount from a decade prior (Fig. 3c). The majority (77%) of all sales come from commercial-stage companies (41.4 bn USD), which represent about 47% of all companies (Fig. 3d). The extraordinary sales of commercial-stage tissue engineering companies are trailed by preclinical stage companies which have net about 11.6 bn USD, constituting 20% of all sales and representing 20% of all companies. Finally, about a third of companies are in the clinical trials phase and yield a small subset of the estimated cumulative sales totaling less than 1 bn USD.

The distribution of companies by product sector varies based on stage. Commercial companies are dominated by the ‘Cells and Biomaterials’ product sector, followed by ‘Stem Cell’ products and then ‘Biomaterials’ (Fig. 3d). In contrast, both preclinical and clinical trials are primarily dominated by companies pursuing stem cell products as their primary offering. We interpret this distribution to suggest that precommercial investigations are primarily interested in the capabilities and efficacies of cellular therapies, which are newer from a historical perspective. In this line of thinking, commercialized companies leverage well-studied and established biomaterials alongside novel understanding of cell behavior to produce their products.

Overall, the commercialization of tissue engineering technologies has continued its healthy expansion.

Ongoing Clinical Trials

The advancement of tissue engineered therapies to commercial translation unsurprisingly relies on the performance of safety and efficacy assessed through clinical trials. In this study, we focus briefly on the U.S. clinical trial landscape to provide one perspective of the advancement of the field. This subpopulation is of interest due to the heightened overall activity of tissue engineering within the United States and the abundant information that is readily available and openly shared.

We searched the ClinicalTrials.gov database for tissue engineering trial entries between 2019 and 2023, representing the previous five years since the last review. There were 3,388 clinical trial entries that satisfied our search criteria. Most studies were in trial phase 1 or 2 or combination trials performing investigations qualifying as both phase 1 and 2 (Fig. 4). These also represented the largest rates of clinical trial failure (e.g., withdrawal, termination, or suspension), as was evidenced by the decreased rate of failure for trials in phase 3. Most trials were interventional, to develop tissue engineered or regenerative medicine therapeutics.

OPEN IN VIEWER

FIG. 4.

Ongoing tissue engineering clinical trials from 2019 to 2023. Clinical trials are stratified by trial phase and status, with a representation of what subset of trials are interventional or observational.

Relative to the preclinical and commercial product sectors, companies in clinical trials make up a small fraction of sales which is to be expected. Interestingly, most of the companies we identified that were in clinical trials were investigating stem cell therapies (68%), followed by therapies involving both cells and biomaterials (27%) and those utilizing only biomaterials (5%) (Fig. 3d). The product sector distribution for clinical trial stage companies in juxtaposition with commercial companies is an interesting one, particularly because clinical trials stage companies immediately precede commercial ones. Nonetheless, the fraction of commercial companies is greatest for cell and biomaterial products. These differences may be clinically driven due to the likelihood of improvement for clinical efficacy when combining cell and biomaterials into a therapeutic or alternatively it may be a conscious business decision and an indication that multimodality approaches incur lower risk due to greater ease in defense of intellectual property. Nonetheless, the volume of companies involved in tissue engineering clinical trials is substantial and harbors great promise for the identification of therapeutic strategies to a host of diseases.

Preclinical Directions

Preclinical-stage companies are responsible for 20% of estimated cumulative sales and make up 20% of identified companies. These companies are operating in the stem cell, biomaterial, and cells and biomaterials product sectors to engineer biological products that can aid in the repair or replacement of lost function.

Conclusions

Over the last 30 years, the tissue engineering and regenerative medicine field has made remarkable strides to expand into a multidisciplinary field. Originating as a promising concept, many advancements have been made following the discovery and implementation of technologies, including additive manufacturing modalities such as 3D bioprinting, reprogrammable iPSCs for therapeutic and diagnostic applications, and self-assembling organoids for in vitro tissue models. While the field has expanded globally, most companies with tissue-engineered products are heavily present in the United States, primarily in the Northeastern and Pacific regions. Internationally, companies are in the Asian Pacific countries of Japan, the Republic of Korea, and the Western European countries of the United Kingdom, Germany, and Italy and minimal presence in South America with one company coming out of Chile. The ‘Stem Cells’ and ‘Cells and Biomaterials’ sectors have shown the largest increase in companies compared to previous data collected, with ‘Stem Cells’ representing 68% of products in clinical trials and ‘Cells and Biomaterials’ representing 54% of products in the commercial stage. ³² Over the last five years, the tissue engineering market has grown by 40 billion USD. Part of this increase is attributable to efforts by the FDA to streamline the regulatory process by reorganizing and using alternative testing methods to address products with low yield or chemistry, manufacturing, and controls challenges when they arise.

To perform our assessment, we made great efforts to cast a wide net when identifying companies internationally, and to do so we replicated methods from several prior publications on commercialization of tissue engineering as a whole.^31–34 However, these methods are not without their limitations. We identified companies from associations with results of database searches for literature and clinical trials using key terms related to tissue engineering. While we succeeded in identifying several thousand entries which we parsed for tissue engineering companies, the choice of databases and search terms may introduce some bias to the results. Second, many of our quantitative findings are reliant on the accuracy of international business databases, which while we believe these to be reliable, ⁵¹ may have some inaccuracies intractable by the authors. For example, in pinpointing estimates of cumulative sales and number of employees attributable to tissue engineering endeavors, we anticipate that our reports are more accurate for smaller organizations than for larger ones with multiple subsidiaries that may or may not also be performing tissue engineering. We attempted to account for this by only including the tissue engineering subsidiaries of large companies performing business in multiple sectors, when possible.

In the future, the dominance of stem cell-based products seen in companies within the clinical trial sector is expected to lead to more commercialization of these products depending upon success in clinical trial results and regulatory approval. The efforts in past 30 years of tissue engineering are being realized through the domination of ‘Cell and Biomaterial’ based products in the commercial sector, highlighting the growth of tissue engineering as a reputable field. While biomaterial products still represent a substantial portion of commercial and preclinical products, the functionalization of these materials with bioactive cellular products is now more dominant in the field—a shift only realized in the last five years.

Despite government and industry investment in the field, there are only a modest number of commercially available tissue engineered products classifiable by the native definitions of the field. The field has therefore embraced parallel or complementary technologies that address the goals of tissue engineering as the science and regulatory frameworks advance toward realization. Some might consider this as a failing of the field. However, considering the audacity of the approach—building implantable tissues—we suggest that the rate of clinical impact of the field is at worst appropriate and perhaps remarkable.

To appropriately triage new therapies, regulatory agencies have pursued adaptations that make clearer how innovative engineered tissues will be scrutinized as potential therapeutics and what role they will play in the assessment of therapies. In the United States, the FDA has responded to the complexity of these products and the significant amount of detail required to review them by establishing the Office of Therapeutic Products in 2022 and making modifications to the regulatory pipeline.^49,52 While significant strides have been made in the last five years, there are still many remaining challenges for tissue engineered products. Production scale-up, product consistency, and reproducibility are all active challenges in the field. The most significant challenge is supplying adequate nutrition and oxygen, which, if solved, will result in achieving the original aspirations of the field: to develop fully functional tissue and organ constructs. In conclusion, over the last 30 years, the tissue engineering and regenerative medicine field has metamorphosized from a visionary concept to a tangible force, driving innovation in both the health care and biotechnology spaces. The field holds the potential to reshape the medical landscape, offering renewed hope for patients, researchers, and clinicians alike.