Dr Paul Campbell gives his perspective on potential research avenues with TenSkin™.

‘Having worked directly with the company whilst on secondment over the past year, it’s been very interesting to assess which of the various skin-related research communities can benefit most from using TenSkin™, the human skin explant model developed by Ten Bio’, states Campbell. ‘The many proof-of-concept demonstrations that we’ve participated in, and now incidentally embodied with clarity in the latest company brochure, underscore the utter versatility of the TenSkin™ platform. Of the areas embraced thus far though, one in particular stands out as ripe and ready to exploit Ten Bio’s technology, and that relates to the testing of microneedle approaches to address challenges in the general area of medicine.’

The development of microneedle-based technologies has matured considerably in the past decade, and as a result, an exciting repertoire of applications addressing several critical biomedical challenges have already been realised. Microneedle array or microarray patches (MAPs) have demonstrated clinical efficacy for the delivery of a range of molecular therapeutics including vaccines, hormones, growth-factors, and a spectrum of topically applied drugs [1]. Administration is straightforward for all such transdermal approaches: a patch consisting of an array of microneedles (inset (A) on the figure below) is pressed into the skin (inset (B)), whereupon the individual microneedles (which are typically cone shaped and several hundred microns in length) penetrate across the full thickness of the stratum corneum, creating an array of micropores (inset (C)), that achieve the efficient and controlled delivery of therapeutic agents.

A variation on this theme is that microneedles may be designed to dissolve in-situ, thus the patch is not removed directly after application, but rather maintained in place for an optimised period to accommodate the dissolution process and accompanying controlled release of any pre-loaded therapeutics directly into the dermal region.  In either case, use of microneedles clearly overcomes the outward barrier function of the stratum corneum so that drugs thus administered have a much less tortuous route to the dermal region, where their action can then be initiated. Transdermal drug delivery via microneedles can thus offer a significant clinical advantage over established delivery approaches.

‘However,..’ states Campbell, ‘a limiting factor at present, especially in the context of microneedle development, optimisation and pre-clinical testing, relates to the outward integrity of the target [skin] substrates upon which the needles are applied, and which might thus affect the clinical relevance of any measurements arising. This is where use of the TenSkin™ platform can achieve optimum results’.

Historically, pre-clinical studies with microneedles have focussed on using animal subjects, with murine models in particular proving both popular and highly useful test subjects for proof of concept and preliminary optimisation [2-4]. The interim drive, and parallel legislations, aimed at reducing animal testing have led researchers to seek alternative substrates, with explant human skin an obvious choice [5-7]. Skin explants offer a clear advantage over other potential target structures such as 3D cell cultures [8], given that the true structural integrity and mechanical properties of the distinct skin layers and their interfaces are retained. As a result, measurements on the insertion forces needed to apply microneedles into explant skin have usefully informed the protocols for downstream clinical trials.  However, there remains several severe limitations with traditional explant usage. These relate to the physical presentation of the tissue lacking inherent integrity provided by its natural tension on the body, and the subsequent extremely limited window of opportunity for assessing any natural physiological response downstream of microneedle insertion.

‘This situation can be remedied through the realisation that real in vivo human skin exists under an natural physiological tension:- by thus assessing and introducing, through the use of Ten Bio’s patented skin culture technology, that same physiological tension to explant skin, we are able to both provide a real human skin platform that reacts to a mechanical force, such as MAP application, just as skin on the body would, but also extend the culture lifetime of our explants to enable evaluation of complex biological responses. Ten Bio’s cultured human skin explant is presented under physiological tension, which extends the useful longevity of the explant beyond a 14-day window whilst retaining a healthy state throughout,’ states Campbell.

‘The tensioned skin platform thus developed, TenSkin™, with its intrinsically extended lifetime, compared with non-tensioned explant counterparts, now opens up the possibility to monitor key physiological processes such as wound healing, immune response and drug delivery in an environment that most closely mimicks true in vivo conditions, and therefore ensuring the reliability and translatability of any research findings.’

To better understand the full range of possibilities that our TenSkin™ system offers the microneedle community, Ten Bio has begun an exciting new collaboration with the research group of Professor Mark Prausnitz at the Georgia Institute of Technology in Atlanta, which has pioneered many of the designs and application avenues in the field. Campbell continues, ‘working directly with one of the world authorities in the development of microneedle technologies represents a priceless opportunity for Ten Bio. Combining the Prausnitz group’s in-depth understanding and broad track record of applications in microneedles with the innovative new TenSkin™ platform will allow us to ascertain the fullest level of improved clinical relevance that this approach affords. Our preliminary findings are certainly positive, and we hope that once the study is completed, this will represent a clear demonstration of the superiority of the TenSkin™ platform over traditional ex vivo alternative substrates for pre-clinical microneedle-based research’.         

Dr Paul Campbell holds an MRC Biomedical Innovation Scholarship facilitating secondment to Ten Bio until 2024.

References

[1] Kim, Y.-C., Park, J.-H., & Prausnitz, M. R. (2012). Microneedles for drug and vaccine delivery. Advanced Drug Delivery Reviews, 64(14), 1547-1568.

[2] Korkmaz, E., Friedrich, E. E., Ramadan, M. H., Erdos, G., Mathers, A. R., & Ozdoganlar, O. B. (2018). Microneedle-based transdermal delivery enables rapid painless induction of protective immunity against influenza virus challenge. AAPS Journal, 20(3), 52.

[3] Chen, X., Prow, T. W., Crichton, M. L., Jenkins, D. W., Roberts, M. S., & Frazer, I. H. (2009). Dry-coated microprojection array patches for targeted delivery of immunotherapeutics to the skin. Journal of Controlled Release, 139(3), 212-220.

[4] Vrdoljak, A., McGrath, M. G., Carey, J. B., Draper, S. J., Hill, A. V. S., O’Mahony, C., & Crean, A. M. (2012). Coated microneedle arrays for transcutaneous delivery of live virus vaccines. Journal of Controlled Release, 159(1), 34-42.

[5] O’Mahony, C., Vrdoljak, A., & Crean, A. M. (2014). Microneedle-mediated intradermal delivery of model macromolecules to human skin explants. Pharmaceutical Research, 31(8), 2168-2178.

[6] Coulman, S. A., Birchall, J. C., Alex, A., Pearton, M., & Hofer, B. (2011). Microneedles and other physical methods for overcoming the stratum corneum barrier for cutaneous gene therapy. Critical Reviews in Therapeutic Drug Carrier Systems, 28(1), 1-57.

[7] Nalluri, B. N., Sharpe, L. A., Tekko, I. A., Sayers, E. J., & Roberts, M. S. (2016). Effect of microneedle array design on the efficiency of transdermal protein delivery into human skin explants. Pharmaceutical Research, 33(1), 233-242.

[8] Ng, W. L., Qi, J. T., Yeong, W. Y., & Naing, M. W. (2018). Proof-of-concept: 3D bioprinting of pigmented human skin constructs. Biofabrication, 10(2), 025005.

May 2023