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International Journal of Bioprinting 3D bioprinting for vascularized skin tissue engineering

bioprinters deposit bioinks, including endothelial cells, in a immediate functionality, but involves challenges related to
layer-by-layer fashion, forming intricate vascular networks the immune system and ethical considerations. Selection of
within a controlled microenvironment. Challenges in the suitable approach should be guided by specific research
this domain include maintaining cell viability, enhancing or therapeutic goals.
the biological properties of biomaterials, and developing
suitable bioinks. On the other hand, in vivo bioprinting 5.1. Development of in vitro vascularized
involves regenerating blood vessels within host organs skin models
to facilitate tissue repair and regeneration. Strategies for Recently, there has been a rapidly growing demand for
in vivo bioprinting may include the direct application of skin models designed in vitro to evaluate pharmaceutical
3D bioprinting into wound sites or the transplantation and cosmetic products or regenerate skin function after
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of encapsulated endothelial cells in specific bioinks. This damage. In 2014, approximately USD 958.8 million
approach necessitates bioink materials being compatible was spent on tissue-engineered skin substitutes, and by
with the host’s immune system. Challenges in this context 2023, the market is expected to reach approximately USD
encompass managing immunological responses, ensuring 3873.5 million. The cost of in vitro toxicological studies
integration within host tissues, and promoting functional in 2016 reached USD 14.2 billion. Previously, it was a
vessel development. Table 4 summarizes the distinctions common practice to assess the efficacy and toxicity of
between in vitro and in vivo bioprinting vascularization skin-targeted compounds through in vivo animal testing,
strategies, highlighting the unique advantages and since many compounds could not be directly tested in
drawbacks associated with each approach and underscoring humans. However, in March 2013, the use of animal
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the importance of selecting the most suitable strategy models to study cosmetic-related compounds was banned.
based on research or therapeutic objectives. Moreover, the failure of animal models to accurately predict
In summary, in vitro bioprinting primarily serves tissue human responses because of physiological differences
engineering and research purposes, while in vivo bioprinting between animals and humans often leads to expensive
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is employed for therapeutic applications within living and unsuccessful clinical trials subsequently. Thus, the
organisms. Each approach presents specific challenges European Parliament and the European Council passed an
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related to biocompatibility and functional integration. amendment (Directive 2003/15/EC) on February 27, 2013.
Both in vitro and in vivo bioprinting for vascularization Currently, the “3 R” principle is emphasized, i.e., refining,
have their own advantages and disadvantages. In vitro reducing, and replacing animal tests whenever possible. 122,125
models allow for the precise fabrication of complex Several approaches have been investigated for the in vitro
vascular networks under controlled conditions, but they development of tissue-engineered constructs with stable,
face challenges related to limited tissue maturation and functional, and perfusable microvessels. The construct
integration post-transplantation. In contrast, in vivo gradually vascularizes after being transplanted into the host
bioprinting enables real-time integration and, potentially, as a result of the host body’s immune response to foreign

Table 4. Comparison between in vitro and in vivo bioprinting strategies for vascularization

Aspect In vitro bioprinting In vivo bioprinting
Environment Controlled lab conditions Real biological environment
Vascular network complexity Precise control possible Limited control, natural networks
Limited maturation, may require further
Tissue maturation Immediate integration, natural maturation
development before transplantation
Transplantation challenges, potential for limited
Integration Real-time integration, immediate functionality
integration
Reduced immune response in vitro, not
Immune response representative of the immune system’s role May trigger immune responses, immune
modulation needed
in vivo
Ethical considerations No ethical concerns Ethical considerations due to the invasive nature
Suitable for drug testing, research, and disease
Applications Tissue regeneration, organ transplantation
modeling
Advantages Precise control, no ethical concerns Immediate functionality, natural integration
Potential immune responses, ethical
Disadvantages Limited maturation, transplantation challenges
considerations

Volume 10 Issue 3 (2024) 100 doi: 10.36922/ijb.1727