Tissue engineered nerve constructs: where do we stand?

Driven by enormous clinical need, interest in peripheral nerve regeneration has become a prime focus of research and area of growth within the field of tissue engineering. While using autologous donor nerves for bridging peripheral defects remains today's gold standard, it remains associated with high donor site morbidity and lack of full recovery. This dictates research towards the development of biomimetic constructs as alternatives. Based on current concepts, this review summarizes various approaches including different extracellular matrices, scaffolds, and growth factors that have been shown to promote migration and proliferation of Schwann cells. Since neither of these concepts in isolation is enough, although each is gaining increased interest to promote nerve regeneration, various combinations will need to be identified to strike a harmonious balance. Additional factors that must be incorporated into tissue engineered nerve constructs are also unknown and warrant further research efforts. It seems that future directions may allow us to determine the "missing link".

Oromandibular reconstruction with vascularized free flaps: a review of 50 cases.

Fifty cases of oromandibular reconstruction using vascularized free flaps to evaluate functional parameters of results were evaluated. There were 23 iliac crest flaps, 17 fibula flaps, 30 ulnar forearm flaps, and 3 radial forearm flaps with bone. Thirteen female and 37 male patients comprised the study, with a mean age of 57.66 years. Squamous-cell carcinoma (SCC) constituted 86% of cases, of which 60% were T4 lesions and 13.9% were recurrent. Anterolateral mandibular defects constituted 48.7%, and the mean bone gap was 8.13 cm. Functional evaluation was based on the University of Washington Questionnaire (UWQ) through phone calls and personal communication. The mean hospital stay was 12.42 days. The external carotid (75%) and facial (18.3%) were the main recipient arteries. The internal jugular (47.05%) was the main recipient vein. Overall flap survival was 95.9%. Three flaps were lost due to unsalvageable venous thrombosis. Major local complications such as partial flap loss, hematoma, and orocervical fistula constituted 10% of cases. Speech was classified as "excellent" and "good" in 43.3% of cases. Swallowing was identified as "excellent" and "good" in 53.3% of cases. Cosmetic acceptance was rated "good" in 63.3% of cases. Vascularized free flap reconstruction of oromandibular defects provides excellent functional and aesthetic results. The majority of patients are able to tolerate a regular diet. Intelligible speech and acceptable appearance are restored, providing patient satisfaction.

Role of ulnar forearm free flap in oromandibular reconstruction.

The ulnar forearm flap is not frequently utilized for oromandibular reconstruction. This study evaluated the usefulness of the ulnar free flap for reconstruction. A retrospective study of 32 patients was conducted. The ulnar forearm flap was combined with an osseous flap in 24 patients. Nine females and 23 males with a mean age of 58.15 years comprised our study population. Squamous-cell carcinoma was the diagnosis in 93.75% of cases (56.25% T4), of which 20% were recurrent. Functional evaluation of swallowing was based on the University of Washington Questionnaire (UWQ). The mean hospital stay was 9.8 days. The external carotid (100%) was the recipient artery, and the internal jugular (74.07%) was the main recipient vein. Overall flap survival was 96.8%. One flap was lost due to unsalvageable venous thrombosis. Major local complications were seen in 9.4% of cases and included partial flap loss, hematoma, and an orocutaneous fistula. At the time of this study, 21 patients were available for functional evaluation. Speech was rated excellent and good in 33.3% of patients. Swallowing was found good in 28.6% of patients. Chewing was rated excellent and good in 47.6% of patients. Cosmetic acceptance was rated good in 71.4% of cases. The ulnar forearm is a useful free flap in oromandibular reconstruction. It is available when the radial artery is the dominant artery of the hand. Being more hidden, it may be more cosmetically accepted. It affords pliable soft tissue for lining and/or covering of oromandibular defects, and can be used as a second choice after other free-flap failures.

Ethical issues at the university-industry interface: a way forward?

This paper forms an introduction to this issue, the contents of which arose directly or indirectly from a conference in May 2001 on Corruption of scientific integrity?--The commercialisation of academic science. The introduction, in recent decades, of business culture and values into universities and research institutions is incompatible with the openness which scientific and all academic pursuit traditionally require. It has given rise to a web of problems over intellectual property and conflict of interest which has even led to corporate sponsors' suppressing unfavourable results of clinical trials, to the detriment of patients' health. Although there are those who see the norms of science developing to recognise the importance of instrumental science aiming at specific goals and of knowledge judged by its value in a context of application, none justifies the covert manipulation of results by vested interest. Public awareness of these problems is growing and creating a climate of opinion where they may be addressed. We suggest a way forward by the introduction of nationally and internationally-accepted guidelines for industrial collaboration which contain proper protections of the core purposes of universities and of the independence of their research. Some codes suggested for this purpose are discussed. We note that some universities are moving to adopt such codes of conduct, but argue the need for strong support from the government through its funding bodies.

Peripheral nerve injury: a review and approach to tissue engineered constructs.

Eleven thousand Americans each year are affected by paralysis, a devastating injury that possesses associated annual costs of $7 billion (American Paralysis Association, 1997). Currently, there is no effective treatment for damage to the central nervous system (CNS), and acute spinal cord injury has been extraordinarily resistant to treatment. Compared to spinal cord injury, damage to peripheral nerves is considerably more common. In 1995, there were in excess of 50,000 peripheral nerve repair procedures performed. (National Center for Health Statistics based on Classification of Diseases, 9th Revision, Clinical Modification for the following categories: ICD-9 CM Code: 04.3, 04.5, 04.6, 04.7). These data, however, probably underestimate the number of nerve injuries appreciated, as not all surgical or traumatic lesions can be repaired. Further, intraabodominal procedures may add to the number of neurologic injuries by damage to the autonomic system through tumor resection. For example, studies assessing the outcome of impotency following radical prostatectomy demonstrated 212 of 503 previously potent men (42%) suffered impotency when partial or complete resection of one or both cavernosal nerve(s). This impotency rate decreased to 24% when the nerves were left intact (Quinlan et al., J. Urol. 1991;145:380-383; J. Urol. 1991;145:998-1002).

Muristerone A-induced nerve growth factor release from genetically engineered human dermal fibroblasts for peripheral nerve tissue engineering.

In this study, human dermal fibroblasts (hDFBs) were genetically modified to release human nerve growth factor (NGF) using an ecdysone-inducible system. NGF cDNA was inserted into the pIND vector and then hDFBs were cotransfected with pIND-NGF and pVgRXR. Muristerone A, an analog of ecdysone, was used as the inducing agent. NGF release from transfected hDFBs was assessed in vitro and in vivo. Transfected hDFBs in the presence of Muristerone A possessed a maximal in vitro release of 8.5 +/- 0.4 pg of NGF/mL per 10(3) cells, demonstrating significantly higher NGF levels compared to control hDFBs. The in vitro release rate curve for transfected hDFBs in the presence of Muristerone A exhibited a maximum of 5.1 +/- 0.2 ng NGF/10(6) cells/day. A PC-12 bioassay demonstrated that the in vitro NGF released is bioactive. When transfected hDFBs in the presence of Muristerone A were placed in vivo in nude rats, NGF levels reach 2074 +/- 257 pg/mL and 1620 +/- 132 pg/mL at 24 and 48 h, respectively. These levels were significantly higher than negative control and wound fluid levels. Results support further in vivo investigation of this molecular "on" switch for peripheral nerve regeneration.

Multidisciplinary care in head and neck cancer.

Head and neck cancer treatment is uniquely suited to multidisciplinary care. A comprehensive list of essential participants consists of a broad spectrum of health care professionals. A spirit of cooperation and mutual respect is the foundation for the synergy that results in the best possible patient care. Reconstructive surgery has emerged as a sophisticated subspecialty that fills a critical role restoring the head and neck patient to maximal health and well-being. The concept of multidisciplinary care, pioneered at the nation's comprehensive cancer centers, should be adopted universally by clinicians seeking to offer the patient with head and neck cancer the best care.

Thrombolytic therapy: what is its role in free flap salvage?

Thrombolytic agents have been demonstrated to improve free flap salvage in animal models. However, clinical evidence regarding their efficacy has been scant. The authors reviewed their experience with flap salvage using thrombolytic therapy in 1,733 free flaps from February 1990 to July 1998. Patients with intraoperative pedicle thrombosis were excluded from this review. Forty-one of the 55 free flaps that were reexplored emergently were identified as having pedicle thrombosis. Of these 41 flaps, 28 free flaps were salvaged (flap salvage group, 68%) and 13 free flaps failed (flap failure group, 32%). Thrombolytic therapy (urokinase in 7 patients, tissue plasminogen activator in 1 patient) was used in six flaps in the flap salvage group and two flaps in the flap failure group. Statistical analysis demonstrated no difference between the two groups with regard to thrombolytic therapy. There was also no difference between the two groups with regard to use of systemic heparin (100-500 U per hour) at the time of pedicle thrombosis or with regard to whether Fogarty catheters were used. Smoking, preoperative radiotherapy, and the use of interpositional vein grafts during initial flap reconstruction had no impact on the outcome of flap salvage. The flap salvage group was reexplored at a mean of 1.5 days compared with the flap failure group, which was reexplored at a mean of 4.2 days (p = 0.007). Early detection of pedicle thrombosis remains the most important factor in the salvage of free flaps. Although these numbers are small and definitive statements cannot be made, the role of thrombolytic agents in free flap salvage requires further clinical evaluation.

Sciatic nerve reconstruction: limb preservation after sarcoma resection.

Limb salvage for extremity sarcoma has become the standard of care when possible. This review attempts to determine the outcome of sciatic nerve reconstruction after surgical tumor resection. The authors' objective was to determine the clinical value of extremity salvage with such a defect. Five patients (two male, three female) were selected from a department database at The University of Texas M.D. Anderson Cancer Center between 1995 and 1999 who met the following criteria: lower limb tumor resection involving a gap in the sciatic nerve with subsequent nerve autograft reconstruction. An additional patient who underwent primary sciatic nerve neurorrhaphy was also included. The average tumor size was 203 cm2. The most common tumor histology was spindle cell sarcoma. The average autograft length was 13 +/- 3.2 cm with one to four cables employed. Currently, 3 patients are still alive. Four of the 5 patients who received sciatic autonerve grafts reported partial distal sensory recovery subjectively. The patient who underwent primary neurorrhaphy has both motor and sensory innervation 42 months after surgery. Although not ideal for all patients, sciatic nerve reconstruction is a viable option for those willing to undergo limb preservation. Notable limitations to daily activity do not appear to be present, and patients are able to ambulate with or without assistive devices. With aggressive rehabilitation, some patients are able to function quite well with this bioprosthesis. Patients should consider, however, that their extremity is on loan. Substantial wound complications or infections may ultimately lead to amputation.

The role of soft tissue reconstruction after melanoma resection in the head and neck.

INTRODUCTION: Reconstruction after wide local excision of melanomas in the head and neck can be formidable. Many tumors lie close to vital structures, and excision must carefully balance preservation of form and function. For small defects, primary closure or skin grafting is satisfactory. However, it has become increasingly evident that more advanced reconstructive procedures can improve the outcome in terms of both function and aesthetics. This study was undertaken to determine the effectiveness of flap closure after wide local excision of melanomas in the head and neck and to develop a set of surgical recommendations on the basis of our experience. METHOD: We reviewed 35 patients who underwent 39 flap closures at The University of Texas, M. D. Anderson Cancer Center after wide local excision of head and neck melanomas. Local flaps were primarily used to close defects after the resection of superficial or intermediate-thickness melanomas. Pedicle and free flaps were used to cover larger defects resulting from the excision of extensive tumors. The flap closures were compared with an analogous database of 560 melanoma resections that underwent primary closure or skin grafting. RESULTS: The mean age of the patient population was 57 years. The most common location for tumor presentation was the cheek, followed by the ear, forehead, and lip. Pathologic findings most commonly demonstrated superficial spreading melanoma, and the average defect size was 30.7 cm2. Local flaps were used most often for reconstruction. The only variable that significantly predicted local recurrence was the depth of the tumor. Local, pedicle, or free flaps did not decrease the ability of detecting local recurrence or increase this number compared with primary closure and skin grafting. Major postoperative complications were detected in seven patients. We found flap closure to achieve excellent functional and aesthetic results. CONCLUSION: Although primary closure is the ideal method of reconstruction for small defects, flap closure provides a versatile and safe alternative when simple closure would yield unsatisfactory results. With careful planning, flap closure offers an exceptional functional and aesthetic result and may even enhance contour defects after extensive neck or parotid dissections. Moreover, our experience with flap closure did not appear to delay the detection of local recurrence and may have even served to decrease the incidence of local failure after wide local excision of head and neck melanomas.

Incidence of hematoma associated with ketorolac after TRAM flap breast reconstruction.

Ketorolac is frequently used as an adjunct for postoperative pain relief, especially by anesthesiologists during the immediate postoperative period. It can be used alone as an analgesic but is more often used to potentiate the actions of narcotics such as morphine or meperidine in an attempt to reduce the total dose and side effects of those drugs. The manufacturer of ketorolac cautions against its use in patients who have a high risk of postoperative bleeding, for fear of increasing the risk of hematoma, but the risk in transverse rectus abdominis musculocutaneous (TRAM) flap patients has never been reported. In a study of 215 patients who had undergone TRAM flap breast reconstruction, it was determined that patients who received intravenous ketorolac (n = 65) as an adjunct to their treatment with morphine administered by use of a patient-controlled analgesia device required less morphine (mean cumulative dose, 1.39 mg/kg) than did patients who did not receive ketorolac (n = 150; mean cumulative dose, 1.75 mg/kg; p = 0.02). There was no increase in the incidence of hematoma in patients who were treated with ketorolac. The data presented in this study suggest that the use of intravenous ketorolac does reduce the need for narcotics administration in patients undergoing TRAM flap breast reconstruction, without significantly increasing the risk of hematoma.

Dermal fibroblasts genetically engineered to release nerve growth factor.

Current surgical strategies for repair of critical nerves involves the transfer of normal donor nerve from an uninjured body location. One possible alternative to autogenous tissue replacement is the development of engineered constructs to replace those elements necessary for axonal proliferation. Delivery of growth factors is one strategy to enhance synthetic nerve constructs. Thus, this study focused on the delivery of nerve growth factor (NGF) by genetic engineering to begin approaching the microenvironment dictated, in part, by Schwann's cells. Rat dermal fibroblasts (DFBs) were modified genetically to release rat NGF. The reporter gene LacZ was used to assess the optimum nonviral transfection method commercially available before NGF transfection. FuGENE6 provided the optimum transfection efficiency (24% maximum, 20.1 +/- 1.9% 5-day average) as measured by beta-galactosidase catalytic activity. NGF release from transfected DFBs was assessed over a 3-day period. Compared with control (no transfection) DFBs and DFBs transfected with vector alone, DFBs transfected with an expression vector encoding rat beta-NGF demonstrated significantly (p < 0.05) higher levels of NGF, with a 3-day maximum of 111 pg NGF per milliliter. When normalized to cell number, NGF-transfected DFBs released 1.2 pg NGF per milliliter/10(3) cells. The NGF-transfected DFBs demonstrated a maximal NGF release rate at day 1 (1.2 ng NGF/10(6) cells per day), followed by a markedly lower, sustained release rate at days 2 and 3 (0.44 ng NGF/10(6) cells per day and 0.48 ng NGF/10(6) cells per day respectively). The release rate curves for control and vector-transfected DFBs also exhibited a maximal NGF release rate at day 1, but were followed by a decreasing release rate, potentially representing in vitro degradation of NGF present in fetal bovine serum. Although not first with the development of growth factor delivery through fibroblasts, these findings suggest that rat DFBs can be modified genetically to act like Schwann's cells to deliver NGF.

Immediate breast reconstruction with the transverse rectus abdominis musculocutaneous flap after skin-sparing mastectomy.

Immediate breast reconstruction with the transverse rectus abdominis musculocutaneous (TRAM) flap after skin-sparing mastectomy is becoming an increasingly performed procedure in patients with ductal carcinoma in situ, early invasive breast cancer, and prophylactic mastectomy. Through a periareolar approach, it is possible to remove the breast parenchyma along with the nipple areola complex, preserving almost all the original skin envelope and the inframmamary fold. The TRAM flap is used to recreate the volume and shape of the original breast. This technique has higher quality and easier reconstruction. The major disadvantages, extensive scar and donor site skin color mismatch, are reduced to a minimum level because the former is limited at the natural border of the nipple areola and the latter can be effectively concealed with proper nipple reconstruction. Thirty-one patients with a mean age of 39 years (range, 26-50 years) who had undergone unilateral or bilateral mastectomy for early breast cancer and immediate breast reconstruction with the pedicled TRAM flap were retrospectively reviewed. Requirements for the skin-sparing mastectomy technique include suitability of donor site tissue for autologous tissue, early breast cancer or ductal carcinoma in situ, and adequate size and shape matching of the contralateral breast. There was no observed local recur- rence during the follow-up period (mean, 20 months; range, 11-30 months). Complications at the recipient site include mastectomy skin flap partial necrosis in 2 patients and cellulitis of the transferred flap in 1 patient. No total or partial flap necrosis was observed. One patient developed abdominal bulging 1 month after the operation, during the administration of chemotherapy. All reconstruction was considered very satisfactory from an aesthetic perspective by the surgeon and the patient. The nicer aesthetic result with oncological safety is achieved with immediate breast reconstruction with the TRAM flap after skin-sparing mastectomy. The risk of local recurrence is not higher compared with more radical surgical techniques.

Brachytherapy: reconstructive options and the role of plastic surgery.

The objectives of this study were to evaluate reconstructive methods for patients receiving brachytherapy after cancer ablation. This retrospective review evaluated 19 patients who received brachytherapy and reconstruction between 1991 and 1998. The average age of the patient was 61.9 years and the average follow-up was 2.9 years. Lesions were located in the upper extremity (N = 6), trunk (N = 2), and lower extremity (N = 11). In all patients, early postoperative brachytherapy was initiated 5 days after wound closure. The average radiation dose was 47 Gy (range, 45-50 Gy) and was delivered over a 3 to 5-day period. In each case, varying numbers of catheters were employed (average, 8 +/- 5 catheters). Free flap coverage was performed in 8 patients, and the latissimus dorsi was used most often. Pedicled regional flaps were employed in 11 patients (58%). Sixteen patients (84%) had additional external beam irradiation, and 10 patients (52%) underwent preoperative chemotherapy. All flaps survived with a demonstrated low complication rate (10%). In 2 patients, partial flap necrosis and infection occurred. Three donor site complications were observed and included wound dehiscence in 2 patients and hematoma in 1 patient. Cumulative effects of external beam radiation and brachytherapy did not affect the complication rate. Location of the defect did not alter the incidence of complications. Wound complications did not delay functional rehabilitation in these patients; however, hospital stay was longer. In 8 patients local recurrence occurred (42%) between 6 and 36 months after surgery whereas in 6 patients (32%) distant metastasis was observed. Ten patients are currently alive without evidence of disease. One of the most important concerns about early postoperative brachytherapy is wound healing. With careful planning and precise reconstructive techniques, the use of brachytherapy as a part of salvage or primary surgery does not lead to increased wound morbidity. Reconstructive procedures and a multidisciplinary approach have allowed the delivery of brachytherapy in these complicated patients with low morbidity.

Advances in head and neck reconstruction.

Head and neck deformities, which can be caused by trauma, congenital defects, infections, or neoplasms, produce a stereotypical constellation of functional and aesthetic deficits, depending on the specific anatomic region. These deformities can be classified into six major anatomic categories: intraoral, mandibular, midfacial, cranial base, cutaneous, and scalp. This article presents a reliable approach to the reconstruction of these six areas that is used at the University of Texas M. D. Anderson Cancer Center. The emphasis is on an analysis of the unique functional and aesthetic problems presented by each of these specific anatomic lesions, and the reconstructive options are selected to maximize outcomes. The problems and limitations of current methods are discussed, and areas of potential development are explored.