Protocol for the BONE-RECON trial: a single-arm feasibility trial for critical sized lower limb BONE defect RECONstruction using the mPCL-TCP scaffold system with autologous vascularised corticoperiosteal tissue transfer.

INTRODUCTION: Reconstruction of critical bone defects is challenging. In a substantial subgroup of patients, conventional reconstructive techniques are insufficient. Biodegradable scaffolds have emerged as a novel tissue engineering strategy for critical-sized bone defect reconstruction. A corticoperiosteal flap integrates the hosts' ability to regenerate bone and permits the creation of a vascular axis for scaffold neo-vascularisation (regenerative matching axial vascularisation-RMAV). This phase IIa study evaluates the application of the RMAV approach alongside a custom medical-grade polycaprolactone-tricalcium phosphate (mPCL-TCP) scaffold (Osteopore) to regenerate bone sufficient to heal critical size defects in lower limb defects. METHODS AND ANALYSIS: This open-label, single-arm feasibility trial will be jointly coordinated by the Complex Lower Limb Clinic (CLLC) at the Princess Alexandra Hospital in Woolloongabba (Queensland, Australia), the Australian Centre for Complex Integrated Surgical Solutions (Queensland, Australia) and the Faculty of Engineering, Queensland University of Technology in Kelvin Grove (Queensland, Australia). Aiming for limb salvage, the study population (n=10) includes any patient referred to the CLLC with a critical-sized bone defect not amenable to conventional reconstructive approaches, after discussion by the interdisciplinary team. All patients will receive treatment using the RMAV approach using a custom mPCL-TCP implant. The primary study endpoint will be safety and tolerability of the reconstruction. Secondary end points include time to bone union and weight-bearing status on the treated limb. Results of this trial will help shape the role of scaffold-guided bone regenerative approaches in complex lower limb reconstruction where current options remain limited. ETHICS AND DISSEMINATION: Approval was obtained from the Human Research Ethics Committee at the participating centre. Results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN12620001007921.

Convergence of scaffold-guided bone regeneration principles and microvascular tissue transfer surgery.

A preclinical evaluation using a regenerative medicine methodology comprising an additively manufactured medical-grade ε-polycaprolactone ß-tricalcium phosphate (mPCL-TCP) scaffold with a corticoperiosteal flap was undertaken in eight sheep with a tibial critical-size segmental bone defect (9.5 cm3, M size) using the regenerative matching axial vascularization (RMAV) approach. Biomechanical, radiological, histological, and immunohistochemical analysis confirmed functional bone regeneration comparable to a clinical gold standard control (autologous bone graft) and was superior to a scaffold control group (mPCL-TCP only). Affirmative bone regeneration results from a pilot study using an XL size defect volume (19 cm3) subsequently supported clinical translation. A 27-year-old adult male underwent reconstruction of a 36-cm near-total intercalary tibial defect secondary to osteomyelitis using the RMAV approach. Robust bone regeneration led to complete independent weight bearing within 24 months. This article demonstrates the widely advocated and seldomly accomplished concept of "bench-to-bedside" research and has weighty implications for reconstructive surgery and regenerative medicine more generally.

Bone Regeneration Exploiting Corticoperiosteal Tissue Transfer for Scaffold-Guided Bone Regeneration.

Contemporary reconstructive approaches for critical size bone defects carry significant disadvantages. As a result, clinically driven research has focused on the development and translation of alternative therapeutic concepts. Scaffold-guided tissue regeneration (SGTR) is an emerging technique to heal critical size bone defects. However, issues synchronizing scaffold vascularization with bone-specific regenerative processes currently limit bone regeneration for extra large (XL, 19 cm3) critical bone defects. To address this issue, we developed a large animal model that incorporates a corticoperiosteal flap (CPF) for sustained scaffold neovascularization and bone regeneration. In 10 sheep, we demonstrated the efficacy of this approach for healing medium (M, 9 cm3) size critical bone defects as demonstrated on plain radiography, microcomputed tomography, and histology. Furthermore, in two sheep, we demonstrate how this approach can be safely extended to heal XL critical size defects. This article presents an original CPF technique in a well-described preclinical model, which can be used in conjunction with the SGTR concept, to address challenging critical size bone defects in vivo. Impact statement This article describes a novel scaffold-guided tissue engineering approach utilizing a corticoperiosteal flap for bone healing in critical size long bone defects. This approach will be of use for tissue engineers and surgeons exploring vascularized tissue transfer as an option to regenerate large volumes of bone for extensive critical size bone defects both in vivo and in the clinical arena.

A preclinical large-animal model for the assessment of critical-size load-bearing bone defect reconstruction.

Critical-size bone defects, which require large-volume tissue reconstruction, remain a clinical challenge. Bone engineering has the potential to provide new treatment concepts, yet clinical translation requires anatomically and physiologically relevant preclinical models. The ovine critical-size long-bone defect model has been validated in numerous studies as a preclinical tool for evaluating both conventional and novel bone-engineering concepts. With sufficient training and experience in large-animal studies, it is a technically feasible procedure with a high level of reproducibility when appropriate preoperative and postoperative management protocols are followed. The model can be established by following a procedure that includes the following stages: (i) preoperative planning and preparation, (ii) the surgical approach, (iii) postoperative management, and (iv) postmortem analysis. Using this model, full results for peer-reviewed publication can be attained within 2 years. In this protocol, we comprehensively describe how to establish proficiency using the preclinical model for the evaluation of a range of bone defect reconstruction options.

The quadriceps Femoris allograft as an extension of the Angiosome concept: A cadaveric-based anatomical feasibility study.

BACKGROUND: Vascularised composite allo-transplantation (VCA) is emerging as a tailored approach for complex tissue reconstruction. This study focuses on the quadriceps VCA as a potential solution for tissue repair, following trauma, necrotising fasciitis/myositis, or tumor ablation. METHODS: Dissections were undertaken in 10 adult cadaveric lower limbs to characterize the blood supply to the quadriceps femoris for en bloc muscle allo-transplantation. A mock cadaveric transplantation was performed to (a) define the best neurovascular VCA design and (b) test the feasibility of the procedure. A review of 54 archival radiograph studies from the institution was also performed to further evaluate the muscle vasculature. RESULTS: In two lower limbs, the quadriceps VCA was harvested designed on the common and superficial femoral vessels and nerve, which revealed a lengthy and bloody dissection, especially of the veins, which could increase clinically with the inability to use a tourniquet for most of the dissection. However, review of our previous archival studies showed that all four quadriceps muscles are supplied within the lateral circumflex femoral angiosome. In a further eight lower limbs, the quadriceps femoris muscle group consistently received its blood supply from the lateral circumflex femoral angiosome, verified by selective lead oxide injections of this artery. The vastus medialis appeared to have a more tenous blood supply distally based on this angiosome. A successful mock cadaveric transplant was performed based on this data. CONCLUSIONS: We suggest that the best neuromuscular quadriceps VCA should be (a) designed on the lateral circumflex femoral pedicle, (b) should be raised from distal to proximal, and (c) should include the descending genicular vessels as a potential supplemental supply to vastus medialis, should all four muscles be required.

A systematic review and meta-analysis of locoregional treatments for in-transit melanoma.

BACKGROUND AND OBJECTIVES: In-transit melanoma (ITM) metastases present a therapeutic challenge and management decisions can be difficult. There are multiple treatments available, with differing efficacy, and supported by different levels of evidence. The primary objective was to perform a systematic review and where suitable, a meta-analysis of the literature reporting on the use of locoregional treatments for the management of ITM. METHODS: An independent review was conducted including a comprehensive search of the National Library of Medicine using PubMed, MEDLINE, Embase, and Cochrane Library databases. Key data were tabulated, synthesized and pooled to calculate relevant weighted effect sizes for each therapy using random-effect models. The statistical heterogeneity was calculated using the Higgins' method. RESULTS: Of the initial 32 612 articles identified, 57 original articles satisfied eligibility criteria. Eight treatment modalities were identified comprising: amputation (7); hyperthermic isolated limb perfusion (15); isolated limb infusion (8); carbon dioxide laser (9); PV-10 intralesional therapy (5); IL-2 intralesional therapy (8); imiquimod (7); diphenylcyclopropenone (3). Only amputation and topical imiquimod were suitable for formal meta-analysis. CONCLUSIONS: All of the assessed therapies have significant selection bias. Variable levels of evidence support the ongoing use of locoregional treatments and these may significantly improve disease-free survival.

Convergence of Scaffold-Guided Bone Reconstruction and Surgical Vascularization Strategies-A Quest for Regenerative Matching Axial Vascularization.

The prevalent challenge facing tissue engineering today is the lack of adequate vascularization to support the growth, function, and viability of tissue engineered constructs (TECs) that require blood vessel supply. The research and clinical community rely on the increasing knowledge of angiogenic and vasculogenic processes to stimulate a clinically-relevant vascular network formation within TECs. The regenerative matching axial vascularization approach presented in this manuscript incorporates the advantages of flap-based techniques for neo-vascularization yet also harnesses the in vivo bioreactor principle in a more directed "like for like" approach to further assist regeneration of the specific tissue type that is lost, such as a corticoperiosteal flap in critical sized bone defect reconstruction.

Clinical Examination of the Extensor Pollicis Brevis: Anatomical Study and Description of a Novel Clinical Sign.

BACKGROUND: The Extensor Pollicis Brevis (EPB) is an extrinsic thumb muscle whose main function is extension of the first metacarpophalangeal joint (MCPJ). It is subject to significant anatomical variation and may be absent, vestigial or have an anomalous distal attachment. Clinical examination of EPB is notoriously difficult and no reliable test has yet been described. We propose a novel test for the accurate examination of EPB. We sought to clarify the anatomical variations of EPB and to validate our clinical test using human cadaveric anatomical tests. METHODS: A structured literature review of all human cadaveric anatomical studies describing the attachments of EPB was performed using MEDLINE and Embase with the key words "Extensor Pollicis Brevis". A cadaveric anatomical study was performed using 18 unembalmed upper limbs. Positive and negative tests were simulated by manipulating the tendons of EPB, Extensor Pollicis Longus (EPL) and Flexor Pollicis Longus (FPL). Changes in tendon tension and joint position were measured and recorded. The EPB anatomy was then determined by dissection. RESULTS: Anatomical variations were present in the majority of wrists, with only 35% of EPB tendons having a distal attachment to the proximal phalanx alone. EPB was absent in 5% of specimens. There was a significant difference between the change in MCPJ position between a positive (36 degrees; 95% CI 25 to 47 degrees) and negative (19 degrees; 95% CI 14 to 25 degrees) clinical test (p = 0.002). CONCLUSIONS: The functional importance of EPB depends on its congenital architecture in addition to the functional demands of the patient. We report a novel clinical test which is effective in demonstrating the integrity of the EPB. A positive test result is observed when a change in MCPJ position that occurs while the interphalangeal joint is brought into flexion from full thumb extension is 25 degrees or more.

Angiosome-Based Allografts: Vascularized Composite Allotransplantation for Tailored Subunit Reconstruction with Volkmann Ischemic Contracture as a Case in Point.

BACKGROUND: As we enter an age with new approaches to tissue reconstruction, the emphasis on the adage "like for like" has become even more relevant. This study illustrates the potential for several tailored vascularized composite allotransplantation reconstructive techniques and, in particular, for the management of Volkmann contracture. METHODS: Twenty fresh cadaver dissections and 30 archival lead oxide radiographic studies were examined to (1) identify potential upper limb vascularized composite allotransplantation donor sites (i.e., elbow, forearm, and flexor tendon complex) and (2) demonstrate a "mock transplant" of the vascularized volar forearm allograft for a severe Volkmann ischemia defect. They were designed without skin to reduce antigenicity. RESULTS: The elbow joint was supplied within the brachial angiosome and the flexor tendon complex of the flexor digitorum superficialis and flexor digitorum profundus by the superficial palmar arch of the ulnar angiosome. The forearm allograft of flexor muscles, median, ulnar, and anterior interosseous nerves, when harvested on the brachial vessels, was supplied within the radial, ulnar, and anterior interosseous angiosomes but could be based on the ulnar artery alone because of intramuscular connections with the other territories. A mock transplant was performed with a distal-to-proximal dissection of the allograft, facilitating the best and fastest technique. CONCLUSIONS: This application of the angiosome concept highlights the anatomical feasibility of the volar forearm vascularized composite allotransplantation donor site focusing on a complex subunit problem in the upper limb-severe Volkmann ischemic contracture. It demonstrates the potential use and immunologic advantage of subdivided and modified nonskin variations of vascularized composite allotransplantation in reconstructive transplantation surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Primary cutaneous melanoma of the scalp: Patterns of recurrence.

INTRODUCTION: Patients with primary melanoma of the scalp have been reported to have worse disease-related outcomes compared with other anatomical regions. There are few studies in the literature specifically addressing recurrence patterns and treatment outcomes for primary scalp melanoma as a discrete anatomical sub-region. We sought to identify key features adversely influencing disease control and survival and to clarify the role of resection plane, margin, and method of reconstruction in the management of this disease process. METHODS: A retrospective clinical study of medical records was performed evaluating all patients with primary melanoma of the scalp treated at two hospitals in southeast Queensland between 2004 and 2014. RESULTS: A total of 107 patients were eligible for analysis. There were 46 recurrences in 38 patients in the cohort accounting for a recurrence rate of 35.5%. The local recurrence rate was 15.9% with 12 in-transit metastases after diagnosis. Regional and distant recurrence rates were 12.1% and 15%, respectively. At a median follow up of 30.5 months, disease-free survival was 47% and overall survival was also 47%. On multi-variate analysis, the deeper resection plane (sub-galeal) had a lower disease-free survival rate compared with the supra-galeal resection plane (P = 0.032). DISCUSSION: Our results support the hypothesis that primary scalp melanoma represents a unique aggressive subcategory with high rates of in-transit disease and poor disease-related and survival outcomes. There is a need for robust prospective comparative studies to address the significance of resection plane in the management of patients with scalp melanoma.

Vascularised bone transfer: History, blood supply and contemporary problems.

BACKGROUND: Since the description of the free fibula flap by Taylor in 1975, many flaps composed of bone have been described. This review documents the history of vascularised bone transfer and reflects on the current understanding of blood supply in an effort to define all clinically described osseous flaps. METHODS: A structured review of MEDLINE and Google Scholar was performed to identify all clinically described bone flaps in humans. Data regarding patterns of vascularity were collected where available from the anatomical literature. RESULTS: Vascularised bone transfer has evolved stepwise in concert with advances in reconstructive surgery techniques. This began with local flaps of the craniofacial skeleton in the late 19th century, followed by regional flaps such as the fibula flap for tibial reconstruction in the early 20th century. Prelaminated and pedicled myo-osseous flaps predominated until the advent of microsurgery and free tissue transfer in the 1960s and 1970s. Fifty-two different bone flaps were identified from 27 different bones. These flaps can be broadly classified into three types to reflect the pedicle: nutrient vessel (NV), penetrating periosteal vessel (PPV) and non-penetrating periosteal vessel (NPPV). NPPVs can be further classified according to the anatomical structure that serves as a conduit for the pedicle which may be direct-periosteal, musculoperiosteal or fascioperiosteal. DISCUSSION: The blood supply to bone is well described and is important to the reconstructive surgeon in the design of reliable vascularised bone suitable for transfer into defects requiring osseous replacement. Further study in this field could be directed at the implications of the pattern of bone flap vascularity on reconstructive outcomes, the changes in bone vascularity after osteotomy and the existence of "true" and "choke" anastomoses in cortical bone.

Cytoreductive surgery and heated intraperitoneal chemotherapy for peritoneal carcinomatosis secondary to mucinous adenocarcinoma of the appendix.

Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a radical but effective treatment option for select peritoneal malignancies. We sought to determine our early experience with this method for peritoneal carcinomatosis secondary to mucinous adenocarcinomas of appendiceal origin. As such, we performed a retrospective clinical study of 30 consecutive patients undergoing CRS with planned HIPEC at the Princess Alexandra Hospital, between June 2009 to December 2012, with mucinous adenocarcinomas of the appendix. CRS was performed in 30 patients, 13 received HIPEC intraoperatively and 17 received early postoperative intra-peritoneal chemotherapy (EPIC) in addition. Mean age was 52.3 years and median hospital stay was 26 days (range 12-190 days). Peritoneal cancer index scores were 0-10 in 6.7% of patients, 11-20 in 20% of patients and >20 in 73.3% of patients. Complete cytoreduction was achieved overall in 21 patients. In total, 106 complications were observed in 28 patients. Ten were grade 3-A, five were grade 3-B and one grade-5 secondary to a fatal PE on day 97. In patients who received HIPEC, there was no difference in disease-free survival (P = 0.098) or overall survival (P = 0.645) between those who received EPIC versus those who did not. This study demonstrates that satisfactory outcomes with regards to morbidity and survival can be achieved with CRS and HIPEC, at a single-centre institution with growing expertise in the technique. Our results are comparable with outcomes previously described in the international literature.