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Despite the success of cell therapies in some areas, such as CAR-T cells for lymphomas, translation to the clinic has generally been much less rapid and impactful than originally anticipated. One of the reasons for this may be that most of the attention has been focused on the cells themselves with less consideration given to their 3D environment. Since this 3D environment is critical in maintaining cell viability and functionality, we believe it warrants as much investigation and planning as the cell therapy itself. In our view, given that biomaterials may be used to create this 3D environment, they will play an essential role in clinical translation of cell therapies.
Range of biomaterials available
A range of biomaterials have potential in the development of cell therapies. Natural biomaterials come from the human body (e.g. hyaluronic acid) or nature (e.g. alginate, which is found in seaweed). They have inherent biocompatibility and may have cell attachment sites.
Synthetic biomaterials used for cell delivery are commonly polymers such as poly(ethylene glycol) or poly(lactic-co-glycolic acid) (PLGA). One of the benefits of biomaterials, in general, is that they can be chemically modified to change their mechanical properties, degradation properties or to add ligands for cell attachment.
In our work, we have used hyaluronic acid as the biomaterial of choice for cell delivery. Naturally occurring hyaluronic acid forms a viscous liquid at high concentrations, but chemically modified derivatives can be synthesised to facilitate formation of hydrogels with improved mechanical strength. Further modification of hyaluronic acid can provide cell attachment ligands which, we have shown, can improve survival of human mesenchymal stem cells in ischaemic sites, when the cells are given time to attach prior to delivery (1).
Delivery requirements
The biomaterial will also need to fit the delivery requirements of the formulation e.g. have a viscosity that allows it to be injected through a catheter or remain intact on surgical insertion. It will also need to be manufactured, in appropriately sized batches, to good manufacturing practice standards and fulfil any regulatory requirements for quality, safety and efficacy for human use. In doing all, or at least some of this, biomaterials should be expected to increase the functionality and therapeutic efficacy of cell therapy products and thus, patient outcomes. A broad range of biomaterials for cell delivery are currently being investigated in pre-clinical work, while a smaller group of biomaterials have progressed to clinical studies. The optimal biomaterial will vary with each application and modification of existing materials may be required to create the ideal biomaterial for a given application.
The clinical translation of hydrogel-based therapies has been limited due to difficulties with minimally invasive injection. Achieving an injectable biomaterial for minimally invasive delivery to the heart is challenging due to the viscous nature of biomaterials, the length of the delivery device (femoral access), the small profile of the injection needle and the blind nature of endocardial delivery. Additionally, therapies of this nature require numerous injections (9–26 injections) to distribute the therapy to various regions of the infarct. For these reasons, it is important to understand the design requirements of minimally invasive catheter delivery in relation to viscous materials/hydrogels. This exemplifies the importance of a multidisciplinary team to aid translation of therapies to the clinic. To meet the delivery requirements of our formulation, we developed a specialised catheter which delivered this cell-loaded hyaluronic acid hydrogel to a porcine heart and have shown that catheter/hydrogel issues can be overcome (2). Our device was developed in collaboration with clinicians and industry to ensure its feasibility for endocardial delivery of our cell-laden biomaterial.
How to choose a biomaterial
Choosing a biomaterial should start with outlining the specific requirements of the therapeutic application, deciding what, if any, chemical modifications to the biomaterial might be needed and in vitro testing of the biomaterial/cell formulation. We have observed that early consideration of the potential for scale-up of the formulation is essential, as large-scale manufacture of biomaterials can be a challenge and cell interactions with the material may differ with batch-to-batch variability. Delivery of the formulation should also be considered at an early stage. We have found consultation with clinicians and end-users to be paramount to this, as they will have to be comfortable using the formulation in a real-world setting. The wide range of factors to consider may mean the preferred biomaterial for a particular application changes over the development process. Initially the most important factor to consider is that the biomaterial is compatible with the cell type to be delivered and does not adversely affect cell viability and activity. The biocompatibility of the entire formulation must then be considered. Once these have been established, delivery requirements, efficacy of the formulation and scale-up should all be considered.
Alginate, for example, has gone through extensive pre-clinical and clinical testing as a biomaterial for injection into the heart wall to improve ventricular wall strength in heart failure. However, it does not naturally have cell attachment sites and its degradation rate is slow due to a lack of specific enzymes to break it down. Small molecular hydrogels have been used to deliver hepatocyte growth factor-modified mesenchymal stem cells to the rat heart. These gels significantly improved cell retention and survival and consequently reduced scar area and improved cardiac function compared to delivery of cells in saline (current gold standard) 14 days after delivery (3). However, small molecular hydrogels such as these have not yet been tested in the clinic.
Biomaterials to enhance cell survival
As well as delivery, biomaterials can be used to protect therapeutic cells from harsh microenvironments in the body and to optimise cell survival by the use of growth factors. For example, studies have looked at the co-delivery of growth factors with cells in hyaluronic acid biomaterials to further advance the therapeutic potential of the formulation. In vitro studies have shown that incorporation of insulin-like growth factor-1-containing PLGA microparticles in a hyaluronic acid hydrogel can produce a dose-dependent increase in cardiac endothelial cell proliferation (4).
Another approach to improve cell survival is to protect cells with a biomaterial-based device, where cells can remain alive to secrete paracrine factors which pass through a porous membrane into the tissue. In 2018, a thermoplastic polyurethane device with a polycarbonate semi-permeable membrane that was attached to the surface of a rat heart post myocardial infarction (MI) was reported. The delivery device contained a methacrylated gelatin cryogel loaded with mouse mesenchymal stem cells. In vitro studies demonstrated that cells remained alive and functional in the biomaterial-loaded device 28 days following delivery. Even with this prolonged survival, cell therapy may require repeated delivery akin to small molecule therapeutics which require frequent dosing for an effect. As well as prolonging cell survival, the device described facilitated minimally invasive repeated delivery of cells to the epicardial surface of the heart seven and fourteen days following initial implantation in vivo. Repeated delivery resulted in a significant improvement in ejection fraction 28 days following MI compared to before MI (5). This approach of using a biomaterial-based device to allow localised minimally invasive repeated delivery of cell therapy may be useful in other applications where a continuous targeted effect is required.
Biomaterials to drive cell therapy for solid tumours
Great progress in the development of CAR-T cells for lymphoma has resulted in the regulatory approval of three cell therapy products. However, production of CAR-T cells requires a lengthy and expensive process and their success in treating solid tumours has been limited to-date. We believe biomaterials can help to overcome both of these problems. Microparticles and nanoparticles formed from various biomaterials, e.g. silica and PLGA, modified with surface ligands, can be produced to more accurately reflect the normal in vivo activation of T cells by antigen presenting cells. This can improve the efficiency and reduce the cost of balanced CD8+/CD4+ T cell expansion, with simultaneous, unbiased expansion possible, instead of producing both cell types separately (6). Similarly, delivery of antigens in biomaterial-based nanoparticles which are rapidly taken up into lymph nodes, extends the residence time of the antigen presentation to dendritic cells and subsequently increases T cell priming (7).
Using biomaterials to maintain T cells at the site of a solid tumour would be expected to have a dual benefit, increasing their contact time with the tumour and reducing their escape into the systemic circulation where they can cause undesirable off-target side-effects. While an optimal system for this is yet to be developed, much pre-clinical work is being performed with promising early results. Intraperitoneal delivery of CAR-T cells in an alginate scaffold significantly improved survival in mice compared to standard intraperitoneal injection of the same cells (8). Similarly, CAR-T cells delivered to mice on a nitinol film significantly improved survival compared to untreated mice (9).
We would expect to see more work like this in the future with biomaterials playing an essential role in improving the therapeutic efficacy of cell therapies. The versatility of biomaterials means that in the future they may incorporate particulate systems for the sustained or responsive release of cytokines or other therapeutics which could act synergistically with the cell therapy.
Significant efforts have thus far been invested in creating sophisticated cell products as therapeutic agents. Similar investment in the incorporation of biomaterials, to enhance their healthcare benefits, must now be made.
References
- L. B. Gallagher et al., Pre-culture of mesenchymal stem cells within RGD-modified hyaluronic acid hydrogel improves their resilience to ischaemic conditions. Acta Biomaterialia 107, 78-90 (2020).
- E. B. Dolan et al., Advanced Material Catheter (AMCath), a minimally invasive endocardial catheter for the delivery of fast-gelling covalently cross-linked hyaluronic acid hydrogels. Journal of Biomaterials Applications 33, 681-692 (2018).
- Z. Liu et al., The influence of chitosan hydrogel on stem cell engraftment, survival and homing in the ischemic myocardial microenvironment. Biomaterials 33, 3093-3106 (2012).
- A. Hameed et al., Insulin-like growth factor-1 (IGF-1) poly (lactic-co-glycolic acid) (PLGA) microparticles – development, characterisation, and in vitro assessment of bioactivity for cardiac applications. Journal of Microencapsulation 36, 267-277 (2019).
- W. Whyte et al., Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir. Nature Biomedical Engineering 2, 416-428 (2018).
- I. I. Cardle, E. L. Cheng, M. C. Jensen, S. H. Pun, Biomaterials in Chimeric Antigen Receptor T-Cell Process Development. Accounts of Chemical Research 53, 1724-1738 (2020).
- H. Wang, D. J. Mooney, Biomaterial-assisted targeted modulation of immune cells in cancer treatment. Nature Materials 17, 761-772 (2018).
- S. B. Stephan et al., Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat Biotechnol 33, 97-101 (2015).
- M. E. Coon, S. B. Stephan, V. Gupta, C. P. Kealey, M. T. Stephan, Nitinol thin films functionalized with CAR-T cells for the treatment of solid tumours. Nature Biomedical Engineering 4, 195-206 (2020).
To explore more about electrospun biomaterials and cell therapy, visit the page.
Blog Authors:
Dr Eimear Dolan, Science Foundation Ireland Royal Society University Research Fellow and Lecturer Biomedical Engineering, National University of Ireland Galway
Dr Joanne O’Dwyer, Irish Research Council Postdoctoral Research Fellow, National University of Ireland Galway
