Development of a Porcine VCA Model Using an External Iliac Vessel-Based Vertical Rectus Abdominus Myocutaneous Flap.

BACKGROUND: Vascularized composite allotransplantation (VCA) involves transplanting a functional and anatomically complete tissue graft, such as a hand or face, from a deceased donor to a recipient. Although clinical VCA has resulted in successful outcomes, high rates of acute rejection and increased requirements for immunosuppression have led to significant long-term complications. Of note, immunosuppressed graft recipients are predisposed to infections, organ dysfunction, and malignancies. The long-term success of VCA grafts requires the discovery and implementation of unique approaches that avoid these complications altogether. Here, we describe our surgical technique and initial experience with a reproducible heterotopic porcine VCA model for the preclinical assessment of approaches to improve graft outcomes. METHODS: Six heterotopic porcine allogeneic vertical rectus abdominis myocutaneous flap transplants were performed using Sinclair donors and Yucatan recipients. Immunosuppressive therapy was not used. Each flap was based on the left external iliac vessel system. Animals were followed postoperatively for surgery-related complications. RESULTS: The six pigs underwent successful VCA and were euthanized at the end of the study. Each flap demonstrated complete survival following vessel anastomosis. For the allogeneic recipients, on average, minimal erythema and healthy flap color were observed from postoperative days 1 to 4. There were no surgery-related animal deaths or complications. CONCLUSION: We have developed a reproducible, technically feasible heterotopic porcine VCA model based on the left external iliac vessel system. Our results demonstrate this model's potential to improve VCA graft outcomes by exploring tolerance induction and rejection biomarker discovery in preclinical studies.

Retinal transplant immunology and advancements.

Several gaps and barriers remain for transplanting stem cells into the eye to treat ocular disease, especially diseases of the retina. While the eye has historically been considered immune privileged, recent thinking has identified the immune system as both a barrier and an opportunity for eye stem cell transplantation. Recent approaches leveraging scaffolds or cloaking have been considered in other tissues beyond immune suppression. This perspective paper outlines approaches for transplantation and proposes opportunities to overcome barriers of the immune system in stem cell transplantation in the eye.

Toxicology, pharmacokinetics, and immunogenicity studies of CCR4-IL2 bispecific immunotoxin in rats and minipigs.

We have developed a diphtheria toxin-based recombinant human CCR4-IL2 bispecific immunotoxin (CCR4-IL2-IT) for targeted therapy of cutaneous T-cell lymphoma (CTCL). CCR4-IL2-IT demonstrated superior efficacy in an immunodeficient mouse CTCL model. Recently, we have compared the in vivo efficacy of CCR4-IL2-IT versus Brentuximab (FDA approved leading drug in CTCL market) in the same immunodeficient mouse CTCL model. The comparison demonstrated that CCR4-IL2-IT was significantly more effective than Brentuximab. In this study, we have performed non-GLP (Good Laboratory Practice) toxicology, pharmacokinetics, immunogenicity studies of CCR4-IL2-IT in both rats and minipigs. CCR4-IL2-IT demonstrated excellent safety profiles in both rats and minipigs. The maximum tolerated dose of CCR4-IL2-IT was determined as 0.4 mg/kg in both rats and minipigs. Complete blood count and chemistry analysis did not show significant difference for all measured parameters between the blood samples of pre-injection versus post-injection from the five-day toxicology studies of CCT4-IL2-IT in both rats and minipigs. Histology analysis did not show difference between the PBS treatment group versus CCR4-IL2-IT treatment group at 50 µg/kg in both rats and minipigs. The half-life of CCR4-IL2-IT was determined as about 45 min in rats and 30 min in minipigs. The antibodies against CCR4-IL2-IT were detected in about two weeks after CCR4-IL2-IT treatment. CCR4-IL2-IT did not induce cytokine release syndrome in a peripheral blood mononuclear cell derived humanized mouse model. The depletion of CCR4+ cell and CD25+ cell (two target cell populations of CCR4-IL2-IT) was observed in minipigs. The excellent safety profile promoted us to further develop CCR4-IL2-IT towards clinical trials.

Treatment of Progressive Hemifacial Atrophy by Cartilage Graft and Free Adipofascial Flap Combined with Three-Dimensional Planning.

BACKGROUND: Progressive hemifacial atrophy (PHA) is a rare disease characterized by progressive atrophy of skin, soft tissue, muscles, and underlying bone structures. For severe PHA patients with obvious bone deformities, skeletal framework reconstruction is needed in addition to soft-tissue augmentation. The authors propose a new combinatorial surgical method using rib cartilage graft and free adipofascial flap for restoring facial symmetry. To improve the surgical accuracy, preoperative three-dimensional planning and printing was used. METHODS: Twelve patients with severe facial atrophy were included in the authors' study. Three-dimensional facial image analyses were performed preoperatively to quantify the facial asymmetry. Rib cartilages were harvested and sculptured to the appropriate shape created by three-dimensional planning and fixed to the atrophic bone. The circumflex scapular artery-based adipofascial flap was transplanted to repair soft-tissue deficiency. A residual small monitor flap was left with the adipofascial flap. A revision surgery was performed to perfect the repair if the contour was suboptimal 6 months postoperatively. RESULTS: The adipofascial flaps survived in all 12 patients. All patients achieved good healing without complications. At 1 more year after surgery, the rib cartilage was still in position and rarely absorbed. The morphologic and volumetric difference between the affected side and the unaffected side was improved significantly postoperatively. All patients were satisfied with the results, and no more additional operations were required. CONCLUSION: The combinatorial surgery of rib cartilage graft and free adipofascial flap in the setting of three-dimensional planning and printing can be a good choice in restoring facial symmetry in severe cases of PHA. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Analysis of Postoperative Distal Radius Fracture Outcomes in the Setting of Osteopenia and Osteoporosis for Patients with Comorbid Conditions.

Purpose: Distal radius fractures (DRFs) are among the most common orthopedic injuries, especially in the elderly. A wide variety of approaches have been advocated as successful treatment modalities; yet, there remains variability in practice patterns of DRF in patients with osteoporosis and osteopenia. Using large data set analysis, we sought to determine the risk profile of operative fixation of DRF in patients with low bone mineral density. Methods: A commercially available health care database, PearlDiver, was queried for all patients who underwent open reduction internal fixation of DRFs between 2010 and 2020. The study population was divided into groups based on the presence or absence of osteopenia or osteoporosis and was further classified by patients who were receiving bisphosphonate therapy. Complication rates were calculated, including rates of malunion, surgical site infection, osteomyelitis, hardware failure, and hardware removal. Five-year future fragility fractures were defined in hip, vertebrae, humerus, and wrist fractures. Chi-square analysis and logistic regression were performed to determine an association between these comorbidities and various postoperative complications. Results: A total of 152,926 patients underwent open reduction internal fixation of a DRF during the study period. Chi-square analysis of major complications at 3 months showed a statistically significant increase in malunion in patients with osteopenia (P = .05) and patients with osteoporosis (P = .05) who underwent open reduction internal fixation. Logistic regression analysis at 12 months after surgery demonstrated that osteopenia was associated with an increased risk of hardware failure (P < .0001), hardware removal (P < .0001), surgical site infection (P < .0001), and malunion (P = .004). Osteoporosis was associated with a significantly increased risk of hardware failure (P = .01), surgical site infection (P < .0001), and malunion (P < .0001). Conclusions: We demonstrated, using large data set analysis, that DRF patients with osteopenia and osteoporosis are predicted to be at increased risk of multiple postoperative complications, and thus, bone density should be strongly considered in treatment planning for these patients. Type of study/level of evidence: Prognostic III.

Distal Bypass to the Deep Palmar Arch for Treatment of a Unique Presentation of Digital Ischemia.

Radial artery occlusion leading to hand ischemia is a serious problem that may require prompt surgical intervention. Due to the rarity of these events, consensus on the most effective surgical approach has not yet been reached. There is even scarce literature on appropriate management of symptomatic radial occlusion in patients with a congenital variation in hand vasculature. We report on a case of a 38-year-old woman with radial artery occlusion who underwent a successful distal radial artery bypass to the deep palmar arch due to a diminutive ulnar artery and the absence of a superficial palmar arch. Radial artery bypass to the deep palmar arch using a reversed vein graft is a viable treatment option for preventing further digital ischemia or necrosis in patients with a compromised vasculature of the hand.

Injectable Hydrogel Guides Neurons Growth with Specific Directionality.

Visual disabilities affect more than 250 million people, with 43 million suffering from irreversible blindness. The eyes are an extension of the central nervous system which cannot regenerate. Neural tissue engineering is a potential method to cure the disease. Injectability is a desirable property for tissue engineering scaffolds which can eliminate some surgical procedures and reduce possible complications and health risks. We report the development of the anisotropic structured hydrogel scaffold created by a co-injection of cellulose nanofiber (CNF) solution and co-polypeptide solution. The positively charged poly (L-lysine)-r-poly(L-glutamic acid) with 20 mol% of glutamic acid (PLLGA) is crosslinked with negatively charged CNF while promoting cellular activity from the acid nerve stimulate. We found that CNF easily aligns under shear forces from injection and is able to form hydrogel with an ordered structure. Hydrogel is mechanically strong and able to support, guide, and stimulate neurite growth. The anisotropy of our hydrogel was quantitatively determined in situ by 2D optical microscopy and 3D X-ray tomography. The effects of PLLGA:CNF blend ratios on cell viability, neurite growth, and neuronal signaling are systematically investigated in this study. We determined the optimal blend composition for stimulating directional neurite growth yielded a 16% increase in length compared with control, reaching anisotropy of 30.30% at 10°/57.58% at 30°. Using measurements of calcium signaling in vitro, we found a 2.45-fold increase vs. control. Based on our results, we conclude this novel material and unique injection method has a high potential for application in neural tissue engineering.

A Report on the Representation of Women in Academic Plastic Surgery Leadership.

BACKGROUND: The year 2017 marked the first year women comprised a majority of U.S. medical school matriculants. While more women are pursuing surgical training, within plastic surgery, there is a steady attrition of women advancing in leadership roles. The authors report the current status of women in academic plastic surgery, from trainees to chairwomen and national leadership positions. METHODS: The Electronic Residency Applications Service, San Francisco Match, National Resident Matching Program, Association of American Medical Colleges, American Council of Academic Plastic Surgeons, Plastic Surgery Education Network, and professional websites for journals and national societies were accessed for demographic information from 2007 to 2017. RESULTS: The number of female integrated pathway applicants remained stable (30 percent), with an increased proportion of female residents from 30 percent to 40 percent. There was an increase in female faculty members from 14.6 percent to 22.0 percent, an increase of less than 1 percent per year. Twelve percent of program directors and 8.7 percent of department heads were women. Nationally, major professional societies and administrative boards demonstrated a proportion of female members ranging from 19 percent to 55 percent (average, 27.7 percent). The proportion of female committee leaders ranged from 0 percent to 50 percent (average, 21.5 percent). Only six societies have had female presidents. No major journal had had a female editor-in-chief. The proportion of female editorial board members ranged from 1 percent to 33 percent (average, 16.1 percent). CONCLUSIONS: The authors' study shows a leak in the pipeline at all levels, from trainees to faculty to leadership on the national stage. This report serves as a starting point for investigating reasons for the underrepresentation of talented women in plastic surgery leadership.

Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates.

Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line-derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for >50 days in a 5-centimeter nerve defect in a rhesus macaque model. The GDNF-eluting conduit (PCL/GDNF) was compared to a median nerve autograft and a PCL conduit containing empty microspheres (PCL/Empty). Functional testing demonstrated similar functional recovery between the PCL/GDNF-treated group (75.64 ± 10.28%) and the autograft-treated group (77.49 ± 19.28%); both groups were statistically improved compared to PCL/Empty-treated group (44.95 ± 26.94%). Nerve conduction velocity 1 year after surgery was increased in the PCL/GDNF-treated macaques (31.41 ± 15.34 meters/second) compared to autograft (25.45 ± 3.96 meters/second) and PCL/Empty (12.60 ± 3.89 meters/second) treatment. Histological analyses included assessment of Schwann cell presence, myelination of axons, nerve fiber density, and g-ratio. PCL/GDNF group exhibited a statistically greater average area occupied by individual Schwann cells at the distal nerve (11.60 ± 33.01 µm2) compared to autograft (4.62 ± 3.99 µm2) and PCL/Empty (4.52 ± 5.16 µm2) treatment groups. This study demonstrates the efficacious bridging of a long peripheral nerve gap in a nonhuman primate model using an acellular, biodegradable nerve conduit.

The Impact of Plastic Surgery Training on Family Planning and Prenatal Health.

BACKGROUND: Plastic surgery trainees who wish to start a family face challenges. This is the first study to collect data directly from residents and fellows to understand issues surrounding childbearing and to propose solutions. METHODS: Following institutional review board approval, an anonymous survey was distributed to all current plastic surgery residents and fellows in the United States. Data regarding demographics, obstetrical complications, parental leave, breastfeeding, and use of assisted reproductive technology were collected. RESULTS: The survey was completed by 307 trainees, for a resident response rate of 27.0 percent. Mean age of the respondents was 31.7 ± 3.8 years, 58.6 percent were married, and 35.3 percent reported at least one pregnancy for themselves or for their partner. Both male (67.4 percent) and female (76.5 percent) respondents intentionally postponed having children because of career. Women were significantly more likely to report negative stigma attached to pregnancy (70.4 percent versus 51.1 percent; p = 0.003) and plan to delay childbearing until after training. Fifty-six percent of female trainees reported an obstetrical complication. Assisted reproductive technology was used by 19.6 percent of trainees. Mean maternity leave was 5.5 weeks, with 44.4 percent taking less than 6 weeks. Mean paternity leave was 1.2 weeks. Sixty-two percent of women and 51.4 percent of men reported dissatisfaction with leave. Sixty-one percent of female trainees breastfed for 6 months and 19.5 percent continued for 12 months. Lactation facilities were available near operating rooms for 29.4 percent of respondents. CONCLUSIONS: Plastic surgery training may negatively impact fertility, obstetrical health, and breastfeeding practices. The data presented in this article provide the groundwork for identifying areas of concern and potential solutions.

Characteristics and Immunomodulating Functions of Adipose-Derived and Bone Marrow-Derived Mesenchymal Stem Cells Across Defined Human Leukocyte Antigen Barriers.

BACKGROUND: Vascularized composite allotransplantation opens new possibilities in reconstructive transplantation such as hand or face transplants. Lifelong immunosuppression and its side-effects are the main drawbacks of this procedure. Mesenchymal stem cells (MSCs) have clinically useful immunomodulatory effects and may be able to reduce the burden of chronic immunosuppression. Herein, we assess and compare characteristics and immunomodulatory capacities of bone marrow- and adipose tissue-derived MSCs isolated from the same human individual across defined human leukocyte antigen (HLA) barriers. MATERIALS AND METHODS: Samples of omental (o.) adipose tissue, subcutaneous (s.c.) adipose tissue, and bone marrow aspirate from 10 human organ donors were retrieved and MSCs isolated. Cells were characterized by flow cytometry and differentiated in three lineages: adipogenic, osteogenic, and chondrogenic. In mixed lymphocyte reactions, the ability of adipose-derived mesenchymal stem cells (ASCs) and bone marrow-derived mesenchymal stem cells (BMSCs) to suppress the immune response was assessed and compared within individual donors. HLA mismatched or mitogen stimulations were analyzed in co-culture with different MSC concentrations. Supernatants were analyzed for cytokine contents. RESULTS: All cell types, s.c.ASC, o.ASC, and BMSC demonstrated individual differentiation potential and cell surface markers. Immunomodulating effects were dependent on dose and cell passage. Proliferation of responder cells was most effectively suppressed by s.c.ASCs and combination with BMSC resulted in highly efficient immunomodulation. Immunomodulation was not cell contact-dependent and cells demonstrated a specific cytokine secretion. CONCLUSION: When human ASCs and BMSCs are isolated from the same individual, both show effective immunomodulation across defined HLA barriers in vitro. We demonstrate a synergistic effect when cells from the same biologic system were combined. This cell contact-independent function underlines the potential of clinical systemic application of MSCs.

Fetal extracellular matrix nerve wraps locally improve peripheral nerve remodeling after complete transection and direct repair in rat.

In peripheral nerve (PN) injuries requiring surgical repair, as in PN transection, cellular and ECM remodeling at PN epineurial repair sites is hypothesized to reduce PN functional outcomes by slowing, misdirecting, or preventing axons from regrowing appropriately across the repair site. Herein this study reports on deriving and analyzing fetal porcine urinary bladder extracellular matrix (fUB-ECM) by vacuum assisted decellularization, fabricating fUBM-ECM nerve wraps, and testing fUB-ECM nerve wrap biocompatibility and bioactivity in a trigeminal, infraorbital nerve (ION) branch transection and direct end-to-end repair model in rat. FUB-ECM nerve wraps significantly improved epi- and endoneurial organization and increased both neovascularization and growth associated protein-43 (GAP-43) expression at PN repair sites, 28-days post surgery. However, the number of neurofilament positive axons, remyelination, and whisker-evoked response properties of ION axons were unaltered, indicating improved tissue remodeling per se does not predict axon regrowth, remyelination, and the return of mechanoreceptor cortical signaling. This study shows fUB-ECM nerve wraps are biocompatible, bioactive, and good experimental and potentially clinical devices for treating epineurial repairs. Moreover, this study highlights the value provided by precise, analytic models, like the ION repair model, in understanding how PN tissue remodeling relates to axonal regrowth, remyelination, and axonal response properties.

Unusual Volar Pulp Location of Glomus Tumor.

Glomus tumors are benign, painful growths originating from glomus bodies and comprise just 1% of tumors arising in the hand, with fewer than 10% in the volar pulp of digits. Hallmark symptoms of glomus tumors include hypersensitivity to cold, heightened pinprick sensitivity, and paroxysmal pain. We report a 72-year-old, right-hand dominant man who presented with pain in the left middle finger, localized to the tip. The fingertip was incredibly sensitive to touch, and his pain increased at night. He reported no recollection of trauma. Palpation of the finger revealed no mass, although it did indicate a focal point of pain within the distal pulp of the digit. Magnetic resonance imaging of the left hand revealed a round 7.0 × 4.0 × 6.0-mm soft tissue lesion along the volar ulnar aspect of the distal third digit. An incision was made in the mid-axial plane, circumscribing and removing the mass bluntly. It was a tan-yellow, soft tissue nodule of 0.8-cm in diameter without stalk or adherences to joints. Pathology revealed the mass was a glomus tumor. Symptoms improved on removal, and he healed without complication. Glomus tumors in the volar digital pulp can be difficult to diagnose. However, the presence of localized pain in the fingertip was reason to consider glomus tumor and proceed with treatment. Complete surgical removal of a glomus tumor is necessary to resolve symptoms and prevent recurrence.

Total Human Eye Allotransplantation: Developing Surgical Protocols for Donor and Recipient Procedures.

BACKGROUND: Vascularized composite allotransplantation of the eye is an appealing, novel method for reconstruction of the nonfunctioning eye. The authors' group has established the first orthotopic model for eye transplantation in the rat. With advancements in immunomodulation strategies together with new therapies in neuroregeneration, parallel development of human surgical protocols is vital for ensuring momentum toward eye transplantation in actual patients. METHODS: Cadaveric donor tissue harvest (n = 8) was performed with orbital exenteration, combined open craniotomy, and endonasal approach to ligate the ophthalmic artery with a cuff of paraclival internal carotid artery, for transection of the optic nerve at the optic chiasm and transection of cranial nerves III to VI and the superior ophthalmic vein at the cavernous sinus. Candidate recipient vessels (superficial temporal/internal maxillary/facial artery and superficial temporal/facial vein) were exposed. Vein grafts were required for all anastomoses. Donor tissue was secured in recipient orbits followed by sequential venous and arterial anastomoses and nerve coaptation. Pedicle lengths and calibers were measured. All steps were timed, photographed, video recorded, and critically analyzed after each operative session. RESULTS: The technical feasibility of cadaveric donor procurement and transplantation to cadaveric recipient was established. Mean measurements included optic nerve length (39 mm) and caliber (5 mm), donor artery length (33 mm) and caliber (3 mm), and superior ophthalmic vein length (15 mm) and caliber (0.5 mm). Recipient superficial temporal, internal maxillary artery, and facial artery calibers were 0.8, 2, and 2 mm, respectively; and superior temporal and facial vein calibers were 0.8 and 2.5 mm, respectively. CONCLUSION: This surgical protocol serves as a benchmark for optimization of technique, large-animal model development, and ultimately potentiating the possibility of vision restoration transplantation surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Clinical Considerations for Vascularized Composite Allotransplantation of the Eye.

Vascularized composite allotransplantation represents a potential shift in approaches to reconstruction of complex defects resulting from congenital differences as well as trauma and other acquired pathology. Given the highly specialized function of the eye and its unique anatomical components, vascularized composite allotransplantation of the eye is an appealing method for restoration, replacement, and reconstruction of the nonfunctioning eye. Herein, we describe conventional treatments for eye restoration and their shortcomings as well as recent research and events that have brought eye transplantation closer to a potential clinical reality. In this article, we outline some potential considerations in patient selection, donor facial tissue procurement, eye tissue implantation, surgical procedure, and potential for functional outcomes.

Ethical Considerations of Whole-Eye Transplantation.

Whole eye transplantation (WET) remains experimental. Long presumed impossible, recent scientific advances regarding WET suggest that it may become a clinical reality. However, the ethical implications of WET as an experimental therapeutic strategy remain largely unexplored. This article evaluates the ethical considerations surrounding WET as an emerging experimental treatment for vision loss. A thorough review of published literature pertaining to WET was performed; ethical issues were identified during review of the articles.

Neck burn reconstruction with pre-expanded scapular free flaps.

BACKGROUND: The reconstruction of neck contracture deformities after severe burns is challenging. This is due to insufficient tissue to resurface the large defect after local flap transfer as well as the poor functional and cosmetic results after traditional methods such as skin grafting. We employed free transfer of pre-expanded scapular flaps to reconstruct postburn neck deformities. METHODS: In the first stage, skin expansion was performed with tissue expanders ranging from 400 to 800 mL according to the neck defect size and expanders were filled to their end volumes. In the second stage, the contracture in the neck was released and the unstable scar was resected. The pre-expanded scapular flap was then harvested and transferred to the neck defect. Flap revisions were performed 3-12 months after flap transfer. RESULTS: A total of 12 flaps (100%) were successful. The contour, colour, and texture of flaps matched well to the nearby skin. The range of motion of the neck was significantly improved. The donor defects were closed directly except for one case, which required skin grafting. CONCLUSIONS: The free tissue transfer of pre-expanded scapular flap is a valuable tool in neck burn reconstruction. It can be used safely and effectively with minimal morbidity in selected patients.

Functional outcomes following multiple acute rejections in experimental vascularized composite allotransplantation.

BACKGROUND: Vascularized composite allotransplantation has become a clinical reality. Patients undergoing vascularized composite allotransplantation have modest functional return. Most patients have had multiple acute rejections. The effect of multiple acute rejections influencing functional outcomes is unknown. This study systematically analyzes the effects of multiple acute rejections on functional outcome. METHODS: Rat functional orthotopic hind-limb transplants were performed from Brown-Norway to Lewis rats. Group 1 consisted of isografts. In group 2, daily cyclosporine was administered to prevent acute rejection. In group 3, recipients did not receive regular immunosuppression but received only pulsed cyclosporine and dexamethasone to rescue acute rejection. The study endpoint was 90 days. Muscle and sciatic nerve biopsy specimens were taken for histologic analyses. Hind-limb function was assessed using sciatic nerve axon density, nerve conduction velocity, and muscle force generated by the gastrocnemius muscle. Novel video kinematics was used to analyze gait. RESULTS: By the endpoint, group 3 animals had 17 ± 5.1 acute rejections. Muscle biopsy showed significant atrophy and fibrosis in group 3 compared with groups 1 and 2. Withdrawal to pin prick was evident by days 31 ± 1.2, 30 ± 2.3, and 31 ± 3.7 in groups 1, 2, and 3, respectively. At the endpoint, there was no significant difference in the axon density or nerve conduction velocity among the three groups, but muscle force generated was significantly less in group 3. Gait was abnormal in group 3 animals compared with other groups. CONCLUSIONS: In this study, multiple acute rejections induced muscle atrophy and fibrosis and consequent decreased function. This emphasizes the importance of preventing acute rejection to achieve optimum function following vascularized composite allotransplantation.

Daily topical tacrolimus therapy prevents skin rejection in a rodent hind limb allograft model.

BACKGROUND: Skin is the most immunogenic component of a composite tissue allograft. Topical immunotherapy is an attractive therapeutic modality with which to provide local immunosuppression, with minimal systemic toxicity. The present study was performed to investigate the potential of topical tacrolimus to prolong survival of the skin component of a composite tissue allograft. METHODS: Wistar Furth-to-Lewis rat orthotopic hind limb transplants were performed. Group I consisted of rats treated with topical tacrolimus; group II, antilymphocyte serum plus 21 days cyclosporine; and group III, antilymphocyte serum plus 21 days of cyclosporine plus topical tacrolimus. In group IV, tacrolimus levels in blood, skin, and muscle were measured in an autograft control group. RESULTS: All animals in group I (n = 8) developed grade III clinical rejection by postoperative day 9. In group II (n = 9), the median onset of grade III rejection was postoperative day 40 (range, postoperative days 34 to 44). In group III (n = 6), two animals developed focal grade III rejection on postoperative days 35 and 56. The remaining four animals reached the 100-day endpoint without grade III rejection. In group IV, tacrolimus levels were low or undetectable in blood, whereas skin levels were 100-fold higher than underlying muscle. CONCLUSIONS: Topical tacrolimus therapy has the potential to prevent skin rejection in a composite tissue allograft. Preoperative depletion of T cells with antilymphocyte serum, along with a short course of systemic immunosuppression, prevents acute rejection, whereas topical tacrolimus inhibits immune cell function in the skin. Concentrations of tacrolimus are substantially higher in skin compared with underlying muscle and peripheral blood. Topical immunotherapy could reduce the morbidity associated with systemic immunosuppression in clinical composite tissue allografts.