Silicone-based implants have been widely used in breast reconstruction but have also been associated with poorly understood complications, including pathologic foreign body responses such as capsular contracture. In this study, we leveraged 3D-printing technology to generate silicone-based implants in a novel, anatomically relevant, prepectoral rat model. We used this model to evaluate the response to an extracellular matrix-based product: ovine-derived reinforced tissue matrix (RTM). Two-piece negative molds were developed through computer-aided design and 3D-printed. The molds were filled with various polydimethylsiloxane mixtures and dip-coated to fabricate implants. Implant material characterization revealed that the implants retained the original 3D-printed mold shape and qualitatively demonstrated a shell with an inner solid gel-like structure. Fabricated implants had smooth surfaces, as well as tunable features including implant stiffness (storage modulus). From initial studies in our rat model, placement of bilateral prepectoral implants allowed assessment of both muscle- and skin-facing capsules and were well-tolerated for at least 12 weeks. Comparison of the foreign body response between RTM-covered and uncovered (control) implants in this model revealed that the capsule thickness did not differ between groups at the 12-week endpoint. However, RTM reduced contractile fibroblasts (alpha-smooth muscle actin) and macrophages (Iba1) compared to the control. Our findings suggested that RTM may improve capsule quality by attenuating cells involved in fibrosis, even when total capsule thickness remains unchanged. However, these changes to cells involved in fibrosis were only observed at this early endpoint and may not predict long-term clinical outcomes.

This article highlights the use of rodents as preclinical models to evaluate the management of nerve injuries, describing the pitfalls and value from rodent nerve injury and regeneration outcomes, as well as treatments derived from these rodent models. The anatomic structure, size, and cellular and molecular differences and similarities between rodent and human nerves are summarized. Specific examples of success and failure when assessing outcome metrics are presented for context. Evidence for translation to clinical practice includes the topics of electrical stimulation, Tacrolimus (FK506), and acellular nerve allografts.

Lymphedema is a chronic condition of impaired lymphatic flow that results in limb swelling and debilitation. The pathophysiology of lymphedema is characterized by lymphatic stasis that triggers inflammation, fibrosis, and adipose tissue deposition in the extremities. Most often, this condition occurs in cancer survivors in the years after treatment with combinations of surgery, radiation, or chemotherapy, with the major risk factor being lymph node dissection. Interestingly, obesity and body mass index are independent risk factors for development of lymphedema, suggesting interactions between adipose and lymphatic tissue biology. Currently, treatment of lymphedema involves palliative approaches, including compression garments and physical therapy, and surgical approaches, including liposuction, lymphovenous bypass, and vascularized lymph node transfer. Emerging lymphedema therapies that focus on weight loss or reducing inflammation have been tested in recent clinical trials, yielding mixed results with no effect on limb volumes or changes in bioimpedance measurements. These studies highlight the need for novel therapeutic strategies that target the driving forces of lymphedema. In this light, animal models of lymphedema demonstrate a role of adipose tissue in the progression of lymphedema and suggest these processes may be targeted in the treatment of lymphedema. Herein, we review both conventional and experimental therapies for lymphedema as well as the defining characteristics of its pathophysiology. We place emphasis on the aberrant fibroadipose tissue accumulation in lymphedema and propose a new approach to experimental treatment at the level of adipocyte metabolism.

Repaired nerve injuries can fail to achieve functional recovery. Therapeutic options beyond surgery, such as systemic tacrolimus (FK506) and electrical stimulation (E‐stim), can improve recovery. We tested whether dual administration of FK506 and E‐stim enhances regeneration and recovery more than either therapeutic alone.

Efficacious therapeutics for peripheral nerve injuries remain incompletely described in the literature. However, over the last several decades, delivery of FK506 (Tacrolimus) and electrostimulation have demonstrated great promise for supplementing surgical advances in treating peripheral nerve injuries. This review describes the discovery, mechanistic investigations, and clinical translation of these strategies to promote functional recovery. FK506 has demonstrated the ability to increase the regeneration rate after nerve injury by a variety of hypothesized mechanisms, yet clinical utility remains limited due to systemic immunosuppression. Local administration of FK506 continues to be an active area of inquiry for minimizing side effects while maintaining its neuroregenerative effects. Electrostimulation of a nerve proximal to the site of surgical nerve repair has demonstrated increased axonal regeneration and accelerated recovery of both motor and sensory nerves. In addition, electrostimulation also appears to improve axon matching during reinnervation from motor to motor and sensory to sensory pathways and is used clinically in our surgeries. However, the specific parameters to best incorporate electrostimulation into the operating theater are still evolving. Utilizing translational rodent and murine models, surgical techniques and these therapeutic strategies have gradually become more viable as safety profiles and mechanisms are gradually understood. This review presents the state of the field for these therapeutic avenues and discusses further areas of research.

PURPOSE: Clinical practices in implant-based breast reconstruction continue to evolve with ongoing innovation in both the surgical approach and implant design. Development of standardized models is increasingly important to evaluate the effect of these changes in the outcomes of implant-based reconstruction. In this study, we designed a physiological rat breast implant model to assess the effects of pre-pectoral and sub-pectoral implant placement on breast implant capsule formation. METHODS: Miniature silicone implants measuring 2cc in diameter were optimized for placement in the pre-pectoral and sub-pectoral planes bilaterally in Lewis rats for an internally controlled model. A submammary approach was simulated in rats by making skin incisions at the inferior aspect of the pectoralis muscle bilaterally. For sub-pectoral implant placement the lateral edge of the pectoralis muscle was elevated, a sub-pectoral plane was established with blunt dissection, and a sterile implant was secured in the sub-pectoral plane with complete pectoralis coverage. For pre-pectoral implant placement, blunt dissection was used on the contralateral side to establish a subcutaneous plane. A sterile implant was secured in this subcutaneous pocket. Samples were harvested at 12 weeks and histological analysis of capsule formation was performed with H&E and Trichrome staining. RESULTS: The rats showed immediate signs of bilateral forelimb use with walking and grasp following recovery from anesthesia. The surgical sites healed well over two-week follow-up with no signs of wound-site mutilation, discomfort, or dehiscence. Histological analysis demonstrated both pre-pectoral and sub-pectoral capsule formation compared to sham surgery samples. Prepectoral implant capsules showed lamellar collagen architecture whereas subpectoral implant capsules demonstrated increased thickness, hypercellularity and synovial metaplasia. CONCLUSIONS: This model demonstrates that a physiological approach with pre-pectoral and sub-pectoral implant placement to model breast implant reconstruction is feasible in rats and thus improves upon previous models that utilize dorsal subcutaneous pockets instead of pectoral planes. These earlier approaches do not replicate the anatomy and mechanics of the clinical prepectoral and subpectoral space. Additionally, this model demonstrates differences in the periprosthetic fibrotic processes in pre-pectoral and sub-pectoral approaches for implant placement. This model facilitates further mechanistic understanding of the physiology and pathology associated with breast implant reconstruction including outcomes such as capsular contracture and BIA-ALCL and will provide a valuable platform to test treatments and strategies that may mitigate them.

Background: Although electrical stimulation (ES) can improve nerve regeneration, the impact of nerve block, such as lidocaine (Lido), on the therapeutic benefits of ES remains unclear. We used a rat tibial nerve transection-and-repair model to explore how either preoperative (PreOp) or postoperative (PostOp) nerve block affects ES-related improvement in regeneration. Methods: Lewis rats were used in 1 of 2 studies. The first evaluated the effects of extraneural Lido on both healthy and injured nerves. In the second study, rats were randomized to 5 experimental groups: No ES (negative control), PreOp Lido, ES + PreOp Lido, PostOp + ES, and ES (positive control). All groups underwent tibial nerve transection and repair. In both studies, nerves were harvested for histological analysis of regeneration distal to the injury site. Results: Application of extraneural Lido did not damage healthy or injured nerve based on qualitative histological observations. In the context of nerve transection and repair, the ES group exhibited improved axon regeneration at 21 days measured by the total number of myelinated fibers compared with No ES. Fiber density and percentage of neural tissue in the ES group were greater than those in both No ES and PreOp Lido + ES groups. ES + PostOp Lido was not different from No ES or ES group. Conclusions: Extraneural application of Lido did not damage nerves. Electrical stimulation augmented nerve regeneration, but Lido diminished the ES-related improvement in nerve regeneration. Clinical studies on the effects of ES to nerve regeneration may need to consider nerve block as a variable affecting ES outcome.

Auditory and vestibular mechanosensory hair cells do not regenerate following injury or aging in the adult mammalian inner ear, inducing irreversible hearing loss and balance disorders for millions of people. Research on model systems showing replacement of mechanosensory cells can provide mechanistic insights into developing new regenerative therapies. Here, we developed lineage tracing systems to reveal the generation of mechanosensory neurons in the Johnston's organ (JO) of intact adult Drosophila, which are the functional counterparts to hair cells in vertebrates. New JO neurons develop cilia and target central brain circuitry. Unexpectedly, mitotic recombination clones point to JO neuron self-replication as a likely source of neuronal plasticity. This mechanism is further enhanced upon treatment with experimental and ototoxic compounds. Our findings introduce a new platform to expedite research on mechanisms and compounds mediating mechanosensory cell regeneration, with nascent implications for hearing and balance restoration.