Hurdles in Translating Science from Lab to Market in Delivery Systems for Cosmetics: An Industrial Perspective

Full text

Advanced Drug Delivery Reviews 205 (2024) 115156
Available online 16 December 2023
0169-409X/© 2023 Elsevier B.V. All rights reserved.
Hurdles in translating science from lab to market in delivery systems for
Cosmetics: An industrial perspective
Sheila Siqueira Andrade
a
,
b
, Alessandra Val´
eria de Sousa Faria
c
, Alioscka Augusto Sousa
d
,
Rodrigo da Silva Ferreira
a
, Nichollas Seram Camargo
b
, Mosar Corrˆ
ea Rodrigues
e
,
Jo˜
ao Paulo Figueir´
o Longo
b
,
e
,
*
a
PlateInnove Biotechnology, Sorocaba, S˜
ao Paulo, Brazil
b
Department of Science and Innovation, Glia Innovation, Goiˆ
ania, Goi´
as, Brazil
c
Department of Biochemistry and Tissue Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil
d
Department of Biochemistry, Federal University of S˜
ao Paulo, S˜
ao Paulo, SP, Brazil
e
Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília, Brasilia, Brazil
HIGHLIGHTS: GRAPHICAL ABSTRACT
•Deep tech start-ups are driving innova-
tion in the cosmetic sector.
•Smart dermal delivery systems promise
new skin disease treatment and
rejuvenation.
•Ongoing innovation is poised to create
beauty products exceeding expectations.
ARTICLE INFO
Keywords:
Translational science
Nanotechnology
Biotechnology
Skin
Cosmetic industry
ABSTRACT
In recent decades, a sweeping technological wave has reshaped the global economic landscape. Fueled by the
unceasing forces of digital innovation and venture capital investment, this transformative machine has left a
signicant mark across numerous economic sectors. More recently, the emergence of ’deep tech’ start-ups,
focusing on areas such as articial intelligence, nanotechnology, and biotechnology, has infused a fresh wave
of innovation into various sectors, including the pharmaceutical and cosmetic industry. This review explores the
signicance of innovation within the cosmetics sector, with a particular emphasis on delivery systems. It assesses
the crucial process of bridging the gap between research and the market, particularly in the translation of
nanotechnology into tangible real-world applications. With the rise of nanotechnology-based beauty ingredients,
we can anticipate groundbreaking advancements that promise to surpass consumer expectations, ushering in a
new era of unparalleled innovation in beauty products.
* Corresponding author.
E-mail address: jplongo@unb.br (J.P.F. Longo).
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/adr
https://doi.org/10.1016/j.addr.2023.115156
Received 12 October 2023; Received in revised form 1 December 2023; Accepted 9 December 2023

Advanced Drug Delivery Reviews 205 (2024) 115156
2
1. Introduction
Over the past decades, the world of technology has witnessed
remarkable advancements that have signicantly inuenced various
economic sectors. These impressive developments have predominantly
emerged from the realm of computational and internet platforms. The
far-reaching effects of this technological revolution can be gauged by the
exponential growth of big-tech digital companies and the substantial
surge in venture capital investments, predominantly directed towards
digital-based start-ups and tech-based spin-offs. These profound changes
have shaped the landscape of the global economy, fostering unprece-
dented opportunities for innovation and growth in all economic areas,
including the pharmaceutical industry and cosmetics [1].
This digital transformative process was triggered during the eighties
when the rst personal computer companies were created, giving access
to the basic instruments and infrastructure needed to start the Internet
movement. Two decades later, smartphones spurred global internet and
cloud tech. This era generated vast, valuable information, beneting all
sectors. Tech companies drove innovations, leading to a thriving funding
industry and value creation [1,2].
For instance, the Start-up Genome Report [3], an important collec-
tion of start-up records, showed that In 2010, 77 % of venture capital
investments targeted digital applications, underscoring global in-
novation’s importance. The venture capital industry matured, exerting
substantial inuence on global innovation trends. Over the following
decade, deep tech investments doubled, rising from 22 % to 45 %, as per
the Start-up Genome Report [3]. Deep tech encompasses AI, blockchain,
life sciences, biotechnology, materials science, nanotechnology, agri-
cultural innovations, and robotics. Pharmaceutical and cosmetic sectors
embraced technology, enhancing research and product development. A
profound understanding of biology, both locally and systemically, is
vital for implementing cutting-edge innovations in translational
research and product development.
Current investment trends indicate that hard sciences, including
companies based on materials science and nanotechnology, are
attracting attention from the venture capital ecosystem [4]. This ten-
dency is conrmed by the last Start-up Genome Report (2023) [3],
which reveals that while all start-up sectors have shown growth over the
last 5 years, deep tech sub-sectors grew 326 % in terms of successful
exits, whereas non-deep tech sub-sectors grew 225 % from 2017 to 2018
to 2021–2022. Moreover, deep tech sectors have also attracted more
Series A investment (35 % increase), in comparison to non-deep tech
companies (21 % increase) [3].
During the SARS-CoV-2 pandemic, all eyes were on vaccine de-
velopers, including the start-up BioNTech. In fact, some of the largest
amounts of venture capital funding ever witnessed were directed to
vaccine development among global pharmaceutical collaborators,
including Genmab, Sano, Genentech, a member of the Roche Group,
Regeneron, Genevant, Fosun Pharma and Pzer.
Additionally, if we follow the list of initial public offers (IPO) of tech
companies in the last few years, there has been a signicant increase in
investment activity, especially within the biotech sector [4,5]. More-
over, we observe that ever more companies with technologies under
development, even early-stages ones, are being targeted by venture
capital funding. This means that hard science development can be car-
ried out not only in traditional universities and research centers, but also
within new start-ups or spin-off companies. We believe that this trend
may have important implications for Ph.D. training strategies, since a
growing number of interesting opportunities will emerge in these types
of organization. Consequently, a new generation of researchers may
assume pivotal roles in research and development processes within
scientic entrepreneurship environments [5,6].
In this context, the current funding scenario is positive for innovation
in the deep tech sectors, which include material sciences and nano-
technologies. Nevertheless, despite this optimistic outlook, various as-
pects still need thorough examination and understanding by both
academic researchers and entrepreneurs in the eld. These consider-
ations are essential for enhancing the efciency of translating knowl-
edge from fundamental scientic research into tangible innovations—an
endeavor that continues to pose signicant challenges in the present
times. Hence, this review article aims to introduce discussions and
highlight key considerations regarding the process of translating science
innovations from the laboratory to the market [7]. As a nanobiotech
group, our discussions will primarily center on the use of delivery sys-
tems for dermal topical applications, including drug delivery and
cosmetic applications.
2. Strategies for translation – Characterization of deep tech
innovation
To begin this section, we dene the term “innovation” to refer to
something new that brings added value. It is crucial to establish this
denition, as true innovation must inherently create value, regardless of
whether it involves the use of technologies or not. Likewise, there exist
numerous technologies that, on their own, may not contribute signi-
cant value and are more appropriately termed as applied science.
However, when we combine exceptional scientic knowledge with
cutting-edge technologies to create value, we can achieve outstanding
innovations. In our discussions, we will focus on science-based in-
novations. Nevertheless, in the present landscape, the development of
deep tech innovation remains a challenge, despite the promising eco-
nomic funding scenario highlighted in the introduction section [8,9].
Within this context, translating deep tech innovations, like various
nanotechnologies, from the laboratory to the market is an arduous and
challenging task. Numerous authors have attempted to shed light on this
matter, and the existing literature consistently points to the intricate and
multidisciplinary nature of this process. Successfully navigating this
innovation journey demands the involvement of professionals from
diverse backgrounds, encompassing expertise in elds such as science,
pre-clinical evaluations, industry-scale up processes, regulation, market
valuation, and more. Given the breadth of expertise required, it is indeed
impractical for a single individual to possess all these skills, highlighting
the signicance of collaborative efforts in the pursuit of innovation.
Therefore, these innovations are often fostered within groups, where
diverse talents and knowledge converge to drive progress and overcome
the challenges inherent in bringing nanotechnology innovations to
market fruition [8].
A crucial initial phase in this context is gaining an understanding of
the primary obstacles that arise during the lab-to-market journey.
Recently, Apodaca et al. (2022) [10] presented an interesting manu-
script, outlining common challenges faced by deep tech ventures,
including nanotechnology. The authors identied specic criteria that
these ventures typically encounter during their innovation development
journey. These dening parameters are broadly characterized by a high
degree of uncertainty, which is inherent to the environment where deep
tech ventures emerge (Fig. 1). Next, we will expound upon these pat-
terns as outlined by the authors.
2.1. Incorporate cutting-edge science or technology to drive innovation
The uncertainty involved in creating something that has, in theory,
never been developed before poses an intrinsic challenge for deep tech
innovations. In that regard, one of the main challenges within the
innovation process is to understand the biological behavior of the new
materials, especially nanomaterials. For example, potential adverse ef-
fects or instability issues can appear during development and testing of
the new material. Furthermore, pre-clinical [11,12] and clinical [13,14]
testing constitutes a pivotal phase in validating preclinical in vitro
ndings. It is crucial to highlight that in the context of dermocosmetic
applications, most markets have moved away from animal testing. As a
result, the substantiation of concepts primarily occurs through clinical
investigations.
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Advanced Drug Delivery Reviews 205 (2024) 115156
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2.2. Deep tech regulatory uncertainty
All the following challenges pertain to the nature of cutting-edge
technologies, particularly new materials. Understandably, the regula-
tory authorities carry doubts related to the safety and efcacy of der-
mocosmetic applications involving novel materials [15]. Questions
related to the biopersistence of the materials are difcult to predict using
traditional regulatory analysis methods. A notable example of this
challenge can be found in the case of COVID-19 vaccines, which were
analyzed by groups of regulatory analysts, in a kind of analysis task force
to approve the vaccine products in record time [16]. Thus, regulatory
uncertainty is a typical obstacle for the translation of deep tech in-
novations from lab to the market.
Furthermore, the timeframe for regulatory analysis can be difcult to
predict, since several of the proposed innovations could be at the
interface of different regulatory areas. For instance, dermal topical ap-
plications can be regulated by either the cosmetic or new drugs sectors.
For most of the regulatory agencies, if the active ingredient is not
absorbed into the bloodstream, the product can potentially be analyzed
as a cosmetic product. However, if the active ingredient reaches the
blood circulation after skin permeation, it should be regulated as a
pharmaceutical drug. For these two possibilities, eventually the same
basic technology is applied. And when innovation involves new prop-
erties, it may necessitate entirely new regulations. An example of this
were the mRNA vaccines, which underwent special analysis due to their
novel characteristics [17].
Another important consideration during the development of these
innovations for dermocosmetic applications is their long-term stability
and their resilience under various physical stress conditions. Predicting
the meta-stability of materials developed using cutting-edge knowledge
is often challenging, and not too easy to be done nowadays. Currently,
most regulatory agencies rely on conventional stability studies, along
with rheological and constitutive analysis, to assess product stability for
these innovative materials. For the nanomedicine applications, there is
ongoing discussions about the appropriate methodologies for under-
standing nanomaterials behavior overtime [15]. However, in the
context of dermocosmetic applications, conventional regulatory
methods continue to be employed to validate and ensure the quality of
the developed materials.
2.3. Industrial scale-up of material science and nanotechnology
innovations
The industrial scale-up of material science and nanoparticle in-
novations presents numerous challenges, particularly concerning the
preparation method and/or the long-term stability of the new material
being produced [7]. For instance, when producing larger batches, it can
be difcult and costly to use organic solvents, often used for nano-
material preparations. This is due to the potential toxicity of solvent
traces or the high costs associated with solvent removal during indus-
trial production.
Moreover, several challenges specic to the nanoscale arise, such as
hyper reactivity, ltration, and regulatory considerations. For instance,
nanoparticles exhibit heightened reactivity, leading to destabilizing in-
teractions with both production reactors and even with other nano-
materials just produced. Not by chance, most of the nanomaterials
industrially produced for dermo-cosmetic applications are of lipid
origin. These materials can be scaled-up without the use of organic
solvents, with colloidal stability achieved with stabilizing surfactants
[7,18].
2.4. Market uncertainty and user acceptance as innovations become
available for widespread use
Humans are usually enthusiastic about innovation and novelty, but
when these innovations interact with their bodies, perceptions can
change. This is not unexpected, particularly when new substances,
chemicals, or materials at the frontier of knowledge come into direct
contact with our bloodstream. This poses a signicant challenge that has
emerged in recent years, as we observed during the development of the
COVID-19 vaccines.
To overcome this potential issue, one strategy could involve devel-
oping nanocarriers with well-known ingredients already listed in in-
ternational pharmacopeias. This strategy could reduce potential
aversion and streamline regulatory analysis required for product
authorization. This approach has also been discussed in the scientic
literature [15,19]. Moreover, this aspect remains intricately tied to the
regulatory oversight of emerging technologies. Ultimately, under-
standing the use of novel technologies for improving human health
necessitates a comprehensive educational effort involving all stake-
holders, encompassing the general public, regulatory bodies, industries,
Fig. 1. Common challenges faced by deep tech ventures, including nanotechnology ventures. Figure made in part with BioRender.com.
S. Siqueira Andrade et al.

Advanced Drug Delivery Reviews 205 (2024) 115156
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and researchers at the forefront of these innovations.
2.5. Section 2 summary
We have identied four primary challenges encountered by deep
tech innovations: incorporating cutting-edge technologies, regulatory
uncertainty, Industrial scale-up production, and addressing market un-
certainties. Successfully translating deep tech innovation from the lab to
the market necessitates a careful consideration of these challenges
across these four domains. It is crucial to emphasize that these chal-
lenges are commonly experienced by innovative companies throughout
their translation journey.
3. Delivery systems for cosmetics – Examples for lab-to-market
translation
3.1. Why nanotechnology for cosmetics applications
In a historical retrospective, the rst nanotech cosmetic products
were developed during the 1980 s. As a pioneering industry, the cos-
metics industry, represented by big companies like Dior, released their
rst products to the market in 1986 [20,21]. During this period, these
companies developed liposomes to protect and extend the shelf life of
active cosmetic ingredients. For comparison, the rst pharmaceutical
nanotech product, Doxil™, was launched on the market in 1994, almost
10 years later [22–24]. This is an important indicator of the cosmetics
industry’s strong desire for innovation. Nowadays, the cosmetics in-
dustry stands as one of the largest users of nanomaterials in the world,
employing both inorganic materials like titanium dioxide and zinc
oxide, which are among the most important nanomaterials in terms of
volume used, and organic nanocarriers like liposomes, lipids, and
polymeric nanoparticles [21].
The motivations behind the use of nanoparticles to improve the
effectiveness of cosmetic products are diverse, and include: (1) protec-
tion of the active ingredient carried; (2) controlled release of one specic
active ingredient over the skin (Fig. 2); (3) increased time of contact
between the active ingredient and the skin; (4) permeation of the skin’s
deeper layers; and (5) delivery of entrapped content to target cells, a
feature that has been of interest within the topical application area. In
other words, the use of nanoparticles aims to improve the effectiveness
of cosmetic active ingredients during topical application [21,25].
Enhancing the stability of active ingredients is a pivotal factor justifying
the utilization of nanomaterials as protective systems. This character-
istic provides long-term stability for molecules prone to instability, such
as peptides or small compounds like ascorbic acid. Nanoencapsulation of
these unstable active molecules stands out as one of the most prevalent
strategies employed to prolong their shelf life [21,26].
Christian Dior (1986) and Lancˆ
ome, the luxury division of L’Or´
eal
(1995), were pioneers as the rst cosmetic companies to embrace the
high-performance potential of nanotechnology. Following their lead,
industry giants such as Est´
ee Lauder and Chanel incorporated nano-
structured delivery systems into their technological advancements [28].
Following these industry leaders, several nanotech raw material
producers, such as Glia Innovation, developed cost-effective production
methods. These methods facilitated the creation of less complex nano-
formulations, such as nanoemulsions and solid lipid nanoparticles.
These formulations were adopted by numerous medium and small
companies in the cosmetic market. The incorporation of these nano-
systems proved vital in providing technological differentiation to these
emerging cosmetic industries. This trend also led to more complex in-
novations, such as the inclusion of target peptide over nanoparticle
surfaces. These peptides guide the nanoparticles to specic cells,
enhancing the safety and effectiveness of topical dermal products [29].
As we will explore in the following sections, it becomes evident that
improving the effectiveness of topical products continues to pose a sig-
nicant challenge. Addressing this challenge necessitates extensive
collaboration between academia and industry, involving regulatory
analysts and industrial chemical engineers, all with the shared goal of
enhancing the functionality of topical skin-applied products. The
complexity of this challenge stems from the intricate nature of human
skin, which serves as the body’s formidable barrier against external
substances, including nanomaterials used in topical applications.
Given its multi-layered cellular structure, crossing the skin barrier is
not a trivial task for any kind of external element, including these
innovative nanocarriers. Moreover, due the lipophilicity of the external
epidermal layers, only small and hydrophobic components can more
easily permeate this organ. That is why the delivery of molecules of
interest to deeper layers is so challenging. In what follows, we will
provide a brief overview of key structural aspects of human skin and
address ways through which nanoparticles can interact with these
structures (Fig. 3) [30].
3.2. Structure and components of the skin
The skin encompasses the entire external surface of the human body.
It is a complex organ comprising three primary layers of compartments:
the epidermis, composed mainly of keratinocyte under degeneration;
the dermis, composed of the connective tissue and broblasts; and the
hypodermis (or subcutaneous tissue), where the adipose tissue is placed.
Each layer serves unique functions and contains various cell types
[31,32]. The skin serves as a protective barrier against various external
factors, such as pathogens, ultraviolet (UV) light, chemicals, and me-
chanical injuries [31]. Additionally it plays a crucial role in regulating
body temperature and controlling the release of water into the
Fig. 2. Controlled release of active ingredients mainly mediated by diffusion. In panel A, the release prole of liposomes containing an active ingredient during bag
dialysis. The methodology was adapted from a previous publication by our research group [27]. In panel B, the controlled release is represented by a lipid nanocarrier
with active ingredients displaced inside the nanostructure and the diffusion movement to the external compartment. Figure made in part with BioRender.com.
S. Siqueira Andrade et al.

Advanced Drug Delivery Reviews 205 (2024) 115156
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environment [33]. Each of these layers has unique anatomical and
functional characteristics.
3.2.1. Epidermis
The epidermis is the outermost layer of the skin and acts as a
formidable barrier against environmental hazards [30]. It consists
mainly of keratinocytes, which produce keratin, a protein that provides
structural integrity to the skin [30,32]. The interesting point is that these
keratinocytes are produced due to the division of local epidermal stem
cells, located at the basal epidermal layer. These cells migrate to the
surface due to the proliferation of the basal cells, and during this journey
they produce keratin, and die when they reach the surface layers. After
dying, the keratinocytes are a package of keratin encased in a hydro-
phobic phospholipid membrane, which was originally the cell mem-
brane. This is the reason why the skin is very impermeable to water.
Moreover, the epidermis also produces melanin, the pigment respon-
sible for skin color and UV protection [34]. The deposition of nano-
materials over the skin surface in high concentrations aims to produce a
deposit of compounds that could potentially diffuse this external
epidermal barrier, or eventually a small portion of these nanomaterials
could permeate among the dead keratinocytes, thus increasing the
transport of these materials through these outer layers of the skin.
Moreover, some nanostructured carriers can deform and penetrate the
skin through small channels formed among the keratinocyte cells [35].
The epidermis is non-vascularized and separated by a basement mem-
brane from the underlying zone of highly vascularized connective tissue,
called the dermis. The dermo-epithelial zone is not linear, but rather is
an interdigitated interface. Keratinocytes form the rete ridges, which
protrude into the dermis. Concurrently, between these rete ridges, the
dermis extends upward and forms the epidermal-dermal structure,
which provides the oxygenation and nutrition of this non-vascularized
layer [36].
3.2.2. Dermis
The dermis lies beneath the epidermis and is primarily composed of
broblasts and the extracellular matrix (ECM), which is formed mainly
by collagen, elastin bers, and some glycosaminoglycans, such as hy-
aluronic acid. These ECM structures provide the skin with strength,
exibility, and elasticity. This layer also houses blood vessels, nerves,
hair follicles, sweat glands, sebaceous glands, and immune cells [30]. It
plays a crucial role in thermoregulation by controlling blood ow and
the release of sweat. Glands within the dermis present both a challenge
and an opportunity for topical applications of delivery systems. The
challenge arises from their secretions, which can “wash” away materials
applied to the skin, reducing delivery effectiveness; and the opportunity
is related to the special anatomical structures within these appendices
that nanoparticles can access. Using this pathway, delivery systems have
a better chance to permeate the skin structures. One of the primary
objectives of using nanoparticles as carriers for active ingredients is to
prolong the contact time between the compound carried and the cell
structures. In this way, the material has a higher chance to diffuse
through the keratinocytes, thus increasing the delivery of the active
ingredient.
Moreover, the nanoscopic size of nanocarriers facilitates their
Fig. 3. Schematic description of the complex structure of human skin. The human skin is mainly structured in three layers: epidermis, dermis, and hypodermis.
The epidermis is further divided into four layers: stratus corneum (most external layer), stratum granulosum, stratum spinosum, and stratum basale (most internal
layer) –highlighted on the left. The dermis contains various cells (predominantly broblast, and microvascularization is guaranteed by the presence and organization
of endothelial cells) and the extracellular matrix enriched with collagen, elastic bers, and glycosaminoglycans. Highlight: desmosomes play a crucial role in
maintaining tissue integrity by forming strong extracellular bonds anchored to the resilient cytoskeleton. The hypodermis primarily consists of preadipocytes and
adipocytes. Figure made with BioRender.com.
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Advanced Drug Delivery Reviews 205 (2024) 115156
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interactions with special anatomical spots created close to the sebaceous
gland and hair follicles. Additionally, these spots become a kind of
reservoir of nanomaterials, signicantly increasing their interactions
with underlying skin structures. Regarding skin vasculature, it is
important to note that endothelial cells (ECs) in the skin (cells that shape
dermal microvessels) share biochemical/molecular features common to
all ECs in the body. They express vWF, the single most widely used
marker for vascular endothelium, which is found in Weibel-Palade
bodies or in the biosynthetic organelles within these cells. Addition-
ally, the expression of CD31, also known as the platelet-endothelial cell
adhesion molecule [PECAM]-1, is shared between both endothelium and
platelets. CD31 is also found in circulating leukocytes. In addition, skin
blood capillaries (as well as capillaries in most other organs) express
vascular endothelial growth factor receptor (VEGFR)-1, −2, and −3. The
expression of all these markers, along with the organization of ECs in the
skin, results in a vasculature system that is unique in several aspects. The
skin contains several functionally distinct vascular units, including loops
within the tips of the papillae, epidermal-dermal ridges, and the sub-
cutaneous plexus. These vascular segments can respond to exogenous or
endogenous triggers individually or conjointly, thereby adapting to the
skin’s specic requirements for oxygenation and nutrition [37,38].
3.2.3. Subcutis or subcutaneous fat
The subcutis, also known as hypodermis or subcutaneous fat, is the
deepest layer of the skin, composed mainly of fat cells (preadipocytes
and adipocytes) and connective tissue. This layer is not part of the skin’s
primary protective barrier, but its roles include fat storage (providing
cushioning and energy storage for the body [39]), connecting the dermis
to muscle and bone, and controlling body temperature [40]. Increased
vascular activity in the dermis can indirectly affect this layer, making its
metabolism more active [41]. Blood vessels, nerves, lymph vessels, and
hair follicles cross through this layer. The thickness of the subcutis layer
varies throughout the body and from person to person.
3.3. Section 3 summary
The skin is a multilayered cell tissue that provide a stable environ-
mental barrier, integrated network of cytoskeletal elements and cellular
junctions. The skin ranks among the body’s most dynamic tissues,
continually regenerating itself and responding to cutaneous insults. The
skin also plays a role in immunologic surveillance, sensory perception,
control of insensible uid loss, and homeostasis in general [42]. As a
multifaceted tissue, with a selective, highly adaptive, self-regulated and
consistent barrier, the skin imposes several obstacles for topical appli-
cation, and to penetrate this intelligent tissue, nanotechnology appears
as an effective, powerful, and multi-scale delivery solution.
4. Science-based deep tech nanoparticles translated from lab to
market for topical skin applications
The cosmetics industry was a pioneer in introducing nanotechnology
products to the market. However, when we examine the investment
landscape for research and innovation, a notable discrepancy emerges
between the cosmetics and pharmaceutical sectors. In particular, the
pharmaceutical industry has made substantial nancial investments
towards the development and application of advanced nanoparticles,
particularly in critical areas such as cancer and immunotherapies
(including vaccines). The predominant focus of the nanotech sector on
pharmaceutical applications is hardly unexpected, considering the
immense potential that nanotechnology holds in advancing the diag-
nosis and treatment of severe diseases and pathologies [43].
As a result of the trends identied, a signicant proportion of de-
livery systems used in dermal cosmetics are alternative applications of
technologies originally designed for systemic drug administration and
other related domains. Most skin delivery systems in current use pre-
dominantly rely on classic lipid-based vesicles, such as liposomes and
micelles, as well as polymeric nanocapsules [44–46]. Still, the true po-
tential of these classic delivery systems has not yet been fully explored
within the cosmetics sector.
In line with the pharmaceutical industry’s trajectory, the utilization
of small biological molecules, including peptides and oligonucleotides,
probably will be pivotal trend for the cosmetic industry. This evolution
mirrors the shift in the pharmaceutical sector from small synthetic
molecules to small biotech molecules. The remarkable achievements of
peptide-focused pharmaceutical companies and the expanding applica-
tions of RNA and DNA in the therapeutic eld have propelled this
transition. It is likely that the cosmetic industry will follow suit, delving
into the development of novel compounds rooted in small biomolecules
to serve as active ingredients in cosmetic products.
Simultaneously, the growing demand for innovation from the cos-
metics companies has impelled emerging nanobiotechnology rms to
drive the development of innovative products tailored for dermal de-
livery applications [47]. Current advancements in dermal innovations
again draw inspiration from technologies initially conceived for phar-
maceutical applications. For us in the eld, this strategy has proven
exceptionally valuable, as it capitalizes on well-established scientic
foundations that have already reached advanced stages of development.
4.1. Opportunities for nanotechnology in dermocosmetics
Two critical issues concerning the development of successful nano-
technologies for use in dermal cosmetics revolve around (1) under-
standing the cell biology of aging cells in the epidermis and dermis and
(2) addressing the structural and biological stability of bioactive pep-
tides used for tissue regeneration and skin renewal. Despite the com-
plexities involved, both vital issues can be effectively addressed through
the application of upgraded and advanced nanotechnology approaches.
Regarding the rst concern (1), studies have shown that in numerous
diseases and even in the aging process, the ECM, which profoundly in-
uences all aspects of cell behavior, undergoes damage, alteration, or
loss [48–50]. The microenvironment in diseased or aged tissues differs
signicantly from a healthy ECM, both in terms of abnormal biochem-
ical components and distinct mechanical properties. Consequently,
when cells, such as endothelial stem cells, are recruited in such envi-
ronments, they receive abnormal cues from the ECM. Even in cases
where mesenchymal stem cells are delivered, inltrating cells nd
themselves exposed to a diseased or aged ECM, hampering their ability
to facilitate tissue repair [50]. Hence, there exists signicant potential
for advanced nanotechnology systems, such as targeted nanocarrier
systems incorporating bioactive molecules, to promote skin rejuvena-
tion by facilitating tissue regeneration, cell renewal, and ECM
remodeling.
Concerning the second point (2), ensuring the structural and bio-
logical stability of peptides is critical in any delivery application. In this
regard, the performance of non-targeted nanocarrier systems may be
suboptimal as they might ineffectively deliver peptides to unintended
locations. Conversely, bio-guided controlled release systems, designed
to interact with specic receptors, have the potential to deliver peptides
precisely to the correct location, mitigating issues related to peptide
stability.
To conclude, the dermocosmetics sector presents numerous exciting
opportunities for nanobiotechnology products to make a substantial
impact. In particular, we recognize an urgent need to develop effective
nanotechnology-based delivery systems engineered to fully leverage the
potential of drug encapsulation and targeted release in dermocosmetic
applications. Such systems hold the promise of tackling various issues,
including the aging process of the skin, more effectively.
4.2. Drawing inspiration from biology
Innovation enterprises are leading in a new era of nanoscale active-
delivery systems specically designed for topical skin applications.
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Advanced Drug Delivery Reviews 205 (2024) 115156
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These original systems draw inspiration from biological designs and are
poised to enhance the performance of dermocosmetic products.
Our group has developed solutions rooted in the biological activities
of platelets. Platelets, which are unique anucleate cells generated during
hematopoiesis, are central players in several homeostatic processes
crucial for tissue stability and maintenance. The multilayered func-
tionality of platelets encompasses various biochemical domains: (i) they
actively contribute to blood clotting and help control bleeding; (ii) they
supply an array of angiogenic and non-angiogenic factors, inducing the
process of angiogenesis; (iii) they assume a pivotal role in wound healing
and tissue regeneration; (iv) they transport soluble factors that facilitate
cell recruitment and phenotype transition required for tissue regenera-
tion; and (v) they modulate immunological processes, regulating both
pro- and anti-inammatory responses [38].
Platelets harbor a distinct reservoir of biochemical content,
including growth factors, which prove invaluable for several natural
biological processes occurring in the skin [51,52]. In this manner,
platelets can be considered an excellent model to inspire creativity and
innovation in the cosmetics industry, especially in the pursuit of pro-
moting skin renewal in a more genuine and natural approach [52].
Platelet biology thereby emerges as a vital source of information for the
advancement and innovation of dermocosmetic products, with a specic
focus on regenerative processes.
Additionally, polymeric nanocarriers developed as delivery vehicles
draw inspiration from the natural processes of cellular communication
[53]. In essence, the functioning of every living organism is dependent
upon a complex set of interactions among different individual cells.
These cells release essential biomolecules, including cytokines, chemo-
kines, and growth factors, along with nano-/micro-structures like
extracellular vesicles that carry numerous bioactive molecules and
surface receptors [52]. The extracellular vesicles engage with target
cells and transmit information through a combination of processes,
including ligand/receptor signaling at the cell surface as well as mem-
brane fusion and endocytosis for the intracellular delivery of vesicular
cargoes. Subsequently, intracellular signaling amplies the received
information, ensuring the execution of a specic cellular response. The
ultimate outcome of this signal transduction process manifests as
changes in cell metabolism, which may include cell growth, survival,
death, proliferation, differentiation, and morphologic changes [54].
For the nanotech investigator, small vesicles serve to transport bio-
logical information and biological content from one site to another.
Hence, our group has developed polymeric nanocarriers to be dispersed
onto and penetrate topical tissues. Moreover, our nanocarriers are
encapsulated with platelet-inspired bioactive peptides to promote tissue
remodeling and regeneration. This approach mirrors the natural cellular
processes by which cells transport essential biomolecules and commu-
nicate with one another within both micro- and macro-environments.
Additionally, our use of platelet-derived molecules mirrors the role
platelets play in tissue regeneration and repair [29].
4.3. Innovation journey
Given the above considerations, we undertook a successful journey
by adopting a platelet-based approach to creating innovative products.
This innovation journey is presented here to illustrate the development
of such products within the cosmetics sector.
Among our achievements is an innovation we refer to as Skinalized
Nanospheres, a creation that consists of bio-guided polymeric nano-
particles carrying biomimetic peptides (bio)inspired by platelet-derived
growth factors [29,51]. The incorporated peptides are developed and
engineered taking a “biotech-educated platelet platform” as the source
of inspiration [52]. These platelet-based peptides naturally act as inter-
cellular communication signals, improving natural physiological events,
such as tissue regeneration, cell renewal, and ECM remodeling, all of
them very important for dermal cosmetic applications. This approach to
innovation led recently to the registration of two novel peptides in the
international cosmetics pharmacopeia, the INCI (International Nomen-
clature of Cosmetic Ingredients) [55].
To lay the groundwork for our innovation, Skinalized Nanospheres,
we rst created a corresponding cell culture scaffold, here dened as the
Skinalized Matrix. This specialized matrix was capable of both entrap-
ping and releasing active biomolecules. As illustrated in Fig. 4A, we
cultivated a monolayer of Human Umbilical Vein Endothelial Cells
(HUVEC) over this scaffold to assess the impact of the released bio-
molecules on HUVEC proliferation and migration. Within this experi-
mental setup, we employed two key biomolecules, namely human von
Willebrand factor (vWF) and cathepsin S (Cat S) [40]. The interactions
and actions of vWF and the cysteine protease Cat S are intricately con-
nected and have been extensively discussed in the context of angio-
genesis, dened as the migration and proliferation of endothelial cells
for the growth of new vessels from existing ones [56,57]. The presence
of vWF and Cat S into the Skinalized Matrix prompted substantial
structural cellular rearrangements, including altered anchoring and
adhesion patterns compared to standard plastic surfaces (Fig. 4B-C).
Within just 24 h of HUVEC culturing, the system demonstrated the
ability to create three cues for contact guidance and induce alterations in
the organization of HUVECs. This was evident through detection of the
endothelial biomarker platelet cell adhesion molecule-1 (PECAM-1)/
CD31, visualized in red using confocal microscopy (Fig. 4D-F). There-
fore, products inspired by platelet biology hold the potential to offer
practical biotechnical solutions for angiogenesis, with direct implica-
tions for the processes of migration and differentiation, to ensure tissue
renewal.
Inspired by all the platelet attributes in relation to wound healing
and tissue regeneration, the next step in our innovation journey involved
the development of an advanced scaffold system, termed InGrowth-Bio,
supplemented with Skinalized Nanospheres. The InGrowth-Bio scaffold
system includes collagen type I, brinogen, and bronectin. In addition,
this matrix system is polymerized at physiological temperature (37 ◦C)
through the proteolytic action of proteases from secreted target cells.
This base matrix provides the required functionality to allow for cell
adhesion, growth, and remodeling. Skinalized Nanospheres, in turn,
incorporate two platelet-based angiogenic growth factor peptides,
which were designed by us taking into account the heparin binding re-
gions of vascular endothelial growth factor (VEGF) and epidermal
growth factor (EGF). Both biomimetic peptides are also appended with
RGD sequences to support further interactions with cells.
The rational design of biomimetic peptides and their integration into
specialized transport systems, such as Skinalized Nanospheres, should
be complemented by quantitative biophysical measurements to validate
peptide-receptor interactions. Within our research group, we employ
surface plasmon resonance (SPR) spectroscopy as a robust tool for
characterizing the afnity of interactions between newly designed
peptides and receptors of interest (like the VEGF receptor) (Fig. 5). In
this technique, receptors are immobilized on a ‘chip’ sensor surface,
while the analyte suspended in buffer is own over this surface. The
interactions are monitored in real-time and in a label-free manner by
detecting signal changes (refractive index changes) through the sensor
surface. These attributes make SPR widely adopted within the phar-
maceutical industry as a convenient method for testing and ranking
various drug molecules based on their binding to receptors of interest.
Likewise, SPR enables us to evaluate multiple peptides efciently in a
systematic and automated fashion, so that the peptide with the most
favorable binding parameters can be selected for further use.
Implementation of the InGrowth-Bio scaffold in combination with
Skinalized Nanospheres yielded remarkable outcomes. Overall, this
platelet-based synthetic approach not only facilitated the proliferation
of HUVEC cells in 2D cultures but also orchestrated the development of a
microvascular network structure in 3D cultures within a brief period of
3 days, all without the need for the addition of recombinant growth
factors (Fig. 6 and Fig. 7). These results signicantly outperformed those
achieved using brin as a base matrix alone (Fig. 6). In addition, these
S. Siqueira Andrade et al.

Advanced Drug Delivery Reviews 205 (2024) 115156
8
ndings may also spark further exploration into the intricate interplay
between sprouting neo-vessels in the surrounding stromal matrix and
platelet-based biomolecules. Understanding this complex relationship
could prove essential for dissecting the maturation and morphogenic
control mechanisms governing the development of vasculature within
dermal microcirculation [58–60].
In addition to the encapsulation and release of active biomolecules
from polymeric nanocarriers, a fundamental aspiration within the eld
of nanotechnology is to precisely control the delivery of molecular
cargoes to specic target cells. Therefore, the nal step in the develop-
ment of our delivery platform involved investigating the hypothesis that
Skinalized Nanospheres could deliver active peptides to these
Fig. 4. The Skinalized Matrix system supports innovation in dermal delivery applications. (A) Graphical representation of the Skinalized Matrix system and its
impact on HUVECs. (B) Phase-contrast image of HUVECs cultured for 24 h on collagen-type I scaffold treated with vWF, cathepsin S, and VEGF peptide. Analysis of
the region marked in yellow is shown in panels D) through F). (C) Phase-contrast image of untreated HUVECs as control. (D-F) Confocal microscopy imaging of
HUVEC re-organization after vWF and Cathepsin S exposure using indirect immunouorescence for nucleus staining (DAPI, D) and endothelial cell staining (CD31/
PECAM-1, Alexa-594, E), with overlay of images shown in F). Scale bars, 20 µm. Antibodies were from Thermo Fisher Scientic (MA, USA). Images were captured
using a Zeiss LSM510 scanning inverted confocal microscope and analyzed with LSM Image Browser 3.2 software (Zeiss, Oberkochen, Germany). Figure made, in
part, with BioRender.com. (For interpretation of the references to color in this gure legend, the reader is referred to the web version of this article.)
Fig. 5. Schematic illustration of SPR assay for evaluating peptide-receptor binding efciency. (A) Schematics of SPR sensor surface showing immobilized
receptors, peptide interactions, and label-free detection via refractive index changes. (B) SPR sensorgram plot showing response signal (resonance units) over time.
The stages of analyte-ligand interaction analysis encompass association (2), equilibrium (3), dissociation (4), and surface regeneration (5). Figure made, in part, with
BioRender.com.
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Advanced Drug Delivery Reviews 205 (2024) 115156
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Fig. 6. ECM-mediated guidance of HUVECs for tissue repair. (A) Schematic illustration of a vessel system comprising InGrowth-Bio plus Skinalized nanospheres
encapsulated with VEGF and EGF peptides. This system mimics a platelet-derived matrix, serving as a scaffold to create 3D structures within a mixed cell envi-
ronment. ECM stiffness, degradability, and adhesive properties can inuence the transition of blood vessel-forming cells between multicellular and single-cell
migration modes. While single cells rapidly inltrate new regions, multicellular migration is necessary for collective blood vessel formation. InGrowth-Bio with
Skinalized nanospheres promotes the formation of blood-vessel structures, crucial for tissue repair. (B) HUVECs were cultured at a density of 3.0 x 10
3
cells/well
(RPMI, 10 % FBS, 1 % 100 U/mL penicillin, 100
μ
g/mL streptomycin) for 24 h. Subsequently, InGrowth-Bio was added to the wells and incubated for 24 h. Thrombin
(1U/mL), Skinalized nanospheres containing VEGF and EGF peptides (20 and 40 ng), and InGrowth-Bio (25 %) were added to the wells and cultured for an additional
24 h. Afterwards, the incubation medium was removed, and HUVECs were xed with PFA (4 % PBS) for 10 min, washed with PBS, permeabilized with Triton X-100
(0.1 % PBS), and blocked with BSA (3 % PBS) for 1 h. Cells underwent three PBS washes and were incubated overnight at 4 ◦C in a humidied chamber with
ActinGreen™ 488 ReadyProbes™ Reagent (AlexaFluor™ 488 phalloidin) and DAPI (Thermo Fisher Scientic, MA, USA), at a 1:1000 dilution for 1 h. Images
captured using Luma Scope microscope (Etaluma Inc, Carlsbad, CA, USA) at 10X magnication (scale bar, 100 µm). (C) Same as (B), except that no HUVECs were
added as a control. (D) Results obtained using a commercial competitor vessel system (Merck, USA). (E) Contrast-phase microscopy imaging illustrates 3 days of
HUVEC culturing within InGrowth-Bio matrix with Skinalized nanospheres. Figure partially created with BioRender.com.
S. Siqueira Andrade et al.

Advanced Drug Delivery Reviews 205 (2024) 115156
10
endothelial cells within a mixture of diverse skin cell types. To conduct
this investigation, we exposed a mixture of various cell types – including
endothelial cells, epithelial/keratinocytes, broblasts, and platelets – to
the Skinalized Nanospheres, which were loaded with a platelet-based
peptide. This specic peptide interacted with the platelet-endothelial
cell adhesion molecule 1 (PECAM-1/CD31) integrin as well as with
the VEGF receptor (albeit weakly). The PECAM-1/CD31 integrin serves
as an anchor for VEGFR1 and plays a critical role in regulating the
proangiogenic properties of endothelial cells by modulating cell–cell
and cell-matrix interactions through its anchorage to VEGFR1 [59]. To
detect specic targeting of the Skinalized Nanospheres to endothelial
cells, we marked the PECAM-1/CD31 integrin with a monoclonal anti-
body and analyzed the mixed cell population by ow cytometry (Accuri
C6, BD, USA). The results conrmed the remarkable precision and ef-
ciency of the Skinalized Nanosphere system in targeting endothelial
cells within a heterogeneous cell population (Fig. 8).
4.4. Section summary - innovation wrap-up
In summary, our research group has developed a robust synthetic
system poised for innovative applications in dermatology and skin care.
This system takes its inspiration from the intricate eld of platelet
biology, where platelets play a central role in promoting tissue regen-
eration and renewal. The translation of the multifaceted complexity
inherent to platelet biology into a synthetic platform became possible
through the implementation of our superior bio-scaffolds, such as
InGrowth-Bio, coupled with the use of complex systems, such as Ski-
nalized Nanospheres carrying platelet-based growth factor peptides.
This system has the capacity to deliver bioactive peptides to specic
endothelial cells within a heterogeneous cellular milieu, and ultimately
to promote the essential angiogenesis process required for tissue repair
and regeneration.
Translating advanced systems, as discussed in this article, presents
Fig. 7. InGrowth-Bio plus Skinalized nanospheres containing VEGF and EGF peptide scaffold for HUVEC culturing. The InGrowth-Bio plus Skinalized
nanospheres containing VEGF and EGF peptides mimic a scaffold matrix for HUVEC culture, providing an environment for building a vascularization network
(indicated by blue arrows). Representative images of three independent experiments are shown. Images were taken by LumaScope microscope (Etaluma Inc,
Carlsbad, CA, USA) at a 10X magnication (scale bar 100 µm) after 24 (A) and 72 (B) hours of culturing. (For interpretation of the references to color in this gure
legend, the reader is referred to the web version of this article.)
Fig. 8. Specic cellular targeting with Skinalized Bio-Guided nanospheres. A mixed cell population was exposed to Skinalized Bio-Guided nanospheres (25 µg/
mL) containing a platelet-based peptide capable of binding to the PECAM-1/CD31 integrin on endothelial cells. The incubations were performed at 37 ◦C for 3.5 h.
Skinalized nanospheres lacking the peptide were used as a control. The cell mix population was subsequently washed and stained with receptor-specic antibodies or
isotype control antibodies to selectively identify different cell types. Flow cytometry analyses were performed using an Accuri C6 ow cytometer. (A) The bar graph
depicts normalized median uorescence intensities for cells treated with Skinalized Bio-Guided nanospheres vs. control nanospheres. Statistical analysis was per-
formed by paired t-test (*p <0.001). (B) Forward- and side-scatter proles of events in the cell mix population, with populations identied by further gating based on
PECAM-1/CD31-. The histogram in the lower panel represents control staining using an isotype-matched control antibody. (C) Same as (B), with populations
identied by further gating based on PECAM-1/CD31 +. Each gure represents the analysis of 10,000 events with SSC (side scatter) on the abscissa and APC
uorescence intensities on the ordinate.
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Advanced Drug Delivery Reviews 205 (2024) 115156
11
challenges, especially in the industrial scale-up of delivery methods.
Two major hurdles include scaling up polymeric nanoparticles, a tech-
nological challenge, and producing peptides in large batches. Existing
protocols, described in the literature, involve methods like solvent
displacement followed by tangential ltration to produce polymeric
nanoparticles [7,61]. For this point, there are different useful strategies
for polymeric nanoparticle industrial scale up. Regarding the second
challenge, involving peptide production, there are three primary tech-
nology trends for a near future: (1) optimizing synthetic peptide pro-
duction through investments in more efcient instruments and
machinery for sequence synthesis.
For this last point, the synthesis performance aims to be more pro-
ductive, and reduce the use of organic solvents; (2) exploring an alter-
native pathway utilizing biotechnology and fermentation processes; and
use of synthetic biology for peptide production. The latter options
probably will offer a cleaner production methods, as they use less
organic solvents [62,63]. However, these two options still have prob-
lems in the peptide preparation, since some unexpected biomolecular
modications could be placed during the biotech production.
Moreover, some interesting innovative strategies are on the horizon
to overcome these challenges such as a more efcient biochemical
production approach for higher titer and purity of peptides and proteins
at the industrial scale [65]. When it comes to in silico design, even the
most effective design strategies should include an experimental valida-
tion step. For this reason, rational peptide design and library screening
should go together to maximize the quality (purication degree) and
bioactivity of new bio-peptide. Therefore, having different protocols
available may be the best way to achieve adequate large-scale peptide
production.
5. Conclusion
Nanotechnology-based beauty ingredients are rapidly gaining access
to mass markets, driven in part by the expression “science sells” – a
response to the growing demand for advanced beauty products among
consumers [64]. Indeed, we live in an extraordinary era, characterized
by the convergence of diverse scientic disciplines. This convergence
has equipped researchers with a formidable array of sophisticated tools,
allowing them to explore and develop innovative solutions. These tools
encompass nanotechnology, OMICS, protein chemistry, additive
manufacturing, biomaterials engineering, computational design, and,
more recently, articial intelligence.
The remarkable advancements in the science of drug delivery, pio-
neered in the pharmaceutical sector, have prompted the cosmetics and
beauty industry to embrace this paradigm as well. The integration of
delivery systems into beauty products represents a profound scientic
response to meet the rising expectations of consumers. This convergence
underscores the cosmetics industry’s commitment to innovation. In
particular, innovative research at the intersection of delivery systems
and small bioactive molecules holds great promise for treating skin
diseases and promoting skin rejuvenation. Anticipating further and
more substantial breakthroughs in this dynamic eld, we can envision a
future where beauty products not only meet but also exceed consumer
expectations.
Funding.
This work was funded by grants from the S˜
ao Paulo Research
Foundation (FAPESP – Fundaç˜
ao de Amparo a Pesquisa do Estado de S˜
ao
Paulo) under grants 2016/14459–3, 2017/26317–1 and 2021/05454–6.
The work also received support from the partnership with the Federal
University of S˜
ao Paulo (UNIFESP) under process number 334/2021.
The corresponding author was also supported by Fundaç˜
ao de Amparo `
a
Pesquisa (FAP-DF/Brazil) under the grant number 00193–00000734/
2021–75.
Declaration of competing interest
The authors declare that they have no known competing nancial
interests or personal relationships that could have appeared to inuence
the work reported in this paper.
Data availability
No data was used for the research described in the article.
Acknowledgments
This work was funded by grants from the S˜
ao Paulo Research
Foundation (FAPESP – Fundaç˜
ao de Amparo a Pesquisa do Estado de S˜
ao
Paulo) under grants 2016/14459–3, 2017/26317–1 and 2021/05454–6.
The work also received support from the partnership with the Federal
University of S˜
ao Paulo (UNIFESP) under process number 334/2021.
The corresponding author was also supported by Fundaç˜
ao de Amparo `
a
Pesquisa (FAP-DF/Brazil) under the grant number 00193–00000734/
2021–75. Moreover, the autthors would like to thank Ricardo J. S.
Torquato from Federal University of S˜
ao Paulo (UNIFESP) for technical
support.
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