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ASTM F3645-25
Standard Guide for Pre-clinical Testing of Materials Used to Regenerate Muscle Following Volumetric Muscle Loss Injuries
Standard Guide for Pre-clinical Testing of Materials Used to Regenerate Muscle Following Volumetric Muscle Loss Injuries
F3645-25
ASTM|F3645-25|en-US
Standard Guide for Pre-clinical Testing of Materials Used to Regenerate Muscle Following Volumetric Muscle Loss Injuries
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F3645 Standard Guide for Pre-clinical Testing of Materials Used to Regenerate Muscle Following Volumetric Muscle Loss Injuries>
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BOS Vol. 13.02 Committee F04
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Significance and Use
4.1 This guide is aimed at providing a range of in vivo model and experimental-related variables that can be used to evaluate current pre-clinical models of VML injury. Additionally, this guide outlines considerations for the primary evaluation of skeletal muscle function and secondary evaluations that can further inform the functional outcomes. It is important to understand the current context of medical product development in this field. Use of this guide is strengthened by the number of products in development that target skeletal muscle regeneration and recovery. The complexity of muscle injuries, relative infrequency of muscle defect injuries, and challenges of clinical translation create challenging scientific questions that would benefit from a more standardized practice. The current clinical standard of care is limited with most surgical repairs limited to providing soft tissue coverage over exposed bone to prevent or mitigate osteomyelitis. Functional repairs are limited by donor site morbidity and generally involve transfer of uninjured vascularized muscle flaps to restore function at major joints (for example, elbow and knee contraction).
4.2 This guide includes a broad historical context of currently used model and experimental-related conditions.
4.3 This guide includes a brief description of the animal models, surgical considerations, and tissue processing as well as the quantitative analysis of tissue specimens. Animal models themselves have yet to be standardized, although due to the heterogeneous nature of VML, a standard model of investigations is likely unsuitable. There is little uniformity currently on the optimal outcome measures to use. Some models are self-curing and thus unlikely to be representative of a true VML injury, which leads to permanent functional deficits. Functional outcomes have yet to be standardized or correlated with clinical outcomes. However, with the primary function of skeletal muscle to generate force, a quantitative measure of muscle force/power/torque should be included. Some models advocate the use of measures of unclear validity for clinical translation, including muscle twitch in rodents or complex gait analysis in quadruped animals. This standard guide will help to identify what defines a VML injury and the types of pre-clinical models that could be used to test VML treatments. Moreover, this standard will provide guidance for VML outcome measures.
4.4 The user is encouraged to utilize appropriate ASTM and other guidelines to conduct cytotoxicity and biocompatibility tests on materials or devices, or both, prior to assessment of the in vivo models described herein.
4.5 It is recommended that safety testing be in accordance with the provisions of the FDA Good Laboratory Practices Regulations 21 CFR 58.
4.6 Safety and effectiveness studies to support IND (investigational new drug), IDE (investigational device exemption), PMA (pre-market approval), or 510K submissions should conform to appropriate FDA guidelines for development biologics (IND) and/or medical devices (IDE/PMA/510K), respectively.
4.7 Animal model outcomes are not necessarily predictive of human results and should, therefore, be interpreted cautiously with respect to potential applicability to human conditions. Models should be designed and interpreted with careful consideration of the challenges of clinical translation. These include the potential relevance of timing and location of injury to human trials, the relatively small numbers of patients with relevant injuries, and confounding of results by infection and delayed repair. This standard will assist in identifying differences in the type of injury, animals used, and testing methods available to most national laboratories and universities.
4.8 The current practices for definitive care following VML and orthopaedic injuries involving concomitant VML injury can be generalized into three phases: (1) immediate field care, (2) acute surgical care, and (3) short-term rehabilitative care. Standardization within these phases is complicated by the site of the injury and polytraumatic nature of the injury that can include damage to the bone, muscle, skin, nerve, and/or vascular network. Prioritization of care among the phases starts with patient survival, minimizing infection risk, limb salvage, and finally tissue rehabilitation. Immediate field care often takes place at the site of injury (for example, field of play, battlefield) and involves fixation of the limb for emergency transport, field dressing to minimize infection risk, and possible tourniquets to reduce blood loss from the injury. These practices prioritize patient survival. Acute surgical care involves surgical procedures and post-operative procedures conducted at a trauma center. Practices include blood transfusion, muscle flaps, nerve allografts, and limb amputation if required for survival (for example, infection). Only after these three phases of care are complete does a patient begin rehabilitation therapy to boost muscle function and recovery. Once the patient has moved to rehabilitation efforts can we use the outcome measures presented in this standard.
4.9 It is recognized that there may not be a single material solution sufficient to treat VML injury. Multiple interventions may be required along the continuum of care, beginning at the point of injury and continuing through the rehabilitation phase. It is also recognized that the optimal timing of interventions has yet to be clearly defined. While the typical clinical scenario involves intervention well after injury has occurred, most animal models evaluate intervention concurrent with or early in the course of injury. Developmental efficiency may be improved by testing potential interventions in series rather than as combination products. The effects of and near-universal need for rehabilitation following repair may also confound results and should be considered in the design and interpretation of animal models.
4.10 The feasibility of performing randomized clinical trials in VML patients is also an outstanding issue. Limited patient populations, difficulties in consenting patients in the setting of acute trauma, lack of civilian correlates of injury, and inability to standardize injuries or systematically measure functional outcomes all remain challenges to be overcome. Clinical development plans should take these issues into account. Surrogate populations should be considered. For example, open tibial fracture often leads to VML, and may be the most common civilian presentation. Where possible, easily quantifiable controls should be used to include the uninjured contralateral limb.
4.11 All of the aforementioned features/metrics are critical to ensure appropriate evaluation of the numerous therapy-related variables that are currently or have previously been evaluated. That is, metrics are important to guidance, but tracking treatment details is key as well. This could be included in the review of the literature in biomaterials alone (large swath of synthetic or natural materials, etc., have already been evaluated), cells (what type of cells—again, many cell types have already been evaluated), or cells plus biomaterials; also multiple combinations have been evaluated, functionalized biomaterials (to include drugs, growth factors, cytokines, etc.).
Scope
1.1 This guide covers general evaluation guidelines for assessment of skeletal muscle and measures that inform skeletal muscle function in animal models of injury, in particular volumetric muscle loss (VML) injury.
1.2 Guidelines include a description and rationale of various animal models utilizing a range of species such as mice, rats, dogs, sheep, and pigs. Outcome measures based on the functional capacity of skeletal muscle, proportional measures, or on histologic and biochemical analyses are briefly described and referenced. The user should refer to specific test methods for additional detail.
1.3 This guide is not intended to include the testing of raw materials, preparation of biomaterials, sterilization, or packaging of product(s). ASTM standards for these steps are available in Section 2.
1.4 This guide is not intended to identify a standard of functional recovery.
1.5 The values stated in SI units are to be regarded as the standard.
1.6 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.
1.7 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.