Somatotopic Configuration of Distal Residual Limb Tissues in Lower Extremity Amputations
Somatotopic Configuration of Distal Residual Limb Tissues in Lower Extremity Amputations
The hypothesis of this research protocol is that we will be able to redesign the manner in
 which lower limb amputations are performed so as to include biological actuators that will
 enable the successful employment of next generation lower extremity prostheses. The specific
 aims of the project are as follows:

 1. To define a standardized approach to the performance of a novel operative procedure for
 both below knee (BKA) and above knee (AKA) amputations

 2. To measure the degree of volitional motor activation and excursion achievable in the
 residual limb constructs, and to determine the optimal configuration and design of such
 constructs

 3. To describe the extent of proprioceptive and other sensory feedback achievable through
 the employment of these modified surgical techniques

 4. To validate the functional and somatosensory superiority of the proposed amputation
 technique over standard approaches to BKA and AKA

 5. To develop a modified acute postoperative rehabilitation strategy suited to this new
 surgical approach
Historical Background

 Lower extremity amputation is among the oldest known surgical procedures in medical history.
 Despite the passage of over two millennia, however, relatively little has changed in the
 operative approach. Currently, lower limb amputation is indicated most frequently for lower
 extremity compromise due to severe peripheral vascular disease, followed in short order by
 trauma, tumors, infections and congenital limb deficiencies. Estimates of frequency of lower
 limb amputations range from 30,000-40,000 cases per year in the United States alone.

 Normal function of the lower limb is enabled through the interplay of multiple muscle groups
 acting in concert. Ambulation is a remarkably orchestrated biomechanical process that is
 dependent upon a complex feedback loop involving the central and peripheral nervous systems
 and the musculoskeletal system. In their native state, the muscles of the lower extremity
 exist in a balanced agonist/antagonist milieu in which volitional activation of one muscle
 leads not only to its contracture, but also passive stretch of its opposite. Changes in
 muscle tension manifest through these changes lead to stimulation of specialized receptors
 within the muscle fibers that transmit joint position information to the cerebral cortex.
 Such feedback, in conjunction with cutaneous sensory information from skin mechanoreceptors,
 provides us with a sense of limb proprioception that ultimately enables high fidelity limb
 control, even in the absence of visual feedback.

 However, the standard operative approach to lower limb amputation at either the below knee
 (BKA) or above knee (AKA) level obliterates many of the dynamic relationships characteristic
 of the uninjured lower extremity. Initial exposure is accomplished through either a
 stair-step (BKA) or fishmouth (AKA) pattern incision, followed by progressive transection of
 muscles, vessels, nerves and bone at the level of the incision. Tissues distal to the site of
 structural transection are discarded, regardless of whether or not there may be viable
 segments, and the proximal residual muscles are layered over the distal transected bone in
 order to provide insulation to this exposed osseous surface. The surrounding skin is then
 advanced over the bone/muscle infrastructure in order to achieve definitive closure. The
 rudimentary approximation of tissues in the distal limb in these approaches results in a
 disorganized scar mass in which normal dynamic muscle relationships are destroyed. The
 uncoupling of native agonist/antagonist muscle pairings results in isometric contraction of
 residual muscle groups upon volitional activation, producing incomplete, unbalanced neural
 feedback to the brain that results in aberrant perception of residual limb position. Such
 disturbed feedback not only results in impaired ambulatory function with prosthetics, but
 also manifests as pathological sensory perception of the extremity in the form of phantom
 limb and phantom pain symptomatology.

 To date, providers and patients have tolerated the limitations of these approaches due to the
 fairly simplistic goal of lower limb amputation: to provide a stable, padded surface for
 prosthesis mounting. Historically, lower limb prostheses have afforded amputees the
 opportunity to recover at least some measure of ambulatory function. Standard lower limb
 prostheses currently afford the wearer the walk in a rudimentary fashion, as well as
 occasionally run. However, such devices have generally not been able to recapitulate the
 complex biomechanics of the human lower limb due to limited ranges of motion and lack of
 feedback control. These limitations have resulted in substantially altered kinematics in
 lower limb amputees that are associated with derangements in energy expenditure profiles that
 worsen with laterality and ascending level.

 An age is dawning, however, in which the capabilities of modern prostheses are broadening
 remarkably. Technological advances including increasingly miniaturized electronics, wireless
 communications and ever-refined positional sensors have enabled prosthetic developers to
 create next-generation bionic limbs with markedly enhanced degrees of freedom over prior
 models. Such prostheses have been demonstrated to markedly improve the energy expenditure of
 amputees who utilize them appropriately. Even more advanced prostheses are currently under
 development that incorporate the ability to provide active intrinsic limb control to
 facilitate complex motor actions such as dancing and balancing on one leg. In addition,
 prototype prosthetics are currently being developed that have the potential to offer sensory
 feedback - both tactile and positional - in a manner never before witnessed. Such
 prosthetics, while not yet available commercially, are presently being utilized in
 experimental settings.

 However, these technological advancements in the sphere of prosthesis development have not
 been matched with surgical advancements with regards to management of the residual limb.
 Classic techniques to lower limb amputation do not provide innervated interfaces that can
 serve as relays for complex prosthesis control; without such biological actuators in the
 residual limb to provide conduits for information exchange, next generation prostheses are of
 little use. Stated another way, next generation prosthetics currently incorporate drivers and
 sensors capable of providing far more enhanced functionality than ever before witnessed, but
 standard approaches to limb amputation do not provide a way of effectively linking these
 prosthetics to their intended beneficiaries. An evolution in the manner in which lower limb
 amputations are performed is now required - one that will provide a biological interface that
 will allow lower limb amputees to take advantage of the enhanced capabilities offered by the
 remarkable prostheses currently under development.

 Previous Pre-Clinical or Clinical Studies

 Recognition of the increased need for effective neural interfaces for prosthetic limbs has
 been evidenced by an expanding number of efforts in this sphere over the past decade. Initial
 efforts to provide high resolution control of distal prostheses were focused primarily on
 direct and indirect brain interfaces, either through placement of electroencephalographic
 scalp sensors or implantable parenchymal electrodes, respectively. However, such endeavors
 have been plagued by poor resolution, inconsistencies in signal acquisition and progressive
 foreign body reactions leading to impulse degradation over time.

 As the limitations of brain interfaces have become more evident, focus has shifted to direct
 peripheral nerve interfaces including interposed sieves and cuffs designed to transduce
 electrical signals directly from individual nerve fascicles to distal prostheses. Such
 monitors have, however, shown little clinical promise due to progressive nerve compression
 secondary to scarring, as well as significant neurological crosstalk and interference in
 biological models.

 As such, the most promising efforts regarding peripheral nerve interface development are now
 within the realm of biological systems. The two leading models in this sphere are as follows:

 -  Targeted Muscle Reinnervation (TMR): TMR is a technique whereby a series of nerve
 transfers is utilized to reinnervate specific target muscles to create additional
 prosthetic control sites after proximal limb amputation. These nerve transfers offer
 intuitive control of distal prostheses because the reinnervated muscles are controlled
 by the same nerves that once innervated the amputated limb. Signals created by the
 residual nerves are amplified by the recipient muscles, which are captured by surface
 electrodes and transduced to the distal prosthesis. TMR procedures have been performed
 on more than 40 patients to date. Limitations of this technique, however, include the
 finite number of available electromyographic signal sites due to anatomic constraints
 and issues with long-term signal fidelity.

 -  Regenerative Peripheral Nerve Interfaces (RPNI): RPNI offers an alternative version of
 an innervated biological interface. An RPNI is a surgical construct that consists of a
 non-vascularized segment of muscle that is coapted to a distal motor or sensory nerve
 ending. Unlike TMR, the RPNI muscle is not recruited from an otherwise normally
 innervated proximal muscle; instead, it is constructed as a free graft from
 orthotopically sourced donor tissue. The muscle segment is gradually reinnervated by the
 redirected nerve ending, which then promotes volitional activation of the muscle segment
 when triggered by the central nervous system. As in TMR, intuitive control occurs
 because the reinnervated muscles are controlled by the same nerves that once innervated
 the amputated limb. Unlike TMR, however, there are no limitations on anatomic sites and
 there does not appear to be problems with long-term signal fidelity.

 While both TMR and RPNIs have demonstrated promise in offering improved functionality to
 patients who have already undergone amputation, neither technique has been incorporated into
 a fundamental redesign of the way in which amputations are performed in the first place; in
 all cases of clinical implementation of TMR or RPNIs reported to date in the literature,
 these techniques have been employed to further optimize the functionality of patients who
 have already experienced limb loss.

 Rationale and Potential Benefits

 This clinical protocol proposes an iteration of the RPNI model, with the intent of
 incorporating these surgical constructs into the design of lower limb amputations at the time
 of limb sacrifice. Given the success of this technique to date, the investigators believe
 that incorporation of innervated muscle segments into residual limb design has the potential
 to provide lower limb amputees with a biological interface for unprecedented prosthetic motor
 control that is not only high resolution but also highly intuitive and capable of restoring
 limb proprioception. In addition, it is anticipated that allowing amputees to have greater
 control of advanced prostheses may offer the potential to normalize gait kinematics, thereby
 correcting alterations in energy expenditure that have been previously reported. Such
 measures hold the promise of optimizing the functional and overall health of lower limb
 amputees, thereby reducing the morbidity currently associated with the amputee status.

 Specific Aims

 The hypothesis of this research protocol is that we will be able to redesign the manner in
 which lower limb amputations are performed so as to include biological actuators that will
 enable the successful employment of next generation lower extremity prostheses. The specific
 aims of the project are as follows:

 1. To define a standardized approach to the performance of a novel operative procedure for
 both below knee (BKA) and above knee (AKA) amputations

 2. To measure the degree of volitional motor activation and excursion achievable in the
 residual limb constructs, and to determine the optimal configuration and design of such
 constructs

 3. To describe the extent of proprioceptive and other sensory feedback achievable through
 the employment of these modified surgical techniques

 4. To validate the functional and somatosensory superiority of the proposed amputation
 technique over standard approaches to BKA and AKA

 5. To develop a modified acute postoperative rehabilitation strategy suited to this new
 surgical approach
Inclusion Criteria:

 -  Males or females between the ages of 18 and 65

 -  Candidates for elective unilateral or bilateral lower extremity amputation at either
 the above knee or below knee level due to traumatic injury, congenital limb
 deformities or progressive arthritis

 -  Must demonstrate sufficiently sound health to undergo the operative procedure,
 including adequate cardiopulmonary stability to undergo general anesthesia
 (specifically, American Society of Anesthesiology Class I or II)

 -  Must have intact inherent wound healing capacity

 -  Must demonstrate adequate communication skills to convey the status of their
 sensorimotor recovery throughout the postoperative phase,

 -  Must exhibit proper level of motivation to comply with postoperative follow up
 requirements.

 -  Must be willing to also consent to protocol #1801183130 at Massachusetts Institute of
 Technology (approved by the Committee on the Use of Humans as Experimental Subjects)
 as some outcome measures will be assessed under this affiliated study

 Exclusion Criteria:

 -  Patients beyond the stated age restrictions

 -  Those with severe illness rendering them unable to undergo the operative procedure
 safely (e.g., unresolved sepsis or cardiopulmonary instability manifest as documented
 coronary artery disease and/or chronic obstructive pulmonary disease).

 -  Patients with impairment in inherent wound healing pathways, such as those with
 primary connective tissue disorders or those on chronic steroid therapy

 -  Patients with extensive peripheral neuropathies (diabetic or otherwise) that would
 potentially inhibit appropriate reinnervation of the surgical constructs

 -  Active smokers; those patients willing to undergo tobacco cessation will need to be
 completely abstinent from tobacco use for at least 6 weeks preoperatively

 -  Patients who are unable to provide informed consent and those with a demonstrated
 history of poor compliance

 -  Pregnant women will not be considered due to the potential risks of general
 anesthesia.

 Patients will not be excluded from participation in the study on the grounds of minority
 status, religious status, race or gender. Non-English speaking patients will not be
 excluded from the study; interpreters will be made available to them for translation of
 both verbal interactions and written documents.