Added: Tobey Henriksen - Date: 12.05.2022 17:32 - Views: 19655 - Clicks: 6156
Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. Complete removal of cancerous tissue and preservation of breast cosmesis with a single breast conserving surgery BCS is essential for surgeons. New and better options would allow them to more consistently achieve this goal and expand the of women that receive this preferred therapy, while minimizing the need for re-excision and revision procedures or more aggressive surgical approaches i.
We have developed and evaluated a regenerative tissue filler that is applied as a liquid to defects during BCS prior to transitioning to a fibrillar collagen scaffold with soft tissue consistency. Using a porcine simulated BCS model, the collagen filler was shown to induce a regenerative healing response, characterized by rapid cellularization, vascularization, and progressive breast tissue neogenesis, including adipose tissue and mammary glands and ducts.
The collagen filler also did not compromise simulated surgical re-excision, radiography, or ultrasonography procedures, features that are important for clinical translation. When post-BCS radiation was applied, the collagen filler and its associated tissue response were largely similar to non-irradiated conditions; however, as expected, healing was modestly slower. This in situ scaffold-forming collagen is easy to apply, conforms to patient-specific defects, and regenerates complex soft tissues in the absence of inflammation. It has ificant translational potential as the first regenerative tissue filler for BCS as well as other soft tissue restoration and reconstruction needs.
Breast cancer is the most commonly diagnosed cancer in women, with over 2 million new cases every year world-wide and approximatelyper year in the United States alone 12. BCS involves removal of the tumor along with a cancer-free margin of healthy tissue negative marginspreferably through a small, cosmetically placed incision. BCS with adjunct radiation is preferred over mastectomy i.
Specifically, for BCS, complete removal of cancerous tissue and preservation of breast shape, appearance, and consistency i. Healing of the complex surgical wound follows, initially with a seroma or hematoma forming in the defect, followed by scar formation and contraction. For surgeons, it is extremely challenging, if not impossible, to predict the cosmetic outcome of BCS, especially given ificant patient variation in breast tumor size, shape, and location, and the unpredictable nature of the tissue repair process, which is compounded by the effects of adjunct radiation therapy.
Because of this, there remains a relatively high level of BCS-related breast deformities, with approximately one-third of women developing dents, distortions, and asymmetry between breasts 78. Such outcomes are known to negatively impact the self-esteem, body image, and intimacy of breast cancer survivors, contributing to overall feelings of insecurity, anxiety, and depression 9 This includes re-excisions due to positive margins as well as revision and reconstruction procedures to repair breast deformities.
Therefore, breast surgeons are in need of new options to further optimize Mature boobs Henderson and cosmetic outcomes of BCS, enabling them to confidently offer this conservative therapy to more patients with satisfying outcomes. At present, there are no commercial products that allow surgeons to predictably restore, reconstruct, or regenerate soft tissues, such as the breast. Furthermore, it is apparent that breast surgeons are actively looking for solutions to this problem.
For example, BioZorb represents a relatively new, three-dimensional, spiral-shaped tumor bed marker intended to mark the surgical cavity for targeted post-operative radiation. However, breast surgeons have used this bioresorbable device with hopes that it would also assist in filling the tissue void and improving cosmetic. Published clinical studies indicate that both surgeons and patients have been uniformly dissatisfied with BioZorb since this implant is relatively expensive, does not ificantly improve outcomes, and gives rise to a hard, palpable lump that lasts for up to 2.
On the other hand, there are two surgical reconstruction options which aim to improve BCS cosmetic outcomes, namely autologous fat grafting also known as lipofilling or fat transfer and oncoplastic surgery 18 Originally fat grafting was used for delayed breast reconstruction procedures, but more recently it has been investigated for use immediately following BCS. As an alternative approach, oncoplastic surgery combines the skills of surgical oncology with the techniques of plastic surgery to reconstruct one or both breasts at the time of lumpectomy.
Oncoplastic procedures include both volume displacement rearrangement of remaining healthy breast tissue and volume replacement reconstruction with various autologous tissue flaps techniques. In the present study, we aimed to develop and evaluate a soft tissue filler that would 1 predictably restore and regenerate damaged tissue and tissue voids, 2 be easily applied, 3 conform to patient-specific defects varying broadly in size and geometry, and 4 not interfere or compromise routine clinical processes and procedures.
In particular, type I oligomeric collagen oligomera highly-purified molecular form of collagen that is readily soluble in dilute acid 2526represents a tunable, in situ forming biomaterial with potential to address many of these de considerations.
Unlike conventional monomeric collagen preparations, namely telocollagen and atelocollagen, oligomer represents small aggregates of full-length triple-helical collagen molecules i. The preservation of these key molecular features provides this natural polymer with desirable but uncommon properties.
More specifically, oligomer retains its fibril-forming self-assembly capacity, which is inherent to fibrillar collagen proteins and yields scaffolds which recreate the structural and biological aling features of collagen scaffolds found in the extracellular matrix ECM component of tissues 25 Further, upon neutralization to physiologic conditions e. Upon in vivo implantation, these scaffolds persist, showing slow metabolic turnover and remodeling, resistance to proteolytic degradation, and no active biodegradation or foreign body response 272829303132 Finally, oligomer supports creation of materials with broadly tunable physical properties, including geometry, architecture random or aligned fibrils, continuous fibril density gradientsand mechanical integrity 30313334353637making it an enabling platform for personalized regenerative medicine.
Here, we evaluated prototype oligomer formulations specifically deed to serve as a regenerative filler for damaged or defective soft tissues, such as the tissue void created by BCS. First, prototype in situ forming collagen scaffolds were characterized based on molecular purity, polymerization self-assembly time, and viscoelastic properties. To evaluate biocompatibility and effectiveness of these scaffolds, simulated lumpectomy procedures were performed on the breasts mammary glands of pigs. Prototype formulations were used to fill a subset of lumpectomy voids, and surgical outcomes were compared to untreated defects no fill; negative control and normal breasts on which no surgery was performed positive controls.
To define the tissue response timeline and gain insight into oligomer mechanism of action, a week longitudinal study was performed. Additionally, a second study was conducted to assess how the collagen scaffold and its associated tissue response was affected by post-operative irradiation. Outcome measures included semi-quantitative visual and palpation-based examination, ultrasonography, radiography, and gross and histological analyses.
Combined, these data provide preclinical support for the use of this regenerative tissue filler during breast conserving surgery. Prototype scaffold-forming collagen formulations were obtained as kits from GeniPhys Zionsville, Indiana. As shown in Fig. Immediately prior to use, the two syringes were ed with the luer-lock adapter Fig. After mixing, the viscous liquid could be injected into various geometries, where it conformed to the shape prior to transitioning into Mature boobs Henderson physically-stable, fibrillar collagen scaffold Fig.
Gels revealed a banding pattern characteristic of oligomeric collagen 25 with no detectable contaminating non-collagenous proteins or other types of collagens Fig. Other functional performance parameters, including polymerization time and viscoelastic properties of formed collagen scaffolds, were measured, with a summary provided in Fig.
Specifically, the concentration of oligomer prior to neutralization was roughly 7. Although scaffold properties are tunable across a broad range of elastic modulus and strength values, the formulations tested here were deed to exhibit viscoelastic properties similar to soft tissues.
Purified liquid collagen forms viscoelastic fibrillar scaffold with soft tissue-like properties. Images represent full length gels and show all relevant lanes. Lane 1: molecular weight standard. Lane 2: type I oligomeric collagen. Uncropped images of the full gel length are shown in Supplementary Figure S1. To evaluate the effectiveness of the scaffold-forming collagen as a regenerative filler for soft tissue defects, a longitudinal study was performed involving simulated lumpectomy procedures on breasts of normal, healthy Yucatan mini-pigs Fig.
Female mini-pigs represent the preferred large animal model for such translational studies Mature boobs Henderson on their size and anatomical and physiological similarities to humans Additionally, pigs generally have twelve mammary glands breastswhich reduced the total of animals required for the studies since each breast could serve as an experimental or control group. Roughly one quarter of breast tissue volume was excised Fig. For collagen-treated breasts, the liquid collagen was mixed and immediately injected into the tissue void, where it conformed to the complex geometry prior to transitioning to a fibrillar collagen Mature boobs Henderson in less than 5 min under these circumstances Fig.
The breast surgeon used her discretion when filling each defect, with applied collagen volumes varying with defect size and geometry. Surgical voids were filled with at least the same volume of collagen as tissue removed, with the majority receiving 1—2 mL more collagen volume. Negative control sites were left untreated no fillwhich is consistent with standard-of-care BCS procedures. All incisions were closed using resorbable sutures and bandaged Fig. Overview of simulated lumpectomy procedure.
Surgical void b before and c after filling with collagen. Surgical sites f immediately following surgery showing bandaging and g 16 weeks following simulated lumpectomy with irradiation. Consistent with what is observed amongst women and men, pig breasts were found to vary in volume, consistency, and composition both within and between individual animals. At the microscopic level Supplementary Fig.
S2mammary glands consisted of multiple lobes, composed of smaller secretory lobules organized as clusters and a system of ducts channels that eventually exited the skin via the nipple. The lobules and ducts were supported by an intralobular stroma, composed predominantly of fibrous type I collagen.
Additionally, collagenous connective tissue was found between lobes interlobular stromaproviding support to the breast and determining its shape. Adipose tissue, which primarily determines breast size, filled the space between the glandular and fibrous connective tissue. When evaluated in unconfined compression, breasts located cranially toward the head were relatively stiff, with an average compression modulus of Progressing caudally toward the tailbreasts increased in fat composition and were Mature boobs Henderson, with an average compression modulus of 6.
To assess biocompatibility and tissue response of the collagen filler, animals were anesthetized at deated time points of 1, 4, and 16 weeks. All breasts were examined visually, palpated, and semi-quantitatively scored in a blinded fashion according to criteria in Supplementary Fig. Collagen-treated and no fill control breasts showed no evidence of erythema redness or eschar sloughing, dead tissue at any time point. Mild edema was evident at 1 week in breasts on which surgery was performed; however, the extent of swelling was similar for both collagen and no fill groups and subsided shortly thereafter.
Such findings are important because they indicate that the collagen filler does not create breast inconsistencies that could be interpreted clinically as residual disease or a source of patient discomfort. All normal breasts received a score of zero. Additionally, when the breast surgeon performed simulated surgical re-excision on collagen-treated breasts, the fill material did not compromise or interfere with the procedure. Collagen filler persists and induces site-appropriate tissue regeneration.
All no surgery breasts scored Mature boobs Henderson. Arrows represent surgical clips placed to mark boundaries of surgical void. Biocompatibility and tissue response of the collagen filler were further defined based on gross and histological examination of transverse sections of breast explants, with comparisons to no fill and normal breast controls. From these analyses, it was apparent that the collagen filler maintained its volume minimized defect contractionwas highly biocompatible, Mature boobs Henderson exhibited a regenerative tissue response in absence of an inflammatory reaction or foreign body response.
As cells infiltrated the scaffold and new breast tissue was generated, it took on a tissue-like appearance that was difficult to discern grossly from surrounding normal tissue Fig. In this case, the surgical clips were useful as markers of the original defect margins Figs.
Upon histological analysis at 1 week, the collagen filler was evident within the tissue Mature boobs Henderson, where it appeared as a homogenous, light pink eosinophilic staining material Fig. Often surrounding the filler was a band of hemorrhage, fibrin, and a few leukocytes, which was attributable to the surgical manipulation of the tissue Fig. At the filler-host tissue interface, there were focally extensive areas of proliferating fibroblasts mesenchymal cells with few small-caliber vessels infiltrating the scaffold edges. The surrounding breast tissue appeared largely normal, with remodeling areas adjacent to the surgical site.
These regions contained aggregates of remodeling epithelial cells, some of which appeared to be ductules while others were more irregularly shaped, suggestive of rudimentary lobules Fig. It is noteworthy that there was no evidence of an inflammatory-mediated foreign body reaction or active biodegradation that is characteristic of conventional implantable materials At the 4-week time point, fibroblasts, along with newly formed vasculature, extended into deeper portions of the collagen filler, with infiltrating cells most abundant at the periphery and dwindling further into the center Fig.
Multifocal aggregates of epithelial cells were observed, which were again consistent with precursors of glandular structures Fig. By 16 weeks, the scaffold was completely cellularized, appearing as mature, remodeled collagen fibers and bundles, with some sites displaying small discernible regions of acellular eosinophilic filler material. Small caliber vessels were present diffusely and evenly distributed throughout the scaffold Fig.Mature boobs Henderson
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