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Cited by 397Bone Tissue Engineering MaterialsTissue Engineering and Regenerative MedicineHydrogels: synthesis, properties, applications

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Design Challenges in Polymeric Scaffolds for Tissue Engineering

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Echeverria Molina, Maria I., Malollari, Katerina G., Komvopoulos, Kyriakos·2021·Frontiers in Bioengineering and Biotechnology
DOI 10.3389/fbioe.2021.617141PMC PMC8236583
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Abstract

Numerous surgical procedures are daily performed worldwide to replace and repair damaged tissue. Tissue engineering is the field devoted to the regeneration of damaged tissue through the incorporation of cells in biocompatible and biodegradable porous constructs, known as scaffolds. The scaffolds act as host biomaterials of the incubating cells, guiding their attachment, growth, differentiation, proliferation, phenotype, and migration for the development of new tissue. Furthermore, cellular behavior and fate are bound to the biodegradation of the scaffold during tissue generation. This article provides a critical appraisal of how key biomaterial scaffold parameters, such as structure architecture, biochemistry, mechanical behavior, and biodegradability, impart the needed morphological, structural, and biochemical cues for eliciting cell behavior in various tissue engineering applications. Particular emphasis is given on specific scaffold attributes pertaining to skin and brain tissue generation, where further progress is needed (skin) or the research is at a relatively primitive stage (brain), and the enumeration of some of the most important challenges regarding scaffold constructs for tissue engineering.

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Figure 1 Schematic representation of different design characteristics of biomaterial scaffolds that are necessary for eliciting the cellular behavior required for a specific tissue application. Effective tuning of the parameters described in each category plays a critical role in the performance of architectured (fibrous and porous), hybrid, and hydrogel scaffolds for tissue generation and repair.
Figure 1 Schematic representation of different design characteristics of biomaterial scaffolds that are necessary for eliciting the cellular behavior required for a specific tissue application. Effective tuning of the parameters described in each category plays a critical role in the performance of architectured (fibrous and porous), hybrid, and hydrogel scaffolds for tissue generation and repair.CC BY · PubMed Central
Figure 2 (A) Representation of various click chemistry reactions used in the fabrication of polymeric scaffolds. (B) Fabrication strategies based on click chemistry: (i) pre-click and (ii) post-click. (C) Schematic illustrating a hydrogel crosslinked by click chemistry and functionalized with ECM-based molecules to promote cell attachment and differentiation. (D) Schematic showing a PDA-coated electrospun scaffold decorated with growth factors to promote cell differentiation. [(B–D) were created with BioRender.com].
Figure 2 (A) Representation of various click chemistry reactions used in the fabrication of polymeric scaffolds. (B) Fabrication strategies based on click chemistry: (i) pre-click and (ii) post-click. (C) Schematic illustrating a hydrogel crosslinked by click chemistry and functionalized with ECM-based molecules to promote cell attachment and differentiation. (D) Schematic showing a PDA-coated electrospun scaffold decorated with growth factors to promote cell differentiation. [(B–D) were created with BioRender.com].CC BY · PubMed Central
Figure 3 Important structure and morphology scaffold parameters affecting cell behavior.
Figure 3 Important structure and morphology scaffold parameters affecting cell behavior.CC BY · PubMed Central
Figure 4 Overview of parameters affecting the degradation rate of scaffolds accompanied by representative examples. (A) Highly reactive functional groups attacked by water molecules. (B) Different scaffold structures: (i) fibrous (Pu and Komvopoulos, 2014), (ii) porous (Han et al., 2014), and (iii) solid (Weir et al., 2004). (C) Various environmental factors (local pH, byproducts, and enzymes) affecting scaffold degradation. (D) Fiber morphology vs. time of plasma treatment showing fiber degradation after a short treatment time and fiber cracking and breakage after long treatment time (Bolbasov et al., 2018). (E) Comparison between a fresh sample and samples degraded for 28 days in PBS at 32°C for shear stress increasing from 3.6 dyn/cm2 (left) to 36 dyn/cm2 (right) (Zheng et al., 2017). (F) Schematic of chain scission and crosslinking induced by radiation.
Figure 4 Overview of parameters affecting the degradation rate of scaffolds accompanied by representative examples. (A) Highly reactive functional groups attacked by water molecules. (B) Different scaffold structures: (i) fibrous (Pu and Komvopoulos, 2014), (ii) porous (Han et al., 2014), and (iii) solid (Weir et al., 2004). (C) Various environmental factors (local pH, byproducts, and enzymes) affecting scaffold degradation. (D) Fiber morphology vs. time of plasma treatment showing fiber degradation after a short treatment time and fiber cracking and breakage after long treatment time (Bolbasov et al., 2018). (E) Comparison between a fresh sample and samples degraded for 28 days in PBS at 32°C for shear stress increasing from 3.6 dyn/cm2 (left) to 36 dyn/cm2 (right) (Zheng et al., 2017). (F) Schematic of chain scission and crosslinking induced by radiation.CC BY · PubMed Central
Figure 5 Parameters affecting the mechanical properties of scaffolds from fabrication to implantation used to create a tissue analog.
Figure 5 Parameters affecting the mechanical properties of scaffolds from fabrication to implantation used to create a tissue analog.CC BY · PubMed Central
Figure 6 Overview of innate immune response upon injury or infection.
Figure 6 Overview of innate immune response upon injury or infection.CC BY · PubMed Central
Figure 7 Examples of recent advances in biomaterial scaffolds for skin wound healing. (A) Gelatin sulfonated silk scaffolds with FGF-2 growth factor. Masson trichrome staining shows the histology of a repaired wound. The treated samples reveal an increase in collagen content with time relative to the control sample (Xiong et al., 2017). (B) Ibuprofen-loaded PLA layered scaffold seeded with fibroblasts and keratinocytes. Wound closure at 1 and 14 days and histological staining of skin samples at 14 days from control wound sites without scaffolds, with acellular scaffold, and cell-seeded scaffold (Mohiti-Asli et al., 2017). (C) Gelatin/chitosan freeze-dried scaffold showing enhanced cell viability (Han et al., 2014). (D) Hybrid PCL/gel fibrous scaffold loaded with MgO particles showing significantly more wound healing compared to controls (Ababzadeh et al., 2020). (E) Porous structure of bovine cardiac ECM-GO functionalized scaffold. Cell viability vs. GO content (Jafarkhani et al., 2020). (F) Decellularized (+Dcell) and non-decellularized (–Dcell) jellyfish bell scaffolds. Fibroblast cell proliferation after 0, 3, and 7 days shows a significant difference between +Dcell and –Dcell at 7 days of culture (Fernández-Cervantes et al., 2020). (G) Schematic of scaffold and cells seeded, histological staining showing differentiated keratinocyte morphology and graft vascularization, and high follicle density engraftment (Abaci et al., 2018).
Figure 7 Examples of recent advances in biomaterial scaffolds for skin wound healing. (A) Gelatin sulfonated silk scaffolds with FGF-2 growth factor. Masson trichrome staining shows the histology of a repaired wound. The treated samples reveal an increase in collagen content with time relative to the control sample (Xiong et al., 2017). (B) Ibuprofen-loaded PLA layered scaffold seeded with fibroblasts and keratinocytes. Wound closure at 1 and 14 days and histological staining of skin samples at 14 days from control wound sites without scaffolds, with acellular scaffold, and cell-seeded scaffold (Mohiti-Asli et al., 2017). (C) Gelatin/chitosan freeze-dried scaffold showing enhanced cell viability (Han et al., 2014). (D) Hybrid PCL/gel fibrous scaffold loaded with MgO particles showing significantly more wound healing compared to controls (Ababzadeh et al., 2020). (E) Porous structure of bovine cardiac ECM-GO functionalized scaffold. Cell viability vs. GO content (Jafarkhani et al., 2020). (F) Decellularized (+Dcell) and non-decellularized (–Dcell) jellyfish bell scaffolds. Fibroblast cell proliferation after 0, 3, and 7 days shows a significant difference between +Dcell and –Dcell at 7 days of culture (Fernández-Cervantes et al., 2020). (G) Schematic of scaffold and cells seeded, histological staining showing differentiated keratinocyte morphology and graft vascularization, and high follicle density engraftment (Abaci et al., 2018).CC BY · PubMed Central
Figure 8 Examples of recent advances in biomaterial scaffolds developed for brain tissue repair after injury. (A) Schematic illustration of the pathophysiology after brain injury illuminating the development of astrogliosis and the increase of the microglial density. (B) Design of HA with clustered VEGF on heparin NPs. The immunostained images of neurons and vessels show that the gel with high clustered VEGF delivery enhanced angiogenesis and neurogenesis (Nih et al., 2018). (C) Urinary bladder-based hydrogel. The immunostained images illustrating ECM hydrogel and cell nucleus show that the hydrogel modulated neuroinflammation and enhanced neurogenesis and angiogenesis (Ghuman et al., 2018). (D) Electrospun fibers with different architectures and porosities infiltrated with human-induced neuronal cell populations. Significantly higher numbers of human iN cells expressed microtubule-associated protein 2 in the thick fibrous scaffolds relative to the 2D controls and thin fibrous scaffolds (Carlson et al., 2016). (E) Fibers incorporated in hydrogels. When implanted into the striatum, the scaffold displayed higher cellular infiltration and a more loosely defined glial boundary. The images show the tissue-scaffold interface—astrocytes (red), macrophages/microglia (green), and cell nuclei (labeled with DAPI, blue) (Rivet et al., 2015). (F) Bio-printed brain-like layer structures (each color represents a different layer). Confocal microscope images of neurons in different layers, colored for the distribution of cells through the z-axis, showing an axon penetrating the adjacent layer (Lozano et al., 2015). (G) Schematic illustration of the production of hydrogel microparticles in a flow-focusing microfluidic device (Nih et al., 2017). These gels can be injected at the location of interest while preserving their structure.
Figure 8 Examples of recent advances in biomaterial scaffolds developed for brain tissue repair after injury. (A) Schematic illustration of the pathophysiology after brain injury illuminating the development of astrogliosis and the increase of the microglial density. (B) Design of HA with clustered VEGF on heparin NPs. The immunostained images of neurons and vessels show that the gel with high clustered VEGF delivery enhanced angiogenesis and neurogenesis (Nih et al., 2018). (C) Urinary bladder-based hydrogel. The immunostained images illustrating ECM hydrogel and cell nucleus show that the hydrogel modulated neuroinflammation and enhanced neurogenesis and angiogenesis (Ghuman et al., 2018). (D) Electrospun fibers with different architectures and porosities infiltrated with human-induced neuronal cell populations. Significantly higher numbers of human iN cells expressed microtubule-associated protein 2 in the thick fibrous scaffolds relative to the 2D controls and thin fibrous scaffolds (Carlson et al., 2016). (E) Fibers incorporated in hydrogels. When implanted into the striatum, the scaffold displayed higher cellular infiltration and a more loosely defined glial boundary. The images show the tissue-scaffold interface—astrocytes (red), macrophages/microglia (green), and cell nuclei (labeled with DAPI, blue) (Rivet et al., 2015). (F) Bio-printed brain-like layer structures (each color represents a different layer). Confocal microscope images of neurons in different layers, colored for the distribution of cells through the z-axis, showing an axon penetrating the adjacent layer (Lozano et al., 2015). (G) Schematic illustration of the production of hydrogel microparticles in a flow-focusing microfluidic device (Nih et al., 2017). These gels can be injected at the location of interest while preserving their structure.CC BY · PubMed Central
Figure 9 Synergy between biochemical behavior, structure and morphology, biodegradability, and mechanical behavior of scaffolds activates cellular behavior, controls cell fate, and drives TE advancement.
Figure 9 Synergy between biochemical behavior, structure and morphology, biodegradability, and mechanical behavior of scaffolds activates cellular behavior, controls cell fate, and drives TE advancement.CC BY · PubMed Central

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Research works printed but not linked: 2

  1. 2020, Tissue Engineering Market Size, Share & Trends Analysis Report by Application (Cord Blood & Cell Banking, Cancer, GI & Gynecology, Dental, Orthopedics, Musculoskeletal, & Spine), by Region, and Segment Forecasts, 2020-2027
  2. Janeway, 2001, Part V - The immune system in health and disease

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Metadata

Authors
Echeverria Molina, M. I., Malollari, K. G., & Komvopoulos, K.
Affiliations
University of California, Berkeley (US)
Corresponding author
Komvopoulos, Kyriakos
ORCID
Venue
Frontiers in Bioengineering and Biotechnology
Publisher
Frontiers Media SA
Published
2021-06-14
Volume
9
Pages
617141-617141
ISSN
2296-4185 (ISSN-L)
DOI
10.3389/fbioe.2021.617141
PMC
PMC8236583
OpenAlex
W3171498185
Cited by
397
References
318
Citations by year
2026: 103 · 2025: 124 · 2024: 89 · 2023: 49 · 2022: 30 · 2021: 2
FWCI
3.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Bioengineering and Biotechnology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Physical Sciences › Materials Science › Biomaterials › Hydrogels: synthesis, properties, applications
Keywords
polymer scaffolds, tissue engineering, biodegradable biomaterials, scaffold design, biodegradation, cell behavior, scaffold architecture, mechanical properties, skin regeneration, brain tissue regeneration

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