Biomaterials for breast reconstruction: Promises, advances, and challenges

Breast reconstruction is the opportunity that provides the chance of having breast after undergoing surgical removal of the breast tissue due to cancer‐related surgery. However, this varies on the stage of the cancer diagnosis and the procedure undertaken. There are many regenerative medicine methods that provide several initiatives and direct solutions to problems such as the development of “bioactive tissue,” which can regenerate adipose tissues with similar normal functions and structures. There have been several studies which have previously explored for the improvement of breast reconstruction including different variations of biomaterials, different fabrication and processing techniques, cells as well as growth factors which enable bioengineers and tissue engineers to reconstruct a suitable breast for patients with breast cancer. Many factors such as shape, proper volume, mechanical properties have been studies but very scattered with not adequate solution for existing patients worldwide. This review article aims to cover recent advances in the biomaterials, which can be used for reconstruction of breasts as well as looking at the various factors that might lead to individuals needing reconstruction and the materials that are available. The focus would be to look at the various biomaterials that are available to use for reconstruction, their properties, and their structural integrity.


| INTRODUCTION
Reconstruction of breast is currently considered as one of the most important aspect when undergoing breast cancer treatment.
There are different factors (lymph nodes and tumor size) that must be taken into consideration when trying to come up with a detailed report on the different techniques and the procedures that are best suited for the individual; as well as whether it meets the particular patient's expectation and needs. The quality of life for these women is the key issue and can cause challenges for surgeons as the psychological and physical impact it has on the patients as a result of the disease plus recovery can sometimes constrain their willingness to change/maintain what they are being/have been offered.
There are different techniques which have been used including pediculate flaps, microsurgical flaps and expander/prostheses (Breastcancer.org, n.d.). Some patients tend to go for the refining technique where they undergo interventions that help to increase the cosmetic outcomes. The different techniques are used to optimize the results; however, it is still not possible to achieve the utopia of perfection as the results expected and the actual outcome can sometimes differ for reasons such as surgical complications (Breastcancer.org, n.d.). In order to optimize the implant quality and the cosmetic results, lipofilling (LF) and acellular dermal matrix (ADM) are used along with the heterologous materials when combined with the right technique.
Breast reconstruction is a technique used to implant new breasts (individual or both) in females for various reasons, a common one being removal of breasts due to breast cancer (complete mastectomy).
There are two categories of reconstruction: immediate and delayed, each of which have their own strengths and weaknesses.

| Biomaterials
As the numbers for the bilateral mastectomy and immediate reconstruction increase, the psychological and the esthetic benefits for reconstruction of breast are accounted for a lot more. It is also increasing its horizon to come up with certain/better biomaterials that would be even better for patients for a longer period and a lot more natural helping to improve the quality of life. Biomaterials have had a big impact on the treatment of injuries and diseases throughout the body; however, no single material is compatible for use for all biomaterial applications, hence the need for constant medical advances. Due to the complexity of issues such as cells reactions to biomaterials, the deigns, synthesis, selection and fabrication of biomaterials are so crucial in order to make the product biomimetic. This involves the mimicking of living tissues or natural materials to serve its purpose for what it is designed for. Certain factors must be taken into consideration when looking into suitable biomaterials for breasts especially for when there is not much else to work with, for example, if someone was to undergo full mastectomy and there is not much skin or tissue to work with. There are certain procedures for postsurgical breast reconstruction that have been developed, which include autologous stromal vascular fraction, platelet-resulting growth factors, biomaterials, and various stem cells. Some of the main biomaterials contain ADM, bone substitute, and injectable, which are applicable for various clinical applications (Zarei & Daraee, 2017).
In most biomaterials, it is integral that the general property of the biological fibrous architecture is similar to the properties of the area of focus. In this scenario, it is vital that the comfort and the wear ability of the biomaterials along with other factors are accounted for.
Due to the complexity of biomaterials and the body (natural reaction) to such biomaterials, certain properties such as wear ability, biodegradation, biocompatibility, nontoxicity, nonallergenic, blood compatibility, and noninflammatory are accounted for. The aims of the biomaterial are to replace, augment, and perform the natural purpose of the breast by using certain techniques that allow the interaction between the biological system (Raghavendra, Varaprasad, & Jayaramudu, 2015). However, there are certain complications with the procedures such as loss of sensation and can no longer breast feed as the original function of the breast cannot be restored due to many complications that arose. Table 1 shows history of breast cancer and reconstruction over time.

| HISTORY OF BREAST RECONSTRUCTION
Every year, approximately 1.7 million women can get a new diagnosis of breast cancer, and this is 11.9% common cancer worldwide Torre et al., 2015). By developing treatments, doctors can reduce the death race (522,000 deaths per year; Ferlay et al., 2015); also, the universal onus of the breast cancer continues to be huge (Maddams, Utley, & Moller, 2012). For example, in the United Kingdom, every year, 14,000 women lose their lives because of this disease. The age of death race and standardized incidence is one of the worst in the world (Jeevan et al., 2009). The people who survive from this disease enable to change their life with some physical, emotional and psychological alterations which of course required multidisciplinary management (Bates, Kearins, Monypenny, Lagord, & Lawrence, 2009;Browne et al., 2008;Lee, Sunu, & Pignone, 2009;Maddams et al., 2012;NIHCE, 2009). Breast cancer treatment has developed considerably; our understanding of the pathophysiology and molecular etiology has developed the path in which first and adjuvant therapies are destined as represented in Table 1 (Mahmood et al., 2013;Tuttle, Habermann, Grund, Morris, & Virnig, 2007).
Compared to 50 years ago, the statistics has doubled but treatments are available that can play a significant role to improve life expectancy (Mahmood et al., 2013).
Around 46,000 women in the United Kingdom are diagnosed annually with breast cancer, and approximately 40% undergo mastectomy as their first therapeutic step (Metcalfe et al., 2008;NIHCE, 2013) and 30% have either direct or late reconstruction.
One of the health care in England (National Institute of Clinical Excellence guidance) advises that all women undergoing breast cancer surgery must be presented directly reconstruction at their primary operation (Neuburger, Macneill, Jeevan, van der Meulen, & Cromwell, 2013;NIHCE, 2013). Suspected patients are firstly undergoing adjuvant treatment and sometimes will be late and therefore reconstruction will be a choice. Patients should be provided with all the choices in order to make the best decision (Neuburger et al., 2013). However, only 21% directly undergo reconstruction (Metcalfe et al., 2008). Patients who are undergoing mastectomy alone have been offered to have a choice for reconstruction (NIHCE, 2013).

| Cancer
Cancer is a disease of genes that causes cells to grow abnormally.  (Thomas, 1991). The growth and differentiation of breast tissue are regulated by several factors including hormones such as progestogen. Figure 1 illustrates the cancer cell production and the different stages that occur for an individual cell.
There are different types of breast cancer, which can either be noninvasive or invasive. Noninvasive breast cancer does not have the ability to spread, which can either be located within the breast or to any other part of the body, that is, ductal carcinoma in situ (DCIS), which is an early type of cancer. In this type of cancer, the cancer cells are present in the ducts (milk) known as "in situ," which do not have the ability to spread. Breast cancer occurs when the malignant tumors develop in the breast. The cells can spread as they move away from the original tumor and enters the lymph vessels and blood vessels and branch into tissues throughout the body (National Breast Cancer Foundation, n.d.).

| Stages of cancer
There are five main stages of cancer, each separated to help diagnose cancer earlier and quicker for better treatment options as shown in

| Cosmetic reasons
There are certain factors that might motivate people to undergo cosmetic surgery for the reconstruction of their breasts (Shiffman, 2001). Factors such as self-esteem, life satisfaction, self-rated physical attractiveness, religiosity, and media consumption all play a crucial part in some women's decision on wanting the procedure (Furnham & Levitas, 2012). Although this can fall under the category of breast reconstruction, it is more considered medically necessary. Reconstructive plastic surgery is performed in order to often restore the function and the normal appearance as well as correct certain deformities that might have been caused for various reasons such as trauma birth defects and medical conditions including cancer (Chrysopoulo & Antonio, 2018).
There is also a procedure known as the revision surgeries. This not only includes the correction of bad surgeries but are also used as secondary surgeries to other treatments such as radiotherapy or overall changes in the patient's overall structure. This includes any changes such as weight or skin elasticity. It can also be used for the

| TYPES OF BREAST RECONSTRUCTION
There are different reconstruction techniques that are available. The two main ones include implant reconstruction and autologous or "flap" reconstruction. The implant reconstruction is when an implant filled with saline or silicone gel is inserted (Middleton, 1998). The implant size varies depending on the size of the patients (their overall build) and the type of surgery they underwent. This is to ensure that the right techniques are used, which are needed for the specifics of what the patient is wanting. Choices also depend on the availability within the area as overtime plastic surgeons can often develop newer techniques especially for techniques such as "flap reconstruction," which can often avoid cutting through muscle donor such as the belly to take tissues from other parts of the body such as buttocks.
Using an implant to rebuild the breast requires less surgery than flap reconstruction as it only involves the chest area and not a tissue donor site. However, this still requires more surgical procedure as well as the possibility of more surgeries in the future as implants can often wear out or develop other issues such as scar tissues forming around the implant or tightness (Breastcancer.org, n.d.). Table 3 below shows the reconstruction types as well as the different strengths and weaknesses. There are also emotional strengths and weaknesses of breast recognition. A more commonly used synthetic material is polylactic acid (PLA).

| CELL SCAFFOLDS
PLA is a polymer that degrades into lactic acid, within the human body. Lactic acid as we know is a naturally occurring chemical that the body can remove easily by oxidation into carbon dioxide and water, or convert into glucose for glycogen. Polyglycolic acid and polycaprolactone have similar degradation mechanisms when compared with PLA. These materials consist of a well-maintained mechanical strength with good structural integrity but exhibit a hydrophobic nature. As a result of this, the hydrophobicity inhibits the material biocompatibility, thus making them less effective for tissue engineering in vivo applications (Wang, Wang, Gu, & Luo, 2016). To correct the lack of biocompatibility, a vast amount of research has been carried out, to combine the hydrophobic materials with hydrophilic and more biocompatible hydrogels.
Hydrogels have superior biocompatibility, but they do not have the structural integrity of PLA, polyglycolic acid, and polycaprolactone.
Researchers have combined two different types of materials from the mentioned materials, so that a synergistic relationship can be created, which gives a more biocompatible tissue scaffold (Bosworth, Turner, & Cartmell, 2013).
There are huge interest in using scaffolds which are fabricated by natural materials including different derivatives of the extracellular matrix (ECM) (Oxford, Reeck, & Hardy, 2019). Studies have evaluated their ability to support cell growth. Protein materials, such as collagen or fibrin, and polysaccharidic materials, such as glycosaminoglycans (GAGs) or chitosan, have shown positivity in terms of cell compatibility, but on the other hand, potential immunogenicity has remained.
Immunogenicity is when an immune response is provoked in the body (Washmuth, 2019). Also, hyaluronic acid in combination with crosslinking agents (e.g., glutaraldehyde or water soluble carbodiimide) has been possible choices as scaffold materials. Functionalized groups of scaffolds, have been useful for the delivery of small molecules (drugs) to specific tissues.
Decellularized tissue is another form of scaffolds. These have been under recent investigation and are the result of isolating the ECM of a tissue from its inhabiting cells, leaving an ECM scaffold of the original tissue. This can then be used in artificial organ and tissue regeneration. The process involves taking the required tissue from the source (animal or human) and lyse or kill the cells within the tissue. It is key for the researchers to avoid damaging the extracellular components and produce a natural ECM scaffold, consisting of the same physical and biochemical functions of the natural tissue (Gilbert, Sellaro, & Bsdylak, 2006).
Once the ECM scaffold has been acquired, it is recellularized with potent stem or progenitor cells. These cells have the ability to differentiate into the original type of tissue. As the cells have been removed from the donor tissue, its immunogenic antibodies are removed. The progenitor cells are taken from the host, so they will not have any adverse effects on the tissue as they are biocompatible.

| Advantage and disadvantage of scaffold design
A key feature of biological scaffolds is that they need to be porous for vascular ingrowth. Because of this, the scaffold should consist of pores that allow cells to interconnect and adhere to one another. Furthermore, the scaffold should ideally release chemicals, which help promote the cell adhesion, proliferation, and differentiation into specialized cells that have the ability to migrate.
Finally, some tissue-engineered scaffolds should be biodegradable depending on their role. This means that the scaffold should be able to break down safely within the body, once the cells have formed into their intended shape. Also, it should prevent the occurrence of a long-term immune reaction. In context, an "ideal" scaffold can be described as one that allows the production of "like for like" tissue, with similar physical and biochemical properties as the tissue it is replacing.
One major flaw in the design of tissue-engineered scaffold is reduction in oxygen and supply of nutrients to some of the cells within the scaffold. The reason for this is because cells migrate deep into the pores of the scaffold to a certain extent. The cells start to get too deep into the pores of the scaffold, so they become shadowed by the layer of cells that have tightly formed above them. As a result of this deep growth, the above layer of cells prevents and blocks any nutrients and oxygen from getting into the cells below.
An innovation called the solid freeform has been designed and its development stages to overcome this flaw. Solid freeform uses The reconstruction types as well as the different strengths and weaknesses

Reconstruction type Strengths Weaknesses
Breast implants Fewer surgery and smaller recovery time compared with tissues flap breast rehabilitation as the thigh, belly, and buttocks by liposuction. This tissue is then processed into liquid and injected into their breast area to recreate the breast. The procedure is described as being "superior" for soft tissue augmentation, due to its range of properties, such as biocompatibility and versatility.
Also, it is nonimmunogenic, so it does not induce any negative immune responses, while having similar mechanical properties to breast tissue. Furthermore, it appears more natural when compared with implants or pedicle flaps and has a minimal complication when healing. As a result of these properties, there has been an increased focus on the potential for adipose tissue engineering to produce sufficient amounts of fat for breast reconstruction. Therefore, adipose tissue engineering requires a stem cell with the capability for the differentiation into mature adipocytes.
LF is another form of fat grafting used to correct minor incorrectness in shape, balance, or position of a reconstructed breast. This procedure has been used for a number of years and is successful, so doctors have thought to believe a complete breast can be reconstructed by this method.
The field of regenerative medicine has found a consistent and reliable source of the required stem cells. The use of adipose tissue has given an abundant and accessible source of adult stem cells, especially adipose-derived stem cells (ADSCs). ADSCs are isolated by less invasive means compared with other stem cells and give a higher yield of cells than bone marrow aspirates or umbilical cord blood. ADSCs are isolated from lipoaspirates obtained via liposuction procedures.
The isolation of ADSCs from adipose tissue is done by digesting it with collagenase, filtering, and centrifuging. Each procedure can produce 90-100% viable ADSCs.
In order to recreate the breast after mastectomy, it will require a lot of maintenance of larger tissue volumes in engineered grafts that are supported by a biocompatible scaffold. Recent literature has suggested that there has been a limited success with "scaffold-free" techniques. The scaffold-free method, induces ADSCs to differentiate into adipocytes, while being stimulated by the supplementation of culture media with ascorbic acid to produce an organization of ECM, which forms sheets that can be assembled into thicker adipose tissue.
As mentioned in the section called "importance of scaffold design" in this literature, it is key that engineered scaffold-based constructs have the correct scaffold material and design selection. This is paramount in overcoming the problems associated with volume retention and vascularization.
In this section, an exploration of existing literature on breast reconstruction using a tissue engineering approach will be explored.
This is intended to give a wider understanding of how tissue engineering for breast reconstruction began and the current findings that have led to further research to be carried out in this field. Researchers have categorized the composites scaffolds into biological and synthetic scaffolds.

| Biological engineered scaffolds
Collagen based Huss and Kratz (2001) founded the first step toward regenerating human autologous breast tissue on a three-dimensional matrix and published their findings. The procedure was conducted by culturing human mammary epithelial cells and adipose tissue on collagen gel in vitro. A growth pattern of large epithelial patches, shaped like fibroblasts, was observed, with preadipocytes in between that had a round shape, which had accumulated into lipids with progression.
In order to survive, cells require adhesive materials. Type I collagen has been found to have an excellent porous structure, making it a suitable scaffold for cell migration and proliferation (Glowacki & Mizuno, 2008). Using this research, a small amount of type I collagen with sponge and saline was injected into a polypropylene cage that had been implanted into a rabbit's bilateral fat pads; other natural biomaterials are represented in Figure 2. The study had reported after 12 months a generation of significant volumes of adipose tissue from surrounding tissue, along with growth factors essential for adipogenesis and angiogenesis (Tsuji et al., 2012). Adipogenesis is a process of cell differentiation, in which preadipocytes become adipocytes and angiogenesis is the development of new blood cells. A drawback to the process was the polypropylene cage used. It was nonabsorbable and found to be too hard for breast reconstruction; so further research will be required to create the optimal scaffold.

Decellularized tissue
Omidi et al. illustrated that DAT (decellularized) scaffolds, which are sourced from different areas of a female (breast or subcutaneous abdominal region and so on), consisted of linear elastic and hyperelastic properties. They also had consistent Young's modulus of previously reported adipose breast tissue (Samani, Zubovits, & Plewes, 2007). This was considered an advantage, as it would mean that DAT scaffolds can be sourced from any of the areas already mentioned, for commercial use. Also, the scaffold would present similar stiffness and deformability when compared with a natural breast, which is under gravity load from prone to a supine body position.
The major limitations of biological scaffolds are rapid enzymatic and hydrolytic degradation, alongside immunogenic response in vivo.
This is the loss of relevant properties in the materials. There are techniques developed to reduce the rate of degradation, like cross linking various agents and enzymatic pretreatment, thus improving robustness and maintaining the integrity. One of the most important factor of a biological scaffold is to provide mechanical support during regeneration until it is mature enough to support itself. Unfortunately, biological materials are unable to conduct this, so current research is looking at other avenues such as synthetic scaffolds.

| Synthetic engineered scaffolds
Majority of synthetic scaffold are synthesized from thermoplastic polymers; thus, they can be subdivided depending on their structures of hydrogel fillers or a solid structure support. Also, other biomaterials are shown in Figure 3.

Hydrogel structure
Similar to biological scaffolds, the biochemical and biomechanical properties of synthetic scaffolds also influence proliferation and adipocyte migration. Hettiarachichi et al. 2012 investigated the stiffness of polyacrylamide gel and its effect on adipocyte differentiation in vitro. It was discovered that the most favorable matrices for scaffolds were those which had a similar stiffness to adipose tissue.
This finding was paramount for a soft tissue support, in order to replace breast tissue.
Other findings found hydrogels as a system that could be used to deliver drugs. As a result of this, polyethylene glycol (PEG) and desaminotyrosyl-tyrosine ethyl ester (DTE) were synthesized to form curcumin-derived hydrogels. This hydrogel had the ability to release active curcumin upon hydrogel degradation .
Further compositions of hydrogel could also be synthesized, by a condensation polymerization protocol, which altered its properties such as concentration of curcumin and swelling ability (Shpaisman, Sheihet, Bushman, Winters, & Kohn, 2012

Solid structure
A polylactide polymer scaffold was created using a 3D printer (Chhaya, Melchels, Holzapfel, Baldwin, & Hutmacher, 2015). It gave the ability to customize the shape and size of the engineered breast, while tailoring the internal morphology, such as porosity and pore size for individual patients. Under observation in vivo (nude rat model) over a dix month period, the polylactide polymer scaffold was able to withstand contraction forces without the loss of any mass. The scaffold had a pore size of 1.5 mm for vascular in growth, and after 24 weeks, 81% of the tissue over all tissue consisted of adipose tissue, which had obviously derived from host adipocytes. Also, there was minimal inflammatory reaction, as the scaffold integrated within the host body, and degraded accordingly the fibrotic capsule that surrounded it.
One of the biggest disadvantages of synthetic scaffolds compared with biological scaffolds is the process of seeding the scaffold with cells and tissue components; there is a lower cellular infinity to synthetic material. To overcome this draw back, Rossi et al. (2018) attempted to produce a hybrid scaffold by combining certain functionalities of a synthetic polymer with a biological matrix, but this was an expensive procedure and produced a highly complex biomaterial.
This form depends on the length of the hydrocarbon chains as waxes tion. This is done by heating the paraffin in a chamber surrounded by warm water prior to injection as represented in Figure 4.
The first report of the use of paraffin injections dates back to a report by Gersuny of Vienna in 1903 (Gersuny, & Harte, 1903). The patient in this report was a young man who had previously undergone a bilateral orchiectomy for tuberculosis disease. According to the report, paraffin was injected into his scrotum in 1899 in order for the patient to pass the physical examination required to join the army.
Paraffin injections were then used predominantly in breast augmentation from 1899 to 1914.
Initially, paraffin injections showed signs of being acceptable; however, complications normally showed up 5-10 years after injection. Complications included pulmonary embolism, migration, ulceration, fistulae, infection, necrosis, and death. All of these complications frequently lead to breast amputation. Figure  H. Lyons Hunt (1926) referred to paraffin injections as an "inexcusable practice" and blamed "beauty doctors" for its continuous use.
This practice was continued in the far east until the 1960s, and deaths continued to be reported from the paraffin injections. In Europe and the United States, some patients injected themselves with paraffin even after the procedure was deemed to be unsafe in order to inflict injury upon themselves to escape military service. Some other patients injected themselves with paraffin in order to enlarge their breast, and this went on for a century.
Other materials  After paraffin was deemed to be unsafe for use, there was a period of around 30 years, where a variety of materials were used for breast augmentation. Injectable materials included vegetable oils, mineral oil, lanolin, beeswax, shellac, epoxy resin, goat's milk, soybean oil, and peanut oil (Bondurant, Enester, & Herdman, 1999).
During this time, many solid materials were also implanted into women's breasts to make them bigger. These solid materials included ivory balls, glass balls, silk fabric, epoxy resin, ground rubber, ox cartilage, sponges, sacs, rubber, Teflon, and glazier's putty.
None of these materials proved to be useful for breast augmentation as they caused complications such as inflammation, severe tissue reactions, and infections.
Liquid silicone  In the 1940s, many physicians and lay clinics turned toward liquid silicone injections for the first time for breast augmentation. Silicones are extensively cross-linked polymers of dimethyl siloxane. In 1943, two companies by the name of "Dow Corning Corporation" and "Corning Glass" started collaborating in the United States, in order to develop silicone products for military purposes during World War II (Peters, 2009). When the war was over, Dow Corning attempted to adapt their product to that of medical-grade silicone.
Near the end of World War II, industrial-grade liquid silicone started being used personally in Japan. Barrels of industrial-grade silicone started mysteriously disappearing from docks in Japan, which were intended for injection into the breasts of "enterprising ladies." This industrial-grade liquid silicone was never produced with intention to be injected into the body and therefore caused many complications within these women.
The complications that we saw with paraffin were repeated with the use of silicone injections, and some complications were even worse due to impurities and additives in the preparation of the material. During the preparation, contaminants were added in order to cause a sclerosis reaction to try to restrict migration to other sites of the body (Vinnick, 1978). Some common contaminants used were croton oil, cobra venom, olive oil, and peanut oil. This caused a variety of adverse effects in the body, such as migration to other parts of the body, inflammation, discoloration, granulomas, ulceration, fistulae, and infection.
In 1960, Dow Corning invented its first commercial medical-grade silicone, labeled "Dow Corning 360." This product was intended for use in waterproofing skin and treating patients with burn; however, many physicians and lay clinics still use this for injection in patients to enlarge breasts. It would often be found that huge volumes of the medical-grade silicone were injected into the breasts under great pressure. It was estimated that in Las Vegas in the 1960s, two physicians injected the silicone into over 10,000 women's breasts over 10 years; however. no record was kept of these women after injection.
By 1965, many complications started to show in the patients who had undergone the injection of the medical-grade silicone (Matton, 1985). Due to these complications, the Food and Drug Administration labeled these injections as new drugs in 1966 (Coleman, 2001) and therefore concluded that some laboratory investigations must take place before it could be safely approved for use. Polyacrylamide hydrogel  Polyacrylamide hydrogel (PAH) is a soft tissue filler substance, consisting of many cross-linked polymers. It has most commonly been used in Ukraine, Russia, and China over the last 15-20 years (Christensen, Breiting, & Aasted, 2003 One hundred sixty-one out of the 183 cases were patients who had injected their breasts and suffered infections and disfigurement.

| Sponges
The first sponge to be used was Ivalon, a polyvinyl alcohol sponge.  (Conway & Dietz, 1962). These sponges also caused capsular contracture in addition to causing infection and erosion. Another implant used around the same time as the previous sponges was that of the polystan sponge (Edgerton & McClary, 1958).
This consisted of fabric tapes, cut by machines and moulded into the shape of a ball by hand. In 1963, Edwards created an implant consisting of a sponge of silastic surrounded by a thin layer of Teflon. The Teflon shell was designed with the intention of preventing capsular contracture; however, it was not successful in doing so, as implants still showed signs of capsular contracture 6-12 months after implantation.
All forms of the sponge implantation technique provided us with similar results, ultimately ending in capsular contracture. This lead to the cut down on breast augmentation using sponge implants in 1963.

| Breast implants
The evolution of breast implants has been a revolution in breast augmentation, stretching over 60 years, first starting in 1963 and extending to the present time.

Silicone gel implants
Silicone gel breast implants were first introduced in 1963 by Cronin and Gerow. Many different types of the implant were produced after their first introduction from 1963 to 1992 as there was no "standard" formula for the silicone gel breast implant. These implants consisted of silicone elastomer shell, varying in thickness (0.075-0.75 mm) depending on the volume of silicone gel destined to be enclosed within the shell (80 cc to 800 cc) (Bondurant et al., 1999). The elasto-  Figure 6a. These implants were produced by dipping a mandrel into a dispersion fluid, and the shell would be removed and injected with gel. The implant caused four women to develop very firm breasts within a year of surgery due to capsular contracture. Capsular contracture was not very well understood at the time, and therefore, it was believed that the firmness of the breasts was due to the firmness of the implant. Due to this common belief, second-generation implants were formed with the intended softer design.
Second-generation implants as represented in Figure 6b were first introduced in 1972, and they were used until the 1980s. They contained a thinner shell wall and also a less viscous gel in an attempt to create a softer implant. The gel consisted of 20% highly crosslinked silicone and 80% low molecular weight chains. When some patients underwent revision surgery on their breast, the implants were found to be disrupted, proving that the second-generation implants were far less durable than that of the first generation (Peters, Smith, & Lugowski, 1996). The third generation consisted a stronger and thicker shell and a more cohesive gel than that of the secondgeneration implant as shown in Figure 6c. They also contained a "barrier layer," placed to reduce the diffusion the low molecular weight silicone oil, which at the time was thought to be the reason for capsular contracture. This barrier was a 0.01 mm thick layer of fluorosilicone on the interior wall of the shell. These implants proved to be much more durable than that of the second-generation implants; however, it was believed that the barrier layer lost effectiveness after only 2-3 years (Peters et al., 1996).
The next implant that was designed was that of the double-lumen implant. This implant has two shells, with the inner layer being filled with gel and the outer layer being filled with saline. This outer layer was designed in order to form another layer to prevent silicone oil diffusion; however, this was not proved to be effective (Yu, Latorre, & Marotta, 1996).

PU-coated implants
The first PU-coated implant was introduced in 1968 by Ashley and Pangman, and it was labeled "Ashley Natural Y implant" (Ashley, 1970). The implant consisted of gel filled silicone implant coated with a layer pf PU of 1.5-2.0 mm thickness. This coating was added with the intention of allowing the implant to retain its shape over long periods.
PU-coated implants quickly became very popular in the 1980s, as they seemed to reduce the cases for capsular contracture within the patient (Capossi & Pennisi, 1981). The rates for capsular contracture dropped significantly with this implant, with only 1-2% after breast augmentation. It was later found that in physiological conditions, such as the patients' breast, the layer of coating on the PU implant would disintegrate over time (Benoit, 1993). When the PU foam undergoes degradation, it releases carcinogenic compounds such as 2,4-toluenediamine (2,4-TDA), which was shown to be toxic in animals (Hester, Ford, & Gale, 1997). This subsequently lead to the removal of the PU implants from the market in 1991 even though it was later revealed that the small amounts of 2,4-TDA released would not provide a significant health risk.

| Extracellular scaffolds
Growth factors are soluble secreted signaling polypeptides, which have the ability to instruct specific cellular responses in a biological environment (Cross & Dexter, 1991). Once a specific cellular response is triggered by the growth factor signal, it can produce a range of cell actions, such as control over migration, proliferation, or differentiation of a specific group of cells and cell survival. In order to bind and modulate the activity of the growth factors, the ECM consists of numerous components, which are notch signaling molecules, traction enabling adhesion molecule, adhesive molecules, and proteoglycan molecules (Ramirez & Rifkin, 2003). Initialization of the signal transmission mechanisms is initiated with the growth factor secretion by a producer cell. By binding to specific transmembrane receptors on the target cells, the growth factor instructs cell behavior. Many complex events consist of machineries that transduce the growth factor F I G U R E 6 Generation Implants.

| Epidermal growth factor receptors-Cancer studies
Growth factors responsible for the stimulation of epidermal growth factor receptors are epidermal growth factor (EGF), transforming growth factor alpha, epigen, amphiregulin, betacellulin, heparinbinding EGF, epiregulin, and neuregulins. These growth factors have the ability to selectively bind to specific epidermal growth factor receptors (Rijal & Li, 2016). The polypeptide EGF is commonly used in breast cancer studies and can be detected in the blood, urine, and milk, with levels being much higher in woman on contraceptives as illustrated in Table 4. Also, ErbB2/HER2 are receptors that are also detected in breast cancers at a 25% amplified rate.

| Acellular dermal matrix
ADM has become a vital part of alloplastic breast reconstruction, with two widely used products being AlloDerm and DermACELL in modern day immediate alloplastic breast reconstruction. ADM is produced by removing cells from human or animal tissue while retaining portions of the ECM. This means that the main components of ADM are elastic fibers and collagen bundles.
Alloplastic breast reconstruction is currently on the rise, with a reported yearly increase of 11% according to a study in 2017 (Panchal & Matros, 2017). ADM's were only introduced in 2009 after they were approved in Canada. Due to European law, human-derived ADM, manufactured outside the EU, cannot receive a CE mark and therefore cannot be used inside the EU. Human-derived ADMs were initially considered expensive and were not made widely available for breast reconstruction due to financial regulations on the healthcare system. A cheaper solution was found to be animal-derived ADMs; however, this was found to cause more complications than the human-derived ADM, and it was concluded that human-derived ADM should be preferred to animal-derived ADM wherever possible.
There are a variety of ADM graft products available on the market already; however, each of these grafts differ in way they are processed to create them and also in their size and thickness. This allows for the grafts to be used in numerous soft tissue applications such as (Qi, You, Li, & Li et al., 2013): • Soft tissue ridge augmentation • Gingival augmentation • Soft tissue augmentation around implants • Exposed root coverage AlloDerm was one of the first human-derived ADMs used in breast reconstruction, and it has been proved to be safe, given the product's success and dominance on the market. However, the industry has grown, and as a result, more products have recently been found on the market with potential improvements such as cost, practicality, and increased vascular ingrowth. One of these new products is DermACELL, which has shown promising results but limited data to prove it can compete with the AlloDerm product.
There have been some common complications found associated with the use of ADM in breast reconstruction, most commonly hematoma, seroma, and infection (Colwell et al., 2011). A systemic review of 16 selected studies of ADM reconstruction concluded a rate of 2% for cellulitis, 5.7% for infection, and 6.9% for seroma, with other complications such as reconstructive failure reported in 5.1% of ADM reconstructions (Ho et al., 2012). Many risk factors could contribute to the possibility of these complications, such as radiation, large breasts, higher intraoperative fill volumes, and increased surface areas  (Selber et al., 2015). Other factors such as a high body mass index (BMI) and smoking could put patients at a high risk of complication.

| DermACELL versus AlloDerm
A study of 95 breasts on 64 patients was conducted at The University of British Columbia to investigate the complications in ADM reconstruction in breast surgery with the use of AlloDerm and DermACELL between January to December of 2016. All patients' physical and medical states were reviewed and breast characteristics were noted.
After surgery, each reconstructed breast was deeply evaluated and analyzed for any possible complications, and the results were noted. Signs of infection were identified as cellulitis, purulent discharge, and systematic illness, whereas seromas were identified by physical examination and treated specifically depending on the size (Donnely, Griffin, & Butler, 2019 A Shapiro-Wilk test was performed to assess whether the data were normally distributed, and an independent t and Mann-Whitney U test was performed. For these data, p values <0.05 were deemed to be significant.  It was concluded that overall, the data did not show any significant differences in the complication rates when comparing DermACELL and AlloDerm groups (Burkhardt, 1984). Age, BMI, skin pattern type, and mastectomy also did not affect complication rates (p = 0.841). A larger implant volume showed signs of increasing the risk complications but however did not reach the significance (p = 0.076); however, it did reach significance in risk for implant replacement (p = 0.041). Capsular contracture in patients without radiation only took place when using DermACELL and also showed significance (p = 0.042).

| Implant-based reconstruction
In most cases, breast reconstruction with implants is a simple procedure that takes up to 2 to 3 h, with a short recovery period. They are advised for patients who are undergoing reconstruction of both breasts or are not suitable for a long operation (Macmillan.org. uk, 2019). Implants are suitable if the patient has skin sparing or nipple sparing mastectomy, where majority of the skin, and in some cases, the nipple, is kept. The implant can come on a variety of sizes and shape (tear drop or round) while being made of a silicon outer cover with a silicone gel or salt water (saline) inside (Middleton, 1998). The outer surface can be smooth or textured. The reconstruction can come in a one-stage or a two-stage procedure (Figure 7). After the operation of placing the expandable implant under the chest is complete, it takes a few weeks for the surrounding tissue to heal. Once healed, the process of stretching the muscle to form the new breast shape begins. Every 1 to 2 weeks, a practitioner will inject the implant with the saline via the valve that is under the skin of the underarm. This is conducted for several weeks, gradually stretching the implant to the required shape and size. It may be inflated more than necessary slightly, to later remove some saline, so that both breasts follow the same contour. Finally, a surgeon will remove the valve during a small operation. Figure 7b illustrate a two-stage procedure that consists of a temporary tissue expander being put under the chest muscle. The temporary tissue expander has a hollow inner chamber, but not a silicone gel outer, such as the permanent expandable implant.
A practitioner injects saline into the expander through a valve, which is located under the skin of the chest, thus increasing its size, and stretching the chest muscle to form the breast shape. Once the temporary implant has expanded to the required expansion, it remains in place for a few months, so the muscle can stretch and grow accordingly.
This implant is then removed by a second operation, so a permanent silicone implant can be put into the space created under the chest muscle as shown in Figure 7c. Finally, the final breast shape is now constructed. A fairly new procedure known as lipomodeling or LF is beneficial, as it gives the patient a chance to improve the shape and appearance of the reconstructed breast. This procedure is described further in the section "Breast Reconstruction using Scaffolds."

| Acellular dermal matrix
Most recently, surgeons have begun to use a type of mesh called an ADM, to support the implant. ADMs are human, bovine, or porcine derived biotechnologically engineered, with a tissue-like end product.
The ADM is used by attaching it to the pectoral (chest) muscle and the chest wall to create a sling, which holds the lower part of the implant in place to give the breast a natural droop.

| Autologous reconstruction
Autologous reconstruction is a tissue flap procedure, which is also use presently to rebuild the shape of the breast post mastectomy (Cancer. org, 2019). The procedure uses tissue from other parts of the body like abdomen, back, thighs, or buttocks to rebuild the breast shape.
They have the ability to look and behave like natural breast tissue, as oppose to breast implants. The most common types of tissue flap procedures are as follows: • Transverse rectus abdominis muscle flap, which uses tissue from the abdomen whereas the differentiation capabilities of the cells into mature cell types can be defined as a potency ability (Zandstra & Nagy, 2001).

Embryonic stem cells
In mammals, there are a variety of stem cells. Embryonic stem cells are isolated from the inner cell mass of blastocysts in early embryonic development. They have the ability to differentiate into many specialized cells such as ectoderm, endoderm, and mesoderm and also maintain the normality of regenerative organs such as blood, skin, or intestinal tissue (Thomson et al., 1998). Due to their ability to differentiate into all of the adult cell types, they are useful for cell replacement therapies for diseases like Parkinson's disease, Alzheimer's disease, and diabetes.

Adult stem cells
Adult stem cells are a group of stem cells that consist of undifferentiated cells found in various tissues of a fully developed mammal. These cells have a large capability of extensive self-renewal, so they act as a repair system for the body by replenishing adult tissue. Also, they can be differentiated into various specialized cell types:

| CONCLUSION AND FUTURE PERSPECTIVES
There are three major tumor subtypes categorized according to ER or PgR expression and ERBB2 + gene amplification in breast cancer.
These subtypes have different risks and treatment approaches. The best therapy for each woman depends on tumor subtype, women preferences, and anatomic cancer stage. Furthermore, involvement in clinical ways with new aimed therapies could have an advantage for women by adding efficient additional therapy stages in the treatment sequence for metastatic breast cancer.
As breast augmentation is one of the most common esthetic surgeries in the world, plastic surgeons strive for perfection. To this date, undesired outcomes are encountered, which leads to revision surgery.
As ADM is on the rise due to its great outcomes in breast reconstruction, it has gained a lot of interest for esthetic use in breast surgery patients. It is believed that the future of breast reconstruction surgery rests in the use of ADM, and this should be developed in order to perfect the modern-day breast reconstructions.
However, there is large difference in treatment between Black African women and White women. Also, these differences are related to presentation characteristics at diagnosis between 1991 and 2005 rather than treatment differences. Moreover, scientists must find a way to treat all women and even stop breast cancer. Why it is difficult to treat Black women than White women?