Nerve function restoration following targeted muscle reinnervation after varying delayed periods

Targeted muscle reinnervation has been proposed for reconstruction of neuromuscular function in amputees.However,it is unknown whether performing delayed targeted muscle reinnervation after nerve injury will affect restoration of function.In this rat nerve injury study,the median and musculocutaneous nerves of the forelimb were transected.The proximal median nerve stump was sutured to the distal musculocutaneous nerve stump immediately and 2 and 4 weeks after surgery to reinnervate the biceps brachii.After targeted muscle reinnervation,intramuscular myoelectric signals from the biceps brachii were recorded.Signal amplitude gradually increased with time.Biceps brachii myoelectric signals and muscle fiber morphology and grooming behavior did not significantly differ among rats subjected to delayed target muscle innervation for different periods.Targeted muscle reinnervation delayed for 4 weeks can acquire the same nerve function restoration effect as that of immediate reinnervation.

Preemptive targeted muscle reinnervation:the single incision approach should be avoided in trans‑tibial traumatic amputation

Dear Editor,Chronic pain is a significant concern after major lower limb amputations that often preclude prosthetic fitting,decrease ambulation,and impact the quality of life[1,2].In the last decade,targeted muscle reinnervation(TMR)has been proposed as a surgical strategy for treating or preventing symptomatic neuromas and phantomlimb phenomena in major amputees[1].This technique involves the transfer of an amputated mixed-motor and sensory nerve to a nearby recipient motor nerve[1,2].Unlike most surgical strategies that aim to hide or protect the neuroma,TMR gives the amputated nerves“somewhere to go and something to do”[2].In a randomized clinical trial on neuroma and phantom pain,Dumanian et al.[1]demonstrated that TMR reduces amputationrelated chronic pain at 1-year post-intervention when compared with the excision and muscle-burying technique,which remains the current gold standard.Valerio et al.[2]also proposed applying TMR at the time of major limb amputation for preventing chronic pain and found that TMR patients experienced less residual limb pain(RLP)and phantom limb pain(PLP)when compared with untreated amputee controls.

Effects of targeted muscle reinnervation on spinal cord motor neurons in rats following tibial nerve transection

Targeted muscle reinnervation(TMR)is a surgical procedure used to transfer residual peripheral nerves from amputated limbs to targeted muscles,which allows the target muscles to become sources of motor control information for function reconstruction.However,the effect of TMR on injured motor neurons is still unclear.In this study,we aimed to explore the effect of hind limb TMR surgery on injured motor neurons in the spinal cord of rats after tibial nerve transection.We found that the reduction in hind limb motor function and atrophy in mice caused by tibial nerve transection improved after TMR.TMR enhanced nerve regeneration by increasing the number of axons and myelin sheath thickness in the tibial nerve,increasing the number of anterior horn motor neurons,and increasing the number of choline acetyltransferase-positive cells and immunofluorescence intensity of synaptophysin in rat spinal cord.Our findings suggest that TMR may enable the reconnection of residual nerve fibers to target muscles,thus restoring hind limb motor function on the injured side.

A review of pain outcomes following targeted muscle reinnervation in lower extremity limb pain

Approximately 75%experience phantom(PLP),residual(RLP),or general(GLP)limb pain following lower extremity amputation.Targeted muscle reinnervation(TMR)is a peripheral nerve transfer that reroutes amputated nerves to motor endplates that can prevent or treat limb pain.This systematic review summarizes pain outcomes following primary and secondary treatment of lower extremity PLP,RLP,and GLP.Primary literature review of three databases-PubMed,EMBASE,MEDLINE-were used for all articles related to TMR and lower extremity limb pain,querying the same keywords:“targeted muscle reinnervation”AND“pain”.Citations were then reviewed and eliminated if only upper extremities were studied or the study lacked pain outcomes.Citations were categorized as primary or secondary TMR.Pain outcomes,including Numerical Rating Scales(NRS)and Patient-Reported Outcome Measurement Information System(PROMIS)Pain scores,were aggregated when appropriate.Ten studies met all inclusion and exclusion criteria after formal review for a total of 431 extremities,of which 79.1%(n=341 limbs)were lower extremities.Average primary TMR PROMIS scores for PLP and RLP were lower than amputees without primary TMR.Average NRS scores and PROMIS Pain scores in secondary TMR demonstrated improvements in PLP,RLP,and GLP.Primary and Secondary TMR does prevent and improve PLP,RLP,and GLP;however,a minority of studies report quantifiable pain outcomes.All future TMR studies should include validated pain outcomes to better quantify the expected pain and quality of life improvements after lower extremity TMR.

Advances in upper limb loss rehabilitation:the role of targeted muscle reinnervation and regenerative peripheral nerve interfaces

Upper limb loss results in significant physical and psychological impairment and is a major financial burden for both patients and healthcare services.Current myoelectric prostheses rely on electromyographic(EMG)signals captured using surface electrodes placed directly over antagonistic muscles in the residual stump to drive a single degree of freedom in the prosthetic limb(e.g.,hand open and close).In the absence of the appropriate muscle groups,patients rely on activation of biceps/triceps muscles alone(together with a mode switch)to control all degrees of freedom of the prosthesis.This is a non-physiological method of control since it is non-intuitive and contributes poorly to daily function.This leads to the high rate of prosthetic abandonment.Targeted muscle reinnervation(TMR)reroutes the ends of nerves in the amputation stump to nerves innervating“spare”muscles in the amputation stump or chest wall.These then become proxies for the missing muscles in the amputated limb.TMR has revolutionised prosthetic control,especially for high-level amputees(e.g.,after shoulder disarticulation),resulting in more intuitive,fluid control of the prosthesis.TMR can also reduce the intensity of symptoms such as neuroma and phantom limb pain.Regenerative peripheral nerve interface(RPNI)is another technique for increasing the number of control signals without the limitations of finding suitable target muscles imposed by TMR.This involves wrapping a block of muscle around the free nerve ending,providing the regenerating axons with a target organ for reinnervation.These RPNIs act as signal amplifiers of the previously severed nerves and their EMG signals can be used to control prosthetic limbs.RPNI can also reduce neuroma and phantom limb pain.In this review article,we discuss the surgical technique of TMR and RPNI and present outcomes from our experience with TMR.

Expanding the top rungs of the extremity reconstructive ladder:targeted muscle reinnervation,osseointegration,and vascularized composite allotransplantation

Osseointegration(OI),targeted muscle reinnervation(TMR),and vascularized composite allotransplantation(VCA)are just a few ways by which our reconstructive ladder is evolving.It is important to recognize that amputation does not necessarily denote failure,but surgeons should strive to find ways to provide these patients with means for obtaining better satisfaction and quality of life postoperatively.TMR and OI have added options for mutilating lower extremity injuries that necessitate amputation.More recently,the senior author(Levin LS)described the"penthouse"floor of the reconstructive ladder being VCA.Despite the advances in VCA over the last 20 years,there are many challenges that face this discipline including indications for patient selection,minimizing immunosuppressive regimens,standardizing outcome measures,establishing reliable protocols for monitoring,and diagnosing and managing rejection.Herein,the authors review TMR,OI,and VCA as additional higher rungs of the reconstructive ladder.

Efficacy of targeted muscle reinnervation for treating and preventing postamputation pain-a systematic review

Aim:Targeted muscle reinnervation(TMR)is a procedure pioneered to improve control of myoelectric prostheses and was fortuitously found to improve postamputation pain by transferring residual nerve ends from an amputated limb to reinnervate motor nerve units in denervated muscles.This study sought to perform a systematic review of the literature regarding the postamputation pain-related outcomes following TMR.Methods:PubMed database was queried using the key term“targeted muscle reinnervation”.Articles were chosen based on the following criteria:(1)clinical studies on TMR;(2)greater than one subject;(3)studies were case-controls,comparative cohort analyses,controlled trials,or randomized controlled trials;and(4)studies included one or more outcomes of interest:prosthetic use and functionality,improvement or persistence of pain,indications,complications,donor nerves,and technical aspects of TMR.Results:Overall,9 studies including 101 upper extremity and 252 lower extremity nerve transfers were analyzed,with nerve transfer type,amputation location,and specific neurotizations reported.Four studies assessed the efficacy of TMR in addressing phantom limb pain(PLP)and residual limb pain(RLP),with 3 out of 4 studies reporting significant improvements in PROMIS(Patient Reported Outcome Measurement Information System)scores in TMR subjects compared to controls.Five additional studies did not analyze PROMIS scores but reported subjective improvements in pain outcomes.Conclusion:Included studies demonstrated TMR had lower maximal pain and pain intensity,behavior and interference compared to the standard of care.Secondary TMR used to treat patients with established painful neuromas also reported improvement in pain compared to baseline.

Lower extremity amputation:the emerging role of targeted muscle reinnervation(TMR)and regenerative peripheral nerve interface(RPNI)

Lower extremity amputation is increasingly prevalent in the United States,with growing numbers of patients suffering from diabetes and peripheral vascular disease.Amputation has significant functional sequelae as more than half of patients are unable to ambulate at one year postoperatively.Improving mobility and decreasing chronic post-amputation pain can significantly improve the quality of life for these patients and reduce the cost burden on the healthcare system.Plastic and reconstructive surgery has been at the forefront of“reconstructive amputation”,in which nerve pedicles can be surgically guided to decrease painful neuroma formation as well as provide targets for myoelectric prosthesis use.We herein review post-amputation outcomes,epidemiology of chronic,post-amputation pain,and current treatments,including total muscle reinnervation and regenerative peripheral nerve interface,which are at the forefront of multidisciplinary treatment of lower extremity amputees.

Complex upper extremity injuries:targeted muscle reinnervation,free functional muscle transfer,and vascularized composite allotransplantation

Restoration of upper extremity function poses a unique surgical challenge.With considerations ranging from ensuring appropriate skeletal support and musculotendinous and ligamentous anatomy,restoring adequate vascularity and innervation,and providing sufficient soft tissue coverage,upper extremity injuries present a diverse range of reconstructive problems.Recent history has been marked by an expansion of novel techniques for addressing these complex issues.Sophisticated modalities,such as targeted muscle reinnervation,free functional muscle transfer,and vascularized composite allotransplantation,have become some of the most powerful tools in the armamentarium of the reconstructive surgeon.This review article aims to define the distinguishing features of each of these modalities and reviews some of their unique advantages and limitations.

Stimulating effect of thyroid hormones in peripheral nerve regeneration:research history and future direction toward clinical therapy

Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions.Despite extensive investigation,testing various surgical repair techniques and neurotrophic molecules,at present,a satisfactory method to ensuring successful recovery does not exist.For successful molecular therapy in nerve regeneration,it is essential to improve the intrinsic ability of neurons to survive and to increase the speed of axonal outgrowth.Also to induce Schwann cell phenotypical changes to prepare the local environment favorable for axonal regeneration and myelination.Therefore,any molecule that regulates gene expression of both neurons and Schwann cells could play a crucial role in peripheral nerve regeneration.Clinical and experimental studies have reported that thyroid hormones are essential for the normal development and function of the nervous system,so they could be candidates for nervous system regeneration.This review provides an overview of studies devoted to testing the effect of thyroid hormones on peripheral nerve regeneration.Also it emphasizes the importance of combining biodegradable tubes with local administration of triiodothyronine for future clinical therapy of human severe injured nerves.We highlight that the local and single administration of triiodothyronine within biodegradable nerve guide improves significantly the regeneration of severed peripheral nerves,and accelerates functional recovering.This technique provides a serious step towards future clinical application of triiodothyronine in human severe injured nerves.The possible regulatory mechanism by which triiodothyronine stimulates peripheral nerve regeneration is a rapid action on both axotomized neurons and Schwann cells.

Exploring the mechanism of neural-function reconstruction by reinnervated nerves in targeted muscles

A lack of myoelectric sources after limb amputation is a critical challenge in the control of multifunctional motorized prostheses. To reconstruct myoelectric sources physiologically related to lost limbs, a newly proposed neural-function construction method, targeted muscle reinnervation(TMR), appears promising. Recent advances in the TMR technique suggest that TMR could provide additional motor command information for the control of multifunctional myoelectric prostheses. However, little is known about the nature of the physiological functional recovery of the reinnervated muscles. More understanding of the underlying mechanism of TMR could help us fine tune the technique to maximize its capability to achieve a much higher performance in the control of multifunctional prostheses. In this study, rats were used as an animal model for TMR surgery involving transferring a median nerve into the pectoralis major, which served as the target muscle. Intramuscular myoelectric signals reconstructed following TMR were recorded by implanted wire electrodes and analyzed to explore the nature of the neural-function reconstruction achieved by reinnervation of targeted muscles. Our results showed that the active myoelectric signal reconstructed in the targeted muscle was acquired one week after TMR surgery, and its amplitude gradually became stronger over time. These preliminary results from rats may serve as a basis for exploring the mechanism of neural-function reconstruction by the TMR technique in human subjects.

Management of symptomatic neuromas:a narrative review of the most common surgical treatment modalities in amputees

Symptomatic neuromas are an all-too-common complication following limb amputation or extremity trauma,leading to chronic and debilitating pain for patients.Surgical resection of symptomatic neuromas has proven to be the superior method of intervention,but traditional methods of neuroma resection do not address the underlying pathophysiology leading to the formation of a future symptomatic neuroma and lead to high reoperation rates.Novel approaches employ the physiology of peripheral nerve injury to harness the regeneration of nerves to their advantage.This review explores the underlying pathophysiology of neuroma formation and centralization of pain signaling.It compares the traditional surgical approach for symptomatic neuroma resection and describes three novel surgical strategies that harness this pathophysiology of neuroma formation to their advantage.The traditional resection of symptomatic neuromas is currently the standard of care for amputation patients,but new techniques including the regenerative peripheral nerve interface,targeted muscle reinnervation,and intraosseous transposition have shown promise in improving patient pain outcomes for postamputation pain and residual limb pain.Symptomatic neuromas are a chronic and debilitating complication following amputation procedures and trauma,and the current standard of care does not address the underlying pathophysiology leading to the formation of the neuroma.New techniques are under development that may provide improved patient pain outcomes and a higher level of care for symptomatic neuroma resection.