Coronavirus disease 2019: A tissue engineering and regenerative medicine perspective

Abstract Current therapies for novel coronavirus disease (COVID‐19) are generally used to manage rather than cure this highly infective disease. Therefore, there is a significant unmet medical need for a safe and effective treatment for COVID‐19. Inflammation is the driving force behind coronavirus infections, and the majority of deaths caused by COVID‐19 are the result of acute respiratory distress syndrome (ARDS). It is crucial to control the inflammation as early as possible. To date, numerous studies have been conducted to evaluate the safety and efficacy of tissue engineering and regenerative medicine (TERM) products, including mesenchymal stem cells (MSCs), and their derivatives (eg, exosomes) for coronavirus infections, which could be applied for the COVID‐19. In this review, first, the impacts of the COVID‐19 pandemic in the present and future of TERM research and products are briefly presented. Then, the recent clinical trials and the therapeutic benefits of MSCs in coronavirus‐induced ARDS are critically reviewed. Last, recent advances in the field of tissue engineering relevant to coronavirus infections, including three‐dimensional platforms to study the disease progression and test the effects of antiviral agents, are described. Moreover, the application of biomaterials for vaccine technology and drug delivery are highlighted. Despite promising results in the preclinical and clinical applications of MSC therapy for coronavirus infections, controversy still exists, and thus further investigation is required to understand the efficacy of these therapies.

TERM is an emerging field that developed over time and secure longterm investment from both public and private sources is needed to help unlock the potential of TERM strategies and to boost research translation and commercialization in this area.

| Virus infection leading to a remarkable reduction in tissue donation and extensive consideration for tissue storage
By having too many patients in the hospitals over the COVID-19 outbreak period, the administration and process of cell and tissue donation programs have consequently slowed down. Moreover, concerns over the virus spread have led to a much smaller number of uninfected potential donors to be interested in donating their cells for research and therapies, 4,5 which further limit the already inadequate donor pool. Besides, warnings about social distancing, to stop the spread of a new coronavirus, are resulting in a significant drop in the tissue supply, specifically blood donation. In March 2020, the American Red Cross declared a severe blood shortage in response to the coronavirus outbreak. Also, during the COVID-19 pandemic, many blood donation centers are closed around the world. 6 To date, there are no reports on the SARS-CoV-2 transmission through the allogeneic blood transfusion, and future studies will clarify the risks of the transfusion-transmitted virus. 6 Also, the cells and tissues that have been donated and stored in tissue banks since the beginning of the COVID- 19

| Current status of MSC-based therapies for acute respiratory distress syndrome
The protective effects of MSCs in the treatment of influenza respiratory infections have been reported previously in preclinical mouse studies. 7-9 Intravenous administration of 5 × 10 5 human bone marrow

Significance statement
The tissue engineering and regenerative medicine communities and industries have been largely impacted by the COVID-19 pandemic. In this article, the impact of the recent pandemic on the present and future of tissue engineering and regenerative medicine research and therapies is highlighted. Then, the potential use of three-dimensional tissue models and benefits and risks of mesenchymal stem cell therapy for the COVID-19 are discussed.   showed that a single infusion of up to 10 million cells/kg PBW was well tolerated and no infusion-associated events or MSCs treatment-related adverse events were reported. 16 In the weeks after infusion, serious adverse events were noticed in three patients. One patient died on day 9, one patient died on day 31, and one patient was discovered to have multiple embolic infarcts of the brain, kidneys, and spleen, but thought to have occurred before the MSC administration based on MRI results. The authors concluded these severe adverse events were not related to MSCs treatment. 16 In a double-blind, multicenter, randomized phase 2a safety trial, 40 patients with moderate to severe ARDS were treated with BM-MSCs (10 × 10 6 /kg PBW) and compared with the placebo group (n = 20) (NCT02097641). 21 The patients were treated within 7 days of ARDS diagnosis. The 28-day mortality rate was not significantly different between the MSCtreated group (30%) and the placebo group (15%). The BM-MSCs treated group had numerically higher mean scores for Acute Physiology and Chronic Health Evaluation III than the placebo group. 21 Still, the sample size in this trial was too small to reliably assess the efficacy of MSCs therapy in ARDS and larger trials are needed.
A recent study was conducted to investigate the impact of  In COVID-19 infection, the host immune system produces an enormous inflammatory response in an attempt to kill the virus, leading to a severe cytokine storm, this process is the main contributor to organ damage in COVID-19. Therefore, avoiding the cytokine storm could be an effective strategy in the treatment of COVID-19. MSCs, due to their powerful immunomodulatory ability not only suppress the cytokine storm but also promote the endogenous repair/regenerative mechanisms in the lungs after the COVID-19 infection. 17,23 ARDS is one of the most severe complications caused by coronaviruses. 24,25 Indeed, respiratory failure from ARDS is the leading cause of mortality in COVID-19 patients. 24,25 Therefore, the management and treatment of ARDS are essential to reduce the mortality rate. It is believed that MSCs regulate the immune system by inhibiting the production of inflammatory cytokines by lymphocytes and induces the production of anti-inflammatory cytokines. Therefore, MSC therapy potentially offers a unique therapeutic option to help COVID-19 patients. However, a greater body of research is required to fully evaluate the potential of MSCs therapy for COVID-19 induced ARDS.

| The potential use of stem cell derivatives for ARDS treatment
Apart from MSCs, their derivatives including exosomes have gained significant attention as a therapeutic strategy to achieve the therapeutic effects of MSCs without the risks and challenges of administering the cells to the patients. 26,27 Exosome-based therapy is an emerging field of biomedical research and the therapeutic effects of stem cells have been attributed to the secreted exosomes. 28,29 Specifically, the potential use of exosomes to ameliorate ARDS in preclinical models is well-documented. 27    A recent study aimed to assess SARS-CoV-2 infectivity. 22 Spike (S) protein of SARS-CoV-2 is composed of two subunits S1 and S2. S1 binds to ACE2 protein, the key entry gate for SARS-CoV-2 that facilitates its penetration into target cells, and S2 fuses on the surface of the cell membrane. 37 Transmembrane serine protease 2 (TMPRSS2) is another host protein that promotes cellular entry of SARS-CoV-2.
Therefore, both ACE-2 and TMPRSS2 are necessary for viral infectivity. 22  organoids. 39 The potential use of human and animal organoids as an experimental virology platform has been discussed somewhere else. 40,41 Human organ-on-chip technology has been developed and extensively used to recapitulate in vivo cellular responses to drugs or toxic agents. 32,42,43 The tissue engineering and organ-on-chip technologies apply engineering principles to biological processes and enable rapid translation of technologies from the benchtop to the bedside. 44 Previous studies reported lung-on-chip models to offer alternative preclinical tools to mimic human alveolar epithelial cells' responses to viral infection due to their capacity to recapitulate organ-level physiology and pathophysiology. 45 infection. 32 Of significance, no significant inhibitory effects for chloroquine was observed in Cmax. This could be explained by the fact that chloroquine may exert its therapeutic effects via mechanism(s) other than contributing to blocking the virus entry. 32 Remdesivir (also known as GS-5734) is an adenosine analog prodrug with excellent potency against severe acute respiratory syndrome and the Middle East respiratory syndrome in human airway epithelial (HAE) cell models. 34,47 Previous studies showed remdesivir might be a promising candidate for the treatment of patients with COVID-19 due to its ability to inhibit viral RNA replication. 48

| BIOMATERIAL-BASED VACCINES
Apart from the development of in vitro models, tissue engineering technologies enable the evolution of the next generation of drug delivery systems and facilitate vaccine development and delivery. 43,44 Tissue-engineered systems allow the controlled extended release of drugs, which are advantageous over multiple injections for clinical practice. Besides, the new generation of biomaterials allows us to target the areas of high viral load specifically and extendedly. Biomaterials able to act as the drug delivery vehicle for the vaccine as well as the adjuvant, and can boost the immune response to the vaccine. 44,50 For H5N1 influenza immunization, Wu et al modified chitosan and developed a thermal-sensitive hydrogel as an intranasal vaccine delivery system. 51 The new adjuvant-free vaccine delivery system prolonged the H5N1 split antigen residence time in the nasal cavity and enhanced the transepithelial transport in the nasal epithelial tissue. The adjuvant-free vaccine delivery system could induce larger antigen-specific systemic immune responses and mucosal IgA immunity in a mouse model. 51 In addition, the tissue engineering concepts have been utilized to develop immunologically active biomaterial constructs. 52 Ali et al fabricated 3-dimensional, macroporous poly(lactideco-glycolide) matrices that slowly released cytokines such as granulocyte-colony stimulating factor and recruited antigenpresenting cells to the matrices. 52 The biomaterial-based vaccines enhanced effective, prolonged, and specific cytotoxic, T-cell mediated immunity, and eradicated the large established melanoma tumors in mice. 53 The in vivo modulation of host immune cells can be achieved with the spatiotemporal control of biochemical and mechanical cues in biomaterials. 54 Mesoporous silica rods of high aspect ratio were fabricated and subcutaneously implanted into mice to form a pocket and formed 3D interparticle spaces and recruited host cells. The sustained release of inflammatory signals and adjuvants from the scaffold modulated the immune cell function and provoked adaptive immune responses. 54 This system has been applied to tumor vaccines in animal models with promising results, 52 64 Particularly when looking at concentrating many liters of cell solution, this must be done promptly (<5 hours) to not compromise cell viability and the functionality of the final product. 64 Volume reduction and filtration steps using appropriate systems at the scale that is required will need to be evaluated accordingly. Most standard laboratory centrifugation systems will not be able to handle large volumes >5 to 10 L. 56 In the separation step, the choice of the enzyme, the time of exposure, and efficiency of each step are critical in ensuring optimal cell survival. For GMP manufacturing, the use of animal-component free materials, in a ready-to-use solution, is preferred and helps to reduce regulatory burden.
6.3 | What can we expect to learn from this pandemic (with new clinical trials approved)?
Acceleration of trials for COVID-19 will present opportunities to collect more data on both the safety and efficacy of MSCs and other cell therapies to treat lung injuries and related complications. However, rational design and a controlled approach to clinical trial design are essential to obtain valuable insights in assessing both the safety and efficacy of treatments. 65 Patient safety is paramount and should never be compromised in any circumstance. Therapeutic developers and cell therapy manufacturers must uphold their moral integrity to deliver products that meet equally stringent requirements to ensure patient safety. From the manufacturing perspective, this also presents an opportunity for product developers to focus on advancing scalable technologies that can meet critical demands like these in the future. As other cell therapy products are developed and mature, manufacturing will remain a challenge if progress is not made on this front. Finally, the cost to manufacture cell therapies will need to go down to make them accessible to everyone. In the Olsen et al article, the relationship between technology S-curve and economics for MSCs describes how the adoption of each technology platform at the production scale will drive the cost down due to efficiencies of scale. 64 The COVID-19 pandemic is forcing us to think big and look ahead into the future. With every crisis, there is a silver lining, and here we are being presented the opportunity to advance cell manufacturing technologies forward to make cell therapies of the future scalable, safe, and affordable.

| CONCLUSIONS
The TERM technologies have the potential to revolutionize the whole healthcare system by restoring damaged tissues and organs, in contrast to other pharmaceuticals and surgical strategies that generally manage rather than cure diseases.
Over the COVID-19 outbreak, the funding for many TERM projects is being cut, which has a significant impact on the present and future of

AUTHOR CONTRIBUTIONS
A.S.: concept and design, manuscript preparation, collection and assembly of data, review and editing, and final approval of the manuscript; L.M., M.L., J.B.: manuscript preparation, discussion, and review and editing.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.