Therapeutic Efficacy of Adipose-Derived Stem Cells Versus Bone Marrow Stromal Cells for Irradiated Mandibular Fracture Repair.

BACKGROUND: Mesenchymal stem cells have immense potential in applications of bone healing and regeneration. However, few studies have evaluated the therapeutic efficacy of adipose-derived stem cells (ASCs) and bone marrow stromal cells (BMSCs) in irradiated bone. The purpose of this study is to compare the ability of ASCs versus BMSCs to enhance healing outcomes in a murine model of irradiated mandibular fracture repair. METHODS: Forty-eight isogenic male Lewis rats underwent radiation therapy followed by mandibular osteotomy with intraoperative placement of either ASCs or BMSCs. Animals were killed on postoperative day 40. Mandibles were analyzed for union rate, biomechanical strength, vascularity, and mineralization. Groups were compared at P < 0.05 significance. RESULTS: The ASC and BMSC groups demonstrated 92% and 75% union rates. Compared with the BMSC group, the ASC group demonstrated a trending increase in maximum load ( P = 0.095) on biomechanical strength analysis and a significant increase in vessel number ( P = 0.001), vessel thickness ( P = 0.035), and vessel volume fraction ( P = 0.007) on micro-computed tomography angiography analysis. No significant differences in bone mineralization were identified on micro-computed tomography analysis. CONCLUSION: This study demonstrates the superior therapeutic efficacy of ASCs over BMSCs in irradiated fracture healing as evidenced by union rate, vascular morphometry, and a trend in biomechanical strength. We posit that the robust vascular response induced by ASCs better recapitulates the sequence and synchronicity of physiologic bone healing compared with BMSCs, thereby improving the reliability of irradiated fracture repair.

Therapeutic Interventions to Reduce Radiation Induced Dermal Injury in a Murine Model of Tissue Expander Based Breast Reconstruction.

BACKGROUND: Radiation therapy (XRT) induced dermal injury disrupts type I collagen architecture. This impairs cutaneous viscoelasticity, which may contribute to the high rate of complications in expander-based breast reconstruction with adjuvant XRT. The objective of this study was to further elucidate the mechanism of radiation-induced dermal injury and to determine if amifostine (AMF) or deferoxamine (DFO) mitigates type I collagen injury in an irradiated murine model of expander-based breast reconstruction. METHODS: Female Lewis rats (n = 20) were grouped: expander (control), expander-XRT (XRT), expander-XRT-AMF (AMF), and expander-XRT-DFO (DFO). Expanders were surgically placed. All XRT groups received 28 Gy of XRT. The AMF group received AMF 30 minutes before XRT, and the DFO group used a patch for delivery 5 days post-XRT. After a 20-day recovery period, skin was harvested. Atomic force microscopy and Raman spectroscopy were performed to evaluate type I collagen sheet organization and tissue compositional properties, respectively. RESULTS: Type I collagen fibril disorganization was significantly increased in the XRT group compared with the control (83.8% vs 22.4%; P = 0.001). Collagen/matrix ratios were greatly reduced in the XRT group compared with the control group (0.49 ± 0.09 vs 0.66 ± 0.09; P = 0.017). Prophylactic AMF demonstrated a marked reduction in type I collagen fibril disorganization on atomic force microscopy (15.9% vs 83.8%; P = 0.001). In fact, AMF normalized type I collagen organization in irradiated tissues to the level of the nonirradiated control (P = 0.122). Based on Raman spectroscopy, both AMF and DFO demonstrated significant differential protective effects on expanded-irradiated tissues. Collagen/matrix ratios were significantly preserved in the AMF group compared with the XRT group (0.49 ± 0.09 vs 0.69 ± 0.10; P = 0.010). ß-Sheet/α-helix ratios were significantly increased in the DFO group compared with the XRT group (1.76 ± 0.03 vs 1.86 ± 0.06; P = 0.038). CONCLUSIONS: Amifostine resulted in a significant improvement in type I collagen fibril organization and collagen synthesis, whereas DFO mitigated abnormal changes in collagen secondary structure in an irradiated murine model of expander-based breast reconstruction. These therapeutics offer the ability to retain the native microarchitecture of type I collagen after radiation. Amifostine and DFO may offer clinical utility to reduce radiation induced dermal injury, potentially decreasing the high complication rate of expander-based breast reconstruction with adjuvant XRT and improving surgical outcomes.

Noncultured Minimally Processed Adipose-Derived Stem Cells Improve Radiated Fracture Healing.

Adipose-derived stem cells mitigate deleterious effects of radiation on bone and enhance radiated fracture healing by replacing damaged cells and stimulating angiogenesis. However, adipose-derived stem cell harvest and delivery techniques must be refined to comply with the US Food and Drug Administration restrictions on implantation of cultured cells into human subjects prior to clinical translation. The purpose of this study is to demonstrate the preservation of efficacy of adipose-derived stem cells to remediate the injurious effects of radiation on fracture healing utilizing a novel harvest and delivery technique that avoids the need for cell culture. Forty-four Lewis rats were divided into 4 groups: fracture control (Fx), radiated fracture control (XFx), radiated fracture treated with cultured adipose-derived stem cells (ASC), and radiated fracture treated with noncultured minimally processed adipose-derived stem cells (MP-ASC). Excluding the Fx group, all rats received a fractionated human-equivalent dose of radiation. All groups underwent mandibular osteotomy with external fixation. Following sacrifice on postoperative day 40, union rate, mineralization, and biomechanical strength were compared between groups at P < 0.05 significance. Compared with Fx controls, the XFx group demonstrated decreased union rate (100% vs 20%), bone volume fraction (P = 0.003), and ultimate load (P < 0.001). Compared with XFx controls, the MP-ASC group tripled the union rate (20% vs 60%) and demonstrated statistically significant increases in both bone volume fraction (P = 0.005) and ultimate load (P = 0.025). Compared with the MP-ASC group, the ASC group showed increased union rate (60% vs 100%) and no significant difference in bone volume fraction (P = 0.936) and ultimate load (P = 0.202). Noncultured minimally processed adipose-derived stem cells demonstrate the capacity to improve irradiated fracture healing without the need for cell proliferation in culture. Further refinement of the cell harvest and delivery techniques demonstrated in this report will enhance the ability of noncultured minimally processed adipose-derived stem cells to improve union rate and bone quality, thereby optimizing clinical translation.

Amifostine Prophylaxis in Irradiated Breast Reconstruction: A Study of Oncologic Safety In Vitro.

BACKGROUND: Indications for adjuvant radiation therapy (XRT) in breast cancer have expanded. Although highly effective, XRT damages surrounding tissues and vasculature, often resulting in delayed or compromised breast reconstruction. Thus, effective yet safe methods of radiation injury prophylaxis would be desirable. Amifostine is a Food and Drug Administration-approved radioprotectant; however, concerns about its potential to also protect cancer remain. The purpose of this study was to evaluate the oncologic safety of amifostine (AMF) in vitro and determine its effect on human breast cancer cells in the setting of XRT. METHODS: One ER+/PR+/Her2- (MCF-7) and two ER-/PR-Her2- (MDA-MB-231, MDA-MB-468) breast cancer cell lines were investigated. Female fibroblasts were used as controls. Cells were treated with WR-1065, the active metabolite of AMF, 20 minutes before 0Gy, 10Gy, or 20Gy XRT. Live and dead cells were quantified; percent cell death was calculated. RESULTS: WR-1065 treatment significantly preserved viability and reduced healthy female fibroblasts death after XRT compared with untreated controls. All three breast cancer cells lines exhibited radiosensitivity with substantial cell death. Cancer cells retained their radiosensitivity despite WR-1065 pretreatment, achieving the same degree of cell death as untreated controls. CONCLUSIONS: This study demonstrated the proficiency of AMF to selectively protect healthy cells from XRT while breast cancer cells remained radiosensitive. These results support the oncologic safety of AMF in breast cancer in vitro. Further investigation is now warranted in vivo to ascertain the translational potential of using AMF as a radioprotectant to improve breast reconstruction after radiation treatment.

Decision Making in Pediatric Plastic Surgery: Autonomy and Shared Approaches.

BACKGROUND: Although shared decision-making is essential to patient-centered healthcare, its role in pediatric plastic surgery remains unclear. The objective of this study was to define the preferred level of involvement in surgical decision-making among children, caregivers, and surgeons. METHODS: The authors surveyed pediatric plastic surgery patients (n = 100) and their caregivers regarding their preferences on child involvement during surgical decision-making. Fleiss' kappa was used to assess agreement between groups. Bivariate Chi-square tests and multinomial logistic regression were used to assess the relationship between decision-making preferences and select demographic factors. RESULTS: Only 34% of children and their caregivers agreed upon their decision-making preferences (k = 0.04). The majority of children (40%) and caregivers (67%) favored shared decision-making between the patient, caregiver, and surgeon. Only 16% of children preferred physician-driven decisions, while 20% of children desired complete autonomy. Children's preferences were significantly associated with their age; the relative risk of children deferring to caregivers or surgeons over a shared approach was lower for adolescents and teens compared to children under 10 years old (relative risk = 0.20; 95% confidence interval: 0.054-0.751; P = 0.02). Caregiver's preferences did not change based on the child's age, but rather were related to the child's gender. Caregivers were more likely to choose the option that gave the child more autonomy when the child was male. CONCLUSIONS: While most caregivers preferred a shared approach to decision-making, children desired greater autonomy, particularly with increasing age. Since there was limited agreement between caregivers and children, surgeons must be cognizant of differing preferences when discussing treatment plans to optimize both patient and parent satisfaction.

Sociodemographic Predictors of Patient Age at Time of Cleft Lip and Palate Repair.

OBJECTIVE: To identify the impact of sociodemographic and health variables on the age at which patients undergo cleft lip repair, cleft palate repair, and primary speech evaluation. DESIGN: A retrospective, noninterventional quality assessment, and quality improvement study was designed. SETTING: This institutional study was performed at Michigan Medicine in Ann Arbor, MI. PATIENTS: All patients born between 2011 and 2014 who received surgical cleft repair, excluded those who were adopted (n = 165). MAIN OUTCOME MEASURE: The age at which patients undergo cleft lip repair, cleft palate repair, and primary speech evaluation. RESULTS: Cleft lip repair was performed significantly later for patients identifying as Asian (18 weeks, P = .01), patients with Child Protective Services contact (19 weeks, P = .01), patients with a significant comorbidity (14 weeks, P = .02), and patients who underwent preliminary lip adhesion surgery (19 weeks, P < .01). Cleft palate repair was performed significantly later for patients identifying racially as Asian (19 weeks, P = .03) and other (22 weeks, P = .03). Preliminary speech and language evaluation were performed significantly later for patients identifying as black (55 weeks, P = .03) and patients diagnosed with an isolated cleft lip (71 weeks, P < .01). CONCLUSIONS: Timing of cleft lip, cleft palate repair, and primary speech and language evaluation are subject to variation which may be predicted by clinically accessible factors. By identifying race, Child Protective Services contact, and care variables as significant predictors of increased patient age at time of intervention, multidisciplinary cleft care teams can proactively allocate patient support resources.

Stem Cells for Bone Regeneration: Current State and Future Directions.

Mesenchymal stem cells (MSCs) are capable of differentiating into osteoblasts, chondrocytes, and adipocytes, each of which is important for musculoskeletal tissue regeneration and repair. Reconstruction and healing of bony defects remains a major clinical challenge. Even as surgical practices advance, some severe cases of bone loss do not yield optimal recovery results. New techniques involving implantation of stem cells and tissue-engineered scaffolds are being developed to help improve bone and cartilage repair. The invasiveness and low yield of harvesting MSCs from the bone marrow (BMSCs) has led to the investigation of alternatives, including adipose-derived mesenchymal stem cells (ASCs). A review of the literature yielded several studies concerning the use of BMSCs and ASCs for the treatment of bone defects in both in vitro and in vivo models. Although both ASCs and BMSCs have demonstrated bone regenerative capabilities, BMSCs have outperformed ASCs in vitro. Despite these in vitro study findings, in vivo study results remain variable. Analysis of the literature seems to conclude there is no significant difference between bone regeneration using ASCs or BMSCs in vivo. Improved study design and standardization may enhance the application of these studies to patient care in the clinical setting.

Perioperative Opioid-Related Harms: Opportunities to Minimize Risk.

Although substantial attention has been given to opioid prescribing in the United States, opioid-related mortality continues to climb due to the rising incidence and prevalence of opioid use disorder. Perioperative care has an important role in the consideration of opioid prescribing and the care of individuals at risk for poor postoperative pain- and opioid-related outcomes. Opioids are effective for acute pain management and commonly prescribed for postoperative pain. However, failure to align prescribing with patient need can result in overprescribing and exacerbate the flow of unused opioids into communities. Conversely, underprescribing can result in the undertreatment of pain, complicating recovery and impairing well-being after surgery. Optimizing pain management can be particularly challenging for individuals who are previously exposed to opioids or have critical risk factors, including opioid use disorder. In this review, we will explore the role of perioperative care in the broader context of the opioid epidemic in the United States, and provide considerations for a multidisciplinary, comprehensive approach to perioperative pain management and optimal opioid stewardship.

Overcoming Nuclear Winter: The Cutting-edge Science of Bone Healing and Regeneration in Irradiated Fields.

BACKGROUND: The incidence of cancer worldwide is expected to be more than 22 million annually by 2030. Approximately half of these patients will likely require radiation therapy. Although radiotherapy has been shown to improve disease control and increase survivorship, it also results in damage to adjacent healthy tissues, including the bone, which can lead to devastating skeletal complications, such as nonunion, pathologic fractures, and osteoradionecrosis. Pathologic fractures and osteoradionecrosis are ominous complications that can result in large bone and soft tissue defects requiring complex reconstruction. Current clinical management strategies for these conditions are suboptimal and dubious at best. The gold standard in treatment of severe radiation injury is free tissue transfer; however, this requires a large operation that is limited to select candidates. METHODS: With the goal to expand current treatment options and to assuage the devastating sequelae of radiation injury on surrounding normal tissue, our laboratory has performed years of translational studies aimed at remediating bone healing and regeneration in irradiated fields. Three therapeutics (amifostine, deferoxamine, and adipose-derived stem cells) have demonstrated great promise in promoting healing and regeneration of irradiated bone. RESULTS: Amifostine confers prophylactic protection, whereas deferoxamine and adipose-derived stem cells function to remediate postradiation associated injury. CONCLUSIONS: These prospective therapeutics exploit a mechanism attributed to increasing angiogenesis and ultimately function to protect or restore cellularity, normal cellular function, osteogenesis, and bone healing to nonirradiated metrics. These discoveries may offer innovative treatment alternatives to free tissue transfer with the added benefit of potentially preventing and treating osteoradionecrosis and pathologic fractures.

Intraoperative Stromal Vascular Fraction Therapy Improves Histomorphometric and Vascular Outcomes in Irradiated Mandibular Fracture Repair.

BACKGROUND: Cell-based treatments have demonstrated the capacity to enhance reconstructive outcomes in recent decades but are hindered in clinical utility by regulatory hurdles surrounding cell culture. This investigation examines the ability of a noncultured stromal vascular fraction derived from lipoaspirate to enhance bone healing during fracture repair to further the development of translatable cell therapies that may improve outcomes in irradiated reconstruction. METHODS: Isogenic male Lewis rats were divided into three groups: fracture, irradiated fracture, and irradiated fracture with stromal vascular fraction treatment. Irradiated groups received a fractioned dose of 35 Gy before mandibular osteotomy. Stromal vascular fraction was harvested from the inguinal fat of isogenic donors, centrifuged, and placed intraoperatively into the osteotomy site. All mandibles were evaluated for bony union and vascularity using micro-computed tomography before histologic analysis. RESULTS: Union rates were significantly improved in the irradiated fracture with stromal vascular fraction treatment group (82 percent) compared to the irradiated fracture group (25 percent) and were not statistically different from the fracture group (100 percent). Stromal vascular fraction therapy significantly improved all metrics of bone vascularization compared to the irradiated fracture group and was not statistically different from fracture. Osteocyte proliferation and mature bone formation were significantly reduced in the irradiated fracture group. Bone cellularity and maturity were restored to nonirradiated levels in the irradiated fracture with stromal vascular fraction treatment group despite preoperative irradiation. CONCLUSIONS: Vascular and cellular depletion represent principal obstacles in the reconstruction of irradiated bone. This study demonstrates the efficacy of stromal vascular fraction therapy in remediating these damaging effects and provides a promising foundation for future studies aimed at developing noncultured, cell-based therapies for clinical implementation.

Assessing the Key Predictors of an Academic Career after Craniofacial Surgery Fellowship.

BACKGROUND: As craniofacial fellowship positions outnumber the availability of academic craniofacial jobs, it is important to understand the factors associated with securing an academic position after fellowship. The purpose of this study was to evaluate the impact of bibliometric indices and trainee demographics on the ability to obtain a full-time academic plastic surgery position on completion of a craniofacial fellowship. METHODS: Craniofacial fellowship graduates between 2009 and 2018 (n = 182) were identified. Initial job placement and demographic data were collected; bibliometric indices at fellowship completion were calculated. Chi-square and Fisher's exact tests and multivariable logistic regression were used to assess the association of select factors with job placement. RESULTS: Of the 48.9 percent of fellows that secured academic positions, 39.3 percent trained at five fellowship institutions. The majority of those completing residency at top institutions for academic surgery and research entered academic positions at fellowship completion. Geography influenced academic placement, as 72.7 percent of trainees in the Northeast secured academic positions. Only 20.3 percent of fellows completed dedicated postgraduate research time, but among these, 70.3 percent entered academic jobs. The h-index (OR, 1.14; p = 0.01) and total manuscripts (OR, 1.04; p = 0.02) were significantly associated with academic practice while adjusting for other covariates. CONCLUSIONS: Although residency training institution, geographic location, and postgraduate research may influence academic placement, the h-index and total manuscripts represent the best predictors of academic careers after craniofacial fellowship. This information is valuable for applicants who aspire to be academic craniofacial surgeons, and for programs and educators who can use these data to identify applicants with a propensity for academics.