INTRODUCTION:

Almost 2.5 billion individuals experience cancer almost every year. There are currently various types of cancer treatment including chemotherapy, radiation therapy, and sophisticated operations. Most data suggests that personalized medicine may be used for accurate patient diagnosis and treatment. The brain metastases are very susceptible to brain metastases in people with lung, breast and colon cancer¹.

50% of patients suffering from pulmonary cancer and 30% of patients suffering from breast cancer are metastasized with substantial amounts in the brain^2,3. Breast carcinoma is the most prevalent common cancer among women, responsible for roughly one out of all cancer deaths in persons in the United States, and that it is the second - leading cause of death in the world, trailing just common diseases. Regardless of constantly evolving possibilities for cancer treatments, there is still demand for a better efficient way for a better outcome. While two dimensional (2-D) crop models have typically been used to understand microenterprises of breast cancer over the past few years, 2D models still have limited performance. Overpowering proof backings that three-dimensional (3D), physiologically important culture models are needed to all the more likely get malignancy movement and foster more viable treatment. Such stages ought to incorporate cancer-specific architectures, applicable physicochemical signs, stromal–disease cell communications, resistant segments, vascular parts, and cell-ECM collaborations found in patient tumors^4,5.Tissue engineering, the use of cell engineering and procedures to produce artificial tissues and organs are one of the most promising ways for alleviating organ scarcity⁶. Appropriate in vitro tumour models are required to study the biological properties of tumour and to evaluate its therapeutic effects. In light of this, there are new discoveries of safe and effective forms of treatment to fight the prevalence of the deadly malignant diseases, however most are still under clinical trial model but with promising results. The cancer originates from an in-situ carcinoma, marked by cell proliferation. This occurs with a complete disruption of the epithelial layer that progresses to base membrane disruption⁷. Furthermore the tumour microenvironment's important properties are recaptured in the technology and models bionic structures and physiological systems are constructed in vitro. These models may be utilised in the research of tumours start, micro-environment interaction, angiogenesis, motility and invasion as well as intra- and extravasation, as robust platforms. Bioprinted models of tumours can also be utilised for the screening and validation of high performance drugs and give the chance for individualised cancer therapy research⁸. The majority of women worldwide are affected by breast cancer, which is increasing in incidence year after year⁹. There are a variety of treatment approaches available for cancer in the current market. Surgical excision, radiation, chemotherapy, and other treatments are the most successful.¹⁰ Many people are unaware that 3D printing technology is not a brand new or recent invention. In 1986, the first successful 3D printing was completed. It's a promising indicator for existing breast cancer treatment approaches^11,12,13. 3D printing is the process where most items, including plastic, steel, power, liquids and even live cells of layers in order to form a 3D project, are made by fusion or deposition of components.When 3D bioprinting implies living cells in the layer to be created in the most sophisticated technologies in cancer therapy^14,15,16. The bio-printing method is a traditional way of creating tissue-like construction that imitates real tissue with the use of biomaterials such as cells and growth cells. The problems of existing breast reconstruction techniques this new technology promises¹⁷. Bio-printing may also be utilized in engineering breast tissue models that act as valuable instruments for cancer research and drug screening applications in line with scientific evidence as well as tissue replacement for beast recovery¹⁸. The creation of tailored medicines or those with various release timings is one of the greatest means of employing 3D printing for biomaterials. This gives seizure therapy for the first 3D printing medication authorized by FDA in 2019¹⁹. It was effectively utilized in pancreatic cancer therapy as a patch for extended release of cancer drugs. This permits the medication, in conjunction with standard chemotherapy medicines poorly in aqueous conditions, to attain a desired tumor site concentration. Research into multidrug tablets is underway. These customized pills would replace a patient with a single tailored pill with many tablets. This is a good approach for breast cancer²⁰. This review explains about the basic concepts of bioprinting in this study covering the design of bioprinter devices, workflow, biomaterials alternatives and present and potential applications.

MATERIALS AND METHODS:

A literature review of publications published between 2016 and 2021 was conducted for this study, mostly using the PUBMED and LILACS databases. Thus, papers in English from systematic reviews, clinical trials, in vitro and in vivo investigations were chosen. We chose 70 articles that were relevant to the topic at hand.

Selecting in -vitro breast cancer models for nanomedicine development:

The model systems vary from 2D cell cultures to in-vivo testing that can be conducted in both large and small animal models. Therefore, the process of selecting a suitable in vitro breast cancer model to be adopted as nanomedicine is a multifaceted process where facts such as its efficacy cost aspects and the ethical concerns are considered. In most cases, during the selection of the core test, MCF7 cell line, TNBC subtype cell line and the TNBC subtypes cell lines are often selected²¹. In conventional cell culture systems, nanomedicine evaluation is often adopted to provide vital information regarding the cell toxicity, mechanisms of action, subcellular localization among other processes. To assess the nanomedicine toxicity, cell viability ascesis are used including luminometric assays, fluorometric and coulometric. For nanomedicine uptake evaluation flow cytometry, confocal microscopy and fluorescence microscopy are employed. Conversely, the action mechanism is analyzed through testing the RNA levels using the functional assays; this in turn predicts the effectiveness in vivo²².

In most cases, the traditional 2D cell structures do not provide conclusive results sufficient enough to nanomedicine treatment predictions. However, there are developments in cell culture, such as the improvement of 3D cell structures. Co-cultures have been developed aimed at overcoming the poor representation of intra tumor heterogeneity, presence of single cell type and the lack of 3D structure necessary for the accurate prediction of the nanomedicine treatment response²³.

Bioprinting:

it is the most common strategy in nanomedicine. This strategy has one major advantage being the high spatial control. However, it has not been heavily explored due to the high expertise needed to conduct the evaluation. Nonetheless, it is already used during organ and tissue fabrication using pattering, which is imperative more especially during biologics. With the advancement in technology, bioprinting is gaining more traction to the advancement in imaging, thus resulting in the increased accuracy of the results.

There are different strategies for nanomedicine in vitro evaluation including co-culture, monolayer cell culture, spheroid, bio printing, organoid and Tumor- on -chip. Due to the lack of precision offered by the other types of nanomedicine evaluation in vitro. Bioprinting has been adopted to solve this problem. Bioprinting entails the creation of a 3D structure through the computer-controlled disposition of biological matter. It adopts the use of different levels of biological material to generate well defined primary cells or cell lines through scaffold free or scaffold based bioprinting²⁴. The highly organized models in bioprinting strategies are used in the evaluation of immunotherapies and their distribution. The adoption of 3D bioprinting in nanomedicine has helped in the early detection of breast cancer.^25,26. This comes in handy to save lives as early detection facilitates early treatment and high degree of survival chance for the patient. 3D bioprinting is the game changer in breast cancer treatment. Additionally, it has improved nanomedicine evaluation and its clinical adaptability. There have been ethical concerns surrounding the development of anti-cancer nanomedicines. Currently, pre-clinical breast cancer animal models are used for evaluation to ascertain the safety and efficacy of the models before advancing to human trials. The precaution adopted from clinical trials is to understand the nanomedicine fate and nature of whole-body distribution features as a guide before official human traits. The animal model mimics the human pathophysiology and is a critical process for the evaluation of any given nanomedicine’s main reason, which main model evaluations, is to promoted the understating of different factors such as include, the animal survival rate, the number mastitis and tumor size^27.These evaluations measure the interactions like targeting efficiency, pharmacokinetics, drug tumor accumulation and pharmacodynamics^28.

3D Bioprinting in modeling breast cancer:

^“A new survey summed up 3D imprinted in vitro malignancy models, featuring progressions made utilizing spheroids, monoculture, and co-culture applications. Examined cancer spheroid arrangement utilizing MCF-7s embodied in conciliatory gelatine clusters^29,30. Afterward, the clusters were utilized to create PEG-Di methacrylate curved wells. The mix of gelatine and PEG permitted for a solitary cancer spheroid development step, dispensing with the need for an extra cultivating step. In another new investigatio³¹ curved PEG-diacrylate hydrogel microstructures empowered the advancement of single BT474 breast cancer spheroids utilizing a 3D projection printing innovation. In both contemplates, hypoxic centers and putrefaction was demonstrated. Showed inconsistencies between a 2D and 3D medication opposition model for temozolomide³²by framing glioma spheroids utilizing a gelatine-alginate-fibrinogen bio ink, bosom disease cells in 3D noticed a higher medication obstruction than those in 2D culture. Two different investigations utilized PEG-based bio inks to make hydrogels with tunable solidness showing a huge contrast somewhere in the range of 2D and 3D microstructures^33,34 while there are numerous instances of 3D printing engineered bio inks for bosom malignancy displaying; there are still not very many 3DBP models that effectively utilize regular bio inks. Matrigel-TM or alginate are usually utilized for 3DBP models, however a hole exists in revealed 3DBP utilizing significant bosom malignant growth-related ECM proteins, for example, collagens type I, III, fibronectin, laminin, different glycoproteins, and proteoglycans. Consolidation of the bosom malignancy related ECM proteins as biochemical signs with the spatial keenness constrained by 3DBP will fill the current hole of bio inks to reproduce local-like bosom malignant growth microenvironments³⁵. Besides, the versatility of 3DBP considers future investigations to research breast cancer cell practices and post-metastatic movement utilizing platforms with definitively designed biophysical properties with a simple change of the local like bosom malignancy microenvironments”

A current 3DBP innovation, freestyle reversible installing of suspended hydrogels (FRESH), is significant for printing progressed design and shows high possibilities for different biomedical applications. Other material innovations incorporate improvement of bio printed in vitro bosom malignancy co-refined model, bioprinting HeLa cells with gelatine/fibrinogen hydrogel to discover contrasts of MMP articulation versus 2D models,³⁶and in any event, bioprinting a cerebrum growth model by expelling glioma undeveloped cells loaded hydrogel. The consideration of spatial control through 3DBP with key biochemical components will have made a new and more exact type of the local like bosom malignant growth microenvironments. With the progressions introduced here, future bearings can be made in the field of customized malignancy research, explicitly restorative medication testing, and duplicating pre/present metastatic microenvironments on viably catch and grow CTCs^36,37Utilizing 3D-bioprinting is a novel technology for developing a new anticancer medicine for breast cancer in humans. Since the turn of the century, drug development for breast cancer has had a poor track record, with 95% of candidate drugs failing to reach the market³⁸. we really need the internal components of the body for our 3D bioprinting process, such as immune cells, fibroblasts associated with cancer, lymphocytes and additional molecules, which are equally important for bio-printing. Raises are made by accurate structural and compositional controls that can be assisted with 3D Bioprinting. For example, in order to study dynamic interaction between these two cell types, a recent model of bio-printed minibrain made up of glioblastoma cells and macrophage has been developed³⁹Micro-extrusion bioprinting is currently the most powerful technology utilized by most researchers. Most evidence shows that bioprinter materials such as gelatin, hyaluronic acid, alginate, and decellularized extra matrix are most common as bioinks to enclosed cells; that they stimulate very well the natural physical and chemical characteristics of the extracellular matrix and are biocompatible, mechanical and structural, integrity and biodegradability⁴⁰. ln one stage, the bio-printing approach principally focuses on the interaction among peptide-conjugation alignment fibers and macrophage breast cancer cells and clinically examines the effect of medication therapy⁴¹. A 3D HER2-positive breast cancer model was also utilized to investigate its response to doxorubicin, and associated response, included in a matrix of adipose-derived mesenchymal stem cells^42,43. The Breast develops under the influence of multiple endocrine pathways, and there many endocrine therapies treatreatd to hormone receptor expressing breast cancer, with avid research joining to further define these molecular targets. Recently, some research has focused on the expression of both the androgen receptor and the glucocorticoid receptor in the differentiation and cancer pathways of the breast, providing novel molecular targets for systemic treatments. Drug development should aim to improve efficacy while reducing adverse effects, a goal that can be achieved only by 3D printing customized medicine^{44, 45,46}. Patients with a pharmacogenetic polymorphism or who use medications with limited therapeutic indices may benefit from customized 3D printing medicines^47,48.

A selection of the material used as a bio ink is the fundamental step in 3D Bio printing:

3D bioink allows biocompatibility and linkages between the gel mixed with the living cells^49,50. when this bioink is prtinted is said to be 3D printing.Bioink is affected by many factors which determine its characteristics, this technique is dependent on single material printing though with current research many materials have been recommended and are in play already. Hinderance by year 2016 was also on few ranges of commercial inks that were compatible with commercial printers, Inks containing natural polymers like chitason,collagen and gelatin have been in play with positive results so far. Another challenge is that cross-linked printable materials should be regulated at body temperatures of between 37^oc and or below to minimize side effects on cells during biomedical application^51,52One of the characteristics of bioink is printability which possed a major challenge back then since the traditional methods involved use of hydrogel materials for layer by layer depositions of materials. Fast forward to 2019 volumetric bioprinting is done by placing the bioink in liquid cells^53,54.

Volumetric bioprinting has reduced the time for carrying out printability another characteristic is that the selected material should be biocompatible to prevent undesirable effects with the cell where its being used^55,56,57. The bioinks should also not be for permanent implants or rather biodegradable and use friendly. The materials used should also be for the final mechanical intended purpose to obtain desirable results. Further finings and research in the fields has really helped in making it easier for bioinks to give this desirable result in biomedical applications^58,59,60.

Techniques for 3D bioprinting:

Bioprinting of wanted tissues might use various methods as per their standards, material requests, and considering their benefits, weaknesses. In light of the standard of activity, 3Dbioprinting can be sorted into three kinds^61,62,63drop based expulsion based, and photocuring-based.

Table 1 Overview for different bioprinting technique

S. No	Types of Bioprinting	Biomaterials Used	Cell Viability/ Resolution	Bio Printing Speed	Advantages	Disadvantages	Ref.
1.	Inkjet –based bioprinting	Low-viscosity suspension of living cells; Biomolecules; Growth factors	~90 % 20–100 µm	Fast (<10,000 droplets/s)	Vast range of abilities, cheaper price, high resolution;high-speed printing; ability to create concentration gradients in three dimensions.	Clogging characteristics of a vertical structure with a poor vertical structure; Cells are subjected to heat and mechanical stress; Materials that can be printed are limited (liquid only).	^63,64
2.	Pressure-assisted bioprinting	Hydrogel; melt; cells; proteins and ceramic materials; solutions, pastes, or dispersions of low to high viscosity; PLGA; tricalcium phosphate (TCP); collagen and chitosan; collagen-alginate-silica composites coated with HA; and agarose with gelatin	40–80 % 200 µm	Slow	There are a variety of materials that can be printed in any dimension;mild (room temperature) circumstances; cellular spheroids are used;Cells are directly incorporated;with a uniform cell distribution	Mechanical rigidity is limited;Gelation time must be precisely timed;To keep forms, the densities of the material and the liquid medium must be precisely matched; viability and low resolution	^65,66,67
3.	Laser-assisted bioprinting	Hydrogel, media, cells, proteins and ceramic materials of varying viscosity	>95 % >20 µm	Medium	Process that does not require the use of a nozzle and is non-contact; High-activity and high-resolution cells are printed;great ink droplet control and precision delivery	High cost; time-consuming and inconvenient;It necessitates the use of a metal coating and is thus susceptible to contamination by metallic particles.	^68,69
4.	Stereolithography	Light-sensitive polymer materials; curable acrylics and epoxies	>90 % ~1.2–200 µm	Fast (<40,000 mm/s)	Nozzle-free and solid freeform technique;highest level of fabrication precision;compatibility with a growing variety of materials;Layer-by-layer printing of light-sensitive hydrogels is possible.	Only applies to photopolymers;polymers that are biocompatible and biodegradable are scarce;persistent hazardous photo-curing reagents have negative consequences;UV radiation has the potential to harm DNA and human skin.	⁷⁰

That is evidence- based safe, effective, and patient centered, timely efficient and equitable⁷¹. This paper proves that operational work place problems and specific technical problems faced by the workers while doing their work. The technological innovation and growth and execution levels in medium scale bio printing industries are highly nonaggressive⁷². Information and Communications Technologies present a range of tools that can be used by teachers to present and demonstrate as part of their teaching as well as something for pupils to use as part of an activity as individuals or in groups⁷³. In general, Career commitment refers to the development of personal career goals by an individual and working towards those goals through the life with involvement⁷⁴. Automation has surely reduced the human efforts and made the new methods for prntings transactions fast convenient and very innovative, giving full satisfaction to customer’s ⁷⁵. Various researches have been done in the world and show that new methods adoption varies based on different factor⁷⁶. Form more hybrid models to improve the efficacy of Technology⁷⁷. Based on the current research findings it is suggested that marketing strategies should focus on making those equipments enjoyable to minimize effect⁷⁸. This presents significant problems. First, the two techniques used for large molecules only work well when the mixture contains roughly equal amounts of constituents, while in biological samples, different proteins tend to be present in widely differing amounts^79,80.

CONCLUSION:

In comparison with the current 2D methods, bioprinting has the biggest benefit, which permits a more realistic, precise and easy 3D tumour modelling. This has resulted in a growing interest among bioprinting technologies in the communities of cancer research to further enlighten the cancer growth, in vivo interactions, drug efficiency, and different forms of cancer therapy. 3D bioprinting have become an enabling tool for screening anticancer drugs and personalized treatment regimens for individual cancer patients. Certainly a novel technical invention becomes an innovative technology to be applied in drug delivery systems, requiring long-term testing, revision and optimization. Bio-printing and personalized medicine are emerging fields which are promising to address challenges encountered with current breast cancer management approaches.

ACKNOWLEDGMENT:

The authors would acknowledge its support for the work.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

ABBREVIATIONS:

DIW- Direct ink writing, FDM-fused deposition modelling LIFT-laser induced forward transfer, LIFT-stereolithography, TERM -Tissue engineering and regenerative medicine,DLP-Digital light processing, SLA-Stereolithography. BP- Biorinting, ECM- Extra cellular matrix.

AUTHOR CONTRIBUTIONS:

Conceptualization and design, R.G; Introduction of cancer I.B.; intermediate cell differentiation. 3D bioprinting of Cancer, R.R schematic illustrations, S.G.; filtration studies, G.K., S.M.M., and R.G.; writing—original draft preparation, R.G, S.M.M and G.M; writing—editing and review, S.M.M; supervision, R.G; All authors have read and agreed to the published version of the manuscript.

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Received on 15.10.2021 Modified on 24.12.2021

Research J. Pharm. and Tech 2022; 15(12):5576-5582.

DOI: 10.52711/0974-360X.2022.00942