A thorough review covering the nascent domain of Surface Engineering on Stem Cells. This short review will cover basic details of Stem Cell Engineering and Cell Culture Surface Engineering.

1. Effect of Surface
Engineering on Stem Cells
Aman Nanavaty

2. Surface engineering is the branch of material science that deals with
the characteristics of solid surfaces. It aims at changing and improving
the mechanical, chemical, magnetic and physical features of solid
surfaces. Surface Engineering has been utilised in many
fi
elds such as
biomedical engineering, aeronautical engineering, automobile
manufacturing, petrochemical industry and industrial engineering.
Examples of Surface Engineering include anti-corrosion coatings,
wear-resistant coatings, surface cleaning (to remove dust and
accretions) and impurity removal.
A stem cell is a type of cell that can self-renew as well as recreate
functional tissues. They act as inde
fi
nitely dividing progenitor cells
and constantly recreate functional tissues. Being the earliest cells in
the lineage, they may either be undifferentiated or partially
differentiated. Different stem cells have different potencies, with
some stem cells giving rise to multiple differentiated cells. Examples
include Hematopoietic Stem Cells and Amniotic Stem Cells. They have
been utilised in gene therapies and molecular biology studies to
understand embryonic development.
These 2
fi
elds may not seem related but the application of surface
engineering on stem cells can be a game-changer for biomedical
engineering, cancer research, cell culture and drug discovery.
Introduction

3. Surface Engineering of Stem Cells entails the manipulation of the cell
membrane, such as modifying the cells’ adherence to the substrate or
regulating its differentiation. Using biochemical modi
fi
cation or
nanoparticle coatings, it is possible to customise the surface
properties, topography and cell physiology.
Although stem cell culture has been practised for many years, certain
challenges remain. Poor cell survival rates, limited substrate
adherence, inhibited cell signalling and cytotoxicity continue to
challenge in vitro studies of cell-material interaction and signalling
pathways. For example, applying a thin layer of biopolymer on stem
cells can help in increasing the lifespan as well as facilitate ef
fi
cient
delivery. Biopolymer coating has been used to increase the ef
fi
ciency
of stem cell transplantation and protect the cells against stress.
Cell Surface Engineering can help stem cells against mechanical stress
and pathogens by reinforcing the cell membrane. This allows for
better survival and attachment of stem cells to culture media, a
problem that regularly hinders researchers. Designing nano-scaffolds
for stem cells in culture can readily improve cell proliferation, survival
and viability by building an ef
fi
cient supporting framework for the
stem cells to attach. Cross-linking of membrane proteins to certain
biomaterials, also called DOCKING, allows researchers to study cell-
material interactions individually.
Effects of Surface Engineering on Stem Cells

4. Direct chemical conjugation of biomolecules such as lipids, PEG and
drugs to the exterior of erythrocytes can aid in better drug delivery
and transfusion. Internal loading of drugs in RBCs can reduce the
cellular integrity and may result in irregular drug release. These
issues resolved by directly conjugating the drug or biomolecule to
the cell membrane, thereby allowing for ef
fi
cient drug delivery
without compromising the survival of RBCs. RBCs have also been
engineered (via hypotonic dialysis) to carry anticancer drugs and
biotin, which can act as Antigen Presenting Cells to stimulate T Cells.
A wide variety of functional biomolecules such as peptides, lipids
and biopolymers are deposited onto the cell membrane of
Mesenchymal Stem Cells to enhance delivery ef
fi
ciency, survival and
signalling. Nanoparticle coatings on stem cells enhance cell
traf
fi
cking, therapeutic delivery and helps to mask cell-surface
antigens. This is extremely useful as we can regulate the
in
fl
ammatory phenotype of our selected carrier cells (immune
system evasion), reducing the risk of potential side-effects.
Through Surface Engineering, we can alter the surface characteristics
of Stem Cells such as rigidity, structural integrity, signalling,
attachment and also regulate cell proliferation. Researchers have
also used chemical modi
fi
cations to change the electrostatic
properties of stem cells, to improve migration and communication.

5. Advantages of Surface Engineering of Stem Cells
Through surface engineering techniques such as hypotonic dialysis,
biotinylation, nanoparticle coating and biopolymer coating, it is
possible to create biocarriers and biovesicles that carry drugs,
stimulators and bioactive compounds.
Researchers can conjugate
fl
uorescent probes and sensors to stem
cells to detect the presence of signalling molecules in the
environment. Dr Karp et al. used surface engineering to attach a
fl
uorescent cell surface sensor to mesenchymal stem cells,
facilitating the detection of PGDF in vitro. Likewise many stem cells
can be engineered to carry cell surface sensors designed to
quantitate certain phenomena or diseases.
The use of stem cells in therapeutic treatments is limited due to
issues such as poor delivery, low survival and potential side-effects.
Poor delivery can be remediated by modifying the cell surface of
stem cells to enhance targeting. Scientists have modi
fi
ed the cell
surface proteins/ligands of Neural Stem Cells and Mesenchymal
Stem Cells to enhance delivery and targeting. Through Surface
Engineering, we can design nano-scaffolds that can improve
adherence of Stem Cells in culture. ECM Mimicry and hydrogels can
also be created by cell surface engineering techniques.

6. Surface Engineering has been used to change various properties of Stem Cells, such as adherence,
signalling, differentiation, connection and proliferation. It has been used to to modify biochemical
activity and cell signalling pathways in vitro. In recent times, many researchers have started exploring
this multi-disciplinary approach to cell culture.
Direct chemical conjugation of biomolecules such as lipids, PEG and drugs to the exterior of
erythrocytes can aid in better drug delivery and transfusion. Internal loading of drugs in RBCs can
reduce the cellular integrity and may result in irregular drug release. These issues resolved by directly
conjugating the drug or biomolecule to the cell membrane, thereby allowing for ef
fi
cient drug delivery
without compromising the survival of RBCs. RBCs have also been engineered (via hypotonic dialysis) to
carry anticancer drugs and biotin, which can act as Antigen Presenting Cells to stimulate T Cells. Surface
Engineering is being used to create chemotherapeutic solutions for cancer and other immune disorders.
Nucleic Acid Aptamers have been coated onto Mesenchymal Stem Cells enhance binding to leukocytes
under dynamic
fl
ow conditions. This thin coating on the cell surface acts as arti
fi
cial adhesion ligands
that enhance binding to target cells. Through this technique, in vitro wound healing has improved.
RGD peptides have been deposited onto certain Stem Cells to improve in vitro substrate adherence,
target binding and af
fi
nity. Peptides and Bioceramics have been used to improve drug delivery
ef
fi
ciency and targeting of Stem Cells in Therapeutic Systems. Hematopoietic Stem Cells that were
conjugated with sialylated glycopolymers were able to recruit and induce natural killer cell activity
better than regular Hematopoietic Stem Cells.
Examples of Surface-Engineered Stem Cells

7. References
1. Park J, Andrade B, Seo Y, Kim MJ, Zimmerman SC, Kong H. Engineering the Surface
of Therapeutic "Living" Cells. Chem Rev. 2018 Feb 28;118(4):1664-1690. doi: 10.1021/
acs.chemrev.7b00157. Epub 2018 Jan 16
2. Xia Wu, Jingyi Liu, Zhiqiang Liu, Guoli Gong, Jian Zha. Microbial cell surface
engineering for high-level synthesis of bio-products. Biotechnology Advances, Volume
55, 2022.
4. Almeida-Pinto J, Lagarto MR, Lavrador P, Mano JF, Gaspar VM. Cell Surface
Engineering Tools for Programming Living Assemblies. Adv Sci (Weinh). 2023
Dec;10(34):e2304040.
5. Zhong Y, Xu L, Yang C, Xu L, Wang G, Guo Y, Cheng S, Tian X, Wang C, Xie R, Wang
X, Ding L, Ju H. Site-selected in situ polymerization for living cell surface engineering.
Nat Commun. 2023 Nov 10;14(1):7285.
6. M. C. Arno, Engineering the Mammalian Cell Surface with Synthetic Polymers:
Strategies and Applications. Macromol. Rapid Commun. 2020, 41, 2000302.
7. Liu L, He H, Liu J. Advances on Non-Genetic Cell Membrane Engineering for
Biomedical Applications. Polymers (Basel). 2019 Dec 5;11(12):2017.