Stem cell-based approaches to enhance nerve regeneration and improve functional outcomes in vascularized composite allotransplantation.

PURPOSE OF REVIEW: The current review will discuss the current understanding of nerve regeneration in vascularized composite allotransplantation (VCA). The success of proximal arm and leg transplants has been hampered by the limitations of nerve regrowth across long distances resulting in poor regeneration and functional recovery. Relevant research in stem-cell therapies to overcome these issues will be reviewed. RECENT FINDINGS: The effect of rejection on nerve regeneration in the VCA may be unpredictable and may be quite different for the nerve allograft. The issues that limit functional outcome are likely common to both VCA and proximal nerve injuries or replantation. Stem-cell therapies have focused on augmenting Schwann cell function and appear promising. SUMMARY: A better understanding of the effects of transplant rejection on nerve regeneration and function, as well as the factors that affect regeneration over long distances may inform further therapeutic approaches for improvement.

Donor nerve sources in free functional gracilis muscle transfer for elbow flexion in adult brachial plexus injury.

BACKGROUND: With complete plexus injuries or late presentation, free functional muscle transfer (FFMT) becomes the primary option of functional restoration. Our purpose is to review cases over a 10-year period of free functioning gracilis muscle transfer after brachial plexus injury to evaluate the effect of different donor nerves used to reinnervate the FFMT on functional outcome. METHODS: A retrospective study from April 2001 to January 2011 of a single surgeon's practice was undertaken. During this time period 22 patients underwent FFMT at Washington University in St Louis, Missouri for elbow flexion. RESULTS: Thirteen patients for whom FFMT was performed for elbow flexion met all of the requirements for inclusion in this study. Average time from injury to first operation was 12.8 months (range 4-60), and average time from injury to FFMT was 29 months (range 8-68). Average follow-up was 31.8 months (range 11-84). The nerve donors utilized included the distal accessory nerve, intercostal with or without rectus abdominis nerves, medial pectoral nerves, thoracodorsal nerve, and flexor carpi ulnaris fascicle of ulnar nerve. Functional recovery of elbow flexion was measured using the MRC grading system which showed 1 M5/5, 5 M4, 4 M3, and 3 M2 outcomes. CONCLUSION: Intraplexal donor motor nerves if available will provide better transferred muscle function because they are higher quality donors closer to the muscle and can be done in one stage without a nerve graft. Otherwise, intercostal, rectus abdominis, or the distal accessory nerve should be used in a staged fashion. © 2016 Wiley Periodicals, Inc. Microsurgery 37:377-382, 2017.

Lower Extremity Reconstruction with Free Gracilis Flaps.

Background There have been significant advancements in lower extremity reconstruction over the last several decades, and the plastic surgeon's armamentarium has grown to include free muscle and fasciocutaneous flaps along with local perforator and propeller flaps. While we have found a use for a variety of techniques for lower extremity reconstruction, the free gracilis has been our workhorse flap due to the ease of harvest, reliability, and low donor site morbidity. Methods This is a retrospective review of a single surgeon's series of free gracilis flaps utilized for lower extremity reconstruction. Demographic information, comorbidities, outcomes, and secondary procedures were analyzed. Results We identified 24 free gracilis flaps. The duration from injury to free flap coverage was ≤ 7 days in 6 patients, 8-30 days in 11 patients, 31-90 days in 4 patients, and > 90 days in 3 patients. There were 22 (92%) successful flaps and an overall limb salvage rate of 92%. There was one partial flap loss. Two flaps underwent incision and drainage in the operating room for infection. Two patients developed donor site hematomas. Four patients underwent secondary procedures for contouring. Our subset of pediatric patients had 100% flap survival and no secondary procedures at a mean 30-month follow-up. Conclusion This study demonstrates the utility of the free gracilis flap in reconstruction of small- to medium-sized defects of the lower extremity. This flap has a high success rate and a low donor site morbidity. Atrophy of the denervated muscle over time allows for good shoe fit, often obviating the need for secondary contouring procedures.

Internal mammary artery perforator propeller flap for contralateral mastectomy defect: A case report.

The internal mammary artery perforator (IMAP) flap can be used as either loco-regional or free flap, and provides thin flexible coverage for defects of the chest wall and cervical regions. In this report, we present a bilateral mastectomy case in which the left mastectomy defect was closed with an IMAP propeller flap harvested from the right breast. Our patient with a history of left breast conservation therapy was diagnosed invasive ductal carcinoma in her left breast 14 years later. On physical examination, the patient's left breast displayed the stigmata of radiotherapy including dark discoloration and firmness to palpation, compared to contralateral pendulous breast. After bilateral mastectomy, an IMAP flap with a size of 26 cm × 11 cm was harvested from right chest and was transposed 180 degrees clockwise in a propeller fashion to the left mastectomy defect without any tension. The flap survived without any complication and the patient was free of recurrence or metastases during the follow-up of 18 months. The patient was satisfied with the outcome. IMAP propeller flap could be harvested safely to the anterior axillary fold in the subcutaneous fat plane. It may provide a large skin paddle especially in large breasted women. © 2016 Wiley Periodicals, Inc. Microsurgery 36:507-510, 2016.

Predictive Value of Nutritional Markers for Wound Healing Complications in Bariatric Patients Undergoing Panniculectomy.

BACKGROUND: Hypoproteinemia and nutritional deficiencies are common after bariatric surgery, and although massive weight loss (MWL) patients experience increased wound complication rates, the association has not been causatively determined. OBJECTIVES: This study investigated preoperative nutritional parameters and wound complications in MWL patients (postbariatric and diet-controlled) undergoing panniculectomy at 2 academic institutions. METHODS: One hundred sixty-one consecutive patients undergoing elective panniculectomy after bariatric surgery or diet-controlled weight loss were identified. Patient demographics and nutritional indices (serum protein, albumin, and micronutrient levels) were analyzed. Complications including wound separation, infection, and operative debridements were compared. Post hoc comparisons tested for correlation between complications and nutritional markers. RESULTS: Postbariatric patients lost an average of 151 lb and presented at an average of 32 months after gastric bypass. Diet-controlled weight loss patients lost an average of 124 lb. Despite MWL, albumin levels were higher in the bariatric group (3.8 vs 3.4 g/dL, P < 0.05). Conversely, bariatric patients experienced increased wound complications (27% vs 14%; P < 0.05). Factors which were found to correlate to increased risk of wound dehiscence and infection were elevated body mass index at time of panniculectomy and amount of tissue removed. Multivariate analysis did not show serum albumin or percent weight loss to independently predict complications. CONCLUSIONS: Bariatric patients presenting for elective operations are at risk for protein and micronutrient deficiency. Despite aggressive replacement and normalization of nutritional markers, bariatric patients experience increased wound complications when compared to nonbariatric patients and traditional measures of nutritional evaluation for surgery may be insufficient in bariatric patients.

Direct radial to ulnar nerve transfer to restore intrinsic muscle function in combined proximal median and ulnar nerve injury: case report and surgical technique.

A distal median to ulnar nerve transfer for timely restoration of critical intrinsic muscle function is possible in isolated ulnar nerve injuries but not for combined ulnar and median nerve injuries. We used a distal nerve transfer to restore ulnar intrinsic function in the case of a proximal combined median and ulnar nerve injury. Transfer of the nonessential radial nerve branches to the abductor pollicis longus, extensor pollicis brevis, and extensor indicis proprius to the motor branch of the ulnar nerve was performed in a direct end-to-end fashion via an interosseous tunnel. This method safely and effectively restored intrinsic function before terminal muscle degeneration.

Transfer of the extensor digiti minimi and extensor carpi ulnaris branches of the posterior interosseous nerve to restore intrinsic hand function: case report and anatomic study.

PURPOSE: To present a technique for restoration of ulnar intrinsic function using a nerve transfer of the extensor carpi ulnaris (ECU) and extensor digiti minimi (EDM) nerve branches of the posterior interosseous nerve (PIN) to the deep branch of the ulnar nerve in the forearm when the anterior interosseous nerve is unavailable. METHODS: We dissected 6 cadaveric upper extremities to identify the location of the EDM and ECU branches of the PIN and their distance to the ulnar nerve near the wrist. We present a case of a high combined median and ulnar nerve injury. We performed transfer of the EDM branch and 1 of the branches to the ECU of the PIN to the motor component of the ulnar nerve for intrinsic hand function. RESULTS: Our anatomic data demonstrate the branching pattern of the PIN and the length of regeneration and nerve graft required. Our patient required a 10-cm nerve graft, and the length of regeneration to reach the wrist was 19 cm. The patient recovered useful but incomplete reinnervation of the intrinsic muscles and rated hand recovery at 70%. CONCLUSIONS: Transfer of the EDM and ECU branches of the PIN to the motor component of the ulnar nerve is feasible with the use of a nerve graft. Using some of the branches to the ECU as well increases the axonal load to maximize muscle reinnervation. CLINICAL RELEVANCE: Proximal ulnar nerve injuries with paralysis of the intrinsic hand muscles lead to severe disability. Distal nerve transfers eliminate key factors that result in poor outcomes by allowing for faster muscle reinnervation. This nerve transfer had no functional donor morbidity and could be useful in the setting of a combined high median and ulnar nerve injury.

Free functional muscle transfer for lower extremity reconstruction.

BACKGROUND: Free functional muscle transfer is a reconstructive strategy for the reconstruction of lost muscle units in the lower extremity after oncologic resection, trauma, compartment syndrome, or severe nerve injuries. Under appropriate circumstances, free functional muscle transfer may be the only suitable reconstructive option. This article reviews the underlying principles of free functional muscle transfer, its application to lower extremity reconstruction, appropriate patient selection, and surgical techniques. METHODS: The underlying principles of free functional muscle transfer, its application to lower extremity reconstruction, appropriate patient selection, and surgical techniques are presented. Commonly used donor muscles appropriate for each type of functional defect are discussed. A review of recent publications on free functional muscle transfer in the lower extremity was also performed. RESULTS: Good functional recovery with a Medical Research Council grade of up to 4/5 and full range of motion can be attained with free functional muscle transfer. Clinical outcomes and specific parameters for published case series in lower extremity free functional muscle transfer are presented and an illustrative case. CONCLUSION: Free functional muscle transfer is a suitable treatment for the appropriate patient to restore essential functions and potentially regain ambulation. However, additional published clinical outcomes are needed and represent a major area for further investigation.

Nerve transfers for femoral nerve palsy: an updated approach and surgical technique.

OBJECTIVE: Femoral nerve palsy results in significant impairment of lower extremity function due to the loss of quadriceps muscle function. The authors have previously described their techniques utilizing the anterior obturator and sartorius nerves for transfer in cases of femoral nerve palsy presenting within 1 year of injury. In the current study, the authors discuss their updated techniques, results, and approach to partial and complete femoral nerve palsies using femoral nerve decompression and nerve transfers. METHODS: They conducted a retrospective review of patients with femoral nerve palsies treated with their technique at the Washington University School of Medicine in 2008-2019. Primary outcomes were active knee extension Medical Research Council (MRC) grades and visual analog scale (VAS) pain scores. RESULTS: Fourteen patients with femoral nerve palsy were treated with femoral nerve decompression and nerve transfer: 4 with end-to-end (ETE) nerve transfers, 6 with supercharged end-to-side (SETS) transfers, and 4 with ETE and SETS transfers, using the anterior branch of the obturator nerve, the sartorius branches, or a combination of both. The median preoperative knee extension MRC grade was 2 (range 0-3). The average preoperative VAS pain score was 5.2 (range 1-9). Postoperatively, all patients attained an MRC grade 4 or greater and subjectively noted improved strength and muscle bulk and more natural gait. The average postoperative pain score was 2.3 (range 0-6), a statistically significant improvement (p = 0.001). CONCLUSIONS: Until recently, few treatments were available for high femoral nerve palsy. A treatment strategy involving femoral nerve decompression and nerve transfers allows for meaningful functional recovery and pain relief in cases of partial and total femoral nerve palsy. An algorithm for the management of partial and complete femoral nerve palsies and a detailed description of surgical techniques are presented.

A Simple Brochure Improves Disposal of Unused Opioids: An Observational Cross-Sectional Study.

BACKGROUND: We evaluated the effectiveness of a simple, low-cost educational brochure in improving disposal rates of unused opioids after outpatient upper extremity surgery. METHODS: This cross-sectional study enrolled eligible adult patients from a peripheral nerve clinic between November 2017 and September 2018. Patients either received or did not receive the educational brochure, which outlined a simple method to dispose of unused opioids and completed a survey at 2 weeks after surgery. We compared the proportion of patients who disposed of unused opioids after surgery between the group that had received the brochure and the group that had not. Categorical data were analyzed with χ2 test, proportions data with binomial tests, and numerical data with Mann-Whitney U test, all with a significance level of P < .05. RESULTS: There were 339 survey respondents. Nineteen patients who did not meet inclusion criteria were excluded. Of the 320 remaining patients, 139 received the brochure and 181 did not. An additional 55 patients were excluded due to preoperative opioid use. Overall, 35.3% of recipients and 38.3% of those who did not receive the brochure used all of their prescribed opioid medication (P = .625; confidence interval = -14.6%-8.8%). Among patients with unused opioid medication, a significantly higher proportion of brochure recipients disposed of the medicine compared with those who did not receive the brochure (46.7% vs 19.6%, P < .001). CONCLUSIONS: Distribution of an educational brochure significantly improved disposal of unused opioids after surgery. This easily implemented intervention can improve disposal of unused opioids and ultimately decrease excess opioids available for diverted use in the community.

Costimulation blockade inhibits the indirect pathway of allorecognition in nerve allograft rejection.

Nerve allografts provide a temporary scaffold for host nerve regeneration. The need for systemic immunosuppression limits clinical application. Characterization of the immunological mechanisms that induce immune hyporesponsiveness may provide a basis for optimizing immunomodulating regimens. We utilized wild-type and MHC class II-deficient mice, as both recipients and donors. Host treatment consisted of triple costimulatory blockade. Quantitative assessment was made at 3 weeks using nerve histomorphometry, and muscle testing was performed on a subset of animals at 7 weeks. Nerve allograft rejection occurred as long as either the direct or indirect pathways were functional. Indirect antigen presentation appeared to be more important. Nerve allograft rejection occurs in the absence of a normal direct or indirect immune response but may be more dependent on indirect allorecognition. The indirect pathway is required to induce costimulatory blockade immune hyporesponsiveness.

Adductor magnus muscle transfer to restore knee extension: Anatomical studies and clinical applications.

BACKGROUND: Loss of knee extension causes significant impairment. Though nerve-based reconstruction is preferable in cases of femoral nerve palsy or injury, these surgeries are not always appropriate if the pathology involves the quadriceps muscles or presentation too late for muscle reinnervation. Muscle transfers are another option that has been underutilized in the lower extremity. We describe the successful restoration of knee extension by adductor magnus muscle transfer without functional donor morbidity, along with anatomical considerations. METHODS: Ten fresh frozen cadaveric lower limbs were dissected at the groin and thigh. In addition, three patients presented with femoral nerve palsy for which nerve-based reconstruction was not appropriate because of late presentation. In these patients, adductor magnus muscle transfers were performed, along with sartorius, gracilis, and tensor fasciae latae transfers if available and healthy. RESULTS: In cadavers, the pedicle for the adductor magnus is at the level of the gracilis and adequate for muscle transfer, with sufficient weavable tendon length. The only major structure at risk is the femoral neurovascular bundle, which is in a reliable anatomic position. Two patients recovered 4/5 active knee extension and ambulation without assistive devices. A third required reoperation for a loosened tendon weave, after which the noted improved stability and strength with ambulation but did not regain strong active knee extension and continued to require a cane. CONCLUSIONS: We present a novel reconstructive approach for loss of quadriceps function in patients, which yields good clinical outcomes, with anatomic and technical details to demonstrate the utility of this technique. Ongoing evaluation of optimal technique and rehabilitation to maximize functional outcomes is still needed.

Nerve transfers: indications, techniques, and outcomes.

This article provides an update of the current strategies of motor and sensory nerve transfers for peripheral nerve lesions of the upper extremity. Indications, techniques, and outcomes are summarized for both well-established transfers used in the management of proximal and brachial plexus injuries as well as those more recently developed for more distal and isolated nerve injuries in the forearm and hand.

Fibrin glue mitigates the learning curve of microneurosurgical repair.

Microneurosurgical technique has a steep learning curve. An alternative to microepineurial suture repair of peripheral nerves that circumvents this learning curve would be ideal. We investigated the effect of surgeon experience on suture versus fibrin glue coaptations in a mouse sciatic nerve graft model. Sixty-four mice received sciatic nerve grafts with either suture or fibrin glue repair by either a naïve surgeon (medical student) or a surgeon with extensive microsurgical experience. Grafts underwent quantitative histomorphometry at 3 weeks postoperatively. Suture repairs performed by the naïve surgeon demonstrated significantly poorer distal regeneration than all other repairs. Histomorphometric parameters of suture and glue repairs performed by the experienced surgeon were not significantly different from the glue coaptation by the naïve surgeon. Fibrin glue may be considered as an alternative to microepineurial suture repair, particularly in the setting of relative surgeon inexperience with microsurgical technique.

Femoral nerve decompression and sartorius-to-quadriceps nerve transfers for partial femoral nerve injury: a cadaveric study and early case series.

OBJECTIVE: Partial femoral nerve injuries cause significant disability with ambulation. Due to their more proximal and superficial location, sartorius branches are often spared in femoral nerve injuries. In this article, the authors report the benefits of femoral nerve decompression, demonstrate the feasibility of sartorius-to-quadriceps nerve transfers in a cadaveric study, describe the surgical technique, and report clinical results. METHODS: Four fresh-frozen cadaveric lower limbs were dissected for anatomical analysis of the sartorius nerve. In addition, a retrospective review of patients with partial femoral nerve injuries treated with femoral nerve decompression and sartorius-to-quadriceps nerve transfers was conducted. Pre- and postoperative knee extension Medical Research Council (MRC) grades and pain scores (visual analog scale) were collected. RESULTS: Up to 6 superficial femoral branches innervate the sartorius muscle just distal to the inguinal ligament. Each branch yielded an average of 672 nerve fibers (range 99-1850). Six patients underwent femoral nerve decompression and sartorius-to-quadriceps nerve transfers. Four patients also had concomitant obturator-to-quadriceps nerve transfers. At final follow-up (average 13.4 months), all patients achieved MRC grade 4-/5 or greater knee extension. The average preoperative pain score was 5.2, which decreased to 2.2 postoperatively (p = 0.03). CONCLUSIONS: Femoral nerve decompression and nerve transfer using sartorius branches are a viable tool for restoring function in partial femoral nerve injuries. Sartorius branches serve as ideal donors in quadriceps nerve transfers because they are expendable, are close to their recipients, and have an adequate supply of nerve fibers.

Role of timing in assessment of nerve regeneration.

Small animal models are indispensable for research on nerve injury and reconstruction, but their superlative regenerative potential may confound experimental interpretation. This study investigated time-dependent neuroregenerative phenomena in rodents. Forty-six Lewis rats were randomized to three nerve allograft groups treated with 2 mg/(kg day) tacrolimus; 5 mg/(kg day) Cyclosporine A; or placebo injection. Nerves were subjected to histomorphometric and walking track analysis at serial time points. Tacrolimus increased fiber density, percent neural tissue, and nerve fiber count and accelerated functional recovery at 40 days, but these differences were undetectable by 70 days. Serial walking track analysis showed a similar pattern of recovery. A "blow-through" effect is observed in rodents whereby an advancing nerve front overcomes an experimental defect given sufficient time, rendering experimental groups indistinguishable at late time points. Selection of validated time points and corroboration in higher animal models are essential prerequisites for the clinical application of basic research on nerve regeneration.

Femoral nerve transfers for restoring tibial nerve function: an anatomical study and clinical correlation: a report of 2 cases.

Sciatic nerve injuries cause debilitating functional impairment, particularly when the injury mechanism and level preclude reconstruction with primary grafting. The purpose of this study was to demonstrate the anatomical feasibility of nerve transfers from the distal femoral nerve terminal branches to the tibial nerve and to detail the successful restoration of tibial function using the described nerve transfers. Six cadaveric legs were dissected for anatomical analysis and the development of tension-free nerve transfers from femoral nerve branches to the tibial nerve. In 2 patients with complete tibial and common peroneal nerve palsies following sciatic nerve injury, terminal branches of the femoral nerve supplying the vastus medialis and vastus lateralis muscles were transferred to the medial and lateral gastrocnemius branches of the tibial nerve. Distal sensory transfer of the saphenous nerve to the sural nerve was also performed. Patients were followed up for lower-extremity motor and sensory recovery up to 18 months postoperatively. Consistent branching patterns and anatomical landmarks were present in all dissection specimens, allowing for reliable identification, neurolysis, and coaptation of donor femoral and saphenous nerve branches to the recipients. Clinically, the patients obtained Medical Research Council Grade 3 and 3+ plantar flexion by 18 months postoperatively. Improved strength was accompanied by improved ambulation in both patients and by a return to competitive sports in 1 patient. Sensory recovery was demonstrated by an advancing Tinel sign in both patients. This study illustrates the clinical success and anatomical feasibility of femoral nerve to tibial nerve transfers after proximal sciatic nerve injury.

Rectus Abdominis Motor Nerves as Donor Option for Free Functional Muscle Transfer: A Cadaver Study and Case Series.

BACKGROUND: Current management of brachial plexus injuries includes nerve grafts and nerve transfers. However, in cases of late presentation or pan plexus injuries, free functional muscle transfers are an option to restore function. The purpose of our study was to describe and evaluate the rectus abdominis motor nerves histomorphologically and functionally as a donor nerve option for free functional muscle transfer for the reconstruction of brachial plexus injuries. METHODS: High intercostal, rectus abdominis, thoracodorsal, and medial pectoral nerves were harvested for histomorphometric analysis from 4 cadavers from levels T3-8. A retrospective chart review was performed of all free functional muscle transfers from 2001 to 2014 by a single surgeon. RESULTS: Rectus abdominis nerve branches provide a significant quantity of motor axons compared with high intercostal nerves and are comparable to the anterior branch of the thoracodorsal nerve and medial pectoral nerve branches. Clinically, the average recovery of elbow flexion was comparable to conventional donors for 2-stage muscle transfer. CONCLUSION: Rectus abdominis motor nerves have similar nerve counts to thoracodorsal, medial pectoral nerves, and significantly more than high intercostal nerves alone. The use of rectus abdominis motor nerve branches allows restoration of elbow flexion comparable to other standard donors. In cases where multiple high intercostal nerves are not available as donors (rib fractures, phrenic nerve injury), rectus abdominis nerves provide a potential option for motor reconstruction without adversely affecting respiration.

Binary imaging analysis for comprehensive quantitative histomorphometry of peripheral nerve.

Quantitative histomorphometry is the current gold standard for objective measurement of nerve architecture and its components. Many methods still in use rely heavily upon manual techniques that are prohibitively time consuming, predisposing to operator fatigue, sampling error, and overall limited reproducibility. More recently, investigators have attempted to combine the speed of automated morphometry with the accuracy of manual and semi-automated methods. Systematic refinements in binary imaging analysis techniques combined with an algorithmic approach allow for more exhaustive characterization of nerve parameters in the surgically relevant injury paradigms of regeneration following crush, transection, and nerve gap injuries. The binary imaging method introduced here uses multiple bitplanes to achieve reproducible, high throughput quantitative assessment of peripheral nerve. Number of myelinated axons, myelinated fiber diameter, myelin thickness, fiber distributions, myelinated fiber density, and neural debris can be quantitatively evaluated with stratification of raw data by nerve component. Results of this semi-automated method are validated by comparing values against those obtained with manual techniques. The use of this approach results in more rapid, accurate, and complete assessment of myelinated axons than manual techniques.

Median to radial nerve transfer for treatment of radial nerve palsy. Case report.

The purpose of this study is to report a surgical technique of nerve transfer to restore radial nerve function after a complete palsy due to a proximal injury to the radial nerve. The authors report the case of a patient who underwent direct nerve transfer of redundant or expendable motor branches of the median nerve in the proximal forearm to the extensor carpi radialis brevis and the posterior interosseous branches of the radial nerve. Assessment included degree of recovery of wrist and finger extension, and median nerve function including pinch and grip strength. Clinical evidence of reinnervation was noted at 6 months postoperatively. The follow-up period was 18 months. Recovery of finger and wrist extension was almost complete with Grade 4/5 strength. Pinch and grip strength were improved postoperatively. No motor or sensory deficits related to the median nerve were noted, and the patient is very satisfied with her degree of functional restoration. Transfer of redundant synergistic motor branches of the median nerve can successfully reinnervate the finger and wrist extensor muscles to restore radial nerve function. This median to radial nerve transfer offers an alternative to nerve repair, graft, or tendon transfer for the treatment of radial nerve palsy.