A Review on Bioengineering the Bovine Mammary Gland: The Role of the Extracellular Matrix and Reconstruction Prospects
Abstract
1. Introduction
2. Macro and Microscopic Characterization of the Bovine Mammary Gland
2.1. The Anatomy of the Bovine Mammary Gland
2.2. Histological Characterization
2.3. The Extracellular Matrix of the Mammary Gland
2.4. Comparative Analysis of the Extracellular Matrix of the Mammary Gland Between Cattle and Small Domestic Ruminants
2.5. The Role of the Extracellular Matrix in the Immune Response During Mastitis
2.6. Therapeutic Strategies for Bovine Mastitis
3. Decellularization Method for Obtaining Extracellular Matrix
3.1. Analysis of Decellularization Efficiency
3.2. Ideal Properties of ECM
4. Recellularization Method
4.1. Cell Types Used for the Recellularization of Parenchymal Organs
4.2. Support Cells
5. Decellularization and Recellularization of the Mammary Gland
3D Printing Is Used for the Recellularization Process
6. Limitations of Extracellular Matrix Recellularization
7. Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
3D | Three-dimensional | TN | Tenascin |
CHAPS | 3Cholamidopropyl dimethylammonio-1propanesulfonate | DAPI | 4,6-diamidino-2-phenylindole |
CS | Chondroitin sulfate | FGFR2 | Fibroblast growth factor receptor-2 |
dECM | Decellularized extracellular matrix | IL-6 | Interleukin-6 |
DS | Dermatan sulfate | H&E | Hematoxylin and eosin |
DAMPs | Damage-associated molecular patterns | pH | Hydrogen ion potential |
ECM | Extracellular matrix | DNA | Deoxyribonucleic acid |
EDTA | Ethylenediaminetetraacetic acid | SGBTR | Scaffold-guided breast tissue regeneration |
EGTA | Ethylene glycol-bis(β)-aminoethyl ether | iPSCs | Induced pluripotent stem cells |
FN | Fibronectin | VEGF | Vascular endothelial growth factor |
FnBPs | Fibronectin-binding proteins | pO2 | Partial pressure of oxygen |
GAGs | Glycosaminoglycans | TGF-β | Transforming growth factor-beta |
LN | Laminin | MSCs | Mesenchymal stem cells |
LN-111 | Laminin-111 | EGFR | Epidermal growth factor receptor |
LN-332 | Laminin-332 | pCO2 | Partial pressure of carbon dioxide |
MMPs | Metalloproteinases | LOX | Lysyl oxidases |
MW | Molecular weight | ESCs | Embryonic stem cells |
SDS | Sodium dodecyl sulfate |
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Mammary Gland Structure | Components | Description | Applications | Reference |
---|---|---|---|---|
Basal lamina | Collagen IV | It is a network-forming class. It is the main component of the basal lamina of the mammary gland. It is a heterotrimer and composed of six possible α chains. It is also a significant basal lamina component and is considered its primary scaffold protein. | It supports the basal lamina structure during embryogenesis and in mammary epithelial cells. | [44] |
Nidogens | Mesodermally derived fibroblasts synthesize sulfated glycoproteins (150 kDa). | They produce Laminins (LN, Ln, Lm, or Lam), which are stabilizing components of the basal lamina. They allow for the connection between LN-111 and collagen IV. | [44] | |
Intra and interlobular stroma | Collagen I | Fibrillar collagen I is the main protein of the stroma of the mammary gland that supports the formation of the mammary duct. | They form bundles of varying thickness and length, associated with other macromolecules of the ECM, which determines their architectural structure. This structure allows the mammary epithelium to be supported during pregnancy and lactation, providing the elastic capacity that enables the tissue to return to its original shape after stretching. | [44,46,47] |
Collagen III | This forms structures with characteristics of fibrillar collagen I and is a homotrimer consisting of a single α chain. | |||
Collagen V | This forms structures with characteristics of fibrillar collagen I. It is a heterotrimer composed of three different α chains. | |||
FN | This is a dimeric glycoprotein (~500 kDa) that mediates cell adhesion, migration, proliferation, and branching morphogenesis. | It is a precursor of the fibril that interacts with other components of the ECM and organizes the interstitial matrix, allowing for the attachment of breast tissue cells. | [44,48,49] | |
TN | Glycoproteins have five members: TN-C, TN-R, TN-W, TN-X, and TN-Y. In the mammary gland, TN-C is transiently expressed in the dense stroma surrounding the budding epithelium during embryogenesis. | TN-X maintains tissue elasticity during lactation. | [44,50] | |
Sparc | It is a small glycoprotein of 32 kDa. | It is upregulated in mammary gland development during the transition from lactation to postpartum involution, and increased collagen and FN levels correlate with this. | [44,51] | |
Laminins (LN, Ln, Lm, or Lam) | The primary protein membrane comprises three polypeptide chains: α, β, and γ. In the mammary gland, LN-111 and LN-332 are abundant at the level of the basement membrane. | They are responsible for acinar formation and induction of contact with epithelial cells. They stimulate milk secretion. | [50] | |
Decoration | This is a decorin core protein (~38 kDa) linked to a single chain of CS or DS. | It controls the spatial alignment of collagen fibers in the stroma. It is crucial for the proper organization of fibrillar collagen. | [44,52] | |
Biglycan | It comprises a 38 kDa core protein covalently linked to two GAG chains (chondroitin sulfate and/or dermatan sulfate) with an overall MW of 150–240 kDa. | It plays a role in inducing the elastic properties of the gland during periods of expansion. | [44,53] | |
Fibrous connective tissue | Elastic fibers | They have components such as elastin, fibulins, and proteoglycans associated with microfibrils, forming elastic fibers. | It provides structural support and elasticity to various tissues during lactation. | [44] |
Characteristic | Bovines | Small Ruminants (Sheep/Goats) | References |
---|---|---|---|
Predominant collagen type | Type I collagen is more abundant, contributing to greater tissue rigidity. | Higher proportion of type III collagen, favoring elasticity. | [55,56,57] |
FN distribution | More abundant in the parenchyma than in the mammary fat pad. | Similar, but with less quantitative detail in studies. | [56,58,59] |
LN distribution | Present in the parenchymal stroma, associated with epithelial organization. | Similar distribution, with analogous structural function. | [56,59] |
Elastic fibers | Not specifically emphasized. | Significant presence, associated with tissue elasticity. | [57,59,60] |
GAG composition | Lower relative proportion of hydrating GAGs. | A higher presence of chondroitin and heparan sulfate contributes to hydration. | [57,58] |
ECM density | High fibrillar density and greater mechanical resistance. | Lower density and a more flexible matrix. | [1,57] |
MMP activity | Moderate activity and slower remodeling. | High activity, facilitating tissue regeneration. | [44,60] |
Methods of Decellularization | Advantages | Disadvantages | Reference | |
---|---|---|---|---|
Physical | Flash freezing | This technique is considered safe because it does not produce residual chemicals and has minimal impact on tissue structure and biochemical composition after decellularization. | Damage or rupture of the ECM due to extremely low temperatures. | [73,79,80,81] |
Mechanical force | Cell rupture followed by washing to remove cellular material. | The application of pressure compromises the integrity of the ECM. | [75,80] | |
Mechanical agitation | Increases exposure to chemical reagents for cell removal. | Damage to the ECM in cases of agitation or excessive sonication. | [73,75] | |
Sonication | Facilitates the penetration of chemical detergents and accelerates the removal of cellular debris. | Potential damage to cell membranes and the ECM due to cavitation. | [82] | |
Chemical | Ionic detergents (SDS) | SDS solubilizes cytoplasmic and nuclear membranes, inducing cell lysis. In the ECM, SDS removes residual cytoplasmic and cellular proteins. | SDS concentrations exceeding 10 μg/mg dry weight can induce cytotoxicity due to the difficulty of removing SDS from decellularized tissues. As it forms strong hydrophobic bonds with ECM proteins, it may disrupt the native tissue structure, deplete GAGs, and damage collagen and other structural proteins. | [73,83] |
Nonionic detergents | Triton X-100 disrupts lipid–lipid and lipid–protein hydrophobic interactions while preserving protein–protein interactions. | Its efficiency varies by tissue type, yielding mixed results regarding ECM integrity and may deplete GAGs. | [82,83] | |
Alkaline and acidic agents | These agents solubilize cytoplasmic components and destroy nucleic acids. | They also result in a significant loss of GAGs from the ECM. | [83,84] | |
Zwitterionic detergents | Compounds such as CHAPS exhibit properties of both ionic and nonionic detergents, facilitating cell removal and ECM disruption similar to Triton X-100. | It may damage ECM proteins depending on the tissue and concentration used. | [81,85] | |
Hypotonic/hypertonic solutions | Induces cell lysis by osmotic shock. | Ineffective in removing residual cell contents. | [83,86] | |
EDTA/EGTA | Disrupts cell–ECM adhesions by chelating divalent metal ions. | It is often used with enzymatic methods, such as trypsin digestion, and has a limited impact when used alone. | [82,87] | |
Enzymatic | Trypsin | Removes specific cell proteins, facilitating decellularization. | Prolonged exposure can disrupt the structure of the ECM, removing essential components such as LN, FN, elastin, and GAGs. | [81,88] |
Endonucleases | Enzymes catalyze the hydrolysis of internal bonds in ribonucleotide and deoxyribonucleotide chains. | They can complicate the removal of intact cells. | [87,88,89] | |
Exonucleases | These enzymes catalyze the hydrolysis of terminal bonds in ribonucleotide and deoxyribonucleotide chains. | Limited impact when used alone. | [81,90] |
Cellular Type | Definition | Advantages | Disadvantages | Applications | Reference |
---|---|---|---|---|---|
Fetal and Adult Cells | Fetal cells: maintain phenotypic markers and spatial organization when cultured on biological scaffolds. Adult cells: include renal/alveolar epithelial cells and fibroblasts, often obtained via biopsy. | Fetal cells: show promising functional capabilities in lung, liver, and kidney scaffolds. Adult cells: ease of acquisition via biopsy. | Fetal cells are unsuitable for clinical applications; adult cells have low proliferative capacity and limited scalability for organ repopulation. | Fetal cells recellularize scaffolds, such as rat lung, liver, and kidney; adult cells are used for kidney and lung recellularization, but are limited by low proliferation. | [108,109] |
ESCs | Pluripotent stem cells can expand in vitro and differentiate into multiple lineages. | High proliferative capacity; ability to differentiate into multiple lineages; influence cell differentiation in organ matrices. | Ethical concerns regarding the source; potential for teratoma formation (tumorigenicity); risk of uncontrolled differentiation. | Widely used in tissue engineering studies for the recellularization of organ scaffolds. | [75,109,110] |
MSCs | Multipotent stem cells isolated from bone marrow or adipose tissue can differentiate into various cell types and support tissue repair. | Robust proliferation in culture; differentiation into multiple lineages; secretion of cytokines and chemokines for tissue repair; provision of stromal support. | Differentiation may be inconsistent across different scaffolds. Require precise culture conditions for lineage-specific differentiation. | Hepatic dECM: accelerates differentiation into hepatocytes; cardiac dECM: differentiates into cardiomyocytes under stimulation; pulmonary dECM: differentiates into epithelial lineages. | [110,111,112,113,114,115] |
iPSCs | Stem cells are generated by reprogramming somatic cells to express pluripotency genes, mimicking ESCs. | Adhere to and proliferate on dECM; express alveolar markers in pulmonary scaffolds; and have pluripotent characteristics similar to ESCs. | Lower adhesion in specific scaffolds (e.g., cardiac dECM); risk of genetic instability; labor-intensive reprogramming process. | Pulmonary dECM: promotes adhesion and proliferation. Cardiac dECM: shows lower adhesion than MSCs, requiring further research to optimize use. | [110,115] |
Species Studied | Cell Type Recellularized | Results | Reference |
---|---|---|---|
Bovine | Sheep skin cells | The new material was a biological scaffold for in vitro skin cell culture. | [126] |
Rat and Human | Normal mammary and breast cancer cells | The study described a novel mammary-specific culture protocol that combines a self-gelling hydrogel comprised solely of an ECM from decellularized rat or human breast tissue with a 3D bioprinting platform. | [127] |
Bovine | No cells were used | A series of in vitro tests demonstrated the consistency and potential of this approach for decellularized xenogenic scaffolds, a concept that had not been explored before. | [128] |
Bovine | Endothelial cells | Potential grafts for the treatment of acute ischemia were developed. | [129] |
Human | Adipose stem cells | The study illustrated the potential of regenerative medicine in terms of mammary gland reconstruction to restore breast physiology and morphology damaged by mastectomy. | [26] |
Minipig | No cells were used | SGBTR regenerates soft tissue by implanting additively manufactured bioresorbable scaffolds filled with autologous fat grafts. | [130] |
Species Studied | Main Results | Reference |
---|---|---|
Multiple eutherian mammals and a marsupial (gray short-tailed opossum) | Successfully created next-generation 3D mammary gland organoids from eight eutherian mammals and the first branched organoid of a marsupial mammary gland, providing a model for studying mammary gland evolution and development. | [141] |
Human mammary epithelial cells | Developed a 3D bioprinting protocol for normal and cancerous mammary epithelial cells into a branched Y shape, facilitating the study of cell positioning in regulating proliferation and invasion. | [94,142] |
Mouse mammary epithelial cells | Detailed the use of a 3D bioprinting platform to control the formation of organoids through the “self-assembly” of mammary epithelial cells, enabling consistent and reproducible cultures of large-scale 3D mammary epithelial tissues. | [143] |
Porcine breast tissue | Developed a method for decellularizing and delipidating porcine breast tissue compatible with hydrogel formation, advancing the development of tissue-engineered breast models. | [94,144] |
Canine mammary gland tumors | Utilized 3D culture methods to model canine mammary gland tumors, providing insights into tumor biology and potential therapeutic approaches. | [145] |
Various organoids | Discussed organoid bioprinting approaches that control the 3D arrangement of organoids, contributing to the development of functional tissue for regenerative medicine. | [138,146] |
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Chissico Júnior, F.; Santos da Silva, T.; Vieira Meirelles, F.; Monzani, P.S.; Fornari Laurindo, L.; Maria Barbalho, S.; Miglino, M.A. A Review on Bioengineering the Bovine Mammary Gland: The Role of the Extracellular Matrix and Reconstruction Prospects. Bioengineering 2025, 12, 501. https://doi.org/10.3390/bioengineering12050501
Chissico Júnior F, Santos da Silva T, Vieira Meirelles F, Monzani PS, Fornari Laurindo L, Maria Barbalho S, Miglino MA. A Review on Bioengineering the Bovine Mammary Gland: The Role of the Extracellular Matrix and Reconstruction Prospects. Bioengineering. 2025; 12(5):501. https://doi.org/10.3390/bioengineering12050501
Chicago/Turabian StyleChissico Júnior, Fernando, Thamires Santos da Silva, Flávio Vieira Meirelles, Paulo Sérgio Monzani, Lucas Fornari Laurindo, Sandra Maria Barbalho, and Maria Angélica Miglino. 2025. "A Review on Bioengineering the Bovine Mammary Gland: The Role of the Extracellular Matrix and Reconstruction Prospects" Bioengineering 12, no. 5: 501. https://doi.org/10.3390/bioengineering12050501
APA StyleChissico Júnior, F., Santos da Silva, T., Vieira Meirelles, F., Monzani, P. S., Fornari Laurindo, L., Maria Barbalho, S., & Miglino, M. A. (2025). A Review on Bioengineering the Bovine Mammary Gland: The Role of the Extracellular Matrix and Reconstruction Prospects. Bioengineering, 12(5), 501. https://doi.org/10.3390/bioengineering12050501