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Acellular Dermal Matrix (ADM) provides mechanical and soft tissue support in implant-based breast reconstruction, and has shown to modulate the healing response. However, skin flap necrosis, edema, and previous radiation therapy can hinder ADM integration. Effective biomaterial integration requires regulating the immune response, fibrosis, and adipocyte-driven functionalization. Extracellular matrix (ECM) hydrogels have demonstrated utility in tissue regeneration, and decreasing inflammation and fibrosis in various tissues. Therefore, we hypothesized that a Decellularized Porcine Dermal (DPD) hydrogel to support ADM integration would prevent excessive fibrosis, regulate the macrophage response, and promote adipogenesis. Exploration of DPD hydrogel during ADM implantation in mice (healthy and radiated) revealed long-term effects of irradiation on implant wound healing. DPD hydrogel rescued radiation-induced fibrosis, restoring capsule thickness of healthy mice, and did not increase the fibroblast migration into the ADM. As a modulating soft tissue filler, DPD hydrogel also promoted adipocyte infiltration in healthy and irradiated mice. Detailed macrophage analysis showed that radiation led to the increase in pro-inflammatory, transition, and reparative markers. Despite relatively subtle effects on individual macrophage phenotype markers, multidimensional flow cytometry analysis revealed that DPD hydrogel temporally regulated two subpopulations. he presence of DPD resulted in significantly reduced CD9 Hi Arg1 Hi CD301b Lo and CD163 Hi CD38 Hi CD301b Hi macrophages in healthy mice at one week, and a significant increase in CD9 High macrophages with low expression of other markers at 6 weeks in irradiated mice. DPD hydrogel promotes a decreased fibrotic, and adipocyte-promoting coordination of wound healing in healthy and irradiated wound beds while not disrupting the immunomodulatory effects of ADM. STATEMENT OF SIGNIFICANCE: Acellular Dermal Matrix (ADM) provides mechanical and soft tissue support in post-mastectomy implant-based breast reconstruction, and positively affects wound healing. Following breast reconstruction, skin flap necrosis, edema, and previous radiation therapy can hinder ADM integration. Effective wound healing and biomaterial integration requires regulating the cellular immune response. Extracellular matrix hydrogels have demonstrated utility in tissue regeneration and decreasing inflammation and fibrosis in various tissues, but has yet to be utilized in the setting of breast reconstruction. Here, we demonstrated that a decellularized dermal hydrogel as an adjunct to ADM, decreases fibrosis and promotes adipogenesis during the coordination of wound healing in healthy and clinically relevant microenvironments that have received radiation therapy while not disrupting the immunomodulatory effects of implanted ADM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Summary: When first described for breast reconstruction, the presence of acellular dermal matrices was associated with increased seroma formation and infection. However, clinical safety data have gradually improved with surgeon experience to an acceptable outcomes profile of acellular dermal matrix-assisted reconstruction when compared to submuscular implant coverage. In fact, acellular dermal matrix use potentially decreases capsular contracture rates and facilitates expansion for staged prepectoral breast reconstruction. Because of new regulatory requirements, the collection of unbiased, well-powered premarket approval data summarizing long-term clinical outcomes will be essential over the coming years to understand the clinical performance of acellular dermal matrix use in breast reconstruction. Currently, the authors can highlight the physiologic benefits of acellular dermal matrix use in breast reconstruction by evaluating the components of surgical wound healing that are favorably augmented by the implanted collagen substrate. Acellular dermal matrix takes advantage of the wound healing cascade to incorporate into the patient's tissues-a process that requires a coordinated inflammatory infiltrate and angiogenesis. The presence of acellular dermal matrix augments and modulates the wound healing process to its advantage by simultaneously increasing the invasion of appropriate cellular constituents to facilitate expeditious healing and accelerate angiogenesis. In this article, the authors summarize the wound healing literature to demonstrate the mechanisms acellular dermal matrices use to biointegrate and the literature in which cellular constituents and soluble growth factors are up-regulated in the presence of acellular dermal matrix. Lastly, the authors use their experimental observations of acellular dermal matrix incorporation to corroborate the literature., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background: Acellular dermal matrix (ADM) supported implant-based reconstruction remains the most commonly performed mode of reconstruction after breast cancer. Acellular dermal matrix clinical usage has reported benefits but requires rapid and efficient vascular and cellular incorporation into the recipient to have the best outcomes. Orderly transition from M1 to M2 macrophage phenotypic profile, coordinated in part by interleukin 4 (IL-4), is an important component of vascular stabilization and remodeling. Using the ADM substrate as a delivery device for immunomodulation of macrophage phenotype holds the potential to improve integration., Methods: Interleukin 4 was adsorbed onto ADM samples and drug elution curves were measured. Next, experimental groups of 8 C57BL/6 mice had 5-mm ADM discs surgically placed in a dorsal window chamber with a vascularized skin flap on one side and a plastic cover slip on the other in a model of implant-based breast reconstruction. Group 1 consisted of IL-4 (5 μg) adsorbed into the ADM preoperatively and group 2 consisted of an untreated ADM control. Serial gross examinations were performed with histology at day 21 for markers of vascularization, mesenchymal cell infiltration, and macrophage lineage., Results: Drug elution curves showed sustained IL-4 release for 10 days after adsorption. Serial gross examination showed similar rates of superficial vascular investment of the ADM beginning at the periphery by day 14 and increasing through day 21. Interleukin-4 treatment led to significantly increased CD31 staining of vascular endothelial cells within the ADM over the control group (P < 0.05) at 21 days. Although vimentin staining did not indicate a significant increase in fibroblasts overall, IL-4 did result in a significant increase in expression of α-smooth muscle actin. The expression of macrophage phenotype markers Arginase1 and iNOS present within the ADM were not significantly affected by IL-4 treatment at the day 21 time point., Conclusions: Acellular dermal matrix has the potential to be used for immunomodulatory cytokine delivery during the timeframe of healing. Using implanted ADM as a delivery vehicle to drive IL-4 mediated angiogenesis and vascular remodeling significantly enhanced vascularity within the ADM substrate., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Prepectoral acellular dermal matrix (ADM)-assisted breast reconstruction has demonstrated improved pain scores, faster return to full range of motion, and an appropriate postoperative safety profile when compared with cohorts with submuscular implant placement; however, there are limited data on aesthetic outcomes. Basic science biointegration research has previously demonstrated faster ADM incorporation with fenestrated compared with confluent ADM. We report the safety profile of anterior support meshed ADM prepectoral breast reconstruction and analyze predictive factors for aesthetic outcomes after gel implant placement., Methods: All consecutive immediate staged prepectoral expander-to-implant breast reconstructions with more than 6 months of follow-up were compared with a partially submuscular cohort for demographics, comorbidities, and postoperative complications. All patients 1 to 3.5 years after gel implant placement were evaluated for the impact of clinical characteristics on aesthetic outcomes., Results: Two hundred twenty-four prepectoral tissue expander placements were compared with 535 partially submuscular tissue expanders with no significant differences in demographics. There was increased wound dehiscence repaired in clinic and insignificantly decreased seromas with prepectoral expander placement. One hundred sixty breasts were reconstructed with gel implants, and 12 underwent autologous reconstruction during the conduct of the study. The remaining 21 patients were continuing expansion, and 3 succumbed to disease progression. Regression analysis of 86 breast reconstructions showed that a body mass index of greater than 30, fat grafting, and highly cohesive anatomic implants decreased rippling, whereas radiation increased capsular contracture (P < 0.05)., Conclusions: Prepectoral meshed ADM breast reconstruction has an equivalent safety profile to partially submuscular ADM-assisted reconstruction and early aesthetic ratings comparable with other published accounts of implant-based reconstruction. Radiated skin envelopes carry higher capsular contracture rates. Thin patients have a higher risk of visible rippling, whereas fat grafting and higher cohesivity implants are associated with less rippling., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ideal acellular dermal matrices (ADM) for breast reconstruction exhibit native extracellular matrix (ECM) structure to allow rapid biointegration and appropriate mechanical properties for desired clinical outcomes. In a novel in vivo model of irradiated breast reconstruction, we describe the cellular and vascular ingrowth of Artia, a porcine product chemically prepared to mimic the biomechanics of human ADM, with retained natural ECM structure to encourage cellular ingrowth., Methods: Utilizing the murine dorsal skinfold model, Artia was implanted into 16 C57bl/6 mice. Eight of the mice received a single dose 35 Gy radiation to the skin, followed by 12 weeks to produce radiation fibrosis and 8 mice served as nonradiated controls. Real-time photoacoustic microscopy of vascular integration and oxygen saturation within the ADM were made over 14 days. At 21 days, vascular ingrowth (CD31), fibroblast scar tissue formation (alpha smooth-muscle actin α-SMA, vimentin), and macrophage function (M2/M1 ratio) were evaluated. Scanning electron microscopy images of Artia were produced to help interpret the potential orientation of cellular and vascular ingrowth., Results: Repeated photoacoustic microscopy imaging demonstrated vascular ingrowth increasing over 14 days, with a commensurate increase in oxygen saturation within both radiated and nonradiated ADM-albeit at an insignificantly lower rate in the radiated group. By day 21, robust CD31 staining was seen that was insignificantly greater in the nonradiated group. Of the fibroblast markers, vimentin expression was significantly greater in the radiated group (P < 0.05). Macrophage lineage phenotype was consistent with remodeling physiology in both radiated and nonradiated groups. Scanning electron microscopy demonstrated transversely organized collagen fibrils with natural porous ECM structure to allow cellular ingrowth., Conclusions: Artia demonstrates appropriate biointegration, with increased oxygen saturation by 14 days, consistent with the performance of other collagen substrates in this model. Radiation fibrosis resulted in higher vimentin expression yet did not impact macrophage phenotype while only modestly decreasing Artia biointegration suggesting that ADM may have a role in reconstructive efforts in a radiated setting. Taken together with its enhanced biomechanics, this porcine ADM product is well poised to be clinically applicable to breast reconstruction.

Introduction: Staged, tissue expander-based implant reconstruction continues to be the most common mode of breast reconstruction after mastectomy and has evolved significantly for the past 60 years. Prepectoral acellular dermal matrix (ADM)-assisted breast reconstruction is gaining popularity with complication rates similar to total submuscular and ADM-assisted partially submuscular reconstruction. Ours is among the first reports comparing postoperative pain and early functional outcomes between 2-stage ADM-assisted prepectoral and partial submuscular breast reconstruction., Methods: Patients reconstructed with a 2-stage, ADM-assisted prepectoral approach were case matched with patients who had undergone ADM-assisted, partial submuscular reconstruction. Demographics and complication rates were compared. Primary outcomes included postoperative pain, number of days until full active shoulder range of motion was achieved, and postoperative days until drain removal., Results: Forty-five breasts among 24 patients were reconstructed with ADM-assisted prepectoral tissue expanders after mastectomy and 90 breasts among 48 patients were reconstructed with ADM-assisted partial submuscular placement. There was a similarly acceptable complication profile between the 2 groups. The prepectoral group had significantly lower inpatient pain scores, required significantly less intravenous opioids and less oral opioids as outpatients. The prepectoral group saw a return to full active range of shoulder motion in half the number days of the partial submuscular group. Drain duration was similar between groups., Conclusions: Prepectoral ADM-assisted breast reconstruction can be performed safely and with significantly less pain and earlier return to function than partial submuscular expander placement. Expander placement exclusively in the prepectoral pocket did not result in increased drain duration while affording patients the benefits of avoiding surgical elevation of the pectoralis muscle.

Background: Acellular dermal matrices have revolutionized alloplastic breast reconstruction. Furthering our knowledge of their biointegration will allow for improved design of these biomaterials. The ideal acellular dermal matrix for breast reconstruction would provide durable soft-tissue augmentation while undergoing rapid biointegration to promote physiologic elasticity and reduced infectious complications. The inclusion of fenestrations in their design is thought to promote the process of biointegration; however, the mechanisms underlying this theory have not been evaluated., Methods: Biointegration of standard and fenestrated acellular dermal matrices was assessed with serial photoacoustic microscopic imaging, in a murine dorsal skinfold window chamber model specifically designed to recapitulate the microenvironment of acellular dermal matrix-assisted alloplastic breast reconstruction. Photoacoustic microscopy allows for a serial, real-time, noninvasive assessment of hemoglobin content and oxygen saturation in living tissues, generating high-resolution, three-dimensional maps of the nascent microvasculature within acellular dermal matrices. Confirmatory histologic and immunohistochemical assessments were performed at the terminal time point., Results: Fenestrated acellular dermal matrices demonstrated increased fibroblast and macrophage lineage host cell infiltration, greater mean percentage surface area vascular penetration (21 percent versus 11 percent; p = 0.08), and greater mean oxygen saturation (13.5 percent versus 6.9 percent; p < 0.05) than nonfenestrated matrices by 2 weeks after implantation. By 21 days, host cells had progressed nearly 1 mm within the acellular dermal matrix fenestrations, resulting in significantly more vascularity across the top of the fenestrated matrix (3.8 vessels per high-power field versus 0.07 vessels per high-power field; p < 0.05)., Conclusions: Inclusion of fenestrations in acellular dermal matrices improves the recellularization and revascularization that are crucial to biointegration of these materials. Future studies will investigate the optimal distance between fenestrations.

Background: Biointegration, a concept involving a dynamic interplay among three processes-inflammation, cellular infiltration, and angiogenesis-is key to understanding the interaction between acellular dermal matrices and the host. The current standard for evaluating acellular dermal matrix biointegration involves histologic analysis at fixed time points; however, the authors' approach uses advanced imaging techniques to serially assess biointegration in real time., Methods: The authors have adapted two advanced imaging techniques-two-photon microscopy and photoacoustic microscopy-to investigate biointegration in a murine deepithelialized dorsal skin-fold window chamber model, specifically engineered to recapitulate the host microenvironment of acellular dermal matrix-assisted breast reconstruction. Four mice per group were assessed. Two-photon imaging of dual-transgenic mice allows for detection of fluorescently labeled perivascular cells, and macrophage lineage cells. Photoacoustic microscopy noninvasively assesses oxygen and hemoglobin concentration in living tissues, generating high-resolution, three-dimensional mapping of the nascent acellular dermal matrix-associated microvasculature and metabolic consumption of oxygen. These outcomes were corroborated by confirmatory histologic analysis at the terminal time point., Results: The acellular dermal matrix/host interface is characterized by robust inflammation (0 to 3 days), increased oxygen consumption and neoangiogenesis in the matrix border zone (10 to 14 days), and vascular and inflammatory cell penetration into the center of the matrix (>21 days)., Conclusion: The data broaden the core knowledge of acellular dermal matrix biology, and serve as a potential template for elucidating the key differences among various commercially available and developmental products to guide the reconstructive surgeon to better select a reconstructive adjunct that meets their specific needs.

Background: Acellular dermal matrices (ADMs) serve as a regenerative framework for host cell integration and collagen deposition to augment the soft tissue envelope in ADM-assisted breast reconstruction-a process dependent on vascular ingrowth. To date noninvasive intra-operative imaging techniques have been inadequate to evaluate the revascularization of ADM., Methods: We investigated the safety, feasibility, and efficacy of sidestream darkfield (SDF) microscopy to assess the status of ADM microvascular architecture in 8 patients at the time of tissue expander to permanent implant exchange during 2-stage ADM-assisted breast reconstruction. The SDF microscopy is a handheld device, which can be used intraoperatively for the real-time assessment of ADM blood flow, vessel density, vessel size, and branching pattern. The SDF microscopy was used to assess the microvascular architecture in the center and border zone of the ADM and to compare the native, non-ADM-associated capsule in each patient as a within-subject control., Results: No incidences of periprosthetic infection, explantation, or adverse events were reported after SDF image acquisition. Native capsules demonstrate a complex, layered architecture with an average vessel area density of 14.9 mm/mm and total vessel length density of 12.3 mm/mm. In contrast to native periprosthetic capsules, ADM-associated capsules are not uniformly vascularized structures and demonstrate 2 zones of microvascular architecture. The ADM and native capsule border zone demonstrates palisading peripheral vascular arcades with continuous antegrade flow. The central zone of the ADM demonstrates punctate perforating vascular plexi with intermittent, sluggish flow, and intervening 2- to 3-cm watershed zones., Conclusions: Sidestream darkfield microscopy allows for real-time intraoperative assessment of ADM revascularization and serves as a potential methodology to compare revascularization parameters among commercially available ADMs. Thr SDF microscopy demonstrates that the periprosthetic capsule in ADM-assisted implant-based breast reconstruction is not a uniformly vascularized structure.