Convergence of Biofabrication Technologies and Cell Therapies for Wound Healing
Abstract
:1. Introduction
2. Significant Cell Populations for Regenerative Skin Wound Therapies
2.1. Keratinocytes
2.2. Fibroblasts
2.3. Platelets
2.4. Stem/Progenitor Cell Therapies
3. Contribution of Matrices to the Improvement of Cell Therapy
3.1. Biofabrication Technologies
3.2. Matrices as Supportive Carriers
3.3. Matrices as Inductive Substrates to Modulate the Biophysical and Biochemical Responses
3.3.1. Biophysical Cues
3.3.2. Matrices for Efficient Delivery of Bioactive Molecules
4. Stem/Progenitor Cells Seeded Matrices in Clinical Settings
5. Current Limitations and Future Opportunities
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
(AMPs) | Antimicrobial peptides |
(RGD) | Arg-Gly-Asp peptide |
(CEA) | Cultured epithelial autograft |
(EGF) | Epidermal growth factor |
(ECM) | Extracellular matrix |
(GelMA) | Gelatin-methacryloyl |
(GHK) | Glycyl-Histidyl-Lysine |
(GFs) | Growth factors |
(HDPs) | Host defense peptides |
(IL) | Interleukin |
(MSCs) | Mesenchymal stem cells |
(PDGF) | Platelet-derived growth factor |
(PRP) | Platelet-rich plasma |
(PCL) | Poly(caprolactone) |
(PDLLA) | Poly(D, L-lactic acid) |
(PLGA) | Poly(lactic-co-glycolic acid) |
(PVA) | Poly(vinyl alcohol) |
(3D) | Three dimensional |
(TGF) | Transforming growth factor |
(2D) | Two dimensional |
(VEGF) | Vascular endothelial growth factor |
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Stem/Progenitor Cells | Treatment Group(s) | Wound Type | Remarks | Reference |
---|---|---|---|---|
Adipose-derived MSCs | Adipose tissue derived MSCs | CLI | - 66.7% of patients showed ulcer healing - The treatment showed the formation of numerous vascular collateral networks | [44] * |
1: Autologous adipose-derived stem and regenerative cells plus traditional methods and advanced dressings 2: Only traditional methods and nonadherent dressings | Chronic ulcer of lower limbs | - There was a reduction in both the diameter and depth of the ulcer - In 6 of 10 cases, there was complete healing of the ulcer | [46] | |
Autologous cultured adipose-derived stroma/SCs | Non-revascularizable critical limb ischemia | - Ulcer evolution and wound healing showed improvement | [47] ** | |
Non-culture-expanded autologous, adipose-derived stromal vascular fraction cells | CLI | - 6 of the 10 patients with non-healing ulcers had a complete closure - There was evidence of neovascularization in 5 patients | [48] * | |
Adipose-derived SCs | Hypertensive leg ulcers | - Wound surfaces constantly and significantly decreased (wound closure rate of 73.2% at month 3 and 93.1% at month 6) - Percentages of fibrin and necrosis decreased, whereas granulation tissue increased significantly - There was no recurrence | [49] * | |
1: Autologous stromal vascular fraction cells plus a wound dressing 2: A standard dressing | Chronic VLU and AVLU | - All VLU patients and 4 of 9 AVLU patients showed complete epithelialization of the ulcers within 71–174 days - In 3 patients with large ulcerations on both legs, ulcerations on the non-treated, contralateral leg also epithelialized (paracrine effects seemed to stimulate the regenerative changes even at a large distance) | [50] | |
Bone marrow derived MSCs | 1: Allogeneic bone marrow-derived MSCs 2: PlasmaLyte A | CLI | - The use of allogeneic BM-MSCs was safe in patients with CLI - All ulcers at two-year follow-up healed in group 2, whereas one patient in group 1 continued to have ulcers but with reduced size | [51] |
1: Bone marrow-derived cells 2: Autologous peripheral blood plus regular wound care treatments | Chronic lower limb wounds due to diabetes mellitus | - The average decrease in wound area at 2 (17.4% vs. 4.84%) and 12 (36.4% vs. 27.32%) weeks was higher in group 1 compared to in group 2 | [52] | |
1: Bone marrow MSCs 2: Bone marrow-derived mononuclear cells 3: normal saline | Diabetic critical limb ischemia | - The ulcer healing rate was significantly higher in group 1 - They reached 100% four weeks earlier than group 2 - Ulcer healing rate in group 2 was significantly higher than in group 3, which appeared at 12 weeks | [53] | |
Autologous bone marrow nuclear cells | Pressure ulcers | - Pressure ulcers had fully healed after a mean time of 21 days in 86.36% of the patients - During a mean follow-up of 19 months, none of the resolved ulcers recurred | [54] * | |
1: Autologous bone marrow aspirate 2: Saline dressings | Chronic wounds | - Group 1 achieved a significant reduction in the wound surface area | [55] | |
Progenitor cells | CD34+ cells isolated from bone marrow | Sacral pressure sore | - The treatment positively affected granulation tissue formation and wound contraction, which showed about a 50% reduction in the pressure sore volume on the treated side versus a 40% reduction on the control side | [45] ** |
Genetically modified epidermal stem cells | Junctional epidermolysis bullosa | - Complete engraftment was achieved following 8 days - Transduced stem cells enabled the regeneration of epidermis | [56] ** | |
Genetically modified epidermal stem cells | Junctional epidermolysis bullosa | - The human epidermis is supported not by equipotent progenitors, but by long-lived stem cells with an extensive self-renewal ability so that they could generate progenitors to renew terminally differentiated keratinocytes | [57] ** | |
Bone marrow-derived mononuclear cells | Mononuclear bone marrow cells | Chronic venous and neuro-ischemic wounds | - The treatment led to a wound size reduction, a markedly increased vascularization, and infiltration of mononuclear cells | [58] ** |
Placental MSCs | 1: Cryopreserved human placental tissue in a human viable wound matrix plus standard compression therapy 2: Standard compression therapy | VLU | - Complete healing in 53% of the cases in group 1 - Reduction in wound size by half (80% in group 1 vs. 25% in group 2) | [59] |
Human placenta-derived mesenchymal stromal-like cells (cenplacel) | DFUs with PAD | - There was preliminary evidence of ulcer healing in seven patients (five complete; two partial) within 3 months of cenplacel treatment - Circulating endothelial cell levels (a biomarker of vascular injury in PAD) were decreased within 1 month - Cenplacel was generally safe and well-tolerated in patients with chronic DFUs and PAD | [60] * | |
Umbilical cord MSCs | 1: Human umbilical cord MSCs plus a percutaneous angioplasty treatment 2: A percutaneous angioplasty treatment | Ulcer wounds | - 3 months after treatment, there was a significant increase in neovessels accompanied by complete or gradual ulcer healing in group 1 | [61] |
Technologies | Biofabrication Mode | Biomaterial Platforms | Biomaterial | Cell Type | Remarks | Reference |
---|---|---|---|---|---|---|
Cell electrospinning | Bioassembly | Nanofibers | Polyvinyl alcohol | Bone marrow-derived SCs | - Good infiltration and cell growth due to the even distribution of the cells throughout the fiber filaments - Acceleration of wound healing and appendage regeneration by promoting granulation tissue repair - Formation of dense and mature collagen fiber structure parallel to the epidermis | [69] |
Extrusion | Bioassembly (vibrational modality) | Shell/core microcapsules | Poly(methyl-methacrylate) | Human dermal fibroblasts | - Decrease of cell viability as long as the number of microcapsules increased - After 72 h incubation, microcapsules did not interfere with cell growth - Slow cell proliferation inside the microcapsules | [70] |
Bioassembly (electrostatic droplet modality) | Microcapsules | Alginate | Human adipose-derived SCs | - Growth of the encapsulated cells in static culture by 3 weeks - Cell survival after injection into a nude mouse - Protection of the cells during injection—potential deterrent to donor cell migration | [71] | |
Soft lithography | Bioprinting | Microgels | Hyaluronic acid modified with photoreactive methacrylates | Fibroblasts | - Uniform distribution of the cells throughout the gel (depending on the crosslinking process) - Maintaining the cell viability (depending on the exposure time of the cells to ultra violet, photoinitiator concentration and exposure to dry air) - Cell-mediated degradation of hydrogels | [72] |
Photolithography | Bioprinting | Microgels | GelMA and graphene oxide | Fibroblasts | - Support of cellular adhesion and spreading with improved viability and proliferation - Robust mechanical properties and excellent flexibility - Able to construct multilayer cell-laden hydrogels | [73] |
Emulsion | Bioassembly | Hydrogels | Sodium alginate | Keratinocyte clusteroids | - Growth of the clusteroids in the hydrogels - Percolation of the clusteroids through the hydrogel and formation of an integral tissue | [74] |
Microfluidics | Bioassembly | Hollow microspheres | Bacterial cellulose | Primary epidermal keratinocytes | - Increased proliferation due to the high porosity of the microsphere scaffold - Enhanced wound healing due to 3D mimicry of the native skin ECM and water retention | [75] |
Bioassembly | Microporous annealed particle gels | Multi-armed poly(ethylene)glycol-vinyl sulfone functionalized with RGD | Dermal fibroblasts, adipose-derived MSCs; bone marrow-derived MSCs | - Cell proliferation and formation of extensive 3D networks by the incorporated cells - Facilitation of the cell migration, rapid cutaneous tissue regeneration and tissue structure formation due to a stably linked interconnected network of micropores | [76] | |
Bioprinting | Bioprinting (inkjet modality) | Hydrogels | Fibrin and collagen | Amniotic fluid-derived SCs and bone marrow-derived MSCs | - Facilitation of quick wound and closure and angiogenesis due to delivery of secreted trophic factors - Greater re-epithelialization - Increased microvessel density - Transient integration of the cells with the surrounding tissue | [77] |
In vitro bioprinting (extrusion modality) | 3D cell-printed full-thickness human skin equivalent | Decellularized ECM-based skin | Endothelial progenitor cells and adipose-derived SCs | - Sufficient recapitulation of the microenvironment physiologically relevant to the skin cells (dense and thick microstructure) - Improved epidermal organization, dermal ECM secretion and barrier function - Acceleration of wound closure, re-epithelization, neovascularization, and blood flow | [78] | |
In vivo bioprinting (extrusion modality) | Two-layered skin construct (hydrogel) | Fibrinogen and collagen | Human fibroblasts and human keratinocytes | - Capable of delivering the cells to the specific target sites - Rapid wound closure, reduced contraction and accelerated re-epithelialization - Regeneration of tissues with a dermal structure and composition similar to healthy skin, with extensive collagen deposition arranged in large, organized fibers, extensive mature vascular formation and proliferating keratinocytes | [79] | |
In vivo bioprinting (extrusion modality) | Skin precursor sheets | Fibrin and hyaluronic acid | Mesenchymal stem/stromal cells | - High cell viability and increased proliferation - Improved re-epithelialization, dermal cell repopulation and neovascularization | [80] |
Growth Factor | Biomaterial Composition | Delivery System | Study Type | Remarks | Ref. |
---|---|---|---|---|---|
IGF and EGF (vitronectin: GF complexes) | HA hydrogel | Surface presentation, physical adsorption | In vitro culture of fibroblasts and keratinocytes Ex vivo model of 3D de-epidermized dermis human skin equivalent | In vitro: the combination of the complexes and HA activated the proliferation of human fibroblasts but not keratinocytes. Ex vivo: the combination improved the proliferative and differentiating layers. HA promoted absorption and transport. | [131] |
EGF | Electrospun nanofibers of PCL-b-PEG | Surface presentation, chemical conjugation | In vitro culture of keratinocytes In vivo model of full-thickness diabetic wounds in mice | In vitro: the conjugation of EGF to nanofibers considerably enhanced the expression of keratinocyte-specific genes. In vivo: the conjugation led to better wound healing outcomes such as wound closure. The expression of EGF-receptor was on a significant rise. | [132] |
EGF | Fibrin gel loaded within chitosan nanoparticles | Controlled sustained release | In vitro culture of fibroblasts | EGF released from the composite gel was bioactive for one week at most. It could activate the proliferation of fibroblasts. | [133] |
VEGF | Two-compartment and bi-functional scaffold from chitosan/collagen-containing PLGA microspheres | Preprogrammed release | In vitro culture of fibroblasts | VEGF showed a linear release behavior over a long period (49 days). The scaffold could support cell adhesion and proliferation. | [134] |
EGF | Photo-cross-linkable pluronic/chitosan hydrogel | Responsive release | In vitro culture of keratinocytes In vivo model of diabetic ulcers in mice | In vitro: EGF contributed to the retention of original phenotypes of keratinocytes. In vivo: EGF had high retention in the hydrogel at the wound site, which was in favor of the proliferation of keratinocytes. The slow release of EGF carried an effect on the keratinocytes proliferation of epidermal cells and supported wound recovery. EGF worked better in the differentiation of epidermal cells into keratinocytes, than in the acceleration of wound healing rates. | [135] |
Polyplexes of bFGF | Electrospun core−sheath fibers from PELA | Gene transfection | In vitro culture of fibroblasts In vivo model of diabetic skin wounds | In vitro: bFGF improved cell proliferation. The transfection continued for over four weeks. In vivo: its release led to considerably high wound recovery with enhanced vascularization, collagen deposition and maturation, complete re-epithelialization and skin appendage restoration. | [136] |
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Hosseini, M.; Dalley, A.J.; Shafiee, A. Convergence of Biofabrication Technologies and Cell Therapies for Wound Healing. Pharmaceutics 2022, 14, 2749. https://doi.org/10.3390/pharmaceutics14122749
Hosseini M, Dalley AJ, Shafiee A. Convergence of Biofabrication Technologies and Cell Therapies for Wound Healing. Pharmaceutics. 2022; 14(12):2749. https://doi.org/10.3390/pharmaceutics14122749
Chicago/Turabian StyleHosseini, Motaharesadat, Andrew J. Dalley, and Abbas Shafiee. 2022. "Convergence of Biofabrication Technologies and Cell Therapies for Wound Healing" Pharmaceutics 14, no. 12: 2749. https://doi.org/10.3390/pharmaceutics14122749